Association between Genetic Polymorphisms and Bleeding in Patients on Direct Oral Anticoagulants.

Objectives: The purpose of our study is to investigate the effects of apolipoprotein B (APOB) and APOE gene polymorphisms on bleeding complications in patients receiving direct oral anticoagulants (DOACs). Methods: A total of 16 single nucleotide polymorphisms (SNPs) in 468 patients were genotyped. Six SNPs of ABCB1 (rs3842, rs1045642, rs2032582, rs1128503, rs3213619, and rs3747802), one SNP of CYP3A5 (rs776746), seven SNPs of APOB (rs1042034, rs2163204, rs693, rs679899, rs13306194, rs13306198, and rs1367117), and two SNPs of APOE (rs429358 and rs7412) were analyzed by a TaqMan genotyping assay. Multivariable logistic regression analysis with selected variables was performed for the construction of a risk scoring system. Two risk scoring systems were compared (demographic factors only vs. demographic factors and genetic factors). Results: In the multivariable analyses, two models were constructed; only demographic factors were included in Model I and both demographic factors and genetic factors in Model II. Rivaroxaban and anemia showed significant association with bleeding in both models. Additionally, ABCB1 rs3842 variant homozygote carriers (CC) and APOB rs13306198 variant allele carriers (AG, AA) had a higher risk of bleeding risk compared with that of wild-type allele carriers (TT, TC) and wild-type homozygote carriers (GG), respectively. Whereas the area under the receiver operating characteristic curve (AUROC) value using demographic factors only was 0.65 (95% confidence interval (CI): 0.56-0.74), the AUROC increased to 0.72 by adding genetic factors (95% CI: 0.65-0.80). The predicted bleeding risks of bleeding in patients with 0, 1, 2, 3, 4, 5, 6, 7 and 8 points from the logistic regression curve were 0.8%, 2.0%, 5.4%, 5.2%, 12.5%, 26.9%, 47.0%, 64.3% and 82.3%, respectively. Conclusions: The study results can be used for enhancing individualized treatment strategies in patients taking DOACs, helping clinicians predict the bleeding risk.

Associations of GNAS and RGS Gene Polymorphisms with the Risk of Ritodrine-Induced Adverse Events in Korean Women with Preterm Labor: A Cohort Study.

Ritodrine, a ß2-adrenergic receptor agonist, is among most commonly prescribed tocolytic agents. This study aimed to evaluate the associations of single nucleotide polymorphisms in GNAS, RGS2, and RGS5 with the risk of ritodrine-induced adverse events (AEs) and develop a risk scoring system to identify high-risk patients. This is the prospective cohort study conducted at the Ewha Woman's University Mokdong Hospital between January 2010 and October 2016. Pregnant women were included if they were treated with ritodrine for preterm labor with regular uterine contractions (at least 3 every 10 min) and cervical dilation. A total of 6, 3, and 5 single nucleotide polymorphisms (SNPs) of GNAS, RGS2, and RGS5 genes were genotyped and compared in patients with and without ritodrine-induced AEs. A total of 163 patients were included in this study. After adjusting confounders, GNAS rs3730168 (per-allele odds ratio (OR): 2.1; 95% confidence interval (95% CI): 1.0-4.3) and RGS2 rs1152746 (per-allele OR: 2.6, 95% CI: 1.1-6.5) were significantly associated with ritodrine-induced AEs. According to the constructed risk scoring models, patients with 0, 1, 2, 3, 4, and 5 points showed 0%, 13%, 19%, 31%, 46%, and 100% risks of AEs. This study suggested that GNAS and RGS2 polymorphisms could affect the risk of AEs in patients treated with ritodrine.

Effect of ITPA Polymorphism on Adverse Drug Reactions of 6-Mercaptopurine in Pediatric Patients with Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis.

