EA041007B1 - USE OF BUSPIRONE FOR THE TREATMENT OF FUNCTIONAL VERTIGO - Google Patents

Description

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 vertigo, persistent postural perceptual vertigo (PPPG, PPPD), postural phobic instability (PFN, PPV), chronic subjective vertigo (CSD, CSD), the effect of which is the possibility of treating functional dizziness, independent of depressive and anxiety states, the rapid onset of a therapeutic effect, the ease of dose titration, the absence of a sedative effect and a favorable safety profile.

Functional (psychogenic) vertigo is one of the most common causes of vertigo complaints. In the general population, functional dizziness accounts for about 15-23% [Brandt T., Dieterich M. Vertigo and dizziness: common complaints. 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 under 45 years of age, functional dizziness ranks first among the causes of complaints of dizziness: it accounts for up to 38% of cases of dizziness [Zamergrad M.V. Age aspects of dizziness.//Neurological journal. 2014. V. 19. No. 3. P. 2128]. In some cases, functional dizziness does not develop primarily, but as a result of some organic vestibular disorder. For example, functional vertigo is a common complication of common vestibular disorders such as benign paroxysmal positional vertigo 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.

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

the vestibular apparatus is exposed to unusual influences, for example, when pitching;

the head or neck is positioned in an unusual way, such as when overextension while painting the ceiling.

The discrepancy between information from different sensory systems explains motion sickness, altitude vertigo, and visual vertigo. The latter most often occurs when watching films with chase scenes, when the visual sensation of movement is not accompanied by appropriate vestibular and somatosensory stimuli.

Another example of functional vertigo is vertigo resulting from too much head movement in zero gravity.

Dizziness that develops due to psychological factors is also defined as functional dizziness, as opposed to organic dizziness that occurs on the basis of 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 on the basis of 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].

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

1) non-systemic dizziness that occurs when standing or walking; at the same time, a neurological examination, including the Romberg test, tandem walking, standing on one leg, does not reveal abnormalities;

2) a constant, sometimes increasing, sometimes weakening feeling of instability or short-term (several seconds or minutes) sensations of coordination disorder;

3) attacks of dizziness may occur spontaneously, but more often develop in a certain situation (on a bridge, on a staircase, 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 quickly consolidate negative associations and the desire to avoid provoking circumstances;

4) anxiety and autonomic disorders develop during and after dizziness, and 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, patients with functional dizziness have poor tolerance to vestibular stimuli since childhood, which gives reason to some authors to associate the patient's sensations with certain disorders in the vestibular system [Furman J.M., Jacob R.G. Psychiatric

- 1 041007 dizziness.//Neurology. 1997 Vol. 48.pp. 1161-1166].

A functional disorder is a health condition that impairs the normal function of a bodily process, but where every part of the body appears completely normal on examination. This contrasts with a structural disorder (in which some part of the body can be seen to function 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 psychiatric disease [Dieterich M., Staab J.P., Brandt T. Functional (psychogenic) dizziness.//Handbook of Clinical Neurology, Vol. 139, Chapter 37, 2016, pp. 447-468], i.e. is not caused by a primary psychiatric disorder such as anxiety or depression, nor is it caused by structural changes in the CNS.

Functional and mental disorders that cause vestibular symptoms are considered separately from each other and from structural vestibular diseases. This is because experimental data show that they occur independently [Brandt T. Phobic postural vertigo.//Neurology. 1996; 46:1515-9; Staab J.P., Ruckenstein M.J. Which comes first? Psychogenic dizziness versus otogenic anxiety.//Laryngoscope 2003, 113: 1714-1718; Staab J.P., Ruckenstein M.J., Expanding the differential diagnosis of dizziness.//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.//J. Neurol., 2008, 255: 420428]. Therefore, their separate contribution to the pathology of the vestibular system should be recognized. Psychiatric disorders that cause vestibular symptoms are defined by the relevant diagnostic criteria in the 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 combined. 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 of vestibular disorders//J. Vestib. Res., 2009, 19(1-2): 1-13], which further defined dizziness as a false or distorted sensation of movement, non-stationarity as a feeling of rocking or rocking when standing upright, an immovable sensation of disordered spatial orientation.

Functional vestibular disorders include, in particular, the following diseases, which are described in detail in the neurootological literature: persistent postural perceptual vertigo, postural phobic instability and chronic subjective vertigo. None of these disorders has 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 J.P., Brandt T. Functional (psychogenic) dizziness// Handbook of Clinical Neurology, Vol. 139, Chapter 37, 2016, pp. 447.468].

One subtype of functional vertigo is persistent postural perceptual vertigo (PPPD). This disease, included in the draft ICD-XI code AA92.1, is a chronic sensation of dizziness, non-rotational in nature, which can increase or decrease periodically, provoked by an upright 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/icd11/browse/l-m/en].

PPPD is defined as a type of vertigo that persists for more than three months without an identifiable etiology [Staab J.P. chronic subjective dizziness; review article//Continuum (Minneap Minn), 2012; 18:1118-41]. This is a somatoform disorder that is the subject of study in otology and neuropsychiatry. It appears that PPPD patients develop a condition that predisposes to persistence of vertigo after an episode of organic or emotional distress. In this state, the postural stability system becomes hyper-reactive for movement, especially under conditions with high visual loads. Thus, PPPD reflects the preservation of a specific pattern of posture 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//J. Neurol. 2005; 252:564-9].

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

(1) persistent wiggling or instability not detectable on physical examination;

(2) worsening of symptoms when standing;

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

- 2 041007 (4) the presence of illness or emotional shock at the onset of symptoms;

(5) concurrent illnesses that generally increase symptoms.

