ABSTRACT
MDL 72.222 is a potent and selective antagonist of excitatory neuronal 5-hydroxytryptamine (5-HT) receptors which has been shown to provide symptomatic benefit in migraine. In the present study, the effects of MDL 72.222 on the flare response to intradermal injection of 5-HT (10(-5), 4 X 10(-5) and 1.6 X 10(-4) mol/l) have been examined in six healthy male volunteers using a double-blind, placebo-controlled, randomized, crossover design. The study consisted of two sessions separated by at least 5 days. Comparison of within and between day responses to 5-HT indicated good reproducibility. Significant attenuation of the flare response to 5-HT, 10(-5) and 4 X 10(-5) mol/l was observed following a slow (4 min) i.v. injection of MDL 72.222, 20 mg. No significant change was observed for the 1.6 X 10(-4) mol/l dose. The investigator was able to guess with a high degree of accuracy the sequence of MDL 72.222 and placebo (100% correct) and the order of 5-HT dose administration (70% correct), providing further evidence of the reproducibility and sensitivity of the method. MDL 72.222 was well tolerated. Thus, a dose of MDL 72.222 previously shown to provide symptomatic relief in migraine attenuates the flare response to intradermal 5-HT in the human forearm. The observation strengthens the view that the beneficial effects of MDL 72.222 in migraine result from blockade of the sensory neuronal stimulant effects of 5-HT and implies a role for 5-HT in the pain production of the acute attack.
Subject(s)
Intradermal Tests , Neurons/drug effects , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Skin Tests , Tropanes/pharmacology , Adult , Double-Blind Method , Humans , Injections, Intradermal , Male , Serotonin/pharmacology , Time FactorsABSTRACT
Clonidine given i.v. at a dose of 0.1 mg and 0.2 mg was found to cause miosis in a placebo controlled double-blind study in six healthy volunteers. In a further single-blind placebo controlled study in three of these volunteers, the alpha 2-adrenoreceptor antagonist RX 781094 at a dose of 0.1 mg/kg i.v. reversed the miosis induced by i.v. clonidine 0.2 mg. At a dose of 0.05 mg/kg the miosis was partially reversed.
Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Clonidine/antagonists & inhibitors , Dioxins/pharmacology , Pupil/drug effects , Humans , IdazoxanABSTRACT
Doxapram administered as a single injection or infusion satisfactorily counteracted the respiratory depression produced by buprenorphrine when administered one hour after the analgesic in healthy subjects. The respiratory stimulant effect was relatively short lived, however, a more prolonged effect was found by study of the displacement of the carbon dioxide response curve.
Subject(s)
Analgesics/pharmacology , Doxapram/pharmacology , Morphinans/pharmacology , Respiratory Insufficiency/drug therapy , Adult , Blood Pressure/drug effects , Carbon Dioxide/blood , Clinical Trials as Topic , Heart Rate/drug effects , Humans , Male , Pupil/drug effects , Respiratory Function Tests , Respiratory Insufficiency/chemically inducedABSTRACT
Buprenorphine was studied to determine the respiratory depressant effect in a double blind comparison with morphine. Buprenorphine produced a more prolonged displacement of the carbon dioxide response curve than morphine. Because of the marked difference in the time effect curves the relative potency was determined at the time of peak effect--3 hours post-administration for buprenorphine (0.15 and 0.3 mg) and 1 hour post administration for morphine (5 and 10 mg). The data from the subjects who received higher doses of buprenorphine (0.6 and 1.2 mg) showed that there was a linear relationship over the dose range 0.15-1.2 mg in terms of respiratory depression.
