Associations between vitamin D status, VDR gene polymorphisms and echocardiographic markers in Polish patients with cardiovascular disease.

Aim: This work was designed to investigate the associations between vitamin D metabolites, VDR gene polymorphisms and echocardiographic markers in a population of patients with cardiovascular disease. Methods: Echocardiographic markers for 42 patients were determined with tissue Doppler techniques. PCR-restriction fragment length polymorphism analysis identified genetic variants ApaI, TaqI, BsmI and FokI. A validated UHPLC-MS/MS method determined vitamin D metabolites. Results: Patients with the ApaI-GT genotype exhibited a lower pressure gradient across the aortic valve than ApaI-TT carriers. BMI, ApaI-GT, TaqI-TC, aortic arch diameter and maximal pressure gradient were significant univariate predictors of hypertension. Conclusion: A potential link exists between VDR gene polymorphisms and cardiovascular function.

Vitamin D levels in the body and variations in the vitamin D receptor gene are linked to specific heart-related markers in Polish patients with heart conditions. What is this article about? Coronary artery disease is a global health issue and the third leading cause of death. While many factors are understood to contribute to coronary artery disease, there is ongoing debate about whether vitamin D deficiency is one of them. In the past 10 years, there has been extensive research on vitamin D deficiency, characterizing it as a kind of 'pandemic' affecting a large portion of the population. Vitamin D deficiency is associated with more severe cardiovascular health issues and a higher risk of mortality. Why did we conduct this study? This study was designed to assess how different forms of vitamin D (created in the body) and genetic differences relate to heart health in people with cardiovascular disease and how they might be linked to markers observed in heart imaging. What were the results & what do they mean? Some genes seem to be more protective against hypertension than others. Some forms of vitamin D and genetic differences were linked to changes in markers observed in heart imaging. Adult patients should consume around 1000 to 2000 IU of vitamin D per day to contribute to better overall heart health.

Iodine deficiency and real-life supplementation ineffectiveness in Polish pregnant women and its impact on thyroid metabolism.

Introduction: Iodine is a pivotal component of thyroid hormones, and its deficiency leads to negative pregnancy outcomes. Therefore, during gestation, additional iodine supplementation is recommended. Objectives: By evaluating a group of women from western Poland, the study updated on iodine status during pregnancy and the effectiveness of iodine supplementation in relation to the maternal and neonatal thyroid function. Patients and methods: A total of 91 women were recruited before the delivery between 2019 and 2021. During the medical interview, the patients declared their dietary supplements intake. Thyroid parameters (TSH, ft3, ft4, a-TPO, a-Tg, and TRAb) were measured in the serum of mothers and in the cord blood of newborns after birth. Urinary iodine concentration (UIC) and urine/creatinine (UIC/crea) ratio were assessed in single urine samples using a validated high-performance liquid chromatography with ultraviolet detection (HPLC-UV). Neonatal TSH screening from dried blood spot was analyzed. Results: Pregnant women showed a median (interquartile range) UIC of 106 (69-156) µg/liter and UIC/crea ratio of 104 (62-221) µg/g, whereas approximately 20% had UIC/crea below 50 µg/g, indicating iodine deficiency. The iodine supplementation ratio was 68%. No significant differences in UIC, UIC/crea and thyroid parameters were found between iodine supplemented and non-supplemented groups; however, the highest ioduria was detected when iodine was supplemented in addition to levothyroxine in comparison with both substances administered separately. Patients with UIC/crea within 150-249 µg/g demonstrated the lowest TSH and a-TPO levels. Screening TSH was above 5 mIU/liter in 6% of children. Conclusions: Despite the national salt iodization and the recommendation to supplement iodine during gestation, the status of the abovementioned microelement and real-life intake revealed the ineffectiveness of the current iodine-deficiency prophylaxis model in pregnancy.

Low on-treatment levels of serum soluble CD8 (sCD8) predict better outcomes in advanced non-small cell lung cancer patients treated with atezolizumab.

