RU2682966C1 - Buspiron combination for treatment of faintness - Google Patents

Abstract

FIELD: medicine; pharmacology.SUBSTANCE: group of inventions relates to medicine and pharmacology, in particular, to new combinations of buspiron with betahistine or piracetam for the treatment of vestibular and non-vestibular faintness. Combination contains in effective amounts buspirone and at least one substance selected from the group including betahistine and piracetam or their pharmaceutically acceptable salts, at the same time, active ingredients are intended for administration in daily dosages: buspirone – 5–100 mg/day; betahistine – 16–1,440 mg/day; piracetam – 200–6,000 mg/day. Also a set for the treatment of vestibular and non-vestibular faintness was found out, containing instructions for use and a pharmaceutical composition for the treatment of vestibular and non-vestibular faintness, containing a combination of drugs and at least one excipient and / or one pharmaceutically acceptable carrier.EFFECT: group of inventions provides an increase in the effectiveness of drugs for the treatment of vestibular and non-vestibular faintness due to the synergistic effect of the drugs combination.11 cl, 5 tbl, 5 ex

Description

The present invention relates to the field of medicine and pharmacology, in particular to new combinations of buspirone with at least one substance selected from the group consisting of betahistine and piracetam, for the treatment of vestibular and bribery dizziness.

Dizziness is often a debilitating condition that causes a feeling of loss of balance and illusory impressions from the movement of the body or the environment of the patient.

The causes of dizziness can be otogenic (as in the case of Meniere's syndrome), i.e. associated with an imbalance of the otovestibular apparatus and the labyrinth, toxic (for example, caused by drugs or alcohol), psychogenic, neurological, associated with blood circulation, tumors or vision (diplopia).

The treatment for dizziness obviously depends on its etiology, but currently symptomatic treatment is based on drugs such as dimenhydrinate, promethazine, and meclosin.

Dizziness is observed in 17-30% of adults in the general population. Distinguish vestibular dizziness (systemic dizziness, vertigo) and brides dizziness (non-systemic dizziness).

Vestibular dizziness

Vestibular dizziness in the broad sense may be due to organic changes in the central and peripheral structures of the vestibular apparatus.

Vestibular dizziness - about 24% of cases of dizziness (3-10% of adults in the general population) - is associated with damage to the peripheral (structure of the inner ear) or central (core and CNS pathways) link of the vestibular apparatus.

The prevalence of certain nosological forms (in% of adults in the general population) of vestibular dizziness: benign positional paroxysmal dizziness (DPPG) - 0.06-0.6% (a number of authors indicate up to 1.6%); Meniere's disease - 0.12-0.5%; vestibular migraine - 0.98%; lesions of the vestibular structures of the central nervous system (bridge, midbrain, cerebellum) that occur as a result of disturbances in the blood flow of the vertebrobasilar system, multiple sclerosis, neurodegenerative processes, and drug administration - about 5% of cases of vestibular dizziness.

Comorbidity of vestibular and mental (anxiety, depression) disorders is about 50%. Vertigo is more likely to be detected in women and people with migraines. The presence of vertigo can cause the secondary development of anxiety disorders.

In certain clinical conditions accompanied by vestibular dizziness, agents such as gentamicin (Meniere's disease) may be used; carbamazepine (vestibular paroxysm); acetazolamide, 4-aminopyridine (episodic ataxia type 2).

Symptomatic treatment of dizziness is aimed at stopping the manifestations of vestibular dysfunction. The main drugs are vestibulosuppressors and antiemetics: dimenhydrinate, metoclopramide, phenothiazines (fluorophenazine, thiethylperazine, thioridazine, promazine), benzodiazepine tranquilizers (nozepam, diazepam, hydazepam). Due to vomiting, these drugs are administered intramuscularly or in the form of suppositories. The duration of their use is dictated by the severity of dizziness. Usually it is limited to 3 days, since these drugs inhibit vestibular compensation.

Nevestibular dizziness

Non-vestibular (not associated with an organic lesion of the vestibular analyzer) dizziness - about 76% of dizziness cases - may be due to various diseases of the nervous system, manifested by instability (polyneuropathy, cerebellar ataxia, frontal dysbasia), cardiovascular disorders (fainting, orthostatic hypotension), but most often has a functional nature (persistent postural perceptual dizziness, previously - chronic subjective dizziness, phobic postural dizziness).

Functional (psychogenic) dizziness is one of the most common causes of dizziness complaints. In the general population, functional dizziness accounts for about 15-23% of dizziness [Brandt T., Dieterich M. Vertigo and dizziness: common complains. 2nd edn. Springer, London: 2013; Obermann M, Bock E, Sabev N et al. Long-term outcome of vertigo and dizziness associated disorders following treatment in specialized tertiary care: the Dizziness and Vertigo Registry (DiVeR) Study. // J. Neurol., 2015, 262 (9): 2083-2091]. Among patients younger than 45 years of age, functional dizziness takes first place among the causes of complaints of dizziness: it accounts for up to 38% of cases of dizziness [Zamergrad M.V. Age-related aspects of dizziness. // Neurological journal. 2014.V.19. Number 3. S.21-28]. In some cases, functional dizziness does not develop primarily, but as a result of any organic vestibular disorder. For example, functional dizziness is a common complication of common vestibular diseases such as benign paroxysmal positional dizziness and vestibular neuronitis.

Functional dizziness occurs as a result of a violation of the interaction between the vestibular, visual and somatosensory systems, which normally together provide spatial orientation. Dizziness can also be caused by physiological stimulation of normally functioning sensory systems or a mismatch between the information received from various sensory systems (motion sickness in a car, altitude dizziness and visually caused dizziness). Another example of functional dizziness is dizziness, which occurs due to too active movement of the head in zero gravity.

Dizziness, which develops in connection with psychological factors, is also defined as functional dizziness, as opposed to organic, arising from structural changes in organs. However, functional disorders are often preceded by organic ones, which increase the functional vulnerability of the organ in stressful situations. The concept of somatoform disorders, adopted in modern international classifications, provides for their diagnosis based on persistent complaints of patients in the absence of pathogenetically caused changes in organs. In essence, this concept is devoid of any significant psychopathological content [Veltishchev D.Yu., Seravina O.F. // Psychiatry, No. 4 (55), 2010].

