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Asian Snakes
Abstract
Asia, the largest landscape on Earth, provides habitat to the majority of Earth’s human beings as well as to a colossal diversity of snakes. More than 150 venomous species, representing several snake families: the Viperidae (e.g., vipers, pit vipers, and Fea’s viper), the Elapidae (e.g., kraits, cobras, king cobras, and Asian coral snakes), and the broad assemblage previously contained within Family Colubridae (e.g., non-front-fanged-colubrids (NFFC snakes), including “rear-fanged” snakes) are known to exist.
Daboia siamensis (Russell’s viper) is a highly venomous and medically important snake in China, as well as much of Asia. There is minimal information on the pharmacological activity of the venom of the Chinese species, and currently no commercially available specific antivenom in China. This has led to the use of non-specific antivenoms to treat D. siamensis envenomation. In this study, the in vitro neurotoxicity and myotoxicity of D. siamensis venom was examined and the efficacy of four antivenoms was investigated, including the recently developed Chinese D. siamensis monovalent antivenom (C-DsMAV) and three commercially available antivenoms (Thai D. siamensis (Thai-DsMAV) monovalent antivenom, Deinagkistrodon acutus monovalent antivenom (DaAV), and Gloydius brevicaudus monovalent antivenom (GbAV). D. siamensis venom (10–30 µg/mL) caused the concentration-dependent inhibition of indirect twitches in the chick biventer cervicis nerve muscle preparation, without abolishing contractile responses to exogenous agonists ACh or CCh, indicating pre-synaptic neurotoxicity. Myotoxicity was also evident at these concentrations with inhibition of direct twitches, an increase in baseline tension, and the partial inhibition of ACh, CCh, and KCl responses. The prior addition of C-DsMAV or Thai-DsMAV prevented the neurotoxic and myotoxic activity of D. siamensis venom (10 µg/mL). The addition of non-specific antivenoms (GbAV and DaAV) partially prevented the neurotoxic activity of venom (10 µg/mL) but failed to neutralize the myotoxic effects. We have shown that D. siamensis venom exhibits in vitro weak presynaptic neurotoxicity and myotoxicity, which can be prevented by the pre-addition of the Chinese and Thai Russell’s viper antivenoms. Non-specific antivenoms were poorly efficacious. There should be further development of a monospecific antivenom against D. siamensis envenomation in China.
Snakebite envenoming (SBE) leads to significant morbidity and mortality, resulting in over 90,000 deaths and approximately 400,000 amputations annually. In sub-Saharan Africa (SSA) alone, SBE accounts for over 30,000 deaths per annum. Since 2017, SBE has been classified as a priority Neglected Tropical Disease (NTD) by the World Health Organisation (WHO).
The major species responsible for mortality from SBE within SSA are from the Bitis, Dendroaspis, Echis and Naja genera. Pharmacologically active toxins such as metalloproteinases, serine proteinases, 3-finger toxins, kunitz-type toxins, and phospholipase A2s are the primary snake venom components. These toxins induce cytotoxicity, coagulopathy, hemorrhage, and neurotoxicity in envenomed victims. Antivenom is currently the only available venom-specific treatment for SBE and contains purified equine or ovine polyclonal antibodies, collected from donor animals repeatedly immunized with low doses of adjuvanted venom. The resulting plasma or serum contains a high titre of specific antibodies, which can then be collected and stored until required. The purified antibodies are either whole IgG, monovalent fragment antibody (Fab) or divalent fragment antibody F(ab’)2. Despite pharmacokinetic and pharmacodynamic differences, all three are effective in the treatment of SBE. No antivenom is without adverse reactions but, the level of their impact and severity varies from benign early adverse reactions to the rarely occurring fatal anaphylactic shock. However, the major side effects are largely reversible with immediate administration of adrenaline and corticosteroids. There are 16 different antivenoms marketed within SSA, but the efficacy and safety profiles are only published for less than 50% of these products.
The true global incidence of envenomations and their severity remain largely misunderstood, except for a few countries where these accidents are rare or are correctly reported. Nevertheless, this information is essential for drawing up guidelines for dealing with snake-bites, to plan drug supplies, particularly antivenin, and to train medical staff on snake-bite treatments. Since the comprehensive review by Swaroop & Grab in 1954 no global survey has been carried out on snake-bite epidemiology. The present article is an attempt to draw the attention of health authorities to snake envenomations and urges them to prepare therapeutic protocols adapted to their needs.
Context:
Non-front-fanged colubroid snakes (NFFC; formerly and artificially taxonomically assembled as "colubrids") comprise the majority of extant ophidian species. Although the medical risks of bites by a handful of species have been documented, the majority of these snakes have oral products (Duvernoy's secretions, or venoms) with unknown biomedical properties/unverified functions and their potential for causing harm in humans is unknown.
Case details:
Described are three cases of local envenoming from NFFC bites inflicted respectively by the mangrove or ringed cat-eyed snake (Boiga dendrophila, Colubridae), the Western beaked snake (Rhamphiophis oxyrhynchus, Lamprophiidae) and the rain forest cat-eyed snake (Leptodeira frenata, Dipsadidae). The effects ranged from mild pain, edema and erythema to severe pain, progressive edema, and blistering with slowly resolving arthralgia; there were no systemic effects.
