Papuan Taipan Research Articles

Oral and IV Varespladib Rescue Experiments in Juvenile Pigs with Weakness Induced by Australian and Papuan Oxyuranus scutellatus Venoms.

Antivenom is currently the standard-of-care treatment for snakebite envenoming, but its efficacy is limited by treatment delays, availability, and in many cases, species specificity. Many of the rapidly lethal effects of envenoming are caused by venom-derived toxins, such as phospholipase A2 (sPLA2); therefore, small molecule direct toxin inhibitors targeting these toxins may have utility as initial and adjunct therapies after envenoming. Varespladib (intravenous, IV) and varespladib-methyl (oral) have been shown to potently inhibit sPLA2s from snake venoms in murine and porcine models, thus supporting their further study as potential treatments for snakebite envenoming. In this pilot study, we tested the ability of these compounds to reverse neurotoxic effects of venom from the Australian and Papuan taipan (Oxyuranus scutellatus) subspecies in juvenile pigs (Sus domesticus). The mean survival time for control animals receiving Australian taipan venom (0.03 mg/kg, n = 3) was 331 min ± 15 min; for those receiving Papuan taipan venom (0.15 mg/kg, n = 3) it was 178 ± 31 min. Thirteen pigs received Australian taipan venom and treatment with either IV or oral varespladib (or with IV to oral transition) and all 13 survived the duration of the study (≥96 h). Eight pigs received Papuan taipan venom followed by treatment: Briefly: Two animals received antivenom immediately and survived to the end of the study. Two animals received antivenom treatment delayed 45 min from envenoming and died within 4 h. Two animals received similarly delayed antivenom treatment and were rescued by varespladib. Two animals were treated with varespladib alone after a 45-min delay. Treatment with varespladib only was effective but required repeat dosing over the course of the study. Findings highlight both the importance of early treatment and, as well, a half-life for the investigational inhibitors now in Phase II clinical trials for snakebite. Varespladib rapidly reversed weakness even when administered many hours post-envenoming and, overall, our results suggest that varespladib and varespladib-methyl could be efficacious tools in the treatment of sPLA2-induced weakness from Oxyuranus envenoming. Further clinical study as initial therapy and as potential method of rescue from some types of antivenom-resistant envenomings are supported by these data.

Habitat-modification by an herbivorous marsupial benefits the Papuan Taipan, Oxyuranus scutellatus canni Slater 1956, within an anthropogenic environment in Central Province, Papua New Guinea

Habitat-modification by an herbivorous marsupial benefits the Papuan Taipan, Oxyuranus scutellatus canni Slater 1956, within an anthropogenic environment in Central Province, Papua New Guinea

Recovery from paralysis

Envenomation Envenoming by snake bite is recorded unsystematically. The World Health Organization reports that more than 5 million people are bitten by snakes annually. They estimate that up to 138,000 die of complications, and many victims are left disabled. Stazi et al . developed a mouse model of envenoming by the Papuan taipan ( Oxyuranus scutellatus ). This snake's poison, taipoxin, is a phospholipase A2 neurotoxin akin to tetanus and botulinum toxins. Taipoxin causes the degeneration of motor axon synaptic transport but does not kill the neurons, and a slow recovery occurs if the victim is given respiratory support. Signaling by the G protein–coupled receptor CXCR4 is implicated in this synaptic pathophysiology. The authors studied the effects of a previously identified agonist of CXCR4, NUCC-390, a nontoxic compound in mice that accelerates regeneration of their synapses, and found that it significantly accelerated recovery from paralysis. NUCC-390 thus has the potential to enhance the recovery of patients hospitalized with neuroparalytic snake envenomation. PLOS Negl. Trop. Dis. 14 , e0008547 (2020).

An agonist of the CXCR4 receptor accelerates the recovery from the peripheral neuroparalysis induced by Taipan snake envenomation.