A functional disorder is a state of health in which a normal physiological process is disturbed, but the pathology of any organ is not detected during the study. This contrasts with a structural disorder (in which it may be found that an organ is functioning abnormally) or a psychosomatic disorder (in which the symptoms are caused by a psychological or mental illness). Thus, it is important to note that functional dizziness is not a mental illness [Dieterich M., Staab J.P., Brandt T. Functional (psychogenic) dizziness // Handbook of Clinical Neurology, Vol. 139, Chapter 37, 2016, pp. 447-468], i.e. not caused by primary psychiatric pathology, such as anxiety disorder or depression, and also not caused by structural changes in the central nervous system.

Functional vestibular disorders include, in particular, the following diseases, described in detail in the neuro-otological literature: persistent postural perceptual dizziness, postural phobic instability, and chronic subjective dizziness. None of these disorders have a pathognomonic symptom or manifestation, but they all have key features that indicate their presence regardless of whether the patient has other diseases [Dieterich M., Staab JP, Brandt T. Functional (psychogenic) dizziness // Handbook of Clinical Neurology, Vol. 139, Chapter 37, 2016, pp. 447-468].

Ataxia is a neurological condition, manifested by a lack of coordination of movements, including gait disorders. Ataxia is a non-specific clinical manifestation involving dysfunction of parts of the nervous system that coordinate movement, such as the cerebellum. Ataxia can be limited to one side of the body. An example of a disease manifested by ataxia is Friedreich's disease.

Effective treatment options for degenerative ataxia are limited. Riluzole, amantadine and varenicline today have the best performance indicators.

There is evidence of the efficacy of acetyl-DL-leucine at a dose of 5 g per day in the symptomatic treatment of cerebellar ataxia [Harini Sarva and Vicki Lynn Shanker "Treatment Options in Degenerative Cerebellar Ataxia: A Systematic Review" Movement Disorders Clinical Practice, Volume 1, Issue 4, December 2014, Pages: 291–298].

Occasional ataxia (EA, familial periodic ataxia or hereditary paroxysmal cerebellar ataxia) is a rare hereditary disease inherited in an autosomal dominant manner. At least two groups of disorders were distinguished: (1) episodic ataxia type 1 (EA-1), which manifests itself without dizziness and is associated with myokimia and (2) episodic ataxia type 2 (EA-2), which is often accompanied by dizziness and is associated with nystagmus. EA-1 and EA-2 have been identified as canalopathies. EA-1 is due to various heterozygous point missense mutations in the voltage-dependent potassium channel delayed rectification (KCNA1 / Kv1.1) gene on chromosome 12p13, while EA-2 is caused by mutations in the P / Q-type CACNL1A4 subunit of the cerebral calcium channel subunit located on the 19p chromosome, which is significantly expressed in the cerebellum [Brandt T., Strupp M. Episodic ataxia type 1 and 2 (familial periodic ataxia / vertigo) Audiol. Neurootol. 1997; 2 (6): 373-83].

Treatment of episodic ataxia includes rehabilitation measures (special exercises to adapt the vestibular apparatus) and pharmacotherapy aimed at stopping the symptoms and achieving vestibular compensation.

Currently, pharmacotherapy of episodic ataxia is reduced to the appointment of acetazolamide and 4-aminopyridine (4-AP).

It has been suggested that the mechanism of action of acetazolamide is to reduce the pH, which prevents the penetration of ions through open calcium channels. Acetazolamide can stabilize channels that cannot be effectively inactivated. Acetazolamide may not work in cases where the mutation affects the pore region of calcium channels, eliminating the stabilizing effect of H ⁺ ions. 4-AR is a potassium channel blocker, and it is usually used when acetazolamide does not give a therapeutic effect [Yue Q, Jen JC, Nelson SF, Baloh RW. Progressive ataxia due to a missense mutation in a calcium channel gene. Am J. Hum. Gen, 1997 61 (5): 1078-87].

Existing Treatment Approaches

The drugs of choice for vestibular dizziness are vasoactive (cinnarizine, cinnarizine and piracetam), H ₁ antihistamines (dimenhydrinate) and vestibulotropic (betahistine).

Dimenhydrinate is characterized by a sedative effect and may have a negative effect on the processes of central vestibular compensation (from a clinical point of view, it is advisable to use a short course of 3 days, mainly to stop dizziness, nausea and vomiting in acute vestibulopathies).

Clinical studies evaluating the effectiveness of drug therapy in individual clinical variants of peripheral and central vestibular pathological conditions accompanied by dizziness are few, which limits the ability to present comparisons for individual classes of drugs / drugs from the standpoint of evidence-based medicine.

Unmet need is due to inadequate control of symptoms and the achievement of long-term goals of therapy in patients with various forms of peripheral and central vestibular dizziness, since available drugs treat only the symptoms of the disease and often slow down the process of vestibular compensation.

Thus, increasing the effectiveness of drugs aimed at treating various forms of dizziness is one of the acute problems of modern medicine, the solution of which is absolutely necessary to improve the quality of life of patients with dizziness.

Buspirone

Buspirone (and its pharmaceutically acceptable salt hydrochloride) is a partial 5-HT1A receptor agonist, which was launched more than 20 years ago by Bristol-Myers Squibb for the oral treatment of anxiety disorders with or without accompanying depression. In 1990, buspirone was launched by the company in collaboration with Menarini to treat generalized anxiety disorder (GAD). The National Cancer Institute (NCI) is currently evaluating the effectiveness of the drug in reducing shortness of breath in patients undergoing chemotherapy for cancer treatment. The National Institute of Neurological Disorders and Stroke (NINDS) is conducting phase II clinical trials regarding the use of buspirone for the treatment of localized epilepsy. The National Institute for Drug Abuse Control (NIDA) is conducting phase II clinical trials regarding the use of buspirone for the treatment and prevention of cocaine dependence.

