Clinical-pharmacological aspects of the choice of phytocomponents for the regulation of the gastrointestinal function

The presentations of dyspepsia include a range of clinical symptoms, each of which has different mechanisms of development, and, therefore, requires different approaches to the correction. In this context, the combination preparations containing components of natural origin with polymodal action on the gastrointestinal tract deserve special attention. Combination of synergistic components: highly bioavailable curcumin and prebiotic fibers; artichoke leaf extract and chamomile flower extract provide simultaneous effects on three key digestive organs: stomach, pancreas and liver. Curcumin has an anti-inflammatory effect, helps to normalize acidity and restore microflora; epithelialization of ulcers; normalization of the gallbladder function; elimination of toxins. It inhibits the processes of primary tumour formation and prevents the development of metastatic processes in gastrointestinal cancer. Pharmaceutical technologies using cyclodextrin as an excipient increase curcumin’s water solubility, dispersibility and absorption, which has been confirmed in several comparative bioavailability studies in healthy volunteers. Chamomile flower extract has anti-inflammatory, antimicrobial, antispasmodic, antiulcer, wound healing and astringent effects. Chamomile is rich in slimy substances that envelop and protect the inflamed mucous membrane, including the stomach, from irritation with hydrochloric acid, bile components, food, and drugs. Mucous substances also have an anti-inflammatory effect and improve digestion. The artichoke facilitates the outflow of bile, affects the secretion of gastric glands, pancreas, increases the enzymatic activity of gastric juice, enhances intestinal motility during its atony, and has a hepatoprotective effect. As can be seen from the above, a combination of these synergistic components can be used in patients with chronic diseases, functional disorders as part of combination therapy, as well as for the prevention of gastrointestinal diseases in healthy people

Pharmacokinetic (Bioavailability) Studies of Magnesium Preparations

In order to obtain valid results when studying the bioavailability of medicinal products containing magnesium salts, it is necessary to take into account endogenous levels of the macroelement in the body. The aim of the study was to conduct a systematic review of the results of clinical studies on the bioavailability of medicinal products containing magnesium, to evaluate the methods used for determining the endogenous level of magnesium, and to establish the necessity for adjusting pharmacokinetic parameters according to the identified endogenous magnesium levels. The review includes data from clinical studies of magnesium bioavailability performed with healthy volunteers and published over the past 5 years. According to the literature review results, the most commonly chosen primary endpoint is urinary magnesium excretion analysis, and the most secondary endpoint is plasma or serum magnesium determination. Data sources for the review included Google’s search engine; PubMed, UpTodate®, ClinicalTrials.gov databases; and official websites of regulatory authorities (EFSA, EMA, and FDA). In most studies, endogenous magnesium levels were taken into account at all blood sampling points, and this provided an opportunity to avoid errors and misinterpretations of the results. Adjustments of pharmacokinetic parameters with regard to endogenous magnesium values were performed differently. Some studies treated endogenous magnesium values as independent variables and compared the values obtained after drug administration with them; other studies treated endogenous magnesium values as a covariate influencing the values obtained and requiring mandatory consideration; two studies involved a classical adjustment of pharmacokinetic parameters, the subtraction of endogenous values from the values obtained after drug administration. The evaluation of endogenous magnesium levels as part of bioavailability studies is necessary to adjust pharmacokinetic parameters and to obtain valid study results. It should be planned beforehand at the time of preparation of the study protocol

The Effect of Angiotensin Receptor and Neprilysin Inhibitors on Quality of Life in Patients with Heart Failure with Reduced Ejection Fraction and Functional Mitral Regurgitation

