Improved transcutaneous therapy system for treating parkinson disease cases

FIELD: medicine.

SUBSTANCE: method involves applying system based on silicon. The system has a mixture of at least one silicon glue of high adhesiveness showing its effectiveness under press action and at least one silicon glue of moderate adhesiveness showing its effectiveness under press action as basic gluing ingredients. The transcutaneous therapy system has surface of 10 to 40 cm2 and comprises 0.1-3.15 mg/cm2 of Rotigotine in free base form as active ingredient for preparing antiparkinsonian drug. The present invention improves patient health state evaluated as 2 units or higher according to UPDRS, part II and III, when compared to placebo, during at least 7 weeks after injection as a result of improved Rotigotine release parameters and provided Rotigotine dose-activity relation optimum.

EFFECT: enhanced effectiveness of treatment.

13 cl, 2 dwg, 3 tbl

 

The scope of the invention

The present invention relates to an effective method for the treatment or relief of symptoms of Parkinson's disease and to the use of percutaneous therapeutic system (TTS) for delivery of the agonist of dopamine receptors rotigotine (rotigotine) in sufficient quantity and with sufficient speed to provide a therapeutically effective to treat or alleviate symptoms of Parkinson's disease.

Prior art

I believe that Parkinson's disease is mainly caused by the degeneration of dopaminergic neurons in a black substance. This actually leads to a decrease in the tonic secretion of dopamine and related dopamine modulation of neural activity in the caudate nucleus and, thus, to a deficit of dopamine in certain areas of the brain. The resulting imbalance of the neurotransmitters acetylcholine and dopamine in the end leads to the symptoms associated with the disease. Usually considered as a disorder of the motor system Parkinson's disease is considered a more complex disorder that involves both motor and non-powered system. This debilitating disease is the main clinical signs including tremor, bradykinesia, rigidity, dyskinesia, gait disorders and speech disorders. Some is which patients these symptoms may be accompanied by dementia. The defeat of the autonomic nervous system may cause orthostatic hypotension, paroxysmal flushing, problems with temperature regulation, constipation and loss of control of bladder and sphincter. Psychological disorders, such as loss of motivation and depression, also can accompany Parkinson's disease.

Parkinson's disease is primarily a disease of middle age and older, and it affects equally both men and women. The highest percentage of occurrence of Parkinson's disease occurs in the age group older than 70 years, where Parkinson's disease has a 1.5-2.5% in this population. The average age of onset is between 58 and 62 years, and the majority of the population Parkinson's disease develops in aged 50 to 79 years. Only in the United States, approximately 800,000 people suffer from Parkinson's disease.

You can follow the link of the early shortcomings of motor function in Parkinson's disease with incipient degeneration igralni dopamineproducing cells. This degeneration of neurons leads to defect dopaminergic pathway, which connects the black substance with a striped body. As the disease can develop intractable motor, autonomic and mental disorders, which means that happens is a progressive degeneration veins receptor mechanisms.

Clinical diagnosis of Parkinson's disease based on the presence of characteristic physical signs. It is known that this disease is at first a gradual slowly progressive and variable clinical manifestations. The data suggest that the dopamine content in the striatum is reduced to 20% below the levels defined in the selected age control groups before the onset of symptoms.

Attempted to treat Parkinson's disease, in particular, L-DOPA (3,4-dihydroxyphenylalanine) (levodopa), which is still the gold standard for therapy of Parkinson's disease. Levodopa passes through the blood-brain barrier in the form of a precursor of dopamine and then in the brain converts into dopamine. L-DOPA improves the symptoms of Parkinson's disease, but it can have severe side effects. In addition, this drug tends to lose its effectiveness after the first two or three years of treatment. After 5-6 years, only 25-50% of patients maintained improvement.

In addition, the main drawback of currently used for the treatment of Parkinson's disease is a possible manifestation of the syndrome fluctuations", leading to state "all-or-nothing", characterized by alternating periods of "enable mobility with dyskinesias and "off" periods with hypokinesia or and what inasia. Patients who have unpredictable or unstable phenomena "on-off" oral antiparkinsonian therapy, are predictable positive response to intravenous administration of L-DOPA and other dopamine agonists, suggesting that fluctuations in the concentrations of drugs in plasma are responsible for the phenomenon of "on-off". The frequency fluctuations "on-off" was also reduced by prolonged infusion of agonists of dopamine receptors of apomorphine and e.g.. However, this route of administration is inconvenient. Therefore, other methods of introduction, providing a more constant plasma level, such as local injection, are useful and previously suggested.

As noted above, one approach to the treatment of Parkinson's disease include agonists of dopamine receptors. Agonists of dopamine receptors (sometimes also referred to as dopamine agonists) are substances that are structurally different from dopamine, associated with different subtypes of dopamine receptors and initiate the action that is comparable with the action of dopamine. To reduce side effects, it is useful to substances selectively contacted by subgroup dopamine receptors, i.e. D2 receptors.

