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Introduction. Microparticles are of great interest for use in various drug delivery systems. The intranasal route of administration holds a special place due to its several advantages, including ease of use, minimal side effects, and the ability for rapid delivery of drug directly to the brain. The drug in the microparticles acts locally, thereby ensuring the release of the drug in the required amount in the target organ. The drug from the nose enters directly into the brain through the olfactory region along the sensory nerves. The development of microparticles with the ability to mucoadhesion on the surface of the nasal mucosa will increase the bioavailability of drugs used in the treatment of diseases and disorders of the central nervous system (CNS).Aim. Development and study of microcapsules with mucoadhesive properties for the intranasal delivery system of levodopa.Materials and methods. Microcapsules (MC) were obtained by ultrasonic electrospraying method on a B-390 encapsulator (BUCHI, Switzerland) followed by filtration under vacuum, washing with deionized water and freeze-drying at –50 °C and 0.05 mBar for 48 h in a FreeZone 1 L dryer (Labconco, USA). The structural features of MC were studied by optical microscopy using Evident CX33 microscope with high-resolution camera (Olympus, Japan). For evaluation of the images, we used ImageView™ software (version x64, 4.11.22376.20230402). Morphology of prepared microcapsules were also detected using a portable ultraviolet light source (Jialitte F114, China) by a digital USB microscope (OT-INL40 1000X, China). The mucoadhesive properties of sodium fluoresceinate-loaded MC were studied using isolated sheep nasal mucosa in an SI60 incubator (Stuart, UK) at 37.0 ± 0.5 °C. Fluorescent images were obtained using a TLC Visualizer 3 high-resolution imaging system (CAMAG®, Switzerland). ImageJ 1.53e software (ImageJ, USA) was used to process the obtained macroscopic images and plot graphs. The encapsulation efficiency, % (EE%) and loading capacity, % (LC%) of levodopa loaded MC were assessed using UV spectrophotometry on an Evolution™ 220 device (Thermo Fisher Scientific, USA) at a wavelength of 202 nm. The release of levodopa from MC was performed using a CE 7smart flow cell (SOTAX AG, Switzerland), method IV (State Pharmacopoeia XV of the Russian Federation), at a temperature of 37 ± 0.5 °C for 3 hours in an artificial nasal fluid (ANF) medium. The amount of released drug was determined using an Evolution™ 220 UV spectrophotometer (Thermo Fisher Scientific, USA) at a wavelength of 202 nm.Results and discussion. A method for MC preparation was developed, the device parameters and the optimal composition of microparticles were selected. Two types of MC were obtained: alginate MC and MC coated with Eudragit® EPO (EPO), which have mucoadhesive properties. The average diameter of alginate MC was 0.365 ± 0.018 mm, EPO-coated MC – 0.426 ± 0.017 mm. Alginate MC are washed off the surface of isolated sheep nasal mucosa 5 minutes after irrigation with ANF, and EPO-coated are retained for 1 hour. EE% of MC with levodopa is above 90 %. LC% of EPO-coated is higher than that of alginate MC. The release of levodopa into the ANF medium from EPO-coated MC was 100 % after just 30 minutes of the study, while for alginate MC it was no more than 60 ± 6.1 % after 3 hours.Conclusion. EPO-coated MCs exhibit mucoadhesive properties on the nasal mucosa surface and their further study is promising for use in intranasal levodopa delivery systems.

Objective: to evaluate the efficacy of antiparkinsonian drugs of different groups considering the frequency-amplitude characteristics in the correction of tremulous hyperkinesis in Parkinson's disease (PD) using tremorography. Material and methods. 172 patients with a confirmed diagnosis of PD were observed. Taking into account age and contraindications, patients were divided into four groups receiving one of four drugs in monotherapy: dopamine receptor agonists (ADR; pramipexole), levodopa (Tidomet forte), anticholinergics (biperiden), amantadines (amantadine sulfate). Before starting treatment and after completion of the selected therapy, patients underwent tremorography to analyse the frequency, amplitude and duration of tremor over time in four standard tests. Results. All antiparkinsonian drugs reduced rest tremor, and the efficacy of pramipexole in treating tremor was comparable to that of levodopa in the early stages of the disease. As the severity of the disease increased, the efficacy of ADRs decreased, whereas levodopa became more important. Amantadine sulfate showed the lowest efficacy in rest tremor. The efficacy of anticholinergics against tremor is high but inconsistent. Conclusion. We demonstrated feasibility of using tremorography in the selection of an individualised treatment programme for patients with shaking hyperkinesis in PD , and the high efficacy of levodopa in shaking hyperkinesis was confirmed.

