Pharmacogenetic markers of development of angioneurotic edema as a secondary side effect to enalapril in patients with essential arterial hypertension.

BACKGROUND: Angioneurotic edema is the most dangerous complication in angiotensin-converting enzyme inhibitors (ACEIs) therapy. Based on the current data, the clinical and genetic predictors of angioedema development are still understudied, which demonstrates the relevance of this study. OBJECTIVE: To reveal the pharmacogenetic predictors of the angioedema as a secondary side effect to enalapril in patients with essential arterial hypertension. METHODS: The study enrolled 111 subjects randomized into two groups: study group, patients with the angioedema as a secondary side effect to enalapril; and control group, patients without adverse drug reaction. All patients underwent pharmacogenetic testing. RESULTS: An association between the development of the angioneurotic edema and the genotypes AA rs2306283 of gene SLCO1B1, TT rs4459610 of gene ACE, and CC rs1799722 of gene BDKRB2 in patients was revealed. CONCLUSION: The findings justify further investigations of the revealed genetic predictors of angioedema with larger-size patient populations.

Genetic markers associated with adverse reactions of radioiodine therapy in thyroid cancer patients.

OBJECTIVES: Radioactive iodine therapy is considered for patients with certain clinicopathological factors that predict a significant risk of recurrence, distant metastases of thyroid cancer or disease-specific mortality. The aim of the study was to investigate the association between polymorphisms of genes, products of which are involved in the processes of DNA damage response and autophagy, and the adverse reactions of radioiodine therapy in thyroid cancer patients. METHODS: The study included 181 patients (37 men, 144 women; median age 56 [41; 66.3] years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. NFKB1, ATM, ATG16L2, ATG10, TGFB1, and TNF polymorphisms were determined by allele-specific realtime-PCR. RESULTS: The frequency of adverse reactions was the following: gastrointestinal symptoms - 57.9 %, local symptoms - 65.8 %, cerebral symptoms - 46.8 %, fatigue - 54.4 %; signs of sialoadenitis six months after radioiodine therapy - 25.2 %. TT genotype carriers of ATG10 rs1864183 had higher frequency of gastrointestinal symptoms (vs. CC+CT), the CC genotype carriers of ATG10 rs10514231 had significantly more frequent cerebral symptoms (vs. CT+TT), as well as AA genotype carriers of TGFB1 rs1800469 (vs. AG+GG). CC genotype of ATG10 rs10514231 increased the incidence of radioiodine-induced fatigue, whereas GA genotype of the ATM rs11212570 had a protective role against fatigue. TGFB1 rs1800469 was associated with signs of sialoadenitis six months after radioiodine therapy. CONCLUSIONS: Genetic factors may contribute to the occurrence of adverse reactions of radioiodine therapy in thyroid cancer patients.

Effects of CYP2D6 allelic variants on therapy with tamsulosin in patients with benign prostatic hyperplasia.

OBJECTIVES: Tamsulosin is a first-line drug for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Despite its high ratings for efficacy and safety, these parameters may vary due to genetic polymorphisms of CYP2D6 enzyme, which is involved in the metabolism of the drug. This variability may have great impact on the therapy of LUTS associated with BPH and may require an individualized approach to drug selection. The aim of the study was to assess the impact of genetic polymorphisms in CYP2D6 on the efficacy and safety of tamsulosin therapy in patients with LUTS associated with BPH. METHODS: The study included 106 patients with LUTS/BPH (N40 according to ICD-10). All patients received monotherapy with tamsulosin 0.4 mg/day for at least 8 weeks. Depending on the severity of symptoms, all patients were divided into 2 groups based on the IPSS score: the first group of patients had moderate symptoms (n=57), and the second group of patients had severe symptoms (n=49). The results of treatment were assessed using the IPSS questionnaire with determination of quality of life (QoL), transrectal ultrasound of the prostate with determination of prostate volume and postvoid residual urine volume, and uroflowmetry. The carriage of allelic variants of CYP2D6 (*3, *4, *9, *10, and *41) were determined by polymerase chain reaction in all patients. RESULTS: In patients with moderate symptoms who was classified as «intermediate¼ metabolizers by CYP2D6, a statistically significant greater reduction in symptoms according to the overall IPSS scale at 8 weeks (p=0.046) and the obstructive symptom subscale starting from 4 weeks of treatment (p<0.05) was shown. Allelic variants of the CYP2D6 gene did not affect the frequency of adverse reactions to tamsulosin. CONCLUSIONS: The results of the study show that in patients with moderate LUTS associated with BPH who are «intermediate¼ metabolizers by CYP2D6, there is a better therapeutic effect of tamsulosin.

