Genetic Risk Factors for Adverse Drug Reactions

The use of medicines may in some cases be associated with the development of drug-induced diseases (DIDs) аnd other adverse drug reactions (ADRs), which leads to an increase in morbidity/mortality rates, and/or symptoms forcing a patient to seek medical attention or resulting in hospitalisation. ADRs may develop due to changes in a patient’s genotype, which entail an inadequate pharmacological response. The aim of the study was to analyse and summarise literature data on genetic risk factors that cause DIDs аnd other ADRs. It was shown that the polymorphism of genes encoding enzymes of drug metabolism (CYP, UGT, NAT, TPMT, EPHX, GST, etc.) or carriers (transporters) of drugs (P-gp, BCRP, MRP, OATP, OCT, etc.) can change the pharmacokinetics of drugs, affecting their activity. Polymorphism of RYR1, CACNA1S, MT-RNR1, VKORC1, and other genes encoding receptors targeted by drugs, and human leukocyte antigen (HLA) gene, may affect drug pharmacodynamics by modifying drug targets or changing the sensitivity of biological pathways to pharmacological effects of medicines. Changes in drug pharmacokinetics and pharmacodynamics may cause DIDs аnd other ADRs. The use of pharmacogenetic tests will allow a personalised approach to patients’ treatment and prevention or timely detection of potential ADRs during therapy. Before prescribing some medicines, clinicians should use recommendations on their dosing based on pharmacogenetic tests, which are posted on the official websites of Pharmacogenomics Research Network (PGRN), Pharmacogenomics Knowledgebase (PharmGKB), and Clinical Pharmacogenetics Implementation Consortium (CPIC). The results of ongoing clinical studies on the effect of gene polymorphism on drug safety will soon allow for higher personalisation of the choice of pharmacotherapy and prevention of many ADRs, including DIDs

Statin-Induced Myopathy

Scientific relevance. Being the main class of medicinal products for dyslipidaemia treatment, statins are widely used in clinical practice in various patient populations. However, statins can cause statin-associated muscle symptoms (SAMS), which are the most frequent and, in some cases, even life-threatening adverse reactions associated with these medicinal products.Aim. The study aimed to perform a systematic review of the epidemiology, classification, and physiological pathogenesis of SAMS, risk factors for this complication, and clinical guidelines for primary care physicians regarding the identification and treatment of patients with SAMS.Discussion. SAMS is an umbrella term that covers various forms of myopathies associated with satin therapy. According to the published literature, the prevalence of SAMS varies considerably and may depend on the study design, inclusion criteria, and the medicinal product used. SAMS has multiple putative pathogenic pathways that include genetically determined processes, abnormalities in mitochondrial function, defects in intracellular signalling and metabolic pathways, and immune-mediated reactions. The main known risk factors for developing SAMS include high-dose statins, drug–drug interactions, genetic polymorphisms, female sex, older age, Asian race, history of kidney, liver, and muscle disease, and strenuous physical activity. Given the lack of universally recognised algorithms for diagnosing SAMS, clinicians should consider the clinical presentation and the temporal relationship between statin therapy and symptoms. Other factors to consider include changes in muscle-specific enzyme levels and, in some cases, the results of blood tests for antibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase.Conclusions. To ensure the safety of statin therapy, it is essential to raise clinicians’ awareness of the risk factors for SAMS, indicative clinical and laboratory findings, and the need for dynamic patient monitoring, including the involvement of clinical pharmacologists

THE POSSIBILITIES OF USING A NEW FIXED-DOSE COMBINATION OF ROSUVASTATIN AND ACETYLSALICYLIC ACID: FOCUS GROUPS OF PATIENTS

The review focuses on the impairment of the carotid, coronary arteries and lower-extremity arterial disease. Systemic involvement of various vascular beds in atherogenesis is emphasized. Epidemiological characteristics of morbidity and mortality from the main clinical manifestations of atherosclerosis - ischemic stroke, ischemic heart disease and lower-extremity arterial disease are given. The current principles of drug therapy are considered from the point of view of improving the prognosis and eliminating ischemia. The basic positions of International and Russian clinical recommendations on the management of patients with the presence of certain clinical manifestations of atherosclerosis are discussed. Detailed administration schemes and the preferred doses of statins and antiplatelet agents depending on the localization of atherosclerotic lesion and the severity of stenosis are described. The target blood lipids levels in the treatment with statins are given. The advantages of statins as drugs that reduce the risk of cardiovascular complications are presented. Current data on the pattern of antiplatelet use, including acetylsalicylic acid, in individuals with clinical manifestations of atherosclerosis are given. The principal tactic of dual antiplatelet therapy and schemes of its use in patients undergoing percutaneous coronary intervention, coronary artery bypass surgery and in individuals with a history of acute coronary disorders are considered

