Reviews on Clinical Pharmacology and Drug Therapy

At the present stage of medical science, an increasing role in the pathogenesis of various groups of diseases is assigned to the mechanisms of epigenetic regulation and posttranslational modifications of proteins. One of these mechanisms is ubiquitylation, which is able to regulate the functional activity of proteins, their stability, and also influence the processes of cell death. Involvement in a large number of metabolic pathways and presently identified associations with oncological, cardiovascular, neurological, and inflammatory diseases makes ubiquitylation of the enzymes involved a promising target to develop new therapy options. In this review, we consider the effect of ubiquitination on the development of diseases of the cardiovascular, nervous systems, diabetes mellitus, as well as the development of possible treatment options.

BACKGROUND: Flavonoids, a class of plant polyphenols, exhibit a wide range of biological (neuro- and immunotropic, antioxidant, anti-inflammatory, epigenome-modulating) properties involved in the mechanisms of management in various pathological processes, including nervous system diseases. Alcoholism is a pervasive social, medical, and economic issue of a modern society. Prolonged exposure to ethanol has a direct and mediated toxic effect on the human body through its metabolites negatively affecting nervous and immune systems that play a major role in adaptation. The ability of bioflavonoids to manage pathological disorders in a wide range of chronic diseases with neuroimmune pathogenesis mechanisms by interacting with specific cell surface receptors can provide therapeutic benefits in alcoholism.

AIM: To assess neurotropic and immunomodulatory properties of a novel curcumin-based bioflavonoid composition during prolonged ethanol consumption.

MATERIALS AND METHODS: The content of bioflavonoids in the composition was measured in aqueous-organic extracts using high-performance liquid chromatography (HPLC). Chronically alcoholized male (CBA×C57Bl/6)F1 mice who received a 10% ethanol solution as the sole source of fluid during six months were administered a bioflavonoid composition during 30 days. Subsequent studies assessed alcohol motivation by consumption of a 10% ethanol solution in free choice with water, as well as behavioral parameters in the open field test, cytokine content in the brain structures (prefrontal cortex, hypothalamus, hippocampus, striatum) using enzyme immunoassay. The intensity of the cellular and humoral immune response was determined by the severity of the delayed-type hypersensitivity response and relative number of splenic antibody-forming cells, respectively.

RESULTS: The quantitative content of bioflavonoids was determined in the composition consisting of curcumin, piperine, soybean isoflavonoids, epigallocatechin-3-gallate, triterpene saponins, and β-carotene. Taking this composition in the context of prolonged ethanol consumption was shown to have a positive effect expressed in correcting the alcoholism-related behavioral phenotype (reduced alcohol motivation, stimulation of locomotor and exploratory activity), accompanied by decreased levels of certain proinflammatory cytokines in the brain structures (most pronounced in the hippocampus). Stimulation of the humoral and cellular immune response was also demonstrated after a course of treatment with the described composition.

CONCLUSIONS: The data support the use of the novel bioflavonoid composition as an additional immunomodulatory and neurotropic agent in the treatment of chronic alcoholism.

BACKGROUND: The effectiveness of antihypertensive therapy may be associated with genetic factors that both influence the degree of increase in blood pressure and determine inter-subject variability of response to antihypertensive treatment.

AIM: To study pharmacodynamic parameters of the effectiveness of therapy with angiotensin II receptor blockers as monotherapy and as part of combination drugs in patients with hypertension, depending on the genetic characteristics of patients, specifically the M235T polymorphism of the angiotensinogen gene.

MATERIALS AND METHODS: The study involved 179 patients from the Moscow region with newly diagnosed stage I–II hypertension, including 141 (78.8%) women and 38 (21.2%) men aged 32 to 69 years, who were randomly assigned to groups receiving irbesartan and valsartan as monotherapy or in combination therapy with hydrochlorothiazide, using a simple randomization method. Genetic polymorphism rs699 (C4072T, M235T) of the AGT angiotensinogen gene was determined after 3 weeks of drug therapy.

RESULTS: After three months of drug therapy, the maximum antihypertensive effect in the group of patients receiving valsartan was observed in CC homozygotes and heterozygotes by the level of decrease in mean daytime systolic blood pressure. In CC homozygotes, a trend was outlined by the level of decrease in mean daytime diastolic blood pressure; in CC homozygotes, by the level of decrease in mean nighttime systolic blood pressure; in CC and TT homozygotes, by the level of decrease in mean nighttime diastolic blood pressure. No statistically significant association of the angiotensinogen gene’s M235T polymorphism genotype with these parameters was found among patients receiving irbesartan.

CONCLUSIONS: The obtained data may indicate a more rapid and stable antihypertensive effect in patients carrying the C allele of the M235T genetic polymorphism of the angiotensinogen gene. Therefore, personalized therapy of arterial hypertension using the detection of the M235T genetic polymorphism in the AGT gene may reasonably include the AT1-receptor blocker valsartan as a starting therapy for the C allele carriers in the Moscow region, as monotherapy or two-component therapy, depending on the stage of hypertension.

Hyperlipidemia is one of the most important risk factors for the development atherosclerotic cardiovascular diseases. The review summarizes data on lipoprotein metabolism and discusses methods pharmacological correction of dyslipidemia. Classification presented Lipid-lowering drugs, pharmacodynamics and pharmacokinetic features, indications for use and side effects of individual representatives, issues of their effectiveness and safety are considered. Prospects for the treatment of dyslipidemia are outlined.