Genetic markers associated with adverse reactions of radioiodine therapy in thyroid cancer patients.

OBJECTIVES: Radioactive iodine therapy is considered for patients with certain clinicopathological factors that predict a significant risk of recurrence, distant metastases of thyroid cancer or disease-specific mortality. The aim of the study was to investigate the association between polymorphisms of genes, products of which are involved in the processes of DNA damage response and autophagy, and the adverse reactions of radioiodine therapy in thyroid cancer patients. METHODS: The study included 181 patients (37 men, 144 women; median age 56 [41; 66.3] years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. NFKB1, ATM, ATG16L2, ATG10, TGFB1, and TNF polymorphisms were determined by allele-specific realtime-PCR. RESULTS: The frequency of adverse reactions was the following: gastrointestinal symptoms - 57.9 %, local symptoms - 65.8 %, cerebral symptoms - 46.8 %, fatigue - 54.4 %; signs of sialoadenitis six months after radioiodine therapy - 25.2 %. TT genotype carriers of ATG10 rs1864183 had higher frequency of gastrointestinal symptoms (vs. CC+CT), the CC genotype carriers of ATG10 rs10514231 had significantly more frequent cerebral symptoms (vs. CT+TT), as well as AA genotype carriers of TGFB1 rs1800469 (vs. AG+GG). CC genotype of ATG10 rs10514231 increased the incidence of radioiodine-induced fatigue, whereas GA genotype of the ATM rs11212570 had a protective role against fatigue. TGFB1 rs1800469 was associated with signs of sialoadenitis six months after radioiodine therapy. CONCLUSIONS: Genetic factors may contribute to the occurrence of adverse reactions of radioiodine therapy in thyroid cancer patients.

Pharmacogenetic predictors of development of secondary to enalapril dry cough in hypertensive patients.

OBJECTIVES: Development of the secondary to ACEI cough leads to discontinuation of the drugs of this group. Assessing the safety of the ACEIs with further development of customized approaches for their administration is a major scientific and practical problem. The objective of this study was to assess the association of the genetic markers with the development of the adverse drug reaction in the form of secondary to enalapril dry cough in the patients with essential arterial hypertension. METHODS: Study involved 113 patients with the secondary to enalapril cough and 104 patients without development of the secondary to enalapril adverse drug reaction. RESULTS: The patients carriers of the genotype AA rs2306283 of gene SLCO1B1 had 2-fold higher odds of developing the dry cough than those with the genotypes AG and GG (ОR=2.01, 95%CI=1.10-3.66, р=0.023). Similarly, the patients heterozygous for rs8176746 of gene АВО had 2.3-fold higher odds of developing the ADR in the form of dry cough than the carriers of the genotypes GG and TT (ОR=2.30, 95%CI=1.24-4.29, р=0.008). CONCLUSIONS: Statistically significant association between the development of the ADR in the form of secondary to enalapril dry cough and polymorphisms rs2306283 of gene SLCO1B1 and rs8176746 of gene ABO was revealed.

CYP2C9 gene polymorphisms influence on antihypertensive effectiveness and hypouricemic effect of losartan among patients with arterial hypertension: an observational study.

