RU2477634C2 - Treating psychological conditions with using m1-muscarinic antagonists - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely psychiatry and may be used for treating depression. For this purpose, a therapeutically effective amount of a combination of telenzepine and one or more antidepressants specified in a group consisting of fluoxetine, sertraline and venlafaxine are introduced in an individual in need thereof. There are also presented a pharmaceutical composition and a kit for treating depression.

EFFECT: group of inventions provides treating depression in an individual, as well as more intensive antidepressant action, than that ensured by introducing any of said drugs separately.

15 cl, 6 dwg, 1 tbl, 1 ex

Description

References to Related Patent Applications

This patent application claims the priority of Provisional application for US patent No. 60/805066 dated June 16, 2006 and Provisional patent application US No. 60/829225 dated October 12, 2006, the disclosure of which in their entirety is incorporated into this application by reference.

A claim for inventions made with federal funding for research and development is not applicable.

FIELD OF THE INVENTION

The present invention relates to the treatment of physiological disorders, including depression, by the administration of a selective antagonist of the M ₁ muscarinic receptor (M ₁ R) alone or in combination with an antidepressant.

State of the art

The neurotransmitter acetylcholine (Ach) interacts with two types of receptors on the membranes of effector cells: with nicotine receptors (nAChR), which are ligand-controlled ion channels, and with muscarinic receptors (mAChR), which are receptors conjugated to G-proteins. In mammals, five subtypes of mAChR have been identified, denoted by symbols from M ₁ to M ₅ . M ₁ -muscarinic receptors (M ₁ R) are found both in the central and peripheral nervous systems, in particular in the cerebral cortex and in the sympathetic ganglia. Muscarinic effects mediated through M ₁ R are mainly investigated using M ₁ R-selective antagonists, and more recently, in mice knocked out using M ₁ R (M ₁ R-null mouse).

Although none of the currently known mAChR antagonists show absolute selectivity for one of the subtypes of muscarinic receptors, drugs such as pirenzepine and telenzepine show a high relative affinity for M ₁ R and are therefore often considered as M ₁ R-selective antagonists. Pirenzepine is used to treat gastric and duodenal ulcers in Europe, Japan and Canada. Telenzepine passed clinical trials with the same indications. At therapeutic doses, both of these agents moderately decrease the secretion of acid and pepsin in the stomach without inhibiting smooth muscle activity, which is characteristic of non-selective mAChR antagonists.

There is some evidence that the M ₁ R receptor subtype may be involved in some aspects of depressive disorders and anxiety. Direct injection of pirenzepine into the adjacent nucleus (pleasure center, or nucleus accumbens) of the rat forebrain leads to an increase in swimming time in the Porsolt swim test (see Chau DT et al., Neuroscience, 2001, vol. 104, No. 3 , p.791-8), which is a standard measure of antidepressant activity. M ₁ R-null mice also show increased swimming time in the Porsolt swimming test, as well as increased social contacts (social contacts) in the social interaction test (see T. Miyakawa et al., J. Neurosci., 2001, vol.21 No. 14, p. 5239-50).

Although pirenzepine and telenzepine are similar in structure to tricyclic antidepressants such as imipramine, it is not known to have psychotropic effects when taken orally for the treatment of gastric ulcer and duodenal ulcer. In addition, in previous studies in mice and rats with systemic administration, pirenzepine showed no behavioral effects (see Rogoz Z., Skuza G., Sowinska H., Pol. J. Pharmacol. Pharm., 1981, vol. 31, p.615-26). The absence of such effects may be explained by the existing observation that pirenzepine cannot significantly penetrate the blood-brain barrier in various animal species, including rodents and humans (see Hammer R, Koss FW, Scand. J. Gastroenterol, Suppl, 1979, vol. 14 No. 57, p. 1-6; Bymaster PP et al., J. Pharmacol. Exp. Ther., 1993, vol. 267, no.1, p. 16-24). For this reason, in the above study of the effect of pirenzepine in the Porsolt swimming test, direct injection of the drug into the brain of the animals studied was used.

Currently, there is a need for new and effective drugs for the treatment of psychological conditions, including depression. The present invention addresses this and other needs.

Disclosure of invention

The present invention provides methods for treating various psychological disorders, including depression, by systemically administering a therapeutically effective amount of one or more muscarinic M ₁ receptor antagonists (M ₁ R selective antagonists). When applying the methods of the present invention in practice, one or more M ₁ R-selective antagonist can be administered without other pharmacological agents or in combination with other pharmacological agents, for example with one or more antidepressants that are not M ₁ R-selective antagonist.

Accordingly, in its first aspect, the present invention provides methods for treating one or more psychological conditions or disorders by systemically administering to a subject in need of such treatment a therapeutically effective amount of one or more M ₁ R-selective antagonists, thereby healing one or more psychological state.

In a related aspect, the present invention provides methods of treating one or more psychological conditions or disorders by administering to a subject in need of such treatment a therapeutically effective amount of a combination of one or more M ₁ R-selective antagonists and one or more non-M ₁ R- antidepressants selective antagonists, as a result of which one or more psychological conditions are cured.

In one embodiment, the psychological disorder is an emotional (affective) disorder. In one embodiment, the psychological disorder is depression. In one embodiment, the psychological disorder is selected from the group consisting of depression, anxiety, social anxiety disorder, agoraphobia (pathological fear of open space), obsessive-compulsive disorder (obsessive neurosis), post-traumatic stress disorder ("Vietnamese syndrome"), bodily dysmorphic disorder, premenstrual dysphoric disorder and substance abuse or dependence.

In another aspect, the present invention provides pharmaceutical compositions comprising a mixture of therapeutically effective amounts of one or more M ₁ R-selective antagonists and one or more antidepressants that are not M ₁ R-selective antagonists.

In another aspect, the present invention provides ready-made kits comprising a mixture of therapeutically effective amounts of one or more M ₁ R-selective antagonists and one or more antidepressants that are not M ₁ R-selective antagonists.

With respect to embodiments for implementing the methods and for pharmaceutical compositions and ready-made kits, in one embodiment, one or more of the M ₁ R-selective antagonist is selected from the group consisting of pirenzepine, telenzepine, and combinations thereof. In one embodiment, the M ₁ R-selective antagonist is telenzepine (racemate or optical isomer). In one embodiment, the M ₁ R-selective antagonist is pirenzepine.

In one embodiment, one or more M ₁ R-selective antagonists are administered without a second pharmacological agent.

In one embodiment, one or more M ₁ R-selective antagonists are administered in combination or together with one or more antidepressants that are not M ₁ R-selective antagonists. In one embodiment, the antidepressant is selected from the group consisting of a selective serotonin reuptake inhibitor (SSRI) and a selective serotonin-norepinephrine reuptake inhibitor (selective serotonin-norepinephrine reuptake inhibitor, SNRI).

In one embodiment, the antidepressant is an SSRI. In one embodiment, the SSRI is selected from the group consisting of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. In one embodiment, the SSRI is selected from the group consisting of citalopram, sertraline, paroxetine, and fluoxetine.

In one embodiment, the antidepressant is an SNRI. In one embodiment, the SNRI is selected from the group consisting of milnacipran, mirtazapine, venlafaxine, duloxetine, desvenlafaxine and sibutramine. In one embodiment, the SNRI is venlafaxine.

Effective results can be achieved without prolonged administration (timed administration) of one or more M ₁ R-selective antagonists. Co-administration of active agents, including antidepressants, also provides effective results without long-term administration.

In one embodiment, one or more of the M ₁ R-selective antagonist is telenzepine (racemate or optical isomer) and one or more antidepressants that are not M ₁ R-selective antagonist is fluoxetine (racemate or optical isomer).

In one embodiment, one or more of the M ₁ R-selective antagonist is telenzepine (racemate or optical isomer) and one or more antidepressants that are not a M ₁ R-selective antagonist is fluvoxamine.

In one embodiment, one or more of the M ₁ R selective antagonist is telenzepine (racemate or optical isomer) and one or more antidepressants that are not a M ₁ R selective antagonist are sertraline or its S enantiomer, Zoloft®.

In one embodiment, one or more of the M ₁ R-selective antagonist is telenzepine (racemate or optical isomer) and one or more antidepressants that are not a M ₁ R-selective antagonist is citalopram (or escitalopram).

In one embodiment, one or more of the M ₁ R-selective antagonist is telenzepine (racemate or optical isomer) and one or more antidepressants that are not a M ₁ R-selective antagonist is paroxetine.

In one embodiment, one or more of the M ₁ R-selective antagonist is telenzepine (racemate or optical isomer) and one or more antidepressants that are not M ₁ R-selective antagonist is venlafaxine (racemate or optical isomer).

In one embodiment, one or more of the M ₁ R-selective antagonist is telenzepine (racemate or optical isomer) and one or more antidepressant that is not a M ₁ R-selective antagonist is desvenlafaxine.

In one embodiment, one or more of the M ₁ R-selective antagonist is telenzepine (racemate or optical isomer) and one or more antidepressant that is not a M ₁ R-selective antagonist is duloxetine.