Envenomation by snakes is a major neglected human disease. Hospitalization and use of animal-derived antivenom are the primary therapeutic supports currently available. There is consensus that additional, not expensive, treatments that can be delivered even long after the snake bite are needed. We recently showed that the drug dubbed NUCC-390 shortens the time of recovery from the neuroparalysis caused by traumatic or toxic degeneration of peripheral motor neurons. These syndromes are characterized by the activation of a pro-regenerative molecular axis, consisting of the CXCR4 receptor expressed at the damaged site in neuronal axons and by the release of its ligand CXCL12α, produced by surrounding Schwann cells. This intercellular signaling axis promotes axonal growth and functional recovery from paralysis. NUCC-390 is an agonist of CXCR4 acting similarly to CXCL12α. Here, we have tested its efficacy in a murine model of neuroparalytic envenoming by a Papuan Taipan (Oxyuranus scutellatus) where a degeneration of the motor axon terminals caused by the presynaptic PLA2 toxin Taipoxin, contained in the venom, occurs. Using imaging of the neuromuscular junction and electrophysiological analysis, we found that NUCC-390 administration after injection of either the purified neuroparalytic Taipoxin or the whole Taipan venom, significantly accelerates the recovery from paralysis. These results indicate that NUCC-390, which is non-toxic in mice, should be considered for trials in humans to test its efficacy in accelerating the recovery from the peripheral neuroparalysis induced by Taipans. NUCC-390 should be tested as well in the envenomation by other snakes that cause neuroparalytic syndromes in humans. NUCC-390 could become an additional treatment, common to many snake envenomings, that can be delivered after the bite to reduce death by respiratory deficits and to shorten and improve functional recovery.

Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom.

There is an unmet need for economical snakebite therapies with long shelf lives that are effective even with delays in treatment. The orally bioavailable, heat-stable, secretory phospholipase A2 (sPLA2) inhibitor, LY333013, demonstrates antidotal characteristics for severe snakebite envenoming in both field and hospital use. A murine model of lethal envenoming by a Papuan taipan (Oxyuranus scutellatus) demonstrates that LY333013, even with delayed oral administration, improves the chances of survival. Furthermore, LY333013 improves the performance of antivenom even after it no longer reverses neurotoxic signs. Our study is the first demonstration that neurotoxicity from presynaptic venom sPLA2S can be treated successfully, even after the window of therapeutic antivenom has closed. These results suggest that sPLA2 inhibitors have the potential to reduce death and disability and should be considered for the initial and adjunct treatment of snakebite envenoming. The scope and capacity of the sPLA2 inhibitors ability to achieve these endpoints requires further investigation and development efforts.

Antivenom production in the alpaca (Vicugna pacos): Monovalent and polyvalent antivenom neutralisation of lethal and procoagulant toxins in Australian elapid venoms

Alpaca (Vicugna pacos), like all other members of the camelid family, produce a unique heavy chain only IgG subclass. This form of IgG has been proposed as having superior neutralising properties and improved safety as compared with conventional mammalian IgG-based immunotherapeutics. The objective of this study was to investigate the potential of alpaca antibodies to neutralise the lethal and procoagulant properties of several Australian elapid snake venoms. Various experimental antivenoms were produced by immunisation of alpaca (Vicugna pacos) with combinations of five Australian elapid snake venoms: tiger snake (Notechis scutatus), eastern brown snake (Pseudonaja textilis), Papuan taipan (Oxyuranus scutellatus canni), mulga snake (Pseudechis australis) and common death adder (Acanthophis antarcticus). Venoms were emulsified in Freund’s Incomplete Adjuvant and alpaca repeatedly immunised. Having previously shown that such alpaca produce persistent venom-specific antibody responses with minimal physiological impact on the animal, the current report demonstrates that polyvalent alpaca antivenom neutralises the lethal effects of three elapid venoms (tiger, brown and Papuan taipan venoms). Such lethality neutralisation was, however, of generally lower potency, but of the same order of magnitude, when compared with bioCSL monovalent antivenoms (brown, tiger and taipan antivenoms). By contrast, the monovalent alpaca tiger and brown snake antivenom were found to be superior to the equivalent bioCSL monovalent antivenoms when considering the neutralisation of the procoagulant effects of the respective immunising venoms. The bioCSL polyvalent antivenom also less potent, when compared with the alpaca taipan monovalent antivenom, against Papuan taipan venom procoagulant neutralisation. These findings support the potential of camelid immunoglobulin for the development of novel elapid specific antivenoms.

