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CL/F Decreased (f + decreased)
Selected AbstractsPopulation pharmacokinetic analysis of varenicline in adult smokersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2009Patanjali Ravva WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? , Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in young adult and elderly smokers and subjects with impaired renal function. , Varenicline pharmacokinetics is linear over the recommended dose range. , Varenicline total clearance is linearly related to its renal clearance. , Both are progressively reduced as renal function declines, which results in a progressive increase in varenicline systemic exposure and prolonged half-life. WHAT THIS STUDY ADDS? , This work provides an integrated model-based analysis of varenicline pharmacokinetics across multiple studies in the target patient population. , The model describes the impact of patient-specific covariates, such as renal function, and provides a rationale for dose adjustment. , The resulting model also provides a means to predict individual-specific drug exposures to clinical responses in subsequent analyses. AIMS To characterize the population pharmacokinetics of varenicline and identify factors leading to its exposure variability in adult smokers. METHODS Data were pooled from nine clinical studies consisting of 1878 subjects. Models were developed to describe concentration,time profiles across individuals. Covariates were assessed using a full model approach; parameters and bootstrap 95% confidence intervals (CI) were estimated using nonlinear mixed effects modelling. RESULTS A two-compartment model with first-order absorption and elimination best described varenicline pharmacokinetics. The final population parameter estimates (95% CI) were: CL/F, 10.4 l h,1 (10.2, 10.6); V2/F, 337 l (309, 364); V3/F, 78.1 l (61.9, 98.9); Q/F, 2.08 l h,1 (1.39, 3.79); Ka, 1.69 h,1 (1.27, 2.00); and Alag, 0.43 h (0.37, 0.46). Random interindividual variances were estimated for Ka[70% coefficient of variation (CV)], CL/F (25% CV), and V2/F (50% CV) using a block covariance matrix. Fixed effect parameters were precisely estimated [most with % relative standard error < 10 and all with % relative standard error < 25], and a visual predictive check indicated adequate model performance. CL/F decreased from 10.4 l h,1 for a typical subject with normal renal function (CLcr = 100 ml min,1) to 4.4 l h,1 for a typical subject with severe renal impairment (CLcr = 20 ml min,1), which corresponds to a 2.4-fold increase in daily steady-state exposure. Bodyweight was the primary predictor of variability in volume of distribution. After accounting for renal function, there was no apparent effect of age, gender or race on varenicline pharmacokinetics. CONCLUSIONS Renal function is the clinically important factor leading to interindividual variability in varenicline exposure. A dose reduction to 1 mg day,1, which is half the recommended dose, is indicated for subjects with severe renal impairment. [source] Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2009Zheng Jiao WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? , Sirolimus is an immunosuppressive agent used for the prophylaxis of renal allograft rejection. , Several conventional pharmacokinetic and population pharmacokinetic studies have been conducted to assess the pharmacokinetic characteristics of sirolimus in White or African-American recipients. WHAT THIS STUDY ADDS? , The population pharmacokinetics of sirolimus in Chinese adult renal transplant recipients was characterized for the first time. , New drug,drug interactions between herbal medicines and sirolimus were identified as the covariates on sirolimus clearance. AIMS This study was aimed at determining the population pharmacokinetics of sirolimus and identifying factors that explain pharmacokinetic variability in de novo Chinese adult renal transplant patients. METHODS Data were retrospectively extracted from a formal multicentre clinical trial, which was originally designed to evaluate the safety and efficacy of ciclosporin dose reduction and ciclosporin elimination in patients receiving sirolimus. All patients received 12-month treatment, i.e. induction therapy with ciclosporin, sirolimus and corticosteroids during the first 3 months followed by either ciclosporin dose reduction or ciclosporin discontinuation thereafter. Eight-hundred and four sirolimus trough blood concentrations (C0) from 112 patients were used to develop a population pharmacokinetic model using the nonmem program. A one-compartment model with first-order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices, ciclosporin daily dose, ciclosporin C0 as well as other commonly used co-medications were explored. RESULTS The typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 10.1 l h,1 (23.8%) and 3670 l (56.7%), respectively. The residual variability was 29.9%. CL/F decreased significantly with silymarin or glycyrrhizin co-therapy in hepatically impaired patients, and with increasing total cholesterol levels or ciclosporin C0. Moreover, CL/F increased nonlinearly with increasing sirolimus daily dose. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5% of the estimates from nonmem. CONCLUSIONS These results provide important information for clinicians to optimize sirolimus regimens in Chinese renal transplant patients. [source] CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver diseaseHEPATOLOGY, Issue 2 2003Maurice G. Emery Previous studies suggest that hepatic cytochrome P450 2E1 (CYP2E1) activity is increased in individuals with chronic alcoholism, nonalcoholic steatohepatitis (NASH), and morbid obesity, and may contribute to liver disease. We studied 16 morbidly obese subjects with varying degrees of hepatic steatosis and 16 normal-weight controls. Obese subjects were evaluated at baseline, 6 weeks, and 1 year after gastroplasty, a procedure that leads to weight loss. Hepatic CYP2E1 activity was assessed by determination of the clearance of chlorzoxazone (CLZ), an in vivo CYP2E1-selective probe. Liver