In one embodiment, one or more of the M ₁ R-selective antagonist is telenzepine (racemate or optical isomer) and one or more antidepressant that is not a M ₁ R-selective antagonist is sibutramine.

In one embodiment, one or more of the M ₁ R-selective antagonist is telenzepine (racemate or optical isomer) and one or more antidepressants that are not a M ₁ R-selective antagonist are milnacipran.

In one embodiment, one or more of the M ₁ R-selective antagonist is telenzepine (racemate or optical isomer) and one or more antidepressants that are not a M ₁ R-selective antagonist are mirtazapine.

In one embodiment, one or more M ₁ R-selective antagonist is telenzepine (racemate or optical isomer) and one or more antidepressant that is not a M ₁ R-selective antagonist is bupropion.

In a related aspect, the present invention provides methods for preparing or using a medicament for treating one or more psychological conditions, a medicament containing a therapeutically effective amount of one or more M ₁ R-selective antagonists. A medicament may not necessarily also contain one or more antidepressants that are not M ₁ R-selective antagonists. Embodiments for a medicament are also described herein.

In some embodiments, the methods and compositions of the present invention include combinations of the pharmacological agents described herein. In some embodiments, the methods and compositions of the present invention consist mainly of combinations of the pharmacological agents described herein.

Definitions

The term “psychological disorder” or “psychological state” interchangeably refers to a disorder of thought or emotion, or a disorder of the brain that leads to a disturbance in the subject’s thinking, sensations (feelings), moods and ability to communicate with other subjects. A psychological disorder or condition may manifest as an inappropriate expression or in no way caused by expression, for example, irritation, sadness, fear, anxiety or other types of sociopathic behavior. Exemplary categories of psychological disorders include, but are not limited to, emotional disorders related to fear disorders, cognitive disorders, impulse control disorders, substance abuse or dependence, attention deficit hyperactivity disorder, eating disorders, motor disorders and sexual dysfunctions . Examples of psychological conditions that can be treated with the methods and compositions of the present invention include, but are not limited to, depression, anxiety, social anxiety disorder, agoraphobia (pathological fear of open space), obsessive-compulsive disorder (obsessive neurosis), post-traumatic stress disorder (“Vietnamese” syndrome ”), bodily dysmorphic disorder, premenstrual dysphoric disorder, and substance abuse or dependence. Psychological disorders are described, for example, in Halgin and Whitboume, Abnormal Psychology: Clinical Perspectives On Psychological Disorders, 4th Edition, 2005, McGraw-Hill College; Barlow and Antony, Handbook of Assessment and Treatment Planning for Psychological Disorders, 2002, Guilford Press; Claridge and Davis, Personality and Psychological Disorders, 2003, Oxford Univ Pr; and Clinical Handbook of Psychological Disorders: A Step-by-Step Treatment Manual, Barlow, Ed., 2001, Guilford Press. Diagnostic indicators for known psychological disorders can be developed with reference to the Diagnostic and Statistical Manual of Mental Disorders (DSM IV, 2000, American Psychiatric Association).

The term “emotional disorder” refers to any mood disorder. Emotional disorders include depression, mania, bipolar disorder (manic-depressive psychosis), seasonal (winter) depression, anxiety, panic. See, for example, Paykel, Handbook of Affective Disorders, 1992, Longman Group Ltd.

The term "depression" refers to a clinical syndrome in accordance with its meaning accepted in the art (see, for example, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR]; American Psychiatric Association, 2000; American Psychiatric Publishing, Inc., Arlington, VA). Symptoms of depression include, but are not limited to, constant despondency, a sense of pessimism, despair, a feeling of helplessness, a sense of worthlessness, a change in mood, agitation, irritability, anxiety, loss of interest in or enjoyment of activities that used to be enjoyed, thoughts of death or suicide, inability to concentrate or make decisions, slow thinking, fatigue, decreased energy, insomnia or drowsiness, loss of appetite or overeating (gluttony ), Weight loss or weight gain, persistent headaches or digestive disorders, chronic pain, and abnormal hormonal circadian rhythms.

The term “addiction to a psychoactive substance” is used in accordance with its commonly understood meaning, known to those skilled in the art. For example, the clinical diagnosis of substance abuse, according to the International Classification of Diseases, requires that an individual meet or manifest three or more of the conditions listed below for some time in the previous year: (1) difficulties in controlling behavior regarding substance intake in plan for the start of intake, end or levels of use; (2) a strong desire or an irresistible urge to take a substance; (3) a progressive neglect of alternative sources of pleasure or interest associated with the use of a psychoactive substance, an increase in the amount of time required to receive or take the substance, or to recover from the action of the substance; (4) persistence in relation to the administration of a substance, despite obvious signs of obvious harmful effects, a depressed state of mind after taking an increased dose, or a cognitive impairment in the substance; (5) signs of resistance, such as the need for increased doses of a psychoactive substance to achieve the effects previously provided by lower doses; (6) the state of the psychological withdrawal syndrome when the intake of the substance is stopped or reduced, as evidenced by: the characteristic withdrawal syndrome for the substance; the use of the same (or close) substance in order to relieve or avoid the symptoms of withdrawal. Further information on substance dependence can be found, for example, on the website nida.nih.gov of the National Institute on Drug Abuse (NIDA).

As used herein, the term “administration” means oral (“po.”) Administration, administration in the form of suppositories, topical (skin) administration, intravenous (“iv”), intraperitoneal (“iv”), intramuscular ("vm"), intrafocal (to the affected area), nasal or subcutaneous ("pk") introduction or implantation of a subject of a device for slow release, for example, a mini-osmotic pump. Administration is carried out in any way, including parenteral and mucosal administration (e.g., oral, nasal nasal, vaginal, rectal or transdermal) Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial administration. Other delivery methods include, but are not limited to, the use of liposome preparations, intravenous infusion, transdermal patches, etc.

The terms “systemic administration” and “systemically administered” refer to a method for administering a compound or composition to a mammal, wherein the compound or composition is delivered to different parts of the body, including a target site for pharmacological action, through the circulatory system. Systemic administration includes, but is not limited to, oral, nasal, rectal and parenteral (for example, administration not through the digestive tract, but in another way, such as intramuscular, intravenous, intraarterial, transdermal and subcutaneous administration), with the proviso that used here, the value of systemic administration does not include direct administration to the area of the brain, not through the circulatory system, but in another way, such as intrathecal (subshell) injection and intracranial administration.

The term "co-administration" refers to the simultaneous presence of two active agents in the blood of an individual. Active agents that are administered together can be delivered simultaneously or sequentially.

As used herein, the terms “treating” and “treating” refer to delaying the onset, slowing or reversing development, or alleviating or preventing either the disease or condition to which the term applies or one or more symptoms of such a disease or condition.

As used herein, the terms “selective antagonist of the M ₁ muscarinic receptor” and “M ₁ R-selective antagonist” refer to an antagonist of the muscarinic acetylcholine receptor that exhibits a preferred interaction with the muscarinic receptor of the M ₁ subtype over muscarinic receptors of the M ₂ subtypes and M ₃ . Examples of M ₁ R-selective antagonists include, but are not limited to, pirenzepine and telenzepine. Preferred binding does not have to be complete. For example, despite a comparable affinity for the M ₁ and M ₄ receptor subtypes, pirenzepine is classified as an M ₁ R-selective antagonist.

Preferred binding of the M ₁ R-selective antagonist can be measured using a competitive displacement method. The M ₁ R-selective antagonist will preferably displace the known M ₁ R-selective ligand (e.g., pirenzepine and / or telenzepine) compared to the known selective M ₂ (e.g., tripitramine, chimbacin, methoctramine) and M ₃ (e.g., darifenacin, hexahydrosiladiphenidol ) ligands. Alternatively, an M ₁ R-selective antagonist will preferably displace a non-selective muscarinic ligand (e.g., quinuclidinyl benzoate (QNB), N-methylscopolamine (NMS)) from the M ₁ receptor subtype compared to displacing a non-selective muscarinic ligand from a bound state with M ₂ subtypes and M ₃ . The comparative effectiveness for crowding out radiolabeled competitors can be expressed as the concentration at which 50% of the competitor is crowded out (IC ₅₀ ), or using the equilibrium dissociation constant (K _d ). The IC ₅₀ value and / or the equilibrium dissociation constant can be calculated using suitable software by introducing the measured values of the labeled ligand in the presence of different exact amounts of unlabeled test compound (e.g. LIGAND (Munson PJ, and Rodbard D., Anal. Biochem. (1980 ) 107: 220-39) or DATAPLOT, National Technical Information Services). The M ₁ R-selective antagonist will have an IC ₅₀ value or a K _d value for binding to an M ₁ receptor subtype that is at least 3 times smaller, preferably at least 10 times smaller, and more preferably at least 30 times less than the IC ₅₀ value or the K _d value for binding to the M ₂ and M ₃ receptor subtypes. A suitable radioligand binding assay using radioactively labeled NMS or QNB is disclosed in Buckley et al., Molecular Pharmacology (1989) 35: 469-76 and Bolden et al., J Pharmacol Exp Ther. (1992) 260: 576-80.

