Melatonin agonist therapy

FIELD: medicine.

SUBSTANCE: present group of inventions refers to medicine, namely therapy and neurology, and concerns a melatonin agonist therapy. As the above melatonin agonist, (lR-Trans)-N-[[2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]methyl]propanamide is administered in effective doses that provides treating or preventing disruption of circadian rhythm or sleep disturbance.

EFFECT: invention provides treating or preventing disruption of circadian rhythm or sleep disturbance.

9 cl, 2 ex, 4 tbl

 

Cross references to related applications

In the present application claims the priority filing date of provisional patent application US No. 60/747,847, located on the simultaneous consideration, filed may 22, 2006, which, thus, is fully included in the present description by reference.

Background of invention

The technical field

The present invention relates to the melatonin agonists for use in the pharmaceutical industry.

The level of technology

The connection that the present invention is designated as MA-1 is a (1R-TRANS)-N-[[2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]methyl]propanamide. It is disclosed in patent US 5,856,529, which is fully incorporated into the present description by reference.

MA-1 is a specific and effective agonist of melatonin receptors MT1R and MT2R in the suprachiasmatic nucleus (SCN), the site of a brain associated with the biological clock. (Kokkola, T. & Laitinen, J.T.Melatonin receptor genes. Ann. Med 30, 88-94 (1998).) I believe that the inclusion of these receptors by melatonin regulates the circadian rhythm, including the cycle of sleep-wakefulness. In accordance with the profile of binding with its receptor, MA-1 is effective chronobiotics activity in preclinical models of acute phase shift and chronic recovery.

In preliminary studies on Asano, that MA-1 is well tolerated in healthy volunteers, with the introduction of single doses up to 300 mg and multiple doses (up to 28 days) up to 150 mg. Also conducted 28-day study in phase II to examine the functioning of MA-1 in elderly patients with primary insomnia. In this study, the MA-1 is not different from placebo in its effect on latent sleepiness and number of night awakenings. Because patients with the lowest levels of melatonin (<5 mg) may benefit from treatment with MA-1 more than placebo, the scheme of this study complicates the understanding of action MA-1 on the cycle of sleep-wakefulness.

The invention

The present invention relates to the discovery of effective doses of MA-1. In the illustrative embodiment, it includes a way of introducing the MA-1 in need of this person, which includes oral administration of MA-1 to a subject in an amount of from about 10 mg to about 100 mg per day.

Detailed description of the invention

The present invention is further described with reference to illustrative embodiments of covers the application of agonist of melatonin, which in this application is referred to as MA-1, for the treatment of sleep disorders and circadian rhythm disorders. MA-1 is white or white with a yellowish reservatum shade powder with a melting point of about 78°C. (DSC) and has the structure which is illustrated by formula 1.

Formula 1: the Chemical structure of MA-1

The present invention includes internal administration to the patient MA, as a rule, adult, normal weight, for example, approximately 70 kg and is usually in the range of from about 45 to about 150 kg, which is needed in this introduction, in doses of approximately 10 mg/day to about 100 mg/day.

Usually the drug is administered in the form of quick release, but the form of controlled-release also fall under the scope of the invention. The drug can be delivered alone or in combination with another active pharmaceutical ingredient.

Through the introduction is usually the oral route, however, you can use other routes of administration, for example, parenteral, intravenous, intramuscular, buccal, diamond-shaped tablets, transdermal, through the mucous membranes, etc. you can Also use forms of controlled release, for example, long-term, pulsed or delayed, including depot forms, such as forms, are described in WO 2003037337 or WO 2004006886.

The composition is preferably prepared in the form of a standard oral dosage forms, each dosage contains from about 5 to about 100 mg of MA-Armin standard dosage form" refers to physically discrete elements, suitable as single dosage forms for humans, each unit contains a predetermined quantity of the active substance, designed in such a way as to obtain the desired prophylactic or therapeutic effect in the implementation of the treatment, in combination with the required pharmaceutical carrier. Thus, for example, an adult patient suffering from disturbances of circadian rhythm, may take 1-4 tablets, each of which contains from about 5 to about 100 mg of MA-1 for a total daily dose of from about 10 to about 100 mg/day. The term "approximately" means, in General, in the range of plus or minus ten percent, except for single-bit integer or fractional values, for which the range is plus or minus one of the last significant digit. Thus, approximately 100 ' comprises from 90 to 110, "approximately 5" includes from 4 to 6, and "approximately 1.5" includes from 1.4 to 1.6. Under no circumstances the term "about" may not include absurd value such as a value greater than 100% or less than zero.

An effective amount, in quantitative terms may vary, for example, depending on the patient, the severity of the violation or symptom being treated, and the route of administration. This dose can be determined by OSU standard research. In General, for system administration, for example oral administration, the dose of MA-1 will be in the range from approximately 10 to approximately 100 mg/day, on one or more standard medicines.

You should take into account that the Protocol introduction, including the number of MA-1 or MA-2, introduced in a particular case will be determined by the attending physician taking into account relevant circumstances, including the condition being treated, the chosen route of administration, age, weight, and response of the particular patient and the severity of the patient's symptoms. Patients must be monitored to detect possible side effects.

Particle size also affects the selected dose. At large particle sizes, i.e., D50 greater than about 100 μm, for example, from approximately 100 to approximately 200 μm, the effective oral dose in the upper limits, i.e., up to approximately 100 mg, whereas particles smaller sizes, i.e., D50 is less than about 100 μm, for example, from about 20 to about 50 microns, suitable lower doses, i.e., less than about 100 mg, for example, from about 10 mg to about 80 mg, and from about 20 mg to about 50 mg (Measurement of particle size, confirming the op is sliding above was performed using laser diffraction using a Malvern Mastersizer. The values of D50 (D10, D90, D100) indicate that 50% (10%, 90%, 100%) particles by weight have a specified diameter or less.) In one embodiment of the invention, the above dose is administered in the form with quick release, i.e., in the form of a medicinal product with an uncontrolled release.