One agonist of dopamine receptors, which IP is was olovely to treat symptoms of Parkinson's disease, is rotigotine (rotigotine). It usually used in the form of hydrochloride. Rotigotine is the international nonproprietary name (INN) of the compound (-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-naphthalenol having the structure shown below

Up to now, there have been described various transdermal therapeutic system (TTS) for administering rotigotine. In WO 94/07468 disclosed transdermal therapeutic system containing hydrochloride rotigotine as an active substance in a two-phase matrix, which is essentially formed of a hydrophobic polymeric material as a continuous phase and the dispersed hydrophilic phase, contained in it, and mainly containing a drug and hydrated silicon dioxide. Silicon dioxide increases the maximum possible load TTS hydrophilic salt. In addition, the preparation of WO 94/07468 usually contains more hydrophobic solvents, substances that increase the permeability, dispersing agents and, in particular, the emulsifier, which is required for emulsification of an aqueous solution of the current start in the lipophilic polymer phase. TTS prepared using such a system, tested on healthy subjects and patients with Parkinson's disease. Average levels of drug medium spans the VA in plasma, obtained from the use of this system was approximately 0.15 ng/ml when using the patch 20 cm2containing 10 mg of rotigotine. This level should be considered as a level too low to achieve a truly effective treatment or relief of symptoms associated with Parkinson's disease.

Various other percutaneous therapeutic systems have been described in WO 99/49852. TTS used in this patent application, contain protective layer inert to the components of the matrix, a self-adhesive layer matrix containing an effective amount of rotigotine or hydrochloride rotigotine, and a protective film which should be removed before use. Matrix system consists of a non-aqueous polymeric adhesive systems based on acrylate or silicone, while the solubility of rotigotine is at least 5% wt./mass. This matrix is essentially free from inorganic silicate particles. In examples 1 and 2 and in figure 1 of WO 99/49852 compare two percutaneous therapeutic system. Their foundations are acrylate or silicone adhesive, respectively. Figure 1 WO 99/49852 shown that silicone patch releases approximately the same amount of the active substance through the skin, as acrylate adhesives. At this point almost the same speed you the population of the medicinal product in in vitro models, regardless of the adhesion test system. Therefore, expect the same allocation rate through human skin.

It should be noted that the content of the drug in the silicon patch in WO 99/49852 was lower than the concentration of the drug in acrylate adhesive. However, this reflects only the difference in solubility of the drug in the appropriate polymeric silicone and acrylate adhesives used in examples 1 and 2, respectively. TTS used in both examples contain the drug at approximately its saturated solubility in the respective adhesive systems. While the acrylate system can dissolve more drugs than silicone system, silicone, in turn, allows you to get the best release of the drug in the skin. Since these two effects compensate each other, thought acrylate and silicone systems, such as used in WO 99/49852, almost equivalent on achievable levels of the drug in the plasma and, therefore, therapeutic efficacy.

Whereas quite discouraging experiments conducted with a silicone preparation of WO 94/07568, TTS-based acrylate from Example 1 WO 99/49852 subjected to clinical trials (research the Oia safety and pharmacokinetics). Average constant speed selection through human skin in vitro that TTS was 15.3 mg/cm2/H. However, it was found that the plasma levels obtained using this TTS were still unsatisfactory and too low to allow effective treatment of Parkinson's disease. 30 mg (20 cm2) the patch resulted in only the average maximum plasma concentration of 0.12 ng/ml, while 5 cm2plaster containing 7.5 mg, resulted in average maximum concentration in plasma 0,068 ng/ml And again these values should be considered as too low to allow valid therapeutic success in the treatment of Parkinson's disease. Thus, in conclusion, as 20 cm2silicone plaster of WO 94/07468 and 20 cm2acrylic plaster of WO 99/49852 failed to provide sufficient levels of the drug in the plasma to provide a satisfactory therapeutic efficacy.

Whereas these experiments, it was very unexpected that transdermal therapeutic system containing rotigotine in free base form in the silicon matrix, could not only provide unexpectedly high levels of rotigotine in plasma, but also a significant therapeutic success when percutaneous treatment of Parkinson's disease. In an hour the particular it was unexpected that transdermal therapeutic system having only 10 or 20 cm2to provide effective treatment of Parkinson's disease in placebo-controlled clinical trial, which is indicated by the improvement in the unified rating scale for Parkinson's disease (UPDRS) 2 units or more, compared with treatment with placebo. In relation to this application "placebo treatment" refers to treatment using percutaneous therapeutic system with similar qualitative composition and with the same regimen, but where the active ingredient (rotigotine) was removed from the percutaneous therapeutic system.

It should be understood that the term "treatment" in relation to this application means the treatment or relief of symptoms of Parkinson's disease, and not the actual reason the treatment of Parkinson's disease, leading to complete recovery.

Summary of the invention

According to the present invention proposed the use of percutaneous therapeutic systems based on silicone, with an area of from 10 to 40 cm2and containing from 0.1 to 3.15 mg/cm2Rotigotine (Rotigotine) as the active ingredient, for the preparation of antiparkinsonian medication, which causes an improvement compared with placebo treatment, patient's condition - people with Parkinson's disease, enwemeka on a standardized scale assessment of Parkinson's disease (UPDRS), parts II and III, 2 units or more, after introduction during the period of time of at least 7 weeks, preferably at least 11 weeks.

Percutaneous therapeutic system based on silicone, as used in the present invention must contain at least one silicon compound, resistant to amines, as a main component. Typically, a silicon compound is an adhesive, effective under pressure, or the mixture and forms a matrix in which you have entered other components of the TTS. In addition, the adhesive(s) should preferably(s) to be pharmaceutically acceptable in the sense that it must be biocompatible, desensibilisation and non-irritating against the skin. Especially preferred silicone adhesives for use in the present invention must satisfy the following requirements:

- save adhesion and cohesion properties in the presence of moisture or sweat, under normal temperature fluctuations,

- possess good compatibility with rotigotine, and other excipients used in the product; in particular, the adhesive should not interact with the amino group, rotigotine.