As used herein, the expression "consisting essentially of" refers to the genera or species of active pharmaceutical agents included in the method or composition, as well as to any excipients that do not have the activity for which the methods or compositions are intended. In some embodiments, the expression “consisting essentially of” specifically excludes the inclusion of one or more additional active agents that are not an M ₁ R-selective antagonist and are not an antidepressant. In some embodiments, additional active agents that may be excluded include one or more of a prolactin inhibitor, a prolactin stimulator, a 5-HT receptor antagonist, a 5-HT receptor agonist, an NK-1 receptor antagonist and / or a dipeptidyl peptidase IV inhibitor.

The terms “controlled release”, “sustained release”, “delayed release” and “sustained release” are intended to mean interchangeably with any drug-containing composition in which the drug release is not immediate, for example, for a “controlled release” composition, oral administration does not result in immediate drug delivery to the absorbable pool. These terms are used interchangeably to mean "non-immediate release" as defined in Remington: The Science and Practice of Pharmacy, 21 ^s1 Ed., Lippencott Williams & Wilkins (2006). As discussed here, immediate and non-immediate release can be determined kinetically using the following equation:

An “absorbable pool” is a solution of an administered drug at a particular absorption site, and the constants k _r , k _a and k _e are first order rate constants for (1) drug release from the composition, (2) absorption and (3) excretion, respectively. For immediate release dosage forms, the drug release rate constant k _{r is} significantly greater than the absorption rate constant k _a . For controlled release formulations, the opposite is true, i.e. k _r << k _a , so that the rate of release of the drug from the dosage form is a speed-limiting step in delivering the drug to the target site.

The terms “sustained release” and “delayed release” are used in their usual sense to mean a drug composition that provides a gradual release of the drug over a long period of time, for example 12 hours or more, and, which is preferred, but not necessary, leads to the maintenance of certain stationary levels of medication in the blood for an extended period of time.

As used herein, the term “delayed release” refers to pharmaceutical preparations that pass through the stomach in an intact form and dissolve only in the small intestine.

As used herein, the terms “synergism” or “synergistic” interchangeably refer to the combined effects of two active agents, which are greater than the additive (total) effects of these agents. Synergism can also be achieved by obtaining an effective effect by combining ineffective doses of two active agents. A measure of synergy is independent statistical validity.

Brief Description of the Figures

Figure 1 shows the effect of intraperitoneal administration of pirenzepine (PZP) on the immobility of CD-I mice in the tail suspension test. Male CD-I mice (n = 10 in each group) were injected with pirenzepine as the free base at doses of 5 mg / kg, 25 mg / kg or 50 mg / kg, as described in the Examples below. Control mice (VEH) were injected with a 10% DMSO solution. * means p <0.05 against VEH.

Figure 2 shows the effect of intraperitoneal administration of telenzepine (TZP) on the immobility time of CD-I mice in a tail suspension test. Male CD-I mice (n = 10 in each group) were administered telenzepine in the form of a free base at doses of 5 mg / kg, 25 mg / kg or 50 mg / kg, as described in the Examples below. Control mice (VEH) were injected with a 10% DMSO solution. * means p <0.05 against VEH. ** means p <0.001 against VEH.

Figure 3 shows the effect of oral administration of telenzepine (TZP) on the immobility time of CD-I mice in a tail suspension test. Male CD-I mice (n = 10 in each group) were administered telenzepine as the free base at doses of 60 mg / kg, 80 mg / kg or 100 mg / kg, as described in the Examples below. Control mice (VEH) were injected with saline. * means p <0.05 against VEH. ** means p <0.01 against VEH.

Figure 4 shows the effect of co-administration of telenzepine (TZP) and sertraline (SRT) on the immobility time of CD-I mice in a tail suspension test. Male CD-I mice (n = 10 in each group) were administered intraperitoneally only telenzepine in the form of a free base (5.0 mg / kg), only sertraline (1.0 mg / kg), or telenzepine (5.0 mg / kg) and sertraline (1.0 mg / kg) as described in the Examples below. Control mice (VEH) were injected with a 10% DMSO solution. ** means p <0.01 against VEH.

Figure 5 shows the effect of co-administration of telenzepine (TZP) and venlafaxine (VEN) on the immobility time of CD-I mice in a tail suspension test. Male CD-I mice (n = 10 in each group) were administered intraperitoneally only telenzepine in the form of a free base (5.0 mg / kg), only venlafaxine (10 mg / kg) or co-administered telenzepine (5.0 mg / kg) and venlafaxine (10 mg / kg) as described in the Examples below. Control mice (VEH) were injected with a 10% DMSO solution. * means p <0.05 against VEH. ** means p <0.01 against VEH. “Aa” means p <0.01 against VEN. “B” means p <0.05 against TZP.

Figure 6 shows the effect of co-administration of telenzepine (TZP) and fluoxetine (FLX) on the immobility time of CD-I mice in a tail suspension test. Male CD-I mice (n = 10 in each group) were intraperitoneally administered only telenzepine in the form of a free base (10 mg / kg), only fluoxetine (4 mg / kg), or telelenzepine (10 mg / kg) and fluoxetine (4) were administered together mg / kg) as described in the Examples below. Control mice (VEH) were injected with a 10% DMSO solution. ** means p <0.01 against VEH.

The implementation of the invention

1. Introduction

As discussed above, previous studies in rats and mice showed that systemic administration of pirenzepine does not lead to any behavioral effects (see Rogoz Z., Skuza G., Sowinska H., Pol. J. Pharmacol. Pharm. 1981, vol.31, p.615-26) and that pirenzepine does not show significant penetration through the blood-brain barrier in various species, including rodents and humans (see Hammer R., Koss FW, Scand. J. Gastroenterol, Suppl., 1979, vol. 14, No. 57, p. 1-6; Bymaster FP et al., J. Pharmacol. Exp. Ther., 1993, vol. 267, No. 1, p. 16-24). Surprisingly, contrary to publications in the literature, the present invention has shown that M ₁ R-selective antagonists, including pirenzepine and telenzepine, can pass through the blood-brain barrier in therapeutic quantities and therefore have useful antidepressant activity when administered systemically. These agents are also useful for treating other psychological conditions that are often treated with antidepressants.

The present invention also shows that the use of M ₁ R-selective antagonists in combination with certain other therapeutic agents provides unexpected synergistic effects, which is beneficial for the treatment of psychological conditions, including depression.

The present invention provides effective pharmacological treatment of depression, anxiety, social anxiety disorder, agoraphobia (pathological fear of open space), obsessive-compulsive disorder (obsessive neurosis), post-traumatic stress disorder ("Vietnamese syndrome"), bodily dysmorphic disorder, premenstrual dysphoric disorder and dysphoric disorder or addiction to psychoactive substances (e.g. nicotine, alcohol, sedatives, etc.) ).. Systemic administration of a selective M ₁ -muscarinic receptor antagonist (M ₁ R-selective antagonist) unexpectedly provides an antidepressant effect. It has surprisingly been found that therapeutically effective amounts of one or more M ₁ R-selective antagonists effective in treating psychological disorders, including depression, can cross the blood-brain barrier when they are systemically administered to a subject. In addition, the joint administration of one or more M ₁ R-selective antagonists and one or more antidepressant agents that are not M ₁ R-selective antagonists unexpectedly provides a stronger antidepressant effect than the effect that is achieved when any of these categories of drugs are administered separately.

2. Methods of treating psychological disorders

but. Conditions to be treated

The methods and compositions of the present invention have found application in the treatment of psychological disorders. Examples of general categories of psychological disorders that can be treated with the methods and compositions of the present invention include, but are not limited to: (1) emotional disorders, anxiety conditions and impulse control disorders (including pathological overeating (gluttony)), (2) disorders related to substance abuse / dependence (e.g. addiction to drugs), (3) cognitive impairment, attention deficit hyperactivity disorder, (4) motor impairment sexual dysfunction, and (5) eating disorders (eg, anorexia nervosa and bulimia nervosa).

The action of acetylcholine on muscarinic receptors in the central nervous system affects various types of behavior, including cognition, understanding, vitality (insomnia), emotions, sensorimotor connections and both reflex and voluntary mobility (Bymaster et al., Curr Drug Targets CNS Neural Disord (2002) 1: 163-181). Muscarinic receptors influence these functions not only through interaction with cholinergic neurons, but also through modulation of the activity of dopaminergic, GABAergic and glutamatergic forebrain / midbrain neurons. Studies of neuro-localization and microdialysis have confirmed that muscarinic receptors and their agonists and antagonists influence these systems, and the direction of modulation (excitation / inhibition) depends on the specific receptor subtype. In particular, local microinjection of the preferred M ₁ / M ₄ antagonist, pirenzepine, leads to a decreased release of dopamine in the striatum (Smolders et al., J Neurochem (1997) 68: 1942-1948). Similarly, by direct injection into the midbrain of the preferred M ₁ / M ₄ antagonist, telenzepine, a decrease in GABA release is observed (Smolders et al., 1997, supra). Similarly, receptor subtype nonselective antagonists, such as scopolamine, cause increased levels of acetylcholine in the forebrain (Izurieta-Sanchez et al., Eur J Pharmacol (2000) 399: 151-160).

