Primary and secondary prevention of stroke and cardiovascular events using evolocumab and alirocumab: Meta-analysis of randomized controlled trials.

OBJECTIVES: Although the clinical role of protein convertase subtilisin kexin type 9 (PCSK9) inhibitors for cholesterol management is increasing, the post-marketing period of use is short compared to other lipid-lowering drugs, so there is still insufficient evidence for their efficacy and safety. In this meta-analysis, we evaluated preventive effects of stroke and cardiovascular (CV) events using evolocumab and alirocumab. MATERIALS AND METHODS: We assessed the relative risk of stroke and CV events after alirocumab or evolocumab treatment in individuals with or without clinical CV diseases compared with that in controls. In addition, we evaluated the relative risk of hemorrhagic stroke. RESULTS: A total of 25 articles were included (median of study duration = 52 weeks). The risk of stroke was significantly decreased after treatment with alirocumab or evolocumab (primary prevention in patients without CV diseases: RR = 0.733; 95% CI, 0.618 - 0.870; secondary prevention in patients with CV diseases: RR = 0.703; 95% CI, 0.562 - 0.880). The risk of CV events also significantly decreased in patients treated with alirocumab or evolocumab (primary prevention: RR = 0.818; 95% CI, 0.777 - 0.861; secondary prevention: RR = 0.725; 95% CI, 0.578 - 0.910). The relative risk of hemorrhagic stroke was not significantly different between PCSK9 inhibitor-treated patients and controls (RR = 1.041; 95% CI, 0.690 - 1.573). CONCLUSION: Our findings indicate that evolocumab and alirocumab are significantly effective without increasing the risk of hemorrhagic stroke. Based on this, the PCSK9 inhibitors can be highly recommended for cholesterol management.

Drug-Drug interactions of docetaxel in patients with breast cancer based on insurance claims data.

Despite an increase in the use of targeted anticancer drugs and immunotherapy, cytotoxic anticancer drugs such as docetaxel continue to play a clinically important role. The aim of this study was to evaluate drug-drug interactions between docetaxel and coadministered medicines in patients with breast cancer a claims database. The Health Insurance Review and Assessment Service (HIRA) database (2017 to 2019) was used in this study. We evaluated the risk of neutropenia (defined using receipt of granulocyte colony-stimulating factor (G-CSF) prescriptions) under docetaxel administration or the coadministration of docetaxel and an interacting anticancer drug (predefined based on approval information obtained from the Korean Ministry of Food and Drug Safety and the Lexicomp electronic database). The propensity score matching method was applied to balance covariates in the case (patients with G-CSF prescriptions) and control (patients without G-CSF prescriptions) groups. We identified 947 female patients with breast cancer prescribed with docetaxel and excluded 321 patients based on inclusion criteria. Of the remaining 626 patients, 280 were assigned to the case group and 346 to the control group. Predefined drugs were coadministered to 71 (11.3%) patients during the 7-day period before and after the administration of docetaxel. Adjusted odds ratios (ORs) calculated using the logistic regression model applied to the propensity score matching showed no significant difference between the administration of docetaxel alone and docetaxel coadministration (adjusted OR, 2.010; 95% confidence interval, 0.906, 4.459). In conclusion, we suggest that coadministration of docetaxel and a predefined interacting drug are not associated with G-CSF prescription.

An Updated Meta-Analysis for Safety Evaluation of Alirocumab and Evolocumab as PCSK9 Inhibitors.

Background: Alirocumab and evolocumab, as protein convertase subtilisin kexin type 9 (PCSK9) inhibitors, have been reported to reduce cardiovascular risk. This meta-analysis is aimed at updating the safety data of PCSK9 inhibitors. Methods: We assessed the relative risk for all treatment-related adverse events, serious adverse events, diabetes-related adverse events, and neurocognitive and neurologic adverse events with PCSK9 inhibitors compared to controls (placebo or ezetimibe). In addition, we conducted a meta-analysis to quantitatively integrate and estimate the adverse event rates in long-term studies. Results: There were no significant differences between PCSK9 inhibitors and controls in the relative risk analysis. In a subgroup analysis of each PCSK9 inhibitor, alirocumab treatment significantly reduced the risk of serious adverse events compared to control treatment (risk ratio (RR) = 0.937; 95% confidence interval (CI), 0.896-0.980), but no significant difference was observed with evolocumab treatment (RR = 1.003; 95% CI, 0.963-1.054). Moreover, alirocumab treatment afforded a significant reduction in the risk of diabetes-related adverse events compared to control treatment (RR = 0.9137; 95% CI, 0.845-0.987). The overall incidence (event rate) of long-term adverse events was 75.1% (95% CI, 71.2%-78.7%), and the incidence of serious long-term event rate was 16.2% (95% CI, 11.6%-22.3%). Conclusions: We suggest that alirocumab and evolocumab are generally safe and well tolerated and that their addition to background lipid-lowering therapy is not associated with an increased risk of adverse events or toxicity.