The prevalence of dry eye syndrome (DES) in Parkinson's disease (PD) reaches 87% and leads to impaired quality of life in many patients.Objective: to evaluate the lacrimal function and the effect of dopaminergic therapy in patients with PD.Material and methods: 43 patients with stage II–III PD according to Hoehn and Yahr (H&Y) receiving therapy with levodopa (n=17), amantadines (n=13) and dopamine receptor agonists (ADR) (n=28) were assessed using Schirmer's test (to estimate tear flow), sialometry, Unified Parkinson's Disease Rating Scale (UPDRSI-IV), Schwab and England Activities of Daily Living scale (Sch&En), the Parkinson’s Disease Questionnaire Summary Index (PDQ-39), the Mini Mental State Examination Scale (MMSE), the Non-Motor Symptom Questionnaire (NMSQ), the American Urological Association Symptom Scale (AUA), the Gastrointestinal Symptom Rating Scale (GSRS), the Bristol Stool Form Scale (BSFS).Results. Lacrimal insufficiency was found in 49% of patients. It occurred more frequently (χ2=9.546; p=0.003) in patients taking amantadine and correlated with the daily dose of amantadine (r-S=-0.359). It did not depend on the intake of ADR and levodopa and their doses but correlated with the UPDRS-IV score (r-S= -0.463), namely with the presence and duration of OFF-periods. Lacrimal insufficiency correlated with the Sch&En score (r-S=0.321) and non-motor parameters: UPDRSI (r-S =-0.302), NMSQ (r-S=-0.435), constipation domain of the GSRS (r-S=-0.362), BSFS (r-S=0.363). It was not related to age, gender, stage and duration of PD, motor symptoms of parkinsonism (assessed during the ON-phase) and was not related to salivation (although it was reduced in 39.5% of patients).Conclusion. Lacrimal insufficiency is observed in half of patients with stage II–III PD; it is related to the presence and duration of OFF-periods, the severity of other autonomic disorders and the use of amantadines, suggesting the role of dopamine dysregulation, neurodegeneration of autonomic centers and anticholinergic therapy in the development of DES in PD.

Parkinson’s disease (PD) is a progressive neurodegenerative disease with various clinical manifestations, its origin not always can be explained only by dopamine deficiency. Long-term treatment with levodopa (especially its intraduodenal administration), as well as clinical manifestations of polyneuropathy, cognitive deficits, postural disorders with freezing of gate, REM sleep behavioral disorders, are more often associated with vitamin B12 deficiency. Several reasons for this association and mechanisms of their development are discussed. Early detection of cobalamin deficiency in PD, especially in patients from high-risk groups, makes it possible to stop this pathological condition timely and prevent irreversible changes. Modern data on the use of high-dose (1000 μ g) oral vitamin B12 are presented, it has comparable clinical efficacy and significant advantages, compared with the parenteral form, in terms of the ease of use and the ability to avoid undesirable postinjection reactions.

Amantadine has begun to be used as a possible alternative in COVID-19 therapy to mitigate its effects. There is anecdotal evidence that patients with Parkinson's disease (PD) treated with amantadine and who test positive for COVID-19 often do not develop clinical manifestations of COVID-19.Objective: to compare the clinical course of COVID-19 in patients with PD who took or did not take amantadine sulfate.Patients and methods. A prospective continuous study included 142 patients with PD who were treated in Republican Clinical Diagnostic Center for Extrapyramidal Pathology and Botulinum Therapy in Kazan from October 2021 to January 2022. Patients filled out a proprietary internally developed questionnaire.Results and discussion. Out of 142 individuals with PD COVID-19 occurred in 77 (54.2%), of which 52.0% had a mild course, 39.0% had a moderate course, 2.6% had a severe course, and in 6.5% the severity of the disease has not been established. Deterioration after COVID-19 infection was noted by 36% of patients: the appearance or increase in motor fluctuations (41%), increased tremor, stiffness or slowness (31%), the appearance of "exhaustion" of the effect of a single dose of levodopa (13%), the appearance or increased dyskinesia (21%), hallucinations (3.5%). Patients taking amantadine sulfate had PD much longer (11.5±5.62 years versus 5.12±3.24 years) and had a more pronounced (III–IV) stage of the disease. These patients were more likely to experience mild COVID-19 (in 60.87% of cases), in contrast to patients not receiving amantadine sulfate (only in 48.15% of cases). There was no correlation between the severity of COVID-19 and levodopa intake.Conclusion. The results of the study showed that patients with PD taking amantadine sulfate are more likely to have a mild course of COVID-19.

The purpose of this paper is a systematic review of articles and research in the context of drugs used and suicide in elderly patients. Suicide in the elderly may be much more frequent than in the younger population. In addition to factors such as mental illness, dementia, deteriorating health, or problems with adapting to old age, the impact of chronic and reliever medications in this age group should also be considered. The greatest challenge of pharmacotherapy in the elderly is polypharmacy, drug interactions, different metabolism, pharmacokinetics and pharmacodynamics of the drugs used, as well as the side effects appearing in chronic therapy. In elderly patients, strong groups of drugs such as benzodiazepines and opioids are used extensively and sometimes too often. These drugs can cause addiction and overdose. Prescribing benzodiazepines alone carries a high risk of suicide. On the other hand, opioids often lead to addiction and abuse of these drugs, which may be associated with the development of respiratory depression. According to estimates by the Centers for Disease Control and Prevention (CDC), suicide accounts for approximately 7% of all opioid overdose deaths. Therapy should be carefully selected with regard to the use of other medications, drug interactions, and possible dependence and drug abuse by patients.The use of some classes of drugs in the elderly requires increased vigilance and control in the context of depression and episodes of suicide attempts. Drugs such as B blockers, digitalis glycosides, NSAIDs, opioids, ACEIs, calcium channel blockers, corticosteroids, diuretics, levodopa, and benzodiazepines can cause symptoms of depression. Older people are more susceptible to side effects of drugs, for example because of polypharmacy and the chronicity of treatment.

