Ex vivo and in vivo assessment of the pharmacological interaction between the monoterpene cinnamaldehyde and antiparasitic drugs

Abstract

Given the growing development of drug resistance in gastrointestinal nematodes of ruminants as well as in soil-transmitted helminth parasites in humans, innovative parasite control strategies are needed. Numerous phytochemical compounds exhibit efficacy against parasites under laboratory conditions, but the in vivo effectiveness remains largely unexplored. This study investigated the effect cinnamaldehyde (CNM) on the pharmacological response of levamisole (LVM) and doramectin (DRM) against nematode naturally-infected lambs, through ex vivo and in vivo assessments. The modulation of the intestinal absorption/secretion by CNM (1.5 mM) was assessed by the diffusion-chamber model using Rho123 (0.5 µM) as substrate to measure their transport across the lamb´s ileum tissue. Two in vivo trials (T) were conducted to evaluate the pharmacological interaction between CNM/DRM and CNM/LVM in lambs infected with resistance nematodes. In T1 the oral co-administration of DRM (0.2 mg/kg) alone or combined with CNM (two doses of 100 mg/kg at 0 and 24 h), both as oral emulsion was evaluated. In T2, lambs received LVM (SC, 3.75 mg/kg) alone or in combination with CNM (two SC doses of 80 mg/kg at 0 and 3h). LVM plasma concentrations were measured by HPLC. The reduction in fecal egg count (FEC) was used as an indicator of the pharmacological response. The presence of CNM decreased Rho123 efflux across the lamb intestine, which may confirm a drug transport-related interaction. The presence of CNM increased the pharmacological response of DRM from 66.3 to 78.0% of FEC reduction. CNM enhanced LVM systemic exposure by increasing the LVM AUC by 20%, but a similar efficacy was obtained compared to the LVM alone treatment (55.5 and 51.4%). The presence of CNM may induce pharmacokinetic/pharmacodynamic interactions both ex vivo and in vivo. These findings provide valuable insights to the search for more effective and sustainable parasite control strategies in both veterinary and human medicine.