Medication for withdrawal syndrome management in opiate dependence

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmacology, and concerns the new application of 5-ethoxy-2-[2-(morpholino)ethylthio]-benzimidazole dihydrochloride (the anxiolytic Afobazole) as a medication for withdrawal syndrome management in opiate dependence. It is shown that Afobazole administered in a single or sub-chronic dose decreases the manifestations of 'spontaneous' or naloxone-caused morphine withdrawal syndrome, i.e. decreases physical morphine dependence.

EFFECT: anxiolytic Afobazole represents an effective medication for correcting the clinical manifestations of opiate withdrawal syndrome.

3 dwg

 

The invention relates to medicine, in particular to pharmacology, and relates to a new use of a known substance (5-ethoxy-2-[2-(morpholino)ethylthio]-benzimidazole dihydrochloride) afobazole (registration certificate № PP-000861 (2005) as a means of acute withdrawal syndrome in dependence on opiates.

Prevention and effective treatment of drug addiction continues to be one of the most relevant and socially significant health problems. The number of persons abusing drugs in our country, according to various estimates, ranging from 1 to 4 million (Eaakira, WAV. Psychiatry and psychopharmacology, 2007, 9 (1): 7; Seaspace, abstract. Diss. Kida. the honey. of Sciences, Moscow, 2005). A significant part of the addict uses injectable route of administration of drugs, with a high proportion of poisoning moderate and severe, associated with the use of opiates (Shirogane, abstract. Diss. Doc. the honey. of Sciences, Moscow, 2011; WAV, abstract. Diss. Doc. the honey. of Sciences, Moscow, 2009). The effectiveness of HIV prevention and drug dependence treatment is largely determined by the presence of the doctor-psychiatrist effective medicines.

Currently in narcological practice to relieve or alleviate symptoms of physical and psychological is depending from opiates taking into account the Constitution of the patient, the history of the disease and comorbidity in our country and abroad apply a medicinal product related to the following pharmacological classes:

1) antagonists (naloxone, naltrexone), agonists (methadone) and mixed agonists-antagonists (buprenorphine) for opiate receptors used for detoxification and relatively rapid edema syndrome (syndrome)

(C.P.O''brien, in: 'The Neurobiology of addiction', 2010, (4): 273-281; P.Lobmaier, M.Gossop et al., Eur. J. Clin. Pharmacol. 2010, 66 (6): 537-45; E.Krupitsky, E.Zvartau, G.Woody, Curr. Psychiatry Rep., 2010, 12 (5): 448-53);

2) benzodiazepine derivative anxiolytics (diazepam) is prescribed to eliminate marked symptoms of anxiety, fear, worry in the spectrum of the syndrome (.Ashton, Curr. Opin. Psychiatry, 2005, 18 (3): 249-55; S.Uzun, .Kozumplik, Psychiatr. Danub., 2010, 22 (1): 90-3);

3) agonists Central α-2-adrenergic receptors (clonidine or lofexidine) is used for the elimination of the signs of the syndrome caused by the activity of the sympathetic nervous system (N.Latt, K.Conigrave et al., Addiction medicine, (8): 214-217, 2009);

4) agonists peripheral µ-opioid receptors, derivatives of piperidine loperamide and Diphenoxylate is used to relieve diarrhea; (D.E.Baker, Rev. Gastroenterol. Disord., 2007, 7, Suppl. 3: S11-8.; S.B.Hanauer, Rev. Gastroenterol. Disord., 2008, 8 (1): 15-20);

5) m-cholinolytics with antimuscarinic activity (hyoscine butylbromide, scopolamine butylbromide, palpitations the second derivative giostsiamina - alkaloid contained in the belladonna) is prescribed for the presence of abdominal pain, cramps and spasms (G.N.Tytgat, Curr, Med Res Opin., 2008, 24 (11): 3159-73);

6) antihistamines derivatives of piperazine (hydroxyzine, atarax) is used to treat sleep disorders; they inhibit the activity of subcortical structures of the Central nervous system, blocking the Central m-holino - and H1-histamine receptors (Tscores, P.Kemp, J.Anal. Toxicol., 2011, 35 (7): 512-5).