It was shown that adhesives, effective under pressure, of a particular type, forming soluble polycondensation polydimethylsilane the new (PDMS)/resin mesh, where the end of the hydroxy-group is covered, for example, trimethylsilyl (TMS) groups, are particularly useful in the practical part of the present invention. Preferred adhesives of this type are BIO-PSA silicone adhesives, effective under pressure, produced by Dow Corning, in particular brand Q7-4201 and Q7-4301. However, you can also use other silicone adhesives.

In other and preferred aspects of the present invention also suggested that percutaneous therapeutic system based on silicone containing two or more than two silicone adhesive as the main adhesive component for this application. May be useful if such a mixture of silicone adhesives contains at least one adhesive, with high adhesion, and at least one adhesive with medium adhesion, to provide the optimal balance between good adhesion and a small fluctuation in the cold. The result of excessive fluidity at cold temperatures may become too soft patch, which easily sticks to the packaging or clothing of the patient. In addition, it seems that such a mixture of adhesives particularly useful for obtaining effective transdermal therapeutic system. It is shown that a mixture of the above Q7-4201 (secondary adhesion) and Q7-4301 (high adhesion) silicone adhesives, effective under pressure and is resistant to amines, in the rough is about equal quantities are particularly useful in the practical part of this invention.

In yet another preferred embodiment of a transdermal therapeutic system based on silicone further comprises a solubilizer. Some such surfactant or amphiphilic substances can be used as solubilization. They must be pharmaceutically acceptable and should be approved for use in drugs. Preferably, the solubilizer also had the effect of improving cohesion percutaneous therapeutic system. Especially preferred example of such a solubilizer is soluble polyvinylpyrrolidone.

Polyvinylpyrrolidone commercially available, e.g. under the trademark Kollidon® (Bayer AG). Other examples include copolymers of polyvinylpyrrolidone and vinyl acetate, polyethylene glycol, polypropyleneglycol, glycerol and glycerol esters of fatty acids or copolymers of ethylene and vinyl acetate.

Percutaneous therapeutic system based on silicone for use in the present invention preferably contains less than 1% of the mass. inorganic silicates, more preferably it is completely free of inorganic silicates.

The water content of the percutaneous therapeutic systems for use in the present invention preferably low enough in order not required of the issue is ivanie water during cooking TTS. Usually the water content of the freshly prepared adhesive is less than 2%, more preferably 1 wt%. or less.

In a particularly preferred embodiment of the present invention percutaneous therapeutic system has a surface area of from 10 to 30 cm2, more preferably from 20 to 30 cm2. Obviously, TTS, having a surface area, for example 20 cm2is pharmacologically equivalent to two 10 cm2the patches or four 5 cm2the patches having the same content of a drug in cm2and you can replace them. Thus, it should be understood that the surface area, as described in this application, refers to the total surface of all TTS, simultaneously injected to the patient.

Providing and applying one or more transdermal therapeutic systems according to the invention have pharmacological advantage over oral therapy is that regular doctor hospital can determine the optimal dose for a particular patient relatively quickly and accurately, for example, by simply increasing the number or size of patches assigned to the patient. Thus, the optimal individual dose can often be identified through the span of time just about 3 weeks with little side effects.

Preference is sustained fashion content rotigotine on the patch is in the range from 0.1 to 2.0 mg/cm 2. Even more preferred is the range from 0.4 to 1.5 mg rotigotine on cm2. If desired 7-day patch, usually require a higher content of medicines. It was found that the content of rotigotine in the range from approximately 0.4 to 0.5% of the mass. it is especially preferred because it ensures the optimal use of a drug contained in the TTS, i.e. after the introduction of TTS remains only a very small residual content of the medicinal product. Detectable dose introduced by such TTS, usually 50% or more, and may reach 80-90% of the amount of drug initially contained in the TTS.

The fact that percutaneous therapeutic system based on silicone described in this invention is able to provide a significant therapeutic effect in respect of the symptoms of Parkinson's disease even when the surface area of from 10 to 30 cm2and, in particular, only 10 or 20 cm2and at low concentrations of pharmaceuticals from approximately 0.4 to 0.5 mg/cm2in particular, approximately 0.45 g/cm2should be considered as another particular advantage provided by the present invention.

Percutaneous therapeutic system used in the present invented and, is usually a patch having a continuous adhesive matrix containing at least in its Central part a drug. However, percutaneous equivalents such patches are also included in the scope of the present invention, such as embodiment, where the drug is inert, but non-adhesive silicone matrix in the Central part of the TTS and surrounded by the adhesive part along the edges of the patch.

In another aspect this invention relates to a method of treating Parkinson's disease by imposing on the patient, in need thereof, percutaneous therapeutic systems based on silicone, with an area of from 10 to 40 cm2and containing from 0.1 to 3.15 mg/cm2rotigotine as an active ingredient, wherein the improvement is that the patient's condition, as measured by standardized rating scale for Parkinson's disease (UPDRS)parts II and III, improved, compared with treatment with placebo, at approximately 2 units or more with the introduction of a time interval of at least 7 weeks. It was also shown that this improvement in UPDRS assessment persisted up to 7 weeks. Thus, the improvement of the UPDRS (parts II+III) assessment, compared with placebo, at least 2 units after the introduction of over 7, preferably 11, weeks, represents a particularly useful aspect of this is about inventions.

Unless otherwise specified, any references to rotigotine in the context of this invention and claims of this application means rotigotine in free base form. In some cases, in rotigotine may contain very small amounts of the hydrochloride rotigotine, but they usually do not exceed 5 wt. -%, based on the amount of free base. More preferably, the content of impurities hydrochloride should be less than 2 wt. -%, more preferably less than 1%, and most preferably rotigotine used in the present invention contains less than 0.1% of the mass. or does not contain any impurities hydrochloride.

