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1.  Bilateral blindness following Russell’s viper bite - a rare clinical presentation: a case report 
Introduction
Russell’s viper (Daboia russelii) is one of the most common medically important snakes reported in Sri Lanka. Its envenomation leads to significant mortality and morbidity with local, hematological, neurological and renal complications. Here we report the case of a patient who presented with bilateral blindness secondary to a bilateral posterior circulation ischemic stroke instead of the usual neurological manifestations of Russell’s viper envenomation. There were no reported cases of cortical blindness following a Russell’s viper bite. Only a few reported cases of ischemic strokes following a Russell’s viper bite were found in the literature.
Case presentation
A 54-year-old Sri Lankan woman developed bilateral blindness due to a posterior circulation infarct following Russell’s viper envenomation.
Conclusion
Ischemic stroke following a Russell’s viper bite is very rare and cortical blindness is not reported as the clinical presentation. Also, we emphasize the importance of considering the possibility of ischemic stroke in patients who develop unusual neurological manifestations following Russell’s viper envenomation.
doi:10.1186/1752-1947-8-99
PMCID: PMC3978077  PMID: 24661603
Blindness; Russell’s viper; Ischemic stroke
2.  Revisiting Russell's Viper (Daboia russelii) Bite in Sri Lanka: Is Abdominal Pain an Early Feature of Systemic Envenoming? 
PLoS ONE  2014;9(2):e90198.
The Russell's viper (Daboia russelii) is responsible for 30–40% of all snakebites and the most number of life-threatening bites of any snake in Sri Lanka. The clinical profile of Russell's viper bite includes local swelling, coagulopathy, renal dysfunction and neuromuscular paralysis, based on which the syndromic diagnostic tools have been developed. The currently available Indian polyvalent antivenom is not very effective in treating Russell's viper bite patients in Sri Lanka and the decision regarding antivenom therapy is primarily driven by clinical and laboratory evidence of envenoming. The non-availability of early predictors of Russell's viper systemic envenoming is responsible for considerable delay in commencing antivenom. The objective of this study is to evaluate abdominal pain as an early feature of systemic envenoming following Russell's viper bites. We evaluated the clinical profile of Russell's viper bite patients admitted to a tertiary care centre in Sri Lanka. Fifty-five patients were proven Russell's viper bite victims who produced the biting snake, while one hundred and fifty-four were suspected to have been bitten by the same snake species. Coagulopathy (159, 76.1%), renal dysfunction (39, 18.7%), neuromuscular paralysis (146, 69.9%) and local envenoming (192, 91.9%) were seen in the victims, ranging from mono-systemic involvement to various combinations. Abdominal pain was present in 79.5% of these patients, appearing 5 minutes to 4 hours after the bite. The severity of the abdominal pain, assessed using a scoring system, correlated well with the severity of the coagulopathy (p<0.001) and the neurotoxicity (p<0.001). Its diagnostic validity to predict systemic envenoming is – Sensitivity 81.6%, Specificity 82.4%, Positive predictive value 91.2%. Thus, abdominal pain is an early clinical feature of systemic Russell's viper bite envenoming in Sri Lanka. However, it is best to judge abdominal pain together with other clinical manifestations on decision making.
doi:10.1371/journal.pone.0090198
PMCID: PMC3936006  PMID: 24587278
3.  Cerebellar infarct with neurogenic pulmonary edema following viper bite 
Russell's viper (Daboia russelli) bites are well known to cause bleeding complications. However, thrombotic complications are rare. We present the case details of a female who was bitten by a Russell's viper (Daboia russelli) in her village. She then developed features of envenomation in the form of hemorrhagic episodes. She received 27 vials of polyvalent anti-snake venom to which the hemorrhagic complications responded. After about 48 h of the bite she developed features of cerebellar infarct along with pulmonary edema which was in all probability neurogenic in origin. She was managed with mechanical ventilation and extra ventricular drainage with good recovery. We discuss the likely pathogenesis of the infarct and pulmonary edema occurring in a patient with viper bite and other features of envenomation.
doi:10.4103/0976-3147.91954
PMCID: PMC3271624  PMID: 22346200
Cerebellar infarct; neurogenic pulmonary edema; viper bitee
4.  Acute myocardial infarction following a Russell’s viper bite: a case report 
Introduction
Snake bite is a common and devastating environmental hazard, especially in rural areas of tropical countries. Acute myocardial infarction caused by snakebite has rarely been reported. To our knowledge we found only 10 cases of Myocardial infarction following a viper bite in English literature.
Case presentation
We report a case of inferior ST elevation myocardial infarction following a Russell’s viper bite in a 37 year old healthy Sri Lankan (South Asian) female with no past history of cardiac disease or cardiac risk factors who died 30 hours following the bite.
Conclusion
The course of events with respect to myocardium suggests a direct toxic effect of the venom on myocardial tissue or coronary vasoconstriction. Physicians should bear in mind the complications and devastating sequela of Myocardial infarction following Russell’s viper bite.
doi:10.1186/1755-7682-6-7
PMCID: PMC3605354  PMID: 24499589
Snake bite; Russell’s viper; Myocardial infarction; ST elevation myocardial infarction
5.  Bioinformatics and Multiepitope DNA Immunization to Design Rational Snake Antivenom 
PLoS Medicine  2006;3(6):e184.
Background
Snake venom is a potentially lethal and complex mixture of hundreds of functionally diverse proteins that are difficult to purify and hence difficult to characterize. These difficulties have inhibited the development of toxin-targeted therapy, and conventional antivenom is still generated from the sera of horses or sheep immunized with whole venom. Although life-saving, antivenoms contain an immunoglobulin pool of unknown antigen specificity and known redundancy, which necessitates the delivery of large volumes of heterologous immunoglobulin to the envenomed victim, thus increasing the risk of anaphylactoid and serum sickness adverse effects. Here we exploit recent molecular sequence analysis and DNA immunization tools to design more rational toxin-targeted antivenom.
