Сравнительный анализ фармакокинетических параметров трансдермальной и инъекционной форм никотинамида

In recent years, oxidative stress, characterized by excess free radicals in the body, has been called the cause of many diseases. There is an active search for drugs with antioxidant properties that are suitable for long-term maintenance therapy. Nicotinamide (NAM), an antioxidant, is used to treat a variety of diseases, usually in oral or injectable form. Given the peculiarities of the drug regimen (dose, prolonged administration), a new dosage form of NAM, a microemulsion-based transdermal patch (TP), containing 20 mg/10 cm2 of NAM, has been proposed.The objective of this work is to compare the pharmacokinetic parameters of intramuscular and transdermal NAM administration in animal experiments for 24 hours.Materials and methods. We used laboratory samples of nicotinamide TP based on a microemulsion-based transdermal delivery emulsion (TDS) with different content of sodium docusate transfer activator. The pharmacokinetics of transdermal and intramuscular injections were studied in male Chinchilla rabbits weighing 3.5–4.0 kg. Plasma NAM levels of the experimental animals were determined by high-performance liquid chromatography using a specially designed method on NUCLEODUR PFP columns (5 μm, 250 × 4.6 mm) using the mobile phase acetonitrile: deionized water. The samples were preliminarily purified by solid-phase extraction using Chromabond C18 Hydra cartridges.Results. When administered intramuscularly, the maximum blood NAM level was 13.3±1 μg/mL; when NAM transdermal forms were applied in the same dosage with different contents of the transfer activator, the levels did not differ significantly – 3.1 and 3.2 μg/mL. It was shown that in transdermal administration of NAM, concentration of the active substance remained at a constant level for ~6 hours. The bioavailability of NAM with transdermal administration was calculated relative to intramuscular administration: 1.43 for TP with 9.8% docusate sodium and 1.84 with 3.3% docusate sodium.Conclusion. NAM has a higher bioavailability when administered transdermally at 20 mg than when administered intramuscularly in the same dose. With transdermal administration, NAM concentration can be maintained at a constant level for a long time, without the jumps that are typical of intramuscular administration.В последние годы окислительный стресс, характеризующийся избыточным содержанием свободных радикалов в организме, называют причиной многих заболеваний. Ведется активный поиск лекарственных средств, обладающих антиоксидантными свойствами и подходящих для длительной поддерживающей терапии. Антиоксидант никотинамид применяют при лечении самых разных заболеваний, как правило, в пероральной или инъекционной форме. Учитывая особенности режима приема препарата (доза, длительный прием), предложена новая лекарственная форма никотинамида – эмульсионная трансдермальная терапевтическая система (ТТС), содержащая 20 мг/10 см2 никотинамида.Целью данной работы является сравнение фармакокинетических параметров внутримышечного и трансдермального введений никотинамида в экспериментах на животных на протяжении 24 ч.Материалы и методы. В работе использовали лабораторные образцы ТТС никотинамида на основе эмульсионной системы чрескожной доставки (СЧД) с различным содержанием активатора переноса докузата натрия. Изучение фармакокинетики при транс дермальном и внутримышечном введениях выполняли на кроликах-самцах породы Шиншилла массой 3,5–4,0 кг. Определение концентрации никотинамида в плазме крови экспериментальных животных проводили методом высокоэффективной жидкостной хроматографии по специально разработанной методике на колонках NUCLEODUR PFP (5 мкм, 250 × 4,6 мм) с использованием подвижной фазы ацетонитрил : вода деионизированная. Предварительно проводили очистку образцов методом твердофазной экстракции с использованием патронов Chromabond С18 Hydra.Результаты. При внутримышечном введении максимальная концентрация никотинамида в крови составила 13,3 ± 1 мкг/мл, а при аппликации трансдермальных форм никотинамида в той же дозировке с разным содержанием активатора переноса достоверно не отличалась и составила 3,1 и 3,2 мкг/мл. Показано, что при трансдермальном введении никотинамида концентрация действующего вещества поддерживалась на постоянном уровне на протяжении ~6 часов. Рассчитана биодоступность никотинамида при трансдермальном введении относительно внутримышечного: 1,43 для ТТС с 9,8% докузата натрия и 1,84 с 3,3% докузата натрия.Заключение. В ходе фармакокинетических исследований показана более высокая биодоступность исследуемого вещества при использовании трансдермальной терапевтической системы никотинамида 20 мг, чем при его внутримышечном введении в той же дозе. Также при трансдермальном введении выявлена возможность поддержания концентрации никотинамида на постоянном уровне длительное время, без скачков, характерных для внутримышечного введения

