Postdoctoral researcher, Minia University
Developing an affordable, non-cold chain therapy of Egyptian snake venoms induced tissue necrosis
Every five minutes, somebody dies from snakebite throughout the world. Ten to twenty thousand Africans lose limbs to amputation each year from snakebite, with lifelong impact on their ability to work and take care of families. According to recent estimates, more than 100,000 people die each year after being bitten by cobras, vipers, and other venomous snakes, and many others suffer debilitating injuries. More than 400,000 people have limbs amputated or rendered useless. That's far more than was previously thought, and it's possible the number could be higher still, since most bites don't occur in places where they are necessarily reported. Therefore, Snakebites are a growing public-health crisis and become the most neglected of the “Neglected Tropical Diseases”. Most venomous snakebites happen in parts of the world that aren't high income, meaning that making antivenom isn't particularly profitable. Compounding the issue is the fact that expensive treatments rarely make it to individuals in most of sub-Saharan Africa (or rural India, Bangladesh, or Pakistan, other places where snakebite is a serious issue). When bitten, people seek out traditional healers, who can't do much to counteract a venomous bite. The search for a solution; the World Health Organization (WHO) is now assessing alternative products that might be used in sub-Saharan Africa, and there are hopes that at least one product might be a viable alternative for FAV-Afrique antivenoms. Therefore, there is a compelling humanitarian need to deliver protocols for production of affordable, toxin-neutralizing reagents that can be applied after snakebite. The product needs to be (i) effective after storage at 35°C for at least 6 months, (ii) cost less than $30/treatment and (iii) have a minimal predicted adverse effect risk in humans. In terms of the proposed research project, we are trying to answer the following question: Are aptamers efficient antivenom tools to neutralize the animal deadly toxins? Aptamers have several advantages that include: (i) they are much smaller and will therefore possess rapid ‘in tissue’ distribution dynamics, (ii) their production is easy, reproducible and cost-effective, (iii) they can easily be stored at ambient temperature, and (iv) they are poorly immunogenic and lack toxicity. For proof of concept that aptamers have the ability to neutralize the lethal action of snake venom toxins, we will focus our interest on the venoms of five medically important snakes in Egypt.
Abstract: Nucleic acid aptamers can be selected from pools of random-sequence oligonucleotides to bind a wide range of biomedically relevant proteins with affinities and specificities that are comparable to antibodies. Aptamers exhibit significant advantages relative to protein therapeutics in terms of size, synthetic accessibility and modification by medicinal chemistry. Despite these properties, aptamers have been slow to reach the marketplace, with only one aptamer-based drug receiving approval so far. A series of aptamers currently in development may change how nucleic acid therapeutics are perceived. It is likely that in the future, aptamers will increasingly find use in concert with other therapeutic molecules and modalities.
Pub.: 02 Jul '10, Pinned: 16 Aug '17
Abstract: Snakebite is common in children especially in the developing countries. This study was undertaken to determine the role of surgery in the treatment of venomous snake bite in pediatric patients.The clinical data of 58 pediatric patients aged 0-16 years who had been treated for venomous snakebite from January 1999 to December 2008 were analyzed.Of the 58 patients, 43 (74.6%) were male. Peak age incidence was around 2-3 years (28.8%). The majority of envenomations occurred in the summer and rainy seasons, especially in the latter, during flooding. The bites occurred during 6 pm to 12 pm in 27 patients (49.0%). The main bite site was the lower extremities in 49 patients (83.9%). The main species of the snake were Malayan pit viper (Calloselasma rhodostoma) in 28 patients (47.5%) and cobra (Ophiophagus hunnah or Naja spp.) in 21 patients (35.6%). Soft tissue necrosis occurred more in cobra bites (47.6%) than viper bites (3.6%). The most common organism identified in necrotic tissue was Morganella morgagnii. Four patients with cobra bite had respiratory failure that required ventilatory support. Compartment syndrome was suspected in 2 patients. Surgical intervention was necessary in 13 patients. Most procedures involved serial wound debridement, followed by skin grafting. One case needed a toe amputation because of necrosis. The average length of hospital stay in patients who needed surgical management was 18.8 days (range: 12.1-25.5 days). There were no mortalities.Surgery plays an important role in the management of snakebite patients, especially for those with cobra bite with tissue necrosis.