Buspirone

Buspirone is an atypical anxiolytic that is highly effective against generalized anxiety disorder [Apter JT, Allen LA. Buspirone: future directions. J Clin Psychopharmacol. 1999; 19 (1): 86-93; Flint AJ. Generalized anxiety disorder in elderly patients: epidemiology, diagnosis and treatment options. Drugs Aging. 2005; 22 (2): 101-14; Gale CK, Millichamp J. Generalized anxiety disorder in children and adolescents. BMJ Clin Evid. 2016; 2016. pii: 1002; Goa KL, Ward A. Buspirone. A preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic. Drugs 1986 Aug; 32 (2): 114-29]. Partial 5-HT1A receptor agonist and D2 receptor antagonist [Loane C, Politis M. Buspirone: what is it all about? // Brain Res. 2012; 1461: 111-8; Newman-Tancredi A, Gavaudan S, Conte C, Chaput C, Touzard M, Verrièle L, Audinot V, Millan MJ. Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S] GTPgammaS binding study. Eur J Pharmacol. 1998; 355 (2-3): 245-56; Tunnicliff G. Molecular basis of buspirone's anxiolytic action. Pharmacol Toxicol. 1991; 69 (3): 149-56], buspirone, apparently, does not slow down the processes of vestibular compensation.

Buspirone differs from typical benzodiazepine anxiolytics in that it does not have an anticonvulsant or muscle relaxant effect. With its use, there is also no known sedative effect, which is associated with more typical anxiolytics. In vitro buspirone showed high affinity for serotonin receptors (5-HT1A). The drug has no significant affinity for benzodiazepine receptors and does not affect binding to GABA receptors in vitro or in vivo when tested in preclinical models. It exhibits a moderate affinity for dopamine D2 receptors in the brain. Some studies show that buspirone may have an indirect effect on other neurotransmitter systems.

Unlike benzodiazepines, the probable anxiolytic mechanism of action of buspirone remains unclear due to conflicting anxiolytic effects in the clinic and in studies using animal models [Bauer MS, Wisniewski SR, Marangell LB, Chessick CA, Allen MH, Dennehy EB, Miklowitz DJ , Thase ME, Sachs GS. Are antidepressants associated with new-onset suicidality in bipolar disorder? A prospective study of participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). J. Clin Psychiatry. 2006; 67 (1): 48-55].

Numerous studies indicate that in an acute experiment, the use of buspirone in rodents leads to anxiolytic action in a narrow and low dose range. This action varies greatly depending on the type of animal and the anxiety model used. At the same time, in a wide range of doses at high doses, the anxiogenic effect is manifested [Collinson N, Dawson GR. On the elevated plus-maze the anxiolytic-like effects of the 5-HT (1A) agonist, 8-OH-DPAT, but not the anxiogenic-like effects of the 5-HT (1A) partial agonist, buspirone, are blocked by the 5-HT1A antagonist, WAY 100635. Psychopharmacology (Berl). 1997; 132 (1): 35-43; de Oliveira Citó Mdo C1, da Silva FC, Silva MI, Moura BA, Macêdo DS, Woods DJ, Fonteles MM, de Vasconcelos SM, de Sousa FC. Reversal of cocaine withdrawal-induced anxiety by ondansetron, buspirone and propranolol. Behav Brain Res. 2012 May 16; 231 (1): 116-23; File SE, Andrews N. Low but not high doses of buspirone reduce the anxiogenic effects of diazepam withdrawal. Psychopharmacology (Berl). 1991; 105 (4): 578-82; Handley SL, McBlane JW. 5HT drugs in animal models of anxiety. Psychopharmacology (Berl). 1993; 112 (1): 13-20. Review Hestermann D, Temel Y, Blokland A, Lim LW. Acute serotonergic treatment changes the relation between anxiety and HPA-axis functioning and periaqueductal gray activation. Behav Brain Res. 2014; 273: 155-65; Inagaki H, Kiyokawa Y, Takeuchi Y, Mori Y. The alarm pheromone in male rats as a unique anxiety model: psychopharmacological evidence using anxiolytics. Pharmacol Biochem Behav. 2010; 94 (4): 575-9; Moser PC. An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone. Psychopharmacology (Berl). 1989; 99 (1): 48-53; Paine TA, Jackman SL, Olmstead MC. Cocaine-induced anxiety: alleviation by diazepam, but not buspirone, dimenhydrinate or diphenhydramine. Behav Pharmacol. 2002; 13 (7): 511-23; Shimada T, Matsumoto K, Osanai M, Matsuda H, Terasawa K, Watanabe H. The modified light / dark transition test in mice: evaluation of classic and putative anxiolytic and anxiogenic drugs. Gen Pharmacol. 1995; 26 (1): 205-10; Söderpalm B, Hjorth S, Engel JA. Effects of 5-HT1A receptor agonists and L-5-HTP in Montgomery's conflict test. Pharmacol Biochem Behav. 1989; 32 (1): 259-65; Varty GB, Morgan CA, Cohen-Williams ME, Coffin VL, Carey GJ. The gerbil elevated plus-maze I: behavioral characterization and pharmacological validation. Neuropsychopharmacology. 2002; 27 (3): 357-70].

The anxiogenic effect of buspirone is of great clinical significance due to the fact that an exacerbation may be observed at the initial stage of chronic treatment with buspirone, which requires careful monitoring of the treatment regimen [Chignon JM, Lepine JP. Panic and hypertension associated with single dose of buspirone. Lancet. 1989; 2 (8653): 46-7; Liegghio NE, Yeragani VK, Moore NC. Buspirone-induced jitteriness in three patients with panic disorder and one patient with generalized anxiety disorder. J Clin Psychiatry. 1988; 49 (4): 165-166; Newton RE, Marunycz JD, Alderdice MT, Napoliello MJ. Review of the side-effect profile of buspirone. Am J Med., 1986; 80 (3B): 17-21].