BACKGROUND: Immunotherapy has changed the paradigm of treating non-small cell lung cancer (NSCLC). But, selecting patients who will achieve long-term benefits from treatment remains unsatisfactory. Here, we investigated the possible use of the soluble form of CD8 antigen (sCD8) in predicting durable disease control after PD-1/PD-L1 blockade. CD8 is a marker of the cytotoxic T lymphocytes. Its soluble form (sCD8) is secreted under activation of the immune system but also has immunosuppressive properties. The data about serum sCD8 in patients dosed with anti-PD-1/PD-L1 drugs are lacking. METHODS AND RESULTS: We included 42 NSCLC patients and collected samples at baseline and for the first 3 months of atezolizumab immunotherapy. The serum sCD8 concentrations were measured with the ELISA kit and correlated with treatment outcomes. Patients with durable (≥ 12 months) disease control presented lower serum sCD8 than those without long-term benefits. The sCD8 levels measured at the end of cycle 2 (sCD8.2) were the earliest time point that successfully differentiated patients (3.76 vs. 9.68 ng/mL, respectively, p < 0.001). Individuals with low sCD8.2 (≤ 4.09 ng/mL) presented longer progression-free survival (HR = 0.061, p < 0.001) and overall survival (HR = 0.104, p < 0.05) compared to individuals with high sCD8.2 (median values unreached vs. 4.4 months and 14.4 months for PFS and OS, respectively). CONCLUSIONS: Serum sCD8 could be an early biomarker of durable disease control after anti-PD-L1 treatment. Higher sCD8 in patients with worse outcomes could suggest the inhibitory effect of sCD8 on cytotoxic T-cells activation.

Selenium Status and Supplementation Effects in Pregnancy-A Study on Mother-Child Pairs from a Single-Center Cohort.

The demand for selenium (Se) increases during pregnancy since this element supports child growth, proper neuronal development and maternal thyroid function. The issue is particularly relevant for populations living in areas with a limited selenium supply, where many pregnant women opt for Se supplementation. The efficiency of this measure is unknown, although it seems vital in the prevention of severe Se deficiency. In order to evaluate this hypothesis, an observational study was conducted in Poland, where Se deficiency is prevalent. Pregnant women were invited to participate in the study and provided serum samples at the end of pregnancy (n = 115). Information on the supplemental intake of micronutrients was recorded in a face-to-face interview. In addition, serum samples were isolated from the cord blood of newborns at delivery (n = 112) and included in the analyses. Thyroid hormone status was evaluated by routine laboratory tests, and Se status was determined by total Se and selenoprotein P (SELENOP) concentrations and extracellular glutathione peroxidase (GPX3) activity. The three parameters of Se status correlated strongly within the group of mothers and within the group of newborns, with an additional significant correlation found among mother-child pairs. One-third of mothers reported additional Se intake, mainly as a component of multi-micronutrient supplements, at a mean (±SD) dosage of 42 ± 14 µg Se/day. Despite this regime, most of the women presented an insufficient Se status, with 79% of mothers displaying serum Se concentrations below 70 µg/L (indicating Se deficiency) and 22% showing levels below 45.9 µg/L (severe Se deficiency). The inadequate Se supply was also reflected in relatively low SELENOP concentrations and GPX3 activity. Neither total Se nor SELENOP or GPX3 levels were significantly higher in the group of mothers reporting the intake of supplements than in the non-supplementing group. Nevertheless, elevated SELENOP concentrations were observed in the subgroup receiving supplements with more than 55 µg/day. We conclude that the self-administered supplementation of small Se dosages was not sufficient to achieve replete Se status in the micronutrient scant area. However, the maternal Se deficit measured by either Se, SELENOP or GPX3 was transferred from mothers to the newborns, as the parameters correlated strongly in the mother-newborn pairs of samples. It is vital to re-evaluate the guidelines concerning pregnancy care and monitoring of micronutrient status during pregnancy, in particular in areas where deficiencies are present.