О возможности терапевтического действия после окончания аппликации трансдермальной системы доставки лекарственных веществ

Background. As scientific knowledge about the peculiarities of the structure and functional properties of the skin increased, it became clearer that during transdermal administration, drug may accumulate in the deep layers of the dermis and subsequently get diffused into the bloodstream even after the transdermal therapeutic system (TTS), also called transdermal patch, had been removed. Objective: to quantify active drug substances remaining in an animal skin after TTS application. Materials and methods. Two previously developed transdermal patches containing Russian-made drug substances were chosen for the study: aminodihydrophthalazinedione sodium (immunomodulator) and bis(1-vinylimidazole-N) zinc diacetate (antidote for carbon monoxide). The study was performed on male Chinchilla rabbits weighing 2.5–3 kg. Five series of experiments were performed for each substance: immediately after removal of the patch, 4 hours later, at week 1, 2 and 3 after removal. High-performance liquid chromatography and atomic absorption spectroscopy methods were used to quantify residual drug substances left in the skin. Results. In the skin flap that was in contact with the aminodihydrophthalazinedione sodium TTS for 24 hours, 0.516 mg of the drug was detected immediately after removal of the patch. Over the next two weeks, the drug substance in the skin decreased with the immunomodulator significantly reducing to 0.41 mg in the first 4 hours. In the skin flap that had been in contact with zinc bis(1-vinylimidazole-N) diacetate for 24 hours, about 1 mg of the drug was present immediately after patch removal. Four hours after removal of the transdermal patch, the quantity of active substance in the skin remained practically unchanged. At week 1 and 2, the quantity of the antidote decreased slightly to ~0.7 mg and ~0.25 mg, respectively. Conclusion. For transdermal application of aminodihydrophthalazinedione sodium, the skin can act as a drug depot and prolong the effect of this drug even after the transdermal patch had been removed. No such effect was found in the case of bis(1-vinylimidazole-N) zinc diacetate, which is apparently due to the different solubility of the drugs in the biotissue.Введение. По мере развития научных знаний об особенностях структуры и функциональных свойств кожи стало понятно, что при чрескожном введении существует вероятность накопления лекарственных веществ в глубоких слоях дермы с последующей их диффузией в кровоток даже после снятия трансдермальной терапевтической системы (ТТС). Целью данной работы явилось установление наличия остаточного количества лекарственного вещества в коже животного после применения трансдермальной терапевтической системы. Материалы и методы. Для исследования выбраны две разработанные ранее ТТС, содержащие отечественные лекарственные субстанции: аминодигидрофталазиндион натрия (иммуномодулятор) и диацетат бис(1-винилимидазол-N) цинка (антидот угарного газа). Исследование проводили на кроликахсамцах породы Шиншилла массой 2,5–3 кг. Для каждой субстанции было выполнено пять серий экспериментов: непосредственно после открепления ТТС, через 4 часа, одну, две и три недели после удаления лекарственной формы. Для определения остаточного количества лекарственных веществ в коже были использованы методы высокоэффективной жидкостной хроматографии и атомно-адсорбционного анализа. Результаты. В кожном лоскуте, контактировавшем с ТТС аминодигидрофталазиндиона натрия в течение 24 часов, сразу после ее открепления присутствовало 0,516 мг лекарственного вещества. На протяжении последующих двух недель наблюдалось снижение содержания лекарственного вещества в коже, причем существенное уменьшение количества иммуномодулятора происходило уже в первые 4 часа и составило 0,41 мг. В кожном лоскуте, контактировавшем с ТТС диацетат бис(1-винилимидазол-N) цинка в течение 24 часов, сразу после ее открепления лекарственное вещество присутствовало в количестве примерно 1 мг. Через 4 часа после удаления ТТС количество активного вещества в коже практически не изменилось. Через одну и две недели количество антидота незначительно снижалось и составило ~0,7 мг и ~0,25 мг соответственно. Заключение. Полученные результаты по чрескожному введению аминодигидрофталазиндиона натрия показали, что кожа может выступать в качестве депо лекарственного вещества и пролонгировать его действие даже после снятия ТТС. В случае с диацетат бис(1-винилимидазол-N) цинка такого эффекта обнаружено не было, что связано, по-видимому, с разной растворимостью исследуемых лекарственных веществ в биоткани

