Pharmaceutical composition and method for treating chronic fatigue syndrome due to its application
FIELD: medicine, pharmaceutics.
SUBSTANCE: the suggested pharmaceutical composition contains 2-ethylthiobenzimidasol hydrobromide at efficient quantity and a pharmaceutically acceptable carrier. Method for preventing and treating chronic fatigue syndrome should be fulfilled due to introducing the mentioned pharmaceutical composition at its daily dosage of 250-1500 mg for 5-20 d to provide the chance for repeating the course of therapy after an interval of 5 d or more. While treating chronic fatigue syndrome one should additionally apply cavinton, adenosine triphosphate, vitamins, cibazone, mesapam to realize the mentioned indication.
EFFECT: higher efficiency.
4 cl, 6 ex, 4 tbl
The invention relates to medicine, in particular to pharmacology, and in particular to pharmaceutical compositions for the treatment of multiple sclerosis, and other neurodegenerative diseases, and chronic fatigue syndrome.
Multiple sclerosis - demyelinizing disease of the Central nervous system of unknown etiology. Multiple sclerosis is characterized by disseminated by demyelination of axons in the brain in the periventricular areas and in the corpus callosum. In the pathogenesis of multiple sclerosis plays a leading role in autoimmune inflammation, manifested in the destruction of myelin-type hypersensitivity delayed-type mechanism which is mediated by Th1 lymphocytes.
The emergence of foci of demyelination in the stem structures of the brain and vertebral-basilar insufficiency are caused by vestibular disorders, multiple sclerosis, resulting in the deterioration of rheological properties of blood, vascular spasm of small and medium caliber. Disorders of vestibular function in the form of permanent or paroxysmal disorders are almost mandatory for multiple sclerosis. Vestibular dysfunction usually manifests itself by symptoms of irritation is the feeling of dizziness, spontaneous nystagmus, impaired Vestibulo-spinal reflexes, spinal functions and others.p> Changes in mental spheres have different clinical manifestations: the asthenic syndrome istiophoridae reactions, obsessive disorders, depression and euphoria, a kind of organic dementia. Depression occurs in 20-30% of patients, with 2-3% experiencing suicidal attempts. The risk of suicide in patients with multiple sclerosis significantly higher than in the population as a whole.
Etiotropic therapy of multiple sclerosis does not currently exist. Comprehensive symptomatic therapy of the disease is aimed at preventing the destruction of brain tissue and suppression of autoimmune inflammation. Therapy includes corticosteroids, adrenocorticotropic hormone (ACTH), interferons, glatiramer acetate, in the acute stage of the disease is prescribed immunosuppressive therapy with cytostatics.
However, the existing scheme of complex therapy of multiple sclerosis has significant drawbacks. Used medication and physical therapy methods do not allow to significantly reduce the severity of neurological symptoms, the speed of their rise or significantly increase the duration of remission. Using these drugs it is impossible to achieve repair defects associated with the destruction of myelin in the membranes of axons, and, consequently, the recovery of the patient.
Secondly, it is not possible also in order to improve the condition of patients and to stem the loss of memory, attention and adequate thinking, as well as to arrest the pyramidal symptoms: dizziness, vision loss and other violations. Additionally, the medications do not eliminate autoimmune component in the pathogenesis of multiple sclerosis and, thus, not able to break the vicious circle of disease progression.
However, corticosteroid therapy in increasing doses gives a number of side effects, manifested in the development of the syndrome Itsenko-Cushing syndrome, hypertension, ulcers, hypertrichosis and other effects, and immunosuppressive therapy significantly increases the risk of infectious diseases.
It is known that the chronic fatigue syndrome, which is now regarded as an independent disease, often occurs in multiple sclerosis. Usually this syndrome manifests itself as the inability to prolonged or repeated execution of the daily routine for the patient, action, and the need for frequent rest. Fatigue affects not only physical, but also mental health. Chronic fatigue significantly affects the quality of life of patients and even in the early stages of the disease limits their ability to work. It is believed that in the development of this syndrome takes part in the immune system that p is another advantage, in particular, increased levels of proinflammatory cytokines in the serum of patients.
Specific treatment for chronic fatigue syndrome does not exist. However, it is suggested, a sufficient number of means and methods of treatment involving the use of fasting, special diets, vitamin therapy, herbal medicine, nutraceuticals and biologically active additives (BAA), adaptogens, antidepressants, some tranquilizers, nootropic agents, chelators, and other tools.
However, all these methods and treatments of chronic fatigue syndrome is symptomatic and does not fully take into account the pathogenetic features of the development and course of the disease.
Known use of drugs on the basis of benzimidazole derivatives for improving mental and physical health of persons in professional activities associated with elevated physical activity, in asthenic conditions; in the complex therapy of traumatic brain injury, disorders of cerebral circulation.
Known application of 2-ethyl-mercaptobenzimidazole bromide as psychotropic drugs, with act-protective psihoenergetichesky and antihypoxic action (EN, 1251374, A1).
It is also known the use in the pharmaceutical compositions of the producers who were 2-ethylthiophenethylamine hydrobromide and hydrochloride, exhibiting weak anxiolytic activity (RU, 2061686, C1).
Known drug belonging to the group of Ecoprotection, providing a mild stimulating effect, in which the active ingredient is 2-ethyl-mercaptobenzimidazole hydrobromide used for the treatment of systemic lupus erythematosus (EN, 2157684, C2). This connection with antihypoxic activity, is used at the edge of psychiatric disorders, when shown the stimulation of mental and physical functions.
