Derquantel and abamectin: Effects and interactions on isolated tissues of Ascaris suum

Startect® is a novel anthelmintic combination of derquantel and abamectin. It is hypothesized that derquantel and abamectin interact pharmacologically. We investigated the effects of derquantel, abamectin and their combination on somatic muscle nicotinic acetylcholine receptors and pharyngeal muscle glutamate gated chloride receptor channels of Ascaris suum. We used muscle-strips to test the effects of abamectin, derquantel, and abamectin + derquantel together on the contraction responses to different concentrations of acetylcholine. We found that abamectin reduced the response to acetylcholine, as did derquantel. In combination (abamectin + derquantel), inhibition of the higher acetylcholine concentration response was greater than the predicted additive effect. A two-micropipette current-clamp technique was used to study electrophysiological effects of the anthelmintics on: (1) acetylcholine responses in somatic muscle and; (2) on l-glutamate responses in pharyngeal preparations. On somatic muscle, derquantel (0.1-30 μM) produced a potent (IC50 0.22, CI 0.18-0.28 μM) reversible antagonism of acetylcholine depolarizations. Abamectin (0.3 μM) produced a slow onset inhibition of acetylcholine depolarizations. We compared effects of abamectin and derquantel on muscle preparations pretreated for 30 min with these drugs. The effect of the combination was significantly greater than the predicted additive effect of both drugs at higher acetylcholine concentrations. On the pharynx, application of derquantel produced no significant effect by itself or on responses to abamectin and l-glutamate. Abamectin increased the input conductance of the pharynx (EC50 0.42, CI 0.13-1.36 μM). Our study demonstrates that abamectin and derquantel interact at nicotinic acetylcholine receptors on the somatic muscle and suggested synergism can occur.

Abamectin acted as a non-competitive antagonist on Ascaris muscle. When combined with derquantel the effect was sometimes bigger than predicted additive effects. Derquantel had no detectable interaction with abamectin on the pharynx.102Highlights► Derquantel is a potent competitive nematode nAChR antagonist. ► Abamectin caused non-competitive antagonism of somatic muscle acetylcholine depolarizations. ► Derquantel had no effect on pharyngeal responses to glutamate or abamectin. ► The effect on somatic muscle at higher acetylcholine concentrations of the combination of abamectin and derquantel was bigger than the predicted additive effect.