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Brevetoxins (BTX) are a group of marine neurotoxins produced by the harmful alga Karenia brevis. Numerous studies have shown that BTX are rapidly accumulated and metabolized in shellfish and mammals. However, there are only limited data on BTX metabolism in fish, despite growing evidence that fish serve as vectors for BTX transfer in marine food webs. In this study, we aimed to investigate the in vitro biotransformation of BTX-2, the major constituent of BTX profiles in K. brevis, in several species of northern Gulf of Mexico fish. Metabolism assays were performed using hepatic microsomes prepared in-house as well as commercially available human microsomes for comparison, focusing on phase I reactions mediated by cytochrome P450 monooxygenase (CYP) enzymes. Samples were analyzed by UHPLC-HRMS(/MS) to monitor BTX-2 depletion and characterize BTX metabolites based on MS/MS fragmentation pathways. Our results showed that both fish and human liver microsomes rapidly depleted BTX-2, resulting in a 72–99% reduction within 1 h of incubation. We observed the simultaneous production of 22 metabolites functionalized by reductions, oxidations, and other phase I reactions. We were able to identify the previously described congeners BTX-3 and BTX-B5, and tentatively identified BTX-9, 41,43-dihydro-BTX-2, several A-ring hydrolysis products, as well as several novel metabolites. Our results confirmed that fish are capable of similar BTX biotransformation reactions as reported for shellfish and mammals, but comparison of metabolite formation across the tested species suggested considerable interspecific variation in BTX-2 metabolism potentially leading to divergent BTX profiles. We additionally observed non-enzymatic formation of BTX-2 and BTX-3 glutathione conjugates. Collectively, these findings have important implications for determining the ecotoxicological fate of BTX in marine food webs.

Tarantula venoms may be a natural source of new vasodilator components useful in pharmacological research. Moreover, biological function data of the venoms are important to enhance the knowledge about the biodiversity and evolution of these species. The present study aims to describe the vasodilatory activity induced by the venom of Poecilotheria ornata on isolated rat aortic rings. This venom induced a vasodilator activity that was significantly reduced after incubation with L-NAME or ODQ. Measurements of nitrite concentrations on rat aorta homogenates showed that the venom significantly increased the basal levels. Moreover, the venom attenuates the contraction induced by calcium. These results suggest that P. ornata venom contains a mixture of vasodilator components that act through the activation of the nitric oxide/cGMP pathway, as well as, through an endothelium-independent mechanism that involves the calcium influx into vascular smooth muscle cells.

The Timber Rattlesnake (Crotalus horridus) is the largest pit viper in the Northern United States and is the prominent venomous snake species indigenous to the bluff land habitats of the Upper Mississippi River Valley (UMRV). Conservation of C. horridus in this geographic region not only preserves the ecosystem's biodiversity and ecological balance, but also assures the continued study of their biomedically important venoms/toxins. Field studies of C. horridus biology and natural history performed from 1985 to 2015 in southeastern Minnesota and western Wisconsin along the Mississippi River showed populations have declined. Consequently, the implementation of improved conservation measures afforded the species protective status in both states. Historically, accounts of Timber Rattlesnake bites in the UMRV have been sparse, and medical consequences of envenomation have had limited documentation. However, in recent decades cases of envenomation by C. horridus have continued to occur. Retrospective analysis of clinical toxinology consultations documented from 1982 to 2020 on cases of envenomation by C. horridus in the UMRV revealed a very low incidence of bites annually and revealed that their venom can induce a rapid and precipitous decline in platelets.

The timely administration of antivenom is the most effective method currently available to reduce the burden of snakebite envenoming (SBE), a neglected tropical disease that most often affects rural agricultural global populations. There is increasing interest in the development of adjunctive small molecule and biologic therapeutics that target the most problematic venom components to bridge the time-gap between initial SBE and the administration of antivenom. Unique combinations of these therapeutics could provide relief from the toxic effects of regional groupings of medically relevant snake species. The application a PRISMA/PICO literature search methodology demonstrated an increasing interest in the rapid administration of therapies to improve patient symptoms and outcomes after SBE. Advice from expert interviews and considerations regarding the potential routes of therapy administration, anatomical bite location, and species-specific venom delivery have provided a framework to identify ideal metrics and potential hurdles for the development of a field-based medical device that could be used immediately after SBE to deliver adjunctive therapies. The use of subcutaneous (SC) or intramuscular (IM) injection were identified as potential routes of administration of both small molecule and biologic therapies. The development of a field-based medical device for the delivery of adjunctive SBE therapies presents unique challenges that will require a collaborative and transdisciplinary approach to be successful.

A 2-year-old female Dachshund had a witnessed timber rattlesnake envenomation. Although rattlesnake envenomations are a common, potentially life-threatening event in companion animals, timber rattlesnake envenomations in the dog are rarely reported. This dog described in this case report had significant hematologic and neurologic clinical derangements consistent with Types A and B rattlesnake venom and a suspected hypersensitivity reaction to the venom. This patient was treated aggressively with antivenom and fully recovered without any persistent neurologic signs at follow-up.