OBJECTIVES: CYP2C9 gene polymorphic variants can decrease the effects of losartan, reducing active metabolite (E-3174) formation. Study aims to determine the influence of *2 (+430C>T; rs799853) and *3 (+1075A>C; rs1057910) CYP2C9 gene polymorphic variants on the hypotensive and uricosuric effect of losartan on patients with arterial hypertension. METHODS: Eighty one patients with stage 1-2 arterial hypertension newly diagnosed with ABMP were enrolled in the study. Physicians started losartan treatment and then we measured urine concentration of E-3174/losartan to estimate CYP2C9 activity. After 3-month losartan treatment we compared effectiveness of the therapy with ABPM and plasma uric acid level between carriers of CYP2C9 *1/*1 and CYP2C9 gene polymorphic variants (*2 and *3). RESULTS: Carriage of CYP2C9*2 and CYP2C9*3 alleles reduced the hypotensive effect of losartan (p<0.001, OR=8.13 (95% CI, 2.75-23.97)). Analysis of the ABPM data revealed that blood pressure was significantly higher in patients with polymorphic genotypes. There was no significant difference in uric acid level in plasma and losartan and its metabolite concentration in urine between genotypes. CONCLUSIONS: Carriage of low function polymorphic variants of the CYP2C9 gene (*2 and *3) reduced the hypotensive effect of losartan according to ABPM and don't affect uric acid level in plasma and E-3174/losartan in urine.

Effect of CYP2D6*4, CYP2D6*10 polymorphisms on the safety of treatment with timolol maleate in patients with glaucoma.

OBJECTIVES: Timolol maleate is used for the treatment of glaucoma and metabolized by cytochrome CYP2D6 in the liver. The aim of this study was the evaluation of the influence of CYP2D6*4 and CYP2D6*10 gene polymorphisms on the safety of medications containing 0.5% of timolol maleate as glaucoma treatment in patients with primary open-angle glaucoma (POAG). METHODS: 105 patients with POAG were prescribed glaucoma medications, containing 0.5% timolol maleate. The safety of glaucoma treatment was determined by electrocardiography (ECG) (to assess heart rate (HR) and PQ interval) and blood pressure (BP) measurements. The real-time polymerase chain reaction method was used for the detection of single nucleotide polymorphisms (SNP). RESULTS: The risk of adverse drug reactions was higher in patients with the CYP2D6*4 GA genotype compared with GG: mean HR change at 1 month (2.88 ± 4.68 and 6.44 ± 5.57, p<0.001) and 6 months (5.14 ± 8.93 and 7.88 ± 5.65, p<0.001), mean PQ interval change at 1 (0.01 ± 0.031 and 0.02 ± 0.022, p=0.003) and 6 months (0.01 ± 0.032 and 0.02 ± 0.024, p=0.003). The risk of adverse drug reactions was higher in patients with the CYP2D6*10 CT genotype compared with CC: mean HR change at 1 month (2.94 ± 4.65 and 6.34 ± 5.66, p<0.001) and 6 months (5.20 ± 8.90 and 7.78 ± 5.75, p<0.001), mean PQ interval change at 1 (0.01 ± 0.032 and 0.02 ± 0.021, p=0.014) and 6 months (0.01 ± 0.033 and 0.02 ± 0.022, p=0.014). CONCLUSIONS: CYP2D6*4 and CYP2D6*10 gene polymorphisms may affect a higher risk of timolol-induced bradycardia and increased PQ interval of treatment medications containing 0.5% of timolol maleate in patients with POAG.

Effect of CYP2C9, PTGS-1 and PTGS-2 gene polymorphisms on the efficiency and safety of postoperative analgesia with ketoprofen.