Clinical variants of the formation of PPPD confirm the special status of this form of vertigo, which reflects disturbances at the level of integration of various sensory modalities, in contrast to the vertigo observed in anxiety disorders. A typical portrait of a patient with PPPD indicates the relationship between the vestibular and non-vestibular components in the formation of a specific clinical picture of PPPD.

The share of PPPD among all variants of vertigo (vestibular and non-vestibular 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 B., Wurthmann S., Naegel S., Ayzenberg I., Diener H.C., Katsarava Z., Obermann M., Persistent Postural-Perceptual Dizziness: A Matter of Higher, Central Dysfunction?//PLoS One.2015;10(11):e0142468). According to the authors of the present invention, approximately 21.4% (unpublished data, 2014). According to modern concepts, anxiety is not a diagnostic criterion for PPPD [Dieterich M., Staab J.P., Brandt T. Functional (psychogenic) dizziness//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, insula, anterior cingulate cortex, prefrontal cortex, superior frontal gyrus, and inferior frontal gyrus. These drugs alter and regulate neuronal conduction 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 J.P., Ruckenstein M.J., Amsterdam J.D. A prospective trial of sertraline for chronic subjective dizziness//Laryngoscope. 2004; 114: 1637-1641].

One of the options for functional dizziness is postural phobic instability (PFN, PPV). Patients presenting with undiagnosed vertigo not explained by an established otoneurological disease are being identified, 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//Neurology. 1996; 46: 1515-1519] described this disease as phobic postural vertigo (unstability) (PPV), but did not fully explain the origin of the symptoms of this disease and did not suggest any treatment.

Functional vestibular syndrome PPV is one of the most common diseases encountered in neurootological practice. According to the German Center for Vertigo and Balance Disorders, it was the second most common diagnosis, found in 15% of 17,700 adult outpatients, second in prevalence 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. 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]. The frequency of this diagnosis in other centers and countries varied significantly: from 2.5% [Ketola S., Niemensivu R., Henttonen A. et al. Somatoform disorders in vertiginous children and adolescents.//Int. J. Pediatr. Otorhinolaryngol., 2009, 73 (7): 933-936] up to 16% [Lopez-Gentili L.I., Kremenchutzky M., Salgado P.//Astatistical analysis of 1300 patients with dizziness-vertigo. Its most frequent cases.//Rev. Neurol., 2003, 36 (5): 417-429], possibly due to 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 the second most common after the migraine syndrome of childhood benign paroxysmal dizziness (39%) [Batu E.D., Anlar B., TopcuMet al. Vertigo in childhood: a retrospective series of 100 children.//Eur. J Paed. Neurol., 2015, 19: 226-232].

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

non-vestibular pseudo-vertigo (feeling of swaying, approaching fall, unstable ground);

dissociation between subjective sensations 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;

improved with exercise or small amounts of alcohol; the onset of the disease from an acute episode (vestibular dizziness, panic attack); personality traits: perfectionism, obsession, tendency to anxiety and depression.

In the early 21st century, Staab and Rukenstein linked the physical symptoms of PPV to behavioral factors [Staab J.P. Chronic dizziness: the interface between psychiatry and neuro-otology.//Curr. Opin. Neu-3 041007 rol. 2006; 19:41-8; Staab J.P. Assessment and management of psychological problems in the dizzy patient.//Continuum (Minneap Minn), 2006; 12:189-213].

Anxiety is treated with great care in the PPV criteria because this dizziness is not due to panic attacks or other forms of anxiety.

The association of postural vertigo with subjective instability of position and gait in patients with normal otoneurological, vestibular, and balance tests (eg, video-oculography including caloric irrigation, neuroimaging) and no other disorder that could explain the symptoms of PPV.

Monosymptomatic subjective balance disorder is associated with standing or walking and presents as a sudden worsening that occurs with or without recognizable triggers and with or without associated anxiety.

Patients with PPV usually have an obsessive personality as their most prominent personality trait, a tendency to heightened introspection, and a need to keep things under control. They tend to be ambitious and make high demands on themselves, and are often easily irritated and prone to fear [Kapfhammer H.P., Mayer C., Hock U. et al. Course of illness in phobic postural vertigo.//Acta Neurol. Scand., 1997, 95: 23-28].

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

PPV can present 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 vertigo in this age group) and the incidence is independent of sex. If left untreated, symptoms worsen, generalization of stimuli develops, and avoidance behavior may increase until the patient is able to leave their apartment unaided.

The 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., Srupp 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.//J. Neurol. neurosurgery. Psychiatry, 1981, 48: 729-735], visual dizziness [Bronstein A.M. The visual vertigo syndrome.//Acta Otolaryngol (Stockh), 1995, 520: 45-48; Bronstein A.M. Vision and vertigo: some visual aspects of vestibular disorders.//J. Neurol., 2004, 251: 381-387], disembarkation syndrome [Murphy T.P. Mal de debarquement syndrome: a forgotten entity.//Otolaryngol. Head Neck Surg., 1993, 109: 10-13].

The pathophysiological mechanisms of PPV may include the perception of involuntary body rocking and random individual head movements as disturbing external perturbations with simultaneous illusory movements of the environment, which can be explained by a temporary mismatch of the efferent signal and back afferentation, which are usually compensated in the norm, i.e. there is a discrepancy between the expected and actual movement [Brandt T., Dieterich M., Srupp M. Vertigo and Dizziness: Common Complaints, 2nd edn. Springer, London, 2013].