Antivenom production in the alpaca (Vicugna pacos): physiological and antibody responses to monovalent and polyvalent immunisation with Australian elapid venoms

Alpaca (Vicugna pacos) are domesticated members of the camelid family that have been shown to produce an IgG subclass that is heavy chain only IgG. This camelid-type IgG has been postulated to have improved neutralising properties and reduced immunogenicity, compared with conventional mammalian IgG. This study was undertaken to describe the physiological and antibody responses of alpaca (Vicugna pacos) used for the production of an experimental camelid antivenom. Various antivenom products were developed by immunisation of alpaca with combinations of five Australian elapid snake venoms: common tiger snake (Notechis scutatus), eastern brown snake (Pseudonaja textilis), Papuan taipan (Oxyuranus scutellatus canni), mulga snake (Pseudechis australis) and common death adder (Acanthophis antarcticus) were emulsified with Freund’s Adjuvant and injected monthly using a low dose multi-site approach. Venom specific immune responses were monitored by ELISA. Physiological effects upon alpaca were monitored by clinical examination combined with serial haematology and biochemical profiles. Serum was harvested once immune responses had peaked and the IgG fraction concentrated by ammonium sulphate precipitate of non-IgG proteins. Total serum IgG and total serum protein concentrations increased and decreased in synchrony with boosting specific antibodies. The difference in serum creatinine kinase concentration measured at 24h after each of the first three immunisations decreased as the alpaca mounted an antibody response to the venom antigens measured by ELISA. In conclusion, alpaca responded to repeated immunisation with various Australian elapid venoms by mounting an increasing antibody response that persisted following prolonged rest with minimal physiological impact on the animal.

Hypotensive and vascular relaxant effects of phospholipase A2 toxins from Papuan taipan (Oxyuranus scutellatus) venom

Phospholipase A2 (PLA2) toxins are common and abundant components of Australasian elapid venoms. These toxins are associated with a range of activities including neurotoxicity, myotoxicity and coagulation disturbances. We have recently reported that sudden cardiovascular collapse induced by Papuan taipan (Oxyuranus scutellatus) venom involves a combination of the release of dilator autacoids and a direct effect on the smooth muscle. In this study, we aimed to isolate PLA2 components from Papuan taipan venom and investigate their contribution to the hypotensive action of this venom. O. scutellatus venom was fractionated using size-exclusion high performance liquid chromatography (HPLC), and fractions screened for activity in anaesthetized rats. Fraction three from O. scutellatus venom (i.e. OSC3, 14.2±1.0% of whole venom) produced a 64% decrease in mean arterial pressure. Reverse-phase HPLC indicated that OSC3 consisted of two major components (i.e. OSC3a and OSC3b). OSC3a and OSC3b produced a significant hypotensive response in anaesthetized rats which were attenuated by prior administration of indomethacin or the combination of mepyramine and heparin. N-terminal analysis indicated that OSC3a and b displayed sequence homology to PLA2 toxins isolated from coastal taipan (O. scutellatus scutellatus) venom. These findings indicate that PLA2 components may play an important role in the development of hypotension and vascular relaxation which may contribute to the effects observed after envenoming by these Australasian elapids.