The affinity of buspirone for a complex of receptors may underlie its biphasic pharmacological effect [Tunnicliff G. Molecular basis of buspirone's anxiolytic action. Pharmacol Toxicol. 1991; 69 (3): 149-56]. Buspirone acts as a complete agonist of 5-HT1A autoreceptors located on the surface of the dendritic neurons of the suture nuclei, reducing the excitation of 5-HT neurons and thereby reducing the release of serotonin in this structure, and thereby activating other brain structures. This mechanism is believed to be partially responsible for the anxiolytic effect of buspirone [Carli M, Prontera C, Samanin R. Evidence that central 5-hydroxytryptaminergic neurones are involved in the anxiolytic activity of buspirone. Br J Pharmacol. 1989; 96 (4): 829-836; Adell A, Sarna GS, Hutson PH, Curzon G. An in vivo dialysis and behavioural study of the release of 5-HT by p-chloroamphetamine in reserpine-treated rats. Br J Pharmacol. 1989; 97 (1): 206-12; Sharp T, Bramwell SR, Grahame-Smith DG. 5-HT1 agonists reduce 5-hydroxytryptamine release in rat hippocampus in vivo as determined by brain microdialysis. Br J Pharmacol. 1989; 96 (2): 283-290; Sprouse JS, Aghajanian GK. Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse. 1987; 1 (1): 3-9].

However, buspirone also has the activity of a postsynaptic 5-HT1A receptor agonist, thereby reducing neuronal excitation. These opposite effects may cause the biphasic anxiety-modulating effect of buspirone [Sillar KT1, Simmers AJ. Presynaptic inhibition of primary afferent transmitter release by 5-hydroxytryptamine at a mechanosensory synapse in the vertebrate spinal cord. J Neurosci. 1994; 14 (5 Pt 1): 2636-47; McNaughton N, Panickar KS, Logan B. The pituitary-adrenal axis and the different behavioral effects of buspirone and chlordiazepoxide. Pharmacol Biochem Behav. 1996; 54 (1): 51-56; Hodges H, Green S, Glenn B. Evidence that the amygdala is involved in benzodiazepine and serotonergic effects on punished responding but not on discrimination. Psychopharmacology (Berl). 1987; 92 (4): 491-504].

The use of buspirone for palliative treatment of neurosis, in which symptoms of anxiety are manifested, is known from the prior art (US 4182763, January 8, 1980); with hyperactivity, attention deficit (EP 0497314, 03/01/1989); for the treatment of drug addiction and dependence (US 5185329, 02/09/1993); for the treatment of anxiety disorders (WO 2005049041, 02/02/2005; US 7678363, 03/16/2010); psychiatric disorders (US 7678363, March 16, 2010); depression (WO 2007144080, 12/21/2007); neurological disorders (WO 2008083204, 07/10/2008).

The systemic use of buspirone or its derivatives for the treatment of pathological conditions associated with immune responses is known (EP0690715, 05.28.2003); for the treatment of disorders of sexual function and reproduction (US 8052982, 08/08/2011) and sexual dysfunction (US 4640921, 02/03/1987); for the treatment of sleep-related respiratory diseases (WO 2000006163, 02.10.2000). The use of buspirone for the treatment of glaucoma (US 7763619, 07/27/2010), pain, neuropathy (US 6511982, 01/28/2003), pruritus (WO 2004084900, 10/07/2004), for the treatment, prevention or alleviation of motor disorders such as Parkinson's disease is known. dyskinesia (US 9186359, 11/17/2015); for injuries of the spinal cord, multiple sclerosis, Parkinson's disease (WO 2015127558, 09/03/2015); apnea (EP 0442424, 12/21/1994), as well as incontinence (WO 1996005817, 02.29.1996), nausea, vomiting (WO 2008149062, 12/11/2008), hot flashes (WO 2011064769, 06/03/2011), autism spectrum disorders ( US 2012108510, May 19, 2011).

Betahistine

Betagistin, an H3 antagonist and weak agonist of H1 histamine receptors, enhances cochlear blood flow, affects the activity of vestibular neurons, changes the production of endolymph in the labyrinth, and therefore the effects of the drug can be expected mainly with dizziness against the background of lesions of the peripheral link of the vestibular analyzer.

betahistine

So a double-blind, cross-over, placebo-controlled study of betahistine dihydrochloride (12 mg) was performed in patients with dizziness of peripheral vestibular origin. Twenty-four patients underwent a study that consisted of two six-week treatment periods. Patients were diagnosed as suffering from Meniere's disease (15 patients), dizziness due to other (indicated) reasons (five patients), or dizziness of unknown origin (four patients). Patients were examined at the beginning of the study and reassessed with an interval of three weeks. In addition, patients recorded the nature, frequency, and severity of their symptoms in a diary. It was found that both episodes of the disease and the severity of dizziness (prevailing complaints) are significantly reduced during treatment with betahistine (p = 0.004). The occurrence of nausea and vomiting was also significantly reduced during treatment with betahistine (p = 0.014 and 0.036, respectively). There were no statistically significant differences in the results of audiometric or vestibulometric tests between the two treatment periods. A general comparison of the two periods, conducted by both patients and the researcher, was significantly favorable for betahistine (p <0.001). All diagnostic groups responded positively to betahistine, confirming the effectiveness of betahistine in the symptomatic treatment of peripheral vestibular dizziness [Oosterveld WJ. Betahistine dihydrochloride in the treatment of vertigo of peripheral vestibular origin. A double-blind placebo-controlled study. J Laryngol Otol. 1984; 98 (1): 37-41].

Piracetam

Piracetam is a nootropic drug, one of the main representatives of this group of drugs, it remains one of the most important in it. It is chemically a pyrrolidone derivative.

2-oxo-1-pyrrolidinacetamide (piracetam)

Piracetam binds to the polar heads of phospholipids and forms mobile complexes of piracetam-phospholipid. As a result, the two-layer structure of the cell membrane and its stability are restored, which in turn leads to the restoration of the three-dimensional structure of membrane and transmembrane proteins and the restoration of their function.

At the level of neurons, piracetam facilitates various types of synaptic transmission, exerting a predominant effect on the density and activity of postsynaptic receptors (data obtained in animal studies). Improves connections between the hemispheres of the brain and synaptic conduction in neocortical structures, improves cerebral blood flow. It has an effect on the central nervous system in various ways: modifies neurotransmission in the brain, improves metabolic conditions conducive to neuronal plasticity, improves microcirculation, affecting the rheological characteristics of the blood. With cerebral dysfunction, it increases concentration and improves cognitive functions, including learning ability, memory, attention and consciousness, mental performance, without having a sedative or psycho-stimulating effect. The use of piracetam is accompanied by significant changes in the EEG (increase in α- and β-activity, decrease in δ-activity). It helps to restore cognitive abilities after various cerebral injuries due to hypoxia, intoxication or electroconvulsive therapy, with encephalopathic disorders, memory disorders, intellectual deficiency, etc., can be used to reduce the manifestations of hypoxia and cerebral ischemia in acute viral neuroinfections [Niss A.I., Umansky K.G. et al. On the effectiveness of piracetam treatment of acute viral neuroinfections. // Journal. neuropathol. and a psychiatrist. - 1985. No. 2. S. 189-195].