OBJECTIVES: Patients undergoing cardiac surgery develop post-sternotomy pain syndrome. The aim of this study was evaluation of the influence of CYP2C9, PTGS-1 and PTGS-2 genes polymorphisms on the efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery. METHODS: The study included 90 patients undergoing cardiac surgery. A real-time polymerase chain reaction was used for the detection of single nucleotide polymorphisms (SNP). Pain intensity was measured by the Numeric Rating Scale (NRS). Dyspeptic symptoms were evaluated using the Gastrointestinal Symptom Rating Scale (GSRS). Acute kidney injury (AKI) was determined by Kidney Disease Improving Global Outcomes criteria. RESULTS: Pain intensity by the NRS score was significantly higher in patients with CYP2C9*3 АA genotype compared to АC genotype: 7 [1,10] and 6 [2,7] (p=0.003); 7 [1,10] and 6 [2,7] (p=0.04); 6 [0; 10] and 5 [2,6] (p=0.04); 5 [0; 8] and 3 [0; 8] (p=0.02), on days 1, 2, 3 and 5 in the postoperative period, respectively. GSRS score was higher in patients with CYP2C9*2 CT genotype compared to CС genotype: 19 [15; 42] and 18 [15,36] (p=0.04), respectively. There were no significant differences in the pain intensity, dyspepsia severity and AKI frequency in patients with homozygous and heterozygous genotypes for PTGS-1 rs10306135, PTGS-1 rs12353214, PTGS-2 rs20417. CONCLUSIONS: CYP2C9*3 and CYP2C9*2 gene polymorphisms may affect efficacy and safety of postoperative analgesia with ketoprofen in patients with coronary artery disease after cardiac surgery.

Using the CYP3A Activity Evaluation to Predict the Efficacy and Safety of Diazepam in Patients With Alcohol Withdrawal Syndrome.

BACKGROUND: Diazepam is one of the most commonly prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on the efficacy and safety of diazepam therapy. OBJECTIVE: The objective of our study was to study the effect of CYP3A isoenzymes activity on the efficacy and safety of diazepam in patients with AWS. METHODS: The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg / day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions. RESULTS: Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP3A4 C>T intron 6 (rs35599367) genotypes: (CC) -9.0 [-13.0; -5.0], (CT+TT) -13.5 [-15.0; -10.0], p = 0.014. The scores on the UKU scale, which was used to evaluate the safety of therapy, were also different: (CC) 7.5 [6.0; 11.0], (CT+TT) 11.0 [8.0; 12.0], p = 0.003. CONCLUSION: Possible relationship between the CYP3A activity, evaluated by the content of the urinary endogenous substrate of the given isoenzyme and its metabolite, the 6-beta-hydroxy cortisol (6-ß-HC) / cortisol ratio, and the efficacy of diazepam was demonstrated. This possible relationship was also supported by the genotyping results. This should be taken into consideration when prescribing this drug to such patients in order to reduce the risk of pharmacoresistance.

Impact of CYP2D6 Polymorphism on Equilibrium Concentration of Fluoxetine in Patients Diagnosed With Major Depressive Disorder and Comorbid Alcohol Use Disorders.

