[Comparative clinical study of pharmacokinetics and bioequivalence of Relonova and Maxalt]. / Sravnitel'noe klinicheskoe issledovanie farmakokinetiki i bioekvivalentnosti preparatov rizatriptana Relonova i Maksalt.

OBJECTIVE: Evaluation of the bioequivalence of the tested Relonova, tablets, 10 mg and Maxalt, tablets, 10 mg drugs on an empty stomach in healthy volunteers. MATERIAL AND METHODS: The pharmacokinetic analysis population included 40 volunteers, the safety analysis population included 40 volunteers. The average age of randomized volunteers (men - 20, women - 20) was 29.3±8.9 years, height 1.71±0.09 m, body weight 70.86±11.66 kg, mean BMI 24.18±2.81 kg/m2. The method used high performance liquid chromatography with tandem mass spectrometric detection. Statistical analysis of the obtained data was performed based on the assumption of a log-normal distribution of the parameters AUC0-72 and Cmax. RESULTS: The ratio of geometric means for the key pharmacokinetic parameters (AUC0-t, AUC0-inf and Cmax) of rizatriptan is close to 90%, CI is within the acceptable range for bioequivalent drugs (80-125%). The intrasubject variability (CVintra) for rizatriptan was 23.74% (Cmax), 10.94% (AUC0-t). The average profiles of the pharmacokinetic curves of rizatriptan when taking the test and reference drugs have similar shapes. Relonova and reference Maxalt are bioequivalent. CONCLUSION: The results of the study make it possible to recommend Relonova for further clinical study and wide practical application.

Pharmacological Properties of Sulfonamide Derivatives, New Inhibitors of Carbonic Anhydrase.

Selective blocking of individual isoforms of carbonic anhydrase (CA) is now one of the main directions in the development of its inhibitors. The new 1,2,4-oxadiazole-containing sulfonamides B12 and B13 predominantly block CA II and CA IX. The study of acute toxicity of B12 and B13 showed their safety. Substance B13 caused a relatively short-term, but rapid (within 30 min) decrease in the intraocular pressure in rabbits, which indicates the promise of its use for the emergency decrease in the intraocular pressure in medical practice. Analysis of the effects of sulfonamides on the functions of CNS showed that compound B12 probably exhibit tranquilizing activity; B13 is promising for the creation of drugs that have an antidepressant effect and at the same time increase the mental and physical performance.

[The state and actual vectors of development of cardiologic care in conditions of region with low density of population].

The study was carried out to assess the state of cardiologic care and to determine current vectors of its development in the region with low population density. The health care system of the Kostroma Oblast was determined as research base. The information and methodological foundation of the study was compiled according results of special studies of patients aged from 8 to 80 years (n=1,400). The combination of research methods was implemented. The main vectors of the modern development of the cardiology service are identified: regional automated monitoring of quality of cardiologic care with operational analysis of its potential by 25 conjugated factors; implementation of continuous quality management technology according proposed algorithm; implementation of the decision-making scheme with allocation of 10 alternatives of achieving effectiveness of medical care according 4 criteria (standard performance, clinical result achievement, patient satisfaction, resources saving);, implementation of personalized approach to patient management.

[Pharmacoeconomic and pharmacogenetic aspects of the implementation of a personalized approach in the treatment of cardiac patients].

PURPOSE: To investigate the possibilities of pharmacoeconomic and pharmacogenetic factors monitoring to assess the effectiveness of treatment of a cardiological profile patients as a part of the implementation of a personalized approach. MATERIAL AND METHODS: 200 patients with arterial hypertension and CHD were examined. Pharmacotherapy was analyzed. ABC/VEN and DDD analysis, pharmacoeconomic analysis were applied. Genetic analysis of the polymorphism of the genes CYP2D6*4 and CYP2D6*10 encoding the subfamily of the cytochrome isoenzyme Р-450 was carried out. An original monitoring method was used to assess the effect of pharmacoeconomic and pharmacogenetic factors on the performance of cardiac care. RESULTS: When conducting a pharmacoeconomic analysis of cases of cardiac care, it was found that the costs of drug therapy are significant and take over 10% of the total costs. However, its effectiveness is insufficient in 58% of cases in inpatient and 37% in outpatient care. The analysis showed that there is an inverse mean correlation between gene polymorphism and clinical performance of cardiac care (r = -0.62) and a direct strong correlation between polypharmacy in pharmacotherapy, not accounting for interdrug interaction and clinical performance (r = 0.89).