Methods and Findings
We developed a novel bioinformatic strategy that identified sequences encoding immunogenic and structurally significant epitopes from an expressed sequence tag database of a venom gland cDNA library of Echis ocellatus, the most medically important viper in Africa. Focusing upon snake venom metalloproteinases (SVMPs) that are responsible for the severe and frequently lethal hemorrhage in envenomed victims, we identified seven epitopes that we predicted would be represented in all isomers of this multimeric toxin and that we engineered into a single synthetic multiepitope DNA immunogen (epitope string). We compared the specificity and toxin-neutralizing efficacy of antiserum raised against the string to antisera raised against a single SVMP toxin (or domains) or antiserum raised by conventional (whole venom) immunization protocols. The SVMP string antiserum, as predicted in silico, contained antibody specificities to numerous SVMPs in E. ocellatus venom and venoms of several other African vipers. More significantly, the antiserum cross-specifically neutralized hemorrhage induced by E. ocellatus and Cerastes cerastes cerastes venoms.
Conclusions
These data provide valuable sequence and structure/function information of viper venom hemorrhagins but, more importantly, a new opportunity to design toxin-specific antivenoms—the first major conceptual change in antivenom design after more than a century of production. Furthermore, this approach may be adapted to immunotherapy design in other cases where targets are numerous, diverse, and poorly characterized such as those generated by hypermutation or antigenic variation.
Editors' Summary
Background.
Of the 3,000 species of snakes worldwide, about 600 are poisonous; poisonous snakes are a particular problem in Africa and Southeast Asia. Because not all victims of snake bites get to hospital, estimates of illness and death caused are very approximate. However, one estimate quoted by the World Health Organization is that 2.5 million snake bites occur each year and 125,000 are fatal. The effects of snake bites vary, obviously depending on which snake does the biting, but immediate effects include swelling (around the bite or of other parts of the body), death of the area around the bite, and blood clotting problems. Nowadays, snake bite is treated with “antivenoms,” which are usually made from immunizing horses or sheep with snake venom. However, these antivenoms contain many different proteins that can themselves trigger unpleasant reactions in the recipient. One problem with developing antivenoms is that venoms contain many hundreds of different proteins, many of which may contribute to the toxic effect.
Why Was This Study Done?
Recent scientific discoveries have led to new ways of finding which parts of an animal's genetic sequence are active in any one particular part of the body, and also whether the proteins produced from these genes are likely to cause illness. A snake's venom gland, where the venom is made, can be analysed this way. The researchers wanted to use this information to develop a more rational way of designing antivenoms.
What Did the Researchers Do and Find?
They studied the venom glands of the carpet viper (Echis ocellatus), the most medically important snake in West Africa. They isolated expressed sequence tags (ESTs) produced by the venom glands. Each EST is a small part of the active part of a gene. They then focused on one group of genes that make proteins called snake venom metalloproteinases (SVMPs), which destroy other proteins, and which cause many of the severe symptoms, such as bleeding, seen after snake bite. They identified seven parts of these SVMPs that were likely to be clinically important, and engineered them into a single string of DNA. This product is known as an immunogen—that is, it can produce an immune response in an animal. And when this immunogen was injected into mice, the researchers found that the serum (the part of the blood that contains antibodies) from these mice did have a specific effect against the SVMPs in snake venom. It also had some effect, again in mice, against bleeding caused by small doses of snake venom.
What Do These Findings Mean?
These results suggest that it is possible to use some of the newest genetic techniques to design immunogens that can be used to make highly specific, toxin-neutralizing antisera. These immunogens are a possible improvement over conventional antivenoms that are raised against whole venom. This approach could mean that lower doses of antivenoms would be needed than for conventional antivenoms. In addition, it may also be possible to design antivenoms that work against different species of snake venom. Results such as this may persuade a company that it is worth investing further in such antivenoms; as with many diseases of the poorer parts of the world, snake bites have not been of great interest to large pharmaceutical companies. In another paper published in PLoS Medicine, José María Gutiérrez et al. discuss the global problem of snake bites.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030184
•  World Health Organization page on animal bites, including snakes
•  MedlinePlus Medical Encyclopedia pages of health information (these pages are most relevant in the US)
Seven epitopes were identified providing valuable sequence and structure/function information of viper venom hemorrhagins. This has created a new opportunity to design toxin-specific antivenoms.
doi:10.1371/journal.pmed.0030184
PMCID: PMC1472699  PMID: 16737347
6.  In Vitro and In Vivo Evaluation of Polyherbal Formulation against Russell's Viper and Cobra Venom and Screening of Bioactive Components by Docking Studies 
The present study emphasizes to reveal the antivenom activity of Aristolochia bracteolata Lam., Tylophora indica (Burm.f.) Merrill, and Leucas aspera S. which were evaluated against venoms of Daboia russelli russelli (Russell's viper) and Naja naja (Indian cobra). The aqueous extracts of leaves and roots of the above-mentioned plants and their polyherbal (1 : 1 : 1) formulation at a dose of 200 mg/kg showed protection against envenomed mice with LD50 doses of 0.44 mg/kg and 0.28 mg/kg against Russell's viper and cobra venom, respectively. In in vitro antioxidant activities sample extracts showed free radical scavenging effects in dose dependent manner. Computational drug design and docking studies were carried out to predict the neutralizing principles of type I phospholipase A2 (PLA2) from Indian common krait venom. This confirmed that aristolochic acid and leucasin can neutralize type I PLA2 enzyme. Results suggest that these plants could serve as a source of natural antioxidants and common antidote for snake bite. However, further studies are needed to identify the lead molecule responsible for antidote activity.
doi:10.1155/2013/781216
PMCID: PMC3600290  PMID: 23533518
7.  Immune Response to Snake Envenoming and Treatment with Antivenom; Complement Activation, Cytokine Production and Mast Cell Degranulation 
Background
Snake bite is one of the most neglected public health issues in poor rural communities worldwide. In addition to the clinical effects of envenoming, treatment with antivenom frequently causes serious adverse reactions, including hypersensitivity reactions (including anaphylaxis) and pyrogenic reactions. We aimed to investigate the immune responses to Sri Lankan snake envenoming (predominantly by Russell's viper) and antivenom treatment.