Levodopa (3-hydroxy-L-tyrosine, the levorotatory isomerof 3,4-dihydroxyphenylalanine) is a biological precursor of the neurotransmitter dopamine and has been the "gold standard" in the treatment of Parkinsons disease for over 50 years. The widespread use of levodopa in clinical practice has not only provided neurologists with unique data from many years of symptomatic replacement therapy for a severe neurodegenerative disease but has also clearly identified several serious problems associated with levodopa absorption and metabolism. This article discusses the modern approaches to personalized medicine, which aim to overcome the numerous difficulties in managing patients with Parkinsons disease and long-term levodopa use. A major focus is the review of strategies for selecting the optimal levodopa dosage regimen in specific patients and the main innovative dosage forms of this drug that improve its pharmacokinetics.

Objective: to assess the predictors and prevalence of adverse drug reactions (ADRs) associated with antiparkinsonian drugs.Materials and methods. 18 clinical studies and randomized controlled trials were included in the analysis. We combined all registered ADRs for each drug and made direct comparisons with odds ratio (OR) and 95% confidence interval (95% CI) calculation.Results and discussion. Levodopa/benserazide (LB) had the best safety profile among levodopa drugs. Levodopa/carbidopa (LC) compared with LB was associated with more frequent development of nausea (OR=2.8; 95% CI: 1.51–5.21), aggravation of parkinsonism (OR=4.44; 95% CI: 2.12–9.28) and dizziness (OR=3.32; 95% CI: 1.5–7.33; p=0.002). Piribedil had the lowest number of ADRs among dopamine receptor agonists. Dizziness was more common with pramipexole and ropinirole than with levodopa (OR=1.82; 95% CI: 1.21–2.74 and OR=1.65; 95% CI: 1.11–2.44 respectively). Increased daytime sleepiness and peripheral edema have also been associated with pramipexole. Arterial hypertension was present in 9.6% of patients prescribed with piribedil. Amantadine compared with pramipexole was associated with a higher risk of hallucinations (OR=2.27; 95% CI: 1.24–4.12) and constipation (OR=2.40; 95% CI: 1.14–5.05). Patients prescribed with selegeline had higher odds of dizziness (OR=3.40; 95% CI: 1.76–6.55) and hallucinations (OR=4.30; 95% CI: 1.83–10.09) compared to rasagiline.Conclusion. Based on the results, we propose a diagram of the relationship between ADRs and their frequency with antiparkinsonian drugs. We hope that the study will find clinical application and allow neurologists to consider the effectiveness and the expected risks of ADRs in the treatment of PD.

Treatment of Parkinson’s disease (PD) includes the administration of dopaminergic and occasionally non-dopaminergic drugs, in mono- or in combination therapy. One of the key drug used to treat Parkinson’s disease is levodopa considered a gold standard. In addition levodopa can also be used as a challenge test to confirm the accuracy of diagnosis of PD known as the “Levodopa challenge test”. However many non levodopa class of drugs are also used and consist of dopamine agonists (ADRs), MAO-B and COMT inhibitors, as well as drugs working on glutamate such as a group of drug with NMDA receptor inhibitor activity (amantadines). The successful treatment of PD therefore depends on the correct choice of drugs to initiate treatment and sustainance of such therapy. The main parameters for personolised treatment include the patient’s age, severity and pattern of motor deficit, the state of cognitive function and lifestyle. Levodopa, although the most effective, is almost invariably associated with motor fluctuations and dyskinesias. Before prescribing levodopa, in addition to MAO-B inhibitors and ADRs, amantadines can be used as a monotherapy. Once replacement of therapy is required, then it is necessary to use a coefficient to calculate an equivalent dose of levodopa known as the levodopa equivalent dose. Progression of PD is inevitable inspite of adequate symptomatic therapy and at the advanced stage of PD approaches for the management of motor complications of levodopa need to be considered. For motor fluctuations these strategies require a change in the dosage regimen of levodopa (daily dose and frequency of intake), as well as the addition of an adjunct drug – ADRs, MAO-B inhibitor or COMT inhibitor. When dyskinesias arise, the management depends on correct identification of the type of dyskiensias. The commonest type of dyskinesia is peak dose dyskinesias related to peak plasma levodopa levels after intake. Amantadine provides a quick and long-lasting antidyskinetic effect which has been confirmed in open label as well as double-blind placebo-controlled studies. Compared to аmantadine chloride, amantadine sulfate has more stable pharmacokinetic parameters and a better safety profile. In addition, parenteral administration of amantadine sulfate can be utilized for severely ill patients with akinetic crisis in PD. Amantadine also has a broad spectrum effect and these may include improvement of fatigue and apathy. Some data also suggest that the use of amantadine in patients may increase life expectancy, improve survival and reduce the risk of dementia.