An examination of cardiovascular collapse induced by eastern brown snake (Pseudonaja textilis) venom

The Pseudonaja genus (Brown snakes) is widely distributed across Australia and bites account for significant mortality. Venom-induced consumption coagulopathy (VICC) and, less often, early cardiovascular collapse occur following envenoming by these snakes. We have previously examined possible mechanism(s) behind the early cardiovascular collapse following Papuan taipan (Oxyuranus scutellatus) envenoming. In the present study, we investigate early cardiovascular collapse in anaesthetized rats following administration of eastern brown snake (Pseudonaja textilis) venom, and prevention of this effect with prior administration of ‘priming’ doses (i.e. doses of venom which caused a transient hypotensive response) of venom. P. textilis venom (5–10μg/kg, i.v.) induced cardiovascular collapse in anaesthetized rats, characterized by a rapid decrease in systolic blood pressure until non recordable. Prior administration of ‘priming’ doses of P. textilis venom (2 and 3μg/kg) or, at least, 4–5 doses of O. scutellatus (2μg/kg, i.v.) or Daboia russelii limitis (20μg/kg, i.v.) venoms prevented cardiovascular collapse induced by P. textilis venom. Moreover, early collapse was also inhibited by prior administration of 2 discrete doses of Acanthophis rugosus venom. Prior administration of commercial polyvalent snake antivenom (500–3000units/kg, i.v.) or heparin (300units/kg, i.v.) also inhibited P. textilis venom-induced cardiovascular collapse. Our results indicate that P. textilis venom-induced cardiovascular collapse can be prevented by prior administration of sub-lethal doses of venom from P. textilis, O. scutellatus, A. rugosus and D. russelii limitis. This suggests that sudden cardiovascular collapse following envenoming is likely to involve a common mechanism/pathway activated by different snake venoms.

Differential Myotoxic and Cytotoxic Activities of Pre‐synaptic Neurotoxins from Papuan Taipan (Oxyuranus scutellatus) and Irian Jayan Death Adder (Acanthophis rugosus) Venoms

Pre-synaptic PLA(2) neurotoxins are important components of many Australasian elapid snake venoms. These toxins disrupt neurotransmitter release. Taipoxin, a pre-synaptic neurotoxin isolated from the venom of the coastal taipan (Oxyuranus scutellatus), causes necrosis and muscle degeneration. The present study examined the myotoxic and cytotoxic activities of venoms from the Papuan taipan (O. scutellatus) and Irian Jayan death adder (Acanthophis rugosus), and also tested their pre-synaptic neurotoxins: cannitoxin and P-EPTX-Ar1a. Based on size-exclusion chromatography analysis, cannitoxin represents 16% of O. scutellatus venom, while P-EPTX-Ar1a represents 6% of A. rugosus venom. In the chick biventer cervicis nerve-muscle preparation, A. rugosus venom displayed significantly higher myotoxic activity than O. scutellatus venom as indicated by inhibition of direct twitches, and an increase in baseline tension. Both cannitoxin and P-EPTX-Ar1a displayed marked myotoxic activity. A. rugosus venom (50-300 μg/ml) produced concentration-dependent inhibition of cell proliferation in a rat skeletal muscle cell line (L6), while 300 μg/ml of O. scutellatus venom was required to inhibit cell proliferation, following 24-hr incubation. P-EPTX-Ar1a had greater cytotoxicity than cannitoxin, inhibiting cell proliferation after 24-hr incubation in L6 cells. Lactate dehydrogenase levels were increased after 1-hr incubation with A. rugosus venom (100-250 μg/ml), O. scutellatus venom (200-250 μg/ml) and P-EPTX-Ar1a (1-2 μM), but not cannitoxin (1-2 μM), suggesting venoms/toxin generated cell necrosis. Thus, A. rugosus and O. scutellatus venoms possess different myotoxic and cytotoxic activities. The proportion of pre-synaptic neurotoxin in the venoms and PLA(2) activity of the whole venoms are unlikely to be responsible for these activities.