INTRODUCTION: Fluoxetine is used in the treatment of patients with recurrent depressive disorder. Some of these patients do not achieve an adequate response to a treatment regimen containing fluoxetine, and many of these patients experience dose-dependent adverse drug reactions. The cytochrome P450 enzyme CYP2D6 is involved in the biotransformation of fluoxetine, the activity of which is quite dependent on the polymorphism of the gene encoding this enzyme. OBJECTIVE: The objective of the study was to investigate the influence of the 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of fluoxetine in patients diagnosed with major depressive disorder and comorbid alcohol use disorder. METHODS: Our study included 101 patients with major depressive disorder and alcohol use disorder (average age: 41.3±14.5 y) who were treated with fluoxetine at an average dose of 26.1±8.7 mg/d. Treatment efficacy was assessed using validated psychometric scales, and the safety/tolerability of the therapy was assessed using the Udvalg for Kliniske Undersogelser Side-Effect Rating Scale. Genotyping was done using a real-time polymerase chain reaction. Therapeutic drug monitoring was performed using high-performance liquid chromatography-mass spectrometry. RESULTS: CYP2D6 genotyping by polymorphic marker 1846G>A (rs3892097) in the 101 patients found that there were 81 patients (80.2%) with the GG genotype ("wild-type," normal metabolism), 20 (19.8%) with the GA genotype (intermediate metabolism), and no subjects with the AA genotype (poor metabolism). Statistically significant results in treatment efficacy as evaluated by Hamilton Rating Scale for Depression scores at the end of the treatment course were found: GG 9.0 [confidence interval (CI): 6.0; 12.0] and GA 12.0 (CI: 9.5; 14.0), P=0.005. Statistically significant results were also obtained for the safety profile as measured by scores on the Udvalg for Kliniske Undersogelser Side-Effect Rating Scale: GG 3.0 (CI 2.0; 4.0) and GA 5.0 (CI: 4.0; 5.0), P<0.001. Finally, a statistically significant difference was found in concentration/dose indicators of fluoxetine in patients with the different genotypes: GG 4.831 (CI: 3.654; 6.204) and GA 7.011 (CI: 5.431; 8.252), P<0.001. CONCLUSION: The effect of the genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of fluoxetine was demonstrated in a group of 101 patients with major depressive disorder and alcohol use disorder.

MicroRNAs as novel biomarkers for rivaroxaban therapeutic drug monitoring.

OBJECTIVES: The aim of this study is to assess micro-RNAs miR-142 and miR-39 as potential biomarkers for drug-monitoring of rivaroxaban among elderly patients with atrial fibrillation. METHODS: The study involved 57 patients with median (ME) age 87 years [80-94 years old] with nonvalvular atrial fibrillation admitted to a multidisciplinary hospital in Moscow. High-performance liquid chromatography with mass-spectrometry detection (HPLC-MS) was carried out to measure rivaroxaban concentrations. Carriership of CYP3A4 and ABCB1 was detected. MiRNA expression levels were measured. The activity of CYP3A4 isoenzyme was measured as the ratio of the concentrations of 6ß-hydroxycortisol and cortisol. RESULTS: The miR-142 expression levels of patients with CC allelic variant polymorphism ABCB1 3435 C>T (rs1045642) were significantly higher compared to CT and TT variants 31.69 ± 1.60 vs. 34.06 ± 1.66 vs. 33.16 ± 1.77 (p=0.021). Carriers of TT allelic variant polymorphism ABCB1 rs4148738 had a higher concentration of the 6-beta-hydroxycortisol in urine compared to CC and CT variants 3,467.35 ± 1,055.53 vs. 3,453.52 ± 1,516.89 vs. 2,593.30 ± 1,172.52 (p=0.029). As for CYP3A4*22, the carriers of CC allelic variant had higher prothrombin time 14.10 ± 2.17 vs. 11.87 ± 0.60 and INR 1.31 ± 0.20 vs. 1.1 ± 0.06 but lower Quick's value 74.52 ± 16.84 vs. 97.55 ± 10.54 (p=0.059). A positive correlation between the Ct miR-142 and the aPTT p=0.019 was noted. Also miR-142 has a correlation with Quick's value p=0.095. There is no statistically significant connection between miR-142 and miR-39 expression levels and the plasma concentration of rivaroxaban (b coefficient=-2.055, SE 3.952, p=0.605 and b coefficient=1.546, SE 9.887, p=0.876 in the linear regression model respectively). CONCLUSIONS: This study has assessed new potential biomarkers for rivaroxaban therapeutic drug monitoring: miR-142 and miR-39.

Olanzapine-Associated Rhabdomyolysis: A Case Report.

