Effect of acitretin on the response to an intravenous glucose tolerance test in healthy volunteers.

The effect of the synthetic retinoid acitretin (A) on the disposition of blood glucose and on the serum insulin response following the IV infusion of 139 mmol glucose over 10 min (IGTT) has been investigated in six healthy subjects. The IGTT was performed on Days 1, 10 and 24. On Days 3 to 10 A 50 mg/d was administered. Several parameters of glucose disposition and insulin response (K-values, AUC) were assessed. As a methodological variant, the profiles over time of blood glucose and serum insulin were evaluated by model calculations using the 'minimal model'. Acitretin did not influence any parameter of glucose disposition. The area under the insulin-time curve (baseline corrected) was significantly decreased from 1.20 mU.min.l-1 on Day 1 to 0.89 mU.min.l-1 on Day 10, and was 0.91 mU.min.l-1 on Day 24. The model-derived 'insulin sensitivity' increased from 13.10(-4) l.mU-1.min-1 on Day 1 to 20.10(-4) l.mU-1.min-1 on Day 10 and was 18.10(-4) l.mU-1.min-1 on Day 24. The results suggest that A increased sensitivity to endogenous insulin. It supports a recent report showing greater insulin sensitivity in patients treated with the synthetic retinoid etretinate.

Pharmacokinetic modelling of the plasma concentration-time profile of the vitamin retinyl palmitate following intramuscular administration.

Seven healthy male volunteers (21-24 y) received by the ventro-gluteal route a single dose of 100,000 I.U. of the vitamin retinyl palmitate (RP) in a water-miscible preparation (W) and 5 weeks later the same dose in an oily solution (S). After administration of W median (range) peak plasma concentrations of 5.6 (4.4-8.7). 10(3) micrograms l-1 were reached after 12 h and high levels persisted for another 50 h. At 144 h levels were still, by a factor 3, higher than baseline. Plasma levels of RP after S remained close to baseline (20-50 micrograms.l-1) suggesting negligibly low bioavailability. The plasma level profile of RP after W could well be described by use of a one-compartment model with Weibull-type absorption and Michaelis-Menten elimination. The median (range) absolute bio-availability (estimates of lower limits) was 42 (32-52) per cent.

Plasma tenoxicam concentrations after single and multiple oral doses.

The pharmacokinetics of single- and multiple-dose administration of tenoxicam 20 mg were evaluated in 8 healthy males. Maximum plasma concentration (Cmax) after the first dose was 2.76 +/- 0.48 micrograms/ml (mean +/- s.d.) and the time to reach Cmax (Tmax) was 5.0 +/- 3.0 h. The area under the plasma concentration-time curve (AUC0-infinity) after a single administration of tenoxicam was 242.5 +/- 73.5 micrograms x h/ml. The elimination half-life (t1/2) was 66.3 +/- 15.8 h and the plasma concentration at 24 hours after dosing (Cmin) was 1.84 +/- 0.33 micrograms/ml. Steady-state plasma concentrations of tenoxicam were virtually reached after 10 consecutive daily doses. At steady-state, Cmax averaged 13.63 +/- 3.33 micrograms/ml and Tmax remained 5.0 +/- 3.0 hours. AUC within a dosing interval at steady-state was 262.2 +/- 67.0 micrograms x h/ml, Cminss was 9.67 +/- 3.25 micrograms/ml, and t1/2 averaged 74.2 +/- 13.3 h. The average fluctuation during multiple-dose administration was 26.8 +/- 8.0% and the accumulation ratio was 5.82 +/- 0.60. Steady-state pharmacokinetic parameters predicted from the first-dose data slightly underestimated observed values, but the results supported the assumption of linear pharmacokinetics during multiple-dose tenoxicam administration.

[Changes in creatine kinase activity in serum following intramuscular injection]. / Veränderung der Kreatinkinase-Aktivität im Serum nach intramuskulärer Injektion.