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

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 the CSD syndrome. Inspired by the available literature on PPV as well as research on movement discomfort 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.//J. Psychopathol. behavior. Assess, 1993, 15: 299-324] and visual dizziness [Bronstein A.M. The visual vertigo syndrome.//Acta Otolaryngol. (Stockh), 1995, 520: 45-48], they identified chronic subjective vertigo [Staab J.P., Ruckenstein M.J. Expanding the differential diagnosis of dizziness.//Arch. Otolaryngol. Head Neck Surg., 2007, 13: 170-176] as a disease in which:

1) there are constant (lasting 3 months) sensations of non-rotating dizziness,

- 4 041007 nausea, heaviness or subjective imbalance;

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

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

4) there are no active organic (i.e. structural or cellular disorders) neurootological diseases, other certain medical conditions that can cause dizziness, the patient is also not taking drugs that can cause dizziness;

5) the results of radiographic imaging of the brain exclude neurootologically significant anatomical lesions;

6) the results of balance tests are in the control range or do not indicate a structural vestibular deficit.

Thus, anxiety states were excluded from the CSD criteria. A comparison of the definitions of CSD and PPV shows several differences. Criteria for CSD emphasize persistent unsteadiness and dizziness. They do not include intermittent attacks of vestibular symptoms. They also focus more closely on symptom provocation with visual stimuli than on standing, even after adding a postural criterion. Psychological elements such as obsessive personality traits, phobic behavior, and mild anxiety and depressive symptoms were excluded because they were considered risk factors or comorbidities rather than core features of the disorder.

According to a large-scale CSD study (345 patients) [Staab J.P., Ruckenstein M. J. Expanding the differential diagnosis of dizziness.//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 had no symptoms of anxiety or mood disorders [Staab J.P. Chronic Subjective Dizziness//Continuum (Mineapp.Minn.). 2012; 18(5 Neurootology): 1118-1141]. Thus, CSD, like PPV, can exist separately from any psychiatric comorbidity (comorbidity).

Triggering events elicit a combination of physiological and behavioral adaptations that are typically expected in response to acute vestibular syndromes or other conditions that impair 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 postural threat [Brown L.A., Gage W.H., Polych M.A. et al. Central set influences on gait. Age dependent effects of postural threat.//Exp. Brain Res., 2002, 145: 286-296; Gage W.H., Sleik R.J., Polych M.A. et al. The allocation of attention during locomotion is altered by anxiety.//Exp. Brain Res., 2003, 150: 385-394].

This means that high-risk balancing strategies, properly evoked by initial adverse events, are still used in CSD patients to manage routine movements and to respond to simple, non-high-risk strategies, spatial and motor stimuli in the environment. Thus, the disease is characterized by an inability to return to normal low-risk postural control. The perception of constant threat extends the use of high-risk postural feedback control mechanisms to situations where it is not needed.

Neurotic response and low extraversion may increase the risk of developing CSD because they decrease the threshold for high-risk postural control involvement. High levels of neurotic response and low levels of extraversion increase the incidence of functional disorders.

Results of functional magnetic resonance [Dieterich M., Staab J.P., Brandt T. Functional (psychogenic) dizziness//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.//Front. behavior. Neurosci., 2015, 9: 334] support the PPV and CSD (and, in addition, PPPD) models, which suggest that their pathophysiological mechanisms involve wide-ranging functional changes in sensory cortical areas (PIVC and visual cortex), areas involved in spatial information processing (hippocampus), postural control (cerebellar vermis), and threat assessment (amygdala), as well as frontal/prefrontal areas that modulate their activity (orbitofrontal cortex, anterior insula, anterior cingulate gyrus). The putative pathophysiological mechanisms of CSD also suggest that hypersensitivity to visual stimuli of movement, complex structures in the environment, and performance of tasks that require constant visual focus are the result of increased visual dependence.

- 5 041007

The existing drug treatment of all forms of functional vertigo is a difficult task that requires close cooperation between a neurologist, a psychotherapist, a psychiatrist and a rehabilitation specialist. According to the current therapeutic principles, treatment consists of psychotherapy (rational and cognitive-behavioral), vestibular rehabilitation and drug therapy. The drugs of choice are selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SSRIs), such as paroxetine, citalopram, fluvoxamine, or sertraline. Sometimes they are combined with tranquilizers (such as lorazepam), which are given in a short course to avoid drug dependence. Tricyclic antidepressants are used as alternative drugs. There are relatively few studies evaluating the effectiveness of drug therapy for vertigo. Open design studies evaluated the efficacy of sertraline, paroxetine, fluvoxamine, fluoxetine, and milnacipran [Staab J.P., Ruckenstein M.J., Solomon D., Shepard N.T. Serotonin Reuptake Inhibitors for Dizziness With Psychiatric Symptoms.//Arch. Otolaryngol. Head Neck Surg., 2002; 128(5): 554560; Staab J.P., Ruckenstein M.J., Amsterdam J.D. A prospective trial of sertraline for chronic subjective dizziness.//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.//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. //J. Vestib. Res. 2007, 17(1): 1-8; Simon N.M., Parker S.W., Wernick-Robinson M., Oppenheimer J.E., Hoge E.A., Worthington J.J., Korbly N.B., Pollack M.H. Fluoxetine for vestibular dysfunction and anxiety: a prospective pilot study.//Psychosomatics. 2005, 46(4): 334-9].