The above drugs can cause serious side effects:

1) antagonists and mixed agonist-antagonist opioid receptors (naloxone, naltrexone, and buprenorphine) may provoke, respectively, acute withdrawal syndrome and respiratory depression in opiate-addicted patients. The syndrome when using naltrexone characterized by the presence of vomiting, psychomotor agitation, and confusion of thought, delirium and depression (E.Van Dorp, A.Yassen, et al., Anesthesiology, 2006, 105 (1): 51-57; N.Latt, K.Conigrave, et al., Addiction medicine, 2009, (8): 199-217). In addition, naltrexone, introduced orally, or implanted in the form of a depot, not able to resolve the anhedonia and depression in dependent heroin patients (A.Tiurina, .Krupitsky, et al., Eur. Neuropsychopharmacol, 2011, 21, suppl. 2: S 166). However, it is currently the only drug antagonist in the form of a depot used for the prevention and treatment of addiction to opiates in Russia (.Krupitsky, .Zvartau, G.Woody Curr. Psychiatry Rep., 2010, 12 (5): 448-53);

2) benzodiazepine anxiolytics cause psychological and physical dependence in the exchange application, including the syndrome of the newborn if the mother has taken this group of drugs during pregnancy, characterized by cognitive impairment (anterograde amnesia), and increased risk of falling in elderly patients (SRO'brien, J.Clin. Psychiatry, 2005, 66, (suppl. 2): 28-33.; S.Uzun, .Kozumplik, et al., Psychiatr. Danub., 2010, 22 (1): 90-3; M.Lader, A.Tylee, J.Donoghue, CNS Drugs, 2009; 23 (1): 19-34);

3) clonidine or lofexidine can cause a sharp drop in blood pressure, possible collapse, cannot be applied when the HELL <100/60 mm RT. Art.; in all cases, therapy should be initiated with a dose of not more than 50 μg monitoring AD (N.Latt, K.Conigrave, et al., Addiction medicine, 2009, 8: 214-217);

4) loperamide and Diphenoxylate can cause abdominal pain and bloating, nausea, vomiting, higher. Less likely to cause a bowel paresis, dizziness, rash (D.E.Baker, Rev. Gastroenterol, Disord., 2007, 7, Suppl. 3: SI 1-8; S.B.Hanauer, Rev. Gastroenterol. Disord., 2008, 8 (1): 15-20);

5) hyoscine butylbromide (scopolamine butylbromide) can cause negative atropinopodobnye effects: dilated pupils, paralysis of accommodation, increased intraocular pressure, increased heart rate, spastic condition of the gastrointestinal tract, biliary tract, and genitourinary tract (G.N.Tytgat, Curr. Med. Res. Opin., 2008, 24 (11): 3159-73; H.Ikegaya, K.Saka, et al., Leg. Med., 2006, 8 (3): 194-7);

6) hydroxyzine (atarax) can cause drowsiness, weakness, headache, dizziness, ringing in the ears, with the possibility of increased sweating, tachycardia, nausea, allergic reactions, dry mouth, urinary retention, higher, impaired accommodation of the eye (Tscores, P.Kemp, et al., J.Anal. Toxicol., 2011, 35 (7): 512-5.; D.Lasic, M.Z.Cvitanovic, Psychiatr. Danub., 2011, 2: 194-7).

Thus, the above drugs from different pharmacological classes, are not always effective for the basic purpose and relatively often exhibit serious side effects, which significantly limits the possibility of their regular use in the clinic to treat conditions according to (Uppsula, Ukr. neurol. and the psychiatrist., 2004, 1: 31-36; D.Hermann, .Klages, et al., Addict. Biol., 2005, 10 (2): 165 to 169; E.L. van Dorp, A.Yassen, A.Dahan, Expert Opin Drug Saf., 2007, 6 (2): 125-32; E. van Dorp, A.Yassen, E.Sarton, Anesthesiology, 2006, 105 (1): 51-7). Newly created medicines must be devoid of these shortcomings.

Blood-derived 2-mercaptobenzimidazole, domestic selective anxiolytic, not belonging to the class of agonists of benzodiazepine receptors. The drug is characterized by a combination of anxiolytic (anti-anxiety) and light stimulus (activating) effects (G.G.Neznamov, S.A.Siuniakov et al., Eksp. Klin. Farmakol., 2001, 64 (2): 15-9 Appendix).

In the spectrum of clinical effects atabase is and allocate the reduction or elimination of anxiety (concern, fears, irritability), tension (anxiety, inability to relax, insomnia, anxiety, phobic syndrome), somatic disorders (muscular, sensory), autonomic reactions (cardiovascular, respiratory, gastrointestinal symptoms, dry mouth, vomiting, tremor, sweating, dizziness), cognitive disorders (loss of concentration, weakness of memory), (G.G.Neznamov, S.A.Siuniakov, et al., Zh.Nevrol. Psikhiatr. Im. S.S.Korsakova, 2005, 105 (4): 35-40; M.A.Reutova, S.A.Siuniakov, et al., Eksp. Klin. Farmakol., 2010, 73 (9): 6-12).