With regard to substance abuse and dependence, mesolimbic dopamine networks are believed to play an important role in the formation and consolidation of such dependence (Berridge and Robinson, Brain Res Brain Res Rev (1998) 28: 309-369; Crespo et al., J Neurosci ( 2006) 26: 6004-6010; Di Chiara and Imperato, Proc Nati AcadSci USA (1988) 85: 5274-5278; Hemandez and Hoebel, Life Sci (1988) 42: 1705-1712). Rodent studies have shown that the specific structure in the striatum, the nucleus accumbens (NAc) adjacent to the nucleus (pleasure center), is involved in the regulation of reward and aversion. NAc is located in the medioventral striatum and can be further subdivided into the subterritory of the sheath (cortex), nucleus, and coracoid process (Zahm and Brog, Neuroscience (1992) 50: 751-767).

Rats themselves will introduce dopamine agonists into the NAc region (Hoebel et al., Psychopharmacology (Berl) (1983) 81: 158-163), and it has been shown that a large number of compounds are known to be addictive and addictive in humans increase extracellular dopamine levels in the NAc region (Di Chiara and Imperato, 1988, supra; Hemandez and Hoebel, 1988, supra; Rada et al., Pharmacol Biochem Behav (1996) 53: 809-816). In contrast, it was found that a decreased level of extracellular dopamine in the nucleus accumbens (pleasure center) accompanies disgust during morphine-induced and nicotine-induced withdrawal symptoms (Acquas and Di Chiara, (1992) J Neurochem 58: 1620-1625; Diana et al ., J Pharmacol Exp Ther (1995) 272: 781-785; Pothos et al., Brain Res (1991) 566: 348-350; Rada et al., Psychopharmacology (Berl) (2001) 157: 105-110). Apparently, the effects of dopamine are mediated through subtypes of receptors D1 and D2. It was shown that the introduction of D1 or D2 dopamine agonists into the cortical region, but not the nucleus of NAc, restores behavior aimed at finding a psychoactive substance in rats that were operantly accustomed to suppress craving for cocaine, but after administration they showed behavior aimed at replacing saline with cocaine (Schmidt et al., Eur J Neurosci (2006) 23: 219-228).

In all likelihood, within the NAc, cholinergic and dopaminergic networks pharmacologically act in opposite directions. Local administration of either atropine (a nonspecific muscarinic antagonist) or mecamylamine (a nonspecific nicotinic antagonist) has been reported to block the increased craving for opiates (Crespo et al., 2006, supra), while morphine reduces acetylcholine levels in NAc (Fiserova et al., Psychopharmacology (Beri) (1999) 142: 85-94; Rada et al., Neuropharmacology (1991) 30: 1133-1136), and naloxone-induced opiate withdrawal syndrome increases acetylcholine levels (Fiserova et al., 1999, supra ; Rada et al., 1991 supra; Rada et al., 1996, supra). A similar phenomenon has been observed in connection with mecamylamine-induced withdrawal syndrome in nicotine-dependent rats (Rada et al., 2001, supra). In support of the broad general link between elevated ACh and anxiety states, ACh is released in NAc when it tastes disgusting (Mark et al., Brain Res (1995) 688: 184-188), stimulating disgust in the brain (Rada and Hoebel, Brain Res (2001) 888: 60-65) and with diazepam withdrawal syndrome (Rada and Hoebel, Eur J Pharmacol (2005) 508: 131-138), alcohol (Rada et al., Pharmacol Biochem Behav (2004) 79 : 599-605) or sugar (Colantuoni et al., Obes Res (2002) 10, 478-488). Thus, attenuation of cholinergic transmission is a therapeutically attractive approach for treating disorders related to abuse and addiction. Such disorders do not have to be purely pharmacological, as can be seen in the sucrose withdrawal syndrome.

Accordingly, the neuropsychiatric use of compounds that preferably have the ability to modulate M ₁ -muscarinic receptors is widespread. Thus, the methods of the present invention find application in the treatment of a large number of conditions, including those that occur in violation of: i) cognitive perception, ii) emotional perception and / or iii) appetite. Conditions within these categories include: (1) emotional disorders, anxiety states, and impulse control disorders (including pathological gluttony), (2) substance abuse / dependence disorders (e.g. drug addiction), (3) cognitive disorders, attention deficit hyperactivity disorder, (4) motor and sexual dysfunctions, and (5) eating disorders (e.g., anorexia nervosa and bulimia nervosa).

Examples of emotional disorders, anxiety disorders, and impulse control disorders include emotional disorders (including, but not limited to, depression, bipolar disorder (manic-depressive psychosis), dysthymic disorder, premenstrual dysphoric disorder), anxiety disorders (including, but not limited to generalized anxiety disorder, social anxiety disorder, panic disorder (episodic paroxysmal anxiety), post-traumatic stress owl disorder (“Vietnamese syndrome”), obsessive-compulsive disorder (obsessive neurosis), agoraphobia (pathological fear of open space), specific phobias, conversion disorders, bodily dysmorphic disorder) and impulse control disorders (including, but not limited to, kleptomania , pyromania, trichotillomania, pathological passion for the game, pathological overeating).

Examples of disorders associated with substance abuse and / or dependence include physical and / or psychological dependence on pharmacological agents, including, but not limited to, nicotine, alcohol, opioids, psychostimulants, sedatives / hypnotics. The term "opioids" includes, but is not limited to, natural, semi-synthetic and unnatural agonists or partial agonists of opioid receptors. The term “psychostimulants” includes, but is not limited to, antagonists involved in the reuptake of dopamine transporters and / or agents that directly stimulate the release of dopamine and include, but are not limited to, cocaine, synthetic dopamine transporter inhibitors, amphetamines, phenmethazine, and methylenedioxyamphetamines .

Examples of cognitive impairment, attention deficit disorder and hyperactivity disorder include cognitive impairment / dysfunction (including, but not limited to, schizophrenia, Alzheimer's disease, mild cognitive impairment, dementia) and attention deficit hyperactivity disorder (e.g., ADD, ADHD).

Examples of motor disorders include, but are not limited to, those disorders that are secondary to Parkinson's disease, Huntington's disease, dyskinesia, dystonia, and tremors. Examples of impaired sexual function include, but are not limited to, premature ejaculation and impaired erection.

Examples of eating disorders include, but are not limited to, anorexia nervosa and bulimia nervosa.

b. Pharmacological Agents

Pharmacological agents used in the methods and compositions of the present invention include one or more active agents, described in detail below, in any pharmaceutically acceptable form, including any pharmaceutically acceptable salts, prodrugs, racemic mixtures, conformational and / or optical isomers, crystalline polymorphs and isotopic variants of one or more pharmacological agent.

i. Selective agonists of M ₁ -muscarinic receptors

The methods of the present invention cure psychological conditions, including depression, by administering to an individual in need of such treatment a therapeutic amount of one or more selective M ₁ -muscarinic receptor antagonists. Muscarinic antagonists are described generally in Chapter 7 of Goodman and Gilman's The Pharmacological Basis of Therapeutics, supra, which is incorporated herein by reference. Examples of selective M ₁ -muscarinic receptor antagonists include pirenzepine and telenzepine, the structures of which are shown below.

Pirenzepine (5,11-Dichloro-11 - [(4-methyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one) is manufactured and marketed as pirenzepine dihydrochloride several pharmaceutical companies, including Azupharma (Stuttgart, Germany), Boehringer Ingelheim (Ingelheim, Germany; sold as Gastrozepin®), Dolorgiet (Bonn, Germany). Pirenzepine can be administered in doses from about 50 mg / day to about 200 mg / day, for example, about 100-150 mg / day, or 50, 100, 150, or 200 mg / day. Alternatively, pirenzepine can be administered in doses from about 0.1 mg / kg / day to about 10 mg / kg / day, usually from about 0.7 mg / kg / day to about 5 mg / kg / day. Analogues of pirenzepine have also found application in the implementation of the methods of the present invention. Chemical analogues of pirenzepine are disclosed, for example, in US Patents No. 3,660,380; 3,743,734 and 5,324,832, the disclosure of each of which in its entirety is included in the present invention by reference for all purposes.

Telenzepine (4,9-dihydro-3-methyl-4 - [(4-methyl-1-piperazinyl) acetyl] -10H-thieno [3,4-b] [1,5] benzodiazepin-10-one) is commercially available , for example, from Tocris Bioscience (Ellisville, MO) and Sigma-Aldrich, Inc. (St. Louis, MO) as telenzepine dihydrochloride. In addition, the synthesis of telenzepine is disclosed in US Patent No. 4,381,301, which is incorporated herein by reference. Telenzepine can be administered in doses from about 0.5 mg per day to about 10 mg per day, for example about 1-5 mg / day or 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg / day. Analogs of telenzepine have also found application in the implementation of the methods of the present invention. Chemical analogs and enantiomers of telenzepine are disclosed, for example, in US Patents No. 3,953,430; 4,168,269; 4,172,831; 4,381,301; 5,140,025 and 5,324,832, the disclosure of each of which in its entirety is included in the present invention by reference for all purposes.

