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Jose Maria Gutierrez – 1st expert on this subject based on the ideXlab platform
A pan-specific antiserum produced by a novel immunization strategy shows a high spectrum of neutralization against neurotoxic snake venomsScientific Reports, 2020Co-Authors: Kavi Ratanabanangkoon, Jose Maria Gutierrez, Kritsada Pruksaphon, Chaiya Klinpayom, Naeem H. QuraishiAbstract:
Snakebite envenomation is a neglected tropical disease of high mortality and morbidity largely due to insufficient supply of effective and affordable Antivenoms. Snake Antivenoms are mostly effective against the venoms used in their production. It is thus crucial that effective and affordable Antivenom(s) with wide para-specificity, capable of neutralizing the venoms of a large number of snakes, be produced. Here we studied the pan-specific antiserum prepared previously by a novel immunization strategy involving the exposure of horses to a ‘diverse toxin repertoire’ consisting of 12 neurotoxic Asian snake toxin fractions/ venoms from six species. This antiserum was previously shown to exhibit wide para-specificity by neutralizing 11 homologous and 16 heterologous venoms from Asia and Africa. We now show that the antiserum can neutralize 9 out of 10 additional neurotoxic venoms. Altogether, 36 snake venoms belonging to 10 genera from 4 continents were neutralized by the antiserum. Toxin profiles previously generated using proteomic techniques of these 36 venoms identified α-neurotoxins, β-neurotoxins, and cytotoxins as predominant toxins presumably neutralized by the antiserum. The bases for the wide para-specificity of the antiserum are discussed. These findings indicate that it is feasible to generate Antivenoms of wide para-specificity against elapid neurotoxic venoms from different regions in the world and raises the possibility of a universal neurotoxic Antivenom. This should reduce the mortality resulting from neurotoxic snakebite envenomation.
coagulotoxic effects by brown snake pseudonaja and taipan oxyuranus venoms and the efficacy of a new AntivenomToxicology in Vitro, 2019Co-Authors: Christina N Zdenek, Kevin Arbuckle, Timothy N. W. Jackson, Bianca Op Den Brouw, Jordan Debono, Luke Allen, Nathan Dunstan, Terry Morley, Maria Herrera, Jose Maria GutierrezAbstract:
Abstract Snakebite is a neglected tropical disease that disproportionately affects the poor. Antivenom is the only specific and effective treatment for snakebite, but its distribution is severely limited by several factors, including the prohibitive cost of some products. Papua New Guinea (PNG) is a snakebite hotspot but the high costs of Australian Antivenoms (thousands of dollars per treatment) makes it unaffordable in PNG. A more economical taipan Antivenom has recently been developed at the Instituto Clodomiro Picado (ICP) in Costa Rica for PNG and is currently undergoing clinical trials for the treatment of envenomations by coastal taipans (Oxyuranus scutellatus). In addition to potentially having the capacity to neutralise the effects of envenomations of non-PNG taipans, this Antivenom may have the capacity to neutralise coagulotoxins in venom from closely related brown snakes (Pseudonaja spp.) also found in PNG. Consequently, we investigated the cross-reactivity of taipan Antivenom across the venoms of all Oxyuranus and Pseudonaja species. In addition, to ascertain differences in venom biochemistry that influence variation in Antivenom efficacy, we tested for relative cofactor dependence. We found that the new ICP taipan Antivenom exhibited high selectivity for Oxyuranus venoms and only low to moderate cross-reactivity with any Pseudonaja venoms. Consistent with this genus level distinction in Antivenom efficacy were fundamental differences in the venom biochemistry. Not only were the Pseudonaja venoms significantly more procoagulant, but they were also much less dependent upon the cofactors calcium and phospholipid. There was a strong correlation between Antivenom efficacy, clotting time and cofactor dependence. This study sheds light on the structure-function relationships of the procoagulant toxins within these venoms and may have important clinical implications including for the design of next-generation Antivenoms.
Global Availability of Antivenoms: The Relevance of Public Manufacturing Laboratories.Toxins, 2018Co-Authors: Jose Maria GutierrezAbstract:
: Snakebite envenoming is a serious global public health problem, and international initiatives, under the coordination of the World Health Organization and its regional offices, are being developed to reduce the impact of this neglected tropical disease. The global availability of safe and effective Antivenoms is one of the key aspects in this global strategy. This review discusses the role of public Antivenom manufacturing laboratories for ensuring the supply of Antivenoms. The difficulties faced by public laboratories are discussed, together with some tasks that need to be implemented for strengthening them. In addition, the concept of ‘redundancy’ in the supply of Antivenoms is emphasized, as a way to cope with the risks associated with the provision of Antivenoms by few manufacturers. In general, the public sector should play a leading role, in Antivenom availability and other aspects as well, within the global struggle to reduce the mortality and morbidity caused by snakebite envenoming.