In neurological practice, it is prescribed for cerebral atherosclerosis, vascular parkinsonism and other diseases with the phenomena of chronic cerebrovascular insufficiency, manifested in impaired memory, attention, speech, dizziness, etc. [Veselsky I. Sh., Voronyuk M. I. Influence of piracetam on central hemodynamics in patients with atherosclerosis with dyscirculatory encephalopathy. // Clinical medicine. - 1986. No. 6. P. 41-44], as well as with changes in cerebral circulation, with coma and subcomatous conditions after brain injuries [Sharava EV, Potapov AA, Kulikov MA The effect of piracetam on the functional activity of the brain in patients with traumatic brain injury. // Journal. neuropathol. and a psychiatrist. - 1988. No. 5. P. 42-48] and intoxication, as well as during recovery therapy after such conditions [Enina G.I., Timofeeva T.N. Piracetam and indicators of cerebral hemodynamics, lipid metabolism and rheological properties of blood in the initial forms of cerebrovascular accident. // Journal. neuropathol. and a psychiatrist. - 1990. No. 11. S. 20-23]. Piracetam is also used for diseases of the nervous system, accompanied by a decrease in intellectual-mnestic functions and disorders of the emotional-volitional sphere.

In psychiatric practice, piracetam is used in patients with neurotic and asthenoadynamic depressive states of various origins with a predominance of signs of adynamia, asthenic and senesto-hypochondriacal disorders, phenomena of idiopathic inhibition, as well as sluggish apathic defective conditions in patients with schizophrenia, various psychoanalysis, and various senile and atrophic processes, in the complex therapy of various mental illnesses. Piracetam can also be used as an adjuvant in the treatment of patients with depressive states that cannot be treated with antidepressants, as well as with poor tolerance of antipsychotics and other psychotropic drugs in order to eliminate or prevent somatovegetative, neurological and psychological complications caused by them.

The therapeutic properties of piracetam are determined by its ability to enhance the integrative activity of the brain and intellectual activity, promote memory consolidation, improve learning processes, restore and stabilize brain functions, including in the elderly and senile [L. Pimenov, S. A. Kalinina ., Churshin A.D. Clinical and hemodynamic efficacy of piracetam (nootropil) in patients with coronary heart disease in the elderly and senile at the outpatient stage of rehabilitation. // Cardiol. - 1992. No. 5. S. 35-38]. When taking, an increase in the action of antianginal drugs, a decrease in the need for nitroglycerin, a regression of signs of heart failure [Pimenov L.T., Churshin A.D., Yezhov A.V. About the ability of piracetam and tocopherol acetate to potentiate the clinical effectiveness of antianginal drugs in patients with coronary heart disease. // Wedge. honey. - 1997. No. 1. S. 32-35].

Piracetam is also used to relieve withdrawal, pre-lirious and delirious conditions in cases of alcoholism and drug addiction, as well as in cases of acute poisoning with alcohol, morphine, barbiturates, etc. The use of piracetam in the complex of drugs for the relief of acute phenomena of alcohol withdrawal reduces the severity of cerebral vascular disorders, reduces dizziness, a feeling of apathy, drowsiness [Entin G. M. Treatment of alcoholism. - M .: Medicine, 1990]. In chronic alcoholism, piracetam is prescribed to reduce the phenomena of asthenia, intellectual-mnestic and other disorders of mental activity.

Piracetam is characterized by very low toxicity, LD ₅₀ for rats is 10.6 g / kg when administered intravenously [AH Gouliaev, A Senning Piracetam and other structurally related nootropics // Brain Research. Brain Research Reviews. - 1994. No. 19 (2). S. 180-222].

In studies on healthy volunteers, piracetam reduced erythrocyte adhesion to vascular endothelium and stimulated the production of prostacyclins in the endothelium. Animal studies have shown that piracetam inhibits vascular spasm and is antagonistic to the action of various vasospastic substances.

In an open multicenter study, 5306 patients (aged 14-96 years) with signs of cerebrovascular insufficiency were treated with piracetam (1200 mg / day) for 4 weeks. Subsequently, 42 patients younger than 45 years old and 270 patients receiving additional therapy were excluded from the analysis. After 4 weeks of piracetam therapy, a general improvement was noted in 88% of patients, no changes in 11.5%, and worsening in 0.5%. The number of patients with dizziness decreased from 3265 to 960 (an improvement of 70.6%), with a decrease in motivation - from 3803 to 1185 (68.8%), with severe fatigue - from 4255 to 1474 (65.4%), with depression - from 2238 to 830 (62.9%), with a decrease in concentration of attention - from 4676 to 1759 (62.4%), with a decrease in adaptation - from 1566 to 623 (60.2%), with tinnitus - from 2064 to 888 (57%), with a decrease in perception - from 4518 to 2086 (53.8%), with sleep disturbance - from 3024 to 1690 (44.1%). The drug tolerance was rated as very good: only 339 (6.6%) patients had minor side effects - sleep disturbances, gastrointestinal upsets, agitation, headaches.

Similar data were obtained during another multicenter study, which evaluated the effectiveness of piracetam in 11654 patients, the average age of which was 64 years. More than 70% of patients had impaired memory. Other disorders were dizziness (650 patients), hypertension (423), headaches (320), and depression (213). Piracetam treatment was carried out for 90 days in various dosages: patients under 60 took 2 capsules 3 times a day (2400 mg / day), patients over 60 took a drinking solution of 1 g three times a day (3 g / day) . Patients were examined before starting therapy, on the 45th and 90th day of treatment. The results of the study showed the high effectiveness of piracetam: 70% of doctors and 90% of patients noted positive effects of the drug and only 7% of patients complained of side effects [Avedisova A.S., Akhapkin R.V., Akhapkina V.I., Verigo N.N. . Piracetam in the light of modern research (analysis of foreign studies) // Psychiatry and psychopharmacotherapy. - 2000. T. 2. No. 6. S. 178-84].

