体外和体内的临床前蛇毒抑制试验确定了金属蛋白酶抑制药物作为潜在的未来治疗蛇咬伤的药物

IF 3.6 Q2 TOXICOLOGY Toxicon: X Pub Date : 2022-06-01 DOI:10.1016/j.toxcx.2022.100118
Stefanie K. Menzies , Rachel H. Clare , Chunfang Xie , Adam Westhorpe , Steven R. Hall , Rebecca J. Edge , Jaffer Alsolaiss , Edouard Crittenden , Amy E. Marriott , Robert A. Harrison , Jeroen Kool , Nicholas R. Casewell
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引用次数: 9

摘要

在撒哈拉以南的非洲,每年有超过25万人受到蛇咬伤的影响。由蛇毒引起的消耗性凝血病(VICC)是由高度丰富的激活凝血酶原的蛇毒金属蛋白酶(SVMPs)消耗凝血因子和消耗纤维蛋白原引起的。目前唯一有效的治疗方法是单价的samr非洲树蛇毒血清。目前迫切需要治疗方案,因为这种抗蛇毒血清通常难以获得,而且每瓶价格为6000美元,大多数蛇咬伤患者通常负担不起。因此,我们研究了四种SVMP抑制剂在体外和体内中和斑疹伤寒弧菌毒液的临床前疗效;基质金属蛋白酶抑制剂marimastat和priomastat,以及金属螯合剂二巯基醇和DMPS。typus的毒液在体外表现出svmp驱动的促凝表型。在体外实验中,Marimastat和priomastat对svmp介导的蛇毒促凝活性具有同等的抑制作用,而二巯基丙醇和DMPS的抑制作用要低得多。然而,当在使用混合性CD1小鼠的临床前小鼠模型中进行测试时,DMPS和marimastat显示出对毒液致命的部分保护,通过延长实验动物的生存时间来证明,而二巯基丙醇和priomastat在测试剂量下没有提供任何保护。本研究的临床前结果表明,DMPS和marimastat具有作为新型小分子药物治疗typus蛇咬伤的潜力。这两种药物之前在临床前模型中已被证明对Echis ocellatus VICC有效,因此我们得出结论,应该进一步探索marimastat和DMPS作为潜在有价值的早期干预疗法,以广泛治疗撒哈拉以南非洲毒蛇咬伤后的VICC。
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In vitro and in vivo preclinical venom inhibition assays identify metalloproteinase inhibiting drugs as potential future treatments for snakebite envenoming by Dispholidus typus

Snakebite envenoming affects more than 250,000 people annually in sub-Saharan Africa. Envenoming by Dispholidus typus (boomslang) results in venom-induced consumption coagulopathy (VICC), whereby highly abundant prothrombin-activating snake venom metalloproteinases (SVMPs) consume clotting factors and deplete fibrinogen. The only available treatment for D. typus envenoming is the monovalent SAIMR Boomslang antivenom. Treatment options are urgently required because this antivenom is often difficult to source and, at US$6000/vial, typically unaffordable for most snakebite patients. We therefore investigated the in vitro and in vivo preclinical efficacy of four SVMP inhibitors to neutralise the effects of D. typus venom; the matrix metalloproteinase inhibitors marimastat and prinomastat, and the metal chelators dimercaprol and DMPS. The venom of D. typus exhibited an SVMP-driven procoagulant phenotype in vitro. Marimastat and prinomastat demonstrated equipotent inhibition of the SVMP-mediated procoagulant activity of the venom in vitro, whereas dimercaprol and DMPS showed considerably lower potency. However, when tested in preclinical murine models of envenoming using mixed sex CD1 mice, DMPS and marimastat demonstrated partial protection against venom lethality, demonstrated by prolonged survival times of experimental animals, whereas dimercaprol and prinomastat failed to confer any protection at the doses tested. The preclinical results presented here demonstrate that DMPS and marimastat show potential as novel small molecule-based therapeutics for D. typus snakebite envenoming. These two drugs have been previously shown to be effective against Echis ocellatus VICC in preclinical models, and thus we conclude that marimastat and DMPS should be further explored as potentially valuable early intervention therapeutics to broadly treat VICC following snakebite envenoming in sub-Saharan Africa.

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来源期刊
Toxicon: X
Toxicon: X Pharmacology, Toxicology and Pharmaceutics-Toxicology
CiteScore
6.50
自引率
0.00%
发文量
33
审稿时长
14 weeks
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