Method of treating hepatic encephalopathy

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to hepatology and neurology, and can be used for using rifaximin for preparing a drug preparation for maintaining hepatic encephalopathy (HE) remission in a subject. That is ensured by daily administration of rifaximin into the subject for approximately 12 months or more, or approximately 1095 days or longer, thereby maintaining the HE remission.

EFFECT: group of inventions provides the stable HE remission, as well as a low antibiotic resistance of the patient's bacterial flora.

16 cl, 34 dwg, 28 tbl, 6 ex

 

RELATED APPLICATIONS

This application is a partial continuation of application for U.S. patent No. 12/572344, filed October 2, 2009, which claims the priority of provisional patent application U.S. No. 61/102349, filed October 2, 2008. This application also claims the priority of provisional patent application U.S. No. 61/183513, filed June 2, 2009, provisional application for U.S. patent No. 61/262525, filed November 18, 2009, provisional application for U.S. patent No. 61/305854, filed February 18, 2010, provisional application for U.S. patent No. 61/306935, filed February 22, 2010, provisional application for U.S. patent No. 61/307417, filed February 23, 2010, and provisional application for U.S. patent No. 61/316796, filed on March 23, 2010. The full content of each of the above applications are therefore included here in the verbal form by reference.

BACKGROUND of INVENTION

The cause of hepatic encephalopathy (HE) is a reversible decrease in the function of the nervous system associated with liver failure and portosystemic venous anastomoses. HE occurs in 1 out of every 3 cases of cirrhosis, in cases of fulminant hepatic failure, registered in the United States (U.S.), and there is almost half of the patients reaching end-stage liver disease. It can occur in any of the age but the peaks match those of fulminant liver disease (peak equal to the period of life between 40 and 50 years) and cirrhosis (peak equal to the end of the period of life between 50 and 60 years).

Apparently, the incidence does NOT increase with the incidence of hepatitis C in the General population and cirrhosis of the aging patient. Sharp HE means a poor prognosis with a 40% probability of life for 1 year. In the art there is a need for compositions and methods for the treatment and prevention of HE.

Moreover, there is also a need for methods for predicting the episode HE exacerbation during treatment or determine when to carry out prophylactic treatment of a subject prior to the occurrence of episodes of exacerbation.

SUMMARY of the INVENTION

There are provided compositions and methods for prevention and treatment of hepatic encephalopathy.

One embodiment is a method of treating or preventing hepatic encephalopathy (HE) in a subject, comprising the introduction of subject-specific gastro-intestinal tract (GI) of the antibiotic. In one embodiment, specific for diseases of the GI antibiotic rifaximin is. In another embodiment, the rifaximin is injected at a dose of 1100 mg/day of rifaximin.

Another embodiment is a method of reducing the risk of an episode of acute hepatic encephalopathy (HE) during treatment for a subject by administration of a specific disease GI antibiotic to a subject suffering from HE.

Another embodiment is a method of conservation of remission of hepatic encephalopathy in a subject by administration of a specific disease GI antibiotic to a subject suffering from HE.

Another embodiment is a method of reducing the frequency of visits to the suffering HE a patient of the hospital, including the introduction of specific diseases of the GI antibiotic to a subject suffering from HE.

In one embodiment, specific for diseases of the GI antibiotic is administered to the subject together with lactulose, before treatment with lactulose or after treatment with lactulose. In one embodiment, the subject or nurse health worker recommended for specific diseases of the GI antibiotic together with lactulose.

In one embodiment, using pharmaceutical labels or liner to a subject or nurse health worker recommended for specific diseases of the GI antibiotic together with lactulose to maintain remission HE or reducing the risk of episodes of HE with obvious clinical kartina is.

In one embodiment, the subject or nurse health worker it is recommended to use two tablets containing 550 mg of rifaximin twice a day together with lactulose. The use of lactulose can be distributed in time so that the subject has remained 2-3 bowel movements in the form of soft stools per day. In one embodiment, lactulose is administered in 15-ml doses, each 15-ml dose contains 10 mg of lactulose.

In one embodiment, subjects in need of treatment by reason and HE has a degree And or In the child-Pugh score, is subjected to the treatment of specific diseases of the GI antibiotic.

In another embodiment, subjects in need of treatment by reason and HE has a degree And or In the child-Pugh score, is subjected to the treatment of specific diseases of the GI antibiotic in combination with lactulose.

In another embodiment, the entities holding the degree or In the child-Pugh score, or carrying out their patronage of the medical practitioner, it is recommended that they are treated for specific diseases of the GI antibiotic. Recommendation and/or instructions may be oral or written, for example, in the pharmaceutical label or package insert.

In another embodiment, the entities holding the degree or In the child-Pugh score, or that their item is Trona health worker, it is recommended that they are treated for specific diseases of the GI antibiotic in combination with lactulose.

In one embodiment, the subject in need of treatment HE and smaller With a degree in child-Pugh score, is subjected to the treatment of specific diseases of the GI antibiotic. In one embodiment, the subject in need of treatment HE and smaller With a degree in child-Pugh score, is subjected to the treatment of specific diseases of the GI antibiotics and lactulose.

In another embodiment, subjects in need of treatment HE or carrying out their patronage of the health worker, inform about the risk of anaphylaxis to treat specific diseases of the GI antibiotic.

In one embodiment, subjects in need of treatment by reason of HE and equal 25 or less than the estimate in the model end-stage liver disease (MELD), is subjected to the treatment of specific diseases of the GI antibiotic.

In another embodiment, subjects in need of treatment by reason of HE and equal 25 or less assessment MELD, is subjected to the treatment of specific diseases of the GI antibiotic in combination with lactulose.

In another embodiment, subjects with 25 or fewer assessment MELD, it is recommended that they are treated special is specific for diseases of the GI antibiotic. The recommendation may be oral or written recommendation, for example, in the pharmaceutical label or package insert.

In another embodiment, subjects with 25 or fewer assessment MELD, it is recommended that they are treated for specific diseases of the GI antibiotic in combination with lactulose.

In one aspect there are provided methods of reducing ammonia levels in blood of a subject comprising administration to the subject an effective amount of rifaximin, thus reducing the levels of ammonia in the blood.

In one embodiment, the subject suffers from impaired excretion of ammonia.

In one embodiment, the violation of excretion of ammonia includes one or more disorders selected from negligible, with clear clinical picture, episodic and/or chronic persistent hepatic encephalopathy (HE).

In one embodiment, the subject suffers minor, with a clear clinical picture, episodic and/or chronic persistent hepatic encephalopathy (HE).

New methods and devices presented here are based partly on the discovery of a correlation between CFF (critical frequency of flicker) and/or the concentration of ammonia in the venous blood and the occurrence of episodes of exacerbation of HE during treatment. In addition, new ways and the mouth of the STS are also based on the detected what is the time-weighted CFF and/or concentration of ammonia in the venous blood is an accurate predictor of the episodes HE exacerbation during treatment and prognosis in subjects with HE.

Accordingly, in one aspect there are provided methods of diagnosing hepatic encephalopathy (HE) in a subject by determining the critical frequency of flicker (CFF) from the subject at two or more points in time, and the reduction of CFF indicates that the subject has hepatic encephalopathy. In a related embodiment, CFF includes time-weighted average CFF. In another related embodiment, the time-weighted CFF includes less than approximately 24 Hertz (Hz).

In another aspect there are provided methods for determining the risk of an episode of HE exacerbation during treatment for a subject by determining the critical frequency of flicker (CFF) from the subject at two or more points in time, and the reduction of CFF indicates that the subject is exposed to an increased risk of an episode of acute NOT during treatment. In a related embodiment, CFF includes time-weighted average CFF. In another related embodiment, the time-weighted CFF includes less than approximately 24 Hertz (Hz). In another embodiment, the time-weighted CFF, with the bringing of 10 Hz, indicates that there is the greatest likelihood of an episode of acute NOT at the time of treatment of the subject.

In another aspect there are provided methods for determining prognosis in a subject having HE, by identifying the critical frequency of flicker (CFF) from the subject at two or more points in time, and the reduction of CFF indicates that in relation to the subject's prognosis is poor. In a related embodiment, CFF includes time-weighted average CFF. In another related embodiment, the time-weighted CFF includes less than approximately 24 Hz or less than approximately 20 Hz.

In another aspect there are provided methods of treating or preventing episode HE by determining the critical frequency of flicker (CFF) from the subject at two or more points in time, the introduction of the subject with a decrease in the mean values of CFF between two points in time effective amount of a specific for diseases of the GI antibiotic (e.g., rifaximin) thereby effecting treatment or prevention of the episode HE. In another embodiment, the subject is administered a specific for diseases of the GI antibiotic, when the time-weighted CFF is less than 20 Hz.

In one embodiment, the subject is also administered lactulose. In another embodiment is sushestvennee risk is increased compared with a control subject without HE.

In related embodiments, the implementation of two or more points in time occur within one week, four weeks, six weeks or more.

In another aspect there are provided methods of diagnosing hepatic encephalopathy (HE) in a subject by determining ammonia levels in the venous blood of the subject at two or more points in time, and the increase in ammonia levels in venous blood indicates that the subject has hepatic encephalopathy.

In one embodiment, the ammonia level in venous blood includes time-weighted average ammonia levels in venous blood. In another embodiment, time-weighted average level of ammonia in the venous blood includes more than approximately 100 µmol/L.

In another aspect there are provided methods for determining the risk of an episode of HE exacerbation during treatment for a subject by determining ammonia levels in the venous blood of the subject at two or more points in time, and increased levels of ammonia in venous blood indicates that the subject is at risk of an episode of HE exacerbation during treatment.

In one embodiment, the ammonia level in venous blood includes time-weighted average ammonia levels in venous blood. In another embodiment, the weighted average is about time the ammonia level in venous blood includes more than approximately 100 µmol/L.

In another aspect there are provided methods for determining prognosis in a subject having HE, by determining the level of ammonia in the venous blood of the subject at two or more points in time, and increased ammonia level in venous blood indicates that in relation to the subject's prognosis is poor.

In one embodiment, the ammonia level in venous blood includes time-weighted average ammonia levels in venous blood. In another embodiment, time-weighted average level of ammonia in the venous blood includes more than approximately 100 µmol/l or more than approximately 110 µmol/L.

In another aspect there are provided methods of treating or preventing episode HE by determining the level of ammonia in the venous blood of the subject at two or more points in time, the introduction of a subject with increased levels of ammonia in venous blood between two points in time effective amount of rifaximin thereby effecting treatment or prevention of the episode HE.

In one embodiment, the ammonia level in venous blood includes time-weighted average ammonia levels in venous blood. In another embodiment, time-weighted average level of ammonia in the venous blood includes more than approximately 100 µmol/l

In another embodiment, the methods also include the introduction of lactulose.

In related embodiments, the implementation of two or more points in time occur within one week, two weeks, three weeks, four weeks, five weeks, six weeks, eight weeks, six months or more. Also included time at any time between them.

In another aspect there are provided methods of treating a subject having HE, including an introduction to the subject an effective amount of a specific for diseases of the GI antibiotics such as rifaximin, thus conducting the treatment of the subject.

In related embodiments, the implementation of specific diseases of the GI antibiotics such as rifaximin, administered for more than 365 days more than 730 days more than 1095 days or for the remaining life of the subject.

In another aspect there are provided methods of diagnosing a neurological disease in a subject by determining the critical frequency of flicker (CFF) from the subject at two or more points in time, and the reduction of CFF indicates that the subject has a neurological disease. The reduction can be between any two points in time, for example between the first and second points in time, between the first and third points in time, between the first and fourth points is AMI time between the second and third points in time, between the second and fourth moments of time, etc.

In a related embodiment, CFF includes time-weighted average CFF. In another embodiment, the neurological disease or disorder comprises Alzheimer's disease or Parkinson's disease. Also included are diseases in which the CFF is subjected to modulation in the subject. The term "modulation", as used here, includes the increase or decrease compared with the initial level or the change compared to any dimension, even if it is not a starting point for the subject. The source level for the subject, you can determine when the subject has not manifested episode HE or episode of another neurological disease, when the subject has recovered or is in remission HE or other neurological diseases.

In another aspect there are provided methods for determining prognosis in a subject having a neurological disease by determining the critical frequency of flicker (CFF) from the subject at two or more points in time, and the reduction of CFF indicates that in relation to the subject's prognosis is poor. Poor prognosis, as used here, includes the forecast of life expectancy that is shorter than the previous forecast.

As indicated in the this embodiment, CFF includes time-weighted average CFF. In another embodiment, the neurological disease or disorder comprises Alzheimer's disease, Parkinson's disease, trauma, migraine, constant headaches, insomnia and other sleep disorders, and/or epilepsy.

In related embodiments, the implementation of two or more points in time occur within one week, four weeks, six months or more.

In another aspect there is provided a computerized methods to identify subjects having a neurological disease by maintaining a database related to CFF subjects at different points in time and at different stages of disease progression, comparison of results of determination of CFF from individuals received at two or more points in time, to the database, receiving from the computer diagnosis of neurologic disease if the subject has the CFF results that fall between measurements.

In one embodiment, CFF includes time-weighted average CFF. In another embodiment, the time-weighted CFF or CFF second or subsequent time includes less than about 24 Hz. In another embodiment, the methods also include managing printer to print a report based on the results of the method.

In another aspect, there provided is acuautla business procedures to reduce health care costs, including the definition of CFF from the subject at two or more points in time, storing the patient information in the computer processor, determining whether the subject has a neurological disease, by definition, decreased if the value of CFF between time and treatment of the subject in accordance with the need for avoidance or deferral of admission.

In another aspect there are provided methods of business activities to reduce health care costs, including the definition of CFF from the subject at two or more points in time, storing patient information within a computer processor, determining whether the subject hepatic encephalopathy, by definition, decreased if the value of CFF between time and treatment of the subject in accordance with the need for avoidance or deferral of admission

Device for determining the risk of the episode HE includes "flicker-block, a measuring device for CFF and the computer algorithm. In another embodiment, the method also includes a storage device capable of storing data related to CFF.

BRIEF DESCRIPTION of FIGURES

Fig.1 represents a diagram in the form of broken, which compares the ingestion of lactulose between subjects receiving placebo, and subjects receiving the reef is Simin.

Fig.2 represents a diagram in the form of a polyline which demonstrates the evaluation by the method of Kaplan-Meier distribution of time until the episode HE exacerbation during treatment.

Fig.3 represents a diagram in the form of a polyline which demonstrates the evaluation by the method of Kaplan-Meier distribution of time to first NOT associated with hospitalization.

Fig.4 is a chart in the form of a polyline which demonstrates the evaluation by the method of Kaplan-Meier distribution of time to first increase in assessments on connu.

Fig.5 represents a diagram in the form of a polyline which demonstrates the evaluation by the method of Kaplan-Meier distribution of time to first increase the degree of "fluttering" of the tremor.

In Fig.6 shows the time to first episode of acute HE, with obvious clinical symptoms during treatment (up to 6 months of treatment, day 170, in the first study) (in case formed in accordance with the assigned treatment (ITT) population).

In Fig.7 shows the comparison of time to first episode of acute HE, with obvious clinical symptoms during treatment in the first study (subjected to treatment with rifaximin group compared with the treated placebo group) and in the second study (new in relation to treatment with rifaximin group).

In Fig.8 demons eroitca comparison of time to first episode of acute HE with a clear clinical picture during exposure to the effects of placebo (in the first study) and after switching on exposure to effects of rifaximin (second study) among treated with placebo in the first study subjects who started taking rifaximin in the second study.

In Fig.9 shows the time to first NOT associated with hospitalization (up to 6 months of treatment, day 170, in the first study).

In Fig.10 shows the time to first NOT due to hospitalization in the first study (in the case of the ITT population).

In Fig.11 shows the time to first increase the assessment on connu (up to 6 months of treatment, day 170, the first study) (in the case of the ITT population).

In Fig.12 shows the time to first increase the degree of "fluttering" of tremor (up to 6 months of treatment, day 170, the first study) (in the case of the ITT population).

In Fig.13 displays the estimates by the method of Kaplan-Meier distribution of time to first exacerbation HE during treatment for the subjects of group continuation treatment with rifaximin, which did not show the episode HE in the first study, in comparison with the treated placebo subjects.

In Fig.14A-B are displayed section obtained using CLDQ results, which are identified by Twa, between the treated placebo and rifaximin groups in the distribution of the frequency is represented in the form of Twa estimates tiredness and General estimates.

In Fig.15 presents the pathogenesis of HE.

In Fig.16 presents the clinical picture is and HE. Classification based on Ferenci P, et al. Hepatology. 2002; 35: 716-721, submitted by the working group WCOG in 1998.

In Fig.17 presents HESA-adaptation assessment connu.

In Fig.18 presents the influence on the patient and those who care for them.

In Fig.19 displayed hospitalization because HE and the impact on the economy.

In Fig.20 shows the effect of hepatic insufficiency on the pharmacokinetics of rifaximin

In Fig.21 demonstrates that exposure of rifaximin significantly less exposure to other antibiotics (Well et al., Int J Antimicrob Agents 10 (1998) 31-38). Patients with the highest hepatic insufficiency exposure of rifaximin in >200 times less than the exposure of rifampin, >35 times less exposure norfloxacin and ≥10 times less exposure neomycin.

In Fig.22 demonstrates the interaction between the drugs: midazolam and rifaximin. No significant inhibition of CYP enzymes and P-glycoprotein or BSEP. Portosystemic anastomoses with hepatic insufficiency may reduce the level of exposure in the liver.

In Fig.23 illustrates the effect on ammonia levels in the blood. Rifaximin, administered at a dose of 1200 mg/day for 5-10 days, reduced the levels of ammonia in the blood (p<0,0001). It was noted corresponding decrease of the HE (p<0.0001) and improved neurological, neuropsychiatric and psychometrically the parameters. Was investigated the correlation between the reduction of ammonia level over time, and HE.

In Fig.24 displayed curves without episodes of exacerbation with estimates by the method of Kaplan-Meier estimates in the study (time to first episode of acute HE up to 6 months of treatment, day 170) (in the case of the ITT population).

In Fig.25 displayed curves without episodes of exacerbation with evaluation according to the method of Kaplan-Meier in the main study (time to first NOT associated with hospitalization for up to 6 months of treatment, day 170) (in the case of the ITT population).

Fig.26 is a diagram in the form of broken, which shows the time to the first episode HE exacerbation during treatment.

Fig.27 is a diagram illustrating the relationship of risks (risk, subjected to treatment with rifaximin group divided by the risk in the treated placebo group) in the case of the risk of occurrence of acute HE with a clear clinical picture for each subgroup.

Fig.28 is a diagram in the form of broken, which shows the time to first NOT associated with hospitalization.

Fig.29 is a block diagram illustrating that the use of lactulose was similar between the control group and the group receiving rifaximin.

Fig.30 is a diagram illustrating the presence of persistence of therapeutic effect in different subgroups, of which the output was administered rifaximin.

In Fig.31 shows the distribution presented in the form of time-weighted average values of the results of the study CFF in accordance with the state of aggravation NOT with a clear clinical picture.

In Fig.32 displayed operating characteristic curve (ROC-curve) in the case of using the results of the study CFF to predict exacerbations HE with a clear clinical picture.

In Fig.33 shows the distribution presented in the form of time-weighted average values of the results related to the concentration of ammonia in the venous blood, in accordance with the state of aggravation NOT with a clear clinical picture.

In Fig.34 displayed operating characteristic curve (ROC-curve) in the case of using ammonia levels in venous blood for prediction of exacerbation of HE with a clear clinical picture.

DETAILED DESCRIPTION of the PRESENT INVENTION

Hepatic encephalopathy, also known as hepatic coma or portal-systemic encephalopathy (PSE) is a serious, rare, complex, episodic, neuropsychiatric syndrome associated with progressive liver disease. Hepatic encephalopathy is a huge burden for the patient, his family and the health system; and the modern standard of service does not meet the requirements. Episodic with obvious HE is liricheskoy pattern is widespread among patients with liver cirrhosis. The disease is rare among individuals in the General population. The episodes HE with a clear clinical picture cause dementia, may appear without the ominous symptom, make the patient unable to look after themselves and often lead to hospitalization. The frequency of hospitalizations due to HE increased from 1993 to over 40,000 patients in 2003 and 2004 50962 patients were hospitalized with a primary diagnosis of HE. HE, as used here, includes, for example, episodic, chronic and persistent minor HE.

The main pathogenesis HE relates to nitrogen-containing substances derived from ulcers, which affect the function of the brain. I believe that the most influential of these compounds is ammonia, a byproduct from the breakdown of proteins, which usually he is neutralized by the liver. However, the correlation between blood levels and mental state when cirrhosis is inaccurate, in part because the blood-brain barrier permeability in relation to ammonia is increased in patients with HE. It was also suggested that other derived from gut toxins are responsible for HE.

In patients with chronic liver disease the occurrence of hepatic encephalopathy followed by a low quality of life compared with the corresponding p is the age of the patients without HE. The episodes HE with a clear clinical picture cause dementia, may appear without the ominous symptom, make the patient unable to look after themselves and often lead to hospitalization. In patients with HE manifested symptoms, including fatigue, daytime sleepiness and lack of perception (score from connu =1), and the confusion and disorientation (score from connu =2) that significantly interfere with daily functioning, and reduced ability to look after themselves. Often this lack of self leads to poor eating habits and lack of doctor's instructions and further develops into more severe symptoms, such as increased drowsiness, and apparent disorientation and dizziness (score from connu =3) or coma (score from connu =4).

It was also found that the medical history, including episodes of HE with a clear clinical picture and severity of episodes HE foretell reduced duration of life of patients with chronic liver disease. In patients with liver cirrhosis and medical history, including episodes of HE with a clear clinical picture, the probability of survival was 42% at 1 year and 23% at 3 years after the manifestation of the episode. In another analysis of episodes of HE grade connu =2 in patients with cirrhosis was associated with a 4-fold increased risk of death.

The authors of this and the finding was determined that there is a correlation between CFF or the concentration of ammonia in the venous blood and the occurrence of episodes of exacerbation of HE during treatment. In addition, the authors of the present invention have determined that the time-weighted CFF or the concentration of ammonia in the venous blood is an accurate predictor of the episodes HE exacerbation during treatment and prognosis in subjects with HE. In another embodiment, the present invention has determined that the subjects continuing reception of rifaximin for an extended period of time, for example more than 1.5 years, continue to find positive effects, such as reduced frequency of episodes of exacerbation of HE during treatment.

In certain embodiments of the implementation there are ways to determine whether the subject has a neurological disease. The presented methods are based on determination of the critical frequency of flicker or ammonia level in venous blood.

Critical frequency of flicker, also called CFF, you can define, for example, using standard methods known in the art. In addition, to measure CFF there are commercial devices that are well known to skilled in the art specialists.

In the analysis of the critical frequency of flicker is used, n is the sample, the correlation between processing at the level of brain oscillating visual stimuli and reduced activity of CNS (Central nervous system) due to the increase in the severity of HE. In this analysis determines the frequency at which a flickering light is perceived by the subject as not flashing light. Reducing this frequency was associated with increasing severity of HE. In one example, a circular light pulses with components 1:1 ratio between the visual impulses and intervals were used, with a gradual decrease in frequency from 0.5 to 0.1 Hz/sec. The frequency of white light, which is initially generated as a high pulse frequency (50 Hz) and which gives the patient the impression of not flashing light, can be reduced gradually to create the subject has the impression that not flashing light changed to flashing. The subject registers this change by pressing the manual switch. Frequency of flickering can be defined multiple times, and it is possible to calculate average values for each subject.

In some embodiments, the implementation of the CFF values tracked over time for each subject. Based on these values you can calculate the area under the curve from CFF-time (AUC), using calculations that are standard in the art. For example, the AUC can be calculated using the trapezoid formula For applying the trapezoid point on the graph connecting the plots a straight line, set perpendicular to the line from the abscissa to each point on the graph and calculate the sum of the areas of triangles and trapezoids created this way, and it corresponds to the AUC.

For exact specifications CFF variations over time for each subject it is possible to calculate the time-weighted value (twa). To calculate the twa analysis results CFF over time or ammonia levels in venous blood expressed in the form:

,

where T represents the time of exposure effects. Thus, taw characterizes the average result: CFF and/or the ammonia level in the venous blood between multiple points in time.

The correlation between twa and the presence or absence of the episode HE exacerbation during treatment can be analyzed using analysis of variance and coefficient of rank correlation coefficient. In addition, you can perform an analysis of ROC curve to assess the correctness of twa for distinguishing between the presence and absence of episodes of exacerbation during treatment. Analysis of the ROC curve in the case of data collected in the Examples have shown that this methodology is highly accurate prognostic factor HE.

These toxic compounds gain access to the systemic circulation as a result of reduced liver function or portosystemic the x venous anastomoses. Once in the brain tissue, the compounds induce changes in neurotransmission, which have an impact on the consciousness and behavior. HE explains the General decline in the activity of the Central nervous system in the presence of nitrogen-containing compounds, which lead to activation of the gamma-aminobutyric acid (GABA) and reduced neurotransmission from glutamate.

Precipitating factors include azotemia (29%), sedatives, tranquilizers, analgesics 24%), gastrointestinal bleeding (18%), food protein in an excessive amount (9%), metabolic acidosis (11%), infection (3%), constipation (3%). Unable to provoke a surgical intervention, in particular the procedure transfemng intrahepatic portosystemic shunting (TIPS). HE, for unknown reasons, is only 2% of cases.

Initial symptoms are subclinical, and their diagnosis is required psychometric testing. There are 4 progressive stages of deterioration, known as criteria West haven (or score Konno), ranging from stage 0 (absence of detectable changes in personality) to stage 4 (coma, decerebration posture, dilated pupils), as discussed in more detail below.

HE manifests in the form of a series of events consisting of psychomotor dysfunction, memory loss, HC is lichnogo reaction time, normalista perception, poor concentration, and in severe cases coma. May experience changes in personality, cognition, behavior and function of the neuromuscular system. Neurological signs may include hyperreflexia, rigidity, mioclauniei and "fluttering" tremor (widely "fluttering" the trembling of the muscles). Can be abnormal cognitive tasks, such as connecting rooms with lines. May be liver stench (sweet breath). Electroencephalogram (EEG) show the three-phase nonspecific medlennovolnova activity, mainly over the frontal lobes. Prothrombin index can be increased to prevent the correction with vitamin K Obtained by computer topography image of the head may be normal or demonstrate General atrophy. In the end, there may be signs of liver disease such as jaundice and ascites.

The diagnosis is NOT carried out on the basis of medical history and studies of physical and mental state, with the necessary clinical elements are information about existing liver disease causing factor(s) and/or previous history of HE. EEG may show medlennovolnova activity, even in mild cases. Elevated levels of ammonia in the serum is typical,but not necessary, and there is a weak correlation between it and the degree of encephalopathy.

Treatment of patients with chronic HE includes 1) providing supportive treatment, 2) the identification and exclusion of precipitating factors, and 3) reducing the load of nitrogen-containing substances from the gut and 4) determining the need for long-term therapy. Loading of nitrogen-containing substances from the intestine is usually reduced using a non-absorbable disaccharide (lactulose) and/or antibiotics.

Lactulose is considered a therapeutic tool first line in the United States. Lactulose is metabolized by intestinal bacteria of the colon, which leads to a decrease in the pH of feces, next to slabitelnom effect and, finally, to the removal of feces. The reduced pH of feces leads to the ionization of ammonia (NH3) to Yon ammonium (NH4+), which is used by bacteria for the synthesis of amino acids and proteins. This leads to lower ammonia levels in serum and improving mental function.

Conventional therapy aimed at lowering the production and absorption of ammonia. Lactulose is usually used in the daily dose, 30-60, However, the dose can be reduced up to 20-40 g TID-QID to spawn 2-3 emptying of the intestine in the form of prospermatogonia stools per day. If lactulose cannot be assigned orally or through nasogastric probe, for example, the PAC is entam with stage 3 and 4 HE, you can assign it in the form of 300 cm3(200 g) held enema.

In the case of acute encephalopathy lactulose can be assigned to either oral, taking into or through nasogastric probe or via retention enema. The usual oral dose of 30 g with subsequent dose every 1-2 hours before emptying. At this point in time, the dose regulate to achieve two or three emptying of the intestine in the form of soft stools per day.

Lactulose public without a prescription. Traditional and relatively tasteless drug, often called " commercial activity "lactulose powder used for preparation of solution for oral administration can be obtained, for example, Bertek Pharmaceuticals, Sugarland, Tex. as KristaloseRTMin containing 10 and 20 g sachets. Lactulose syrups, usually sold as laxatives include CephulacRTM, ChronulacRTM, CholacRTMand EnuloseRTM. These syrups can be used instead lactulose powder using a sufficient quantity of syrup to provide the desired dose of lactulose; usually named syrups contain about 10 g of lactulose 15 ml of syrup.

Active in the gastrointestinal tract antibiotics of a wide range of actions, including neomycin, metronidazole, vancomycin and paromomycin, usage is demonstrated together with lactulose or without it. Modern guidelines recommended intake of neomycin at a dose of 1-2 g/day, with periodic monitoring of kidney and annual control of hearing or metronidazole in a dose of 250. Lactulose can cause diarrhea, leading to dehydration, NOT provoking factor. In addition, the disgust of the patient caused by excessively sweet taste of lactulose, limits compliance with doctor's instructions for taking lactulose. In addition, the scheme of doses, which is connected with the rhythms of emptying of the bowel and side effects, consisting of flatulence, bloating, diarrhoea (which leads to dehydration and acidosis, complicate prolonged use of lactulose.

The use of antibiotics for the treatment HE prevents associated with prolonged use of toxicity. In particular, systemic absorption of neomycin, metronidazole and ampicillin resulted in rare cases of nephrotoxicity, ototoxicity, S. enterocolitis and/or the formation of resistant bacterial strains. In addition, neomycin inhibits only aerobic bacteria. Metronidazole slowly metabolized in patients with liver dysfunction, capable of interactions with alcohol (call disulfiramopodobnuu effect), and high levels in the blood can lead to seizures.

One specific gastro-intestinal tract antibiotic is reef is ximin. Rifaximin is a non-aminoglycoside, a semisynthetic antibiotic derived from rifamycin O. He is a non-systemic, not absorbed by the broad-spectrum antibiotic for oral administration, providing specific effect on enteric pathogens of the gastro-intestinal tract. Found that rifaximin has in the treatment HE advantage with respect to the previously used antibiotics; for example, he shows little systemic absorption (<0.4 percent), regardless of the meal or the presence of disease of the gastrointestinal tract and does not demonstrate accumulation in plasma using high or repeated doses. The lack of systemic absorption makes rifaximin is safe and well-tolerated, thereby improving the adherence of the doctor the patient and reducing the side effects associated with currently known treatments.

Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic belonging to the class of antibiotics rifamycin, for example pyrido-imidazo-rifamycin. Rifaximin display a wide range of its antibacterial activity, for example, in the gastrointestinal tract against localized in the gastrointestinal tract bacteria that cause infectious diarrhea syndrome level becomes too low bowel, excessive would be try the growth of bacteria in the small intestine, Crohn's disease and/or pancreatic insufficiency. It was reported that rifaximin has little systemic absorption due to its chemical and physical properties (Descombe J. J. et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int. J Clin Pharmacol Res, 14 (2), 51-56, (1994)).

Rifaximin described in Italian patent IT 1154655 and EP 0161534. In the patent EP 0161534 described a process for the production of rifaximin using rifamycin O as source material (The Merck Index, XIII Ed., 8301). In U.S. patent No. 7045620 B1 describes a polymorphic forms of rifaximin. Mentioned applications and patents are incorporated here by reference in their entirety for all purposes.

Antibiotic class of rifaximin is, for example, the compound having the structure of formula I:

where A can be a structure of A1:

or the structure of A2:

where-x - is a covalent chemical bond or anything; R represents hydrogen or acetyl;

R1and R2independently represent hydrogen, (C1-4)alkyl, benzyloxy, mono - and di(C1-3)alkylamino(C1-4)alkyl, (C1-3)alkoxy(C1-4)alkyl, hydroxymethyl, hydroxy(C2-4)alkyl, nitro, or R1and R2together with two consecutive atoms the carbon of the pyridine nucleus form a benzene ring, unsubstituted or substituted by one or two methyl or ethyl groups; R3is a hydrogen atom or nothing; provided that when A represents A1, -x - is nothing, and R3is a hydrogen atom; with the further proviso that when A represents A2, -x - is a covalent chemical bond, and R3is none.

It also describes the connection defined above, in which A represents a structure of A1or A2above, -x - is a covalent chemical bond or anything; R represents hydrogen or acetyl, R1and R2independently represent hydrogen, (C1-4)alkyl, benzyloxy, hydroxy(C2-4)alkyl, di(C1-3)alkylamino(C1-4)alkyl, nitro, or R1and R2together with two consecutive carbon atom of the pyridine nucleus form a benzene ring, and R3is a hydrogen atom or nothing; provided that when A represents A1, -x - is nothing, and R3is a hydrogen atom; with the further proviso that when A represents A2, -x - is a covalent chemical bond, and R3is none.

It also describes the connection defined above, in which A represents a structure of A1or A2/sub> above, -x - is a covalent chemical bond or anything; R represents acetyl, R1and R2independently represent hydrogen, (C1-4)alkyl, or R1and R2together with two consecutive carbon atom of the pyridine nucleus form a benzene ring, and R3is a hydrogen atom or nothing; provided that when A represents A1, -x - is nothing, and R3is a hydrogen atom; with the further proviso that when A represents A2, -x - is a covalent chemical bond, and R3is none.

It also describes the connection defined above, which is a 4-deoxy-4'-methyl-pyrido[1',2'-1,2]imidazo[5,4-c]rifamycin SV. It also describes the connection defined above, which is a 4-deoxy-pyrido[1',2':1,2]imidazo[5,4-c]rifamycin SV.

It also describes the connection defined above, in which A is A structure described above, -x - is a covalent chemical bond or anything; R represents hydrogen or acetyl; R1and R2independently represent hydrogen, (C1-4)alkyl, benzyloxy, mono - and di(C1-3)alkylamino(C1-4)alkyl, (C1-3)alkoxy(C1-4)alkyl, hydroxymethyl, hydroxy(C2-4)alkyl, nitro, or R1and R 2together with two consecutive carbon atom of the pyridine nucleus form a benzene ring, unsubstituted or substituted by one or two methyl or ethyl groups; R3is a hydrogen atom or nothing; provided that when A represents A1, -x - is nothing, and R3is a hydrogen atom; with the further proviso that when A represents A2, -x - is a covalent chemical bond, and R3is none.

