Combination of medicinal agents comprising mirtazapine for treatment of depression and associated disorders

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a combination comprising mirtazapine or its pharmaceutically acceptable salt or solvate and hepiron, or its pharmaceutically acceptable salt or solvate but optionally in combination with one or some pharmaceutically acceptable carriers. The combination of amounts of hepiron and mirtazapine provide the more favorable effect of this combination as compared with additional effects of each preparation taken separately. Proposed combination can be used in treatment of depression and associated disorders. Also, the invention represents a new method for treatment of depression and associated disorders. The combination of mirtazapine and hepiron shows the better effects in more number of patients as compared with effect of each separate preparation that involve less amounts of adverse effects.

EFFECT: improved and valuable medicinal properties of combination.

5 cl, 5 tbl, 2 ex

 

The invention relates to the combination, including mirtazapine, the package containing the standard dosage forms, including mirtazapine, and to a method of treatment of depression and related disorders.

Disorders of the Central nervous system such as depression and anxiety are illnesses that affect people of all ages. Although there are many effective drugs for the treatment of these diseases, currently available treatments often do not meet the needs. Most interestingly, approximately one third of subjects with depression and anxiety no positive results of treatment and recovery in the group that received effective treatment, slow, upon the occurrence of the effect at the earliest 2 weeks after start of medication.

Mirtazapine (Org 3770; disclosed in U.S. patent No. 4062848) or newly introduced gepirone (disclosed in U.S. patent No. 4423049) are examples of modern medicines for the treatment of depression and anxiety, have a favorable side effect profile and a very low risk of fatal overdose. For more effective treatment there is hope that the various mechanisms of action of drugs provide the possibility of complementary applications, see the following, patients who do not respond to one drug may respond to another drug. Sometimes drugs with the same therapeutic indication are prescribed as a combined therapy in order to benefit from such a complementary effect, although in General it is not recommended to combine antidepressant drugs because of the risk of cumulative adverse effects or synergistic toxic interactions (Schweitzer and Tuckwell, Drug Safety, Vol.19, pp. 455-464, 1998). Usually, if an individual patient is the apparent positive impact of known combinations of drugs, the positive effect is due to only one of the drugs in combination. More desirable is really a synergistic effect of the two drugs with the same indication for use, in the sense that the individual effect of the combination exceeds the additional effect effects of both drugs. We know only a very small number of synergistic interactions between therapeutic drugs, which was adopted in the treatment of diseases of the Central nervous system. The large amount of data available in relation to the so-called augmentative therapy of treatment-resistant depression by adding lithium to an antidepressant drug. The use of such a combination rossmar is provided with caution due to side effects lithium (Hardy et al., Journal Clin. Psychopharmacology, vol.17, pp. 22-26, 1997). The results of applying the combination of lithium with mirtazapine were opened with the presentation of favorable data, but the gain is not so pronounced, so this combination should be selected as a treatment for depressive disorders the first choice (Bruijn et al., Journal Clin. Psychiatry, Vol.59, pp. 657-663, 1998).

Therefore, all the more surprising, then found a synergistic effect of mirtazapine and gepirone. This invention provides a combination comprising a number of mirtazapine or its pharmaceutically acceptable salt or MES and a certain amount of gepirone or its pharmaceutically acceptable salt or MES, optionally in Association with one or more pharmaceutically acceptable carriers, and the number of gepirone and the number of mirtazapine is such that the effect of combination of more favorable than the additional effects of the amounts of each drug separately. Thus, gepirone and mirtazapine really have a synergistic interaction when the application for the treatment of depression and related disorders. As a consequence, the combined use of mirtazapine and gepirone has the best effects in a larger number of patients compared with each drug separately. The best effect may be fewer side effects and is more rapid or more complete recovery of individual patients, or in General the treatment group patients. Preferred is the use of combination in the treatment of the previously mentioned treatment-resistant depression, also known as refractory depression, or in the treatment of untreatable depression.

Thus, the present invention relates to the introduction of two different psychotropic drugs from different pharmacological categories, each drug enhances therapeutic efficacy of another drug in the treatment of depression and related disorders.

Following clarification of terms used above are used to better explain what is represented by this invention.

The name of the drug mirtazapine also applies to the individual (R) and (S) enantiomers of mirtazapine. They can be used in the form of their salts, essentially free, i.e. associated with less than 5%, preferably less than 2%, in particular less than 1% of the other enantiomer, or as mixtures of these enantiomers in any ratio, including a racemic mixture, which contains essentially equal amounts of the two enantiomers.

In the absence of other indications, all the quantities of active ingredients are masses of mirtazapine or gepirone as the basis. In accordance with the terminology in this description of medication gepirone and mirtazapine depict ablaut the active ingredients or active components of the combination.

