ЭФФЕКТИВНОСТЬ И БЕЗОПАСНОСТЬ НОВОГО РОССИЙСКОГО НЕНУКЛЕОЗИДНОГО ИНГИБИТОРА ОБРАТНОЙ ТРАНСКРИПТАЗЫ ЭЛСУЛЬФАВИРИНА В ПЕРВОЙ ЛИНИИ ЛЕЧЕНИЯ ВИЧ-ИНФЕКЦИИ В КОМБИНАЦИИ С ДВУМЯ НУКЛЕОЗИДНЫМИ/НУКЛЕОТИДНЫМИ ИНГИБИТОРАМИ ОБРАТНОЙ ТРАНСКРИПТАЗЫ – ИССЛЕДОВАНИЕ 96 НЕДЕЛЬ

A randomized multicenter 96-week study of an elsulfavirine (ESV),  non-nucleoside reverse transcriptase inhibitor (NNRTI) of novel  generation, in combination with 2 nucleoside/ nucleotide reverse  transcriptase inhibitors (NRTIs) was conducted in naive HIV adult  patients, divided by 2 parts: 1) partially blind comparative to  efavirenz (EFV) 48-week study, 2) open-label observational study  during additional 48 weeks. High virological and immunological  effectiveness maintained during the study: proportion of patients  with HIV RNA <50 copies/ml in 48 weeks achieved 81,6%, in 96  weeks – 83,9% (MITT-analysis) and 91% (if patients withdrawn from the study due to other reasons not related to treatment were excluded). No resistance mutations were found in patients with viral  replication blips (HIV RNA 50-1300 copies/ml). CD4+-lymphocytes  count was increased by 187,5 at week 48 and 251,0 cells/mcl at  week 96. Good tolerability and safety were confirmed during second year of treatment: no additional safety data which could influence  benefit/risk ratio were recorded as well as withdrawal from the  treatment due to adverse events. Serious adverse events, connected with treatment, allergic reactions were not registered during the whole 96-week study. Conclusion. Results of the 96-week study confirm earlier data from  48-week study on high efficacy and safety of ESV. Based on these  data ESV was included into “National recommendations on  dispensary follow-up and treatment of patients with HIV-infection” as the first-line ART regime in combination with 2 NRTIs.Проведено многоцентровое рандомизированное исследование элсульфавирина (ESV) –  ненуклеозидного ингибитора обратной транскриптазы (ННИОТ) нового поколения в  комбинации с 2 нуклеотидными/нуклеозидными ингибиторами обратной транскриптазы  (НИОТ) у взрослых пациентов с ВИЧ-инфекцией, ранее не получавших АРТ, длительностью  96 недель, состоявшее из 2 этапов: 1) частично слепое, сравнительное с эфавирензом (EFV) исследование – 48 недель, 2) открытое наблюдательное исследование – дополнительные 48 недель. Наблюдалась высокая вирусологическая и иммунологическая эффективность  лечения, устойчивая в течение 96 недель: доля пациентов с неопределяемым уровнем РНК  ВИЧ <50 копий/мл через 48 недель составила 81,6%, через 96 недель – 83,9% (MITT- анализ) и 91% (без учета пациентов, выбывших по не связанным с лечением причинам). Ни  в одном случае всплесков репликации вируса (РНК ВИЧ от 50 до 1300 копий/мл) не  выявлено мутаций резистентности ВИЧ к препаратам. Прирост медианы количества CD4+- лимфоцитов через 48 недель составил 187,5 клеток/мкл, через 96 недель – 251,0 клетку/ мкл. Подтверждена хорошая переносимость и безопасность лечения в течение второго года  исследования: не выявлено каких-либо новых значимых данных в отношении безопасности,  негативно влияющих на соотношение польза/риск, не зарегистрировано  случаев отмены лечения из-за нежелательных явлений. На протяжении 96 недель не  зарегистрированы серьезные нежелательные явления, связанные с приемом препарата,  аллергические реакции. Заключение. Результаты 96-недельного исследования подтверждают полученные ранее  (по итогам 48 недель применения) данные о высокой эффективности и безопасности  элсульфавирина. На основании полученных результатов элсульфавирин включен в «Национальные рекомендации по диспансерному наблюдению и лечению больных ВИЧ- инфекцией» в качестве режима первой линии АРТ в комбинации с 2 препаратами группы НИОТ

Small shelly fossils and carbon isotopes from the early Cambrian (Stage 3-4) Mural Formation of western Laurentia