Discussion:
Although these three taxa occasionally inflict bites with mild to moderate local effects, there is no current evidence of systemic involvement. Two of these cases were reported to one of the authors for medical evaluation, and although verified, thus constitute reliably reported cases, but low-quality evidence. Type-1 local hypersensitivity may contribute to some cases, but most local effects observed or reported in these three cases were consistent with the effects of venom/oral product components.
Snakebite is classified by the WHO as a neglected tropical disease. Envenoming is a significant public health problem in tropical and subtropical regions. Neurotoxicity is a key feature of some envenomings, and there are many unanswered questions regarding this manifestation. Acute neuromuscular weakness with respiratory involvement is the most clinically important neurotoxic effect. Data is limited on the many other acute neurotoxic manifestations, and especially delayed neurotoxicity. Symptom evolution and recovery, patterns of weakness, respiratory involvement, and response to antivenom and acetyl cholinesterase inhibitors are variable, and seem to depend on the snake species, type of neurotoxicity, and geographical variations. Recent data have challenged the traditional concepts of neurotoxicity in snake envenoming, and highlight the rich diversity of snake neurotoxins. A uniform system of classification of the pattern of neuromuscular weakness and models for predicting type of toxicity and development of respiratory weakness are still lacking, and would greatly aid clinical decision making and future research. This review attempts to update the reader on the current state of knowledge regarding this important issue.
Snake bite is a major public problem in the rural tropics. In southern Nepal, most deaths caused by neurotoxic envenomation occur in the village or during transport to health centers. The effectiveness of victims' transport by motorcycle volunteers to a specialized treatment center, combined with community health education, was assessed in a non-randomized, single-arm, before-after study conducted in four villages (population = 62,127). The case-fatality rate of snake bite decreased from 10.5% in the pre-intervention period to 0.5% during the intervention (relative risk reduction = 0.949, 95% confidence interval = 0.695-0.999). The snake bite incidence decreased from 502 bites/100,000 population to 315 bites/100,000 population in the four villages (relative risk reduction = = 0.373, 95% confidence interval = 0.245-0.48), but it remained constant in other villages. Simple educational messages and promotion of immediate and rapid transport of victims to a treatment center decreased the mortality rate and incidence of snake bite in southeastern Nepal. The impact of similar interventions should be assessed elsewhere.
The present study aims to assess the different types of costs for treatment of snake bite patients, to quantify household economic impact and to understand the coping mechanisms required to cover the costs for snake bite patients in Bangladesh. The patients admitted to four tertiary level hospitals in Bangladesh were interviewed using structured questionnaires including health-care-related expenditures and the way in which the expenditures were covered. Of the snakes which bit the patients, 54.2% were non-venomous, 45.8% were venomous and 42.2% of the patients were given polyvalent antivenom. The total expenditure related to snake bite varies from US$4 (US$1 = Taka 72) to US$2294 with a mean of US$124 and the mean income loss was US$93. Expenditure for venomous snake bite was US$231, which is about seven times higher than non-venomous snake bite (US$34). The treatment imposes a major economic burden on affected families, especially in venomous snake bite cases.
Envenoming from snakebites is most effectively treated by antivenom. However, the antivenom available in South Asian countries commonly causes acute allergic reactions, anaphylactic reactions being particularly serious. We investigated whether adrenaline, promethazine, and hydrocortisone prevent such reactions in secondary referral hospitals in Sri Lanka by conducting a randomised, double-blind placebo-controlled trial.
In total, 1,007 patients were randomized, using a 2 × 2 × 2 factorial design, in a double-blind, placebo-controlled trial of adrenaline (0.25 ml of a 1∶1,000 solution subcutaneously), promethazine (25 mg intravenously), and hydrocortisone (200 mg intravenously), each alone and in all possible combinations. The interventions, or matching placebo, were given immediately before infusion of antivenom. Patients were monitored for mild, moderate, or severe adverse reactions for at least 96 h. The prespecified primary end point was the effect of the interventions on the incidence of severe reactions up to and including 48 h after antivenom administration. In total, 752 (75%) patients had acute reactions to antivenom: 9% mild, 48% moderate, and 43% severe; 89% of the reactions occurred within 1 h; and 40% of all patients were given rescue medication (adrenaline, promethazine, and hydrocortisone) during the first hour. Compared with placebo, adrenaline significantly reduced severe reactions to antivenom by 43% (95% CI 25-67) at 1 h and by 38% (95% CI 26-49) up to and including 48 h after antivenom administration; hydrocortisone and promethazine did not. Adding hydrocortisone negated the benefit of adrenaline.
Pretreatment with low-dose adrenaline was safe and reduced the risk of acute severe reactions to snake antivenom. This may be of particular importance in countries where adverse reactions to antivenom are common, although the need to improve the quality of available antivenom cannot be overemphasized.
