journal article
LitStream Collection
Home
Ivashchenko, Dmitriy V.; Rudik, Anastasia V.; Poloznikov, Andrey A.; Nikulin, Sergey V.; Smirnov, Valeriy V.; Tonevitsky, Alexander G.; Bryun, Eugeniy A.; Sychev, Dmitriy A.
2018 Drug Metabolism and Drug Interactions
doi: 10.1515/dmpt-2017-0036pmid: 29727298
AbstractBackground:Phenazepam (bromdihydrochlorphenylbenzodiazepine) is the original Russian benzodiazepine tranquilizer belonging to 1,4-benzodiazepines. There is still limited knowledge about phenazepam’s metabolic liver pathways and other pharmacokinetic features.Methods:To determine phenazepam’s metabolic pathways, the study was divided into three stages: in silico modeling, in vitro experiment (cell culture study), and in vivo confirmation. In silico modeling was performed on the specialized software PASS and GUSAR to evaluate phenazepam molecule affinity to different cytochromes. The in vitro study was performed using a hepatocytes’ cell culture, cultivated in a microbioreactor to produce cytochrome P450 isoenzymes. The culture medium contained specific cytochrome P450 isoforms inhibitors and substrates (for CYP2C9, CYP3A4, CYP2C19, and CYP2B6) to determine the cytochrome that was responsible for phenazepam’s metabolism. We also measured CYP3A activity using the 6-betahydroxycortisol/cortisol ratio in patients.Results:According to in silico and in vitro analysis results, the most probable metabolizer of phenazepam is CYP3A4. By the in vivo study results, CYP3A activity decreased sufficiently (from 3.8 [95% CI: 2.94–4.65] to 2.79 [95% CI: 2.02–3.55], p=0.017) between the start and finish of treatment in patients who were prescribed just phenazepam.Conclusions:Experimental in silico and in vivo studies confirmed that the original Russian benzodiazepine phenazepam was the substrate of CYP3A4 isoenzyme.
Ahmadimanesh, Mahnaz; Shadnia, Shahin; Rouini, Mohammad Reza; Sheikholeslami, Behjat; Ahsani Nasab, Sara; Ghazi-Khansari, Mahmoud
2018 Drug Metabolism and Drug Interactions
doi: 10.1515/dmpt-2017-0040pmid: 29727299
AbstractBackground:Seizure is one of the important symptoms of tramadol poisoning, but its causes are still unknown. The aim of this study is to find a relationship between tramadol and the concentrations of its metabolites versus the incidence of seizures following the consumption of high doses of tramadol.Methods:For this purpose, the blood samples of 120 tramadol-intoxicated patients were collected. The patients were divided in two groups (seizure and non-seizure). The concentrations of tramadol and its metabolites (M1, M2 and M5) were measured by using a high-performance liquid chromatography method. The relationship between tramadol and the levels of its metabolites and seizure incidences was also investigated.Results:In 72% of the patients, seizures occurred in the first 3 h after the ingestion of tramadol. The seizure incidences were significantly correlated with the patients’ gender, concentrations of tramadol, M1 and M2 and the history of previous seizures (p<0.001). The average concentration of M2 was significantly higher in males (p=0.003). A previous history of the use of sedative-hypnotics and the co-ingestion of benzodiazepines and other opioids were shown to significantly decrease the rate of seizure. The rate of seizure was directly related to the concentrations of tramadol and its metabolites. Higher M2 concentration in males can be considered a reason for increased incidences of seizures in males. The plasma concentration of M1 affected the onset of seizure.Conclusions:Therefore, it can be concluded that differences in the levels of the metabolites can affect the threshold of seizure in tramadol-intoxicated patients.
Pearce, Brendon; Abrahams-October, Zainonesa; Xhakaza, Lettilia; Jacobs, Clifford; Benjeddou, Mongi
2018 Drug Metabolism and Drug Interactions
doi: 10.1515/dmpt-2017-0039pmid: 29624501
AbstractBackground:Single nucleotide polymorphisms in promoter regions have been shown to alter the transcription of genes. Thus, SNPs in SLC22A2 can result in inter-individual variable response to medication.Methods:The objective of the study was to investigate the effect of the African-specific promoter polymorphisms on the SLC22A2 gene expression levels in vitro. These included rs572296424 and rs150063153, which have been previously identified in the Xhosa population of South Africa. The promoter region (300 bp) for the two haplotypes was cloned into the pGLOW promoterless GFP reporter vector. The GFP expression levels of each haplotype was determined in the HEK293 cells using a GlowMax Multi-Detection E7031 luminometer in the form of light emission.Results:The relative promoter activity suggests that no significant variation exists between the expression levels of the WT and -95 haplotypes and the -95 and -156 haplotypes (p=0.498). However, the relative promoter activity of the WT haplotype in comparison to the -156 haplotype displayed a significant difference in expression level (p=0.016).Conclusions:The data presented here show that the African-specific promoter polymorphisms can cause a decrease in the SLC22A2 gene expression levels in vitro, which in turn, may influence the pharmacokinetic profiles of cationic drugs.
