Brain metabolites in ISIAH and Wistar rats

Hypertension is one of the most common human diseases. This disease leads to serious disturbances such as myocardial infarction and stroke. Due to the development of nuclear magnetic resonance spectroscopy (NMRS), a decrease in neuron viability in different parts of the brain in humans with hypertension has been shown. Translation of NMRS tools to the clinic requires the accumulation of empirical data about neurometabolic changes in a strictly controlled experiment. It is particularly interesting to compare the metabolic parameters of laboratory animals with normal and high blood pressure kept in standard conditions on exactly the same diet. In this study, cortex and hypothalamus metabolites of ISIAH and Wistar male rats at the age of 8–9 weeks were examined. Cortex and hypothalamus metabolites were measured in animals under isoflurane anesthesia using proton magnetic resonance spectroscopy (1Н MRS). Processing of primary data using Partial least squares Discriminant Analysis (PLS-DA) allowed us to identify the main discriminating axis (Y1), its variations reflecting the predominance of excitatory neurometabolites (glutamine and glutamate) over inhibitory ones (GABA and glycine). In the cortex, the values of the Y1-axis were lower in ISIAH than in Wistar rats. This fact indicates a decrease in cortical excitability in hypertensive animals. By contrast, in the hypothalamus, the values of the Y1-axis were higher in ISIAH than in Wistar rats and the predominance of excitatory neurometabolites positively correlated with the level of mean blood pressure, which agrees well with the view of caudal hypothalamic activation in hypertensive animal models

Antisense oligonucleotides for the arterial hypertension mechanisms study and therapy

Arterial hypertension is one of the most common chronic diseases in adults all over the world. This pathology can not only reduce patients’ life quality, but can also be accompanied by a number of complications. Despite the fact that there is a large group of antihypertensive drugs on the market, mainly representing different combinations of inhibitors of the renin-angiotensin system, adrenoreceptor blockers in combination with diuretics, there is no generally accepted “gold standard” for drugs that would not have side effects. The review discusses the main aspects of antisense oligonucleotides use in the context of arterial hypertension. It is well known that the medical implementation of antisense oligonucleotides aims to block the expression of particular genes involved in the pathology development, and a key advantage of this technique is a high selectivity of the effect. However, with the undoubted advantages of the method, there are difficulties in its application, related both to the properties of the oligonucleotides themselves (insufficient stability and poor penetration into cells), and to the variety of mechanisms of the origin of a particular pathology, arterial hypertension, in our case. The review provides a brief description of the main molecular targets for antisense treatment of hypertensive disease. The newest targets for therapy with oligonucleotides – microRNAs – are discussed. The main modifications of antisense nucleotides, designed to increase the duration of their effects and simplify the delivery of this type of drugs to the targets are discussed, in particular, combining antisense oligonucleotides with adenovirus-based expression vectors. Particular attention is given to antisense oligonucleotides in the complex with nanoparticles. The review discusses the results of the use of titanium dioxide (TiO2) containing antisense nanocomposites for the angiotensin converting enzyme in rats with stress induced arterial hypertension (ISIAH). It was shown that the use of antisense oligonucleotides continues to be a promising technique for studying the mechanisms of various forms of hypertensive disease and has a high potential for therapeutic use

Metabolic profile of blood serum in experimental arterial hypertension

The etiology of essential hypertension is intricate, since it employs simultaneously various body systems related to the regulation of blood pressure in one way or another: the sympathetic nervous system, renin-angiotensin-aldosterone and hypothalamic-pituitary-adrenal systems, renal and endothelial mechanisms. The pathogenesis of hypertension is influenced by a variety of both genetic and environmental factors, which determines the heterogeneity of the disease in human population. Hence, there is a need to perform research on experimental models – inbred animal strains, one of them being ISIAH rat strain, which is designed to simulate inherited stress-induced arterial hypertension as close as possible to primary (or essential) hypertension in humans. To determine specific markers of diseases, various omics technologies are applied, including metabolomics, which makes it possible to evaluate the content of low-molecular compounds – amino acids, lipids, carbohydrates, nucleic acids fragments – in biological samples available for clinical analysis (blood and urine). We analyzed the metabolic profile of the blood serum of male ISIAH rats with a genetic stress-dependent form of arterial hypertension in comparison with the normotensive WAG rats. Using the method of nuclear magnetic resonance spectroscopy (NMR spectroscopy), 56 metabolites in blood serum samples were identified, 18 of which were shown to have significant interstrain differences in serum concentrations. Statistical analysis of the data obtained showed that the hypertensive status of ISIAH rats is characterized by increased concentrations of leucine, isoleucine, valine, myo-inositol, isobutyrate, glutamate, glutamine, ornithine and creatine phosphate, and reduced concentrations of 2-hydroxyisobutyrate, betaine, tyrosine and tryptophan. Such a ratio of the metabolite concentrations is associated with changes in the regulation of glucose metabolism (metabolic markers – leucine, isoleucine, valine, myoinositol), of nitric oxide synthesis (ornithine) and catecholamine pathway (tyrosine), and with inflammatory processes (metabolic markers – betaine, tryptophan), all of these changes being typical for hypertensive status. Thus, metabolic profiling of the stress-dependent form of arterial hypertension seems to be an important result for a personalized approach to the prevention and treatment of hypertensive disease