Venoms from tarantulas contain low molecular weight vasodilatory compounds whose biological action is conceived as part of the envenomation strategy due to its propagative effects. However, some properties of venom-induced vasodilation do not match those described by such compounds, suggesting that other toxins may cooperate with these ones to produce the observed biological effect. Owing to the distribution and function of voltage-gated ion channels in blood vessels, disulfide-rich peptides isolated from venoms of tarantulas could be conceived into potential vasodilatory compounds. However, only two peptides isolated from spider venoms have been investigated so far. This study describes for the first time a subfraction containing inhibitor cystine knot peptides, PrFr-I, obtained from the venom of the tarantula Poecilotheria regalis. This subfraction induced sustained vasodilation in rat aortic rings independent of vascular endothelium and endothelial ion channels. Furthermore, PrFr-I decreased calcium-induced contraction of rat aortic segments and reduced extracellular calcium influx to chromaffin cells by the blockade of L-type voltage-gated calcium channels. This mechanism was unrelated to the activation of potassium channels from vascular smooth muscle, since vasodilation was not affected in the presence of TEA, and PrFr-I did not modify the conductance of the voltage-gated potassium channel K_v10.1. This work proposes a new envenomating function of peptides from venoms of tarantulas, and establishes a new mechanism for venom-induced vasodilation.

In vivo studies of botulinum neurotoxin type A (BoNT-A) enabled characterization of its activity in the nociceptive sensory system separate from its preferred action in motor and autonomic nerve terminals. However, in the recent rodent studies of arthritic pain which employed high intra-articular (i.a.) doses (expressed as a total number of units (U) per animal or U/kg), possible systemic effects have not been conclusively excluded. Herein we assessed the effect of two pharmaceutical preparations, abobotulinumtoxinA (aboBoNT-A, 10, 20, and 40 U/kg corresponding to 0.05, 0.11, and 0.22 ng/kg neurotoxin) and onabotulinumtoxinA (onaBoNT-A, 10 and 20 U/kg corresponding to 0.09 and 0.18 ng/kg, respectively) injected into the rat knee, on safety-relevant readouts: digit abduction, motor performance and weight gain during 14 days post-treatment.

The i. a. toxin produced dose-dependent impairment of the toe spreading reflex and rotarod performance, which was moderate and transient after 10 U/kg onaBoNT-A and ≤20 U/kg aboBoNT-A doses, and severe and long-lasting (examined up to 14 days) after ≥20 U/kg of onaBoNT-A and 40 U/kg aboBoNT-A. In addition, lower toxin doses prevented the normal weight gain compared to controls, while higher doses induced marked weight loss (≥20 U/kg of onaBoNT-A and 40 U/kg aboBoNT-A).

Commonly employed BoNT-A formulations, depending on the doses, cause local relaxation of the surrounding muscles and systemic adverse effects in rats. Thus, to evade possible toxin unwanted local or systemic spread, careful dosing and motor testing should be mandatory in preclinical behavioral studies, irrespective of the sites and doses of toxin application.

Africa remains one of the regions with the highest incident and burden of snakebite. The goal of the World Health Organization to halve the global burden of snakebite by 2030 can only be achieved if sub-optimal access to antivenoms in the most affected regions is addressed. We identified upstream, midstream, and downstream factors along the antivenom value chain that prevent access to antivenoms in the African region. We identified windows of opportunities that could be utilized to ensure availability, accessibility, and affordability for snakebite endemic populations in Africa. These include implementation of multicomponent strategies such as intensified advocacy, community engagement, healthcare worker trainings, and leveraging the institutional and governance structure provided by African governments to address the challenges identified.

During the production of snake antivenoms, the animals used as immunoglobulin source are subjected to processes that could deteriorate their physical condition. Therefore, these conditions must be carefully designed and validated. In this work, the immunization and bleeding protocols applied to horses used to produce the African polyspecific antivenom EchiTAb-plus-ICP were evaluated regarding their effects on the horses' health. The study focused on horses that had been previously immunized with venoms and then received periodic booster venom injections for antivenom production. It was found that the periodic immunization with 5 mg of a mixture of venoms of Bitis arietans, Echis ocellatus, Dendroaspis polylepis, and Naja nigricollis did not induce systemic signs of envenomation, and only caused mild swelling at the injection site, which did not evolve to abscesses, fistulas, or fibrosis. Three consecutive days of bleeding, collecting 6–8 L of blood per day, and self-transfusing the red blood cells (RBC) in the second and third days, did not induce evident cardiorespiratory alterations. However, this procedure caused significant reductions in RBC, hematocrit, hemoglobin, and total plasma protein values. Seven weeks after bleeding, these parameters were recovered, and horses were ready for the next immunization/bleeding cycle. The intravenous administration of equine albumin, at a dose of 2 g/kg body weight, increased the apparent plasma volume and the albumin concentration. However, this procedure induced early adverse reactions and transient alterations of the serum levels of the enzyme gamma-glutamyl transferase (GGT), thus suggesting some degree of hepatic injury. It was concluded that immunization and bleeding as described in this work do not cause significant clinical alterations in the horse's health, except for a transient drop in some hematological parameters. The albumin-based fluid therapy used does not hasten the recovery after bleeding but instead induces adverse events in the animals.