If it is desired, the optional dose can be adjusted according to body weight according to the following methodological principles: suitable quantities for larger particles constitute up to approximately 1.5 mg/kg; suitable quantities for smaller particles include a dose of less than approximately 1.5 mg/kg, for example, from about 1 mg/kg to approximately 1.2 mg/kg, from about 3 mg/kg to about 7 mg/kg

Treatment continued until until patients will not recover normal circadian rhythm, that is, up until the normal daily activity of the patient will not be inhibited circadian rhythm disorders or, in the case of sleep disorders, as long as the patient will not sleep properly, that is, until, Coca normal daily activity of the patient will not be inhibited by sleep disorders. In some cases, treatment can continue after reaching these endpoints to reduce in which the probability of recurrence

For therapeutic or prophylactic use, the MA-1 or MA-2 will usually be in the form of a pharmaceutical composition containing as the principal active ingredient at least one such compound in combination with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and fillers used according to standard methods.

MA-1 is very soluble or freely soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycol (PEG-300 and PEG-400), and only weakly soluble in water. The native pH of a saturated solution of MA-1 in water is 8.5 and its water solubility is practically not affected by the pH value.

Pharmaceutical compositions suitable according to the present invention include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous), transdermal, bronchial or nasal administration. Thus, if you use a solid medium prepared drug can be tableted, placed in a hard gelatin capsule in powder form or in the form of pellets or in the form of tablets or cakes. A solid carrier can contain obsidian the tide fillers, such as binders, excipients, oiling agents for tablets, substances that cause disintegration, wetting agents, and others. If it is desired, the tablet may be coated with film coating according to standard techniques. If you use a carrier liquid, the drug can be in the form of a syrup, emulsion, soft gelatin capsule, sterile tools for injection, aqueous or non-aqueous liquid suspensions, or may be presented as a dry product for restore water or other suitable filler prior to use. Liquid preparations may contain conventional excipients, such as suspendresume tools, emulsification, wetting agents, non-aqueous excipients (including edible oils), preservatives, and fragrances and/or dyes. For parenteral administration, the carrier will usually contain sterile water, at least largely, but can also be used saline solutions, glucose solutions and the like, you can Also use suspension for injection, which can be applied generally accepted suspendresume substances. Also in parenteral dosage forms can be added conventional preservatives, buffering agents and other Extremely useful is the introduction the of the compounds of formula 1 in the form of orally dosed drugs. The pharmaceutical compositions can be prepared using conventional techniques appropriate to the desired medicines containing suitable quantities of MA-1 or MA-2. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th edition, 1985.

In the preparation of pharmaceutical compositions for use according to the invention the active ingredient or active ingredients can usually be mixed with a carrier, or diluted by a carrier, or incorporated into a carrier, which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid substance, which acts as a filler, excipient or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, pellets, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), ointments containing, for example, up to 10 wt.% active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable carriers and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum Arabic, FOSFA the calcium, alginates, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl - and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Pharmaceutical preparations can additionally contain oil, wetting agents, emulsification and suspendresume tools, preservatives, sweeteners or flavors. The composition of the invention can be prepared in such a way as to ensure rapid, prolonged or delayed release of the active ingredient after administration to the patient.

The composition is preferably prepared in a standard dosage form, each dosage unit contains from about 0.1 to about 100 mg of the active component. The term "standard dosage form" refers to physically discrete elements that are appropriate in the form of a single dosage forms for humans and other mammals, each unit contains a predetermined quantity of the active substance, designed in such a way as to obtain the desired prophylactic or therapeutic effect in the implementation of the treatment, in combination with the required pharmaceutical carrier. Thus, for example, an adult patient suffering from depressive disorders, m which can take 1-4 tablets each of which contains 5-100 mg of MA-1, which can be taken once, twice or three times a day and can improve his or her conditions for from about one to about 12 weeks.

Typical standard dosage form can be a capsule of size 0 or size 1, containing 20, 50 or 100 mg of MA-1, as well as anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate. It is recommended to keep at temperature between 15 to 20°C, protect from moisture and light.

In accordance with one embodiment of the present invention, D50 to enter MA-1 is less than approximately 100 μm, for example, from about 20 to about 50 microns, or from about 30 to 40 microns.

MA-1 can also be prepared in the form of drug controlled release, for example, a slow, continuous or pulsed release. MA-1 can also be administered concomitantly with other therapeutic drugs, including, but not limited to, treatment with other antidepressants or other treatment means treatment for other emotional disorders. Thus, the invention encompasses, for example, the introduction of MA-1 or MA-2 in combination with the other is on melatonergic antagonists or other means, inducing sleep.

Examples

The examples below are illustrative and do not limit the invention, and illustrate the usefulness of the MA-1 for the prevention and treatment of symptoms of depressive disorders.

Example 1.

A clinical study was performed to assess the safety of MA-1, and to determine the ability of the MA-1 to move the cycle of sleep/awakening after shifting forward on 5 hours of sleep. The study was randomized, double-anonymous, parallel-group, with control as a placebo. It consisted of a period of outpatient screening for 2-4 weeks followed by a period of stay in the hospital for 8 days. After acclimatization to laboratory sleep, sleep time moved forward for 5 hours. The primary objectives of this study was to investigate the exposure-response on the MA-1 moving circadian release of endogenous melatonindosage rhythm that is measured by the appearance of melatonin in the twilight (DLMO, biomarker cycle of sleep-wakefulness), the study of exposure-response on the MA-1 on the average performance parameters of sleep, which is measured by PSG, the study of exposure-response on the MA-1 on deviations objective neurobehavioral measures of performance when the productive time that is measured by using to photoresistance continuous testing indicators and to assess the safety and tolerability of MA-1. This study was performed on forty-five healthy volunteers of both sexes aged 18 to 50 years. Randomized thirty-nine subjects. The results of this study are presented below.

