Usefulness of simultaneous and sequential monitoring of glucose level and electrocardiogram in monkeys treated with gatifloxacin under conscious and nonrestricted conditions.

Abstract

Drug-induced cardiac electrophysiological abnormalities accompanied by hypoglycemia or hyperglycemia increase the risk for life-threatening arrhythmia. To assess the drug-induced cardiotoxic potential associated with extraordinary blood glucose (GLU) levels, the effect of gatifloxacin (GFLX) which was frequently associated with GLU abnormality and QT/QTc prolongations in the clinic on blood GLU and electrocardiogram (ECG) parameters was investigated in cynomolgus monkeys (n=4) given GFLX orally in an ascending dose regimen (10, 30, 60 and 100 mg/kg). Simultaneous and sequential GLU and ECG monitoring with a continuous GLU monitoring system and Holter ECG, respectively, were conducted for 24 h under free-moving conditions. Consequently, GFLX at 30 and 60 mg/kg dose-dependently induced a transient decrease in GLU without any ECG abnormality 2-4 h postdose. Highest dose of 100 mg/kg caused severe hypoglycemia with a mean GLU of <30 mg/dL, accompanied by remarkable QT/QTc prolongations by 20-30% in all animals. In contrast, hyperglycemia without QT/QTc prolongations was noted 24 h after dosing in one animal. A close correlation between GLU and QTc values was observed in animals treated with 100 mg/kg, suggesting that GFLX-induced hypoglycemia enhanced QT/QTc prolongations. Furthermore, the 24-h sequential GLU monitoring data clearly distinguished between GFLX-induced GLU abnormality and physiological GLU changes influenced by feeding throughout the day. In conclusion, the combined assessment of continuous GLU and ECG monitoring is valuable in predicting the drug-induced cardio-electrophysiological risk associated with both GLU and ECG abnormalities.

• Authors: Yu Yoshimatsu, Tomomichi Ishizaka, Katsuyoshi Chiba, Kazuhiko Mori
• Journal: Experimental animals (Exp Anim) Vol. 67 Issue 2 Pg. 281-290 (May 10 2018) ISSN: 1881-7122 [Electronic] Japan
• PMID: 29311442 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Fluoroquinolones
• Gatifloxacin

Topics

• Administration, Oral
• Animals
• Blood Glucose (metabolism)
• Consciousness (physiology)
• Dose-Response Relationship, Drug
• Electrocardiography (drug effects)
• Female
• Fluoroquinolones (administration & dosage, adverse effects)
• Gatifloxacin
• Humans
• Hypoglycemia (chemically induced, diagnosis, prevention & control)
• Long QT Syndrome (chemically induced, diagnosis, prevention & control)
• Macaca fascicularis
• Male
• Monitoring, Physiologic
• Motor Activity (physiology)
• Predictive Value of Tests