Saw-scaled viper venom antiserum solution for injection 10ml ampoules

BACKGROUND: The World Health Organization's strategy to halve snakebite mortality and morbidity by 2030 includes an emphasis on a risk-benefit process assessing the preclinical efficacy of antivenoms manufactured for sub-Saharan Africa. To assist this process, we systematically collected, standardised and analysed all publicly available data on the preclinical efficacy of antivenoms designed for sub-Saharan Africa. METHODOLOGY/PRINCIPAL FINDINGS: Using a systematic search of publication databases, we focused on publicly available preclinical reports of the efficacy of 16 antivenom products available in sub Saharan Africa. Publications since 1999 reporting the industry standard intravenous pre-incubation method of murine in vivo neutralisation of venom lethality (median effective dose [ED50]) were included. Eighteen publications met the criteria. To permit comparison of the several different reported ED50 values, it was necessary to standardise these to microlitre of antivenom resulting in 50% survival of mice challenged per milligram of venom (μl/mg). We were unable to identify publicly available preclinical data on four antivenoms, whilst data for six polyspecific antivenoms were restricted to a small number of venoms. Only four antivenoms were tested against a wide range of venoms. Examination of these studies for the reporting of key metrics required for interpreting antivenom ED50s were highly variable, as evidenced by eight different units being used for the described ED50 values. CONCLUSIONS/SIGNIFICANCE: There is a disturbing lack of (i) preclinical efficacy testing of antivenom for sub Saharan Africa, (ii) publicly available reports and (iii) independent scrutiny of this medically important data. Where reports do exist, the methods and metrics used are highly variable. This prevents comprehensive meta-analysis of antivenom preclinical efficacy, and severely reduces the utility of antivenom ED50 results in the decision making of physicians treating patients and of national and international health agencies. Here, we propose the use of a standardised result reporting checklist to resolve this issue. Implementation of these straightforward steps will deliver uniform evaluation of products across laboratories, facilitate meta-analyses, and contribute vital information for designing the clinical trials needed to achieve the WHO target of halving snakebite morbidity and mortality by 2030.

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Introduction: India, with nearly 60 venomous snake species, has just one commercially available antivenom, the Indian polyvalent antivenom (IPAV). The hump-nosed pit viper ( Hypnale hypnale ), an indigenous venomous snake, causes considerable morbidity and at time mortality for which we have no commercially available antivenom. However, most clinicians rely purely on the clinical syndromes and end up using the available IPAV for H. hypnale envenomation. Methods: Between April 2017 and December 2022, we reviewed 41 cases of H. hypnale envenomation, comparing clinical and laboratory profiles of patients who received IPAV with those who did not. Results: Local signs of envenomation were seen in 39 (95.12%) cases, with the most common being edema or swelling at the bite site. Eight (19.5%) patients developed coagulopathy, and two developed renal failure during their hospital stay. Among the 39 envenomated individuals, 13 received polyvalent snake antivenom. Over half of those receiving antivenom had hypersensitivity reactions. Patients who received antisnake venom (ASV) had increased intensive care unit stay, duration of hospitalization, and hospital expenses as compared to patients who did not. There was one death among the patients who received antivenom. Conclusion: H. hypnale viper envenomation is associated with local and systemic signs of envenomation, with coagulopathy being a common complication. Administering the current polyvalent antivenom to victims of H. hypnale bites did not reduce the morbidities or prevent mortality; instead, it exposes them to additional risks associated with ASV administration.