BACKGROUND: An increased risk of bleeding during rivaroxaban administration is associated with polymorphism of genes involved in its biotransformation, as well as with the use of drugs inhibiting shared metabolic pathways. However, the data are inconsistent.

AIM: To study specifics of drug-drug interactions between rivaroxaban and a P-glycoprotein inhibitor (using verapamil as an example) depending on the polymorphism of the CYP3A4 (rs35599367) and CYP3A5 (rs776746) genes in patients aged 80 years and older with non-valvular atrial fibrillation.

MATERIALS AND METHODS: A total of 128 patients (median age 87.5 years [83; 90], 75% women) were examined. All patients underwent genotyping for the studied gene variants, determination of the minimum steady-state concentration of rivaroxaban (C_{min, ss}), standardization of the minimum steady-state concentration of rivaroxaban per daily dose (C_{min, ss}/D), determination of prothrombin time in plasma, and analysis of medical documentation for the occurrence of clinically significant minor bleeding.

RESULTS: Compared to patients receiving rivaroxaban without calcium channel blockers, co-administration of rivaroxaban and verapamil in carriers of the CC variant of the CYP3A4 gene resulted in higher values of C_{min, ss} (73.8 [49; 113.5] vs. 40.5 [25.6; 73.3] ng/mL), C_{min, ss}/D (2.5 [1.7; 4.0] vs. 4.7 [2.9; 7.7] ng/mL/mg), prothrombin time (14.8 [13.3; 17.3] vs. 14.0 [12.6; 14.5] s) and clinically significant minor bleeding [10/30 (33.3%) vs. 6/45 (13.3%) cases], p < 0.05. In carriers of the GG variant of the CYP3A5 gene, the same regimen resulted in higher values of C_{min, ss} (74.7 [50.6; 108.8] vs. 40.2 [25.7; 72.3] ng/mL), C_{min, ss}/D (4.6 [3.0; 7.3] vs. 2.5 [1.7; 4.0] ng/mL×mg), prothrombin time (14.6 [12.8; 15.2] vs. 14.0 [12.6; 14.5] s) and clinically significant minor bleeding [10/27 (37%) vs. 5/40 (12.5%) cases], p < 0.05. Furthermore, in carriers of the GA+AA variant of the CYP3A5 gene, this regimen resulted in higher values of C_{min, ss} (88.1 [5.5; 88.1] vs. 52.8 [25.0; 77.2] ng/mL), C_{min, ss}/D (5.7 [0.4; 5.7] vs. 3.5 [1.7; 5.2] ng/mL×mg), p < 0.05. The combined use of rivaroxaban with verapamil in carriers of the CT variant of the CYP3A4 gene was not observed in our sample.

CONCLUSIONS: Carriers of the homozygous wild-type CYP3A4/A5 genotype showed high pharmacokinetic variability to the administration of verapamil (a strong P-glycoprotein inhibitor and a moderate CYP3A4 inhibitor).

Medicinal plants have been used since ancient times to prepare medicines in the form of extracts. Alcoholic and aqueous extracts of various parts of medicinal plants may contain potentially useful chemical compounds with biological activity. Therefore, extracts of some plants are still used to obtain effective and even potent medicines. It is believed that some medicinal plants contain chemical compounds that can have a protective effect on the kidneys in their diseases. However, the existing information on renal-tropic drugs obtained from medicinal plant raw materials and on the biological activity of extracts of medicinal plants does not allow us to draw unambiguous conclusions. A critical analysis of the information is required to sift out the “wheat from the chaff”. In this regard, the article provides a critical review of the available information on the pharmacological activity of extracts of medicinal plants claiming to have a renal protective effect. A list of information and features of the therapy of kidney diseases using extracts of various medicinal plants is provided. It has been shown that the development of effective herbal therapy for the treatment of severe renal diseases requires a systematic study of such properties of finished drugs (extracts) as the volume of solvent (alcohol or water). Attention is drawn to the fact that the analysis of information is not possible without taking into account the single, daily and course dose of water (or alcohol), as well as the physico-chemical properties of the extract taken. Only after taking into account these factors of therapy, it will be possible to critically re-evaluate the therapeutic effect of the applied extracts of medicinal plants, taking into account the dose of water and the physico-chemical properties of the corresponding extracts for specific kidney diseases. Most likely, it is advisable to analyze the effectiveness of specific extracts in such kidney diseases as acute renal failure, nephrotic syndrome and chronic interstitial nephritis. It should be noted that in chronic renal failure, the patient may have a different glomerular filtration rate, namely, be below 30 ml/min. In this regard, different glomerular filtration in patients may have different effects on the pharmacokinetics of drugs, including water and table salt. In addition, it is reported that researchers ignoring the osmotic activity of extracts does not allow taking into account the osmotic component of their effect on diuresis. Also, the traditional approach to the treatment of critical conditions in renal failure includes dialysis and renal replacement therapy, which are difficult to access for some rural residents due to their geographical and economic location. Therefore, it is necessary to take into account the effect of medicinal plant extracts not only on patients, but also on the clinical effectiveness of dialysis and renal replacement therapy. The article analyzes the available information from other sides as well. Certain herbs in herbal collections have proven nephroprotective properties nephroprotective properties. In particular, it is reported that today extracts of plants such as Kanchnar (bauhinia raznolistnaya), Kushmanda (Benincasa Hispid) and Yeshtimadu (licorice naked) can have a more reliable renal protective effect. Nevertheless, the renal-protective activity of these plant extracts has not been scientifically substantiated.