Methodology/Principal Findings
Plasma concentrations of Interleukin (IL)-6, IL-10, tumor necrosis factor α (TNFα), soluble TNF receptor I (sTNFRI), anaphylatoxins (C3a, C4a, C5a; markers of complement activation), mast cell tryptase (MCT), and histamine were measured in 120 Sri Lankan snakebite victims, both before and after treatment with antivenom. Immune mediator concentrations were correlated with envenoming features and the severity of antivenom-induced reactions including anaphylaxis. Envenoming was associated with complement activation and increased cytokine concentrations prior to antivenom administration, which correlated with non-specific systemic symptoms of envenoming but not with coagulopathy or neurotoxicity. Typical hypersensitivity reactions to antivenom occurred in 77/120 patients (64%), satisfying criteria for a diagnosis of anaphylaxis in 57/120 (48%). Pyrogenic reactions were observed in 32/120 patients (27%). All patients had further elevations in cytokine concentrations, but not complement activation, after the administration of antivenom, whether a reaction was noted to occur or not. Patients with anaphylaxis had significantly elevated concentrations of MCT and histamine.
Conclusions/Significance
We have demonstrated that Sri Lankan snake envenoming is characterized by significant complement activation and release of inflammatory mediators. Antivenom treatment further enhances the release of inflammatory mediators in all patients, with anaphylactic reactions characterised by high levels of mast cell degranulation but not further complement activation. Anaphylaxis is probably triggered by non allergen-specific activation of mast cells and may be related to the quality of available antivenom preparations, as well as a priming effect from the immune response to the venom itself.
Author Summary
Snakebites cause life-threatening symptoms including uncontrolled bleeding and paralysis. The body's immune responses to snake venom may contribute to the severity of these symptoms but have not been well characterized in humans. Treatment with antivenom is potentially lifesaving, but also carries risk, as severe allergic reactions (anaphylaxis) are common. Anaphylaxis occurs when mast cells, triggered by either allergen-specific antibodies, other immunological mechanisms, or non-immune mechanisms, release mediators that cause skin rashes, shortness of breath and, in severe cases, life-threatening hypotension and/or hypoxia. We have studied 120 snakebite victims in Sri Lanka, both before and after treatment with antivenom. Our results have shown snakebite triggers activation of the complement cascade (an important part of the body's innate immune defence) and production of proinflammatory mediators. In addition, we have demonstrated a quite astonishing level of immune activation after antivenom treatment in virtually every person treated, regardless of whether they had a reaction to the antivenom. Half of the patients treated experienced anaphylaxis, with clear evidence of mast cell activation. Anaphylaxis to antivenom is unlikely to be triggered by allergen-specific antibodies, as patients had not been previously exposed to antivenom, but may be related to the quality of available antivenom preparations, as well as a priming effect from the immune response to the venom itself.
doi:10.1371/journal.pntd.0002326
PMCID: PMC3723557  PMID: 23936562
8.  Acute Demyelinating Encephalomyelitis After Anti-venom Therapy in Russell’s Viper Bite 
Journal of Medical Toxicology  2010;6(3):318-321.
Introduction
Russell’s viper is a commonly encountered venomous snake in India. Morbidity and mortality following envenomation and the treatment thereof are frequent. We report a rarely seen complication after a treated Russell’s viper bite.
Case Report
A 36-year-old male farmer received 30 vials polyvalent anti-snake venom after a viper bite to his right leg. Improvement in initial hematemesis and circulatory shock was followed by acute renal failure managed with regular hemodialysis. He displayed no abnormalities on neurological examination at admission. Fourth day onwards his neurologic status started deteriorating with development of behavioral abnormalities, hemi-spatial neglect of left upper limb, paralysis of left facial nerve, left upper limb, and right lower limb. Acute disseminated encephalomyelitis was confirmed on magnetic resonance imaging (MRI) of brain with typical spectroscopic characteristics. High dose methyl prednisolone was administered and a rapid recovery followed.
Conclusion
Russels viper bite followed by treatment with antivenom may be complicated by the development of immune complex mediated demyelination and development of acute disseminated encephalomyelitis. MRI spectroscopy helps in early identification of demyelination and in a definite diagnosis. Treatment with corticosteroids was associated with resolution of symptoms in this case.
doi:10.1007/s13181-010-0015-8
PMCID: PMC3550494  PMID: 20237970
Snake bite; Acute disseminated encephalomyelitis; Antivenom
9.  Life threatening intracerebral haemorrhage following saw- scaled viper (Echis carinatus) envenoming-authenticated case report from Sri Lanka 
Background
Echis carinatus (Saw scaled viper {SSV}) is a venomous snake found in the parts of Middle East and Central Asia. SSV envenoming is characterized by local swelling and coagulopathy. Various bleeding manifestations are commonly seen with SSV envenoming. In contrast to other part of Asia, saw scale viper envenoming has not been reported to cause life threatening haemorrhagic manifestations in Sri Lanka.
Case presentation
We report a 19 years old healthy boy who developed massive left temporo-parietal intra cerebral haemorrhage following Echis carinatus (Saw scaled viper) bite in Sri Lanka.
Conclusion
Although subspecies of SSV in Sri Lanka is regarded as a ‘non lethal venomous snake’, the occurrence of rare potentially fatal complications such as intracerebral haemorrhage should be considered in their management. This case report is intended to bring the awareness of this fatal complication of SSV envenoming in Sri Lanka.
doi:10.1186/1471-227X-13-5
PMCID: PMC3636000  PMID: 23565979
10.  The Global Burden of Snakebite: A Literature Analysis and Modelling Based on Regional Estimates of Envenoming and Deaths 
PLoS Medicine  2008;5(11):e218.
Background
Envenoming resulting from snakebites is an important public health problem in many tropical and subtropical countries. Few attempts have been made to quantify the burden, and recent estimates all suffer from the lack of an objective and reproducible methodology. In an attempt to provide an accurate, up-to-date estimate of the scale of the global problem, we developed a new method to estimate the disease burden due to snakebites.
Methods and Findings
The global estimates were based on regional estimates that were, in turn, derived from data available for countries within a defined region. Three main strategies were used to obtain primary data: electronic searching for publications on snakebite, extraction of relevant country-specific mortality data from databases maintained by United Nations organizations, and identification of grey literature by discussion with key informants. Countries were grouped into 21 distinct geographic regions that are as epidemiologically homogenous as possible, in line with the Global Burden of Disease 2005 study (Global Burden Project of the World Bank). Incidence rates for envenoming were extracted from publications and used to estimate the number of envenomings for individual countries; if no data were available for a particular country, the lowest incidence rate within a neighbouring country was used. Where death registration data were reliable, reported deaths from snakebite were used; in other countries, deaths were estimated on the basis of observed mortality rates and the at-risk population. We estimate that, globally, at least 421,000 envenomings and 20,000 deaths occur each year due to snakebite. These figures may be as high as 1,841,000 envenomings and 94,000 deaths. Based on the fact that envenoming occurs in about one in every four snakebites, between 1.2 million and 5.5 million snakebites could occur annually.
