The respiratory effects of intravenously infused almitrine were evaluated in healthy volunteers. In the dose range 0-25-1-0 mg/kg/hour it caused large and dose-dependent increases in hypoxic chemosensitivity, which were longlasting and more persistent than the drug' s retention in the plasma. Increases in sensitivity to hypercapnia were much less and were detected only when the plasma almitrine exceeded 200 ng/ml. Small increases in resting ventilation and metabolic rate with a decrease in mixed venous carbon dioxide tension occurred only at the highest infusion rate. The findings accord with an action of almitrine in the peripheral chemoreceptors, which may be of therapeutic value in managing some cases of respiratory failure.Almitrine is a piperazine derivative which stimulates respiration in animals by an effect on the peripheral chemoreceptors but has no central activity. Thus its administration to anaesthetised dogs increases the neural discharge from their carotid body chemoreceptors, causing hyperpnoea only if the carotid sinus and vagus nerves are intact. Such stimulation evoked by intravenous injection of the drug is prolonged.' The principal biological function of the peripheral chemoreceptors is to increase ventilation in hypoxia,2 whereas most of the ventilatory response to hypercapnia is mediated centrally.3 The present study was done to examine the respiratory effects and their duration when almitrine was infused intravenously in healthy man. Respiratory measurements were obtained not only during breathing of room air but also during the inhalation of either carbon-dioxide-enriched or hypoxic gas mixtures. In the first part of the investigation double-blind, placebo-controlled studies were performed with the drug given in a single dosage. Then the activity of the drug was examined on separate test days with three different doses.
MethodsThe experimental subjects were 15 healthy medical students or were male and one was female. Three subjects participated in both parts of the study. All were familiarised with the respiratory test procedures on a previous occasion and participated in the study after giving informed consent.For placebo-controlled studies 12 subjects were given successive 45-minute infusions of almitrine (0.5 mg/kg/h) and placebo intravenously. These were allocated randomly but equally under doubleblind conditions to separate treatment groups 1 and 2. In group 1 placebo preceded almitrine and in group 2 the order of infusion was reversed. Respiratory measurements were made beforehand (baseline) and near the end of each infusion period.In the study of dose-response relationships almitrine was infused in six subjects at different rates (0.25, 0-5 and 1-0 mg/kg/h) under single-blind conditions on three test days separated by intervals of at least one week. Again the infusions lasted 45 minutes and respiratory measurements were made before (baseline) and near the end of each infusion.Respiratory measurements were performed during a 20-minute period, to determine in turn (a) vent...
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