Geoffrey K Isbister – 2nd expert on this subject based on the ideXlab platform
Current research into snake Antivenoms, their mechanisms of action and applications.Biochemical Society Transactions, 2020Co-Authors: Anjana Silva, Geoffrey K IsbisterAbstract:
Snakebite is a major public health issue in the rural tropics. Antivenom is the only specific treatment currently available. We review the history, mechanism of action and current developments in snake Antivenoms. In the late nineteenth century, snake Antivenoms were first developed by raising hyperimmune serum in animals, such as horses, against snake venoms. Hyperimmune serum was then purified to produce whole immunoglobulin G (IgG) Antivenoms. IgG was then fractionated to produce F(ab) and F(ab’)2 Antivenoms to reduce adverse reactions and increase efficacy. Current commercial Antivenoms are polyclonal mixtures of antibodies or their fractions raised against all toxin antigens in a venom(s), irrespective of clinical importance. Over the last few decades there have been small incremental improvements in Antivenoms, to make them safer and more effective. A number of recent developments in biotechnology and toxinology have contributed to this. Proteomics and transcriptomics have been applied to venom toxin composition (venomics), improving our understanding of medically important toxins. In addition, it has become possible to identify toxins that contain epitopes recognized by Antivenom molecules (Antivenomics). Integration of the toxinological profile of a venom and its composition to identify medically relevant toxins improved this. Furthermore, camelid, humanized and fully human monoclonal antibodies and their fractions, as well as enzyme inhibitors have been experimentally developed against venom toxins. Translation of such technology into commercial Antivenoms requires overcoming the high costs, limited knowledge of venom and Antivenom pharmacology, and lack of reliable animal models. Addressing such should be the focus of Antivenom research.
Antivenom cross neutralisation in a suspected asian pit viper envenoming causing severe coagulopathyToxicon, 2014Co-Authors: Geoffrey K Isbister, Kalana Maduwage, Colin B. PageAbstract:
There is evidence of cross-neutralisation between common toxin groups in snake venoms and therefore the potential for Antivenoms to be effective against species they are not raised against. Here we present a 49 year old female bitten by an unknown pit-viper in Nepal. She developed a venom induced consumption coagulopathy with an unrecordable international normalised ratio and undetectable fibrinogen. On return to Australia 5 days post-bite she was treated successfully with one Antivenom raised against Malayan pit viper and green pit viper venoms (Haemato-polvalent Antivenom from Thailand) and then subsequently with another Antivenom raised against American pit-viper venoms (Antivipmyn). Presumed pit viper venom was detected in patient sera with an enzyme immunoassay against Hypnale hypnale venom. There was increased absorbance before Antivenom compared to non-envenomed control samples, which then decreased after the administration of each Antivenom. The recurrence of venom detected by enzyme immunoassay between Antivenom doses was accompanied by a recurrence of the coagulopathy. Cross reactivity between the unknown venom and both Antivenoms was supported by the fact that no venom was detected in the pre-Antivenom samples after they were incubated in vitro with both Antivenoms. This case and investigation of the venom and Antivenoms suggest cross-neutralisation between pit vipers, including pit vipers from different continents. Crown
current treatment for venom induced consumption coagulopathy resulting from snakebitePLOS Neglected Tropical Diseases, 2014Co-Authors: Kalana Maduwage, Geoffrey K IsbisterAbstract:
Venomous snakebite is considered the single most important cause of human injury from venomous animals worldwide. Coagulopathy is one of the commonest important systemic clinical syndromes and can be complicated by serious and life-threatening haemorrhage. Venom-induced consumption coagulopathy (VICC) is the commonest coagulopathy resulting from snakebite and occurs in envenoming by Viperid snakes, certain elapids, including Australian elapids, and a few Colubrid (rear fang) snakes. Procoagulant toxins activate the clotting pathway, causing a broad range of factor deficiencies depending on the particular procoagulant toxin in the snake venom. Diagnosis and monitoring of coagulopathy is problematic, particularly in resource-poor countries where further research is required to develop more reliable, cheap clotting tests. MEDLINE and EMBASE up to September 2013 were searched to identify clinical studies of snake envenoming with VICC. The UniPort database was searched for coagulant snake toxins. Despite preclinical studies demonstrating Antivenom binding toxins (efficacy), there was less evidence to support clinical effectiveness of Antivenom for VICC. There were no placebo-controlled trials of Antivenom for VICC. There were 25 randomised comparative trials of Antivenom for VICC, which compared two different Antivenoms (ten studies), three different Antivenoms (four), two or three different doses or repeat doses of Antivenom (five), heparin treatment and Antivenom (five), and intravenous immunoglobulin treatment and Antivenom (one). There were 13 studies that compared two groups in which there was no randomisation, including studies with historical controls. There have been numerous observational studies of Antivenom in VICC but with no comparison group. Most of the controlled trials were small, did not use the same method for assessing coagulopathy, varied the dose of Antivenom, and did not provide complete details of the study design (primary outcomes, randomisation, and allocation concealment). Non-randomised trials including comparison groups without Antivenom showed that Antivenom was effective for some snakes (e.g., Echis), but not others (e.g., Australasian elapids). Antivenom is the major treatment for VICC, but there is currently little high-quality evidence to support effectiveness. Antivenom is not risk free, and adverse reactions can be quite common and potentially severe. Studies of heparin did not demonstrate it improved outcomes in VICC. Fresh frozen plasma appeared to speed the recovery of coagulopathy and should be considered in bleeding patients.