Comparative safety and efficacy of low- or moderate-intensity statin plus ezetimibe combination therapy and high-intensity statin monotherapy: A meta-analysis of randomized controlled studies.

Statin is highly recommended for dyslipidemia to prevent atherosclerosis-related cardiovascular diseases and death. The aim of this study was to compare the efficacies and safeties of low/moderate-intensity statin plus ezetimibe combination therapy vs. high-intensity statin monotherapy. Meta-analysis was conducted on data included in published studies performed to compare the effects of the two treatments on lipid parameters and hs-CRP. Safety-related parameters were also evaluated. Eighteen articles were included in the meta-analysis. In terms of efficacy, low/moderate-intensity statin plus ezetimibe reduced LDL-C (SE = 0.307; 95% CI 0.153-0.463), TC (SE = 0.217; 95% CI 0.098-0.337), triglyceride (SE = 0.307; 95% CI 0.153-0.463), and hs-CRP (SE = 0.190; 95% CI 0.018-0.362) significantly more than high-intensity statin therapy. In terms of safety, the two treatments were not significantly different in terms of ALT elevation, but high-intensity statin increased AST and CK significantly more than combination therapy. This analysis indicates that low/moderate-intensity statin plus ezetimibe combined therapy is more effective and safer than high-intensity statin monotherapy, which suggests the addition of ezetimibe to statin should be preferred over increasing statin dose and that high-intensity statin should be used more carefully, especially in patients with related risks.

Comparison of Efficacy and Safety of Statin-Ezetimibe Combination Therapy with Statin Monotherapy in Patients with Diabetes: A Meta-Analysis of Randomized Controlled Studies.

INTRODUCTION: Dyslipidemia in diabetes mellitus is characterized by hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and elevated low-density lipoprotein cholesterol (LDL-C). Additionally, the potentially increased risk of morbidity and mortality following atherosclerotic cardiovascular diseases should be considered in the treatment of dyslipidemia in patients with diabetes. METHODS: We performed a meta-analysis of the published data to compare the effects of HMG-CoA reductase inhibitor (statin)-ezetimibe combination therapy and statin monotherapy on lipid and glucose parameters in patients with diabetes. We also compared safety based on the adverse events reported for the two groups. RESULTS: In total, 17 articles were included in this meta-analysis. In the efficacy assessment, the combination treatment afforded a significantly greater reduction in LDL-C than did statin monotherapy (standard difference in means 0.691; 95% confidence interval 0.534-0.847). A significantly greater improvement effect was observed in the levels of HDL-C, total cholesterol, triglyceride, and apolipoprotein B, but not apolipoprotein A1, with combination therapy than with statin monotherapy. Additionally, combination therapy reduced fasting blood glucose levels more significantly than did statin monotherapy. In terms of safety, there were no significant differences in treatment-related adverse events between the two treatments. CONCLUSIONS: Statin-ezetimibe combination therapy enhances levels of LDL-C and other lipids without increasing the risk of adverse events compared with statin monotherapy. The present meta-analysis presents valid evidence for appropriate drug regimens to treat dyslipidemia in patients with diabetes. REGISTRATION: PROSPERO Identifier Number CRD42021244578.

Interrupted Time Series Analysis of Changes in Zolpidem Use Due to Media Broadcasts.

