WO2019035741A1 - Use of buspirone for treating functional dizziness - Google Patents

Abstract

The invention relates to the field of medicine and pharmacology, and specifically to a novel use of buspirone or a pharmaceutically acceptable salt thereof for treating functional dizziness, persistent postural-perceptual dizziness (PPPD), phobic postural vertigo (PPV), and chronic subjective dizziness (CSD), the effect of the invention lying in the possibility of treating functional dizziness that is independent of depressive and anxious states, a clinically optimal speed of onset of therapeutic action, ease of dose titration, a lack of a sedative effect, and a favorable safety profile.

Description

 Use of Buspirone for the treatment of functional dizziness

The invention relates to the field of medicine, pharmacology, namely, the new use of buspirone or its pharmaceutically acceptable salt for the treatment of functional dizziness, persistent postural perceptual dizziness (PPPD), postural phobic instability (PFN, PPV), chronic subjective dizziness (CSH, CSD), the effect of which lies in the possibility of treating functional dizziness, which is not dependent on depressive and anxious states, the rapid onset of the therapeutic effect, titration of the dose, the absence of sedation and a favorable safety profile.

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

 Functional vertigo results from a disruption in the interaction between the vestibular, visual, and somatosensory systems, which normally jointly provide spatial orientation. Dizziness can also be caused by physiological stimulation of normally functioning sensory systems.

This type of vertigo develops when: - there is a discrepancy between the information coming from the three systems - vestibular, visual and somatosensory;

 - the vestibular apparatus is subjected to unusual influences, for example, when rolling;

 - the head or neck is placed unusually, for example, when over-bending during the painting of the ceiling.

 The discrepancy between the information coming from different sensory systems, due to rocking in the car, high-altitude dizziness and visually caused dizziness. The latter most often occurs when watching movies with chase scenes, when the visual sensation of movement is not accompanied by corresponding vestibular and somatosensory stimuli.

 Another example of functional vertigo is vertigo, which is caused by too active movement of the head in zero gravity.

 Dizziness, developing due to psychological factors, is also defined as functional dizziness, as opposed to organic, arising from structural changes in organs. However, functional impairment is often preceded by organic, which increase the functional vulnerability of the body in stressful situations. The concept of somatoform disorders, adopted in modern international classifications, provides for their diagnosis based on the persistent complaints of patients in the absence of pathogenetically determined changes in organs. Essentially, this concept is devoid of any significant psychopathological content [Veltischev D.Yu., Seravina OF // Psychiatry, N ° 4 (55), 2010].

 The following diagnostic criteria were proposed for the diagnosis of functional vertigo [Brandt T., Huppert D., Dieterich M. Phobic postural vertigo: a first follow-up II J Neurol. 1994. V.241. N.4. p.191 -195]:

1) dizziness of a non-systemic nature that occurs when standing or walking; neurological examination, including Romberg's test, tandem walking, standing on one leg, does not reveal deviations from the norm; 2) constant, then growing, then weakening sense of instability or short-term (several seconds or minutes) sensations of coordination disorder;

 3) attacks of vertigo may occur spontaneously, but often develop in a particular situation (on the bridge, on the stairs, in an empty room or on the street, in a store, in a crowd, in a restaurant or at a concert); characterized by a tendency to the rapid consolidation of negative associations and the desire to avoid provoking circumstances;

 4) anxiety and autonomic disorders develop during and after dizziness, with attacks with anxiety and without it can alternate;

 5) tendency to obsessive states, mild depression;

 6) the onset of the disease usually coincides with stress, a serious illness or an organic disease of the vestibular system.

 Often, in patients with functional dizziness, poor tolerance of vestibular stimuli has been noted since childhood, which gives grounds for some authors to link the patient's feelings with certain disorders in the vestibular system [Furman J.M., Jacob R.G. Psychiatric dizziness II Neurology. 1997. Vol. 48. pp. 1161-1166].

 A functional disorder is a health condition that impairs the normal function of the bodily process, but where each part of the body looks completely normal in the study. This contrasts with a structural disorder (in which one can see that some part of the body is not functioning normally) 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 psychiatric disease [Dieterich M., Staab J.P., Brandt T. Functional (psychogenic) dizziness II Handbook of Clinical Neurology, Vol. 139, Chapter 37, 2016, pp. 447-468], i.e. It is not caused by primary psychiatric disorders, such as anxiety disorder or depression, and is also not caused by structural changes in the central nervous system.

The functional and mental disorders that cause vestibular symptoms are treated separately from each other and from structural vestibular diseases. This is due to the fact that the experimental data show that they occur independently [Brandt T. Phobic postural vertigo II Neurology. 1996; 46: 1515-9; Staab JP, Ruckenstein MJ Which comes first? Psychogenic dizziness versus otogenic anxiety II Laryngoscope 2003, 113: 1714-1718; Staab JP, Ruckenstein MJ, Expanding the differential diagnosis of dizziness. II Arch. Otolaryngol. Head Neck Surg., 2007, 13: 170- 176; Eckhardt-Henn A, Best C, Bense S et al., Psychiatric comorbidity in different organic vertigo syndromes II J. Neurol., 2008, 255: 420-428]. Therefore, it is necessary to recognize their separate contribution to the pathology of the vestibular system. Psychiatric disorders that cause vestibular symptoms are determined by the appropriate diagnostic criteria in ICD-10 (WHO, 1993), and the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5: American Psychiatric Association, 2013).

 Functional vertigo is a functional disorder characterized by vestibular symptoms. The term "vestibular symptoms" is used to refer to dizziness, instability, and vertigo in combination. This is consistent with the nomenclature proposed by the Committee for the Classification of Vestibular Disorders of the Barany Society [Bisdorff A, von Brevern M, Lempert T et al. Classification of vestibular symptoms: towards an international classification // J. Vestib. Res., 2009, 19 (1- 2): 1-13], which additionally identified dizziness as a false or distorted sensation of movement, non-stationarity, as a feeling of swinging or swinging in a vertical position, a real feeling of disordered spatial orientation.

 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 other diseases are active [Dieterich M., Staab JP, Brandt T. Functional (psychogenic) dizziness II Handbook of Clinical Neurology, Vol. 139, Chapter 37, 2016, pp. 447-468].

One of the subtypes of functional vertigo is persistent postural perceptual vertigo (PPPD). This disease, included in the ICD-проект project under code AA92.1, represents chronic sensation of vertigo non-obstructive nature, which may periodically increase or decrease, provoked by the vertical position, visual stimulation, active and passive head movements, and often occurs after acute or recurrent vestibular diseases [International Classification of Diseases, 11th Revision, http: // apps. who.int/classifications/icdl l / browse / lm / en].

 PPPD is defined as a type of vertigo that persists for more than three months without identifiable etiology [Staab J.P. Chronic subjective dizziness; review article II Continuum (Minneap Minn), 2012; 18: 1118-41]. This is a somatoform disorder, which is the subject of the study of otology and neuropsychiatry. Patients with PPPD appear to develop a condition that predisposes to maintaining vertigo after a case of organic or emotional disorder. With this condition, the postural stability system becomes hyper-reactive for movement, especially in conditions with high visual loads. Thus, PPPD reflects the preservation of a particular pattern of postural control that was taken during the acute phase of the disease [Huppert D, Strupp M, Rettinger N, Hecht J, Brandt T. Phobic postural vertigo - a long-term follow up (5 to 15 years) of 106 patients II J Neurol. 2005; 252: 564-9].

