Toxicokinetics and toxicity of centhaquin in dogs

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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 (2-[2-(4-(3-methylphenyl)-1-piperazinyl)] ethyl-quinoline) is a highly effective resuscitative agent. It acts on α2B and α2A adrenergic receptors with more selectivity towards α2B adrenergic receptors. We carried out comparative studies between centhaquin and status quo resuscitative agents grouped into 3 different categories: (1) fluids such as Lactated Ringer’s, hypertonic saline; (2) adrenergic agents such as norepinephrine and (3) fresh blood. Our results using (1) a rat model of fixed pressure blood loss, (2) rabbit model of uncontrolled bleeding with trauma, and (3) 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 (1) acts on venous α2B adrenergic receptors to produce constriction and increase venous return to the heart; (2) stimulates sodium sense in the brain (through brain α2B adrenergic receptors) to increase the intravascular blood volume; and (3) stimulates central α2A adrenergic receptors to produce a decrease in SVR. We have prepared highly pure water soluble (>99.6%) 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 5 ± 3 ºC when stored in amber glass vials for more than 36 months. Toxicological studies, as per OECD guidelines, in mice, rats and rabbits show 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 centhaquin in mice, rats and rabbits was found to be 1.0 mg/kg compared to effective dose of 0.01 mg/kg. Pharmacokinetic studies indicate a short half-life in rat and dog. Pharmazz had a type B pre-IND meeting (PIND127938) with the USFDA and received the comments with recommendation to conduct a repeated dose toxicology and toxicokinetics in dogs with at least 3/sex/dose in the main group and 2/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.