Media has become a major source of information on health and plays a role in the decision-making process on health topics. We aimed to evaluate the association between zolpidem use and media broadcasts that reported the suicide risk. We obtained the data of adult outpatients who have been prescribed zolpidem or other hypnotics from the National Patient Sample database (2015-2017). We evaluated the change in zolpidem or other hypnotic prescription trends based on the prescription rate and average daily prescribed dose before and after July 2016, using interrupted time series analysis. A total of 129,787 adult patients had at least one zolpidem prescription in 3 years. The prescription rate of zolpidem after the broadcast decreased significantly by 0.178% (95% confidence interval (CI): -0.214, -0.142), whereas that of other hypnotic users did not differ from that before the broadcast (-0.020%, 95% CI: -0.088, 0.047). However, the trends in the prescription rate before and after the broadcast did not differ for zolpidem and other hypnotics. Broadcasting medication safety through major public media could have an effect on medication use. After broadcasting about the suicide risk of zolpidem, its overall prescription rate decreased immediately, but the trend was not changed.

Eye, hepatobiliary, and renal disorders of erlotinib in patients with non-small-cell lung cancer: A meta-analysis.

BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors used to treat EGFR mutation positive non-small-cell lung cancer (NSCLC). Skin rash and diarrhea are well-known and common adverse events in patients receiving erlotinib, whereas other adverse events, including eye, liver, or renal disorders have not been evaluated adequately. This meta-analysis aimed to evaluate the ocular, hepatobiliary, and renal toxicities of erlotinib in patients with NSCLC cancers. METHODS: In total, sixty studies were assessed, and the results of the included studies were quantitatively integrated using meta-analysis. The incidence of ocular, hepatobiliary (alanine aminotransferase [ALT] and bilirubin elevations; other hepatic adverse events), and renal adverse events were estimated. Additionally, the erlotinib-treated groups and the control groups (placebo or other treatment) were compared with respect to ocular disorders and ALT elevation. The study protocol has been registered in the International Prospective Register for Systematic Reviews (PROSPERO) CRD42018093758. RESULTS: The overall incidence of ocular disorders was 3.30% (95% confidence interval [CI] 2.20%-5.00%). The incidence of ALT elevation, bilirubin elevation, and other hepatobiliary disorders was 6.40% (95% CI 3.90%-10.4%), 3.80% (95% CI 2.30%-6.10%), and 1.00% (95% 0.60%-1.80%), respectively. The incidence of renal disorder was 3.10% (95% CI 1.90%-5.00%). The risk of ocular toxicity in the erlotinib treatment group was significantly increased (risk ratio = 2.91; 95% CI 1.70-4.98) compared to that in the control group. ALT elevation was not significantly different between the two groups. CONCLUSION: Based on the results, careful monitoring of ocular toxicity in patients receiving erlotinib should be recommended and closer monitoring of hepatic toxicity should be also recommended in patients with liver-related risk factors.

Diet and lipid-lowering drug use among people with dyslipidemia in Korea.

BACKGROUND AND OBJECTIVES: Obesity and diet contribute to the development of hypercholesterolemia; therefore, controlling blood lipid concentration through diet is essential. To understand the role of diet in controlling blood lipid concentration, we evaluated the food and nutrient intakes, anthropometry, and blood lipid concentrations of adults with dyslipidemia with or without lipid-lowering drug use. METHODS AND STUDY DESIGN: For this crosssectional study, three-year data were obtained from the 6th-7th Korean National Health and Nutrition Examination Survey (2015-2017). Patients with dyslipidemia were categorized as users (1,734) or nonusers (856) of lipidlowering drugs. RESULTS: Age, education level, marital status, self-reported health status, hypertension, diabetes, and alcohol intake were significantly different between users and nonusers (p<0.05). Multiple logistic regression analysis revealed a significant association between hypertension and diabetes and blood cholesterol status among users. Total cholesterol, triglycerides, and low-density lipoprotein cholesterol were significantly lower in users than in nonusers. During the study period, intake of saturated fatty acids increased significantly among users and nonusers, and intakes of vitamins A and C decreased significantly with potential detrimental health effects. However, intakes of n-3 fatty acids and dietary fiber significantly increased in users and nonusers with potential health benefits. Intakes of vegetables and fish significantly increased in users. No associations were observed between intakes of nuts, fruits, or vegetables and blood cholesterol status. CONCLUSIONS: Changes in personal behaviors of dyslipidemic patients need reinforcement for effective blood lipid management, particularly for optimal food intake patterns, whether lipid-lowering drug users or nonusers.

