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The pharmacokinetics and the endocrine profile of a new low molecular somatostatin derivative, SMS 201\p=n-\995, were investigated in a group of 35 normal subjects. Clearance studies (n = 6) for this peptide showed a prolonged half-life in plasma, 113 min, following single sc injections of 50 or 100 \ g=m\ g. Arginine stimulation tests (n = 6) were conducted immediately and 180 min after sc injection of 50 \ g=m\ g of SMS 201\p=n-\995. The stimulatory effect of arginine on GH and insulin was counteracted by the peptide at the P < 0.001 and P < 0.02 significance level, respectively. Delayed arginine stimulation revealed a persistent blockade of the GH release (P < 0.02), whereas a recovery of the insulin response was observed. Plasma

1 Eight double-blind, randomized, placebo-controlled, single-dose, cross-over studies were carried out to evaluate the usefulness of testing the acute analgesic effect of drugs in out-patients with non-migrainous headache. 2 The reference compounds were either (1) aspirin, (2) a combination of aminopyrine, caffeine and butalbarbital (Optalidon®), and (3) a combination of (2) with dihydroergotamine (Tonopane).3 The test compounds were (1) proquazone, (2) fluproquazone and (3) and (4), new formulations of Optalidon® and Tonopan® in which the aminopyrine was replaced by propyphenazone. They were all found to be active. 4 A significant, dose-response relationship was established for aspirin (250, 500 and 1000 mg). 5 It is concluded that the non-migrainous headache model is a practical, reproducible and sensitive method for the investigation of the acute efficacy of analgesics.

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A method for the evaluation of the efficacy of mild analgesic drugs in outpatients with nonmigrainous headache is described. During the 3-hour drug evaluation period, patients were required to record at hourly intervals their pain intensity using both a verbal rating and a visual analog scale, their pain relief, and the occurrance of side effects. The results obtained in six studies consisted of comparisons of reference compounds aspirin (1000 mg) and two analgesic combinations (containing aminophenazone, caffeine, and butalbital); test medications aspirin (500 mg), codeine (30 mg), proquazone (300 mg), and new formulations of the two analgesic combinations (aminophenazone replaced by propyphenazone); and, in every study, placebo. In a seventh study, the analgesic effects of three doses aspirin (250, 500, and 1000 mg) were compared with that of placebo. Every study was conducted under double-blind, complete crossover conditions, and between 24 and 36 patients were used in each study. Using parametric and nonparametric statistical analyses, the reference compounds and the majority of the test medications exhibited significant analgesic properties. Also, a highly significant dose--response effect was demonstrated for aspirin. It is concluded that the headache model is a practicable, reliable, and sensisive method for the evaluation of the effectiveness of mild analgesic drugs.

A study was made of a number of factors that might be responsible for the unreliable results obtained in experimentally induced pain in man. In a randomised, double-blind, cross-over study on 32 healthy, male volunteers, the ischaemic pain test [14] and several psychological tests were performed. The influence of the following factors on the pain test results were examined: (a) ingestion of single, oral doses of 1000 mg aspirin (ASA) and placebo, (b) practice effect, (c) initial pain sensitivity, (d) anxiety, coping behaviour, attitude to the experiment and personality factors. The analgesic activity of ASA could not be demonstrated. An interaction between primary pain sensitivity and the sequence of drug administration was found. Furthermore, anxiety had a marked influence on the test results. Using experimental pain models reliable results are not to be expected as anxiety fluctuates intra- and interindividually in an unpredictable and uncontrollable manner.

A new radioimmunoassay (RIA) for the specific measurement of dihydroergotamine (DHE), sufficiently sensitive for the determination of low plasma concentrations, has been used to investigate the pharmacokinetics of unchanged DHE. In a randomized cross-over trial, eight healthy male volunteers received single doses of DHE 5 mg, 10 mg and 20 mg orally and 0.1 mg and 0.5 mg intravenously. It was possible to determine plasma concentrations and urinary excretion of DHE over the following 48 h. A long terminal plasma elimination phase of unchanged DHE (half-life 15 h) was found. A similar terminal elimination half-life was also calculated from urine data. The multi-exponential decline in plasma DHE with a long terminal half-life suggests that distribution into a deep compartment contributes to the long-lasting effect of the drug. Plasma protein binding was 93%. Despite extensive tissue distribution (Vz = 33 l/kg) and a high plasma clearance (CLP = 2 l/min), dose-independent linear pharmacokinetics was observed. The present assay was at least 20-times more specific than the polyvalent RIA used previously and appears suitable to explore the pharmacokinetics of unchanged DHE in patients on low-dose therapy. The long terminal elimination half-life of DHE only reported previously in studies using 3H-labelled drug, and considered to be due to metabolites, was also true for the parent compound. This, in addition to the sustained pharmacological activity of the 8'-hydroxy metabolite already shown, provides a further explanation for the long duration of action of DHE in animals and man.

Extensive pharmacokinetic (PK) profiles after oral dosing of 300 mg cyclosporin A (CsA) were determined in whole blood by radioimmunoassay (RIA) in 14 healthy male volunteers, using two-compartment models with either first order (M1) or zero order (M0) absorption. According to zero order absorption the mean of the following PK parameters was determined: terminal half-life = 12.1 +/- 5.0 h, apparent volume of distribution at steady-state = 5.6 +/- 2.11 X kg-1, apparent clearance = 0.51 +/- 0.11 l X h-1 X kg-1. The time lag between drug ingestion and first blood level was short, 0.38 +/- 0.11 h. Drug absorption lasted for 2.8 +/- 1.6 h. The end of absorption was indicated in each individual by a sharp drop in blood levels. The observations support the assumption that CsA is absorbed in the upper part of the small intestine with a clear-cut termination (absorption window). This assumption may explain the high degree of variability in the bioavailability of CsA.