Distinct pathophysiological mechanisms of Heterometrus laoticus and Lychas mucronatus scorpion venoms on cardiovascular and renal functions

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  Distinct pathophysiological mechanisms of Heterometrus laoticus and Lychas mucronatus scorpion venoms on cardiovascular and renal functions Abstract Background:    Heterometrus laoticus and Lychas mucronatus are widely distributed in Southeast Asia, yet their pathophysiological effects of both venoms remain poorly characterized due to low human fatality rates. This study compared their venom compositions and acute cardiovascular and renal effects. Methods:   Anesthetized male New Zealand White rabbits were monitored for blood pressure (BP), heart rate (HR), and renal clearance following intravenous administration of crude venom (0.5 mg/kg). Venom components were identified via LC-MS/MS, and hematological/biochemical parameters were assessed. Results:    H. laoticus venom induced a rapid, transient hypotension ( p < 0.05), followed by a mild, prolonged hypotensive phase (up to 120 min). Conversely, L. mucronatus venom elicited a biphasic response: ...

In vitro-in vivo discord: a preclinical study of AZD2716 and its racemate with comparison to varespladib for the development of snake venom sPLA2 inhibitors

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In vitro-in vivo discord: a preclinical study of AZD2716 and its racemate with comparison to varespladib for the development of snake venom sPLA2 inhibitors

Abstract

We evaluated a family of repurposed sPLA2 inhibitors as novel candidate snakebite envenoming therapeutics. Stereospecific (R)-7 AZD2716 and its racemic mixture were compared to varespladib in an in vitro sPLA2 assay against a sample of 26 venoms from medically important snake species from five continents. All compounds demonstrated potent nano- to picomolar IC50 values, comparable to the benchmark inhibitory profile of varespladib. Surprisingly, however, this in vitro efficacy did not translate to survival in an in vivo mouse model under GLP standard conditions at an independent third party laboratory. In animal rescue studies evaluating both oral and IV dosing against the same four high sPLA2 venoms, varespladib demonstrated more consistent survival duration versus the chirally separated AZD2716 enantiomer and racemate following single-dose intravenous or two-dose oral drug administration. Additionally, the stereospecific AZD2716 did not provide the same survival advantage as the racemic mixture and neither molecule resulted in the same survival advantage as varespladib in vivo (p < 0.05), despite similar in vitro potency. These findings highlight the importance of following in vitro inhibition assays with preclinical studies in drug candidate selection for lead compounds and advancement to clinical development.
Hearth, J. L., Surovtseva, Y., Karjala, Z., Casewell, N. R., Giang, K., & Lewin, M. R. (2026). In vitro-in vivo discord: A preclinical study of AZD2716 and its racemate with comparison to varespladib for the development of snake venom sPLA2 inhibitors. Toxicon: X, 100243. https://doi.org/10.1016/j.toxcx.2026.100243