Comparison of efficacy and safety of combination therapy with statins and omega-3 fatty acids versus statin monotherapy in patients with dyslipidemia: A systematic review and meta-analysis.

OBJECTIVE: Dyslipidemia is a major risk factor for the development of cardiovascular disease. Both statins and omega-3 fatty acids demonstrate beneficial effects on lipid concentrations. The goal was to evaluate the safety and efficacy of combination therapy with statins and omega-3 fatty acids. METHODS: We performed a systematic review and meta-analysis of published data to compare the safety and efficacy of combination therapy with statins and omega-3 fatty acids versus statin monotherapy in patients with dyslipidemia. Six articles were assessed in the present meta-analysis (quantitative assessment) and qualitative assessment. RESULTS: In terms of efficacy, the combination treatment afforded a significantly greater reduction in total cholesterol/high-density lipoprotein cholesterol than statin alone did [standard difference in means = -0.215; 95% confidence interval (CI) -0.359--0.071]. However, there was no significant difference in low-density lipoprotein (LDL) cholesterol between the 2 groups. Qualitative assessment of other lipid parameters was performed. Combination therapy with statins and omega-3 fatty acids was generally more effective on lipid concentration than statin monotherapy. In terms of safety, there were no significant differences in total adverse events between the 2 groups. Gastrointestinal adverse events were found to be significantly increased in patients receiving combination therapy using the fixed-effects model (relative risk = 0.547; 95% CI 0.368-0.812). CONCLUSIONS: We suggest that combination therapy with statins and omega-3 fatty acids enhances lipid profile, except LDL cholesterol, compared with statin monotherapy. Nevertheless, statin and omega-3 fatty acid combination should be cautiously recommended, taking into account the clinical importance of LDL cholesterol and safety issues associated with their concomitant use.

Meta-analysis update of association between dopamine transporter SLC6A3 gene polymorphism and smoking cessation.

The SLC6A3 gene is involved in the dopamine pathway, which influences smoking behavior. This study was conducted to present updated results of a meta-analysis to evaluate the association between SLC6A3 polymorphism and smoking cessation. In total, eight studies were assessed, and 9-repeat alleles and no 9-repeat alleles were compared by smoking cessation outcomes. No significant association between SLC6A3 genotype and smoking cessation was observed for the main analysis (odds ratio = 1.128; 95% confidence interval = 0.981-1.298). In conclusion, the genetic variations in SLC6A3 are not associated with smoking cessation, which is not consistent with the results of the previous meta-analysis.

Cardiac toxicities of lapatinib in patients with breast cancer and other HER2-positive cancers: a meta-analysis.

PURPOSE: Lapatinib is a tyrosine kinase inhibitor that targets the human epidermal growth factor receptor 2 (HER2) and the epidermal growth factor receptor (EGFR/HER1), and there are concerns about its cardiac toxicity. Recent studies of lapatinib have reported cardiac adverse events; however, the results have been inconsistent among the studies. The aim of our study was to estimate the cardiac toxicity of lapatinib in patients with breast cancer and other HER2-positive cancers. METHODS: To evaluate the cardiotoxicity of lapatinib, the results of previous studies were quantitatively integrated using meta-analysis. Forty-five articles regarding cardiac adverse events, including left ventricular dysfunction, left ventricular ejection fraction (LVEF) decrease, arrhythmia, and other cardiac adverse events, were assessed. As a subgroup analysis in patients with breast cancer, 26 studies of lapatinib-induced cardiac adverse events were assessed. RESULTS: The overall incidence of cardiac adverse events was 2.70% (95% confidence interval [CI] 1.60-4.50%). The incidences of left ventricular dysfunction and LVEF decrease were 1.60% (95% CI 1.30-2.00%) and 2.20% (95% CI 1.30-3.60%), respectively. The overall incidence of cardiac adverse events was 3.00% (95% CI 1.50-6.10%) in patients with breast cancer, which was marginally higher than the rate in patients with all type of cancers. CONCLUSION: The overall incidence of lapatinib-induced cardiac toxicity was relatively low based on an indirect comparison with trastuzumab. However, careful monitoring of cardiac toxicity is still needed when patients are treated with lapatinib because the related risk factors have not been clearly identified.