In some embodiments, racemic telenzepine preparations are introduced containing a mixture of the (+) and (-) enantiomers of telenzepine. In some embodiments, the (+) or (-) enantiomer of telenzepine is administered. Telenzepine exists in two chirally different states separated by an activation barrier of 35.5 kcal / mol (Eveleigh et al., Mol Pharmacol (1989) 35: 477-483; and Schudt et al., Eur J Pharmacol (1989) 165: 87 -96). The form (+) of telenzepine has potent antimuscarinic activity, while the form (-) is much less active. The selectivity of telenzepine probably varies in different anatomical regions, and the (+) form is 400 times more effective on cortical receptors compared to the (-) isomer; on the receptors of the heart, the selectivity is less, and the form (+) is only 50 times more effective than form (-) (Eveleigh et al., supra). The two forms slowly transform into each other with a half-life of approximately 200 hours at 90 degrees (Eveleigh et al., Supra). Numerous studies have confirmed that the two forms have different activities (Eitze, Eur J Pharmacol (1990) 180: 161-168; Eveleigh et al., Supra; Feifel et al., Eur J Pharmacol (1991) 195: 115-123; Kilian et al., Agents Actions Suppl 34: 131-147; Schudt et al., supra).

ii. Antidepressants

Antidepressant agents that are not M ₁ R-selective antagonists for use in the present invention are not limited in their mechanism of action, and any class of antidepressants is applicable. For example, tricyclic antidepressants (TCAs) and their analogues, serotonin reuptake inhibitors and their prodrugs, monoamine oxidase inhibitors (MAOIs), serotonin agonists and their prodrugs, norepinephrine reuptake inhibitors can be administered in combination with one or more M ₁ R-selective antagonists. dopamine reuptake inhibitors and serotonin reuptake activators. Serotonin reuptake inhibitors include both selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). Norepinephrine reuptake inhibitors include both specific norepinephrine reuptake inhibitors and mixed noradrenaline-dopamine reuptake inhibitors (NDRIs). Serotonin, norepinephrine and dopamine reuptake inhibitors, or “triple reuptake inhibitors”, have also found use in the present invention. Other categories of antidepressants may also be used, for example, tetracyclic antidepressants maprotiline or mianserin, or agents such as trazodone, nefazodone or buspirone; corticotropin releasing factor receptor 1 antagonists (CRF1), as well as compounds that are active against psychoses or bipolar disorders, including amoxapine, clozapine, risperidone, olanzapine, quetiapine and aripiprazole.

Tricyclic antidepressants for use in the present invention include amineptin, amitriptyline, clomipramine, desipramine, doxepin, dotiepin, imipramine, nortriptyline, protriptyline, trimipramine, amoxapine and muscle relaxant cyclobenzaprine. Other tricyclic antidepressants and their analogues may also be used.

In one embodiment, an effective amount of one or more M ₁ R-selective antagonists is administered in conjunction with an effective amount of a selective serotonin reuptake inhibitor. Examples of selective serotonin reuptake inhibitors include citalopram, escitalopram, fluoxetine (racemate or optical isomer), fluvoxamine, paroxetine and sertraline (and its S enantiomer, Zoloft®), although SSRIs not listed here can also be used. In one embodiment, citalopram (or escitalopram) is administered in conjunction with one or more M ₁ R-selective antagonists. In one embodiment, an effective amount of fluoxetine (racemate or optical isomer) is co-administered. In one embodiment, an effective amount of fluvoxamine is co-administered. In one embodiment, an effective amount of sertraline (or its S enantiomer, Zoloft®) is co-administered. In one embodiment, an effective amount of paroxetine is co-administered. In one embodiment, an effective amount of duloxetine is co-administered.

In one embodiment, an effective amount of one or more serotonin-norepinephrine reuptake inhibitors is co-administered with one or more M ₁ R-selective antagonists. Examples of serotonin-norepinephrine reuptake inhibitors include milnacipran, mirtazapine, venlafaxine (racemate or optical isomer), duloxetine, (-) 1-dimethylaminomethyl-5-methoxybenzocyclobutan-1-yl) cyclohexanol (S33005sene DVS) DVS23005Sin DV -233 SR and sibutramine, although not listed here, SNRIs may also be used. Although the mechanism of action of mirtazapine may differ from the mechanism of action of other SNRIs, given its apparent dual serotonergic and norepinephrine action, in the present invention it is considered as representative of the SNRI class antidepressants. In one embodiment, an effective amount of venlafaxine (racemate or optical isomer) is co-administered. In one embodiment, an effective amount of desvenlafaxine is co-administered. In one embodiment, an effective amount of sibutramine is co-administered. In one embodiment, an effective amount of duloxetine is co-administered. In one embodiment, an effective amount of milnacipran is co-administered. In one embodiment, an effective amount of mirtazapine is co-administered.

In other embodiments, an effective amount of one or more norepinephrine reuptake inhibitors is administered in conjunction with one or more M ₁ R-selective antagonists. Examples of selective noradrenaline reuptake inhibitors include roboxetine and atomoxetine.

In one embodiment, an effective amount of one or more norepinephrine-dopamine reuptake inhibitors is administered together with one or more M ₁ R-selective antagonists. Examples of norepinephrine-dopamine reuptake inhibitors include amineptin, modafinil, GW353162 and bupropion. In the case of bupropion, it is assumed that its metabolites are responsible for blocking reverse noradrenergic uptake. In one embodiment, an effective amount of bupropion is co-administered.

In one embodiment, an effective amount of one or more triple reuptake inhibitors (serotonin-noradrenaline-dopamine) is administered in conjunction with one or more M ₁ R-selective antagonists. Examples of triple reuptake inhibitors include indatralin, SEP-225289, DOV 216.303 and (+) - 1- (3,4-dichlorophenyl) -3-azabicyclo- [3.1.0] hexane hydrochloride (DOV 21,947).

Monoamine oxidase inhibitors for use in the present invention include befloxatone, brofaromine, deprenyl, isocarboxazide, moclobemide, pargyline, phenelzine, selegiline and tranylcypromine, together with their forms for controlled release and transdermal delivery.

Antidepressants that can be administered together with the M ₁ R-selective antagonist include maprotiline, tianeptine, nefazodone and trazodone.

Suitable dosages of antidepressants, inter alia, will depend on the route of administration chosen and the composition. For example, tricyclic antidepressants are administered at a dose of from about 25 to about 600 mg / day, and usually at a dose of from about 75 to about 300 mg / day.

Serotonin reuptake inhibitors are administered at a dose of from about 5 to about 400 mg / day, and are usually administered at a dose of from about 20 to about 250 mg / day. In particular, when practicing the methods of the present invention, venlafaxine (racemate or optical isomer) can be administered in an amount of from about 9 mg to about 225 mg per dose and is usually administered in an amount of about 37.5 mg, 75 mg, 150 mg or 225 mg per dose. Venlafaxine is usually administered in an amount of about 25-550 mg / day and usually about 37.5-375 mg / day, more usually about 75-225 mg / day and most usually about 37.5, 75, 150, 225 or 300 mg / day. If appropriate for a particular patient, the daily dose of venlafaxine may be divided and may be administered in one, two, three, four or more doses per day. Desvenlafaxine may be administered at a dose of about 50-600 mg / day, for example, about 50, 100, 200, 400 or 600 mg / day. Sertraline (or its S-enantiomer, Zoloft®) can be administered in doses in the range of about 50-200 mg / day, usually about 100-150 mg / day. Fluoxetine (racemate or optical isomer) can be administered in doses in the range of about 5-50 mg / day, usually about 20-40 mg / day. Fluvoxamine can be administered in doses in the range of about 50-300 mg / day, usually about 100-200 mg / day. Paroxetine can be administered in doses in the range of about 10-50 mg / day, usually about 20-40 mg / day.

In carrying out the methods of the present invention, citalopram (or escitalopram) can be administered at a dose of about 5-60 mg / day, and preferably about 10, 20 or 30 mg / day. Typically, citalopram is administered once a day, for example, in the morning or in the evening. However, for some patients, citalopram is given two or more times a day. Mirtazapine can be administered at a dose of about 5-100 mg / day, for example about 7.5, 15, 30, 45, or 90 mg / day. Milnacipran can be administered at a dose of about 25-200 mg / day, for example about 25, 50, 100, 150 or 200 mg / day.

Atypical antidepressants, including bupropion, nefazodone and trazodone, are administered at a dose of about 50-600 mg / day and usually about 150-400 mg / day. Bupropion can be administered at a dose of about 25-300 mg / day, for example about 25, 50, 100, 150, 200, 300 mg / day. Monoamine oxidase inhibitors are usually administered at a dose of about 5-90 mg / day and usually about 10-60 mg / day.

iii. Combinations of Pharmacological Agents

In some embodiments, one or more M ₁ R-selective antagonists are administered together or combined with one or more antidepressants that are not M ₁ R-selective antagonists. M ₁ R-selective antagonists and antidepressants are described above.