Comprehensive clinical trial using transdermal therapeutic system described here, showed that all of a sudden it is possible to achieve and ensure continuous stimulation of dopamine receptors in patients with Parkinson's disease, leading to a marked improvement clinically relevant UPDRS during the period of time of at least 7 weeks. Specifically, clinical trials using plaster of example, get listed in the description, has resulted in the following improvements FAS UPDRS (part II and III) evaluation after the introduction of a period of 11 weeks. (see table 1).

Table 1
The size of the p patch The number of rotigotineImprovement in UPDRS compared with placebo treatmentp (one-sided)
10 cm24.5 mg-2,1480,0393
20 cm29.0 mg-3,1230,0063
30 cm213.5 mg-4,9090,0000
40 cm218,0 mg-5,0350,0000

The acronym FAS stands for "full of the analyzed group" and thus refers to the analysis, including all patients who were included in this study. UPDRS assessment and research plan in detail explained in the example of the clinical trials below. Figure 1 presents a chart illustrating the average change from baseline UPDRS (II+III) total estimated starting from 0 days to the end of treatment in this study. Figure 1 compares the results of treatment of the present invention with placebo treatment. Statistically significant improvements can, in particular, watch for patches with an area of 20 cm2or more, although the effect of 10 cm2the patch should be regarded as an improvement. Value, denoted as p in the above table represents a one-sided p-value obtained from statistical the data evaluation tests.

While the improvement in UPDRS assessment equal to 2, compared with placebo, can already be called a success, improvement, equal to 3, 4 or even 5 or more units, will be an even greater therapeutic success and, as such, represents a preferred aspect of the present invention.

Additional tests, including pharmacokinetics, the ratio of the dose-activity, compliance and safety of the medicinal product, confirmed therapeutic usefulness of percutaneous therapeutic systems based on silicone used in the application.

This invention and the best way of its implementation in more detail will be explained in the following non-limiting examples.

Sample preparation

Percutaneous therapeutic system using a combination of adhesives, silicone type, effective under pressure, were prepared as follows.

The hydrochloride of (-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-naphthalenol (hydrochloride rotigotine, 150 g) was added to a solution of 17,05 g NaOH in 218 g of ethanol (96%). The resulting mixture was stirred for approximately 10 minutes. Then was added 23.7 g nutrifaster buffer solution (8,35 g Na2HPO4HN2O and 16,07 g NaH2PO4×2H2O in to 90.3 g of water). Insoluble or precipitated in the sediment solid substances is and was separated from the mixture by filtration. The filter was washed 60,4 g of ethanol (96%) to produce ethanol solution rotigotine in the form of a free base, free from particles.

The solution of the free base of rotigotine (346,4 g) in ethanol (35% wt./mass.) mixed with and 36.2 g of ethanol (96%). The resulting solution was mixed to homogeneity with 109 g of an ethanol solution containing 25% of the mass. polyvinylpyrrolidone (KOLLIDON® 90F), 0,077% of the mass. an aqueous solution of sodium bisulfite (10% wt.), 0.25% mass. of ascorbyl palmitate and 0.63% of the mass. DL-alpha-tocopherol. To the mixture was added 817,2 g silicone adhesive resistant amines having high stickiness (BIO-PSA® Q7-4301, manufactured by Dow Corning) (74% of the mass. solution in heptane), usd851.8 g silicone adhesive resistant amines having an average adhesion (BIO-PSA® Q7-4201, manufactured by Dow Corning) (71% of the mass. solution in heptane) and 205,8 g petroleum ether (heptane), and all components were mixed to obtain a homogeneous dispersion.

This dispersion was applied onto a suitable polyester releasing the lining (SCOTCHPACK® 1022) suitable squeegee, and the solvent is continuously removed in a drying Cabinet at temperatures up to 80°C for approximately 30 minutes to obtain containing the drug adhesive matrix with a coating weight of 50 g/m2. The dried matrix film was stratified film-lining of polyester-type (SCOTCHPACK® 1109)OTDELENIE patches of the desired size was squeezed from the received layered material (for example 10 cm 220 cm2, 30 cm2and tightly Packed in packages in nitrogen atmosphere.

In the following table 2 shows the composition in mg/20 cm2transdermal therapeutic system according to the present invention containing the combination of two adhesives, silicone type, effective under pressure (PSA).

Table 2
The components of the compositionAmount (mg)
Rotigotine (base)9,00
Polyvinylpyrrolidone2,00
Silicone BIO-PSA® Q7-430144,47
Silicone BIO-PSA® Q7-420144,46
Ascorbyl palmitate0,02
DL-alpha-tocopherol0,05
Metabisulphite sodium0,0006
Coating weight matrix50 g/m2

Clinical trials

Methods:

TTS with rotigotine prepared in the above example was tested in a multicenter, placebo-controlled, double-blind, randomized clinical trials, covering more than 300 patients with Parkinson's disease, and was confirmed by obtaining effective relief of symptoms of Parkinson's disease patients suffering from this disease when lifespan is m time of introduction (11 weeks of which 4 weeks was the period of determining and 7 weeks were a period of maintenance) with the introduction of once per day. At this time, the patients received no other dopaminergic drugs.

After 4-7 days of preparatory open placebo period 329 patients randomized to placebo or one of four daily doses of rotigotine (the content of the drug in the patch 4.5 mg, 9.0 mg, 13.5 mg, or 18 mg) and subsequent 4-week period for determining doses, a 7-week period of maintenance doses, 1-week period, reducing the dose and 2-week observation period for safety double-blind. The research plan (treatment plan) is illustrated in more detail in figure 2.

