DETERMINATION OF PHARMACOKINETIC PARAMETERS AND FACTORS INFLUENCING THE PHARMACOKINETIC PARAMETERS OF PHENYTOIN IN THAI CHILDREN WITH EPILEPSY

Objective: Phenytoin displays nonlinear pharmacokinetics due to the saturation of its’ metabolizing enzymes, thus making dosing adjustments a challenge in clinical practice. However, data on the pharmacokinetic parameters of phenytoin in pediatric patients with epilepsy in Thailand remain lacking. This study aimed to determine the pharmacokinetic parameters of phenytoin, and the factors influencing them in epileptic Thai children using therapeutic drug monitoring data. Methods: Steady state phenytoin plasma concentrations were collected from 96 Thai children with epilepsy aged ≤ 15 y. For individuals having a single steady-state concentration (Css) on one dosage, the Vmax was determined by fixing Km = 4.5 mg/l. For patients with two values for Css with different dosages, the Ludden method was used to determine Vmax and Km. Influences on Vmax and Km by demographic factors including age, sex, weight, serum albumin, and the use of CYP2C9 inducers (carbamazepine, phenobarbital, folic acid, and vigabatrin) and inhibitors (valproic acid and topiramate) were determined by linear mixed-effects regression. Results: The majority of patients had sub-therapeutic plasma concentrations of phenytoin. The Vmax and Km were estimated to be 9.84 mg/kg/d and 2.32 mg/l, respectively. Age and weight significantly influenced Vmax, whereas Km had no significant influencing factors. Conclusion: The Vmax estimated in this study is different from other populations previously reported. Our results suggest that increased phenytoin dosages may be required to achieve optimal concentrations due to the sub-therapeutic concentrations reported here. The results from this study are beneficial for phenytoin dosage individualization in Thai children

Alternative medicine and herbal remedies in the treatment of erectile dysfunction: A systematic review

Objectives: To systematically review and discuss the current evidence from placebo-controlled clinical trials that investigated the use of alternative medicines and herbal remedies in the management of erectile dysfunction (ED). Methods: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)- based systematic review using specific keyword combinations was conducted on the PubMed and Scopus databases. Randomised controlled trials investigating herbal medicine in at least one group and using the International Index of Erectile Function (IIEF) as an outcome in patients primarily diagnosed with ED were included for review. Results: Following the literature search, screening and eligibility analysis, a total of 42 articles were included. The 42 articles were categorised as single herb extractions (n = 14), combination herbal formula (n = 5), combination of herbal formula and non-herbal nutraceuticals (n = 7), non-herbal nutraceuticals (n = 5), acupuncture and moxibustion (n = 2), diet and nutrition (n = 3), exercise (n = 5), and topical treatments (n = 1). Based on the results, Korean ginseng, Pygnogenol and Prelox, Tribulus terrestris, Lepidium meyenii, L-arginine, acupuncture and lifestyle interventions were the more predominantly investigated treatments interventions for ED. Conclusions: Panax ginseng, Pygnogenol, Prelox and Tribulus terrestris have promising evidence as herbal products, alongside L-arginine as a nutritional supplement, for ED based on IIEF outcomes, and warrant further clinical investigation. The mechanisms of action remain unclear, but each of these appears to in part increase nitric oxide synthesis. Importantly, improved diet and exercise should be considered, particularly in patients with obesity or diabetes mellitus

Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

Contains fulltext : 153170.pdf (publisher's version ) (Open Access)Tenofovir (TFV) is eliminated by renal excretion, which is mediated through multidrug-resistant protein 2 (MRP2) and MRP4, encoded by ABCC2 and ABCC4, respectively. Genetic polymorphisms of these transporters may affect the plasma concentrations of tenofovir. Therefore, the aim of this study was to investigate the influence of genetic and nongenetic factors on tenofovir plasma concentrations. A cross-sectional study was performed in Thai HIV-infected patients aged >/=18 years who had been receiving tenofovir disoproxil fumarate at 300 mg once daily for at least 6 months. A middose tenofovir plasma concentration was obtained. Multivariate analysis was performed to investigate whether there was an association between tenofovir plasma concentrations and demographic data, including age, sex, body weight, estimated glomerular filtration rate (eGFR), hepatitis B virus coinfection, hepatitis C virus coinfection, duration of tenofovir treatment, concomitant use of ritonavir-boosted protease inhibitors, and polymorphisms of ABCC2 and ABCC4. A total of 150 Thai HIV-infected patients were included. The mean age of the patients was 43.9 +/- 7.2 years. The mean tenofovir plasma concentration was 100.3 +/- 52.7 ng/ml. In multivariate analysis, a low body weight, a low eGFR, the concomitant use of ritonavir-boosted protease inhibitors, and the ABCC4 4131T --> G variation (genotype TG or GG) were independently associated with higher tenofovir plasma concentrations. After adjusting for weight, eGFR, and the concomitant use of ritonavir-boosted protease inhibitors, a 30% increase in the mean tenofovir plasma concentration was observed in patients having the ABCC4 4131 TG or GG genotype. Both genetic and nongenetic factors affect tenofovir plasma concentrations. These factors should be considered when adjusting tenofovir dosage regimens to ensure the efficacy and safety of a drug. (This study has been registered at ClinicalTrials.gov under registration no. NCT01138241.)