Influence of Genetic and Epigenetic Factors of P2Y12 Receptor on the Safety and Efficacy of Antiplatelet Drugs.

PURPOSE: P2Y12 receptor inhibitors are drugs that decrease the risk of stent thrombosis and lower the long-term risk of non-stent-related myocardial infarction and stroke. They inhibit the binding of adenosine diphosphate (ADP) to the P2Y12 receptor and effectively reduce platelet reactivity. However, considerable variability in the pharmacodynamics response contributes to a failure of antiplatelet therapy; this phenomenon is especially notorious for older drugs, such as clopidogrel. Some genetic polymorphisms associated with these drugs' metabolic pathway, especially in the CYP2C19 gene, can significantly decrease antiplatelet efficacy. There are few reports on the variability stemming from the target of this drug class that is the P2Y12 receptor itself. RESULTS AND CONCLUSION: This review summarizes the results of research that focus on the influence of P2Y12 genetic polymorphisms on the pharmacodynamics and the efficacy of P2Y12 inhibitors. We found that the conclusions of the studies are unequivocal, and despite several strong candidates, such as G52T (rs6809699) or T744C (rs2046934), they may not be independent predictors of the inadequate response to the drug. Most probably, P2Y12 genetic polymorphisms contribute to the effect exerted by other gene variants (such as CYP2C19*2/*3/*17), drug interactions, or patient habits, such as smoking. Also, epigenetic modifications, such as methylation or miRNA levels, may play a role in the efficacy of antiplatelet treatment.

Vitamin D Metabolism Gene Polymorphisms and Their Associated Disorders: A Literature Review.

BACKGROUND: Vitamin D is a fat-soluble vitamin, and it is a potential key factor in maintaining a healthy status. Various observational studies have reported the association between vitamin D deficiency and an elevated risk of osteoporosis, cardiovascular disease, diabetes mellitus, and certain types of cancer. The number of studies that investigates the genetic determinants of vitamin D hydroxy metabolism has been growing. Still, its association with the genetic variants remains unclear, particularly those genes related to vitamin D metabolism. AIMS: This work is a comprehensive review of available evidence of the effect of genetic variants on vitamin D metabolism and their impact on vitamin D status in the human body, disorders including coronavirus disease 2019 infection, and its importance for clinical investigators and public health. RESULTS: Genome-wide association studies and candidate gene studies show that genetic factors are influencing the circulating levels of vitamin D. These genetic changes are implicated in various pathways of vitamin D, such as metabolism and transport. It is also involved in the formation of the ternary complex (vitamin D receptor - retinoid receptor - transcription factor II B). CONCLUSION: Linkage studies may fail to identify replicated genetic architecture of vitD metabolism. Genome-wide association studies and the candidate gene approach have shown reproducible influences of gene control on vitD status.

Metabolic Characteristics of Hashimoto's Thyroiditis Patients and the Role of Microelements and Diet in the Disease Management-An Overview.

Hashimoto's thyroiditis (HT) is the most common autoimmune disease and the leading cause of hypothyroidism, in which damage to the thyroid gland occurs due to the infiltration of lymphocytes. It is characterized by increased levels of antibodies against thyroid peroxidase and thyroglobulin. In this review, we present the metabolic profile, the effectiveness of micronutrient supplementation and the impact of dietary management in patients with HT. For this current literature review, the databases PubMed, Cochrane, Medline and Embase were reviewed from the last ten years until March 2022. This article provides a comprehensive overview of recent randomized controlled trials, meta-analyses, and clinical trials. Many patients with HT, even in the euthyroid state, have excess body weight, metabolic disorders, and reduced quality of life. Due to frequent concomitant nutritional deficiencies, the role of vitamin D, iodine, selenium, magnesium, iron and vitamin B12 is currently debated. Several studies have underlined the benefits of vitamin D and selenium supplementation. There is still no specific diet recommended for patients with HT, but a protective effect of an anti-inflammatory diet rich in vitamins and minerals and low in animal foods has been suggested. There is insufficient evidence to support a gluten-free diet for all HT patients. Pharmacotherapy, along with appropriate nutrition and supplementation, are important elements of medical care for patients with HT. The abovementioned factors may decrease autoantibody levels, improve thyroid function, slow down the inflammatory process, maintain proper body weight, relieve symptoms, and prevent nutritional deficiencies and the development of metabolic disorders in patients with HT.