Pharmaceutically acceptable salts include the acid additive salts, such as hydrochloric, fumaric, maleic, citric or succinic acid, and these acids are mentioned only as an illustration and without implied limitation.

The terms "pharmaceutically acceptable carriers and excipients" refers to those substances which are known in this field as valid for use as a filling or supporting material in pills, tablets, capsules, etc. compounds are usually approved for this purpose by the health authorities and are inactive as pharmacological tools. Data collection pharmaceutically acceptable carriers and excipients can be found in the guidance Handbook of Pharmaceutical Excipients (2ndedition edited by A.Wade and P.J.Weller; Published by the American Pharmaceutical Association, Washington, and The Pharmaceutical Press, London, 1994). In particular, lactose, starch, cellulose derivatives and the like or mixtures thereof can be used as carriers for the active components of the combination in accordance with this invention.

The term "combination" refers to any form of representation which may be declared intention of the combined use of mirtazapine and gepirone. Such a combination of mirtazapine and gepirone may herein also be referred to as "the combination in accordance with and is gaining". It should be understood that the compounds of this combination can be administered simultaneously or in the same or in different pharmaceutical compositions, or sequentially. If you are consistent introduction, the delay in the introduction of a second (or more) of the active ingredient should not be such that it was lost favorable consequence effective combination of active ingredients. The minimum requirement for the combination in accordance with this invention is that the combination should be designed for combined use with a favorable consequence of the effective combination of active ingredients. The proposed use of the combination can be carried out by means of the provision, provisions, equipment and/or other aid in applying the combination in accordance with the invention. For example, the combination can be made suitable by adding instructions or AIDS or even the defining conditions of the combined application. Determine the conditions of the combined application may, for example, be based on the characteristics of the pharmacist preparing the standard dosage forms of the active ingredients of this combination. Thus, the active ingredients can be in a separate standard the dosage forms, but the combination may have a specific pharmacist identifies a condition requiring the application of standard dosage forms of combination in sequence and/or at the specified time point. Preferred the determining factor for the combined application is, of course, the inclusion of both active components of the combination in a single pharmaceutical composition.

Thus, in accordance with one aspect of the present invention is a pharmaceutical composition comprising mirtazapine or its pharmaceutically acceptable salt or MES and gepirone or its pharmaceutically acceptable salt or MES.

The effects of mirtazapine and gepirone separately usually referred to as the antidepressant effects, implying the effects that improve mood in patients with depression. However, the effects of these drugs are not limited effect in patients with depression. It is known that under certain other diseases and symptoms that affects the Central nervous system, also have improved under the influence of treatment with mirtazapine and gepirone. In more General terms, these drugs possess psychotropic activity. This term refers here to any impact on the functioning of the Central nervous system, which can IP alsowhat to influence the behaviour and well-being mammals, in particular people.

The term "depression and related disorders" refers to medicine that can understand a specialist in this area using their knowledge of the modern use of antidepressant drugs. These disorders, known as respond positively to treatment with drugs classified as antidepressants, are considered to describe the present invention as the treatment of disorders related to depression. Such disorders are, for example, disorders associated with anxiety, such as panic disorder, neurosis obsessive-compulsive disorder, post-traumatic stress disorder or chronic pain syndromes. It is well known that antidepressant drugs have more favorable effects on behavior and mental functioning, which are not limited impact on depression. The invention also includes a use for anxiety, which are used antidepressant drugs, that is, with long-term use for the long-term effect, which should be distinguished from the use of typical anxiolytic drugs, also referred to as minor tranquilizers that have acute effect of relief of anxiety and often have a sedative effect. The latter anxiolytic/with datiny effect is usually attributed to interactions with the GABA-a receptors in the brain.

Such pharmacological information can lead to putting drugs into various categories. Regardless of medical categories, such as anxiolytic, antidepressant, neuroleptic," etc., or chemical categories, such as "tetracyclines", "benzodiazepines", etc., drugs can be classified on the basis of pharmacological mechanism. In this sense, gepirone often classified as medicinal products, other than mirtazapine. While mirtazapine referred to as "α2-blocker" or "noradrenergic and selective serotonergic antagonist" ('NASA'), gepirone known as "partial 5-HT1Aagonist".