The effect of intramuscular injections of two multivitamin preparations, two excipient preparations without vitamins, and a placebo preparation (glycine 2.5%) on serum creatine kinase activity (S-CK) in ten healthy volunteers (three female, seven male) aged between 23 and 25 years was investigated. One of the multivitamin preparations contained no lidocaine, the other 1% lidocaine. The one excipient formulation was isoosmotic, while the other contained added saline to bring it to the same degree of hyperosomolarity as the multivitamin formulation without lidocaine. The formulations were administered by deep ventrogluteal injection by means of a standardized injection technique. Blood samples were taken before and 6, 12, 24 and 48 h after injection. Following the administration of all the formulations except that of the glycine 2.5%, a marked increase in S-CK activity (1260 I.U./l) was observed 12 h after injection (normal range: male: 47-243 I.U./l, female: 39-226 I.U./l). The relative standard deviation for the 12 h S-CK value was 66.4-97.3%. On applying a threeway analysis of variance to the parameter S-CKmax, no significant differences (alpha = 5%) were found between the effects of the multivitamin and excipient formulations. There was a difference between these and glycine 2.5%, however. There were significant differences between individual volunteers but no significant differences based on the sequence in which the injections were given. With regard to the parameter S-CK AUC (area under the curve, trapezoidal rule), a significant difference (alpha = 5%) was observed only between glycine 2.5% and the multivitamin formulation containing 1% lidocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of influence of etretinate on the intestinal absorption of D-xylose and of phytomenadione (vitamin K1) as representatives of hydrophilic and lipophilic compounds.

The possible influence of the aromatic retinoid etretinate (Tigason ) on the intestinal absorption of D-xylose and phytomenadione (vitamin K1) has been studied in 7 healthy male volunteers between 22 and 25 years of age. D-xylose and phytomenadione were selected as being representative of water-soluble and fat-soluble test compounds, respectively. Following an oral dose of 25 g D-xylose the plasma levels and urinary excretion pattern of the compound were followed over 6 h. The plasma concentrations of phytomenadione after an oral dose of 20 mg of the vitamin were measured over 14 h. These absorption tests were performed before (baseline) and at the end of a 3-week treatment period with 25 mg b.i.d. etretinate. In addition some parameters on the serum lipid status pre and post etretinate treatment were monitored. The pharmacokinetic and biochemical determinants after treatment with etretinate were referenced to the pretreatment values and nonparametric confidence intervals (a less than 0.05) for these ratios were calculated. With respect to the area, AUC, under the D-xylose plasma concentration--time curve (0.79 less than or equal to RAUC = 1.00 less than or equal to 1.17) as well as to the cumulative amount excreted into urine over 6 h (0.90 less than or equal to RSUM = 1.04 less than or equal to 1.28) and to renal clearance (0.91 less than or equal to Rcl = 1.05 less than or equal to 1.25), no effect of etretinate on absorption and/or renal handling of D-xylose was discernible.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies of mefloquine bioavailability and kinetics using a stable isotope technique: a comparison of Thai patients with falciparum malaria and healthy Caucasian volunteers.

1 A mefloquine hydrochloride tablet (250 mg base equivalent to 4.8 +/- 0.6 mg kg-1; mean +/- s.d.) and deuterium labelled mefloquine hydrochloride solution (250 mg base) were given to six adult male Thai patients with acute falciparum malaria and six healthy Swiss adult male volunteers (equivalent to 3.5 +/- 0.1 mg kg-1). 2 The relative bioavailability of the tablet formulation derived from comparison of the areas under the plasma concentration-time curves was similar in both groups; 87 +/- 11% and 89 +/- 10% (mean +/- s.d.). 3 The rate of drug absorption appeared to be similar in the two groups but peak plasma mefloquine concentrations were approximately three times higher in the Thai patients (1004 +/- 276 ng ml-1 for the tablet and 1085 +/- 280 ng ml-1 for the suspension) compared with the Swiss volunteers (319 +/- 73 ng ml-1 for the tablet, and 369 +/- 121 ng ml-1 for the suspension). 4 Estimates of the oral clearance CLpo of unlabelled mefloquine were significantly lower (17.5 +/- 4.4 ml h-1 kg-1) in the Thai patients compared with 28.8 +/- 3.5 ml h-1 kg-1 in the Swiss volunteers; P less than 0.05). Terminal elimination half-lives were significantly shorter in the patients (10.3 +/- 2.5 days) than in the volunteers (16.7 +/- 1.9 days; P less than 0.005). Differences of a similar magnitude were observed when comparing the pharmacokinetic parameters derived from the deuteromefloquine plasma concentrations. 5 Both genetic and disease related factors are likely to account for the large pharmacokinetic differences between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of effect of tenoxicam on glibornuride kinetics and response.