Современные представления о проблеме ортостатической гипотензии

Recent literary data reports an increase in the prevalence of orthostatic hypotension (ОН) with age and with the presence of comorbidities. In addition, ОН is associated with a high risk of major adverse cardiovascular and cerebrovascular events and may contribute to cognitive impairment and the onset of dementia. Moreover, OH is one of the main risk factors for falls, especially among elderly patients. The review covers recent national and foreign studies focusing on this problem, and presents an updated definition of ОН, its modern classification, pathophysiology, peculiarities of the ОН course in the elderly, guidelines on OH diagnosis and treatment. Particular attention is given to the secondary ОН, commonly known as drug-induced ОН. Its prevalence increases with increased number of medications taken. A list of drugs that may induce ОН and treatment approaches to polypragmasia are provided.На сегодняшний день имеется много литературных данных, о том, что частота встречаемости ортостатической гипотензии (ОГ) увеличивается с возрастом и при наличии сопутствующей патологии. Кроме того, ОГ ассоциируется с повышенным риском серьезных неблагоприятных цереброваскулярных и коронарных событий, может способствовать нарушению когнитивных функций и развитию деменции, а также является одним из главных факторов риска падений, особенно у пожилых пациентов. В данном обзоре обобщены современные отечественные и зарубежные литературные данные о данной проблеме, представлены обновленное определение ОГ, её современная классификация, патофизиология, особенности течения ОГ у пожилых людей, рекомендации по диагностике и лечению. Особое внимание в обзоре уделено одной из форм вторичной ОГ - лекарственно индуцированной ОГ, частота встречаемости которой увеличивается с увеличением количества принимаемых лекарственных препаратов. Подробно представлены перечень лекарственных препаратов, вызывающих ОГ и методы борьбы с полипрагмазией

Drug-induced pulmonary artery hypertension

Pulmonary arterial hypertension is a condition characterized by an increase in mean pressure in the pulmonary artery. This pathology is associated with high mortality, and specific therapy for pulmonary arterial hypertension does not affect the cause of the disease and is extremely expensive. In this regard, it is especially important to study the modifiable etiological factors of pulmonary arterial hypertension. One such factor is drugs. One of the leading groups of drugs-inductors is anorexigenic drugs. It was the representatives of this group, such as aminorex, who were the first inducers of pulmonary hypertension. Moreover, this adverse reaction was so significant that it led to the withdrawal of these drugs. Currently, the leading role in the context of drug-induced pulmonary hypertension is played by such drugs as anticancer, antiviral drugs, and interferons. These drugs lead to pulmonary hypertension through various pathophysiological mechanisms. The leading measures to prevent this pathology are to limit the use of culprit medications, reduce the spread of HIV infection, since several groups of drugs can be used to treat HIV-infected patients, leading to the development of pulmonary hypertension

Drug-Induced Atrial Fibrillation / Atrial Flutter

Drug-induced atrial fibrillation / flutter (DIAF) is a serious and potentially life-threatening complication of pharmacotherapy. Purpose of the work: systematization and analysis of scientific literature data on drugs, the use of which can cause the development of DIAF, as well as on epidemiology, pathophysiological mechanisms, risk factors, clinical picture, diagnosis and differential diagnosis, treatment and prevention of DIAF. Analysis of the literature has shown that many groups of drugs can cause the development of DIAF, with a greater frequency while taking anticancer drugs, drugs for the treatment of the cardiovascular, bronchopulmonary and central nervous systems. The mechanisms and main risk factors for the development of DIAF have not been finally established and are known only for certain drugs, therefore, this section requires further study. The main symptoms of DIAF are due to the severity of tachycardia and their influence on the parameters of central hemodynamics. For diagnosis, it is necessary to conduct an electrocardiogram (ECG) and Holter monitoring of an ECG and echocardiography. Differential diagnosis should be made with AF, which may be caused by other causes, as well as other rhythm and conduction disturbances. Successful treatment of DIAF is based on the principle of rapid recognition and immediate discontinuation of drugs (if possible), the use of which potentially caused the development of adverse drug reactions (ADR). The choice of management strategy: heart rate control or rhythm control, as well as the method of achievement (medication or non-medication), depends on the specific clinical situation. For the prevention of DIAF, it is necessary to instruct patients about possible symptoms and recommend self-monitoring of the pulse. It is important for practitioners to be wary of the risk of DIAF due to the variety of drugs that can potentially cause this ADR

A Statistical Test of Heterogeneous Subgraph Densities to Assess Clusterability

Determining if a graph displays a clustered structure prior to subjecting it to any cluster detection technique has recently gained attention in the literature. Attempts to group graph vertices into clusters when a graph does not have a clustered structure is not only a waste of time; it will also lead to misleading conclusions. To address this problem, we introduce a novel statistical test, the-test, which is based on comparisons of local and global densities. Our goal is to assess whether a given graph meets the necessary conditions to be meaningfully summarized by clusters of vertices. We empirically explore our test’s behavior under a number of graph structures. We also compare it to other recently published tests. From a theoretical standpoint, our test is more general, versatile and transparent than recently published competing techniques. It is based on the examination of intuitive quantities, applies equally to weighted and unweighted graphs and allows comparisons across graphs. More importantly, it does not rely on any distributional assumptions, other than the universally accepted definition of a clustered graph. Empirically, our test is shown to be more responsive to graph structure than other competing tests