Prospective studies of snake bite patients in Chittagong, Bangladesh, included five cases of bites by greater black kraits (Bungarus niger), proven by examination of the snakes that had been responsible. This species was previously known only from India, Nepal, Bhutan and Burma. The index case presented with descending flaccid paralysis typical of neurotoxic envenoming by all Bungarus species, but later developed generalized rhabdomyolysis (peak serum creatine kinase concentration 29,960 units/l) with myoglobinuria and acute renal failure from which he succumbed. Among the other four patients, one died of respiratory paralysis in a peripheral hospital and three recovered after developing paralysis, requiring mechanical ventilation in one patient. One patient suffered severe generalized myalgia and odynophagia associated with a modest increase in serum creatine kinase concentration. These are the first cases of Bungarus niger envenoming to be reported from any country. Generalized rhabdomyolysis has not been previously recognized as a feature of envenoming by any terrestrial Asian elapid snake, but a review of the literature suggests that venoms of some populations of Bungarus candidus and Bungarus multicinctus in Thailand and Vietnam may also have this effect in human victims. To investigate this unexpected property of Bungarus niger venom, venom from the snake responsible for one of the human cases of neuro-myotoxic envenoming was injected into one hind limb of rats and saline into the other under buprenorphine analgesia. All animals developed paralysis of the venom-injected limb within two hours. Twenty-four hours later, the soleus muscles were compared histopathologically and cytochemically. Results indicated a predominantly pre-synaptic action (β-bungarotoxins) of Bungarus niger venom at neuromuscular junctions, causing loss of synaptophysin and the degeneration of the terminal components of the motor innervation of rat skeletal muscle. There was oedema and necrosis of extrafusal muscle fibres in envenomed rat soleus muscles confirming the myotoxic effect of Bungarus niger venom, attributable to phospholipases A₂. This study has demonstrated that Bungarus niger is widely distributed in Bangladesh and confirms the risk of fatal neuro-myotoxic envenoming, especially as no specific antivenom is currently manufactured. The unexpected finding of rhabdomyolysis should prompt further investigation of the venom components responsible. The practical implications of having to treat patients with rhabdomyolysis and consequent acute renal failure, in addition to the more familiar respiratory failure associated with krait bite envenoming, should not be underestimated in a country that is poorly equipped to deal with such emergencies.
This is the first book to present a multidisciplinary approach to venomous snake research. As well as focusing on the medical aspects of snake venoms and the effects of snakebites, the book examines the evolution and ecology of venomous snakes, which are so crucial in the search for snakebite antidotes. The book has been written to be accessible to an audience of varied scientific backgrounds. Due to the wide range of information, it will be of great interest to scientists and students involved in any aspect of venomous snake research, whilst also appealing to the growing band of amateur enthusiasts.
Since 1957, Sawaiet al. (1967) have extensively investigated snake bites by Habu (Trimeresurus flavoviridis) on the Amami and Okinawa Islands in Japan. In 1968 and 1969, Sawai and Tseng (1973) also investigated the actual state of snake bites in Taiwan (Formosa). In 1971 and 1972, Sawai et al. (1972) planned an investigation on venomous snake bites in Southeast Asia and India supported by a grant in aid for the Oversea Scientific Survey from the Ministry of Education of Japan, and carried out investigation on snake bites in Taiwan, the Philippines, Thailand, Malaysia, Indonesia, and India. The purpose of these studies was to make comparisons of the situations of venomous snake bites in different areas in Southeast Asia and India and to contribute to the improvement in the methods for treatment and prophylaxis adapted in each area. This report concerns the investigation carried out in 1972 on snake bites in India.
Sea snakes are the most abundant and widely dispersed of the world’s venomous reptiles. Around the coastal seas of the Indian and western Pacific oceans, fishermen encounter sea snakes every day. Sea snake venoms are highly toxic. One “drop” (about 0.03 ml) contains enough venom to kill three adult men; some sea snake species can eject seven to eight such “drops” in a single bite. Fortunately for fishermen, sea snakes are not aggressive, and even when they do bite man, rarely inject much of their highly toxic venom. If this were not the case, deaths from sea snakebite would probably stop all sea fishing in many parts of Asia—and in these vast areas, fish are a most valuable source of high-quality protein.
Among the wide variety of biologic substances present in snake venoms, nerve growth factor (NGF) is one of the most curious. As it is presently understood, NGF is an agent that regulates the growth and differentiation of neurons of sympathetic and, in some cases, sensory neural tissue (Levi-Montalcini and Angeletti, 1968). There are three principal characteristic biologic effects of NGF:
1.
Halo fiber outgrowth from explanted dorsal root or sympathetic ganglia (chick embryo) in culture;
2.
Sympathetic ganglion enlargement in vivo in neonatal mice, characterized by both hyperplasia and hypertrophy;
3.
Immunosympathectomy, the destruction of sympathetic chain ganglia by the in vivo injection of antiserum to NGF. There is however, no known exocrine function for NGF.
A venomous snakebite is not always followed by evidence of envenomation and certainly is not always followed by death. Most snakebites are “startled” bites or “defensive” bites as Reid (1957) calls them and the snake frequently does not inject venom even though several human lethal doses of venom may be present in the venom glands at the time of the bite (Reid, 1957).
Snakebite is an important cause of morbidity and mortality in Bangladesh. Recent countrywide epidemiological survey estimated an annual incidence of 623/100,000 and 6,041 deaths annually. The prevalent groups of venomous snakes are cobras, kraits, and vipers. Bites are common during the monsoon and are mostly related to occupational activities. The identification of two previously unrecorded species (Bungarus walli, B. niger) among specimens brought to hospitals by victims has pointed out the deficiency of geo-epidemiological data and strongly argues for further research.