Pub.: 31 Aug '11, Pinned: 16 Aug '17
Abstract: Snake venom hemorrhagic metalloproteinases (SVMPs) of the PI, PII and PIII classes were compared in terms of tissue localization and their ability to hydrolyze basement membrane components in vivo, as well as by a proteomics analysis of exudates collected in tissue injected with these enzymes. Immunohistochemical analyses of co-localization of these SVMPs with type IV collagen revealed that PII and PIII enzymes co-localized with type IV collagen in capillaries, arterioles and post-capillary venules to a higher extent than PI SVMP, which showed a more widespread distribution in the tissue. The patterns of hydrolysis by these three SVMPs of laminin, type VI collagen and nidogen in vivo greatly differ, whereas the three enzymes showed a similar pattern of degradation of type IV collagen, supporting the concept that hydrolysis of this component is critical for the destabilization of microvessel structure leading to hemorrhage. Proteomic analysis of wound exudate revealed similarities and differences between the action of the three SVMPs. Higher extent of proteolysis was observed for the PI enzyme regarding several extracellular matrix components and fibrinogen, whereas exudates from mice injected with PII and PIII SVMPs had higher amounts of some intracellular proteins. Our results provide novel clues for understanding the mechanisms by which SVMPs induce damage to the microvasculature and generate hemorrhage.
Pub.: 25 Apr '15, Pinned: 16 Aug '17
Abstract: The deliberations and conclusions of a Hinxton Retreat convened in September 2015, entitled "Mechanisms to reverse the public health neglect of snakebite victims" are reported. The participants recommended that the following priority actions be included in strategies to reduce the global impact of snake envenoming: (a) collection of accurate global snakebite incidence, mortality and morbidity data to underpin advocacy efforts and help design public health campaigns; (b) promotion of (i) public education prevention campaigns; (ii) transport systems to improve access to hospitals and (iii) establishment of regional antivenom-efficacy testing facilities to ensure antivenoms' effectiveness and safety;
Pub.: 26 Nov '16, Pinned: 16 Aug '17
Abstract: Animal-derived antivenoms constitute the mainstay in the therapy of snakebite envenoming. The efficacy of antivenoms to neutralize toxicity of medically-relevant snake venoms has to be demonstrated through meticulous preclinical testing before their introduction into the clinical setting. The gold standard in the preclinical assessment and quality control of antivenoms is the neutralization of venom-induced lethality. In addition, depending on the pathophysiological profile of snake venoms, the neutralization of other toxic activities has to be evaluated, such as hemorrhagic, myotoxic, edema-forming, dermonecrotic, in vitro coagulant, and defibrinogenating effects. There is a need to develop laboratory assays to evaluate neutralization of other relevant venom activities. The concept of the 3Rs (Replacement, Reduction, and Refinement) in Toxinology is of utmost importance, and some advances have been performed in their implementation. A significant leap forward in the study of the immunological reactivity of antivenoms against venoms has been the development of "antivenomics", which brings the analytical power of mass spectrometry to the evaluation of antivenoms. International partnerships are required to assess the preclinical efficacy of antivenoms against snake venoms in different regions of the world in order to have a detailed knowledge on the neutralizing profile of these immunotherapeutics.
Pub.: 16 May '17, Pinned: 16 Aug '17
Abstract: Snakebite envenoming is a neglected public health challenge of compelling importance in many regions of the world, particularly sub-Saharan Africa, Asia, Latin America and Papua-New Guinea. Addressing the problem of snakebite effectively demands an integrated multifocal approach, targeting complex problems and involving many participants. It must comprise: (a) Acquisition of reliable information on the incidence and mortality attributable to snakebite envenoming, and the number of people left with permanent sequelae. (b) Improvements in production of effective and safe antivenoms, through strategies aimed at strengthening the technological capacity of antivenom manufacturing laboratories. (c) Increasing the capacity of low-income countries to produce specific immunogens(snake venoms) locally, and to perform their own quality control of antivenoms. (d) Commitments from regional producers to manufacture antivenoms for countries where antivenom production is not currently feasible. (e) Implementation of financial initiatives guaranteeing the acquisition of adequate volumes of antivenom at affordable prices in low-income countries. (f) Performance of collaborative studies on the safety and effectiveness of antivenoms assessed preclinically and by properly designed clinical trials. (g) Development of antivenom distribution programmes tailored to the real needs and epidemiological situations of rural areas in each country. (h) Permanent training programmes for health staff, particularly in rural areas where snakebites are frequent.(i) Implementation of programmes to support those people whose snakebites resulted in chronic disabilities. (j) Preventive and educational programmes at the community level, with the active involvement of local organizations and employing modern methods of health promotion. Such an integrated approach, currently being fostered by the Global Snake Bite Initiative of the International Society on Toxinology and by the World Health Organization, will help to alleviate the enormous burden of human suffering inflicted by snakebite envenoming.