This paper presents the case of a 20-year-old patient with a suspected diagnosis of paranoid schizophrenia. He was prescribed oral olanzapine at a dose of 10 mg per day, and the treatment was associated with rhabdomyolysis (serum creatine kinase = 9,725 U/L on day four of the therapy). On suspicion of its contribution to rhabdomyolysis, olanzapine was immediately withdrawn. Pharmacogenetic testing demonstrated that the patient's CYP2D6 genotype was *4/*4 (1846G>A, rs3892097). Based on these results, the patient was switched to trifluoperazine, a medication that is not metabolized by the CYP2D6 isoenzyme. Subsequently, the patient recovered well and was discharged without any nephrological sequelae. The presented case demonstrates that pharmacogenetic-guided personalization of treatment may allow selecting the best medication and determining the right dosage, resulting in the reduced risk of adverse drug reactions and pharmacoresistance.

MicroRNAs as novel biomarkers for rivaroxaban therapeutic drug monitoring.

OBJECTIVES: The aim of this study is to assess micro-RNAs miR-142 and miR-39 as potential biomarkers for drug-monitoring of rivaroxaban among elderly patients with atrial fibrillation. METHODS: The study involved 57 patients with median (ME) age 87 years [80-94 years old] with nonvalvular atrial fibrillation admitted to a multidisciplinary hospital in Moscow. High-performance liquid chromatography with mass-spectrometry detection (HPLC-MS) was carried out to measure rivaroxaban concentrations. Carriership of CYP3A4 and ABCB1 was detected. MiRNA expression levels were measured. The activity of CYP3A4 isoenzyme was measured as the ratio of the concentrations of 6ß-hydroxycortisol and cortisol. RESULTS: The miR-142 expression levels of patients with CC allelic variant polymorphism ABCB1 3435 C>T (rs1045642) were significantly higher compared to CT and TT variants 31.69 ± 1.60 vs. 34.06 ± 1.66 vs. 33.16 ± 1.77 (p=0.021). Carriers of TT allelic variant polymorphism ABCB1 rs4148738 had a higher concentration of the 6-beta-hydroxycortisol in urine compared to CC and CT variants 3,467.35 ± 1,055.53 vs. 3,453.52 ± 1,516.89 vs. 2,593.30 ± 1,172.52 (p=0.029). As for CYP3A4*22, the carriers of CC allelic variant had higher prothrombin time 14.10 ± 2.17 vs. 11.87 ± 0.60 and INR 1.31 ± 0.20 vs. 1.1 ± 0.06 but lower Quick's value 74.52 ± 16.84 vs. 97.55 ± 10.54 (p=0.059). A positive correlation between the Ct miR-142 and the aPTT p=0.019 was noted. Also miR-142 has a correlation with Quick's value p=0.095. There is no statistically significant connection between miR-142 and miR-39 expression levels and the plasma concentration of rivaroxaban (b coefficient=-2.055, SE 3.952, p=0.605 and b coefficient=1.546, SE 9.887, p=0.876 in the linear regression model respectively). CONCLUSIONS: This study has assessed new potential biomarkers for rivaroxaban therapeutic drug monitoring: miR-142 and miR-39.

The Frequency of the Minor Polymorphisms in the CYP2C19, VEGFR-2 Genes, and Clinical Outcomes in Russian and Buryat Patients with Acute Coronary Syndrome.