Predefined effective primary outcome was a change in daily activity and motor components generally accepted standardized assessment of Parkinson's disease (UPDRS II/III) between baseline and last assessment during treatment (week 11).

In Parts II and III of the UPDRS evaluated and defined by the following clinical parameters for patients with Parkinson's disease:

II. DAILY ACTIVITY

A. Speech

0=Normal.

1=Minor defeat. There is no difficulty in understanding.

2=Moderate lesions. Sometimes asked to repeat statements.

3=severe defeat. Frequently asked to repeat the utterance.

4=Illegible almost all the time.

B. Salivation

0=Normal.

1=Slight but definite excess of saliva in mouth; may have nighttime drooling.

2=Moderate excess saliva; may have minimal drooling.

3=marked excess of saliva with some drooling.

4=marked salivation, requiring constant napkin or handkerchief.

Century Swallowing

0=Normal.

1=Occasionally choking.

2=a Choking from time to time.

3=Requires soft food.

4=Required NG (nasogastric) tube or gastric feeding.

, Handwriting

0=Normal.

1=Bit slow or small.

2=Moderately slow or small; all words legible.

3=Strongly modified; not all words are legible.

4=most of the words are illegible.

D. Cutting food and handling utensils

0=Normal.

1=a Little slow and clumsy, but no help is required.

2=Can cut most food, though awkward and slow, need some help.

3=Food should be chopped someone to outsiders, but still can be slow to eat.

4=Requires feeding strangers.

E. Dressing

0=Normal.

1=a Little slow, but the help is not required.

2=needs help from time to time when fastening buttons, slipping hands into the sleeves.

3=Third is : of great assistance but maybe some things to do.

4=Helpless.

J. Hygiene

0=Normal.

1=a Little slow, but the help is not required.

2=you Need help taking a shower or bath; or extreme slowness with hygienic care.

3=Need help for washing, brushing teeth, combing hair, bath.

4=Catheter-balloon Foley or other mechanical means.

3. Turning in bed and take note of bed linen

0=Normal.

1=a Little slow and clumsy, but no help is required.

2=Can be rotated independently or make a bed, but with great difficulty.

3=May start but not turn or not to lay the sheets on their own.

4=Helpless.

I. Fall (not associated with freezing)

0=No.

1=Rare drop.

2=Falling occasionally, less than once a day.

3=Fall, on average, once a day.

4=Fall more than once per day.

K. Freezing when walking

0=No.

1=Rarely freezes when walking; may be present indecision.

2=Freezing when walking from time to time.

3=Frequent freezing. From time to time the fall of the cold.

4=Frequent falls when cold.

L. Walk

0=Normal.

1=Slight difficulty. Can not shake hands or may be inclined to drag their feet.

3=Severe gait disturbance, need help.

4=unable to walk even with help.

M. Tremor (symptomatic complaints tremor any part of the body)

0=Absent.

1=Insignificant and has infrequently.

2=Moderate; concerned about the patient.

3=Serious; prevents many activities.

4=Visible; prevents most activities.

N. Sensory complaints related to parkinsonism

0=No.

1=Rarely occurs numbness, tingling or slight pain.

2=there is Often numbness, tingling or pain; not worried.

3=Frequent pain.

4=Excruciating pain.

III. RESEARCH MOTOR FUNCTION

O. Speech

0=Normal.

1=Slight loss of expression, diction and/or fullness of the sound.

2=Monotone, slurred but understandable; the mean defeat.

3=marked defeat, the difficulty of understanding.

4=Incomprehensible.

P. Expression

0=Normal.

1=Minimum hypomimia may be normal impassive, expressionless face.

2=Slight, but definitely abnormal weakening of the expressiveness of the face.

3=Moderate hypomimia; lips some time disconnected.

4=Maskoobraznoe or immobile persons with severe or complete loss of expression;lips disconnected at % inch of 0.625 cm) or more.

R. Tremor at rest (head, upper and lower extremities)

0=Absent.

1=Slight and occurs infrequently.

2=Small amplitude and constant. Or moderate in amplitude, but is only intermittently.

3=Moderate amplitude and occurs most of the time.

4=Visible in amplitude and present most of the time.

C. hand Tremor during activity or when a certain body position 0=No.

1=Insignificant; present activities.

2=Moderate amplitude; present activities.

3=Moderate amplitude, the delay position of the body, as well as at work.

4=Perceptible amplitude; prevents food.

So Rigidity (measured by passive movement of major joints in patients relaxed in a sitting position. The symptom of "gears" should be ignored)

0=Absent.

1=Slight or detectable only when activated mirror or other movements.

2=small to moderate.

3=Noticeable, but easily achieved full range of motion.

4=Heavy, range of motion is achieved with difficulty.

U. Blows fingers (Patient hits thumb with index finger in rapid succession)

0=Normal.

1=Slightly delayed and/or reduced in amplitude of the E.

2=Moderate violation. A certain and early fatigue. Can be a rare stop in motion.

3=Serious violation. Frequent hesitation at the start of the movement and stop what is happening in the movement.

4=can Hardly do the job.

F. hand Movements (Patient pushes and compresses the hands in rapid succession)

0=Normal.

1=Slightly delayed and/or reduced in amplitude.

2=Moderate violation. A certain and early fatigue. Can be a rare stop in motion.

3=Serious violation. Frequent hesitation at the start of the movement and stop what is happening in the movement.

4=can Hardly do the job.