HPLC Analysis of the Urinary Iodine Concentration in Pregnant Women.

Iodine is an essential component for fetal neurodevelopment and maternal thyroid function. Urine iodine is the most widely used indicator of iodine status. In this study, a novel validated ion-pair HPLC-UV method was developed to measure iodine concentration in clinical samples. A sodium thiosulfate solution was added to the urine sample to convert the total free iodine to iodide. Chromatographic separation was achieved in a Pursuit XRs C8 column. The mobile phase consisted of acetonitrile and a water phase containing 18-crown-6-ether, octylamine and sodium dihydrogen phosphate. Validation parameters, such as accuracy, precision, limits of detection and quantification, linearity and stability, were determined. Urinary samples from pregnant women were used to complete the validation and confirm the method's applicability. In the studied population of 93 pregnant women, the median UIC was lower in the group without iodine supplementation (117 µg/L, confidence interval (%CI): 95; 138) than in the supplement group (133 µg/L, %CI: 109; 157). In conclusion, the newly established ion-pair HPLC-UV method was adequately precise, accurate and fulfilled validation the criteria for analyzing compounds in biological fluids. The method is less complicated and expensive than other frequently used assays and permits the identification of the iodine-deficient subjects.

The Overview on the Pharmacokinetic and Pharmacodynamic Interactions of Triazoles.

Second generation triazoles are widely used as first-line drugs for the treatment of invasive fungal infections, including aspergillosis and candidiasis. This class, along with itraconazole, voriconazole, posaconazole, and isavuconazole, is characterized by a broad range of activity, however, individual drugs vary considerably in safety, tolerability, pharmacokinetics profiles, and interactions with concomitant medications. The interaction may be encountered on the absorption, distribution, metabolism, and elimination (ADME) step. All triazoles as inhibitors or substrates of CYP isoenzymes can often interact with many drugs, which may result in the change of the activity of the drug and cause serious side effects. Drugs of this class should be used with caution with other agents, and an understanding of their pharmacokinetic profile, safety, and drug-drug interaction profiles is important to provide effective antifungal therapy. The manuscript reviews significant drug interactions of azoles with other medications, as well as with food. The PubMed and Google Scholar bases were searched to collect the literature data. The interactions with anticonvulsants, antibiotics, statins, kinase inhibitors, proton pump inhibitors, non-nucleoside reverse transcriptase inhibitors, opioid analgesics, benzodiazepines, cardiac glycosides, nonsteroidal anti-inflammatory drugs, immunosuppressants, antipsychotics, corticosteroids, biguanides, and anticoagulants are presented. We also paid attention to possible interactions with drugs during experimental therapies for the treatment of COVID-19.

Pharmacokinetic Drug-Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients.

Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug-drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy.

Vitamin D Receptor Gene Polymorphism and Vitamin D Status in Population of Patients with Cardiovascular Disease-A Preliminary Study.

The association between vitamin D receptor (VDR) polymorphism and the risk of cardiovascular diseases (CVD) remains unclear. This study aimed to assess a relationship between the VDR genotypes, plasma concentrations of vitamin D metabolites, and the occurrence of cardiovascular and metabolic disorders. Fifty-eight patients treated for various cardiological afflictions were included. Identification of VDR polymorphisms: ApaI, TaqI, BsmI, and FokI were carried out using the PCR-RFLP method. Plasma concentrations of 25-hydroxyvitamin-D2, 25-hydroxyvitamin-D3, and 3-epi-25-hydroxyvitamin D3 were assessed by the UPLC-MS/MS method. Lower incidence of BsmI AA genotype in the studied patients was observed compared with healthy controls, but the difference was insignificant. Among patients with the TT genotype, frequency of hypertension was higher than among carriers of other ApaI genotypes (p < 0.01). In addition, carriers of the TT ApaI, TC TaqI, and GA BsmI genotypes had an increased risk of obesity, while the presence of the FokI TT genotype was associated with a higher incidence of heart failure and hypertension. In conclusion, the BsmI AA genotype can be protective against CVD, but this observation needs study on a larger group of patients. Particular VDR genotypes were associated with 25-hydroxyvitamin-D levels, and the mechanism of this association should be further investigated.

