Explore the vast range of titles available.

Co-administration of valsartan (VAL) and hydrochlorothiazide (HCT) has been used to regulate blood pressure. Compliance with a multiple medication regimen can be difficult for some patients; therefore, a combination of VAL + HCT tablets may be a suitable alternative. This study was conducted to compare the rate and extent of absorption of VAL and HCT after oral administration as a fixed-dose combination (FDC) tablet and concomitant administration of the individual drugs under fasting conditions in healthy Egyptian subjects. The study was extended to investigate any potential interaction between VAL and HCT. This study was conducted as an open-label, randomized study with 2 parts (parts I and II), with each part consisting of 4 single-dose treatment periods with a crossover design and 2-week washout periods. Blood samples were collected up to 48 hours postdose, and plasma was analyzed for VAL and HCT concentrations by using HPLC. The pharmacokinetic properties of each drug after co-administration of VAL and HCT were compared with those of each drug administered alone. Tolerability was assessed by physical examination and verbally questioning subjects regarding their well-being and any feelings of discomfort. All events reported by the subjects were recorded in adverse-event forms. Forty-eight healthy subjects were enrolled (24 in each part), and all subjects completed the study. None of the participants showed any sign of adverse drug reactions during or after the completion of the study. Statistical analysis confirmed that the 90% CIs for AUC and Cmax of VAL/HCT FDC and VAL + HCT were within the commonly accepted bioequivalence range of 0.8 to 1.25. As a result, from an in vivo pharmacokinetic perspective, 1 FDC tablet could be considered interchangeable in medical practice with the 2 individual reference tablets. However, the 90% CIs between VAL alone and when administered with HCT, either as FDC or concomitantly, indicated the presence of an interaction between VAL and HCT, which would significantly decrease the systemic exposure and intensity of VAL absorption. The co-administration of HCT with VAL decreased the AUC and Cmax of HCT nonsignificantly compared with administration of HCT alone. Both VAL/HCT FDC and VAL + HCT were well tolerated. The safety/efficacy profile of VAL + HCT co-administration therapy could be extended to the VAL/HCT FDC tablet. The interaction of HCT with other angiotensin-receptor blockers should be investigated to determine whether this interaction is limited to VAL or if other angiotensin-receptor blockers have the same pharmacokinetic interactions. Further studies are necessary to determine the role of efflux and influx transporters on VAL and HCT disposition and pharmacokinetics.

This is a comparative pharmacokinetics study of linezolid (Lzd), and two novel oxazolidinone antibacterial agents—PH027 and PH051—in rabbits to determine if the discrepancy between the in vitro and in vivo activities of the novel compounds is due to pharmacokinetic factors. The pharmacokinetics after IV and oral administration, plasma protein binding and tissue distribution for the three compounds were compared. The elimination half-lives were 52.4 ± 6.3, 68.7 ± 12.1 and 175 ± 46.1 min for Lzd, PH027 and PH051, respectively. The oral bioavailability for Lzd, PH027 and PH051 administered as suspension were 38.7%, 22.1% and 4.73%, which increased significantly when administered as microemulsion to 51.7%, 72.9% and 13.9%. The plasma protein binding were 32–34%, 37–38% and 90–91% for Lzd, PH027 and PH051. The tissue distribution for PH027 and PH051 in all investigated tissues were higher than that for Lzd. It can be concluded that the lower bioavailability of PH027 and PH051 compared to Lzd when administered as suspension is the main cause of their lower in vivo activity, despite their comparable in vitro activity. Differences in the other pharmacokinetic characteristics cannot explain the lower in vivo activity. The in vivo activity of the novel compounds should be re-evaluated using formulations with good oral bioavailability.

The urinary ratio of 6 beta-hydroxycortisol/cortisol (6 beta-OHC/C) as a biomarker of CYP3A4 metabolizing activity has been studied in Egyptian patients with chronic liver cirrhosis associated with previous hepatic Schistosomiasis infection to determine any possible alteration in enzyme activity. The ratio of 6-beta OHC/C was determined in morning urine samples collected from 8:00 a.m. to 12:00 p.m. in healthy adults (n = 36) and patients with liver cirrhosis (n = 57). The median age for control was 27 years (range: 18-50 years) and 50 years (range: 27-75 years) for patients. 6 beta-OHC was detected in urine by ELIZA kits (Stabiligen, France). Patients with liver cirrhosis were categorized according to Child Pugh Classification into Child B (n = 28) and Child C (n = 29) classes. Cholestasis was observed in 9/28 of Child B class and 8/29 of Child C class of patients. The control subjects showed gender-related difference in the urinary ratio of 6 beta-OHC/C. A significant reduction (P < 0.001) in 6 beta-OHC/C ratio was observed only in Child C patients in comparison with control subjects. Regression analysis showed a significant correlation (P < 0.05) between 6 beta-OHC/C ratio and serum albumin. The influence of cholestasis on the urinary ratio of 6-beta OHC/C was observed on cirrhotic patients of Child B class. In conclusion, patients with chronic liver cirrhosis might have a reduction of metabolizing activity of CYP3A4 enzymes which could be identified by measuring the urinary ratio of 6 beta-OHC/C. This reduction is more apparent in severe liver injury (Child C class). Therefore, it is important to understand the metabolic fate of drugs metabolized by 3A4 enzymes in patients with liver cirrhosis to avoid drug accumulation that might lead to development of drug toxicity.