In this case, to date, it is not known to use the combined buspirone with betahistine and buspirone with piracetam for the treatment of dizziness.

The following are definitions of terms that are used in the description of the present invention.

“Medicinal product (preparation)” - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology.

"Pharmaceutical composition" means a composition comprising a combination according to the invention and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, dispersants, delivery vehicles, such as preservatives, stabilizers, fillers, disintegrants, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterials tal agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on their nature, method of administration of the composition and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, such as parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, such as aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of disintegrating and dispersing agents are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium and calcium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds, or obtained on purpose. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, fumarates, succinates, tartrates, mesylates malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like, preferably hydrochlorides and maleates (A detailed description of the properties of such salts is given in Berge SM, et al., “Pharmaceutical Salts” // J. Pharm. Sci. 1977, 66 : 1-19). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like. In addition, tetraalkylammonium hydroxides, choline, tetramethylammonium, tetraethylammonium and the like can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

More preferably, in the present invention, the pharmaceutically acceptable salt of buspirone is buspirone hydrochloride; preferred pharmaceutically acceptable salts of betahistine are dihydrochloride, maleate, mesylate, betahistine dimesilate.

The term “treatment” means any treatment for a disease or condition in a subject, including 1) suppressing the development of a disease or condition, which means stopping or suppressing the development of clinical symptoms, and / or 2) reducing the intensity of the symptoms of the disease or condition, which means regression of clinical symptoms.

The term “therapeutically effective amount” means an amount of a combination of the compounds of the present invention or any derivatives thereof that (1) treats or prevents a particular disease, condition or disorder, (2) alleviates, improves or eliminates one or more symptoms of a particular disease, condition or disorder , or (3) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder set forth herein.

The term "pharmaceutically acceptable" means that the substance or composition to which this term is applied must be compatible, in terms of chemistry and / or toxicology, with the other ingredients that make up the drug, and is safe for anyone who is being treated with this substance or composition, in applicable doses.

The terms "comprising", "contains" means that these combinations, compositions and kits include the listed components, but do not exclude the inclusion of other components.

The authors of the present invention have found that the use of buspirone in combination with at least one substance selected from the group consisting of betahistine and piracetam, gives an unexpected synergistic effect in the treatment of vestibular and bribery dizziness.

Technical Results:

- expansion of the arsenal of drugs for the treatment of vestibular and brides dizziness;

- increased efficiency in reducing bridesmaid dizziness due to the synergistic effect of a combination of betahistine and piracetam.

The task is carried out, and the technical result is achieved by obtaining a combination for the treatment of vestibular and brides dizziness, containing in effective amounts (a) buspirone and (b) at least one substance selected from the group comprising betahistine and piracetam, or their pharmaceutically acceptable salts .

According to preferred embodiments, the specified technical result is also achieved by the fact that:

- a pharmaceutically acceptable salt selected from the group consisting of buspirone hydrochloride and betahistine dihydrochloride;

- active substances are administered in daily dosages:

buspirone - 5 - 100 mg / day;

betahistine - 16 - 1440 mg / day;

piracetam - 200 - 6000 mg / day;

- the introduction of the mentioned combination is carried out by injection;

- the introduction of the said combination is administered orally.

The task is also carried out, and the technical result is achieved by obtaining a pharmaceutical composition for the treatment of vestibular and brides dizziness, containing in effective amounts a combination of (a) buspirone and (b) a substance selected from the group comprising betahistine and piracetam, or their pharmaceutically acceptable salts, and at least one excipient and / or at least one pharmaceutically acceptable carrier.

According to preferred embodiments, the specified technical result is also achieved by the fact that:

- a pharmaceutically acceptable salt selected from the group consisting of buspirone hydrochloride and betahistine dihydrochloride;

- active substances are administered in daily dosages:

buspirone - 5 - 100 mg / day;

betahistine - 16 - 1440 mg / day;

piracetam - 200 - 6000 mg / day.

- active substances are included in mass ratios:

Buspirone: betahistine from 1: 288 to 6.25: 1;

buspirone: piracetam from 1: 1200 to 1: 2.

- the introduction of the above pharmaceutical composition is administered orally.

The task is also carried out, and the technical result is achieved by obtaining a kit for the treatment of vestibular and brides dizziness, containing instructions for use and a pharmaceutical composition containing in an effective amount of buspirone or its pharmaceutically acceptable salt, at least one excipient and / or at least one a pharmaceutically acceptable carrier and a pharmaceutical composition comprising in an effective amount of at least one substance selected from a group comprising betahistine and piracetam, or a pharmaceutically acceptable salt thereof, at least one excipient and / or at least one pharmaceutically acceptable carrier.

The subject of the present invention is also the use of a combination of either a pharmaceutical composition or a kit of the present invention for the treatment of vestibular and bridy dizziness.

The task is also carried out, and the technical result is achieved by using the aforementioned combination or the said pharmaceutical composition, or the said kit for the treatment of vestibular and bridy dizziness.

According to preferred embodiments, the specified technical result is also achieved by the fact that:

- the introduction of said combination or said pharmaceutical composition or said kit is administered orally;

- the introduction of said combination or said pharmaceutical composition or said kit is carried out by injection;

- active substances in the composition of said combination, said pharmaceutical composition or said kit are administered in dosages:

Buspirone - 5-100 mg / day;

betahistine - 16-1440 mg / day;

piracetam - 200-6000 mg / day.

The combination, composition or kit of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally). The clinical dosage of the agent of the present invention in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients, their metabolic rate and excretion from the body, as well as on the age, gender and stage of the patient’s disease, with a daily dose in adults usually of 5 - 100 mg of buspirone, 16 - 1500 mg of betahistine and 200 - 6000 mg of piracetam. Therefore, when using the combination, composition or kit of the present invention as dosage units, the above effective dosage should be taken into account, with each dosage unit containing 5-100 mg buspirone and 16-1,500 mg betahistine and / or 200-6000 mg piracetam. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

The following examples illustrate but do not limit the invention.