The disadvantages of existing approaches to the treatment of functional dizziness can be considered: 1) the need for long-term titration of the dose of SSRIs and SNRIs, 2) the slow onset of the therapeutic effect, 3) the frequent increase in symptoms of the disease at the beginning of treatment (especially when using SSRIs), 4) a relatively large number of side effects 5) the negative effect 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 unexpectedly found that buspirone (8-[4-[4-(2pyrimidinyl)piperazin-1-yl]butyl]-8-azaspiro[4.5]decan-7,9-dione) can be effectively used to treat various types of functional vertigo.

buspirone (1)

Buspirone (and its hydrochloride) is a partial 5-HT1A receptor agonist that was marketed over 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 for the treatment of generalized anxiety disorder (GAD). The National Cancer Institute (NCI) is currently evaluating the drug's effectiveness in reducing breathlessness in patients who are undergoing chemotherapy for cancer. The National Institute of Neurological Disorders and Stroke (NINDS) is conducting clinical trials//phases regarding the use of buspirone for the treatment of localized epilepsy. The National Institute on Drug Abuse (NIDA) is conducting clinical trials//phases regarding the use of buspirone for the treatment and prevention of cocaine addiction.

Buspirone is an atypical anxiolytic highly effective against generalized anxiety disorder [Apter J.T., Allen L.A. Buspirone: future directions.//!. Clin. Psychopharmacol. 1999; 19(1): 86-93; Flint A.J. Generalized anxiety disorder in elderly patients: epidemiology, diagnosis and treatment options.//Drugs Aging. 2005; 22(2): 101-114; Gale C.K., Millichamp J. Generalized anxiety disorder in children and adolescents//BMJ Clin. Evidence. 2016 Jan 13; 2016 pii: 1002; Goa K.L., Ward A. Buspirone. A preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic.//Drugs. 1986, 32(2): 114-29]. Being a 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., Verriele L., Audinot V., Millan M.J. 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 Sep; 69(3): 149-56], buspirone, apparently, does not 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

- 6 041007 known sedative effect, which is associated with more typical anxiolytics. In vitro, buspirone has shown high affinity for serotonin (5-HT1A) receptors. The drug has no significant affinity for benzodiazepine receptors and does not affect GABA binding in vitro or in vivo when tested in preclinical models. It shows moderate affinity for the D2 dopamine 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 not fully understood due to conflicting anxiolytic effects in the clinic and in animal models [Bauer M.S., Wisniewski S.R., Marangell L.B., Chessick C.A., Allen M.H., Dennehy E.B., Miklowitz D.J., Thase M.E., Sachs G.S. 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 works 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 animal species and the anxiety model used. At the same time, an anxiogenic effect is manifested in a wide range of doses at high doses [Collinson N., Dawson G.R. 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 Cit0 Mdo C., da Silva F.C., Silva M.I., et al. Reversal of cocaine withdrawal-induced anxiety by ondansetron, buspirone and propranolol//Behav Brain Res. 2012; 231(1): 116-23; File S.E., Andrews N. Low but not high doses of buspirone reduce the anxiogenic effects of diazepam withdrawal//Psychopharmacology (Berl). 1991; 105(4): 578-82; Handley S.L., McBlane J.W. 5HT drugs in animal models of anxiety//Psychopharmacology (Berl). 1993; 112(1): 13-20; 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; 273:15565; 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 P.C. An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone//Psychopharmacology (Berl). 1989; 99(1): 48-53; Paine T.A., Jackman S.L., Olmstead M.C. Cocaineinduced 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; Soderpalm B., Hjorth S., Engel J.A. Effects of 5-HT1A receptor agonists and L-5-HTP in Montgomery's conflict test.//Pharmacol Biochem Behav. 1989; 32(1): 259-65; Varty G.B., Morgan C.A., Cohen-Williams M.E., Coffin V.L., Carey G.J. The gerbil elevated plus-maze I: behavioral characterization and pharmacological validation.//Neuropsychopharmacology. 2002 Sep;27(3):357-70].

The anxiogenic effect of buspirone is of great clinical significance due to the fact that exacerbation may occur at the initial stage of chronic treatment with buspirone, which requires careful monitoring of the treatment regimen [Chignon J.M, Lepine J.P. Panic and hypertension associated with a single dose of buspirone.//Lancet. 1989; 2(8653): 46-7; Liegghio N.E., Yeragani V.K., Moore N.C. Buspironeinduced jitteriness in three patients with panic disorder and one patient with generalized anxiety disorder.//J Clin Psychiatry. 1988; 49(4): 165-6; Newton R.E., Marunycz J.D., Alderdice M.T., Napoliello M.J. Review of the side-effect profile of buspirone.//Am. J. Med. 1986; 80(3B): 17-21].

The affinity of buspirone to the receptor complex 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 full agonist of 5-HT1A autoreceptors located on the surface of dendritic neurons of the raphe 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 partly 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., Sama G.S., Hutson P.H., Curzon G. An in vivo dialysis and behavioral study of the release of 5-HT by p-chloroamphetamine in reserpine-treated rats. Br. J Pharmacol. May 1989;97(1):206-12; Sharp T., Bramwell S.R., Grahame-Smith DG. 5-HT1 agonists reduce 5-hydroxytryptamine release in rat hippocampus in vivo as determined by brain microdialysis. Br. J Pharmacol. Feb 1989; 96(2):283-90; Sprouse J.S., Aghajanian G.K. Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse. 1987; 1(1):3-9].

However, buspirone also works as a postsynaptic 5-HT1A receptor agonist, thereby reducing neuronal excitation. These opposite effects may be responsible for the biphasic anxiety-modulating effect of buspirone [Sillar KT1, Simmers A.J. Presynaptic inhibition of primary afferent transmitter release by 5-hydroxytryptamine at a mechanosensory synapse in the vertebrate spinal cord. J Neurosci. May 1994; 14(5Ptl):2636-47; McNaughton N., Panickar K.S., Logan B. The pituitary-adrenal axis and the different behavioral effects of buspirone and chlordiazepoxide. Pharmacol Biochem Behav. May 1996;

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54(1):51-6; 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):491504].