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BACKGROUND: Antivenom is the treatment of choice for snakebite, which annually kills an estimated 32,000 people in sub-Saharan Africa and leaves approximately 100,000 survivors with permanent physical disabilities that exert a considerable socioeconomic burden. Over the past two decades, the high costs of the most polyspecifically-effective antivenoms have sequentially reduced demand, commercial manufacturing incentives and production volumes that have combined to create a continent-wide vacuum of effective snakebite therapy. This was quickly filled with new, less expensive antivenoms, many of which are of untested efficacy. Some of these successfully marketed antivenoms for Africa are inappropriately manufactured with venoms from non-African snakes and are dangerously ineffective. The uncertain efficacy of available antivenoms exacerbates the complexity of designing intervention measures to reduce the burden of snakebite in sub-Saharan Africa. The objective of this study was to preclinically determine the ability of antivenoms available in Kenya to neutralise the lethal effects of venoms from the most medically important snakes in East Africa. METHODS: We collected venom samples from the most medically important snakes in East Africa and determined their toxicity in a mouse model. Using a 'gold standard' comparison protocol, we preclinically tested the comparative venom-neutralising efficacy of four antivenoms available in Kenya with two antivenoms of clinically-proven efficacy. To explain the variant efficacies of these antivenoms we tested the IgG-venom binding characteristics of each antivenom using in vitro IgG titre, avidity and venom-protein specificity assays. We also measured the IgG concentration of each antivenom. FINDINGS: None of the six antivenoms are preclinically effective, at the doses tested, against all of the most medically important snakes of the region. The very limited snake polyspecific efficacy of two locally available antivenoms is of concern. In vitro assays of the abilities of 'test' antivenom IgGs to bind venom proteins were not substantially different from that of the 'gold standard' antivenoms. The least effective antivenoms had the lowest IgG content/vial. CONCLUSIONS: Manufacture-stated preclinical efficacy statements guide decision making by physicians and antivenom purchasers in sub-Saharan Africa. This is because of the lack of both clinical data on the efficacy of most of the many antivenoms used to treat patients and independent preclinical assessment. Our preclinical efficacy assessment of antivenoms available in Kenya identifies important limitations for two of the most commonly-used antivenoms, and that no antivenom is preclinically effective against all the regionally important snakes. The potential implication to snakebite treatment is of serious concern in Kenya and elsewhere in sub-Saharan Africa, and underscores the dilemma physicians face, the need for clinical data on antivenom efficacy and the medical and societal value of establishing independent preclinical antivenom-efficacy testing facilities throughout the continent.

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Snake venoms as tools for hunting are primarily aimed at the most vital systems of the prey, especially the nervous and circulatory systems. In general, snakes of the Elapidae family produce neurotoxic venoms comprising of toxins targeting the nervous system, while snakes of the Viperidae family and most rear-fanged snakes produce hemotoxic venoms directed mainly on blood coagulation. However, it is not all so clear. Some bites by viperids results in neurotoxic signs and it is now known that hemotoxic venoms do contain neurotoxic components. For example, viperid phospholipases A2 may manifest pre- or/and postsynaptic activity and be involved in pain and analgesia. There are other neurotoxins belonging to diverse families ranging from large multi-subunit proteins (e.g., C-type lectin-like proteins) to short peptide neurotoxins (e.g., waglerins and azemiopsin), which are found in hemotoxic venoms. Other neurotoxins from hemotoxic venoms include baptides, crotamine, cysteine-rich secretory proteins, Kunitz-type protease inhibitors, sarafotoxins and three-finger toxins. Some of these toxins exhibit postsynaptic activity, while others affect the functioning of voltage-dependent ion channels. This review represents the first attempt to systematize data on the neurotoxins from “non-neurotoxic” snake venom. The structural and functional characteristic of these neurotoxins affecting diverse targets in the nervous system are considered.

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BACKGROUND: Snakebite envenoming kills more than more than 20,000 people in Sub-Saharan Africa every year. Poorly regulated markets have been inundated with low-price, low-quality antivenoms. This review aimed to systematically collect and analyse the clinical data on all antivenom products now available in markets of sub-Saharan Africa. METHODOLOGY/PRINCIPAL FINDINGS: Our market analysis identified 12 polyspecific and 4 monospecific antivenom products in African markets. Our search strategy was first based on a systematic search of publication databases, followed by manual searches and discussions with experts. All types of data, including programmatic data, were eligible. All types of publications were eligible, including grey literature. Cohorts of less than 10 patients were excluded. 26 publications met the inclusion criteria. Many publications had to be excluded because clinical outcomes were not clearly linked to a specific product. Our narrative summaries present product-specific clinical data in terms of safety and effectiveness against the different species and envenoming syndromes. Three products (EchiTabPlus, EchiTabG, SAIMR-Echis-monovalent) were found to have been tested in robust clinical studies and found effective against envenoming caused by the West African carpet viper (Echis ocellatus). Four products (Inoserp-Panafricain, Fav-Afrique, SAIMR-Polyvalent, Antivipmyn-Africa) were found to have been evaluated only in observational single-arm studies, with varying results. For nine other products, there are either no data in the public domain, or only negative data suggesting a lack of effectiveness. CONCLUSIONS/SIGNIFICANCE: Clinical data vary among the different antivenom products currently in African markets. Some products are available commercially although they have been found to lack effectiveness. The World Health Organization should strengthen its capacity to assess antivenom products, support antivenom manufacturers, and assist African countries and international aid organizations in selecting appropriate quality antivenoms.

