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.

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.

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.

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.

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.

Pharmacokinetics of hederacoside C, an active ingredient in AG NPP709, in rats.

1. Hederacoside C (HDC) is one of the active ingredients in Hedera helix leaf extract (Ivy Ex.) and AG NPP709, a new botanical drug to treat acute respiratory infection and chronic inflammatory bronchitis. However, information regarding its pharmacokinetic properties remains limited. 2. Here, we report the pharmacokinetics of HDC in rats after intravenous administration of HDC (3, 12.5, and 25 mg/kg) and after oral administration of HDC, Ivy Ex., and AG NPP709 (equivalent to 12.5, 25, and 50 mg/kg HDC). 3. Linear pharmacokinetics of HDC were identified upon its intravenous administration at doses of 3-25 mg/kg. Intravenous administration of HDC results in relatively slow clearance (1.46-2.08 mL/min/kg) and a small volume of distribution at steady state (138-222 mL/kg), while oral administration results in a low absolute oral bioavailability (F) of 0.118-0.250%. The extremely low F of HDC may be due to poor absorption of HDC from the gastrointestinal (GI) tract and/or its decomposition therein. 4. The oral pharmacokinetics of HDC did not differ significantly among pure HDC, Ivy Ex., and AG NPP709.

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.

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.

Protective effects of vitamin E on chemotherapy-induced peripheral neuropathy: a meta-analysis of randomized controlled trials.

PURPOSE: This study aimed to investigate the neuroprotective effects of vitamin E for preventing chemotherapy-induced peripheral neuropathy (CIPN). METHODS: A comprehensive search from 1973 through July 2011 identified randomized controlled trials (RCTs) that reported the preventive effects of vitamin E on CIPN. The relative risk (RR) of CIPN with vitamin E supplementation, compared with placebo, was assessed with the Bayesian random effect model and expressed as RR with a 95 % credible-interval (CrI). Bayesian outcome probabilities were calculated as the probability (P) of RR < 1. RESULTS: Five RCTs, involving 319 patients, were identified. Upon pooling these RCTs, vitamin E supplementation (300 - 600 mg/day) had a significant effect on CIPN prevention (RR 0.43; 95 % CrI 0.10 - 1.00, P = 97.5 %). Subgroup analysis by chemotherapeutic agent type was only available for cisplatin and showed that vitamin E supplementation significantly reduced the incidence of CIPN (RR 0.26; 95 % CrI 0.06 - 0.89, P = 98.1 %). Furthermore, there were no adverse effects caused by vitamin E supplementation in any of the RCTs. CONCLUSION: Available data included in this meta-analysis show that vitamin E supplementation might significantly prevent CIPN. Currently, however, the data are insufficient to confidently conclude the true value. Large-scale, rigorously designed RCTs are needed to confirm the role of vitamin E supplementation in CIPN prevention.

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.

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.

Pharmacokinetics and correlation analysis of cilostazol in healthy Korean subjects.

BACKGROUND: Cilostazol is frequently used to treat and prevent thrombosis in Korean patients. PATIENTS AND METHODS: We performed the pharmacokinetic and correlation analysis of cilostazol in Korean healthy subjects. A total of male 78 volunteers was subjected to three separate bioequivalence studies in which 100 mg of cilostazol was administered. AUC, t(1/2), and C(max) were 12,100 ± 4,880 ng×h/ ml, 11.1 ± 4.4 hours, and 827 ± 361 ng/ml, respectively. RESULTS: ALT was positively correlated with age and C(max) was positively correlated with AUC, but negatively correlated with body weight. CONCLUSION: We suggest that the unique pharmacokinetic parameters and interrelationship can help to understand the pharmacokinetics of cilostazol in Korean subjects.

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.

Pharmacokinetics and first-pass metabolism of astaxanthin in rats.

Astaxanthin is a carotenoid with antioxidant, anti-cancer and anti-inflammatory properties. The pharmacokinetics of astaxanthin after its intravenous (5, 10, and 20 mg/kg) and oral (100 and 200 mg/kg) administration and its first-pass extraction ratios after its intravenous, intraportal or intragastric (20 mg/kg) administration were evaluated in rats. The pharmacokinetic parameters of astaxanthin were dose dependent after its intravenous administration, due to the saturable hepatic metabolism of astaxanthin, but dose independent after oral administration. The gastrointestinal absorption of astaxanthin followed the flip-flop model. The hepatic and gastrointestinal first-pass extraction ratios of astaxanthin were approximately 0·490 and 0·901, respectively. Astaxanthin was metabolised primarily by hepatic cytochrome P-450 1A1/2 in rats. Astaxanthin was unstable up to 4 h incubation in four rat gastric juices and up to 24 h incubation in various buffer solutions having a pH of 1-13. The tissue/plasma ratios of astaxanthin at 8 and 24 h after its oral administration (100 mg/kg) were greater than unity for all tissues studied, except in the heart, at 8 h, indicating that the rat tissues studied had high affinity for astaxanthin.

Effects of astaxanthin on oxidative stress in overweight and obese adults.

Oxidative stress is caused by an imbalance between the antioxidant and the reactive oxygen species, which results in damage to cells or tissues. Recent studies have reported that oxidative stress is involved in obesity, in addition to many other human diseases and aging. A prospective, randomized, double-blind study was performed to investigate the effect of astaxanthin (ASX), which is known to be a potent antioxidant, on oxidative stress in overweight and obese adults in Korea. Twenty-three adults with BMI > 25.0 kg/m(2) enrolled in this study and were randomly assigned to two dose groups: ASX 5 mg and 20 mg once daily for 3 weeks. Malondialdehyde (MDA), isoprostane (ISP), superoxide dismutase (SOD) and total antioxidant capacity (TAC), as oxidative stress biomarkers, were measured at baseline and 1, 2 and 3 weeks after ASX administration. Compared with baseline, the MDA (by 34.6% and 35.2%) and ISP (by 64.9% and 64.7%) levels were significantly lowered, whereas SOD (by 193% and 194%) and TAC (by 121% and 125%) levels were significantly increased in two dose groups after the 3 week intervention. This study revealed that supplemental ASX for 3 weeks improved oxidative stress biomarkers by suppressing lipid peroxidation and stimulating the activity of the antioxidant defense system.

Positive effects of astaxanthin on lipid profiles and oxidative stress in overweight subjects.

Astaxanthin, a carotenoid, has antioxidant activity as well as many positive effects, such as anticancer and anti-inflammatory effects. We performed a randomized, double-blind, placebo-controlled study to investigate the effects of astaxanthin on lipid profiles and oxidative stress in overweight and obese adults in Korea. In total, 27 subjects with body mass index >25.0 kg/m(2) were enrolled and randomly assigned into two groups administered astaxanthin or placebo capsules for 12 weeks. Total cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB) were measured before and after intervention. Malondialdehyde (MDA), isoprostane (ISP), superoxide dismutase (SOD), and total antioxidant capacity (TAC), as oxidative stress biomarkers, were measured at baseline and at 4, 8, and 12 weeks after intervention. LDL cholesterol and ApoB were significantly lower after treatment with astaxanthin, compared with the start of administration, whereas none of the lipid profiles was changed in the placebo group. At the baseline, all four biomarkers were not significantly different between the two groups. Compared with the placebo group, MDA and ISP were significantly lower, but TAC was significantly higher in the astaxanthin group at 12 weeks. These results suggest that supplementary astaxanthin has positive effects by improving the LDL cholesterol, ApoB, and oxidative stress biomarkers.

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.

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.