In vivo and in vitro cardiovascular effects of Papuan taipan (Oxyuranus scutellatus) venom: Exploring “sudden collapse”

‘Sudden collapse’ following envenoming by some Australasian elapids is a poorly understood cause of mortality. We have previously shown that Oxyuranus scutellatus venom causes cardiovascular collapse in anaesthetized rats. Prior administration of a sub lethal dose of venom attenuated the response to subsequent administration of higher (lethal) venom doses. In this study, we investigated the possible mechanisms mediating this ‘protective effect’. Papuan taipan venom (5μg/kg, i.v.) produced a small transient hypotension in anaesthetized rats, while 10μg/kg resulted in a 73±12% decrease in arterial pressure. Venom (20μg/kg or 50μg/kg) produced cardiovascular collapse in all animals tested (n=12). Cardiovascular collapse by 50μg/kg venom was prevented by prior administration of ‘priming’ doses of venom (5, 10 and 20μg/kg). Also, prior administration of indomethacin (30mg/kg, i.v.) or heparin (300units/kg, i.v.) prevented sudden collapse induced by venom (20μg/kg). Venom was without effect in isolated hearts indicating that a direct cardiac effect was unlikely to be responsible for ‘sudden collapse’. Venom induced endothelium-dependent and -independent relaxation in pre-contracted rat mesenteric artery rings which was inhibited by indomethacin, IbTx and Rp-8-CPT-cAMPs. This relaxation was markedly reduced upon second exposure. Our results indicate that cardiovascular collapse induced by O. scutellatus venom may be due to a combination of release of dilator autacoids and to direct relaxation of vascular smooth muscle involving the cAMP/protein kinase A cascade. Further work will involve identification of the venom component(s) responsible for this action and may provide insight into the management of envenomed patients.

Variations in the pharmacological profile of post-synaptic neurotoxins isolated from the venoms of the Papuan ( Oxyuranus scutellatus canni) and coastal ( Oxyuranus scutellatus scutellatus) taipans

Based on murine LD 50 values, the taipans (i.e. Oxyuranus microlepidotus, Oxyuranus scutellatus and Oxyuranus scutellatus canni) are the most venomous snake genus in the world. Despite this, little is known about the toxins contained in their venoms. The aim of the present study was to isolate and characterise post-synaptic neurotoxins from the venoms of the Papuan taipan ( O. s. canni) and coastal taipan ( O. scutellatus), and to compare their pharmacology. A 6770 Da toxin (i.e. α-oxytoxin 1) and a 6781 Da toxin (i.e. α-scutoxin 1) were isolated from the venoms of O. s. canni and O. scutellatus, respectively, using reverse-phase high performance liquid chromatography. Both α-oxytoxin 1 (0.3–1 μM) and α-scutoxin 1 (0.1–1 μM) caused concentration-dependent inhibition of indirect twitches in the chick biventer cervicis nerve-muscle preparation. Contractile responses to exogenous carbachol (CCh), but not potassium chloride (KCl), were inhibited by both toxins, suggesting a post-synaptic mode of action. The inhibitory effect of α-oxytoxin 1 was reversed by washing. Cumulative concentration–response curves to CCh were obtained in the presence and absence of the toxins with the subsequently determined pA 2 of α-scutoxin 1 being 44.7-fold higher than α-oxytoxin 1 (i.e. 8.38 ± 0.59 versus 7.62 ± 0.04). The current study shows that Papuan taipan and coastal taipan venom both contain potent post-synaptic neurotoxins which exhibit different pharmacological profiles. The effect of α-oxytoxin 1 is atypical of most snake venom post-synaptic neurotoxins displaying a ‘competitive’ mode of action, whereas α-scutoxin 1 possesses pseudo-irreversible or non-competitive activity.

Isolation and Pharmacological Characterization of Cannitoxin, a Presynaptic Neurotoxin from the Venom of the Papuan Taipan (Oxyuranus scutellatus canni)