The study evaluated the safety and efficacy of four parallelnyh doses of MA-1 (10 mg, 20 mg, 50 mg and 100 mg) compared with the introduction of the placebo phase shift the circadian cycle, sleep parameters in the main period of sleep and activity of the subject. After signing the informed consent in writing, subjects who met the inclusion criteria/exclusion screening and baseline, were included in the stationary part of the study duration of 8 days. All studies on patients was conducted in a sleep laboratory with a separation in time, in which subjects are not affected by any temporary benchmarks. During the first three nights, the subjects were given a placebo 30 minutes before bedtime (11 p.m) in a simple blind study. During this period, the measured source data for performance indicators. At 17:00 on day 3, subjects began a 19-hour pre-const Pozovi (CF) segment, during this time, the subjects remained seated in a semi-horizontal position and approximately every hour between 7:00 a.m. to 12:00 am took blood samples. The purpose of pre-CU is egment was measuring circadian rhythm, each subject before the start of the segment of the night shift. In day 4, subjects randomized to exercise once daily treatment in one of the five treatment groups. Additionally, the modes of sleep and wakefulness subjects moved forward 5 hours, so that subjects were required to sleep at approximately 18:00-2:00 at night. Was carried out by treatment and time shift supported within 3 days. During this time I recorded the performance. To measure the phase of the circadian rhythm at the end of the study, immediately after the segment treatment at day 7 was carried out 24-hour post-CF. When conducting this study, each patient took about 500 ml of blood. When conducting the research investigated the security (EOS), while visiting on day 8, and during follow-up visits. The planned number of patients to register amounted to 40 persons, but in reality investigated 45.

The particle size of the MA-1 used in this study were:

D10D50D90D100
10 µm115 mcm316 µm631 mcm

Assume that for maximum efficiency the peaks Konzentrat the th MA-1 in plasma must be the same over time, when patients go to sleep. Since the maximum plasma concentrations (Cmax) are reached in 30 minutes - 1 hour after oral administration4,5then the MA-1 was injected 30 minutes before bedtime. Placebo control was used to separate the action of the medicinal product from the influences of other components of the treatment in the study population during the treatment period.

Selected oral dose was based on data safety and efficiency, obtained in the previous preclinical and clinical studies MA-1. Pharmacological models of acute and chronic phase shift in vitro was shown chronobiotics activity for doses in the range of from 1 to 5 mg/kg Extrapolation of these data to humans confirms that the dose from 0.14 up to 0.71 mg/kg, or from 10 to 50 mg for a subject weighing 70, should effectively shift the cycle of sleep-wakefulness. Despite the fact that they are not optimally designed to assess chronobiotics potential MA-1, in clinical trials CN116-002 evaluated the impact of MA-1 on the circadian cycle of sleep-wakefulness. The results of this study indicate that 50 mg of MA-1 consistently shifts circadian rhythms. Doses selected for the study (10, 20, 50 and 100 mg), fall within the expected range of effective doses. The security of the selected doses for this study confirmed the existence of the governmental earlier clinical studies. In phase 1 clinical trials of single oral dose of from 1 to 300 mg MA-1 was safe and well tolerated by healthy subjects. Additionally, the safety and tolerability MA-1 at doses up to 150 mg was shown in the daily introduction within 28 days of healthy subjects and elderly subjects with chronic insomnia. The highest dose in the study, 100 mg, is also a safe limit, confirmed in both studies, phase I single and multiple dose increase and in the research phase II.

For evaluation in the study of circadian cycle of sleep-waking, measured the levels of melatonin in plasma. Start of production of melatonin, or the beginning of the production of melatonin in the twilight (DLMO) is associated with the beginning of the dream. DLMO is a standard marker, which often use to estimate the phase of circadian rhythm4. For assessment MA-1 cycles of the sleep-wakefulness, watched DLMO from the subjects before and after treatment. For this study, DLMO was defined as the time when the production of melatonin reaches 25% night peak (MEL25% rise) fitted curve phase melatonin7.

Since light has a significant bias effect on the release of melatonin, the light levels in a sleep laboratory accurately regulated. Subjects were exposed to the action of light with and what tensionally 25 Lux angle of view (in the room of the maximum intensity of the fluorescent light is 50 Lux) when waking sections of the Protocol, except for the first 6 hours WED segment. Chose twenty-five Luxe angle of view, because this low intensity reduces the effect of light on the phase shift, and is also consistent with insolation, which is exposed on the work of many replacement workers. Subjects were exposed to the action of light with an intensity of less than 2 Lux angle of view (maximum intensity in the room is 8 Lux) during the first 6 hours WED segments. We measured the production of melatonin, including the beginning and the maximum concentration in plasma, with the implementation of the CF part of the Protocol. To eliminate the influence of light on endogenous melatonin secretion chose low light intensity.

DLMO

DLMO is a biomarker of circadian cycle of sleep-wakefulness. One of the primary objectives of this study is to investigate the exposure-response MA-1 on the cycle of sleep-wakefulness that is estimated using the DLMO. Curve melatoninbuy phase, the levels of melatonin in plasma (PG/ml) was measured once every 30 minutes during the first 14 hours WED segments and every hour during the remaining WED segments. The full curve melatoninbuy phase built so that it was possible to determine peak concentrations of melatonin. Based on the peak concentrations of melatonin were determined DLMO, in the form of 25% of the peak. When performing double-anonymous cured the I (days 4-6), melatonin levels in plasma were measured every 30 minutes from 16:00 until 2:00 in the morning. This window of time was evaluated for content DLMO. To determine whether any dose of MA-1 to induce a phase shift in the circadian rhythm, compared the differences between DLMO in the days of treatment and baseline values for the subject of the treated MA-1, on the differences between the DLMO in the days of treatment and baseline values for subjects treated with placebo.

The sleep efficiency

Another primary objective of this study is to investigate exposure-response MA-1 on the average values of the performance parameters of sleep. The sleep efficiency (sleep time /time in bed * 100%) was measured using polysomnography (PSG). For research subjects used different sensors with tape or paste which, by means of which recorded the EEG, eye movements, muscle tone, body movement, heart rate and respiration. Also performed an audiovisual fixation. PSG registration was carried out during episodes of sleep in the days 1, 2, 3, 4, 5, 6 and 7 of this study (denoted nights 1-7). The effectiveness of the sleep of the subjects submitted to the treatment of MA-1, was compared with the effectiveness of the sleep of subjects treated with placebo. Data PSG in the night 3 and 7 were not analyzed.