 The diagnostic algorithm is reduced to the use of diagnostic criteria and the exclusion of other reasons. The differential diagnosis may include vestibular migraine, panic attacks, some other conditions. PPPD is a chronic disease that can last for months or years and is characterized by the following main aspects:

 (1) constant wiggle or instability not detectable during physical examination;

 (2) worsening of symptoms while standing;

 (3) worsening of symptoms with head movement or complex visual stimuli;

 (4) the presence of a disease or emotional shock at the onset of symptoms;

 (5) simultaneous diseases, which mainly increase the symptoms.

The clinical variants of the formation of PPPD confirm the special status of this form of vertigo, reflecting the disturbances at the level of integration of various sensory modalities, in contrast to the vertigo observed b in anxiety disorders. A typical portrait of a patient with PPPD demonstrates the interrelation of the vestibular and the bibenibular component in the formation of a particular clinical picture of PPPD.

 The share of PPPD among all variants of vertigo (vestibular and bibliobular or systemic and non-systemic) ranges from 14.6% (T. Brandt, M. Dieterich, M. Strupp Vertigo and Dizziness: Common Complaints. London: Springer, 2013) to 23% ( Holle D., Schulte-Steinberg V., Wurthmann S., Naegel S., Ayzenberg I., Diener HC, Katsarava Z., Obermann M., Persistent Postural-Perceptual Dizziness: A Matter of Higher, Central Dysfunction II PloS One . 2015; 10 (ll): e0142468). According to the authors of the present invention, about 21.4% (unpublished data, 2014). According to current views, anxiety is not a diagnostic criterion for PPPD [Dieterich M., Staab J.P., Brandt T. Functional (psychogenic) dizziness II, Handbook of Clinical Neurology, Vol. 139, Chapter 37, 2016, pp. 447-468].

 Currently, the drugs of choice for the treatment of PPPD are selective serotonin reuptake inhibitors (SSRIs). Serotonin is the primary neurotransmitter for the amygdala, insular lobe (insula), anterior cingulate cortex, prefrontal cortex, superior frontal gyrus and inferior frontal gyrus. These drugs alter and regulate the conductance of neurons through central vestibular neurons that respond to movement. With proper use of SSRIs, symptom reduction can be achieved in up to 70% of people, approximately three months after treatment [Staab JP, Ruckenstein MJ, Amsterdam JD. A prospective trial of sertraline for chronic subjective dizziness II Laryngoscope. 2004; 114: 1637-1641].

One of the options for functional vertigo is postural phobic instability (PFN, PPV). Patients who have undiagnosed dizziness, not explained, are identified by a neurological disease, even with the full range of diagnostic tests offered today. Clinical tests show normal results. Until recently, these patients were classified in the group of persons with psychogenic disorders. Psychiatric syndromes also do not explain the symptoms found in these people. In 1996, Brandt [Brandt T. Phobic postural vertigo II Neurology. 1996; 46: 1515-1519] described the disease as phobic postural dizziness (instability) (PPV), but in full least explained the origin of the symptoms of this disease and did not offer any treatment.

 Functional vestibular syndrome PPV is one of the most common diseases encountered in neuro-otological practice. According to the German Center for Vertigo and Balance Disorders, this was the second most common diagnosis found in 15% of 17,700 adult outpatients, second only to benign paroxysmal positional vertigo [Brandt T, Dieterich M, Strupp M. Vertigo and Dizziness: Common Complaints 2nd edn. Springer, London, 2013]. According to another territorial medical institution specializing in vertigo, 23% of 3113 patients suffered from PPV [Obermann M., Bock E., Sabev N. et al. The dizziness and the Vertigo Registry (DiVeR) Study. II J. Neurol., 2015, 262 (9): 2083-2091]. The frequency of this diagnosis in other centers and countries varied considerably: from 2.5% [Ketola S, Niemensivu R, Henttonen A et al. Somatoform disorders in vertiginous children and adolescents. I I Int. J. Pediatr. Otorhinolaryngol., 2009, 73 (7): 933-936] to 16% [Lopez- Gentili L.I., Kremenchutzky M., Salgado P. // Astatistical analysis of 1300 patients with dizziness-vertigo. Its most frequent cases. II Rev. Neurol., 2003, 36 (5): 417-429], possibly due to the different sensitivity of diagnostic approaches. In childhood and adolescence, functional and psychiatric causes of vestibular symptoms, including PPV, account for up to 21% of diagnoses. They are second in frequency after migraine syndrome of child benign paroxysmal dizziness (39%) [Batu ED, Anlar B, TopcuMet al. Vertigo in childhood: a retrospective series of 100 children. II Eur. J. Paed. Neurol., 2015, 19: 226-232].

 The following criteria for postural phobic instability, which were proposed by T. Brandt, are known:

 - Bride-fibular "pseudo-giddiness" (feeling of swaying, approaching a fall, unstable soil);

 - dissociation between subjective sensations and objective signs;

- typical provoking factors: in the metro, on the bridge, during a performance, in a store, etc.; - the desire to avoid situations provoking dizziness;

 - improvement during physical exertion or when taking a small amount of alcohol;

 - the onset of the disease from an acute episode (vestibular dizziness, panic attack);

 - personality traits: perfectionism, compulsiveness, tendency to anxiety and depression.

 At the beginning of the 21st century, Staab and Rukenstein associated the physical symptoms of PPV with behavioral factors [Staab J.P. Chronic dizziness: the interface between psychiatry and neuro-otology. II Curr. Opin. Neurol. 2006; 19: 41-8; Staab JP. Assessment and management of psychological problems in the dizzy patient. II Continuum (Minneap Minn), 2006; 12: 189-213].

 PPV criteria for anxiety is spoken with great caution, because this dizziness is not the result of panic attacks or other forms of anxiety.

 The combination of postural vertigo with subjective instability of position and gait in patients with normal otoneurological indications, vestibular and balance tests (for example, video oculography, including caloric irrigation, neuroimaging) and the absence of other disorders that could explain the symptoms characteristic of PPV.

 A monosymptomatic subjective imbalance is associated with standing or walking and is manifested as a sudden deterioration that occurs with or without recognizable triggers and with or without accompanying anxiety.

 Patients with PPV usually have an obsessive personality as the most pronounced personality trait, a tendency toward increased self-analysis and the need to keep everything under control. They are usually ambitious and make high demands on themselves, and are often easily irritated and prone to manifestation of fear [Kapfliammer NR, Mayer C, Hock U. et al. Course of illness in phobic postural vertigo. II Acta Neurol. Scand., 1997, 95: 23-28].

PPV is the most common cause of dizziness. young people. Subsequent studies have confirmed that PPV is a unique nosological unit that can be clearly separated from mental disorders, such as panic disorder with or without agoraphobia. [Kapfhammer HP, Mayer C, Hock U. et al. Course of illness in phobic postural vertigo. II Acta Neurol. Scand., 1997, 95: 23-28].

 PPV can occur in adults of any age, but there is a bimodal distribution with peaks in the second and fifth decades (this is the most common form of dizziness in this age group), the incidence does not depend on gender. If untreated, symptoms worsen, generalization of stimuli develops, and avoidance behavior may increase until the patient is able to leave his apartment without help.

