NEUTRALIZATION OF LOCAL TISSUE DAMAGE INDUCED BY BOTHROPS ASPER (TERCIOPELO) SNAKE VENOM (original) (raw)
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Tissue damage and inflammation induced by snake venoms
Some characteristics of the local tissue damage and inflammatory reactions induced by snake venoms were analyzed in a mouse model. Tissue damage was studied by intravital, light, and electron microscopic techniques, and by the use of biochemical markers. Detailed information on the early development and dynamics of local tissue damage was obtained by intravital microscopy. Main alterations were microvascular plasma leakage, hemorrhage, blood flow disturbances, thrombosis, and myonecrosis. A new technique for the quantification of myonecrosis in vivo was established, based on the principle of MTT reduction. The method was tested for its usefulness in the evaluation of antibody-mediated neutralization of myotoxicity.
Experimental pathology of local tissue damage induced by Bothrops asper snake venom
Toxicon, 2009
Envenomations by Bothrops asper are often associated with complex and severe local pathological manifestations, including edema, blistering, dermonecrosis, myonecrosis and hemorrhage. The pathogenesis of these alterations has been investigated at the experimental level. These effects are mostly the consequence of the direct action of zincdependent metalloproteinases (SVMPs) and myotoxic phospholipases A 2 (PLA 2 s). SVMPs induce hemorrhage, blistering, dermonecrosis and general extracellular matrix degradation, whereas PLA 2 s induce myonecrosis and also affect lymphatic vessels. In addition, the prominent vascular alterations leading to hemorrhage and edema may contribute to ischemia and further tissue necrosis. The mechanisms of action of SVMPs and PLA 2 s are discussed in detail in this review. Venom-induced tissue damage plays also a role in promoting bacterial infection. A prominent inflammatory reaction develops as a consequence of these local pathological alterations, with the synthesis and release of abundant mediators, resulting in edema and pain. However, whether inflammatory cells and mediators contribute to further tissue damage is not clear at present. Muscle tissue regeneration after venom-induced pathological effects is often impaired, thus resulting in permanent tissue loss and dysfunction. SVMP-induced microvessel damage is likely to be responsible of this poor regenerative outcome. Antivenoms are only partially effective in the neutralization of B. asper-induced local effects, and the search for novel toxin inhibitors represents a potential avenue for improving the treatment of this serious aspect of snakebite envenomation.
Toxicon, 2007
Despite preventing death after snakebites, there is little evidence that polyvalent antivenoms (PAVs) protect against myotoxicity and local damages. We evaluated antibothropic Brazilian PAVs from three manufacturers against the myotoxicity and hemorrhagic activity of Bothrops jararacussu and B. jararaca venoms, respectively, by using two protocols: preincubation of PAVs with venom, and i.v. pretreatment with PAVs, prior to the venom inoculation. In this investigation, we used doses of PAVs ranging from 0.4 to 4.0 mL/mg of venom equivalent up to 10 times the amount recommended by the producers for the clinical practice in Brazil. In our preincubation protocol in vivo, PAVs antagonized myotoxicity of B. jararacussu venom by 40–95%, while our pretreatment protocol antagonized myotoxic activity by 0–60%. Preincubation of antivenoms with B. jararaca venom antagonized its hemorrhagic activity by 70–95%, while pretreatment antagonized hemorrhagic activity by 10–50%. Although all PAVs demonstrated partial antagonism against both venoms, the magnitude of these effects varied greatly among the manufactures. The results suggest that the current clinical doses of these PAVs may have negligible antimyotoxic effect.
Archives of Toxicology, 2019
Snakebite envenomation is a serious medical problem in many developing tropical and subtropical countries. Envenomation is registered by the World Health Organization as a neglected tropical disease due to critical shortages in the production of antivenom. Envenomation causes more than 100,000 deaths annually. Snakebites result in several effects to include edema, blistering, hemorrhage, necrosis and respiratory paralysis. Antivenom is the preferred treatment for the systemic effects of snakebite envenomation, though these are often ineffective in neutralizing venom toxin-induced local tissue damage. To effectively treat snakebites, it is important to determine the lethal potency and pathophysiological effects induced by specific snake venoms. In the current study, we compared the lethality, and the hemorrhagic and dermonecrotic activities of venoms from three snakes in Egypt that are the primary causes of local tissue necrosis. Our data show that the intraperitoneal median lethal doses (LD 50) for Cerastes cerastes, Echis carinatus and Naja nigricollis venoms are 0.946, 1.744 and 0.341 mg/kg mouse body weight, respectively. These results indicated that N. nigricollis venom is the most toxic and significantly accelerated the time of death compared to the other two venoms. However, no hematoma or associated edema appeared upon sub-plantar injection of N. nigricollis venom into the mice hind paw. Two hours following intradermal injection of C. cerastes and E. carinatus venoms, macroscopic analysis of the inner surface of mouse skin showed severe hemorrhagic lesions, whereas only insignificant hemorrhagic lesion appeared in mice injected with the highest dose of N. nigricollis venom. Furthermore, the minimum necrotic doses (MND) for the same venoms were 43.15, and 70.87 µg/mouse, or not observed in the case of N. nigricollis venom, respectively. These LD 50 values and pathophysiological results can be used to guide development of antivenom against bites by these dangerous Egyptian snakes.