David A Warrell – 3rd expert on this subject based on the ideXlab platform
a multicomponent strategy to improve the availability of Antivenom for treating snakebite envenomingBulletin of The World Health Organization, 2014Co-Authors: Jose Maria Gutierrez, Robert A. Harrison, David A Warrell, Juan J. Calvete, Thierry Burnouf, Ulrich Kuch, David J WilliamsAbstract:
Snakebite envenoming is a common but neglected public health problem, particularly in impoverished rural regions of sub-Saharan Africa, Asia and Latin America. The only validated treatment for this condition is passive immunotherapy with safe and effective animal-derived Antivenoms. However, there is a long-lasting crisis in the availability of these life-saving medications, particularly in sub-Saharan Africa and parts of Asia. We herein advocate a multicomponent strategy to substantially improve the availability of safe and effective Antivenoms at the global level. This strategy is based on: (i) preparing validated collections of representative venom pools from the most medically dangerous snakes in high-risk regions of the world; (ii) strengthening the capacity of national Antivenom manufacturing and quality control laboratories and their regulatory authorities and establishing new facilities in developing countries through technology transfer, as an integral part of efforts to develop their biological products industry; (iii) getting established laboratories to generate Antivenoms for various regions of the world; and (iv) getting governments and relevant organizations to give snakebite envenoming due recognition within national and international public health policy frameworks. These ways of making Antivenom available should be complemented by actions to improve health information systems, the accessibility of Antivenoms, the training of medical and nursing staff, and community-based education. Such a multicomponent strategy involving stakeholders on many levels could help consolidate sustainable improvements in Antivenom availability worldwide.
Antivenom therapy of carpet viper echis ocellatus envenoming effectiveness and strategies for delivery in west africaToxicon, 2013Co-Authors: Abdulrazaq G Habib, David A WarrellAbstract:
Abstract In West Africa, response to specific, geographically appropriate, Antivenom is often dramatic following carpet viper ( Echis ocellatus ) envenoming with rapid restoration of blood coagulability and resolution of spontaneous haemorrhage. Envenoming from Australasian snakes causing similar coagulopathies may respond less dramatically and the effectiveness of Antivenom is being questioned. Here we have reviewed and re-analysed all published preclinical and clinical studies on envenoming and Antivenom therapy conducted in West Africa to determine the effectiveness of Antivenom. 22 studies provided relevant information: 12 observational studies, 4 RCTs and 6 preclinical studies. Four comparative studies confirmed statistically significant protection against mortality ranging from 57 to 87% using specific Antivenoms compared to non-specific or no Antivenoms. Meta-analysis estimated combined Odds Ratio (95% CI) of 0.25 (0.14–0.45) of dying among those treated with specific Antivenom or 75% (95% CI: 55–86%) protection against death. Mortality more than doubled during times when stocks of reliable Antivenoms ran out, with Relative Risk (95% CI)] of 2.33 (1.26–4.06). Serum kinetics of venom antigen/Antivenom levels also confirmed that decline of venom antigen levels coincided with resolution of coagulopathy while decline of Antivenom levels was associated with venom antigen reappearance and recurrence of coagulopathy. Preclinical and Antivenomics analysis confirmed efficacy of regionally appropriate Antivenoms against E. ocellatus and related species’ venoms in Sub-Saharan Africa but not against Asian Echis carinatus venom. Antivenoms raised against E. carinatus were ineffective in human studies. In West Africa, specific Antivenom is effective in managing carpet viper envenoming. A centralized hub-and-spoke strategy is suggested for broadening Antivenom access to endemic rural areas together with instituting quality assurance, standardization and manpower training. Benefits, risks, cost-effectiveness and feasibility of the approach should be formally assessed.
pan african polyspecific Antivenom produced by caprylic acid purification of horse igg an alternative to the Antivenom crisis in africaTransactions of The Royal Society of Tropical Medicine and Hygiene, 2005Co-Authors: Jose Maria Gutierrez, Guillermo Leon, Ermila Rojas, Lil Quesada, Javier Nunez, G D Laing, Mahmood Sasa, J M Renjifo, A Nasidi, David A WarrellAbstract:
A polyspecific Pan-African Antivenom has been produced from the plasma of horses immunized with a mixture of the venoms of Echis ocellatus, Bitis arietans and Naja nigricollis, the three most medically important snakes in sub-Saharan Africa. The Antivenom is a whole IgG preparation, obtained by caprylic acid precipitation of non-IgG plasma proteins. The Antivenom effectively neutralizes the most important toxic activities of the three venoms used in the immunization in standard assays involving preincubation of venom and Antivenom before testing. This Antivenom compares favourably with other Antivenoms designed for use in Africa with respect to neutralization of the toxins present in the venom of E. ocellatus. Caprylic acid fractionation of horse hyperimmune plasma is a simple, convenient and cheap protocol for the manufacture of high quality whole IgG Antivenoms. It constitutes a potentially valuable technology for the alleviation of the critical shortage of Antivenom in Africa.