6-Mercaptopurine (6-MP) is a cornerstone of the maintenance regimen for pediatric acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphatase (ITPA) is considered a candidate pharmacogenetic marker that may affect metabolism and 6-MP-induced toxicities; however, the findings are inconsistent. Therefore, we attempted to evaluate the effect of ITPA 94C>A polymorphism on 6-MP-induced hematological toxicity and hepatotoxicity through a systematic review and meta-analysis. A literature search for qualifying studies was conducted using the PubMed, Web of Science, and Embase databases until October 2021. Overall, 10 eligible studies with 1072 pediatric ALL patients were included in this meta-analysis. The results indicated that ITPA 94C>A was significantly associated with 6-MP-induced neutropenia (OR 2.38, 95% CI: 1.56−3.62; p = 0.005) and hepatotoxicity (OR 1.98, 95% CI: 1.32−2.95; p = 0.0009); however, no significant association was found between the ITPA 94C>A variant and 6-MP-induced leukopenia (OR 1.75, 95% CI: 0.74−4.12; p = 0.20). This meta-analysis demonstrated that ITPA 94C>A polymorphism could affect 6-MP-induced toxicities. Our findings suggested that ITPA genotyping might help predict 6-MP-induced myelosuppression and hepatotoxicity.

The Association between ABCG2 421C>A (rs2231142) Polymorphism and Rosuvastatin Pharmacokinetics: A Systematic Review and Meta-Analysis

Although several studies have revealed the association between rosuvastatin pharmacokinetics and the ABCG2 421C>A (rs2231142) polymorphism, most studies were conducted with small sample sizes, making it challenging to apply the findings clinically. Therefore, the purpose of this study is to perform a meta-analysis of the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. We searched three electronic databases, EMBASE, PubMed, and Web of Science, using search terms related to ABCG2 gene polymorphisms and rosuvastatin. In addition, we reviewed studies published before 12 August 2021, to examine the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. To examine the magnitude of the association, the log geometric mean difference (lnGM) and 95% confidence intervals (CIs) were calculated and interpreted as the antilogarithm of a natural logarithm (elnGM). The meta-analysis was performed using Review Manager (version 5.4) and R Studio (version 4.0.2). Subgroup analysis was performed according to race and the types of mean values. Among the 318 identified studies, a total of 8 studies involving 423 patients is included in this meta-analysis. The A allele carriers of ABCG2 421C>A showed 1.5 times higher in both AUC0-∞ (lnGM = 0.43; 95% CI = 0.35−0.50; p < 0.00001) and Cmax (lnGM = 0.42; 95% CI = 0.33−0.51; p < 0.00001) than non-carriers, while there was no significant difference in Tmax and half-life. There was no significance in the pharmacokinetic parameters of the subgroups using either ethnicity or mean values. This meta-analysis demonstrates that subjects carrying the A allele of ABCG2 421C>A show significantly increased AUC0-∞ and Cmax values compared to subjects with the CC genotype. Therefore, information about ABCG2 genotypes might be useful for individualized rosuvastatin therapy.

Genetic Factors of Renin-Angiotensin System Associated with Major Bleeding for Patients Treated with Direct Oral Anticoagulants.

The purpose of this study was to identify the renin-angiotensin system (RAS)-related genetic factors associated with bleeding and develop the bleeding risk scoring system in patients receiving direct oral anticoagulants (DOACs). This study was a retrospective analysis of prospectively collected samples from June 2018 to May 2020. To investigate the associations between RAS-related genetic factors and major bleeding, we selected 16 single nucleotide polymorphisms (SNPs) from five genes (namely, AGT, REN, ACE, AGTR1, and AGTR2). Multivariable logistic regression analysis was employed to investigate the independent risk factors for bleeding and to develop a risk scoring system. A total of 172 patients were included in the analysis, including 33 major bleeding cases. Both old age (≥65 years) and moderate to severe renal impairment (CrCl < 50 mL/min) increased the risk of bleeding in the multivariable analysis. Among RAS-related polymorphisms, patients carrying TT genotype of rs5050 and A allele of rs4353 experienced a 3.6-fold (95% CI: 1.4-9.3) and 3.1-fold (95% CI: 1.1-9.3) increase in bleeding, respectively. The bleeding risk increased exponentially with a higher score; the risks were 0%, 2.8%, 16.9%, 32.7%, and 75% in patients with 0, 1, 2, 3, and 4 points, respectively. Although this study is limited to a retrospective study design, this is the first study to suggest RAS-related genetic markers and risk scoring systems, including both clinical and genetic factors, for major bleeding in patients receiving DOAC treatment.

Association of P450 Oxidoreductase Gene Polymorphism with Tacrolimus Pharmacokinetics in Renal Transplant Recipients: A Systematic Review and Meta-Analysis.