Conclusions
Snakebites cause considerable morbidity and mortality worldwide. The highest burden exists in South Asia, Southeast Asia, and sub-Saharan Africa.
Janaka de Silva and colleagues estimate that globally at least 421,000 envenomings and 20,000 deaths occur each year due to snakebite.
Editors' Summary
Background.
Of the 3,000 or so snake species that exist in the world, about 600 are venomous. Venomous snakes—which exist on every continent except Antarctica—immobilize their prey by injecting modified saliva (venom) that contains toxins into their prey's tissues through their fangs—specialized, hollow teeth. Snakes also use their venoms for self defense and will bite people who threaten, startle or provoke them. Snakebites caused by the families Viperidae (for example, pit vipers) and Elapidae (for example, kraits and cobras) are particularly dangerous to people. The potentially fatal effects of being “envenomed” (having venom injected) by these snakes include widespread bleeding, muscle paralysis, and tissue destruction (necrosis) around the bite site. Bites from these snakes can also cause permanent disability. For example, snakebite victims, who tend to be young and male, may have to have a limb amputated because of necrosis. The best treatment for any snakebite is to get the victim to a hospital as soon as possible where antivenoms (mixtures of antibodies that neutralize venoms) can be given.
Why Was This Study Done?
Although snakebites occur throughout the world, envenoming snakebites are thought to pose a particularly important yet largely neglected threat to public health. This is especially true in rural areas of tropical and subtropical countries where snakebites are common but where there is limited access to health care and to antivenoms. The true magnitude of the public-health threat posed by snakebites in these countries (and elsewhere in the world) is unknown, which makes it hard for public-health officials to optimize the prevention and treatment of snakebites in their respective countries. In this study, therefore, the researchers develop and apply a new method to estimate the global burden of snakebite.
What Did the Researchers Do and Find?
The researchers systematically searched the scientific literature for publications on snakebites and deaths from snakebites and extracted data on snakebite deaths in individual countries from the World Health Organization (WHO) mortality database. They also contacted Ministries of Health, National Poison Centers, and snakebite experts for unpublished information (“grey” literature) on snakebites. Together, these three approaches provided data on the number of snakebite envenomings and deaths for 135 and 162 countries, respectively. The researchers then grouped the 227 countries of the world into 21 geographical regions, each of which contained countries with similar population characteristics, and used the results of studies done in individual countries within each region to estimate the numbers of snakebite envenomings and deaths for each region. Finally, they added up these estimates to obtain an estimate of the global burden of snakebite. Using this method, the researchers estimate that, worldwide, at least 421,000 envenomings and 20,000 deaths from snakebite occur every year; the actual numbers, they suggest, could be as high as 1.8 million envenomings and 94,000 deaths. Their estimates also indicate that the highest burden of snakebite envenomings and death occurs in South and Southeast Asia and in sub-Saharan Africa, and that India is the country with the highest annual number of envenomings (81,000) and deaths (nearly 11,000).
What Do These Findings Mean?
These findings indicate that snakebites cause considerable illness and death around the world. Because of the careful methods used by the researchers, their global estimates of snakebite envenomings and deaths are probably more accurate than previous estimates. However, because the researchers had to make many assumptions in their calculations and because there are so few reliable data on the numbers of snakebites and deaths from the rural tropics, the true regional and global numbers of these events may differ substantially from the estimates presented here. In particular, the regional estimates for eastern sub-Saharan Africa, a region where snakebites are very common and where antivenoms are particularly hard to obtain, are likely to be inaccurate because they are based on a single study. The researchers, therefore, call for more studies on snakebite envenoming and deaths to be done to provide the information needed to deal effectively with this neglected public-health problem.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050218.
This study is further discussed in a PLoS Medicine Perspective by Chippaux
The MedlinePlus Medical Encyclopedia has a page on snakebites (in English and Spanish)
The UK National Health Service Direct health encyclopedia has detailed information about all aspects of snakebites
Wikipedia has pages on venomous snakes and on snakebites (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The World Health Organization provides information about antivenoms and about efforts to increase access to antivenoms in developing countries (available in several languages)
A previous article in PLoS Medicine also discusses the neglected problem of snakebite envenoming: Gutiérrez JM, Theakston RDG, Warrell DA (2006) Confronting the Neglected Problem of Snake Bite Envenoming: The Need for a Global Partnership. PLoS Med 3(6): e150
doi:10.1371/journal.pmed.0050218
PMCID: PMC2577696  PMID: 18986210
11.  A Randomised Controlled Trial of Two Infusion Rates to Decrease Reactions to Antivenom 
PLoS ONE  2012;7(6):e38739.
Background
Snake envenoming is a major clinical problem in Sri Lanka, with an estimated 40,000 bites annually. Antivenom is only available from India and there is a high rate of systemic hypersensitivity reactions. This study aimed to investigate whether the rate of infusion of antivenom reduced the frequency of severe systemic hypersensitivity reactions.
Methods and Findings
This was a randomized comparison trial of two infusion rates of antivenom for treatment of non-pregnant adult patients (>14 y) with snake envenoming in Sri Lanka. Snake identification was by patient or hospital examination of dead snakes when available and confirmed by enzyme-immunoassay for Russell’s viper envenoming. Patients were blindly allocated in a 11 randomisation schedule to receive antivenom either as a 20 minute infusion (rapid) or a two hour infusion (slow). The primary outcome was the proportion with severe systemic hypersensitivity reactions (grade 3 by Brown grading system) within 4 hours of commencement of antivenom. Secondary outcomes included the proportion with mild/moderate hypersensitivity reactions and repeat antivenom doses. Of 1004 patients with suspected snakebites, 247 patients received antivenom. 49 patients were excluded or not recruited leaving 104 patients allocated to the rapid antivenom infusion and 94 to the slow antivenom infusion. The median actual duration of antivenom infusion in the rapid group was 20 min (Interquartile range[IQR]:20–25 min) versus 120 min (IQR:75–120 min) in the slow group. There was no difference in severe systemic hypersensitivity reactions between those given rapid and slow infusions (32% vs. 35%; difference 3%; 95%CI:−10% to +17%;p = 0.65). The frequency of mild/moderate reactions was also similar. Similar numbers of patients in each arm received further doses of antivenom (30/104 vs. 23/94).