Serum sCD25 Protein as a Predictor of Lack of Long-Term Benefits from Immunotherapy in Non-Small Cell Lung Cancer: A Pilot Study.

Prognosis of advanced non-small cell lung carcinoma (NSCLC) is poor. Even though it can improve with anti-PD-1/PD-L1 agents, most patients do not respond to treatment. We hypothesized that the serum soluble form of the unit α of the interleukin-2 receptor (sCD25) could be used as a biomarker of successful immunotherapy in NSCLC. We recruited patients dosed with atezolizumab (n = 42) or pembrolizumab (n = 20) and collected samples at baseline and during the treatment. Levels of sCD25 were quantified with the ELISA kits. Patients with a high sCD25 at baseline (sCD25.0 ≥ 5.99 ng/mL) or/and at the end of the fourth treatment cycle (sCD25.4 ≥ 7.73 ng/mL) progressed faster and lived shorter without the disease progression and serious toxicity. None of the patients with high sCD25 at both time points continued therapy longer than 9.3 months, while almost 40% of patients with low sCD25 were treated for ≥12.3 months. There was a 6.3-times higher incidence of treatment failure (HR = 6.33, 95% CI: 2.10-19.06, p = 0.001) and a 6.5-times higher incidence of progression (HR = 6.50, 95% CI: 2.04-20.73, p = 0.002) in patients with high compared with low sCD25.0 and sCD25.4. Serum levels of sCD25 may serve as a non-invasive biomarker of long-term benefits from the anti-PD-1/PD-L1s in NSCLC.

New Methods Used in Pharmacokinetics and Therapeutic Monitoring of the First and Newer Generations of Antiepileptic Drugs (AEDs).

The review presents data from the last few years on bioanalytical methods used in therapeutic drug monitoring (TDM) of the 1st-3rd generation and the newest antiepileptic drug (AEDs) cenobamate in patients with various forms of seizures. Chemical classification, structure, mechanism of action, pharmacokinetic data and therapeutic ranges for total and free fractions and interactions were collected. The primary data on bioanalytical methods for AEDs determination included biological matrices, sample preparation, dried blood spot (DBS) analysis, column resolution, detection method, validation parameters, and clinical utility. In conclusion, the most frequently described method used in AED analysis is the LC-based technique (HPLC, UHPLC, USLC) combined with highly sensitive mass detection or fluorescence detection. However, less sensitive UV is also used. Capillary electrophoresis and gas chromatography have been rarely applied. Besides the precipitation of proteins or LLE, an automatic SPE is often a sample preparation method. Derivatization was also indicated to improve sensitivity and automate the analysis. The usefulness of the methods for TDM was also highlighted.

Measurement of plasma 25-hydroxyvitamin D2, 25-hydroxyvitamin D3 and 3-epi-25-hydroxyvitamin D3 in population of patients with cardiovascular disease by UPLC-MS/MS method.