Rifaximin is a compound having the structure of formula II:

In certain embodiments of the implementation of the antibiotic comprises one or more of the following classes of antibiotics: rifamycin, aminoglycoside, amphenicol, ansamycins, β-lactam, carbapenem, a cephalosporin, cephamycin, monobactam, oxazepam, lincosamide, the macrolide, polypeptide, tetracycline or 2,4-diaminopirimidina. Given as examples of antibiotics these classes are listed below.

Rifaximin display a wide range of antibacterial activity in the gastrointestinal tract against localized in the gastrointestinal tract bacteria that cause infectious diarrhea, including anaerobic strains. It was reported that rifaximin has little systemic absorption BL is due to its chemical and physical properties (Descombe J. J. et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14. (2), 51-56, (1994)).

If you don't want to be limited to any specific scientific theories, rifaximin acts by binding to the beta subunit of bacterial-dependent deoxyribonucleic acid RNA polymerase, resulting in inhibition of RNA synthesis in bacteria. It is active against many gram-positive and gram-negative bacteria, and aerobic and anaerobic. In vitro data show that rifaximin is active with respect to the genera Staphylococcus, Streptococcus, Enterococcus and Enterobacteriaceae. Bacterial recovery or increasing resistance to antimicrobial agents in the intestinal flora does not occur frequently and have no clinical significance. Currently rifaximin permitted in 17 countries outside the United States and licensed by Management under the control over products and medicines (FDA) for the United States in may 2004.

It should be understood that both the foregoing General description and the following detailed description are merely exemplary and illustrative, and not limiting of the claimed invention. In this application the use of the singular includes the plural, except where otherwise indicated. In this application the use of "or" means "and/or", except where stated otherwise. In addition, use the of the term "including", as well as other forms, such as "includes" and "included", is not a limitation. Also, terms such as "element" or "component" include both elements and components comprising one unit and elements and components, which include more than one subunit, except where otherwise indicated. Also the use of the term "portion" may include the component part or all of component.

All documents or portions of documents, cited in this application, including, but without limitation, patents, patent applications, articles, books and monographs included therefore in the verbal form in their entirety by reference for any purpose.

One embodiment is a method of treating or preventing hepatic encephalopathy (HE) by introducing to the subject a therapeutically effective amount of a specific for diseases of the gastrointestinal tract (GI) of the antibiotic. Examples of specific diseases of the gastrointestinal tract antibiotics include antibiotics class rifamycin, such as rifaximin.

Presented here options of implementation relate to the detection efficiency for specific diseases of the gastrointestinal tract (GI) of antibiotics in the case of treating or preventing hepatic encephalopathy. Options for implementation include primeneniyu specific GI diseases antibiotics to prevent the occurrence of symptoms HE, as well as increasing the time before the first episode HE exacerbation during treatment. In one embodiment, the time until the first episode HE exacerbation during treatment was determined by time to increase assessment Konno to grade ≥2 (for example, 0 or 1 to ≥2) or increase the assessment on Konno and "fluttering" tremor average of one degree for each evaluation, for those patients who had an assessment for Konno on the source level =0. In another embodiment, the time until the first episode HE exacerbation during treatment was determined by time to any increase in comparison with the initial level or assessment Konno (degree of mental status), or the degree of "fluttering" of the tremor, with estimates by the method of Kaplan-Meier cumulative percent of subjects with any increase in days 28, 56, 84, 112, 140 and 168.

Another option was to determine the time until the first associated with HE hospitalization or time to development of spontaneous bacterial peritonitis (SBP). Another option was the average change compared with the initial concentration of ammonia in the blood over time, or the average change compared to baseline values of critical frequency of flicker from time to time. As an additional option was provided average daily consumption of lactulose in the dynamics of time offset compared to the original the level of the estimates for connu over time or offset in comparison with the initial level degrees "fluttering" of tremor over time. Except where otherwise indicated, the offset value is the change in this value compared with the value at baseline.

Other indicators of the effectiveness of the treatments described here included mean change compared to baseline assessments conducted by using a questionnaire for evaluation of chronic liver disease (CLDQ), with time; the average change compared to baseline ratings on a scale of drowsiness of Apsara over time and the proportion of subjects who had a score on a scale of drowsiness of Apsara, component >10. Assessment of the severity of persistent chronic hepatic encephalopathy may also be based on, for example, estimates for connu.

In another embodiment, the subject suffering from hepatic encephalopathy (HE), affected, or are in remission, you can assign the antibiotic class rifamycin for approximately 24 weeks to 24 months. During the treatment HE antibiotic class rifamycin may be administered to a subject for 12 months or longer, for example during the lifetime of the subject. In one embodiment, the antibiotic is prescribed daily until the death of the subject.

One variant of implementation relates to a method of reducing the entity of the risk of occurrence of an episode of exacerbation during treatment by introducing the subject of the specific is someone for GI disease antibiotic. In one embodiment, in the case of subjects who showed the last episode HE for equal to or more than 90 days before the start of treatment, the risk of exacerbation during treatment was reduced by 58%. In another embodiment, the risk of exacerbation during treatment was decreased by approximately 30-70%. In another embodiment, the risk is reduced by approximately 40-70%. One alternative implementation is to reduce the risk of episodes of hepatic encephalopathy with a clear clinical picture in patients with HE. In one embodiment, patients are patients over the age of 18.

In one embodiment, in the case of subjects who showed the last episode HE for more than 90 days before the introduction of specific diseases of the GI of the antibiotic, the risk of exacerbation during treatment was reduced by approximately 60%. In another embodiment, the risk of exacerbation during treatment was decreased by approximately 2-80%.

In another embodiment, in the case of subjects with two or fewer episodes of HE in the six-month period prior to treatment, the risk of an episode of acute NOT at the time of treatment was reduced by approximately 56%. In one embodiment, the risk of an episode of acute NOT at the time of treatment was reduced by approximately 20-70%.

In another embodiment, in the case of entities that have more than two episodes HE sistemica the hydrated period before treatment, the risk of an episode of acute NOT at the time of treatment was reduced by approximately 63%. In another embodiment, the risk was reduced by approximately 30-80%.

In one embodiment, a therapeutically effective amount specific for diseases of the gastrointestinal tract (GI) of the antibiotic includes from about 1000 mg to about 1200 mg/day.

In one embodiment, a therapeutically effective amount specific for diseases of the GI antibiotic comprises from about 1100 mg to about 1200 mg/day.

In accordance with one embodiment a therapeutically effective amount specific for diseases of the GI antibiotic includes approximately 1150 mg/day.

In another embodiment, therapeutically effective amount is the destination schema one capsule or tablet of the drug two times every day, each tablet contains approximately 550 mg specific for diseases of the GI antibiotics such as rifaximin.

In one embodiment, therapeutically effective amount is the destination schema two capsules or tablets three times each day, with each capsule includes approximately 200 mg specific for diseases of the GI antibiotic.

In one embodiment, a therapeutically effect the active number is the dose component 275 mg specific for diseases of the GI antibiotic, administered four times a day. In another embodiment, 275 mg specific for diseases of the GI antibiotic is administered in the form of two dosage forms twice a day.

Another embodiment is a method of maintaining the remission is NOT the subject through the introduction of subject-specific disease GI antibiotic.

Another embodiment is a method of increasing the time to hospitalization for treatment of HE through the introduction of subject-specific disease GI antibiotic. In one embodiment, the introduction of specific diseases of the GI antibiotic decreases the incidence of hospitalization for approximately 48%. In another embodiment, specific for diseases of the GI antibiotic decreases the incidence of hospitalization for approximately 13 to approximately 69%.

In one embodiment, the specific treatment for the disease GI antibiotic maintains remission of the subject.

In one embodiment, specific for diseases of the GI antibiotic is administered to the subject within six months, one year, two to three years, or daily until the death of the subject.

In one embodiment, score Konno for the subject is improved compared to the initial level after the introduction of specifices the CSO for diseases of the GI antibiotic.

In one embodiment, quality of life (QoL) improved compared to baseline levels by introducing a specific for diseases of the GI antibiotic during the course of treatment with rifaximin. In one embodiment, the improved quality is improved AUC or TWA defined by means of a questionnaire for assessment of chronic liver disease (CLDQ).

In one embodiment, specific for diseases of the GI antibiotic is administered to the subject together with lactulose, before treatment with lactulose or after treatment with lactulose. In one embodiment, the subject or nurse health worker recommended for specific diseases of the GI antibiotic together with lactulose. In one embodiment, using pharmaceutical labels or liner to a subject or nurse health worker recommended for specific diseases of the GI antibiotic together with lactulose to maintain remission HE or reducing the risk of episodes of HE with a clear clinical picture. In one embodiment, the subject or nurse health worker it is recommended to use two tablets containing 550 mg of rifaximin twice a day together with lactulose. The use of lactulose can be distributed during the time that the subject has remained 2-3 operon is of the intestine in the form of soft stools per day. In one embodiment, lactulose is administered in 15-ml doses, each 15-ml dose contains 10 mg of lactulose. Under normal distribution in time, the subject may start with one dose or partial dose a day, and then eventually go to a 15-ml doses to achieve their ultimate indicator in the form of 2-3 bowel movements in the form of soft stools per day.

In one embodiment, subjects in need of treatment by reason and HE has a degree And or In the child-Pugh score, is subjected to the treatment of specific diseases of the GI antibiotic. In another embodiment, subjects in need of treatment by reason and HE has a degree And or In the child-Pugh score, is subjected to the treatment of specific diseases of the GI antibiotic in combination with lactulose. In another embodiment, the entities holding the degree or In the child-Pugh score, or carrying out their patronage of the medical practitioner, it is recommended that they are treated for specific diseases of the GI antibiotic. The recommendation may be oral or written recommendation, for example, in the pharmaceutical label or the liner. In another embodiment, the entities holding the degree or In the child-Pugh score, or carrying out their patronage of the medical practitioner, it is recommended that they are treated for specific diseases of the GI antibi the tick in combination with lactulose. In one embodiment, the subject in need of treatment HE and smaller With a degree in child-Pugh score, is subjected to the treatment of specific diseases of the GI antibiotic. In one embodiment, the subject in need of treatment HE and smaller With a degree in child-Pugh score, is subjected to the treatment of specific diseases of the GI antibiotics and lactulose.

In another embodiment, subjects in need of treatment HE or carrying out their patronage of the health worker, inform about the risk of anaphylaxis to treat specific diseases of the GI antibiotic.

In one embodiment, specific for diseases of the GI antibiotic is administered with one or more compounds selected from Align, Alinia (nitazoxanide), lactulose, pentasa, cholestyramine, sandostatin, vancomycin, lactose, amitiza, flagyl, zegerid, prevacid and miralax.

In one embodiment, after treatment for specific diseases of the GI antibiotic reduced score from Konno (the degree of the mental state of the subject.

In one embodiment, after treatment for specific diseases of the GI antibiotic time to increase assessment connu compared with the initial level increases.

In one embodiment, after treatment with ecification for GI disease antibiotic delay to increase assessment Konno is approximately 54%. For example, the delay time in % to increase assessment connu may be from about 30% to about 70%.

In another embodiment, the introduction of specific diseases of the GI antibiotic prevents the increase in the assessment on connu. For example, the introduction of specific diseases of the GI of the antibiotic increases the time required to increase the valuation on connu compared with the initial level.

In one embodiment, the introduction of specific diseases of the GI antibiotics leads to increased time to increase compared with the initial level degree "fluttering" of the tremor.

In another embodiment, the introduction of specific diseases of the GI antibiotic causes the delay to increase the degree of "fluttering" of the tremor.

In another embodiment, the introduction of specific diseases of the GI antibiotics leads to increased time to the first related to HE hospital.

In another embodiment, the introduction of specific diseases of the GI antibiotic leads to an increase in the time to development of spontaneous bacterial peritonitis (SBP).

In another embodiment, the introduction of specific diseases of the GI antibiotic leads to a decrease in the concentration of ammonia in the blood compared to baseline levels after the introduction of rivax is mine. For example, reducing the concentration of ammonia in the blood compared with the initial level to 170 days can reach approximately 6 µg/DL.

In another embodiment, the introduction of specific diseases of the GI antibiotics leads to increased values of critical frequency of flicker compared to baseline levels after administration of rifaximin.

In another embodiment, the introduction of specific diseases of the GI antibiotic leads to decrease over time, daily consumption of lactulose compared with baseline levels after administration of rifaximin.

In another embodiment, the introduction of specific diseases of the GI antibiotic leads to reduce the daily intake of lactulose with approximately 7 doses of lactulose to approximately 2 doses of lactulose.

In another embodiment, the introduction of specific diseases of the GI antibiotic leads to the use of lactulose, which is increased in the initial stage compared to baseline levels. For example, the use of lactulose may occur approximately 1-30 days.

In another embodiment, the introduction of specific diseases of the GI antibiotic leads to displacement with time estimates for connu at baseline after administration of rifaximin. For example, the bias of the estimates for Konno on the source level may be the add up to approximately 1 - approximately 2.

In another embodiment, the introduction of specific diseases of the GI antibiotic leads to a shift over time in comparison with the initial level degrees "fluttering" of the tremor.

In another embodiment, the introduction of specific diseases of the GI antibiotic leads to a change with time in comparison with the initial level of the evaluations conducted using the questionnaire for evaluation of chronic liver disease (CLDQ).

In another embodiment, the introduction of specific diseases of the GI antibiotic leads to changes over time compared to baseline ratings on a scale of drowsiness of Apsara after administration of rifaximin.

As is known, the estimation of the model of end stage liver disease (MELD) can be used to predict the severity of liver disease based on the level of creatine in serum levels of total bilirubin in serum and international normalized ratio for prothrombin index - INR. It is established that the assessment MELD applicable for the prediction of mortality in patients with compensated and decompensated cirrhosis. The maximum value given in the case of MELD is 40. All values greater than 40, provides an assessment =40.

In another embodiment, subjects with MELD comprising from about 1 to 24, d is was garofali treatment for HE, when using the introduction of specific GI diseases antibiotics. In another embodiment, subjects with MELD, constituting less than 10 or equal to 10, reacted to the treatment of specific diseases GI antibiotics. In another embodiment, subjects with MELD constituting from about 11 to 18, reacted to the treatment of specific diseases GI antibiotics. In another embodiment, subjects with MELD between 19 and 24, reacted to the treatment of specific diseases GI antibiotics. In one embodiment, subjects in need of treatment by reason of HE and equal 25 or less assessment MELD, is subjected to the treatment of specific diseases of the GI antibiotic. In another embodiment, subjects in need of treatment by reason of HE and equal 25 or less assessment MELD, is subjected to the treatment of specific diseases of the GI antibiotic in combination with lactulose. In another embodiment, subjects with 25 or fewer assessment MELD, it is recommended that they are treated for specific diseases of the GI antibiotic. The recommendation may be oral or written recommendation, for example, in the pharmaceutical label or the liner. In another embodiment, subjects with 25 or fewer assessment MELD, it is recommended that they are treated for specific diseases is GI antibiotic in combination with lactulose.

In one embodiment, provided herein is a method of treating or preventing HE through the introduction of patient 1100 mg of rifaximin in the day for more than 28 days.

Another embodiment is a method of reducing the application lactulose for the subject. This method includes the appointment of rifaximin to a subject being treated with lactulose, and lower consumption of lactulose. For example, lactulose consumption can be reduced by 1, 2, 3, 4, 5, 6 or more cups in a standard doses of lactulose compared with baseline levels. Alternatively, the use of lactulose can be reduced by 5, 10, 15, 20, 25, 30, 34, 40, 45, 50, 55, 60, 65 or 70 g of lactulose compared with baseline levels. In one embodiment, the use of lactulose on the source level is its non-use.

In one embodiment, provided herein is a method of saving remission is NOT the subject, including an introduction to the subject of 500 mg of rifaximin twice daily (BID).

Another embodiment is a method of increasing the time to hospitalization for the treatment of HE, including an introduction to the subject of 500 mg of rifaximin twice daily.

The term "introduction" or "appointment" includes routes of administration to a subject-specific GI diseases antibiotics to perform scheduled for functions Examples of routes of administration, which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, podvoloshino), oral administration, inhalation, rectal and transdermal administration. The pharmaceutical preparations can be administered using forms appropriate for each route of administration. For example, these drugs are administered in tablets or capsule form, is injected through injection, inhalation, administered in the form of eye lotions, eye drops, ointment, suppository, etc. administered by injection, infusion or inhalation; use place using a lotion or ointment, and is administered rectally, using suppositories. Oral administration is preferred. The injection can be bolus or may be by continuous infusion. Depending on how the introduction of specific diseases of the GI antibiotic can be coated with a selected material or put in it to protect it from natural conditions which may adversely affect its ability to perform the intended function. Specific diseases of the GI antibiotic can be administered separately or in combination or with another agent or agents described above or with a pharmaceutically acceptable carrier, or both with the other. Specific diseases of the GI antibiotic can be administered prior to the introduction of other agents is a, simultaneously, agent, or after the introduction of this agent. In addition, specific for GI disease the antibiotic can also be given in the form of a prodrug, which is converted to its active metabolite, or more active metabolite in vivo.

Introduction "in combination with" one or more additional therapeutic tools include concurrent and sequential introduction in any order.

As will be obvious to the skilled in the art specialist, applicable in vivo dose that is prescribed, and the particular mode of administration will vary depending on the age, weight and the type of mammal being treated, the specific compounds and the specific use for which these compounds are used. Determination of the levels of the effective dose, i.e. the dose levels required to achieve the desired result, can be performed skilled in the art specialist with pharmacological methods. Usually the clinical application of products for men start at low dose levels with higher doses to achieve the desired effect.

As used here, "increase" or "decrease" value measurements, except where otherwise indicated, is usually set in comparison with the value and the output level. For example, the increase in time to hospitalization of subjects exposed to treatment, can be set in comparison with the value at baseline time to hospitalization of subjects that are not subjected to such treatment. In some cases, increase or decrease the dimension values can be set based on the context in which the term is used.

"The media", as used here, include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal, which(OE) subject to their influence in the used doses and concentrations. Often physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate and including other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine, monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; hepatoblastoma agents such as EDTA; polyalcohols, xylytol, so is e as mannitol or sorbitol; soleobrazutaya protivoiona such as sodium; and/or nonionic surfactants such as TWEEN, polyethylene glycol (PEG).

The term "effective amount" includes an amount effective in the required doses and within the required time periods to achieve the desired result, for example, sufficient to treat or prevent HE from the patient or subject. An effective amount specific for diseases of the GI antibiotic may vary according to factors such as the picture of the disease, the age and weight of the subject, and the ability of specific diseases of the GI antibiotic to call the desired response in the subject. Scheme of doses can be subjected to regulation to ensure optimal response to therapy. The effective amount also represents a number, in which therapeutically beneficial effects outweigh any toxic or detrimental effects (e.g., side effects) specific for diseases of the GI antibiotic.

"Improve", "easing", "improvement" or etc., include, for example, to identify improvement or detectable change corresponding improvement that is the subject or at least the small part of the subjects, for example at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%,98%, 100% or in the range, the boundaries of which are any two of these values. Such an improvement or change may be detected in the treated subjects compared to subjects not treated with rifaximin, where not subjected to treatment subjects have, or are developing, the same or similar disease, condition, symptom or so on a Weakening of the disease, condition, symptom or improve parameter validation can be determined subjectively or objectively, for example, through self-assessment by the subject(s), evaluating practitioner or by conducting an appropriate analysis or measurement, including, for example, assessment of quality of life, such as assessment questionnaire for evaluation of chronic liver disease (CLDQ), to slow the progression of the disease(s) or condition(s), reduce the severity of the disease(s) or condition(s) or using a suitable assay(s) level or activity(s) of the biomolecule(s), cells(cell), or to identify episodes NOT the subject. The improvement may be transient, prolonged or constant, or it may be variable at relevant times during or after administration to a subject-specific disease GI antibiotic or its application in the analysis or other method described herein or in the above link, in the example, the time frame listed below, or after approximately 1 hour after administration or application-specific diseases of the GI antibiotic to about 28 days, or 1, 3, 6, 9 months or more after a subject(s) received such treatment.

"Modulation", such as symptom level or biological activity of the molecule or etc., says, for example, that the symptom or activity or similar detectable increased or decreased. Such increase or decrease may be observed in treated subjects compared to subjects not treated for specific diseases of the GI antibiotic where not subjected to treatment subjects have, or are developing, the same or similar disease, condition, symptom or similar Such increase or decrease may be at least approximately 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 1000% or more or is within any range, the boundaries of which are any two of these values. Modulation can be determined subjectively or objectively, for example, through self-assessment by the subject, evaluating practitioner or by conducting an appropriate analysis or measurement, including, for example, assessment of quality of life or appropriate analyses of the level or activity of molecules, glue is OK or migration of cells from the subject. Modulation may be transient, prolonged or permanent or it may be variable at relevant times during or after administration to a subject-specific disease GI antibiotic or its application in the analysis or other method described herein or in the above link, for example, in the time frames below, or after approximately 1 hour after administration or application-specific diseases of the GI antibiotic to approximately 3, 6, 9 months or more after a subject(s) received for specific diseases of the GI antibiotic.

The term "modulate" can also refer to an increase or decrease in the activity of cells in response to exposure to exposure to specific diseases of the GI antibiotic, such as inhibition of proliferation and/or inducing differentiation of at least a subpopulation of cells in the animal, so that achieves the desired end result, such as a therapeutic effect specific to GI disease antibiotic used to treat, can be increased or decreased in the course of a particular treatment.

It is assumed that the term "obtaining", as in "obtaining specific for diseases of the GI antibiotic" includes a purchase, synthesis or otherwise acquire specific for diseases of the GI antibiotic.

p> Used here, the phrase "parenteral administration" and "injected parenterally include, for example, routes of administration other than enteral administration and local administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intra-articular, pagkapanalo, subarachnoid, vnutriploschadochnye and epigastric injection and infusion.

Pharmaceuticals

Options for implementation also provides pharmaceutical compositions comprising an effective amount of rifaximin described herein, and a pharmaceutically acceptable carrier. In a further embodiment, the effective amount is effective to treat a bacterial infection, Crohn's disease, hepatic encephalopathy, associated with antibiotic colitis and/or diverticulosis the subject of suffering, in addition, liver failure.

Options for implementation also provides a pharmaceutical composition comprising rifaximin and a pharmaceutically acceptable carrier. The dose can be selected, for example, on the basis of the desired degree of systemic absorption, half-life excretion, serum concentration, etc., Cook is, for example, the pharmaceutical compositions include, in addition, excipients, for example, one or more of a diluent, a binder agent, a lubricating substance, disintegrant, dye, corrigenda or sweetener. One song can make tablets for the selected coating and without it, hard and soft gelatin capsules, tablets, sugar coated, cakes, wafer sheets, pellets and powders in sealed bags. For example, the composition can be for local use, for example, in the form of ointments, lipsticks, creams, gels and lotions.

In the embodiment, rifaximin is administered to the subject using a pharmaceutically acceptable preparation, such as pharmaceutically acceptable drug that provides continuous delivery of the subject of rifaximin for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks or four weeks after the introduction of the subject of the pharmaceutically acceptable preparation.

In certain embodiments of the implementation of these pharmaceutical compositions are suitable for topical application or oral administration to a subject. In other embodiments, implementation, described more fully below, presents here the pharmaceutical compositions may be specially for administration in solid or liquid form, including forms that are appropriate for the following: (1) oral administration, for example, as liquid medicines (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, in the form of a cream, ointment or spray applied to the skin; (4) vnutrivlagalishnogo or intrarectal use, for example, in the form of a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.

The expression "pharmaceutically acceptable" refers to containing rifaximin compositions and/or dosage forms which are, according to the results of a thorough medical check-UPS, suitable for bringing into contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, correspond to a valid relationship between benefit and risk.

The expression "pharmaceutically acceptable carrier" includes a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in the transfer or transportation of the considered chemical forms from one organ, or portion of the body, to another organ, or body part. Each carrier is pre is respectfully "acceptable" in the sense of it is compatible with other ingredients of the product and is not harmful for the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) powdered tragakant; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and waxes for suppositories; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as etiloleat and tillaart; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) the ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

The compositions may also contain moisturizers, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, and the e dye, release agents, coating agents, sweeteners, corrigentov and flavouring agents, preservatives and antioxidants.

Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.,; (2) oil-soluble antioxidants, such as ascorbyl palmitate, bottled hydroxyanisol (BHA), bottled hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, etc.,; and (3) metallopeptidase agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.,

Compositions containing the disclosed here forms of rifaximin, include compositions suitable for oral, intranasal, topical application (including transbukkalno and sublingual), rectal, vaginal injection, spray application and/or parenteral administration. The composition can be in the force of custom is presented in the form of a standard dose and can be prepared by any methods well known in the field of pharmacy. The amount of active ingredient which can be combined with the material of the medium to create a form with a single dose will vary depending on being cured is Yu master, the specific method of administration. The amount of active ingredient which can be combined with the material of the medium to create a form with a single dose will typically be such number of connections that causes therapeutic effect. As a rule, on the basis of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

Methods of preparing these compositions include the stage of connection of rifaximin with the carrier and, optionally, one or more additional ingredients. Typically, the drugs are prepared by uniformly and direct connection of rifaximin with liquid carriers or finely dispersed solid carriers, or with those, and with the other, and then, if necessary, the stage of forming of the product.

Compositions suitable for oral administration may be in the form of capsules, sachets, pills, tablets, pellets (using a flavored basis, usually sucrose and Arabian gum or tragakant), powders, granules or in the form of a solution or suspension in aqueous or non-aqueous liquid, or as an emulsion in a liquid type oil-in-water or water-in-oil", or as an elixir or syrup, or as pastilles using an inert base, such as gelatin and glycerin, or sucrose or Arabian gum) and/or in the form of liquids for rinsing the mouth and so on, each of them contains a given number of rifaximin as an active ingredient. The compound may be administered in bolus dosage porridge or paste.

Used herein, the term "pharmaceutical composition" (or agent or drug) refers to a chemical compound, composition, agent, or drug, is able to call the desired therapeutic effect when properly administered to a patient. It does not need certainly more than one type of ingredient.

The composition can be in the form of tablets, capsules, powders, granules, pellets, liquid or gel preparations. Tablets and capsules for oral administration may be in a form suitable for submission to a single dose, and may contain conventional excipients. Their examples include binders such as syrup, Arabian gum, sorbitol, tragakant and polyvinylpyrrolidone; excipients, such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycerol; lubricant for tableting, such as magnesium stearate, silicon dioxide, talc, polyethylene glycol or silica; disintegrant, such as potato starch; or acceptable spaceways the substance, such as sodium laurylsulfate. Tablets may be coated according to methods well known in normal pharmaceutical practice. Liquid preparations for oral administration can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for restore water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspendresume agents, for example sorbitol syrup, methylcellulose, starch syrup, gelatin, hydrogenated edible fats, emulsifying agents, for example lecithin, orbitonasal or Arabian gum; non-aqueous media (including edible oils), for example almond oil, fractionated coconut oil, related to fats, esters of fatty acids and, for example, glycerol, propylene glycol, or ethyl alcohol; preservatives, such as methyl - or propyl-para-hydroxybenzoate or sorbic acid, and, optionally, conventional corrigentov or dyes.

Expression system introduction, injected systemically", "peripheral introduction" and "enter perifericheskie", as used here, means the introduction of specific diseases of the GI antibiotic, drug or other material from us the conditions, so he got into the system of the subject and thus was subject to metabolism and other like processes, for example, subcutaneous administration.

The phrase "therapeutically effective amount" specific for diseases of the GI antibiotic refers to the number of specific diseases of the GI antibiotic, which is effective, upon introduction to a subject a single dose or multiple doses, inhibition of bacterial growth and/or invasion or relieving symptoms such as episodes HE related to bacterial growth in the subject. "Therapeutically effective amount" also refers to the amount of a therapy (e.g., compositions comprising specific for diseases of the GI antibiotic), which is sufficient to reduce the severity of HE in the subject.

Used herein, the terms "prevent (preventing" and "prevention (avoidance)" refer to the prevention of relapse, occurrence or development episodes HE or one or more symptoms of HE. The warning includes the protection of the occurrence and severity of episodes HEs.

Used herein, the term "prophylactically effective amount" refers to the number of therapy (e.g., compositions comprising specific for diseases of the GI antibiotic), which is sufficient to gain and to prevent the development recurrence or occurrence of episodes or to enhance or improve the prophylactic effect(s) of another therapy.

"Rifaximin", as here used, includes solvate and polymorph forms, including, for example, α, β, γ, δ, ε, η, ζ and amorphous forms of rifaximin. These forms are described in detail, for example, in USSN 11/873841; USSN 11/658702; EP 050046352, filed may 3, 2005; USPN 7045620; US 61/031329 and G. C. Viscomi, et al, CrystEngComm, 2008, 10, 1074-1081 (April 2008). Each of these reference documents so incorporated by reference in full.

Forms of rifaximin can mainly be used in the production of possessing antibiotic activity of medicinal preparations containing rifaximin for oral and topical use. The medicinal preparations for oral use may contain one or more forms of rifaximin together with other excipients, for example diluting agents such as mannitol, lactose and sorbitol; binding agents such as starch, gelatin, sugars, cellulose derivatives, natural gums and polyvinylpyrrolidone; lubricating agents such as talc, stearates, hydrogenated vegetable oils, polyethylene glycol and silica colloid; disintegrants, such as starches, cellulose, alginates, gums and setcompany polymers; dyes, korrigentami and podcasti the firs.

Medicines may contain specific for diseases of the gastrointestinal tract antibiotics together with the usual excipients, such as white petrolatum, white wax, lanolin and its derivatives, stearyl alcohol, red iron oxide, propylene glycol, talc, sodium lauryl sulphate, polyoxyethylene ethers of fatty alcohols, disodium edentate, glycerol palmitostearate, polyoxyethylene esters of fatty acids, carpetmuncher, glycerylmonostearate, propilenglikolmonostearata, gidromolot, polyethylene glycol, sodium starch glycolate, methyl cellulose, hydroxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, aluminum silicate and magnesium colloid, titanium dioxide, propylene glycol, the colloidal silicon dioxide or sodium alginate.

As used here, "exacerbation of HE during treatment" includes, for example, the increase in the assessment on connu to grade ≥2 (for example, 0 or 1 to ≥2) or of 1 degree increase in each of the assessments on Konno and "fluttering" of tremor for those entities which have a rating on connu at baseline =0.

As used here, "the time before the first episode HE exacerbation during treatment" includes, for example, the time interval between the date of the first administration of rifaximin and the date of first episode of acute HE.

Site is planned, what used herein, the term "episode HE exacerbation during treatment" includes explicit, clinical significant deterioration of the function of the nervous system caused by toxic substances accumulating in the blood, which leads to the harmful effect when self-treatment and often leads to hospitalization. The episode HE exacerbation during treatment is also defined as the increase in the assessment on connu to ≥2 (i.e., 0 or 1 to ≥2) or of 1 degree increase in each of the assessments on Konno and "fluttering" of tremor for those entities which have a rating on connu at baseline =0.

There are ways to determine whether the subject has a neurological disease by identifying CFF the subject at two or more points in time. In cited as examples of variants of implementation times can defend on 1, 2, 3, 4, 5, 6 or 7 days; or 2, 3 or 4 weeks; or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months or at any time between any two specified values. In other embodiments, implementation of the control subject can be carried out with regular intervals for life.

In these ways it is envisaged that the decrease in CFF between measurements at two or more points in time indicates the approximation of the probability of the episode HE exacerbation during treatment. In addition, if subje the t has a value twa CFF in time, constituting less than 24 Hz, this indicates that there is an increased probability of the episode HE this subject. Therefore, the decrease in CFF between measurements at two or more points in time or twa of 24 Hz or less, indicates that the subject has HE, has increased the likelihood of an episode of acute HE, during his treatment of the subject, and/or that it should be treated with rifaximin. Thus, based on the data collected to date, in one embodiment, there are provided methods for determining the presence of HE the subject, predicting the occurrence of an episode of acute HE or determining the prognosis for the subject by determining that CFF the subject below 24 Hz, and CFF below 24 Hz indicates that the subject is HE, he is likely to be the episode HE exacerbation during treatment, or in respect of him, the forecast is bad. In certain embodiments of the implementation of the CFF, which constitutes less than 24 Hz, indicates that must be entered for specific diseases of the GI antibiotics such as rifaximin.

There are prognostic methods based on the determination of the CFF or twa CFF, and twa CFF, constituting less than 24 serves as a sign of poor prognosis, or decrease in CFF or twa CFF between measurements at different points in time is the prize of the ACOM a poor prognosis. Poor prognosis includes the life expectancy of the subject for less 2, 3, 4, 5, 6, 7, 8 or more years, or as described here, or in the opinion of the healthcare professional, entity or person, observing the subject.

In other embodiments, implementation, there are ways to determine whether the subject HE or his exposure increased the risk of manifestation of the episode HE exacerbation during treatment by measuring the ammonia level in the venous blood of the subject at two or more points in time, and increased ammonia level in venous blood indicates the presence of HE the subject has increased the likelihood of an episode of acute HE, during his treatment, and/or that it should be treated for specific diseases of the GI antibiotics such as rifaximin. In certain embodiments implement the ammonia level in venous blood is a time-weighted average level of ammonia in the venous blood.

The concentration of ammonia in the venous blood can be determined using methods known to the skilled in the art specialist. The accuracy of the determination of ammonia depends on the sampling. It is preferable to whole blood. In one particular method described here, the blood taken from a vein without plugging in insulated tube with EDTA. The sample is placed on ice immediately after selecting the a and mixing. The sample is placed in cold conditions, for example on the ice for about ten minutes, and then centrifuged. The plasma is separated from the sample within fifteen minutes from the time of sampling and frozen. Hemolyzed samples should not be used for further analysis.

The frozen sample is subjected to enzymatic analysis to determine the amount of ammonia present in the sample. Ammonia sample is mixed with α-Ketoglutarate and restored by adenine dinucleotide phosphate (NADPH) to form L-glutamate and NADP and water. The reaction catalyzes glutaraldehydes. The result determined spectrophotometrically by checking the decrease of optical density at 340 nm due to NADPH oxidation. This reduction is proportional to the concentration of ammonia.