[The main results of clinical trials of the efficacy, safety and pharmacokinetics of the perspective anti-tuberculosis drug makozinone (PBTZ169)].

Tuberculosis is a chronic infectious disease, usually localized in the respiratory system and representing one of the most important global social and biomedical health problems associated with the spread of therapy-resistant forms (multidrug-resistant and extensively drug-resistant tuberculosis). One of the most promising targets for the development of antimycobacterial drugs is the enzyme DprE1, which is involved in the synthesis of the cell wall of mycobacteria. In the series of DprE1 inhibitor drugs, the most advanced drug is PBTZ169 (INN maсozinone). Clinical trials (CT) of the efficacy and safety of macozinone are conducted by the pharmaceutical company LLC NEARMEDIC PLUS in the Russian Federation, and in other countries (Sponsors: Innovative Medicines for Tuberculosis Foundation, cole polytechnique fdrale de Lausanne and Bill and Melinda Gates Foundation). The publication describes results of completed I, IIa and Ib phases CT, conducted in the Russian Federation. AIM: The goal of phase I CT was to assess the safety, tolerability and pharmacokinetics (PK) of PBTZ169, 40 mg capsule, after single and multiple administration under fasting conditions in increasing doses in healthy volunteers. The goal of phase IIa CT was to study the efficacy (in terms of early bactericidal activity EBA), safety and PK of the drug PBTZ169, 80 mg capsules, in various doses, when used as monotherapy in patients with newly diagnosed respiratory tuberculosis with bacterial excretion and retained sensitivity to isoniazid and rifampicin. The purpose of phase Ib CT was to evaluate the safety, tolerability, PK of PBTZ169, 80 mg capsule, after single, double and multiple administration under fasting conditions in increasing doses, as well as the effect of food on its bioavailability in healthy volunteers. MATERIALS AND METHODS: The data of 100 healthy volunteers and 15 patients with newly diagnosed pulmonary tuberculosis, who received the study medication PBTZ169, capsules 40 mg and 80 mg, in the dose range 40 mg 1280 mg of PBTZ169, obtained during phase I, IIa and Ib CTs were analyzed. During I phases CTs, safety, tolerability, and PK of the drug after a single and multiple administration under fasting condition and after meals at rising doses were evaluated. The safety assessment included evaluation of AE/SAE, vital signs, ECG results, and laboratory tests results in the safety population. In the course of phase IIa CT, in addition to safety, tolerance, and PK evaluation, the efficacy of the drug (in terms of EBA) using sputum culture on agar with CFU/ml counting (main method) and quantitative PCR method (auxiliary method) was evaluated. RESULTS: During all CTs, a high safety and tolerability profile was shown, the main PK parameters of the drug and the efficacy were described. PBTZ169 demonstrated linear PK in the dosage range up to 640 mg after single and multiple administration, a statistically significant of EBA of the drug after monotherapy at the dose of 640 mg/day was demonstrate, and it was concluded that the preferred regimen of the drug PBTZ169 intake is administration after meals. Good tolerability and a favorable safety profile of the drug in the studied doses range were demonstrate during all the CTs. CONCLUSION: One of the most promising and currently studied drugs-inhibitors of DprE1, a new target for the cell wall of mycobacteria, is PBTZ169 or macozinone, which is being develop by the Russian pharmaceutical company NEARMEDIC PLUS ltd.

[Effect of physicochemical properties on the pharmacokinetic parameters of the new representative of benzothiazinones antituberculosis drug macozinonе].

