Hypotensive and bradycardic effects of talipexole (B-HT 920) in anaesthetized rabbits are antagonized by metoclopramide but not by yohimbine.

The interactions of talipexole (B-HT 920) and clonidine with selective alpha-adrenoceptor antagonists, yohimbine (alpha 2) and prazosin (alpha 1), as well as with dopamine receptor antagonists, metoclopramide (D2), domperidone (D2) and SCH23,390 (D1) were investigated in anaesthetized rabbits after i.v. administration. Both talipexole (0.03-0.1 mg/kg) and clonidine (0.01-0.03 mg/kg) dose-dependently induced hypotension and bradycardia. Talipexole had a shorter duration of action. The hypotensive effect of the alpha 2-adrenoceptor and D2 agonist talipexole (0.03 mg/kg) was antagonized by pretreatment with metoclopramide (3 mg/kg) or domperidone (0.3-3 mg/kg), but not with yohimbine (3 mg/kg), prazosin (0.1 mg/kg) or SCH23,390 (1 mg/kg). Its bradycardic effect was antagonized only by metoclopramide (3 mg/kg). The hypotensive and bradycardic effects of clonidine (0.03 mg/kg) were most effectively antagonized by yohimbine (0.3-3 mg/kg). These findings indicate that in anaesthetized rabbits after i.v. administration, talipexole may lower blood pressure by peripheral, and heart rate by central, dopamine D2 agonism.

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, 0.2, and 0.3 mg pramipexole and placebo were studied over a period of 24 hours. Pramipexole decreased serum prolactin levels in a dose-dependent manner, with a maximum effect after 2 to 4 hours. Serum levels of human growth hormone were dose-dependently increased; however, this effect was only significant 2 hours after drug administration. Furthermore, a slight increase in serum cortisol levels and a slight decrease in serum thyrotropin levels was observed. Our findings show for the first time pharmacodynamic effects of pramipexole after single oral doses in healthy volunteers. The compound was well tolerated and showed an endocrine profile similar to other dopamine D2-agonists.

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. CNS effects were evaluated by a multiple reaction time task, a finger tapping test and a self-rating scale (Bf-S von Zerssen) to assess mood state. Epinastine attenuated the wheal size in response to histamine in a dose-dependent manner. In addition, all epinastine dosages had a distinctly faster onset of action than terfenadine. All active treatments (5 mg, 10 mg, 20 mg epinastine and 60 mg terfenadine) attained their maximum effects 4 h after administration. At this time point and also 12 h after administration, 20 mg of epinastine were significantly more effective than 60 mg of terfenadine. Single 10 mg and 20 mg doses of epinastine were as effective as terfenadine given twice daily, and significantly more effective than placebo 24 h after drug administration (i.e. 12 h after the second dose of terfenadine). The psychometric tests for CNS effects did not reveal any difference among epinastine, terfenadine and placebo. In conclusion, epinastine is one of the most effective peripherally acting H1 antagonist which lacks significant CNS side effects and is suitable as a once daily dosage regimen.

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 immediate bronchoconstriction, slight hemodynamic changes, and PAF-related subjective side effects. Premedication with WEB-2086 (40 mg) completely prevented any increase in airway resistance after PAF inhalation, as well as development of most of the cardiovascular and side effects induced by PAF. The clear protection against PAF-induced pharmacologic effects can be explained by the specific PAF-antagonistic activity of WEB-2086. The method described in this article may be applied as a useful tool for looking at PAF-antagonistic activity in healthy volunteers.

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. The effects on hemodynamics and other laboratory values could be considered negligible. Overdoses of 12 and 24 micrograms resulted in a dose-dependent increase in systolic blood pressure, pulse rate, tremor amplitude, alpha-AMP and lactic acid, as well as in a decrease of diastolic blood pressure and potassium. These effects may be partly attributable to beta 2-receptor stimulation. The method described in this paper can be applied as a useful tool for determination of beta 2-adrenergic activity in healthy volunteers, independent of the conventional methods which are used to evaluate efficacy of bronchodilators by the degree of bronchial muscular relaxation.