Some studies using a 5-HT1A antagonist indicate the presence of an anxiogenic and anxiolytic effect of buspirone, mediated by its interaction with D2-like and 5HT1A receptor systems, respectively [Collinson N1, Dawson G.R. 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 5HT(1A) partial agonist, buspirone, are blocked by the 5 -HT1A antagonist, WAY 100635. Psychopharmacology (Berl). 1997 Jul; 132(1):35-43].

It has recently been shown that buspirone also acts as a D3 and D4 receptor antagonist with a higher binding affinity compared to D2 receptors [Mello NK1, Fivel P.A., Kohut S.J., Bergman J. Effects of chronic buspirone treatment on cocaine self-administration. neuropsychopharmacology. February 2013; 38(3):455-67].

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

The prior art knows the use of buspirone for the palliative treatment of neurosis, in which symptoms of anxiety appear (US 4182763, 08.01.1980); with hyperactivity, attention deficit (EP 0497314, 03/01/1989); for the treatment of drug addiction and dependence (US 5185329, 09.02.1993); for the treatment of anxiety disorders (WO 2005049041, 06/02/2005; US 7678363, 03/16/2010); psychiatric disorders (US 7678363, 03/16/2010); depression (WO 2007144080, December 21, 2007); neurological disorders (WO 2008083204, 07/10/2008).

Known systemic use of buspirone or its derivatives for the treatment of pathological conditions associated with immune responses (EP 0690715, 28.05.2003); for the treatment of disorders of sexual function and reproduction (US 8052982, 08.11.2011) and sexual dysfunction (US 4640921, 03.02.1987); for the treatment of sleep-related respiratory diseases (WO 2000006163, February 10, 2000). Known use of buspirone for the treatment of glaucoma (US 7763619, 07/27/2010), pain, neuropathy (US 6511982, 01/28/2003), itching (WO 2004084900, 07/10/2004), for the treatment, prevention or alleviation of movement disorders such as Parkinson's disease , dyskinesia (US 9186359, 11/17/2015); with spinal cord injuries, multiple sclerosis, Parkinson's disease (WO 2015127558, 09/03/2015); apnea (EP 0442424, 12/21/1994), as well as use for 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, 05/19/2011).

The authors of the present invention surprisingly found that buspirone reduces the manifestation of dizziness in patients with all forms of functional dizziness (PPPD, CSD and PPV). The authors believe that the fact that, despite the anxiolytic effect of this drug, the hypothalamic-pituitary-adrenal system is activated and the peripheral concentration of adrenaline and norepinephrine increases, is also promising in terms of the use of buspirone in patients with functional dizziness. 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) are present in the region 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 withdrawal 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]. It is also believed that serotonin agonists (and, in particular, 5-HT1A receptors) can prevent motion sickness [Marcus D.A., Furman J.M. Prevention of motion sickness with rizatriptan: a double-blind, placebo-controlled pilot study. Med. sci. Monitor. 2006 Jan: PI17]. 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 seem to be the lack of sedation and muscle relaxant effect, the controlled nature of dose titration, and the favorable safety profile of buspirone.

At the same time, dizziness is a frequent side effect of buspirone when it is used in patients who do not suffer from functional dizziness (Karamanolis G.P., Panopoulos S., Denaxas K., Karlaftis A., Zorbala A., Kamberoglou D., Ladas S.D., Sfikakis P.P.. The 5 -HT1A receptor agonist buspirone improves esophageal motor function and symptoms in systemic sclerosis: a 4-week, open-label trial Arthritis Res Ther 2016 Sep 1; 18:195; Le Foll B., Payer D., Di Ciano P. , Guranda M., Nakajima S., Tong J., Mansouri E., Wilson A.A., Houle S., Meyer J.H., Graff-Guerrero A., Boileau I. Occupancy of Dopamine D3 and D2 Receptors by Buspirone: A [11C] -(+)-PHNO PET Study in Humans Neuropsychopharmacology 2016 Jan 41(2):529-37 Epub 2015 Jun 19 Sutherland S.M., Adler L.A., Chen C., Smith M.D., Feltner D.E. An 8-week, randomized controlled trial of atomoxetine, atomoxetine plus buspirone, or placebo in adults with ADHD J. Clin. Psychia- 8 041007 try. 2012 Apr; 73(4):445-50. Epub 2012 Jan 10; Frey J. M., M intzer M.Z., Rush C.R., Griffiths R.R. Buspirone is differentiated from diazepam in humans using a three-response drug discrimination procedure. Psychopharmacology (Berl). 1998 Jul; 138(1):6-26; Sramek J.J., Tansman M., Suri A., Hornig-Rohan M., Amsterdam J.D., Stahl S.M., Weisler R.H., Cutler N.R. Efficacy of buspirone in generalized anxiety disorder with coexisting mild depressive symptoms. J.Clin. Psychiatry. 1996 Jul; 57(7):287-91). Thus, the reduction in the manifestation of dizziness in patients with all forms of functional dizziness under the action of buspirone is unexpected for a person skilled in the art.

The following are definitions of terms that are used in the description of the 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 distributing agents, delivery vehicles, such as preservatives, stabilizers, fillers, grinders, humectants, emulsifiers, suspending agents, thickeners, sweeteners, flavors, flavors, antibacterial agents, fungicides, lubricants, sustained delivery regulators, the choice and proportion 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, as well as 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 the like. The composition may also include isotonic agents such as 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 grinders and spreaders are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, topical 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 form of administration, as a mixture with conventional pharmaceutical carriers. Suitable unit administration forms include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

A 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 compounds, or prepared specially. In particular, base salts can be prepared specifically from 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, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (For a detailed description of the properties of such salts, see Berge S.M., et al., Pharmaceutical Salts//J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specifically prepared by reacting a purified acid with a suitable base, whereby 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 derived are sodium hydroxide, carbonate, 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 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, ornitine, and arginine, can be used as amino acids.