The Papuan taipan (Oxyuranus scutellatus canni) is widely distributed throughout much of Papua New Guinea. Although neurotoxicity is a major symptom of envenomation, no neurotoxins have been isolated from this venom. Using a series of size exclusion chromatography steps, we report the isolation of cannitoxin, a presynaptic neurotoxin (44,848 Da) that represents approximately 16% of the whole venom. The toxin displayed high phospholipase A2 (PLA2 activity (330 +/- 5 micromol/min/mg) and caused concentration-dependent (11-66 nM) inhibition of indirect (0.2 ms; 0.1 Hz; supramaximal V) twitches of the chick biventer cervicis nerve-muscle preparation without effecting nicotinic receptor agonists. Prior addition of CSL Taipan antivenom (5 U/ml) or inhibition of phospholipase A2 activity by incubation with 4-bromophenacyl bromide prevented the inhibition of twitches. Cannitoxin is composed of three different subunits, alpha, beta, and gamma, with the possibility of two beta isomers. However, only the alpha subunit displayed in vitro neurotoxic activity of its own. Thus, cannitoxin is similar in structure and pharmacology to taipoxin, which has been isolated from the closely related Australian species O. scutellatus scutellatus (coastal taipan).

A pharmacological examination of venom from the Papuan taipan: ( Oxyuranus scutellatus canni)

The Papuan taipan ( Oxyuranus scutellatus canni) is the third most venomous terrestrial snake in the world, however, little is know about the pharmacology of the venom. In the chick biventer cervicis muscle, venom (10 μg/ml) abolished nerve-mediated twitches (time to 90% inhibition ( t 90) 44±5 min, n=9). This inhibition was unaffected by prior incubation of the venom with the phospholipase A inhibitor 4-bromophenacyl bromide (4-BPB; 0.72 mM) ( t 90 48±7 min, n=8). The mouse phrenic nerve diaphragm preparation displayed greater sensitivity to venom (10 μg/ml) ( t 90 25±1 min, n=6). In the chick biventer muscle, venom (10 μg/ml) significantly inhibited responses to acetylcholine (1 mM) and carbachol (20 μM), but not KCl (40 mM), indicating activity at post-synaptic nicotinic receptors. Venom (10 μg/ml) did not affect direct muscle stimulation. Venom (3–30 μg/ml) produced dose-dependant contractions of the guinea-pig ileum. Contractile responses were significantly inhibited by indomethacin (1 μM) or prior incubation of the venom with 4-BPB (0.72 mM) indicating involvement of a PLA component. In rat phenylephrine (0.3 μM) precontracted aortae, venom (3–100 μg/ml) produced endothelium-independent relaxation which was unaffected by prior incubation of venom (30 μg/ml) with 4-BPB (0.72 mM). In anaesthetised rats, 10 μg/kg (i.v.) venom produced rapid respiratory and cardiovascular collapse while 5 μg/kg (i.v.) venom produced only a small transient decrease in mean arterial blood pressure. Prior administration of 5 μg/kg (i.v.) venom enabled subsequent administration of 10 and 100 μg/kg (i.v.) venom without respiratory or cardiovascular collapse. Further work is required to identify specific toxins with the above pharmacological activity.

P18 Haemostatic changes induced in 84 humans bitten by the Papuan taipan (Oxyuranus scutellatus canni) and recovery following antivenom

Haemophilia and Haemostasis Centre, Department of Haematology, Royal Free Hospital and School of Medicine, London, UK

Failure of 3,4-diaminopyridine and edrophonium to produce significant clinical benefit in neurotoxicity following the bite of Papuan taipan ( Oxyuranus scutellatus canni)

Progressive systemic neurotoxicity is a common feature in patients envenomed following the bite of a Papuan taipan ( Oxyuranus scutellatus canni). Respiratory paralysis, which commonly results, accounts for considerable morbidity and mortality. Established neurotoxicity does not respond to antivenom. In this study, a combination of clinical and electrophysiological variables was used to assess the effect of edrophonium and 3,4-diaminopyridine in patients with significant neurotoxicity. Both drugs produced minor electrophysiological and clinical changes in envenomed patients. This effect was maximal when the 2 drugs were used in combination, but was insufficient to be of significant clinical benefit. Neither drug can be recommended for use in the management of Papuan taipan bite.