In other embodiments, implementation, there are ways to determine whether the subject has a neurological disease by measuring CFF between two or more points in time. The decrease in CFF between points in time indicates whether the subject has a neurological disease. In certain embodiments of the implementation of the CFF is a twa measurement results CFF.

In accordance with one embodiment there is provided a database having a data structure, which is th contains a number of CFF or ammonia levels in venous blood, from the subjects. Also at least one database includes a data structure that contains a number of links between CFF or levels of ammonia in the venous blood and the degree of disease in subjects and which defines the business rules to perform the methods. These bisness rules may include established methods for determining the presence of HE the entity or its exposure to the risk of manifestation of the episode HE exacerbation during treatment. Also bisness rules may include established methods for determining if the subject has a neurological disease. Diagnosis or prognosis can be optionally selected using the new software for systems and methods presented here. In this situation, the systems and methods, including new configuration software will automatically perform the methods presented here, without additional user input.

There are ways to determine whether the subject has a neurological disease by identifying CFF the subject at two or more points in time.

In particular, one such additional method provided here includes new software, which includes a number of software modules or components that are on the server within the system, for creating and filling the database for skin is of diagnostic and prognostic methods of the present invention. In other words, in one embodiment, systems and methods provide for the establishment and regulation of specific rules for a specific client and intellectual centralized management. Specialist with an average level of competence in the art will understand upon reading this description, that different ways of implementation include new software, which includes a number of software modules or components on the managed computer system or network of the present invention, such as servers, sending the remote clients and receiving remote clients, to facilitate the methods of the present invention.

As used here, "time to first associated with hospitalization HE" includes, for example, the length of time between date of first dose of rifaximin and the date of first related to HE hospital.

As used here, "time to increase compared to the baseline assessment connu" includes, for example, the length of time between date of first dose of rifaximin and the date of the first increase assessment connu.

As used here, "time to increase compared with the initial level degree "fluttering" tremor" includes, for example, the length of time between date of first dose of rifaximin and the date of the first increased the degree I "fluttering" of the tremor.

As used here, "average change compared to baseline assessment tiredness by means of a questionnaire for assessment of chronic liver disease (CLDQ) at the end of treatment (EOT)" represents the average score from baseline levels established prior to the first injection of rifaximin.

As used here, "average change compared with the initial concentration of ammonia in the blood EOT" includes the average rating to the baseline established prior to the first injection of rifaximin.

As used here, "time to diagnosis of spontaneous bacterial peritonitis (SBP)" includes, for example, the length of time between date of first dose of rifaximin and the date of the first episode of SBP.

As used here, "average change compared to baseline levels at each successive level values of the critical frequency of flicker determine, for example, compared to the baseline established prior to the first injection of rifaximin.

"Specific for diseases of the GI antibiotic" as used here, includes the antibiotic, which, as you know, has an effect on GI disease. Applicable specific GI diseases antibiotics are, for example, the antibiotic class rifamycin (e.g., rifaximin), neomycin, metronidazole, teicoplanin, ciprofloxacin, d is xicillin, tetracycline, Augmentin, cephalexin, penicillin, ampicillin, kanamycin, rifamycin, vancomycin, rifaximin, and combinations thereof. Even more preferred are specific for GI diseases antibiotics with low adsorption system, such as rifaximin. Low systemic absorption include, for example, constituting less than 10% absorption, constituting less than 5% adsorption, constituting less than 1% of the adsorption component and less than 0.5% adsorption. Low adsorption system also includes, for example, comprising about 0.01 to 1% absorption, comprising about 0.05-1% adsorption, comprising approximately 0.1-1% adsorption, comprising about 1-10% adsorption or component approximately 5-20% adsorption.

As used here, "subject" includes organisms which can suffer from disease of the digestive tract or other violation of fed treatment with rifaximin, or which in other respects could benefit from introduction of rifaximin, as described here, such as which people and non-people entities. Preferred subjects include which people subjects. The term "non-humans animals" includes, for example, all vertebrates, such as mammals, such as rodents, such as mice, and not mammals, such as non-human primates, n is an example of a sheep, dog, cow, chickens, amphibians, reptiles, etc. are Prone to disease of the digestive tract, is meant to include subjects at risk of developing the disease of the digestive tract or an infectious disease of the digestive tract, for example, subjects suffering from hepatic encephalopathy, hepatic failure or reduced liver function, immunosuppression, subjects who were in contact with other entities with a bacterial infection, doctors, nurses, actors, travelling in remote areas, in which, as is known, the accumulated bacteria that cause traveler's diarrhea, and so on

The phrase "prophylactically effective amount" of a compound refers to the amount of the compounds of formula I, formula II or a compound otherwise described herein, which is effective after administration of a single dose or multiple doses to a subject to prevent or treat hepatic encephalopathy.

Another variant implementation includes industrial products, which include, for example, a container containing a pharmaceutical composition suitable for oral administration of rifaximin in combination with printed label instructions, in which the above discussion, when a particular dosage form of prolongue the remission HE or prevents or deferreth episodes HE in the future. The dose can be modified for administration to a subject suffering HE or she includes labelling in respect of the introduction to a subject suffering from HE. Given as examples of dosage forms and protocols introduction described below. The composition will be contained in any suitable container that can hold and distribute the doses, dosage form and which will not significantly affect the composition and will also physically associated with a corresponding marking. Marking instructions may correspond to the methods of treatment described herein previously. The marking can be connected with the container by any means of preserving their physical approach, as a non-limiting example, they both may be contained within the packaging material, such as a carton or a plastic film, or it can be linked with the instructions attached to the container, for example, with glue, which does not obscure the marking instructions, or by using other methods of connection or deduction.

In one embodiment, the instructions will inform and/or consult a health worker prescribing medicine physician, pharmacist or entity must advise the patient suffering from hepatic encephalopathy, about h what about the introduction of rifaximin can induce cytochrome P450. In another embodiment, the instructions will inform the subject and/or health care provider about the fact that there is an extended period of time of remission or time to relapse in subjects taking rifaximin. In another embodiment, the instructions will inform the subject and/or a health worker or health care provider that rifaximin does not change significantly CmaxAUC0-tor AUC0-∞midazolam. In another embodiment, the instructions will inform the subject and/or a health worker or health care provider that rifaximin does not increase the risk of long QT.

Packaged compositions are also provided and can include a therapeutically effective amount of rifaximin contained in tablets or capsules. There is also provided sets, such as sets to ensure HE the subject. The kits may contain, for example, rifaximin and instructions regarding application for the treatment of the subject in case HE. Instructions in respect of the application may contain information about the regulations, information on dosages, storage information, etc.,

Kits can include pharmaceutical drugs for specific diseases GI antibiotics together with a pharmaceutically acceptable solutions, media is the excipients.

Forms of rifaximin can mainly be used in the production of possessing antibiotic activity of medicinal preparations containing rifaximin for oral and topical use. The medicinal preparations for oral use may contain one or more forms of rifaximin (e.g., α or β or γ), together with other excipients, for example diluting agents such as mannitol, lactose and sorbitol; binding agents such as starch, gelatin, sugars, cellulose derivatives, natural gums and polyvinylpyrrolidone; lubricating agents such as talc, stearates, hydrogenated vegetable oils, polyethylene glycol and silica colloid; disintegrants, such as starches, cellulose, alginates, gums and setcompany polymers; dyes, korrigentami and sweeteners.

Solid preparations specific for diseases of the gastrointestinal tract antibiotics, administered orally include, for example, coated tablets, and without him, hard and soft gelatine capsules, tablets, sugar coating, pellet, wafer sheets, pellets and powders in sealed bags.

Medicines may contain specific for diseases of the gastrointestinal tract antibiotics together with the usual excipients, such as b is large vaseline, white paraffin, lanolin and its derivatives, stearyl alcohol, red iron oxide, propylene glycol, talc, sodium lauryl sulphate, polyoxyethylene ethers of fatty alcohols, disodium edentate, glycerol palmitostearate, polyoxyethylene esters of fatty acids, carpetmuncher, glycerylmonostearate, propilenglikolmonostearata, gidromolot, polyethylene glycol, sodium starch glycolate, methyl cellulose, hydroxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, aluminum silicate and magnesium colloid, titanium dioxide, propylene glycol, silicon dioxide colloidal, or sodium alginate.

Criteria West haven (score from connu)

Determine mental status changes can be implemented, for example, through assessment Konno (also known as assessment of West haven). Score from Konno was widely used as an indicator of the mental state in the studies HE and is based on criteria Parsons-Smith, modified Horse. "Fluttering" tremor is not taken into account when assessing the condition of the subject using the criteria for connu listed below.

Below is the scale used in the assessment system for connu.

Degree 0 = no detectable changes in personality or behavior

Grade 1 = slight disadvantage informed the project, euphoria or anxiety; shortened duration of concentration; decreased ability to add or subtract

Degree 2 = lethargy; disorientation in time; obvious personality change; inappropriate behavior

Grade 3 = drowsy before proparacaine consciousness, response to stimuli; confusion; explicit disorientation; improper behavior

Degree 4 = coma; the inability to check the mental state

HE is defined as a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction, diagnosed after the exclusion in the usual manner other known neurological diseases. HE is a major complication of cirrhosis of the liver, damaging 30-45% of patients. In 2006 the CDC (Center for control and prevention of diseases caused cirrhosis as the 12th leading cause of death from disease in the United States. HE impresses the consciousness of the patient's personality, intellect, and function of the neuromuscular system and can range from minor violations of knowledge to coma. HE, as used here, includes, for example, episodic, chronic and persistent minor HE.

In the intestine intestinal bacteria act on the nitrogen-containing substance to form ammonia. In Fig.15 presents the situation that HE is not affected entities: ammonia remove without an is from the blood, as it passes through the liver where it is converted to urea and excreted by the kidneys. Cirrhosis of the ammonia from the intestine bypasses the damaged liver due to vascular anastomoses. This leads to an increase of ammonia in the blood, which takes place in the brain, giving rise to the formation of glutamine from the amino acid glutamate. Excessive amounts of glutamine leads to many harmful effects on the function of the brain; it inhibits neurotransmission, interfere with the mitochondrial energy metabolism and leads to swelling of astrocytes.

The clinical picture HE classified in accordance with the scheme shown in Fig.16. Associated with cirrhosis of the HE - of course, the distribution - refers to the type C. Type C HE divided into classes: episodic, persistent chronic and insignificant HE. Options in the form of episodic and chronic persistent NOT represent obvious by clinical condition and therefore is designated as having a clear clinical picture. Picture episodic HE includes the violation of any of the functions of the nervous system, noted above. As suggested by the term "episodic", there are periods between episodes when symptoms are not detected. Episodes may be induced by factors such as constipation, infection, who gidratatsiya, gastrointestinal bleeding and some medicines. If the cause is not installed immediately, the episode is called spontaneous.

The episodes HE can usually be reversed with treatment, but they are often recurrent. HE is a clinical diagnosis, which is put with the help of some tools, including the assessment of the West haven or evaluation connu. When using for about 30 years, the estimation algorithm HESA (Fig.17) is a relatively new tool used to precisely specify criteria for connu. Neuromuscular dysfunction can be identified by call the "fluttering" of the tremor. Often measure the ammonia level in the blood to confirm the diagnosis. Neurophysiological tests such as the critical frequency of flicker and electroencephalogram, are potentially very useful to confirm the clinical data. Criteria for Konno is increasing extent for connection with an increase in neurological disorders (in the range from 0 = no disturbance to 4 = coma).

Grade 1, 2 and 3 represent the increase:

- violations of creation - ranging from small lack of awareness to sleepiness;

- violations of intellectual abilities and personality changes.

This assessment can be done quickly, for it requires a modest couch the participation of conducting a survey of physician or interaction from the patient, and often used the information obtained from the family or those who care for the sick, to assist in determining the severity of the episodes HE, when the consciousness of the patient is confused.

Whereas patients with HE grade 1 can cope at home those who have care of them, if any worsening to grade 2 or higher may require hospitalization or even the use of intensive therapy. Criteria for Konno is used to increase the degree to communicate with the increase in neurological disorders, (which is in the range from 0 = no disturbance to 4 = coma). Grade 1, 2 and 3 represent increasing violations of creation, intellectual abilities and personality changes. This assessment can be done quickly, for it takes a slight complicity conducting a survey of physician or interaction from the patient, often used the information obtained from the family or those who care for the sick, to assist in determining the severity of episodes of HE.

Whereas patients with HE grade 1 can cope at home those who have care of them, if any worsening to grade 2 or higher may require hospitalization or even the use of intensive therapy.

There is a similar classification system for "fluttering" of the tremor. If the patient does NOT ask to keep your hands as needed, will be monitoring the sterile jerky, the so-called "fluttering" tremor. Podkidyvajut number of shocks, and given a score from 0 = no aftershocks up to 4 - almost continuous flying tremor. This is a simple test, but it requires willing to help and being in the mind of the patient.

HE is a vicious cycle of dysfunction and disability, which has a dramatic effect on patients, their families and the health care system. Very early disturbances of behavior, personality, intelligence and consciousness have an impact on social and family life of the patient and the ability to save your work. As the deterioration it affects the ability of self-care, compliance with doctor's instructions, not following the doctor's instructions further enhances the symptoms HE and frequency of episodes. As a result, patients may need help at home, and they often find themselves in the ER (emergency medical services) or on the hospital bed. Heavy HE can be life-threatening case, but it often drains QOL (quality of life) of patients and their families; some of those who care for the sick, equate their experience of care for patients with unpredictable sporadic Alzheimer's disease. The impact on caregiver shown in Fig.18.

On the basis of impact on health, the number of payments HE has increased more than two from 1993 to 2007. See the e Fig.19. Costs increased from approximately 13 thousand to 30 thousand for each hospitalization. Therefore, the goal of therapy HE include, for example, bringing acute episodes to rapid resolution and prevention of recurrent episodes. To achieve these goals requires a safe and effective therapy that is well tolerated during long-term treatment. There are serious limitations in relation to long-term use permitted in current therapies. Target the most frequently used not absorbable disaccharides, lactulose intestinal flora is responsible for the production of ammonia. It exerts its effects mainly through treatment with frequent emptying of the bowel. Treatment with lactulose is based on the individual dose distribution, the goal is 2-3 loose stools a day - unfortunately, this goal is often exceeded. In the case of ten unpredictable liquid chairs in day care from home - even in case of long lasting care store may become impossible or shy. Patients develop a disability because of lactulose, and not HE, for which it was prescribed. Severe diarrhea can cause dehydration and electrolyte abnormality, which may even provoke an episode of HE. Nausea is not uncommon. It is clear that these factors can lead to bad hell is esii and limit long-term use.

Other permitted treatment is neomycin. However, prolonged use is strictly limited to its damaging side effects, including nephrotoxicity and a sensorineural hearing loss patients with progressive liver disease are the most vulnerable. Not surprisingly, the security profile neomycin is not conducive to long-term therapy. Taking into account the shortcomings associated with lactulose and neomycin - it is obvious that there is an unmet need for safe, effective and well-tolerated long-term therapy. Hepatic encephalopathy is a serious neurological complication of progressive liver disease, which undermines the quality of life, ability to self-service and compliance with doctor's instructions and frequently leads to hospitalization.

There are limited treatment options HE, and remains an unmet need for safe, effective and well tolerated therapy for long-term treatment. For 30 years there was a new treatment that is causing the dementia disease. The doctors were quite amazed data on the efficacy, tolerability and safety of rifaximin and a positive experience when you use this medication, even before the advent of exciting new data tested the I, presented here and which make rifaximin, is not excluded, the most widely used therapy based on antibiotics for HE.

Study 3001 was intended for continuous monitoring of patients to ensure the accuracy and completeness of data collection about the aggravation during treatment. After screening the patients entered the treatment period, which included weekly visits to patients and those who cared for them, and/or telephone contact with them. The subjects kept within certain Protocol 168 days. Full collection of data on episodes of exacerbation during treatment, and mortality ensured the reliability of the research. Presentation of the facts concerning each patient, showing the aggravation HE during treatment, adverse events (AE) leading to the end of treatment, SAE or death, were presented in the NDA (application for approval of a new drug). Key criteria for entry into the study included:

- patients with progressive liver disease;

patients showing at least 2 episodes of HE within 6 months from the time of screening, documented in medical records with severity equal to the assessment for connu ≥2;

and at screening and at baseline the subjects had a score on connu = 0 or 1, the MELD score in less than or equal to 25, Yves their case did not require consent for patient participation in the study who takes care of him;

patients were excluded if they had a condition that could interfere with the evaluation Protocol, used alcohol within 14 days, sedatives within 7 days or evidence of drug dependence in the present.

HESA unites both clinical components are mounted, and neurophysiological tests. For administration will require approximately 45 minutes. It was used as a means to establish a consistent quantitative assessment connu all research centres. It provided continuous strengthening of standards and replenishment definitions.

Fig.17 briefly includes clinical assessment and neurophysiological tests HESA. Rifaximin provided a significant protective effect, as demonstrated by a decrease of 58% of the risk of the episode HE exacerbation during treatment with significant highly p-value. The use of rifaximin striking fact that 78% of patients now had no episodes of exacerbation within 6 months. In contrast, in the placebo group, only 54% maintained remission HE. In a population of patients suffering from the private side effects, with limited livelihood and shortened lifespan rifaximin can provide significant benefits by preventing deterioration of their crazy the mental status and motor skills.

Just had 104 episodes, registered at 299 participating in the study patients. For components, the authors present invention using descriptive statistics, using the analysis of proportions that satisfy the condition. 86 episodes, or 83% of all episodes, consisted of patients exhibiting grade on connu ≥2, 37% of patients treated with placebo, and 20% of patients treated with rifaximin, which leads to significant in high p-value.

Eighteen (18) episodes, or 17% of all episodes included in the following category of patients showing deterioration assessment Konno and the degree of "fluttering" tremor of 1 each, 9% of patients treated with placebo, and 2% of patients treated with rifaximin, which also provides significant highly p-value.

The constancy of the effect assists in determining whether brought the benefit of one or some of the subgroups, or whether the observed effect, as a rule, in all subgroups of patients. It is important that a study was conducted on the relationship between therapeutic effect and subgroup to install uniformity of response across all subgroups. None of the subgroups was not a significant relationship. Risk is less than 1 indicate a result in favor of rifaximin and respect the of risks greater than 1 - in favor of placebo. The result observed in all subgroups, again and again reflects the clinical use of rifaximin. This permanence of the result, combined with the lack of communication between therapeutic effect and subgroup confirms the strength of the overall therapeutic effect.

This effect persisted over all subgroups with varying degrees of severity, when he refers to the assessment of MELD and extent of the child-Pugh score. Again there is no relationship between subgroup and therapeutic effect, and evaluation of therapeutic effect is approximately the same for all groups. Finally, analyses of subgroups shows a striking constancy of the risk reduction observed in the analysis of the primary outcome measure for all groups.

Analysis of time related to HE of hospitalization resulted in 50% reduction of risk with a significant p-value. A large proportion of episodes HE either led to direct hospital admission, or occurred during the hospitalisation. It was found that the time before HE caused hospitalization (defined as the time prior to admission, which is a direct consequence of HE) and time to hospitalization for all causes decreased use of rifaximin, and these analyses show a risk reduction of 56% and 30%, respectively.

Other outcomes have included, for example, gramado first deterioration assessments connu or "fluttering" tremor regardless did this change to the episode HE exacerbation during treatment; quality of life according to patients, in particular fatigue, which is defined by CLDQ; changes of ammonia in the blood, which is believed to be the main neurotoxin responsible for HE; and critical frequency of flicker. Time to first deterioration assessment connu reflects the risk reduction of 54%. Time to deterioration in the assessment of "fluttering" tremor shows a reduction of 35% in the trend analysis p-values. These data represent changes in each area of the manifestations throughout the test. The results show that treated with rifaximin patients feel better. The questionnaire used 7-point Likert scale, with 1 = all the time; 7 = single moment. Thus, higher values reflect better quality of life. The changes observed here in each podskali, speaks about the change at each scale, which is improved by 1 point compared with placebo. The changes that the authors of the present invention is observed in the level of ammonia and CFF are statistically significant and reflect improvements in favor of rifaximin. These results confirm therapeutic effect of rifaximin.

Were undertaken studies to assess exposure aggravation during treatment and the special is licnosti. In patients with lower estimated CFF and fatigue, and a higher concentration of ammonia in the blood there is a large probability of exacerbation NOT during treatment. These data provide additional evidence that the primary outcome measure is an objective and clinically meaningful. In the case study 3002 data were collected about the exacerbations NOT during treatment to provide supporting information regarding the effect of rifaximin in the prevention of relapse HE.

In study 3002 treatment were subjected to three populations, including those subjected to treatment with rifaximin patients study 3001; treated with placebo in study 3001 patients that have fallen in this study, and new patients with HE.

If subjected to treatment with rifaximin patients who remained in remission throughout the study 3001, demonstrated long-term benefits during their participation in the study 3002. Frequency HE exacerbation during treatment if treated with rifaximin patients was lower than in the group treated with placebo in study 3001, which demonstrates a reduction of 90% risk of exacerbation of HE during treatment. Note that approximately 60% of these patients do not worsening after almost 3 years. 82, for example, is by treatment of placebo subjects in study 3001 were included in the study 3002, and they tracked the aggravation. After inclusion in the open study and obtain rifaximine they observed a reduction of risk by 79% compared to the manifestation in them of exacerbations in the test 3001.

In all treated with rifaximin populations demonstrates increased 2.6 times the risk of mortality from all causes in the case of subjects under evaluation by Konno constituting at least 2.

The following example will deal with new and unknown aspects of rifaximin:

- in vitro and in vivo pharmacological activity of rifaximin, which may contribute to its clinical benefits;

- associated with ADME (absorption, distribution, metabolism and excretion) properties of rifaximin, including pharmacokinetics and his destiny associated with excretion and metabolism; and

- the study of drug-drug interactions.

Regarding the mechanism of action, rifaximin is associated with beta-subunit of bacterial DNA-dependent RNA polymerase, resulting in inhibition of RNA synthesis in bacteria. In vivo rifaximin reduces the intensity of the symptoms of bacterial diarrhea, and most of the dose is not absorbed and concentrated in the gut, with high concentrations in the intestinal lumen, the components of the estimated 8000 µg/g stool. Interestingly, the treatment of traveler's diarrhea occurs without the considerable changes in the total mass of pathogens in the gut.

In vitro rifaximin exerts many effects in less inhibitory concentrations, including, for example, the increase in dissolved plasmids, reducing the transfer of plasmids and reduced virulence.

It was found that the effects of rifaximin on mammalian cells, including, for example, ways of processing, such as P-gp and 3A4, can be increased in the intestine. Rifaximin attaches to the epithelial cells and resistance to bacterial colonization and internalization regardless of the effects on bacteria and decreases the production and absorption from the intestine of neurotoxins, the main example of which is ammonia, which lead to HE in patients with hepatic impairment.

In this example, 50 patients treated with rifaximin at a dose of 1200 mg/day showed a statistically significant decrease in the level of ammonia in the blood. This reduction was accompanied by a significant improvement in the overall extent HE and specific goals HE. While isolated concentration of ammonia in the blood can be variable, consecutive measurements in individual patients, were associated with the severity of HE.

Rifaximin is a member of the class of antibiotics rifamycin. Functional group, shown in green, features rifaximin from other rifamycins and leads to specific diseases of the intestine is active.

Rifaximin belong to BCS class 4; poorly soluble and poorly absorbed compounds. He is also a substrate of P-glycoprotein, effluxing vector. These properties lead to very low absorption when administered orally. The small fraction that is absorbed is excreted through three mechanisms: biliary, metabolic and renal. Rifaximin is subjected to elimination during the first passage through excretion in the bile as unchanged of rifaximin. There is one known metabolite; almost not detectable in healthy subjects, and very low in patients with NO, approximately 2.5% of the original exposure. As in healthy subjects, subjects with liver disease, the excretion of rifaximin kidney is <0.4 percent. Introduce oral rifaximin is excreted almost entirely as unchanged of rifaximin in the faeces. The pharmacokinetics of rifaximin in the steady state was investigated in healthy subjects and in subjects with hepatic insufficiency. Exposure is quite low in all the studied populations.

In healthy volunteers, the average Cmaxis less than 4 ng/ml, See Fig.20. With increasing liver failure AUC and Cmaxincrease accordingly. Even at their peak exposure values remain low is, in the ng/ml range. The increase in exposure in patients with hepatic insufficiency fully described in the literature and can be explained by several factors, including, for example, protein binding, decreased blood flow through the liver and reduced ability to metabolize. Limited access to the liver due to shunting of blood to bypass the liver and reduced metabolism due to reduced enzyme activity of hepatocytes can reduce hepatic clearance. Either or both of these two factors may be responsible for reduced clearance of rifaximin and the increase in exposure in patients with hepatic impairment.

For the sake of presenting this exhibition in additional context, see Fig.21, which presents data for rifaximin in comparison with other antibiotics, using a logarithmic scale because of the significant differences.

Patients with the highest liver failure and nebolsine the exposure levels in plasma have levels of rifaximin, which is more than 200 times lower than the levels achieved with the use of systemic antibiotics, such as rifampin, is represented in blue. They are also more than 10 times below the levels of exposures observed with oral administration of neomycin, shown here in pink, which is read, is not absorbed. In this population, is also often used norfloxacin for the prophylaxis of SBP; it is a systemic antibiotic exposure levels in plasma, exceeding more than 35 times those of rifaximin. Here we investigated the ability of rifaximin to call drug-drug interactions. Rifaximin is not inhibited to a significant degree any major drug metabolizing enzyme P450, P-glycoprotein or BSEP in subjects with normal liver function. Knowing that other members of this class may cause interactions through activation of important drug metabolizing enzymes, particularly CYP3A4, we studied the possibility of this induction in clinical studies. The effect of rifaximin on midazolam, classic CYP3A4 substrate, was investigated in healthy volunteers. After 16 days from the introduction of 550 mg of rifaximin three times per day, a dose in excess of 50% of the dose used in the case of HE, the AUC of midazolam was reduced by 10%. See the Fig.22. In contrast, rifampin decreases the AUC of midazolam by 95% in similar experiments. This difference reflects not only the difference in the in vitro activity between rifampin and rifaximin, but the difference in in vivo distribution between the two compounds on the basis of low-level exposure in the liver and si is a dark exposure of rifaximin. Based on these data, the authors of the present invention do not expect a clinically significant drug interactions in subjects with normal liver function. In conclusion, in vitro and in vivo data indicate that rifaximin has a bacteriostatic mechanisms, as well as the ability to reduce bacterial adhesion and virulence. It reduces the levels of ammonia (see Fig.23) that is associated with improvement in patients with HE. The most important difference of rifaximin from other rifamycins is its extremely low solubility and absorption by oral administration, resulting aimed at the gut therapeutic effects and limited systemic exposure. Although liver disease leads to increased systemic exposure of rifaximin, the highest exposure levels that can be detected by the use of rifaximin significantly lower than those observed when using other system and not absorbable antibiotics for oral administration. Along with this low systemic exposure comes minimized the risk of drug-drug interactions.

Presented here options of implementation apply to all drugs for local application, for example, in the form of ointments, lipsticks, creams, gels and lotions.

In the case of solid dosage forms of rifaximin on what I oral administration (capsules, pills, pills, pills, powders, granules, etc.,), the active ingredient is usually mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or diluents, such as starches, lactose, sucrose, glucose, lures and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or Arabian gum; (3) hygroscopic substances, such as glycerol; (4) disintegrants, such as agar-agar, calcium carbonate, potato or manioc starch, alginic acid, certain silicates and sodium carbonate; (5) inhibitors of dissolution such as paraffin; (6) absorption accelerators, such as Quaternary ammonium compounds; (7) wetting agent such as, for example, acetyloxy alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulphate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type may also be used as fillers in soft and containing solid fill is spruce gelatin capsules, using such excipients as lactose or milk sugar and high molecular weight glycols, etc.

The tablet can be prepared by extrusion or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binder (for example, gelatin or hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant or dispersant. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered active ingredient with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions described herein, such as tablets, capsules, pills and granules, may optionally save or be prepared with coatings and shells, such as intersolubility coatings and other coatings well known in the production of pharmaceuticals. They can also be to provide slow or controlled release of the active ingredient in them, using, for example, hypromellose in various PR the portions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They can be sterilized by, for example, filtration through a retaining bacteria filter or by incorporating sterilizing means in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable media immediately before use. These compositions may also optionally contain opalescent components and may have such a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally, the slow way. Examples of coating compositions which can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulating form, if appropriate together with one or more above described excipients.

Liquid dosage forms for oral administration of rifaximin include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain commonly used in the art, inert diluents, such as, for example, water or other solvents, soljubilizatory and emulsifiers such as ethyl alcohol, from rapelay alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, groundnut, corn oil, oil of savuti, olive, Kastoria and sesame oil), glycerin, tetrahydrofuranyl alcohol, glycols and ether of sorbitol and fatty acids, and mixtures thereof.

Besides inert diluents, compositions for oral administration may include auxiliary agents such as wetting agents, emulsifiers and suspendresume agents, sweeteners, corrigentov, colouring agents, flavouring agents and preservatives.

Suspensions, in addition to rifaximin may contain suspendresume agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene esters of sorbitol, esters sorbitan, microcrystalline cellulose, aluminum Metagalaxy, bentonite, agar-agar and tragakant, and mixtures thereof.

Pharmaceutical compositions for intrarectal or vnutrivlagalishnogo applications can be submitted in the form of suppositories which can be prepared by mixing of rifaximin with one or more suitable not cause irritation with excipients or carriers, which include, for example, cocoa butter, polyethylene glycol, paraffin for suppositories or a salicylate, and which is solid at on the th temperature, but liquid at body temperature and therefore will melt in the cavity of the rectum or vagina and release of the active ingredient.

Compositions that are suitable for vnutrivlagalishnogo application, also include pessaries, tampons, creams, gels, pastes, foams or aerosol preparations containing such carriers as are known in the art, are suitable.

Dosage forms for local administration or percutaneous administration of rifaximin include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and pharmaceutical forms for inhalation. Rifaximin may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or gases-displacers that may be required.

Ointments, pastes, creams and gels may contain, in addition to rifaximin, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragakant, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and spray solutions may contain, in addition to rifaximin, such excipients as lactose, tal, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprayable solutions can additionally contain customary propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

In the alternative case, rifaximin can be entered using the aerosol. It successfully carried out by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. Can be used non-aqueous suspension (e.g., containing gas propellant in the form of a fluorocarbon). Preferred are ultrasonic aerosol devices, because they minimize the impact on the agent shear forces, which can lead to degradation of the connection.

Water spray is prepared, for example, by preparing an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the necessary conditions for a specific connection, but typically include nonionic surfactants (Tweens®), Pluronics® or polyethylene glycol), non-toxic proteins like serum albumin, esters sorbitan, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or polyalcohols, xylytol. Aerosols are usually made from isotonic solutions.

Pharmaceutical compositions suitable for parenteral administration may include rifaximin in sochetaniem or more pharmaceutically acceptable, sterile, isotonic aqueous or nonaqueous solutions, dispersion systems, suspensions or emulsions, or sterile powders which can be recreated in a sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostatic, dissolved substances, which give the drug isotonicity with the blood of the intended recipient, or suspendresume agents or thickeners.

Examples of suitable aqueous and nonaqueous carriers which may be used in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.,) and their suitable mixtures of vegetable oils, such as olive oil, and injectable esters of organic acids, such as etiloleat. Proper liquid state may be stored, for example, by applying a coating such as lecithin, by storing the required particle size in the case of dispersions and by using surface-active substances.

These compositions may also contain auxiliary agents such as preservatives, wetting means, emulsifiers and dispersing agents. The prevention of the action of microorganisms can be ensured by including different breakdown of an InterMedia is selected and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, etc. may be Desirable also enable agents to give isotonicity, such as sugars, sodium chloride, etc. in the composition. In addition, the inclusion of agents which delay absorption such as aluminum monostearate and gelatin, may cause long the absorption of the injectable pharmaceutical form.

In some cases, to extend the effect of the medicinal product, it is desirable the change of absorption of the drug. This can be done by applying a liquid suspension of crystalline salt or amorphous material having a very poor solubility in water. The degree of absorption of the drug may depend on its degree of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of the drug form is accomplished by dissolving or suspension of the drug in an oil medium.

Injectable depot forms can be prepared by creating microencapsulated matrices of rifaximin in biorazlagaemykh polymers, such as polylactide-polyglycolide. Depending on the ratio of drug and polymer and the nature of the particular polymer used can counter which can regulate the rate of release of the drug. Examples of other biorazlagaemykh polymers include poly(orthoevra) and poly(anhydrides). Injectable drugs in depot forms are also prepared by the seizure of the drug in liposomes or microemulsions that are compatible with the tissue of the body.

When rifaximin administered to humans and animals as a medicinal product, it may be administered by itself or in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with pharmaceutically acceptable carrier.

Regardless of the method of introduction of rifaximin, which can be used in the pharmaceutical compositions of the present invention are pharmaceutically acceptable dosage form using known skilled in the art experts of ways.

You can modify the actual dose levels and the dynamics of the introduction of active ingredients in pharmaceutical compositions, to obtain the amount of active ingredient that is effective to achieve the desired therapeutic response in case of a specific subject, composition and method of administration, without being toxic to the subject. Cited as an example of the range of doses ranges from about 25 to 3000 mg per day.

XIFAXAN, trade nae is the W for rifaximin, permitted for the following two applications:

1) traveler's Diarrhea: 200 mg of rifaximin prescribed for the treatment of patients (age ≥12 years) with traveler's diarrhea caused by noninvasive strains of Escherichia coli. Containing rifaximin tablets should not be taken by patients with diarrhea complicated by fever or blood in the stool or diarrhea due to pathogens other than Escherichia coli.

2) Hepatic encephalopathy: Containing 550 mg of rifaximin tablets are prescribed for the preservation of remission of hepatic encephalopathy in patients age ≥18 years.

To reduce the formation of drug-resistant tool bacteria and maintain the effectiveness of rifaximin and other antibacterial drugs, rifaximin in the treatment of infection should be used only to treat or prevent infections that are proven or when there is strong suspicion caused by susceptible bacteria. If there is information about the culture and sensitivity should be considered when selecting or modifying antibacterial therapy. In the absence of such data, local epidemiological features and characters sensitivity may contribute to the empiric selection of therapy.

