Effect on bioavailability of admixing the contents of lansoprazole capsules with selected soft foods.

OBJECTIVE: This study was designed to compare the bioavailability of lansoprazole when administered as an intact capsule and when the contents are admixed with various soft foods. BACKGROUND: Patients sometimes cannot swallow or have difficulty swallowing intact capsules such as lansoprazole. To enable them to ingest the drug, the contents of the capsule can be admixed with small amounts of soft foods. METHODS: Twenty-four healthy adult volunteers participated in this single-dose, 4-period crossover study by ingesting the contents of a 30-mg lansoprazole capsule that had been emptied into either a tablespoon of yogurt (regimen A), Ensure pudding (regimen B), or cottage cheese (regimen C), or given as an intact capsule (regimen D) during the first study period. The regimen assignments were rotated at weekly intervals so that each subject received each regimen. Blood samples were obtained over the 12-hour period after administration of each regimen, and pharmacokinetic parameters were determined. RESULTS: Of the 23 subjects who completed all 4 periods of the study, 18 were male and 5 were female. Their mean (+/- SD) age was 33.3+/-11.6 years, and their ages ranged from 19 to 52 years. No statistically significant differences between regimens were detected in mean maximum concentration, area under the curve (AUC) from time zero to the last measurable concentration, and AUC from time zero to infinity (AUC0-infinity) using analysis of variance. A statistically significant difference was detected in the time to maximum concentration between regimens C and D at 2.1 and 1.5 hours, respectively (P < or = 0.05). Bioavailability was assessed by the two 1-sided tests procedure using a 90% CI for the AUC0-infinity ratio of test-to-reference regimens. The 90% CIs were all within an acceptable equivalence range of 0.80 to 1.25. CONCLUSION: These results indicate similar bioavailabilities between the regimen in which the lansoprazole capsule was emptied and administration of the intact capsule. However, they may have limitations in predicting the results in ill, elderly, or very young patients.

Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers.

The pharmacokinetic interaction between indinavir and ritonavir was evaluated in five groups of healthy adult volunteers to explore the potential for twice-daily (b.i.d.) dosing of this combination. All subjects received 800 mg of indinavir every 8 h (q8h) on day 2. In addition, subjects in group I received one dose of 800 mg of indinavir on day 1 and 800 mg of indinavir q8h on day 17. Subjects in Groups II and IV each received one dose of 600 mg of indinavir on days 1 and 17, and subjects in groups III and V each received one dose of 400 mg of indinavir on days 1 and 17. During days 3 to 17, ritonavir placebo or ritonavir at 200, 300, 300, or 400 mg q12h was given to groups I, II, III, IV, and V, respectively. Ritonavir at steady state probably inhibited the cytochrome P-450 3A metabolism of indinavir and substantially increased plasma indinavir concentrations, with the area under the plasma concentration-time curve (AUC) increasing up to 475% and the peak concentration in serum (Cmax) increasing up to 110%. The Cmax/trough concentration ratio decreased from 50 in standard q8h regimens to less than 14 when indinavir was administered with ritonavir. For a constant indinavir dose, an increase in the ritonavir dose yielded similar indinavir AUCs, Cmaxs, and concentrations at 12 h (C12s). For a constant ritonavir dose, an increase in the indinavir dose resulted in approximately proportional increases in the indinavir AUC, less than proportional increases in Cmax, and slightly more than proportional increases in C12. Ritonavir reduced between-subject variability in the indinavir AUC and trough concentrations and did not affect indinavir renal clearance. With the altered pharmacokinetic profile, indinavir likely could be given as a b.i.d. combination regimen with ritonavir. This could potentially improve patient compliance and thereby reduce treatment failures.

Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir.

OBJECTIVE: To assess the pharmacokinetic interaction between ritonavir and saquinavir. METHODS: Ritonavir and saquinavir were administered in single doses to six groups of healthy volunteers in a two-way (saquinavir alone and ritonavir plus saquinavir for groups I through V) and a three-way (ritonavir alone, saquinavir alone, and ritonavir plus saquinavir for group VI) crossover manner with the following doses: group I, 200 mg saquinavir and 300 mg ritonavir; group II, 200 mg saquinavir and 600 mg ritonavir; group III, 400 mg saquinavir and 300 mg ritonavir; group IV, 400 mg saquinavir and 600 mg ritonavir; group V; 600 mg saquinavir and 200 mg ritonavir; group VI, 600 mg saquinavir and 600 mg ritonavir. RESULTS: Coadministration of ritonavir markedly increased the area under the plasma concentration-time curve (AUC) and peak concentration of saquinavir (> 50-fold and 22-fold, respectively). For a constant ritonavir dose, the pharmacokinetics of saquinavir were relatively proportional to dose. For a constant saquinavir dose, the increase in saquinavir concentration tended to be less than proportional to ritonavir dose. Ritonavir reduced intersubject variability in the saquinavir AUC from 60% to 28%. The in vivo inhibition constant was 0.025 +/- 0.020 micrograms/ml with noncompartmental estimation and 0.0164 +/- 0.0004 micrograms/ml with nonlinear mixed-effects model compartmental analysis. Saquinavir showed no clinically significant effect on the pharmacokinetics of ritonavir (+6.4% in AUC). The regimens were well tolerated. CONCLUSIONS: The large effect of ritonavir on the pharmacokinetics of saquinavir is consistent with a large reduction of saquinavir first-pass metabolism and postabsorptive clearance. Given the limited bioavailability of saquinavir given in the hard gelatin capsule formulation, this drug interaction is expected to have implications in the use of protease inhibitors in the management of human immunodeficiency virus infection.

Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects.

The multiple-dose pharmacokinetics of ritonavir were investigated in four groups of human immunodeficiency virus-positive male subjects (with 16 subjects per group) under nonfasting conditions; a 3:1 ritonavir:placebo ratio was used. Ritonavir was given at 200 (group I), 300 (group II), 400 (group III), or 500 (group IV) mg every 12 h for 2 weeks. The multiple-dose pharmacokinetics of ritonavir were moderately dose dependent, with the clearance for group IV (6.8 +/- 2.7 liters/h) being an average of 32% lower than that for group I (10.0 +/- 3.2 liters/h). First-pass metabolism should be minimal for ritonavir. The functional half-life, estimated from peak and trough concentrations, were similar among the dosage groups, averaging 3.1 and 5.7 h after the morning and evening doses, respectively. The area under the concentration-time curve at 24 h (AUC24) and apparent terminal-phase elimination rate constant remained relatively time invariant, but predose concentrations decreased 30 to 70% over time. Concentration-dependent autoinduction is the most likely mechanism for the time-dependent pharmacokinetics. The Km and initial maximum rate of metabolism (Vmax) values estimated from population pharmacokinetic modeling (nonlinear mixed-effects models) were 3.43 microg/ml and 46.9 mg/h, respectively. The group IV Vmax increased to 68 mg/h after 2 weeks. The maximum concentration of ritonavir in serum (Cmax) and AUC after the evening doses were an average of 30 to 40% lower than the values after the morning doses, while the concentration at 12 h was an average of 32% lower than the predose concentration, probably due to protracted absorption. Less than 2% of the dose was eliminated unchanged in the urine. Triglyceride levels increased from the levels at the baseline, and the levels were correlated with baseline triglyceride levels and AUC, Cmax, or predose concentrations.

Determination of a new 5-lipoxygenase inhibitor, zileuton, and its inactive N-dehydroxylated metabolite in plasma by high performance liquid chromatography.

A rapid and sensitive assay was developed for the measurement of plasma concentrations of zileuton racemate, a potent inhibitor of 5-lipoxygenase. Zileuton and its inactive N-dehydroxylated metabolite were extracted from human, monkey, and rat plasma by use of a solid-phase extraction column (Analytichem Bond Elut). The compounds were then separated by reverse-phase high performance liquid chromatography (HPLC) on a Supelcosil LC-18 column and quantified on the basis of ultraviolet absorption at 260nm relative to an internal standard. The extraction recovery of zileuton, as determined by HPLC assay, was 77.9 +/- 1.7%. Recovery of the metabolite was 85.8 +/- 0.7%. Calibration curves for both compounds were linear over the zileuton concentration range 0.01 to 10.0 mg/L (correlation coefficients > 0.987), while the intra- and interassay coefficients of variation were < 15.6%. In practice, > 97% of blinded daily spiked control samples for zileuton and > 90% of those for the metabolite were within 10% of their target concentrations.

Moment-length relations of rectus femoris muscles of speed skaters/cyclists and runners.

The purpose of this study was to investigate the possible existence of systematic differences between moment-length properties of the rectus femoris muscle of cyclists/speed skaters and runners. In cycling/speed skating the rectus femoris is used at a shorter length than in running because of the pronounced flexion at the hip joint. It was speculated that using the rectus femoris chronically at different lengths would result in different moment-length relations for the two groups of athletes. Moment-length relations of rectus femoris muscles were determined using an adaptation of procedures outlined in the literature. Four subjects in each group performed 13 isometric knee extensions on a Cybex II dynamometer in each of three testing sessions. Knee and hip angles were varied in a systematic way to allow the determination of moment-length relations over a wide range of normal rectus femoris lengths. It was found that cyclists tended to be stronger at short compared with long rectus femoris lengths, whereas the opposite was true for runners. This finding may be associated with an adaptation of the rectus femoris muscle to the requirements of cycling and running or may show an inherited difference in the muscles of the athletes that existed before they became involved in their respective sports. The data of this study do not allow us to distinguish between these two possible factors.

[Computed tomography of lung contusion. An experimental study]. / Computertomographie der Lungenkontusion. Eine experimentelle Studie.

A new experimental model has been developed to determine whether computed tomography has any advantages for the investigation of lung contusions. In 27 dogs, chest wall deformation was produced at speeds varying from 17.3 m/sec to 45.7 m/sec, leading to lung contusion. After the injury, 27 out of 27 (100%) CT examinations demonstrated the contusions, but only nine out of 24 (37.5%) were seen on conventional radiographs. In contrast to conventional radiography, which either failed to show the presence of a contusion, or which under-estimated the extent by more than one cm, in more than half the cases CT agreed with the pathological findings in more than 90%. No lung contusions were found at autopsy which had not been demonstrated by CT.

Basic and applied research at the TRIUMF meson factory.

The TRIUMF 520 MeV H- cyclotron produces intense beams of protons, pions and muons supporting basic research in nuclear, particle and solid-state physics, nuclear chemistry and biomedicine, and applied research in electromagnetic breeding of nuclear fuel, proton radiography, radioisotope production and cancer treatment.