Association between catechol-O-methyltransferase (COMT) Val/Met genotype and smoking cessation treatment with nicotine: a meta-analysis.

AIM: Catechol-O-methyltransferase (COMT) is one of the major degradative pathways of dopamine and COMT Val/Met polymorphisms are associated with the enzyme activity, which is related to dopamine involvement in the nicotine addiction process. However, the reported results of several genetic studies are not consistent. MATERIALS & METHODS: We reviewed the smoking cessation outcomes among previously reported studies by comparing COMT polymorphism. A total of five studies were assessed in the present meta-analysis and the Met/Met, Val/Met or Val/Val genotype were compared with respect to smoking cessation outcomes. RESULTS: As the results, any significant association between COMT polymorphism and smoking cessation were not observed. In the subgroup analysis for evaluating the association between COMT polymorphism and smoking cessation therapy, three studies were assessed by comparing two groups (Met/Met vs Val/Met plus Val/Val). A significant association between COMT polymorphism and smoking cessation was observed (odds ratio: 1.871 and 95% CI: 1.382-2.534). CONCLUSION: The COMT polymorphisms are associated with the outcomes following smoking cessation treatment with nicotine.

Lack of association between DRD2 Taq1A gene polymorphism and smoking cessation therapy: a meta-analysis.

Recent studies have reported that genetic factors are significantly associated with smoking behavior, but the influence of the smoking behavior-related genes on smoking cessation treatment is still not clear. We analyzed the smoking cessation outcomes among previously reported studies involving participants who underwent smoking cessation therapy by comparing the following DRD2 Taq1A gene polymorphism using meta-analysis. In total, nine studies including 2,851 participants were assessed and the A1 allele carriers and A2 homozygotes were compared with respect to smoking cessation outcomes by meta-analysis. No significant association was observed for the main analysis (OR = 0.900; 95% CI, 0.751 - 1.078). In subgroup analysis, three studies were assessed by comparing participants with the A1/A1, A1/A2, and A2/A2 genotypes. A significant association between the DRD2 Taq1A polymorphism and< smoking cessation therapy was observed between the A1/A1 and A1/A2 genotypes (OR = 2.967; 95% CI 1.737 - 5.068) and between the A1/A2 and A2/A2 genotypes (OR = 0.547; 95% CI 0.392 - 0.762), but not between the A1/A1 and A2/A2 genotypes (OR = 1.269; 95% CI 0.746 - 2.157). This study is the first meta-analysis to evaluate and quantitatively integrate the association between the DRD2 Taq1A polymorphism and smoking cessation therapy. A significant relationship between DRD2 Taq1A polymorphism and smoking cessation therapy was not observed.

Safety and efficacy of fibrate-statin combination therapy compared to fibrate monotherapy in patients with dyslipidemia: a meta-analysis.

BACKGROUND: Dyslipidemia is a major risk factor for the development of cardiovascular disease. Treatment with fibrate, statins, or other lipid-lowering drugs prevents primary or recurrent cardiovascular events. However, all lipid-lowering drugs have side effects, which may become more severe if combination therapy is prescribed. METHODS: We performed a meta-analysis of published data to compare the safety and efficacy of fibrates alone, compared to fibrate-statin combinations, in patients with dyslipidemia. Six articles were assessed in terms of the efficacy of therapy and nine from the viewpoint of therapeutic safety. RESULTS: In terms of efficacy, fibrate-statin combinations afforded significantly greater reductions in the levels of total cholesterol (SE=-2.248; 95% CI 1.986-2.510), LDL cholesterol (SE=-2.274; 95% CI 2.015-2.533), and triglycerides (SE=-0.465; 95% CI 0.272-0.658) compared to fibrate alone. In terms of safety, treatment with fibrate alone was associated with a significant decrease in the number of kidney-related adverse events (RR=-0.547; 95% CI 0.368-0.812), compared to treatment with fibrate-statin combinations. CONCLUSION: We suggest that treatment with a fibrate-statin combination affords clinical benefits that are superior to treatment with fibrate alone, but increases the risk of side effects (particularly renal). Therapy should thus be carefully monitored.