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The limitations posed by currently available antivenoms have emphasized the need for alternative treatments to counteract snakebite envenomation. Even though exact epidemiological data are lacking, reports have indicated that most global snakebite deaths are reported in India. Among the many problems associated with snakebite envenomation, issues related to the availability of safer and more efficient antivenoms are of primary concern. Since India has the highest number of global snakebite deaths, efforts should be made to reduce the burden associated with snakebite envenoming. Alternative methods, including aptamers, camel antivenoms, phage display techniques for generating high-affinity antibodies and antibody fragments, small-molecule inhibitors, and natural products, are currently being investigated for their effectiveness. These alternative methods have shown promise in vitro, but their in vivo effectiveness should also be evaluated. In this review, the issues associated with Indian polyvalent antivenoms in neutralizing venom components from geographically distant species are discussed in detail. In a nutshell, this review gives an overview of the current drawbacks of using animal-derived antivenoms and several alternative strategies that are currently being widely explored.

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BACKGROUND: Snake bite envenoming (SBE) is one neglected tropical disease that has not received the needed attention. The sequelae of burdensome disability and mortality impact the socioeconomic life of communities adversely with little documentation of SBE in health facility records in Ghana. This study details SBE and snake distribution, habits/habitats, type of venom expressed and clinical manifestations. METHODOLOGY: We conducted a structured thematic desk review of peer reviewed papers, books and reports from repositories including PubMed, World Health Organization (WHO) and Women's & Children's Hospital (WCH) Clinical Toxinology Resources using bibliographic software EndNote and search engine Google Scholar with the following key words; snakes, medical importance, snake bites, venom and venom type, envenomation, symptoms and signs, vaccines, venom expenditure, strike behaviour and venom-metering + Ghana, West Africa, Africa, World. We also reviewed data from the District Health Information Management System (DHIMS) of the Ghana Health Service (GHS). Outcome variables were organized as follows: common name (s), species, habitat/habit, species-specific toxin, clinical manifestation, antivenom availability, WHO category. FINDINGS: Snake bites and SBE were grouped by the activity of the expressed venom into neurotoxic, cardiotoxic, haemorrhagic, cytotoxic, myotoxic, nephrotoxic and procoagulants. Neurotoxic snake bites were largely due to elapids. Expressed venoms with cardiotoxic, haemorrhagic, nephrotoxic and procoagulant activities principally belonged to the family Viperidae. Snakes with venoms showing myotoxic activity were largely alien to Ghana and the West African sub-region. Venoms showing cytotoxic activity are expressed by a wide range of snakes though more prevalent among the Viperidae family. Snakes with neurotoxic and haemorrhagic venom activities are prevalent across all the agro-ecological zones in Ghana. CONCLUSION/SIGNIFICANCE: Understanding the characteristics of snakes and their venoms is useful in the management of SBE. The distribution of snakes by their expressed venoms across the agro-ecological zones is also instructive to species identification and diagnosis of SBE.

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Echis species (saw-scaled vipers) are WHO Category 1 medically significant venomous snakes with potent procoagulant venoms, which cause lethal venom-induced consumptive coagulopathy in human victims. Despite clinical presentations of bites varying significantly between individuals within the same species, the contribution of age-related changes in the venom biochemistry has not been investigated. This study investigated the ontogenetic changes in Echis pyramidum pyramidum venom and its impact on therapeutic efficacy. The efficacy of various antivenoms (Echitab, Echitab+ ICP, Inosan MENA, Inosan Pan African, and SAVP-Echis) was tested against both venom phenotypes. While both neonate and adult venoms were procoagulant, there were differences in the underlying biochemistry. Neonate venom was found to potently pathophysiologically activate Factor VII and Factor X, and to a lesser degree Factor XII. In contrast, adult venom was a slower clotter, less potent in activating FVII, equipotent with neonate venom on FXII, and inactive on FX. This is the first documentation of FVII and FXII activation for any Echis venom. The significant ontogenetic toxicological variations in Echis species were shown to impact antivenom efficacy. Among the tested antivenoms, SAVP-Echis was the most effective against both venom phenotypes, with adult venom being better neutralized. These findings suggest the need for a reconsideration of venom mixture selection in antivenom production through the inclusion of neonate venom. Additionally, the results indicate differential ontogenetic predatory ecology, providing a foundation for future natural history investigations.

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