The problem of choice: original drug or generic? Emphasis on rosuvastatin

An increase in the life expectancy of the population and the number of polymorbid patients with a combination of two or more diseases in different age categories, including among young people, has led to a significant increase in the cost of medical care in the field of public health. The transition from original drugs to generic ones has become a common measure to contain these costs. While this is an important goal for healthcare systems around the world, the impact of this practice on patient outcomes needs to be carefully considered. In some cases, generics may represent a suitable alternative to branded products, but this is not always the case. In particular, studies have shown that changing the drug can negatively affect not only patients' adherence to treatment, but also clinical outcomes, and a subsequent increase in the total cost of treatment, therefore, the use of generics in clinical practice still causes caution and concerns on the part of both the doctor and the patient. Due to the high prevalence of dyslipidemia and hypercholesterolemia both worldwide and in Russia, in this review the problem of choosing an original drug or generic is described by the example of such a hypolipidemic agent as rosuvastatin. According to numerous studies, rosuvastatin is one of the most potent and widely prescribed statins. Considering that most of the clinically significant effects of this drug are demonstrated in relation to its original form, the review emphasizes the importance of prescribing the original drug rosuvastatin in routine clinical practice

Heart failure as a risk factor of adverse drug reactions. Part 2: potential changes in pharmacokinetics of some drugs

Drug administration, can be potentially associated with adverse drug reactions (ARDs), including serious ones, contributing to an increase in the risk of death or the development of conditions that potentially increase mortality and / or morbidity and / or become the cause of clinical manifestations, requiring the patient to seek medical attention or hospitalization - so called drug-induced diseases (DID). Some pathological conditions, like chronic heart failure (CHF), are potential risk factors for DID due to changes in the pharmacokinetics and pharmacodynamics of drugs. For example, after oral administration of fosinopril, the average T1/2 value in patients with CHF II - III NYHA functional class was 14.2 (±7.3) hours, and in healthy individuals of the control group - 11.0 (±5.2) hours. Values of AUC per os and Cmax were also slightly higher in patients with heart failure (HF) than in healthy individuals, and Cl per os, on the contrary, were lower. After intravenous administration of fosinopril, similar results were observed. Another example is the altered absorption of furosemide in patients with decompensated heart failure. Thus, in patients with heart failure, as the edema syndrome is corrected, the time to the onset of the maximum drug concentration in the blood serum (Tmax ) decreases by 27 % and Cmax increases by 29 %, which may indicate a decrease in the slowdown in the absorption rate (by 57 %). Since furosemide is mainly excreted in the urine unchanged, the observed changes in Cmax and Tmax could be associated with delayed gastric emptying, decreased intestinal motility, or edema of the intestinal wall. Individual selection of the dose and dosing regimen, taking into account the characteristics of the pharmacokinetics of drugs in patients with CHF, will help improve the quality of life and prevent potential ADR

Food-drug interaction as a risk factor of drug-induced diseases: epidemiology, risk factors, potential mechanisms of interaction

Any drug is potentially associated with the risk of adverse drug reactions (ADRs), the incidence of which in developed and developing countries is estimated at 6.3 (3.3—11.0) and 5.5 % (1.1—16.9), respectively. Many ADRs increase mortality and / or morbidity and / or cause clinical manifestations that require a patient to seek medical help or hospitalization; a special term has been introduced — drug-induced diseases. Food can interact with drugs and increase the risk of ADRs, including serious ones. The simultaneous intake of food and drugs can affect the bioavailability, pharmacokinetics, pharmacodynamics and therapeutic efficacy of drugs due to changes in drug absorption and metabolism. A striking example of the effect of food on the pharmacokinetic profile of drugs is the change in the bioavailability of the tyrosine kinase inhibitor lapatinib: compared with taking on an empty stomach, the bioavailability of lapatinib in a single dose of 1 500 mg after taking it together with high-calorie standard food increases by an average of 325 % — 4.25 times. In other words, the concentration of the drug in the blood serum after taking one tablet at the same time with food is comparable to taking 4 tablets on an empty stomach. Currently, there are no recommendations for choosing a dosage regimen for drugs depending on the qualitative and quantitative composition of food, as well as taking into account potential interactions with food components, although these recommendations are extremely necessary for patients and healthcare professionals. In this regard, this article summarizes the data available at the time of writing in open sources concerning the effect of food on the absorption and metabolism of drugs, and also describes the possible mechanisms of interaction