Conclusions
A slower infusion rate would not reduce the rate of severe systemic hypersensitivity reactions from current high rates. More effort should be put into developing better quality antivenoms.
Trial Registration
www.slctr.lk SLCTR/2007/005
doi:10.1371/journal.pone.0038739
PMCID: PMC3377702  PMID: 22719932
12.  Purification and Functional Characterisation of Rhiminopeptidase A, a Novel Aminopeptidase from the Venom of Bitis gabonica rhinoceros 
Background
Snake bite is a major neglected public health issue within poor communities living in the rural areas of several countries throughout the world. An estimated 2.5 million people are bitten by snakes each year and the cost and lack of efficacy of current anti-venom therapy, together with the lack of detailed knowledge about toxic components of venom and their modes of action, and the unavailability of treatments in rural areas mean that annually there are around 125,000 deaths worldwide. In order to develop cheaper and more effective therapeutics, the toxic components of snake venom and their modes of action need to be clearly understood. One particularly poorly understood component of snake venom is aminopeptidases. These are exo-metalloproteases, which, in mammals, are involved in important physiological functions such as the maintenance of blood pressure and brain function. Although aminopeptidase activities have been reported in some snake venoms, no detailed analysis of any individual snake venom aminopeptidases has been performed so far. As is the case for mammals, snake venom aminopeptidases may also play important roles in altering the physiological functions of victims during envenomation. In order to further understand this important group of snake venom enzymes we have isolated, functionally characterised and analysed the sequence-structure relationships of an aminopeptidase from the venom of the large, highly venomous West African gaboon viper, Bitis gabonica rhinoceros.
Methodology and Principal Findings
The venom of B. g. rhinoceros was fractionated by size exclusion chromatography and fractions with aminopeptidase activities were isolated. Fractions with aminopeptidase activities showed a pure protein with a molecular weight of 150 kDa on SDS-PAGE. In the absence of calcium, this purified protein had broad aminopeptidase activities against acidic, basic and neutral amino acids but in the presence of calcium, it had only acidic aminopeptidase activity (APA). Together with the functional data, mass spectrometry analysis of the purified protein confirmed this as an aminopeptidase A and thus this has been named as rhiminopeptidase A. The complete gene sequence of rhiminopeptidase A was obtained by sequencing the PCR amplified aminopeptidase A gene from the venom gland cDNA of B. g. rhinoceros. The gene codes for a predicted protein of 955 amino acids (110 kDa), which contains the key amino acids necessary for functioning as an aminopeptidase A. A structural model of rhiminopeptidase A shows the structure to consist of 4 domains: an N-terminal saddle-shaped β domain, a mixed α and β catalytic domain, a β-sandwich domain and a C-terminal α helical domain.
Conclusions
This study describes the discovery and characterisation of a novel aminopeptidase A from the venom of B. g. rhinoceros and highlights its potential biological importance. Similar to mammalian aminopeptidases, rhiminopeptidase A might be capable of playing roles in altering the blood pressure and brain function of victims. Furthermore, it could have additional effects on the biological functions of other host proteins by cleaving their N-terminal amino acids. This study points towards the importance of complete analysis of individual components of snake venom in order to develop effective therapies for snake bites.
Author Summary
Snake bite is a major neglected public health issue causing an estimated 125,000 deaths each year, predominantly within poor communities living in rural areas of countries in South East Asia and Africa. Current treatments for snake bites are costly and have limited effectiveness, thus there is a need to develop novel therapeutics. In order to do this the toxic components of snake venom need to be clearly understood. Enzymes called aminopeptidases have been noticed in several snake venoms, but their functions have not been characterised. Related enzymes are also present in mammals, where they are involved in the maintenance of blood pressure and brain function. To further understand this important group of enzymes within snake venom we have purified and analysed the function and structure of an aminopeptidase from the venom of the West African gaboon viper. Our results suggest that this enzyme could also affect the maintenance of blood pressure and brain function in victims of snake bites. Along with other snake venom components, aminopeptidases might be a potential therapeutic target for developing novel treatments for snake bites.
doi:10.1371/journal.pntd.0000796
PMCID: PMC2919393  PMID: 20706583
13.  Comparative in-vivo toxicity of venoms from South Asian hump-nosed pit vipers (Viperidae: Crotalinae: Hypnale) 
BMC Research Notes  2012;5:471.
Background
Envenoming by south Asian hump-nosed pit vipers (Genus: Hypnale) is a significant health issue in Sri Lanka and in peninsular India. Bites by these snakes frequently lead to local envenoming, coagulopathy and acute renal failure even resulting in death. Recently the genus was revised and the existence of three species viz H. hypnale, H. nepa and H. zara were recognized. There is, however, a paucity of information on the toxicity of the venoms of these species. Hence, we compared the toxic effects of the three Hypnale venoms using BALB/c mice.
Findings
Intraperitoneal median lethal doses (LD50) for H. hypnale, H. zara and H. nepa venoms were 1.6, 6.0 and 9.5 μg protein/g respectively. Minimum haemorrhagic doses for venoms of H. hypnale, H. zara and H. nepa were 3.4, 11.0 and 16.6 μg protein/mouse respectively. The minimum necrotic doses for the same venoms were 15.0, 55.1 and 68.2 μg protein/mouse respectively. Severe congestion and petecheal haemorrhages were observed in lungs, kidneys, liver and the alimentary tract. Histopathogical examination of kidneys revealed proximal tubular cell injury and acute tubular necrosis with intact basement membrane indicating possible direct nephrotoxicity. Hypnale venoms caused pulmonary oedema, hepatocellular degeneration and necrosis, focal neuronal degeneration in brain and extramedullary haemopoiesis in spleen. H. hypnale venom caused all above histopathological alterations at lower doses compared to the other two.