Most of the bites produce no features of envenoming. Among the venomous bites, main clinical features include neurotoxicity with local tissue necrosis in cobra bites, neurotoxicity in most krait (Bungarus sp.) bites, and neurotoxicity and myonecrosis in B. niger and local swelling with or without coagulopathy in green pit viper bites. In addition to the burden of acute morbidity and mortality, the injuries inflicted by the envenoming bites of snakes in Bangladesh frequently result in permanent disability and its associated long-term socioeconomic consequences.
In spite of recent scientific progress in management of the snakebite victim, treatment of this eminently treatable condition is complicated by social, cultural, geographical, economical, and ecological issues. The price of antivenom (AV) is still beyond reach of many people. Government supply is limited. The private sector has little interest in producing this only marginally profitable product because of limited demand. Polyvalent AV produced in India is being used in Bangladesh, exposing the victim to an unnecessarily wide spectrum of antibodies and to potentially fatal anaphylactic AV reactions. Yet the outcome is satisfactory enough to encourage its continuing use.
Objective:
To evaluate the use of 250 mL of a 7.5% sodium chloride solution, both with and without added dextran 70, for the prehospital resuscitation of hypotensive trauma patients.Design:
Double-blind randomized trial.Setting:
Six trauma systems served by helicopter transport.Patients:
Injured patients with systolic blood pressures less than 90 mm Hg at any time in the field or during helicopter transport.Interventions:
Infusion of study solution, in the field or during transport, followed by conventional isotonic solutions as needed. Solutions studied in four cohorts were as follows: (1) lactated Ringer's; (2) 7.5% sodium chloride (hypertonic saline); (3) 7.5% sodium chloride combined with 6% dextran 70; and (4) 7.5% sodium chloride combined with 12% dextran 70.Main Outcome Measures:
Blood pressure response; survival to time of hospital discharge among the treatment groups; and survival compared with that predicted by norms from the Major Trauma Outcome Study (MTOS).Results:
The mean (±SD) change in systolic blood pressure on arrival in the emergency department was significantly higher in the hypertonic saline solution group than that in the lactated Ringer's solution group (34±46 vs 11±49 mm Hg, P<.03). Overall survival in the four treatment groups was 49%, 60%, 56%, and 45% (not statistically significant). Survival in the hypertonic saline solution group, however, was significantly higher than that predicted by the MTOS norms (60% vs 48%, P<.001). Survival to hospital discharge in patients with baseline Glasgow Coma Scale scores of 8 or less was correlated with treatment group (P<.05 by logistic regression and P<.01 by Cox proportional-hazards analysis; with survival in the hypertonic saline solution group [34%] vs lactated Ringer's solution group [12%]).Conclusions:
Prehospital infusion of 250 mL of 7.5% sodium chloride is associated with an increase in blood pressure and an increase in survival to hospital discharge compared with survival predicted by the MTOS norms. Patients with low baseline Glasgow Coma Scale scores seem to benefit the most from 7.5% sodium chloride resuscitation. Hypertonic saline solution without added dextran 70 is as effective as the more expensive solutions that contain dextran 70.(Arch Surg. 1993;128:1003-1013)
Envenoming by colubrid snakes is rarely reported. However, some colubrid snakes (e.g. Rhabdophis tigrinus and Rhabdophis subminiatus) have caused severe systemic envenoming. We report here the first case of a bite with systemic envenoming by Balanophis ceylonensis, an opisthoglyphous natricine colubrid, in Sri Lanka. A 33-year-old healthy male field biologist was bitten while handling the snake for photography. Within 5 min of the bite on the dorsum of the right hand, he reported severe occipital headache, photophobia, chills and transient loss of consciousness. He vomited blood-stained gastric contents and bled from venepuncture sites. He had a markedly elevated INR and positive D-dimer test suggestive of significant coagulopathy that was treated with infusions of fresh frozen plasma. He recovered and left hospital after 96 h and subsequent investigations, including electroencephalogram, were normal. We conclude that B. ceylonensis should be regarded as a medically significant venomous snake. This case highlights the need for further studies of the oral secretions (venoms) of colubrid snakes.
We report here original data on the biological basis of prolonged neuromuscular paralysis caused by the toxic phospholipase A2 β-bungarotoxin. Electron microscopy and immunocytochemical labeling with anti-synaptophysin and anti-neurofilament have been used to show that the early onset of paralysis is associated with the depletion of synaptic vesicles from the motor nerve terminals of skeletal muscle and that this is followed by the destruction of the motor nerve terminal and the degeneration of the cytoskeleton of the intramuscular axons. The postjunctional architecture of the junctions were unaffected and the binding of fluorescein-isothiocyanate-conjugated α-bungarotoxin to achetylcholine receptor was not apparently affected by exposure to β-bungarotoxin. The re-innervation of the muscle fiber was associated by extensive pre- and post-terminal sprouting at 3 to 5 days but was stable by 7 days. Extensive collateral innervation of adjacent muscle fibers was a significant feature of the re-innervated neuromuscular junctions. These findings suggest that the prolonged and severe paralysis seen in victims of envenoming bites by kraits (elapid snakes of the genus Bungarus) and other related snakes of the family Elapidae is caused by the de-pletion of synaptic vesicles from motor nerve terminals and the degeneration of the motor nerve terminal and intramuscular axons.