Effects of type 2 diabetes mellitus on the population pharmacokinetics of rifampin in tuberculosis patients.

Diabetes mellitus (DM) is a well-known risk factor to develop tuberculosis (TB). Some reports indicate the serum concentrations of anti-TB drugs are lower in patients with TB and DM than those with TB only. Therefore, we developed a nonlinear mixed-effects model (NONMEM) to determine the population PK parameters of rifampin and assessed the effects of DM status in patients with TB. One-compartment linear modeling with first-order absorption was evaluated using the 206 plasma samples of rifampin from 54 patients with DM. Based on the final model, DM affected the absorption rate constant (ka) and the volume of distribution (Vd) of rifampin. The body mass index (BMI) of the patients affected rifampin clearance (CL). The ka of rifampin in patients with TB and DM was greater than that in patients with TB only. Further, the predicted Vd in patients with DM was greater than that in patients without DM. As Vd is inversely correlated with plasma concentrations, the rifampin concentrations were predicted to be lower in the patients with DM. The authors recommend administering the greater doses of rifampin for the treatment of TB in patients with DM compared with the doses for the patients without DM to prevent treatment failure.

Pharmacokinetics of tolbutamide and its metabolite 4-hydroxy tolbutamide in poloxamer 407-induced hyperlipidemic rats.

Under hyperlipidemic conditions, there are likely to be alterations in the pharmacokinetics of CYP2C11 substrates following decreased expression of CYP2C11, which is homologous to human CYP2C9. The pharmacokinetics of tolbutamide (TB) and its metabolite 4-hydroxy tolbutamide (4-OHTB) were evaluated as a CYP2C11 probe after intravenous and oral administration of 10 mg/kg tolbutamide to poloxamer 407-induced hyperlipidemic rats (HL rats). Changes in the expression and metabolic activity of hepatic CYP2C11 and the plasma protein binding of tolbutamide in HL rats were also evaluated. The total area under the plasma concentration-time curve (AUC) of tolbutamide in HL rats after intravenous administration was comparable to that in controls due to their comparable non-renal clearance (CLNR ). The free fractions of tolbutamide in plasma were comparable between the control and HL rats. The 4-hydroxylated metabolite formation ratio (AUC4-OHTB /AUCTB ) in HL rats was significantly smaller than that in the control rats as a result of the reduced expression of hepatic CYP2C11 (by 15.0%) and decreased hepatic CLint (by 28.8%) for metabolism of tolbutamide to 4-OHTB via CYP2C11. Similar pharmacokinetic changes were observed in HL rats after oral administration of tolbutamide. These findings have potential therapeutic implications, assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Since other sulfonylureas in clinical use are substrates of CYP2C9, their hepatic CLint changes have the potential to cause clinically relevant pharmacokinetic changes in a hyperlipidemic state.

Safety and efficacy of statin treatment alone and in combination with fibrates in patients with dyslipidemia: a meta-analysis.

BACKGROUND: Dyslipidemia is a major risk factor for cardiovascular disease and is treated with many effective lipid-lowering agents. Statins are often used alone or in combination with fibrates. Combination therapy is more effective due to their comparative actions, but the increased incidence of side effects should be considered carefully. RESEARCH DESIGN AND METHODS: A meta-analysis of published data was conducted to compare the safety and efficacy of statins alone versus statins plus fibrates in patients with dyslipidemia. In total, nine articles were assessed for efficacy analysis and ten articles were assessed for safety analysis. RESULTS: In the efficacy analysis, a combination of statins and fibrates provided significantly greater reductions in total cholesterol (SE = 0.430; 95% CI 0.315-0.545), LDL cholesterol (SE = 0.438; 95% CI 0.321-0.555) and triglycerides (SE = 0.747; 95% CI 0.618-0.876), and a significantly greater increase in HDL cholesterol (SE = 0.594; 95% CI 0.473-0.715) than treatment with statins alone. In the safety analysis, treatment with statins alone was associated with a significant reduction in the numbers of total adverse events (RR = 0.665; 95% CI 0.539-0.819), liver-related adverse events (RR = 0.396; 95% CI 0.206-0.760) and kidney-related adverse events (RR = 0.146; 95% CI 0.075-0.285). CONCLUSION: We suggest that treatment with statins plus fibrates provides clinical benefits over treatment with statins alone but increased risks, especially of hepatic or renal side effects, should be monitored carefully.