Conclusion
Hypnale venoms cause similar pathological changes with marked differences in the severity of the toxic effects in vivo. Therefore, differences in the severity of the clinical manifestations could possibly be seen among bite victims of the three Hypnale species.
doi:10.1186/1756-0500-5-471
PMCID: PMC3494509  PMID: 22932058
Hypnale; Nepa; Zara; Venom; Toxicity; Histopathology
14.  A Study on the Clinico-Epidemiological Profile and the Outcome of Snake Bite Victims in a Tertiary Care Centre in Southern India 
Background: Snake bite is a common medical emergency and an occupational hazard, more so in tropical India, where farming is a major source of employment. The available data on the epidemiology of snake bite from the Indian subcontinent are sparse. Snake bite is a neglected disease that afflicts the most impoverished inhabitants of the rural areas in the tropical developing countries.
Aims: This study was carried out to describe the epidemiology, arrival delays, clinical features, complications, and the outcome of snakebites which were seen in a tertiary care hospital of southern India.
Setting: Sri Chamarajendra District Hospital which is attached to the Hassan Institute of Medical Sciences, Hassan, Karnataka, India.
Study Design: A record–based, retrospective, descriptive study.
Materials and Methods: One hundred eighty patients of snake bite were studied from January 2010 to December 2011. The data on the demographic factors, clinical features and complications, details of the treatment which was received and the outcome of the snake bite victims were recorded and analyzed.
Results: Among a total 180 cases of snake bite, there were 108 cases of viper bite which presented with haematotoxic manifestations and 74 elapid bites had neuroparalytic manifestations. The victims were predominantly males (60.5%) and they were aged 20-40 years. A majority of the victims are from the rural areas (81.1%) and most of the bites occurred during the day time (70.5%), mainly on the lower limbs (67.2%). The highest number of cases occurred during July- September. Most of the victims were farmers (54.4%) and plantation workers (30.5%), which suggested that snake bite was an occupational hazard. A reaction to the ASV was noted in 12.7% of the patients and the mortality rate in our study was 3.8%.
Conclusion: In the tropics, snake bite is a rural and an occupational hazard among farmers, plantation workers, herders and hunters. Regular public health programmes regarding the prevention, pre –hospital management (first aid) and the importance of the early transfer to the hospital should be emphasized.
doi:10.7860/JCDR/2012/4842.2685
PMCID: PMC3576766  PMID: 23450135
Anti-snake venom; Envenomation; Epidemiology; Snake-bite; Southern India
15.  Purification, crystallization and preliminary X-ray structural studies of a 7.2 kDa cytotoxin isolated from the venom of Daboia russelli russelli of the Viperidae family 
A cytotoxin from Indian Russell’s viper (D. russelli russelli) venom having multifunctional activity has been crystallized in space group P41. Larger crystals diffracted to 1.5 Å but were found to be twinned; preliminary data were therefore collected (2.93 Å) from a smaller crystal.
A cytotoxin (MW 7.2 kDa) from Indian Russell’s viper (Daboia russelli russelli) venom possessing antiproliferative activity, cardiotoxicity, neurotoxicity and myotoxicity has been purified, characterized and crystallized. The crystals belong to the tetragonal space group P41, with unit-cell parameters a = b = 47.94, c = 50.2 Å. Larger crystals, which diffracted to 1.5 Å, were found to be twinned; diffraction data were therefore collected to 2.93 Å resolution using a smaller crystal. Molecular-replacement calculations identified two molecules of the protein in the asymmetric unit, which is in accordance with the calculated V M value.
doi:10.1107/S1744309106005963
PMCID: PMC2197197  PMID: 16511326
cytotoxins; Russell’s viper; antiproliferative activity
16.  Posterior circulation ischemic stroke following Russell's viper envenomation 
Ischemic stroke following viper bite is rare. We report a case of posterior circulation ischemic infarction following viper bite in a previously healthy woman. Soon after being bitten by the snake on the left leg, she developed local redness, echymosis and one hour later became drowsy. On examination she had skew deviation of eyes and down gaze preference, generalized hypotonia. A CT scan of brain showed infarcts in cerebellar hemispheres and occipital lobes on both sides and that was confirmed on magnetic resonance imaging of brain. Her coagulation profile was deranged. Most common and serious central nervous system complication following snake bite is intracranial hemorrhage. Ischemic stroke commonly involves anterior circulation. Bilateral cerebellar and occipital infraction is not yet reported in literature. Exact cause for the development of infarction is not clear. The possible mechanisms of infarction in this scenario are discussed. Patient was treated with anti-snake venom and showed a good recovery. Early imaging and early treatment with anti-snake venom is important for a favorable outcome.
doi:10.4103/0972-2327.91957
PMCID: PMC3271473  PMID: 22346023
Viper envenomation; ischemic stroke; posterior circulation
17.  Saw-Scaled Viper Bites in Sri Lanka: Is It a Different Subspecies? Clinical Evidence from an Authenticated Case Series 
The saw-scaled viper (SSV) (Echis carinatus) is considered to be a highly venomous snake in Sri Lanka despite any published clinical justification. Being a rarity, the clinical profile of SSV bites is not well established in Sri Lanka. We report a series of 48 (n-48) SSV bites from the Northern Province of Sri Lanka. The majority (65%) of victims had evidence of local envenoming at the site of the bite; however, 29% showed spontaneous bleeding and 71% had coagulopathy. There were no deaths in the series. The envenoming was mild in contrast to the mortality and significant morbidity associated with SSV bites in West Africa and some parts of India. These observations need to be further explored with laboratory studies to identify the venom components, study of morphological characteristics, and genetic profiling of the Sri Lankan SSV to see if it is different from the subspecies found elsewhere.
doi:10.4269/ajtmh.2012.11-0447
PMCID: PMC3269276  PMID: 22302858
18.  Bites by foreign venomous snakes in Britain. 
British Medical Journal  1978;1(6127):1598-1600.