The objective of the present invention is to 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, providing a clinically optimal rate of onset of a therapeutic effect, ease of dose titration, minimizing the sedative effect, improving the safety 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 dizziness;

functional vertigo is postural phobic instability;

functional dizziness is chronic subjective dizziness;

the pharmaceutically acceptable salt of buspirone is buspirone hydrochloride;

Another object of this invention is the use of a pharmaceutical composition of buspirone for the treatment of functional vertigo. At the same time, said pharmaceutical composition of buspirone contains buspirone or a pharmaceutically acceptable salt thereof 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 dizziness;

functional vertigo is postural phobic instability;

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;

the dosage form is selected from the group consisting of tablets, capsules and injections;

the dosage form is a sustained release dosage form;

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

Buspirone is used at a dose of 15 mg once a day;

Buspirone is used in combination with selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SSRIs), tranquilizers or tricyclic antidepressants.

Pharmaceutical compositions may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, auxiliary agents and/or carriers used in the pharmaceutical field. The pharmaceutical composition, along with buspirone or its pharmaceutically acceptable salt according to 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 obtain common forms. Binders, lubricating agents, disintegrants, solvents, diluents, stabilizers, suspending agents, flavoring agents are used in oral forms; in injection forms, antiseptic agents, solubilizers, stabilizers are used; topical forms use bases, diluents, lubricating agents, antiseptic agents.

Drugs may be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally, or topically). The clinical dosage of the buspirone-containing agent of the present invention in patients may be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, the rate of their metabolism and excretion from the body, as well as depending on the age, sex and stage of the disease of the patient, while the daily dose in adults is usually 10-500 mg, preferably 50-300 mg. Therefore, during preparation from the pharmaceutical composition of the drug of the present invention in the form of dosage units, it is necessary to take into account the above effective dosage, with each

- 10 041007 the dosage unit of the drug should contain 10-500 mg of buspirone, preferably 50-300 mg. As directed by your doctor or pharmacist, these drugs may be taken several times over a period of time (preferably one to six times).

More preferred is the use of buspirone or a pharmaceutically acceptable salt thereof for the treatment of functional vertigo, persistent postural perceptual vertigo, postural phobic instability, chronic subjective vertigo, where buspirone is used at a dose of 5-100 mg/day, preferably 10-60 mg/day, more preferably 15-45 mg/day.

More preferred is the use of buspirone, or a pharmaceutically acceptable salt thereof, for the treatment of functional vertigo, persistent postural perceptual vertigo, postural phobic instability, chronic subjective vertigo, where buspirone is used at a dose of 15 mg once daily, preferably as a sustained release formulation.

More preferred is the use of buspirone or a pharmaceutically acceptable salt thereof for the treatment of functional vertigo, persistent postural perceptual vertigo, postural phobic instability, chronic subjective vertigo, where buspirone is used in combination with selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors. (SSRIs), tranquilizers or tricyclic antidepressants.

The following exemplary embodiments of the inventions illustrate but do not limit the invention.

Examples of the implementation of the inventions

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

One of the closest models for studying the effect of buspirone on functional vertigo is the so-called Suok test on rodents. The test is based on keeping the balance of the animal on an elevated horizontal rod (for mice) or a narrow bar (for rats). Animal balance control (falls and misses) is assessed. Suok's modified light-dark test is the same equipment. Half of the rod or bar is brightly lit (the aversive area) in a dark experimental room. In the modified test, the same parameters are evaluated. The Suok test allows you to reliably determine the status and presence of anxiety and imbalance in rodents. Summarizing, the studies conducted on the described model allow an integral assessment of the behavioral and neurological aspects of anxiety/vestibular disorders. Such studies demonstrate the possibility of screening potential drugs that affect the vestibular apparatus.

Buspirone (or its hydrochloride) in the Suok test significantly reduced functional vertigo in rodents compared to placebo.

Example 2 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 being conducted, where participants in the study include patients who have undiagnosed dizziness that is not explained by an otoneurological disease using a full range of diagnostic tests.

Patients describe dizziness as a feeling of insecurity, unsteadiness, a sense of derealization and impending loss of consciousness. Often there is a condition that patients can compare to a feeling of motion sickness: a feeling of an unstable, swaying surface on which patients stand or walk, and at the same time there is a feeling of slight nausea. As a result, it seems to patients that they walk unevenly, that they are rocking from side to side, but from the side, gait disturbances are not noticeable even to close people. These sensations are constantly present, intensifying on the street, in the subway, in large stores or during emotional stress. Throughout the entire period of the disease, attacks of systemic dizziness are absent.

Patients underwent laboratory blood and urine tests, ECG, echocardiography, ultrasound duplex scanning of the brachiocephalic arteries, MR tomography of the brain, MR angiography of the cerebral arteries, evoked stem, visual and somatosensory potentials, radiography of the cervical spine.

The study included only those patients in whom no abnormalities were detected during somatic and neurological examination, in particular, there were no organic CNS lesions affecting the vestibular analyzer. In particular, nystagmus, signs of latent vestibular dysfunction were not detected during clinical otoneurological examination under the control of videonystagmography. Patients had to clearly perform index coordinating tests. Dysdiadochokinesis, dysmetria were excluded. In the Romberg test, patients had to be stable. In the complicated Romberg test with closed eyes, as a rule, pronounced uncertainty was noted, but the test was performed satisfactorily. In selected patients, gait disturbances, including tandem and flank, were not detected. The Fukuda test must be negative. So

- 11 041007 organic lesions of the nervous system were excluded.