Six hemorrhagic toxins have been isolated from Crotalus atrox (western diamondback rattlesnake) venom. All of them contain one mole of zinc per mole of protein, although the molecular weights vary from 24,000 to 68,000. All have proteolytic activity when tested on dimethyl-casein. Removal of zinc eliminates the hemorrhagic and proteolytic activities. Proteolytic specificity of hemorrhagic toxin a is highly specific and hydrolyzes the X-Leu bond. Hemorrhagic toxin b is less specific and hydrolyzes the X-Phe, X-Ser, and X-Leu bonds.
There are several types of myonecrotic [muscle damaging) toxins, and of those, myotoxin a from C. viridis viridis (prairie rattlesnake) venom is the most extensively investigated. Myotoxin a consists of 42 amino acid residues with 3 disulfide bonds. There is no similarity in amino acid sequence and disulfide bond positions when compared to well-known post-synaptic neurotoxins (both Type I and II) of snake venoms. It is rather curious and interesting to note that there is some amino acid sequence homology between myotoxin a and ribonuclease. Electron microscopy of peroxidase-conjugated myotoxin a shows that myotoxin a specifically atlaches to the sarcoplasmic reticulum. Myotoxin a also has weak hemolytic activity, indicating that the membrane damaging activity is not restricted to muscle tissue.
Sea snakes are common venomous reptiles found in the warmer waters of the Pacific and Indian Oceans. The most common circumstance for sea snake bite is an accidental encounter by a fisherman while emptying a fishing net. The venom is extremely toxic and most significant on the nervous and musculoskeletal systems. Significant envenomation occurs in about 20% of bites, with death occurring in about 3% of bites. Death most often occurs from respiratory arrest secondary to neurotoxicity. Myotoxins may cause muscle pain and stiffness and lead to clinically significant rhabdomyolysis and possible acute renal failure. Sea snake bites should all be considered a medical emergency. Immobilization of the victim with compression of the envenomed area is important first aid, followed by transporting the victim to an emergency medical facility. Artificial ventilation and hydration with crystalloid may be important lifesaving maneuvers. Sea snake antivenom may be critical for survival in a significant envenomation.
A multivariate analysis of the population systematics of Russell's viper, based on scalation and colour pattern characters, reveals that the populations of this viper constitute two well-defined taxa: a western form, comprising all populations from the Indian subcontinent, and an eastern form, comprising all populations from east of the Bay of Bengal. The two forms could be considered either as subspecies of one species, or as two separate species, depending on the species concept used. Within the western form, there is no clear pattern of geographic variation. Within the eastern form, the populations from the Lesser Sunda Islands are clearly divergent from the populations of mainland Asia and Java. The conventionally recognized subspecies of Vipera russelli fail to portray this pattern of geographic variation. There is no clear relationship between the pattern of geographic variation in morphology and the pattern of geographic variation in the clinical effects of the venom in human bite victims: some populations with considerable differences in venom effects are equally distinct morphologically, whereas other populations with equally strong venom differences are morphologically very similar. The distribution of Russell's viper can be attributed to Pleistocene changes in climate and sea level, coupled with the viper's ecological requirements, which appear to include a seasonally dry climate.
R. M. Kini and S. Iwanaga. Structure - function relationships of phospholipases II: charge density distribution and the myotoxicity of presynaptically neurotoxic phospholipases. Toxicon24, 895 – 905, 1986.—The charge density distribution of 24 phospholipases A2 has been examined to identify the involvement of charged amino acid residues in the determination of the pharmacological properties of these proteins. There is no characteristic difference between the presynaptically neurotoxic and non-neurotoxic phospholipases, however, presynaptically neurotoxic phospholipases which are also myotoxic have a distinct charge distribution pattern. There is a characteristic cationic site around residues 79 – 87. This site has a relatively fixed position with respect to the hydrophobic ‘neurotoxic’ region, on the NH2 terminal side. This cationic region is located on the outer surface in the three-dimensional structure of phospholipase, just before hydrophobic helix E, and is available for interaction with membranes. Such a characteristic region is absent in non-myotoxic phospholipases which are either presynaptically active or inactive. On the other hand, myotoxins, a group of non-enzymatic proteins inducing myotoxicity, also possess such characteristic regions of cationic and hydrophobic sites.
Snake bite is a common and frequently devastating environmental and occupational disease, especially in rural areas of tropical developing countries. Its public health importance has been largely ignored by medical science. Snake venoms are rich in protein and peptide toxins that have specificity for a wide range of tissue receptors, making them clinically challenging and scientifically fascinating, especially for drug design. Although the full burden of human suffering attributable to snake bite remains obscure, hundreds of thousands of people are known to be envenomed and tens of thousands are killed or maimed by snakes every year. Preventive efforts should be aimed towards education of affected communities to use proper footwear and to reduce the risk of contact with snakes to a minimum through understanding of snakes' behaviour. To treat envenoming, the production and clinical use of antivenom must be improved. Increased collaboration between clinicians, epidemiologists, and laboratory toxinologists should enhance the understanding and treatment of envenoming.
