Department of Veterinary Clinical Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
Division of Research Ophirex, Inc., Corte Madera, CA 94925, USA.
Toxins (Basel). 2023 Sep 7;15(9):557. doi: 10.3390/toxins15090557.
Antivenom is currently the standard-of-care treatment for snakebite envenoming, but its efficacy is limited by treatment delays, availability, and in many cases, species specificity. Many of the rapidly lethal effects of envenoming are caused by venom-derived toxins, such as phospholipase A2 (sPLA2); therefore, small molecule direct toxin inhibitors targeting these toxins may have utility as initial and adjunct therapies after envenoming. Varespladib (intravenous, IV) and varespladib-methyl (oral) have been shown to potently inhibit sPLA2s from snake venoms in murine and porcine models, thus supporting their further study as potential treatments for snakebite envenoming. In this pilot study, we tested the ability of these compounds to reverse neurotoxic effects of venom from the Australian and Papuan taipan () subspecies in juvenile pigs (). The mean survival time for control animals receiving Australian taipan venom (0.03 mg/kg, = 3) was 331 min ± 15 min; for those receiving Papuan taipan venom (0.15 mg/kg, = 3) it was 178 ± 31 min. Thirteen pigs received Australian taipan venom and treatment with either IV or oral varespladib (or with IV to oral transition) and all 13 survived the duration of the study (≥96 h). Eight pigs received Papuan taipan venom followed by treatment: Briefly: Two animals received antivenom immediately and survived to the end of the study. Two animals received antivenom treatment delayed 45 min from envenoming and died within 4 h. Two animals received similarly delayed antivenom treatment and were rescued by varespladib. Two animals were treated with varespladib alone after a 45-min delay. Treatment with varespladib only was effective but required repeat dosing over the course of the study. Findings highlight both the importance of early treatment and, as well, a half-life for the investigational inhibitors now in Phase II clinical trials for snakebite. Varespladib rapidly reversed weakness even when administered many hours post-envenoming and, overall, our results suggest that varespladib and varespladib-methyl could be efficacious tools in the treatment of sPLA2-induced weakness from envenoming. Further clinical study as initial therapy and as potential method of rescue from some types of antivenom-resistant envenomings are supported by these data.
抗蛇毒血清是目前治疗蛇咬伤的标准治疗方法，但由于治疗延迟、供应情况以及在许多情况下的物种特异性，其疗效有限。蛇毒衍生毒素（如磷脂酶 A2 [sPLA2]）会导致许多迅速致命的中毒作用；因此，针对这些毒素的小分子直接毒素抑制剂可能具有作为中毒后的初始和辅助治疗的效用。在小鼠和猪模型中，已证实瓦瑞沙布丁（静脉注射，IV）和瓦瑞沙布丁-甲（口服）能够有效抑制蛇毒液中的 sPLA2，因此支持进一步研究它们作为蛇咬伤治疗的潜在方法。在这项初步研究中，我们测试了这些化合物逆转幼年猪（）中来自澳大利亚和巴布亚棕伊蛇（）亚种的毒液神经毒性作用的能力。接受澳大利亚棕伊蛇毒液（0.03 mg/kg，n = 3）的对照组动物的平均存活时间为 331 min ± 15 min；接受巴布亚棕伊蛇毒液（0.15 mg/kg，n = 3）的动物存活时间为 178 ± 31 min。13 头猪接受澳大利亚棕伊蛇毒液并接受 IV 或口服瓦瑞沙布丁治疗（或 IV 到口服转换），所有 13 头猪在研究期间（≥96 h）均存活。8 头猪接受巴布亚棕伊蛇毒液，随后接受治疗：简而言之：2 只动物立即接受抗蛇毒血清治疗并存活至研究结束。2 只动物在中毒后 45 min 延迟接受抗蛇毒血清治疗，并在 4 h 内死亡。2 只动物接受类似延迟的抗蛇毒血清治疗并被瓦瑞沙布丁挽救。2 只动物在 45 min 延迟后单独接受瓦瑞沙布丁治疗。瓦瑞沙布丁单独治疗有效，但在研究过程中需要重复给药。研究结果既强调了早期治疗的重要性，也强调了目前正在进行 II 期临床试验的研究抑制剂的半衰期。瓦瑞沙布丁即使在中毒后数小时给药也能迅速逆转虚弱，总体而言，我们的结果表明，瓦瑞沙布丁和瓦瑞沙布丁-甲可能是治疗 sPLA2 诱导的中毒性虚弱的有效工具。这些数据支持将其作为初始治疗并作为某些类型抗蛇毒血清抵抗中毒的潜在挽救方法进行进一步的临床研究。