Although the active ingredients of the combination can be administered as the pure chemicals, it is preferable to present them as pharmaceutical compositions, referred to in this context as a "pharmaceutical composition". Suitable compositions include compositions suitable for perorally, rectal, intranasal, local (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. Pharmaceutical compositions in embodiments of the present invention include mirtazapine or gepirone or a combination together with one or not is how many pharmaceutically acceptable carriers or excipients and, optionally, other therapeutic means. The present invention also provides a composition in accordance with the invention for use in the treatment of depression and related disorders. In addition, the invention includes the use of mirtazapine and gepirone in the manufacture of a medicinal product, comprising mirtazapine and gepirone, which has psychotropic activity with improved efficiency in the treatment of, in particular, depression and related disorders. This medicine has enhanced effect and fewer side effects compared with each drug separately. The use of the drug, preferably for the treatment of treatment-resistant depression. The invention also includes the use of mirtazapine and gepirone in the manufacture of drugs for injection in combination (simultaneously or sequentially), respectively, with gepirone, or mirtazapine for the treatment of depression and related disorders.

An important aspect of the present invention is that it provides a method of treatment of an individual species of vertebrate, e.g. a mammal, including a sick man, suffering from depression or a related disorder, and the treatment method includes introducing an effective amount of mirtazapine is in combination with gepirone. The desired daily dose for the treatment is preferably represented as a single dose or in two or three split doses at appropriate intervals throughout the day. In practice this means, among other things, the provision of standard dosage forms, including mirtazapine, and a standard dosage forms, including gepirone, or in combination to provide a standard dosage forms, comprising mirtazapine and gepirone for the introduction of the recipient or the reception by the recipient for treatment.

Thus, in one embodiment of the invention the mixture of mirtazapine and gepirone may be represented in the form of a pharmaceutical composition in a standard dosage form, for example, the input in the form of tablets, pills, capsules and the like forms. Such dosage forms are known in this field, for example, as described in the standard reference, Gennaro et al., Remington''s Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990 (see, in particular, part 8: Pharmaceutical Preparations and Their Manufacture). By means of pharmaceutically acceptable liquids, these compounds can also be applied in the form of injectable preparation in the form of solution, suspension, emulsion or aerosol form, such as spray for intranasal use.

To obtain pharmaceutical compositions, and more specifically the standard Lek is stannah forms, the present invention also includes a method of obtaining a pharmaceutical composition comprising mirtazapine and gepirone, and the method includes providing the Association a number of mirtazapine (or its pharmaceutically acceptable salt) and a number of gepirone (or its pharmaceutically acceptable salt) with one or more pharmaceutical excipients.

Currently, pharmaceutical compositions often are prescribed to the patient in "packages for the patient", containing a number of standard dosage forms, or other means for introducing a metered standard dosage forms for use within a certain period of treatment in one package, usually in a blister pack. Packing for the patient have an advantage over traditional formulations, when the pharmacist selects provided to patients drug drug from delivery nasypnoy", so that the patient always has access to the package insert contained within the packaging for the patient, which is usually absent in traditional formulations. It was shown that the inclusion of a package insert improves patients ' adherence to instructions of doctor. Thus, the invention also includes a pharmaceutical composition as described here previously, in combination with packaging material suitable for these compositions. In what aka the packaging for the patient's proposed use of the composition for the combined treatment of depression or related disorders can be represented in the form of instructions, support assets, provisions, equipment and/or other means of using the most appropriate use of the composition for treatment. Such measures make the packaging for the patient particularly suitable and adapted for use in the treatment combination of the present invention.

In particular, one embodiment includes a package containing separate standard dosage forms, one or more of which contain mirtazapine or its pharmaceutically acceptable salt and one or more of which contain gepirone or its pharmaceutically acceptable salt. The package contains a sufficient number of tablets, capsules or the like for the treatment of a patient within a predetermined period of time, for example within 2 weeks, 1 month or 3 months.

Applying a combination of the present invention should provide the active ingredients in order to make available to them an effective amount for the treatment. The number of combinations of mirtazapine (or its pharmaceutically acceptable salt or MES) and gepirone (or its pharmaceutically acceptable salt or MES)required to provide efficient effects, be sure to vary and ultimately be granted at the discretion of the practitioner. Factors to consider include the route of administration and the nature of the composition, m is cel body, the age and General condition of the recipient and the nature and severity of a subject to treatment of disease.

In General, a suitable dose of mirtazapine for the introduction of man will be in the range from 0.05 to 5 mg/day/kg of body weight of the recipient, preferably from 0.1 to 1.0 mg/day/kg body weight.

A suitable dose of gepirone for introducing a person will typically be in the range of from 0.01 to 3 mg/day/kg of body weight of the recipient, preferably from 0.05 to 0.7 mg/day/kg body weight.

