Acute and subacute oral toxicity of artemisinin-hydroxychloroquine sulfate tablets in beagle dogs

Abstract

Artemisinin-hydroxychloroquine sulfate tablets (AH) are regarded as a relatively inexpensive and novel combination therapy for the treatment of various forms of malaria, particularly aminoquinoline drugs-resistant strains of Plasmodium falciparum. Our aim was to conduct acute and subacute oral toxicity studies in non-rodents to obtain more nonclinical data on the safety of AH. Acute toxicity evaluation was performed in beagle dogs at single doses of 230, 530, 790, 1180, 2660, and 5000 mg/kg. Beagle dogs at doses of 0, 56, 84, and 126 mg/kg were used to assess subacute toxicity for 14 days. The approximate lethal dose range for acute oral administration of AH in dogs is found to be 790–1180 mg/kg, and toxic symptoms prior to death include gait instability, limb weakness, mental fatigue, tachypnea, and convulsion. Repeated doses of AH in dogs caused vomiting, soft feces, decreased activity, anorexia, and splenic red pulp vacuolation. Of note, AH could reduce body weight gain and prolong the QTc interval of individual dogs. Therefore, the no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of oral administration of AH for 14 days in dogs are determined to be 84 mg/kg and 126 mg/kg, respectively.

Keywords:

• Artemisinin
• hydroxychloroquine sulfate
• acute toxicity
• subacute toxicity
• dogs
• evaluation
• safety

Acknowledgements

The authors would like to thank all technicians who conducted the studies.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The work was support by the Natural Science Foundation of China [Grant Number 81873218 and 82074301], the Science and Technology Project of Guangdong Province [Grant Number 2021A0505030060 and 2020A0505090009], and the Chinese Medicine Cooperation Special Program of the National Administration of Traditional Chinese Medicine [Grant Number GZYYGJ2021].