Stress and arterial hypertension: ISIAH rat strain

The main views of the issue of stress and hypertension are briefly reviewed. It is well known that stress is one of the major risk factors for cardiovascular disease development. Increase in blood pressure is a typical manifestation of the acute stress response. This fact is the reason to hypothesize that chronic stress causes the development of hypertensive disease. An association of hypertension with psychological stress in humans was shown in several works. In addition, it was demonstrated that hypertension was accompanied by an increase in sympathetic tone. On the other hand, there were many population studies in which no association was found between different types of chronic stress and arterial hyper­tension. Thus, the question is far from being answered. Even in the cases when one managed to obtain a signi­ficant hypertensive effect in experimental studies with emotional stress, it was difficult to explain the mechanisms mediating the formation of stressinduced hypertension. To clarify the situation, one of the authors of this review decided to begin the breeding of a rat strain with increased blood pressure response to emotional stress. This breeding gave rise to inbred rats with persistent stress-induced arterial hypertension. A brief history of the development of the genetic model ofstress-induced arterial hypertension, the ISIAH rat strain, is given. A retrospective review of the studies performed with ISIAH rats is presented. The contribution of genotype changes in the neuroendocrine systems involved in stress and blood pressure regulation to the development ofstress-dependent hypertension in the ISIAH rat strain is shown

GC-based chemoprofile of lipophilic compounds in Altaian Ganoderma lucidum sample

The presented data contains information about component composition of lipophilic compounds in Ganoderma lucidum fungal body sample obtained using gas chromatography and subsequent mass spectrometry

Формирование клинико-статистических групп для оплаты лечения злокачественных новообразований в модели 2019 года

The article addresses the model of diagnosis-related groups (DRG) updated according to the new tariffs in the compulsory medical insurance. Especially emphasized are changes made in the DRG model of 2019, which resulted from the previous work on the development and revision of the clinical recommendations in oncology, as well as the regulation changes in the healthcare system. In addition, the article describes the functioning of the DRG model in 2018 and the payment for cancer care and also provides examples from the practice of chemotherapy. The modifications made in the 2019 model are carefully discussed in terms of: expanding the list of oncological diagnoses, creating and characterizing new DRG groups, updating the coding system and the structure of reference books, changing the Guidebook recommendations and the Instruction related to oncological groups. Clarifications are given regarding frequently asked questions on payments for the medical care in oncology within the current DRG model.  В статье рассматривается развитие модели клинико-статистических групп (КСГ) и заложенных в нее новых принципов и подходов к формированию тарифов в системе ОМС. Отдельно делается акцент на изменениях, внесенных в модель КСГ 2019 года, которые были продолжением работы по разработке и пересмотру клинических рекомендаций по профилю «Онкология», а также обусловлены рядом изменений в нормативно правовом регулировании в области здравоохранения. В статье описываются определенные результаты функционирования модели КСГ в 2018 году и особенности оплаты онкологической помощи, с описанием практики использования схем лекарственной терапии в 2018 году. Подробно рассматриваются нововведения модели 2019 года в части: расширения перечня онкологических диагнозов, принципа формирования новых групп и описание их содержания, нововведения в кодировании и в структуре справочников, изменений в Методические рекомендации и Инструкцию, затрагивающих клинико-профильную группу «Онкология». Отдельно даются разъяснения по часто задаваемым вопросам, касающимся оплаты медицинской помощи по профилю «Онкология» в рамках действующей модели КСГ. 