 Differential diagnosis of PPV includes structural vestibular disorders, other diseases, and psychiatric syndromes. The most important functional and psychiatric syndromes include the following [Brandt T, Dieterich M, Strupp M Vertigo and Dizziness: Common Complaints, 2nd edn. Springer, London, 2013]: panic disorder with or without agoraphobia; other mental or medical disorders that cause panic attacks or chronic anxiety; fear of open space [Marks J.M. Space "phobia": a pseudo-agoraphobic syndrome. II J. Neurol. Neurosurg. Psychiatry, 1981, 48: 729-735], visual dizziness [Bronstein A.M. The visual vertigo syndrome. II Acta Otolaryngol (Stockh), 1995, 520: 45-48; Bronstein A.M. Vision and vertigo: some visual aspects of vestibular disorders. II J. Neurol., 2004, 251: 381-387], landing syndrome [Murphy T.P. Mai de debarquement syndrome: a forgotten entity. II Otolaryngol. Head Neck Surg., 1993, 109: 10-13].

 The pathophysiological mechanisms of PPV can include the perception of involuntary body swing and random individual head movements as disturbing external disturbances with simultaneous illusory movements of the environment, which can be attributed to the temporal mismatch of the efferent signal and reverse afferentation, which are usually normally compensated, i.e. there is a discrepancy between the expected and actual movement [Brandt T., Dieterich M., Strupp M. Vertigo and Dizziness: Common Complaints, 2nd edn. Springer, London, 2013].

The next of the subtypes of functional dizziness is chronic subjective dizziness (CSH, CSD). The term chronic subjective dizziness is used to describe a common type. dizziness, which cannot be attributed to one of the other types and for which physical examination is usually normal. CSD patients often suffer from a sudden injury of the vestibular system, a neurological network that maintains a sense of balance. Even after this initial trauma has been resolved, people with CSD usually describe a vague sense of instability that worsens when triggers are triggered in their environment, such as high places, being on moving objects, or being in traffic conditions such as busy streets or crowds .

 Since the early 2000s, Staab and his colleagues [Staab J.P., Ruckenstein M.J. Expanding the differential diagnosis of dizziness. Arch. Otolaryngol. Head Neck Surg., 2007, 13: 170-176] began a series of studies that led to the description of CSD syndrome. Inspired by the available literature on PPV, as well as studies of discomfort when moving in space [Jacob R. G., Woody S.R., Clark D. B. et al. Discomfort with space and motion: a possible marker of vestibular dysfunction assessed by the Situational Characteristics Questionnaire. II J. Psychopathol. Behav. Assess, 1993, 15: 299-324] and visual vertigo [Bronstein A.M. The visual vertigo syndrome. II Acta Otolaryngol (Stockh), 1995, 520: 45-48], they identified chronic subjective vertigo [Staab J.P., Ruckenstein M.J. Expanding the differential diagnosis of dizziness. II Arch Otolaryngol. Head Neck Surg., 2007, 13: 170- 176] as a disease in which:

 1) there are persistent (duration 3 months) feelings of non-rotating dizziness, nausea, severity or subjective imbalance;

 2) there is a chronic (duration of 3 months) hypersensitivity to one's own movement, which does not relate to specific directions, and to movements of objects in the environment;

 3) symptoms worsen in conditions with complex visual stimuli, such as grocery stores or shopping centers, or when performing precise visual tasks, such as reading or using a computer;

4) there are no active organic (that is, structural or cellular disorders) neuro-otological diseases, other certain medical conditions that may cause dizziness, the patient also does not take medicines that may cause dizziness; 5) the results of radiographic visualization of the brain exclude neuro-otologically significant anatomical lesions;

 6) equilibrium test results are in the control range or do not indicate structural vestibular deficiency.

 Thus, anxiety states were excluded from the CSD criteria.

A comparison of CSD and PPV definitions shows several differences. Criteria for CSD emphasize persistent imbalance and dizziness. They do not include intermittent vestibular symptoms. They also focus more intently on provoking symptoms with visual stimuli than on an upright position, even after adding a postural criterion. Psychological elements, such as obsessional personality traits, phobic behavior and mild anxiety and depressive symptoms, were excluded because they were considered risk factors or comorbidities, and not the main signs of disorder.

 According to a large-scale CSD study (345 patients) [Staab J.P.,

Ruckenstein M.J. Expanding the differential diagnosis of dizziness. II Arch Otolaryngol. Head Neck Surg., 2007, 13: 170-176] the duration of the disease ranged from months to several years with an average duration of 4.5 years. Patients with CSD often, but not always, experience anxiety and depressive disorders. In a diagnostic study of patients with CSD, 60% of patients had clinically significant symptoms of anxiety, and 45% had clinically significant symptoms of depression, but, importantly, 25% of patients did not have anxiety or mood disorders [Staab JP. Chronic Subjective Dizziness II Continuum (Mineapp.Minn.). 2012; 18 (5 Neurootology): 1118-1141]. Thus, CSD, like PPV, can exist separately from any psychiatric comorbidities (comorbidity).

The provoking events trigger a combination of physiological and behavioral adaptations that are usually expected in response to acute vestibular syndromes or other conditions that disturb balance function. These include a shift in sensory integration in favor of visual or somatosensory inputs, increased attention to head and body movement, and increased caution when walking. All these adaptations were observed in healthy people with a postural threat [Brown LA, Gage WH, Polych MA et al. Central set influences on gait. Age-dependent effects of postural threat. II Exp. Brain Res., 2002, 145: 286-296; Gage WH, Sleik RJ, Polych MA et al. The allocation of attention during the locomotion is altered by anxiety. II Exp. Brain Res., 2003, 150: 385-394].

 This means that high-risk balance strategies, properly triggered by initial adverse events, in patients with CSD are still used to manage routine movements and respond to simple, low-risk, spatial and motor stimuli in the environment. Thus, the disease is characterized by the inability to return to normal postural control of low risk. The perception of a persistent threat extends the application of high-risk control mechanisms for postural feedback to situations where this is not required.

 Neurotic reaction and low extraversion can increase the risk of developing CSD, as they reduce the threshold for engaging high-risk postural control processes. High levels of neurotic reaction and low levels of extraversion increase the incidence of functional disorders.

