Safety pharmacology assessment of Ethanamizuril, a novel triazines coccidiostat

Highlights

• A safety pharmacology study of triazines coccidiostats was conducted for the first time.

• No adverse effects caused by Ethanamizuril in the respiratory, cardiovascular and central nervous systems were found.

• It provides a reliable basis for the safe use of Ethanamizuril in future.

Abstract

In the current study, to support the safety pharmacology assessment of Ethanamizuril as a new potent anticoccidial agent of triazine compounds, the effects of Ethanamizuril on the central nervous system, cardiovascular system and respiratory system were investigated. Using locomotor activity test, climbing behavior test and nembutal subthreshold hypnotic test at each time point after oral administration of Ethanamizuril to mice, the effects on the central nervous system were evaluated. An assessment of Ethanamizuril effects on the cardiovascular and respiratory system were performed by the use of a telemetry system in conscious beagle dogs. The results showed that the treatment of Ethanamizuril had no effects on motor activity, behavioral changes, coordination, and sensory/motor reflex responses in mice. There were also no changes in heart rate, blood pressure, and electrocardiogram at all doses and each time points in beagle dogs. Our data suggested that Ethanamizuril showed no adverse effects on the central nervous system, cardiovascular system, and respiratory system.

Introduction

Coccidiosis is caused by development and reproduction of multiple species of the Eimeria protozoa, which results in considerable impairment of growth and feed utilization in poultry industry. The substantial economic burden caused by avian coccidiosis is estimated to be more than US$3 billion annually to the industry worldwide (Ritzi et al., 2014; Kadykalo et al., 2018). To prevent the outbreak of coccidiosis, coccidiostats were added to the chicken feed. The long-term using of the drugs has made the Eimeria spp. develop resistant to them in many geographic regions (Peek and Landman, 2011; Yang et al., 2015; Lan et al., 2017). Triazines, including diclazuril and toltrazuril, that have been used globally in the prevention and treatment of protozoal diseases, most commonly in coccidiosis of veterinary interest, but have generated resistance problems in recent years (Zhang et al., 2014; Stock et al., 2018). The drug resistance of coccidia is a potential threat to poultry farming that makes it crucial to seek out for new anticoccidial drugs.

More recently, a novel coccidiostat, Ethanamizuril (EZL) has been independently developed by the Shanghai Veterinary Research Institute of the Chinese Academy of Agricultural Sciences in recent years (Zhao et al., 2017). EZL belongs to triazine compounds (The chemical structure of EZL is shown in Fig. 1). The studies on EZL with 10 mg/kg in feed showed a high anticoccidial activity on Eimeria tenella, anticoccidia indexes (ACI) of which were 185–190. EZL mainly acted on the schizogony stage of Eimeria tenella, with peak activity during the second-generation merozoite stage (Li et al., 2020). Furthermore, at the recommended dose (10 mg/kg in the feed or 10 mg/l in the drinking water), EZL has displayed excellent effectiveness against other Eimeria protozoa such as Eimeria. necatrix, Eimeria. acervulina, and Eimeria. Maxima. It's even effective for coccidian which resistance to diclazuril and toltrazuril (both belong to triazine compounds), which illustrates its future wide application prospective. The chemical synthesis of this compound has been published in China Patent No. ZL 2013105527952 (Zhang et al., 2015) and Japan Patent No. 6106798.

Veterinary drugs used in livestock breeding can enter the human body through its residues and threaten human health (Patel et al., 2018). As a novel coccidiostat with the potential to be used widely in poultry industry for the prevention and treatment of coccidiosis in future, the safety pharmacology evaluations have not been investigated although many characteristics of EZL have been revealed in toxicology studies. The safety pharmacology core battery was investigated in the present study.