Secondary efficacy parameter

Other polysomnographically parameters

Sleep parameters were recorded during all episodes of sleep (from 23:00 to 7:00 a.m. on nights 1, 2, and 3 and from 18:00 until 2:00 in the night 4, 5, 6 and 7). From these records were identified latent sleepiness (waiting for stable sleep) and Wake after sleep onset (WASO). PSG in the night 3 and 7 were not analyzed.

Research of efficiency

The primary variables of effectiveness

The secretion of melatonin in the twilight

Peak melatonin was determined from the values of melatonin from the subject as the average of the maximum values obtained during the night of 3 night and 7; if the samples for the determination of melatonin in one of these days did not take (or if you got the wrong samples during the period when it should be a peak of melatonin), then the peak of the melatonin peak was the next day. For the primary analyses, was calculated edge amount in the form of a 25% peak melatonin (DLMO25%). DLMO was calculated by linear interpolation of these values melatonin and appropriate periods of time.

Analyzed the differences in DLMO25% between day endpoint of the study (nights 4, 5 and 6) source value (night 3) by pairwise comparison of each dose group with placebo, using a linear model univariate analysis of variance (ANOVA)used in SAS® (SAS® Institute, Cary, North Carolina). Average values were calculated using the method Nakanishi the squares in SAS®. Standard deviation was calculated using static output in SAS®. Other statistical tests are also presented graphically. They included: linear regression of response depending on the exposure (dose, AUC, or Cmax), nonparametric rank correlation coefficient Kendall Tau and nonparametric rank correlation coefficient Spearman.

The sleep efficiency

Other primary result of interest is the sleep efficiency (SE). SE (%) is defined as total sleep time divided by the time allowed as an opportunity to sleep, multiplied by 100%. Also analyzed SE during parts of the night, including the first and second half of the night, and the first, second and final third of the night. The time allowed for sleep, was 8 hours (480 minutes).

The effectiveness of the treatment (nights 4, 5 and 6) relative to the original values (night 2) was based on the differences between the values of SE in these days. Also expected total average efficiency of sleep at night 4, 5 and 6 and compared with the original values. The same initial values and days of the end points used for parts of the night tests. Analyzed the difference in SE between the day of the end point of the study and an initial value by pairwise comparison of each dose group with placebo, using the model of lineing the univariate analysis of variance (ANOVA) in SAS® (SAS® Institute, Cary, North Carolina). Average values were determined using the method of least squares in SAS®. Standard deviation was calculated using static output in SAS®. Other statistical tests are also presented graphically. They included: linear regression of response depending on the exposure (dose, AUC, or Cmax), nonparametric rank correlation coefficient Kendall Tau and nonparametric rank correlation coefficient Spearman.

Secondary (s) variable (s) efficiency

DLMO Time to start and the minimum effective dose

Time (day), which is the maximum shift of the circadian period was determined by comparing DLMO25% relative to the original values and treated nights for all subjects, as described above. Additionally, it was also determined the minimum effective dose by comparing DLMO25% relative to the original values and treated nights, as described above. The first dose with statistically significant p-value in ANOVA with pairwise opposition was considered as the minimum effective dose.

Results for sleep and PSG

Hidden drowsiness (waiting for stable sleep and waking after sleep onset (WASO) was measured using PSG in night 1, 2, 4, 5 and 6.

Analyzed the differences in these sleep parameters between the day of the end point of research is the development and initial value by pairwise comparison of each dose group with placebo, using the linear model univariate analysis of variance (ANOVA) in SAS® (SAS® Institute, Cary, North Carolina). Average values were determined using the method of least squares in SAS®. Standard deviation was calculated using static output in SAS®. Other statistical tests are also presented graphically. They included: linear regression of response depending on the exposure (dose, AUC, or Cmax), nonparametric rank correlation coefficient Kendall Tau and nonparametric rank correlation coefficient Spearman.

Primary efficacy results

11.1.1.1 Shift start the selection of melatonin in twilight

In this study, the beginning of the allocation of melatonin in twilight25%, LOQ5(DLMO25%, LOQ5) is defined as the time when the production of melatonin reaches 25% of the maximum concentration of melatonin (MELmax) and for samples below the limit of quantitation (LOQ) studies melatonin has established 5 PG/ml LOQ5 represents half of the minimum level of quantification for research (10 PG/ml) and is more likely to be important for the assessment of samples below the limit of quantitation, which is set to a value of zero.

MA-1, when compared with placebo, is able to induce a shift forward in DLMO25%, LOQ5 in lane is th night treatment (night 4), when compared with the baseline DLMO25%, LOQ5(night 3) depending on the dose (table 11.1.1).

Table 11.1.1
Changes DLMO25%,LOQ5between night 4 night and 3, depending on dose*
DLMO25%, LOQ5changes, includingDose group
Placebo10 mg20 mg50 mg100 mg
N=6N=8N=7N=4N=5
-0,48±0,84±0,18-1,14-0,50-2,74±1,95
(0,0276)
*Values changes in DLMO (mean ± CO) expressed for each dose group exhibiting confirmation statistically significant influence. For p-values (in parenthesis) compared the dose group with placebo, using ANOVA with against what postavleniya.

Changes in the efficiency of the dream

The ability of MA-1 to adjust the sleep disruption caused by the phase shift forward, examined by comparing changes in efficiencies of sleep in subjects who were treated MA-1, when the phase shift forward relative changes in sleep efficiency in the treatment of placebo in the phase shift forward. The sleep efficiency (sleep time /opportunity to sleep * 100%) was measured objectively by polysomnographically registrations during the night. This study analyzed polysomnographically register initial values (nights 1 and 2) and treated 4 nights,

5 and 6.

Full night sleep efficiency

MA-1 is able to minimize violations full night sleep efficiency between night 4 and night 2 depending on the dose. (Table 11.1.2).

The effectiveness of sleep in the study of parts of the night

The sleep efficiency was also compared for parts of the night by dividing the whole night into three parts. MA-1 improves sleep in the middle third of the night, depending on the dose. (Table 11.1.2).