Results of functional magnetic resonance [Dieterich M., Staab JP, Brandt T. Functional (psychogenic) dizziness II Handbook of Clinical Neurology, Vol. 139, Chapter 37, 2016, pp. 447-468; Indovina I, Riccelli R, Chiarella G et al. Role of the insula and vestibular system in patients with chronic subjective dizziness: an fMRI study using sound-evoked vestibular stimulation. II Front. Behav. Neurosci., 2015, 9: 334] confirm models of PPV and CSD (and, in addition, PPPD), which suggest that their pathophysiological mechanisms include large-scale functional changes in the sensory areas of the cortex (PIVC and visual cortex), the areas involved in spatial information processing (hippocampus), postural control (cerebellar worm) and threat assessment (almond-shaped body), as well as frontal / prefrontal areas that modulate their activity (orbitofrontal cortex, anterior islet lobe of the large brain, anterior part th gyrus). The putative pathophysiological mechanisms of CSD also suggest that hypersensitivity to visual stimuli of movement, complex structures in the environment, and tasks that require constant visual focus are the result of increased visual dependence. Existing drug treatment for all forms of functional vertigo is a difficult task that requires close interaction between a neurologist, a psychotherapist, a psychiatrist and a rehabilitation specialist. According to the currently existing therapeutic principles, treatment consists of psychotherapy (rational and cognitive-behavioral), vestibular rehabilitation and drug therapy. From drugs, the drugs of choice are selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline (SSRIHS), such as paroxetine, citalopram, fluvoxamine or sertraline. Sometimes they are combined with tranquilizers (for example, lorazepam), which are prescribed in a short course in order to avoid drug dependence. Tricyclic antidepressants are used as alternative drugs. There are relatively few studies evaluating the effectiveness of drug therapy for vertigo. An open-design study evaluated the effectiveness of sertraline, paroxetine, fluvoxamine, fluoxetine, and milnacipran [Staab JP, Ruckenstein MJ, Solomon D., Shepard NT Serotonin Reuptake Inhibitors for Dizziness With Psychiatric Symptoms. II Arch. Otolaryngol. Head Neck Surg., 2002; 128 (5): 554-560; Staab JP, Ruckenstein MJ, Amsterdam JD A prospective trial of sertraline for chronic subjective dizziness. II Laryngoscope, 2004, 114 (9): 1637-41; Horii A., Mitani K., Kitahara T., Uno A., Takeda N., Kubo T. Paroxetine, a selective serotonin reuptake inhibitor, reduces depressive symptoms and subjective handicaps in patients with dizziness. II Otol. Neurotol. 2004, 25 (4): 536-43; Horii A., Uno A., Kitahara T., Mitani K., Masumura C, Kizawa K., Kubo T. Effects of fluvoxamine on anxiety, depression, and subjective handicaps of chronic dizziness patients with or without neuro-otologic diseases. II J. Vestib. Res. 2007, 17 (1): 1-8; Simon NM, Parker SW, Wernick-Robinson M., Oppenheimer JE, Hoge EA, Worthington JJ, Korbly NB, Pollack MH Fluoxetine for a vestibular dysfunction and anxiety: a prospective pilot study II Psychosomatics. 2005, 46 (4): 334-9].

The disadvantages of the existing approaches to the treatment of functional dizziness can be considered: 1) the need for prolonged titration of the dose of SSRIs and SSRIs, 2) the slow onset of therapeutic effect, 3) frequent increase in symptoms of the disease at the beginning of treatment (especially when using SSRIs), 4) relatively large number of side effects , 5) the negative impact of these drugs on the processes of vestibular compensation (vestibular compensation slows down when using antihistamines, GABAergic drugs (benzodiazepines), drugs with anticholinergic activity, and possibly drugs with dopaminergic activity).

 The authors of the present invention have unexpectedly found that buspirone (8- [4- [4- (2-pyrimidinyl) piperazin-1 -yl] butyl] -8-azaspiro [4.5] decane-7,9-dione) can be effectively used for treatment of various types of functional vertigo.

 Buspirone (1)

Buspirone (and its hydrochloride) is a partial 5-HT1A receptor agonist that was introduced to the market more than 20 years ago for the oral treatment of anxiety disorders with or without accompanying Bristol-Myers Squibb. In 1990, Buspirone was launched by the company in collaboration with Menarini for the treatment of generalized anxiety disorder (GAD). Currently, the National Cancer Institute (NCI) is evaluating the effectiveness of the drug in reducing dyspnea in patients who are undergoing chemotherapy for cancer treatment. The National Institute of Neurological Disorders and Stroke (NINDS) is conducting Phase II clinical trials on the use of buspirone for the treatment of localized epilepsy. The National Institute on Drug Abuse Control (NIDA) is conducting Phase II clinical trials on the use of buspirone for treating and preventing coca addiction.

Buspirone - 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 the elderly patients: epidemiology, diagnosis and treatment options II Drugs Aging. 2005; 22 (2): 101-114; Gale CK, Millichamp J. Generalised anxiety disorder in children and adolescents II BMJ Clin Evid. 2016 Jan 13; 2016. pii: 1002; Goa KL, Ward A. Buspirone. An preliminary review of its pharmacological properties and anxiolytic. II Drugs. 1986, 32 (2): 114-29]. Being a 5-HT1A receptor partial agonist and D2-receptor antagonist [Loane C, Politis M. Buspirone: What is it all about? II Brain Res. 2012; 1461: 111-8; Newman-Tancredi A, Gavaudan S, Conte C, Chaput C, Touzard M, Verriele L, Audinot V, Millan MJ. Agonist and Antagonist 5-HT1A receptors a [35S] GTPgammaS binding study II Eur. J. Pharmacol. 1998; 355 (2-3): 245-56; Tunnicliff G. Molecular basis of buspir one's anxiolytic action II Pharmacol Toxicol. 1991 Sep; 69 (3): 149-56], buspirone does not seem to slow down the processes of vestibular compensation.

 Buspirone (and its hydrochloride) differs from typical benzodiazepine anxiolytics in that it does not have an anticonvulsant or muscle relaxant effect. It also lacks the well-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 the binding of GABA in vitro or in vivo when tested in preclinical models. It exhibits moderate affinity for brain 02-dopamine receptors. Some studies suggest that buspirone may have an indirect effect on other neurotransmitter systems.

 In contrast to benzodiazepines, the probable anxiolytic mechanism of action of buspirone remains not fully elucidated due to contradictory anxiolytic effects in the clinic and in animal models [Bauer MS, Wisniewski SR, Marangell LB, Chessick CA, Allen MH, Dennehy EB, Miklowitz DJ, Thase ME, Sachs GS. Are antidepressants associated with suicidal ity in bipolar disorder new-onset? A Bipolar Disorder Program (STEP-BD) II. Clin Psychiatry. 2006; 67 (1): 48-55].

Numerous studies indicate that in an acute experiment, the use of buspirone in rodents leads to an anxiolytic effect 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, an anxiogenic effect appears [Collinson N, Dawson GR. 5-HT (lA) agonist, 8-OH-DPAT, 5-HT (lA) partial agonist, buspirone, are blocked by the 5-HT1A antagonist, WAY 100635. II Psychopharmacology (Berl). 1997; 132 (1): 35-43; de Oliveira Cito Mdo C, da Silva FC, Silva MI, et al. Reversal of cocaine withdrawal-induced anxiety by ondansetron, buspirone and propranolol II Behav Brain Res. 2012; 231 (1): 116-23; File SE, Andrews N. Low, but not reduce the amount of buspirone reduce psychopharmacology (Berl). 1991; 105 (4): 578-82; Handley SL, McBlane JW 5HT drugs in animal models of anxiety II Psychopharmacology (Berl). 1993; 112 (1): 13-20; Hestermann D, Temel Y, Blokland A, Lim LW. Acute serotonergic treatment changes between anxiety and HPA-axis functioning and periaqueductal gray activation II Behav. Brain Res. 2014; 273: 155-65; Inagaki H, Kiyokawa Y, Takeuchi Y, Mori Y. A unique anxiety model: psychopharmacological evidence using anxiolytics II Pharmacol Biochem Behav. 2010; 94 (4): 575-9; Moser PC Psychpharmacology (Berl) test. 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. II Gen. Pharmacol. 1995; 26 (1): 205-10; Soderpalm B, Hjorth S, Engel JA. Effects of 5-HT1A receptor agonists and L-5-HTP in Montgomery's conflict test. II Pharmacol Biochem Behav. 1989; 32 (1): 259-65; Varty GB, Morgan CA, Cohen-Williams ME, Coffin VL, Careyral characterization and pharmacological validation. II Neuropsychopharmacology. 2002 Sep; 27 (3): 357-70].

