Toxicokinetics and toxicity of centhaquin in dogs

In spite of resuscitation hypovolemic shock is responsible for major portion of posttraumatic death Most of these deaths occur during the first six hours of trauma and many of these deaths are preventable There is an urgent need for better treatment options in hemorrhagic shock We pioneered that centhaquin methylphenyl piperazinyl ethyl quinoline is a highly effective resuscitative agent It acts on B and A adrenergic receptors with more selectivity towards B adrenergic receptors We carried out comparative studies between centhaquin and status quo resuscitative agents grouped into different categories fluids such as Lactated Ringer s hypertonic saline adrenergic agents such as norepinephrine and fresh blood Our results using a rat model of fixed pressure blood loss rabbit model of uncontrolled bleeding with trauma and a pig model of massive blood loss indicate that centhaquin is highly effective in reducing the mortality following hypovolemic shock Unlike other resuscitative agents vasopressors centhaquin increased mean arterial pressure by increasing stroke volume and cardiac output and decreased heart rate and systemic vascular resistance SVR The proposed mechanism is that centhaquin acts on venous B adrenergic receptors to produce constriction and increase venous return to the heart stimulates sodium sense in the brain through brain B adrenergic receptors to increase the intravascular blood volume and stimulates central A adrenergic receptors to produce a decrease in SVR We have prepared highly pure water soluble andgt centhaquin citrate and completed chemical and physical characterization studies Identification analytical method development and validation for centhaquin have been completed Stability studies show that centhaquin is stable at C when stored in amber glass vials for more than months Toxicological studies as per OECD guidelines in mice rats and rabbits show LD andgt mg kg mg kg and mg kg respectively The No Observed Adverse Effect Level N O A E L of centhaquin in mice rats and rabbits was found to be mg kg compared to effective dose of mg kg Pharmacokinetic studies indicate a short half life in rat and dog Pharmazz had a type B pre IND meeting PIND with the USFDA and received the comments with recommendation to conduct a repeated dose toxicology and toxicokinetics in dogs with at least sex dose in the main group and sex dose for the recovery groups We therefore plan to conduct toxicity and toxicokinetic studies of centhaquin in Beagle dogs as required by the USFDA Toxicological and toxicokinetic studies of this novel compound may reveal metabolic pathways and metabolites that are innovative and provide better understanding of the pharmacological actions of centhaquin Hypovolemic shock is a serious state that results from excessive blood loss leading to inadequate tissue perfusion and oxygenation There are limited options available to treat this condition We discovered that centhaquin is a highly effective resuscitative agent that has good safety profile In this proposal we are aiming to conduct toxicity and toxicokinetic studies of centhaquin in dogs as required by USFDA to file an IND with the goal to develop and commercialize centhaquin as a novel resuscitative agent