Compositions (formulations) in accordance with this invention can be obtained by any method well known in the field of pharmacy, for example, using methods such as the methods described in the publication Gennaro et al., Remington''s Pharmaceutical Sciences (18thed., Mack Publishing Company, 1990 (see, in particular, part 8: Pharmaceutical Preparations and Their Manufacture). Such methods include the step of providing the Association the active ingredient with the carrier which constitutes one or more additional ingredients. Such additional ingredients include those ingredients that are commonly used in this field, such as fillers, binders, diluents, disintegrating agents, lubricants, colorants, flavoring agents and wetting agents.

Formulations suitable for oral administration may be presented as discrete units such as pills, tablets is EDI or capsules, each of which contains a defined amount of the active ingredient (ingredient; in the form of powder or granules; as solution or suspension. Active ingredient (ingredients) may also be present in the form of a bolus or pasta or can be contained within liposomes.

Compositions for rectal injection can be presented in the form of suppositories or enemas.

For parenteral administration, suitable formulations include aqueous and non-aqueous sterile solutions for injection. The formulations may be presented in containers of single or multiple doses, for example in sealed vials, ampoules, and can be stored in a lyophilized condition requiring before use, only the addition of sterile liquid carrier, for example water.

Formulations suitable for administration by intranasal inhalation include powder of small particles or aerosols, which can be generated by spray applying a measured dose of the composition, dispensers or insufflation.

For the manufacture of standard dosage forms, such as tablets, provides for the use of conventional additives such as fillers, colorants, polymeric binder, and the like. In General, may be any pharmaceutically acceptable additive, which does not interfere with the function Akti is different compounds. Appropriate quantities of the active ingredients are, for example, a tablet comprising from 1 to 50 mg of mirtazapine and usually from 1 to 30 mg of gepirone. In the specific example of the obtained tablet containing 15 mg of mirtazapine and 10 mg of gepirone.

Mirtazapine can be obtained using the method described in U.S. patent No. 4062848, which is included here as a reference.

Gepirone may be obtained by a method known in this field. Usually the connection is produced by the methods described in U.S. patent No. 4423049. Pharmaceutical compositions containing gepirone, disclosed in U.S. patent 5478572.

The contents of these documents are included in this description by reference.

Further, the invention is illustrated by the following examples.

Quantitative analyses of the antidepressant activity was conducted for evidence that the combination of mirtazapine and gepirone may increase their antidepressant action. Selected quantitative analyses was a security test and test balls hiding in mice and the study of EEG activity during sleep and wakefulness (ACSO) in rats.

Example 1

Test protective hiding

A test was designed stashing balls and confirmed its validity as a preclinical analysis of potential anxiolytic activity (Andrews and Broekkamp (1993) Procedures to idntify anxiolytic or anxiogenic agents. In Behavioural Neuroscience, ed. A Sahgal, pp.37-54. IRL Press, Oxford). The test balls hiding places not subjected to any exposure of mice to a new environment containing 25 balls (located on the surface, covered with sawdust). It has been suggested that reducing the number of bulbs, hid mouse represents the effect similar to the anxiolytic or antidepressant such effect.

Gepirone in isolated subcutaneous (s/C) the introduction of reduced stashing balls at 50% effective dose (ED50) 2.16 mg/kg Mirtazapine with isolated p/to the introduction of reduced stashing balls at the ED505,5 mg/kg Was conducted three separate series of experiments, in which three single doses of mirtazapine (0.3, 1, and 3 mg/kg) were co-injected s/C with a range of doses of gepirone (0; 0,1; 0,3; 1 and 3 mg/kg). Co-administration of mirtazapine and gepirone dose-dependent reduced ED50of gepirone as you increase the dose of mirtazapine (see Table I).

Table I

Effects of combined treatment with gepirone and mirtazapine on behavior during the test stashing the balls to determine the anxiolytic/antidepressant activity. In columns shows the scheme of treatment with pre-treatment, in minutes, of the administered dose and the calculated ED50
mg/kgMirtazapine (mg/kg)ED50of gepirone (mg/kg)
Gepirone (-30')0, 0,3, 1, 3, 102,16
Mirtazapine (-30')0, 2,2, 4,6, 10, 225,5
Gepirone(-30')/Mirtazapine (-40')0,30, 0,1, 0,3, 1,30,75
Gepirone(-30')/Mirtazapine (-40')10, 0,1, 0,3, 1,30,5
Gepirone (-30')/Mirtazapine (-40')30, 0,1, 0,3, 1,30,4