It should be noted that a significant portion of the above disorders characterized by withdrawal symptoms of opiates (withdrawal syndrome)observed in the clinic (.Stimmel, Pain, analgesia and addiction: the pharmacologic treatment of pain, 1983, (6): 97-133; N.Latt, K.Conigrave et al., Addiction medicine, 2009, 8: 199-217), and in experimental models of dependence (P.M. Dougherty, J. Pearl, et al., Neuropharmacology, 1987, 26 (11): 1595-600; N.Dafny, P.M.Dougherty, Brain Res. Bull., 1993, 31 (5): 491-2.; Magisterskie, Sviridov et al., The experts. and the wedge. pharmacology, 1992, 55 (1): 21-24; Magisterskie, Evernow, Experts. and the wedge. pharmacology, 2011, 74 (10): 12-16).

Positive properties of CA due to its unique mechanism of action mediated affinity for Sigma (σ)receptors that fundamentally differentiate the drug from the benzodiazepine anxiolytics (Sberezheny, Tiantou et al. Bull. The former is EP. Biol. Med., 2009, 148 (1): 42-44).

It is known that Sigma-1 and Sigma-2 receptors are intracellular endoplasmic patterns polyfunctional purpose playing an important role in the development of various pathological conditions, including, in the formation of dependence on cocaine (Tmoigne, R.Martin-Fardon, et al., Neurosci. Biobehav. Rev., 2002, 26 (4): 499-52), alcohol and methamphetamine (Maurice T, M.Casalino, .Lacroix, et al., Pharmacol. Biochem. Behav., 2003, 74 (4): 869-76; R.R.Matsumoto, Expert Rev. Clin. Pharmacol. 2009, 2 (4): 351-8), in the development of depression and amnesia in the mechanisms of pain (Tmoigne, ..Su, Pharmacol. Ther., 2009, 124 (2): 195-206), are involved in the mechanisms of neuroprotection (R.R.Luedtke, .Perez, S.H.Yang, Brain Res., 2011, 12: 31). Sigma-1 agonists, DTG and PRE-084, modulate reaction Samovodene cocaine with their prior use in rats (J.L.Katz, ..Su, .Hiranita, et al., Pharmaceuticals (Basel), 2011, 4 (6): 880-914; .Hiranita, P.L.Soto, et al., J.Pharmacol. Exp. Ther., 2010, 332 (2): 515-24).

Afobazole activates Sigma-1 receptors and glial elements (J.Cuevas, A.Rodriguez, A.Behensky et al., J.Pharmacol. Exp. Ther., 2011, 339 (1): 161-72.), reduces the severity of extrapyramidal disorders caused by haloperidol (Sberezheny, Tlhabiwe, Experts. and the wedge. Pharmacol., 2009, 72 (1): 15-18), and reduces the analgesic effect of morphine in mice (Lghlt, Vinjukov, Sberezheny, Experts. and the wedge. Pharmacol. 2009, 72 (1): 22-23).

Thus, the ability of CA to be active agonist of the Sigma-1 receptor, to reduce vyrazhennost the effects of opiates, as well as the absence of negative side effects allow it to be used as a means of acute withdrawal syndrome of morphine. In the available literature up to the present time there are no instructions on the use of CA for this purpose.

The present study performed on 100 outbred rats male (nursery RAMS Pole) with an average weight 260 g (240-280 g) in the active phase of the experiment. Animals were divided into experimental and control groups (10 animals in each group) and were maintained in standard vivarium conditions for 7 days prior to the start of the experiment. During this period, daily for 10-15 minutes for each group of animals was "handling" to reduce stress during subsequent testing. Consumption of food and water is not restricted. Changes of body weight of the rats was recorded in the 1st, 3rd, 5th and 15th days of the experiment. In animals of the experimental groups was developed dependence on morphine and evaluated behavior in open field (OP) in accordance with the standard, previously developed scheme (Magisterskie, Sviridov et al., The experts. and the wedge. Pharmacol., 1992, 55 (1): 21-24); Magisterskie, Evernow, Experts. and the wedge. Pharmacol., 2011, 74 (10): 12-6). The research procedure consisted in the following. The analyte and the solvent (distilled water) was injected intraperitoneally. Rats who m of experimental groups of morphine hydrochloride was administered for 5 days at doses of 10 and 20 mg/kg, 2 times per day (10.00-18.00) with an interval of 8 hours. This daily dose was increased stepwise: 1 day, 20 mg/kg (10+10 mg/kg), in the 2nd day 30 mg/kg (10+20 mg/kg), a 3-day 40 mg/kg (20+20 mg/kg), 4-day 40 mg/kg (20+20 mg/kg)on the 5th day of morphine were administered a single dose of 20 mg/kg Control animals received equal volume of solvent according to the same scheme, and experimental animals.

In the 1st series of experiments testing the animal for the presence of specific signs of withdrawal syndrome of morphine was performed on the 5th day from the start of injection of morphine for 5 minutes in the OP, in the interval from 17.00 to 20.00 hours, 15 minutes after administration of the antagonist of opiate receptors naloxone (“Du Pont De Nemours Int. S.A., Swiss) at a dose of 1 mg/kg for provocations or solvent, replacing the last second infusion of morphine. Afobazole (aqueous 1% solution, 5 mg/kg) was administered once on day 5 experience for 15 min prior to naloxone (30 min before testing) or sub-chronic, daily for 5 days once for 30 minutes to 1 injection of morphine.