X. Rapid alternating movements of hands (pronation-supination movements of hands, vertically and horizontally, with the highest possible amplitude, both hands at the same time)

0=Normal.

1=Slightly delayed and/or reduced in amplitude.

2=Moderate violation. A certain and early fatigue. There may be rare stop motion.

3=Serious violation. Frequent hesitation at the start of the movement and stop what is happening in the movement.

4=can Hardly do the job.

C. the Ability of the legs (the Patient stomping the heel on the ground in rapid succession, lifting the whole leg. The amplitude must be at least 3 inches (7.5 cm).

0=But is normal.

1=Slightly delayed and/or reduced in amplitude.

2=Moderate violation. A certain and early fatigue. There may be rare stop motion.

3=Serious violation. Frequent hesitation at the start of the movement and stop what is happening in the movement.

4=can Hardly do the job.

Hours getting up from chair (Patient attempts to rise from a chair with a straight back, with the patient's arms crossed on chest). 0=Normal.

1=Slow; or you may need more than one attempt.

2=Proceeds from the handles of the seat.

3=Tend to fall back and may have to try more than once, but can stand alone.

4=can't get up by yourself.

W. Posture

0=Normal straight.

1=Not quite straight, slightly hunched posture; may be normal for an older person.

2=Moderately hunched posture, definitely abnormal; there can be a slight tilt to one side.

3=Severely hunched posture with kyphosis; may be a moderate slope to one side.

4=marked inclination with extremely abnormal posture.

S Gait

0=Normal.

1=slow, you may face while going short steps, but not mincing gait (accelerated steps) or propulse.

2=with difficulty, but it doesn't want, or need a little help; can businessaffiliate mincing gait, short steps or propulse.

3=Severe gait disturbance requiring assistance.

4=can't walk, even with help.

E. Postural stability (Response to sudden, strong posterior offset produced by stretching the shoulders, when the patient stands erect with eyes open and slightly spread legs. The patient is prepared.)

0=Normal.

1=Metropulse, but returns to its original position without assistance.

2=the Absence of postural response; fall, if you don't support the researcher.

3=Very unstable, prone spontaneously lose balance.

4=unable to stand without assistance.

AA. Bradykinesia and hypokinesia of the body (Combining slowness, hesitation, reduced arm swing, small amplitude and poverty of movement in General).

0=No.

1=Minimal slowness, giving the movement a regular character; may be normal for some persons Possibly reduced amplitude.

2=Mild slowness and poverty of movement, which is definitely abnormal. An alternative, slightly reduced amplitude.

3=Moderate slowness, poverty or small amplitude of movement.

4=marked slowness, poverty or small amplitude of movement.

Total UPDRS score is determined from separate estimations following the way:

First, for each patient participating in the study, determine the original value. It is done by summing the individual estimates UPDRS parts II and III, the settings on 0 day, i.e. before treatment. Any definition UPDRS assessment during the course of treatment will then be compared to this initial value and record changes relative to the original values. Finally, the average improvement in UPDRS II+III 77 day (week 11) relative to the original level is determined by averaging all the participating test subjects. The resulting value indicate the FAS (full analyzed group) randomized mean change from baseline total UPDRS assessment (II+III) and is applied to the y-axis of Figure 1. The term "randomized" refers to the fact that patients in advance randomized to different predefined dose.

It is known that patients suffering from Parkinson's disease, have relatively strong placebo effect, that is, even the placebo treatment improves to some extent UPDRS assessment of patients with Parkinson's disease. Therefore, it is important to compare any effects treatment drug level UPDRS improvement obtained in the treatment of placebo with the same duration. Final evaluation of the improvement, therefore, make the relative treatment effect is lacebo with the same duration.

The results:

There was a significant, dose-dependent improvement in UPDRS II/III estimates between baseline and 11 weeks, when applying the TTS according to the present invention, in particular for at 9.0, 13.5 and 18 mg groups compared with placebo. This result can be seen from Figure 1 and the following table:

Table 3
The size of the patchThe number of rotigotineImproved mean total UPDRS II+III compared with treatment with placebo for 11 weeksp (one-sided)
10 cm24.5 mg-2,1480,0393
20 cm29.0 mg-3,1230,0063
30 cm213.5 mg-4,9090,0000
40 cm218,0 mg-5,0350,0000

Rotigotine, with the introduction of using the TTS according to the invention is usually well tolerated. Skin reactions at the site of overlap were usually mild and occurred with placebo patches, but were more common among subjects randomized into groups with higher dosages. Between the groups regarding patient vital signs, laboratory tests and ECG were not different./p>

Conclusions:

The above results showing for the first time in a placebo-controlled study that dopamine agonist (rotigotine), percutaneous insertion and once a day through specific TTS, leads to clinical improvement with satisfactory tolerance and safety in patients with Parkinson's disease at an early stage.

This result could not be obtained either using acrylic percutaneous therapeutic system of WO 99/49852 or when using silicone percutaneous therapeutic system of WO 94/07468. In the light of the indicated prior art, this result should be regarded as extremely surprising and useful for patients with Parkinson's disease.

1. The use of percutaneous therapeutic systems based on silicone containing a mixture of at least one effective under the pressure of a silicone adhesive, with high adhesion, and at least one effective under pressure silicone adhesive with a medium stickiness, as the main adhesive component, with an area of from 10 to 40 cm2and containing from 0.1 to 3.15 mg/cm2rotigotine (rotigotine) in free base form as the active ingredient, for the preparation of antiparkinsonian medication, which causes an improvement compared with placebo treatment,the patient's condition - person with Parkinson's disease, as measured by standardized rating scale for Parkinson's disease (UPDRS)parts II and III, 2 units or more after injection for at least 7 weeks.