XIFAXAN, a trade name for rifaximin allowed for the following two applications:/p>

1) Diarrhoea travellers

200 mg of rifaximin prescribed for the treatment of patients (age ≥12 years) with traveler's diarrhea caused by noninvasive strains of Escherichia coli.

Rifaximin should not be taken by patients with diarrhea complicated by fever or blood in the stool or diarrhea due to pathogens other than Escherichia coli.

2) Hepatic encephalopathy

550 mg of rifaximin prescribed to reduce the risk of recurrence of hepatic encephalopathy (NO) with a clear clinical picture in patients age ≥?18. In trials of rifaximin for the treatment HE 91% of patients received both lactulose. Differences in therapeutic effect in those patients who did not take at the same time lactulose, it was impossible to determine.

Rifaximin has not been studied in patients with scores in the MELD (model of end stage liver disease)>25, and only 8.6% of patients in the controlled trial had evaluation MELD above 19. There is an increase in systemic exposure in patients with more severe hepatic dysfunction.

Rifaximin can be given orally with or without food. For the treatment of traveler's diarrhea patients should take one 200-mg tablet three times a day for 3 days. For the treatment of hepatic encephalopathy patients should take one 550 mg tablet twice on the HB.

Containing rifaximin tablets is contraindicated in patients with hypersensitivity to rifaximin, any of the antimicrobial agents of the class rifamycin or any of the components in the containing rifaximin tablets. Hypersensitivity reactions have included exfoliative dermatitis, angioedema and anaphylaxis.

Not, it was found that rifaximin is effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than Escherichia coli.

It is necessary to stop the use of rifaximin in case of worsening symptoms of diarrhea or save them for more than 24-48 hours and should be considered an alternative therapy based on antibiotics.

Rifaximin is effective in cases of traveler's diarrhea due to Campylobacter jejuni. The efficacy of rifaximin in the case of traveler's diarrhea caused by Shigella spp. and Salmonella spp., has not been proven. Rifaximin should not be taken by patients who may have a suspicion that Campylobacter jejuni, Shigella spp. or Salmonella spp. are causing disease pathogens.

About associated with Clostridium difficile diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including rifaximin, and its severity can range from mild diarrhea to causing death if the and. Treatment with antibacterial agents alters the normal flora of the colon, which can lead to the overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Producing hypertoxin strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients, with diarrhea after antibiotic use. A careful history, since CDAD was reported to occur over two months after the introduction of antibiotics.

In the case of suspected or confirmed CDAD may require termination of ongoing antibiotic use not directed against C. difficile. Appropriate infusion and electrolyte therapy, replenishment of proteins, antibiotic treatment of C. difficile, and surgical evaluation should be instituted in accordance with the clinical picture.

It is unlikely that the prescription of rifaximin in the case of traveler's diarrhea in the absence of a proven or strongly suspected bacterial infection or a prophylactic benefit to the patient, but it increases the risk of formation of drug-resistant tool bacteria.

In patients with severe pécs is internal failure there is an increase in systemic exposure. In toxicity studies in animals have not been achieved systemic exposure that have been identified in patients with severe hepatic insufficiency. Clinical trials were limited to patients with MELD scores in <25. Therefore, there should be caution in the introduction of rifaximin patients with severe hepatic insufficiency (with the degree With the child-Pugh score).

The safety of taking 200 mg of rifaximin three times a day has been evaluated in patients with travellers ' diarrhoea, consisting of 320 patients in two placebo-controlled clinical trials, with 95% of patients received treatment with rifaximin for three or four days. The average age of the study population was approximately 31.3 (18-79) years, while approximately 3% were aged ≥65 years, 53% were male, and 84% were Caucasian race, 11% were americanidiot race.

Discontinuation of treatment due to adverse reactions reported in 0.4% of patients. Adverse reactions leading to discontinuation of treatment were loss of taste sensations, dysentery, weight loss, anorexia, nausea and irritation of the nasal passage.

All adverse reactions when taking 200 mg of rifaximin three times a day, which was met with a frequency of ≥2% in two placebo-controlled trials, which were combined, are presented in table 2. (These include adverse reactions, which can be explained by the underlying disease.)

The following adverse reactions manifested by body system, have also been reported in <2% of patients taking rifaximin, in two placebo-controlled clinical trials, in which 200-mg tablets taken three times a day in case of traveler's diarrhea. The following adverse reactions include adverse reactions regardless of causal relationship with exposure to the effects of the drug:

Table 29
All adverse reactions occurring with a frequency of ≥2% among patients receiving XIFAXAN tablets, 600 mg/day in placebo-controlled trials
Preferred term in MedDRA (medical dictionary for regulatory activities)Number (%) of patients
The XIFAXAN tablets, 600 mg/day (N=320)Placebo N=228
Flatulence36 (11,3%)45 (19,7%)
Headache31 (9.7 per cent)21 (9,2%)
Abdominal pain, unspecified23 (7,2%)23 (10.1 per cent)
Rectal tenes23 (7,2%)20 (8,8%)
Urgent need for defecation19 (5,9%)21 (9,2%)
Nausea17 (5,3%)19 (8,3%)
Constipation12 (3,8%)8 (3,5%)
Hyperthermia10 (3,1%)10 (4,4%)
Vomiting, unspecified7 (2,2%)4 (1,8%)

Disorders associated with the circulatory and lymphatic systems: lymphocytosis, monocytosis, neutropenia.

Disorders related to the ear and the inner ear: ear pain, motion sickness, ringing in the ears.

Gastrointestinal disorders: abdominal distension, diarrhea, unspecified, dry throat, deviations in the chair, not specified, violations of gum, unspecified, inguinal hernia, unspecified, dry lips, discomfort in the stomach.

General disorders and States in the introduction: chest pain, fatigue, malaise, pain, unspecified, weakness.

Infection and infestation by parasites: dysentery, unspecified, infection of the respiratory tract, unspecified, upper respiratory infection, unspecified.

Injury and poisoning: solar erythema.

Tests: aspartate aminotransferase increased, blood in stool, blood in the urine, reduced weight.;

Metabolic disorders and disorders of the alimentary origin: anorexia, dehydration.

Disorders associated with the musculoskeletal system, connective tissue and bones: pain in joints, muscle cramps, myalgia, pain in the neck.

Nervous system disorders: abnormal dreams, dizziness, migraine, unspecified, fainting, loss of taste sensations.

Psychiatric disorders: insomnia.

Disorders related to the kidneys and urinary ways: polyuria, dysuria, true hematuria, polyuria, proteinuria, urinary frequency.

Violations associated with breathing, chest and mediastinum: dyspnoea, unspecified, irritation of the nasal passage, rhinopharyngitis, pharyngitis, pharyngeal-esophageal pain, rhinitis, unspecified, rhinorrhea.

Skin disorders and diseases of the subcutaneous tissue: clamminess, rash, not installed, increased sweating; and

vascular disorders: flushing.

Hepatic encephalopathy

Presents data below reflect exposure treatment is the s 550 mg of rifaximin 348 patients includes 265 patients treated for 6 months, and 202 patients, treated for more than a year (the average duration of exposure to treatment was 364 days). Security reception 550 mg of rifaximin twice daily to reduce the risk of recurrence of hepatic encephalopathy with a clear clinical picture was evaluated in a 6-month, placebo-controlled clinical trial (n=140) and in long-term complementary study (n=280). The average age of the study population was 56.26 vertical (range: 21-82) years; approximately 20% of patients were patients age ≥65 years, 61% were men, 846 were Caucasian race, and 4% were black. 91% of patients in the trial received both lactulose. All adverse reactions that occur with a frequency of ≥5% and with a higher frequency in subjects treated 550 mg of rifaximin than in the treated placebo group in the 6-month test, presented in table 27. (These include adverse reactions, which can be explained by the underlying disease).

Table 30
Adverse reactions occurring in ≥5% of patients receiving XIFAXAN, and with greater frequency than in the placebo group
Preferably the second term in MedDRA (medical dictionary for regulatory activities) Number (%) of patients
The XIFAXAN tablets, 550 mg twice daily, N=140Placebo N=228
Peripheral edema21 (15,0%)13 (8,2%)
Nausea20 (14,3%)21 (13,2%)
Dizziness18 (12,5%)13 (8,2%)
Fatigue17 (12,1%)18 (11,3%)
Ascites16 (11,4%)15 (9,4%)
Muscle spasms13 (9,3%)11 (0,9%)
Itching13 (9,3%)10 (6,3%)
Abdominal pain12 (8,0%)13 (8,2%)
Bloating11 (7,9%)12 (7,5%)
Anemia11 (7,9%)6 (3,8%)
Ka is spruce 10 (7,1%)11 (6,9%)
Depression10 (7,1%)8 (5,0%)
Insomnia10 (7,1%)11 (6,9%)
Rhinopharyngitis10 (7,1%)10 (6,3%)
Pain in the upper abdomen9 (6,4%)8 (5,0%)
Pain in joints9 (6,4%)4 (2,5%)
Back pain9 (6,4%)10 (6,3%)
Constipation9 (6,4%)10 (6,3%)
Dyspnoea9 (6,4%)7 (4,4%)
Hyperthermia9 (6,4%)5 (3,1%)
Rash7 (5,0%)6 (3,8%)

The following adverse reactions manifested by body system, have also been reported in placebo-controlled clinical trial in b is more than 2%, but less than 5% of patients taking oral 550 mg rifaximin twice daily in case of hepatic encephalopathy. The following adverse reactions include adverse reactions occurring with greater frequency than in the treated placebo group, regardless of causal relationship with exposure to the effects of drugs.

Disorders related to the ear and the inner ear dizziness.

Gastrointestinal disorders: pain in the lower abdomen, pain when pressed on the stomach, dry mouth, bleeding from varicose veins of the esophagus, stomach discomfort.

General disorders and States in the introduction: chest pain, generalized edema, a disease like influenza, pain, unspecified.

Infections and parasite infestations: cellulitis, pneumonia, rhinitis, upper respiratory infection, unspecified.

Injury, poisoning and related procedures complications: contusion, fall, associated with the procedure pain.

Tests: increased weight.

Metabolic disorders and disorders of the alimentary origin: anorexia, dehydration, hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia.

Disorders associated with the musculoskeletal system, connective tissue and bones: myalgia, pain in extremity.

Nervous system disorders: amnesia, the infringement of the attention, hypoesthesia, memory impairment, tremor.

Psychiatric disorders: confusion.

Violations associated with breathing, chest and mediastinum: nosebleeds; and

vascular disorders: hypotension.

The following adverse reactions have been installed during the application of rifaximin after his permission. As reports of these reactions were obtained voluntarily from a population of unknown size, it is impossible to conduct the evaluation frequency. These reactions have been chosen for exclusion due to either their seriousness, frequency of messages, or causal connection with rifaximin.

Infections and parasite infestations

There have been reports of cases associated with C. difficile colitis.

There were reports of hypersensitivity reactions, including exfoliative dermatitis, rash, angioedema (swelling of face and tongue and difficulty swallowing), hives, redness, itching, and anaphylaxis. These reactions occurred within 15 minutes from the introduction of the drug.

In vitro studies have shown that rifaximin is not inhibited isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 cytochrome P450 in concentrations ranging from 2 to 200 ng/ml do Not assume that rifaximin is to inhibit these enzymes in clinical application.

The results of in vitro studies the Finance talked about that rifaximin induces CYP3A4. However, it is assumed that in patients with normal liver function rifaximin in the recommended scheme of doses will induce CYP3A4. It is unknown whether rifaximin to have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function, which have elevated concentrations of rifaximin.

The results of in vitro studies talked about the fact that rifaximin is a substrate of P-glycoprotein. It is unknown whether concomitant drugs that inhibit P-glycoprotein, to increase the systemic exposure of rifaximin.

Rifaximin was teratogenic in rats at doses comprising from 150 to 300 mg/kg (greater than approximately 2.5 to 5 times the clinical dose for traveler's diarrhea [600 mg/day] and in approximately 1.3 to 2.6 times the clinical dose for hepatic encephalopathy [1100 mg/day], to bring it in line with the surface area of the body). Rifaximin was teratogenic in rabbits at doses of components of 62.5 to 1000 mg/kg (greater than approximately 2-33 times the clinical dose for traveler's diarrhea [600 mg/day] and about 1.1-18 times the clinical dose for hepatic encephalopathy [1100 mg/day], to bring it in line with the surface area of the body). These effects include cleft the sky, Ignatiy, shortening of the lower jaw bones, hemorrhage, not fully open eyes, small eyes, brachygnathia, incomplete ossification, and increased lumbar-thoracic vertebrae.

Research capacity for reproduction were performed on rats in doses exceeding up to 2.5 to 5.0 times (to bring it in accordance with the surface area of the body) dose and in rabbits at doses exceeding up to 2.0-33,0 times (to bring it in accordance with the surface area of the body) dose for a person, and did not reveal the facts reduce fertility or harm to the fetus due to rifaximin.

The pharmacokinetics of rifaximin has been evaluated in two studies in patients with hepatic insufficiency. In the first study, the maximum concentration in plasma, are presented as the mean (standard deviation), which is 13.5 (14,8) ng/ml, were detected in patients with hepatic encephalopathy 3 hours after the first dose of rifaximin, which was administered in the dose of 800 mg three times a day for 7 days; less than 0.1% of the administered dose was selected in the urine within 7 days. Due to limited systemic absorption of rifaximin special adjustments doses are not recommended in patients with hepatic insufficiency. In the second study, patients were administered rifaximin dose 550 mg twice a day. The values of the systemic exposure of rifaximin (Cmaxin the steady state, are presented as the mean (standard deviation) in patients with hepatic insufficiency with degrees according To the child-Pugh score was 19.5 (11,4) ng/ml and 25.1 (12,6) (ng·h/ml (approximately 5.7 and 7.4-fold higher, respectively, than the values of Cmaxin the steady state in healthy individuals). In the case of this increase systemic exposure of rifaximin in patients with hepatic impairment no adjustment is required doses of rifaximin due to its local action - action in the gastrointestinal tract and low systemic bioavailability.

Given as examples doses contain rifaximin, a non-aminoglycoside semi-synthetic, non-systemic antibiotic derived from rifamycin SV. Rifaximin is a structural analog of rifampin. The chemical name of rifaximin - (2S,16Z, 18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxyphenolic-[1,11,13]trientine)benzofuro[4,5-e]pyrido[1,2-a]-benzimidazole-1,15(2H)-dione,25-acetate. Empirical formula C43H51N3O11and its molecular weight is 785,9.

Given as examples containing rifaximin tablets for oral administration coated and contain 200 is g or 550 mg of rifaximin. Each tablet contains colloidal silicon dioxide, pence edetate, glycerol palmitostearate, gidromolot, microcrystalline cellulose, propylene glycol, red iron oxide, sodium starch glycolate, talc and titanium dioxide.

The dose effectiveness of rifaximin in reducing the severity of hepatic encephalopathy (HE) was established in a double-blind study using a range of doses (component 600, 1200 or 2400 mg total daily dose for 7 days) in patients with grade 1, 2 or 3 HE, all groups showed improvement compared with baseline levels, defined in terms of the many symptoms HE; mean change (improvement) estimates of the prevalence of symptoms was -0,064, -0,103 and -0,107 in the groups receiving a total daily dose comprising 600 mg, 1200 mg and 2400 mg, respectively.

In table 28 summarizes the average pharmacokinetic parameters of rifaximin plasma 14 healthy subjects after a single oral 400-mg dose, administered by 2×200-mg doses, and 12 healthy subjects after a single 550-mg dose in the States after a meal and on an empty stomach.

Table 31
The effect of food on the pharmacokinetic parameters are presented as mean value±standard deviation,after a single 400-mg dose of rifaximin (N=14)
The effect of food on the pharmacokinetic parameters are presented as mean value±standard deviation
One 400-mg dose of rifaximin (N=14)One 550-mg dose of rifaximin (N=12)
After a mealOn an empty stomachAfter a mealOn an empty stomach
Cmax (ng/ml)3,80±1,329,63±5,93Android 4.04±1,514,76±4,25
Tmax (h)1,21±0,471,90±1,520,75 (between 0.30 to 1.05)*1,50 (0,50-4,08)*
The period of existence (h)5,85±4,345,95±1,881,83±1,384,84±1,34
AUCt (ng·h/ml)18,35±9,4834,70±9,2311,1±4,1522,5±12,0
*Average range

Rifaximin can be administered with or without food. Since systemic absorption of rifaximin is low and the introduction of the state of fasting, and with the introduction within 30 minutes from Breakfast with a high fat content, rifaximin can be administered with or without food.

14C-rifaximin was administered as a single dose of 4 healthy men. Average total release of radioactivity in urine and faeces 3 subjects within 168 hours after administration was 96,94±5,64% of the dose. The radioactivity was eliminated almost exclusively in faeces (RUB 96.62±5,67% of the dose), while only a small percentage of dose (mean value of 0.32% of the dose) was excreted with urine. Analysis of extracts of faeces showed that rifaximin is excreted as unchanged drug. The amount of radioactivity in the urine (<0.4% of the dose) suggests that rifaximin is poorly absorbed from the gastrointestinal tract and almost exclusively and completely excreted in feces as unchanged drug. Average pharmacokinetic parameters of rifaximin were Cmax of 4.3±2.8 ng/ml and AUCt of 19.5±16.5 ng·h/ml, with a median Tmax=1,25 hours

Diarrhoea travellers

Systemic absorption of rifaximin (200 mg three times daily) was evaluated in 13 subjects infected with shigellosis, on days 1 and 3 of a three-day course of treatment. Concentration retaxim is on plasma and exposure were low and variable. No evidence of accumulation of rifaximin after repeated administration for 3 days (9 doses). The maximum concentration of rifaximin in plasma after administration of 3 and 9 consecutive doses ranged from 0.81 to 3.4 ng/ml on day 1 and from 0.68 to 2.26 ng/ml on day 3. As assessment AUC0-the last timewas 6,95±5,15 ng·h/ml on day 1 and 7,83±4,94 ng·h/ml on day 3. Rifaximin is not suitable for the treatment of systemic bacterial infections because of limited exposure after oral administration.

Hepatic encephalopathy

After administration of a single dose and multiple doses of rifaximin comprising 550 mg, in healthy subjects the mean time to maximum concentration in plasma was approximately an hour. Pharmacokinetic (PK) parameters were highly variable, and based on AUC factor accumulation amounted to 1.37.

Pharmacokinetics in patients with hepatic insufficiency (degrees a and b liver failure in the child-Pugh score), the host 550 mg of rifaximin twice daily, was evaluated in an open study of rifaximin. The exposure value of rifaximin (AUCτ) in subjects with grades a and b according to child-Pugh score (118 and 161 ng·h/ml, respectively) was exceeded in approximately 9.6 and 13.1 times those detected in healthy subjects after oral administration twice a day d is C, components of 550 mg (12,3 ng·h/ml), respectively. Interregional variability in pharmacokinetics in healthy subjects were generally similar to those determined in subjects with hepatic impairment.

Rifaximin can be administered with or without food.

Pharmacokinetic studies in animals have shown that 80-90% of the oral input of rifaximin are concentrated in the gut, with less than 0.2% is concentrated in the liver and kidneys, and less than 0.01% in other tissues. In adults with infectious diarrhea subjected to treatment with rifaximin at a dose of 800 mg weekly for three days, the concentration of rifaximin in the faeces amounted on average approximately 8000 µg/g day after completion of treatment.

In the study of mass balance, after oral administration of 400 mg14C-rifaximin healthy volunteers, from 96,94% of the total output RUB 96.62% of the injected radioactivity was separated from faeces almost entirely as unchanged drug, and 0.32% allocated with urine, mainly as metabolites, together with 0,03% as unchanged drug. Rifaximin was caused 18% of radioactivity in plasma. This suggests that the adsorbed rifaximin undergoes metabolism together with insignificant excretion by the kidneys unchanged drug. The enzymes responsible is e for the metabolism of rifaximin, unknown.

In a separate study, rifaximin was found in the bile after cholecystectomy in patients with intact mucous membrane of the gastrointestinal tract, suggesting excretion of rifaximin in the bile.

Liver failure

Systemic exposure of rifaximin was significantly increased in patients with hepatic impairment compared with healthy subjects. The mean AUC in patients with hepatic insufficiency degree With the child-Pugh score twice as high as that in patients with hepatic insufficiency extent And the child-Pugh score (see table 28).

In vitro studies of drug interactions have shown that rifaximin in concentrations ranging from 2 to 200 ng/ml, not inhibited isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 cytochrome P450 in human liver. In in vitro models of induction of hepatocytes found that rifaximin induces 3A4 isoenzyme of cytochrome P450 (CYP3A4) isoenzyme, which is known to induce rifampin. Two clinical studies drug-drug interactions with the use of midazolam and contraceptives for oral administration containing ethinylestradiol and norgestimate showed that rifaximin (200 mg twice daily for 3 days) did not change the pharmacokinetics of these drugs, and rifaximin at a dose of 550 mg three times a day is a period of 7 or 14 days only led to slightly reduced exposure of midazolam after a single oral dose of midazolam.

In in vitro study found that rifaximin induces CYP3A4 in the concentration component of 0.2 μm.

The results of in vitro studies suggest that rifaximin is a substrate of P-glycoprotein. In the presence of an inhibitor of P-glycoprotein - verapamil coefficient efflux of rifaximin was reduced by more than 50% in vitro. The effect of inhibition of P-glycoprotein on rifaximin has not been defined in vivo.

The inhibitory effect of rifaximin on the carrier of P-gp was observed in in vitro study. The effect of rifaximin on the carrier of P-gp has not been defined in vivo.

The effect of rifaximin at a dose of 200 mg, administered orally every 8 hours for 3 days and within 7 days on the pharmacokinetics of midazolam, administered once or in a dose of 2 mg intravenously, or at a dose of 6 mg orally, was determined in healthy subjects. Found no significant differences in the characteristics of systemic exposure or elimination of intravenous or oral midazolam or its main metabolite, 1'-hydroxymidazolam between midazolam by itself or together with rifaximin. Therefore, rifaximin, as installed, does not have a significant effect on the activity of CYP3A4 in the intestine or liver in the case of scheme a dose of 200 mg three times a day.

After administration of rifaximin at a dose of 550 mg three times a day for 7 days and 14 days healthy su is yuktam average AUC of midazolam, once entered oral dose of 2 mg was 3.8% and 8.8% lower, respectively, than after administration of midazolam by itself. Average Cmaxmidazolam was also decreased by 4-5% when rifaximin was administered for 7-14 days after injection of midazolam. This degree of interaction is not considered to be clinically significant.

The effect of rifaximin on CYP3A4 in patients with reduced liver function, which have increased systemic exposure is not known.

Contraceptives for oral administration, containing 0.07 mg of ethinyl estradiol and 0.5 mg of norgestimate

In the study of contraceptives for oral administration used the open cross-sectional study in 28 healthy which female subjects to determine whether the changes rifaximin, oral, injected at a dose of 200 mg three times a day for 3 days (scheme of doses in the case of traveler's diarrhea), the pharmacokinetics of injected in a single dose contraceptives for oral administration, containing 0.07 mg of ethinyl estradiol and 0.5 mg of norgestimate. The results showed that rifaximin did not change the pharmacokinetics entered as a single dose of ethinyl estradiol and norgestimate.

Data in vitro studies suggest that rifaximin is a substrate of P-glycoprotein. Rifaximin is a weak inhibitor of P-gp in the oxygen the set pieces (50 μm), far above that expected in the plasma after oral administration of doses of rifaximin only partially inhibited the transfer of the model substrate P-gp. Therefore, not expected to have clinically significant interactions with other drugs that are affected by P-glycoprotein.

Rifaximin is excreted mainly in feces. After oral administration of 400 mg of rifaximin 14C398 healthy volunteers, approximately 97% of the dose was excreted with the faeces, almost entirely as unchanged drug, and 0.32% was eliminated in the urine.

Rifaximin is a non-aminoglycoside, a semisynthetic antibiotic derived from rifamycin SV, it is a structural analog of rifampin. The mechanism of action of rifaximin-dependent inhibition of DNA-dependent RNA polymerase which is the target microorganisms, leading to suppression of initiation of the formation of chains in the synthesis of RNA.

A lower degree of destruction of faecal pathogens in patients being treated with rifaximin compared with fluoroquinolones and aminoglycosides and no change of intestinal flora means a unique mechanism of action. Rifaximin may alter the virulence factors of enteric bacterial pathogens without destroying them, which is detected by the use of subtherapeutic the peer medicines, and associated with colonization of fimbria enterotoxigenic E. coli. Rifaximin caused morphological changes in sensitive and resistant bacterial strains already in the concentrations of the components from 1/32 MIC.1 Rifaximin reduced the viability and virulence of resistant bacteria, which suggests that in the case of exposure to pathogens in vivo effects of sub-MIC drugs will be undermined not only by their physiological functions, but will not be fully expressed encoded virulence genes and antibiotic resistance.

Rifaximin has in vitro antimicrobial activity against numerous gram-positive and gram-negative bacteria, such as Escherichia coli. Studies on animals and humans indicate negligible systemic absorption of rifaximin (< 1%) after oral administration. Little systemic absorption of rifaximin from the gastrointestinal tract minimizes potential adverse reactions associated with systemically absorbable antibiotics. Rifaximin is delivered in high concentrations in the gastrointestinal tract, which is the site of action of a therapeutic agent.

Rifaximin acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase, resulting in inhibition of sin is ESA RNA in bacteria.

It was shown that the Escherichia coli developed resistance to rifaximin in vitro. However, the clinical significance of this effect has not been studied.

Rifaximin is a structural analog of rifampin. Organisms, characterized by high values of minimum inhibitory concentration (MIC) of rifaximin, also characterized by increased values of MIC of rifampin. Cross-resistance between rifaximin and other classes of antimicrobial agents has not been studied.

In clinical research, infectious diarrhea, described here, it was found that rifaximin is effective associated pathogen.

If HE believe that rifaximin has an effect on the flora of the gastrointestinal tract.

In vitro study of the sensitivity was performed in accordance with the method of dilutions in agar of the National Committee for clinical laboratory standards (NCCLS) M7-A612. However, the correlation between sensitivity and clinical outcome has not been established.

It was shown that the Escherichia coli developed resistance to rifaximin in vitro. However, the clinical significance of this effect has not been studied. Rifaximin is a structural analog of rifampin. Organisms, characterized by high values of minimum inhibitory concentration (MIC) of rifaximin, also characteristic is caresource increased values of MIC of rifampin. Cross-resistance between rifaximin and other classes of antimicrobial agents has not been studied.

Malignant neuroma in the heart were significantly increased in male rats Crl:CD® (SD) who received rifaximin using enteral feeding for two years at doses of 150-250 mg/kg/day (doses greater than 2.4 to 4 times recommended in the case of traveler's diarrhea dose of 200 mg three times a day and in excess of 1.3-2.2 times as recommended in the case of hepatic encephalopathy dose of 550 mg twice daily, based on comparisons of the relative surface area of the body). Increase in tumors was not in Tg mice.rasH2 that oral was administered rifaximin for 26 weeks at doses of components 150-2000 mg/kg/day (doses greater than 1.2-16 times recommended in the case of traveler's diarrhea daily dose and exceeding 0.7-9 times recommended in case of hepatic encephalopathy daily dose, based on comparisons of the relative surface area of the body).

The carcinogenic potential of rifaximin studied in ongoing within 2 years of the study using rats CD. Daily oral administration at dose levels ranging from 20, 50, 250 mg/kg/day, did not bring evidence of a carcinogenic effect.

Also in a study using mice Tg.rasH2 daily administration via enteral feeding retaxim is on at doses up to 1500 mg/kg/day (in the case of males) and 2000 mg/kg/day (in the case of females) for 26 weeks did not increase the incidence of tumors compared with which the media control.

Rifaximin was not genotoxic in the analysis of reverse mutations in bacteria, the analysis of chromosomal aberrations, the analysis of micronucleus in bone marrow of rats, the analysis preparative DNA synthesis in rat hepatocytes or the analysis of mutations CHO/HGPRT. No effect on fertility in male or female rats after administration of rifaximin in doses up to 300 mg/kg (greater than approximately 5 times the clinical dose of 600 mg/day and approximately 2.6 times the clinical dose of 1100 mg/day, to bring it in line with the surface area of the body).

The results of toxicity studies by oral administration of multiple doses on rats, rabbits and dogs showed a slight toxic effect of rifaximin in doses exceeding 6-68 times the clinical dose for traveler's diarrhea (600 mg/day) for up to 39 weeks.

Held for 26 weeks study using oral input Tg mice.rasH2 of rifaximin in doses up to 1500 mg/kg/day (in the case of males) and 2000 mg/kg/day (in the case of females) 2/25 female mice at a dose of 2000 mg/kg / day appeared disheveled hair and crooked with low frequency, which did not reach statistical significance.

Oral administration of rifaximin for 3-6 months caused a proliferation of connective tissue in the liver of rats (50 mg/kg/day) and fatty PE the Yeni dogs (100 mg/kg/day). However, the levels of the drug in plasma were not determined in these studies. Subsequently rifaximin investigated at doses up to 300 mg/kg/day to rats for 6 months and 1000 mg/kg/day for dogs over 9 months, and found no signs of hepatotoxicity. Maximum related to plasma AUC values0-8h on the basis of toxicity studies for 6 months in rats and 9 months dogs (range: 42-127 ng·h/ml) were below the maximum, related to the plasma AUC values0-8h in patients with cirrhosis (range: 19-306 ng·h/ml).

The efficacy of rifaximin taken in a dose of 200 mg orally three times a day for 3 days, was evaluated in 2 randomized, conducted in many centres, double-blind, placebo-controlled studies in adult subjects with travellers ' diarrhoea. One study was conducted in clinics in Mexico, Guatemala and Kenya (study 1). Another study was carried out in Mexico, Guatemala, Peru and India (study 2). Samples of faeces were taken before treatment and on days 1-3 after completion of treatment to determine intestinal pathogens. The predominant pathogen in both studies was Escherichia coli.

Clinical efficacy of rifaximin was estimated by the time to return to normal, decorated stull and disappearance of symptoms. First is cnym the ultimate measure of effectiveness was the time before last is not formed stool (TLUS), which was defined as the last period of time before the latter is not formed stool, after which declared clinical recovery. Table 29 presents the average TLUS and the number of patients that achieved clinical recovery, formed in accordance with the assigned treatment (ITT) population studies 1. Duration of diarrhoea was significantly less in patients treated with rifaximin than patients flu placebo. To the category of patients that achieved clinical recovery was attributed more patients treated with rifaximin than patients in the placebo group.

Table 32
Clinical response in study 1 (ITT population)
XIFAXAN (n=125)Placebo (n=129)Assessment (97,5% confidence interval)A p-value of
Average TLUS (h)32,558,61,78and(1,26, 2,50)is 0.0002
Clinical recovery99 (79,2) 78 (60,5)18,7b(5,3, 32,1)0,001
aThe risk ratio
bThe difference in degrees

The degree of destruction of microbes (defined as the absence of the source of the pathogen in the culture of feces after 72 hours of treatment) in case study 1 are presented in table 30 for patients with any pathogen at baseline and for the subpopulation of patients with Escherichia coli at the source level. Escherichia coli was the only pathogen present in sufficient quantities to make possible comparisons between treatment groups.

Although rifaximin had microbiological activity similar to that of placebo, he demonstrated a clinically significant reduction in duration of diarrhea and a greater degree of clinical recovery than placebo. Therefore, to patients should be based on the clinical response to therapy and microbiological reactions.

Table 33
The degree of destruction of microbes in subjects with the pathogen at baseline in case study 1
RifaximinPlacebo/b>
In the amount of48/70 (68,6)41/61 (67.2 per)
E. coli38/53 (71,7)40/54 (74,1)

The results of study 2 confirmed the results presented in case study 1. In addition, this study also presented evidence that subjected to treatment with rifaximin subjects with fever and/or blood in the faeces at baseline had an increased TLUS. In the case of these subjects the degree of clinical recovery were lower than in the case of entities without fever or blood in the faeces at source level. Many of the patients with fever and/or blood in the feces (diarrhea syndromes similar to syndromes dysentery) had invasive pathogens, mainly Campylobacter jejuni isolated from the source of excrement.

Also in this study, if the most part subjected to treatment with rifaximin subjects in which Campylobacter jejuni isolated as the sole pathogen at baseline, the treatment was not successful, and the resulting degree of clinical recovery in these patients was 23.5% (4/17). In addition to the absence of differences from placebo, the degree of destruction of microbes in the case of entities with Campylobacter jejuni allocated n is the source level, were much lower degrees of destruction of microbes observed in the case of Escherichia coli.

In not linked open, pharmacokinetic study of rifaximin taken orally at a dose of 200 mg every 8 hours for 3 days, infection with Shigella flexneri 2a were subjected to 15 adult subjects, 13 of which developed diarrhea or dysentery, and they were subjected to treatment with rifaximin. Although it is an open challenge using the intrusion was insufficient to evaluate the efficacy of rifaximin in the treatment of shigellosis were made the following observations: eight patients received back treatment with ciprofloxacin or due to the lack of response to treatment with rifaximin within 24 hours (2), either because they developed severe dysentery (5), or due to re-emergence of Shigella flexneri in faeces (1); five of the 13 subjects received ciprofloxacin, although in their case there was no data on severe disease or relapse.

The efficacy of rifaximin taken at a dose of 550 mg orally twice daily, was evaluated in a randomized, placebo-controlled, double-blind conducted in multiple centers within 6 months of the trial in adult subjects from the USA, Canada and Russia, which were defined as patients in remission (component 0 or 1 score connu) hepatic encephalopathy (E). Eligible subjects had ≥2 episodes of HE-related chronic liver disease in the previous 6 months.

Total of 299 subjects were subjected to randomization to receive either rifaximin (n=140) or placebo (n=159) in this study. The average age of patients was 56 years (range: 21-82); 81% of patients were patients aged <65 years of age, 61% were male, and 86% were Caucasian race. At baseline, 67% of patients had grade on connu =0, and 68% had a degree of "fluttering" tremor =0. Patients had evaluation MELD, components or ≤10 (27%) or 11-18 (64%) at baseline. Patients with MELD score>25 in the study were not included. Nine percent of patients had a degree With the child-Pugh score. 91% of patients in each being treated with the study group at the same time took lactulose. In each duct of the study patients were excluded from the study after the manifestation of the episode HE exacerbation during treatment. Other causes premature termination of the study included adverse reactions (rifaximin 6%; placebo 4%), the requirement to discontinue the patient (rifaximin 4%; placebo 6%) and others (rifaximin 7%; placebo 5%).