Example 2

The study of the EEG

The aim of this study was the characterization of the effects on the behavior of the sleep-wakefulness in rats one of gepirone and gepirone after joint injection with mirtazapine. For this additionally examined the impact of one of mirtazapine. The behavior of the sleep-wakefulness were analyzed using electroencephalographic (EEG) recordings, electromyographic (EMG) recordings and recording movements. On the basis of these signals the behavior of the sleep-wakefulness automatically classified for 2-second period 6 subclasses: active wakefulness, passive wakefulness, light sleep, deep sleep, dream intermediate stages and sleep with systemdigital eyes (REM) (Ruight et al. A large scale automated system for rat sleep staging. I. Methodology and technical aspects. Electroenceph. and Clin. Neurophysiol.; 1989; 73:52-64). Each experiment was carried out simultaneously on 32 adult male rats Sprague-Dawley (Harlan Olac, Bicester, UK, mass 250-800 g), divided into 4 groups of treatment. Throughout the experiment the animals were housed in cages for registration of the studied parameters and extracted from them only for the injection of the carrier or the compounds (compounds). Each experiment consisted of 3 phases. The first phase ("phase"), starting at 10 am and had a different duration from 2 to 5 h, served as the adaptation period and were used to assess the quality of recorded signals, EEG and EMG. And the second and third stage started at 14 h 30 min in two consecutive days and lasted every 15.5 hours At the beginning of the second phase, all groups received treatment by the media, in the beginning of the third phase, all groups received their studied the connection (connection). One of the treatment groups were generally treated by the media on both stages and served as a baseline for other groups in the experiment. Conducted separate experiments, which investigated various single dose or gepirone (1,0; 3,0; 10.0 mg/kg), or mirtazapine (2,2; 4,6; 10 mg/kg), or mirtazapine (2.2 mg/kg) in combination with gepirone (1,0; 3,0; 10.0 mg/kg). Gepirone was dissolved in 0.9% NaCl wt./about. in the waters of the (physiological solution); mirtazapine was dissolved in 5% wt./about. Mulgofen (EL 719, GAF) in physiological solution of 0.9% wt./about. NaCl in water).

Regardless comparable manner previously investigated a large number of reference compounds (Ruigt et al., Computer-based prediction of psychotropic drug classes based on a discriminant analysis of drug effects on rat sleep. Neuropsychobiology; 1993; 28:138-154) of various classes of psychotropic drugs (antidepressants [HELL], antipsychotics [APS], sleep AIDS, [SS], anxiolytic drug [ALS], stimulants [STIM], anticonvulsants [PSWD] in various doses compared with placebo [PLATZ] to determine their effects on the behavior of the sleep-wakefulness in rats. Profiles of the effects of these compounds in the active doses were subjected to differential analysis of deviations from these 6 classes of psychoactive drugs, and placebo was added as another class. The resulting differential function was used to forecast the field of therapeutic application of one of gepirone and after joint injection with mirtazapine.

Results

Caused by drug type changes the behavior of the sleep-wakefulness after intraperitoneal administration of mirtazapine, gepirone and mirtazapine in combination with gepirone presented in Tables II, III and IV. The table lists the effects of the investigated compounds on NESCO what are indicators hypnogram, used for further classification in the next two 3-hour periods after treatment and during the 5-hour dark period from the 9th to the 14th hour after treatment.

Table II

Overall impact during the period from 0 to 3 h after injection (data are expressed as the percent change compared to control values)
MedicationThe Myrtle.Hair.Hair.Hair.Hair. + Myrtle.Hair. + Myrtle.Hair. + Myrtle.
Dose2,21,03,010,01,0+2,23,0+2,210,0+2,2
N (drug/control)8/76/58/56/57/66/77/7
The median duration
Active wakefulness19-58*-8 7229-14100
Passive wakefulness-513156*19822229*346*
Intermediate sleep-85*-11-76-100*-97*-90*-100*
The REM sleep-88*4-83*-100*-85*-100*-100*
Superficial sleep7238-2-3-10-57*
Deep sleep13-2-21-63*55-41*-93*
The latency from time of injection to
Deep sleep-362424268341017632
Sleep REM273360*673*73206504
*p<0,05 (U criterion Mann-Witney)

Finally, the profiles of the effects of gepirone, mirtazapine, and combinations of gepirone and mirtazapine was calculated on the basis vectors obtained by changes in the organization of the sleep-wakefulness, as shown in the tables above. For each dose was calculated the probability that the connection belongs to one of the 7 defined classes.

These values are presented in Table V in the form of probability values and they testify that a dose of 2.2 mg/kg mirtazapine has only a weak antidepressant profile (22%). Gepirone at a dose of 3.0 mg/kg has a very weak antidepressant profile (28%) and behaves like an anxiolytic drug at a dose of 10.0 mg/kg (63%).