There are conflicting results regarding the effect of the P450 oxidoreductase (POR) *28 genotype on the tacrolimus (TAC) pharmacokinetics (PKs) during the early post-transplantation period in adult renal transplant recipients. Thus, we characterized the impact of POR*28 on TAC PKs. We conducted a systematic review on the association between POR*28 and PKs of TAC in adult renal transplant recipients. Structured searches were conducted using PubMed, Web of Science, and Embase. TAC standardized trough concentration (ng/mL per mg/kg) data were extracted. Mean differences (MD) and their corresponding 95% confidence intervals (CIs) were used to identify the differences between the POR*28 genotype and PKs of TAC. The subgroup analysis was conducted according to CYP3A5 expression status. Six studies (n = 1061) were included. TAC standardized trough concentrations were significantly lower in recipients with the POR*28 allele compared to recipients with POR*1/*1 (MD: 8.30 ng/mL per mg/kg; 95% CI: 1.93, 14.67; p = 0.01). In the subgroup analysis, TAC standardized trough concentrations were lower for subjects who were POR*28 carriers than those who were POR*1/*1 in CYP3A5 expressers (MD: 20.21 ng/mL per mg/kg; 95% CI: 16.85, 23.56; p < 0.00001). No significant difference between POR*28 carriers and POR*1/*1 was found in the CYP3A5 non-expressers. The results of our meta-analysis demonstrated a definite correlation between the POR*28 genotype and PKs of TAC. Patients carrying the POR*28 allele may require a higher dose of TAC to achieve target levels compared to those with POR*1/*1, especially in CYP3A5 expressers.

Effects of Ephedrine-Containing Products on Weight Loss and Lipid Profiles: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Ephedrine, the main active ingredient of mahuang, may lead to weight loss; however, it can also induce cardiovascular side effects. As ephedrine use remains controversial, this study aimed to systematically review previous studies on ephedrine-containing products and perform meta-analysis of the existing evidence on weight, blood pressure (BP), heart rate, and lipid change effects of ephedrine-containing products. We searched for placebo-controlled randomized studies in PubMed, Web of Science, and EMBASE until July 2021 using the following search terms: (ephedr* OR mahuang) AND ("weight loss" OR obes* OR overweight). Mean differences (MDs) and 95% confidence intervals (CIs) were calculated to evaluate the effects of ephedrine-containing products on weight, BP, heart rate, and lipid profiles. A total of 10 articles were included. Compared with the placebo group, the ephedrine-containing product group was associated with greater weight loss, with an MD of -1.97 kg (95% CI: -2.38, -1.57). In the ephedrine-containing product group, the mean heart rate was 5.76 beats/min higher than in the placebo group (95% CI: 3.42, 8.10), whereas intergroup differences in systolic and diastolic BP were not statistically significant. The ephedrine-containing product group had a significantly higher mean high-density lipoprotein cholesterol level (MD: 2.74 mg/dL; 95% CI: 0.94, 4.55), lower mean low-density lipoprotein cholesterol level (MD: -5.98 mg/dL; 95% CI: -10.97, -0.99), and lower mean triglyceride level (MD: -11.25 mg/dL; 95% CI: -21.83, -0.68) than the placebo group. Compared with placebo, the ephedrine-containing products showed better effects on weight loss and lipid profiles, whereas they caused increased heart rate. The ephedrine-containing products may be beneficial to obese or overweight patients; however, close monitoring is needed, especially heart rate monitoring.

Association between Statin Use and Sensorineural Hearing Loss in Type 2 Diabetic Patients: A Hospital-Based Study.

Statins have emerged as protective agents against sensorineural hearing loss (SNHL) associated with dyslipidemia, but the effects of statins on SNHL are not consistent. The purpose of this study was to investigate the association between statin use and the risk of SNHL using a hospital cohort. This nested case-control study included type 2 diabetic patients over the age of 18 years without a history of hearing loss. Of these, 1379 patients newly diagnosed with SNHL or tinnitus were classified as cases, and 5512 patients matched to the cases based on age, sex, and index year were classified as controls. Chi-squared tests were used to compare categorical variables between the two groups. Odds ratios (ORs) and adjusted odds ratios (AOR) were calculated from univariate and multivariable unconditional logistic regression analyses, respectively. There was a significant difference in the prevalence of statin use between the cases and controls (53.7% vs. 61.2%, respectively; p < 0.001). The use of statins in type 2 diabetic patients significantly reduced the risk of SNHL or tinnitus by 24.8% (95% CI 14.2-34.1%, p < 0.001) after controlling for confounders. Similar results were found for the association between statin use and SNHL (AOR = 0.706; 95% CI 0.616-0.811, p < 0.001). The protective effects of statins against SNHL were consistent regardless of age and sex. The use of statins for type 2 diabetic patients was significantly associated with a reduced risk of SNHL, regardless of age and sex. Further studies are needed, especially large cohort studies, to evaluate the long-term protective effects of statins.