biopsy tissue was obtained during surgery for histopathology. Both the total and unbound oral CLZ clearance (Clu/F) was elevated approximately threefold in morbidly obese subjects compared with controls (P < .001). The Clu/F was significantly higher among subjects with steatosis involving >50% of hepatocytes, compared with those with steatosis in ,50% of hepatocytes (P = .02). At postoperative week 6 and year 1, the median body mass index (BMI) of subjects who underwent gastroplasty decreased by 11% and 33%, total oral CLZ clearance declined by 16% (P < .01) and 46% (P < .05), and Clu/F decreased by 18% (P < .05) and 35% (P = .16), respectively. Moreover, those subjects with a year 1 BMI <30 kg/m2 exhibited a median Clu/F that was 63% lower (P = .02) than the respective clearance for all other subjects. In conclusion, hepatic CYP2E1 activity is up-regulated in morbidly obese subjects. A positive association between the degree of steatosis and CYP2E1 activity preoperatively and between the extent of obesity and CYP2E1 activity postoperatively, suggests that CYP2E1 induction is related to or caused by hepatic pathology that results from morbid obesity. [source] Photoreflectance studiesof N- and Ga-face AlGaN/GaN heterostructures confininga polarisation induced 2DEGPHYSICA STATUS SOLIDI (B) BASIC SOLID STATE PHYSICS, Issue 2 2003A. T. Winzer Abstract Photoreflectance measurements have been carried out in order to determine the electric field strength F within the topmost layers of Ga-face polarity AlxGa1,xN/GaN and N-face polarity GaN/AlxGa1,xN/GaN heterostructures containing high-mobile polarisation induced 2DEGs. For both types of samples F decreased from 400 kV/cm at room temperature up to 200 kV/cm when cooling down the structure to T = 5 K. Our results strongly emphasise the existence of surface donor and surface acceptor states of the Ga- and N-face samples, respectively. The temperature dependence of F is explained by the change of the piezoelectric and spontaneous polarization. From self-consistent conduction band calculations the bare surface potential was obtained. (© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Functional protease-activated receptors in the dorsal motor nucleus of the vagusNEUROGASTROENTEROLOGY & MOTILITY, Issue 4 2010H. Wang Abstract Background, Protease-activated receptors (PARs), a family member of G-protein coupled receptors, are present and functionally active in a wide variety of cells. The object of this study was to demonstrate the presence and function of PAR-1 and PAR-2 in the dorsal motor nucleus of the vagus (DMV). Methods, DMNV neurons were isolated from neonatal rat brainstems using micro-dissection and enzymatic digestion. Neurons were cultured in Neurobasal medium A containing 2% B27 supplement. Intracellular calcium concentration ([Ca2 + ]i) was measured using fura-2 based microspectrometry. Expression of PARs was detected by RT-PCR and immunofluorescent staining. Key Result, Thrombin and PAR-1 agonist peptide activate PAR-1 with a maximum change in [Ca2 + ]i expressed as ,F/F0 of 229 ± 14% and 137 ± 7%, respectively. Trypsin and PAR-2 agonist peptide activate PAR-2 with a maximum ,F/F0 change of 258 ± 12% and 242 ± 10%, respectively. Inhibition of phospholipase C (PLC) by U73312 (1 ,m) decreased the maximal change in ,F/F0 induced by PAR-1 activation from 140 ± 17% to 21 ± 3%, while the PAR-2-mediated maximal change in ,F/F0 decreased from 185 ± 21% to 19 ± 6%. Blockade of IP3 receptor with 2APB inhibited the maximal change in ,F/F0 due to PAR-1 and PAR-2 activation by 72 ± 13% and 71 ± 20% respectively. PAR-1 immnuoreactivity was present in DMV neurons. Increase in transcripts for PAR-1 and PAR-2 were detected in DMV tissues derived from IBD rats relative to control animals. Conclusions & Inferences, Our results indicate that PAR-1 and PAR-2 are present in the DMV neurons, and their activation leads to increases in intracellular calcium via signal transduction mechanism that involves activation of PLC and the production of IP3. [source] Total Atrioventricular Nodal Ablation Increases Atrial Fibrillation Burden in Patients with Paroxysmal Atrial Fibrillation Despite Continuation of Antiarrhythmic Drug TherapyJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 12 2003RIK WILLEMS M.D. Introduction: Total atrioventricular nodal (TAVN) ablation and pacing is an accepted and safe treatment for patients with drug-refractory paroxysmal atrial fibrillation (AF). Many patients develop permanent AF within the first 6 months after TAVN ablation. This usually is ascribed to the cessation of antiarrhythmic drug therapy. We hypothesized that TAVN ablation itself creates an atrial substrate prone to AF. Methods and Results: Patients participating in the Atrial Pacing Periablation for Paroxysmal Atrial Fibrillation (PA3) study who remained on stable antiarrhythmic drug therapy throughout follow-up were included in this analysis. AF burden and the development of persistent AF in the preablation period were compared to two consecutive postablation periods. Echocardiographic changes also were evaluated. Twenty-two patients remained on stable drug therapy (9 men and 13 women, age 59 ± 3 years). One patient developed persistent AF preablation compared to 10 postablation (P < 0.05). AF burden preablation was 3.0 ± 1.2 hours/day and increased to 10.4 ± 2.2 hours/day and 11.8 ± 2.3 hours/day in the two postablation follow-up periods (P < 0.05). In patients with fractional shortening (FS) >30% prior to ablation, FS decreased significantly from 39.4%± 1.3% to 36.4%± 1.7% (P < 0.05). In contrast, in patients with a FS ,30% prior to ablation, FS increased from 27%± 0.8% to 33.6 ± 1.7% (P < 0.05). Conclusion: TAVN ablation increases AF burden and facilitates the development of persistent AF in patients with paroxysmal AF despite the continuation of antiarrhythmic drugs. Loss of AV and/or interventricular synchrony may lead to altered cardiac hemodynamics resulting in atrial stretch and increasing AF burden. (J Cardiovasc Electrophysiol, Vol. 14, pp. 1296-1301, December 2003) [source] | ||||||||||