Клинико-экономический анализ и оценка влияния на бюджет применения имплантируемых кардиовертеров-дефибрилляторов в Российской Федерации

Objective: to evaluate cost-effectiveness and budget impact of using single and dual chamber implantable cardioverter-defibrillators (ICD) adjunctive to the standard drug therapy (DT) compared to the standard DT alone for the primary and secondary prevention of sudden cardiac death (SCD).Material and methods. Original partitioned survival analysis model was developed to assess the cost-effectiveness of using ICD within the modelling horizon of 8 years. The following model outcomes were used: life years and quality-adjusted life years (QALY). Primary prevention model was focused on patients after myocardial infarction with left ventricular ejection fraction (LVEF) ≤30%, whilst secondary prevention model considered cardiac arrest survivors and/or patients diagnosed with ventricular tachycardia or ventricular fibrillation with LVEF ≤35%. The model summarizes treatment effect and costs for ICD and DT specific to the healthcare system of the Russian Federation (RF). The main scenario accounted for ICD implantation cost in accordance with general reimbursement price asserted in the high technology medical care list part 2 (HТMC 2). Additionally, alternative scenario of ICD reimbursement level was developed to account for general tariff split onto singleand dual-chamber ICD implantation reimbursement tariffs which can be financed through high technology medical care list part 1 (HТMC 1). Budget impact analysis compared the costs of using ICD within the current volume of the annual increase in ICD implantations and a threefold increased volume of ICD implantations.Results. By the end of the modelling period, additional 34% of patients survived in the ICD group compared to the DT group. Incremental cost-effectiveness ratio (ICER) per 1 QALY constituted 2.8 and 2.2 million rubles for primary and secondary prevention, respectively. ICER values are slightly above or lower than the willingness-to-pay threshold of 2.5 million rubles per 1 QALY in the RF in the segment of primary and secondary SCD prevention, respectively. Additional HТMC 1 scenario incorporating lower ICD implantation prices resulted in an average ICER drop by 13% compared to HTMC 2. Overall patient population requiring SCD prevention comprised of 7,161 and 3,341 patients in primary and secondary prevention, respectively. Budget impact analysis showed that threefold rise in the ICD implantations rate will require additional 648 million rubles for primary prevention cohort to provide additional 573 patients with ICD, and 230 million rubles for secondary prevention cohort with additional 267 patients covered with ICD. ICD reimbursement price drop within the HТMC 1 scenario will save 133 million rubles and allow to provide additional 143 patients with ICDs for a given budget.Conclusion. ICD is a cost-effective option of secondary prevention of SCD. Additional analysis of ICD reimbursement price drop drives ICER downwards to a considerable extent which in turn increases the accessibility of ICDs to patients. In scenario of ICD implantation financing within HТMC 1, ICD is established to be a cost-effective option for primary and secondary prevention of SCD in the RF.Цель: оценка клинико-экономической эффективности и анализ влияния на бюджет (АВБ) применения одно- и двухкамерных имплантируемых кардиовертеров-дефибрилляторов (ИКД) в сочетании со стандартной лекарственной терапией (ЛТ) по сравнению со стандартной ЛТ для первичной и вторичной профилактики внезапной сердечной смерти (ВСС).Материал и методы. Построена оригинальная модель распределенной выживаемости пациентов с риском ВСС для проведения анализа «затраты–эффективность» с горизонтом моделирования 8 лет. В качестве исходов модели были использованы годы жизни и годы жизни с поправкой на качество (англ. quality-adjusted life year, QALY). Модель первичной профилактики ВСС включала пациентов после инфаркта миокарда с фракцией выброса левого желудочка (ФВЛЖ) 30% и менее, модель вторичной профилактики ВСС – больных после остановки сердца и/или имеющих желудочковую тахикардию или фибрилляцию желудочков с ФВЛЖ 35% и менее. Модель позволяет прогнозировать затраты на лечение и исходы пациентов, использующих ИКД или ЛТ в условиях системы здравоохранения Российской Федерации (РФ). Основной сценарий учитывает стоимость имплантации прибора по единому тарифу для всех типов ИКД в рамках второго перечня высокотехнологичной медицинской помощи (ВМП 2). Дополнительно моделировали сценарий со снижением тарифа на имплантацию ИКД за счет разгруппировки существующего единого тарифа на два: для однои двухкамерных ИКД в отдельности в рамках первого перечня ВМП (ВМП 1). С помощью АВБ сравнивали затраты на использование ИКД в рамках текущего объема ежегодного прироста имплантаций ИКД и повышенного (трехкратного) объема прироста.Результаты. На конец горизонта моделирования дополнительный прирост выживаемости в группе ИКД по сравнению с группой ЛТ составил 34%. Инкрементальный показатель «затраты–эффективность» (англ. incremental cost-effectiveness ratio, ICER) за 1 QALY в основном сценарии составил 2,8 и 2,2 млн руб. в сегментах первичной и вторичной профилактики ВСС соответственно. Полученное значение по первичной профилактике незначительно превышает, а по вторичной профилактике находится ниже референтного значения ICER (порога готовности платить), составляющего в РФ 2,5 млн руб. за 1 QALY. Моделируемое снижение стоимости тарифа на установку ИКД в рамках перечня ВМП 1 улучшает затратную эффективность (снижает ICER) в среднем на 13% от сценария ВМП 2. Суммарная популяция пациентов, нуждающихся в первичной и вторичной профилактике ВСС, составляет около 7161 и 3341 человека соответственно. Моделирование трехкратного прироста числа ИКД по отношению к текущим объемам обеспеченности в АВБ позволяет дополнительно обеспечить 573 пациента в рамках первичной профилактики ВСС, затратив дополнительно 638 млн руб., и 267 пациентов в рамках вторичной профилактики ВСС при размере дополнительных затрат 230 млн руб. Снижение стоимости имплантации ИКД в сценарии ВМП 1 способствует повышению доступности данной технологии за счет высвобождения дополнительных средств в размере 133 млн руб., позволяющих выполнить дополнительные операции по установке приборов ИКД 143 пациентам при первичной и вторичной профилактике ВСС суммарно.Заключение. ИКД является затратно-эффективной технологией в сегменте вторичной профилактики ВСС. Снижение стоимости ИКД в результате разгруппировки тарифа ВМП 2 значительно повышает клинико-экономическую эффективность данной технологии и способствует ее доступности для пациентов. Таким образом, при финансировании имплантаций по разгруппированным тарифам в рамках перечня ВМП 1 ИКД является затратно-эффективной опцией первичной и вторичной профилактики ВСС в РФ

