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.

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.

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.

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.

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.

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.

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.

Protective effects of Haematococcus astaxanthin on oxidative stress in healthy smokers.

Free radicals induced by cigarette smoking have been strongly linked to increased oxidative stress in vivo, contributing to the pathobiology of various diseases. This study was performed to investigate the effects of Haematococcus astaxanthin (ASX), which has been known to be a potent antioxidant, on oxidative stress in smokers. Thirty-nine heavy smokers (≥20 cigarettes/day) and 39 non-smokers were enrolled in this study. Smokers were randomly divided into three dosage groups to receive ASX at doses of 5, 20, or 40 mg (n=13, each) once daily for 3 weeks. Oxidative stress biomarkers such as malondialdehyde, isoprostane, superoxide dismutase, and total antioxidant capacity, and ASX levels in plasma were measured at baseline and after 1, 2, and 3 weeks of treatment. Compared with baseline, the plasma malondialdehyde and isoprostane levels decreased, whereas superoxide dismutase level and total antioxidant capacity increased in all ASX intervention groups over the 3-week period. In particular, isoprostane levels showed a significant dose-dependent decrease after ASX intake. The results suggest that ASX supplementation might prevent oxidative damage in smokers by suppressing lipid peroxidation and stimulating the activity of the antioxidant system in smokers.

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.