In 1970-7 17 people in Britain were the victims of 32 bites by foreign venomous snakes. Crotalus atrox caused eight of these bites, Bitis arietans five, and the remaining 19 bites were caused by 12 different species. All the victims were bitten while handling the snake, and 24 bites were incurred by private individuals in their own homes. Poisoning was negligible in 17 of the 32 bites but life-threatening in at least two cases. Thus in the early stages snake bite may be unpredictable as a clinical problem. All victims of snake bite should be observed for at least 12 hours to assess the severity of poisoning and to ensure rational treatment. Local necrosis developed in six cases and resulted in prolonged illness in five of these cases; local incision was carried out and many have been a casual factor. Comprehensive stocks of antivenoms for treating bites by foreign venomous snakes are held by the National Health Services in Liverpool and London. Antivenom is indicated (a) for potentially serious systemic poisoning, as evidenced by hypotension, electrocardiographic changes, neurtrophilia, and acidosis (after viper or elapid bites), abnormal bleeding or non-clotting blood after viper bites; and ptosis or glossopharyngeal palsy after elapid bites; and (b) for bites from snakes whose venom causes local necrosis, to prevent or minimise this unpleasant complication. For effective antivenom treatment intravenous infusion is mandatory.
PMCID: PMC1605402  PMID: 656831
19.  Randomised Controlled Double-Blind Non-Inferiority Trial of Two Antivenoms for Saw-Scaled or Carpet Viper (Echis ocellatus) Envenoming in Nigeria 
Background
In West Africa, envenoming by saw-scaled or carpet vipers (Echis ocellatus) causes great morbidity and mortality, but there is a crisis in supply of effective and affordable antivenom (ISRCTN01257358).
Methods
In a randomised, double-blind, controlled, non-inferiority trial, “EchiTAb Plus-ICP” (ET-Plus) equine antivenom made by Instituto Clodomiro Picado was compared to “EchiTAb G” (ET-G) ovine antivenom made by MicroPharm, which is the standard of care in Nigeria and was developed from the original EchiTAb-Fab introduced in 1998. Both are caprylic acid purified whole IgG antivenoms. ET-G is monospecific for Echis ocellatus antivenom (initial dose 1 vial) and ET-Plus is polyspecific for E. ocellatus, Naja nigricollis and Bitis arietans (initial dose 3 vials). Both had been screened by pre-clinical and preliminary clinical dose-finding and safety studies. Patients who presented with incoagulable blood, indicative of systemic envenoming by E. ocellatus, were recruited in Kaltungo, north-eastern Nigeria. Those eligible and consenting were randomly allocated with equal probability to receive ET-Plus or ET-G. The primary outcome was permanent restoration of blood coagulability 6 hours after the start of treatment, assessed by a simple whole blood clotting test repeated 6, 12, 18, 24 and 48 hr after treatment. Secondary (safety) outcomes were the incidences of anaphylactic, pyrogenic and late serum sickness-type antivenom reactions.
Findings
Initial doses permanently restored blood coagulability at 6 hours in 161/194 (83.0%) of ET-Plus and 156/206 (75.7%) of ET-G treated patients (Relative Risk [RR] 1.10 one-sided 95% CI lower limit 1.01; P = 0.05). ET-Plus caused early reactions on more occasions than did ET-G [50/194 (25.8%) and 39/206 (18.9%) respectively RR (1.36 one-sided 95% CI 1.86 upper limit; P = 0.06). These reactions were classified as severe in 21 (10.8%) and 11 (5.3%) of patients, respectively.
Conclusion
At these doses, ET-Plus was slightly more effective but ET-G was slightly safer. Both are recommended for treating E. ocellatus envenoming in Nigeria.
Trial Registration
Current Controlled Trials ISRCTN01257358
Author Summary
Snake bite threatens millions of poor rural folk throughout Africa. In Nigeria, as in many countries of sub-Saharan Africa, it takes a terrible toll on human life and limb. Over the years, the news for those exposed to snake bite has been generally bad: withdrawal of antivenom manufacturers, increasing cost and, most recently, the marketing of ineffective or fake antivenoms in the region. Our paper reports encouraging results achieved by two antivenoms created as a direct consequence of the present crisis in antivenom supply for Africa. They have been assessed in the most powerful trial ever attempted in this field. The trial showed that in people with non-clotting blood following carpet viper bite, the commonest cause of snake bite morbidity and mortality in the West African savannah, administration of the antivenoms- EchiTAb G and EchiTAb Plus-ICP led to permanent restoration of blood clotting in 76% and 83% of the patients within 6 hours, respectively. Generally mild early adverse reactions were recorded in 19% and 26%, respectively. Both antivenoms proved effective and acceptably safe and can be recommended for treating carpet viper envenoming in Nigeria.
doi:10.1371/journal.pntd.0000767
PMCID: PMC2910709  PMID: 20668549
20.  A Study on the Acute Kidney Injury in Snake Bite Victims in A Tertiary Care Centre 
Introduction: Snake bite is a common medical emergency and an occupational hazard, more so in tropical India, where farming is a major source of employment. Viper bites are more common than other poisonous snakebites in humans. The World Health Organization has estimated that there are approximately 1,25,000 deaths among 2,50,000 poisonous snake bites worldwide every year, of which India accounts for 10,000 deaths. Acute kidney Injury (AKI) is an important consequence of a snake bite and its proper supportive management after the anti-venom administration is of utmost importance, for a good patient outcome.
Aims and Objectives: 1. To assess the risk factors and the prognostic factors in snake-bite induced Acute Kidney Injury.2. To determine the outcome of snake bite patients with AKI in a tertiary care centre in Karnataka, India.
Methodology: This prospective study was carried out at Vijaynagar Institute of Medical Sciences, Bellary, Karnataka, India. This institute is a referral government hospital in north Karnataka, India.
Study Design: This was a prospective and descriptive type of study.
Results: A total of 246 cases of venomous snakebite were included in this study, who were admitted in the hospital from November 2007 to October 2008. Among the AKI and the non-AKI patients, Illiteracy was more among the patients who suffered from AKI (75%). In our study, among all the patients (both AKI and non-AKI patients), viper bite was the commonest and it was seen in 31(91.6%) cases among the AKI patients and in 142 (67.6%) cases among the non-AKI patients. In our study, a majority of the patients who developed AKI had initially visited traditional healers before visiting our hospital, which was found to be statistically significant. In the present study, disseminated intravascular coagulation (DIC) and intravascular haemolysis were found to be predominant among the AKI patients. The “Bite to Needle” time was significantly more in the patients who developed AKI as compared to that in those who developed non-AKI. Out of 36 patients who suffered from AKI, 28 (77.7%) patients survived. Among them, 27(96.7%) patients developed cellulitis, 25(89.5%) had regional lymphadenopathy, 22(81.2%) were bitten at their lower limbs, and 6 (23.8%) patients developed bleeding manifestations.