Therapeutic drug monitoring of antiretroviral drugs in HIV-infected patients

Item does not contain fulltextINTRODUCTION: Therapeutic drug monitoring (TDM) may be beneficial when applied to antiretroviral (ARV). Even though TDM can be a valuable strategy in HIV management, its role remains controversial. Areas covered: This review provides a comprehensive update on important issues relating to TDM of ARV drugs in HIV-infected patients. Articles from PubMed with keywords relevant to each topic section were reviewed. Search strategies limited to articles published in English. Expert commentary: There is evidence supporting the use of TDM in HIV treatment. However, some limitations need to be considered. The evidence supporting the use of routine TDM for all patients is limited, as it is not clear that this strategy offers any advantages over TDM for selected indications. Selected groups of patients including patients with physiological changes, patients with drug-drug interactions or toxicity, and the elderly could potentially benefit from TDM, as optimized dosing is challenging in these populations

Pharmacogenetics-based population pharmacokinetic analysis of tenofovir in Thai HIV-infected patients

AIM: To develop a population pharmacokinetic model and identify sources of variability, genetic and nongenetic factors, of tenofovir. METHODS: The ABCC2 and ABCC4 polymorphisms were genotyped in 342 patients. A nonlinear mixed effects model was used to develop the population pharmacokinetic model and investigate the influence of these polymorphisms and other patient specific covariates on the pharmacokinetics of tenofovir. RESULTS: The estimated glomerular filtration rate calculated by the Cockcroft and Gault equation, concomitant use of lopinavir/ritonavir and ABCC4 3463A>G polymorphism were associated with tenofovir apparent oral clearance (CL/F). The use of lopinavir/ritonavir decreased tenofovir CL/F by 25%. Patients carrying ABCC4 3463 AG or GG had a tenofovir CL/F 11% higher than those with genotype AA. CONCLUSION: Renal function, co-medication and genetic variation impact the pharmacokinetics of tenofovir. These factors should be taken into consideration to guide the individual tenofovir disoproxil fumarate dosage regimen in Thai HIV-infected patients

Le développement de la motivation dans le but d'acquérir les compétences dans le cadre du cours d'éducation physique

Rencontrer la motivation des élèves en EP, grâce à la technique induite, à l'organisation de situations compétitives, ou à la coopération

Factors associated with daily tenofovir exposure in Thai subjects taking combination antiretroviral therapy

Contains fulltext : 155259.pdf (publisher's version ) (Closed access)Tenofovir (TFV) exposure is associated with antiretroviral efficacy and risk of kidney disease. There is evidence of high interindividual variability of the pharmacokinetics of TFV. The effect of several clinical conditions on the pharmacokinetics of TFV has been observed and may partly explain its variability. We assessed factors influencing the pharmacokinetics of TFV in Thai patients. Thirty participants (50% female) taking efavirenz- or ritonavir-boosted protease inhibitor-based regimens were investigated. Intensive pharmacokinetic sampling was performed over 24 h. Multivariate geometric mean regression models adjusted for covariates with p</=0.2 in univariate analysis were developed. The median age was 41 years. Five participants [three taking a protease inhibitor (PI) and two taking efavirenz (EFV)] had mild renal dysfunction [estimated glomerular filtration rate (eGFR) 60-90 ml/min/1.73 m(2); range 72-89]. TFV AUC0-24 was 23% (95% CI 1-49%; p=0.04) higher in those taking PI vs. EFV, 39% (95% CI 5-84%; p=0.02) higher in those with mild renal dysfunction, and reduced by 16% (95% CI 5-26%; p=0.008) with each 10 kg body weight increase, after adjusting for sex and duration of TFV exposure. In PI-treated subjects TFV AUC0-24 increased by 3% (0.3-6%; p=0.03) for each mg.h/liter increase in ritonavir (RTV) AUC0-24 after adjusting for sex, weight, mild renal impairment, and proximal renal tubular dysfunction. Significantly higher TFV exposures were independently associated with PI regimens, mild renal impairment, lower body weight, and increasing RTV AUC0-24. Clinicians should be aware of the effect of these factors on TFV exposure when this drug is prescribed

Short Communication: Aging Not Gender Is Associated with High Atazanavir Plasma Concentrations in Asian HIV-Infected Patients

Item does not contain fulltextAbstract Physiological effects of aging make the older population more susceptible to adverse drug events and drug-drug interactions. We evaluated the impact of aging and gender on the pharmacokinetics (PK) of atazanavir/ritonavir (ATV/r) 300/100 mg once daily (qd) in 22 well-suppressed HIV-infected patients. This was a 24-h intensive PK study. Subjects were HIV-1-infected adults aged >/=18 years with HIV RNA 42 years) group. Gender, weight, duration of ATV/r therapy, and proportion treated with tenofovir disoproxil fumarate (TDF)-containing regimens did not differ between both groups. Patients from the aging group had a reduced creatinine clearance (91 versus 76 ml/min). The older group had a higher atazanavir exposure with median AUC0-24 71.2 vs. 53.1 mg.h/liter, Cmax 8.5 vs. 5.5 mg/liter, and Ctrough 1.17 vs. 0.78 mg/liter, and slower apparent clearance (3.5 vs. 4.8 liter/h). Ten patients (91%) from the older group and 36% from the younger group had ATV Ctrough levels higher than the proposed upper limit for toxicity of 0.85 mg/liter. Females had a lower body weight (BW) (46 versus 63 kg) than the males, but atazanavir concentrations in females were greater. However, in multivariate analysis, older age was the only significant predictor for higher atazanavir concentrations. Parameter estimate for age and atazanavir AUC after adjusting for gender and BW was 2.17 (95% CI 1.01-3.33). That is, for every year increase in age, AUC increases by approximately 2 mg.h/liter. Age seems to be an important factor influencing atazanavir pharmacokinetics. Patients from the aging group appeared to have higher atazanavir exposure compared to the younger group. Further PK explorations of ATV in the extremely aged population are warranted