Describes an Internet-based, interactive, learner-centered, asynchronous instructional module for pharmacokinetics that requires minimal computer knowledge to operate. Main components are concept presentation, a simulation exercise, and self-assessment questions. The module has been found effective in teaching the steady state concept at the undergraduate level and is well received by students. (MSE)

The urinary ratio of 6 ß-hydroxycortisol/cortisol (6 ß-OHC/C) as a biomarker of CYP3A4 metabolizing activity has been studied in Egyptian patients with chronic liver cirrhosis associated with previous hepatic Schistosomiasis infection to determine any possible alteration in enzyme activity. The ratio of 6-ß OHC/C was determined in morning urine samples collected from 8:00 a.m. to 12:00 p.m. in healthy adults (n = 36) and patients with liver cirrhosis (n = 57). The median age for control was 27 years (range: 18-50 years) and 50 years (range: 27-75 years) for patients. 6 ß-OHC was detected in urine by ELIZA kits (Stabiligen, France). Patients with liver cirrhosis were categorized according to Child Pugh Classifi cation into Child B (n = 28) and Child C (n = 29) classes. Cholestasis was observed in 9/28 of Child B class and 8/29 of Child C class of patients. The control subjects showed gender-related difference in the urinary ratio of 6 ß-OHC/C. A significant reduction (P < 0.001) in 6 ß-OHC/C ratio was observed only in Child C patients in comparison with control subjects. Regression analysis showed a signifi cant correlation (P < 0.05) between 6 ß-OHC/C ratio and serum albumin. The infl uence of cholestasis on the urinary ratio of 6-ß OHC/C was observed on cirrhotic patients of Child B class. In conclusion, patients with chronic liver cirrhosis might have a reduction of metabolizing activity of CYP3A4 enzymes which could be identifi ed by measuring the urinary ratio of 6 ß-OHC/C. This reduction is more apparent in severe liver injury (Child C class). Therefore, it is important to understand the metabolic fate of drugs metabolized by 3A4 enzymes in patients with liver cirrhosis to avoid drug accumulation that might lead to development of drug toxicity.

Summary The urinary ratio of 6 β-hydroxycortisol/cortisol (6 β-OHC/C) as a biomarker of CYP3A4 metabolizing activity has been studied in Egyptian patients with chronic liver cirrhosis associated with previous hepatic Schistosomiasis infection to determine any possible alteration in enzyme activity. The ratio of 6-β OHC/C was determined in morning urine samples collected from 8:00 a.m. to 12:00 p.m. in healthy adults (n = 36) and patients with liver cirrhosis (n = 57). The median age for control was 27 years (range: 18–50 years) and 50 years (range: 27–75 years) for patients. 6 β-OHC was detected in urine by ELIZA kits (Stabiligen, France). Patients with liver cirrhosis were categorized according to Child Pugh Classification into Child B (n = 28) and Child C (n = 29) classes. Cholestasis was observed in 9/28 of Child B class and 8/29 of Child C class of patients. The control subjects showed gender-related difference in the urinary ratio of 6 β-OHC/C. A significant reduction (P <0.001) in 6 β-OHC/C ratio was observed only in Child C patients in comparison with control subjects. Regression analysis showed a significant correlation (P < 0.05) between 6 β-OHC/C ratio and serum albumin. The influence of cholestasis on the urinary ratio of 6-β OHC/C was observed on cirrhotic patients of Child B class. In conclusion, patients with chronic liver cirrhosis might have a reduction of metabolizing activity of CYP3A4 enzymes which could be identified by measuring the urinary ratio of 6 β-OHC/C. This reduction is more apparent in severe liver injury (Child C class). Therefore, it is important to understand the metabolic fate of drugs metabolized by 3A4 enzymes in patients with liver cirrhosis to avoid drug accumulation that might lead to development of drug toxicity.

The primary objective of this investigation was to compare the extent of brain distribution of the lactone and the carboxylate forms of camptothecin (CPT) and topotecan (TPT) in awake freely moving rats. The plasma concentration-time profiles of the lactone and the carboxylate forms of CPT and TPT were determined simultaneously after a single i.v. administration of the lactone form of each drug. Also, the brain extracellular fluid (ECF) concentration-time profiles were characterized utilizing the microdialysis technique. This technique allowed serial sampling of the brain ECF in awake rats. CPT-lactone in plasma declined biexponentially with a terminal half-life of 102+/-25.2 min. During the elimination phase, the plasma concentration of CPT-carboxylate was approximately ten times the concentration of CPT-lactone. The brain ECF to plasma distribution ratio measured as the ratio of the AUC in the brain ECF to the AUC in plasma was 0.51+/-0.08 for CPT-lactone, and 0.26+/-0.21 for CPT-carboxylate. The terminal half-life for TPT-lactone was 64.0+/-9.4 min. During the elimination phase, the TPT-carboxylate concentration was higher than that of TPT-lactone but the carboxylate to lactone concentration ratio was much lower than that of CPT. The brain ECF to plasma distribution ratio was 0.38+/-0.12 for TPT-lactone, and 0.21+/-0.06 for TPT-carboxylate. CPT and TPT are distributed to the brain ECF most probably by passive diffusion across the blood-brain barrier. Although the brain ECF to plasma distribution ratio for CPT-lactone was higher than that for TPT-lactone, the brain ECF concentrations of TPT-lactone were significantly higher than the CPT-lactone brain ECF concentrations. The relatively high brain ECF to plasma distribution ratio of these two drugs makes them potential candidates for first-line treatment of CNS tumors.