Summary
Intravenous dose-response relationships were used to correlate neuromuscular paralysis with the effects of fazadinium ( AH 8165 ) on autonomic mechanisms in anaesthetized cats and rhesus monkeys and with cardiovascular effects in man. In cats and monkeys neuromuscular paralysis of the twitch responses of the gastrocnemius muscle by fazadinium was accompanied by impairment of the vagally induced bradycardia, but cardiovascular disturbances were small. Blockade of sympathetic mechanisms and hypotension were only evident with supra-maximal doses. In man tachycardia was a common occurrence and in some patients hypertension occurred with doses of the drug needed for complete neuromuscular paralysis.
Fazadinium was three to four times more potent in rhesus monkeys than in cats and its course of action was considerably longer. The potency of the drug in man corresponded more closely to that in cats than in rhesus monkeys but its course of action in patients was similar to that in monkeys.
In man, dose-response curves were constructed for the contractions of the adductor pollicis muscles elicited by tetanic and single twitch stimuli applied to the corresponding ulnar nerves. The onset of paralysis of the tetanic contractions after the intravenous injection of fazadinium (0.4 mg/kg) occurred within two minutes, but recovery was slow and about 50 minutes were needed for its completion. Depression of the simultaneously recorded twitch responses was less marked, slower in onset and recovery was slightly more rapid. These effects were similar to those obtained with tubocurarine (0.2 mg/kg) but the action of fazadinium was slightly shorter.
Tetanic-tension ratios were computed after 30 and 50 per cent recovery from neuromuscular blockade in man. These ratios were lower with fazadinium than with tubocurarine and indicated that tetanic fade was greater and more persistent after fazadinium than after tubocurarine.
ésumé
On a administré par voie IV du Fazadinium (AH 8165) au chat et au singe de type Rhésus afin d’étudier les relations de doses à effet sur les mécanismes autonomes. Cette étude a aussi été faite chez l’homme pour les effets cardiovasculaires du produit.
Chez le chat et le singe, la paralysie du muscle gastrocnemien de la jambe a été accompagnée par une diminution de la bradycardie vaguale. De même on n’a observé que des effets sympathiques minimes alors que chez certains patients les doses nécessaires à 1’obtention d’une paralysie neuromusculaire ont entraîné une hypertension artérielle.
On a noté chez le singe une puissance d’action 3 à 4 fois plus grande que chez le chat ainsi qu’une plus longue durée d’action.
Chez l’homme, la puissance a été comparable à celle du Fazadinium chez le chat et la durée d’action plus longue.
On a pu établir chez l’homme des courbes représentant les relations dose/effet en observant la contraction de l’adducteur du pouce après application de stimuli téaniques ou isolés aux nerfs correspondants. On a observé une contraction soutenue avec une dose de 0.5 mg/kg après 40 sec. Le retour à la normale s’est fait après 50–60 minutes.
De même on a enregistré simultanément la réponse aux fasciculations. Le temps d’apparition a été plus long, la réponse moins marquée et la durée d’action plus courte. Ces effets sont similaires à ceux obtenus avec 0.2 mg/kg de DTC.
Le rapport tétanos/tension étudié après 30–50 pour cent de récupération chez l’homme, s’est révé1é inférieur avec le Fazadinium comparé à la DTC et l’affaiblissement tétanique (Tetanic fade) plus persistant.
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References
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Hughes, R., Payne, J.P. & Sugai, N. Studies on fazadinium bromide (AH 8165): A new non-depolarizing neuromuscular blocking agent. Canad. Anaesth. Soc. J. 23, 36–47 (1976). https://doi.org/10.1007/BF03004993
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DOI: https://doi.org/10.1007/BF03004993