11.1.2 Secondary efficacy results

11.1.2.1 DLMO shift - time to start and the minimum effective dose

As described in detail in section 11.1.1.1, MA-1, when compared with placebo, is able to induce a shift forward DLMO25%, LOQ5on the first night of treatment (night 4) when compared with the original mn what values (night 3) depending on the dose (table 11.1.1, Figure 11.1.1). Whereas nonparametric analysis clearly indicates complete dependence of the effect of dose, believe that the dose of MA-1 100 mg is the minimum effective dose for DLMO shift, because it is the first dose with a statistically significant p-value in ANOVA with contrasts.

11.1.2.2 Other sleep parameters

In addition to the effectiveness of sleep, investigated the relationship exposure-response MA-1 on hidden drowsiness, maintaining sleep, and sleep architecture.

Hidden drowsiness

MA-1, when compared with placebo can reduce the expectation of stable sleep (LPS) on the first night of treatment (night 4) when compared with baseline (night 2) (table 11.1.3).

Table 11.1.3
Change hidden sleepiness between night 4 and night 2 depending on dose*
DoseWaiting for a stable sleep (min)
Placebo (N=8)15,13±each holding 21.25
MA-1
10 mg (N=8)
-8,25±16,34
(0,0034)
MA-1
20 mg (N=8)
5,00
MA-1
50 mg (N=7)
-3,71±10,97br/> (0,0193)

DoseWaiting for a stable sleep (min)
MA-1
100 mg (N=6)
-4,17±6,93
(0,0214)
*Variation of the latent sleepiness (mean ± CO) expressed for each dose group exhibiting confirmation statistically significant influence. For p-values (in parenthesis) compared the dose group with placebo, using ANOVA with the oppositions.

Maintaining sleep

Table 11.1.4
Change maintaining sleep between night 4 and night 2 depending on dose *
DoseWASO (min)WASO (% points)
Placebo(N=7)77,00±91,0117,22±19,69
MA-1 10 mg (N=8)40,56of 8.37
MA-1 20 mg (N=8)31,196,91
MA-1 50 mg (N=7)31,21 6,61
MA-1 100 mg (N=7)8,50±20,39
(0,0452)
1,85±4,29
(0,0391)
*The significance of changes maintenance of sleep (mean ± CO) expressed for each dose group exhibiting confirmation statistically significant influence. For p-values (in parenthesis) compared the dose group with placebo, using ANOVA with the oppositions.

Awakening after sleep onset (WASO) was calculated as a unit of time (number of minutes during which the subject woke up after a deep sleep) and cut (the length of time during which the subject woke up in the time interval from a deep sleep to turn on the light). Statistical significance was achieved if the dose of MA-1 100 mg was compared with placebo in WASO as for the unit of time and the segment (table 11.1.4). While the dose-effect, which was measured using non-parametric tests was not statistically significant, linear regression analysis of changes WASO for each of the tested doses indicates that a dose of MA-1 100 mg able to minimize the violation of Wake after sleep onset between day 4 and day 2 for most of this group of treated patients.

Sleep architecture and REM p is lamost

MA-1 does not change the percentage of time for each stage of sleep between night 4 and night 2.

On the night of 4, MA-1 is able to minimize the violation of REM polarity caused by the phase shift forward by increasing the number of REM episodes during the final third of the night. After 4 hours on the night of 4, watched fewer cumulative REM episodes compared with placebo for higher doses of MA-1. It is a violation of REM polarity is not observed in the night 2.

Additional analyses assessed the cumulative REM intervals for one third of the night. MA-1 is able to induce a dose-dependent increase in the number of REM episodes during the final third of the night, which is consistent with the preservation of REM sleep patterns at night 2 before phase shift forward.

Example 2.

A multicenter, randomized, double-anonymous, placebo-controlled, parallel group study was performed to investigate the efficacy and safety of single oral doses of VEC-162 (20, 50 and 100 mg) compared to placebo in healthy men and women with induced transient insomnia. Randomized approximately 400 subjects in the approximate ratio of 1:1:1:1 in group to treat.

In General, the period of screening started from 14 to 35 days before the beginning of the evaluation period, which was day 1. Before day 1, subjects were asked to increase their sleep up to 9 hours per night. At night the 1 was injected drug or placebo approximately 30 minutes from switching on the light.

The primary efcacy variable was LPS. LPS is defined as the period of time passing from off the light before deep sleep. In this study, deep sleep is defined as the point at which begins the 10-minute uninterrupted sleep. Sleep was determined on the basis of polysomnography (PSG).

Secondary parameters of efficacy was the following:

Awakening after sleep onset (WASO): WASO is defined as the elapsed time awake between sleep early and the lights are switched on during the night 1 as specified by the PSG.

The latent period nearstore (LNA): LNA is defined as the number of minutes before reaching any stage of sleep.

Total sleep time (TST): TST is defined as the number of minutes awake during the whole time in bed.

The specific size of the MA-1 used in this study were:

D10D50D90D100
5 µm25 microns72 microns316 µm

Illustrative results included the following.

- Waiting for a stable sleep (LPS): Improvement compared with placebo 21,5 (p<0,001), 26,3 (p<0,001), and 22.8 (p<0,001) minutes to DL the dose of 20, 50 and 100 mg respectively.

- The latent period nearstore (LNA): Improvement compared with placebo 11,1 (p<0,006), and 14.3 (p<0,001), and 12.3 (p<0.002) minutes for doses of 20, 50 and 100 mg respectively.

- Awakening after sleep onset (WASO): Improvement compared with placebo 24,2 (p<0,02), 33,7 (p=0.001), and 17.5 (p-value of 0.081) minutes for doses of 20, 50 and 100 mg respectively.

Total sleep time (TST): the Improvement compared with placebo 33,7 (p<0,002), 47,9 (p<0,001) and 29.6 (p<0,005) minutes for doses of 20, 50 and 100 mg respectively.

This study also showed that the VEC-162 well tolerated at all doses.

On the basis of the results obtained in examples 1 and 2, we can draw the following conclusions. These findings include, but are not limited to.