Association between ADCY9 Gene Polymorphisms and Ritodrine Treatment Outcomes in Patients with Preterm Labor.

The purpose of this study was to investigate the genetic effects of ADCY9 on ritodrine responses in patients with preterm labor. Five single nucleotide polymorphisms (SNPs) of the ADYC9 gene in 163 patients in preterm labor were genotyped: rs879619, rs2601796, rs2531988, rs2531995, and rs2230739. Additionally, rs598961 of the PDE4B gene and rs1042719 of the ADRB2 gene were included for analysis. Patients with CC genotype of ADCY9 rs879619 had a 2.0-fold (95% confidence interval [CI]: 1.3, 3.2) higher hazard of time to delivery than T allele carriers. Patients with combined genotypes of CC in ADCY9 rs879619, AA in PDE4B rs598961, and GC, CC in ADRB2 rs1042719 showed a greater hazard of time to delivery than patients with other combinations (adjusted hazard ratio [AHR] 3.2; 95% CI: 1.7, 6.3), whereas patients carrying the C allele of ADCY9 rs2531995, G allele of PDE4B rs598961, and GG genotype of ADRB2 rs1042719 had a lower hazard of time to delivery than patients carrying other genotypes (AHR 0.4; 95% CI: 0.2, 0.7). Regarding ritodrine-induced adverse drug events (ADEs), height less than 160 cm and CC genotype of ADCY9 rs2531995 showed a greater risk of ADEs. The results of our study suggest that ADCY9 polymorphisms could affect the efficacy and safety of ß2-adrenergic agonists.

Effects of SLCO1B1 and SLCO1B3 Genetic Polymorphisms on Valsartan Pharmacokinetics in Healthy Korean Volunteers.

Purpose: This study aimed to examine OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) on the pharmacokinetics of valsartan. Twenty-five subjects were genotyped for 16 single-nucleotide polymorphisms of the SLCO1B1 and SLCO1B3 genes. Methods: After a single dose of 160 mg of valsartan was orally administered to healthy male volunteers, drug concentrations were assayed up to 48 h. The 25 subjects were genotyped for 16 single-nucleotide polymorphisms (SNPs) of the SLCO1B1 and SLCO1B3 genes. Subjects were classified into groups according to their SLCO1B1*1B haplotype; 23 subjects were carriers of SLCO1B1*1B and two subjects were included in the reference group with SLCO1B1*1A/*1A. Alternations of the splicing factor-binding site pattern caused by the given mutation were evaluated with the Human Splicing Finder (HSF) 3.1. Results: The subjects who carried SLCO1B1*1B showed a 2.3-fold higher clearance than those without the *1B haplotype. Mean Cmax and AUCinf were reduced by 45% and 54%, respectively, in the SLCO1B1*1B genotype group compared to the reference group with the *1A/*1A genotype (p < 0.01). The carriers of the rs4149153 T allele of SLCO1B3 had a 27% lower mean Cmax and a 1.5-fold higher Vd compared to homozygotic CC carriers (p < 0.05). In a combined analysis of SLCO1B1 and SLCO1B3, subjects not carrying SLCO1B1 *1B and carrying SLCO1B3 rs4149153 T allele showed a 1.6-fold higher clearance than those with the other genotypes, whereas mean Cmax and AUClast were reduced by 35% and 42%, respectively (p < 0.05), in the subjects. HSF 3.1 analysis showed that rs4149153 could cause alterations of the acceptor splice site (TAAATACTAAAGAC to TAAATATTAAAGAC) with scoring change (from 72.57 to 71.92, difference = -0.9). Conclusion: It was found that plasma exposure to valsartan is significantly decreased in SLCO1B1*1B carriers and carriers of the rs4149153 T allele of SLCO1B3, possibly as a result of increased hepatic uptake.

