Abstract 17521: Safety and Efficacy of Centhaquin as a Novel Resuscitative Agent for Hypovolemic Shock

Abstract

Centhaquin (PMZ-2010) is a cardiovascular active agent (0.01 to 0.05 mg/kg) which has been shown to have resuscitative effect in a (1) rat model of fixed pressure blood loss, (2) rabbit model of uncontrolled bleeding with trauma, and (3) pig model of massive blood loss. PMZ-2010 produced a decrease in heart rate and vascular resistance; however, it increased mean arterial pressure by increasing cardiac output. We embarked on studies to develop PMZ-2010 as a resuscitative agent for hypovolemic shock. Toxicological studies were carried out and intravenous injection of PMZ-2010 in mice, rats and rabbits showed LD50 >100 mg/kg, 79.43 mg/kg and 9.55 mg/kg, respectively. The No Observed Adverse Effect Level (N.O.A.E.L.) of PMZ-2010 determined after repeated (28 days) intravenous injections of different doses in mice, rats and rabbits was found to be 1.0 mg/kg. A 14 day repeated dose toxicity study of PMZ-2010 (0.01, 0.10 and 1.0 mg/kg, iv) in canine model (beagle dog) was conducted and there were no clinical symptoms of toxicity in low and middle whereas in high dose (1.0 mg/kg) temporary sluggishness, shivering and salivation was observed, while biochemical profile was normal in all groups. We conducted a single center randomized, double-blind, placebo-controlled, single and multiple-ascending dose phase I study in healthy male subjects to evaluate the safety of PMZ-2010 (NCT02408731). The study population comprised 6 cohorts of 4 subjects each, which were randomized so that 3 subjects received the active drug and 1 subject received placebo. For single ascending dose cohorts, the initial dose of PMZ-2010 was 0.005 mg/kg, iv infusion. Based on the safety and tolerability of the administered dose, subsequent escalation of doses 0.01, 0.05 0.10 and 0.15 mg/kg was performed and maximum tolerated dose (MTD) was found to be 0.10 mg/kg. For multiple-ascending dose cohorts, the initial dose/day of PMZ-2010 was equal to maximum tolerated dose (MTD) 0.10 mg/kg (3 X 0.033 mg/kg/day) for 2 days. Subsequent escalation of dose was done up to 2 times MTD 0.20 mg/kg (3 X 0.067 mg/kg/day) for 2 days. It is concluded that MTD of PMZ-2010 in humans is 0.10 mg/kg and can be safely used for its resuscitative effect. (Mr. Tajuddin and Dr. D. Chilkoti are acknowledged for assisting in clinical studies).