Aim: To determine the differences in the frequencies of polymorphic variants at the rs4244285(*2), rs4986893 (*3), rs12248560 (*17), loci of the CYP2C19 gene, and the rs2305948 locus of the VEGFR-2 gene in patients receiving clopidogrel treatment as part of a 30-day clinical outcome trial in the Russian and Buryat regions of East Siberia. Methods: The study included 118 Russian (from Irkutsk) and 109 Buryat (from Ulan-Ude) patients with emergency admission for percutaneous coronary interventional treatment of acute coronary syndrome (ACS). The patients were stratified by the presence of the CYP2C19*2, CYP2C19*3, CYP2C19*17 alleles, and the VEGFR-2 rs2305948 allele. Safety and efficacy endpoints were analyzed 30 days following coronary stenting (CS). Results: There was no significant difference found in the Russian and Buryat patients in terms of the frequency of the CYP2C19*2 minor allele (10.2% in the Russian against 12.8% in the Buryat patients, odds ratio [OR] = 1.167, confidence interval [CI] 0.729-2.323). However, the frequency of the CYP2C19*3 allele was significantly higher in the Buryat patients than in the Russian patients (12.8% vs. 2.1%), OR = 5.600, CI 2.579-17.974; while in the Russian patients the frequency of the CYP2C19*17 allele was higher than the Buryat patients (23.3% in Russian patients vs. 10.1% in Buryat, OR = 2.500, CI 1.587-4.618). No significant differences were found in the prevalence of the VEGFR-2 rs2305948 alleles between the two groups of patient populations (12.5 in Buryat patients vs. 11.5% in Russian, OR = 1.040, CI 0.614-1.980). The Buryat patients were highly significantly more likely to experience adverse effects associated with the inefficacy of clopidogrel treatment, that is, early recurrent ischemic pains after CS, than the Russian patients (χ2 = 11.325, p < 0.001). Conclusion: The Buryat patients receiving clopidogrel treatment after CS have a reduced risk of small or large hemorrhages, and an increased risk of thrombotic complications compared with Caucasians. These results suggest that other antiplatelet drugs should be used for treating the Buryat patients with ACS.

How do CYP2C19*2 and CYP2C19*17 genetic polymorphisms affect the efficacy and safety of diazepam in patients with alcohol withdrawal syndrome?

Background Diazepam is one of the most commonly prescribed tranquilizers for therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on its efficacy and safety. The objective of our study was to investigate the effect of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy and safety of diazepam in patients with AWS. Methods The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg/day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions. Results Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP2C19 681G>A (CYP2C19*2, rs4244285) genotypes: (CYP2C19*1/*1) -8.5 [-15.0; -5.0], (CYP2C19*1/*2 and CYP2C19*2/*2) -12.0 [-13.0; -9.0], p = 0.021. The UKU scale scores, which were used to evaluate the safety of therapy, were also different: (CYP2C19*1/*1) 7.0 [6.0; 12.0], (CYP2C19*1/*2 and CYP2C19*2/*2) 9.5 [8.0; 11.0], p = 0.009. Patients carrying different CYP2C19 -806C>T (CYP2C19*17, rs12248560) genotypes also demonstrated differences in therapy efficacy and safety rates. Conclusions Thus, the effects of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy of diazepam were demonstrated.

Effects of CYP2C19*2 polymorphisms on the efficacy and safety of phenazepam in patients with anxiety disorder and comorbid alcohol use disorder.

Introduction: Phenazepam therapy can often be ineffective and some patients develop dose-related adverse drug reactions. Aim. The purpose of this research was to study the effect of the CYP2C19*2 (681G>A, rs4244285) in patients with anxiety disorders and alcohol dependence taking phenazepam therapy. Materials & methods: Patients (175 males, average age: 37.16 ± 7.84 years) received phenazepam in tablet form for 5 days. Genotyping was performed by real-time polymerase chain reaction. Results: The statistically significant differences in the UKU Side-Effect Rating Scale scores on the fifth day of therapy: (CYP2C19*1/*1) 2.00 [1.00; 2.00), (CYP2C19*1/*2) 7.00 (7.00; 7.00), (CYP2C19*2/*2) 9.00 (8.00; 9.00), p < 0.001. Conclusion: This study demonstrated the different efficacy and safety of phenazepam in patients with different genotypes of CYP2C19*2.

An improved extraction protocol for therapeutic dabigatran monitoring using HPLC-MS/MS.

