Negative lusitropic property of nifekalant identified using ventricular pressure-volume loop analyses in anesthetized monkeys

Abstract

The present study was conducted to clarify multiple cardiohemodynamic and electrophysiological properties including inotropic/lusitropic effects of nifekalant, a class III antiarrhythmic drug, in an isoflurane-anesthetized monkey. Nifekalant was administered intravenously at the therapeutic dose of 0.3 mg/kg over 10 min to male cynomolgus monkeys (n=4), followed by higher dose of 1 (n=3) or 3 mg/kg (n=1) that was limited due to arrythmogenicity. Left ventricular (LV) pressure-volume (PV) analysis revealed that the 0.3 mg/kg dose of nifekalant induced a negative lusitropic effect, recognized as a decrease in maximal rate of reduction in LV pressure and a prolonged isovolumic relaxation time. Nifekalant also decreased heart rate and increased LV end-diastolic pressure, but had no effects on the other cardiohemodynamic parameters examined. Electrophysiological analysis showed nifekalant at 0.3 mg/kg prolonged QT/QTc intervals with no evidence of arrhythmia. Higher doses of nifekalant induced ventricular arrhythmia in 3 out of 4 animals, in which both the short-term and long-term variability of the QT interval increased just before the occurrence of arrhythmia. In conclusion, a therapeutic dose of nifekalant had no effect on inotropic activity or cardiac compliance, whereas it showed negative lusitropic properties and QT/QTc prolongation in isoflurane-anesthetized monkeys. In addition, higher doses of nifekalant showed remarkable QT/QTc prolongation leading to arrhythmogenicity, which showed good accordance with clinical findings. Caution should be paid to negative lusitropic properties as well as arrhythmogenisity for the safe use of nifekalant.

The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model

“…The preservation of biological activities during the conjugation process is the apogee of this platform, offering significant advantages over traditional drug development and the possibility of improved therapeutic outcomes for complex diseases. C-192, despite its complex structure and a limited number of animal subjects, demonstrated stable physical properties and acceptable pharmacokinetic profiles [65][66][67][68], highlighting the clinical feasibility of UniStac. C-192 presents an ideal PK profile, making it suitable for weekly administration in clinical practice.…”

Trastuzumab-Induced Negative Chronotropic and Lusitropic Effects in Cynomolgus Monkeys

“…The cynomolgus monkey was selected because it is one of the most commonly used laboratory animals in nonclinical toxicity and safety pharmacology studies, 12,13 and there are available background data of cardiovascular evaluation using the PV loop method for representative inotropic/lusitropic drugs in this species. 10,14,15 The animals were placed individually in stainless steel cages (W 594 mm • D 870 mm • H 1015 mm) (Shintoyo Seisakusho Inc, Saitama, Japan) and housed in the following environments: room temperature, 18-288C; relative humidity, 30%-70%; illumination, 300 luces or more; lighting, 12-hour light (7:00 to 19:00); and ventilation, 10 to 20 air changes/h. For environmental enrichment, throughout the experimental period, toys were placed in the housing cages of all animals and side dishes were given once a day except holidays.…”

Trastuzumab-induced negative chronotropic and lusitropic effects in cynomolgus monkeys

“…The cynomolgus monkey was selected because it is one of the most commonly used laboratory animals in nonclinical toxicity and safety pharmacology studies, 12,13 and there are available background data of cardiovascular evaluation using the PV loop method for representative inotropic/lusitropic drugs in this species. 10,14,15 The animals were placed individually in stainless steel cages (W 594 mm • D 870 mm • H 1015 mm) (Shintoyo Seisakusho Inc, Saitama, Japan) and housed in the following environments: room temperature, 18-288C; relative humidity, 30%-70%; illumination, 300 luces or more; lighting, 12-hour light (7:00 to 19:00); and ventilation, 10 to 20 air changes/h. For environmental enrichment, throughout the experimental period, toys were placed in the housing cages of all animals and side dishes were given once a day except holidays.…”