Table III

Exposure during the period from 3 to 6 h after injection (data are expressed as the percent change compared to control values)
MedicationThe Myrtle.Hair.Hair.Hair.Hair. + Myrtle.Hair. + Myrtle.Hair. + Myrtle.
Dose2,21,03,010,01,0+2,23,0+2,210,0+2,2
N (drug/control)8/76/58/56/57/66/77/7
The median duration
Active wakefulness68630-1836-8160*
Passive wakefulness17513-4010-24
Intermediate sleep-74*3264*56-639-76
The REM sleep-52*20-3-50*-2-13-99*
Superficial sleep108 -235-163-25
Deep sleep19-5-6-1935549
*p<0,05 (U criterion Mann-Witney)

Table IV

Exposure during the period from 9 to 15 h after injection (data are expressed as the percent change compared to control values)
Product fromThe Myrtle.Hair.Hair.Hair.Hair. + Myrtle.Hair. + Myrtle.Hair. + Myrtle.
Dose2,21,03,010,01,0+2,23,0+2,210,0+2,2
N (drug/control)8/76/58/56/57/66/77/7
The median duration /td>
Active wakefulness-16-16-37*-23*2-33-33
Passive wakefulness-838557-24-57-57
Intermediate sleep111-236108*-26256256
The REM sleep22-1240644047*47*
Superficial sleep271467231-26*-26*
Deep sleep202-7-5-4124*124*
*p<0,05 (U criterion Mann-Witney)

However, gepirone at a dose of 3.0 mg/kg in combination with mirtazapine dose of 2.2 mg/kg clearly has a mark as an antidepressant already with a high probability of 68% (see numbers written in bold font in table V). In the dose of 10 mg/kg combination has assessed the scores as an antidepressant (46%) with possible properties of stimulants (32%) and anxiolytic drug (22%).

25
Table V

Classification effects of the investigated compounds (mirtazapine, gepirone) for seven different classes using the procedure of differential analysis in comparison with a number of established reference compounds from different classes. Probability estimation in points given in percentage for each therapeutic class
Dose (mg/kg)HELLAPSSTIMALSSSPSUDPLATZ
Placebo062018151150
Mirtazapine2,222302029916
Placebo01620141034
Gepirone1,01310620735
3,028140159296
10,01631263060
Placebo03202513948
Mirtazapine + Gepirone2,2+1,0470215111114
2,2+3,0680026050
2,2+10,04603222000
AD = antidepressant; APS = antipsychotic agent; SS = sedative; ALS = anxiolytic agent; STIM = stimulus means; PSWD = anticonvulsant drug; PLAC = placebo.

Conclusion

The combination of gepirone and mirtazapine was reduced ED50in the test stashing balls and increased the indicator points antidepressant activity according to the EEG registration beyond simple additional effect, estimated by the one-introduction and, thus, demonstrated a synergistic effect of the combined treatment.

1. Combination for the treatment of depression and related disorders, which is a pharmaceutical composition that includes an effective amount of mirtazapine or its pharmaceutically acceptable salt or MES and gepirone or its pharmaceutically acceptable salt or MES.

2. The combination according to claim 1, which additionally comprises one or more pharmaceutically acceptable carriers.

3. The combination according to claim 1 for the manufacture of a medicinal product having antidepressant activity with improved efficiency.

4. A method of treating depression or related disorders in an individual of the species of vertebrates, which includes treatment of the specified individual an effective amount of mirtazapine comb the nation with gepirone.

5. Set for the patient, containing means for introducing a measured standard doses, and the set for the patient contains mirtazapine and gepirone and means to utilize the combination according to claim 1 or 2.



 

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SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical tricyclic antidepressants combined with selective reverse serotonin capture inhibitors. Anxious version of subpsychotic level depressive syndrome of endogenous genesis being treated, intravenous drop-by-drop infusion of 2.-4.0 ml of 1% amitriptiline solution per 200 ml of physiologic saline is applied in 12-14 procedures combined with selective reverse serotonin capture inhibitor given per os, Zoloft is per os administered as the inhibitor at a dose of 50-100 mg. Then, supporting Zoloft therapy is applied at a dose of 100 mg during 3 months. Atypic version of depressive syndrome of subpsychotic level and endogenous genesis is treated with intravenous drop-by-drop infusion of 1.25% Melipramine solution at a dose of 2.0-4.0 ml per 200 ml of power supply source in 12-14 infusions combined with a reverse serotonin capture inhibitor. Paxyl is taken at a peroral dose of 40-60 mg as the inhibitor. Then, supporting Paxyl therapy is applied at a dose of 40-60 mg during 3 months.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications; accelerated depressive syndrome relief.