In the 1st series were formed by the following experimental groups: 1 - active control "morphine xp (5 days) + naloxone", 2 - "morphine xp (5 days) + afobazole 1 times+naloxone", 3 - "morphine xp (5 days) + CA (5 days) + naloxone", 4 - control "H2O xp (5 days) + CA (5 days) + naloxone", 5 - control "H2O xp (5 days) + naloxone".

In the 2nd series of the experts the cops animals were tested on day 6, after 24 hours after injection of morphine, without the introduction of naloxone. Afobazole was administered according to the same scheme as in the 1-series, once or sub-chronic in 5 days.

In the 2nd series of experiments were formed by the following experimental groups: 1 - active control "morphine xp (5 days) + H2O", 2 - "morphine xp (5 days) + afobazole 1-fold", 3 - "morphine xp (5 days)+CA (5 days), 4 - control "H2O xp (5 days) + CA (5 days), 5 - control "H2On xp (5days) + H2On xp (5 days)".

For all groups registered observationsa reactions of animals (locomotor activity (YES), racks, grooming, defecation) and specific features WITH morphine (16 indicators diarrhea, gnashing of teeth, shaking, disorders of posture, piloerection, ptosis, attempts to escape, cramps, convulsions, vocalization, shaking paws, shaking his head, rhinorrhea, dyspnea, nasal bleeding, chewing). Discrete signs of abstinence were assessed quantitatively (diarrhea - in points, shaking and gnashing of teeth - the number of acts) and alternative, and the rest in an alternative form according to the principle of "Yes"-"no". Total index (SI) of severity for each animal and the mean values for experimental and control groups was calculated on the basis of alternative signs at the maximum possible value of C equal to 16 points. The average value of you is arnosti WITH-morphine XP + naloxone and morphine XP + H 2O" (active control) was taken as 100%. The obtained data were statistically processed (nonparametric test Mann-Whitney-U-test).

The invention is illustrated by the following examples

Example 1. The influence of CA on the withdrawal syndrome of morphine caused by naloxone

In this study it is shown that the used scheme is the introduction of morphine allows to obtain animals with a relatively high index of total index (SI) of the syndrome of 9.4 points on the background of the action of naloxone (1, active control, "morphine xp (5 days) + naloxone), which is consistent with literature data, showing the possibility of the formation of morphine dependence in rats during its introduction 2-3 times a day, in increasing doses, within 3-20 days (N.Dafny, .Brown, .F.Burks, ..Rigor, .. Neurology, 1979, 64: 216-224).

Single injection of animals with significant differences in the dose of 5 mg/kg to the test in the OP markedly reduces SI WITH (up 4.8 points, or 49%, P<0.01, group 2, figure 1), and also significantly reduces the severity of some of the most important signs of physical dependence, such as violations of the poses (70%, P<0,01), cramps (67%, P<0,05), shaking (93%, P<0,01), diarrhea (44%, P<0.05), and ptosis (51%, P<0.05), and vocalization (76%, P<0,01). Daily (sub-chronic) introduction the effects of the same dose of 5 mg/kg had a similar but less pronounced effect on SI, do you who they further enhance the effect, marked at 1-fold introduction (decrease of C WITH 33%, P<0.01, group 3, figure 1). Animals of groups 4 and 5, there were only sporadic behavioral responses characteristic of dependent animals, and the level of C were, respectively, 15 and 18% from the level C to the animals of group 1.

Example 2. The influence of CA on the "spontaneous" syndrome of morphine in rats

Group 1 - "morphine xp (5 days) + H2On" (active control) was less pronounced (6.4)than in the corresponding group with naloxone (9.4 points). In groups of animals 2 - "morphine xp (5 days) + afobazole 1-fold and 3 - "morphine xp (5 days) + afobazole 5 days", which was recorded "spontaneous" (24 hours after discontinuation of morphine), blood, entered once or sub-chronic, almost equally reduced intensity total index, respectively, 64 and 72%, P<0,01 (figure 2), as well as significantly reduces the severity of individual symptoms FROM morphine, such as cramps (100%, P<0.05), and ptosis (80%, P<0,05), disorders of posture (100%, 0,01), shaking (100%, P<0.01), and gnashing of teeth (84%, P<0.05), and vocalization (87%, P<0.01), and attempts to escape (80%, P<0,01). The results obtained in this series of experiments, the direction of effects comparable with data for series 1 (see example 1), however, the effect of afobazole on individual figures and the total index was in the expressed significantly stronger (group 2, 3, figures 1 and 2, the differences between the respective groups significant at P<0,01). In particular, certain manifestations of physical dependence, such as cramps, shaking, disorders of posture, try to escape, almost completely eliminated the 1-multiple or sub-chronic introduction of afobazole.