The differential diagnosis of PPV included structural vestibular disorders, other medical conditions, and psychiatric syndromes. The most important functional and psychiatric syndromes included the following: panic disorder with or without 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:

non-vestibular pseudo-vertigo (feeling of swaying, approaching fall, unstable ground);

dissociation between subjective sensations and objective signs;

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

improved with exercise or small amounts of alcohol;

the onset of the disease from an acute episode (vestibular dizziness, panic attack); personality traits: perfectionism, obsession, tendency to anxiety and depression.

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

The Beck Depression Index and the Spielberg test were used to determine concomitant anxiety and depressive states.

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

Standard indicators:

0-9: indicates minimal depression;

10-18: indicates mild depression;

19-29: indicates mild depression;

30-63: indicates severe depression.

The Spielberger test (State-Trait Anxiety Inventory, STAI) consists of 20 statements related to anxiety as a state (anxiety state, reactive or situational anxiety) and 20 statements to define anxiety as a disposition, personality trait (personal anxiety questionnaire) [Spielberger C.D. , Gorsuch R.L., Lushene R.E. Manual for the Strait - Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press; 1970].

According to those in the table. 1 questions NN 1-20 assesses reactive anxiety (anxiety as a state). On questions NN 21-40 (located in the 2nd table), personal anxiety is assessed (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 for each scale is 20 points, the maximum is 80 points.

16 patients (32%) are identified with a moderate level of depression and anxiety.

Patients are divided into 5 groups:

placebo group, buspirone 5mg/day group, buspirone 15mg/day group, buspirone 30mg/day group, buspirone 100mg/day group.

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

To assess the condition of patients with functional dizziness before treatment and after 12 weeks, the Dizziness Handicap Inventory test is used [Dieterich M., Staab J.P., Brandt T. Functional (psychogenic) dizziness//Handbook of Clinical Neurology, Vol. 139, Chapter 37, 2016, pp. 447-468]. The purpose of this scale is to identify the difficulties that may arise due to the state of vertigo. For 25 questions, mark the answers always or not, or sometimes for each question. Each answer is scored from 0 to 4 points. The highest score is 100 (severe condition), the lowest score is 0 (no dizziness). Estimated scores are used to track changes.

Statistical processing of safety parameters and presentation of the results of the study of the use of buspirone for the treatment of functional dizziness 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 given in table. 1.

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Table 1

Group Change in Mean Group Dizziness Handicap Inventory at the End of Week 12 from Baseline 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 (significance level p<0.05) in the level of functional dizziness PPV in the groups treated with buspirone was revealed, compared with 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 conditions.

Example 3 Use of buspirone for the treatment of postural perceptual vertigo.

To study the use of buspirone (or its hydrochloride) for the treatment of postural perceptual vertigo, clinical trials were carried out in accordance with example 2, where as volunteers in the study included patients who go to an outpatient appointment with a neurologist with complaints of dizziness, unsteadiness when walking, which disturb them during the last 6-7 months.

Patients underwent laboratory blood and urine tests, ECG, echocardiography, ultrasound duplex scanning of the brachiocephalic arteries, MR tomography of the brain, MR angiography of the cerebral arteries, evoked stem, visual and somatosensory potentials, radiography of the cervical spine.

The study included only those patients who did not reveal abnormalities during somatic and neurological examination. In particular, no organic CNS lesions affecting the vestibular analyzer were found, as described above in Example 2 above. Thus, organic lesions of the nervous system and dizziness caused by psychiatric syndromes were excluded.

The algorithm for diagnosing PPPD is reduced to the use of diagnostic criteria and the exclusion of other causes. The differential diagnosis included vestibular migraine, panic attacks, and some other conditions.

Diagnostic criteria:

(1) persistent wiggling or instability not detectable on physical examination;

(2) worsening of symptoms when standing;

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

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

(5) concurrent illnesses that generally increase symptoms. The study included 65 men and women aged 18 to 68 years with a verified diagnosis of persistent postural perceptual vertigo.

To determine concomitant anxiety and depressive conditions, the Beck Depression Index and the Spielberg test are used in accordance with example 2.

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

Patients are divided into 5 groups:

placebo group, buspirone 5mg/day group, buspirone 15mg/day group, buspirone 30mg/day group, buspirone 100mg/day group.

Method of application: inside, 1 time per day and always at the same time, in the morning, regardless of food intake 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 presentation of the results of the study of the use of buspirone for the treatment of functional dizziness was carried out in accordance with the Rules of Good Clinical Practice of the Eurasian Economic Union using the SPSS Statistics 19.0 statistical package. The research results are given in table. 2.

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table 2

Group Change in Mean Group Dizziness Handicap Inventory at the End of Week 12 from Baseline Visit placebo -0.9±0.1 Buspirone 5 mg/day -2.9±0.2 * Buspirone 15 mg/day -8.9±0.2 * Buspirone 30 mg/day -10, GCD * Buspirone 100 mg/day -12.8±0.2 *

* - difference from the placebo group p<0.05.

The study revealed a significant statistically significant reduction (significance level p<0.05) in the level of functional vertigo PPPD in 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 conditions.

Example 4 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 dizziness, clinical trials were carried out in accordance with example 2, where as volunteers, the study included patients who go to an outpatient appointment with a neurologist complaining of dizziness, a vague feeling of unsteadiness, which worsens when triggered in their surroundings, such as high places, being on moving objects, or being in traffic conditions, such as busy streets or crowds of people.