Any common disease (including Parkinson’s disease) is inevitably overgrown with myths. As a result, not scientifically grounded approaches based on the principles of evidence-based medicine, but irrational ideas, especially often of a pharmacophobic nature, begin to dominate in primary clinical practice among doctors and patients. In clinical practice, we can often face to a situation when doctors, dogmatically accepting the principle of delayed initiation of levodopa therapy, for a long time try to guide the patient on other antiparkinsonian drugs, despite the obvious ineffectiveness of such therapy and the increasingly growing immobility of the patient. This phenomenon, based on the irrational beliefs of not only doctors, but also patients in the toxicity of levodopa, is commonly referred to as levodopa phobia. Levodopa phobia, along with the emergence of a new generation of dopamine agonists (DAs), whose ability to delay the development of fluctuations and dyskinesias has been proven in a series of placebo-controlled studies, as well as the erroneous interpretation of the withdrawal syndrome of DAs as evidence of their high effectiveness, have led to the widespread use of this class. drugs. However, the use of DA turned out to be associated with an increased risk of such adverse events as daytime sleepiness, leg edema, impulsive-compulsive disorders, and withdrawal syndrome. All this served as the basis for the appearance of “dopamine agonists phobia”, which can lead to unjustifiably early prescription of levodopa and the development of dyskinesias. What is the optimal way for managementof PD patients today? In our opinion, the patient management formula that doctors should adhere to should be as follows: early prescription of dopaminergic drugs (more often DAs or levodopa) is necessary, which provides a quick possible, albeit incomplete, correction of a motor defect, which would be sufficient to preserve the patient’s motor activity, including his professional activity; as the symptoms increase, an escalation of antiparkinsonian therapy with the sequential addition of levodopa (or DAs), MAO B inhibitors, amantadines is necessary.

Parkinson’s disease is a multifactorial disorder of the nervous system, the main features of which are progressive degeneration of dopaminergic neurons in the nigra pars compacta nigrostriatal tract and subsequent deficiency of the neurotransmitter dopamine in the areas of the brain, leading to the loss of motor function, the emergence of non-motor symptoms, rigidity, akinesia or bradykinesia, motor block, and decline in cognitive functions. Parkinson’s disease has high prevalence throughout the world, and has no curative treatment in modern medicine. The available drugs such as anticholinergics, levodopa and a DOPA-decarboxylase inhibitor provide symptomatic relief only. Although dopaminergic therapy is the standard treatment of motor disabilities associated with Parkinson’s disease, it does not managed all the aspects of the disease. For this reason, the increasing numbers of patients are looking for more holistic approach to the treatment of this disease. Mucuna pruriens L. – an annual self-pollinating legume plant, can be considered as a potential complementary therapy for patients with Parkinson’s disease, as it is an extremely rich source of levodopa. Numerous studies have shown that Mucuna pruriens extracts restore biochemical and behavioral abnormalities in animals with the experimental model of Parkinson’s disease. The plant also demonstrates some antioxidant activity. The clinical effects of high-dose Mucuna pruriens are similar to levodopa, but have a more favorable tolerance profile. If long-term use of Mucuna pruriens proves safe and effective in controlled clinical trials, it could become a sustainable complementary therapy for the treatment of Parkinson’s disease, especially in low-income countries.

Aim. Evaluation of the impact of tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives on L-DOPA effects in the tail suspension test.Materials and methods. Some tetrahydropyrido[2,1-b][1,3,5]thiadiazines exhibit a pronounced antidepressant and adaptogenic activity. We selected compounds that demonstrated the most potent antidepressant effect in the Porsolt’s forced swim test. We chose to combine two approaches in the study: estimation of the antidepressant drug impact on levodopa effects and the tail suspension test. Caffeine sodium benzoate, amitriptyline and fluoxetine were chosen as the reference compounds. Studies of the 1,3,5-thiadiazine effects on levodopa activity were undertaken to ground detailed downstream analyses of associated responses in the dopaminergic neurotransmitter system. We measured the rectal temperature in laboratory rats prior to and after tail suspension and the total active time during 5 min in the test.Results. Administration of levodopa at a dose of 150 mg/kg led to a reduction in rectal temperature and the total time of physical activity in rats in the tail suspension test. The dosage of 500 mg/kg led to a temperature increase of 0.7°C prior to and after the stress and a longer maintenance of physical activity. Rats exhibited exophthalmos and polyuria.Levodopa at a 150 mg/kg dosage in combination with caffeine sodium benzoate did not cause a significant increase in the body temperature and prolonged physical activity by 69% in the test vs. the control group. Amitriptyline in combination with levodopa at a dose of 150 mg/kg triggered a temperature increase of 1.3°C prior to and 1.85°C after tail suspension, thus leading to a prolonged physical activity. Levodopa at a dose of 150 mg/kg in combination with fluoxetine led to elevation of the body temperature by 0.6°C prior to and 0.55°C after the stress. The total active time exhibited a declining trend.The substance TD-0348 reveals an antidepressant activity. Physical active time increased by 32% in the test vs. the control group. Temperature elevation by 1.15°C prior to and 1.25°C after the stress suggests activation of the autonomic nervous system. TD-0470 in combination with levodopa (150 mg/kg) led to a rectal temperature elevation by 0.4°C prior to and 0.7°C after tail suspension. Physical activity was prolonged compared to the levodopa-treated group (150 mg/ kg). TD-0479 led to a temperature elevation by 0.85°C prior to and 0.95°C after the stress and caused polyuria. Treatment with TD-0164 did not provide sufficient data to suggest an impact on dopamine metabolism.Conclusions. The compounds TD-0348, TD-0470 and TD-0479 affect physiological processes in experimental rats in response to treatment with L-DOPA at a dose of 150 mg/kg, which suggests the autonomic nervous system (ANS) activation. TD-0470 exhibits antidepressant properties. Treatment with TD-0164 does not provide sufficient data to evaluate its dopamine-related effects.