Known application of 2-ethyl-mercaptobenzimidazole bromide in the treatment of patients with primary billiary cirrhosis as an immunomodulating means acting on cellular immunity and contribute to the effectiveness of other, used in the treatment of cirrhosis, drugs directed action (EN, 2188012, C2).
It is known the use of Ecoprotection containing as active ingredient a derivative of 2-ethylthiophenethylamine hydrobromide monohydrate, for the treatment of Duchenne muscular dystrophy - Becker (EN, 2173144, C2). However it is noted that the derivative due to the structural similarity to purine bases adenine and guanine increases the synthesis of mitochondrial enzymes, increasing the energy potential of the muscle tissue and stimulating will oxidize is the super-regenerative processes. Increasing the energy potential of the muscle tissue contributes to the activation of the synthesis of proteins and enzymes, resulting in decreased permeability of the membranes of myocytes, promotes muscle regeneration, slow ministrations process.
It is known the use of a medicinal product containing 2-ethylthiophenethylamine hydrobromide monohydrate, as a means of increasing the body's resistance to hypoxia and reducing efficiency when performing heavy physical exertion or exposure to adverse factors, as well as to eliminate polipragmazie, for the prevention of occupational hearing loss (EN, 2017483, C1), prevention of acute attacks of glaucoma during geomagnetic storms (EN, 2019161, C1).
Known application of 2-ethylthiophenethylamine hydrobromide for the treatment of the hypothalamic-pituitary insufficiency in women (EN, 2138263, C1) using the effect of increasing the resistance of the brain to asphyxia and circulatory hypoxia, which is manifested by a pronounced increase in brain blood circulation, improve oxygen supply to the brain, and the effect of inhibition of the degradation of the energy functions of mitochondria neuroglial cells.
Strengthening education mitochondrial enzymes and structural proteins of the mitochondria provides the increase of energy products and maintaining a high degree the Yeni conjugacy oxidation from phosphorylation.
Maintaining a high level of ATP synthesis in the lack of oxygen contributes to pronounced antihypoxic and anti-ischemic activity of benzimidazole derivatives, pharmaceutical compositions based on these compounds increase the synthesis of antioxidant enzymes and possess a strong antioxidant effect.
The purpose of the invention is to develop medicines and treatment of multiple sclerosis, and other neurodegenerative diseases and chronic fatigue syndrome.
In the claimed invention was set the task of finding medicines can have concomitant psychotropic and immunotropic action and thereby significantly reduce the pathological effects associated with neurodegenerative consequences of the destruction of myelin in multiple sclerosis, pathological effects in other neurodegenerative diseases and chronic fatigue syndrome.
Analysis of the above data revealed common features in the effectiveness of the actions on the Central nervous and immune systems of medicines on the basis of benzimidazole derivatives.
The task was solved by the development of pharmaceutical compositions containing as active ingredient a derivative of benzimidazole that have a marked stimulating and immunomodulatory effects, as well as the development of methods of treatment for these diseases.
Study of the biological activity of derivatives of benzimidazole, confirming the effectiveness of the drug for the treatment of multiple sclerosis, and other neurodegenerative diseases and chronic fatigue syndrome were performed using 2-ethylthiophenethylamine hydrobromide on the following experimental models.
Example 1. The influence of benzimidazole derivatives on neurochemical indices of neurodegeneration in rats, caused by the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
As experimental models of neurodegenerative pathology that causes persistent violations of specific neurons, activation of lipid peroxidation of membranes, blockade of membrane transport and intracellular metabolism of the neurotransmitters used the neurotoxin MPTP (Schneider&Kovelowski, 1990). Experiments were performed on adult male Wistar rats.
The toxin was administered to rats intraperitoneally twice a day in a dose of 20 mg/kg, then the animals were decapotable, extracted from brain striatum and studied the secretory capacity of this brain structure, providing cognitive and motor activity in ex vivo perfusion of slices of the brain by well-known methods (Kereczen et al., 1984; Bulygin et al., 1996). The group under pitnych animals with simulated neurodegenerative disorders have also introduced 2-ethylthiophenethylamine hydrobromide (hereinafter EBIG) at a dose of 50 mg/kg vnutribruchinno.
As the investigated parameters were used quantitative content of the neurotransmitter dopamine and its metabolite - dioxygenase acid (hereinafter DOHUK) in isolated fragments striatum of rat brain. The results of the tests are presented in table. 1.
From the results shown in table 1, it is seen that a single injection of the neurotoxin MPTP (group 2) inhibits the metabolism of the neurotransmitter dopamine, which is accompanied by decrease in the concentration of DOHUK by 44% compared with control. The introduction of the neurotoxin MPTP for 5 days (group 3) induced a decrease in the secretion of the neurotransmitter dopamine to 33% compared with control. Introduction 2-ethylthiophenethylamine hydrobromide dose of 50 mg/kg (group 4) restores the secretion of dopamine to 118%, which indicates its ability to compensate for these effects of neurotoxic brain damage.
Example 2. The influence of benzimidazole derivatives on behavioral symptoms of neurodegeneration induced in rats by the neurotoxin MPTP.
It is known that the destructive effects of the neurotoxin MPTP on secretory processes of the striatum of the brain at the level of whole organism manifests itself as symptoms of oligodontia, tremor and muscular rigidity. The change of these indicators was studied in experiments on rats l the Wistar Institute, which was injected neurotoxin MPTP (20 mg/kg) or the neurotoxin MPTP (20 mg/kg) in combination with 2-ethylthiophenethylamine the hydrobromide (50 mg/kg), as described in example 1.
