Toxicokinetics and toxicity of centhaquin in dogs

尽管复苏，低血容量性休克是创伤后死亡的主要原因。 大多数死亡发生在创伤的前六个小时，其中许多死亡是 是可以预防的。对于失血性休克，迫切需要更好的治疗方案。我们开创了 2-[2-(4-(3-甲基苯基)-1-哌嗪基)]乙基喹啉是一种高效的 复苏剂。它作用于α2B和α2A肾上腺素能受体，对α2B有更高的选择性 肾上腺素能受体。我们对森他喹和现状进行了比较研究。 复苏药物分为三类：(1)液体，如乳酸林格氏液、高渗液 生理盐水；(2)肾上腺素能药物，如去甲肾上腺素；(3)新鲜血液。我们的结果使用(1)一只大鼠 定压失血模型，(2)兔创伤失血模型，(3)猪 大出血模型显示森他喹在降低死亡率方面非常有效。 低血容量性休克后。与其他复苏药物(血管升压药)不同的是，centhquin增加了 平均动脉压通过增加每搏量和心输出量；以及降低心率和 全身血管阻力(SVR)。其作用机制是Centhquin(1)作用于静脉。 α2B肾上腺素能受体产生收缩并增加静脉返回心脏；(2)刺激 大脑中的钠感觉(通过脑α2B肾上腺素能受体)增加血管内血液 (3)刺激中枢α-2A型肾上腺素能受体，使SVR降低。我们有 制备了高纯度的水溶性(&gt；99.6%)柠檬酸森特奎因，并完成了化学和物理性质 定性研究。森他喹的鉴定、分析方法的建立及验证 已经完工了。稳定性研究表明，塞他喹在琥珀中储存时，在5±3℃下稳定 玻璃瓶的使用时间超过36个月。毒理学研究，根据经合组织的指南，对小鼠、大鼠和 兔LD50和GT分别为100 mg/kg、79.43 mg/kg和9.55 mg/kg。未观察到的不良反应 效果级别(N.O.A.E.L.)森他喹在小鼠、大鼠和兔体内的残留量为1.0 mg/kg 有效剂量为0.01 mg/kg。药代动力学研究表明，该药在大鼠和狗体内的半衰期较短。 Pharmazz与美国食品和药物管理局举行了B型Pre-IND会议(PIND127938)，并收到了评论 建议在狗身上进行重复剂量的毒理学和毒代动力学研究，至少 主要组为3/性别/剂量，恢复组为2/性别/剂量。因此，我们计划进行 按照美国食品和药物管理局的要求，进行森特喹在Beagle犬体内的毒性和毒代动力学研究。毒理学 对这种新化合物的毒代动力学研究可能揭示代谢途径和代谢物 具有创新性，有助于更好地了解森他喹的药理作用。

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.