Patients underwent laboratory tests of blood and urine, ECG, echocardiography, ultrasound duplex scanning of the brachiocephalic arteries, MP-tomography of the brain, MP-angiography of the cerebral arteries, evoked stem, visual and somatosensory potentials, radiography of the cervical spine.

The study included only those patients who did not reveal abnormalities during somatic and neurological examination. In particular, no organic CNS lesions affecting the vestibular analyzer were found, as described above in Example 2 above. Thus, organic lesions of the nervous system and dizziness caused by psychiatric syndromes were excluded.

After exclusion of organic lesions and differential diagnosis according to example 2, the following criteria are used to determine the diagnosis of CSD:

1) persistent (lasting 3 months) sensations of non-rotating dizziness, lightheadedness, heaviness, or subjective imbalance;

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

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

4) there are no active physical (i.e. structural or cellular) neurootological diseases, other certain medical conditions that can cause dizziness, the patient is also not taking drugs that can cause dizziness;

5) the results of radiographic imaging of the brain exclude neurootologically significant anatomical lesions;

6) the results of balance tests are in the control range or do not indicate a structural vestibular deficit.

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

To determine concomitant anxiety and depressive conditions, the Beck Depression Index and the Spielberg test are used in accordance with example 2.

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

Patients were divided into 5 groups:

placebo group, Buspirone 5 mg daily group, Buspirone 15 mg daily group, Buspirone 30 mg daily group, Buspirone 100 mg daily group.

Claims (17)

Method of application: inside, 1 time per day and always at the same time, in the morning, regardless of food intake for 12 weeks. To assess the condition of patients with functional dizziness before and after treatment 12 weeks used the Dizziness Handicap Inventory test as described above. Estimated scores were used to track changes. Statistical processing of safety parameters and presentation of the results of the study of the use of buspirone for the treatment of functional dizziness was carried out in accordance with the Rules of Good Clinical Practice of the Eurasian Economic Union using the SPSS Statistics 19.0 statistical package. The research results are given in table. 3. Table 3 Group Change in Mean Group Dizziness Handicap Inventory at the End of Week 12 from Baseline Visit placebo -0.8±0.1 Buspirone 5 mg/day -2.2±0.2 * Buspirone 15 mg/day -7.7±0.2 * Buspirone 30 mg/day -9.1±0.2 * Buspirone 100 mg/day -10.5±0.2 * * - difference from the placebo group p<0.05. The study revealed a significant statistically significant reduction (significance level p<0.05) in the level of functional dizziness CSD 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 conditions. Example 5 Preparation of pharmaceutically acceptable salts of buspirone. This compound contains ionic groups (secondary, tertiary amines) and can form salts, which are obtained by methods known in the art. For example, to a solution of buspirone in ether, HCl in ethanol is added in a molar ratio of 1: 1.1 to precipitate the hydrochloride. The resulting salt precipitate is recrystallized from a mixture of EtOAc/EtOH 1:1. Buspirone hydrochloride is obtained with a yield of 98.5%, LC MS m/z 422 (M+l). Example 6. Obtaining a drug in the form of tablets. 1600 mg of starch, 1600 mg of milled lactose, 400 mg of talc and 1000 mg of buspirone or a pharmaceutically acceptable salt thereof are mixed and pressed into a bar. The resulting bar is crushed into granules and sifted through sieves, collecting granules with a size of 14-16 mesh. The resulting granules are tableted into suitable tablet form, each weighing 560 mg. Example 7. Obtaining a drug in the form of capsules. Thoroughly mix buspirone or its pharmaceutically acceptable salt with lactose powder in a ratio of 2:1. The resulting powder mixture is packaged in 300 mg gelatin capsules of a suitable size. Example 8 Preparation of a drug in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injections. Mix 500 mg of buspirone or its pharmaceutically acceptable salt 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. CLAIM 1. The use of buspirone or a pharmaceutically acceptable salt thereof for the treatment of functional vertigo. 2. Use according to claim 1, characterized in that said functional vertigo is persistent postural perceptual vertigo. 3. Use according to claim 1, characterized in that said functional vertigo is postural phobic instability. 4. Use according to claim 1, characterized in that said functional vertigo is chronic subjective vertigo. 5. Use according to claim 1, characterized in that the pharmaceutically acceptable salt of buspirone is buspirone hydrochloride. 6. The use of a pharmaceutical composition of buspirone for the treatment of functional dizziness, wherein said pharmaceutical composition of buspirone contains buspirone or a pharmaceutically acceptable salt thereof in a therapeutically effective amount and at least one - 15 041007 pharmaceutically acceptable carrier. 7. Use according to claim 6, characterized in that said functional vertigo is persistent postural perceptual vertigo. 8. Use according to claim 6, characterized in that said functional vertigo is postural phobic instability. 9. Use according to claim 6, characterized in that said functional vertigo is chronic subjective vertigo. 10. Use according to claim 6, characterized in that the pharmaceutically acceptable salt of buspirone is buspirone hydrochloride. 11. Use according to claim 6, characterized in that the pharmaceutical composition is a sustained release composition. 12. The use according to claim 6, characterized in that the pharmaceutical composition of buspirone is used in a dosage form placed in a pharmaceutically acceptable package, and said dosage form contains buspirone in a therapeutically effective amount. 13. Use according to claim 12, characterized in that the dosage form is selected from the group consisting of tablets, capsules and injections. 14. Use according to claim 12, characterized in that the dosage form is a sustained release dosage form. 15. Use according to claim 6, characterized in that buspirone is used at a dose of 5-100 mg/day. 16. The use according to claim 6, characterized in that buspirone is used at a dose of 15 mg once a day. 17. Use according to claim 6, characterized in that buspirone is used in combination with selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), tranquilizers or tricyclic antidepressants. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2