Gamma-Hydroxybutyrate: Toxicokinetics, Toxicodynamics and Treatment Strategies

描述（由申请人提供）：γ-羟基丁酸酯（GHB）是一种流行的滥用药物，通常在夜总会和“狂欢”中与酒精一起摄入，或作为药物辅助性侵犯的手段。高娱乐剂量和过量之间的范围很窄，因此急性中毒和过量是常见的。在与伽马-羟丁酸中毒有关的死亡临床报告中，呼吸抑制和呼吸停止是死亡的主要原因。对伽马-羟丁酸过量的有效药物治疗尚待确定。长期目标是确定治疗战略，以提高与伽马--羟丁酸中毒有关的发病率和死亡率，当伽马--羟丁酸单独摄入或与乙醇一起摄入时。我们已经报道，由于通过单羧酸转运蛋白（MCT）转运，GHB在肾脏中经历浓度依赖性重吸收，并且MCT抑制剂（如L-乳酸盐）的给药可增加GHB的肾脏和总清除率，降低脑细胞外液GHB浓度，并减少大鼠的睡眠时间。本竞争性更新的目的是使用呼吸抑制的临床相关终点，确定MCT抑制作为GHB过量治疗策略的治疗潜力，单独使用或与其他潜在有效策略联合使用。我们的具体目标是：（1）GHB引起的呼吸抑制的特征和确定改善GHB过量期间呼吸测量的治疗策略。本研究的目的是使用选择性神经递质受体拮抗剂来确定GHB诱导的呼吸抑制的机制。(2)确定口服GHB过量的有效治疗策略。我们假设MCT对GHB从肠道的吸收很重要，MCT抑制剂将降低GHB的生物利用度，并增加口服GHB中毒后的肾脏和总清除率。(3)GHB-酒精相互作用的表征和口服GHB/酒精过量的有效治疗策略的确定。我们假设高浓度的乙醇会增强GHB诱导的呼吸抑制，并会增加GHB中毒致死的风险。(4)多次接触伽马--羟丁酸后的毒代动力学和毒代动力学特征和确定有效的治疗策略。我们的假设是，过量使用GHB导致组织中MCT表达增加，导致转运和处置改变，以及对呼吸抑制的耐受性。本提案中的研究将评价口服和静脉注射MCT抑制剂（单独使用或与神经递质受体拮抗剂联合使用）的使用，以改善呼吸措施并预防GHB过量致死。这项研究是重要的，因为它解决了毒理学效应，呼吸抑制，介导GHB死亡，并在临床相关条件下应用该终点。通过将治疗策略与不同的作用机制相结合，这项研究将确定哪些药理干预措施具有治疗危及生命的GHB过量的治疗潜力。

DESCRIPTION (provided by applicant): γ-Hydroxybutyrate (GHB), a popular drug of abuse, is commonly ingested with alcohol at nightclubs and "raves", or as a means of drug-facilitated sexual assault. The range between high recreational doses and overdose is narrow, so that acute intoxications and overdoses are common. Respiratory depression and arrest represent the major cause of death in clinical reports of fatality associated with GHB intoxication. Effective pharmacological treatment for GHB overdoses has yet to be identified. The long-term objective is to identify treatment strategies that improve rates of morbidity and mortality associated with GHB intoxication, when GHB is ingested alone or with ethanol. We have reported that GHB undergoes concentration-dependent reabsorption in the kidney, due to transport by monocarboxylate transporters (MCTs), and that the administration of MCT inhibitors, such as L-lactate, can increase the renal and total clearances of GHB, decrease brain extracellular fluid concentrations of GHB, and decrease sleep time in rats. The purpose of this competing renewal is to determine the therapeutic potential of MCT inhibition as a treatment strategy for GHB overdose, alone and in combination with other potentially effective strategies, using the clinically relevant endpoint of respiratory depression. Our specific aims are: (1) Characterization of GHB-induced respiratory depression and identification of treatment strategies that improve measures of respiration during GHB overdose. The purpose of this aim is to identify the mechanism of GHB-induced respiratory depression using selective neurotransmitter receptor antagonists. (2) Identification of effective treatment strategies for oral GHB overdoses. We hypothesize that MCTs are important for the absorption of GHB from the intestine, and that MCT inhibitors will decrease the bioavailability of GHB, as well as increasing its renal and total clearances following oral GHB intoxication. (3) Characterization of the GHB-alcohol interaction and identification of effective treatment strategies for oral GHB/alcohol overdoses. We hypothesize that high concentrations of ethanol will potentiate GHB-induced respiratory depression, and will increase the risk of fatality due to GHB intoxication. (4) Characterization of the toxicokinetics and toxicodynamics of GHB after multiple exposures and identification of effective treatment strategies. Our hypothesis is that binge use of GHB results in both increased expression of MCTs in tissues leading to altered transport and disposition, as well as tolerance to respiratory depression. Studies in this proposal will evaluate the use of oral and IV administered MCT inhibitors, alone or combined with neurotransmitter receptor antagonists, to improve measures of respiration and prevent fatality with GHB overdoses. This research is significant as it addresses the toxicodynamic effect, respiratory depression, mediating GHB fatality, and applies this endpoint under clinically relevant conditions. By combining treatment strategies with different mechanisms of action, this research will determine which pharmacological interventions have therapeutic potential to treat life-threatening GHB overdoses.