Min Jung Chang

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.

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.

Cardiovascular Effect of Incretin-Based Therapy in Patients with Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis.

Background To assess the cardiovascular (CV) risk associated with the use of incretin-based therapy in adult patients with type 2 diabetes mellitus (T2DM) primary prevention group with low CV risks. Methods The clinical studies on incretin-based therapy published in medical journals until August 2014 were comprehensively searched using MEDLINE, EMBASE and CENTRAL with no language restriction. The studies were systemically reviewed and evaluated for CV risks using a meta-analysis approach and where they meet the following criteria: clinical trial, incidence of predefined CV disease, T2DM with no comorbidities, age > 18 years old, duration of at least 12 weeks, incretin-based therapy compared with other antihyperglycaemic agents or placebo. Statistical analyses were performed using a Mantel-Haenszel (M-H) test. The odds ratios (OR) and their 95% confidence interval (CI) were estimated and displayed for comparison. Results A total of 75 studies comprising 45,648 patients with T2DM were selected. The pooled estimate demonstrated no significance in decreased CV risk with incretin-based therapy versus control (M-H OR, 0.90; 95% CI, 0.81–1.00). Conclusions This meta-analysis suggests that incretin-based therapy show no significant protective effect on CV events in T2DM primary prevention group with low CV risks. Prospective randomized controlled trials are required to confirm the results of this analysis.

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

PurposeLapatinib 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.MethodsTo 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.ResultsThe 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.ConclusionThe 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.

Population pharmacokinetics of remifentanil in critically ill patients receiving extracorporeal membrane oxygenation

Extracorporeal membrane oxygenation (ECMO) is associated with pharmacokinetic (PK) changes of drugs. It presents considerable challenges to providing optimal dosing regimens for patients receiving ECMO. We aimed to describe the population PK of remifentanil in critically ill adult patients receiving venoartrial extracorporeal membrane oxygenation (VA-ECMO) and to identify determinants associated with altered remifentanil concentrations. The population PK model of remifentanil was developed using nonlinear mixed effects modelling (NONMEM). Fifteen adult patients who received a continuous infusion of remifentanil during VA-ECMO participated in the study. The PK of remifentanil was best described by a one-compartment model with additive and proportional residual errors. Remifentanil concentrations were affected by sex and ECMO pump speed. The final PK model included the effect of sex and ECMO pump speed on clearance is developed as followed: clearance (L/h) = 366 × 0.502sex × (ECMO pump speed/2350)2.04 and volume (L) = 41. Remifentanil volume and clearance were increased in adult patients on VA-ECMO compared with previously reported patients not on ECMO. We suggest that clinicians should consider an increased remifentanil dosing to achieve the desired level of sedation and provide a dosing regimen according to sex and ECMO pump speed.

Population pharmacokinetics of moxifloxacin, cycloserine, p-aminosalicylic acid and kanamycin for the treatment of multi-drug-resistant tuberculosis

Control of multi-drug-resistant tuberculosis (MDR-TB) requires extensive, supervised chemotherapy because second-line anti-TB drugs have a narrower therapeutic range than first-line drugs. This study aimed to develop population pharmacokinetic (PK) models for second-line drugs in patients with MDR-TB, evaluate the recommended dosage regimens and, if necessary, suggest new dosage regimens. A prospective, single-centre PK study was performed on second-line anti-TB drugs in patients with MDR-TB. Moxifloxacin, cycloserine, p-aminosalicylic acid (PAS), kanamycin and other second-line drugs were administered to the patients. Plasma concentrations were analysed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Population PK models were developed using non-linear mixed effect modelling (NONMEM, Version 7.30; ICON Development Solutions, Ellicott City, MD, USA). Simulations were performed using the calculated PK parameters. The respective absorption rate constant, apparent clearance and apparent volume of distribution values were as follows: 0.305/h, 9.37 L/h and 56.7 L for moxifloxacin; 0.135/h, 1.38 L/h and 10.5 L for cycloserine; 0.510/h, 30.8 L/h and 79.4 L for PAS; and 1.67/h, 3.75 L/h and 15.2 L for kanamycin. The simulations showed that the following dosage regimens were more likely to be within the recommended concentration ranges than the raw data in this study: 200 mg of moxifloxacin once daily (QD) (patient weight <50 kg) and 400 mg of moxifloxacin QD (patient weight ≥50 kg), 500-750 mg of cycloserine QD, 4.95-6.6 g of PAS twice daily and 750-1000 mg of intramuscular kanamycin QD. These findings indicate that the recommended doses should be revised to improve the clinical outcomes of MDR-TB treatment.

Population Pharmacokinetics and Dose Optimization of Teicoplanin during Venoarterial Extracorporeal Membrane Oxygenation

ABSTRACT The pharmacokinetics (PK) of drugs are known to be significantly altered in patients receiving extracorporeal membrane oxygenation (ECMO). However, clinical studies of the PK of drugs administered during ECMO are scarce, and the proper dosing adjustment has yet to be established. We developed a population PK model for teicoplanin, investigated covariates influencing teicoplanin exposure, and suggested an optimal dosing regimen for ECMO patients. Samples for PK analysis were collected from 10 adult patients, and a population PK analysis and simulations were performed to identify an optimal teicoplanin dose needed to provide a >50% probability of target attainment at 72 h using a trough concentration target of >10 μg/ml for mild to moderate infections and a trough concentration target of >15 μg/ml for severe infections. Teicoplanin was well described by a two-compartment PK model with first-order elimination. The presence of ECMO was associated with a lower central volume of distribution, and continuous renal replacement therapy (CRRT) was associated with a higher peripheral volume of distribution. For mild to moderate infections, an optimal dose was a loading dose (LD) of 600 mg and a maintenance dose (MD) of 400 mg for ECMO patients not receiving CRRT and an LD of 800 mg and an MD of 600 mg for those receiving CRRT. For severe infections, an optimal dose was an LD of 1,000 mg and an MD of 800 mg for ECMO patients not receiving CRRT and an LD of 1,200 mg and an MD of 1,000 mg for those receiving CRRT. In conclusion, doses higher than the standard doses are needed to achieve fast and appropriate teicoplanin exposure during ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.)

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.

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.