Follman Kristin E, Morris Marilyn E
Pharmaceutical Sciences, University at Buffalo, United States.
Pharmaceutical Sciences, University at Buffalo, United States
J Pharmacol Exp Ther. 2022 May 3;382(1):21-30. doi: 10.1124/jpet.122.001108.
High doses of the partial agonist of the GABA receptor, γ-hydroxybutyric acid (GHB), causes respiratory depression that can lead to death. Previously, it has been shown that GABA receptor antagonism is able to prevent respiratory depression and sedation when inhibitors are pre-administered. In order to treat GHB overdoses, safety and efficacy of a treatment strategy at various times after GHB administration is necessary, in order to more closely replicate a true overdose situation. Preliminary studies developed an assay for SGS742 and determined its pharmacokinetics in rats. The effects of SGS742 on GHB-induced respiratory depression were evaluated when SGS742 administration was delayed 1 and 2 hours after intravenous or oral administration of GHB or γ-butyrolactone, a GHB prodrug. SGS742 reversed GHB-induced respiratory depression in a dose-dependent manner at both time points tested, with no effects on its toxicokinetics. However, some of the dosing paradigms resulted in toxicity in the form of tremors, seizures or abnormal movements. The tremors/seizures occurred in a manner that was dependent on both the dose and timing of SGS742 administration, and were not altered with pretreatment with gabazine, a GABA receptor inhibitor, and only partially reduced with pretreatment with NCS382, a selective GHB receptor antagonist. Additional studies with a second GABA antagonist SCH50911 demonstrated similar effects, producing reversal of respiratory depression but producing tremors and abnormal movements. Further studies are necessary in order to identify the potential use of GABA antagonism as a treatment strategy for GHB overdoses. There is no current treatment for overdoses of the drug of abuse γ-hydroxybutyric acid (GHB). Since the toxicodynamic effects of GHB, including respiratory depression and lethality, are mediated through GABA receptor agonism, GABA receptor antagonists may represent a therapeutic strategy to treat overdoses. This study demonstrates that while GABA receptor antagonists are effective as a pretreatment, they are less effective when administered at times after GHB administration and their administration is also associated with time- and dose-associated toxicity.
高剂量的γ-氨基丁酸（GHB）受体部分激动剂γ-羟基丁酸会导致呼吸抑制，甚至可能致死。此前研究表明，预先给予GABA受体拮抗剂能够预防抑制剂所致的呼吸抑制和镇静作用。为了治疗GHB过量中毒，有必要研究在GHB给药后不同时间进行治疗的安全性和有效性，以便更真实地模拟实际过量中毒情况。初步研究开发了一种针对SGS742的检测方法，并测定了其在大鼠体内的药代动力学。当在静脉注射或口服GHB或其前体药物γ-丁内酯后1小时和2小时延迟给予SGS742时，评估了SGS742对GHB诱导的呼吸抑制的影响。在两个测试时间点，SGS742均以剂量依赖性方式逆转了GHB诱导的呼吸抑制，且对其毒代动力学无影响。然而，某些给药方案导致了震颤、癫痫发作或异常运动等毒性反应。震颤/癫痫发作的发生方式取决于SGS742的给药剂量和时间，且用GABA受体抑制剂加巴嗪预处理后无变化，而用选择性GHB受体拮抗剂NCS382预处理仅部分减轻。使用第二种GABA拮抗剂SCH50911的进一步研究显示了类似的效果，即逆转呼吸抑制，但产生震颤和异常运动。为了确定GABA拮抗剂作为GHB过量中毒治疗策略的潜在用途，还需要进一步研究。目前尚无针对滥用药物γ-羟基丁酸（GHB）过量中毒的治疗方法。由于GHB的毒效学作用，包括呼吸抑制和致死性，是通过GABA受体激动介导的，GABA受体拮抗剂可能是治疗过量中毒的一种治疗策略。本研究表明，虽然GABA受体拮抗剂作为预处理有效，但在GHB给药后再给药时效果较差，且其给药还与时间和剂量相关的毒性有关。