Of 860 snakes brought to 10 hospitals in Sri Lanka with the patients they had bitten, 762 (89%) were venomous. Russell's vipers (Daboia russelii) and hump-nosed pit vipers (Hypnale hypnale) were the most numerous and H. hypnale was the most widely distributed. Fifty-one (6%) were misidentified by hospital staff, causing inappropriate antivenom treatment of 13 patients. Distinctive clinical syndromes were identified to aid species diagnosis in most cases of snake bite in Sri Lanka where the biting species is unknown. Diagnostic sensitivities and specificities of these syndromes for envenoming were 78% and 96% by Naja naja, 66% and 100% by Bungarus caeruleus, 14% and 100% by Daboia russelii, and 10% and 97% by Hypnale hypnale, respectively. Although only polyspecific antivenoms are used in Sri Lanka, species diagnosis remains important to anticipate life-threatening complications such as local necrosis, hemorrhage and renal and respiratory failure and to identify likely victims of envenoming by H. hypnale who will not benefit from existing antivenoms. The technique of hospital-based collection, labeling and preservation of dead snakes brought by bitten patients is recommended for rapid assessment of a country's medically-important herpetofauna.
Snake venom contains mixture of bioactive proteins and polypeptides. Most of these proteins and polypeptides exist as monomers, but some of them form complexes in the venom. These complexes exhibit much higher levels of pharmacological activity compared to individual components and play an important role in pathophysiological effects during envenomation. They are formed through covalent and/or non-covalent interactions. The subunits of the complexes are either identical (homodimers) or dissimilar (heterodimers; in some cases subunits belong to different families of proteins). The formation of complexes, at times, eliminates the non-specific binding and enhances the binding to the target molecule. On several occasions, it also leads to recognition of new targets as protein-protein interaction in complexes exposes the critical amino acid residues buried in the monomers. Here, we describe the structure and function of various protein complexes of snake venoms and their role in snake venom toxicity.
In Sri Lanka, the Spectacled cobra (Naja naja) inflicts fatal bites. This hospital-based prospective study describes 25 cases of proven cobra bites, including 10 (40%) males and 15 (60%) females with a median age of 36 years (range 13-70 years). In 22 cases (88%) bites occurred in the daytime and in 13 cases (52%) they occurred at the victim's home compound. The site of the bite was the upper limb in 10 cases (40%), and 12 patients (48%) had applied a tourniquet. There were 5 dry bites (20%), 20 local reactions (80%), 9 cases of neurotoxicity (36%) and 3 cases of coagulopathy (12%). Eight patients (32%) had severe local necrosis-five underwent desloughing and skin grafting and two (including one of the above) had fasciotomy and compartmental decompression of the upper limb. Two patients died (case fatality rate 8%; 95% CI 0.98-26.03) due to rapidly spreading necrosis of the upper limb. Four patients (16%; 95% CI 4.53-36.08) developed respiratory paralysis; their median time from bite to assisted ventilation was 2h (range 2-5h) and the median duration of ventilation was 24h (range 18-24h). Envenomed patients received Indian polyvalent antivenom. The findings highlight the magnitude of local necrosis, respiratory paralysis and antivenom failure in Spectacled cobra bite in Sri Lanka. Coagulopathy requires verification with robust laboratory tests.
Expired antivenoms may be useful in countries where snake envenoming is common and supplies are limited. This study examined the activity of expired Australasian antivenoms. Expired CSL snake antivenoms, including taipan, brown snake and polyvalent antivenoms, were used. The most current antivenom was used as the reference to compare expired antivenoms. Binding activity was assessed by enzyme immunoassay. Neutralisation of venom clotting effects was assessed by a modified clotting test using changes in optical density. Neutralisation of the in vitro neurotoxic effects of taipan venom was determined using a chick biventer cervicis nerve-muscle preparation. All antivenom batches remained active, with gradual deterioration in activity and binding over time. All batches of taipan antivenom at concentrations equivalent to the administration of one vial (including one 15 years expired) prevented clotting by taipan venom. Brown snake antivenoms also prevented clotting, except two that were 10 years old. All expired taipan/polyvalent antivenom prevented in vitro neurotoxicity at concentrations consistent with antivenom treatment. Freeze-thawing the antivenom or leaving it at room temperature for 3 days caused only small decreases in activity. CSL antivenoms are more robust than indicated on their label and maintain useful activity long past their nominated expiry dates.
The incidence of Echis carinatus (saw-scaled or carpet viper) bite and its mortality have been investigated in the Nigerian savanna region. A geographical area was defined in which the snake was particularly abundant and bites were frequent. Perennial and seasonal fluctuations in incidence and mortality, the circumstances in which bites occurred and the types of people bitten were studied at Bambur, Zaria, Kaltungo and Gombe hospitals. Peak incidence coincided with the increase in farming during the rains whereas percentage mortality seemed to be greatest during the cold dry season. The majority of the patients were young males bitten on the foot while walking or farming. A review of the world literature indicated that E. carinatus was the principal cause of snake bite morbidity wherever data were available throughout its wide geographical range. Official statistics have seriously underestimated this important rural health problem.