Aim. To compare the change in quality of life indicators and the main clinical and instrumental parameters in patients with chronic heart failure (CHF) and functional mitral regurgitation (FMR) under the influence of sacubitril/valsartan compared with valsartan in an outpatient practice.Material and Methods. The study included 90 patients with chronic FMR, who were observed for 12 months. They received sacubitril/valsartan or valsartan. Efficiency criteria were: the difference between groups in scores according to the Kansas questionnaire for patients with cardiomyopathy; MR degree parameters (change in effective regurgitation orifice area, vena contracta width, MR volume and MR fraction); indicators of the severity of myocardial remodeling (left ventricular EF; the level of N-terminal brain natriuretic propeptide), exercise tolerance based on a 6-minute walk test, a change in the functional class of heart failure according to NYHA.Results. In a treatment efficacy analysis, the Kansas City Cardiomyopathy Questionnaire–Overall Summary Score improved by 22.1 points in the sacubitril/valsartan group and by 4.5 points in the valsartan group (p<0.001). EF, exercise tolerance, and the number of patients transitioning from NYHA functional class III to II increased in the sacubitril/valsartan group (p<0.05). Also, in this group, the effective area of the regurgitation opening, the width of the vena contracta, the volume of regurgitation, the fraction of regurgitation, and the level of N-terminal brain natriuretic propeptide (p<0.05) decreased more pronouncedly (p<0.05).Conclusion. Compared with valsartan, treatment with sacubitril/valsartan leads to a significant improvement in the quality of life in patients with FMR and HF with reduced EF, which is largely associated with a change in NT-proBNP, echocardiographic characteristics of the severity of MR and the degree of myocardial remodeling

Debating capabilities of biochemical markers of liver function in patients with alcoholic liver cirrhosis

Introduction. The diagnosis of alcohol-related liver disease is limited by the lack of a tool to reliably identify whether the present deterioration in the patient’s condition is due to alcohol consumption or other causes.Purpose. to conduct a comparative assessment of the clinical and diagnostic significance of liver function biochemical indicators (AST, ALT, GGT, ALP) and their calculated derivatives (AST/ALT, GGT/ALP, GGT/GGTn, ALP/ALPn) as markers of alcohol consumption in patients with alcoholic liver cirrhosis.Material and methods. The observational study included 112 men over 18 years of age with alcohol-related liver cirrhosis. The patients were assessed the severity of liver cirrhosis according to the Child-Pugh scale, performed general and biochemical blood tests, coagulation test, assessment of the fact of alcohol consumption by the level of phosphatidylethanol. An analysis was made of the relationship between alcohol consumption and changes in laboratory parameters of liver function, with the determination of their sensitivity and specificity.Results. Patients with Child-Pugh B cirrhosis who consumed alcohol on phosphatidylethanol had higher levels of plasma albumin, GGT, and lower values of creatinine, direct and total bilirubin, urea, and aPTT compared with patients who did not drink alcohol (p < 0.05). Alcohol-drinking patients with class C cirrhosis have higher ALT levels compared with abstinent patients with the same severity of cirrhosis (p < 0.05). The relationship between the fact of alcohol consumption, determined by the level of phosphatidylethanol, and the ratio of GGT of patients to the normal GGT value, as well as between the ratio of GGT to alkaline phosphatase and the degree of increase in GGT, turned out to be statistically significant. To assess the fact of alcohol consumption, the level of serum GGT > 65 IU/ l (75.5%) has the highest sensitivity, the highest specificity is the ratio of the patient’s GGT to the normal value of GGT > 2 (82.9%).Conclusion. Compared with the known 100% sensitivity and > 92% specificity of Peth as a alcohol biomarker, among the biochemical indicators of liver function and their calculated derivatives, GGT > 65 IU/l have the greatest sensitivity or specificity (respectively, 75.5% and 65%) and GGTnorm. > 2 (37.7% and 82.9%, respectively), which makes it possible to use the totality of these parameters as an indicator of the continued impact on the patient of the main etiological factor of alcohol-related liver cirrhosis in the routine practice of most medical organizations of the Russian Federation