Thus, afobazole significantly reduced the value of both the total index caused by naloxone and "spontaneous" WITH morphine.

Example 3. The influence of CA on the dynamics of changes in body weight in animals that are dependent on morphine

Relative reduction of body weight in animals is an important indicator for the development of dependence on opiates. (Magisterskie, Spheroidal, et al., The experts. and the wedge. pharmacology, (1992), 55 (1): 21-24).

In this experiment involved 4 groups of animals. Found that animals that are dependent on morphine (group 1 - "morphine xp (5 days) + naloxone"), there is a significant loss of body weight by 15 th day of the experiment (23%, P<0.05) in comparison with the control group 4 "H2On xp (5 days) + naloxone". In the group of rats, which, along with morphine daily entered afobazole (group 3 - "morphine xp (5 days) + CA (5 days) + naloxone"), changes in body weight by the end of the experiment (day 15) showed recovery with body mass is almost the same as the control the values. In group 2 "morphine xp (5 days) + afobazole 1 times + naloxone" this effect was observed in the form of trends.

Description of the drawings

Figure 1 Effect of afobazole on withdrawal syndrome in morphine-induced naloxone

On the x-axis presents groups of animals: 1 - active control "morphine xp (5 days)+naloxone"; 2 - "morphine xp (5 days) + afobazole 1 times + naloxone"; 3 - "morphine xp (5 days) + CA (5 days) + naloxone"; 4 - control "H2O xp (5 days) + CA (5 days) + naloxone"; 5 - control "H2O xp (5 days) + naloxone".

On the y - axis the value of the total index (SI) of the syndrome of morphine for each experimental group, expressed in %; 100% accepted value of C for group 1 (active control). * - P<0,05; ** - P<0,01 when compared with group 1.

Figure 2 Effect of afobazole on the syndrome at 24 h after discontinuation of morphine

On the x-axis presents groups of animals: 1 - active control "morphine xp (5 days) + H2O", 2 - "morphine xp (5 days) + afobazole 1-fold", 3 - "morphine xp (5 days) + CA (5 days), 4 - control "H2O xp (5 days) + CA (5 days), 5 - control "H2O xp (5 days) + H2O xp (5 days)".

The y-axis is the value of the total index (SI) of the syndrome of morphine for each experimental group, expressed in %; 100% accepted value of C for group 1 (active control). * - P<0,05; ** - P<0,01 when compared with the GRU who sing 1.

Figure 3 Effect of afobazole on the dynamics of body weight of the rats dependent on morphine

The horizontal axis shows the days of the experiment; on the y - axis the average body weight of animals for each group (1-4), expressed in %. Taken as 100% values of body weight at day 1 of the experiment. 1 - active control "morphine xp (5 days) + naloxone"; 2 - "morphine xp (5 days) + afobazole 1 times + naloxone"; 3 - "morphine xp (5 days) + CA (5 days) + naloxone"; 4 - control "H2O xp (5 days) + naloxone".

* - P<0,05 significant differences when comparing group 1 with group 3 and 4.

The use of 5-ethoxy-2-[2-(morpholino)ethylthio]-benzimidazole dihydrochloride, afobazole as a means of acute withdrawal syndrome in dependence on opiates.



 

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4 dwg, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (I) in free form or in form of a pharmaceutically acceptable salt or solvate, which are useful in treating inflammatory or obstructive airways, pulmonary hypertension, pulmonary fibrosis, liver fibrosis, muscle diseases and systemic skeletal disorders and other diseases which are mediated by activity of the ALK-5 receptor or ALK-4 receptor. The invention also relates to a method of producing compounds of formula (I) and pharmaceutical compositions. In formula , T is a pyridin-2-yl which is optionally substituted in one position with R1; T1 is a pyridinyl which is optionally substituted in one or two positions with R1, R2, R5, C1-C4-alkoxy group, C1-C4-alkoxycarbonyl or cyano group; and Ra and Rb are independently hydrogen; C1-C8-alkyl, optionally substituted in one, two or three positions with R4; C3-C10-cycloalkyl, which is optionally substituted in one or two positions with a hydroxy group, amino group, C1-C8-alkyl, C1-C8-alkoxy group, halogen, cyano group, oxo group, carboxy group or nitro group; or C6-C15-aryl, optionally substituted in one, two or three positions with a halogen, hydroxy group, amino group, cyano group, oxo group, carboxy group, nitro group or R5; R1 is C1-C8-alkyl; R2 is C6-C15-aryl, optionally substituted in one, two or three positions with a halogen, hydroxy group, R1, R5, C1-C8-alkylthio group, amino group, C1-C8-alkylamino group, etc. The rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of using said compounds.