The anxiogenic effect of buspirone is of great clinical importance 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. II Lancet. 1989; 2 (8653): 46-7; Liegghio NE, Yeragani VK, Moore NC Buspirone-induced jitteriness and generalized anxiety disorder. II J Clin Psychiatry. 1988; 49 (4): 165-6; Newton RE, Marunycz JD, Alderdice MT, Napoliello MJ Review of the side-effect profile of buspirone. II Am. J. Med. 1986; 80 (3B): 17-21]. The affinity of buspirone for a complex of receptors may underlie its bi-phase pharmacological effect [Tunnicliff G. Molecular basis of buspir -one's anxiolytic action. II Pharmacol Toxicol. 1991; 69 (3): 149-56]. Buspirone acts as a complete 5-HT1 A agonist of autoreceptors located on the surface of dendritic neurons of the suture nuclei, reducing the excitation of 5-HT neurons and thus reducing the release of serotonin in this structure, and thereby activating other brain structures. This mechanism is considered 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 Apr; 96 (4): 829-36; Adell A, Sarna GS, Hutson PH, Curzon G. An in vivo dial-up of the p-chloroamphetamine in reserpine-treated rats. Br J Pharmacol. 1989 May; 97 (l): 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 Feb; 96 (2): 283-90; Sprouse JS, Aghajanian GK. Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse. 1987; l (l): 3-9].

 However, buspirone also works as an agonist for postsynaptic 5-HT1A receptors, thereby reducing neuronal arousal. These opposite effects can cause the bi-phase anxiety-modulating effect of buspirone [Sillar KT1, Simmers AJ. Presynaptic inhibition of the afferent transmitter release of 5-hydroxytryptamine at a vertebrate spinal cord. J Neurosci. 1994 May; 14 (5 Pt l): 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 May; 54 (l): 51-6; Hodges H, Green S, Glenn B. Evidence that is not affected by discrimination.Psychopharmacology (Berl). 1987; 92 (4): 491-504].

Some studies using the 5-HT1A antagonist suggest the presence of the anxiogenic and anxiolytic effect of buspirone mediated by its interaction with D2-like and 5-HT1A receptor systems, respectively [Collinson Nl, Dawson GR. 5-HT (lA) agonist, 5-OH-DPAT, but not the anxiolytic-like effects of the 5- HT (1A) partial agonist, buspirone, are blocked by the 5-HT1A antagonist, WAY 100635. Psychopharmacology (Berl). 1997 Jul; 132 (l): 35-43].

 Recently, buspirone has also been shown to act as an antagonist of D3 and D4 receptors with a higher binding affinity compared with D2 receptors [Mello NK1, Five PA, Kohut SJ, Bergman J. Effects of chronic buspirone treatment on cocaine self-administration. Neuropsychopharmacology. 2013 Feb; 38 (3): 455-67].

 It was found that, despite the anxiolytic effect, buspiron activates the hypothalamic-pituitary-adrenal stress system and increases the peripheral concentration of adrenaline and noradrenaline through a central mechanism of action.

From the prior art it is known to use buspirone for the palliative treatment of neurosis, in which symptoms of anxiety appear (US4182763, 01/08/1980); with hyperactivity, attention deficit (EP0497314, 03/01/1989); for the treatment of drug addiction and addiction (US5185329, 02/09/1993); for the treatment of anxiety disorders (WO2005049041, 02.06.2005; US7678363, 03/16/2010); psychiatric disorders (US7678363, 03/16/2010); depression (WO2007144080, 12.21.2007); neurological disorders (WO2008083204, 07/10/2008).

The systemic use of buspirone or its derivatives for the treatment of pathological conditions associated with immune responses is known (EP0690715, 28.05.2003); for the treatment of disorders of sexual function and reproduction (US8052982, 08/11/2011) and sexual dysfunction (US4640921, 02/03/1987); for the treatment of sleep-related respiratory diseases (WO2000006163, 10.02.2000). The use of buspirone for the treatment of glaucoma (US7763619, 07/27/2010), pain, neuropathy (US6511982, 01.28.2003), itching (WO2004084900, 10/07/2004) for treating, preventing or alleviating movement disorders such as Parkinson’s disease, dyskinesia ( US9186359, 11/17/2015); with spinal cord injuries, multiple sclerosis, Parkinson's disease (WO2015127558, 09/03/2015); apnea (ЕР0442424, 21.12.1994), as well as use for incontinence (WO 1996005817, 02.29.1996), nausea, vomiting (WO2008149062, 11.12.2008), tides (WO2011064769, 03.06.2011), autism spectrum disorders (US2012108510, 19.05 .2011). The authors of the present invention unexpectedly found that buspirone reduces the manifestation of dizziness in patients with all forms of functional vertigo (PPPD, CSD and PPV). The authors believe that in terms of the use of buspirone in patients with functional dizziness, the fact that despite the anxiolytic effect of this drug, the hypothalamic-pituitary-adrenal system is activated and its peripheral concentration of adrenaline and noradrenaline increases, seems to be promising. Being sympathomimetics and penetrating the blood-brain barrier, these substances have a stimulating effect on vestibular compensation. The role of serotonin receptors in the processes of vestibular compensation has not been fully studied. However, it is known that serotonin receptors (5HT-1, 2 and 7) exist in the area of the vestibular nuclei [Soto E, Vega R, Sesena E. Neuropharmacological basis of vestibular system disorder treatment. J Vestib Res. 2013; 23 (3): 119-37], and abrupt cancellation of SSRIs is often accompanied by a distinct and severe dizziness [Soto E, Vega R, Sesena E. Neuropharmacological basis of vestibular system disorder treatment. J Vestib Res. 2013; 23 (3): 119-37]. Serotonin agonists (and, in particular, 5-HT1A receptors) are also believed to prevent rocking [Marcus DA, Furman JM. Prevention of motion sickness with rizatriptan: a double-blind, placebo-controlled pilot study. Med Sci Monit. 2006 Jan: PI1- 7]. Thus, there is reason to believe that buspirone, by stimulating certain mechanisms of vestibular compensation, may be a promising drug for the treatment of functional vertigo. Additional advantages, apparently, can be the absence of sedation and muscle relaxant effect, the controlled nature of dose titration and the favorable safety profile of buspirone.

Vertigo is a frequent side effect of buspirone when it is used in patients who do not suffer from functional vertigo (Karamanolis GP, Panopoulos S, Denaxas K, Karlaftis A, Zorbala A, amberoglou D, Ladas SD, Sfikakis PP. The 5-HT1 A receptor agonist buspirone improved esophageal motor scorrosis: a 4-week open-label trial Arthritis Res Ther. 2016 Sep 1; 18: 195; Le Foil B, Payer D, Di Ciano P, Guranda M, Nakajima S, Tong J, Mansouri E, Wilson AA, Houle S, Meyer JH, Graff-Guerrero A, Boileau I. Occupancy of Dopamine D3 and D2 Receptors by Buspirone: A [HC] - (+) - PHNO PET. Neuropsychopharmacology. 2016 Jan; 41 (2): 529-37. Epub 2015 Jun 19; Sutherland SM, Adler LA, Chen C, Smith MD, Feltner DE. An 8-week, randomized controlled trial of atomoxetine, atomoxetine plus buspirone, or placebo in adults with ADHD. J Clin Psychiatry. 2012 Apr; 73 (4): 445-50. Epub 2012 Jan 10; Frey JM, Mintzer MZ, Rush CR, Griffiths RR. Buspirone is differentiated from diazepam in humans using a three-response drug discrimination procedure. Psychopharmacology (Berl). 1998 Jul; 138 (l): 16-26; Sramek JJ, Tansman M, Suri A, Hornig-Rohan M, Amsterdam JD, Stahl SM, Weisler RH, Cutler NR. Efficacy of buspirone in generalized anxiety disorder with coexisting mild depressive symptoms. J Clin Psychiatry. 1996 Jul; 57 (7): 287-91). Thus, a reduction in the manifestation of vertigo in patients with all forms of functional vertigo under the action of buspirone is unexpected for a person skilled in the art.