Electrophysiological findings in patients envenomed following the bite of a Papuan taipan ( Oxyuranus scutellatus canni)

Electrophysiological studies were done on patients with systemic neurotoxicity following the bite of a Papuan taipan ( Oxyuranus scutellatus canni). Evoked compound muscle action potentials decreased and increased in tandem with clinical deterioration and recovery. Nerve conduction velocities did not change in envenomed patients and were consistent with control studies. Repetitive nerve stimulation studies showed decrementai responses in envenomed patients with post-tetanic potentiation followed by post-tetanic exhaustion. The findings are consistent with studies in vitro which suggested that the major action of neurotoxins in Australian taipan venom is at the synapse. The observation that electrophysiological data correlate closely with the clinical condition of the patient has potential application in the assessment of interventions in the management of snake bite victims.

Snake bites by the Papuan taipan (Oxyuranus scutellatus canni): paralysis, hemostatic and electrocardiographic abnormalities, and effects of antivenom.

One hundred sixty-six patients with enzyme immunoassay-proven bites by taipans (Oxyuranus scutellatus canni) were studied in Port Moresby, Papua New Guinea. One hundred thirty-nine (84%) showed clinical evidence of envenoming: local signs were trivial, but most developed hemostatic disorders and neurotoxicity. The blood of 77% of the patients was incoagulable and 35% bled spontaneously, usually from the gums. Fifty-one per cent had microscopic hematuria. Neurotoxic signs (ptosis, ophthalmoplegia, bulbar paralysis, and peripheral muscular weakness) developed in 85%. Endotracheal intubation was required in 42% and mechanical ventilation in 37%. Electrocardiographic abnormalities (sinus bradycardia and septal T wave inversion) were found in 52% of a group of 69 unselected patients. Specific antivenom raised against Australian taipan venom was effective in stopping spontaneous systemic bleeding and restoring blood coagulability but, in most cases, it neither reversed nor prevented the evolution of paralysis even when given within a few hours of the bite. However, early antivenom treatment was associated statistically with decreased incidence and severity of neurotoxic signs. The low case fatality rate of 4.3% is attributable mainly to the use of mechanical ventilation, a technique rarely available in Papua New Guinea. Earlier use of increased doses of antivenoms of improved specificity might prove more effective.

The efficacy of antivenom in the treatment of bites by the Papuan taipan ( Oxyuranus scutellatus canni)

A prospective series of 156 patients systemically envenomed following the bite of a Papuan taipan ( Oxyuranus scutellatus canni) were studied. All patients were treated with appropriate antivenom and clinical course and outcome were compared. The proportion of patients requiring intubation was significantly smaller, and the time to resolution of neurotoxicity and discharge from hospital significantly shorter, in patients receiving antivenom no more than 4 h after the bite. No significant difference in outcome was demonstrated between patients receiving antivenom at various times after 4 h. No difference was demonstrated in the times to restoration of coagulability between the 2 groups. The only significant difference between a small number of patients given 2 vials of antivenom and patients given a single vial at the same time after envenoming was a marginally shorter duration of intubation in those who required it. The study suggests that, to achieve significant clinical benefit in Papuan taipan bite, antivenom must be given as early as possible.

Coagulopathy following bites by the Papuan taipan (Oxyuranus scutellatus canni).

The mechanisms of haemostatic failure were studied in 87 patients bitten by the Papuan taipan (Oxyuranus scutellatus canni). Eighty (92%) had evidence of a coagulopathy on laboratory testing; 36 (41.4%) developed spontaneous systemic bleeding, although this was rarely of clinical significance. Coagulation assays in 48 completely defibrinated patients showed marked reductions in factors V and VIII and reductions in factors II, IX, XI, XII and XIIIA. There was a reduction in plasminogen and alpha 2-antiplasmin levels and both total and cross-linked fibrin(ogen) degradation products (FDP) levels were elevated. The mean platelet count was initially decreased and fell further during admission. Similar but less severe changes were seen in patients who were mildly defibrinated. Following treatment with antivenom, fibrinogen levels rose rapidly and coagulability was restored within 6-12 h in 93% of patients. These abnormalities may be primarily attributable to the prothrombin activator present in taipan venom, but it is likely that other uncharacterized venom components contributed.