The primary outcome measure was time to first episode of acute HE, with obvious clinical symptoms during treatment. Episode aggravation HE with a clear clinical picture at the time the I treatment was defined as a clear deterioration of the function of the nervous system and increase the valuation on connu to degree ≥2. In the case of patients with assessment Konno at baseline =0, the episode of acute HE, with obvious clinical symptoms during treatment was defined as up to 1 increase in estimates for Konno and component 1 degree "fluttering" of the tremor.

Episodes of exacerbation of HE with a clear clinical picture during treatment showed 31 of 140 subjects (22%) being treated with rifaximin group and 73 of 159 subjects (46%) being treated with the placebo group during the 6-month treatment period. Comparison of the estimates by the method of Kaplan-Meier curves without episodes of exacerbation showed that rifaximin significantly reduces the risk of exacerbation of HE during treatment by 58% during a 6-month treatment period. Below in Fig.24 presents a curve without episodes of exacerbation with estimates by the method of Kaplan-Meier for all subjects (n=299) of this study.

Therapeutic effect of rifaximin at a dose of 550 mg in reducing the risk of relapse is HE with obvious clinical symptoms during treatment was not controversial when the results were evaluated in accordance with the following demographic and baseline characteristics: gender, grade Konno at baseline, duration available at this time of remission and diabetes. Differences in therapeutic effect could not be assessed due to the small sample size in the following subpopulations: in subpopulations PAC the clients are not Caucasian race (n=42), with MELD score at baseline >19 (n=26), with the degree With the child-Pugh score (n=31) and patients not receiving simultaneously lactulose (n=26).

In Fig.25 shows the relationship of risks manifestations of HE with a clear clinical picture during treatment (risk, subjected to treatment with rifaximin group divided by the risk in the treated placebo group) for each subgroup, 95% confidence interval, determined in accordance with the Cox proportional hazards model. P-values for differences between the treated rifaximin and placebo groups was determined using the logarithmic rank criterion.

Associated with HE of hospitalization were registered in the case 19 of 140 subjects (14%) and 36 of 159 subjects (23%) treated with rifaximin and placebo groups, respectively. Rifaximin caused a significant reduction in risk associated with HE hospitalizations during the 6-month treatment period; the risk ratio: risk subjected to treatment with rifaximin group relative to the risk in the treated placebo group was 0,500 (95% confidence interval: 0,287-0,873) (p=0,0129). The subjects in the treated with rifaximin group were decreased by 50% the risk of hospitalization due to HE during the 6-month treatment period compared with the treated placebo group. See the Fig.26: Time is I first connected with HE hospitalizations in the study HE (up to 6 months of treatment, day 170) (in case formed in accordance with the assigned treatment (ITT) population).

Associated with HE hospitalization (hospitalization, which is a direct consequence HE or hospitalization complicated HE) were registered in the case 19 of 140 subjects (14%) and 36 of 159 subjects (23%) treated with rifaximin and placebo groups, respectively. Rifaximin caused a significant reduction in risk associated with HE hospitalizations during the 6-month treatment period; the risk ratio: risk subjected to treatment with rifaximin group relative to the risk in the treated placebo group was 0,500 (95% confidence interval: 0,287-0,873) (p=0,0129). The subjects in the treated with rifaximin group were decreased by 50% the risk of hospitalization due to HE during the 6-month treatment period compared with the treated placebo group. See the Fig.26: Time to first associated with HE hospitalizations in the study HE (up to 6 months of treatment, day 170) (in the case of the ITT population).

Comparison of the estimates by the method of Kaplan-Meier curves without hospitalizations showed that rifaximin significantly reduces the risk associated with HE hospitalizations by 50% during the 6-month treatment period. Comparison of the estimates by the method of Kaplan-Meier curves without hospitalizations shown in Fig.25.

Research Chu is reality to antimicrobial agents bacteria, that grow aerobically, were performed in accordance with the methods of dilutions in agar as described in the Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. National Committee for Clinical Laboratory Standards, Sixth Edition, Wayne PA. Approved Standard NCCLS Document M7-A6 January 2003; 23 (2).

Highly significant protective effect of rifaximin were noted in regard to time to any increase in comparison with the initial level of assessment Konno and time to any increase in comparison with the initial level degree "fluttering" of the tremor at their independent analysis; risk ratio: risk subjected to treatment with rifaximin group relative to the risk in the treated placebo group was 0,463 (95% confidence interval: 0,312-0,685) (p<0,0001) for the risk of occurrence of increased assessment Konno (i.e., deterioration in mental status) and 0,646 (95% confidence interval: 0,414-1,008) (p=0,0523) for the risk of occurrence of increasing the degree of "fluttering" of tremor (i.e., deterioration of the function of the neuromuscular system) during the 6-month treatment period.

Since lactulose was often used at the same time therapeutic tool was undertaken analysis of the use of lactulose at baseline and during the study to ensure that therapeutic effect of rifaximin is not modified. At baseline and during the test was not razlichiya the use of lactulose between being treated with rifaximin group and the control group. Thus, the results of a study demonstrating the efficacy of rifaximin did not influence the use of lactulose.

In addition, subgroups of patients were subjected to analyses in the MELD and child-Pugh score to determine any differences between the exposed treatment with rifaximin groups. It was found that the positive effects of rifaximin is not limited to the severity of liver disease. In addition, it was also found that there is no significant Association between different subgroups and effect. Accordingly, all these studies showed a risk reduction in favor of rifaximin. In Fig.28 illustrates that there has been a constant therapeutic effect on all the different subgroups, which was administered rifaximin.

About associated with Clostridium difficile diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including rifaximin, and its severity can range from mild diarrhea to causing the death of colitis. Treatment with antibiotics alters the normal flora of the colon, which can lead to the overgrowth of C. difficile. Patients can develop watery and bloody stools (with stomach cramps and fever, with or without them) even after two or more months after the last dose of antibiotic. If diarrhea occurs during therapy or not reduced the raised or increased during therapy, advise patients to contact a physician as soon as possible.

Should inform patients about the increase in systemic exposure of rifaximin in patients with severe hepatic insufficiency (degree With the child-Pugh score).

EXAMPLES

Should be fully understood that embodiments of the present invention, as should be understood, is not limited to the examples which will now be described, but on the contrary, the present invention, as should be understood, includes any and all applications provided here, and all equivalent variations within the specialist qualification medium qualification level.

EXAMPLE 1: effect of rifaximin on subjects with hepatic insufficiency

Subjects were instructed to ingest one tablet containing 550 mg of rifaximin, 2 times a day, approximately every 12 hours. Rifaximin can be given in combination with other drugs, such as lactulose, antidepressants, anti-inflammatory drugs, methadone, issued by receptor and non-prescription drugs (e.g., By reverse phoneTM(eszopiclone) and Ambien® (zolpidem-tartrate), and antihistamines, diuretics, laxatives or stool softeners, neurontina (gabapentin) and lyrics (pregabalin).

the label of lactulose was optional for the subjects. In the case of entities receiving lactulose, it was distributed over time (3-7)-day observation period in accordance with generally accepted medical practice.

The degree of "fluttering" tremor

"Fluttering" tremor was determined using the holding entity stretched out both hands and forearms dorsal flexion of the wrist and open fingers for ≥30 seconds. "Fluttering" tremor was determined in accordance with the sequence of 5 degrees, such as 0 degrees and 4 = no abnormal movements, in comparison with almost continuous "fluttering" movements, respectively, as presented below:

Degree 0 = no tremor;

Degree 1 = rare "flying" movement;

Degree 2 = periodic, irregular "fluttering" of the movement;

Grade 3 = frequent "fluttering" of the movement; and

Degree 4 = almost continuous "fluttering" of the movement.

Efficiency regarding the extent of the "fluttering" of the tremor was defined as time to any increase in comparison with the initial level degree "fluttering" of the tremor. Time to increase the degree of "fluttering" of the tremor was calculated as the number of days from the first dose of rifaximin to the origin of the increase compared with the initial level degree "fluttering" of the tremor.

The episode HE exacerbation during treatment

Determined the relative risk of symptoms of EPI is the one HE exacerbation during treatment (for example, the degree in accordance with the assessment by Konno ≥2 (for example, 0 or 1 to ≥2) or an increase of 1 degree each of the assessments on Konno and "fluttering" tremor) for each subject in the test, take either rifaximin or placebo. In the analysis using methods for analyzing time survival compared time to first episode of HE exacerbation during the treatment for the treated with rifaximin group relative to the treated placebo group. Time to first episode of HE exacerbation during treatment was calculated as the number of days from the first dose of rifaximin to the origin of HE exacerbation during treatment (for example, the degree in accordance with the assessment by Konno ≥2, or an increase of 1 degree each of the assessments on Konno and "fluttering" of tremor).

Altered mental status was determined using the assessment Konno (also known as assessment of West haven). Score from Konno was widely used as an indicator of the mental state at the research HE and is based on criteria Parsons-Smith, modified Horse. The scale used in the assessment system for connu described above.

The subjects had a score on connu, component 0 or 1. The increase in the assessment on connu to grade ≥2 was considered to be the episode HE exacerbation during treatment.

Algorithm for the evaluation of hepatic encephalopathy(HESA)

Algorithm for the evaluation of hepatic encephalopathy (HESA) is a method that uses clinical and neuropsychological assessment to determine the mental state. Validation of the algorithm was performed previously, and set its correlation with the criteria for connu.

The study CFF recognized as the quantitative determination of CNS dysfunction, and uses the correlation between processing at the level of brain oscillating visual stimuli and its subsequent deterioration due to the increase in the severity of HE. The study CFF was provided, and a statistically significant greater improvement study results CFF was observed in the treated with rifaximin subjects compared with the treated placebo subjects (p=0,0320).

Critical frequency of flicker (CFF) was determined for each subject at screening, at baseline, at visits 3 through 14 and at the time of completion of the study, using the merge flashed by Lafayette (Lafayette Instrument Company, Inc). Circular light pulses with components 1:1 ratio between the visual impulses and intervals were used, with a gradual decrease in frequency from 0.5 to 0.1 Hz/sec. The frequency of white light, which is initially generated as a high pulse frequency (50 Hz) and which gives the patient the impression of not flashing light is a, gradually reduced to create a patient experience that is not flashing light changed to flashing. The patient was registered this change by pressing the manual switch. The frequency of the flickering was determined 8 times, and on the basis of these data was calculated averages for each patient. The study was performed in a quiet palestininas room without distracting noise, and it took about 10 minutes.

Assess the critical frequency of flicker

Critical frequency of flicker (CFF) was determined for each subject using a special device to determine the CFF. CFF is the frequency at which the subject observes the transition flashing light flashing light, and is measured in Hertz (Hz). CFF is an objective assessment of mental status. It is established that the value of CFF=39 Hz is the boundary between subjects, showing HE (for example, grade connu ≥1), and subjects without symptoms HE (for example, grade connu =0), while a lower value CFF indicates more severe HE(43).

CFF was determined on a continuous scale, and it represented the average value of the 8 individual studies of transitions from of flicker fusion to the flickering made in rapid succession.

Ammonia concentration

Taking samples of venous blood (10 ml) and determined the end of the ation of ammonia using methods known in this technical field.

Time to increase compared to the baseline or assessment Konno (degree of mental status), or the degree of "fluttering" tremor

To analyze time to first episode of HE exacerbation during treatment, used methods for analysis of time left to live for estimating the treatment effect of rifaximin on time to increase compared to the baseline or assessment Konno (degree of mental status), or the degree of "fluttering" of the tremor. Time to increase or assessment connu, or the degree of "fluttering" of the tremor was calculated as the number of days from the first dose of rifaximin to the origin of the increase compared to the baseline or assessment connu, or the degree of "fluttering" of the tremor. Analysis of time to increase or assessment connu, or the degree of "fluttering" of the tremor was based on comparing the time to the specified episode between the treated rifaximin and placebo groups.

Time to first associated with hospitalization HE

Determined the effect of rifaximin on time to first related to HE hospital. Time to first associated with HE of hospitalization was calculated as the number of days from the first dose of rifaximin to the first hospitalization for related with HE episode. Analysis of time to first related what HE hospitalization was based on comparison of time to hospitalization between the treated rifaximin and placebo groups.

Time to development of spontaneous bacterial peritonitis

Determined the effect of rifaximin on the time to development of spontaneous bacterial peritonitis (SBP). Time to development of SBP was calculated as the number of days from the first dose of rifaximin to the time of sampling fluid from the abdominal cavity, which was a positive test for the presence of SBP. Analysis of time to the development of SBP was based on comparing the time until the specified event between the treated rifaximin and placebo groups.

The average change compared with the initial concentration of ammonia in the blood and values of critical frequency of flicker over time

Were obtained mean values and mean changes from baseline concentration of ammonia in the blood and values of critical frequency of flicker. Analyses of concentrations of ammonia in the blood and values of critical frequency of flicker based on quantitative values (and not on quality degrees). Associated with treatment differences of the average change compared to baseline levels of these parameters were estimated using the mixed effect model using fixed effects (factors) and time values to the initial values.

The average daily consumption of lactulose over time

Daily consumption subject lactulose use is ovali to calculate the average daily consumption of lactulose during each month. Estimated associated with treatment differences of the average change compared to baseline average daily consumption of lactulose.

CLDQ

CLDQ includes 29 questions in the following six areas manifestations: abdominal symptoms (three questions), fatigue (five questions), systemic symptoms (five questions), activity (three questions), emotional state (eight questions) and anxiety (five questions). Pooled estimates across the CLDQ and on each of the six areas manifestations were calculated and summarized at baseline and at days 28, 56, 84, 112, 140 and 168 using descriptive statistics. Associated with treatment differences of the average change of the overall assessment and evaluations on specific areas manifestations compared to baseline levels by day 28, 56, 84, 112, 140 and 168 summarized and compared between treatments.

Associated with treatment differences of the average change compared to baseline levels at the end of treatment (EOT) was defined as change compared to baseline levels in the EOT assessment tiredness by means of a questionnaire for assessment of chronic liver disease (CLDQ). Also determined the average change compared with the initial concentration of ammonia in the blood in EOT.

Assessment of quality of life

SF-36, the questionnaire for evaluation of chronic liver disease (CLDQ) and the scale of drowsiness Apsara used for the determining of health-related quality of life. Containing 29 questions in the questionnaire CLDQ consists of the following areas manifestations: fatigue, activity, emotional state, abdominal symptoms, systemic symptoms and anxiety.

The scale of drowsiness Apsara

Total scale scores drowsiness of Apsara was calculated and summarized at baseline and at days 28, 56, 84, 112, 140 and 168 using descriptive statistics. Associated with treatment differences of the average change of the overall scores compared to baseline levels by day 28, 56, 84, 112, 140 and 168 summarized and compared between treatments.

Fig.1 represents a diagram in the form of broken, which compares the ingestion of lactulose between subjects receiving placebo, and subjects receiving rifaximin, as described here.

Fig.2 represents a diagram in the form of a polyline which demonstrates the evaluation by the method of Kaplan-Meier distribution of time until the episode HE exacerbation during treatment for receiving the placebo group and receiving rifaximin group. As indicated, there was an increase in time before the episodes HE exacerbation during treatment in the case of entities receiving rifaximin compared with subjects receiving placebo.

Fig.3 represents a diagram in the form of a polyline which demonstrates the evaluation by the method of Kaplan-Meier time distribution is to first NOT associated with hospitalization. As indicated, there was an increase in the time prior to admission in the case of entities receiving rifaximin compared with subjects receiving placebo.

Fig.4 is a chart in the form of a polyline which demonstrates the evaluation by the method of Kaplan-Meier distribution of time to first increase in assessments on connu. As indicated, there was an increase in time to first increase in assessments on connu in the case of entities receiving rifaximin compared with subjects receiving placebo.

Fig.5 represents a diagram in the form of a polyline which demonstrates the evaluation by the method of Kaplan-Meier distribution of time to first increase the degree of "fluttering" of the tremor. As indicated, there was an increase in time to first increase the degree of "fluttering" tremor in the case of entities receiving rifaximin compared with subjects receiving placebo.

EXAMPLE 2

The following table presents additional evidence of preferential use of specific GI diseases antibiotics such as rifaximin for the treatment of subjects suffering from HE.

td align="center"> 4
Table 1
The time before occurrence of the episode, HE exacerbation during treatment
Placebo (N=159)550 mg of rifaximin twice daily (N=140)
DaysBe-
the size of risk
Manifestations episodesThe total manifestation of episodesThe conditional probability of episodes (standard error)Survival is
VA - resistant
Be-
the size of risk
Manifestations episodesThe total manifestation of the historicdsThe conditional probability of episodes (standard error)Survival is
VA - resistant
[0 to 28)1582020of 0.13 (0.03 in)1,000014013130,09 (0,02)1,0000
[28-56)13723430,17 (0,03)0,8734126170,03 (0,02)0,9071
[56-84)11314570,12 (0,03)0,72621206230,05 (0,02)0,8783
[84-140)981067of 0.10 (0.03 in)0,63631127300,06 (0,02)0,8344
[140-168)84673of 0.07 (0.03 in)0,5713981310,01 (0,01)0,7820
>=168380730,00 (0,00)0,5305 460310,00 (0,00)0,7740
The risk ratio: 0,421
95% confidence interval: (0,276, 0,641)
p-value: <0,0001

Table 2
The time before occurrence of the episode, HE exacerbation during treatment in accordance with baseline assessment konu
Placebo (N=107)550 mg of rifaximin twice daily (N=93)
DaysBe-
the size of risk
Manifestations episodesThe total manifestation of episodesThe conditional probability of episodes (standard error)Survival is
VA - resistant
Subject
the size of risk
Manifestations episodesThe total manifestation of the historicdsThe conditional probability of episodes (standard error)Survival is
VA - resistant
[0 to 28) 10713130,12 (0,03)1,00009311110,12 (0,03)1,0000
[28-56)9316290,17 (0,04)0,8779813140,04 (0,02)0,8817
[56-84)777360,09 (0,03)0,7269771150,01 (0,01)0,8491
[84-140)69541of 0.07 (0.03 in)0,6608753180,04 (0,02)0,8380
[140168) 61445of 0.07 (0.03 in)0,6129681190,01 (0,01)0,8042
>=168270450,00 (0,00)0,5724320190,00 (0,00)0,7924
The risk ratio: 0,441
95% confidence interval: (0,258, 0,754)
p-value: 0,0028

Table 3
The time before occurrence of the episode, HE exacerbation during treatment in accordance with the prior use of lactulose
Placebo (N=142)550 mg of rifaximin twice daily (N=123)
DaysBe-
the size of risk
Manifestations episodesThe conditional probability of episodes (standard error)Survival-VA - resistantSubject
the size of risk
Manifestations episodesThe total manifestation of the historicdsThe conditional probability of episodes (standard error)Survival-VA - resistant
[0 to 28)1411919of 0.13 (0.03 in)1,00001231212of 0.10 (0.03 in)1,0000
[28-56)12121400,17 (0,03)0,86521104160,04 (0,02)0,9024
[56-84)1001353of 0.13 (0.03 in)0,751 1045210,05 (0,02)0,8696
[84-140)8610630,12 (0,03)0,622197728of 0.07 (0.03 in)0,8278
[140-168)73568of 0.07 (0.03 in)0,5498841290,01 (0,01)0,7678
>=168330680,00 (0,00)0,5121390290,00 (0,00)0,7586
The risk ratio: 0,424
95% confidence interval: (0,274, 0,655)
p-value: 0,0001

Table 4
Time to first occurrence NOT associated with hospitalization
Placebo (N=159)550 mg of rifaximin twice daily (N=140)
DaysBe-
the size of risk
Manifestations episodesThe total manifestation of episodesThe conditional probability of episodes (standard error)Survival is
VA-resistant
Be-
the size of risk
Manifestations episodesThe total manifestation of the historicdsThe conditional probability of episodes (standard error)Survival is
VA - resistant
[0 to 28)15411110,07 (0,02)1,0000138660,04 (0,02)1,0000
[28-56)11 1425of 0.11 (0.03 in)0,92861354100,03 (0,02)0,9564
[56-84)1067320,07 (0,02)0,82931135150,04 (0,02)0,9258
[84-140)868400,09 (0,03)0,77431005200,05 (0,02)0,8848
[140-168)662420,03 (0,02)0,7023863230,04 (0,02)0,8403
>=168/td> 300420,00 (0,00)0,6810390230,00 (0,00)0,8108
The risk ratio: 0,521
95% confidence interval: (0,313, 0,868)
p-value: 0,0107

Table 5
Time to any increase in comparison with the initial level of assessment konu
Placebo (N=159)550 mg of rifaximin twice daily (N=140)
DaysBe-
the size of risk
Manifestations episodesThe total manifestation of episodesThe conditional probability of episodes (standard error)Survival is
VA - resistant
Be-
the size of risk
Manifestations episodesThe total manifestation of the historicdsConditional probability is the outer coat of episodes (standard error) Survival is
VA - resistant
[0 to 28)15626260,17 (0,03)1,000013917170,12 (0,03)1,0000
[28-56)12521470,17 (0,03)0,83331195220,04 (0,02)0,8777
[56-84)10015620,15 (0,04)0,6928109931of 0.08 (0.03 in)0,8407
[84-140)8010720,13 (0,04)0,5883945 360,05 (0,02)0,7713
[140-168)62577of 0.08 (0.03 in)0,5143790360,00 (0,00)0,7302
>=168270770,00 (0,00)0,472937137of 0.03 (0.03 in)0,7302
The risk ratio: 0,463
95% confidence interval: (0,312, 0,685)
p-value: <0,0001

Table 6
The time before occurrence of the episode, HE exacerbation during treatment in accordance with baseline assessment MELD
Placebo (N=44)550 mg of rifaximin twice daily (N=34)
Days Be-
the size of risk
Manifestations episodesThe total manifestation of episodesThe conditional probability of episodes (standard error)Survival is
VA - resistant
Be-
the size of risk
Manifestations episodesThe total manifestation of the historicdsThe conditional probability of episodes (standard error)Survival is
VA - resistant
[0 to 28)4422of 0.05 (0.03 in)1,00003411of 0.03 (0.03 in)1,0000
[28-56)42460,10 (0,05)0,954533010,00 (0,00)0,9706
[56-84)38 17of 0.03 (0.03 in)0,863632010,00 (0,00)0,9706
[84-140)373100,08 (0,04)0,84093212of 0.03 (0.03 in)0,9706
[140-168)334140,12 (0,06)0,772728020,00 (0,00)0,9398
>=168140140,00 (0,00)0,679113020,00 (0,00)0,9398
The risk ratio: 0,71
95% confidence interval: (0,039, 0,754)
p-value: 0,0197

Table 7
The time before occurrence of the episode, HE exacerbation during treatment in accordance with baseline assessment MELD
Placebo (N=159)550 mg of rifaximin twice daily (N=140)
DaysBe-
the size of risk
Manifestations episodesThe total manifestation of episodesThe conditional probability of episodes (standard error)Survival is
VA - resistant
Be-
the size of risk
Manifestations episodesThe total manifestation of the historicdsThe conditional probability of episodes (standard error)Survival is
VA-resistant
[0 to 28)8615150,18 (0,04)1,0000858 80,09 (0,03)1,0000
[28-56)7013280,19 (0,05)0,8246772100,03 (0,02)0,9059
[56-84)5611390,20 (0,05)0,6703733130,04 (0,02)0,8822
[84-140)457460,16 (0,05)0,5387686190,09 (0,03)0,8459
[140-168)362480,06 (0,04)0,453958 1200,02 (0,02)0,7713
>=168160480,00 (0,00)0,4284270200,00 (0,00)0,7580
The risk ratio: 0,329
95% confidence interval: (of € 0.195, 0,556)
p-value: <0,0001

Table 8
The time before occurrence of the episode, HE exacerbation during treatment in accordance with baseline assessment MELD
Placebo (N=14)550 mg of rifaximin twice daily (N=11)
DaysBe-
the size of risk
Manifestations episodesThe total manifestation of episodesThe conditional probability of episodes (standard error)Vyziva resistantBe-
by the th risk
Manifestations episodesThe total manifestation of the historicdsThe conditional probability of episodes (standard error)Vyziva resistant
[0 to 28)14330,21 (0,11)1,000011110,09 (0,09)1,0000
[28-56)11470,36 (0,15)0,785710010,00 (0,00)0,9091
[56-84)7290,29 (0,17)0,500010340,30 (0,14)0,9091
[84-140)5 090,00 (0,00)0,35717040,00 (0,00)0,6364
[140-168)4090,00 (0,00)0,35717040,00 (0,00)0,6364
>=1682090,00 (0,00)0,35713040,00 (0,00)0,6364
The risk ratio: 0,403
95% confidence interval: (0,123, 1,313)
p-value: 0,1315

Table 9
The time before occurrence of the episode, HE exacerbation during treatment in accordance with the prior use of lactulose
Placebo (N=134)550 mg of rifaximin twice daily (N=127)
DaysBe-
the size of risk
Manifestations episodesThe total manifestation of episodesThe conditional probability of episodes (standard error)Vyziva resistantBe-
the size of risk
Manifestations episodesThe total manifestation of the historicdsThe conditional probability of episodes (standard error)Vyziva resistant
[0 to 28)1341818of 0.13 (0.03 in)1,000012712120,09 (0,03)1,0000
[28-56)11520380,17 (0,04)0,8652114416 0,04 (0,02)0,9055
[56-84)9514520,15 (0,04)0,71471086220,06 (0,02)0,8737
[84-140)809610,11 (0,04)0,60941006280,06 (0,02)0,8252
[140-168)68566of 0.07 (0.03 in)0,5408881290,01 (0,01)0,7754
>=168310660,00 (0,00)0,5011410 290,00 (0,00)0,7666
The risk ratio: 0,399
95% confidence interval: (0,2586, 0,618)
p-value: <0,0001

Table 10
Time to any increase in comparison with the initial level degree "fluttering" tremor
Placebo (N=159)550 mg of rifaximin twice daily (N=140)
DaysBe-
the size of risk
Manifestations episodesThe total manifestation of episodesThe conditional probability of episodes (standard error)Survival is
VA-resistant
Be-
the size of risk
Manifestations episodesThe total manifestation of the historicdsThe conditional probability of episodes (standard error)Survival is
VA-resistant
[0 to 28)15420 20of 0.13 (0.03 in)1,000013713130,10 (0,02)1,0000
[28-56)1201535of 0.13 (0.03 in)0,86971167200,06 (0,02)0,9048
[56-84)914390,04 (0,02)0,7610101727of 0.07 (0.03 in)0,8499
[84-140)76645of 0.08 (0.03 in)0,7275873300,03 (0,02)0,7910
[140-168)61 449of 0.07 (0.03 in)0,6701741310,01 (0,01)0,7637
>=168271500,04 (0,04)0,626234132of 0.03 (0.03 in)0,7534
The risk ratio: 0,646
95% confidence interval: (0,414, 1,008)
p-value: 0,0523

Table 11
The average change compared with the initial concentration of ammonia in the blood (µg/DL)
Evaluation timePlacebo (N=159)550 mg of rifaximin twice daily (N=140)P-value
Day 28
n126121
The average value is 89,388,4
Standard deviation48,1949,02
Medianof 87.074,0
The minimum value225
The maximum value315326
The change compared to baseline levels by day 28
n1171170,6268
Average-1,1of-2.1
Standard deviation48,3244,37
Median1,0-2,0
Min the minimum value -252-164
The maximum value133176

Table 12
The average change compared to baseline in the study of the critical frequency of flicker (Hz)
Evaluation timePlacebo (N=159)550 mg of rifaximin twice daily (N=140)P-value
Day 140
n7087
Average38,738,7
Standard deviation5,474,76
Median38,838,9
The minimum value26 27
The maximum value5049
The change compared to baseline levels by day 140
n70870,0266
Average1,11,4
Standard deviation4,104,84
Median0,91,5
The minimum value-12-15
The maximum value1212

td align="center"> 0,4
Table 13
The average change compared to baseline in the study of the critical frequency of flicker (Hz)
Evaluation timePlacebo (N=159)550 mg of rifaximin twice daily (N=140)P-value
The end of the study
n155139
Average37,6of 37.8
Standard deviation5,984,88
Medianof 37.9of 37.8
The minimum value2125
The maximum value5049
The change compared to baseline levels by the end of the research
n1551390,0320
Average0,9
Standard deviation4,704,75
Median0,20,1
The minimum value-12-14
The maximum value1611

Table 14
The number of subjects at each level of change compared to the baseline assessment konu
in accordance with the treatment group
Evaluation timeStatisticsPlacebo (N=140)550 mg of rifaximin twice daily (N=140)The odds ratio
(550 mg of rifaximin twice daily/placebo)
95% confidence interval for odds ratioP-value
The change compared to baseline levels by the end of the research
-1n (%)18 (11,5%)26 (18.7 per cent)2,46(1,49, 4.09 to)0,0005
0n (%)100 (63,7%)101 (72,7%)
1n (%)29 (18,5%)10 (7,2%)
2n (%)9 (5,7%)2 (1,4%)
3n (%)1 (0,6%)0
n157139
Average0,2-0,1
Standard deviation0,740,56
Median0,00,0
The minimum value-1-1
The maximum value32

Table 15
The number of subjects at each level of change compared with the initial level degree "fluttering" of tremor in accordance with the treatment group/td>
Evaluation timeStatisticsPlacebo (N=140)550 mg of rifaximin twice daily (N=140)The odds ratio
(550 mg of rifaximin twice daily/placebo)
95% confidence interval for odds ratioP-value
The change compared to baseline levels by the end of the research
-2n (%)1 (0,6%)1 (0,7%)1,88(1,10, 3,23)0,0207
-1n (%)14 (8,9%)18 (12,9%)
0n (%)114 (72,6%)108 (77,7%)
1n (%)18 (11,5%)10 (7,2%)
2n (%)8 (5,1%)2 (1,4%)
3n (%)1 (0,6%)0
4n (%)1 (0,6%)0
n157139
Average0,20,0
Standard deviation0,760,54Median0,00,0
The minimum value-2-2
The maximum value42

Table 16
The average change compared to baseline total scale scores drowsiness of Apsara
Evaluation timePlacebo (N=159)550 mg of rifaximin twice daily (N=140)P-value
Day 28
n9187
Average9,1 10,0
Standard deviation4,845,51
Median8,09,0
The minimum value00
The maximum value2123
The change compared to baseline levels by day 28
n90860,593
Average-1,1-0,2
Standard deviation4,793,53
Medianof-1.00,0
The minimum value-17 -14
The maximum value147

Table 17
Time to first occurrence associated with hospitalization HE
Placebo (N=159)550 mg of rifaximin twice daily (N=140)
DaysBe-
the size of risk
Manifestations episodesThe total manifestation of episodesThe conditional probability of episodes (standard error)Survival is
VA - resistant
Be-
the size of risk
Manifestations episodesThe total manifestation of the historicdsThe conditional probability of episodes (standard error)Survival is
VA-resistant
[0 to 28)15511110,07 (0,02) 1,0000139440,03 (0,01)1,0000
[28-56)13212230,09 (0,03)0,9288130480,03 (0,02)0,9711
[56-84)1087300,06 (0,02)0,84401194120,03 (0,02)0,9411
[84-140)884340,05 (0,02)0,78931065170,05 (0,02)0,9094
[140-168)722360,03 0,02) 0,7535922190,02 (0,02)0,8665
>=168340360,00 (0,00)0,7325430190,00 (0,00)0,8475
The risk ratio: 0,500
95% confidence interval: (0,287, 0,873)
p-value: 0,0129

EXAMPLE 3: Rifaximin does not induce CYP3A4

Induction of CYP3A4 by rifaximin was marked on the basis of a reduction of about 25% of the AUC of midazolam. The highest systemic exposure is expected for the most part, which is the target patient population.

When rifaximin was administered orally at high doses (1650 mg/day) for at least 7 days, the average CmaxAUC0-tand AUC0-∞for midazolam was reduced to <25%. Rifaximin is a potential inducer of CYP3A4 in vitro studies have shown that it has a lower induction activity than rifampin. The estimated concentration of rifaximin in the intestinal lumen is priblizitel is but 5 μm. In in vitro study, the activity of CYP3A4 was increased 1.7 fold and 1.8-fold at a concentration of rifaximin, part 1 μm and 10 μm; rifampin in the same concentrations increased the activity of CYP3A4 in 3.7 times and 4 times, respectively. In addition, suppose that the result aimed at the gut distribution of rifaximin its mechanism of induction of CYP3A4 is limited to the intestine, without the need for induction in the liver as a result of its low systemic exposure. I.e. in the case of rifaximin there is a separation of induction in the intestine and liver. This, as demonstrated in the studies described here on the receiving rifaximin people, confirmed by the absence of induction, when either intravenously or orally was administered midazolam after administration of rifaximin at a dose of 200 mg three times daily for up to 7.

Without wanting to be limited to any specific scientific theory believe that any risk of induction of CYP3A4 in the liver, probably further reduced in patients with hepatic insufficiency, in which case a significant part of the portal blood flow go as a result of the presence of anastomoses bypassing the liver;3therefore, increased systemic exposure they must be accompanied by a proportional decrease effect on hepatocytes, and patients should not be exposed to the actual increase in the risk of induction of CYP3A4 in pecan is.

EXAMPLE 4: Study of drug interactions

Two clinical studies drug-drug interactions were carried out using a containing 200 mg of rifaximin tablets, and one study drug-drug interactions - using contains 500 mg of rifaximin tablets. There were two studies conducted with the use of midazolam, a known substrate for CYP3A4, and 1 study using contraceptives for oral administration containing ethinylestradiol and norgestimate, to evaluate the effect of rifaximin on the pharmacokinetics of these drugs. Based on the results of these studies and in vitro studies induction and inhibition using fractions isolated from human liver, is not expected to have clinically significant drug interactions with rifaximin.

Although in vitro studies have shown the ability of rifaximin to interact with cytochrome P450 3A4 (CYP3A4), clinical investigation of drug-drug interactions have shown that rifaximin does not have a significant effect on the pharmacokinetics of midazolam neither presystemic level or at the system level. Additional clinical investigation of drug-drug interactions revealed no effect of rifaximin on the presystemic metabolism of contraceptive for pearling the application, containing ethinylestradiol and norgestimate. Therefore, clinically significant interactions with drugs, metabolisable isoenzymes of cytochrome P450 person, not expected.