Neurodegenerative disease with brain iron accumulation type 5 (OMIM: 300894) manifests itself with early-onset epilepsy, mental retardation with stereotypies that resemble Rett syndrome, and motor disorders under the mask of cerebral palsy in childhood; since adolescence, patients usually have aggravation of parkinsonism and develop complications, such as torsion dystonia. We analyzed medical records of 5 female patients aged between 2.5 and 6 years. There were no family relationships between patients’ families. All children had problems with their motor skills: 4 out of 5 patients could only crawl; none of them could walk independently. We also observed severe speech disorders in these patients: they had no expressive speech along with reduced understanding of speech. Their behavior was characterized by contact disorders and multiple stereotypies. All children had no self-service skills. The assessment of neurological status demonstrated uniform symmetrical paresis (score 3–4; 100 % of cases), increased muscle tone of the extrapyramidal type (40 % of cases), and diffuse muscle hypotension with ataxia (40 % of cases). One patient (with autistic-like behavior) had no motor disorders. Magnetic resonance imaging showed non-specific changes in 100 % of cases (diffuse cortical / subcortical atrophy, secondary hydrocephalus ex vacuo). One patient was found to have hypointense signal in the substantia nigra and globus pallidus on follow-up T2‑weighted magnetic resonance images obtained at the age of 6 years. All patients presented with epilepsy: West syndrome (n = 1), Lennox–Gastaut syndrome (n = 1), focal epilepsy with asymmetric tonic seizures (n = 1), and focal epilepsy with febrile generalized tonic-clonic seizures (n = 2). Remission for more than 1 year was achieved in 4 out of 5 patients. The following electroencephalographic patterns were identified before treatment initiation: hypsarrhythmia with transformation into epilepsy with a pattern of continued spike-and-wave activity during sleep (n = 1), multi-regional epileptiform activity with a tendency to diffuse spread and predominance in the frontal region (n = 3), and regional epileptiform activity in the frontocentral area (n = 1). The initial therapy with first-line drugs was highly effective and ensured remission in 3 patients; one patient had remission in response to hormone therapy; one patient continued to have seizures despite polytherapy with antiepileptic drugs. Interictal epileptiform activity was completely blocked by treatment in 2 cases; the rest of the patients had transformation of epilepsy into benign epileptiform discharges of childhood (n = 3).

Rationale: Treatment of Parkinson's disease has been by now symptomatic. The literature on the efficacy and side effects of levodopa has been contradictory. Some authors mention an anti-depressant effect of the agent, while others believe that it is exactly levodopa that eventually induces the occurrence of depressive symptoms. Aim: To reproduce the OHDA-hemiparkinsonism rat model with subsequent assessment of both external and structural manifestations of the disorder, as well as to study the efficacy of levodopa for motor and non-motor symptoms of parkinsonism. Materials and methods: The study was performed in 52 male Wistar rats. The disease model included stereotaxic administration of neurotoxic 6-OHDA into the pars compacta of the substantia nigra. At 2 months after the administration, the animals underwent test for motor (Rotarod, cylinder, ketamine-induced rotation in the rotometer) and non-motor abnormalities (open field, social interest, conditioned escape response). Results: In 18% of the animals no hemiparkinsonism symptoms were found. 32% of rats had only motor symptoms, whereas in 50% of the animals both motor and non-motor symptoms were noted. Levodopa could partially correct the motor abnormalities, with augmentation of depressive-like behavior. Conclusion: Levodopa has shown its partial efficacy in correction of the motor symptoms caused by administration of 6-OHDA neurotoxin; however, it caused such side effects as augmentation of depressive-like behavior and anxiety.

Levodopa remains the gold standard of treating Parkinson's disease (PD). However, the inevitable complication of levodopa therapy is druginduced dyskinesias, which significantly limits the therapeutic capabilities of this group of drugs and requires treatment adjustment. At the same time, patients with PD show not only a wide interindividual variability in the response to levodopa treatment, but also differences in the frequency and time to onset of drug-induced dyskinesias. Therefore, genetic predisposition can play an important role in the development of complications of levodopa therapy.The paper reviews modern literature on the impact of mutations in the genes, the products of which are involved in the exchange of levodopa and are capable of provoking or, conversely, levelling the development of drug-induced dyskinesias in order to determine the possibilities of expanding the personalized approach to treating patients with PD.