Pub.: 03 Dec '09, Pinned: 16 Aug '17
Abstract: The development of snake antivenoms more than a century ago should have heralded effective treatment of the scourge of snakebite envenoming in impoverished, mostly rural populations around the world. That snakebite still exists today, as a widely untreated illness that maims, kills and terrifies men, women and children in vulnerable communities, is a cruel anachronism. Antivenom can be an effective, safe and affordable treatment for snakebites, but apathy, inaction and the politicisation of public health have marginalised both the problem (making snakebite arguably the most neglected of all neglected tropical diseases) and its solution. For lack of any coordinated approach, provision of antivenoms has been pushed off the public health agenda, leading to an incongruous decline in demand for these crucial antidotes, excused and fed by new priorities, an absence of epidemiological data, and a poor regulatory framework. These factors facilitated the infiltration of poor quality products that degrade user confidence and undermine legitimate producers. The result is that tens of thousands are denied an essential life-saving medicine, allowing a toll of human suffering that is a summation of many individual catastrophes. No strategy has been developed to address this problem and to overcome the intransigence and inaction responsible for the global tragedy of snakebite. Attempts to engage with the broader public health community through the World Health Organisation (WHO), GAVI, and other agencies have failed. Consequently, the toxinology community has taken on a leadership role in a new approach, the Global Snakebite Initiative, which seeks to mobilise the resources, skills and experience of scientists and clinicians for whom venoms, toxins, antivenoms, snakes and snakebites are already fields of interest. Proteomics is one such discipline, which has embraced the potential of using venoms in bio-discovery and systems biology. The fields of venomics and antivenomics have recently evolved from this discipline, offering fresh hope for the victims of snakebites by providing an exciting insight into the complexities, nature, fundamental properties and significance of venom constituents. Such a rational approach brings with it the potential to design new immunising mixtures from which to raise potent antivenoms with wider therapeutic ranges. This addresses a major practical limitation in antivenom use recognised since the beginning of the 20th century: the restriction of therapeutic effectiveness to the specific venom immunogen used in production. Antivenomic techniques enable the interactions between venoms and antivenoms to be examined in detail, and if combined with functional assays of specific activity and followed up by clinical trials of effectiveness and safety, can be powerful tools with which to evaluate the suitability of current and new antivenoms for meeting urgent regional needs. We propose two mechanisms through which the Global Snakebite Initiative might seek to end the antivenom drought in Africa and Asia: first by establishing a multidisciplinary, multicentre, international collaboration to evaluate currently available antivenoms against the venoms of medically important snakes from specific nations in Africa and Asia using a combination of proteomic, antivenomic and WHO-endorsed preclinical assessment protocols, to provide a validated evidence base for either recommending or rejecting individual products; and secondly by bringing the power of proteomics to bear on the design of new immunising mixtures to raise Pan-African and Pan-Asian polyvalent antivenoms of improved potency and quality. These products will be subject to rigorous clinical assessment. We propose radically to change the basis upon which antivenoms are produced and supplied for the developing world. Donor funding and strategic public health alliances will be sought to make it possible not only to sustain the financial viability of antivenom production partnerships, but also to ensure that patients are relieved of the costs of antivenom so that poverty is no longer a barrier to the treatment of this important, but grossly neglected public health emergency.
Pub.: 07 Jun '11, Pinned: 16 Aug '17