There were two studies conducted to assess the possibility of drug interactions with midazolam. The first study was an open, randomized, crossover, study drug-drug interactions, designed to evaluate the effect of rifaximin at a dose of 200 mg, administered orally every 8 hours (Q8H) for 3 days and within 7 days on the pharmacokinetics of midazolam, administered either in a single dose of 2 mg intravenously, or at a dose of 6 mg orally. Found no significant differences in the characteristics of systemic exposure or elimination of intravenous or oral midazolam or its main metabolite, 1'-hydroxymidazolam between midazolam by itself or together with rifaximin. Therefore, rifaximin, as installed, does not have a significant effect on the activity of CYP3A4 in the intestine or liver.

In the second study, open study of drug-drug interactions, examined the effects on orally administered midazolam in a dose of 2 mg of rifaximin at a dose of 550 mg three times daily at a dose within 7 and 14 consecutive days. In this study set the Leno, that rifaximin is a weak inducer of CYP3A4; given the low systemic exposure of rifaximin, I believe that this interaction will be limited to the gastrointestinal tract. This induction is dose-dependent and dependent on the duration of doses. When rifaximin was administered orally at high doses (1650 mg/day) for at least 7 days, the average CmaxAUC0-tand AUC0-∞for midazolam was reduced to <25%.

In vitro hERG activity and in vitro binding of rifaximin with protein

In in vitro studies hERG rifaximin in concentrations up to 300 μm failed to achieve 50% inhibition of currents in hERG potassium channels. Due to the precipitation of rifaximin at 300 μm IC50according to estimates exceeded 100 µm. In fact, 50% inhibition could not be achieved; at 100 μm, the average inhibition was 34.5%. Most Cmaxmarked in patients with liver failure in this study was at 52.2 ng/ml (to 0.0664 μm); the largest share of free plasma observed in the subset of plasma samples from patients involved in this study amounted to 44.7%. Using these numbers, the maximum expected exposure time in free plasma could be of 0.03 μm, which is ≥3000-fold decrease compared with the highest concentration at which reef is Simin could be investigated in experiments using hERG. This degree of safety is significantly greater than 30-fold partition between the IC50for hERG and Cmaxunrelated connection, which is usually associated with minimizing the risk of clinically significant prolongation of QT.

EXAMPLE 5: Time to first episode of exacerbation during treatment

Parameter efficiency for the first study was the occurrence of an episode of acute HE, with obvious clinical symptoms during treatment. Episodes of acute HE, with obvious clinical symptoms during treatment was determined through the use of assessment Konno (or degrees West haven) and the degree of "fluttering" of the tremor. Episode aggravation HE with a clear clinical picture during treatment, defined in the case of the first study was a clear, significant clinical deterioration in the function of the nervous system, which can lead to harmful effects for self-medication and leads to hospitalization. Based on a target performance indicator, time to first episode of acute HE, with obvious clinical symptoms during treatment, has highly significant protective effect of rifaximin (p<0,0001 for differences in relative risk between groups). Treatment rifaximin decreased by 57.9%, compared with placebo, the risk of occurrence of acute HE with a clear clinical picture during the 6-month p the period of treatment.

In addition, this study also showed that based on the time to first exacerbation HE with a clear clinical picture during treatment also demonstrates a highly significant protective effect of rifaximin in the analysis of specific geographic regions, North America in comparison with Russia.

Treatment with rifaximin leads to fewer episodes of HE with a clear clinical picture, which otherwise can make the patient unable to work, can reduce the burden on family members who must care for the patient, and reduces the costs of hospitalization in this patient population and the burden on the health care system.

Similar results were demonstrated in a second study, for example, in regard to time to first episode of acute HE, with obvious clinical symptoms during treatment: assessment according to the method of Kaplan-Meier time to first episode of acute HE, with obvious clinical symptoms during treatment were similar between the treated with rifaximin group in the first study and new subjects, subjected to treatment with rifaximin, in this second study. Also similar were the proportion of subjects who showed worsening of HE with a clear clinical picture during treatment in a subject to treatment with rifaximin group in the first study (22%, 31 of 140 PAC is Entov [subjected to treatment with rifaximin group]) and in the new subjected to treatment with rifaximin group second study (27,6%, 54 of 196).

When subjected to treatment with placebo in the first study, the subjects switched to treatment with rifaximin in the entry in the second study, was observed protective effect of rifaximin reduced by 70% the risk of occurrence of acute HE, with obvious clinical symptoms during treatment with rifaximin in a second study compared with the previous manifestation in them during treatment with placebo in the first study. This decline occurred despite an aging population with chronic liver disease and probably its progressive character.

The results of the second study also showed that the protective effect of rifaximin was long: evaluation of the time to the first exacerbation of HE during treatment demonstrated long-term preservation of the absence of acute HE, when subjected to treatment with rifaximin subjects in remission after participating in the first study, followed in the second study (up to 680 days of treatment with rifaximin; average duration of effects was 168 days in the first study and 253 days in the second study). Was below the frequency of episodes of exacerbation for these HE treated with rifaximin subjects regarding subjected to treatment with placebo in the first study subjects, indicating the reduction of ciclopista aggravation HE by treatment with rifaximin.

The estimate of the critical frequency of flicker (CFF), a recognized measure of CNS dysfunction, was the final performance indicator in the first study. In studies CFF is used, for example, the correlation between processing at the level of brain oscillating visual stimuli and reduced activity of CNS (Central nervous system) due to the increase in the severity of HE. In this study determined the frequency at which a flickering light is perceived as not flashing. Reducing this frequency was associated with increasing severity of HE. Also the increase of ammonia in the blood, the other end of the indicator in the first study is a quantitative assessment associated with effects on the CNS underlying the HE with a clear clinical picture.

Comparison of changes from baseline at study end results CFF and ammonia levels in venous blood showed a statistically significant greater improvement in the course of the study in the treated with rifaximin group than in the treated placebo group (p=0,0320 for changes in CFF and p=0,0391 for changes in the levels of ammonia in venous blood). In the first study was a marked correlation between the results for CFF and aggravation HE with a clear clinical picture (the primary measure of effectiveness). In the first study was of the mouth is determined, that there is a correlation between the levels of ammonia in the venous blood and the occurrence of acute HE with a clear clinical picture during treatment.

The results for the other of efficacy endpoints also demonstrated protective effects of rifaximin. In particular, the other end of the performance indicator in the form of time related to the first hospitalization HE showed reduced risk if subjected to treatment with rifaximin subjects.

In the first study, the analysis of time to first associated with HE hospitalization (e.g., hospitalization, which is a direct consequence HE or hospitalization complicated HE) showed that the reduction in the risk of hospitalization because HE was 50% in the treated with rifaximin group compared with the treated placebo group during the 6-month treatment period. The coefficient associated with hospitalization HE was 0.38 cases/years of exposure to the effects of patients (PEY) in the case of exposure to rifaximin in comparison with 0,78 cases/PEY in the event of exposure to placebo after casting to exposure exposure.

In the first study the risk HE caused hospitalization (for example, only hospitalization, which is the direct consequence of HE) was decreased by 56% in the treated with rifaximin group compared with the evaluation of the options in the placebo treatment group. The coefficient caused hospitalization HE was 0.30 cases/PEY in the treated with rifaximin group compared with 0,72 cases/PEY in the treated placebo group.

In the first study, the risk of hospitalization for all causes decreased by 30% in the treated with rifaximin group compared with the treated placebo group. The rate of hospitalisation for all causes was 0.92 cases/PEY in the treated with rifaximin group compared with 1.31 cases/PEY in the treated placebo group.

In the second study low coefficient caused hospitalization HE remained at levels corresponding to those in the first study: the coefficient caused hospitalization HE was 0.29 cases/PEY, and the rate of hospitalisation for all causes was 0.66 cases/PEY in the second study. Consistently low coefficient associated with the HE-caused hospitalization HE had been subjected to treatment with rifaximin subjects in the first study and the second study was at least partly a result of the conservation of remission HE proved in subjects with end-stage liver disease.

Hepatic encephalopathy followed by a low quality of life compared with the corresponding age of patients without HE. In patients with HE manifested symptoms, including us what alot, daytime sleepiness and lack of perception (score from connu =1), and the confusion and disorientation (score from connu =2) that significantly interfere with daily functioning, and reduced ability to look after themselves. Often this lack of self can lead to poor eating habits and lack of doctor's instructions and may further develop into more severe symptoms, such as increased drowsiness, and apparent confusion and clouding of consciousness, which require hospitalization. Treatment with rifaximin prevents associated with HE/NOT due to hospitalization, thereby improving the functional status of the patient and helping someone who cares for the patient; and reducing economic costs associated with cirrhosis of the liver and related HE.

In the United States there are limited treatment options for patients with relapsed HE. Neomycin sulfate is allowed only for additional treatment measures in hepatic coma. Conventional therapy aimed at lowering the production and absorption of ammonia. Neabsorbiruemye disaccharides, such as lactulose or lactitol, are commonly used as first-line therapy for HE. There is evidence that neabsorbiruemye disaccharides reduce the levels of ammonia in the plasma by changing the metabolism of nitrogen in the intestinal the flora and increase the excretion of nitrogen in faeces. Active in GI broad-spectrum antibiotics, including neomycin, metronidazole, vancomycin and paromomycin, was used together with lactulose or without it. These antibiotics seems to be acting indirectly through the inhibition of the decomposition of urea dominiruyushie bacteria, thus reducing the production of ammonia and other potential toxins. In modern manuals are recommended (not FDA approved) therapy based on antibiotics using neomycin or metronidazole as an alternative treatment neabsorbiruemye the disaccharides.

Common side effects of therapy with readsorbing disaccharides (e.g., lactulose) include unpleasant taste, which may limit compliance with doctor's instructions, scheme of doses, which is connected with the rhythms of emptying of the bowel and side effects on the GI, such as bloating, cramps in the abdominal Department and diarrhea. When using lactulose was registered diarrhea that leads to dehydration, significant consequence for patients with HE, because electrolyte abnormality may increase the severity of HE and lead to renal dysfunction.

The use of systemically absorbable antibiotics, such as neomycin, to ensure HE is preventing ototoxicity and nephrotoxicity associated with a long inim application. The frequency of occurrence caused by the use of aminoglycosides nephrotoxicity significantly higher in patients with advanced sick liver than in patients without liver disease. Frequency caused by the use of aminoglycoside nephrotoxicity in the General population is 3-11%. Leitman said that the nephrotoxicity occurs in 73% of patients with liver disease compared to 34% of patients without liver disease, which was intravenously injected aminoglycoside during hospitalization; and Cabrera reported that damage to the renal tubules or functional renal failure was noted in 60% of treated with aminoglycosides (intravenous during hospitalization) in patients with cirrhosis. In addition, the high degree of mortality and permanent kidney damage was observed in patients with cirrhosis, have been caused by the use of aminoglycosides damage to the renal tubules. Therefore, at the present time in various places believe that aminoglycosides are contraindicated in patients with progressive liver disease.

Rifaximin is an attractive therapy for the treatment of patients with HE, because he had demonstrated the efficiency, suitable safety profile, and because of deficiencies in the system of aminoglycosides and not absorbable disaccharides Rifaximin oblad the em wide spectrum of in vitro antibacterial activity against gram-positive and gram-negative bacteria and against aerobic and anaerobic isolates.

Since rifaximin is poorly absorbed after oral administration, the drug is selectively active in the gastrointestinal tract. In addition, there is a low risk of drug-drug interactions with the use of rifaximin. Rifaximin is characterized by a lesser degree of destruction of pathogens in the faeces compared to other commonly used antibacterial agents and causes minor changes in the intestinal flora, which suggests that rifaximin has a mechanism of action distinct from other commonly used medicines for intestinal bacterial infection, such as fluoroquinolones. The risk of developing resistance to antibiotics is low during continuous treatment with rifaximin compared with other systemic antibiotics, such as neomycin, perhaps because the resistance is mediated by a mutation in the DNA of the host cell, and is not based on the plasmid.

The retrospective analysis of outpatient maps and histories found that the number and duration of hospitalizations due to HE, the overall cost of treatment and outcome indicators HE (the degree of "fluttering" of the tremor score from connu) were strongly reduced compared to treatment with lactulose in patients with HE who took lactulose daily for 6 months the Germans, and then took rifaximin daily for 6 months.

The first study was designed to overcome the shortcomings of previous studies published in the literature (e.g., heterogeneous populations of subjects, small population size, small length and unintended outcomes for the mental state).

First, the duration of treatment was increased to 6 months. Hoped that this greater duration will occur episode NOT a greater number of subjects than in the case of limitations of the study ≤6 weeks. Also the long duration of treatment gave the opportunity to evaluate the safety of rifaximin in the long term in subjects with chronic liver cirrhosis and associated recurrent, with a clear clinical picture, episodic HE. The study examined the implications HE, with regard to patient care and economic costs, through the assessment of hospitalizations due to episodes of HE as a key secondary outcome measure effectiveness.

To assess the episodes HE with a clear clinical picture through the use of clinically significant criteria in the first study and the second study the deterioration of mental status was determined by using valuation p is connu (criteria West haven), and severity of neuromuscular pathologies were determined using the degree of "fluttering" of the tremor. Score from connu ranges from grade 0 (no detectable changes in personality) to grade 4 (coma, decerebration poses, advanced pupils). Score from Konno is recommended and widely used gold standard for determining the degree of deterioration of the mental state when HE with a clear clinical picture. "Fluttering" tremor is associated with neuromuscular system symptom HE with a clear clinical picture, which increases in severity with the deterioration of the function of the nervous system.

In the case of the first studies the control group received a corresponding pill-placebo parallel to the treatment with rifaximin in the active group. The second study was an ongoing, open study of the extension of treatment to assess security in the long term rifaximin at a dose of 550 mg twice daily in subjects with recurrent, episodic, with a clear clinical picture is NOT in the history of the disease. In addition to the security definitions in the study was determined by assessment Konno and the degree of "fluttering" of the tremor to determine the protective effect of rifaximin from the aggravation HE with a clear clinical picture during treatment within vplo the ü up to approximately 1 year from the subjects, which concluded that lasted up to 6 months of treatment with rifaximin, and then entered in the second study; subjects who received placebo in the first study and switched to treatment with rifaximin in the second study; and subjects with HE in the history of the disease, which was included in the second study as new entities.

Using the scheme of doses (550 mg twice daily) was based on past clinical experience with rifaximin in patients with HE and other populations of subjects. In several previous studies, rifaximin was safe and effective in subjects with HE dose, component 1200 mg per day, with at the same time take lactulose or without it. In a 6-month study of rifaximin in comparison with neomycin (14 days of treatment and 14 days without treatment in a month), rifaximin at a dose of 1200 mg/day and neomycin (3 g/day) had comparable efficacy in patients with HE. The group of antibiotics - aminoglycosides are contraindicated in patients with progressive liver disease because of the risk of nephrotoxicity.

The ultimate efficacy endpoint was time to first episode of acute HE, with obvious clinical symptoms during treatment. Episode aggravation HE with obvious clinical symptoms during treatment was defined as an increase in the assessment Konno to grade ≥2 (for example, 0 or 1 to ≥2) or reaching increase in the assessment on Konno and component 1 degree "fluttering" tremor in the case of entities, who entered the study with an estimate of Konno =0. Time to episode HE exacerbation during treatment was the length of time from the first dose of the investigational medicinal product to the first episode of exacerbation of HE with a clear clinical picture during treatment. Subjects who completed the study and did not show an episode of exacerbation of HE with a clear clinical picture during treatment, were examined during their 6-month visit. With the subjects who completed the study early for reasons other than acute HE, with obvious clinical symptoms during treatment, have established a relationship after 6 months from randomization to establish showed whether the subjects episode of acute HE, with obvious clinical or other consequence (for example, the state of death); and, if the subject had no episode of acute HE with a clear clinical picture to contact him, he was checked during communication with him. Therefore, successfully carried out a complete collection of data on episodes of exacerbation of HE with a clear clinical picture up to 6 months after randomization. Subjects in the study had ≥2 episodes of HE with a clear clinical picture, is equivalent to evaluating connu ≥2, within 6 months prior to screening (i.e., the subjects had documented, recurrent HE with a clear clinical picture). At the time of assessment on the source level is e subjects were in remission grade Konno, equal to 0 or 1. The episode HE exacerbation during treatment, as defined above, was a clear deterioration of the function of the nervous system.

The other end of the performance results in the first study included, for example:

1) time to first associated with HE hospitalization;

2) time to any increase in comparison with the initial level of assessment Konno (degree of mental status);

3) time to any increase in comparison with the initial level degree "fluttering" tremor;

4) the average change compared to baseline assessments tiredness with CLDQ at the end of treatment; and

5) average change compared to baseline ammonia concentrations in venous blood at the end of treatment.

Here are presented the results of the first study and second study. The first study was a double-blind, randomized, placebo-controlled study that evaluated the efficacy and safety of rifaximin at a dose of 550 mg twice daily compared with placebo. Subjects in remission proven recurrent, with a clear clinical picture, NOT episodic, associated with chronic cirrhosis of the liver, were subjected to randomization at day 0 (visit 2) in accordance with the ratio of 1:1 for the purpose of rifaximin at a dose of 550 mg twice daily or placebo is for 6 months. The primary outcome measure of effectiveness was the time until the onset of the HE with a clear clinical picture. Aggravation HE with obvious clinical symptoms during treatment was defined as an increase in assessment Konno to grade ≥2 (for example, 0 or 1 to ≥2) or up to 1 increase in estimates for Konno and component 1 degree "fluttering" tremor in the case of subjects who entered the study with an estimate of Konno =0. Subjects were excluded from the study during an episode of acute HE with a clear clinical picture. After participating in the first study subjects could participate in an open study of prolongation of treatment (second study).

Total of 299 subjects were subjected to randomization to receive rifaximin (140 subjects) or placebo (159 subjects). All subjected to randomization, patients received at least 1 dose of investigational medicinal product. Only 251 (84%) (116 [subjected to treatment with rifaximin], 135 [treated placebo]) subjects completed the study as specified in the Protocol (for example, treated for 6 months or were excluded from the study during acute HE with a clear clinical picture).

Subjects in the study had ≥2 episodes of HE with a clear clinical picture, is equivalent to evaluating connu ≥2, within 6 months prior to screening (e.g., subjects had the relapsing HE with a clear clinical picture). At the time of assessment at baseline subjects were in remission grade connu equal to 0 or 1. Episode of exacerbation during the treatment of HE with a clear clinical picture was a clear deterioration of the function of the nervous system. Episodes of exacerbation of HE with a clear clinical picture during treatment showed 31 of 140 subjects treated with rifaximin group and 73 of 159 subjects in the treated placebo group during the 6-month treatment period (up to day 170). Comparison of the estimates by the method of Kaplan-Meier estimates of time to exacerbation NOT with a clear clinical picture between groups showed a protective effect of rifaximin (p<0,0001). These data show that treatment with rifaximin decreased by 57.9% compared with placebo, the risk of occurrence of acute HE, with obvious clinical symptoms during treatment. Treatment with rifaximin leads to fewer episodes of HE with a clear clinical picture, which otherwise can make the patient unable to work, can reduce the burden on family members who must care for the patient, and reduces the costs of hospitalization in this patient population and the burden on the health care system.

It is established that these prognostic factors are prognostic factors of episodes of exacerbation of HE with a clear clinical picture at the time cured the I: age at baseline (p=0,0160), assessment in MELD (p=0,0003), duration confirmed remission at this time (p=0,1089) and the number of previous episodes of HE (p=0,0022). These data show that treatment with rifaximin resulted in a decrease of 60% compared with placebo, the risk of occurrence of an episode of acute HE with a clear clinical picture during the study (p<0,0001).

Time to first associated with HE and hospitalization frequency associated with HE hospitalizations and hospitalizations for all causes

Associated with hepatic encephalopathy hospitalization (hospitalization, which is a direct consequence HE or hospitalization complicated HE) were registered in the case 19 of 140 subjects and 36 of 159 subjects treated with rifaximin and placebo groups, respectively. Rifaximin had a protective effect associated with HE hospitalizations during the 6-month treatment period. In the case of subjects treated with rifaximin group were decreased by 50% the risk of hospitalization due to HE during the 6-month treatment period compared with the treated placebo group. The coefficient associated with hospitalization HE was 0.38 events/PEY in the case subjected to treatment with rifaximin group compared with 0.78 cases/PEY in the case of the treated placebo group.

Hospitalization caused by pechanec the Oh encephalopathy (only hospitalization, an immediate consequence HE), were registered in the case 15 of 140 subjects and 33 of 159 subjects treated with rifaximin and placebo groups, respectively. Rifaximin had a protective effect HE caused hospitalization during 6-month treatment period; the risk ratio: risk subjected to treatment with rifaximin group relative to the risk in the treated placebo group was 0,438 (95% confidence interval: 0,238-0,807) (p=0,0064) for the risk HE caused hospitalization. In the case of subjects treated with rifaximin group has decreased by 56% risk of hospitalization due to HE during the 6-month treatment period compared with the treated placebo group. The coefficient caused hospitalization HE was 0.30 cases/PEY in the case subjected to treatment with rifaximin group compared with 0,72 cases/PEY in the case of the treated placebo group.

The frequency of hospitalization for all causes was higher in the treated with rifaximin group (46 of 140) than in the treated placebo group (60 of 159) (reduction of 30% in the treated with rifaximin group compared with the treated placebo group). The rate of hospitalisation for all causes, after reducing the exposure of subjects effects was 0,90 the limit/PEY in the treated with rifaximin group and 1.26 cases/PEY in the treated placebo group. The coefficient associated with hospitalization HE was 0.38 events/PEY in the case subjected to treatment with rifaximin group and 0.78 cases/PEY in the case of the treated placebo group. Treatment with rifaximin prevents associated with HE hospitalizations, thereby improving the quality of life of the patient and caregiver for the patient, and reducing the economic costs associated with cirrhosis of the liver and related HE.

Time to any increase in comparison with the initial level of assessment Konno and time to any increase in comparison with the initial level degree "fluttering" tremor

Protective effect of rifaximin was observed for both of these outcomes when independent analysis; risk ratio: risk subjected to treatment with rifaximin group relative to the risk in the treated placebo group was 0,463 (95% confidence interval: 0,312-0,685) (p<0,0001) for the risk of occurrence of increased assessment Konno and 0,646 (95% confidence interval: 0,414-1,008) (p=0,0523) for the risk of increasing the degree of "fluttering" of tremor during 6-month treatment period.

The change compared with the initial level of ammonia levels in venous blood at study end

The subjects in the treated with rifaximin group were observed large decrease ammonia levels in venous blood than podvergnutykh treatment placebo subjects (p=0,0391).

It is established that there is a high degree of correlation between the levels of ammonia in the venous blood, quantitative assessment, which is associated with effects on the CNS underlying the HE with a clear clinical picture, and the occurrence of acute HE with a clear clinical picture is determined through clinical assessment Konno (or combination of assessment Konno and the degree of "fluttering" of tremor).

Tracking estimates for Konno and degrees "fluttering" tremor: changes compared to the baseline estimates for Konno and degrees "fluttering" tremor

It was noted the beneficial effect of treatment with rifaximin compared to placebo for the proportion of subjects who have had changes that constitute -1 (improvement) or 0 (no change); or 1, 2 or 3 (deterioration) assessment connu compared to the baseline level at the end of treatment (last estimated at subsequent levels or assessment during acute HE). In subjected to treatment with rifaximin group compared with the treated placebo group, a large proportion of subjects showed changes in estimates for connu constituting -1, or showed no change (77,1% compared to 53.9 per cent), and a smaller proportion of the subjects had changes in estimates for Konno, components 1, 2, 3 or 4. Thus, treatment with rifaximin was more effective than placebo treatment in preventing the adsene assessment Konno (2,46 times in comparison with placebo, p≤0,0001).

In case of changes compared to the baseline level at the end of treatment the degree of "fluttering" of tremor, a significantly large proportion of subjects treated with rifaximin group compared with the treated placebo group had no change compared with initial level degrees "fluttering" of the tremor, the components of -2, -1 and 0 (88,5% in comparison with 77,0%), and significantly smaller proportion of subjects had changes, components 1, 2, 3 or 4 (up 11.6% compared with 23.2 per cent). Thus, treatment with rifaximin was more effective than treatment with placebo in the prevention of the deterioration degree "fluttering" of tremor (1,92 times in comparison with placebo, p=0,0262).

Changes compared to the baseline results for CFF

Increase CFF results reflect improving nervous system function in patients with HE. The subjects in the treated with rifaximin group had a significantly large increase CFF results compared to the baseline level at the end of treatment than subjects in the treated placebo group. Mean changes (± standard deviation [SD]) of the results of the CFF was 0,945 (± 4,75) subjected to treatment with rifaximin group compared with 0,355 (± 4,70) in the treated placebo group (p=0,0320 for differences between groups). It was found that similar levels of ammonia in the venous blood, CFF is high the prognostic factor of acute HE.

The average duration of exposure to the effects of the investigational medicinal product was 168 days (range: 10-178) subjected to treatment with rifaximin group and 110 days (range: 6-176) in the treated placebo group. Only 64 of the subject (33 [subjected to treatment with rifaximin group] and 31 [in the treated placebo group]) received treatment for 141-168 days and 98 subjects (57 [subjected to treatment with rifaximin group] and 41 [in the treated placebo group]) received treatment for >168 days. Associated with duration of exposure influence the results do not contradict the data that a smaller proportion of subjects treated with rifaximin group than in the treated placebo group showed worsening of HE with a clear clinical picture, which is the reason for the termination of the study (per Protocol subjects were excluded from the study after HE exacerbation with a clear clinical picture).

The proportion of subjects who had resulting from the treatment (THOSE) adverse reactions (AE) (TEAE), severe TEAE associated with drug TEAE resulting from the treatment of SAE, TEAE leading to discontinuation of treatment, and subjects who died, were similar between the treated with rifaximin and placebo groups. Only 79.9% of subjects (239 of 299) showed TEAE the course of the study. The most common TEAE (e.g., ≥10% of all subjects [United groups: rifaximin plus placebo]), manifested by the subjects were the following: diarrhea (10,7% [rifaximin] in comparison with 13,2% [placebo]), nausea (14.3% in comparison with 13,2%), peripheral edema (15% compared with 8.2 percent), fatigue (12,1% compared with 11.3%), dizziness (12.9% compared to 8.2%), ascites (11,4% compared to 9.4%) and headache (10% compared with 10.7 per cent).

The second study is an ongoing, open study prolonging treatment, which evaluated the safety in the long term rifaximin at a dose of 550 mg twice daily in subjects with relapsed, with a clear clinical picture, NOT episodic in history. All eligible subjects had a history of illness episodes HE with a clear clinical picture with documented weight, equivalent to evaluating connu ≥2, within 12 months prior to screening (required ≥1 qualification episode), evaluation connu ≤2 in the evaluation at baseline, and they either participated in the first study, or were new subjects. Unlike the first study did not require the exclusion of subjects from the study after developing episodes of exacerbation of HE with a clear clinical picture during treatment.

Just 267 subjects were included in the surveys, and 208 were active during the interim clinical cutoff. Gathered additional data for the initial report until the time of freezing the database.

The study determined the estimates for Konno and the degree of "fluttering" of the tremor. Therefore, it was possible to identify time to the episode of acute HE with a clear clinical picture for subjects who completed the 6-month treatment with rifaximin, and then entered in a second study, subjects who received placebo in the first study, and then began to receive rifaximin in the second study, and for new subjects who started treatment with rifaximin in the second study. In the case of subjects who took rifaximin for up to 680 days (1.9 years), episodes of exacerbation of HE with a clear clinical picture appeared in all 72 of 266 subjects (27,1%): 54 of 196 subjects (27.6 per cent) in the group began treatment with rifaximin and 18 of 70 subjects (25.7 per cent) in the group continue treatment with rifaximin.

Profiles of time to first exacerbation HE were similar between group treatment with rifaximin in the first study and the group began treatment in the second study. Was awarded a long-term protective effect of rifaximin in subjects who started to receive rifaximin in the first study and continued to receive it in the second study (environments is their duration of exposure to the effects of rifaximin was 168 days in the first study and 253 days in the second study).

Only 133 of 266 subjects were hospitalized for any reason: 98 in the group began treatment with rifaximin and 35 in the group continue treatment with rifaximin. After reduction to the duration of exposure of subjects effects this is the rate of hospitalisation constituting 0,60 cases/PEY. Only 59 were hospitalized due to episodes of HE (for example, HE caused). After reduction to the duration of exposure of subjects to the impact of this is a factor NOT due to hospitalization, components 0.29 cases/PEY. Low NOT due to hospitalization was consistent between treatment with rifaximin in the second study (0.29 cases/PEY) and those in the first study (0.30 cases/PEY) at least partly as a result of conservation of remission HE proved in subjects with end-stage liver disease. Tracking estimates for Konno and degrees "fluttering" tremors: the use of rifaximin up to 18 months, as a rule, did not change or improved compared to the baseline assessment Konno and the degree of "fluttering" of the tremor. During the last visit to 70.7% of the subjects (188 of 266 subjects) had no change, and 20.3% (54 of 266) had improvement of the estimates for connu compared with the initial level, which means that the mental state has not been changed or improved in the majority of chastisement (91%) during the treatment period. Of the 84 subjects (70 subjects group began treatment with rifaximin and 14 subjects the group to continue treatment with rifaximin) who entered the study with estimates on connu, components 1, 2, or 3 (for example, those entities, in which case identify improvement was possible), 54 subject (54/84=64,3%) demonstrated an average of 1-degree (47 subjects; 56,0%) or 2-degree (7 subjects; 8,3%) improvement from baseline at last visit, registered for the preliminary analysis. All subjects were able to deterioration over time, and 24/266 subjects (9,0%) has been declining by 1 or 2 degrees.

The use of rifaximin up to 18 months, usually do not modify or improve the degree of "fluttering" of tremor, like the estimates for connu. At the last visit 77,1% of the subjects (205 of 266 subjects) had no change, and 16.2% (43 of 266) had improvement of degrees "fluttering" of tremor compared with the initial level, which means that associated with the neuromuscular system symptoms associated with increased neurological pathology, has not changed in 83,3% of the subjects during the treatment period. Of the 67 subjects (55 subjects group began treatment with rifaximin and 12 subjects of group renewal treatment with rifaximin) who entered the study with degrees "fluttering" tremor =1, 2, or 3 (for example, those subje the tov, in the case where improvement was possible), 43 subject (43/67=64,2%) demonstrated an average of 1 degree (34 subjects; 50,7%), 2 degrees (4 subjects; 6.0%) or grade 3 (5 subjects; 7,5%) improvement from baseline at last visit, registered for the preliminary analysis. All subjects were able to deterioration over time, and 18/266 subjects (6.8 per cent) has been declining by 1, 2 or 4 degree; frequency deterioration degree "fluttering" of tremor were similar between the group began treatment with rifaximin (12/196 subjects; 6.1%) and the group continue treatment with rifaximin (6/70 subjects; 8,6%).

The average duration of exposure to the effects of medicines in a second study was 253 days (range: 7-680) in the group began treatment with rifaximin (subjects who received placebo in the first study, or subjects who did not participate in the first study), 265,5 days (range: 10-673) in the group continue treatment with rifaximin (subjects who received rifaximin in the first study and the second study) and 255 days (range: 7-680) in the group treated with rifaximin subjects (all subjects who received rifaximin in the second study). During this preliminary analysis, the majority of subjects received rifaximin for 6 to <a 9 month old is in (21,4%) and from 9 to < 12 months (32,3%).

During this preliminary analysis were reported TEAE in 230 subjects (86,5%). The most frequently occurring TEAE (e.g., ≥10% of all subjects) exhibited by the subjects were the following: peripheral edema (15,8%); urinary tract infection (12.8%), and nausea (12,8%); and abdominal pain (10.5%) and ascites (10.5 per cent). Please note that NOT associated with signs and symptoms was not considered an AE unless they meet the definition of a SAE, and therefore the number of subjects with HE, included in the efficacy analysis (72 subjects; 27,1%) exceeds the number of subjects with HE, considered in the safety analyses of (57 subjects; 21,4%).

The intensity of the greater part of TEAE was low to moderate, with 40.2 per cent of the subjects showed at least 1 TEAE that the evaluation of the researcher was heavy. The frequency of TEAE that was thought are associated with the investigational drug were comparable between the group began treatment with rifaximin (7.7%) and the group continue treatment with rifaximin (7,1%). 47,4% of the subjects showed resulting from the treatment of SAE.

In Fig.1 illustrates the evaluation by the method of Kaplan-Meier time to first episode of acute HE with a clear clinical picture in accordance with the treatment group formed in accordance with the assigned treatment (ITT) population. Table 18 presents estimates by the method of Ka is Lana-Meier proportion of subjects which showed exacerbation of HE with a clear clinical picture during the treatment period, and the results of the statistical analyses. Subjects who completed the study and did not show an episode of exacerbation of HE with a clear clinical picture, checked during their 6-month visit. With the subjects who completed the study early for reasons other than acute HE, with obvious clinical symptoms during treatment (for example, liver transplantation, AE, requirements of the subject), has established a relationship after 6 months from the date of randomization to establish showed whether the subjects episode of exacerbation of HE with a clear clinical picture or other consequence (for example, the state of death). Subjects without acute exacerbation of HE with a clear clinical picture was examined during communication with them, or death in the time that came before. Therefore, successfully carried out a complete collection of data on episodes of exacerbation of HE with a clear clinical picture up to 6 months.

Table 18
The first study: evaluation according to the method of Kaplan-Meier estimates and statistical analyses of time to first exacerbation HE with a clear clinical picture (up to 6 months of treatment, day 170) (in the case of ITT population)
Placebo (N=159)Rifaximin (N=140)
The time of treatment (days)Subject - the size of riskaThe number of episodesbThe total number of episodesThe probability of episodes (SE)cProbability
napravleniya acute NOT with a clear clinical pictured
Subject - the size of riskaThe number of episodesbThe total number of episodesThe probability of episodes (SE)cProbability
napravleniya acute NOT with a clear clinical pictured
0-<281582020of 0.13 (0.03 in)1,000014013130,09 (0,02)1,0000
28-<5613723430,17 (0,03) 0,87341264170,03 (0,02)0,9071
56-<8411314570,12 (0,03)0,72621206230,05 (0,02)0,8783
84-<140981067of 0.10 (0.03 in)0,63631127300,06 (0,02)0,8344
140-<16884673of 0.07 (0.03 in)0,5713981310,01 (0,01)0,7820
≥168380730 0,53054603100,7740
The risk ratio: 0,421e
95% confidence interval: (0,276, 0,641)
p-value: <0,0001
aThe number of subjects at risk at the time of treatment, expected in accordance with the method using the table of survival. On the assumption that the tested patients were at risk for half of the time, only half of them were taken into account when expressing the number of subjects at risk.
bThe number of episodes that occur at the time of treatment.
cAssessment of the probability of acute NOT with a clear clinical picture at the time of treatment. Standard error (SE) installed on the Greenwood formula.
dAssessment of the probability of napravleniya acute NOT with a clear clinical picture until at least the beginning of the next period of time of treatment.
eAssessment of risk (risk of exacerbations HE with obvious clinical symptoms in a subject to treatment with rifaximin group compared with those in the treated placebo group), installed in accordance with the tvii with the Cox proportional hazards model. The P-value is based on statistics of deposits.