MA-1 is well tolerated at doses of 10, 20, 50 and 100 mg.

MA-1, when compared with placebo, induces shift forward DLMO25%, LOQ5on the first night of treatment, depending on the dose.

MA-1 minimizes the violation of the effectiveness of sleep a night and the middle third of the night), caused by phase shift forward.

MA-1 minimizes the violation of REM polarity caused by the phase shift forward by increasing the number of REM episodes during the final third of the night.

MA-1 minimizes the violation of Wake after sleep onset (WASO), caused by phase shift forward.

MA-1 improves the hidden drowsiness, which is increased by the phase shift forward.

- Value is s C maxincrease approximately in proportion to dose. AUC is increased approximately in proportion to dose.

- The exposure is not affected by age, weight, height, gender, creatinine clearance, or the original ALT levels.

50 mg is more effective dose than 100 mg, although both doses are well tolerated, indicating that a single oral dose of approximately 50 mg preferred relative to a single oral dose of approximately 100 mg

20 mg comparable or higher than 100 mg in efficiency, although 100 mg is well tolerated, indicating that a single oral dose of approximately 20 mg preferred relative to a single oral dose of approximately 100 mg

- Oral dose of from about 20 to about 50 mg effective for the treatment of sleep disorders.

- Oral dose of from about 20 to about 50 mg effective for the treatment of disorders of sleep disorders, with the introduction of approximately 1/2 hour before bedtime.

The invention also includes a method of marketing MA-1, which includes the distribution of health workers or patients of any one or more of the preceding conclusions.

The above description of the various aspects of the invention are presented for purposes of illustration and description. It is not intended to be exhaustive or to ohraniat izopet is the description of a particular form, and possible modifications and changes. Such modifications and changes fall under the scope of the invention covered by the claims.

1. A method of treating disturbances of circadian rhythm, or sleep disorders in a patient suffering from this disorder, involving oral administration to a subject a pharmaceutical composition comprising from 20 mg to 50 mg 1(R-TRANS)-N-[[2-(2,3-dihydro-4-benzofuranyl)cyclopropyl] methyl [propanamide (MA-1), where D 50 for MA-1 is from 20 μm to 50 μm.

2. The method according to claim 1, in which the dose is 50 mg per day.

3. The method according to claim 1, in which the dose is 20 mg per day.

4. The method according to claim 1, in which the MA-1 is administered prior to or within about 2 hours before bedtime.

5. The method according to claim 1, in which the MA-1 is administered in about half an hour before bedtime.

6. The method according to claim 1, in which the state that treat or prevent is a long latent sleepiness and MA-1 administered orally at a dose of 20 mg/day.

7. The method according to claim 1, in which the state that treat or prevent is a long latent sleepiness and MA-1 administered orally at a dose of 50 mg/day.

8. A method of treating disturbances of circadian rhythm, or sleep disorders in a patient suffering from this disorder, involving oral administration to a subject a pharmaceutical composition comprising more than about 50 mg 1(R-Tran is)-N-[[2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]methyl]propanamide (MA-1), and in which D 50 for MA-1 is 100 μm or more.

9. The method according to claim 8, in which D 50 for MA-1 is 100 μm.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention provides new imidazo[1,2-b]pyridazine compounds covered by general structural formula (I) wherein the radicals and symbols have the values presented in the patent claim, and pharmaceutically acceptable salts thereof. The compounds of structural formula (I) are effective both for treating or preventing the diseases related to GABA receptor inhibition, anxiety, epilepsy, sleep disorders, including insomnia, and for inducing a sedative-hypnotic, anaesthetic effect, sleep and muscle relaxation.

EFFECT: there are presented methods for preparing the above compounds, and also intermediate compounds for preparing them.

21 cl, 4 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns a pharmaceutical composition for sublingual or buccal administration of the active ingredients of a low to poor water-solubility. As an active ingredient, the composition contains a solution of a hormone specified in a group consisting of melatonin, oestrogens, progesterone, testosterone and dihydrotestosterone in a pharmaceutically acceptable solvent, adsorbed or absorbed on particles of a pharmaceutically acceptable carrier. The invention also concerns methods for preparing and using the above pharmaceutical composition.

EFFECT: what is presented is the new composition for sublingual or buccal administration of the active ingredients of a low to poor water-solubility.

19 cl, 4 ex, 2 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is the use of 7-chlor-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzodiazepin-6-one or a pharmaceutically acceptable salt thereof for treating various types of insomnia (terminal one, insomnia in an individual under min. 65 years, for the relief of wakefulness after the beginning of a sleep, for the prolongation of total sleep time after the beginning of a sleep - versions), pharmaceutical compositions for the appropriate application (versions) and methods of treating the various types of insomnia (versions).

EFFECT: invention is effective in treating insomnia, maintaining the sleep, terminal insomnia, including in the aged; the compound has a short half-life, ie 3-4 hours (so it causes no residual sedative action), and improves the daily activity in the aged suffering diurnal drowsiness.

61 cl, 29 dwg, 10 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and salts thereof wherein R1 represents -A11-A12-; R2 represents tetrahydrofurylmethyl, tetrahydropyranylmethyl or tetrahydropyranyl; A11 represents a single bond, methylene or 3,2-ethylene; A12 represents C1-6 alkyl, C3-6 cycloalkyl or C3-6 cycloalkyl containing methyl; R3 represents methoxy, cyano, cyclobutyloxymethyl, methoxymethyl or ethoxymethyl; and R4 represents methoxy or chlorine. Also, the invention also refers to a pharmaceutical composition possessing corticotrophin-releasing factor (CRF) receptor antagonist activity, containing a compound of formula (I), to a therapeutic/preventive agent, and a method of treating the diseases specified in the patent claim.

EFFECT: there are presented the compounds of formula (I) as corticotropin-releasing factor (CRF) receptor antagonists.

20 cl, 2 dwg, 2 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new halogenised pyrazolo[1,5-a]-pyrimidines of general formula (I) and their pharmaceutically acceptable salts possessing affinity with respect to α1-,α2 subunits of a GABAA receptor. In formula R represents alkyl(C1-C6); R1 is specified in a group consisting of alkyl(C1-C6) and alkinyl(C1-C6); X represents a halogen atom, and Y is specified in a group consisting of -CO- and -SO2. The invention refers to intermediate enamine compounds and methods for preparing them.

