Gamma-Hydroxybutyrate: Toxicokinetics, Toxicodynamics and Treatment Strategies

描述(由申请人提供)：γ-羟丁酸酯(GHb)，一种流行的滥用药物，通常在夜总会和“狂欢派对”中与酒精一起摄入，或作为药物促进的性侵犯的手段。娱乐性高剂量和过量之间的范围很窄，因此急性中毒和过量服药很常见。在与GHB中毒相关的死亡临床报告中，呼吸抑制和呼吸骤停是主要的死亡原因。对GHB过量的有效药物治疗尚未确定。长期目标是确定治疗策略，以提高单独或与乙醇一起摄入GHB时与GHB中毒相关的发病率和死亡率。我们已经报道，由于单羧酸转运体(MCT)的转运，GHb在肾脏中经历浓度依赖的重吸收，而MCT抑制剂如L-乳酸可以增加大鼠肾脏对GHb的清除量和总清除量，降低脑细胞外液中GHb的浓度，并减少睡眠时间。这项竞争性更新的目的是确定MCT抑制作为GHB过量治疗策略的治疗潜力，单独使用呼吸抑制这一临床相关终点，并与其他潜在有效策略结合使用。我们的具体目标是：(1)描述GHB引起的呼吸抑制的特征，并确定改善GHB过量期间呼吸测量的治疗策略。本研究的目的是利用选择性神经递质受体拮抗剂探讨GHB引起呼吸抑制的机制。(2)确定口服GHB过量的有效治疗策略。我们假设MCT对从肠道吸收GHB很重要，MCT抑制剂将降低GHB的生物利用度，并在口服GHB后增加其肾脏和总清除量。(3)GHB-酒精相互作用的表征和确定口服GHB/酒精过量的有效治疗策略。我们假设高浓度的乙醇会加重GHB引起的呼吸抑制，并会增加GHB中毒致死的风险。(4)多次暴露后GHB的毒代动力学和毒理动力学特征，并确定有效的治疗策略。我们的假设是，过量使用GHB会导致组织中MCTs表达增加，导致运输和处置的改变，以及对呼吸抑制的耐受性。这项建议中的研究将评估口服和静脉注射MCT抑制剂的使用，单独使用或与神经递质受体拮抗剂联合使用，以改善呼吸测量并防止GHB过量造成的死亡。这项研究具有重要意义，因为它解决了毒力效应、呼吸抑制、调节GHB死亡的问题，并将这一终点应用于临床相关条件。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物干预措施具有治疗威胁生命的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.