As the investigated parameters were taken the severity of oligodontia, which were assessed in terms of their locomotor activity in open field test and rigidity of the muscles, which was evaluated in arbitrary units by well-known methods (Voronin et al., 2000). The results are shown in table. 2.
|The influence of benzimidazole derivatives on behavioral symptoms of neurodegeneration caused by the neurotoxin MPTP and BIG in rats|
|no group||Used substances, dose, mode of administration, the number of animals n||The severity of oligodontia, in % of the control||Muscle rigidity, in conventional units - points|
|1||Control, saline, n=8||100±12||0,3|
|2||MPTP (20 mg/kg once a day for 5 days), n=6||10±4*||1,0*|
|3||MPTP (20 mg/kg once a day for 5 days)+BIG (50 mg/kg, once a day), n=6||55±6#
(black is C 1 h)
(after 3 h)
As you can see from the table. 2 introduction within 5 days of the toxin leads to reduction of motor activity of animals 10 times and increased muscle rigidity 3 times. A single injection of 2-ethylthiophenethylamine hydrobromide dose of 50 mg/kg within 1 hour provides a partial restore mobility and complete disappearance of muscular rigidity, which indicates its ability to compensate for behavioral symptoms of neurotoxic brain damage.
Example 3. The influence of benzimidazole derivatives on the symptoms of poor attention and orientation in space of mice caused by the excitatory amino acid l-glutamate in neurotoxic concentration.
As an experimental model of impaired attention and orientation in space, which is a consequence of neurodegenerative processes, used the test of exploratory behavior in animals to cross the maze (method described Salimov, 1988; Salimov et al., 1995; Salimov et al., 1995). Studies were conducted on adult male C57BL.
As a damaging factor used bilateral application for the frontal cortex of mice (coordinates: F - 2.0, L - 1.4, N - 0.6) 5 μl 1.0 mM solution of l-glutamate. It is known that the concentration of l-glutamate has neurotoxic action is eat (Finkbeiner, Stevens, 1988; Crabbe, Dorsa, 1989; Meldrum, Garthwaite, 1990) and within 1-2 hours causes local destruction of about 95% of glutamate-sensitive neurons in the area of software, the recovery of which is not happening, at least in the next month. Testing was performed one week after application. 2-ethylthiophenethylamine the hydrobromide was administered intraperitoneally at a dose of 50 mg/kg 30 minutes prior to testing. The results are given in table 3.
|The influence of benzimidazole derivatives on the motor activity and orientation in space of mice|
|no group||The model tests, the substance, the mode of administration, dose, number of animals n||The duration of the examination of the maze to criterion 12 transitions||The number of transitions until the first full crawl maze|
|1||Application of saline (control), n=25||224,3±14||4,7±0,2|
|2||Application of l-glutamate, once, n=25||304,9±33,3***||7,4±0,6***|
|3||Application of l-glutamate in combination with ABIG week (p the following l-glutamate, 50 mg/kg, once a day), n=25||216,6±12,1###||4,8±0,2 ###|
|Note: *** and ### indicate statistically significant difference from the introduction of saline solution and neurotoxic application of l-glutamate, respectively.|
From table. 3 shows that the neurotoxic applique l-glutamate caused significant disturbances in attention and orientation in space, which was manifested in the form of increasing the number of transitions until the first full traversal of the maze. Application of l-glutamate evoked slower exploratory activity of mice that were manifested in the form of increasing the duration of the examination of the maze to criterion 12 transitions. A single injection of 2-ethylthiophenethylamine hydrobromide dose of 50 mg/kg completely eliminated these behavioral manifestations neurotoxicity of l-glutamate.
Example 4. The influence of benzimidazole derivatives on the symptoms of chronic fatigue in mice, caused by the introduction of sub-chronic neuroleptic haloperidol.
As an experimental model of chronic fatigue syndrome used the time evaluation of complex sensorimotor (research) activity in mice exposed to sub-chronic course of neuroleptic haloperidol.
As shown by measuring the binding of the labeled agonist DOP is minovich receptors daily administration of haloperidol in 2-3 weeks at doses above 0.5 mg/kg leads to an increase in the number of D2 dopamine receptors in the striatum (Joseph et al., 1983; Fleminger et al., 1983; Hitri et al., 1978) and in the adjacent core (Seeger et al., 1982; Wolffgramm et al., 1990; Hitri et al., 1978)observed for at least 7 days after discontinuation of haloperidol. There are chronic problems of complex sensorimotor (research) activity (Salimov et al., 2000).