In some embodiments, one or more M ₁ R-selective antagonists are administered together or combined with one or more 5-HT2c receptor agonists. Examples of 5-HT2 s receptor agonists include 1- (t-chlorophenyl) piperazine (m-CPP), mirtazapine, APD-356 (lorcaserin), SCA-136 (vabikazerin), ORG-12962, ORG-37684, ORG-36262, ORG-8484, Ro-60-175, Ro-60-0332, VER-3323, VER-5593, VER-5384, VER-8775, LY-448100, WAY-161503, WAY-470, WAY-163909, MK- 212, BVT.933, YM-348, IL-639, IK-264, ATH-88651, ATHX-105 and the like (see, for example, Nilsson BM, J. Med. Chem. 2006, 49: 4023-4034 )

In some embodiments, one or more M ₁ R-selective antagonist is administered together or combined with m-CPP. In some embodiments, one or more M ₁ R-selective antagonist is administered together or combined with mirtazapine. In some embodiments, one or more M ₁ R-selective antagonists are administered together or combined with lorcaserin. In some embodiments, one or more M ₁ R-selective antagonists are administered together or combined with Ro-60-175. In some embodiments, one or more M ₁ R-selective antagonist is administered together or combined with Ro-60-0332.

In some embodiments, a combination of one or more M ₁ R-selective antagonists, one or more antidepressants that are not M ₁ R-selective antagonists, and one or more 5-HT2c receptor agonists is administered.

iv. Isomers

All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereoisomers), racemates, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs and tautomers of therapeutic agents are included of the present invention.

v. Isotopes

The present invention also includes isotope-labeled variants of therapeutic agents where one or more atoms are replaced by one or more atoms having a specific atomic mass or mass numbers. Isotope-labeled variants of therapeutic agents and their prodrugs, as well as isotope-labeled pharmaceutically acceptable salts of therapeutic agents and their prodrugs are included in the present invention. In certain circumstances, replacing with a heavier isotope, such as deuterium ( ² N), can provide increased metabolic stability, which provides therapeutic benefits such as increased in vivo half-life or reduced dosage. Isotope-labeled variants of the therapeutic agents of the present invention and their prodrugs can usually be obtained according to methods known to those skilled in the art by replacing an isotope-labeled reagent with an isotope-labeled reagent.

from. Introduction

i. Duration of Administration

Typically, one or more M ₁ R-selective antagonists are administered to an individual over an extended period of time. The methods of the present invention can last for at least 20 days, in some embodiments for at least 40, 60, 80 or 100 days and in some embodiments for at least 150, 200, 250, 300, 350 days, 1 year or more. Certain individuals receive treatment by the methods of the present invention for more than one year, for example, for at least 400, 450, 500, 550, 600, 650, 700, 800, 900, 1000 days. However, individuals can be successfully treated with the methods of the present invention for 2 years, 3 years, 4 years or more.

ii. Introduction schedule

Typically, when implementing the methods of the present invention, effective amounts of one or more M ₁ R-selective antagonists administered together with one or more antidepressants can be administered together or separately, simultaneously or at different times. M ₁ R-selective antagonists and antidepressants, independently of one another, may be administered one, two, three, four times a day, or more or less often depending on need. Preferably, one or more M ₁ R-selective antagonists and one or more antidepressants are administered once a day. Preferably, one or more M ₁ R-selective antagonists and one or more antidepressants are administered at the same time, for example, as a mixture. One or more M ₁ R-selective antagonists and one or more antidepressants may be administered as a sustained release composition.

For certain patients, the methods of the present invention are carried out by the simultaneous administration of one or more M ₁ R-selective antagonists and one or more antidepressants from the very beginning of treatment. For certain patients, the methods of the present invention are carried out by first administering one or more M ₁ R-selective antagonists and only then sequentially co-administering one or more antidepressants. The patient may first receive one or more M ₁ R-selective antagonists on their own for 3 days, 5 days, 7 days, 10 days, 14 days, 20 days, or 30 days before the administration of one or more antidepressants.

One or more M ₁ R-selective antagonists can be administered prophylactically to prevent symptoms of psychological conditions in a subject at risk of developing such conditions, or therapeutically to improve symptoms of a psychological state over an extended period of time.

iii. Route of administration

In general, the administration of one or more M ₁ R-selective antagonists alone or in combination with one or more antidepressants can be achieved in various ways, including oral, buccal, parenteral administration, including intravenous, intradermal, subcutaneous, intramuscular, transdermal, transmucosal, intranasal, etc. introduction. One or more M ₁ R-selective antagonists may be administered by the same or different routes of administration when they are administered together with one or more antidepressants.

In some embodiments, one or more M ₁ R-selective antagonists, alone or in combination, may be administered in a local rather than systemic manner, for example, as a composition for deposition or for sustained release.

iv. Methods for determining suitable dosages

The administered doses for M ₁ R-selective antagonists and antidepressants are in accordance with the dosages and modes of administration used by those skilled in the art. General guidelines for acceptable dosages of all pharmacological agents used in the methods of the present invention are given in Goodman and Oilman's The Pharmacological Basis of Therapeutics, 11th Edition, 2006, supra, and in the Physicians' Desk Reference (PDR), for example, in 59 ^th (2005 ) or 60 ^th (2006) Editions, Thomson PDR, each of which is incorporated herein by reference. Published dosages for M ₁ R-selective antagonists are given for indications other than treatment aimed at improving the condition in depression or other psychological conditions. In the compositions and methods of the present invention, effective dosages of M ₁ R-selective antagonists and antidepressants for practicing the present invention may be equal to or less (for example, 25, 50, 75 or 100%) than dosages published for other indications.

Suitable dosages of one or more M ₁ R-selective antagonists and antidepressants will vary depending on several factors, including the chosen route of administration, composition, patient response to treatment, severity of condition, weight of the subject, and decision of the attending physician. Dosage may be increased or decreased over time, as is required for an individual patient. Typically, the patient is first given a low dose, which is then increased to the effective doses tolerated by the patient.

The determination of the effective amount is the responsibility of a person skilled in the art, especially in light of the detailed disclosure of the present invention presented herein. Typically, an effective or effective amount of a combination of one or more M ₁ R-selective antagonists and one or more antidepressants is determined by first administering a low dose or a small amount of M ₁ R-selective antagonist per se and then gradually increasing the administered doses or dosages, adding a second or third medication, if necessary, until the desired effect is observed in the subject receiving the treatment with minimal or no toxic side effects. Applicable methods for determining the appropriate dose and dosage regimen for administering a combination of the present invention are described, for example, in Goodman and Oilman's The Pharmacological Basis of Therapeutics, 11th Edition, 2006, supra; Physicians' Desk Reference (PDR), supra; in Remington: The Science and Practice of Pharmacy, 21st Edition, 2006, supra; and Martindale: The Complete Drug Reference, Sweetman, 2005, London: Pharmaceutical Press., and Martindale, Martindale: The Extra Pharmacopoeia, 31st Edition, 1996, Amer Pharmaceutical Assn, each of which is incorporated herein by reference.

The amount and dosage range can be individually selected in order to provide plasma levels of active compounds that are sufficient to provide a therapeutic effect. Preferably, therapeutically effective serum levels are achieved by administering a single daily dose, although the administration of effective multiple daily doses is also included in the present invention. In the case of local administration or selective absorption, the effective local concentration of the drug may not correspond to the concentration in the blood plasma. A person skilled in the art will be able to optimize therapeutically effective local dosages without long experimentation.

3. Pharmaceutical compositions

The present invention further provides pharmaceutical compositions comprising a mixture of a therapeutically effective amount of one or more M ₁ R-selective antagonists and one or more antidepressants. In some embodiments, M ₁ R-selective antagonists are selected from the group consisting of telenzepine, pirenzepine, and mixtures thereof.

In certain embodiments, the pharmaceutical compositions include one or more antidepressants, which are a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a norepinephrine reuptake inhibitor, a dopamine reuptake inhibitor, a norepinephrine reuptake inhibitor (norepinephrine NDRI), serotonin-noradrenaline-dopamine reuptake inhibitor, serotonin reuptake activator, serotonin agonist and prodrugs thereof. In one embodiment, the pharmaceutical composition includes one or more antidepressants selected from the group consisting of venlafaxine (racemate or optical isomer), duloxetine, fluoxetine (racemate or optical isomer), citalopram, escitalopram, fluvoxamine, paroxetine, S33003, DV33fax, DVS ), DVS-233 SR, bupropion, GW353162, sibutramine, atomoxetine and sertraline (or its S enantiomer, Zoloft®).

In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and SSRI. In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and citalopram (or escitalopram). In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and sertraline (or its S-enantiomer, Zoloft®). In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and fluoxetine (racemate or optical isomer). In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and fluvoxamine. In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and paroxetine.

In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and SNRI. In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and venlafaxine (racemate or optical isomer). In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and desvenlafaxine. In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and duloxetine. In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and milnacipran. In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and mirtazapine.

In one embodiment, the pharmaceutical composition comprises therapeutically effective amounts of telenzepine or pirenzepine and bupropion.