The influence of antyhypertensive therapy of valsartan and fixed combination with hydrochlorothiazide use on pulse-wave velocity and central arterial pressure in patients with arterial hypertension of 1-2 grades in international VICTORY clinical trial

Objective - to explore influence of valsartan monotherapy use and its use in combination with hydrochlorothiazide (HCTZ) on pulse-wave velocity (PWV) and central arterial pressure (CAP) in patients with arterial hypertension (AH) of 1-2 grades in international VICTORY clinical trial. Materials and methods. The international multicenter prospective randomized clinical study VICTORY that lasted for 16 weeks included patients with 1-2 grades AH. In patients who previously received antihypertensive therapy a 7 days washout period was carried out. All patients started their therapy with 80 mg valsartan (Valsacor®, KRKA, Slovenia); in Russia the starter dose of Valsacor®, KRKA was 160 mg in previously treated patients that did not influence the study results. If after 4 weeks of treatment BP was more than 140/90 mm hg (more than 130/80 mm hg in high risk patients or in diabetes mellitus patients) the dose of valsartan was increased to 160 mg (320 mg in Russia) or diuretic in fixed combination with valsartan was added (160 mg valsartan/12.5 mg HCTZ): Valsacor® H 160 (KRKA, Slovenia). If target BP after 8 weeks of treatment was not reached valsartan dose was increased to 320 mg or fixed combination of valsartan and diuretic (160 mg/12.5 mg) was used. If target BP after 12 weeks of treatment was not reached - valsartan and diuretic 320 mg/12.5 mg were used. PWV and CAP (SphygmoCor®, AtCorMedical) were assessed at baseline and after 16 weeks of treatment. The primary endpoints were assessment of the impact of studied medications on aortic stiffness, aortic augmentation index and comparison of absolute medians of reached central and peripheral BP reduction with baseline value. Results. Of 365 patients included in the study 74 were included in PWV and CAP study subgroup. Valsartan and its combination with HCTZ were effective in CBP reduction. The mean absolute reduction of central systolic and diastolic BP after 16 weeks of treatment was 19.7±12.9 mm hg and 13.9±8.5 mm hg, respectively (

Лекарственно-индуцированные поражения легких противоопухолевыми препаратами: распространенность, некоторые препараты и механизмы их воздействия. Часть 2

The article analyzes 49 publications on adverse drug reactions occurring during therapy with antitumor drugs. It presents data on pneumotoxicity and its clinical manifestations for such anticancer drugs as bleomycin, busulfan, cyclophosphamide, chlorambucil, methotrexate, nitrosourea derivatives, and taxanes, while the mechanisms of lung injury are not entirely clear and require further research. The prevention of drug-induced lung injury requires raising awareness among practicing physicians of different specialties, primarily general practitioners, rheumatologists, clinical immunologists, pulmonologists, phthisiologists, and oncologists due to non-specific manifestations of drug-induced lung injury and the use of antitumor drugs for other diseases apart from cancer.Проанализировано 49 источников литературы о нежелательных лекарственных реакциях, возникающих при терапии противоопухолевыми препаратами. Представлены данные о пневмотоксичности и ее клинических проявлениях для таких противоопухолевых препаратов, как блеомицин, бусульфан, циклофосфамид, хлорамбуцил, метотрексат, производные нитрозомочевины, таксаны, при этом механизмы развития поражения легких не совсем ясны, что требует дальнейших исследований. Для профилактики лекарственно-индуцированного поражения легких необходима информированность практикующих врачей разных специальностей, прежде всего терапевтов, ревматологов, клинических иммунологов, пульмонологов, фтизиатров, онкологов, ввиду неспецифичности симптомов лекарственно-индуцированного поражения легких и применения противоопухолевых лекарственных средств не только при развитии онкологических заболеваний

Breast cancer incidence following low-dose rate environmental exposure: Techa River Cohort, 1956–2004

In the 1950s, the Mayak nuclear weapons facility in Russia discharged liquid radioactive wastes into the Techa River causing exposure of riverside residents to protracted low-to-moderate doses of radiation. Almost 10 000 women received estimated doses to the stomach of up to 0.47 Gray (Gy) (mean dose=0.04 Gy) from external γ-exposure and 137Cs incorporation. We have been following this population for cancer incidence and mortality and as in the general Russian population, we found a significant temporal trend of breast cancer incidence. A significant linear radiation dose–response relationship was observed (P=0.01) with an estimated excess relative risk per Gray (ERR/Gy) of 5.00 (95% confidence interval (CI), 0.80, 12.76). We estimated that approximately 12% of the 109 observed cases could be attributed to radiation