Studies were conducted on adult male C57BL. Haloperidol at a dose of 1 mg/kg was administered intraperitoneally once a day for 12 days. Investigated sensorimotor activity in mice cross the maze by a known method (Salimov, 1988; Salimov et al., 1995; Salimov et al., 1995) through day after sub-chronic administration of neuroleptic haloperidol. 2-ethylthiophenethylamine hydrobromide (BIG) was administered intraperitoneally at a dose of 50 mg/kg 30 min before the test. The results are given in table 4.
|The influence of benzimidazole derivatives for the violation of a complex sensorimotor (research) activity caused by the introduction of sub-chronic haloperidol and derived EBIG|
|no group||Used substances, dose, mode of administration, kolichestvennyh n||The duration of the examination of the maze to criterion 12 transitions||The number of transitions until the first full crawl maze|
|1||The introduction of saline solution (control), n=25||248,5±a 12.7||5,6±0,3|
|2||The introduction of haloperidol (1 mg/kg once a day for 12 days), n=25||369,1±39,2***||4,9±0,2|
|3||The introduction of haloperidol (1 mg/kg, once a day||256,6±15,4###||5,1±0,4|
|for 12 days) in combination with BIG (the next day after a course of haloperidol once daily, 50 mg/kg), n=25|
|Note: *** and ### indicate statistically significant difference from the introduction of saline solution and neuroleptic haloperidol, respectively.|
Table 4 shows that the introduction of neuroleptic haloperidol causes chronic difficulty (slow) research activity, which was manifested in the form of increasing the time required animals to make 12 transitions from a sleeve in the sleeve of the maze. A single injection of 2-ethylthiophenethylamine hydrobromide made through the day after the last injection of haloperi the Ola, completely eliminate these symptoms difficulties of research activities.
The pharmaceutical composition according to the invention, containing a biologically active ingredient is a derivative of benzimidazole, was applied in a clinical setting for the treatment of 10 patients with multiple sclerosis and 10 patients suffering from chronic fatigue syndrome.
Example 5. Using 2-ethylthiophenethylamine hydrobromide for treating multiple sclerosis.
The pharmaceutical composition according to the invention, containing a biologically active ingredient is a derivative of benzimidazole, for example 2-ethylthiophenethylamine hydrobromide, can be used according to the invention, for the prevention and treatment of multiple sclerosis and other neurodegenerative diseases in a daily dose of 500-1500 mg a course 20-25 days with the possibility of repetition of a course of treatment over a two-week interval.
The proposed method of treatment used in the treatment of multiple sclerosis in 10 patients with different clinical forms of the disease. As an example of the efficacy and safety of treatment of multiple sclerosis 2-ethylthiobenzimidazole the hydrobromide here is an extract from the history.
Patient P. 47 years old (case history No. 201/46). Diagnosis: Multiple sclerosis, spinal the Orme, recurring-limitiruyuscaya form. 2 the severity.
She became ill in 1990, when there was a sudden weakness in the legs, numbness, blurred vision. Three months function has fully recovered. In 1997 after exercise there is a weakness in the hands, disturbed coordination, deteriorated vision. Was treated with piracetam, pentoxifylline, multivitamins, symptoms slowly regressed. Last exazerbation since may 2003.
In the study of the nervous system: the knee and Achilles reflexes above right, hyperesthesia level D9 by conduction type, violated the deep sensitivity of the lower extremities, the symptom Barre with both lower extremities, abdominal reflexes are absent, incoordinate when performing EOR, instability in the Romberg position, positive symptom Neri, limiting the volume of active movements of the cervical and lumbar spine, mainly rotary and lateroflexion.
Admission: blood - Hb - 126 g/l, er 4,4 1012l-1a colour indicator - 0,87; L - 7,5·10 l: eosinophils - 1%, basophils - no, a young shape - no, stab - 2%, segmented - 74%, lymphocytes - 16%, monocytes 7%, and ESR - 9.0 mm/hour. Glucose - 5.17 mmol/l, creatinine is 71.5 mmol/l, creatine - of 20.5 Ámol/L.
Urinalysis: color - yellow; transparency is incomplete; the reaction of the acid; protein - no; glucose - no; the cylinders and the epithelium of the kidney is absent; erythrocytes - no; leukocytes 0-1 in the field of view; flat epithelium - 0-1 in the field of view; bacteria in large quantities.
ECG: heart rate 70 / min, sinus rhythm, blockage of the left anterior branch of bundle of his, signs of left ventricular hypertrophy.
Echocardiography: moderate sclerosis of the aorta, heart cavity is not expanded.
Brain MRI: no pathological changes.
Treatment: piracetam, pentoxifylline, vitamins, massage. 2-ethylthiophenethylamine hydrobromide patient received three times daily 250 mg orally. The drug lasted for three weeks.
On the background of therapy was achieved clinical and MRI tomographic remission. The patient had normal clinical and immunological parameters. Objectively improved mental and physical condition that was characterized by a decrease in the severity of the pathological symptoms of multiple sclerosis, increase muscle strength of the lower extremities, increase physical activity, improve coordination of movements. Significantly improved memory and speed of mental processes. Improved mood and sleep. The patient was discharged under the supervision of the precinct neurologist with a recommendation to continue the treatment ethylthiobenzimidazole on an outpatient basis.p> In connection with the above-described mechanism of action of benzimidazole derivatives, such as 2-ethylthiophenethylamine hydrobromide, on the Central nervous system and the immune system of patients with multiple sclerosis pharmaceutical composition according to the invention may be applied to the treatment of other neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, a daily dose of 750-1500 mg course duration 20 days repeatable treatment over a two-week interval.
Example 6. Using 2-ethylthiophenethylamine hydrobromide for treating chronic fatigue syndrome.
The pharmaceutical composition according to the invention, containing a biologically active substance benzimidazole derivatives, such as 2-utilitiesa, can be applied, according to the invention, for the treatment of chronic fatigue syndrome in a daily dose of 500-1000 mg course for 15-20 days with the possibility of repetition of a course of treatment over a two-week interval.
A clinical study of the effectiveness of the pharmaceutical compositions according to the invention, for example, containing as active ingredient 2-ethylthiophenethylamine hydrobromide, for the treatment of chronic fatigue syndrome (CFS) was performed in a group of 10 patients. As an example of efficiency is the treatment of CFS method according to the invention provide a statement of medical history.