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

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

"Pharmaceutically acceptable salt" means relatively non-toxic organic and inorganic salts of acids and bases, as claimed in the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of compounds, or prepared specifically. In particular, salts of the bases can be obtained specifically, starting from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are the hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valerate, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (Detailed description of the properties of such salts is given in Berge SM, et al., "Pharmaceutical Salts" II J. Pharm. Sci. 1977, 66: 1-19) . Salts of the claimed acids can also be specifically prepared by reacting the purified acid with a suitable base, and metal salts and amines can be synthesized. TO Metals 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 derived are hydroxide, carbonate, bicarbonate and sodium 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 chosen that have sufficient basicity to form a stable salt and are suitable for medical use (in particular, they must 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, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. The basic amino acids lysine, ornithine and arginine can be used as amino acids.

 The present invention is the search for new promising drugs that do not have the disadvantages of benzodiazepine anxiolytics, for the treatment of functional dizziness.

 Technical results of the present invention:

 - the possibility of treating functional dizziness, independent of depressive and anxiety states,

 ensuring a clinically optimal rate of onset of therapeutic effect,

 - ease of dose titration,

 - minimization of sedation,

 - Improved security profile.

 The problem is solved, and the result is achieved by using buspirone or its pharmaceutically acceptable salt for the treatment of functional dizziness.

 The technical result is also achieved by the fact that:

- functional dizziness is persistent postural perceptual vertigo; - functional vertigo is postural phobic imbalance;

 - functional dizziness is chronic subjective dizziness;

 - The pharmaceutically acceptable salt of Buspirone is Buspirone hydrochloride;

 Another object of this invention is the use of the pharmaceutical composition of buspirone for the treatment of functional dizziness. Moreover, the said pharmaceutical composition of buspirone contains buspirone or its pharmaceutically acceptable salt in a therapeutically effective amount, and at least one pharmaceutically acceptable carrier.

 The technical result is also achieved by the fact that:

 - functional dizziness is persistent postural perceptual vertigo;

 - functional vertigo is postural phobic imbalance;

 - functional dizziness is chronic subjective dizziness;

 - The pharmaceutically acceptable salt of Buspirone is Buspirone hydrochloride;

 - the pharmaceutical composition is a sustained release composition;

 - the pharmaceutical composition of buspirone is used in a dosage form placed in a pharmaceutically acceptable package, while the dosage form contains buspirone in a therapeutically effective manner;

 - dosage form selected from the group including tablets, capsules and injections;

 - dosage form is a dosage form with a slow release.

 - Buspirone is used in a dose of 5-100 mg / day;

- Buspirone is used in a dose of 15 mg once a day; - Buspirone is used in combination with selective serotonin reuptake inhibitors (SSRIs), selective serotonin reuptake inhibitors and noradrenaline (SSRIHS), tranquilizers or tricyclic antidepressants.

Pharmaceutical compositions may include pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are diluents, auxiliary agents and / or carriers used in the pharmaceutical field. The pharmaceutical composition along with buspirone or its pharmaceutically acceptable salt of the present invention may include other active substances, including those with activity, provided that they do not cause undesirable effects.

 If necessary, the use of the pharmaceutical composition of the present invention in clinical practice, it can be mixed with traditional pharmaceutical carriers.

 The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to make common forms. In oral forms, binders, lubricants, disintegrating agents, solvents, diluents, stabilizers, suspending agents, flavoring agents are used; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used. Drugs can be administered orally or parenterally.

(for example, intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of an agent containing buspirone according to the present invention in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their rate of exchange and elimination from the body, and also depending on the age, sex and stage of the patient’s disease, This daily dose in adults is usually 10-500 mg, preferably 50-300 mg. Therefore, during the preparation of the pharmaceutical composition of the drug of the present invention in the form of dosage units, it is necessary to take into account the aforementioned effective dosage, with each dosage unit of the drug should contain 10-500 mg of buspirone, preferably 50-300 mg. In accordance with the instructions of the physician or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

 It is more preferable to use buspirone or its pharmaceutically acceptable salt for the treatment of functional dizziness, persistent postural perceptual dizziness, postural phobic instability, chronic subjective dizziness, where buspirone is used in a dose of 5-100 mg / day, preferably 10-60 mg / day, more preferably 15-45 mg / day.

 It is more preferable to use buspirone or its pharmaceutically acceptable salt for the treatment of functional dizziness, persistent postural perceptual dizziness, postural phobic instability, chronic subjective dizziness, where buspirone is used in a dose of 15 mg once a day, preferably as a delayed release composition.

 It is more preferable to use buspirone or its pharmaceutically acceptable salt for the treatment of functional dizziness, persistent postural perceptual dizziness, postural phobic instability, chronic subjective dizziness, where buspirone is used in combination with selective serotonin reuptake inhibitors (SSRIs, and other active inhibitors). (SSRI), tranquilizers or tricyclic antidepressants.

 The following embodiments of the invention illustrate, but not limit the invention.

Examples of the implementation of inventions

 Example 1. Evaluation of the effectiveness of buspirone in reducing dizziness in suok test in mice.

One of the close models for studying the effect of buspirone on functional vertigo is the so-called Suok test in rodents. The test is based on keeping the balance of the animals on a raised a horizontal rod (for mice) or a narrow bar (for rats). Equilibrium control of animals is assessed (falls and slips). Suok's modified lit-dark test represents the same equipment. Half a rod or slat is brightly lit (aversive region) in a dark experimental room. In the modified test, the same parameters are estimated. Suok test allows to reliably determine the status and presence of anxiety and imbalance in rodents. Summarizing, the studies conducted on the described model allow the integral assessment of the behavioral and neurological aspects of anxiety / vestibular disorders. Such works demonstrate the possibility of screening potential drugs affecting the vestibular apparatus.

 Buspirone (or its hydrochloride) in the Suok test significantly reduced functional vertigo in rodents compared with placebo. Example 2. The use of buspirone for the treatment of postural phobic instability.

 To study the use of buspirone for the treatment of postural phobic instability, clinical trials are conducted, where participants in the study include patients who have undiagnosed dizziness, not explained by a neuropsychiatric disease using a full range of diagnostic tests.

 Patients describe dizziness as a feeling of insecurity, instability, a sense of derealization and impending loss of consciousness. Often there is a condition that patients can compare with the sensation of motion sickness: a feeling of an unstable, swaying surface on which patients stand or are walking, and at the same time a feeling of slight nausea. As a result, it seems to patients that they walk unevenly, that they are being pumped from side to side, but from the side of the gait disturbance they are not visible even to close people. These sensations are constantly present, intensifying on the street, in the subway, big stores or under emotional stress. During the entire period of the disease there are no attacks of systemic vertigo.

