1. The pharmacokinetics of Dalal-peptide T-NH2 (peptide T) was determined during phase I clinical trials in patients with acquired immunodeficiecy disease (AIDS) and AIDS related complex (ARC). Drug levels were determined by specific RIA, and in some cases with HPLC analysis, after intraveneous (i.v.) or intranasal (i.n.), via metered sprayer, administration.
2. The plasma kinetics appeared to be bi-phasic with a first compartment half-life of 30 to 60 minutes and a second plasma clearence rate of 4 to 6 hours, observed for both routes of administration. Peptide T, in one individual was confirmed to be present at 6 hrs in plasma, determined after HPLC isolation followed by specific RIA.
3. Bioavailabilty, determined for a 2 mg test dose in six individuals was 9.3 ± 6.9 nmol/L. Peak plasma levels of 41 ± 30 nmol/L after 10 mg i.n., 2.8 ± 5.9 nmol/L after 2mg i.n., and 0.13 ± 0.07 nmol/L after 0.4 mg i.n. were observed. In two individuals tested, peptide T was detected in CSF at levels 20% of the corresponding plasma level 90 and 145 minutes post i.v. administration. Peptide T was not detected in urine. I.N. administration was well tolerated for times up to 21 months. 相似文献
Summary The kinetics of a single 5-mg oral dose of the thienodiazepine clotiazepam was evaluated in a series of patients with biopsy-proven cirrhosis, and in patients with renal insufficiency requiring maintenance hemodialysis, compared to healthy matched controls. Clotiazepam volume of distribution (Vz) was significantly smaller in cirrhotic patients than in controls (1.83 vs 2.57 l/kg), and total clearance was likewise reduced (2.15 vs 3.15 ml/min/kg). Elimination half-life was similar between groups (10.0 vs. 10.2h). There were no significant differences between renal failure and control patients in clotiazepam Vz, oral clearance, or elimination half-life. Thus cirrhosis is associated with reduced clearance of clotiazepam, probably due to impairment of its microsomal oxidation. However clotiazepam disposition is not significantly altered in dialysis-dependent renal insufficiency patients.Supported in part by Grant OC 10/6–4 from Deutsche Forschungsgemeinschaft, and Grant MH-34223 from the United States Public Health Service. 相似文献
The primary objectives of this study were to determine the maximum tolerated dose (MTD) of paclitaxel administered by 3-h infusion to patients with solid tumors, and to characterize the pharmacokinetics of a 3-h infusion in comparison with those of a 24-h infusion. Twenty-seven patients each received one of six levels of paclitaxel, 105, 135, 180, 210, 240 and 270 mg/m2, with premedication. Two patients given 240 mg/m2 and one patient given 270 mg/m2 unexpectedly had grade 3/4 hypotension just after finishing the paclitaxel infusion. Peripheral neuropathy was also dose-limiting at 270 mg/m2. Although granulocytopenia was significantly less severe than with a 24-h infusion, more than half of the patients experienced grade 4 toxicity at doses of 240 or 270 mg/m2. Severe hypersensitivity reactions (HSRs) were not observed. Pharmacokinetic studies using high performance liquid chromatography demonstrated proportionally greater increases in the peak plasma concentration and area under the curve, and decreases in clearance and volume of distribution with increasing dose, suggesting non-linear pharmacokinetics of paclitaxel when given by 3-h infusion. The MTD of paclitaxel given as a 3-h infusion was determined to be 240 mg/m2 with dose-limiting toxicities of granulocytopenia, peripheral neuropathy and hypotension. Hypotension just after infusion, induced by 3-h infusion of paclitaxel, is a new observation which has not been reported previously. The recommended dose for phase II study is 210 mg/m2. Although hypotension was observed as an unexpected toxic effect, paclitaxel could be administered safely over 3 h with premedication and proper monitoring, resulting in reduced myelotoxicity and with no increase in the incidence of HSRs as compared with a 24-h infusion. 相似文献
Summary Eight healthy volunteers participated in an open crossover study to assess the effect of a standardised meal on the systemic availability of a single oral dose of fenoldopam mesylate 100 mg. Subjects were studied on four separate occasions, twice fasting and twice fed in randomised, balanced order. Plasma and urine samples were obtained before and at regular intervals up to 25 h post dose. Measurement of fenoldopam (SK&F 82526) and its 8-sulphate metabolite (SK&F 87782) were by means of HPLC-EC analysis. Area under the plasma concentration time curve (AUC) and maximum detected plasma concentration (Cmax) for fenoldopam and SK&F 87782 were significantly reduced whereas time to maximum concentration was significantly increased with food. Using AUC's for fenoldopam and SK&F 87782, mean relative bioavailabilities were 35% and 81% respectively under fed compared with fasting conditions. Twenty-four hour excretion of fenoldopam was significantly reduced with food, but excretion of SK&F 87782 was apparently unchanged. Mean relative bioavailabilities calculated from these data were 83% and 86% respectively. Relatively large inter-subject variability in AUC and Cmax were seen, but intra-subject variability was not marked. Mild symptoms associated with vasodilation were reported on all study days. 相似文献
In a double-blind, placebo-controlled study, the pharmacokinetic, encephalotropic, and psychotropic properties of a new metabolically active thienyl-piperazine derivative were studied in ten elderly subjects in their sixties by means of quantitative EEG and psychometric analyses. At weekly intervals, they received randomized single oral doses of placebo; 75 mg, 150 mg, and 300 mg tenilsetam (CAS 997); and 3.2 g piracetam as reference drug. Blood sampling EEG recordings, psychometric and psychophysiological tests, as well as the monitoring of blood pressure, heart rate, and side effects were carried out at 0, 2, 4, 6, 8, and 24 hr. Pharmacokinetic investigations showed that CAS 997 was rather well absorbed, as peak concentrations were observed consistently at 2 hr and were clearly dose-dependent. The terminal half-life was between 18 and 22 hr, as compared with 6 hr for the reference drug piracetam, which also exhibited plasma peaks at 2 hr. Computer-assisted spectral analyses of the EEG showed a significant CNS effect of CAS 997 as compared with placebo, characterized by an increase of alpha activity, decrease of delta activity, and fast beta activity, as well as by tendency towards an augmentation of total power and decrease of the centroid and centroid deviation of the total beta activity. Partly similar though less pronounced alterations were exhibited by 3.2 g piracetam. Such changes were described previously by us after several other antihypoxidotics/nootropics and are indicative of improvement in vigilance. Dose/treatment–efficacy calculations demonstrated 75 and 150 mg CAS 997 superior both to placebo and the reference compound but also to the highest given dosis (300 mg CAS 997). Time–efficacy calculations showed two pharrnacodynamic peaks: one in the 4th and another one in the 8th to 24th hour. The time lag between pharmacokinetic and -dynamic changes may be due to the penetration of the drug through the blood brain barrier to a deep compartment receptor as well as to the formation of active metabolites. Psychometric investigations showed only small and inconsistent psychotropic effects after single doses of CAS 997 in elderlies. Evaluation of pulse rate, blood pressure, and side effects showed a good tolerability of both drugs. 相似文献