The patient Including age 29 (No. 2995/180) Diagnosis: chronic fatigue Syndrome. Neurasthenia with syncopal attacks.
Sick since 1993 after traumatic situations in life. Complains of constant headaches, General weakness, weakness in the lower extremities, noise in the head, fatigue, irritability, tearfulness, or fainting.
In the study of the nervous system installed: deep reflexes increased, D=S, quickened by functional type, finger tremor of the upper extremities, incoordinate when performing dynamic coordinatory samples from two sides (functional).
When receiving a blood test: Hb - 130 g/l; er - 4,5 10 l; colour index is 0.86; Rt - 8%; L - 4,4 10 l of them e - 6%, B - no, M - no, n - no, P - 6%, 47%, L - 37%, M 4%; Tr - 270. ESR - 7 mm/h. Blood clotting - 10 minutes
Glucose - is 5.06 mmol/l, urea - 6.6 mmol/l, bilirubin - 16.5 mmol/l, protein 59 g/l, cholesterol - 5,64 mmol/l, PETIT - 87%.
Urinalysis: color straw-yellow, transparency is incomplete, density - 1010 g/l, reaction - acidic, protein, glucose - no, the cylinders, the epithelium of the kidneys - not detected. Er - no, L is the unit in the field of view.
ECG - heart rate - 77 min, the position of the electrical axis of the heart's normal sinus rhythm.
EEG - light diffuse changes in the bioelectrical activity of the brain.
Treatment: Cavinton, ATP, vitamins, with bison, medazepam, 2-ethylthiophenethylamine hydrobromide patient received daily 750 mg orally for 15 days.
As a result of therapy was achieved significant improvement in the General condition of the patient. Deep reflexes were normal, significantly improved coordination, disappeared tremor of the upper extremities. Frequency and intensivnosti headaches decreased significantly. Improved mood, appetite, complaints of weakness does not apply. The patient was discharged with the recommendation to hold a second course of therapy 2-ethylthiobenzimidazole the hydrobromide in a month on an outpatient basis.
Thus, from the above test results, the pharmaceutical compositions according to the invention, in particular the biological activity of its akvtivnyh ingredient - benzimidazole derivatives, in particular 2-ethylthiophenethylamine hydrobromide in respect of the violations caused by multiple sclerosis, and other neurodegenerative diseases and chronic fatigue syndrome can make the following conclusion.
The pharmaceutical composition according to the invention is an effective medicine for the treatment of multiple sclerosis, and other neurodegenerative diseases and chronic fatigue syndrome while using ways of treatment of these diseases according to the invention.
Use roizvodnykh benzimidazole or their pharmacologically acceptable salts as active ingredients of pharmaceutical compositions allows you to create a pharmaceutical composition of a wide range of in particular for neurology and immunology. Derivatives of benzimidazole affect the Central nervous and the immune system of warm-blooded animals, which depending on the amount of the active ingredient in the drug, dose, conditions, and mode can be selected optimal.
The pharmaceutical composition according to the invention may, as an active ingredient to contain a composition of several active compounds such as benzimidazole and nicotinic acid, which is highly compatible and depending on the biological activity can, for example, to increase the efficiency of drug in the body.
This pharmaceutical composition according to the invention can be a solution of the active ingredient in a pharmaceutically acceptable liquid carrier or solvent, such as water, saline, buffer solutions.
In addition, the pharmaceutical composition according to the invention may be a fine powder of the active ingredient, suitable for use in injection solutions, applications, preparation of other medicines.
Derivatives of benzimidazole according to the invention are soluble in water or in alcohol, saline solution, buffer rastv the arts or compatible with the ingredients increasing their solubility.
Oral introduction is usually the preferred way for introducing medicines into the body, because this method is the most convenient and acceptable to the patient. The pharmaceutical compositions according to the invention can be made in the form of funds for oral administration such as tablets, granules, beads, powders, capsules, suspensions, emulsions. This pharmaceutical composition may further comprise a means of improving the bioavailability, such as microcrystalline cellulose, or, for example, biologically active additives to reduce the content of biologically active ingredient in a dose of medication. Or, alternatively, may be made in the form of spontaneously dispersible concentrate which, when mixed with distilled water or alcohol solution creates water microemulsion, fusobacteria, with an enhanced ability of penetration and distribution.
Rapid absorption of the active ingredient of the pharmaceutical compositions according to the invention, can be achieved by parenteral injection, for clinical conditions is traditional, but less appropriate for self-medication. In this case, it is effective delivery of the drug in the body's rectal is doing, using suppositories, enemas, soft gelatin capsules, suppositories, for example in the form of solid dosage forms suitable configuration, which either melt at body temperature, or dissolved or dispersed in the cavity, covered with mucous membrane.
Specialists in the field of medicine it is known that to improve the adsorption of biologically active substances having poor solubility in water or in any electoral environments, the active ingredient of the pharmaceutical composition in the form of a highly saturated solution in solid form can be encapsulated in one or more lamellar membrane containing lipids such as liposomes, allowing to deliver the active ingredient in a specific field.
According to the invention, in the pharmaceutical compositions of derivatives of benzimidazole and their salts may be contained in liposomal form, for example in a multiphase liposomal delivery system of medicine that is stable and can be easily diluted with water in pharmaceutical compositions from the state of the diluted liquid to a gel, which is important for derivative compounds poorly soluble in the acidic environment of the gastrointestinal tract, but also extends the application of higher doses of the active ingredient with the introduction of oral.