INTRODUCTION: Tuberculosis (TB) is one of the top ten causes of death worldwide. Improvement of the treatment options via development of new drugs and treatment regimens that would be more convenient for patients is one of key options of improving the effecacy of the TB prevention and careis. Since the creation of new treatment regimens by minimizing the number of the drugs used and reducing the duration of treatment is the most promising and correct direction, macozinone, a new candidate of the benzothiazinone series, can become the basis for development of new chemotherapy regimens for drug-resistant forms of TB including the combination of macozinone with the most effective modern anti-TB drugs. AIM: Comparative evaluation of the pharmacokinetic properties of macozinone capsules 80 mg and the new dosage form a dispersible tablet for preparation of oral solution. MATERIALS AND METHODS: Solubility of the substance macozinone in biorelevant media in vitro, permeability of macozinone in the test Caco-2 in vitro, as well as pharmacokinetics of macozinone in dogs in vivo were evaluated. RESULTS: The solubility assessment in biorelevant media showed that the average limit of macozinone substance dissolution in the pH 5.0 acetate buffer solution was from 6 to 9 mg/l, in FaSSIF medium (fasted) from 2.5 to 4 mg/l, and in FeSSIF medium (after meals) from 16.8 to 29 mg/l. It is established that the cell permeability of the pharmaceutical substance macozinone in the CACO-2 test system is on average 2.510-6cm/s in the forward direction from the apical to basolateral cell membrane, and 1.510-6cm/s in the reverse direction, which corresponds to low permeability. The main pharmacokinetic parameters of macozinone dispersable tablets 160 mg, after dosing with food and on an empty stomach, as well as capsules 80 mg, when administered on an empty stomach in vivo studies in dogs are presented. DISCUSSION: The specific physicochemical properties of macozinone, the problems of developing the new dosage form, as well as ways of solving some of them are presented. CONCLUSION: In the process of new dosage forms development, the existing chemical properties of the macozinone substance should be considered. One of the promising ways of increasing bioavailability and, consiquently, efficacy is development a fundamentally new drug form with modified release within the absorption window.

Development of Clinical Pharmacology in the Russian Federation.

PURPOSE: The article aims to provide the history, organization, and approaches to clinical pharmacology in the Russian Federation. METHODS: This article is based on major international and Russian documents, along with groundbreaking historical facts and scientific articles related to the development of modern clinical pharmacology the Russian Federation. FINDINGS: Improving the quality of drug therapy is the main goal of clinical pharmacology in the Russian Federation. Decisions of the World Health Organization, scientific achievements, and the work of well-known scientists among the world community and in the Russian Federation have strongly influenced the development of clinical pharmacology the Russian Federation. Clinical pharmacology in the Russian Federation addresses a wide range of problems; it actively engages in modern scientific research, education; and clinical practice. Clinical pharmacologists participate in studies of new drugs and often have a specific area of expertise. IMPLICATIONS: The future development of clinical pharmacology in the Russian Federation will be related to improvements in training, refinement of the framework that regulates clinical pharmacologists, and the creation of clinical pharmacology laboratories with modern equipment.

[Clinical course and outcomes of myocardial infarction in women].

We selected all case histories of patients living in the area served by the Syktyvkar policlinic #3 and treated in Republican Cardiological Dispensary in 2003-2009 with diagnosis of myocardial infarction (MI). Data on survival of patients after MI (mean duration of follow-up 4.6 years) was derived from information on date and cause of death of patients obtained from statistical office of the policlinic. Overall we analyzed data on 778 patients (46.3% women, mean age 63.7 years). For detection of independent factors related to lethal outcome we used binary logistic regression, for assessment of survival we used Kaplan-Meier method and Cox regression model of proportional hazards. From positions of gender differences we assessed pharmacoepidemiology of MI, efficacy of thrombolytic therapy, determined factors of hospital and long term mortality. No increase of risk of hospital or long term mortality associated with female sex was revealed by multifactorial analysis. Greatest prognostic significance in relation to unfavorable outcome irrespective of patients sex was established for the following factors: age, severity of MI course, severity of renal dysfunction. In acute period of MI in addition to these factors we revealed unfavorable influence of hyperglycemia and protective role of preceding hypertensive disease.

[Renal functional state in patients with myocardial infarction].

AIM: To study renal dysfunction in patients with myocardial infarction (MI). SUBJECTS AND METHODS: 670 case histories of patients diagnosed with acute coronary syndrome, including 369 (55.8%) men and 292 (44.2%) women at the age of 33 to 85 years (mean age 64.8 +/- 11.7 years), were retrospectively studied. The authors considered comorbidities and analyzed complaints, history data, and the results of physical examinations, biochemical blood tests for plasma glucose, troponin, MB fractions of creatine phosphokinase and creatinine, and cholesterol in all the patients. Instrumental studies involved electro- and echocardiography. Glomerular filtration rate (GFR) was estimated using the MDRD formula. The patients were divided into groups according to GFR values: 1) > 90 ml/min/1.73 m2; 2) 60 to 89 ml/min/1.73 m2; 3) 30 to 59 ml/min/1.73 m2; 4) less than 30 ml/min/1.73 m2. RESULTS: Most patients were found to have a moderate or significant reduction in kidney function. Worsening renal function in patients with MI was associated with advanced patient age, the lower proportion of men in the patient structure, the higher prevalence of concomitant cardiovascular diseases, such as arterial hypertension, chronic heart failure, and prior MI, and diabetes mellitus. CONCLUSION: The findings suggest that kidney dysfunction is of essential value in developing the multiplicity of comorbidities in patients with MI. The wide introduction of a GFR calculating method in daily medical practice will be able to adequately and timely identify renal filtration function and to make a correction into a treatment regimen, thus decreasing the number of poor outcomes.