Association between ABCA1 Gene Polymorphisms and Plasma Lipid Concentration: A Systematic Review and Meta-Analysis.

BACKGROUND: Although ABCA1 gene polymorphisms may be associated with the plasma lipid concentration, the literature has not shown a consistent pattern. In this study, we attempted to elucidate the association between the ABCA1 69C>T, 825V>I, and 230R>C polymorphisms and the plasma lipid concentration through a systematic review and meta-analysis. METHODS: We selected studies published up to October 2020 in the PubMed, Web of Science, and Embase databases according to inclusion and exclusion criteria. The mean difference (MD) and 95% confidence interval (CI) were used to assess the relationship between the presence of ABCA1 69C>T, 825V>I, and 230R>C and plasma lipid levels. Meta-analysis was performed using Review Manager (version 5.3). Both Begg's test and Egger's regression test of the funnel plot were performed using R Studio software (version 3.6.0) to identify publication bias. RESULTS: We analyzed the data on the ABCA1 69C>T polymorphism involving 14,843 subjects in 11 studies, 825V>I polymorphism involving 2580 subjects in 5 studies, and 230R>C polymorphism involving 4834 subjects in 4 studies. The T allele carriers in 69C>T, II carriers in 825V>I, and C carriers in 230R>C had lower high-density lipoprotein cholesterol levels; the MD (95% CI) was -0.05 mmol/L (95% CI: -0.09 to -0.01, p = 0.02), -0.05 mmol/L (95% CI: -0.09 to -0.00, p = 0.03), and -0.1 mmol/mL (95% CI: -0.12 to -0.07 mmol/L, p < 0.00001), respectively. In the case of 230R>C, the serum total cholesterol concentration of C carriers was significantly lower than that of RR carriers (-0.2 mmol/L, 95% CI: -0.3 to -0.11, p < 0.0001). CONCLUSION: This meta-analysis demonstrates that the ABCA1 69C>T, 825V>I, and 230R>C polymorphisms could affect the plasma lipid concentration. As the plasma lipid concentration may be related to various diseases, ABCA1 genotyping could be useful for the management of lipid levels.

Gene Polymorphisms of the Renin-Angiotensin System and Bleeding Complications of Warfarin: Genetic-Based Machine Learning Models.

BACKGROUND: This study aimed to investigate the effects of genetic variants and haplotypes in the renin-angiotensin system (RAS) on the risk of warfarin-induced bleeding complications at therapeutic international normalized ratios (INRs). METHODS: Four single nucleotide polymorphisms (SNPs) of AGT, two SNPs of REN, three SNPs of ACE, four SNPs of AGTR1, and one SNP of AGTR2, in addition to VKORC1 and CYP2C9 variants, were investigated. We utilized logistic regression and several machine learning methods for bleeding prediction. RESULTS: The study included 142 patients, among whom 21 experienced bleeding complications. We identified a haplotype, H2 (TCG), carrying three SNPs of ACE (rs1800764, rs4341, and rs4353), which showed a significant relation with bleeding complications. After adjusting covariates, patients with H2/H2 experienced a 0.12-fold (95% CI 0.02-0.99) higher risk of bleeding complications than the others. In addition, G allele carriers of AGT rs5050 and A allele carriers of AGTR1 rs2640543 had 5.0- (95% CI 1.8-14.1) and 3.2-fold (95% CI 1.1-8.9) increased risk of bleeding complications compared with the TT genotype and GG genotype carriers, respectively. The AUROC values (mean, 95% CI) across 10 random iterations using five-fold cross-validated multivariate logistic regression, elastic net, random forest, support vector machine (SVM)-linear kernel, and SVM-radial kernel models were 0.732 (0.694-0.771), 0.741 (0.612-0.870), 0.723 (0.589-0.857), 0.673 (0.517-0.828), and 0.680 (0.528-0.832), respectively. The highest quartile group (≥75th percentile) of weighted risk score had approximately 12.0 times (95% CI 3.1-46.7) increased risk of bleeding, compared to the 25-75th percentile group, respectively. CONCLUSION: This study demonstrated that RAS-related polymorphisms, including the H2 haplotype of the ACE gene, could affect bleeding complications during warfarin treatment for patients with mechanical heart valves. Our results could be used to develop individually tailored intervention strategies to prevent warfarin-induced bleeding.