Optimal Aerodynamic Shape Optimization of a Paraglider Airfoil Based on the Sharknose Concept

The effects of classical air inlet configurations on the aerodynamic performance of a paraglider airfoil are firstly presented. Followed by conducting gradient-based aerodynamic shape optimization of the baseline airfoil used in the investigation of the classical air inlets. Different air inlet configurations are introduced to the optimized profile, and there effects on the aerodynamic performance are then compared to the initial and optimized airfoils. The Reynolds averaged Navier-Stokes equations (RANS) are solved for the flow field around the closed and open airfoils. The canopy is assumed to be smooth, rigid and impermeable. Results are focused on both of lift and drag coefficients for performance analysis and on the internal pressure coefficient which can be critical for a real flexible wing regarding the risk of collapse

VALIDATION OF THE MACNEW QUESTIONNAIRE FOR THE ASSESSMENT OF HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH ISHEMIC HEART DISEASE

Background. Recently, a greater emphasis is being placed on health-related quality of life (HRQL) in both global and Russian practice. In many countries HRQL in patients with ischemic heart disease (IHD) is assessed by a disease-specific questionnaire – The MacNew Heart Disease HRQL questionnaire (MacNew) – that has been validated in many countries, but not yet in Russia.Aim. To validate Russian MacNew questionnaire in patients with different clinical types of ICD.Material and methods. Direct and reverse translation of the MacNew questionnaire was performed in accordance with the protocol of international HeartQol study. The patients (n=322) with angina, myocardial infarction, and heart failure were enrolled into the study and completed the Short-Form 36 (SF-36), the Hospital Anxiety and Depression Scale (HADS) and the Mac-New at the baseline; approximately 20% of the patients were reexamined 2 weeks later. The conceptual framework, reliability and validity of the Russian version of MacNew HRQL questionnaire were assessed.Results. The Russian version of MacNew questionnaire demonstrated sufficient internal consistency with Cronbach’s α exceeding 0.80. High test-retest reliability of the questionnaire was established in the total sample of ICD patients (0.949; p<0.01). Factor analysis in general substantiated the conceptual model of the Russian version of MacNew and its satisfactory content validity. Convergent validity was confirmed by strong correlations between the subscales of Russian MacNew questionnaire and conceptually similar subscales of the SF-36 survey (in the total sample and in separated clinical groups. Discriminant validity of the Russian version of MacNew was also confirmed differentiating patients with different SF-36 health transition and patients with and without anxiety and depression (HADS questionnaire).Conclusions. The Russian version of MacNew HRQL questionnaire has demonstrated adequate reliability and validity as compared with the original method. It can be recommended for the assessment of life quality in Russian-speaking patients with various types of ICD in daily clinical practice and research work

VALIDATION OF THE MACNEW QUESTIONNAIRE FOR THE ASSESSMENT OF HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH ISHEMIC HEART DISEASE

