However, due to the reasons highlighted above, we argue that the relevance of the death or survival of an animal observed in rodent lethality studies, lethality prevention studies or rescue models, to an envenomed human with snakebite is usually highly questionable. the post-synaptically acting -neurotoxins. These toxins are present in venoms from a range of snakes, including many species that do not result in paralysis in humans (Barber et al., 2013; Youngman et al., 2021). The proportion of -neurotoxins in snake venoms is known to be associated with the prey selectivity of the venoms (Harris et al., 2020), Benzenepentacarboxylic Acid which further suggests that these particular toxins are animal-specific. The two major forms of -neurotoxins, i.e., long-chain (LNTx) and short-chain (SNTx), bind to the same region of the -subunit of the nAChR, resulting in inhibition of neurotransmission at the skeletal neuromuscular junction. Current knowledge about the relevance of snake venom -neurotoxins in human envenoming and paralysis is largely based on projections from data generated from rodent, avian, and amphibian pharmacological models (Silva et al., 2017). However, using skeletal muscle mass from several animals, including rodents, non-human primates and humans, a largely neglected study, dating back to 1985, showed that human nAChR have an exceptionally low affinity for SNTx compared to LNTx, while both groups bind with high affinity to mouse nAChRs (Ishikawa et al., 1985). Consistent with these observations, in a functional study using human and rat nAChR, we recently exhibited that the human nAChR is usually more resistant to snake SNTx compared to the rat nAChR, as evidenced by marked differences in the velocity of the reversibility of toxin-mediated inhibition of the human nAChR (Silva et al., 2018). The experiments, with and without numerous mutations Fes of the human and rat nAChR, showed that this species difference is due to the absence of large aromatic amino acid residues at positions 187 and 189 in loop C of the subunit of the human nAChR. This is in contrast to rats, mice, and nAChRs in other animals commonly used for screening, including sp.) and south American Bushmasters (sp.) (Gutirrez et al., 1988; Bard et al., 1994; Diniz-Sousa et al., 2020). Although -neurotoxins are mostly found in elapids and colubrids, they are present even in some viperid venoms that do not cause neurotoxicity in humans, such as Puff adders (Wang et al., 2020; Youngman et al., 2021) hence the utility of these assays remains thin. There are other examples in which animal models do not represent human envenoming. Plasma from several large animals, including rats, were shown to be resistant to concentrations of procoagulant toxins several orders of magnitude greater compared to humans, from viperids such as and elapids such as venom suggesting it to be a poor model for venom-induced acute kidney injury (Wijewickrama Benzenepentacarboxylic Acid et al., 2018). VICC, AKI and thrombocytopaenia only occurred with experimental venom doses that were unrealistically higher than what Benzenepentacarboxylic Acid is observed in actual human envenomings, making it difficult to match the real-life envenoming scenarios in humans (Tan et al., 2012; Romanelli et al., 2021; Thomazini et al., 2021; Yamamoto et al., 2021). Conversation Among the WHO approved list of essential quality control parameters for routine quality control screening of antivenoms, the sole parameter that is used to assess the pharmacological/therapeutic efficacy of antivenom is the lethality neutralisation test (World Health Organisation, 2017; Patra et al., 2021). The WHO guidelines for the production, control and regulation of snake antivenom immunoglobulins, published in 2017, says that Despite reservations concerning the physiological relevance of these animal (murine) models to human envenoming and the harm that these assays cause to the animals, they are used by both manufacturers and regulatory government bodies worldwide for determining venom lethality (LD50) and antivenom neutralizing capacity (ED50) as these are currently the only validated means of assessing venom toxicity and antivenom neutralizing potency (World Health Organisation, 2017). Further, it says Benzenepentacarboxylic Acid Non-sentient or assays as alternatives to the standard venom LD50 and Benzenepentacarboxylic Acid antivenom ED50 assessments have been promoted. Unfortunately, such systems have not been developed to the point where they can fully replace the above-mentioned preclinical assays. Further, the WHO statement states that in the absence of effective alternatives, the continued use of experimental animals is still justified by the considerable benefits to human health of these preclinical assays (World Health Organisation, 2017). The fundamental assumption behind screening venoms, toxins and antivenoms, using rodent lethality models in relation to human envenoming, is that the toxins possessing the highest rodent lethality are the most medically important toxins in human envenoming (Lauridsen et al., 2016; Calvete.
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