Twenty cases of cobra bite in farmers from the central region of Thailand are reported. Ptosis is the earliest sign of cobra bite and is an important diagnostic indication of systemic poisoning. Restlessness, irregular breathing and mental confusion are warning signs of respiratory paralysis. Antivenom for cobra bite was administered intravenously together with symptomatic and supportive treatment; 19 patients survived and 1 died from cerebral anoxia.
Venom entered the eyes of 9 patients spat at by the spitting cobra, Naja nigricollis. In 5 the only effect was a simple conjunctivitis but 4 had corneal ulceration, 1 developed anterior uveitis indicating absorption of venom in the anterior chamber, and 2 were permanently blinded. Treatment of this rare emergency is discussed: immediate irrigation of the eye with water, careful examination for corneal abrasion, and prevention of secondary infection are recommended. The value of local specific antivenom is unproven.
Epidemiological features as reflected by 101 patients with unequivocal sea-snake bite received in north-west Malaya are reviewed. Enhydrina schistosa caused over half the bites, including seven of the eight fatal bites. It is the most dangerous sea-snake to man. Over 90 per cent of the victims were male and 80 of the 101 patients were fishermen bitten at their job. Most victims were bitten on the lower limb through treading on the snake, and this resulted in more cases of serious poisoning than upper limb bites (caused through handling nets, sorting fish and so on). Only 14 cathers were bitten (through treading on the sea-snake; no bathers were bitten while swimming). In patients coming to hospital more than six hours after the bite, there was a four-fold increase in serious poisoning compared with patients coming within six hours of the bite. Thus, as time elapses after the bite, the victim is less likely to seek medical help unless poisoning is severe. Despite the lethal toxicity of sea-snake venom, in patients seen during 1957-61 before sea-snake antivenom became available, the mortality was only 10 per cent. Trivial or no poisoning followed in 80 per cent of the bites. On the other hand, of 11 patients (20 per cent) with serious poisoning, over half (six patients) died despite supportive hospital treatment. These epidemiological features observed in Malaya probably apply to most fishing folk along Asian coastlines where sea-snakes abound. If this is so, sea-snake bite must be a common hazard feared by millions of fishing folk, and a common cause of illness and death. But it is unlikely that the extent of this problem will be revealed to orthodox medicine for many decades because most fishing villages are far from medical centres; and even if hospitals or medical centres are available, fishing folk are usually reluctant to attend them. Only one species of sea-snake, Pelamis platurus, extends to the east coasts of Africa and west coasts of the tropical Americas, but for various reasons this species does not appear to constitute much of a hazard to fishing folk in these areas. Although bathers are occasionally bitten along Asian coasts, when they inadvertently tread on a sea-snake, the risk of sea-snake bite in this area is extremely low. The prevention of sea-snake bite and poisoning is considered. Highly effective antivenom is now available for treating victims with serious poisoning; death should not occur provided adequate medical treatment is given within a few hours of the bite. The main problem is provision of adequate medical care at rural medical centres and overcoming the reluctance fishing folk often have in attending these centres.
Two phospholipases A2 (PLA2s), designated as RV-4 and RV-7 were purified from venom of the Taiwan Russell's viper (Vipera russelli formosensis) by gel-filtration and reverse-phase HPLC. Their primary structures were solved by both protein sequencing and cDNA cloning and sequencing. The cDNA synthesized was amplified by the polymerase-chain reaction using a pair of synthetic oligonucleotide primers corresponding to the N- and the C-terminal flanking regions of the enzymes. The deduced amino acid sequences of RV-4 and RV-7 were 92% identical to those of the vipoxin and vipoxin inhibitor, respectively, from the Bulgarian Vipera a. ammodytes. RV-4 itself was neurotoxic, whereas RV-7 had much lower enzymatic activity and was not toxic. The low enzymatic activity of RV-7 may be attributed to five acidic residues at positions 7, 17, 59, 114 and 119, which presumably impair its binding to aggregated lipid substrates. Based on the sequence comparison among all the known group II PLA2s, residues 6, 12, 76-81, and 119-125 were identified as important for the neurotoxicity. RV-4 and RV-7 exist in the crude venom as heterodimers, which were again formed by mixing together the HPLC-purified RV-4 and RV-7. Moreover, RV-7 inhibited the enzymatic activity of RV-4 in vitro but potentiated its lethal potency and neurotoxicity. It is suggested that RV-7 may facilitate the specific binding of RV-4 to its presynaptic binding sites, probably by preventing its non-specific adsorption.
Snakes which had been killed and brought to hospital with the patients they had bitten were collected in 80 district and provincial hospitals throughout 67 provinces in Thailand in order to establish the geographical distribution and relative medical importance of the venomous species. Of the 1631 snakes collected, 1145 were venomous: Malayan pit vipers (Calloselasma rhodostoma), green pit vipers (Trimeresurus albolabris) and Russell's vipers (Daboia russelii) were the most numerous, while T. albolabris, C. rhodostoma and spitting cobras ('Naja atra') were the most widely distributed. In 22 cases, non-venomous species were mistaken for venomous ones and antivenom was used unnecessarily. The Malayan krait (Bungarus candidus) was confused with B. fasciatus in 5 cases and B. fasciatus antivenom was used inappropriately. The study extended the known ranges of most of the medically-important venomous species in Thailand. Correct identification of venomous snakes is especially important in Thailand because the locally-produced antivenoms are monospecific. The technique of hospital-based collection, labelling and preservation of dead snakes brought by bitten patients is recommended when rapid assessment of a country's medically important herpetofauna is required.