20 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula III which possess the properties of JAK pathway inhibitors and JAK-kinase inhibitors. In formula III: X is specified in a group consisting of C1-C10alkyl, amino, halogen, carboxyl, carboxylic acid ester, C2alkynyl, substituted tri-C1-C6alkylsilyl; R represents hydrogen; the cycle A is specified in a group consisting of C6aryl, bicycloheptene, five-and sis-member mono- or 10-member bicyclic heteroaryl including 1 to 3 heteroatoms specified in a group of heteroatoms, including N, O or S, and five- or six-member mono- or 10-member bicyclic heterocycle, including 1 to 2 heteroatoms specified in a group of heteroatoms, including N or O; p means 0, 1, 2 or 3; each of R2 is independently specified in a group consisting of C1-C6alkyl, C1-C4alkyl substituted by 1 to 3 substitutes. The other substitute and radical values are specified in the patent claim.

EFFECT: compounds may be used in preparing a therapeutic agent for T-cell mediated autoimmune disease, for treating or preventing allograft rejection in a recipient, for treating or preventing a type IV hypersensitivity reactions, which includes administering the above agent containing the compound according to cl 1-11, in an amount effective to treat the autoimmune disease or the allograft rejection or the type IV hypersensitivity.

23 cl, 7 dwg, 12 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-hydroxylsulphonamide derivatives of formula or , where R1 is H; R2 is H; n is 0; b is an integer in the range of 1-4; R3, R4, R5, R6 and R7 are independently selected from H, halogen, carboxyl, carboxyl ester selected from a group including -C(O)O-morpholino, -C(O)O-C1-C8alkyl and -C(O)O-substituted C1-C8alkyl, where the substitute is morpholino; acylamino, which is a -C(O)NRaRb group, where Ra and Rb are independently C1-C8alkyl, or Ra and Rb together with a nitrogen atom to which they are bonded form morpholino; and sulphonylamino, which is a SO2NR2 group, where two groups R, together with a nitrogen atom to which they are bonded, form morpholino; R8 is selected from halogen and carbonylamino, selected from a -CONH-substituted C1-C8alkyl, where the substitute is morpholino; and -CONR2, where two groups R, together with a nitrogen atom to which they are bonded, form morpholino; C is a heteroaromatic ring which contains cyclic fragments Q9, Q10, Q11, Q12, Q13 and Q14, which are independently selected from C, CH and S, under the condition that at least one of the fragments Q9, Q10, Q11, Q12, Q13 and Q14 is S. The invention also relates to a method of modulating nitroxyl levels, a method of treating diseases which respond to treatment with nitroxyl, a treatment set and a pharmaceutical composition containing compounds of formula (I) or (III).

EFFECT: compounds of formula (I) or (III) for treating diseases which respond to treatment with nitroxyl.

20 cl, 5 ex, 4 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and aims at therapy of tuberculosis. What is used is a combination of formula (I), (S)-N-[[3-[3-fluor-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-xazolidinyl]methyl]cetamide, or a pharmaceutically acceptable salt thereof in combination with at least two agents, for preparing a therapeutic agent for treating tuberculosis after the individual has undergone the initial therapeutic phase.

EFFECT: use of the declared group of inventions provides a high therapeutic effect of treating tebrculosis.

12 tbl, 8 ex, 10 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to tetrahydroimidazo[1,5-a]pyrazine derivatives of formula I or to their pharmaceutically acceptable salts (I), wherein: Ar represents phenyl, wherein phenyl is additionally substituted by 1-3 substitutes independently specified in halogen; R1 represents trifluoromethyl; R2 is specified in a group consisting of hydrohyl, alkyl having 1 to 4 carbon atoms, alkoxyl having having 1 to 4 carbon atoms, cycloalkyl representing a 5-6-member monocyclic ring group consisting of carbon completely, and -NR4R5, wherein each alkoxyl is optionally substituted by one group specified in a group consisting of phenyl and -OC(O)OR8; R3 is specified in a group consisting of a hydrogen atom and alkyl having 1 to 4 carbon atoms; each of R4 and R5 is independently specified is a group consisting of a hydrogen atom, alkyl having 1 to 4 carbon atoms, cycloalkyl representing a 3-8-member monocyclic ring group consisting of carbon completely, phenyl and pyridinyl, wherein each alkyl or phenyl is optionally substituted by one or more group specified in a group consisting of halogen, a cyano group, -SO2R7, -NR4R5 and -C(=O)OCH3; or R4 and R5 together with an atom, whereto attached form a 5-6-member heterocycle wherein the 5-6-member heterocycle optionally contains one or more N, O or S atom, and each 5-6-member heterocycle is optionally substituted by one or more groups consisting of halogen, hydroxyl, an amino group, alkyl having 1 to 4 carbon atoms, hydroxyalkyl 1 to 4 carbon atoms, -SO2R7, -C(O)NR4R5, -C(O)R7, =O; R7 represents alkyl 1 to 4 carbon atoms; and R8 is specified in a group consisting of alkyl 1 to 4 carbon atoms, and cycloalkyl representing a 5-6-member monocyclic ring group consisting of carbon completely. The invention also refers to methods for preparing them, a pharmaceutical composition having dipeptidyl peptidase IV inhibitory activity and containing said derivatives.