The extraordinary window of phosphatised and phosphatic Small Shelly Fossils (SSFs) during the early and middle Cambrian is an important testament to the radiation of biomineralising metazoans. While SSF are well known from most Cambrian palaeocontinents during this time interval, western Laurentia has relatively few SSF faunas. Here we describe a diverse SSF fauna from the early Cambrian (Stage 3-4) Mural Formation at three localities in Alberta and British Columbia, Canada, complemented by carbon isotope measurements to aid in a potential future bio-chemostratigraphic framework. The fauna expands the recorded SSF assemblage diversity in western Laurentia and includes several brachiopods, four bradoriids, three chancelloriids, two hyoliths, a tommotiid and a helcionellid mollusc as well as echinoderm ossicles and specimens of Microdictyon, Volborthella and Hyolithellus. New taxa include the tommotiid genus Canadiella gen. nov., the new bradoriid species Hipponicharion perforata sp. nov. and Pseudobeyrichona taurata sp. nov. Compared to contemporaneous faunas from western Laurentia, the fauna is relatively diverse, particularly in taxa with originally phosphatic shells, which appear to be associated with archaeocyathid buildups. This suggests that the generally low faunal diversity in western Laurentia may be at least partly a consequence of poor sampling of suitable archaeocyathan reef environments. In addition, the tommotiid Canadiella filigrana appears to be of biostratigraphic significance in Cambrian Stage 3 strata of western Laurentia and the unexpected high diversity of bradoriid arthropods in the fauna also suggests that this group may prove useful for biostratigraphic resolution in the region

AN ADULT WITH MYOCARDIAL INFARCTION AND KAWASAKI DISEASE

Kawasaki disease — an acute systemic vasculitis with often involvement of coronary arteries — develops almost only in children. The most serious signs of Kawasaki disease are coronaritis and coronary arteries aneurisms. Aneurism thrombosis is possible complication of the disease and potential cause of myocardial infarction in youths. The case study presented of Kawasaki disease, complicated by myocardial infarction development in adult patient

Possibilities of adaptive design implementation in clinical trials of next-in-class drugs

The article investigates the possibility of streamlining the methodology of clinical studies of next-in-class drugs by implementing an adaptive design. Next-in-class drugs are original drugs with known biological targets, similar in structure and mode of action to already existing well-established innovative products. The results of phase II-III clinical trials are illustrated by three investigational products of different pharmacological classes, including a DPP-4 inhibitor (Diabetes mellitus type 2), factor Xa inhibitor (VTE prevention in orthopedic surgery), and NNRTI (HIV). A two-stage «seamless» adaptive design was developed for the clinical trials. In all the three studies the non-inferiority hypothesis was tested versus the standards of care. The adaptive design in DPP-4 inhibitor study made it possible to assess the efficacy and safety of two consecutive treatment regiments (mono- and combination therapy). The optimal doses for factor Xa inhibitor and NNRTI were selected at Stage 1, and their efficacy and safety were tested at Stage 2. The non-inferiority vs. standards of care was successfully demonstrated for all investigational products. The introduction of the adaptive design resulted in the optimization of the clinical programs of the next-in-class drugs

Adaptive design in clinical development of next-in-class drugs

The study objective was to assess the perspectives of the adaptive design methods in clinical development of the next-in-class drugs of different pharmacological groups including hypoglycemic agents, anticoagulants and anti-HIV drug

THE PROPANORM EFFICACY IN RAPID RELIEF OF SYMPTOMS OF PAROXYSMAL AURICULAR FIBRILLATION

In aim to study efficacy and safety of propafenone (Propanorm), open prospective поп randomized study in-patients with paroxysmal form of auricular fibrillation (AF) was carried out. 31 patients - 16 men (51,6 % ) and 15 women (48,4 % ) with mean age 58, 1± 8 years were included in the study. The paroxysmal form AF was observed in 29 patients (93,5 % ), persistent form - in 2 patients (6,5 % ). The reason of arrhythmia in 21 patients (67,7 % ) was ischemic heart disease, in 12 patients (38,7 % >) - arterial hypertension, in 2 patients (6,4 % ) - rheumatic heart diseases, in 1 patient (3,2 % ) - idiopathic AF. The medication for rapid relief of symptoms of paroxysmal auricular fibrillation was administered in single stress dose 600 mg per os. Propanorm restored the rhythm in 74,2 % > patients. The disorder of intraventricular conduction on EKG became evi-dentin 7 patients (22,5 % ) in time from 2to 16. 5 hours (on average 5, 1 hour), atrioventricular heart block of I stage - in 2 patients (6,45 % ), aberrant ventricular complex - in 2 patients (6,45 % ), pacemaker migration and sinus bradycardia - in 1 patient (3,2 % ). This disorders eliminated independently without special intervention. Extracardiac side effects during single intake were not observed. Propafenone appeared to be high-performed antiarrhythmic medication in rapid relief of symptoms of paroxysmal auricular fibrillation. Its application is possible in the outpatient setting