Colloid fluid solutions are frequently used as plasma volume expanders in the critically ill. As a group, these nonblood volume replacement solutions have in common a number of potential adverse effects. Intravascular volume overload, dilutional coagulopathy, extravascular extravasation across leaky capillary membranes, and anaphylactoid reactions may all occur with administration of any colloid. In addition, individual agents have unique toxic effects. Renal dysfunction has been associated with dextran 40, myocardial depression with albumin, hypotension with purified plasma protein, and hyperamylasemia with hetastarch. Because no ideal colloidal solution exists, knowledge of type, severity, and clinical significance of adverse effects is important in determining the appropriate plasma volume expander and monitoring its effects.
Three patients bitten by the world's largest species of venomous snake, the king cobra (Ophiophagus hannah), were observed in Myanmar (Burma). All three were involved in the famous snake dance in Yangon (Rangoon) Zoological Gardens. One patient showed no signs of envenoming despite a sustained bite, another developed only signs of local envenoming, but in a third there was severe neurotoxic envenoming requiring mechanical ventilation for 64 1/2 hours, episodes of hypotension and massive swelling of the bitten limb. This patient showed some signs of recovery before delayed treatment with specific antivenom. It is possible that all three patients had some immunity to king cobra venom resulting from traditional 'immunization' achieved by scratching venom into the skin. The literature on king cobra bites is reviewed and recommendations given for antivenom and ancillary treatments.
Renal function was monitored in 24 patients with systemic envenoming following proven Russell's viper bite. In all patients, blood clotted within 20 min on admission. In 15 cases severe defibrination (systemic envenoming) developed during the next 3-5 d. None of the patients received antivenom before admission but enzyme-refined monospecific antivenom was given to those who developed signs of systemic envenoming. Specific antigen was detected by enzyme immuno-assay in all 21 subjects tested. Nine patients whose renal function remained normal did not develop systemic envenoming, and recovered without any treatment even though venom antigen was detectable in their serum. Ten patients developed mild renal dysfunction and systemic envenoming, but recovered after treatment with antivenom alone. The remaining 5 patients, all of whom were oliguric from admission, developed acute renal failure despite treatment with antivenom, but some recovered after peritoneal dialysis. Serum venom antigen levels were high in the last 2 groups, but there was some overlap. Albuminuria, found only in patients who became systemically envenomed, was associated with high fractional sodium excretion in those who developed acute oliguric renal failure. Albuminuria may appear before a gross clotting defect is detectable. It is an indication for antivenom and spot measurements might prove a useful early predictor of outcome.
An improved enzyme immunoassay technique (EIA) was used in the diagnosis of 311 suspected Russell's viper bite cases in Myanmar [Burma], 181 of whom (58%) had systemic envenoming. Russell's viper venom was detected in the sera of 175 (56.3%), cobra or green pit viper venoms in 4 (1.3%), and no venom in the remaining 132 (42.4). Among 175 of these patients who failed to bring the dead snake, EIA achieved a specific diagnosis of Russell's viper envenoming in 101 (58%). The serum venom antigen concentration was higher in patients with systemic envenoming than in those with local or no envenoming and it increased with the development of coagulopathy. Stomach contents were examined in 101 Russell's vipers responsible for bites. The presence of prey, usually a rodent, in the snake's stomach, indicating that it had eaten recently, did not influence the severity of envenoming, the initial venom level, or the percentage circumference increase and the extent of local swelling in the bitten limb. One hundred and fifty-five Russell's vipers responsible for bites showed a bimodal distribution of total lengths. The smaller snakes had probably been born that year. Longer snakes were responsible for more severe envenoming, a shorter interval between the bite and the detection of incoagulable blood, and more extensive local swelling with a greater percentage circumference increase of the bitten limb; but their bites were not associated with higher initial venom antigenaemia or a greater risk of developing acute renal failure.
Following envenomization by Echis carinatus sochureki, a professional snake handler developed a profound coagulopathy manifested by hemorrhage from the bite site, venipuncture sites and gums; coagulation testing revealed prothrombin and partial thromboplastin times greater than 150 seconds, a fibrinogen of 0 mg%, and marked elevation of fibrin degradation products. In addition, protein C antigen levels were undetectable. The coagulopathy was treated with cryoprecipitate; two different antivenoms were also administered with uncertain benefit. Subsequently, the properties of the venom and antivenoms were studied. Venom did not directly clot fibrinogen; however, venom concentrations as low as 0.2 micrograms/ml caused significant prothrombin activation. In addition, venom activated protein C in the absence of thrombomodulin, and this activity was inhibited by hirudin. The ability of four commercial antivenoms to neutralize the venom prothrombinase and hemorrhagic activity was measured. Three of the four antivenoms partially neutralized venom-induced prothrombin activation. Extreme differences in efficacy were found among the four antivenoms in neutralizing venom hemorrhagic activity in mice. This case illustrates the difficulty in managing the complex coagulopathy that can result from exotic snake envenomization, and identifies a new coagulant property of Echis carinatus venom (protein C activation).