In combination, one or more M ₁ R-selective antagonists and one or more antidepressants can be administered to a subject, for example, a human patient, a pet such as a cat or dog, independently or together in the form of their pharmaceutically acceptable salts or in the form pharmaceutical compositions, where these compounds are mixed with suitable carriers or excipient (s) in a therapeutically effective amount, for example, in doses effective to achieve the desired result in reducing ps symptoms hologicheskogo state.

The combination of the M ₁ R-selective antagonist and antidepressant of the present invention can be included in many compositions for therapeutic administration. More specifically, the combination of the present invention can be prepared in the form of pharmaceutical compositions, together or separately, by mixing with suitable pharmaceutically acceptable carriers or solvents and can be prepared in the form of preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules , pills, powders, granules, dragees, gels, suspensions, ointments, solutions, suppositories, injections, inhalations and aerosols.

Suitable compositions for use in the present invention can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st Edition, 2006, supra; Martindale: The Complete Drug Reference, Sweetman, 2005, London: Pharmaceutical Press .; Niazi, Handbook of Pharmaceutical Manufacturing Formulations, 2004, CRC Press; and Gibson, Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form, 2001, Interpharm Press, which are incorporated herein by reference. The pharmaceutical compositions described herein can be produced by a method known to those skilled in the art, for example by conventional mixing, dissolving, granulating, dragee-milling, powdering, emulsion preparation, encapsulation, encapsulation or lyophilization process. The following methods and excipients are provided for the purpose of examples and are not limiting.

In one embodiment, a combination of the M ₁ R-selective antagonist and antidepressant is formulated for delivery as a composition for sustained release, controlled release, sustained release, long-term release or delayed release, for example, in a semi-permeable matrix of solid hydrophobic polymers containing a therapeutic agent. Various types of sustained release materials have been developed and are well known to those skilled in the art. Presently available sustained release formulations include coated tablets, multicomponent or bead systems, matrix technologies using hydrophilic or lipophilic materials, and wax-based tablets with pore-forming excipients (see, for example, Huang et al. Drug Dev. Ind. Pharm. 29:79 (2003); Pearnchob et al. DrugDev. Ind. Pharm. 29: 925 (2003); Maggi et al. Eur. J. Pharm. Biopharm. 55:99 (2003); Khanvilkar et al., Drug Dev. Ind. Pharm. 228: 601 (2002); and Schmidt et al., Int. J. Pharm. 216: 9 (2001)). Systems for sustained release may, depending on their composition, release compounds within hours or days, for example within 4, 6, 8, 10, 12, 16, 20, 24 hours or more. Typically, sustained release compositions can be prepared using natural or synthetic polymers, for example polymeric vinyl pyrrolidones, such as polyvinyl pyrrolidone (PVP); hydrophilic carboxyvinyl polymers; hydrophobic and / or hydrophilic hydrocolloids such as methyl cellulose, ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; and carboxypolymethylene.

Sustained or delayed release compositions can also be prepared using natural ingredients such as minerals, including titanium dioxide, silica, zinc oxide and clay (see US Patent 6,638,521, which is incorporated herein by reference). Examples of delayed release compositions that can be used in the delivery of a combination of the M ₁ R-selective antagonist and antidepressant of the present invention include those described in US Patent Nos. 6,635,680; 6,624,200; 6,613,361; 6,613,358, 6,596,308; 6,589,563; 6,562,375; 6,548,084; 6,541,020; 6,537,579; 6,528,080 and 6,524,621, each of which is incorporated herein by reference. Interesting controlled release compositions include those described in US Pat. Nos. 6,607,751; 6,599,529; 6,569,463; 6,565,883; 6,482,440; 6,403,597; 6,319,919; 6,150,354; 6,080,736; 5,672,356; 5,472,704; 5,445,829; 5,312,817 and 5,296,483, each of which is incorporated herein by reference. One of ordinary skill in the art will readily select other suitable compositions for sustained release.

For oral administration, a combination of the M ₁ R-selective antagonist and antidepressant can be easily prepared by combining with pharmaceutically acceptable carriers that are well known in the art. Such carriers allow the preparation of compounds in the form of tablets, pills, dragees, capsules, emulsions, lipophilic and hydrophilic suspensions, liquids, gels, syrups, suspensions, suspensions, and the like for oral administration to a patient in need of treatment. Pharmaceutical compositions for oral administration can be obtained by mixing the compounds with a solid excipient, optionally grinding the resulting mixture, and preparing granules from this mixture after adding suitable excipients, if desired, to form the core of tablets or dragees. Suitable excipients are, in particular, excipients such as sugars, including lactose, sucrose, mannitol or sorbitol, cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone (PVP). If desired, disintegrating agents such as crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added.

Pharmaceutical compositions that can be administered orally include two-part hard capsules made of gelatin, as well as sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Compound capsules may contain the active ingredients in admixture with an excipient, such as lactose, a binding agent, such as starch, and / or lubricants, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers can be added. All compositions for oral administration must be in a dosage form (dosage?) Suitable for such administration.

The core of the dragee is provided with an appropriate coating. For this purpose, concentrated sugar solutions may be used, which may not necessarily contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, glazing solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablet or dragee coating to identify or characterize different combinations and doses of active compounds.

The compounds can be prepared for parenteral administration by injection, for example, by bolus injection or continuous infusion. For injection, a combination of the M ₁ R-selective antagonist and antidepressant can be formulated by diluting, suspending or emulsifying it in an aqueous or non-aqueous solvent such as vegetable oil and other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizing agents, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives. Preferably, the combination of the present invention can be prepared as an aqueous solution, preferably in physiologically compatible buffers, such as Hanks solution, Ringer's solution or buffered saline. Compositions for injection can be provided in a single-use form, for example in ampoules, or in multi-dose containers with the addition of a preservative. The compositions may be in such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain necessary agents, such as suspending, stabilizing and / or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compounds in a water-soluble form. In addition, suspensions of the active compounds can be prepared as injectable oily suspensions. Suitable lipophilic solvents or carriers include fixed fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds, which provides highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

Systemic administration can also be carried out transmucosally or transdermally. For transmucosal or transdermal administration, a suitable penetrating substance is used in the composition to overcome the corresponding barrier. For topical administration, the agents are prepared in the form of ointments, creams, balms, powders and gels. In one embodiment, the transdermal delivery agent may be DMSO. Transdermal delivery systems may include, for example, patches. For transmucosal administration, a suitable penetrating substance necessary to overcome the corresponding barrier is used in the composition. Such penetrating agents are widely known in the art. Examples of transdermal delivery compositions that may find use in the present invention include those described in US Pat. Nos. 6,589,549; 6,544,548; 6,517,864; 6,512,010; 6,465,006; 6,379,696; 6,312,717 and 6,310,177, each of which is incorporated herein by reference.

For buccal administration, the compositions can be used in the form of tablets or lozenges, which are prepared by standard methods.

In addition to the compositions described previously, a combination of the M ₁ R-selective antagonist and antidepressant of the present invention can also be formulated as a deposited preparation. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be mixed with suitable polymeric or hydrophobic materials (for example, in the form of an emulsion in an acceptable oil), or with ion-exchange resins, or in the form of sparingly soluble derivatives, for example, sparingly soluble salts.

The pharmaceutical compositions may also include suitable carriers or excipients in the form of a solid or gel phase. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.

4. Ready-made sets

The pharmaceutical compositions of the present invention can also be provided in the form of ready-made kits. In certain embodiments, the kit of the present invention includes one or more M ₁ R-selective antagonists and one or more antidepressants in separate compositions. In certain embodiments, the finished kits include one or more M ₁ R-selective antagonists and one or more antidepressants in the same composition. In certain embodiments, the ready-made kits provide one or more M ₁ R-selective antagonists and one or more antidepressants independently as a uniform dosage composition throughout the course of treatment. In certain embodiments, the ready-made kits provide one or more M ₁ R-selective antagonists and one or more antidepressants independently in varying dosages during the course of treatment, either decreasing or increasing, but usually increasing to an effective dosage level in accordance with the needs of the individual.

In one embodiment, the finished kits include one or more pharmaceutical compositions comprising one or more M ₁ R-selective antagonists selected from the group consisting of telenzepine and pirenzepine.

In certain embodiments, the finished kits include one or more antidepressants selected from the group consisting of a selective serotonin reuptake inhibitor (SSRI), a selective serotonin-noradrenaline reuptake inhibitor (SNRI), a noradrenaline reuptake inhibitor, a dopamine reuptake inhibitor, an inhibitor norepinephrine-dopamine (NDRI), a serotonin-noradrenaline-dopamine reuptake inhibitor and mixtures thereof. In one embodiment, the finished kits include one or more pharmaceutical compositions comprising one or more antidepressants selected from the group consisting of venlafaxine (racemate or optical isomer), fluoxetine (racemate or optical isomer), duloxetine, paroxetine, citalopram, escitalopram, flocam, S33005, DVS-233 (desvenlafaxine), DVS-233 SR, bupropion, GW353162, sibutramine, atomoxetine and sertraline (or its S enantiomer, Zoloft®).

In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and SSRI. In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and citalopram (or escitalopram). In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and sertraline (or its S enantiomer, Zoloft®). In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and fluoxetine (racemate or optical isomer). In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and fluvoxamine. In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and paroxetine.

