Toxicokinetics and toxicity of centhaquin in dogs

Centhaquin 在狗体内的毒代动力学和毒性

• 批准号: 9345650
• 负责人: Manish S Lavhale
• 金额: $ 27.71万
• 依托单位: PHARMAZZ, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-20 至 2018-11-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9345650
• 关键词: Adrenergic Agents; Adrenergic Receptor; Amber; Biochemical; Blood; Blood Coagulation Factor; Blood Pressure; Blood Volume; Brain; Canis familiaris; Cardiac Output; Categories; Cessation of life; Chemicals; Chemistry; Citrates; Clinical; Colloids; Comparative Study; Dose; Drug Kinetics; Erythrocytes; Family suidae; Glass; Goals; Guidelines; Half-Life; Heart; Heart Rate; Hemorrhage; Hemorrhagic Shock; Hour; Hypovolemic Shock; Lactated Ringer' s Solution; Lead; Lethal Dose 50; Liquid substance; Metabolic Pathway; Metabolic acidosis; Modeling; Morbidity - disease rate; Mus; No-Observed-Adverse-Effect Level; Norepinephrine; Organ; Oryctolagus cuniculus; Patients; Perfusion; Peripheral Resistance; Pharmacologic Actions; Plasma; Process; Published Comment; Pulse Pressure; Rattus; Recommendation; Recovery; Resuscitation; Rights; Safety; Saline; Sodium; Stroke Volume; Tissues; Toxic effect; Toxicokinetics; Toxicology; Trauma; United States Food and Drug Administration; Universities; Validation; Vasoconstrictor Agents; Venous; Vial device; Water; analytical method; animal rule; constriction; crystalloid; histopathological examination; innovation; intravenous injection; meetings; method development; mortality; novel; pressure; quinoline; sex

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.

尽管进行了复苏，但低血容量性休克是造成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，其中许多死亡是在 可以预防的目前迫切需要更好的治疗方法来治疗失血性休克。我们开创 centhaquin（2-[2-（4-（3-甲基苯基）-1-哌嗪基）]乙基-喹啉）是一种非常有效 复苏剂它作用于α2B和α2A肾上腺素能受体，对α2B更有选择性 肾上腺素能受体我们对centhaquin和现状进行了比较研究 复苏剂分为3个不同的类别：（1）液体，如乳酸林格氏液，高渗 生理盐水;（2）肾上腺素能药物，如去甲肾上腺素和（3）新鲜血液。我们使用（1）大鼠的结果 固定压力失血模型，（2）创伤不受控制出血的兔模型，和（3）猪 大量失血模型表明centhaquin在降低死亡率方面非常有效 低血容量性休克与其他复苏剂（血管加压药）不同，centhaquin增加了 通过增加每搏输出量和心输出量增加平均动脉压;以及降低心率， 全身血管阻力（SVR）。其机制可能是centhaquin（1）作用于静脉 α2B肾上腺素能受体产生收缩并增加静脉回流至心脏;（2）刺激 钠在大脑中的感觉（通过大脑α2B肾上腺素能受体），以增加血管内血液 （3）刺激中枢α2A肾上腺素能受体，使SVR降低。我们有 制备了高纯度的水溶性（>99.6%）柠檬酸centhaquin， 表征研究。centhaquin的鉴别、分析方法开发和验证 已完成稳定性研究表明，centhaquin在琥珀色中储存时在5 ± 3 ºC下稳定 玻璃瓶超过36个月。毒理学研究，根据OECD指南，在小鼠、大鼠和 家兔的LD_（50）分别>100 mg/kg、79.43 mg/kg和9.55 mg/kg。无明显不良 效应水平（N. O. A. E. L）centhaquin在小鼠、大鼠和兔中的最低剂量为1.0 mg/kg， 至有效剂量0.01 mg/kg。药代动力学研究表明，在大鼠和犬中的半衰期较短。 Pharmazz与USFDA进行了B类IND前会议（PIND 127938），并收到了评论 建议在犬中进行重复给药毒理学和毒代动力学研究， 主研究组3只/性别/剂量，恢复组2只/性别/剂量。因此，我们计划进行 按照USFDA的要求，在比格犬中进行centhaquin的毒性和毒代动力学研究。毒理学 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产物， 是创新的，并提供了更好地了解centhaquin的药理作用。