Parkinson’s disease is the second most common (after Alzheimer’s) neurodegenerative disease. All over the world, there is a search for new drugs aimed at the treatment of Parkinson’s disease. Till up to the present, there is no “ideal” medicine that can completely cure this disease and has minimal adverse side effects. Belgorod research institute of pharmacology of living systems is studying Rapitalam, a new drug for the treatment of tremulous Parkinson’s disease. This is an agonist of the mGluR4 group of metabotropic receptors.The aim of the article is to study Rapitalam influence on the oxotremorine-induced tremor in rats.Methods. The study comprised 60 rats (6 groups of 10 males), which were administered intragastrically with the studied substances for 10 days. All the animal groups except Control group 1, were administered with Rapitalam and the reference drug Levodopa. 30 minutes after Rapitalam and Levodopa, they were administered abdominally with the solution of Oxotremorine at the dose of 1.5 mg/kg. The animals of Control group 1, instead of Oxotremorine, were similarly administered with a solvent of 0.9% sodium chloride in the equivalent volume.Results. In comparison with the reference group, Rapitalam at the dose of 3 mg/kg significantly reduced the severity of tremor 50 min. after its administration. The same effect took place 30 min after the administration of Oxotremorine at the dose of 10 mg/kg. At the dose of 3 and 10 mg/kg, Rapitalam also decreased the number of rats in the group (in %) with the signs of tremor 60 min. and 50 min. after the administration of Oxotremorine, respectively.Conclusion. The study revealed that Rapitalam has a pronounced anti-tremor effect. Its administration at the studied doses reduced the symptoms of Oxotremorine-induced tremor in rats.

Te lecture presents modern concept of the symptoms, diagnosis and treatment of dementia with Lewy bodies (DLB), which accounts for about 10% of cases of dementia. Te nosological status of DLB and the problem of ratio of DLB and Parkinson’s disease which, apparently, represent two phenotypic variants of one neurodegenerative process («diseases with Lewy bodies») are considered in historical aspect. Approaches to the diagnosis and coding of DLB in accordance with ICD-10 are proposed. Te role of cholinesterase inhibitors, antipsychotics, levodopa, rasagiline and other drugs in the treatment of patients with DLB is аnalyzed.

Objective – a description of clinical cases of impulsive­compulsive disorders in Parkinson,s disease. The first clinical case. Patient N., 75 years old, suffering for 15 years from Parkinson,s disease, akinetic­rigid form of the disease, stage 4 by Hyun–Yar. Since 2009, he received levodopa/carbidopa 250/25 mg 5 times/day (daily dose of 1250 mg of levodopa); pramipexole 3.5 mg per day (daily dose 3.5 mg), amantadine sulfate 100 mg 5 times/day (daily dose 500 mg). While taking antiparkinsonian drugs the patient developed behavioral disorders such as dopamine disregulatory syndrome combined with punding, hypersexuality and compulsive shopping accompanied by visual hallucinations. The total equivalent dose of levodopa was 1600 mg per day. The second clinical case. Patient R., 52 years old, suffers from Parkinson,s disease about 5 years, a mixed form. She complained of slowness of movement, tremor in her left hand, sleep disturbances, poor mood. The clinic was appointed piribedil 50 mg 3 times per day. Despite the fact that the patient took only one of dopaminergic drugs in a therapeutic daily dose, she developed impulsive­compulsive disorder as hyper­ sexuality, compulsive shopping and binge eating. Results. In the first clinical case for correction of behavioral disorders in patients with Parkinson,s disease levodopa/carbidopa dose was reduced to 750 mg per day (3/4 Tab. 4 times a day); added to levodopa/benserazide dispersible 100 mg morning and levodopa/benserazide 100 mg before sleep (total dose of levodopa of 950 mg per day). Amantadine sulfate and pramipexole were canceled. It was added to the therapy of atypical neuroleptic clozapine dose 6,25 mg overnight. After 3 months marked improvement, regressed visual hallucina­ tions, improved family relationships, background mood became more stable. The patient continue to sing karaoke, but this hobby has be­ come less intrusive. In the second clinical event correction impulsive­compulsive disorders piribedil was replaced with pramipexole 1.5 mg prolonged form one time a day. At the control examination after 3 months behavioral disorders completely regressed.Conclusion. This article describes two clinical cases of impulsive­compulsive disorders in patients with Parkinson s disease, methods of di­ agnosis and correction capabilities of these disorders.

Rotigotine is a new, non-ergot dopamine receptor agonist (DRA) formulated as a transdermal drug delivery system. This article reviews the clinical efficacy and tolerability of Rotigotine transdermal patch in Parkinson's disease (PD) and discusses the results of clinical trials of Rotigotine in early- and late-stage PD. The Rotigotine transdermal patch is efficacious in the treatment of PD. Drug-related adverse events (AEs) include side effects typical for DRA, which are generally mild or moderate in intensity. The most common AEs are local reactions that are mild or moderate. Once-daily administration of the rotigotine transdermal patch is effective in the treatment of patients with early-stage PD as monotherapy and in combination with levodopa in late-stage PD and in inadequate morning motor control despite antiparkinsonian treatment.

Objective: To assess the dynamics of cognitive impairments (CI) in patients with Parkinson's disease (PD) during L-dopa therapy., Material and Methods: The randomized clinical study included 41 patients with a refined diagnosis of PD 2.5-3.5 stages by Hoehn-Yahr scale, mainly with akinetic-rigid and mixed forms, and with CI associated with PD. All patients were on levodopa therapy. The average duration of the disease was 5 years. The study participants were randomized into two groups according to the design. To assess the dynamics of CI, a neuropsychological study was carried out twice with an interval of 6 months: in group I - at the «peak and outcome» of L-DOPA therapy, and in group II - at the «outcome and peak» of levodopa therapy, respectively. Assessment of cognitive functions (CF) was carried out using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-Cog), Geriatric Depression Scale (GDS)., Results: The statistically significant improvement of CF at the «peak» of levodopa drugs and the deterioration at the «outcome» of L-DOPA therapy in the form of an increase in CI ( p <0.05) was revealed., Conclusion: CI in PD, in a certain extent, may be dependent on L-DOPA therapy as well as motor manifestations. The most dependent on L-DOPA therapy CF were attention, speech, executive and visual-spatial functions.