Heart failure as a risk factor of adverse drug reactions. Part 1: potential changes in pharmacokinetics

The use of many drugs is associated with the risk of adverse drug reactions (ADRs), including those that increase mortality and / or morbidity and / or seek medical help or hospitalization, so called «drug-induced diseases» (DID). There is a number of factors that increase the risk of DID (risk factors) including comorbid diseases (for example, chronic kidney disease, hepatic impairment, obesity etc.). These pathologic conditions induce changes in pharmacokinetics (PK) and pharmacodynamics of drugs, thereby increasing the risk of ADRs. One of these diseases is heart failure (HF). Most studies of PK changes were conducted among patients with LVEF from 40 to 45 %, and excluded patients with concomitant diseases that could affect the PK of drugs (for example, serious liver and / or kidney diseases), therefore in polymorbid patients, trial findings may not be applicable. HF may be associated with a decrease in bioavailability, a decrease in volume of distribution, a change in the activity of cytochrome P450 isoenzymes, etc. Individual dose and dosage regimen adjustment can significantly reduce risks, improve the quality of medical care and improve the prognosis in patients with heart failure

Drug-induced intracerebral hemorrhage

Intracerebral hemorrhage (ICH), which is a form of hemorrhagic stroke, is an extremely serious disease. This pathology is characterized by very high levels of disability and mortality. Despite the improvement in the treatment of those diseases that can lead to ICH, its frequency is currently increasing, which is largely due to the use of drugs, in which case the term «drug-induced intracerebral hemorrhage» (DI ICH) is used. One of the main reasons for drug-induced ICH is an increase in the frequency of prescribing anticoagulant therapy for the prevention of ischemic stroke in atrial fibrillation, as well as dual antithrombotic therapy. In addition to anticoagulants, thrombolytic drugs can lead to the development of this pathology. According to the literature, an increase in the risk of developing ICH is also associated with therapy with antidepressants from the group of selective serotonin reuptake inhibitors, as well as high doses of statins. Risk factors for this adverse reaction are age, smoking, hypertension, and thrombocytopenia. Treatment of DI ICH is an extremely difficult task and includes the withdrawal of the culprit medication, antihypertensive therapy, correction of intracranial hypertension, and, in some cases, the administration of antidotes. The main method of prevention is the use of antiplatelet drugs and other drugs, the use of which is associated with an increased risk of developing DI ICH, in strict accordance with modern protocols and recommendations

Prospects for using a perindopril/amlodipine combination in patients with hypertension and/or coronary artery disease and COVID-19: focus on the endothelium

The outbreak of the coronavirus disease 2019 (COVID-19) pandemic is an ongoing public health emergency that has caused unprecedented morbidity and mortality. COVID-19 is a disease caused by severe acute respiratory syndromerelated coronavirus 2 (SARS-CoV-2), which affects not only the lungs but also the cardiovascular system. A strong theoretical justification for the multisystem effect of COVID-19 is the close relationship between it and endothelial dysfunction, which, according to expert consensus, is crucial for the pathogenesis and severity of the disease. Endothelial dysfunction is considered as the main pathophysiological process in the severe and/or prolonged course of COVID-19, and is probably the common denominator of many clinical aspects of severe COVID-19. This review presents scientific data on the effect of perindopril and amlodipine in patients with hypertension and/or coronary heart disease and COVID-19 on endothelial function

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

Drug-induced liver damage with cholestasis

The liver is the main organ responsible for the biotransformation and elimination of drugs, and therefore its function is often impaired by different medications. In this article, the authors inform practical health care professionals about the possible liver damage with cholestasis caused by drugs (DILI). Most often, DILI is caused some antibacterial drugs, steroids, barbiturates and some other drugs. DILI has no pathognomonic clinical manifestations. tte scientific literature describes both an asymptomatic increase of “liver” enzymes and the development of acute liver failure. Important diagnostic methods are the collection of anamnesis (especially the medicinal one), analysis of blood biochemical tests, and data from visual diagnostic methods. If the patient has DILI, it is necessary, whenever possible, to stop intake of a drug. ttere are no specific drugs recommended for pharmacotherapy of DILI but there is some the positive effect of ademetionine and ursodeoxycholic acid. ttere are no specific preventive measures for DILI. Healthcare practitioners are recommended not to use drugs off-label, optimize pharmacotherapy and fight with polypharmacy, monitore biochemical tests regularly etc