Risk Scoring System of Mortality and Prediction Model of Hospital Stay for Critically Ill Patients Receiving Parenteral Nutrition.

Predicting the clinical progression of intensive care unit (ICU) patients is crucial for survival and prognosis. Therefore, this retrospective study aimed to develop the risk scoring system of mortality and the prediction model of ICU length of stay (LOS) among patients admitted to the ICU. Data from ICU patients aged at least 18 years who received parenteral nutrition support for ≥50% of the daily calorie requirement from February 2014 to January 2018 were collected. In-hospital mortality and log-transformed LOS were analyzed by logistic regression and linear regression, respectively. For calculating risk scores, each coefficient was obtained based on regression model. Of 445 patients, 97 patients died in the ICU; the observed mortality rate was 21.8%. Using logistic regression analysis, APACHE II score (15-29: 1 point, 30 or higher: 2 points), qSOFA score ≥ 2 (2 points), serum albumin level < 3.4 g/dL (1 point), and infectious or respiratory disease (1 point) were incorporated into risk scoring system for mortality; patients with 0, 1, 2-4, and 5-6 points had approximately 10%, 20%, 40%, and 65% risk of death. For LOS, linear regression analysis showed the following prediction equation: log(LOS) = 0.01 × (APACHE II) + 0.04 × (total bilirubin) - 0.09 × (admission diagnosis of gastrointestinal disease or injury, poisoning, or other external cause) + 0.970. Our study provides the mortality risk score and LOS prediction equation. It could help clinicians to identify those at risk and optimize ICU management.

Association between CYP3A5 Polymorphism and Statin-Induced Adverse Events: A Systemic Review and Meta-Analysis.

Purpose: Cytochrome P450 (CYP) is involved in the metabolism of statins; CYP3A5 is the main enzyme responsible for lipophilic statin metabolism. However, the evidence of the association between CYP3A5*3 polymorphism and the risk of statin-induced adverse events remains unclear. Therefore, this study aimed to perform a systematic review and meta-analysis to investigate the relationship between the CYP3A5*3 polymorphism and the risk of statin-induced adverse events. Methods: The PubMed, Web of Science, and EMBASE databases were searched for qualified studies published until August 2020. Observational studies that included the association between statin-induced adverse events and the CYP3A5*3 polymorphism were reviewed. The odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. The Mantel-Haenszel method was used to provide the pooled ORs. Heterogeneity was estimated with I2 statistics and publication bias was determined by Begg's and Egger's test of the funnel plot. Data analysis was performed using Review Manager (version 5.4) and R Studio (version 3.6). Results: In total, data from 8 studies involving 1614 patients were included in this meta-analysis. The CYP3A5*3 polymorphism was found to be associated with the risk of statin-induced adverse events (*3/*3 vs. *1/*1 + *1/*3: OR = 1.40, 95% CI = 1.08-1.82). For myopathy, the pooled OR was 1.30 (95% CI: 0.96-1.75). The subgroup analysis of statin-induced myopathy revealed a trend, which did not achieve statistical significance. Conclusions: This meta-analysis demonstrated that the CYP3A5*3 polymorphism affected statin-induced adverse event risk. Therefore, CYP3A5 genotyping may be useful to predict statin toxicity.

Influence of CYP2C9 Genetic Polymorphisms on the Pharmacokinetics of Losartan and Its Active Metabolite E-3174: A Systematic Review and Meta-Analysis.

This study aimed to investigate the influence of CYP2C9 genetic polymorphisms on the pharmacokinetics of losartan and its active metabolite, E-3174, through a systematic review and meta-analysis. Eight studies published before March 2021 were included in this study. We used PubMed, the Cochrane Library, EMBASE, and Web of Science, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The data analysis was conducted through Review Manager (RevMan), version 5.3, and R software. We found that healthy volunteers with CYP2C9*2 or *3 carriers had higher area under the curve (AUC0-∞) of losartan (mean difference (MD) 0.17 µg·h/mL; 95% confidence intervals (CI): 0.04, 0.29) and lower AUC0-∞ of E-3174 (MD -0.35 µg·h/mL; 95% CI: -0.62, -0.08) than those with CYP2C9*1/*1. Subjects with CYP2C9*2 or *3 carriers showed lower maximum concentration (Cmax) of E-3174 than those with CYP2C9*1/*1 (MD -0.13 µg/mL; 95% CI: -0.17, -0.09). For half-life, subjects with CYP2C9*2 or *3 carriers had longer half-lives of losartan and E-3174 than those with CYP2C9*1/*1 (MD 0.47 h; 95% CI: 0.32, 0.61 and MD 0.68 h; 95% CI: 0.44, 0.92, respectively). This meta-analysis suggests that the pharmacokinetics of losartan and E-3174 are associated with the CYP2C9 polymorphisms.