Also what about the, in the pharmaceutical compositions according to the invention the pharmaceutically acceptable carrier may be a composition comprising a pharmacologically active additives.
Thus, according to the invention, pharmacologically active additives can be selected from the group including stabilizers, dispersing agents, flavoring agents, emulsifiers, conditioners, means of improving the bioavailability, one of which may be a means to increase the solubility of sparingly soluble compounds, for example the solvent dimethyl sulfoxide (DMSO).
In many diseases it is advisable to use different methods of local effects on the disease process, especially in the presence of contraindications to systemic therapy, such as liver or kidneys, and other vital organs. One of the ways local impact is the use of external drug products containing analgesic, anti-inflammatory, immunomodulatory or antiseptic medicines.
It is known that, on the basis of skin sensitivity, the probability of its irritation and transdermal absorption capacity (hygroscopicity skin), the pH of the pharmaceutical preparation for external use it is desirable to maintain in the range of 4-8, more preferably in the range of 5-7. the hen pH is too low (3.0 and less) high acidity causes severe skin irritation. When pH is too high (9.0, and more), transdermal absorption of the active ingredient is reduced, skin irritation increases, and the drug is painted in yellow color. The optimal pH values for transdermal absorption from 4 to 8.
To enhance the transdermal absorption (suction) of the active ingredient in the pharmaceutical compositions according to the invention, may contain effective amounts of so-called power absorption, for example, organic bases such as triethanolamine, crotamiton, esters of fatty acids with medium chain length, 1-menthol, benzyl alcohol and similar substances. Organic base facilitates the release of active ingredient from the basics, because it makes it more water soluble due to the formation of salts. Organic base acts as a pH regulator to the medicinal product.
To regulate the pH of the medicinal product can also be used alkali compounds (potassium hydroxide and sodium, triethanolamine, diisopropanolamine, monoethanolamine and others).
Solutions hydrochloride, acetates, phosphates, hydrobromides, nitrates, sulfates and other organic salts of benzimidazole derivatives have a pH of 4-7, which creates a good perspective is s create medicines for external use.
The pharmaceutical composition for external use can be a gel-emulsion containing as an active ingredient derived, for example, 2-ethylthiophenethylamine hydrobromide, according to the invention, a hydrophilic polymer, an oily substance, non-ionic surface-active agent, alkaline compounds or organic base as a pH regulator environment and water. Thus derivatives of 2-ethylthiophenethylamine hydrobromide, according to the invention, chemically compatible with these ingredients, do not cause allergic reactions and is well tolerated by patients.
Voronina T.A., Waldman EA, Neronova LN. Guidelines for the study of the antiparkinsonian activity of pharmacological substances. Century book: Manual on experimental (preclinical) study of new pharmacological substances, Moscow, JSC "Remedium", 2000, 398 S.
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Wolffgramm j, Rommelspacher H., Buck E. Ethanol reduces tolerance, sensitization, and up-regulation of D2 receptors after subchronic haloperidol. Pharmacology, Biochemistry and Behavior, 1990, v.36, p.907-914.
1. Pharmaceutical composition for the treatment of chronic fatigue syndrome, containing biologically active ingredient and farm citiesi acceptable carrier, characterized in that the biologically active ingredient contains 2-utilitiesa hydrobromide in an effective amount and a pharmaceutically acceptable carrier liquid.
2. The pharmaceutical composition according to claim 1, characterized in that the carrier liquid selected from the group comprising water, alcohol, physiological fluids, buffer solutions.
3. Method for the prevention and treatment of chronic fatigue syndrome by injection of a medicinal product, wherein the administered pharmaceutical composition according to claim 1 or 2 in a daily dose of 250-1500 mg within 5-20 days with the possibility of repeating the treatment after a break lasting 5 or more days.
4. The method according to claim 3, characterized in that additionally used in reverse, ATP, vitamins, sibazon, medazepam.
SUBSTANCE: method involves applying peptide containing amino acid sequence of Thr-R1-Lue-Ile-Asp-Asn-Asn-Ala-Thr-Glu-Glu-Ile-Leu-Tyr, where R1 is the D-alanine (SEQ ID N:2) for treating patients for neurodegenerative disorder or myelinogenesis disorder by introducing effective dose of this peptide. Given disorders for which the medicament has proved to be useful are polyneuropathy, mononeuropathy, neuroma, nerve compression, nerve injury, contusion, tumor or incomplete spinal cord transection, infarction or injury of brain stem cells, thalamus or cerebral cortex, compression, rupture or inflammation of dorsal ganglia roots, postpoliosyndrome, traumatic or ischemic injury of central or peripheral nervous system, disseminated sclerosis.
EFFECT: enhanced effectiveness of treatment.
6 cl, 3 dwg, 6 tbl
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to using compound of the formula (I) for preparing a medicinal preparation in treatment of cerebrospinal sclerosis. Invention provides the enhancement of treatment effectiveness.
EFFECT: valuable medicinal property of preparation.
