The 14-day repeated-dose toxicity study of a fixed-dose combination, QXOH/levobupivacaine, via subcutaneous injection in beagle dogs.

Abstract

QXOH-Levobupivacaine (LB) is a fixed-dose combination of 35-mM QXOH and 10-mM LB. It was developed for perioperative analgesia because of its long-acting analgesic effect. The purpose of this study was to evaluate the potential toxicity of QXOH-LB in beagle dogs in accordance with the Guidance on the repeated-dose toxicity published by the China Food and Drug Administration. Groups of five male and five female beagle dogs received normal saline, QXOH-LB (2, 4, and 8 mg/kg, calculated as QXOH), QXOH (2, 4, and 8 mg/kg), or LB (2 mg/kg, equals the concentration of LB in 8-mg/kg QXOH-LB group) at the volume of 1 mL/kg once per day for 14 days through subcutaneous injection. No mortality was observed. Dogs in the control group as well as animals treated with 2-mg/kg QXOH or QXOH-LB exhibited normal behaviors. Clinical signs of toxicity in dogs treated with 4 and 8 mg/kg of QXOH or QXOH-LB included decreased activity, unsteady gait, jerks, tremors, vocalization, emesis, ataxia, lateral/sternal recumbency, deep/rapid respiration, and gasping. Additionally, neurological function was found to be affected by QXOH and QXOH-LB at the doses of 4 and 8 mg/kg. All clinical signs were recovered within 24 h. The no-observed-adverse-effect level of QXOH and QXOH-LB was considered to be 2 mg/kg. Toxicokinetic data showed that exposure to QXOH and LB increased as QXOH-LB doses were increased from 4 to 8 mg/kg. There was no evidence of drug accumulation or any effect of gender.

• Authors: Jie Zhang, YuJun Zhang, Qinqin Yin, Jun Yang, Yi Kang, Deying Gong, Jin Liu, WenSheng Zhang
• Journal: Journal of applied toxicology : JAT (J Appl Toxicol) Vol. 41 Issue 8 Pg. 1241-1261 (08 2021) ISSN: 1099-1263 [Electronic] England
• PMID: 33184925 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 John Wiley & Sons, Ltd.

Chemical References

• Anesthetics, Local
• Drug Combinations
• QX-OH
• Lidocaine
• Levobupivacaine

Topics

• Anesthetics, Local (administration & dosage, toxicity)
• Animals
• Blood Coagulation (drug effects)
• Blood Pressure (drug effects)
• Body Temperature (drug effects)
• Dogs
• Drug Combinations
• Electrocardiography (drug effects)
• Female
• Levobupivacaine (administration & dosage, toxicity)
• Lidocaine (administration & dosage, analogs & derivatives, toxicity)
• Male
• Nervous System (drug effects)
• Respiratory Rate (drug effects)