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

COMPARATIVE ANALYSIS OF THE EFFICACY OF FIXED-DOSE COMBINATIONS OF AMLODIPINE/LISINOPRIL AND BISOPROLOL/HYDROCHLORTHIAZIDE IN PATIENTS WITH ESSENTIAL ARTERIAL HYPERTENSION COMBINED WITH OBESITY AND OVERWEIGHT

Aim. To study the characteristics of the daily profile of blood pressure (BP) and heart damage in patients with essential hypertension (HT), depending on the presence of obesity as well as the antihypertensive and organoprotective effects of fixed-dose combinations of amlodipine/lisinopril and bisoprolol/hydrochlorothiazide in hypertensive patients with obesity or overweight.Material and methods. 60 patients with untreated HT, stage II, degree 1-2 (51.7% of men, aged 53.6±0.8 years) were examined. 24-hour BP monitoring and transthoracic echocardiography with calculation of myocardial stiffness parameters were performed in all patients. Hypertensive patients with obesity and overweight were randomized into groups treated with fixed-dose combinations amlodipine/lisinopril (n=25) or bisoprolol/hydrochlorothiazide (n=30). Doses of drugs were titrated until the target BP was achieved. The follow-up was 12 weeks.Results. Patients with HT and obesity (n=28) compared with hypertensive patients without obesity (n=32) had greater systolic BP (SBP) variability at night (p<0.05) and a morning surge in SBP (p<0.01), end systolic volume (p<0.05), systolic volume (p<0.01),right ventricle anterior-posterior dimension (p<0.001), right atrium volume (p<0.01), the thickness of the interventricular septum (p<0.01) and the posterior wall (p<0.001) of the left ventricle (LV), significantly lower LV global longitudinal systolic 2D-strain (p<0.001), coefficient of diastolic and end-systolic LV elastance (p<0.05 for both). At the end of the follow-up period patients in the amlodipine/lisinopril group compared to patients in the bisoprolol/hydrochlorothiazide group had a greater decrease in the mean daily pulse BP (-10.8 vs -5.4 mm Hg, respectively; p<0.05) and variability of SBP in daytime (-2.8±0.8 vs -0.9±0.3 mm Hg, respectively; p<0.05). Only patients in the amlodipine/lisinopril group had a significant decrease in the variability of SBP (from 12.2±0.8 to 10.9±0.5 mm Hg; p<0.05) and diastolic BP (from 9.3±0.5 to 8.4±0.4 mm Hg; p<0.001) at night. Patients in the amlodipine/lisinopril group compared to patients in the bisoprolol/hydrochlorothiazide group had a greater increase in the left atrium strain (p<0.01), 2D-strain of LV and a greater decrease in the LV end diastolic stiffness (-21.39±2.45 vs -3.54±1.57 mm Hg/ml, respectively; p<0.001), the LV end systolic elastance (-16.15±2.14 vs -12.85±1.37 mm Hg/ml, respectively; p<0.05), and LV myocardial mass index (-13.2±0.9 vs -8.4±0.7 g/m2, respectively; p<0.01), the thickness of the interventricular septum and the posterior wall of the LV.Conclusion. Untreated hypertensive obese patients in comparison with hypertensive patients without obesity have higher BP level variability during the night and early morning SBP surge, greater sizes of the heart chambers and LV myocardial wall thickness, higher LV myocardium stiffness. In obese or overweight patients with HT, a fixed-dose combination of amlodipine/lisinopril, compared with the fixed-dose combination of bisoprolol/hydrochlorothiazide, resulted in a more significant decrease in pulse BP and variability of systolic and diastolic BP at night, contributed to a more pronounced improvement in the elastic properties of the left atrium and LV myocardium and decrease in LV hypertrophy