Patients were subjected to laboratory tests of blood and urine, ECG, EchoCG, ultrasound duplex scanning of the brachiocephalic arteries, MP tomography of the head brain, MP-angiography of cerebral arteries, caused by stem, visual and somatosensory potentials, radiography of the cervical spine.

 The study included only those patients in whom no abnormalities were detected during the somatic and neurological examination, in particular, no organic lesions of the central nervous system affecting the vestibular analyzer were detected. In particular, no nystagmus and signs of latent vestibular dysfunction were detected during the clinical otoneurological examination under the control of videonystagmography. Patients were required to clearly perform index coordinating tests. Excluded disdiadohokinez, dysmetria. In the Romberg sample, patients had to be resistant. In Romberg's complicated test with closed eyes, as a rule, there was marked uncertainty, but the test was performed satisfactorily. No gait disturbances, including tandem and flanking, were detected in selected patients. Sample Fukuda should be negative. Thus, organic lesions of the nervous system were excluded.

 Differential diagnosis of PPV included structural vestibular disorders, other medical diseases, and psychiatric syndromes. The most important functional and psychiatric syndromes included the following: panic disorder with or agoraphobia; other mental or medical disorders that cause panic attacks or chronic anxiety; spatial phobia, visual dizziness, depressive syndrome.

 After exclusion of organic lesions and differential diagnosis, the following criteria were used to determine the diagnosis of PPV:

 • bride's biblical “pseudo-giddiness” (swaying sensation, approaching fall, unstable soil);

 • dissociation between subjective feelings and objective signs;

 • typical provoking factors: in the subway, on the bridge, during a performance, in a store, etc.;

 • the desire to avoid situations provoking dizziness;

• improvement during exercise or when taking a small amount of alcohol; • onset of the disease from an acute episode (vestibular dizziness, panic attack);

 • personality traits: perfectionism, obsession, anxiety and depression.

 As a result, 50 men and women aged from 18 to 65 years old were included in the study with a verified diagnosis of “postural phobic instability”.

 The Beck Depression Index and Spielberg Test were used to determine the associated anxiety and depressive states.

 The Beck Depression Index (BDI), first published in 1961 [Beck A.T., Ward S.N., Mendelson M., Mock J., Erbaugh J. Anderna for depression II Arch. Gen. Psychiatry. 4 (6): 561-71, 1961], which consists of twenty-one questions about how the subject felt last week. Each question has a set of at least four possible answers, varying in intensity. When a test is evaluated, a value from 0 to 3 is assigned to each answer, and then the total score is compared with a key to determine the severity of the depression.

 Standard indicators:

 0-9: indicates minimal depression;

 10-18: indicates mild depression;

 19-29: indicates moderate depression;

 30-63: indicates severe depression.

 The Spielberger test (State-Trait Anxiety Inventory, STAI) consists of 20 statements relating to anxiety as a state (state of anxiety, reactive or situational anxiety) and 20 statements on the definition of anxiety as disposition, personality trait (personal anxiety questionnaire) [Spielberger CD ., Gorsuch RL, Lushene RE Manual for the Strait- Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press; 1970].

 For those in Table 1 issues NN 1-20, reactive anxiety is evaluated (anxiety as a state). For questions NN 21-40 (located in table 2), personal anxiety is evaluated (anxiety as a property).

The level of anxiety up to 30 points is considered low, from 30 to 45 points - moderate, from 46 points and above - high. The minimum score on each scale is 20 points, the maximum is 80 points. Define 16 patients (32%) with moderate levels of depression and anxiety.

 Patients are divided into 5 groups:

 placebo group,

 group taking buspirone 5 mg per day,

 group receiving buspirone 15 mg per day,

 group receiving buspirone 30 mg per day,

 group receiving buspirone 100 mg per day.

 Method of application: inside, 1 time per day and always at the same time, in the morning, regardless of the meal for 12 weeks.

 To assess the state of patients with functional dizziness before treatment and after 12 weeks, use the Dizziness Handicap Inventory test [Dieterich M., Staab J.P., Brandt T. Functional (psychogenic) dizziness II Handbook of Clinical Neurology, Vol. 139, Chapter 37, 2016, pp. 447-468]. The purpose of this scale is to identify difficulties that may arise due to the state of dizziness. On the 25 questions mark the answers "always" or "no" or "sometimes" for each question. Each answer is rated from 0 to 4 points. The highest score is 100 (severe), the lower score is 0 (no dizziness). Estimated points are used to track changes.

 Statistical processing of safety parameters and registration of the results of the study of the use of buspirone for the treatment of functional vertigo were performed in accordance with the Good Clinical Practice Rules of the Eurasian Economic Union using the statistical package SPSS Statistics 19.0. The research results are summarized in Table 1.

 Table 1.

Change in the average index of the Dizziness Handicap Inventory Group at the end of the 12th

Group of weeks compared to baseline

 a visit

 Placebo -0.7 ± 0.1

 Buspirone 5 mg / day -2.7 ± 0.2 *

Buspirone 15 mg / day -7.1 ± 0.2 * Buspirone 30 mg / day -8.3 ± 0.2 *

 Buspirone 100 mg / day -9.5 ± 0.2 *

 * - difference from the placebo group, p <0.05.

In the course of the study, a significant statistically significant decrease (level. Significance p <0.05) of the level of functional dizziness of PPV was found in the groups taking buspirone compared to the group taking placebo. At the same time, the effectiveness of treatment does not depend on the presence or absence of concomitant depressive or anxiety states. Example 3. The use of buspirone for the treatment of postural perceptual vertigo.

 For a study of the use of buspirone (or its hydrochloride) for the treatment of postural perceptual vertigo, clinical trials were conducted in accordance with Example 2, where the volunteers in the study included patients who are referred to an outpatient admission to a neurologist with complaints of dizziness, instability when walking, who are concerned their last 6-7 months.

 Patients underwent laboratory tests of blood and urine, ECG, EchoCG, ultrasound duplex scanning of the brachiocephalic arteries, MP tomography of the brain, MP angiography of the cerebral arteries caused by stem, visual and somatosensory potentials, x-rays of the cervical spine.

 The study included only those patients who did not show abnormalities during somatic and neurological examination. In particular, no organic CNS lesions were detected that affect the vestibular analyzer, as described above in Example 2 above. In this way, organic damage to the nervous system and vertigo caused by psychiatric syndromes were excluded.

The PPPD diagnostic algorithm is reduced to the use of diagnostic criteria and the exclusion of other reasons. The diagnosis included vestibular migraine, panic attacks, some other conditions. Diagnostic criteria:

 (1) constant wiggle or instability not detectable during physical examination;

 (2) worsening of symptoms while standing;

 (3) worsening of symptoms during head movement or in the presence of complex visual stimuli;

 (4) the presence of a disease or emotional shock at the onset of symptoms;

 (5) simultaneous diseases, which mainly increase the symptoms. The study included 65 men and women aged 18 to 68 years with a verified diagnosis of persistent postural perceptual dizziness.

 To determine the associated anxiety and depressive states, the Beck Depression Index and the Spielberg test are used in accordance with Example 2.

 Of these, 18 patients were identified (28%) with moderate levels of depression and anxiety.

 Patients are divided into 5 groups:

 placebo group,

 group taking buspirone 5 mg per day,

 group receiving buspirone 15 mg per day,

 group receiving buspirone 30 mg per day,

 group receiving buspirone 100 mg per day.

