Rapid In vitro techniques for the assessment of the membrane-stabilizing activity of drugs

Abstract

Membrane-stabilizing activity (MSA) is a pharmacological property possessed by many drugs of different therapeutic classes (e.g. adrenergic receptor blockers, antidepressants, opiate analgesics, anaesthetics, barbiturates, tranquillizers and Class I antiarrhythmic drugs). Although it may not be of great importance in therapeutic dosage, M S A may become significant in overdosage, by exerting a local anaesthetic action in the myocardium and CNS, as was reported in a recent case of fatal propanolol poisoning (Hong, Yang & Chiang, 1983). In a recent preliminary study of records of deaths due to poisoning in this country between 1975 and 1983, and of total numbers of prescriptions issued during that period for the chemicals concerned, we found that some 30% of all fatal poisonings were caused by agents possessing MSA. Al though the pharmacological mechanisms involved in these cases of overdose were diverse, there were some indications that further study of the possible contribution o f MSA to the lethal toxicity of drugs and poisons would be useful and that the testing of new drugs should include an assessment of this activity as one index of their potential to cause fatal poisoning when taken in overdose. We have identified and compared some simple and rapid in vitro unicellular assays for the quantitative assessment of MSA. The erythrocyte osmotic lysis test has been reported to correlate on a 1:1 drugconcentrat ion basis with the frog sciatic nerve conduction inhibition test (Seeman, 1972) and in the trans-membrane migration human sperm motility test (Hong, Chaput de Saintonge & Turner, 1981a), MSA is considered to be the major pharmacological property being measured (Hong & Chiang, 1984). Again, the potency of local anaesthetics in both rat and frog sciatic nerve tests has been shown to correlate with results obtained for sperm motility inhibition (Hong, 1982). We report here an initial assessment of a new assay using a ciliated protozoon, Tetrahymena pyriformis, the findings on a range of drugs being compared with those obtained in the erythrocyte osmotic lysis and sperm motility tests.