АНАЛЬГЕТИЧЕСКИЙ ПОТЕНЦИАЛ АГОНИСТОВ ПУРИНОВЫХ РЕЦЕПТОРОВ И ВИТАМИНОВ ГРУППЫ B В ЛЕЧЕНИИ ДИАБЕТИЧЕСКОЙ ПОЛИНЕЙРОПАТИИ

The efficacy and safety of purine receptor agonists in patients with chronic pain have been analysed. The data on the clinical application of purine analgesia in the management of pain syndrome are reviewed. The use of purine analgesia for the treatment of patients with chronic neuropathic pain is scientifically justified. The central mechanisms of purine receptor agonists and their analgesic activity are described in detail. It has been shown that purine receptor agonists have a strong analgesic effect and a narrow range of side effects, and they effectively relieve neuropathic pain by influencing the purinergic regulatory mechanism. The mechanisms of the analgesic effect of B vitamins (B1, B6, B12) that have their own analgesic potential are considered — which is of great importance in the pharmacotherapy of polyneuropathies. It should be noted that the prescription of B vitamins is pathogenetically justified in diabetic polyneuropathy, and a combination of B vitamins is more efficacious than a monotherapy.Проанализированы эффективность и безопасность агонистов пуриновых рецепторов у пациентов с хронической болью. Проведен обзор данных о клиническом применении пуриновой анальгезии в купировании болевого синдрома. Научно обосновано использование пуриновой анальгезии для лечения пациентов с хронической нейропатической болью. Подробно описаны центральные механизмы агонистов пуриновых рецепторов и их анальгетическая активность. Показано, что агонисты пуриновых рецепторов отличаются сильным анальгетическим действием, узким спектром побочных эффектов и, воздействуя на пуринергический регуляторный механизм, эффективно купируют нейропатическую боль. Рассмотрены механизмы анальгетического эффекта витаминов группы В (В1, В6, В12), обладающих собственным анальгетическим потенциалом, что имеет важное значение в фармакотерапии полинейропатий. Отмечается, что при диабетической полинейропатии назначение витаминов группы В патогенетически обосновано, при этом подчеркивается, что комбинация витаминов группы В более эффективна, чем монотерапия

Pharmacogenetic Aspects of Postoperative Anesthesia with Ketoprofen in Cardiac Surgery Patients

Aim. Evaluation of the effect of polymorphisms of the CYP2D6, CYP2C8 genes on the efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery.Material and methods. The study included 90 patients with an established diagnosis of coronary artery disease and postoperative period after cardiac surgery. Patients received ketoprofen 100 mg intramuscularly 2 times a day for 5 days. The intensity of pain was rated by Numeric Rating Scale. The severity of dyspepsia was assessed by the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire. DNA was isolated from venous blood using an automated system. Single nucleotide polymorphisms CYP2C8 (C>T) rs11572080, CYP2D6*4 (1846G>A) rs3892097 were determined by the real-time polymerase chain reaction method.Results. In patients with genotypes GA and GG for the allelic variant CYP2D6*4, significant differences in the intensity of pain syndrome were found on days 4 and 5 of the postoperative period: 3,91±2,17 and 4,95±1,8 points (p=0,04), 3,52±1,95 and 4,5±1,7 points (p=0,04) in patients with GA and GG genotypes on days 4 and 5, respectively. In patients with the CT genotype for the CYP2C8 rs11572080, the severity of dyspepsia by GSRS was significantly higher than in patients with the CC genotype: 22,67±7,64 and 18,97±4,25 points, respectively.Conclusion. Patients with the GA genotype for the CYP2D6*4 allelic variant showed a lower intensity of pain syndrome than the GG genotype. In patients with the CT genotype for the CYP2C8 rs11572080, higher dyspepsia was revealed than in the CC genotype