EFFECT: invention also refers to a method for preparing the compounds of formula (I), the based pharmaceutical compounds, to the use of said compounds for preparing said drug preparation for treating or preventing anxiety, epilepsy, sleep disorders, including insomnia, as well as for inducing a sedative-hypnotic effect, anaesthesia and muscular relaxation.

23 cl, 6 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating and/or preventing depressions. The pharmaceutical composition contains an active substance presented by a selective serotonin reuptake inhibitor (SSRI) specified in a group of fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine differing by the fact that as an active substance, it additionally contains N-acetyl-5-methoxytryptamine (melatonin) in the following proportions, mg: selective serotonin reuptake inhibitor (SSRI) - 10-30 mg, melatonin - 3-8 mg. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a capsule, by a soft dosage form - a rectal suppository.

EFFECT: pharmaceutical composition provides treating depressions and has a number of additional therapeutic properties: easing falling asleep and relieving sleeping disorders, recovering circadian rhythm and seasonal rhythm with reducing a risk of side effects of SSRI.

3 cl, 14 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new (-)-stereoisomer of formula (I) wherein X is H, or its pharmaceutically acceptable salt which agonise GABA receptor, to a pharmaceutical composition on the basis of the presented compound, to a method for preparing the (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt, to a method for inducing or maintaining general anaesthesia, to a method for promoting pain management and to a method for promoting pain management and to a method for prototyping antiemetic activity with the use of the presented (-)-stereoisomer or its pharmaceutically acceptable salt, as well as to a new diastereoisomer (-)-2,6-di-fluoro-butylphenyl ester of carbamic acid of formula (II) wherein R1 represents a chiral amino group, and X is H, or to its pharmaceutically acceptable salt.

EFFECT: preparing the pharmaceutically acceptable salt which agonise GABA receptor.

14 cl, 15 ex, 8 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new (-)-stereoisomer of formula (I) wherein X is H, or its pharmaceutically acceptable salt which agonise GABA receptor, to a pharmaceutical composition on the basis of the presented compound, to a method for preparing the (-)-stereoisomer of formula (I) or its pharmaceutically acceptable salt, to a method for inducing or maintaining general anaesthesia, to a method for promoting pain management and to a method for promoting pain management and to a method for prototyping antiemetic activity with the use of the presented (-)-stereoisomer or its pharmaceutically acceptable salt, as well as to a new diastereoisomer (-)-2-fluoro-butyl-6-isopropylphenyl ester of carbamic acid of formula (II) wherein R1 represents a chiral amino group, and X is H.

EFFECT: preparing the pharmaceutically acceptable salt which agonise GABA receptor.

16 cl, 12 ex, 6 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a dietary and pharmaceutical composition containing ligustilide to be applied in a method of treating or preventing depression, generalised anxiety disorders, dysphoria, obsessive-compulsive behaviour, and affective disorders, as well as to a non-therapeutic application of the dietary composition containing ligustilide.

EFFECT: higher efficacy of the applied derivatives.

6 cl, 17 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is a dosage form containing a drug substance for treating insomnia, containing a layer or a matrix-surrounding coating wherein a drug substance is dissolved or dispersed with said drug substance released after a time of delay (at least 1 hour after the introduction) which is not substantially accompanied by the drug substance release, and the coating material contains less than 5 % of substances which possess an ability to swell or gelate, and the matrix contains an release control agent.

EFFECT: invention provides exactly establishing and observing the time of delay before the active substance release that enables the patient to work before sleeping, being in the non-sleepy state.

20 cl, 3 dwg, 8 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to a composition for appetite suppression and body weight stimulation, as well as to a composition possessing antidepressant and antiasthenic activity. Use of the composition containing Griffonia simplicifolia extract as an L-tryptophan or 5-hydroxytryptophan source and Klamath algae extract for preparing a product for sublingual or nasal administration to suppress appetite and to stimulate weight loss in an individual. Use of the composition containing Griffonia simplicifolia extract as the L-tryptophan or 5-hydroxytryptophan source and Klamath algae extract for preparing the product for sublingual or nasal administration, possessing antidepressant and antiasthenic activity for improving attention, tone and mood in an individual. A composition for appetite suppression and weight loss stimulation. A composition for tone and mood improvement possessing natural antidepressant activity, and for attention and mental energy improvement ensured by an antiasthenic effect.

EFFECT: compositions are effective to suppress appetite, to stimulate weight loss, as well as to improve tone and mood, and to improve attention and mental energy.

12 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a drug preparation for preventing the development of cardiovascular diseases in individuals of a high-risk group. A capsule for preventing the development of cardiovascular diseases in individuals of a high-risk group which contains acetylsalicylic acid tablets coated by partially hydrolised polyvinyl alcohol (PVA), tablets of simvastatin and pravastatin coated by hydroxypropyl methylcellulose (HPMC) and tablets of lisinopril, ramipril or perindopril coated by partially hydrolised polyvinyl chloride. Using the capsule in producing the drug preparation for preventing the development of cardiovascular diseases in individuals of a high-risk group.

EFFECT: capsule is stable at variable temperature and relative humidity, as well as resistant to decomposition of the active ingredients under exposure to light.

8 cl, 29 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention relates to system of peroral delivery of medications with controlled release into intestine region, which includes therapeutically active component, selected from sodium diclofenac, oxprenolol, methoprolol, nifedipine, indomethacin, ibuprofen, isosorbide, theophylline and pharmaceutically acceptable carrier. As pharmaceutically acceptable carrier the system contains polymer carrier based on interpolyelectrolyte complex, obtained by interaction of cross-linked polyacrylic acid (polyanion) with dimethylaminoethyl methacrylate copolymer and neutral esters of methacrylic acid (polycation).

EFFECT: invention ensures controlled release along entire intestine, dose reduction and prolonged action of active component.

