Pharmacodynamic methods for investigating antiasthma drugs in healthy volunteers.

The investigation of bronchoactive drugs in healthy volunteers may be divided into studies on the drug effects on basal airway calibre, the effects on induced bronchoconstriction and the examination of the pharmacokinetic and side effect profile of new chemical entities. In the studies presented in this paper, whole body plethysmography was used to assess the pharmacological activity of three new development compounds. In the first example, bronchodilatation was measured after administration of an anticholinergic drug.

Phase I clinical trials with WAL 2014, a new muscarinic agonist for the treatment of Alzheimer's disease.

The safety, tolerability and pharmacological activity of WAL 2014, a new centrally-acting M1 agonist were examined in two clinical studies (0.5-80 mg and 100-160 mg). Single increasing p.

Neuroendocrine and side effect profile of pramipexole, a new dopamine receptor agonist, in humans.

The effects and tolerability of pramipexole, a new dopamine D2-receptor agonist, on prolactin, human growth hormone, thyrotropin, cortisol, and corticotropin levels were investigated in a randomized, double-blind, crossover study in 12 healthy volunteers. Single oral doses of 0.1, 0.

Pharmacodynamics, pharmacokinetics and safety profile of the new platelet-activating factor antagonist apafant in man.

Platelet-activating factor (PAF) is a unique phospholipid mediator with multifunctional properties. Evidence generated in experimental studies suggests that PAF plays a pathogenetic role in anaphylactic, inflammatory and immunogenic reactions. Apafant (WEB 2086, CAS 105219-56-5), a novel synthetic PAF receptor antagonist, was administered to a total of 101 healthy volunteers within 5 studies to investigate its pharmacologic activity, pharmacokinetic behaviour and safety profile.

Antihistaminic activity and side effect profile of epinastine and terfenadine in healthy volunteers.

New H1-receptor antagonists are assessed not only for their H1 antihistaminic activity but also for their central nervous system (CNS) side effects. Fifteen healthy subjects received a once daily dose of 5 mg, 10 mg or 20 mg of epinastine, or a twice daily dose of 60 mg of terfenadine or placebo in a randomized double-blind (double-dummy) crossover study. The response to histamine-induced skin wheals was compared.

Inhibitory effects of the new PAF acether antagonist WEB-2086 on pharmacologic changes induced by PAF inhalation in human beings.

Recent research on asthma mediators has concentrated more and more on platelet-activating factor (PAF), which is one of the most potent bronchoconstrictors known thus far. Inhalant PAF challenge in healthy volunteers may provide a mean of testing PAF antagonists. The usefulness of the PAF provocation test in measuring the pharmacologic activity of a new PAF antagonist, WEB-2086, has been examined in 12 healthy volunteers in a double-blind, placebo-controlled, within-subject crossover study.

PAF-induced platelet aggregation ex vivo as a method for monitoring pharmacological activity in healthy volunteers.

Platelet aggregation induced ex vivo by aggregating factors such as adrenaline, ADP, collagen or PAF may be useful as a model for describing drug effects in humans. In the two studies reported here, PAF-induced platelet aggregation ex vivo was used as an indicator of the pharmacological activity in healthy volunteers of the newly developed specific PAF-antagonist WEB 2086. In intravenous and inhalative single rising dose tolerance trials this method proved useful for monitoring the pharmacological action of the compound tested.

Safety, tolerability, and pharmacologic activity of multiple doses of the new platelet activating factor antagonist WEB 2086 in human subjects.

The safety, tolerability, and pharmacologic activity of WEB 2086, a novel, specific platelet activating factor antagonist, were examined in two double-blind, placebo-controlled, within-subject crossover studies. In each study, WEB 2086 (three times 40 mg/day or three times 100 mg/day) was administered for 7 days to 12 healthy volunteers. Pharmacologic activity of the compound was monitored with ex vivo platelet activating factor-induced platelet aggregation.

Non-invasive evaluation of hemodynamic, tremorogenic and biochemical effects in response to beta-adrenoceptor stimulation.

1, 4, 12 and 24 micrograms SOM 1397 CL, a new beta 2-adrenergic bronchodilator, were administered by inhalation to 10 healthy volunteers in a double-blind, placebo-controlled, within-subject crossover study in order to assess circulatory, tremorogenic and biochemical effects. 1 microgram SOM 1397 CL did not cause any relevant changes in the measured parameters. After administration of 4 micrograms a slight but continuous increase in tremor amplitude and c-AMP was observed.

Bronchospasm induced by methacholine inhalation as a model for testing of bronchospasmolytics in healthy volunteers.

Provocation tests with acetylcholine, methacholine, histamine and carbachol are used as models for measuring bronchospasmolytics in patients with bronchial hyperreactivity. The possibilities of the methacholine provocation test for the measurement of bronchospasmolytic agents in healthy volunteers have been examined. The relevance of this method will be shown by the example of the effects of two beta 2-mimetics in comparison to placebo.

Inhibitory effect of oral WEB 2086, a novel selective PAF-acether antagonist, on ex vivo platelet aggregation.

WEB 2086 is a novel PAF-acether antagonist, whose pharmacological action in man has only been preliminarily defined. Twelve healthy male volunteers received oral doses of 5, 30 and 90 mg and over the following 24 h inhibition of 5 x 10(-8) M PAF-acether-induced platelet aggregation ex vivo was studied as an indicator of pharmacological activity. WEB 2086 inhibited PAF-acether-induced platelet aggregation in all the doses tested, with the maximum effect 1 to 2 h after administration.

Pharmacodynamics of the new H1-antagonist 3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine hydrochloride in volunteers.

The inhibitory effects of 3-amino-9,13b-dihydro-1H-dibenz[1,5-a]azepine hydrochloride (WAL 801 CL), a new H1-receptor antagonist, on histamine-induced skin wheals were studied in 9 volunteers. The study was a double-blind, randomized (Latin square) change-over, intraindividual comparison of the effects of single doses of 2,6 and 18 mg WAL 801 CL and of placebo and 2 mg ketotifen on skin wheals induced by intradermal injections of 5 micrograms hystamine 1, 2, 4, 6 and 8 h after administration of the drugs. The injection of 5 micrograms was also made prior to each drug administration.

Antihistamine activity and central effects of WAL 801 CL in man.

The tolerability and antihistaminic activity of WAL801 CL, a new, peripherally acting H1-receptor antagonist, have been evaluated in a double-blind, placebo-controlled, within-subject cross-over study. WAL801 CL 8 mg b.d.