[Pulmonary pathology in patients with systemic lupus erythematosus].

AIM: To characterize pulmonary lesion in systemic lupus erythematosus (SLE) on the basis of clinical device and biochemical examination regarding features of the disease onset and development. MATERIAL AND METHODS: The study included 60 SLE patients. Mean age 41.1 +/- 1.32 years. Mean SLE duration 12.42 +/- 1.06 years. Activity according to the SLEDAI and ECLAM indices--16.23 +/- 0.93 and 3.09 +/- 0.18 scores, respectively. The comparison groups: 30 patients with bronchial asthma (BA), 15--with chronic bronchitis (CB), 15--with chronic obstructive bronchitis (COB), 30 healthy donors. The following parameters were studied: spirometric, bodyplethismographic evidence, diffuse ability of the lungs (DAL), plasm concentrations of adrenaline, noradrenaline, dopamine, serotonine, histamine, hemodynamics, anxiety, depression, social adaptation (quality of life) and vegetative dysfunctions. Statistics were obtained with BIOSTATISTIKA program. RESULTS: DAL depends on duration of SLE, severity of lung hypertension (LH), severity of anemia. LH in SLE deteriorated vegetative disorders and social adaptation. Lowering of plasm dopamine concentration was accompanied with LH, formation of vegetative dysfunction and worse social adaptation. CONCLUSION: Affection of the lungs in SLE patients runs without evident clinical symptoms. Initial signs of lung affection manifest with low DAL, LH, moderate restrictive, obstructive and mixed disorders of external respiration function.

[Cerebral pathology in inactive rheumatism]. / Tserebral'naia patologiia v neaktivnoi faze revmatizma.

AIM: Characterization of cerebral pathology in inactive phase of rheumatism. MATERIALS AND METHODS: Clinical, experimental psychological examinations were performed in 110 rheumatic patients with inactive disease. Computer tomography of the head was carried out in 45 patients. RESULTS: Psychic defects were absent only in 2.73% of the examinees. The rest had different neurotic symptoms manifest as panic attacks (> 50% of cases) or mildpsychoorganic shifts (60.91% of cases). Computer tomography of the brain has revealed hypodensive foci, deformed subarachnoid spaces and cerebral ventricles, hydrocephalia in 66.67% of the patients. These occurred more frequently in patients with psychoorganic syndrome or valvular heart diseases. CONCLUSION: Treatment and rehabilitation of rheumatic patients should also include measures to correct psychic and cerebral abnormalities frequently present in such patients.

[The risk factors for unfavorable outcomes in rheumatism]. / Faktory riska neblagopriiatnykh iskhodov revmatizma.

A prospective study was made of environmental factors effects on unfavorable cardial and cerebral outcomes of rheumatic fever (RF) assessed functionally, biochemically and psychologically. Some of RF predisposing factors (female sex, frequent nasopharyngeal infections, poor housing and occupational conditions) negatively affect outcomes of primary RF and contribute to emergence of valvular disease. The initial attack of activity I or III degree, pronounced carditis, active rheumatic process at discharge, recurrences, absence of year-round prophylaxis allow prognostication of valvular heart disease. The majority of the factors promoting valvular and circulatory disorders also contribute to the onset of psychic abnormalities, astheno-organic syndrome, in particular.

[The evaluation of the efficacy of carbamazepine and valproic acid in the alcohol postintoxication syndrome based on ethanol and acetaldehyde kinetics and the content of biogenic monoamines]. / Otsenka éffektivnosti karbamazepina i val'proevoi kisloty pri alkogol'nom postintoksikatsionnom sindrome po kinetike étanola i atsetal'degida i soderzhaniiu biogennykh monoaminov.

The effects of carbamazepine and valproic acid on disturbances of behaviour, elimination of ethanol, acetaldehyde from the blood, the contents of adrenaline, noradrenaline, dopamine, serotonin, 5-hydroxyindoleacetic acid and histamine in the brain and blood in alcoholic postintoxication syndrome were studied on male albino rats. Carbamazepine and valproic acid were shown to reduce the behavioural manifestations of the syndrome, to increase elimination of ethanol and acetaldehyde, to normalize the levels of the mediators in the brain tissues, particularly in the thalamus.