БЛИЖАЙШИЕ РЕЗУЛЬТАТЫ МУЛЬТИМОДАЛЬНОГО ЛЕЧЕНИЯ АДЕНОКАРЦИНОМЫ ПРЕДСТАТЕЛЬНОЙ ЖЕЛЕЗЫ В НОВОСИБИРСКОЙ ОБЛАСТИ

The short-term performance criteria (PSA blood level and prostate volume) were analyzed concerning the complex (hormonal and radiation) treatment of 57 patients with prostate adenocarcinoma, stratified into three disease progression risk groups. Two treatment regimens were differed in the duration of neoadjuvant hormone therapy: 9 or 32 ± 13 months in combination with external beam radiation therapy with a total dose 76–80 Gy. Statistical analysis of the multimodal treatment efficiency criteria of patients with high risk of prostate adenocarcinoma showed the best result (significant decrease of PSA blood level) using a single 9-month course of hormone therapy and subsequent external beam radiation therapy. The prostate volume indicator in the applicable mode of radiation therapy has mixed dynamics, and requires further study as a multimodal treatment effectiveness criterion.Изучены ближайшие критерии эффективности – уровень простатспецифического антигена (ПСА) и объем предстательной железы (ПЖ) – комплексного (гормонального и лучевого) лечения 57 пациентов с аденокарциномой ПЖ, стратифицированных по 3 группам риска прогрессирования заболевания. Использованы 2 схемы лечения, различающиеся по длительности неоадъювантной гормонотерапии: 9 мес или 32 ± 13 мес в сочетании с дистанционной лучевой терапией с суммарной дозой 76–80 Гр. У пациентов с высоким риском прогрессирования опухолевого процесса продемонстрирована достоверно высокая эффективность комбинированного метода лечения с наилучшими показателями снижения уровня ПСА в группе 9-месячного курса гормонотерапии. Показатель объема органа в применяемом режиме лучевой терапии имеет разнонаправленную динамику и требует дальнейшего изучения в качестве критерия эффективности мультимодального лечения

Diagnosis-related groups and payments for the treatment of malignant neoplasms in the model of 2019

The article addresses the model of diagnosis-related groups (DRG) updated according to the new tariffs in the compulsory medical insurance. Especially emphasized are changes made in the DRG model of 2019, which resulted from the previous work on the development and revision of the clinical recommendations in oncology, as well as the regulation changes in the healthcare system. In addition, the article describes the functioning of the DRG model in 2018 and the payment for cancer care and also provides examples from the practice of chemotherapy. The modifications made in the 2019 model are carefully discussed in terms of: expanding the list of oncological diagnoses, creating and characterizing new DRG groups, updating the coding system and the structure of reference books, changing the Guidebook recommendations and the Instruction related to oncological groups. Clarifications are given regarding frequently asked questions on payments for the medical care in oncology within the current DRG model