Machine Learning Approaches for Predicting Bisphosphonate-Related Osteonecrosis in Women with Osteoporosis Using VEGFA Gene Polymorphisms.

OBJECTIVE: This nested case-control study aimed to investigate the effects of VEGFA polymorphisms on the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in women with osteoporosis. METHODS: Eleven single nucleotide polymorphisms (SNPs) of the VEGFA were assessed in a total of 125 patients. Logistic regression was performed for multivariable analysis. Machine learning algorithms, namely, fivefold cross-validated multivariate logistic regression, elastic net, random forest, and support vector machine, were developed to predict risk factors for BRONJ occurrence. Area under the receiver-operating curve (AUROC) analysis was conducted to assess clinical performance. RESULTS: The VEGFA rs881858 was significantly associated with BRONJ development. The odds of BRONJ development were 6.45 times (95% CI, 1.69-24.65) higher among carriers of the wild-type rs881858 allele compared with variant homozygote carriers after adjusting for covariates. Additionally, variant homozygote (GG) carriers of rs10434 had higher odds than those with wild-type allele (OR, 3.16). Age ≥ 65 years (OR, 16.05) and bisphosphonate exposure ≥ 36 months (OR, 3.67) were also significant risk factors for BRONJ occurrence. AUROC values were higher than 0.78 for all machine learning methods employed in this study. CONCLUSION: Our study showed that the BRONJ occurrence was associated with VEGFA polymorphisms in osteoporotic women.

Machine Learning Approaches to Predict Hepatotoxicity Risk in Patients Receiving Nilotinib.

Background: Although nilotinib hepatotoxicity can cause severe clinical conditions and may alter treatment plans, risk factors affecting nilotinib-induced hepatotoxicity have not been investigated. This study aimed to elucidate the factors affecting nilotinib-induced hepatotoxicity. Methods: This retrospective cohort study was performed on patients using nilotinib from July of 2015 to June of 2020. We estimated the odds ratio and adjusted odds ratio from univariate and multivariate analyses, respectively. Several machine learning models were developed to predict risk factors of hepatotoxicity occurrence. The area under the curve (AUC) was analyzed to assess clinical performance. Results: Among 353 patients, the rate of patients with grade I or higher hepatotoxicity after nilotinib administration was 40.8%. Male patients and patients who received nilotinib at a dose of ≥300 mg had a 2.3-fold and a 3.5-fold increased risk for hepatotoxicity compared to female patients and compared with those who received <300 mg, respectively. H2 blocker use decreased hepatotoxicity by 11.6-fold. The area under the curve (AUC) values of machine learning methods ranged between 0.61-0.65 in this study. Conclusion: This study suggests that the use of H2 blockers was a reduced risk of nilotinib-induced hepatotoxicity, whereas male gender and a high dose were associated with increased hepatotoxicity.

Effect of biocompatible peritoneal dialysis solution on residual renal function: a systematic review of randomized controlled trials.

INTRODUCTION: Residual renal function (RRF) plays an important role in outcome of peritoneal dialysis (PD) including mortality. It is, therefore, important to provide a strategy for the preservation of RRF. The objective of this study was to evaluate relative protective effects of new glucose-based multicompartmental PD solution (PDS), which is well known to be more biocompatible than glucose-based conventional PDS, on RRF compared to conventional PDS by performing a systematic review (SR) of randomized controlled trials. METHODS: We searched studies presented up to January 2014 in MEDLINE, EMBASE, the COCHRANE library, and local databases. Three independent reviewers reviewed and extracted prespecified data from each study. The random effects model, a more conservative analysis model, was used to combine trials and to perform stratified analyses based on the duration of follow-up. Study quality was assessed using the Cochrane Handbook for risk of bias. Eleven articles with 1,034 patients were identified for the SR. RESULTS: The heterogeneity of the studies under 12 months was very high, and the heterogeneity decreased substantially when we stratified studies by the duration of follow-up. The mean difference of the studies after 12 months was 0.46 mL/min/1.73 m(2) (95% confidence interval = 0.25 to + 0.67). CONCLUSION: New PDS showed the effect to preserve and improve RRF for long-term use compared to conventional PDS, even though it did not show a significant difference to preserve RRF for short-term use.