4 cl, 4 dwg, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to obtaining cPLA2 inhibitors of formula (A1): , where Ar, R, z, R10, n1, n3, X2, R12, R13 and R14 have values, given in invention formula, or pharmaceutically acceptable salts of said compound, which includes reaction of corresponding compound of formula II: [Ar-(R)2-SO2-1]qM, where M and q have values, given in formula of invention, with reagent, carrying substituting halogen atom, in presence of catalytic amount of water and cocatalyst with formation of corresponding compound of formula III: Ar-(R)z-SO2-X, where X represents halogen; and reaction of formula III compound with corresponding compound of formula (B1): , where R12 represents phenyl, substituted with group -(CH2)n4-COOH, where carboxyl group is protected by protective group, with obtaining of sulfonamide; and if necessary, conversion of obtained compound into form of its pharmaceutically acceptable salt. In addition, claimed invention relates to novel intermediate compounds for obtaining cPLA2 inhibitors and to methods of obtaining intermediate compounds for obtaining cPLA2 inhibitors.

EFFECT: method improvement.

26 cl, 2 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I) wherein R means phenyl which can have one or more substitutes - halogen; or its pharmaceutically acceptable salt.

EFFECT: compounds may be used in CRTH2-mediated diseases, such as asthma, allergic rhinitis, etc.

16 cl, 13 dwg, 13 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof, in which: one of A, B, C and D denotes N, and the rest independently denote CH and C(R1); m equals a whole number from 1 to 4; n equals a whole number from 0 to 4; R1 denotes halogen; R2 and R3 denote hydrogen; R4 is selected from H, C1-6alkyl; Ar denotes aryl, optionally substituted with one or more halogen atoms; X denotes -C(Ra)(Rb)-, where Ra and Rb denote H; Y denotes -S(O)2-. The invention also relates to a pharmaceutical composition having CRTH2 receptor antagonist properties and containing a compound of formula I, to use of a compound of formula I when producing a drug for treating or preventing CRTH2 mediated diseases and a method for antagonistic action on CRTH2 receptor in mammals.

EFFECT: novel compound, which can be useful as a CRTH2 receptor antagonist, is obtained and described.

16 cl, 6 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and aims at treating cancer. There are used methods and a composition containing 1-[(4-chlorphenyl)methyl] -1H-indole-3-carboxalhyde and/or its analogues or derivatives.

EFFECT: group of invention enables higher clinical effectiveness in cancer ensured by inhibiting mutant RAS-protein activity.

24 cl, 6 tbl, 4 ex, 36 dwg

FIELD: medicine.

SUBSTANCE: claimed invention relates to medicine, namely, to gynecology, and can be applied for treatment of patients with inflammatory diseases of internal female genital organs. For this purpose conventional drug therapy and sessions of hyperbaric oxygenation (HBO) are carried out. Starting from the first day of treatment, against the background of drug therapy one time per day every day carried out are 6-8 sessions of HBO. First 3-4 sessions of HBO are carried out with duration 40-50 minutes each, with pressure in pressure chamber 1.1-1.3 atm. Following sessions of HBO are carried out for 35-45 minutes each with pressure in pressure chamber 1.4-1.6 atm. From the second day of treatment to patient additionally daily after sessions of HBO during 8-10 days intravenously by drip infusion introduced are 10 ml of medication cytoflavin in solution per 200 ml of 5% glucose solution. Rate of cytoflavin introduction on first 3 days constitutes 120 drops per minute. On remaining 5-7 days cytoflavin is introduced at rate 60 drops per minute. Conventional drug therapy is continued during 6 days after finishing the last session of HBO.

EFFECT: method makes it possible to essentially reduce treatment terms, as well as quantity of complications and side effects.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to traumatology and orthopaedics, and can be used for treating degenerative-dystrophic musculoskeletal diseases and posttraumatic adhesive processes. That is ensured by preparing a suspension of the following composition: the ointments Indometacin, Chondroxide, Essaven gel in proportions 1:1:1 mixed with the preparation Karipazim 50 mg dissolved in physiologic saline 5 ml, 2 % Trental and vitamin E solution 100 IU. The prepared suspension is introduced to the patient by phonophoresis within 5 minutes per a field. The therapeutic course is 15-20 procedures.

EFFECT: invention allows reducing total length of rehabilitation of the patients and increasing a remission period endured by an integrated effect on a pathological process during each therapeutic procedure.

3 ex, 4 dwg

FIELD: medicine.

SUBSTANCE: what is offered is application of amide N-(6-phenylhexanoyl)glycin-L-triptophane (GB-115, dipeptide, previously known as a psychotropic substance) as an agent for visceral pain management. Evident analgesic activity of the compound is shown in a visceral pain model (writhing test). An analgesic effect of GB-115 is exceeded in efficiency by morphine, nevertheless is comparable in antinociception intensity to the nonsteroidal anti-inflammatory drug diclofenac. Naltrexone iodide, a nonselective peripheral opioid receptor antagonist completely prevents GB-115 from displaying analgesic properties that testifies to GB-115 interaction with peripheral opioid receptors. The k-opioid receptor blockade by norbinaltorphimine, a selective k-receptor antagonist, arrests pharmacological effects of GB-115.

EFFECT: drug is characterised by a unique spectrum of receptor reactions and the absence of side effects, practically nontoxic, does not cause sedation and respiratory depression peculiar to opioid analgesics, does not exhibit ulcerogenic effects and action of a hematosis process inherent in NSAIDs.

6 dwg, 3 tbl

FIELD: medicine.

SUBSTANCE: it is suggested to apply tris-(2-hydroxyethyl)ammonium salt of 1-benzylindolyl-3-thioacetic acid earlier known as a stabilizer of cell membrane as preparation to treat autoimmune diseases. The property of the above-mentioned salt to inhibit T-dependent activation of B-lymphocytes, under conditions of decreased medullary function and body leukopenia should enable to develop new pharmacological preparation for treating autoimmune diseases, such as, for example, systemic lupus, rheumatoid polyarthritis, transplant's detachment at transplanting either organs or bony marrow.

EFFECT: higher efficiency of application.

4 ex, 3 tbl

Up!