2. The use according to claim 1, where the transdermal therapeutic system based on silicone further comprises a solubilizer.

3. The use according to claim 2, where the solubilizer is a polyvinylpyrrolidone.

4. The use according to claim 1, where the transdermal therapeutic system based on silicone contains less than 1 wt.% inorganic silicates.

5. The use according to claim 4, where percutaneous therapeutic system based on silicone free from inorganic silicates.

6. The use according to claim 1, where the transdermal therapeutic system has an area of from 10 to 30 cm2.

7. The use according to claim 1, where the transdermal therapeutic system contains from 0.1 to 1.5 mg/cm2rotigotine.

8. The use according to claim 1, where the transdermal therapeutic system is a patch with an area of from 10 to 30 cm2and the content of rotigotine from 0.4 to 0.5 mg/cm2in the adhesive matrix is silicone-based.

9. A method of treating Parkinson's disease by imposing on the patient suffering from this disease, percutaneous therapeutic systems based on silicone containing a mixture of at least one effective under the pressure of a silicone adhesive, it is found high stickiness, and at least one effective under pressure silicone adhesive with a medium stickiness, as the main adhesive component, with an area of from 10 to 40 cm2and containing from 0.1 to 3.15 mg/cm2rotigotine in free base form as the active ingredient, where the improvement is that the patient's condition, as measured by standardized rating scale for Parkinson's disease (UPDRS)parts II and III, improved, compared with placebo treatment, 2 units or more, after introduction during the period of time of at least 7 weeks.

10. Percutaneous therapeutic system based on silicone for the treatment of Parkinson's disease, which has a size of from 10 to 30 cm2and contains from 0.4 to 0.5 mg/cm2rotigotine in free base form as an active ingredient in a matrix containing a mixture of at least one effective under the pressure of a silicone adhesive, with high adhesion, and at least one effective under pressure silicone adhesive with a medium stickiness, as the main adhesive component.

11. Transdermal therapeutic system of claim 10, which contains less than 1 wt.% inorganic silicates.

12. Transdermal therapeutic system of claim 10, which further comprises a solubilizer.

13. Percutaneous therapeutic system p is 12, where the solubilizer is a polyvinylpyrrolidone.



 

Same patents:

FIELD: medicine.

SUBSTANCE: device has Dacron sack usable as envelope introducible into soft tissues of the head. The envelope has two 0.5 mm thick liver tissue leaflets between which hypothalamus tissue leaflets taken from young animal brain and black substance or isolated suprarenal gland medullary substance cells or that of human glands or the like cells taken from human embryo. The Dacron envelope is 25-30 cm long, 5 mm wide and 2 mm thick.

EFFECT: enhanced effectiveness of treatment.

2 cl, 1 dwg

FIELD: medicine.

SUBSTANCE: biotransplant has active ingredient like culture of genetically unmodified neuron trunk cells taken from anterior brain of the first pregnancy trimester human embryo or periventricular region of brain of 15-20 gestation weeks and selectively reproduced under cultivation conditions to the amount of 107-109 pluripotent non-differentiated cells in neurospheres having 50-500 mln of neuron trunk cells and 2 ml of physiologic saline. Method involves introducing 50-500 mln of neuron trunk cells and 2 ml of physiologic saline in one stage in endolumbal way.

EFFECT: enhanced effectiveness of treatment; accelerated repair and improvement of injured brain functions; stable treatment results.

5 cl, 1 tbl

FIELD: pharmacology.

SUBSTANCE: invention provides a pharmaceutical combination influencing central nervous system function, which contains (i) at least one compound influencing central nervous system function; (ii) at least one compound beneficially affecting central nervous system, and compound assisting first compound to cross blood-brain barrier, namely an agent for endonasal administration manifesting reflex, preferably neuro- and vasoactive action on nasal mucosa structures and receptors, basically receptors of vomeronasal organ and trigeminal nerve systems; (iii) active oxygen forms selected from hydrogen superoxide, hydrogen peroxide, NO-, and CO-active compounds; and (iv) pharmacological stabilizer.

EFFECT: lowered doses and reduced adverse effects.

22 cl, 2 tbl, 8 ex

The invention relates to medicine and can be used to obtain biologically active substances from the blood serum of animals and birds, are useful for the treatment or correction of a hearing impairment, sexual activity, spatial memory; and to increase physical endurance, stimulate proliferation of embryonic brain cells; useful in Parkinson's disease

The invention relates to sulfonylacetanilide General formula I

in which R1and R2each independently of the other denotes H, A, -(CH2)n-Ar or R1and R2both together are a single rich heterocycle with the nitrogen atom, Z represents H, A, CF3Hal or OA, a is alkyl with 1-6 carbon atoms, Ar denotes a one - or disubstituted by Deputy Z is phenyl, provided that Z cannot be a hydrogen atom, Hal represents F, Cl, Br or I, n is 1 or 2, or a physiologically acceptable salt or solvate

The invention relates to the field of organic chemistry, particularly to substituted 2-phenyl-1-(3,4-dihydroxy-5-nitrophenyl)-1-ethanones

The invention relates to the pharmacy and relates to pharmaceutical compositions for the treatment of Parkinson's disease and Parkinson syndromes