Фармакокинетические исследования (исследования биодоступности) препаратов магния

In order to obtain valid results when studying the bioavailability of medicinal products containing magnesium salts, it is necessary to take into account endogenous levels of the macroelement in the body. The aim of the study was to conduct a systematic review of the results of clinical studies on the bioavailability of medicinal products containing magnesium, to evaluate the methods used for determining the endogenous level of magnesium, and to establish the necessity for adjusting pharmacokinetic parameters according to the identified endogenous magnesium levels. The review includes data from clinical studies of magnesium bioavailability performed with healthy volunteers and published over the past 5 years. According to the literature review results, the most commonly chosen primary endpoint is urinary magnesium excretion analysis, and the most secondary endpoint is plasma or serum magnesium determination. Data sources for the review included Google’s search engine; PubMed, UpTodate®, ClinicalTrials.gov databases; and official websites of regulatory authorities (EFSA, EMA, and FDA). In most studies, endogenous magnesium levels were taken into account at all blood sampling points, and this provided an opportunity to avoid errors and misinterpretations of the results. Adjustments of pharmacokinetic parameters with regard to endogenous magnesium values were performed differently. Some studies treated endogenous magnesium values as independent variables and compared the values obtained after drug administration with them; other studies treated endogenous magnesium values as a covariate influencing the values obtained and requiring mandatory consideration; two studies involved a classical adjustment of pharmacokinetic parameters, the subtraction of endogenous values from the values obtained after drug administration. The evaluation of endogenous magnesium levels as part of bioavailability studies is necessary to adjust pharmacokinetic parameters and to obtain valid study results. It should be planned beforehand at the time of preparation of the study protocol.При исследованиях биодоступности препаратов, содержащих соли магния, для получения корректных результатов необходимо учитывать эндогенный уровень этого макроэлемента в организме. Цель работы — провести систематический обзор результатов клинических исследований по изучению биодоступности лекарственных препаратов, содержащих магний, оценить используемые методы определения эндогенного уровня магния и необходимость корректировки фармакокинетических параметров с учетом выявленных эндогенных значений магния. В обзор включены данные клинических исследований по изучению биодоступности магния, выполненные с участием здоровых добровольцев и опубликованные за последние 5 лет. Источниками данных для обзора послужили поисковая система Google, базы данных PubMed, UpToDate®, ClinicalTrials.gov, официальные сайты регуляторных органов (EFSA, EMA и FDA). Анализ литературы показал, что в качестве первичной конечной точки чаще всего выбирают анализ экскреции магния с мочой, а в качестве вторичной точки — определение магния в плазме или сыворотке крови. В большинстве исследований эндогенный уровень магния учитывали во всех точках забора крови, и данный факт позволил избежать ошибок и неправильной трактовки результатов. Корректировку фармакокинетических параметров с учетом эндогенных значений магния проводили по-разному. В одних исследованиях эндогенные значения магния рассматривались как независимые переменные и с ними сравнивали значения, полученные после применения препаратов; в других исследованиях эндогенные значения магния рассматривались как ковариата, влияющая на полученные значения и требующая обязательного учета; в двух исследованиях была проведена классическая корректировка фармакокинетических параметров — вычитание эндогенных значений из значений, полученных после применения препаратов. Оценка эндогенного уровня магния в рамках изучения его биодоступности необходима для корректировки фармакокинетических показателей, получения достоверных результатов исследования и должна быть запланирована заранее при подготовке протокола клинического исследования

Spontaneous and induced secretion of the pro-inflammatory and anti-inflammatory cytokines in patients with type 2 diabetes mellitus and diabetic foot syndrome

AIMS: Investigation of spontaneous and induced secretion of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and the anti-inflammatory chemokine C-C Motif Chemokine Ligand 18 (CCL18) by monocytes isolated from blood of patients with long-term type 2 diabetes mellitus (T2DM), both with or without foot ulcers and the effect of the course use of the combined metabolic drug Kokarnit as part of complex therapy on the dynamics of the severity of symptoms of DSPN and the cytokine phenotype in patients with long-term non-healing ulcers of the lower extremities MATERIALS AND METHODS: 121 patients with T2DM, 79 without diabetic foot syndrome (DFS) and 42 patients with DFS were included. CD14+ monocytes were isolated from patients’ blood and stimulated by interferon-γ (IFN-γ) and interleukine-4 (IL-4) for induction of pro- and anti-inflammatory monocyte activation, respectively. The concentrations of TNF-α and CCL18 in the culture medium were measured using ELISA on day 1 and day 6 after cell stimulation in all patients before taking the combined metabolic drug Kokarnit. Then they were randomly allocated either to the control group (57 people), to whom Kokarnit was added to standard treatment, or to the comparison group. After a 9-day course of application of Kokarnit, the dynamics of indicators was evaluated on a TSS scale. Assessment of cytokine status was carried out in 18 people with long-term non-healing ulcerative defects of the lower extremities, on the first and ninth day of treatment. RESULTS: A correlation was found between HbA1c and levels of stimulated secretion of TNFα (r=0.726, p=0.027), CCL18 (r=-0.949, p=0.051) in patients with DSPN. In all patients with different duration of VDS, an increase in secretion of TNF-α and CCL18 was observed (p<0.05). However, stimulation of anti-inflammatory activation was not observed in patients with ulcerative defects lasting more than 6 months (p=0.033). The use of cocarnit in these patients had a decrease in stimulated secretion of TNFα and an increase in CCL18. Throughout the entire observation period with the therapy, the score for the symptoms of polyneuropathy on the TSS scale in patients of the control group was statistically significantly higher. CONCLUSION: Against the background of therapy in patients of the main group, a statistically significant dynamics of indicators on the TSS scale was established. The cytokine modulating ability of Kokarnit to switch the cytokine status into the category of anti-inflammatory

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