EFFICACY AND SAFETY OF ALBAREL IN PATIENTS WITH MILD, MODERATE AND SEVERE HYPERTENSION

The aim of the study was to evaluate the efficacy and safety (influence on carbohydrate, lipid and mineral metabolism, as well as nitrogen-excreting function of kidneys) of monotherapy with rilmenidine in patients with mild to moderate AH, as well as treatment of patients with severe AH as multiple combined treatment. 43 patients with essential AH I-HI degree, aged 22 to 79, were enrolled in this open label study after signing an informed consent form. Enrolled patients were divided into 2 groups. Group 1 included 20 outpatients. They received monotherapy with rilmenidine 1 mg daily. Duration of treatment was 12 weeks. Group 2 was comprised of 23 subjects admitted to an in-patient clinic. Those subjects received Albarel 1 mg or 2 mg daily as a component of multiple antihypertensive therapy. Albarel was administered 7-10 days following the admission to clinic as a second to fifth hypotensive drug. Albarel's combinations with diuretics, ACE inhibitors, calcium antagonists, beta-blockers. The result is - monotherapy with Albarel 1-2 mg daily allows to achieve target BP in 77, 8 % patients with mild to moderate AH. With Albarel as a component of multiple therapy target BP is achieved in 65, 2 % patients with severe AH. Effectively decreasing BP Albarel does not change its daily profile. It has no influence on renal function, carbohydrate metabolism, and electrolyte content of blood. Albarel is well tolerated. Adverse effects included mouth dryness and drowsiness, was noted in 2, 33 % cases and did not require drug withdrawal

Возможности применения адаптивного дизайна в клинических исследованиях препаратов «next-in-class»

The article investigates the possibility of streamlining the methodology of clinical studies of next-in-class drugs by implementing an adaptive design. Next-in-class drugs are original drugs with known biological targets, similar in structure and mode of action to already existing well-established innovative products. The results of phase II-III clinical trials are illustrated by three investigational products of different pharmacological classes, including a DPP-4 inhibitor (Diabetes mellitus type 2), factor Xa inhibitor (VTE prevention in orthopedic surgery), and NNRTI (HIV). A two-stage «seamless» adaptive design was developed for the clinical trials. In all the three studies the non-inferiority hypothesis was tested versus the standards of care. The adaptive design in DPP-4 inhibitor study made it possible to assess the efficacy and safety of two consecutive treatment regiments (mono- and combination therapy). The optimal doses for factor Xa inhibitor and NNRTI were selected at Stage 1, and their efficacy and safety were tested at Stage 2. The non-inferiority vs. standards of care was successfully demonstrated for all investigational products. The introduction of the adaptive design resulted in the optimization of the clinical programs of the next-in-class drugs.Изучена возможность оптимизации методологии клинических исследований лекарственных препаратов «next-in-class» путем внедрения адаптивного дизайна. Препараты «next-in-class» - это оригинальные защищенные патентом препараты, действующие на известные биомишени и по структуре и механизму действия напоминающие уже существующие успешно зарекомендовавшие себя препараты. Результаты клинических исследований II-III фазы представлены на примере трех лекарственных препаратов различных фармакологических классов: ингибитор ДПП-4 (сахарный диабет 2 типа), ингибитор Ха фактора (профилактика ВТЭ) и ННИОТ (ВИЧ-инфекция). В исследованиях был применен адаптивный «бесшовный» двухэтапный дизайн. Во всех исследованиях тестировалась гипотеза неуступающей эффективности (non-inferiority) по сравнению с препаратами стандартной терапии. Благодаря применению адаптивного дизайна для ингибитора ДПП-4 в рамках одного исследования последовательно изучены эффективность и безопасность двух режимов лечения (моно- и комбинированная терапии); для ингибитора Ха фактора и ННИОТ на первом этапе исследования подобрана оптимальная доза, а на втором - оценены ее эффективность и безопасность. Для всех исследуемых препаратов была успешно доказана неуступающая эффективность по сравнению с существующими стандартами терапии. Путем внедрения адаптивного дизайна оптимизирована программа клинических исследований препаратов «next-in-class»