Progressive supranuclear palsy (PSP) is a heterogeneous progressive neurodegenerative disease characterized by onset after 50 years old, Parkinson's syndrome, early development of postural instability, absence or transient reaction to levodopa drugs, neuropsychological disorders, dysphagia and dysarthria and eye movement disorders. The review provides an analysis of modern data on etiology, clinical presentation, differential diagnosis of the disease. The morphological picture and neuroimaging features, as well as modern ideas about treatment, are described. A great clinical polymorphism of the disease, as well as its similarity to other neurodegenerative diseases, manifested by Parkinson's syndrome, complicates the diagnosis of PSP. Establishing an accurate diagnosis makes it possible to determine the prognosis and further tactics of patient management.

The article presents data from recent studies on the mechanisms of action and clinical efficacy of amantadines, and also describes a possible protective effect against COVID-19.

Speech disorders are widely spread in patients with Parkinson's disease, and these symptoms are only getting worse as the disease progresses. Nevertheless, only a few percent of the population have an access to an adequate and qualified care. This review describes the pathophysiology of parkinsonian speech disorders, methods of diagnostics and monitoring and treatment modalities, which include pharmacotherapy, speech therapy and surgical approaches. The authors believe that treatment of parkinsonism-related speech disorder is an integral part of a multidisciplinary patient care.

Aim: To optimize therapy with levodopa preparations in relation to the rate of disease progression., Material and Methods: Eighty-six patients with Parkinson's disease (PD) were studied. Rate of progression was assessed by time of developing the 3rd stage of the disease. Patient state was assessed using MDS-UPDRS, MMSE, verbal activity test, clock drawing test, Beck depression scale, apathy scale and scale of autonomic disorders., Results and Conclusion: In 37 patients, early prescription of levodopa preparations (on average 1,7 years after disease onset) facilitates a decrease in the rate of progression assessed by time of developing the 3rd stage of the disease (7,3±4,4 vs 5,8±2,8 years). Despite early levodopa prescription, dyskinesias developed in the same timeframe as in case of delayed prescription (7,5 vs 7,9 years since onset). Clinical features asymmetry as the disease progresses, behavior disorders in rapid eye movement sleep phase during premotor stage, and orthostatic hypotension can be predictors of the high risk of complications of levodopa therapy. More severe axial disturbances are an adverse predictor of more severe course of the disease, the low levodopa efficacy, and the low risk of dyskinesia. Therefore, delayed prescription of levodopa facilitates the rate of progression, wherein the development of medicinal dyskinesias depends, to a greater extent, on the duration of disease rather than on time of treatment onset.

Aim: To study the efficacy of replacement of the single daily dose of two-component levodopa by three-component levodopa in work capable patients with Parkinson's disease with motor fluctuations during the most active working hours., Material and Methods: The study included 157 patients from 19 Russian centers specialized in extrapyramidal pathology. The period of highest working activity was analyzed in all patients. In these patients, the previous treatment with two-component levodopa was replaced by three-component levodopa in the equivalent dose. Other antiparkinsonian treatment remained unchanged during the study period. The duration of the study was 1 month., Results and Conclusion: The single replacement of two-component levodopa by stalevo allows increasing the optimal working activity by 19% and improving patient's state.

Aim: To evaluate the efficacy of the combined use of citicoline (neipilept) and levodopa/carbidopa (nakom) in the rotenone model of Parkinson's disease in rats., Material and Methods: Rotenone was administrated during 14 days in dose 2 mg/kg/day subcutaneously. The duration of treatment was 7 days, intragastrically. Alteration of locomotor behavior components, muscular rigidity in resistance to passive flexion in the ankle joint and signs of extrapyramidal disorders were assessed., Results and Conclusion: Combined therapy led to the decrease in muscle rigidity (the decrease of gibbosity in resistance to passive flexion in the ankle joint). There was a decrease in oligokinesia that emerged in higher vertical and horizontal locomotor activity of experimental animals, decrease in the time of head turning during climbing down the pole and total time of climbing down the pole. The combination of drugs had a more pronounced therapeutic effect on extrapyramidal disorders compared to monotherapy.

The disbalance of autonomic heart regulation (AHR) develops already in the presymptomatic stage of Parkinson's disease. The early symptomatic stage is accompanied by the aggravation of heart dysfunction due to the shift of the autonomic balance towards the increase of sympathetic and decrease of parasympathic effect on the heart. Coronary disorders concomitant to Parkinson's disease increase a risk of life threatening arrhythmia and sudden death syndrome not only in the early symptomatic stage but also in the presymptomatic stage. L-DOPA effectively restores the structure of AHR and prevents the risk of life threatening arrhythmia only in the presymptomatic stage of Parkinson's disease.