Episodes of exacerbation of HE with a clear clinical picture during treatment showed 31 of 140 subjects treated with rifaximin group and 73 of 159 subjects in the treated placebo group during the 6-month period after randomization (up to day 170). Comparison of the estimates by the method of Kaplan-Meier estimates of time to exacerbation of HE with a clear clinical picture between groups showed a protective effect of rifaximin (p<0,0001). These data indicate that treatment with rifaximin decreased by 57.9% compared with placebo, the risk of occurrence of acute NOT with a clear clinical picture in the course of this study. Treatment with rifaximin leads to fewer episodes of HE with a clear clinical picture, which otherwise can make the patient unable to work, can reduce the burden on family members who must care for the patient, and reduces the costs of hospitalization in this patient population and the burden on the health care system.

To study the possible effect of prognostic factors on the manifestation of an episode of acute HE, with obvious clinical symptoms during treatment were studied following prognostic factors:

- Gender (male versus female)

- Age

- Race (Caucasian race sravnenie not Caucasian)

- Area of study (North America versus Russia)

Assessment in MELD

- Score from Konno (0 vs. 1)

Diabetes at baseline (presence versus absence)

- Duration confirmed remission at the moment, and

- The number of episodes HE within the last 6 months prior to randomization.

Strong independent predictors of episodes of acute HE, with obvious clinical symptoms during treatment were age at baseline (p=0,0160), assessment in MELD (p=0,0003), duration confirmed remission at this time (p=0,1089) and the number of previous episodes of HE (p=0,0022).

These data show that treatment with rifaximin after bringing it in line with the significant prognostic factors led to a decrease of 60% compared with placebo, the risk of occurrence of an episode of acute HE with a clear clinical picture in the course of this study. The most important prognostic factors were age (p=0,0315) and assessment MELD at baseline (p=0,0003).

The results indicate that highly significant protective effect of rifaximin (p<0,0001) from episodes of exacerbation of HE with a clear clinical picture remained in the presence of statistically significant competing factors.

In the second study, the average duration of exposure to the impact of drug is the means was 253 days (range: 7-680) in the group began treatment with rifaximin (subjects, who received placebo in the first study, or subjects who did not participate in the first study), 265,5 days (range: 10-673) in the group continue treatment with rifaximin (subjects who received rifaximin in the first study and the second study) and 255 days (range: 7-680) in the group treated with rifaximin subjects (all subjects who received rifaximin in the second study).

In the case of subjects who took rifaximin for up to 680 days (1.9 years), episodes of exacerbation of HE with a clear clinical picture appeared in all 72 of 266 subjects (27,1%): 54 of 196 subjects (27.6 per cent) in the group began treatment with rifaximin and 18 of 70 subjects (25.7%) in the group continue treatment with rifaximin. In Fig.2 compares subjects who participated in a double-blind randomized first study with new treated with rifaximin subjects in long-term open study, a second study.

Estimation by the method of Kaplan-Meier time to first episode of acute HE, with obvious clinical symptoms were similar between subjects treated with rifaximin group in the first study and new subjected to treatment with rifaximin subjects in the second study. Also similar proportion of subjects had worsening of HE with a clear clinical picture in under Ergneti treatment with rifaximin group in the first study (22%, 31 140 [group treatment with rifaximin]) and in the new subjected to treatment with rifaximin group second study (27,6%, 54 of 196). After bringing it in line with the duration of exposure exposure ratios episodes of exacerbation HE was 0,62 cases/PEY in the treated with rifaximin group in the first study, compared with 0.38 events/PEY for new subjected to treatment with rifaximin subjects in the second study. These data indicate that the protective effect of acute HE, with obvious clinical symptoms in subjects who received the rifaximin was consistent between the 2 studies.

Note to Fig.7, the estimate of the distribution of survival on the y-axis represents the proportion of subjects without the aggravation HE with a clear clinical picture during treatment.

The data of the first studies related to the time to first episode of acute HE with a clear clinical picture during the treatment, presents subjected to treatment with rifaximin group (small dashes) and treated placebo group (straight line). The data of the second research pertaining to the time before the first episode of exacerbation of HE with a clear clinical picture in the new subjected to treatment with rifaximin group, represented by dashes.

In Fig.8 presents the results of the tracking subjects who, treated with placebo in the first study, after they switched to treatment with rifaximin in the second study. Aggravation HE with a clear clinical picture showed 15 out of 82 subjects during treatment rifaximin compared with 39 out of 82 subjects during treatment with placebo. A striking protective effect of rifaximin was noted when comparing the estimates by the method of Kaplan-Meier estimates of time to first exacerbation HE with a clear clinical picture between treatment placebo in the first study and by treatment with rifaximin in the second study. The risk ratio: risk subjected to treatment with rifaximin group relative to the risk in the treated placebo group was 0,302 (95% confidence interval: 0,166-0,549, p<0,0001 for differences between groups in relative risk). This result reflects a reduction of 70% of the risk of occurrence of acute HE, with obvious clinical symptoms during treatment with rifaximin in a second study compared with previous treatment with placebo in the first study.

Note to Fig.8, the estimate of the distribution of survival on the y-axis represents the proportion of subjects without the aggravation HE with a clear clinical picture during treatment. The data of the first studies related to the time to first episode of acute HE with a clear clinical picture presented on Letojanni for the treated placebo group. On the right panel presents the time to first exacerbation HE with a clear clinical picture in a second study among subjects treated with placebo in the first study (n=82) who switched to treatment with rifaximin in the second study. The vertical line between the left and right panels serves to mark the end of double-blind study and the beginning of open research.

In Fig.9 illustrates the time-to-first associated with hospitalization (e.g., hospitalization, which is a direct consequence HE or hospitalization caused HE) in accordance with the treatment group in the ITT population in the first study. In table 19 presents estimates of the shares of the subjects exposed first associated with HE hospitalization during the treatment period, and the results of the statistical analyses. Subjects who were excluded from the study prior to admission because HE and the completion of the 6-month treatment period, were examined during the suspension. Associated with hepatic encephalopathy hospitalization were registered in the case 19 of 140 subjects and 36 of 159 subjects treated with rifaximin and placebo groups, respectively. Rifaximin had a protective effect associated with HE hospitalizations during the 6-month treatment period; the risk ratio: risk in exposed l is the increase in the rifaximin group relative to the risk in the treated placebo group was 0,500 (95% confidence interval: 0,287-0,873, p=0,0129) for the risk associated with NOT hospitalization. This risk reflects the 50% reduction in risk compared with placebo, the risk of hospitalization due to HE during the 6-month treatment period. In accordance with these results, the coefficient associated with hospitalization HE was 51% lower (0.38 events/PEY in the case subjected to treatment with rifaximin group compared with 0.78 cases/PEY in the case of the treated placebo group) subjected to treatment with rifaximin group in the first study, after reduction to the duration of exposure, exposure.

Note to Fig.9, estimate of the distribution of survival on the y-axis represents the proportion of subjects without NOT associated with hospitalization. The dotted line reflects subjected to treatment with rifaximin group, and the solid line reflects the treated placebo group. Not full circles and not shaded triangles represent the audited entities. Subjects who were excluded from the study prior to admission because HE and the completion of the 6-month treatment period, were examined during the suspension. Write about associated with hepatic encephalopathy hospitalization did in CRF (registration card of the patient) during hospitalization associated with NOT.

Table 19 The first study: evaluation according to the method of Kaplan-Meier estimates and statistical analyses of time to first associated with HE hospitalization (up to 6 months of treatment, day 170) (in the case of ITT population)
Placebo (N=159)Rifaximin (N=140)
The time of treatment (days)Subject - the size of riskaThe number of episodesbThe total number of episodesThe probability of episodes (SE)cThe probability of the absence NOT associated with hospitalizationdSubject - the size of riskaThe number of episodesbThe total number of episodesThe probability of episodes (SE)cThe probability of the absence NOT associated with hospitalizationd
0-<2815511110,07 (0,02)1,000013944 0,03 (0,01)1,0000
28-<5613212230,09 (0,03)0,9288130480,03 (0,02)0,9711
56-<841087300,06 (0,02)0,84401194120,03 (0,02)0,9411
84-<140884340,05 (0,02)0,78931065170,05 (0,02)0,9094
140-<168722360,03 (0,02)0,7535922 190,02 (0,02)0,8665
≥1683403600,73254301900,8475
Abbreviations: CI = confidence interval; SE = standard error.
aThe number of subjects at risk at the time of treatment, expected in accordance with the method using the table of survival. On the assumption that the tested patients were at risk for half of the time, only half of them were taken into account when the expression in
number of subjects at risk.
bThe number of cases arising in the period of time of treatment.
cAssessment of the probability of an event NOT associated with hospitalization at the time of treatment. Standard error (SE) installed on the Greenwood formula.
dAssessment of the probability of absence associated with NOT hospitalized until at least the beginning of the next period of time of treatment.
eAssessment of risk (risk related is Anna from HE hospital subjected to treatment with rifaximin group compared with those in the treated placebo group), installed in accordance with the Cox proportional hazards model. The P-value is based on statistics of deposits.

It was also determined the effect of treatment with rifaximin on NOT due to hospitalization (for example, hospitalization, which is the direct consequence of HE). In Fig.5 shows the time to first HE caused hospitalization in accordance with the treatment group in the first study.

Hospitalization caused by hepatic encephalopathy, were registered in the case 15 of 140 subjects and 33 of 159 subjects treated with rifaximin and placebo groups, respectively. Rifaximin had a protective effect HE caused hospitalization during 6-month treatment period; the risk ratio: risk subjected to treatment with rifaximin group relative to the risk in the treated placebo group was 0,438 (95% confidence interval: 0,238-0,807, p=0,0064) for the risk HE caused hospitalization. In the case of subjects treated with rifaximin group were observed decrease of 56% risk of hospitalization due to HE during the 6-month treatment period compared to placebo. The coefficient caused hospitalization HE was 0.30 cases/PEY in the case subjected to treatment with rifaximin group compared with 0,72 cases/PEY in the case of the treated placebo group is s.

Note to Fig.10, the estimate of the distribution of survival on the y-axis represents the proportion of subjects without hospitalizations caused NOT. The dotted line reflects subjected to treatment with rifaximin group, and the solid line reflects the treated placebo group. Not full circles and not shaded triangles represent the audited entities. Subjects who were excluded from the study prior to admission, was checked at the time of the exception.

It was also determined the effect of treatment with rifaximin on hospitalization for all causes. In the first double-blind study, 46 of 40 subjected to treatment with rifaximin subjects and 60 of 159 treated with placebo were hospitalized due to any SAE. The risk of hospitalization for all causes was reduced by 30% in the treated with rifaximin group compared with the treated placebo group (p=0,0793 for differences between groups in relative risk). The rate of hospitalisation for all causes was 0.92 cases/PEY in the treated with rifaximin group compared with 1.31 cases/PEY in the treated placebo group. These data suggested that treatment with rifaximin reduced the costs associated with NOT/NOT due to hospitalization compared with placebo treatment in the first study. Low ratio is knitted with the HE-caused hospitalization HE repeatedly observed during treatment with rifaximin in the first study (0.38 events/PEY) and in the second study (0.29 cases/PEY), at least partly as a result of conservation of remission HE proved in subjects with end-stage liver disease.

In Fig.11 shows how the time to any increase in comparison with the initial level of assessment connu in accordance with the treatment group formed in accordance with the assigned treatment (ITT) population. Table 20 presents estimates of the proportion of subjects who had any increase in the assessment on connu during the treatment period, and the results of the statistical analyses. Subjects who were excluded from the study before the onset of the increase in assessment Konno and the completion of the 6-month treatment period, were examined during the suspension. By determining the time to any increase in comparison with the initial level of assessment connu you can compare the deterioration in the near future in mental state between subjects in the treated with rifaximin and placebo groups, even if the impairment does not reach the setting of acute HE (for example, increasing the estimate by Konno from 0 to 1). Increase assessment connu were registered in the case 37 of 140 subjects and 77 of 159 subjects treated with rifaximin and placebo groups, respectively. It was noted highly significant protective effect of rifaximin; risk ratio: risk subjected to treatment what s the rifaximin group relative to the risk in the treated placebo group was 0,463 (95% confidence interval: 0,312-0,685, p=0.0001) for the risk of occurrence of increased assessment Konno (for example, deterioration of mental status) during the 6-month treatment period.

Table 20
The first study: evaluation according to the method of Kaplan-Meier estimates and statistical analyses of time to first increase the assessment on connu (up to 6 months of treatment, day 170) (in the case of ITT population)
Placebo (N=159)Rifaximin (N=140)
The time of treatment (days)Subject - the size of riskaThe number of episodesbThe total number of episodesThe probability of episodes (SE)cThe probability of the absence of increase in assessment connudSubject - the size of riskaThe number of episodesbThe total number of episodesThe probability of episodes (SE)cThe probability of the absence of increase in assessment connud
0-<28 15626260,17 (0,03)1,000013917170,12 (0,03)1,0000
28-<5612521470,17 (0,03)0,83331195220,04 (0,02)0,8777
56-<8410015620,15 (0,04)0,6928109931of 0.08 (0.03 in)0,8407
84-<1408010720,13 (0,04)0,5883945360,05 (0,02)0,7713
140-<16862577of 0.08 (0.03 in)0,51437903600,7302
≥1682707700,472937137of 0.03 (0.03 in)0,7302
Abbreviations: CI = confidence interval; SE = standard error.
aThe number of subjects at risk at the time of treatment, expected in accordance with the method using the table of survival.
bThe number of cases arising in the period of time of treatment. On the assumption that the tested patients
were at risk for half of the time, only half of them were taken into account when expressing the number of subjects at risk.
cEstimation by the method of Kaplan-Meier estimates of the probability of increasing the estimate by Konno in promesed the time of treatment. Standard error (SE) installed on the Greenwood formula.
dAssessment of the probability of no increase in the assessment connu until at least the beginning of the next period of time of treatment.
eAssessment of risk (the risk of increasing the estimate by Konno in subjected to treatment with rifaximin group compared with those in the treated placebo group), established in accordance with the Cox proportional hazards model. The P-value is based on statistics of deposits.

In Fig.12 illustrates the time to any increase in comparison with the initial level degree "fluttering" of tremor in accordance with the treatment group in the ITT population. Table 21 presents estimates of the proportion of subjects who had any increase in the degree of "fluttering" of tremor during treatment period, and the results of the statistical analyses. Subjects who were excluded from the study before the onset of the increase in the degree of "fluttering" of the tremor and the completion of the 6-month treatment period, was checked at the time of the exception.

By determining the time to any increase in comparison with the initial level degree "fluttering" of the tremor was possible to compare the deterioration in the near future in the functioning of the neuromuscular system between the subjects in the treated reef is simina and placebo groups. Increasing the degree of "fluttering" of tremor were registered in the case 32 of 140 subjects and 50 of 159 subjects treated with rifaximin and placebo groups, respectively. Was observed protective effect of rifaximin from increasing the degree of "fluttering" of tremor (for example, deterioration in the functioning of the neuromuscular system), which showed a trend towards statistical significance; the risk ratio: risk subjected to treatment with rifaximin group relative to the risk in the treated placebo group was 0,646 (95% confidence interval: 0,414-1,008, p=0,0523) for the risk of occurrence of increasing the degree of "fluttering" of tremor during 6-month treatment period.

Table 21
The first study: evaluation according to the method of Kaplan-Meier estimates and statistical analyses of time to first increase the degree of "fluttering" of tremor (up to 6 months of treatment, day 170) (in the case of ITT population)
Placebo (N=159)Rifaximin (N=140)
The time of treatment (days)Subject - the size of riskaThe number of episodes is s bThe total number of episodesThe probability of episodes (SE)cThe probability of the absence of increasing the degree of "fluttering" tremordSubject - the size of riskaThe number of episodesbThe total number of episodesThe probability of episodes (SE)cThe probability of the absence of increasing the degree of "fluttering" tremord
0-<281542020of 0.13 (0.03 in)1,000013713130,10 (0,02)1,0000
28-<561201535of 0.13 (0.03 in)0,86971167200,06 (0,02)0,9048
56-<84914 390,04 (0,02)0,7610101727of 0.07 (0.03 in)0,8499
84-<14076645of 0.08 (0.03 in)0,7275873300,03 (0,02)0,7910
140-<16861449of 0.07 (0.03 in)0,6701741310,01 (0,01)0,7637
≥168271500,04 (0,04)0,626234132of 0.03 (0.03 in)0,7534
Abbreviations: CI = confidence interval; SE = redeclarations error.
aThe number of subjects at risk at the time of treatment, expected in accordance with
a method using a table of survival. On the assumption that the tested patients were at risk for half of the time, only half of them were taken into account when expressing the number of subjects at risk.
bThe number of cases arising in the period of time of treatment.
cAssessment of the probability of increasing the degree of "fluttering" of the tremor at the time of treatment. Standard error (SE) installed on the Greenwood formula.
dAssessment of the probability of no increase in the degree of "fluttering" tremor until at least the beginning of the next period of time of treatment.
eAssessment of risk (the risk of increasing the degree of "fluttering" of tremor in a subject to treatment with rifaximin group compared with those in the treated placebo group), established in accordance with the Cox proportional hazards model. The P-value is based on statistics of deposits.

Entities have established their level of fatigue through the use of a 7-item scale from the worst response (1, high degree of fatigue) to the best response (7, minor fatigue). B is whether there are insignificant differences between the treated placebo and rifaximin groups in changes from baseline assessments of fatigue using the CLDQ. The average rating of fatigue (standard deviation) was 3,34 (1,406) in comparison with 3,28 (1,326) at baseline and 3,51 (1,529) in comparison with 3,57 (1,527) treated with placebo and rifaximin groups, respectively. Because of altered mental status and condition of the neuromuscular system, the subjects could not complete the assessment using the CLDQ during an episode of acute HE with a clear clinical picture.

Table 22 summarizes the changes compared to the baseline level at the end of treatment the ammonia level in venous blood in accordance with the treatment group in the first study.

In the first study ammonia levels in venous blood were highly variable during the study. However, in subjects treated with rifaximin group were significantly large decrease ammonia levels in venous blood than in subjects treated with placebo (p=0,0391). It is established that ammonia levels in venous blood, quantification, which is associated with effects on the CNS underlying the HE with a clear clinical picture, are highly predictive factor for the occurrence of exacerbations HE with a clear clinical picture is determined through clinical assessment Konno (or combination of assessment Konno and the degree of "fluttering" tremor), which thus emphasizes the reliability and clinical relevance of the primary performance indicator. A significant correlation between the primary outcome measure of effectiveness and levels of ammonia in venous blood evidence on the reliability and clinical relevance of the primary performance indicator in the first study.

Table 22
The first study: changes in mean values (standard deviation) compared with the initial level of ammonia level in venous blood in accordance with the treatment group (in the case of ITT population)
Placebo, N=159 (µg/DL)Rifaximin N=140 (mg/DL)
Initial leveln=146n=132
The level of ammonia in the form of the mean value (standard deviation)90,3 (52,48)87,9 (47,76)
The change compared with the initial level at the end of the treatmentn=141n=132
The level of ammonia in the form of the mean value (standard deviation)88,4 (45,75)83,9 (45,02)
The end of the treatmentn=131n=125
Mean change (standard deviation) level of ammonia-0,3 (58,13)-5,7 (of 46.77)
Note: the Value at baseline was the last of the available values to the first dose
investigational medicinal product, and the value of the end of treatment was the last of the available values at subsequent levels, identified during the treatment period.

The second study

In the second study the use of rifaximin up to 18 months, as a rule, did not change or improved assessment connu. During the last visit to 70.7% of the subjects (188 of 266 subjects) had no change, and 20.3% (54 of 266) had improvement of the estimates for connu compared with the initial level, which means that the mental state has not been changed or improved in most of the subjects (91%) during the treatment period. The use of rifaximin up to 18 months, usually do not modify or improve the degree of "fluttering" of tremor, like the estimates for connu. At the last visit 77,1% of the subjects (205 of 266 subjects) had no change, and 16.2% (43 out of 26) had improvement of degrees "fluttering" of tremor compared with the initial level, which means that associated with the neuromuscular system symptoms associated with increased neurological pathology, has not changed in 83,3% of the subjects during the treatment period. In the case of the second study last visit is the last visited registered for the preliminary analysis.

No change or improvement assessments on connu was observed in the case of >85% of the subjects during treatment with rifaximin for up to 840 days; the average duration of exposure exposure (± standard deviation) for the entire treatment with rifaximin was 273,8 (160,92) days (the results on exposure to the effects presented in detail in the ISS module 5.3.5.3.2). Only 65.5% of subjects (220 of 337) had no changes assessment Konno, and 21.1% (71 of 337) had improvement assessment connu compared with baseline at last visit. Also no changes or improvements degrees "fluttering" of the tremor was noted in the case of >90% of the subjects during treatment with rifaximin. No change compared with initial level degree "fluttering" of the tremor was registered in the case of 75.2% of the subjects (252 of 337), and 17.3% had improvement.

Of the 118 subjects who entered the study with estimates on connu ≥1, for example, those entities, in which case the improvement was possible, 62,2% (71 of 118) prodem who has Staropoli improvement compared with baseline levels prior to the assessment connu =0 when the last assessment. From 99 subjects who entered the study with the degree of "fluttering" tremor ≥1, i.e., those entities in which the improvement of the degree of "fluttering" of the tremor was possible to 58.6% (58 out of 99) demonstrated improved degree of "fluttering" of tremor compared to the baseline level at the end of the study.

Changes compared to the baseline estimates for Konno and degrees "fluttering" of the tremor at the last visit were similar among the subjects of the group began treatment with rifaximin in the second study (for example, those who began to receive rifaximin in study 3002), entities of the group continue treatment with rifaximin (for example, those who received rifaximin in the first study and the second study), and all subjects treated with rifaximin (for example, those who received rifaximin in the first study or in the second study).

These results confirm the results of the first study, in which treatment with rifaximin was significantly more effective than placebo treatment in the prevention of the deterioration of assessment Konno (2,46 times in comparison with placebo, p<0,0001) and in preventing the deterioration degree "fluttering" of tremor (1,92 times in comparison with placebo, p=0,0262).

Changes compared to the baseline survey results CFF (first study)

Increase research results CFF reflect the improved nervous system function in patients with HE. In subjects treated with rifaximin group were significantly large increase results for CFF compared to the baseline level at the end of treatment than those treated with placebo subjects (table 23). Mean changes (± standard deviation) results for CFF was 0,945 (± 4,75) subjected to treatment with rifaximin group compared with 0,355 (± 4,70) in the treated placebo group (p=0,0320 for differences between groups).

There was a high degree of correlation between the quantitative assessment of the results of the CFF and the occurrence of acute HE with a clear clinical picture is similar to the correlation between the latter and the levels of ammonia in the venous blood.

Table 23
Changes in mean values (standard deviation) compared with the baseline survey results CFF in accordance with the treatment group (in the case of ITT population)
Placebo, N=159 (Hz)Rifaximin N=140 (Hz)
Initial leveln=159n=14
Result for CFF as mean values (standard deviation)90,3 (52,48)87,9 (47,76)
The end of the treatmentn=155n=139
Result for CFF as mean values (standard deviation)88,4 (45,75)83,9 (45,02)
The change compared with the initial level at the end of the treatmentn=155n=139
Mean change (standard deviation) of the CFF-0,3 (58,13)-5,7 (of 46.77)
Note: the Value at baseline was the last of the available values to the first dose of the investigational medicinal product, and the value of the end of treatment was the last of the available values at subsequent levels, identified during the treatment period.

Was performed a retrospective analysis of outpatient maps and histories of 145 patients with HE who received lactulose dose of 30 ml twice a day for ≥6 months, and C who were treated with rifaximin at a dose of 400 mg 3 times/day for ≥6 months. Striking differences were observed in favor of treatment with rifaximin. Compliance with doctor's instructions on ≥75% was significantly better during treatment with rifaximin than during treatment with lactulose; 92% compared with 31% of patients who received ≥75% of the planned doses of rifaximin and lactulose, respectively. The total number of hospitalizations, duration of hospitalization, outcome indicators HE and treatment costs were comparable between the 2 treatment regimens. Significantly fewer hospitalizations (0.5 in comparison with 1.6) and days in hospital (2,5 compared with 7.3 days) was recorded in case of treatment with rifaximin compared with treatment with lactulose (p<0,001), and related hospitalization costs per patient were $14222 compared to $56635 during treatment with rifaximin and lactulose, respectively.

As for the final performance HE at the end of the periods of treatment, "fluttering" tremor was registered in the case of 63% (rifaximin) compared with 93% (lactulose) patients (p<0,001), and assessment connu =3 or 4 were observed in the case of 6% (rifaximin) compared to 25% (lactulose) patients (p<0,001). In addition, significantly more patients had diarrhea, flatulence and abdominal pain during treatment with lactulose than during treatment with rifaximin (p<0,001).

Hospitalization and treatment costs were analyzed at Ana who ize outpatient maps and histories of 39 patients with liver transplantation, which showed equal 2 assessment NOT connu in the time period from January 2004 to November 2005. Twenty-four patients were treated with lactulose and 15 were subjected to treatment with rifaximin. Was registered nineteen hospitalizations in the case treated with lactulose group and 3 of hospitalization in case subjected to treatment with rifaximin group. The average length of stay was significantly less in case subjected to treatment with rifaximin group than in the case of the treated lactulose group (3.5 days [range, 3 - 4] compared with 5.0 days [range, 3-10] [p<0,001]). Average annual total treatment costs (hospitalization, visits to the emergency room and the cost of medicines) of each patient was $7958 if subjected to treatment with rifaximin group and $13285 if subjected to treatment with lactulose group. Although the cost of rifaximin was significantly higher than the cost of lactulose, the total cost of treatment (hospitalization plus the cost of the drug) were 1.67 times higher in patients who were treated with lactulose.

The duration of therapeutic effect of rifaximin

The data of the second study provide information about the long duration of the effect of rifaximin in from the Oseni protection of episodes of exacerbation of HE with a clear clinical picture during treatment. For subjected to treatment with rifaximin subjects of the first study who were in remission at the end of the study (treatment within 6 months), was monitored during the open second study (n=60). In Fig.15 shows the time to the first episode HE exacerbation during treatment for the subjects of group a resumption of treatment with rifaximin (the first study plus the second study) and treated with placebo in the first study subjects. The frequency of exacerbations HE with a clear clinical picture in these subjects group resumption of treatment with rifaximin compared with that in the case treated with placebo in the first study subjects. The frequency of an episode of acute HE if subjected to treatment with rifaximin subjects was significantly lower than in the case of the treated placebo in the first study group (ratio: frequency group resumption of treatment with rifaximin to that in the treatment group placebo was 0,0797 after bringing it in line with the time of exposure, effect, p<0,0001 for differences between rifaximin and placebo.

These results showed that rifaximin has had a lasting effect beginning in the first study and continued in the second study (mean duration of exposure to the effects of rifaximin SOS is alali 168 days in the first study and 253 days in the second study).

Note to Fig.13, the estimate of the distribution of survival on the y-axis represents the proportion of subjects without acute NOT with a clear clinical picture during treatment. Dotted lines reflect subjected to treatment with rifaximin subjects of the first study who were in remission at the end of the study (treatment within 6 months) and tracked during the open second study (n=60), and the solid line reflects the treated placebo group in the first study. Vertical line serves as a mark of the end of double-blind study and the beginning of open research. Not shaded circles represent the tested subjects treated with placebo in the first study group, and not the filled triangles represent the audited entities of the group continue treatment with rifaximin. Subjects who were excluded from the study before the first episode of exacerbation of HE with a clear clinical picture, was checked at the time of the exception.

Unlike the first study, in which subjects were excluded from the study after developing, they have a first episode of acute HE with a clear clinical picture, subjects were able to continue treatment with rifaximin in the second study after developing acute HE with a clear clinical picture. Therefore evaluated the frequency obstr the of HE with a clear clinical picture over time during treatment with rifaximin. Table 24 presents the episodes of exacerbation of HE with a clear clinical picture in accordance with the total number of episodes HE in the course of the study.

In the group of all subjects treated with rifaximin, 27,1% of the subjects (72 of 266) had ≥1 episode of acute HE with a clear clinical picture. Of the 72 subjects with acute exacerbation of HE most of them had 1 (44 subjects) or 2 (18 subjects) episode. Ten subjects had 3 or more episodes of exacerbation of HE in the second study.

Table 24
Second study: episodes of exacerbation of HE with a clear clinical picture in accordance with the number of repeat episodes
The group began treatment with rifaximin, N=196, n (%)The group continued treatment with rifaximin, N=70, n (%)The group of all subjects treated with rifaximin, N=266 n (%)
Subjects with ≥1 episode of acute HE with a clear clinical picture54 (27,6)18 (25,7)72 (27,1)
The total number of episodes HE during research
134 (17,3) 10 (14,3)44 (16,5)
212 (6,1)6 (8,6)18 (6,8)
34 (2,0)04 (1,5)
41 (0,5)1 (1,4)2, (0,8)
51 (0,5)01 (0,4)
601 (1,4)1 (0,4)
102 (1,0)02 (0,8)
Reduction: HE = hepatic encephalopathy
aThe number of episodes of HE. In each case the number of episodes with a clear clinical picture subjects are only counted once. For example, if the subject showed 3 episodes, it was included only in the number, showing 3 episodes, and did not take into account also in the ranks 2 and 1 of the episode.

The effect of rifaximin on the frequency of episodes HE with obvious clinical symptoms (heaviness HE)

The effect of treatment with rifaximin on the frequency of episodes HE with avnonline.com picture (for example, the severity of HE), number of episodes of HE in the first study or in a second study compared with the number of episodes HE in the absence of treatment with rifaximin. Of 6 months period of time prior to the first study or average of 12 months period of time before the second study compared treatment with rifaximin in any of the two studies. The period of time of participation in the first study had no effect on the amount of events in the absence of treatment with rifaximin, therefore, in the case of subjects who passed the second examination without episode HE in the first study consisting of 12 months period of time before the second study used for comparison. The majority of subjects in the second study (152 of 266) also participated in the first study. The episodes HE with a clear clinical picture in the second study were combined with those in the first study, because, in contrast to the first study, subjects in the second study could stay on the treatment of rifaximin after developing their episode of acute HE. The number of episodes HE with a clear clinical picture, shown during the 6-month or 12-month intervals prior to the first treatment or before the second treatment was known. Despite the fact that 30.8% of subjects had >2 episodes of HE during the 6-month or 12-month period of lying is neither to treatment with rifaximin, only 3.6% of the subjects had >2 episodes of HE during treatment with rifaximin up to 840 days (average duration of exposure exposure =253 days [approximately 8 months]) in the first study, plus the second study. This difference in the frequency of episodes HE, when subjects received rifaximin compared with no treatment with rifaximin shows a strong effect of rifaximin in weakening susceptibility to episodes with a clear clinical picture in patients with recurrent HE with a clear clinical picture associated with severe liver disease.

Hepatic encephalopathy is a serious, rare, complex, episodic, neuropsychiatric syndrome associated with progressive liver disease. Hepatic encephalopathy is a huge burden for the patient, his family and the health care system. The episodes HE with a clear clinical picture cause dementia, make the patient unable to look after themselves and often lead to hospitalization. Rifaximin has been granted orphan drug status by reading HE, as the disease is a serious and constantly causing dementia, and there is a low incidence of HE in the General population. There is also an unmet need for treatment for patients with NOT because of deficiencies in the current standard the mouth of the service.

Without wanting to be limited to any specific scientific theories suggest that the mechanism of action of rifaximin-dependent inhibition of DNA-dependent RNA polymerase which is the target microorganisms, leading to suppression of initiation of the formation of chains in the synthesis of RNA. Rifaximin is characterized by a lesser degree of destruction of pathogens in the faeces compared to other commonly used antibacterial agents and causes minor changes in the intestinal flora, which suggests that rifaximin has a mechanism of action distinct from other commonly used medicines for intestinal bacterial infection, such as fluoroquinolones. Antibacterial properties of rifaximin seems, are the result of bactericidal activity at concentrations of rifaximin greater than or equal to the MIC, and changes in morphology and physiological functioning of bacteria that are mentioned in sub-MIC concentrations.

Here was unexpectedly found that the risk of developing resistance to antibiotics is low during continuous treatment with rifaximin compared with other systemic antibiotics, such as neomycin. Low risk of developing resistance to the antibiotic during treatment with rifaximin, perhaps due to the fact that the resistance of the reef is Cimino not mediated by a plasmid, instead, you want a stable mutation in the DNA of the host cell; therefore, the spread of resistance and cross-resistance to other antibiotics through mechanisms based plasmids are excluded. Also bacteria in places outside of the gastrointestinal tract is not exposed to significant selective pressure due to the negligible systemic concentrations of rifaximin. In addition, microbiological data of the study patients with ulcerative colitis who received high doses of rifaximin, testified that resistant to rifaximin bacterial colonies formed during in vivo exposure to the effects of rifaximin were unstable, and the sensitivity was returning after a short period of interrupted treatment.

Treatment with rifaximin leads to fewer episodes of HE with a clear clinical picture, which otherwise can make the patient unable to work, can reduce the burden on family members who must care for the patient, and reduces the costs of hospitalization in this patient population and the burden on the health system. The following is the results of the second survey in regard to time to first episode of acute HE with a clear clinical picture.