 Method of application: inside, 1 time per day and always at the same time, in the morning, regardless of the meal for 12 weeks.

 To assess the condition of patients with functional dizziness before treatment and after 12 weeks, use the Dizziness Handicap Inventory test in accordance with Example 2.

Statistical processing of safety parameters and the design of the results of the study of the use of buspirone for the treatment of functional vertigo was performed in accordance with the Rules of Good Clinical Practice of the Eurasian Economic Union using the statistical package SPSS Statistics 19.0. The research results are summarized in Table 2. Table 2.

 - difference from the placebo group, p <0.05.

In the course of the study, a significant statistically significant decrease (significance level p <0.05) of the functional dizziness level of PPPD was detected in the buspirone groups compared with the placebo group. At the same time, the effectiveness of treatment does not depend on the presence or absence of concomitant depressive or anxiety states.

Example 4. The use of buspirone for the treatment of chronic subjective vertigo.

 To study the use of buspirone (or its hydrochloride) for the treatment of chronic subjective vertigo, clinical trials were carried out in accordance with Example 2, where the volunteers included patients who are referred to an outpatient consultation with a neurologist complaining of dizziness, a vague sense of instability, which worsens when triggers are triggered in their surroundings, such as high places, being on moving objects, or being in motion, such as busy streets Whether the crowds.

Patients underwent laboratory tests of blood and urine, ECG, EchoCG, ultrasound duplex scanning of the brachiocephalic arteries, MP tomography of the brain, MP angiography of the cerebral arteries caused by stem, visual and somatosensory potentials, x-rays of the cervical spine. The study included only those patients who did not show abnormalities during somatic and neurological examination. In particular, no organic CNS lesions were detected that affect the vestibular analyzer, as described above in Example 2 above. In this way, organic damage to the nervous system and vertigo caused by psychiatric syndromes were excluded.

 After exclusion of organic lesions and differential diagnosis in accordance with Example 2, the following criteria are used to determine the diagnosis of CSD:

 1) constant (duration 3 months) feelings of non-rotating dizziness, nausea, severity or subjective imbalance;

 2) there is a chronic (duration of 3 months) hypersensitivity to one's own movement, which does not relate to specific directions, and to movements of objects in the environment;

 3) symptoms worsen in conditions with complex visual stimuli, such as grocery stores or shopping centers, or when performing precise visual tasks, such as reading or using a computer;

 4) there are no active physical (that is, structural or cellular) neuro-otologic diseases, other specific medical conditions that may cause dizziness, the patient also does not take medicines that may cause dizziness;

 5) the results of radiographic visualization of the brain exclude neuro-otologically significant anatomical lesions;

 6) equilibrium test results are in the control range or do not indicate structural vestibular deficiency.

 The study included 45 men and women aged 18 to 65 years with a verified diagnosis of chronic subjective dizziness.

 To determine the associated anxiety and depressive states, the Beck Depression Index and the Spielberg test are used in accordance with Example 2.

 Of these, 12 patients were identified (27%) with moderate levels of depression and anxiety.

The patients were divided into 5 groups: placebo group,

 Buspirone 5 mg per day,

 Buspirone 15 mg per day,

 group receiving buspirone 30 mg per day,

 group taking buspirone 100 mg per day.

 Method of application: inside, 1 time per day and always at the same time, in the morning, regardless of the meal for 12 weeks.

 To assess the condition of patients with functional dizziness before treatment and after 12 weeks, the Dizziness Handicap Inventory test was used as described above. Estimated points used to track changes.

 Statistical processing of parameters. the safety and formalization of the results of the study of the use of buspirone for the treatment of functional vertigo were performed in accordance with the Rules of Good Clinical Practice of the Eurasian Economic Union using the statistical package SPSS Statistics 19.0. The research results are summarized in Table 3.

Table 3.

- difference from the placebo group, p <0.05. In the course of the study, a significant statistically significant decrease (significance level p <0.05) of the level of functional dizziness of CSD was found in the groups treated with buspirone compared to the group treated with placebo. At the same time, the effectiveness of treatment does not depend on the presence or absence of concomitant depressive or anxiety states. Example 5. Obtaining pharmaceutically acceptable salts of buspirone.

 This compound contains ionic groups (secondary, tertiary amines) and can form salts, which are prepared by methods known in the art.

 For example, to a solution of buspirone in ether and add HCl in ethanol in a molar ratio of 1: 1.1 to precipitate the hydrochloride. The resulting precipitate is recrystallized from EtOAc / EtOH 1: 1. Buspirone hydrochloride is obtained with a yield of 98.5%, LC MS m / z 422 (M + l).

Example 6. Getting the drug in pill form. 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg of buspirone or its pharmaceutically acceptable salt are mixed, and pressed into a bar. The resulting bar is crushed into granules and sieved through sieves, collecting granules of 14-16 mesh. The resulting granules are tabletted into a suitable tablet form weighing 560 mg each.

Example 7. Getting the drug in the form of capsules. Buspirone or its pharmaceutically acceptable salt is thoroughly mixed with a lactose powder in a ratio of 2: 1. The resulting powdered mixture is packaged in 300 mg gelatin capsules of suitable size.

Example 8. Obtaining a medicinal product in the form of injection compositions for intramuscular, intraperitoneal or subcutaneous injection. 500 mg of buspirone or its pharmaceutically acceptable salt 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 and pharmacology.

Claims

CLAIM 1. The use of buspirone or its pharmaceutically acceptable salt for the treatment of functional dizziness.  2. The use according to claim 1, characterized in that said functional vertigo is persistent postural perceptual vertigo.  3. The use according to claim 1, characterized in that said functional vertigo is postural phobic instability.  4. The use according to claim 1, characterized in that said functional dizziness is chronic subjective dizziness.  5. The use according to claim 1, characterized in that the pharmaceutically acceptable salt of buspirone is buspirone hydrochloride.  6. The use of the pharmaceutical composition of buspirone for the treatment of functional dizziness, said pharmaceutical composition of buspirone containing buspirone or its pharmaceutically acceptable salt in a therapeutically effective amount, and at least one pharmaceutically acceptable carrier.  7. The use according to claim 6, characterized in that said functional vertigo is persistent postural perceptual vertigo.  8. The use according to claim 6, characterized in that said functional vertigo is postural phobic instability.  9. The use according to claim 6, characterized in that said functional dizziness is chronic subjective dizziness.  10. The use according to claim 6, characterized in that the pharmaceutically acceptable salt of buspirone is buspirone hydrochloride. 11. The use according to claim 6, characterized in that the pharmaceutical composition is a composition with a slow release. 12. The use according to claim 6, wherein the pharmaceutical composition of buspirone is used in a dosage form placed in a pharmaceutically acceptable package, said dosage form containing buspirone in a therapeutically effective amount.  13. The use according to claim 12, characterized in that the dosage form is selected from the group including tablets, capsules and injections.  14. The use according to claim 12, wherein the dosage form is a sustained release dosage form.  15. The use according to claim 6, characterized in that buspirone is used in a dose of 5- 75 mg / day. 16. The use according to claim 6, characterized in that buspirone is used in a dose of 15 mg once a day.  17. The use according to claim 6, characterized in that buspirone is used in combination with selective serotonin reuptake inhibitors (SSRIs), selective serotonin and noradrenaline reuptake inhibitors (SSRIs), tranquilizers or tricyclic antidepressants.