EFFECT: there are produced new compounds and composition on their basis which can find application in medicine for treating type 2 diabetes mellitus or hyperglycemia.

17 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an aminopropylidene derivative presented by formula wherein R1 and R2, which may be identical or different, represent hydrogen or a substitute specified in the following (a)-(c), provided the case of both representing hydrogen is excluded: (a) carbonyl substituted with hydroxy, alkoxy or hydroxy alkylamino, (b) carbonylalkyl substituted by hydroxy or alkoxy, and (c) acrylic acid including its alkyl ester, R3 and R4, which may be identical or different, represent hydrogen, alkyl which may be substituted by phenyl or cycloalkyl, or R3 and R4, which together form a heterocyclic ring with a nitrogen atom bound thereto, represent pyrrolidino, piperidino, which may be substituted by oxo or piperidino, piperazinyl substituted by alkyl or penyl, morpholino or thiomorpholino; A means oxo or is absento, B represents canbon or oxygen; one of X and Y represents carbon, while the other one represents sulphur, a part represented by a dash line represents a single bond or a double bond, and a wavy line represents a cys-form and/or a transform. Also, the invention refers to a pharmaceutical composition exhibiting histamine receptor antagonist activity on the basis of said compounds.

EFFECT: there are produced new compounds and pharmaceutical compositions thereof, which can be used in medicine for treating asthma, allergic rhinitis, pollen allergy, hives and atopic dermatitis.

10 cl, 12 tbl, 58 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to substituted oxazolidinones of formula (I), wherein R1 means methyl, ethyl, n-propyl, methoxy, methoxymethyl or ethoxymethyl, R2 means hydrogen or methyl, and R3 means a group of formulas or , wherein * means an attachment point to an oxopyridine ring, n means number 1, 2, 3 or 4, m means number 1 or 2, R4 means hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, 2-hydroxyet-1-yl, 3-hydroxyprop-1-yl or 4-hydroxycyclohex-1-yl, R5 means hydrogen, methyl or ethyl, or R4 and R5 together with a nitrogen atom whereto attached, form a ring of morpholin-4-yl, a ring of 4-methyl-piperazin-1-yl or 4-hydroxy-piperidine-1-yl, R6 means hydrogen, cyclopropyl, cyclobutyl, 2-hydroxyet-1-yl, 3-hydroxyprop-1-yl, 2-methoxyet-1-yl, 3-methoyprop-1-yl, 4-hydroxycyclohex-1-yl, tetrahydrofuran-2-ylmethyl or 1,4-dioxan-2-ylmethyl, R7 means hydrogen, methyl or ethyl, or R6 and R7 together with a nitrogen atom whereto attached, form a ring of pyrrolidin-1-yl, a ring of 2-methoxymethyl-pyrrolidin-1-yl, a ring of 1,1-dioxo-morpholin-4-yl, a ring of 1,4-oxazepan-4-yl, a ring of 4-methyl-piperazin-1-yl or 4-hydroxy-piperidine-1-yl, or to physiologically acceptable salts thereof. The invention also concerns a method for preparing said compounds.

EFFECT: there are prepared new compounds which can find application in medicine for treating and/or preventing the diseases caused by thrombembolia.

8 cl, 2 tbl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1), in which Ar is a group of formula (Ar-1) or (Ar-2), in which R1 is a halogen, R2 is hydrogen, R3 is hydrogen, R4 is hydrogen, alkyl or alkenyl, X is a nitrogen atom or CH, R5 and R6 are each hydrogen and h equals 1; 1 equals 1 or 2; m equals 1 or 2; n equals 0, 1 or 2; o equals an integer from 0 to 3, under the condition that n and o are equal to 0 at the same time. Values of group A are as given in claim 1 of the invention. Described also is a pharmaceutical composition having agonistic activity with respect to 7 serotonin (5-HT4-receptors), which contains a compound of formula (1) and an agent which stimulates enterokinesis or improves functioning of the alimentary canal, which contains a compound of formula (1) as an active ingredient.

EFFECT: novel compounds are obtained and described, which have strong affinity towards 4 serotonin receptors, which are useful as an agent which stimulates enterokinesis or an agent which improves functioning of the alimentary canal.