Conclusion: This study concludes that acute kidney injury occurs in 14.6% of the victims of snake bite. The common manifestations include cellulitis, bleeding manifestations and gangrene at the site of the bite.
doi:10.7860/JCDR/2013/5495.2957
PMCID: PMC3681054  PMID: 23814727
Acute Kidney Injury; Snake bite; Dialysis
21.  Haemolytic Uremic Syndrome a Hitherto Unreported Complication of Humpnosed Viper Envenomation 
Merrem’s humpnosed viper bite is known to cause incoagulable blood, acute renal failure, acute respiratory distress syndrome, Raynaud’s phenomenon and gangrene of the distal limb. Venom-induced consumptive coagulopathy (VICC) is the commonest coagulopathy that occurs following snake envenomation which is characterised by prolonged clotting times. In a small proportion of patients with VICC, microangiopathy is also seen. The authors report a novel case of haemolytic uraemic syndrome following a merrem’s humpnosed viper bite, which highlights the need for comprehensive and serial haematological evaluation to detect the condition and initiate timely plasma exchange. The authors recommend screening of all victims of humpnosed viper bite for haemolytic uremic syndrome which might otherwise be overlooked and stress the need for further studies to see the role of haemolytic uremic syndrome following humpnosed viper bite.
doi:10.1007/s12288-012-0156-9
PMCID: PMC3636351  PMID: 24426353
Humpnosed viper; Haemolytic uraemic syndrome; Acute kidney injury
22.  Phylogenetic analysis of serine proteases from Russell's viper (Daboia russelli siamensis) and Agkistrodon piscivorus leucostoma venom 
Toxicon  2011;58(2):168-178.
Serine proteases are widely found in snake venoms. They have variety of functions including contributions to hemostasis. In this study, five serine proteases were cloned and characterized from two different cDNA libraries: factor V activator (RVV-V), alpha fibrinogenase (RVAF) and beta fibrinogenase (RVBF) from Russell's viper (Daboia russelli siamensis), and plasminogen activator (APL-PA) and protein C activator (APL-C) from Agkistrodon piscivorus leucostoma. The snake venom serine proteases were clustered in phylogenetic tree according to their functions. KA/KS values suggested that accelerated evolution has occurred in the mature protein coding regions in cDNAs of snake venom serine proteases.
doi:10.1016/j.toxicon.2011.05.014
PMCID: PMC3303153  PMID: 21640745
Russell's viper; Agkistrodon piscivorus leucostoma; Snake venom serine protease; RT-PCR; cDNA
23.  Pyrazolo[3,4-d]pyrimidines as inhibitor of anti-coagulation and inflammation activities of phospholipase A2: insight from molecular docking studies 
Journal of Biological Physics  2013;39(3):419-438.
Phospholipase A2 (PLA2), isolated from Daboia russelli pulchella (Russell’s viper), is enzymatically active as well as induces several pharmacological disorders including neurotoxicity, myotoxicity, cardiotoxicity, anti-coagulant, hemolytic, and platelet effects. Indomethacin reduces the effects of anti-coagulant and pro-inflammatory actions of PLA2. Pyrazolo[3,4-d]pyrimidines constitute a class of naturally occurring fused uracils that posses diverse biological activities. The in-silico docking studies of nine pyrazolo[3,4-d]pyrimidine molecules have been carried out with the X-ray crystal structure of Russell’s viper PLA2 (PDB ID: 3H1X) to predict the binding affinity, molecular recognition, and to explicate the binding modes, using AUTODOCK and GLIDE (Standard precision and Extra precision) modules, respectively. Docking results through each method make obvious that pyrazolo[3,4-d]pyrimidine molecules with trimethylene linker can bind with both anti-coagulation and enzymatic regions of PLA2.
Electronic supplementary material The online version of this article (doi: 10.1007/s10867-013-9299-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s10867-013-9299-7
PMCID: PMC3689367  PMID: 23860918
Pyrazolo[3,4-d]pyrimidines; PLA2; Molecular docking; AUTODOCK4.2; Schrödinger; ADME calculatioin
24.  Bilateral parotid enlargement following snake bite: A rare sign 
Snakebite is a common medical emergency in India. Unusual complications may occur after viper bite. Bilateral parotid enlargement after viper bite is a rare entity. An 18-year old gentleman presented to our hospital with history of viper bite. On examination he had cellulitis of right lower limb. He developed swelling of both the parotid glands 12 h after admission. He developed coagulopathy, acute renal failure and died within 48 h of hospital admission. Development of parotid swelling after snake bite is associated with poor prognosis. This case is found worth reporting as it is an unusual complication having prognostic value.
doi:10.1016/S2221-1691(13)60041-6
PMCID: PMC3627177  PMID: 23593596
Snakebite; Parotid swelling; Coagulopathy
25.  Dosage Comparison of Snake Anti-Venomon Coagulopathy  
This study was done to determine whether high or low dose ofanti-snake venom (ASV) is better incoagulopathy invictims of envenoming by vipers. This retrospective study was conducted on the 154 patients (Mean age ± SD, Range) of viper snake bites who were referred to the emergency ward of Razi Hospital, Ahvaz, Iran over 2 years period (2004-2006).According to the treatment dosage the patients were divided in two groups include group 1(78 cases), low dose regimen and group 2 (76 cases), high dose one. In group 1, the treatment was performed by administration of 4 to 6 vials of ASV through intravenous infusion.In group 2, the patients were given 5 to 10 vials of ASV as an initial dose. In low dose regimen, the number of received packed red blood cell was higher (14 vs. 3) in comparison with high dose group. The number of ASV vials the patients received was 5.5and 21.06 in group 1 and 2, respectively (5.5±1.7 vs. 21.06±10.89; p < 0.01).The difference in frequency of coagulopathy complications, and need for using packed red blood cell were statistically significant(96.2% and 17.9% in group 1 vs. 34.2% and 3.9% in group 2, p < 0.01).It seems that cautious usage of high dose of ASV (10-20 vials) without very special concerns about the cost, dose, and without hazardous side effects is essential for the routine management of sever snake envenoming.
PMCID: PMC3985248  PMID: 24734082
Snake bite; Anti-snake venom; Iranian snakes; Coagulopathy complication

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