Vitamin D has a potential role in protecting against cardiovascular disease (CVD). Serum 25-hydroxyvitamin D (25D) is the most widely used indicator of vitamin D status in the human body. 25D is estimated as total of 25-hydroxyvitamin D2 (25D2) and 25-hydroxyvitamin D3 (25D3). However, the presence of 3-epi-25-hydroxyvitamin D3 (3epi25D3) can affect 25D measurement. In this research a novel validated UPLC-MS/MS technique was developed to measure three vitamin D metabolites, 25D2, 25D3 and 3epi25D3 in human plasma. A liquid-liquid extraction using hexane was applied for isolation of the analytes from the samples. A chromatographic separation was achieved in a Kinetex F5 analytical column with isocratic elution (water and methanol with 0.1% methanoic acid, 20:80 v/v). Mass spectrometry detection of the metabolites was performed in a triple-quadruple tandem mass spectrometer under positive ion mode. Concentrations of the analytes were estimated in plasma samples of 54 patients. Validation parameters of the UPLC-MS/MS method, including linearity, precision, accuracy, and stability, fulfilled the requirements for bioanalytical assays. The deficient concentration of 25D (<20 ng/mL) was stated in over 60% of patients. 3epi25D3 was present in 78% of samples and its relative amount ranged from 0 to 54.1% of 25D concentration. The analysis of 25D2, 25D3 and 3epi25D3 by the validated UPLC-MS/MS method in plasma of patients with CVD permitted the classification of the patients with insufficient levels of 25D. 3epi25D3 might be relevant in the classification of vitamin D status.

Correction to: Population pharmacokinetic approach for evaluation of treosulfan and its active monoepoxide disposition in plasma and brain on the basis of a rat model.

The original version of this article, published on 30 May 2020 contained a mistake.

Pharmacokinetic Interaction between Sorafenib and Atorvastatin, and Sorafenib and Metformin in Rats.

The tyrosine kinase inhibitor sorafenib is the first-line treatment for patients with hepatocellular carcinoma (HCC), in which hyperlipidemia and type 2 diabetes mellitus (T2DM) may often coexist. Protein transporters like organic cation (OCT) and multidrug and toxin extrusion (MATE) are involved in the response to sorafenib, as well as in that to the anti-diabetic drug metformin or atorvastatin, used in hyperlipidemia. Changes in the activity of these transporters may lead to pharmacokinetic interactions, which are of clinical significance. The study aimed to assess the sorafenib-metformin and sorafenib-atorvastatin interactions in rats. The rats were divided into five groups (eight animals in each) that received sorafenib and atorvastatin (ISOR+AT), sorafenib and metformin (IISOR+MET), sorafenib (IIISOR), atorvastatin (IVAT), and metformin (VMET). Atorvastatin significantly increased the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of sorafenib by 134.4% (p < 0.0001) and 66.6% (p < 0.0001), respectively. Sorafenib, in turn, caused a significant increase in the AUC of atorvastatin by 94.0% (p = 0.0038) and its metabolites 2-hydroxy atorvastatin (p = 0.0239) and 4-hydroxy atorvastatin (p = 0.0002) by 55.3% and 209.4%, respectively. Metformin significantly decreased the AUC of sorafenib (p = 0.0065). The AUC ratio (IISOR+MET group/IIISOR group) for sorafenib was equal to 0.6. Sorafenib did not statistically significantly influence the exposure to metformin. The pharmacokinetic interactions observed in this study may be of clinical relevance in HCC patients with coexistent hyperlipidemia or T2DM.

Population pharmacokinetic approach for evaluation of treosulfan and its active monoepoxide disposition in plasma and brain on the basis of a rat model.

PURPOSE: Efficacy of treosulfan, used in the treatment of marrow disorders, depends on the activity of its monoepoxy-(EBDM) and diepoxy compounds. The study aimed to describe the pharmacokinetics of treosulfan and EBDM in the rat plasma and brain by means of mixed-effects modelling. METHODS: The study had a one-animal-per-sample design and included ninty-six 10-week-old Wistar rats of both sexes. Treosulfan and EBDM concentrations in the brain and plasma were measured by an HPLC-MS/MS method. The population pharmacokinetic model was established in NONMEM software with a first-order estimation method with interaction. RESULTS: One-compartment pharmacokinetic model best described changes in the concentrations of treosulfan in plasma, and EBDM concentrations in plasma and in the brain. Treosulfan concentrations in the brain followed a two-compartment model. Both treosulfan and EBDM poorly penetrated the blood-brain barrier (ratio of influx and efflux clearances through the blood-brain barrier was 0.120 and 0.317 for treosulfan and EBDM, respectively). Treosulfan plasma clearance was significantly lower in male rats than in females (0.273 L/h/kg vs 0.419 L/h/kg). CONCLUSIONS: The developed population pharmacokinetic model is the first that allows the prediction of treosulfan and EBDM concentrations in rat plasma and brain. These results provide directions for future studies on treosulfan regarding the contribution of transport proteins or the development of a physiological-based model.