Example 1. Evaluation of the effectiveness of drugs with vestibular dizziness.

Symptoms similar to those of vestibular dizziness are observed in rats that have lost vestibular function as a result of unilateral labyrinectomy. The loss of vestibular function in this case is not complete and irreversible: normally, vestibular compensation begins to occur over time.

Rats: In the experiments, adult Spreg-Dawley rats were used, having a body weight of 370-400 grams. Rats were kept in temperature-controlled boxes (with a temperature of 21 ° C) with a 12-hour cycle of day and night and plenty of water and food.

Formation of study groups: 160 Sprague-Dawley rats were randomly assigned to 16 groups of equal composition (N = 10), differing in the type of drug administered and the dosage. Formed groups of rats are briefly described in table 1 below.

Dosage and administration: The study was carried out for 3 drugs (buspirone, betahistine, piracetam), each of which was administered in 3 different doses, and for 2 combinations (buspirone + betagistin, buspirone + piracetam), each of which was also administered in three doses. The control was a group of rats receiving only the vehicle (placebo group). Dosage information is given in table 1 below. All drugs were administered intravenously (in the tail vein) 30 minutes before surgery and then once a day for the entire duration of the study. All doses are calculated per person.

Table 1. Study groups formed by the types of drugs and dosages administered.

(N = 10 rats in each group) carrier only Buspirone mg / day 5 fifty one hundred carrier only group number 1 (placebo) group number 2 group number 3 group number 4 Betahistine
mg / day 16 group number 5 group number 9 720 group number 6 group number 10 1440 group number 7 group number 8 Piracetam
mg / day 200 group number 11 group number 15 2400 group number 12 group number 16 6000 group number 13 group number 14

Surgery: A unilateral labyrinthectomy was performed as described previously [Park BR, Suh JS, Kim MS, et al. Effect of sensory deprivation or electrical stimulation on acute vestibular symptoms following unilateral labyrinthectomy in rabbit. Acta Otolaryngol Suppl 1995; 519: 162Y7]. Briefly, rats were anesthetized with isoflurane (Sigma), after which the auditory ossicles in the middle ear cavity were removed to allow access to the oval window. A small hole was made around the oval window using a surgical microscope. The membranous labyrinth was surgically removed through this opening using a small rectangular hook. The success of the operation was indicated by the appearance of spontaneous nystagmus, impaired motor ability and coordination after recovery from anesthesia.

Assessment of motor activity: was carried out in an open field according to the method described by [Drago F, Nardo L, Rampello L, Raffaele R. Vestibular compensation in aged rats with unilateral labyrinthectomy treated with dopaminergic drugs. Pharmacol Res. 1996; 33 (2): 135-140], with slight modifications. Rats were placed inside a circular illuminated platform (20 cm in diameter, 35 cm high), the bottom of which was divided into 27 zones of the same size. The behavior of each animal was monitored for 3 minutes and the number of zones in which the animals were located at least with their forelimbs (horizontal locomotor activity), as well as the number of episodes when the animals stood on their hind legs (vertical locomotor activity with the forepaws kept on weight) were recorded .

Assessment of coordination: the ability to coordinate and perform actions was evaluated using a rotating rod test. Rats were placed on a cylindrical rod (7 cm in diameter), the rotation speed of which was increased during the experiment from 4 to 40 revolutions per minute. Then, for 300 seconds, the time until the first fall was recorded for each animal. In this format, the test was repeated three times with an interval of 30 minutes. The results of all tests for each animal received a single estimate - the average number of seconds before the fall.

Assessment of motor activity and coordination was performed on the 5th, 7th and 9th day after the operation.

Formation of a general assessment for the group: according to the test results for each group, a single assessment was formed, which is the arithmetic average of individual estimates for ten animals in the group. Thus, each group received a set of 6 ratings: an assessment of locomotor activity on the 5th, 7th, and 9th days after the operation and a coordination assessment on the 5th, 7th, and 9th days after the operation. All data are shown in tables 2 and 3.

^# , ^* , ^$ - a significant difference from the expected (calculated) additive effect of the combination of buspirone + betahistine, calculated on the basis of the effects of buspirone and betahistine separately, at each dose level for each time point (significance level p <0.05) .

^# , ^* , ^$ - significant difference from the expected (calculated) additive effect of the combination of buspirone + piracetam, calculated on the basis of effects from the use of buspirone and piracetam separately, at each dose level for each time point (significance level p <0.05) .

Statistical analysis: statistical differences between groups were evaluated using paired t-student test (at a significance level of p <0.05).

Results: In general, the functional state of the animals, recorded in the first week after surgery, was better in the groups receiving any drug, compared with the placebo group, which was administered only the carrier. The groups receiving the combination of drugs on the 5th and 7th day showed the highest recovery rates, significantly different from the mono-administration and placebo groups. Moreover, the observed effect was super-additive at each concentration level.

Conclusions: thus, a synergistic effect was shown for the combinations of buspirone + betahistine, buspirone + piracetam when administered in the indicated doses.

Example 2. Evaluation of the effectiveness of drugs in reducing brides dizziness.

Non-vestibular dizziness can be modeled for rodents under rotation for a predetermined period of time.

Rats: the study involved adult Sprague-Dawley rats having a body weight of 350-370 grams. Rats were kept in temperature-controlled boxes (with a temperature of 21 ° C) with a 12-hour cycle of day and night and plenty of water and food.

Formation of study groups: 160 Sprague-Dawley rats were randomly assigned to 16 groups of equal composition (N = 10), differing in the type of drug administered and the dosage. Formed groups of rats are briefly described in table 1 above.

Dosage and administration: The study was carried out for 3 drugs (buspirone, betahistine, piracetam), each of which was administered in 3 different doses, and for 2 combinations (buspirone + betagistin, buspirone + piracetam), each of which was also administered in three doses. The control was a group of rats receiving only the vehicle (placebo group). Dosage information is given in table 1 above. All drugs were administered intravenously (in the tail vein) daily for a week before the start of testing. All doses are calculated per person.