Effects of CYP4F2 gene polymorphisms on warfarin clearance and sensitivity in Korean patients with mechanical cardiac valves.

BACKGROUND: Recently, a single nucleotide polymorphism of CYP4F2 (rs2108622) was reported to have a significant relationship with the stable warfarin dose. However, the underlying mechanism of CYP4F2 effects on the stable warfarin dose has not been studied. This study aimed to examine the effects of cytochrome P450 (CYP) 4F2 gene on warfarin clearance and sensitivity in Korean patients with mechanical heart valves. METHODS: One hundred ninety-one patients with mechanical heart valves who were on anticoagulation therapy with warfarin and maintained international normalized ratio levels of 2-3 for 3 consecutive times were followed up, retrospectively. Warfarin enantiomer concentrations were determined by a validated high-performance liquid chromatography method. Genotypes of vitamin K epoxide reductase complex subunit 1, CYP2C9, CYP2C19, CYP4F2, human microsomal epoxide hydroxylase, calumenin, and γ-glutamyl carboxylase were determined. RESULTS: From multiple linear regression models, vitamin K epoxide reductase complex subunit 1, CYP2C9, CYP4F2, and age were found to have significant effects on warfarin stable dose. The stable warfarin daily doses of patients with the CC, CT, and TT genotypes in the CYP4F2 gene were 5.34 ± 2.04, 5.33 ± 1.64, and 6.55 ± 2.12 mg, respectively. The higher dose requirements in patients with TT alleles in CYP4F2 were attributable to a low warfarin sensitivity (international normalized ratio/warfarin plasma concentration); the warfarin sensitivity in CC, CT, and TT genotypes was 2.1 ± 1.2, 1.0 ± 0.4, and 0.8 ± 0.6, respectively. The similarity between the dose requirements of patients with CT and CC alleles was explained through the combined result of warfarin sensitivity and clearance outcomes. Apparent plasma (S)- and (R)-warfarin clearances were found to be 37.7% and 34.1% lower in CT genotype patients than in CC genotype patients, respectively. CONCLUSIONS: The dose variability in CYP4F2 genotypes was attributable to both warfarin clearance and sensitivity differences.

Effects of amines on percutaneous absorption of alendronate.

OBJECTIVE: The aim of this study was to examine the effects of amines on the permeation of alendronate using solution formulations and pressure-sensitive adhesive (PSA) transdermal delivery systems (TDS). MATERIALS AND METHODS: Monoethanolamine (MEA), diethanolamine (DEA), triethanolamine (TEA), diethylamine (DEYA), and triethylamine (TEYA) at concentrations of 3, 6, and 10% were added to propylene glycol (PG) containing 6% caprylic acid. In vitro and in vivo experiments were conducted using alendronate solution and PSA TDS formulations. RESULTS: When using saturated solution formulations, 3% TEA and 10% DEYA showed high permeation rates of 8.20 ± 0.80 and 7.87 ± 0.18 µg/cm(2)/h, respectively. The maximum permeation flux of 1.79 ± 0.28 µg/cm(2)/h from 1 mg/ml solution was obtained with the addition of 10% DEYA followed by the addition of 10% TEYA (1.72 ± 0.72 µg/cm(2)/h). The highest enhancement factor of 1.86 was obtained with alendronate PSA TDS containing 10% MEA compared with no amine. In the in vivo study, the amount remaining to be excreted (ARE) at time 0 (Ae(∞)) and ARE at time t [Ae(t)] differed between TDS and oral delivery significantly (P < 0.01). The TDS containing 10% MEA showed the highest Ae(∞) (19.5 ± 6.93 µg), which was 2.7- and 2.2-fold, compared with oral and no amine administration, respectively. CONCLUSION: Based on the results, TDS with 10% MEA in PG containing 6% caprylic acid could be a good candidate for the alendronate TDS.