The pharmacokinetics of glibornuride (25 mg i.v.) and the accompanying insulin and glucose responses were characterized in eight human subjects in the presence and absence of steady-state tenoxicam (20 mg p.o./day for 2 weeks). Tenoxicam affected neither the pharmacokinetic parameters of glibornuride (systemic clearance, volume of distribution and biological half-life) nor the responses of plasma insulin and blood glucose to glibornuride. The single i.v. dose of glibornuride had no detectable effect on the kinetics of tenoxicam.

Plasma concentrations in pyrimethamine and sulfadoxine and evaluation of pharmacokinetic data by computerized curve fitting.

For the determination of the plasma concentration profiles of pyrimethamine and sulfadoxine after the administration of 1 tablet of Fansidar, highly specific analytical methods are needed as the pyrimethamine concentration is low (0.2 - 0.02 mg/litre) and the concentration ratio of the two components in the plasma is high (> 1: 500). The microbiological method described in this paper fulfils these requirements for high specificity and sensitivity (the sensitivity limit for sulfadoxine is 1 mg/litre and for pyrimethamine is 0.013 mg/litre).Pharmacokinetic data were evaluated for 14 volunteers after administration of 1 tablet of Fansidar, and a computer simulation of multiple dosing (1 tablet per week) was performed.

The subacute effect of bromazepam on psychomotor activity and subjective mood.

In a double-blind study, fifty-five healthy, male medical students received a tranquilizer (bromazepam, 'Lexotanil') or placebo according to dosage group (placebo, 1.5 mg and 3 mg bromazepam). The subjects were randomly allocated to three groups (placebo: n = 19; 1.5 mg: n = 19; and 3 mg: n = 17). Dependent variables tested were the subjective assessment of performance and the level of activation (self-rating), and aspects of psychomotor function were assessed using the standard testing devices. The medication was administered for a total of 14 days. The testing times reported here were: before start, and after 7 and 14 days of administration of serum or placebo. The subjective evaluation (self-rating) such as performance assessment and level of activation demonstrated no changes related to either the medication or the length of time elapsed. The objective measures of performance revealed two main effects: lengthening of time of reaction to optical stimuli during the course of the study, especially in the higher bromazepam dosage group (sedative effect). This sedative effect was, however, relatively weak since, despite this observation, there was a significant training effect in the 3 mg group with regard to attentiveness and alertness testing. The results were also evaluated for a possible effect on driving ability. In the group studied here and at the relatively low dosage administered, any possible negative influence can be disregarded.

5-Fluorouracil: a comparative pharmacokinetic study and preliminary results of a clinical phase I study.

Until now it was unknown, whether 5-fluorouracil (5-FU) would be absorbed sufficiently after oral application, so that therapeutical effects could be expected. For this reason a comparative pharmacokinetic study of intravenous versus oral application was performed on six patients, as well as a pilot study on 13 patients with adenocarcinomas of different origins. The results show that 5-FU is absorbed rapidly. The biological availability increases with higher dose, which would indicate a saturation of the "first pass" in the liver. The clinical study shows partial remission in seven patients, with hepatoma and tolerable signs of bone marrow depression, decrease of hemoglobin, leukocytes and platelets after oral application of 5-FU in doses of 1,000-1,250 mg on days 1, 3, 5, 8, 10, and 12. 5-FU can therefore be given successfully at an adequate dose by the oral route.

Effect of intravenous glibornuride and tolbutamide on myocardial contractility.

The acute effects of therapeutic doses of intravenous tolbutamide and glibornuride on the systolic time intervals (QS2c, LVETc, PEPc and PEP/LVET) were examined in 5 healthy volunteers. Blood sugar was maintained constant throughout the study. No significant changes of these intervals as well as of heart rate and blood pressure were observed. Therefore, it is concluded that tolbutamide and glibornuride have no acute positive inotropic action.