摘要：

High doses of the partial agonist of the GABA(B) receptor, gamma-hydroxybutyric acid (GHB), cause respiratory depression that can lead to death. Previously, it has been shown that GABA(B) receptor antagonism is able to prevent respiratory depression and sedation when inhibitors are preadministered. To treat GHB overdoses, safety and efficacy of a treatment strategy at various times after GHB administration are necessary 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 gamma-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 GABAA receptor inhibitor, and only partially reduced with pretreatment with NCS382, a selective GHB receptor antagonist. Additional studies with a second GABA(B) antagonist SCH50911 demonstrated similar effects, producing reversal of respiratory depression but producing tremors and abnormal movements. Further work is necessary to identify the potential use of GABA(B) antagonism as a treatment strategy for GHB overdoses. SIGNIFICANCE STATEMENT There is no current treatment for overdoses of the drugGHB. Since the toxicodynamic effects of GHB, namely sedation and respiratory depression, are mediated through GABA(B) receptor agonism, GABA(B) receptor antagonists may represent a therapeutic strategy to treat overdoses. This study demonstrates that although GABA(B) 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 doseassociated toxicity, namely tremors or seizures.

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