4 cl, 5 dwg, 1 tbl
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to novel substituted 2-aryl-3-(heteroaryl)imidazo[1,2-a]-pyrimidines of the formula (I):
or to their pharmaceutically acceptable salts wherein: (a) R1 is taken among the group consisting of -NH2, C1-5-alkylamino-, di-C1-5-alkylamino-, phenylmethylamino-group; (b) Y is taken among the group consisting of hydrogen atom (H), halogen atom, piperidine, OR4, SR4, -SO2CH3, NHR4 and NR4R5 wherein R4 and R5 are taken independently among hydrogen atom (H), α-alkylphenyl-C1-5-alkyl, linear or branched alkyl substituted optionally with C3-5-carbocycle, phenyl or substituted phenyl wherein indicated phenyl can be substituted with one or some substituted taken among C1-5-alkoxy-group; (c) R2 represents from one to five members taken independently among the group including hydrogen atom (H), halogen atom, trifluoromethyl; (d) R3 represents hydrogen atom (H), or radicals R3 taken in common form aromatic ring; (e) X represents nitrogen atom (N) or -CH. Also, invention relates to methods for preparing indicated compounds and to a method for treatment based on these compounds. Invention provides preparing novel compounds that can be used in relief states by reducing the level of inflammatory cytokines, for example, the indicated state represents proliferative (rheumatic) arthritis.
EFFECT: valuable medicinal properties of compounds and compositions.
40 cl, 1 tbl, 4 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.
EFFECT: valuable medicinal properties of compounds.
17 cl, 496 ex
FIELD: organic chemistry, vitamins, medicine, pharmacy.
SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.
EFFECT: valuable medicinal properties of compounds.
13 cl, 3 sch, 3 tbl, 6 ex
FIELD: chemistry of peptides, medicine.
SUBSTANCE: invention relates to compound of the structure: N-methyl-(D-Leu-D-Val-D-Phe-D-Phe-D-leu)-NH2 designated for using as an active component in manufacturing a medicinal agent used for inhibition of natural β-amyloid peptides aggregation in patients suffering with disorder associated with β-amyloidosis and in treatment of Alzheimer's disease. Also, invention relates to a pharmaceutical composition, a method for inhibition of natural β-amyloid peptides, a method for detection of natural β-amyloid, a method for detection for the presence or absence of natural β-amyloid peptides in biological sample and to a method for treatment of patient with disorder associated with β-amyloidosis.
EFFECT: improved method for detecting, valuable medicinal properties of agent.
14 cl, 5 tbl, 5 dwg, 9 ex
FIELD: organic chemistry.
SUBSTANCE: invention relates to new lipoic acid derivatives of general formula Ia
1, wherein n = 0-4, integer; -X-Y represents -O(CH2)r-, -CO-N(R3)-(CH2)r-, -N(R4)-CO-(CH2)r; -X'-Y' represents -(CH2)r-, -(CH2)r-N(R3)-(CH2)r-, -(CH2)r-CO-N(R3)-(CH2)2-; R3 and R4 are the same or different and represent hydrogen or alkoxycarbonyl; r = 0-4, integer; Ω represents piperazinyl, piperidyl or phenyl. Also disclosed are method for production the claimed derivatives and pharmaceutical composition, containing the same. Compounds are useful as NO-syntase inhibitors and/or reagents mediating redox state of thiol groups.
EFFECT: new lipoic acid derivatives.
7 cl, 17 ex
FIELD: organic chemistry, chemical technology, biochemistry.
SUBSTANCE: invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives of the general formula (1):
eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):
wherein R1, R2 and R3 have above given values; R5 represents hydroxyl or chlorine atom, and to their applying for preparing compounds of the general formula (1.2):
wherein R1, R2 and R4 have above given values.
EFFECT: valuable medicinal and biochemical properties of compounds.
6 cl, 4 tbl, 5 ex
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to applying compounds of the general formula (1):
as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):
. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.
EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.
3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):
wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.
EFFECT: valuable medicinal properties of compounds.
7 cl, 1 tbl, 98 ex
FIELD: medicine, pharmacology.
SUBSTANCE: the suggested preparation contains isosorbide dinitrate, interpolymeric complex of polymetacrylic or polyacrylic acid and polyethylene glycol, lactose and/or microcrystalline cellulose and a slipper, and, also, method to obtain the mentioned preparation has been suggested due to mixing the components followed by dry granulation. The preparation provides prolonged maintenance of concentration of active substance at therapeutically efficient level.
EFFECT: higher efficiency of application.
9 cl, 8 ex, 3 tbl
FIELD: veterinary science.
SUBSTANCE: the suggested preparation contains dense propolis, vegetable oil, extract out of dead bees based upon glycerol, lanolin, honeycombs' cutting off, moreover, all the components should be taken at certain quantitative ratio, weight%: honeycombs' cutting off 15-20, dense propolis 20-25, extract out of dead bees upon glycerol 7.5 -10, lanolin 20-25, vegetable oil - the rest, moreover, honeycombs' cutting off includes honey residues. The preparation in question is of high biological activity, provides shortened terms for recovery in animals and excludes allergic reactions.
EFFECT: higher efficiency for therapy.
1 cl, 8 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to a combined medicinal agent used in treatment of arterial hypertension. The proposed agent comprises the combination of enalapril maleate and hydrochlorothiazide as an active component, and also sodium hydrocarbonate, starch, lactose, iron oxide and stearate as accessory substances. The proposed agent is stable in storage and releases the active component easily.
EFFECT: improved and valuable properties of agent.