Application of a drug-interaction detection method to the Korean National Health Insurance claims database.

Drug interactions (DIs) constitute a serious problem and are considered to contribute to 6-30% of all adverse events (AEs). The use of existing data, including claims data, is expected to be helpful in detecting unknown DIs by complementing conventional spontaneous reporting systems. In the present study, an 'Ω shrinkage measure' was applied to the Korean National Health claims database to test the potential of the claims database as a DI surveillance resource. A well-known DI between non-steroidal anti-inflammatory drugs (NSAIDs) and diuretics was analyzed using the model. International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes related to DIs were assigned to the AEs of the DIs: I50, I50.0, I50.1, I50.9, R60, R60.1, R60.9, and J81. An elevated occurrence of AEs versus the expected level was observed using a two-sided 95% lower credibility interval limit above zero, Ω025=0.245, which was the screening limit. The result was consistent with the actual DI between the two drugs. The finding indicates that the claims data have the potential to be used as a DI surveillance resource and that the Ω shrinkage measure may be a promising tool for detecting DIs in claims data.

Effects of ACE and ADD1 gene polymorphisms on blood pressure response to hydrochlorothiazide: a meta-analysis.

Hydrochlorothiazide (HCTZ) is used to treat uncomplicated hypertension. However, many studies have reported the variance of inter-individual response to HCTZ. A meta-analysis of published data was conducted to evaluate the pharmacogenetic associations of ACE I/D and ADD1 Gly460Trp polymorphisms with blood pressure changes during HCTZ therapy. To analyze the influence of ACE I/D polymorphism, 4 studies including 1,439 patients were assessed and the 3 genotypes were compared (II vs. ID, II vs. DD, and ID vs. DD) with respect to blood pressure changes. A significant association between ACE and blood pressure change was observed for the comparison of the II and DD (standard differences in means = 0.256; 95% CI, 0.109 - 0.403). For ADD1 Gly460Trp polymorphism, 4 studies including 1,001 patients were assessed, and GlyGly vs. GlyTrp, GlyGly vs. TrpTrp and GlyTrp vs. TrpTrp genotype comparisons were analyzed. A significant association between ADD1 and blood pressure change was observed for the comparisons of GlyGly vs. GlyTrp (standard differences in means= 2.78; 95% CI, 0.563 - 4.99) and GlyGly vs. TrpTrp (standard differences in means = 1.80; 95% CI, 1.38 - 2.22). This study is the first meta-analysis to evaluate the influences of ACE and ADD1 polymorphisms on blood pressure responses to HCTZ to combine the inconsistent results of previous studies.

Inhibitory effects of astaxanthin, ß-cryptoxanthin, canthaxanthin, lutein, and zeaxanthin on cytochrome P450 enzyme activities.

Astaxanthin, ß-cryptoxanthin, canthaxanthin, lutein and zeaxanthin, the major xanthophylls, are widely used in food, medicine, and health care products. To date, no studies regarding the inhibitory effects of these xanthophylls on the nine CYPs isozymes have been reported. This study investigated the reversible and time-dependent inhibitory potentials of five xanthophylls on CYPs activities in vitro. The reversible inhibition results showed that the five compounds had only a weak inhibitory effect on the nine CYPs. Lutein did not inhibit the nine CYPs activities. Astaxanthin weakly inhibited CYP2C19, with an IC50 of 16.2 µM; and ß-cryptoxanthin weakly inhibited CYP2C8, with an IC50 of 13.8 µM. In addition, canthaxanthin weakly inhibited CYP2C19 and CYP3A4/5, with IC50 values of 10.9 and 13.9 µM, respectively. Zeaxanthin weakly inhibited CYP3A4/5, with an IC50 of 15.5 µM. However, these IC50 values were markedly greater than the Cmax values reported in humans. No significant IC50 shift was observed in the time-dependent inhibition screening. Based on these observations, it is unlikely that these five xanthophylls from the diet or nutritional supplements alter the pharmacokinetics of drugs metabolized by CYPs. These findings provide some useful information for the safe use of these five xanthophylls in clinical practice.