28 cl, 233 ex, 29 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a phenylpyrazol derivative presented by formula (1) or to its pharmaceutically acceptable salt: wherein R1 and R2, which may be identical or different, each represents C1-C6 alkyl, or R1 and R2 are coupled together with an adjacent nitrogen atom to form a 5-6-merous saturated heterocylic ring (wherein the mentioned saturated heterocylic ring may be substituted by halogen or C1-C6 alkyl), n represents an integer 0 to 2, T represents a hydrogen atom, halogen or C1-C6 alkyl, and R has one of formulas (I)-(V), (VII) or (VIII):

(wherein Z1 and Z2, which may be identical or different, each represents -CH2-, -O- or -NR11-, p represents an integer 0 to 3, q represents an integer 0 to 1, r and s which may be identical or different, which represents an integer 0 to 2, R3 represents halogen, C1-C6 alkyl, or hydroxy, R4 and R5 which may be identical or different, each represents a hydrogen atom, C1-C6 alkyl (wherein said C1-C6 alkyl may be substituted by hydroxy, hydroxy- C1-C6 alkoxy, C2-C7 alkoxycarbonyl or carboxy), or formula -(CH2)m-Ar1 (wherein Ar1 represents wherein (wherein said phenyl is substituted by halogen or C1-C6 alkyl), and m represents an integer 0 to 1), R6 represents oxo, R7 represents a hydrogen atom or C1-C6 alkyl, R8 represents C1-C6 alkyl (wherein said C1-C6 alkyl may be substituted by halogen), C1-C6 alkoxy (wherein said C1-C6 alkoxy is substituted by halogen) or formula -(CH2)1-Ar2 (wherein Ar2 represents phenyl (wherein said phenyl is substituted by C1-C6 alkoxy, hydroxyl or cyano) or pyridinyl, and 1 represents an integer O to 1), G represents -CO- or -SO2-, R9 represents C1-C6 alkyl, C1-C6 alkoxy, phenyl (wherein said phenyl may be substituted by halogen or pyridinyl, and R11 represents C1-C6 alkyl)}.

EFFECT: there are produced new compounds and a preventive or therapeutic agent on the basis of said compounds which can find application in medicine for treating dementia, Alzheimer's disease, attention deficit/hyperactivity disorder, schizophrenia, epilepsy, convulsions of central genesis, eating behaviour disorders, obesity, diabetes, hyperlipidemia, sleep disturbances, narcolepsy, sleeping apnoea syndrome, circadian rhythm disorder, depression or allergic rhinitis.

12 cl, 3 tbl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where: A is CA1; E is CE1; W is (CH2)n; Y is (CH2)P; n and p are independently equal to 0 or 1; R1 is a phenyl which is substituted with a phenyl {which is optionally substituted with a halogen, hydroxy, CH(O), CO2H, C1-4alkyl, C1-4alkyl-(N(C1-4alkyl)2), C1-4alkyl(NH2), C1-4alkyl(NH(C1-4alkyl)), C1-4hydroxyalkyl, CF3, C1-4alkylthio, C1-4alkyl(heterocyclyl) or C1-4alkylNHC(O)O(C1-4alkyl)} or a heterocyclyl; and the heterocyclyl is optionally substituted with C1-6alkyl; R2 is NHC(O)R3; and R3 is C1-4alkyl {substituted with NR7R8 or a heterocyclyl}, C3-7cycloalkyl (optionally substituted with a NR43R44 group) or a heteroaryl; where R7, R8, R43 and R44 are as defined in claim 1; wherein the heteroaryl is optionally substituted with a halogen, C1-4alkyl, CF3, C1-4alkoxy, OCF3, heterocyclyl or an amino(C1-4alkyl) group; R7 and R8 are independently C1-6alkyl; A1, E1 and G1 are independently hydrogen or halogen; unless otherwise stated, the heterocyclyl is optionally substituted with C1-6alkyl; R25 is C1-6alkyl; R50 is hydrogen or C1-6alkyl (optionally substituted with a NR51R52 group); R30, R36, R40, R42 or R44 is independently hydrogen, C1-6alkyl(optionally substituted with hydroxy, C1-6alkoxy, C1-6alkylthio, C3-7cycloalkyl (which is optionally substituted with hydroxy) or NR45R46), C3-7cycloalkyl (optionally substituted with a hydroxy(C1-6alkyl) group) or a heterocyclyl (optionally substituted with C1-6alkyl); R29, R35, R39, R41, R43, R45, R46 and R51 are independently hydrogen or C1-6alkyl; where the heterocyclyl is a non-aromatic 5- or 6-member ring containing one or two heteroatoms selected from a group comprising nitrogen and oxygen; and where the aryl is phenyl or naphthyl; and where the heteroaryl is an aromatic 5- or 6-member ring, optionally condensed with another ring (which can be carbocyclic and aromatic or non-aromatic), having one or two heteroatoms selected from a group comprising nitrogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a PDE4-mediated disease state.

10 cl, 81 dwg, 15 tbl, 375 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

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