A new sample extraction protocol was developed for pharmacokinetic studies of dabigatran with high-performance liquid chromatography separation - electrospray ionization time-of-flight mass spectrometry analysis. After protein precipitation with acetonitrile, free dabigatran and its metabolites are separated into water phase by water-dichloromethane liquid-liquid extraction to purify the sample from proteins and endogenous lipophilic compounds. Chromatographic separation was achieved on an Agilent Zorbax SB-CN column (150 × 4.6 mm, 5 µm)) using 0.1% aqueous solution of formic acid and acetonitrile (80:20) as the mobile phase. Agilent Zorbax SB-CN column was selected to improve sample resolution and to avoided early elution of dabigatran previously seen when using a C18 column. The extended calibration curve was constructed from 5 to 1000 ng/L while precision and accuracy were assessed at four levels across the linear dynamic ranges. Within-run precision was <5.6% and the between-run precision was <3.9%. The method accuracy ranged from 89.8% to 104.4%. The developed method was successfully applied to 30 patient samples to evaluate antithrombotic efficacy and anticoagulant activity of dabigatran following knee endoprosthesis surgery.

ADME pharmacogenetics: future outlook for Russia.

This systematic review reflects the results of pharmacogenetic studies in the Russian Federation aimed at studying the genes involved in the drug biotransformation system. The works of Russian researchers found by us are mostly devoted to microsomal liver oxidation enzymes (metabolism) and membrane transporter systems (absorption and excretion). This review presents population-ethnic and associative clinical studies on the genes of the CYP450 system, noncytochrome oxidation enzymes (SULT1A1, CES1), membrane transporter system genes (ABCB1, SLCO1B1) and warfarin biotransformation enzymes (VKORC1, GGCX). The information is structured in the form of 11 tables, divided by regions of the Russian Federation.

Effects of CYP2C19*17 polymorphisms on the efficacy and safety of bromodigyrochlorophenylbenzodiazepine in patients with anxiety disorder and comorbid alcohol use disorder.

Background Bromodihydrochlorophenylbenzodiazepine (Phenazepam®) is used in the therapy of anxiety disorders in patients with alcohol dependence. However, Phenazepam therapy often turns out to be ineffective, and some patients develop dose-related adverse drug reactions (ADR): severe sedation, dizziness, headache, dyspepsia, falling, etc. That ensures the effectiveness of this category of patients. Despite the popularity of Phenazepam® as an anxiolytic drug, there is currently no accurate data on its biotransformation, as well as the effect of polymorphism of a gene on the efficacy and safety of bromodihydrochlorophenylbenzodiazepine in patients. The aim of our study was to study the effect of the polymorphism of the CYP2C19 gene on the efficacy and safety index of Phenazepam® for patients with anxiety disorders, using algorithms for optimizing the therapy of Phenazepam® to reduce the risk of pharmacological resistance and increase the effectiveness of therapy. Methods The study was conducted on 86 Russian patients suffering from alcohol dependence. Patients with trauma anxiety disorders received bromdihydrochlorphenylbenzodiazepine in tablets at a dose of 4.0 [2.0; 6.0] mg per day for 5 days. Genotyping was carried out by the method of polymer chain reaction in real time with allele-specific hybridization. Efficiency and safety assessment was carried out using psychometric scales and scales of Hospital Anxiety and Depression Scale (HADS) severity scores. Results Based on the results of the study, statistically significant differences in the number of scores on the scale of HADS severity of CYP2C19 CT on the third day of therapy were the following: (CC) 10.00 [9.00; 11.00], (CT) 14.00 [13.00; 16.00], (TT) 18.00 [17.00; 19.00], p=0.00, and also on the fifth day: (CC) 6.00 [5.00; 7.00], (CT) 17.50 [16.25; 19.75], (TT) 22.50 [20.00; 24.00], p=0.00. ADRs in patients with different genotypes for this polymorphic marker did not differ. Conclusions Thus, it has been shown that the polymorphism of the CYP2C19 gene may influence the effectiveness indices of Phenazepam therapy in patients with anxiety disorders comorbid with alcohol dependence. This should be taken into account in the appointment of this drug in this way in order to increase effectiveness of therapy and improve the quality of life.