The invention relates to pharmaceutical

The invention relates to a new compound of the formula I

in which R represents an aromatic acyl fragment, which optionally has one or more substituents, which may be the same or different and which are selected from hydroxy, methoxy and amino

The invention relates to medicine, namely to psychiatry and pharmacotherapy of borderline mental disorders

The invention relates to sulfonylacetanilide General formula I

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

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)

or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).

EFFECT: improved preparing methods.

10 cl, 2 sch, 25 tbl, 7 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new anellated carbamoyl azaheterocycles of the general formula (1)

or (2) possessing the inhibitory effect on protein kinase activity, a focused library comprising these compounds, and pharmaceutical composition based on thereof. In the general formula (1) or (2) R1 represents hydrogen atom or optionally substituted (C1-C6)-alkyl; R2 and R3 represent independently of one another hydrogen atom, inert substitute, optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; R4 represents optionally substituted (C1-C6)-alkyl, optionally substituted (C3-C8)-cycloalkyl, optionally substituted phenyl, optionally substituted aryl, optionally substituted heterocyclyl; A and B in common with carbon and nitrogen atoms joined to the form an optionally substituted and optionally condensed azaheterocycle; D and F in common with carbon atoms joined form an optionally substituted and optionally condensed phenyl or aryl, optionally substituted and optionally condensed azaheterocycle. K and L in common with carbon and nitrogen atoms joined to them form an optionally substituted azaheterocycle. Also, invention related to methods for preparing compounds of the general formulae (1) or (2).

EFFECT: improved preparing methods.

10 cl, 2 sch, 25 tbl, 7 ex

FIELD: chemical-pharmaceutical industry, medicine, pharmacy.

SUBSTANCE: invention relates to a spontaneously dispersing composition comprising N-benzoylstaurosporin, a hydrophilic component, a lipophilic component and a surface-active substance taken in the definite ratio of components. Also, invention relates to a method for treatment of the patient needing administration of N-benzoylstautosporin as a component of the spontaneously dispersing composition. The composition possesses the enhanced level of biological availability or diminished variability of the biological availability levels and effectiveness.

EFFECT: improved and valuable properties of composition.

13 cl, 3 dwg, 2 tbl, 5 ex

FIELD: medicine, psychiatry.

SUBSTANCE: additionally to prescribing atypical neuroleptic preparations of antinegative impact it is necessary prescribe the course of electroconvulsive therapy: 2 seances weekly, the course consists of 8 seances. The procedure should be conducted by applying deprivane anesthesia followed by introducing myorelaxant (listhenon) and ligature control for convulsive activity. Electrodes should be put bilaterally, the impact comes at voltage of 80-120 V for 0.3-0.8 sec. The innovation enables to decrease side effects and complications due to matching special mode that combines atypical neuroleptics and electroconvulsive therapy.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: chemico-pharmaceutical industry.

SUBSTANCE: the suggested composition contains prostaglandin-like compound as an active component and it , also, deals with the method to treat disorders of external secretion that includes application of efficient quantity of prostaglandin-like compound for a person who needs such a treatment. The composition is of high efficiency at treating disorders inactivity of lacrimal and sudoriferous glands being of high bioavailability and nontoxic.

EFFECT: higher efficiency of therapy.

33 cl, 5 ex, 7 tbl

FIELD: oncology.

SUBSTANCE: method comprises administering to an animal, requiring this treatment, in a synergetic mode, therapeutically effective amount of (i) agent selected from group including cytotoxic agents and cytostatic agents and (ii) compound of formula I (given in description) or pharmaceutically acceptable salt thereof. Method provides synergic antitumor effect when using diminished doses of one or both active ingredients, prevents or slows development of multidrug resistance of tumor while ensuring destruction of both proliferative and non-proliferative tumor cells.

EFFECT: enabled use of reduced doses of drugs.

7 cl, 23 dwg, 6 tbl, 25 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds comprising 2-aminopyridin-3-sulfonic fragment of the general formula (1) or their pharmaceutically acceptable salts, N-oxides or hydrates possessing properties of antagonists of glutamate-induced calcium ions transport, in particular, neuroprotective effect. Also, invention relates to the focused library for the search of biologically active leader-compounds comprising at least one heterocyclic compound of the general formula (1) and to pharmaceutical composition if form of tablets, capsules or injections placed into pharmaceutically acceptable package containing compounds of invention as an active substance. In compound of the general formula (1) R1 represents hydrogen atom; R2 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; or R1 and R2 in common with nitrogen and sulfur atoms to which they are bound form optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazabenzocyclohepten-8-one. Also, invention discloses methods for preparing different compounds of the general formula (1).

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

10 cl, 4 sch, 4 tbl, 9 ex

FIELD: organic chemistry, biochemistry, pharmacy.