In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and SNRI. In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and venlafaxine (racemate or optical isomer). In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and desvenlafaxine. In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and duloxetine. In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and milnacipran. In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and mirtazapine.

In one embodiment, the kit includes therapeutically effective amounts of telenzepine or pirenzepine and bupropion.

Information confirming the possibility of carrying out the invention

The following Examples are intended to illustrate, but not to limit the scope of the present invention.

Example 1

Andidepressant effect: To assess the antidepressant effect of the compounds, a tail suspension test was used. The test was adapted from the original method described by Steru et al. (Steru L et al., Psychopharmacol 85: 367-70, 1985; Steru L et al., Prog Neuro-Psychopharmacol & Biol Psychiat 11: 659-71, 1987) and a later modification of Crowley et al. (Crowley JJ et al., Pharmacol Biochem Beh 78 (2): 269-74,2004). Male CD-I mice aged seven to eight weeks (25-35 grams) were kept before testing for one week under standard conditions. The mice (n = 8-10 for each dose group) were injected intraperitoneally (WB) or the test compound orally (po), after which they were returned to the cells for a certain period of time (45-60 min) before testing. After that, with the help of adhesive tape, the mice were suspended by the tail to a tension measuring device. Over the next 6 minutes, activity was recorded using a computer, which was classified as: 1) Stillness, 2) Attempts to break free, or 3) Active attempts to break free, based on the intensity of movements recorded by the tension measuring device. Total Stillness was calculated and expressed in seconds. In this study, mice that received only vehicle typically spent about 30% of the test stationary time, while pre-treatment with antidepressants significantly reduced the duration of this total immobility. The effect of processing is shown in Table 1 and in Figures 1-6 both in the form of the Time Spent in the Stationary State (in seconds ± SEM (standard error of the mean)), and% Decrease in Stationarity = [1- (Processing Stationary / Stationary with Carrier )] × 100%. Similar inscriptions in the Dose Column in Table 1 show the values obtained in the same experiment (to facilitate comparison between treatment with individual compounds and co-administrations). Statistical analysis was performed using a one-way ANOVA test (variant analysis) followed by a Bonferroni multiple comparison test with a general alpha value of 0.05. In table 1, asterisks (*) indicate a reliable effect compared to mice treated with a vehicle, while letters (a or b) mean a reliable action compared to mice treated with only one compound ("a" is a significant difference from antidepressant and "b "- a significant difference from telenzepine). In Table 1, one character means p <0.05, two characters mean p <0.01, and three characters mean p <0.001. In the respective figures, the symbols for indicating statistical certainty may be different.

Table 1 Compound Dose (mg / kg) Carrier Stillness Time (sec) Processing Stillness Time (sec) Decreased immobility time p-values 5 (vb) ^a 115 ± 16 80 ± 14 thirty% n.d. 5 (v.b.) ^b 114 ± 19 90 ± 18 21% n.d. 5 (vb) ^d 125 ± 14 159 ± 23 -27% n.d. 10 (v.b.) ^c 97 ± 20 64 ± 15 34% n.d. Telenzepine 25 (v.b.) ^d 125 ± 14 84 ± 07 33% * 50 (v.b.) ^d 125 ± 14 61 ± 11 51% *** 60 (bp) ^e 130 ± 21 71 ± 15 45% * 80 (bp) ^e 130 ± 21 82 ± 18 37% * 100 (bp) ^e 130 ± 21 59 ± 10 55% ** 5 (vb) ^f 123 ± 20 137 ± 15 -eleven% n.d. Pirenzepine 25 (w) ^f 123 ± 20 90 ± 17 27% n.d. 50 (v.b.) ^f 123 ± 20 76 ± 12 38% * 4 (vb) ^c 97 ± 20 97 ± 11 0% n.d. Fluoxetine 4 (vb) ^g 146 ± 18 81 ± 16 45% ** 20 (v.b.) ^g 146 ± 18 82 ± 16 45% ** 40 (v.b.) ^g 146 ± 18 53 ± 14 64% *** 1 (v.b.) ^a 115 ± 16 87 ± 14 24% n.d. 5 (v.b.) ^h 121 ± 17 63 ± 08 48% ** Sertraline 20 (v.b.) ^h 121 ± 17 50 ± 16 59% ** 40 (v.b.) ^h 121 ± 17 44 ± 15 64% *** 3 (v.b.) ⁱ 112 ± 15 103 ± 21 8% n.d. 10 (v.b.) ⁱ 112 ± 15 116 ± 20 -four% n.d. Venlafaxine 10 (v.b.) ^b 114 ± 19 103 ± 15 10% n.d. 30 (v.b.) ⁱ 112 ± 15 31 ± 09 72% *** Telenzepine + Fluoxetine 10 + 4 ^s (b.p.) 97 ± 20 45 ± 09 54% ** Telenzepine + Sertraline 5 + 1 ^a (b.b.) 115 ± 16 66 ± 12 43% *** Telenzepine + Venlafaxine 5 + 10 ^b (v.b.) 114 ± 19 29 ± 09 75% **, aa, b

Comments on the action of compounds

As shown in table 1, the systemic administration of one pirenzepine at a dose of 50 mg / kg intraperitoneally (figure 1) or one telenzepine at a dose of 25 mg / kg intraperitoneally (figure 2) or 60 mg / kg orally (figure 3) provides a significant reduction in immobility.

When telenzepine was administered together with an antidepressant, all three tested combinations showed that subactive doses of each of the compounds can combine and provide significant effects, which are generally considered synergistic. The combination of telenzepine + venlafaxine showed the highest effectiveness among all the tested combinations. The combined administration of telenzepine and venlafaxine provided a significant (p <0.01) reduction in immobility by 75%, which is significantly different from the decrease by 31%, which could be expected with simple additivity (figure 5). Similarly, co-administration of 10 mg / kg telenzepine + 4 mg / kg fluoxetine provided a significant (p <0.01) reduction in immobility by 54%, which is higher than the effect expected from the contribution of each of the individual compounds (Figure 6). The combined introduction of telenzepine and sertraline provided a significant reduction in immobility by 43% (figure 4).

Combinations of selective M ₁ R antagonists and antidepressants have shown that the “effective dose” of an antidepressant compound can be dramatically reduced by co-administration with M ₁ R antagonists (for example, telenzepine). The dose of venlafaxine can be reduced by 3 times (up to 10 mg / kg) and at the same time it will still remain effective when co-administered with 5 mg / kg telenzepine. Compare a 72% reduction in immobility with a single dose of 30 mg / kg venlafaxine and a 75% reduction in immobility with a combined 10 mg / kg of venlafaxine and 5 mg / kg of telenzepine. Similarly, the dose of sertraline can be reduced by 5 times (up to 1 mg / kg) and still maintain effectiveness when co-administered with 5 mg / kg TZP. Compare a 48% reduction in immobility with 5 mg / kg sertraline alone and a 43% reduction in immobility with 1 mg / kg of sertraline and 5 mg / kg telenzepine. It was found that the effective dose of fluoxetine can be reduced by about 7 times (to 4 mg / kg) when co-administered with 10 mg / kg TZP.

You must understand that the Examples and embodiments described herein have an illustrative function only and that a person skilled in the art can make numerous modifications and changes that will be within the spirit and scope of the present invention and within the scope of the appended claims. All publications, patents, and patent applications cited herein are included in their entirety for any purpose.

Claims (15)

1. A method of treating depression, comprising administering to a subject in need of such treatment a therapeutically effective amount of a combination of telenzepine and one or more antidepressants, which are selected from the group consisting of fluoxetine, sertraline and venlafaxine. 2. The method of claim 1, wherein the antidepressant is fluoxetine. 3. The method according to claim 1, in which the antidepressant is sertraline. 4. The method according to claim 1, in which the antidepressant is venlafaxine. 5. The method according to claim 1, in which telenzepine and one or more antidepressants are administered systemically. 6. The method according to claim 1, in which telenzepine and one or more antidepressants are administered simultaneously. 7. The method according to claim 1, in which telenzepine and one or more antidepressants are administered sequentially. 8. A pharmaceutical composition for treating depression, comprising a mixture of therapeutically effective amounts of telenzepine and one or more antidepressants, which are selected from the group consisting of fluoxetine, sertraline and venlafaxine. 9. The pharmaceutical composition of claim 8, wherein the antidepressant is fluoxetine. 10. The pharmaceutical composition of claim 8, in which the antidepressant is sertraline. 11. The pharmaceutical composition of claim 8, in which the antidepressant is venlafaxine. 12. The pharmaceutical composition of claim 8, in which the delivery of telenzepine and one or more antidepressants is carried out by delayed release. 13. A kit for treating depression, comprising a combination of therapeutically effective amounts of telenzepine and one or more antidepressants, which are selected from the group consisting of fluoxetine, sertraline and venlafaxine. 14. The kit according to item 13, in which telenzepine and one or more antidepressants are in various dosage forms. 15. The kit according to item 13, in which telenzepine and one or more antidepressants are in the same dosage form.

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