8 cl, 1 tbl, 5 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to a ketoconazole-base antifungal pharmaceutical composition. The composition is prepared as a solid medicinal formulation. The composition comprises the following components, wt.-%: ketoconazole, 50.5-75.0; lactose, 1.0-12.0; starch, 5.0-25.0; polyvinylpyrrolidone, 2.0-12.0; stearic acid or calcium, magnesium or zinc stearate or mixture of indicated compounds, 0.2-1.2; aerosil and/or talc, 0.5-10.0. The novel antifungal composition comprises ketoconazole in the amount 50 wt.-%, not less, and it satisfies Pharmacopoeia requirements, stable in storage for 2 years, not less, and shows high therapeutic activity.
EFFECT: improved and valuable medicinal and pharmaceutical properties of composition.
3 cl, 2 tbl, 6 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention proposes a composition comprising as active components pyridoxine hydrochloride and doxylamine succinate and a disintegrating agent that provide the following dissolving pattern: 20-90% of the total amount of each component among pyridoxine hydrochloride and doxylamine succinate are dissolved in 5-120 min. The composition is made preferably as a tablet with an enterosoluble envelope. The tablet has a core comprising pyridoxine hydrochloride and doxylamine succinate, and inactive excipients also. The composition is used in treatment of nausea, vomiting being especially in pregnancy. The composition provides rapid and simultaneous release of synergetic pair of indicated active components.
EFFECT: improved and valuable properties of composition.
24 cl, 2 dwg, 9 tbl, 3 ex
SUBSTANCE: method involves administering preparation like 1% histochrome solution in the amount of 5 ml daily during five days. The first intravenous histochrome injection is carried out slowly. The following ones are intravenously introduced drop-by-drop.
EFFECT: enhanced effectiveness of treatment; no adverse side effects.
2 cl, 4 dwg, 5 tbl
SUBSTANCE: system is distinguished by reduced formation of oxidation decomposition products during transdermal therapeutic system storage time that is related to at least one active substance containing in given system capable of being oxidized with hyperoxides. The transdermal therapeutic system is characterized in that peroxidation number (POZ) sum of auxiliary substances in the drug containing one or several active substances relative to proportion selected according to transdermal therapeutic system formulation is not greater than 20.
EFFECT: reduced quantity of oxidation products.
FIELD: medicine, oncology.
SUBSTANCE: invention relates to method for malignant tumor treatment (including cancer, sarcoma, melanocytoma) in human by ectasceine ET743 intravenous infusion in dose of 500-1650 mug/m2 of surface are; to similar treatment by combination of ET743 with antiemetic agent; as well as to relative composite preparation. Method of present invention provides clinical amelioration in subject suffering from progressive or metastasing cancer and improves treatment effectiveness of diseases being progressed after known chemotherapy.
EFFECT: new effective method for cancer treatment; drug with good acceptability.
31 cl, 3 ex, 1 tbl
FIELD: medicine, phytotherapy, infectious diseases, pharmaceutical industry.
SUBSTANCE: invention relates to a method for preparing ointment used in erysipelas treatment. Method for preparing ointment used in erysipelas treatment involves milling washed and dried viper's-bugloss roots (Echium rubrum, Jacg, family Boraginaceae) and their extraction with melted butter under the definite conditions. Then extract is infused at stirring for a definite time, macerate is filtered off at cooling to a definite temperature and poured off. Extraction is carried out twice, vegetable raw residues are squeezed out, and prepared sap is combined with first two extracts, settled for a definite time and bottled. Method provides preparing ointment that promotes to effective treatment of erysipelas and reducing treatment period.
EFFECT: improved preparing method, valuable medicinal properties of ointment.
FIELD: chemical-pharmaceutical industry, medicine, pharmacy.
SUBSTANCE: invention relates to a spontaneously dispersing composition comprising N-benzoylstaurosporin, a hydrophilic component, a lipophilic component and a surface-active substance taken in the definite ratio of components. Also, invention relates to a method for treatment of the patient needing administration of N-benzoylstautosporin as a component of the spontaneously dispersing composition. The composition possesses the enhanced level of biological availability or diminished variability of the biological availability levels and effectiveness.
EFFECT: improved and valuable properties of composition.
13 cl, 3 dwg, 2 tbl, 5 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to benzimidazole derivatives or their salts useful in medicine of the general formula (1): wherein R1 and R2 can comprise similar or different values and represent independently of one another hydrogen atom, halogen atom, cyano-group, hydroxyl group, alkyl group comprising 1-4 carbon atoms, alkoxy-group comprising 1-4 carbon atoms, trifluoromethyl group; A represents unsubstituted, linear alkylene group comprising 1-7 carbon atoms; E represents group -COOR3 comprising 1-6 carbon atoms; G represents unsubstituted, linear alkylene group comprising 1-6 carbon atoms; M represents a simple bond or -S(O)m- wherein m represents a whole number in the range 0, 1 or 2; J represents substituted or unsubstituted heterocyclic group comprising 4-10 carbon atoms and one heteroatom in ring taken among the group consisting of nitrogen atom or sulfur atom excluding unsubstituted pyridine ring; a substitute in indicated aromatic heterocyclic group is taken among halogen atom, cyano-group, linear alkyl group comprising 1-6 carbon atoms, linear alkoxy-group comprising 1-6 carbon atoms, trifluoromethyl group and trifluoromethoxy-group wherein one or more indicated substituted can be replaced by random positions in ring; X represents methane group (-CH=). Also, invention relates to a pharmaceutical composition used in inhibition of human chymase activity based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for prophylaxis and/or treatment of inflammatory disease, cardiovascular disease, allergic disease, respiratory disease or osseous either cartilaginous metabolic disease.
EFFECT: valuable medicinal properties of compounds and composition.
14 cl, 3 tbl, 20 ex