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

The invention relates to a new one with selective affinity to T6receptors, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]triazines General formula I, where X denotes a =C(R4)- or =N-, R1denotes phenyl, optionally substituted by one or more radicals of lower alkyl, halogen, lower alkoxygroup, tolyl, pyridyl, naphthyl or thiophenyl, R2denotes hydrogen, (ness.)alkyl, (ness.)thioalkyl or hydroxy(ness.) alkoxygroup, R3denotes amino(ness.)alkylamino, di(ness.)alkylamino, piperazinil, optionally substituted by one or more radicals, lower alkyl, benzyl, phenyl or hydroxy(NISS

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of amidines of the general formula (I):

wherein R1 means alkyl; R2 means alkyl, alkenyl, alkynyl or cyanoalkyl; R3 means hydrogen atom; n = 0 or 1; X means -(CH2)m- wherein m = 0 or 1; A means heterocyclic 5-membered aryl radical comprising sulfur atom (S), or to salts of these compounds, their preparing and using as medicinal agents. Also, invention relates to using abovementioned derivatives for preparing a medicinal agent designated for inhibition of activity of NO-synthases (NOS) and/or monoaminoxidases (MAO).

EFFECT: improved preparing method, valuable medicinal properties of compounds.

6 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention proposes using percutaneous therapeutic system inducing high plasma levels of rotigotin for producing anti-parkinsonic medicinal agent and a method for treatment of Parkinson's disease. Proposed system involves rotigotin in the concentration from 0.1 to 3.15 mg/cm2 in form of free base and silicone representing a mixture of at least one pressure-sensitive stick silicone adhesive (Q7-4301) and at least one pressure-sensitive silicone adhesive with mean stickness (Q7-4201). This provides an average plasma concentration of rotigotin from 0.4 to 2.0 ng/ml for 24 h after its applying.

EFFECT: enhanced medicinal effectiveness of system.

10 cl, 2 tbl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in stomatology in the topical anesthesia. The pharmaceutical composition comprising articaine hydrochloride and epinephrine hydrochloride and accessory substances, such as sodium metabisulfite, sodium chloride and water for injection involves additionally glycine and pH-regulating substance taken in the definite ratio of components. Invention provides preparing the preparation that is stable, non-toxic and doesn't cause allergic response reactions and elicits highly expressed infiltration and conducting anesthetic activity, good tissue tolerance and activity promoting to accelerated wound-healing in the post-operative period.

EFFECT: improved and valuable medicinal properties of composition.

3 cl, 3 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biphenylsulfonylcyanamides of the formula (I): wherein R1 means: 1. (C1-C8)-alkyl; 4. -CnH2n-nn-Y wherein nn = 0 or 2 and n = 0-4, and n is not 0 or 1 if nn = 2; 5. CnH2n-nn-Y wherein nn = 0 or 2 and n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with amino-group or NR(22)R(23); R2 means: 2. (C1-C)-alkyl; 4. (C2-C12)-alkenyl; 5. (C2-C8)-alkynyl; 6. -CnH2n-nn-Z wherein nn = 0 or 2; n = 0-4, and n is not or 1 if nn = 2; 7. -CnH2n-nn-Z wherein nn = 0 or 2; n = 1-4, and n is not 1 if nn = 2, and 1 hydrogen atom in bivalent residue CnH2n-nn is substituted with a residue taken among a series: 1. phenyl; 3. NR(22)R(23); 5. COOR(16); R3 and R4 mean hydrogen atom; R5, R6 and R7 mean independently of one another hydrogen atom (H), (C1-C8)-alkyl; SO2-(C1-C4)-alkyl, F, Cl, Br, J, OR(10) wherein R(10) means hydrogen atom, (C1-C4)-alkyl that is substituted if necessary with methoxy- or ethoxy-group; R(9) means OR(13) wherein R(13) means hydrogen atom, H,(C1-C8)-alkyl;X means carbonyl group, -CO-CO- or sulfonyl group; Y and Z mean independently of one another: 1. phenyl, 1-naphthyl, 2-naphthyl; 2. one of residues determined in cl. 1 substituted with 1-5 similar or different residues taken among a series: phenyl, F, Cl, Br, J, CF3, SOqR(18), OR(16), NR(19)R(20), -CN, NO2, COR(9), or two residues form methylenedioxy-group; 3. furyl, thienyl, pyridyl, benzimidazolyl, indolyl, benzothiophenyl, dihydroquinazolinyl; 5. (C3-C10)-cycloalkyl wherein cyclopropyl, cyclopentyl, cyclohexyl and indalyl are preferable; 6. one of residues determined in cl. 5 substituted with phenyl; R(16) means: 1. hydrogen atom; 2. (C1-C4)-alkyl; 3. (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; R(19) and R(20) mean independently: hydrogen atom (H), (C1-C4)-alkyl; R(22) and R(23) mean independently of one another hydrogen atom (H) or CO-OR(24) wherein R924) means -CnH2n-phenyl wherein n = 1-4; q = 2; and their physiologically acceptable salts. Compound of the formula (I) inhibit sodium-dependent chloride-bicarbonate exchange "NCBE".

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 cl, 2 tbl, 568 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

Dressing material // 2270646

FIELD: medicine, in particular dressing materials based on polymeric hydrogel coats.

SUBSTANCE: dressing material contains polymer film with polymeric hydrogel layered on the surface thereof. Said film is made of biocompatible optically transparent polymer having open holes with diameter of D = 0.01-3.0 mum and density of N = (103-109) 1/cm2, and polymeric hydrogel contains chitosan hydrogel. Dressing material of present invention prevents microorganism infiltration into wound and may be easily attached to wound surface.

EFFECT: improved dressing material with bacteriostatic action.

24 cl, 4 dwg, 8 ex

Up!