Background. Recently, a greater emphasis is being placed on health-related quality of life (HRQL) in both global and Russian practice. In many countries HRQL in patients with ischemic heart disease (IHD) is assessed by a disease-specific questionnaire – The MacNew Heart Disease HRQL questionnaire (MacNew) – that has been validated in many countries, but not yet in Russia.Aim. To validate Russian MacNew questionnaire in patients with different clinical types of ICD.Material and methods. Direct and reverse translation of the MacNew questionnaire was performed in accordance with the protocol of international HeartQol study. The patients (n=322) with angina, myocardial infarction, and heart failure were enrolled into the study and completed the Short-Form 36 (SF-36), the Hospital Anxiety and Depression Scale (HADS) and the Mac-New at the baseline; approximately 20% of the patients were reexamined 2 weeks later. The conceptual framework, reliability and validity of the Russian version of MacNew HRQL questionnaire were assessed.Results. The Russian version of MacNew questionnaire demonstrated sufficient internal consistency with Cronbach’s α exceeding 0.80. High test-retest reliability of the questionnaire was established in the total sample of ICD patients (0.949; p&lt;0.01). Factor analysis in general substantiated the conceptual model of the Russian version of MacNew and its satisfactory content validity. Convergent validity was confirmed by strong correlations between the subscales of Russian MacNew questionnaire and conceptually similar subscales of the SF-36 survey (in the total sample and in separated clinical groups. Discriminant validity of the Russian version of MacNew was also confirmed differentiating patients with different SF-36 health transition and patients with and without anxiety and depression (HADS questionnaire).Conclusions. The Russian version of MacNew HRQL questionnaire has demonstrated adequate reliability and validity as compared with the original method. It can be recommended for the assessment of life quality in Russian-speaking patients with various types of ICD in daily clinical practice and research work.</p

RUSSIAN VERSION OF PHQ-2 AND 9 QUESTIONNAIRES: SENSITIVITY AND SPECIFICITY IN DETECTION OF DEPRESSION IN OUTPATIENT GENERAL MEDICAL PRACTICE

Aim. Current study aimed to adapt and evaluate the psychometric properties of Russian versions of Patient Health Questionnaires 2 and 9 (PHQ-2 and PHQ-9) used for detection of depression in general medical practice worldwide.Material and methods. Questionnaires were translated into Russian and adapted with regard to linguistic features of population. A study was performed on a sample of 193 patients (130 female, 63 male, mean age 34,6±11,4), who attended general practitioners in outpatient practice department of NRC for Preventive Medicine. Patients filled in PHQ-2 and –9 questionnaires in presence of clinical psychologist and then assessed for depression by a psychiatrist (using ICD-10 criteria).Results. The optimal measures of sensitivity and specificity corresponded to cut-off scores of 3 for PHQ-2 (66,2% and 87,4% respectively) and 10 for PHQ-9 (68,9% and 93,3% respectively). Russian questionnaires were found to success in sensitivity, specificity and their positive predictive values are comparable to similar research data reported in literature. Article discusses the principles of implementation of the studied scales for depression screening in general medical practice

Aerodynamic performance of the DeSiReH high-lift laminar wing at free flight and ETW in-tunnel conditions

The current research concerns a half-model high-lift configuration inside the European Transonic Wind Tunnel (ETW) at landing regime. The influence of the wind-tunnel walls (both slotted and closed) is investigated and the numerical results are compared with measured data. The investigated model is a three-element landing configuration with Krueger device and flap. All calculations are performed on structured grids using EWT-TsAGI code. The computed in-tunnel results are in good agreement with uncorrected experimental data, with maximum lift predicted at the same angle of attack. The slotted wall configuration produces less wall interference than the closed wall configuration

DEVELOPMENT AND VALIDATION OF THE METHOD OF VITAMINE E DETERMINATION IN MICROEMULSION COMPOSITIONS BY HIGH-EFFECTIVE LIQUID CHROMATOGRAPHY

The results of development and validation of the method of vitamin E detrmination in microemulsion compositions suitable for its controlling in transdermal delivery systems and also for the incoming control of tocopherol acetate oil solutions presents in the article. The method is based on the vitamin E extraction from the microemulsion by a mixture of acetonitrile - ethyl acetate (80:20) and subsequent analysis by reversed-phase HPLC. The main validation characteristics of the method meet the eligibility criterias. The analytical area of the methodology was from 0.1 to 10.0 mg/g vitamin E concentration. The results of method approbation on transdermal delivery system laboratory samples on microemulsions based are presented