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

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

FIELD: medicine, obstetrics.

SUBSTANCE: invention relates to a method for treatment of delivery activity weakness. Method involves simultaneous administration of prostaglandin F in the concentration 12.5 mcg/ml at the rate 8 mcg/min and adenosine triphosphate sodium in the concentration 0.25 mcg/ml at the rate 0.25 mcg/min. Infusion continues up to end of the second stage of delivery. Method provides enhancing the delivery activity, increasing rate of uterine orifice opening on the background of the reduced dose of prostaglandin.

EFFECT: improved treatment method.

3 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry.

SUBSTANCE: invention relates to quinuclidine compounds of the formula (I) , its salts or their hydrates wherein R1 represents hydroxyl group; W represents: (1) -CH2-CH2-; 2) -CH=CH-, or 3) -C≡C-; HAr represents 5-10-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom that in addition to the group -X-Ar can be substituted with 1-3 groups taken among: (1) halogen atom; (2) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl group substituted optionally with: (a) hydroxy-group; (b) (C1-C6)-alkoxycarbonyl; (c) (C1-C6)-alkanoyl optionally substituted with (C1-C6)-alkoxy-group; (d) hydroxylated (C3-C8)-cycloalkyl; (e) (C1-C6)-alkoxy-group; (f) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom, or (g) cyano-group; (3) (C1-C6)-alkoxy-group optionally substituted with: (a) hydroxy-group; (b) (C1-C6)-alkoxy-group optionally substituted with (C1-C6)-alkoxy-group; (c) halogen atom; (d) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (e) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (4) (C1-C6)-alkylthio-group optionally substituted with (C1-C6)-alkoxy-group or hydroxy-group; (5) 5-6-membered heterocyclyloxy-group comprising 1-2 oxygen atoms in heterocycle; (6) amino-group represented by the formula: -N(R3)R4 wherein R3 and R4 are similar or different and each represents hydrogen atom or group taken among: (a) (C1-C6)-alkyl group; (b) (C1-C6)-alkoxy-(C1-C6)-alkyl group; (c) carbonyl substituted with (C6-C14)-aryl; (d) (C6-C14)-arylsulfonyl or (e) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (7) (C3-C8)-cycloalkyl or cycloalkenyl hydrocarbon group optionally substituted with: (a) oxo-group or (b) hydroxy-group; (8) (C6-C14)-aromatic hydrocarbon ring optionally substituted with: (a) (C1-C4)-alkylene dioxy-group or (b) hydroxy-group; (9) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with: (a) cyano-group or (b) (C1-C6)-alkoxy-group; (10) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with one or some groups taken among: (a) hydroxy-group; (b) halogen atom; (c) cyano-group; (d) (C1-C6)-alkoxycarbonyl; (e) (C1-C6)-alkyl; (f) (C1-C6)-alkoxy-group that is optionally substituted with halogen atom or (C1-C6)-alkoxy-group; (g) (C1-C6)-alkanoyl; (h) (C1-C6)-alkoxy-(C1-C6)-alkyl; (i) oxo-group; (j) (C1-C4)-alkylenedioxy-group; (k) (C3-C8)-cycloalkylalkoxy-group or (C3-C8)-cycloalkenylalkoxy-group; (11) carbamoyl of the formula: -CO-N(R5)R6 wherein R5 and R6 can be similar or different and represent hydrogen atom, (C6-C14)-aryl wherein indicated aryl is optionally substituted with halogen atom, or (C3-C8)-cycloalkyl; or R5 and R6 form in common 3-6-membered ring; (12) carbonyl optionally substituted with (C1-C6)-alkoxy-group; X represents: (1) a simple bond; (2) (C1-C6)-alkylene chain; (3) (C1-C6)-alkenylene chain; (4) (C1-C6)-alkynylene chain; or (5) formula: -Q- wherein Q represents oxygen atom or sulfur atom; Ar represents: (1) (C6-C14)-aromatic hydrocarbon ring optionally substituted with one or some groups taken among: (a) halogen atom; (b) (C1-C4)-alkoxy-group or (c) (C1-C6)-alkylthio-group; or (2) 5-6-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom. Compounds of the formula (I) show inhibitory activity with respect to a squalene-synthesizing enzyme. Also, the invention relates to an inhibitor of squalene-synthesizing enzyme and the corresponding medicinal composition based on compound of the invention, a method for prophylaxis and treatment of disease wherein inhibition of squalene-synthesizing enzyme is effective. Also, invention proposes some methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable of medicinal and biochemical properties of com[pounds and composition.

25 cl, 10 tbl, 214 ex

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