Impact of genetic variants of selected cytochrome P450 isoenzymes on pharmacokinetics and pharmacodynamics of clopidogrel in patients co-treated with atorvastatin or rosuvastatin.

PURPOSE: Impaired antiplatelet effect of clopidogrel (CLP) can result from drug-drug interactions and genetic polymorphisms of drug-metabolizing enzymes. The aim of the study was to evaluate the effect of genetic polymorphisms of ABCB1 and the selected cytochrome P450 isoenzymes on the pharmacodynamics and pharmacokinetics of CLP and its metabolites in patients co-treated with atorvastatin or rosuvastatin. METHODS: The study involved 50 patients after coronary angiography/angioplasty treated with CLP and atorvastatin (n = 25) or rosuvastatin (n = 25) for at least 6 months. Plasma concentrations of CLP, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive CLP carboxylic acid metabolite were measured by UPLC-MS/MS method. Identification of the CYP2C19*2, CYP2C19*17, CYP3A4*1G, CYP1A2*1F, and ABCB1 C3435T genetic polymorphisms was performed by PCR-RFLP, while platelet reactivity units (PRU) were tested using the VerifyNow P2Y12 assay. RESULTS: There were significant differences in the pharmacokinetic parameters of the H4 active metabolite of CLP in the atorvastatin and rosuvastatin group divided according to their CYP2C19 genotype. There were no significant associations between CYP3A4, CYP1A2, and ABCB1 genotypes and pharmacokinetic parameters in either statin groups. In the multivariate analysis, CYP2C19*2 genotype and non-genetic factors including BMI, age, and diabetes significantly affected platelet reactivity in the studied groups of patients (P < 0.01). In the atorvastatin group, CYP2C19*2, CYP3A4*1G, and ABCB1 C3435T TT genotypes were independent determinants of PRU values (P < 0.01). CONCLUSION: The CYP2C19*2 allele is the primary determinant of the exposition to the H4 active metabolite of clopidogrel and platelet reactivity in patients co-treated with atorvastatin or rosuvastatin.

Serum endocan concentration and its correlation with severity of hypertensive disorders in pregnancy.

Introduction: Endocan plays a role in the development of vascular tissue in health and disease and is an indicator of endothelial cells activation and angiogenesis.Objective: The aim of this study was to investigate the relationship between endocan serum levels and various types of hypertensive disorders in pregnant women.Patients and methods: We created three study groups (preeclampsia [n = 60], chronic hypertension [n = 39], gestational hypertension [n = 58]) and the control group consisting of 59 healthy pregnant women. The endocan serum concentration was assessed using commercially available ELISA kit.Results: There were no statistically significant differences in endocan serum levels (pg/mL) in each study group compared to controls. The multiple regression did not reveal significant differences between endocan levels in each study group after adjustment for prepregnancy BMI. We did not find any significant correlations between the endocan serum level and patients' age, gestational age (GA) at sample collection, prepregnancy BMI, systolic blood pressure, diastolic blood pressure, and 24-hour urinary protein excretion in each analyzed group. Moreover, in the preeclamptic participants, we did not observe a significant relationship between the endocan concentration and the features indicating the severity of the disease other than elevated blood pressure. There were no differences in endocan serum level in preeclampsia subgroups: early-onset versus late-onset and mild versus severe preeclampsia.Conclusions: Endocan is not involved in the pathogenesis of hypertensive disorders in pregnant women and could not be regarded as a marker of endothelial dysfunction in these cases.