Preliminary Assessment of Rx 72601, a New Anticholinesterase in Man: Reversal of Competitive Neuromuscular Blockade

Abstract

The effect of RX 72601, neostigmine plus atropine, or saline on neuromuscular blockade with (+)-tubocurarine was studied in a double blind trial in four healthy male volunteers. 2 The methods used to assess neuromuscular function were voluntary grip strength and indirectly evoked muscle twitches. The muscarinic action was assessed by measuring intestinal motility with a pressure sensitive radio pill, and auscultation of the abdomen. Blood pressure and pulse rate were also recorded. The degree of acetylcholinesterase inhibition achieved in whole blood was determined before and at intervals after the administration of the anticholinesterases. 3 Both RX 72601 (0.66-0.83 mg) and neostigmine (2.5 mg) completely reversed the neuromuscular blockade produced by tubocurarine, but the time course of reversal differed. RX 72601 (0.66-0.83 mg) produced similar inhibition of acetylcholinesterase in whole blood to neostigmine (2.5 mg). The doses of RX 72601 used caused minimal stimulation at muscarinic sites as evidenced by the limited effect on pulse rate and intestinal activity. 4 It was concluded that RX 72601 could be safely used to reverse the effects of neuromuscular blockade without the need for premedication with atropine.

Temperature and Behavioural Responses Induced in the Unanaesthetized Cat by the Central Administration of Rx72601, a New Anticholinesterase

“…In addition, results from earlier work in both animals (Metcalf & Dettmar, 1975;G. Metcalf, G. Shilcock & M.H. Smith, unpublished observations) and man (Dettmar et al, 1974b) when applied to the present experiments suggest that the doses used would cause virtually complete inhibition of acetylcholinesterase in the restricted areas of drug application. Alternatively, most of the previous studies have used carbachol as the cholinomimetic agent; this drug is known to stimulate both muscarinic and nicotinic receptors in the periphery, and Myers (1974) has suggested that behavioural responses produced by this drug may result from stimulation of CNS receptors with muscarinic characteristics.…”

“…A higher dose of RX7260 1 produced mydriasis and nystagmus. This duration of action corresponds to the duration of acetylcholinesterase inhibition previously measured in vivo (Dettmar et al, 1974b).…”

“…cis-2-(3-hydroxy-phenyl)-1 -pyrrolidino cyclohexane methobromide (Dettmar, Lewis, Metcalf, Readhead, Smith, Gillett, Hedges & Richens, 1974a;Dettmar, Metcalf, Smith, Gillett, Hedges & Richens, 1974b) was injected into the ventricles, or perfused at selected diencephalic sites, in the conscious cat. This compound is one of a series of anticholinesterases recently developed (Lewis, Readhead, Metcalf, Smith & McNally, 1973) and was considered suitable for the present study because it has been shown to lack direct agonist activity at post-synaptic cholinoceptor sites (C.F.C.…”

Evaluation of Rx 72601 as an Anti-Curare Agent

“…A similar biochemical result was obtained in man, suggesting that this same dose would be effective in reversing the effects of non-depolarizing muscle relaxants in a clinical situation. This suggestion has now been confirmed in volunteer studies where it was found that 10 /*g/kg RX 72601 was effective in reversing partial neuromuscular block-ade induced by tubocurarine (Dettmar, Gillett et al, 1974).…”

“…Doses necessary to exert these so-called anti-curare effects had only minimal effects on the cardiovascular and respiratory systems, so that there was no need to pretreat animals with atropine before the administration of RX 72601. These favourable animal results have since been extended in human volunteer studies (Dettmar, Gillett et al, 1974) where the standard combination of neostigmine plus atropine was compared with RX 72601 given alone for both its anticurare properties and the incidence of cholinergic stimulation at muscarinic sites. The results obtained confirmed the ability of RX 72601 to reverse neuromuscular blockade produced by nondepolarizing relaxants and the lack of side effects produced by the drug.…”