Rat strains feature different resistances to stress. The increased production of nitric oxide (NO) in the August strain prevents the appearance of ulcerous lesions of gastric mucosa and behavioral changes induced by restraint stress. Wistar rats feature a lower level of NO production and are more sensitive to restraint stress compared to the August rats according to both the ulcer pathology and behavioral indices. The stress-induced release of catecholamines was reproduced by experimental hyperfunction of the dopaminergic (DA) system induced by the introduction of L-DOPA. Introduction of NO synthase inhibitor N omega-nitro-L-arginine (L-NNA) enhanced the L-DOPA-induced behavioral changes. This effect was more pronounced in the August strain. The introduction of the exogenous NO donor, dinitrosyl iron complexes (DNIC), limited the behavioral disturbances induced by L-DOPA in both rat strains. The protective effect of DNIC in conditions of the DA system hyperfunction is similar to the effect of a D2 blocker sulpiride. Thus, NO has a central antistress effect, apparently, mediated by limiting the release of catecholamines.

Many years' studies in functional neurochemistry have provided a concept of the functionally induced biochemical heterogeneity of neurons and their subcellular components, which is formed during ontogenesis as the functions of the central nervous system are developed. It has been established that it manifests itself at the systemic, cellular, and subcellular levels: (1) between brain formations which constitute the single functional system; (2) between the neurons of various morphofunctional types (associative, efferent, afferent ones) between the neurons and the glia; (3) between individual components (the nucleus and the cytoplasm) of a neuron and its subcellular (synaptosomes, mitochondria, synaptosomal membranes) components. It is concluded that the functionally determined biochemical heterogeneity and morphofunctional features found in animals of various strains may be regarded as one of the ways of compensatory, rehabilitative, and adaptative processes in the central nervous system.

As many as 59 patients aged 35 to 74 years suffering from mitral valvular disease (MVD) were examined for excretion of dopamine (DA), noradrenaline (NA) and adrenaline, parameters indicating the activity of the sympathoadrenal system. Administration of L-DOPA brought about a significant increase of excretion of all catecholamines in all the patients under 59 years and in those aged 60 to 74 years. In patients with stage I and IIA heart failure, DA excretion rose 50-fold in response to L-DOPA administration, in those with stage IIB and III, 17-fold (p less than 0.001). In patients suffering from MVD, no age-associated differences were revealed in the levels of catecholamines and ICM. In patients suffering from MVD with the predominance of stenosis and in those with stage I and IIA heart failure, background excretion of NA was significantly higher than in patients suffering from MVD with the predominance of heart failure (p less than 0.01). Administration of L-DOPA was followed by an appreciable increment of NA exactly in patients suffering from MVD with the predominance of stenosis (p less than 0.001). In the majority of patients with stage III heart failure refractory to multimodality treatment, the L-DOPA test revealed the smallest increment of DA; its excretion rose only 12-fold. Therefore, the progress of heart failure entails a decrease of the reserve potentialities of the sympathoadrenal system, marked by less output of its mediators.

Patients (41) suffering from diabetes mellitus complicated by microangiopathies aged from 16 to 72 years were examined; diabetes of moderate severity was diagnosed in 20 patients (the I group), and severe-in 21 (the II group). Basic STH level after L-DOPA oral loading was studied in 60 and 90 minutes in all of these patients, and ti proved to be elevated in both groups. Following L-DOPA loading the peak of increase in the first group was found on the 60th minute, and in the II group-on the 90th minute. Basic STH secretion diminished in 16 patients after anginin treatment; this could apparently be attributed to improvement in the function of the hypothalamohypophysial system.

A study of somatotropic and gonadotropic functions in male adolescents with functional retardation of physical and sexual development has shown an important role of the deficiency of gonadotropins, especially FSH, in the pathogenesis of this condition. LH secretion in retarded physical development (RPD) is lowered to a lesser degree and positively correlates with testosterone deficiency. The feedback in the hypothalamohypophyseogonadal function in RPD is less frequently affected and to a lesser degree than gonadotropic functions. Of the tested methods (tests with TRH, L-DOPA and bromocriptine) STH reserves are better revealed with L-DOPA and TRH tests, gonadotropic reserves, especially LH,--with TRH and bromocriptine tests. The stimulating TRH effect on the growth hormone is indicative of the versatility and nonspecificity of its action on the pituitary gland in functional developmental disorders.

Administration of 1-DOPA into healthy persons increased its excretion with urine and elevated the adrenaline secretion. The increase of catecholamines excretion was not observed in aged patients with hypertension; the data obtained suggest that the synthesis of catecholamines with utilization of DOPA was inhibited. In patients with ulcerous disease excretion of 1-DOPA was not increased after its administration, but secretion of catecholamines was decreased during the day time. Under ulcerous disease 1-DOPA appears to be used in process unrelated to synthesis of catecholamines.

A study was made of 38 persons, including 25--with acromegaly, 5--with chromophobic adenomas of the hypophysis, 3--with diencephalic tumours and 5 healthy individuals. STH, TTH and ACTH were determined in the blood plasma with the aid of radioimmunological methods under basic conditions and L-DOPA loading (10 mg per 1 kg of weight) with insulin (0.10 U/kg). There was an increase in the plasma content of STH, TTH and ACTH with a maximum 60 min after the administration of L-DOPA. In the patients with acromegaly STH increased considerably, and in cases with chromophobic adenomas and diencephalic tumours--less. ACTH level was also elevated. STH and ACTH level rose after insulin hypoglycemia. Possible mechanisms of a stimulating action of L-DOPA and insulin are discussed.