Protective effect was reproducible: the result is, related to the time to first episode of acute HE, with obvious clinical symptoms, were similar between the treated with rifaximin group in the first study and new subjected to treatment with rifaximin subjects in the second study; and 22% and 27.6% of subjects showed aggravation HE with obvious clinical symptoms in a subject to treatment with rifaximin group in the first study and new subjected to treatment with rifaximin group in the second study, respectively. After bringing it in line with the duration of exposure effects, the coefficients of episodes of exacerbation HE was 0,62 cases/PEY in the case subjected to treatment with rifaximin group in the first study, compared with 0.38 events/PEY in the case of new subjected to treatment with rifaximin subjects in the second study. These data suggest that the protective effect of acute HE, with obvious clinical symptoms in subjects who received rifaximin was consistent between the 2 studies. In addition, when subjected to treatment with placebo in the first study, the subjects switched to treatment with rifaximin in the entry in the second study, there was a striking protective effect of rifaximin when comparing estimates by the method of Kaplan-Meier estimates of time to first exacerbation with obvious HE is liricheskoy pattern between treatment placebo in the first study and by treatment with rifaximin in the second study. The risk ratio: risk subjected to treatment with rifaximin group relative to the risk in the treated placebo group was 0,302 (95% confidence interval: 0,166-0,549, p<0,0001 for differences between groups in relative risk). This result reflects a reduction of 70% of the risk of occurrence of acute HE, with obvious clinical symptoms during treatment with rifaximin in a second study compared with the previous treatment placebo in the first study. This decline occurred despite an aging population with chronic liver disease and probably its progressive character.

Protective effect of rifaximin was long: estimation by the method of Kaplan-Meier estimates of time to first exacerbation HE during treatment demonstrated long-term preservation of the absence of acute HE, when subjected to treatment with rifaximin subjects in remission after participating in the first study, followed in the second study (up to 680 days of treatment with rifaximin; the average duration of exposure, the impact was 168 days in the first study and 253 days in the second study). Was significantly lower frequency of episodes of exacerbation for these HE treated with rifaximin subjects regarding subjected to treatment with placebo in the first study subjects, the decree is their to reduce the number of episodes of acute HE, with the help of treatment with rifaximin (p< of 0.0001 for differences in relative risk between treated with rifaximin and placebo groups).

The results for the other end of the performance indicators also showed a statistically significant protective effects of rifaximin. In the first study, the analysis of time to first associated with HE hospitalization (e.g., hospitalization, which is a direct consequence HE or hospitalization complicated HE) showed that the reduction in the risk of hospitalization because HE was 50% in the treated with rifaximin group compared with the treated placebo group during the 6-month treatment period (p=0,0129 for differences in relative risk between groups). In the first study, the risk is NOT caused hospitalization (for example, hospitalization, which is the direct consequence of HE) was reduced by 56% (p=0,0064 for differences in relative risk between groups), and the risk of hospitalization for all causes decreased by 30% in the treated with rifaximin group compared with the treated placebo group (p=0,0793 for differences in relative risk between groups). In the first study, the risk of hospitalization for all causes decreased by 30% in the treated with rifaximin group compared with the treated placebo group (p=0,0793 for having Alicia in relative risk between groups). The rate of hospitalisation for all causes was 0.92 cases/PEY in the treated with rifaximin group compared with 1.31 cases/PEY in the treated placebo group.

In the second study low coefficient NOT due to hospitalization remained at levels corresponding to those in the first study: the coefficient is NOT due to hospitalization was 0.29 cases/PEY, and the rate of hospitalisation for all causes was 0.66 cases/PEY in the second study. Consistently low coefficient associated with the HE-caused hospitalization HE had been subjected to treatment with rifaximin subjects in the first study and the second study was at least partly a result of the conservation of remission HE proved in subjects with liver disease at the final stage.

Improving the quality of life of subjects with HE, which was administered rifaximin

HE manifests in the form of a series of events consisting of a deteriorating mental condition, psychomotor dysfunction, deterioration of memory, increased reaction time, normalista perception, poor concentration, disorientation, and in severe cases coma. The symptoms of HE patients have adverse consequences in terms of health-related patient quality of life and lead to a reduced ability to self-service. The questionnaire for the assessment of chronic liver disease (CLDQ) is an approved tool to determine health-related quality of life in subjects with chronic liver disease. The average change compared to baseline assessments tiredness with CLDQ at the end of treatment was 1 of 5 key secondary endpoints in this study. In addition, the average change compared to baseline estimates using CLDQ (overall assessment and evaluation in each area of manifestations) at each subsequent evaluation and at the end of treatment was one of the tertiary of efficacy endpoints pre-specified in the study Protocol.

CLDQ was used at baseline, on days 28, 56, 84, 112 and 140, and at day 168 or at the end of treatment. CLDQ includes 29 questions in the following six areas manifestations: abdominal symptoms (three questions), fatigue (five questions), systemic symptoms (five questions), activity (three questions), emotional state (eight questions) and anxiety (five questions). There was a high degree of correlation between signs of fatigue and the severity of liver disease defined by clinical evaluations. Therefore, the manifestation of fatigue has been identified as a key secondary outcome measure in the case of this study.

Entities have established their level of fatigue through the use of a 7-item scale from the worst response (1, high degree of fatigue) to the best response (7, minor fatigue). Other items the phenomena and the overall score was also established on a 7-point scale, thus higher scores indicate better quality of life, and lower scores reflect lower quality of life. For example, 1 of 5 questions on fatigue was "how Much time within the last 2 weeks You were tired?" Answer options were "all the time", "most of the time", "most of the time", "some of the time", "a little time", "almost no time" and "no time". For they have established a degree of 1 (highest degree of fatigue), 2, 3, 4, 5, 6 and 7 (no fatigue), respectively.

In contrast to the analysis of change compared with the initial level below the AUC analysis includes the results obtained using the CLDQ during the whole time of participation of the subject in the study.

Analysis of area under the curve and time-weighted average value (Twa) of the results obtained through the questionnaire for evaluation of chronic liver disease

When the initial analysis of the survey data were slight differences between the treated placebo and rifaximin groups in changes from baseline assessments of fatigue using the CLDQ and assessments as other areas of manifestations with CLDQ. The average rating of fatigue (standard deviation) was 3,34 (1,406) in comparison with 3,28 (1,326) on the outcome of the second level and 3,51 (1,529) in comparison with 3,57 (1,527) during the last assessment in the treated placebo and rifaximin groups, respectively.

In this example, the answers to the questions CLDQ was tracked over time for each subject and determined the area under the curve (AUC). In the case of those subjects who showed the episodes HE exacerbation during treatment obtained by CLDQ data reflect the amount of impressions to episodes of exacerbation. Since not all subjects remained in the study during the same time period, the value of AUC was brought to the time of exposure exposure (T), to obtain a value called the time-weighted value (Twa), as shown below:

Thus, Twa characterizes the average change obtained using CLDQ response compared with baseline levels throughout the trial, given to the duration of exposure, exposure.

As shown below in Fig.14A-B, there is a clear section obtained using CLDQ results, which are identified by Twa, between the treated placebo and rifaximin groups in the distribution of the frequency is represented in the form of Twa estimates tiredness and General assessments. The offset distribution in frequency towards higher estimates have been subjected to treatment with rifaximin subjects points to the best answer; i.e., improved quality of life and less fatigue in the case of, for example, is by treatment with rifaximin group compared with the treated placebo group. Similar differences between groups in favor subjected to treatment with rifaximin group were observed in the frequency distributions in the case of additional defined using CLDQ manifestations.

In table 25 presents summarized in the form of Twa results obtained using CLDQ assessments on all areas of manifestations and received by CLDQ estimates manifestations of fatigue in accordance with the treatment group formed in accordance with the assigned treatment (ITT) population. The time-weighted assessment tiredness and total scores were significantly higher in the treated with rifaximin group than in the treated placebo group (p=0,0087 [manifestation of fatigue] and p=0,0093 [manifestations] for differences between groups in favor subjected to treatment with rifaximin group). Time-weighted average of the estimates obtained using the CLDQ for other manifestations were also significantly higher in the treated with rifaximin group than in the treated placebo group (p=0,0090 [abdominal symptoms], p=0,0160 [systemic symptoms], p=0,0022 [activity], p=0,0065 [emotional state] and p=0,0436 [concern] for differences between groups in favor subjected to treatment with rifaximin group.

The differences in the averages presented in the form of Twa estimates between treatment groups (rifaximin minus placebo) composition of the Yali 0,72 for signs of fatigue and 0.75 for all manifestations. The difference, amounting to 0.5 points is considered significant, and the difference of 0.8 points, is considered "large" when using 7-point scales for definitions of quality of life.

Related to the discussion on the literature data, comparing subjects without cirrhosis, liver disease extent And the child-Pugh score and the degree of C in the child-Pugh score, suggests that the components of 0,5-1,0 differences obtained using CLDQ estimates are clinically significant. The mean differences in overall ratings of symptoms in subjects without cirrhosis compared with subjects with the degree And the child-Pugh score (without cirrhosis minus the pistons And the child-Pugh score) was 0.6 subjects in the United States and 0.3 in the study of subjects in Spain. Large mean differences in overall ratings manifestations was reported for the transition from the state without cirrhosis to a degree With the child-Pugh score (without cirrhosis minus degree With the child-Pugh score): average of 1.3 difference in held in the United States the study of 1.0 difference in carried out in Spain to study.

Table 25
The area under the curve and time-weighted average value for the obtained by using the CLDQ results (in the case of ITT population)
Obtained using CLDQ resultsRifaximin (N=140)Placebo (N=159)A p-value ofand
The manifestation of fatigue
Assessment at baselinen=81n=86
The mean value (standard deviation)3,37 (1,304)3.46 in (1,363)
Median (minimum value, maximum value)3,40 (1,0, 5,8)3,40 (1,4, 6,4)
Twa (evaluation)n=82n=86
The mean value (standard deviation)3,242 (1,7619)2,522 (1,7538)p=0,0087
Median (minimum value, maximum value)3,600 (0,29, 6,51)2,365 (0,27, 6,25)
All symptoms
Assessment at baselinen=82n=87
The mean value (standard deviation)4,18 (1,184)or 4.31 (1,058)
Median (minimum value, maximum value)4,25 (1,6, 6,7)4,29 (1,7, 6,6)
Twa (evaluation)n=83n=87
The mean value (standard deviation)3,692 (1,8607)2,943 (1,8480)p=0,0093
Median (minimum value, maximum value)4,249 (0,39, 6,70)2,926 (0,46, 6,63)

Findings from research using CLDQ analysis

When it is obtained through CLDQ results of the study were analyzed throughout exposure to the effects of the investigational medicinal product by calculating the Twa, the actors in the lead is bent to treatment with rifaximin group had significantly less fatigue and a significantly higher quality of life in General, than the subjects in the treated placebo group. For example, are presented as median values (± standard deviation) evaluation of fatigue - Twa was 3,24 (1,76) subjected to treatment with rifaximin group and 2,42 (1,75) in the treated placebo group (p=0,0087 in favor subjected to treatment with rifaximin group). Significant differences in obtained using CLDQ results - Twa in favor subjected to treatment with rifaximin group also noted for obtained using CLDQ overall assessment manifestations (p=0,0093) and for each of the other areas of the manifestations that are component parts of the CLDQ, including abdominal symptoms (p=0,0090), systemic symptoms (p=0,0160), activity (p=0,0022), emotional state (p=0,0065) and anxiety (p=0,0436).

Importantly, these data indicate that treatment with rifaximin resulted in significantly improved quality of life compared to treatment with placebo during the 6-month treatment period in subjects with liver cirrhosis and HE relapsed with a clear clinical picture, before showing again HE emerged with a clear clinical picture, and without refutation data. This suggests that patients in this study registered improvements in each area of the display in comparison with the treated placebo group. Observed statistics is automatic significant difference between the treated with rifaximin and placebo groups is consistent with clinically significant differences, marked in the case of entities with increasing severity of liver disease, defined by evaluating the child-Pugh score.

Correlation between CFF and aggravation HE with a clear clinical picture during treatment

As a check on the reliability and clinical significance of the primary outcome measure examined the correlation between the quantitative results for the CFF and the occurrence of acute HE with a clear clinical picture (the primary measure of effectiveness), which was determined on the basis of clinical symptoms using assessment Konno (or combination of assessment Konno and the degree of "fluttering" of tremor).

The CFF values were tracked over time for each subject, and it was noted that on average, subjects who showed aggravation, had lower values CFF than subjects who did not show an episode of the aggravation. And, in addition, it was noted that the area under the curve from CFF-time (AUC) can be used to accurately define variations in CFF over time for each subject in the form of a time-weighted value (twa). Since not all subjects remained in the study during the same time period, twa has led to the time of exposure exposure (T).

The results of the study CFF over time represented in the form:

where T represents the time of exposure effects. Thus, twa characterizes the average CFF throughout the test.

The correlation between twa and the presence or absence of the episode HE exacerbation during treatment can be analyzed using analysis of variance and coefficient of rank correlation coefficient. In addition, you can perform an analysis of ROC curve to assess the accuracy of twa for distinguishing between the presence and absence of episodes of exacerbation during treatment. In the case of the ROC-curve build a graph of the relative number of significantly positive (sensitivity) on the relative number of false positive (1-specificity). Diagnostic study with a perfect distinction has a ROC curve that passes through the upper left corner (100% sensitivity, 100% specificity). Therefore, the closer the ROC curve is to the upper left corner, the higher the overall accuracy of the study.

In Fig.31 and 32 and table 26 shows that the difference between the distributions of frequency twa, corresponding to the presence (mean =12,5 Hz) and the absence of episodes of acute NOT during treatment (mean =32.7 Hz), was statistically significant (p<0,0001). There was also a correlation between the mean twa and the presence or absence of an episode of acute NOT at the time of treatment (coefficient of rank correlation coefficient =of-0.62; p<0,0001).

Table 26
The area under the curve and time-weighted average value for the results of the study CFF (in the case of ITT population)
The results of the study CFF,No acute NOT, N=195The aggravation, N=104A p-value ofand
AUC1-168 days)(Hz×day)n=194n=99
The mean value (standard deviation)5455,07 (1918,260)2090,24 (1648,022)
Median (minimum value, maximum value)6037,0 (137,4, 8189,4)1610,2 (175,7, 7092,9)
Twa (Hz)bn=194n=99
The mean value (standard deviation)32,67 (11,487)to 12.52 (9,868)lt; 0,0001
Median (minimum value, maximum value)36,2 (0,8, 49,0)9,6 (1,1, 42,5)
CFF: critical frequency of flicker; AUC: area under the curve from CFF time; twa: time-weighted average value
athe p-value calculated using covariance analysis with the effects of treatment and the study area as independent variables.
bThe coefficient of rank correlation coefficient between the twa and the presence or absence of acute HE =of-0.62; p<0,0001.

The analysis of ROC curve twa for diagnosing acute door CFF showed that the area under the curve =0,88 (95% confidence interval from 0.84 to 0.92). Values close to 1, and finding the ROC curve closest to the upper left corner, are considered to be diagnostically significant.

Thus, it was established that the CFF, which is a recognized, physiologically relevant measure associated with HE is highly prognostic factor HE exacerbation during treatment, as determined by an increase in the assessment on connu to grade ≥2 (i.e., 0 or 1 to ≥?2) or of 1 degree increase in each of the assessments on Konno and "fluttering" tremor in the case of subjects who entered the study with an estimate of Konno =0. The fact that this metric enables a distinction to be highly statistically significant way, proves the reliability and clinical relevance of the primary performance indicator.

EXAMPLE 6: the correlation between the levels of ammonia in venous blood and episodes HE exacerbation during treatment

The subjects, who were prescribed rifaximin marked significant decrease ammonia levels in venous blood than those treated with placebo subjects (p=0,0391, see table 27). Ammonia levels in venous blood were determined at screening, at baseline, day 28, day 84 and day 168/at the end of treatment.

Table 27
Presented as mean values (standard deviation) changes compared with the initial level of ammonia level in venous blood according
Placebo, N=195 (µg/DL)Rifaximin, N=104 (µg/DL)A p-value ofand
Initial leveln=146n=132
The average (root-mean-square of klonnie) the ammonia level 90,3 (52,48)87,9 (47,76)
The end of the treatmentn=141n=132
The average (standard deviation) level of ammonia88,4 (45,75)83,9 (45,02)
The change compared to baseline levels by the end of the treatmentn=131n=125
The mean (standard deviation) change in the level of ammonia-0,3 (5813)-5,7 (of 46.77)p<0,0391
Note: the Value at baseline was the last of the available values to the first dose of the investigational medicinal product, and the value of the end of treatment was the last of the available values at subsequent levels, identified during the treatment period.
athe p-value was calculated using covariance analysis with the effects of treatment and research, and baseline as independent is simich variables.

It is established that there is a high degree of correlation between the levels of ammonia in the venous blood, quantitative assessment, which is associated with effects on the CNS underlying the HE with a clear clinical picture, and the occurrence of acute HE with a clear clinical picture is determined through clinical evaluation. This high degree of correlation is in accordance with the correlation between the results of the study CFF and the occurrence of acute HE with a clear clinical picture.

Laboratory values of ammonia in venous blood was tracked over time for each subject. To bring to the time of exposure exposure value twa was calculated the same way as in the analysis of CFF.

The correlation between twa ammonia and the presence or absence of the episode HE exacerbation during treatment was investigated as described for CFF.

In Fig.33 and table 28 shows that the difference between the distributions of frequency twa, corresponding to the presence (mean =102,4 µmol/l) and absence of episodes of acute NOT during treatment (average =85,4 µmol/l) was statistically significant (p=0,0079). There was also a correlation between the mean twa and the presence or absence of an episode of acute NOT during treatment (coefficient of rank correlation coefficient =0,22; p=0,0005).

Table 28
The area under the curve and time-weighted average value for the concentration of ammonia in venous blood (in the case of ITT population)
The concentration of ammonia in the venous blood,No acute NOT, N=195The aggravation, N=104A p-value ofand
AUC(1-168 days)(µmol/l×day)n=173n=68
The mean value (standard deviation)2304,83 (1211,428)2763,93 (1160,357)
Median (minimum value, maximum value)2038,5 (499,5, 9153,0)2787,8 (76,81,5)
Twa (µmol/l)bn=173n=68p=0,0079
The mean value (standard deviation)85,36 (44,87)102,37 (42,98)
Median (minimum value, maximum value)75,5 (18,5, 339,0)103,25 (37,0, 284,5)
AUC: area under the curve of concentration of ammonia from time to time; twa: time-weighted average value
athe p-value calculated using covariance analysis with the effects of treatment and the study area as independent variables.
bThe coefficient of rank correlation coefficient between the twa and the presence or absence of acute HE=0,22; p=0,0005.

The analysis of ROC curve twa for diagnosing acute HE levels of ammonia in venous blood showed that the area under the curve =0,64 (95% confidence interval of 0.57-0,72) (see Fig.34). Values close to 1, and finding the ROC curve closest to the upper left corner are considered diagnostically significant.

Thus, it was found that the ammonia level in the venous blood, which is a recognized, physiologically relevant measure associated with HE is highly prognostic factor HE exacerbation during treatment, as determined by an increase in the assessment on connu to grade ≥2 (i.e., 0 or 1 to ≥2) or of 1 degree increase in each of the assessments on Konno and "fluttering" of tremor in case the subjects, who entered the study with an estimate of Konno =0. The fact that this metric enables a distinction to be highly statistically significant way between the presence or absence of acute NOT, proves the reliability and clinical relevance of the primary performance indicator.

The incorporation by reference

The contents of all references, patents that are pending patent applications and published patents, cited throughout this application, included therefore in verbal form by reference.

Equivalents

Skilled in the art specialists distinguish, or will be able to install using no more than the usual experiments, many options, equivalent to specific variants of implementation of the present invention described herein. It is assumed that such equivalents are covered by the following claims.

1. The use of rifaximin for getting medicines to maintain remission of hepatic encephalopathy (NO) in the subject, comprising daily administration of rifaximin to a subject for about 12 months or more, thereby maintaining remission NOT.

2. Application under item 1, additionally including the introduction of lactulose.

3. Application is on p. 1, in which rifaximin is administered to the subject within about 12 to about 24 months.

4. Application under item 1, in which rifaximin is administered to a subject to death.

5. Application under item 1, in which the subject is administered from about 1000 mg to about 1200 mg/day of rifaximin.

6. Application under item 5, in which the subject is administered approximately 1100 mg of rifaximin in the day.

7. Application under item 6, in which the subject is injected 550 mg of rifaximin twice daily (BID).

8. Application under item 1, in which the subject is identified as being in remission NOT until the introduction of rifaximin.

9. Application under item 8, in which the remission is defined score on connu 0 or 1.

10. The use of rifaximin to obtain drugs from hepatic encephalopathy (NO) in the subject, comprising daily administration of rifaximin to a subject for about 1095 days or longer, thereby healing NOT.

11. Application under item 10, further including the introduction of lactulose.

12. Application under item 10, in which rifaximin is administered to a subject to death.

13. Application under item 10, in which the subject is administered from about 1000 mg to about 1200 mg/day of rifaximin.

14. Application under item 13, in which the subject is administered approximately 1100 mg of rifaximin in the day.

15. Application under item 14, in which the subject is injected 550 mg of rifaximin twice on the Ni (BID).

16. Application under item 1 or 10, in which during the treatment period there is a low coefficient caused by/related with NOT hospitalization.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention relates to sports medicine. Method includes carrying out interval hypoxic training with breathing gas mixture with simultaneous influence on central nervous system by pulse electric current. Before interval hypoxic training additionally realised is introduction of neuropeptide Semax in dose of two drops in each nasal passage. Interval hypoxic training is carried out at least four times by breathing gas mixture, which contains 9.5% of oxygen. Influence by electric current is realised with pulse duration 0.25-0.28 ms, current power 0.9 mA and frequency of pulses 1250 Hz for 60 minutes.

EFFECT: method ensures acceleration of organism readjustment to functioning in extreme conditions of influence, ensures increase of work efficiency.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry, namely to a cholinergic agent. A mixture of bornyl acetate and camphene taken in a certain ratio possessing the cholinergic action.

EFFECT: above mixture possesses the pronounced cholinergic action.

3 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to fumarate salts of 2-(cyclohexylmethyl)- N-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulphonamide, to based on them pharmaceutical compositions, method of their obtaining and methods of their application.

EFFECT: obtained are novel salts of 2-(cyclohexylmethyl)- N-{2-[(2S)-1-methylpyrrolidin-2yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulphonamide, possessing properties of H3 histamine receptor antagonists.

16 cl, 9 dwg, 8 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of biotechnology, namely to novel tetrapeptides, representing Acetyl-(D-Lys)-Lys-Arg-Arg-amide; Acetyl-Lys-(D-Lys)-Arg-Arg-amide; Acetyl-Lys-Lys-(D-Arg)-Arg-amide; Acetyl-Lys-Lys-Arg-(D-Arg)-amide; Acetyl-(D-Lys)-Lys-(D-Arg)-Arg-amide; Acetyl-Lys-(D-Lys)-(D-Arg)-Arg-amide; Acetyl-Lys-(NMe-Lys)-Arg-Arg-amide; Acetyl-Lys-Lys-(NMe-Arg)-Arg-amide; Acetyl-(D-Lys)-(D-Lys)-(D-Arg)-(D-Arg)-amide; Acetyl-(D-Arg)-(D-Arg)-(D-Lys)-(D-Lys)-amide, which possess cerebroprotective and antiamnestic activity.

EFFECT: claimed peptides produce stimulating impact on cholinergic processes in brain, are of low toxicity and are promising for application in medical practice as active component of medications.

11 cl, 5 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and (II), which possess the blocking activity on voltage-sensitive sodium channels, such as TTX-S channels, and their pharmaceutically salts. In general formula (I) and (II), R1 represents -CF3, -CHF2, -OCF3, -OCHF2, -OCH2CHF2/ -OCH2CF3, -OCF2CHF2; -OCF2CF3, -OCH2CH2CF3, -OCH(CH3)CF3, -OCH2C(CH3)F2, -OCH2CF2CHF2, -OCH2CF2CF3, OCH2CH2OCH2CF3, -NHCH2CF3, -SCF3, -SCH2CF3, -CH2CF3 -CH2CH2CF3, -CH2OCH2CF3 and -OCH2CH2OCF3; R2 is specified in (1) hydrogen, (2) halogen (3) -On-C1-6 alkyl, (4) -On-C3-6 cycloalkyl, (5) -On-phenyl, (6) -On-heterocyclic group, (7) -NR7 (C=O)R8; wherein n is equal to 0 or 1, p is equal to 1, 2; R3 and R4 represents hydrogen or C1-6 alkyl, X represents carbon atom; Y represents hydrogen or C1-6 alkyl; Ar represents 4-pyridyl, 4-pyrimidyl or 6-pyrimidyl, which is substituted in the 2nd position by a substitute, which is independently specified in (1) -(C=O)-NR7R8, (2) -NR7(C=O)R8; R9 is specified in: (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, wherein alkyl is unsubstituted or substituted by hydroxyl; q is equal to 1, 2 or 3; R10 independently represents hydrogen, C1-6 alkyl, C2-6alkenyl, C3-7 cycloalkyl or phenyl, which is unsubstituted or substituted by one or substitutes independently specified in hydroxyl, -On-C1-6 alkyl and -C3-7 cycloalkyl.

EFFECT: preparing the compounds possessing the blocking activity on voltage-sensitive sodium channels.

7 cl, 2 tbl, 1281 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, in particular to a composition, the application of the composition and a method of treating abuse with substances, causing painful addiction in a subject. The composition contains a carbamoyl compound, or its pharmaceutically acceptable salt, or an ester as an active ingredient and the method includes the introduction of a therapeutically effective quantity of the carbamoyl compound, or its pharmaceutically acceptable salt, or the ester.

EFFECT: composition is used for the treatment of abuse with substances, causing painful addiction in a subject, as well as to an improvement of behaviour associated with the abuse.

14 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: cerebroprotective and antineurotic agent containing an active ingredient presented by a dry extract of meadowsweet (Filipendula ulmaria (L.) Maxim.) prepared according to a certain procedure, and additive agents - lactose, microcrystalline cellulose, potato starch, magnesium stearate taken in certain proportions.

EFFECT: agent possesses the expressed cerebroprotective and antineurotic activity.

2 cl, 5 tbl, 9 ex

FIELD: pharmacology.

SUBSTANCE: pharmaceutical composition possessing the sedative and spasmolytic action and containing valerian tea, motherwort tea, hawthorn tea, peppermint tea with a number of biologically active substances in each of the teas, and an antihistamine preparation of diphenhydramine hydrochloride; as ingredients of the biologically active substances, the composition contains flavonoids in a certain amount.

EFFECT: composition possesses the high sedative therapeutic effect, the improved therapeutic effect in treating psychoemotional disorders, including in women suffering from menopausal syndrome.

2 tbl, 3 ex

FIELD: pharmacology.

SUBSTANCE: sedative and spasmolytic agent containing valerian tea, motherwort tea, hawthorn tea, peppermint tea with a complex of biologically active substances in each of the teas, and an antihistamine preparation of diphenhydramine hydrochloride. As ingredients of the biologically active substances, the composition contains carboxylic acid esters and menthol in a certain amount.

EFFECT: agent has no side effect, as dry mouth, and possesses the more pronounced therapeutic action in treating psychoemotional disorders.

2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and can be used as a hepatotrophic, lipotropic agent in gastroenterology, as well as for treating cardiac and cerebral atherosclerosis, in neurology in the lower extremity artery diseases (endarteritis). The agent contains tabletted powders of diisopropylammonium dichloroacetate, microcrystalline cellulose, lactose and excipients presented by Aerosil, Primogel and calcium stearyl fumarate.

EFFECT: agent possesses no toxicity, has the high adsorption properties, the apparent anti-inflammatory action, and provides metabolism and the liver regeneration.

3 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: according to a known method of treating the liver disease accompanying type 2 diabetes mellitus involving the baseline therapy of diabetes mellitus and prescribed hepatoprotectors, the above hepatoprotector is presented by Mexicor in a daily therapeutically effective dose of not less than 16 weeks. The therapeutically effective dose of Mexicor makes 100 mg 4 times a day.

EFFECT: higher clinical effectiveness ensured by eliminating the liver disease more prominently, reducing the length of treatment, normalising the liver function test results over a short period of time, and avoiding any side effects.

2 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine and aims at treating the non-alcoholic fatty liver disease. Increasing a transaminase level to three normal values inclusively requires applying essential phospholipids for 2-3 months twice a year that is followed by using statin 10-20 mg in a combination to ursodeoxycholic acid 15-20 mg/kg for 3-6 months. If the transaminase level exceeds three normal values, the treatment is isolated and includes ursodeoxycholic acid 15-20 mg/kg for 3-6 months.

EFFECT: method enables providing the higher clinical effectiveness of the non-alcoholic fatty liver disease.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to endocrinology, and can be used for treating non-alcoholic liver disease accompanying type 2 diabetes mellitus. The declared preparation Mexicor provides reducing manifestations of cytolysis and cholestasis, decreasing the steatosis index, enables improving metabolic lipid and glycaemic values and reducing insulin resistance. Mexicor is applied in a daily therapeutically effective dose of 100 mg 4 times a day for at least 16 weeks.

EFFECT: high pharmacological activity of Mexicor has been shown by achieving the pronounced and stable elimination of fatty liver disease that enables reducing the length of treatment with no side effects.

2 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and describes a method for compensating a disturbed intestinal bile inflow in patients with the external biliary drainage. A method for the deficient bile replacement with the external biliary drainage consists in conducting a background therapy, prescribing a therapeutic formulation containing the following ingredients: ursodeoxycholic acid 12-15 mg/kg/day (up to 20 mg/kg) in 2-3 doses, Eslidin (soya lecithin phospholipids 300 mg; methionine 100 mg, soya oil up to 550 mg) 1 capsule 3 times a day at mealtimes; Milaif 0.2 g 3 times a day.

EFFECT: invention enables improving the patient's health condition and relieving a pain syndrome by a safe and technically easy method.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a novel derivative of N-acylanthranilic acid, represented by the following general formula 1, or to its pharmaceutically acceptable salt, in which R1, R2, R3, X1, X2, X3, X4 and A are determined in the invention formula.

EFFECT: invention relates to an inhibitor of collagen production, a medication for treating diseases, associated with the excessive production of collagen, containing N-acylanthranilic acid derivative Formula 1.

FIELD: chemistry.

SUBSTANCE: hepatoprotective agent based on a lipid fraction from an alcohol extract of perforated thallome ulva - Ulva fenestrate P. et R., containing less than 70% membrane-active lipid components, including not less than 20% essential phospholipids with content of polyunsaturated fatty acids of the n-3 series of not less than 55%.

EFFECT: agent has effective hepatoprotective action, speeds up restoration of stages of metabolic reactions, thereby providing normalisation of biochemical properties of carbohydrate and lipid exchange.

5 tbl

FIELD: biotechnology.

SUBSTANCE: hepatoprotector is used as peptide ACTH (4-7) -PGP (Semax) having the formula Met-Glu-His-Phe-Pro-Gly-Pro.

EFFECT: use of the said peptide with the aim of hepatoprotection under condition of the development of free-radical oxidation of hepatocytes enables to improve the efficiency of treatment of liver diseases accompanied by intensification of free radical oxidation processes.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula [I] or to its pharmaceutically acceptable salt, wherein A represents optionally substituted alkyl, wherein the substitute represents identical or different 1-3 groups specified in aryl optionally substituted by 1-3 groups specified in alkyl, halogen, alkoxy and alkanoyl; cycloalkyl optionally substituted by 1-3 groups specified in alkyl and halogen; hydroxy; alkoxy; halogen; an amino group and oxo; an optionally substituted carbocyclic group specified in a mono- and bicyclic group, wherein an aromatic ring and cycloalkyl are condensed; optionally substituted aryl, an optionally substituted completely saturated 5- or 6-merous monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, wherein the substitute of optionally substituted aryl, the optionally substituted carbocyclic group and the optionally substituted heterocyclic group for A represents identical or different 1-3 groups specified in alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen; cycloalkyl optionally substituted by alkyl or alkoxy; alkoxy optionally substituted by halogen; halogen; hydroxy; oxo; heterocycle; alkyl sulphonyl; and mono- or dialkylcarbamoyl, optionally substituted amino, wherein the substitute represents identical or different 1 or 2 alkyl or aryl, or optionally substituted carbamoyl, wherein the substitute represents identical or different 1 or 2 alkyls optionally substituted by aryl, X represents optionally substituted methylene or -O-, wherein the substitute of optionally substituted methylene for X represents alkoxy or hydroxy, Q represents N or C-R4, L1 represents a single bond, methylene, -CH=CH-, -O-, -CO-, -NR11-, -NR11CO-, -CONR11- or -CH2NR11-, L2 represents a single bond, -CR6R7- or a bivalent 5- or 6-merous completely saturated monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, R1 and R2 are identical or different, and each represents hydrogen, alkyl or halogen, R3 and R4 are identical or different, and each represents hydrogen, alkyl, alkoxy, cyano or halogen, R1 and R3 are optionally bond thereby forming 5- or 6-merous cycloalkane, or a 5- or 6-merous aliphatic heterocycle containing oxygen atom, R5 represents a carboxyl group, an alkoxycarbonyl group or a bioisosteric group of the carboxyl group, R6 and R7 are identical or different, and each represents hydrogen or alkyl, or R6 and R7 are bond thereby forming cycloalkane, R8 represents hydroxy, alkanoylamino or alkyl sulphonylamino, R9 and R10 represent hydrogen or halogen, and R11 represents hydrogen or alkyl. Besides, the invention refers to specific compounds of formula [I], a drug based on the compound of formula [I], using the compound of formula [I], a method of treating based on using the compound of formula [I], and an intermediate compound of formula [II].

EFFECT: there are prepared new compounds possessing the agonist activity on thyroid hormone β receptor.

18 cl, 36 tbl, 344 ex

FIELD: medicine.

SUBSTANCE: managing pregnancy in females suffering from overweight on their 26-30 weeks of pregnancy involves measuring an S-wave velocity in the hepatic tissue by acoustic pulse-wave elastometry. If an average value is 1.41 ms or more, hepatic protectors are administered.

EFFECT: reducing a rate of obstetric complications in the pregnant women suffering from overweight.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclic indolysincarboxamides and azaindolysincarboxamides of formulas Ia and Ib:

presented below, wherein the values of R, Ra, R10, R20, R30, R40, Y, n, p and q are specified in cl. 1 of formula. What is described is a method for preparing them.

EFFECT: compounds exhibit rennin-inhibitory activity that enables using them in the pharmaceutical composition and for treating hypertension.

11 cl, 4 tbl, 17 ex

Up!