Equipment: The test is based on maintaining equilibrium with rats on a narrow bar raised above the ground (width 3 cm, length 1 m). Preliminarily, for 2 minutes, the rats were rotated at a speed of 50 rpm in a closed compartment, after which they were moved to a narrow bar, brightly lit at the start, and the animals were monitored for 120 seconds. In this format, the experiment was repeated three times with an interval of 30 minutes.

Assessment of equilibrium control by animals: carried out by counting the number of falls from the bar and misses when moving along it for each animal. Further, for the group, a general score is formed, which is the arithmetic mean of all individual ratings.

Statistical analysis: statistical differences between groups were evaluated using paired t-student test (at a significance level of p <0.05).

Results: The data obtained are shown in tables 4 and 5. The combination of buspirone with any of the claimed drug significantly reduced functional dizziness in rats compared with placebo and the corresponding mono-administration groups. Moreover, for the tested combinations when administered in the indicated doses, a synergistic effect of their action was observed (Tables 4 and 5).

Table 4. The effect of buspirone and betahistine, used individually or in combination, on the ability to maintain balance when modeling the conditions for the appearance of brides dizziness.

Treatment Group
No. Balance Control Assessment
(number of falls and misses) A drug mg / day (arithmetic mean of individual ratings in the group, art. deviation) Placebo - one 13.3 (0.67) Buspirone 5 2 10.5 (0.73) fifty 3 10.1 (0.53) one hundred four 9.7 (0.89) Betahistine 16 5 9.8 (0.69) 720 6 9.9 (0.82) 1440 7 8.9 (1.1) Buspirone + betahistine 100 + 1440 8 4.9 (0.50) ^* 5 + 16 9 5.5 (0.90) ^# 50 + 720 10 5.1 (0.60) ^$

^# , ^* , ^$ - a significant difference from the expected (calculated) additive effect of the combination of buspirone + betahistine, calculated on the basis of effects from the use of buspirone and betahistine separately, at each dose level (significance level p <0.05).

Table 5. The effect of buspirone and piracetam, used individually or in combination, on the ability to maintain balance when modeling the conditions for the appearance of brides dizziness.

Treatment Group
No. Balance Control Assessment
(number of falls and misses) A drug mg / day (arithmetic mean of individual ratings in the group, art. deviation) Placebo - one 13.3 (0.67) Buspirone 5 2 10.5 (0.73) fifty 3 10.1 (0.53) one hundred four 9.7 (0.89) Piracetam 200 eleven 11.9 (0.85) 2400 12 11.1 (0.60) 6000 13 10.5 (0.75) Buspirone + Piracetam 100 + 6000 fourteen 5.2 (0.50) ^# 5 +200 fifteen 5.0 (0.90) ^* 50 + 2400 16 5.7 (0.50) ^$

^# , ^* , ^$ - a significant difference from the expected (calculated) additive effect of the combination of buspirone + piracetam, calculated on the basis of effects from the use of buspirone and piracetam separately, at each dose level (significance level p <0.05).

Example 3. Obtaining a drug in the form of tablets. 1600 mg of starch, 1600 mg of ground lactose, 400 mg of talc are mixed with a combination of 64 mg of buspirone and 936 mg of betahistine or a combination of 20 mg of buspirone and 980 mg of piracetam and pressed into a block. The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 500 mg each.

Example 4. Obtaining a drug in the form of capsules. A combination of 64 mg of buspirone and 936 mg of betahistine or a combination of 20 mg of buspirone and 980 mg of piracetam and lactose powder in a ratio of 2: 1 are thoroughly mixed. The resulting powder mixture is packed into 300 mg gelatin capsules in a suitable size.

Example 5. Obtaining a medicinal product in the form of injection compositions for intramuscular, intraperitoneal or subcutaneous injection. A combination of 32 mg of buspirone and 468 mg of betahistine or a combination of 10 mg of buspirone and 490 mg of piracetam are mixed with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water. The resulting solution is filtered and placed in 1 ml ampoules, which are sealed.

The invention can be used in medicine, pharmacology.

Claims (19)

1. A combination for the treatment of vestibular and bribery dizziness, containing in effective amounts (a) buspirone and (b) at least one substance selected from the group comprising betahistine and piracetam or their pharmaceutically acceptable salts, while the active substances are intended for administration in daily dosages: Buspirone - 5-100 mg / day; betahistine - 16-1440 mg / day; piracetam - 200-6000 mg / day. 2. The combination of claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of buspirone hydrochloride and betahistine dihydrochloride. 3. The combination according to claim 1, characterized in that the introduction of the said combination is carried out by injection. 4. The combination according to claim 1, characterized in that the introduction of the said combination is carried out orally. 5. A pharmaceutical composition for the treatment of vestibular and bribery dizziness, containing in effective amounts a combination according to any one of paragraphs. 1 or 2 and at least one excipient and / or at least one pharmaceutically acceptable carrier. 6. The composition according to p. 5, characterized in that the active substances are in mass ratios: Buspirone: betahistine from 1: 288 to 6.25: 1; buspirone: piracetam from 1: 1200 to 1: 2. 7. The composition according to p. 5, characterized in that the introduction of the composition is carried out orally. 8. A kit for treating vestibular and brides dizziness, characterized in that said kit contains instructions for use and a pharmaceutical composition comprising buspirone or a pharmaceutically acceptable salt thereof, at least one excipient and / or at least one pharmaceutically acceptable carrier, and a pharmaceutical composition comprising at least one substance selected from the group consisting of betahistine and piracetam or a pharmaceutically acceptable salt thereof, at least one a excipient and / or at least one pharmaceutically acceptable carrier, while the active substances are intended for administration in daily dosages: Buspirone - 5-100 mg / day; betahistine - 16-1440 mg / day; piracetam - 200-6000 mg / day. 9. The use of a combination according to claim 1, a pharmaceutical composition according to claim 5 or a kit according to claim 8 for the treatment of vestibular and bridesmaid dizziness. 10. The use according to claim 9, characterized in that the administration of the combination according to claim 1, the composition according to claim 5, or the kit according to claim 8, is administered orally. 11. The use according to claim 9, characterized in that the introduction of a combination according to claim 1, a composition according to claim 5 or a kit according to claim 8, is carried out by injection.