Fedorinov, Denis S.; Mirzaev, Karin B.; Ivashchenko, Dmitriy V.; Temirbulatov, Ilyas I.; Sychev, Dmitriy A.; Maksimova, Nadezda R.; Chertovskih, Jana V.; Popova, Nyurguiana V.; Tayurskaya, Ksenia S.; Rudykh, Zoya A.
2018 Drug Metabolism and Drug Interactions
doi: 10.1515/dmpt-2018-0004pmid: 29738309
AbstractBackground:The focus of the study is to determine the prevalence of CYP2C19 alleles, associated with the risk of changes in the pharmacological response to clopidogrel and proton pump inhibitors in patients with acute coronary syndrome (ACS) and gastric ulcer from Russian and Yakut ethnic groups.Methods:The research included 411 patients with ACS (143 Russians and 268 Yakuts) and 204 patients with histologically confirmed gastric ulcer (63 Russians and 141 Yakuts). Genotyping of 681G>A and 636G>A polymorphisms was performed by using polymerase real-time chain reaction.Results:In both ethnic groups, Hardy-Weinberg equilibrium was followed in a distribution of alleles and genotypes in the population (p>0.05). The 681A allele frequency in the Yakut ethnic group was higher than in the Russian group: 17.53% vs. 8.39% (p=0.001). No statistically significant difference was found in the frequency of 636A in Yakuts and Russians with ACS: 3.92% vs. 3.50% (p=0.840). While comparing the frequency distribution of alleles 681A (13.49% vs. 14.54%, p=0.878) and 636A (7.94% vs. 7.80%, p=1) in patients with a gastric ulcer from Russian and Yakut ethnic groups, no significant difference was found in carrier frequency.Conclusions:The results of the present study may be helpful for developing guidelines for CYPC19 genotype-directed antiplatelet therapy for Yakut and Russian patients.
Srećković, Branko; Soldatovic, Ivan; Colak, Emina; Mrdovic, Igor; Sumarac-Dumanovic, Mirjana; Janeski, Hristina; Janeski, Nenad; Gacic, Jasna; Dimitrijevic-Sreckovic, Vesna
2018 Drug Metabolism and Drug Interactions
doi: 10.1515/dmpt-2017-0013pmid: 29624500
AbstractBackground:Abdominal adiposity has a central role in developing insulin resistance (IR) by releasing pro-inflammatory cytokines. Patients with metabolic syndrome (MS) have higher values of homocysteine. Hyperhomocysteinemia correlates with IR, increasing the oxidative stress. Oxidative stress causes endothelial dysfunction, hypertension and atherosclerosis. The objective of the study was to examine the correlation of homocysteine with siMS score and siMS risk score and with other MS co-founding factors.Methods:The study included 69 obese individuals (age over 30, body mass index [BMI] >25 kg/m2), classified into two groups: I-with MS (33 patients); II-without MS (36 patients). Measurements included: anthropometric parameters, lipids, glucose regulation parameters and inflammation parameters. IR was determined by homeostatic model assessment for insulin resistance (HOMA-IR). ATP III classification was applied for diagnosing MS. SiMS score was used as continuous measure of metabolic syndrome.Results:A significant difference between groups was found for C-reactive protein (CRP) (p<0.01) apolipoprotein (Apo) B, HOMA-IR and acidum uricum (p<0.05). siMS risk score showed a positive correlation with homocysteine (p=0.023), while siMS score correlated positively with fibrinogen (p=0.013), CRP and acidum uricum (p=0.000) and homocysteine (p=0.08). Homocysteine correlated positively with ApoB (p=0.036), HbA1c (p=0.047), HOMA-IR (p=0.008) and negatively with ApoE (p=0.042).Conclusions:Correlation of siMS score with homocysteine, fibrinogen, CRP and acidum uricum indicates that they are co-founding factors of MS. siMS risk score correlation with homocysteine indicates that hyperhomocysteinemia increases with age. Hyperhomocysteinemia is linked with genetic factors and family nutritional scheme, increasing the risk for atherosclerosis.
Erden, Abdulsamet; Bilgin, Emre; Kılıç, Levent; Sarı, Alper; Armağan, Berkan; Büyükaşık, Yahya; Kalyoncu, Umut
2018 Drug Metabolism and Drug Interactions
doi: 10.1515/dmpt-2018-0002pmid: 29715182
AbstractBackground:Relapsing polychondritis (RP) is a rare autoimmune disorder, and myelodysplastic syndrome (MDS) is accompanied by RP at variable rates. Herein, we report a case with RP and MDS who responded dramatically to 5-azacitidine for MDS.Case presentation:With conventional immunosuppressive treatment, our patient had several episodes of different side effects, including infections. With the diagnosis of MDS and initiation of azacitidine treatment, all the manifestations of RP disappeared, and remission was achieved for MDS. Although he had relapses of either RP or MDS after several years of azacitidine treatment, all relapses were controlled well with the initiation of azacitidine treatment every time.Conclusions:Azacitidine should be kept in mind as a treatment option for RP patients with MDS.
Showing 1 to 8 of 8 Articles