Abstract Objectives To evaluate the association between CYP2C9 and VKORC1 polymorphisms and warfarin therapy outcomes in Kazakh patients following cardiac surgery, with a focus on dose requirements, INR stabilisation and bleeding complications. Methods A retrospective cohort study was conducted among 186 Kazakh patients (108 men and 78 women; mean age 59.2 ± 8.4 years) who underwent cardiac surgery and received warfarin therapy for at least 3 months. Clinical data and pharmacogenetic results were analysed from electronic medical records. The studied variants included CYP2C9 (2, 3) and VKORC1 (−1639G>A). Associations between genotype groups, warfarin dose requirements, INR control and adverse events were assessed. Results Patients with the CYP2C9 3/3 genotype required the lowest mean daily warfarin dose (1.9 ± 0.4 mg), whereas CYP2C9 1/1 carriers required the highest dose (4.8 ± 0.6 mg). Genotype-guided dosing was associated with faster INR stabilisation compared with conventional dosing (12.3 ± 3.9 vs. 20.5 ± 5.7 days) and a lower incidence of clinically significant bleeding events (6.2 vs. 14.8 %). Conclusions The findings demonstrate that *CYP2C9* and *VKORC1* variants contribute to variability in warfarin response among Kazakh patients after cardiac surgery. Incorporating pharmacogenetic information into clinical decision-making may improve dose individualisation, anticoagulation control and treatment safety. Further prospective multicentre studies are required to confirm these findings.
Abstract Objectives To evaluate the impact of the TNF-α promoter SNP -308G/A on therapeutic response, serum drug levels, and immunogenicity of TNF inhibitors in chronic inflammatory rheumatic diseases. Methods This cross-sectional, multicentric study included 73 patients: 32 with rheumatoid arthritis (RA) and 41 with spondyloarthritis (SpA). Serum drug levels (SDL) and anti-drug antibodies (ADA) were quantified by ELISA (Promonitor ® ). Genotyping for SNP -308 was performed via PCR-RFLP. Therapeutic response was assessed at 6 months using delta DAS28 and EULAR response in RA and delta Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI20 and BASDAI50 responses in SpA patients. Results In RA, the heterozygous G/A genotype was significantly associated with a greater reduction in median DAS28 compared to G/G (p=0.039) and a higher proportion of good EULAR responders (p=0.154). In SpA, G/A carriers showed larger decreases in BASDAI scores though differences were not statistically significant. Across both diseases, the G/A genotype was associated with significantly higher median serum drug levels (p=0.032). No association was observed between SNP -308G/A and ADA positivity. Conclusions The TNF-α -308G/A polymorphism may be a predictive marker of TNF inhibitor efficacy in RA, potentially influencing serum drug levels while immunogenicity appears unaffected. Larger prospective studies are needed to confirm these findings and explore additional determinants of TNF inhibitor response.
OBJECTIVES:Withania somnifera (WS) is known for its adaptogenic benefits; however, its beneficial effects in neurodegenerative diseases have not been fully explored. MicroRNAs (miRNAs) are small noncoding RNAs whose role(s) in modulating the effects of WS in neurodegeneration are yet unknown. This study aimed to investigate the impact of WS on miRNA expression in the SK-N-SH human neuroblastoma cell line. METHODS:We employed high-throughput sequencing to identify miRNAs with altered expression following dose-dependent and temporal treatment with WS. RESULTS:Our findings revealed that miRNA expression profiles were significantly altered in WS-treated cells. In the dose comparison (100 μg/mL vs. 50 μg/mL), 21 miRNAs were modulated at 3 h (18 upregulated and 3 downregulated), whereas 7 miRNAs were modulated at 9 h (3 upregulated and 4 downregulated). In the temporal comparison (9 h vs. 3 h), 9 miRNAs were modulated at 50 μg/mL (6 upregulated and 3 downregulated), whereas 30 miRNAs were modulated at 100 μg/mL (4 upregulated and 26 downregulated). Bioinformatics analyses, including target prediction and functional enrichment, revealed that these WS-modulated differentially expressed miRNAs were significantly enriched in neurodegenerative, apoptotic, and inflammatory pathways. Finally, 51 novel miRNAs were identified post-WS treatment. CONCLUSIONS:Taken together, our results indicate that WS may be beneficial in neurodegenerative disease and healthy aging by modulating noncoding miRNAs.
Allergic diseases are common among women of reproductive age, which necessitates the use of antihistamine therapy during pregnancy while ensuring safety for both the mother and the foetus. The study aimed to determine the safety profile, pharmacological characteristics, and clinical consequences of antihistamine use during pregnancy for the maternal-foetal system. A systematic review of scientific publications for the period 2020-2025 was carried out using the PRISMA methodology with a search in five international databases, which allowed us to select 45 relevant sources analyzing pathophysiology, pharmacology, and clinical consequences. It has been established that maternal immunoglobulins of class E are transported across the placental barrier, where they may sensitise foetal mast cells in utero. Hormonal changes during pregnancy induce polarisation of the immune response towards Th2 with progressive suppression of eosinophils by 17-22 % in the second trimester and by 20-42 % in the third trimester. Population cohort studies covering more than 1.2 million pregnancies have found no statistically significant associations between the use of second-generation antihistamines and major congenital malformations, spontaneous abortions or premature births. Physiological changes during pregnancy modify the pharmacokinetic parameters of drugs, reducing plasma protein concentrations by 20-40 %, However, cetirizine and loratadine demonstrate a favourable safety profile based on data from more than 186,000 exposures in Scandinavian registries, and the relative infant dose remains below the 5 % safety threshold. The findings support the use of second-generation antihistamines as first-line therapy for allergic diseases in pregnancy and provide an evidence base for selecting safe pharmacological agents at different gestational stages.
OBJECTIVES:Ecstasy is commonly abused due to entactogenic effects. Although our previous studies on isolated perfused rat model confirmed inhibition of CYP2D6 by MDMA, the time for enzyme recovery was different when mirtazapine and tramadol were used as substrates. Therefore, present study intended to investigate CYP2D6 inhibition by MDMA using dextromethorphan as a well-known probe. Two different concentrations of dextromethorphan were used at therapeutic and saturated level to clarify observations. METHODS:Thirty-two rats were divided into two groups (dextromethorphan concentration: 2 µM or 300 µM). Each group was divided into four subgroups. Except for control, three treatment subgroups received a single dose of MDMA (1 mg/kg) 1 h, 1 week, and 1 month before liver perfusion, respectively. RESULTS:Mean metabolic ratio using therapeutic dextromethorphan concentration showed a statistically significant decrease only in the 1-hour group compared to control. The results of the mean metabolic ratio using the saturated concentration showed a reduction in all treatment groups (p-value<0.05). CONCLUSIONS:It can be concluded that the isoenzyme behavior can be completely different using therapeutic vs. saturated probe concentrations. The best explanation for the duality observed in metabolic behavior seems to be the dependence of the metabolite on enzymatic pathway.