The American journal of …, 2000
The effectiveness of the chelating agent CaNa 2 EDTA and the peptidomimetic matrix metalloproteinase inhibitor batimastat (BB-94) to inhibit local tissue damage induced by Bothrops asper snake venom was studied in mice. Both compounds totally inhibited proteolytic, hemorrhagic, and dermonecrotic effects, and partially reduced edema-forming activity, when incubated with venom prior to injection. Much lower concentrations of batimastat than of CaNa 2 EDTA were required to inhibit these effects. In addition, batimastat, but not CaNa 2 EDTA, partially reduced myotoxic activity of the venom. When the inhibitors were administered at various time intervals after envenomation at the same site of venom injection, both compounds were effective in neutralizing local hemorrhage and dermonecrosis if administered rapidly after venom. Inhibition was not as effective as the time lapse between venom and inhibitor injections increased. Owing to the relevance of metalloproteinases in the pathogenesis of local tissue damage induced by B. asper and other pit viper venoms, it is suggested that administration of peptidomimetic metalloproteinase inhibitors or CaNa 2 EDTA at the site of venom injection may represent a useful alternative to complement antivenoms in the neutralization of venom-induced local tissue damage.
Toxicon, 2007
Despite preventing death after snakebites, there is little evidence that polyvalent antivenoms (PAVs) protect against myotoxicity and local damages. We evaluated antibothropic Brazilian PAVs from three manufacturers against the myotoxicity and hemorrhagic activity of Bothrops jararacussu and B. jararaca venoms, respectively, by using two protocols: preincubation of PAVs with venom, and i.v. pretreatment with PAVs, prior to the venom inoculation. In this investigation, we used doses of PAVs ranging from 0.4 to 4.0 mL/mg of venom equivalent up to 10 times the amount recommended by the producers for the clinical practice in Brazil. In our preincubation protocol in vivo, PAVs antagonized myotoxicity of B. jararacussu venom by 40-95%, while our pretreatment protocol antagonized myotoxic activity by 0-60%. Preincubation of antivenoms with B. jararaca venom antagonized its hemorrhagic activity by 70-95%, while pretreatment antagonized hemorrhagic activity by 10-50%. Although all PAVs demonstrated partial antagonism against both venoms, the magnitude of these effects varied greatly among the manufactures. The results suggest that the current clinical doses of these PAVs may have negligible antimyotoxic effect. r
The efficacy of two antivenoms against the venom of North American snakes
Toxicon, 2003
Mortality due to snake envenomation is not a major problem in the United States with approximately 8–12 deaths per year, but envenomation is a serious problem that can result in functional disability, loss of extremities, and a costly recovery. Physicians encounter different clinical situations with each new snakebite victim because of the geographical variations in snake venoms. The best and most acceptable form of treatment is the use of antivenom; however, it must be administered as soon as possible since it is not so effective at reducing local signs of envenomation such as necrosis. The antivenom in the United States is in short supply, expensive and may not even be the most effective for neutralizing all North American snake venoms. In this study, we tested two antivenoms. The first was a Crotalidae Polyvalent Fab fragment with Ovine origin (FabO) manufactured in London, and the second was Antivipmyn, a Mexican manufactured antivenom that is F(ab′)2 fragment produced in horse (Fab2H). The efficacy of the two antivenoms was tested with 15 different snake venoms found in North America. Three different assays were used to test the efficacy of the antivenoms, the in vivo serum protection test (ED50), antihemorrhagic and anticoagulant. The Fab2H antivenom was most effective in neutralizing the hemorrhagic activity of 78% of the hemorrhagic venoms used in this study. In the ED50 assay, the Fab2H antivenom was effective in neutralizing all venoms used in this study, while FabO neutralized all but C. m. molossus venom. However, in most cases, FabO required less antivenom than Fab2H antivenom to neutralize three LD50.