The Experts below are selected from a list of 261 Experts worldwide ranked by ideXlab platform
Wayne C. Hodgson - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis mulga snake in the anesthetised rat
Clinical Toxicology, 2014Co-Authors: Andrew Hart, Wayne C. Hodgson, Margaret A Oleary, Geoffrey K. IsbisterAbstract:Context. Myotoxicity is a common clinical effect of snake envenoming and results from either local or systemic myotoxins in snake venoms. Although numerous myotoxins have been isolated from snake venoms, there has been limited study on the relationship between the time course of venom concentrations (pharmacokinetics) and the time course of muscle injury measured as a rise in creatine kinase (CK) (pharmacodynamics). Objective. The aim of this study was to develop an in vivo model of myotoxicity to investigate the time course of myotoxicity and the effect of antivenom. Materials and methods. Anesthetised rats were administered Pseudechis australis (mulga snake) venom either through i.v., i.m. or s.d. route, including a range of doses (5–100 μg/kg). Serial blood samples were collected for measurement of venom using enzyme immunoassay and measurement of CK and creatinine. Antivenom was administered before, 1 and 6 h after venom administration to investigate its effect on muscle injury. Plots of venom and CK ...
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Species differences in the neuromuscular activity of post-synaptic neurotoxins from two Australian black snakes (Pseudechis porphyriacus and Pseudechis colletti).
Toxicology letters, 2013Co-Authors: Andrew Hart, Geoffrey K. Isbister, Paul O'donnell, Nicholas A. Williamson, Wayne C. HodgsonAbstract:Abstract Bites by Australian black snakes (Pseudechis spp.) do not cause neurotoxicity in human envenoming. This is unusual as in vitro neurotoxicity has been reported for all Pseudechis spp. venoms. The present study aimed to identify, isolate and characterise neurotoxins from the venoms of Pseudechis porphyriacus and Pseudechis colletti to elucidate the reason for the lack of neurotoxicity in humans. α-Elapitoxin-Ppr1 and α-elapitoxin-Pc1 were isolated from P. porphyriacus and P. colletti, respectively, using reverse-phase high performance liquid chromatography. Each toxin consisted of 62 amino acids with molecular weights of 6746.5 Da and 6759.6 Da, respectively. α-Elapitoxin-Ppr1 and α-elapitoxin-Pc1 caused concentration-dependent (0.1–0.3 μM) inhibition of indirect twitches in the chick biventer cervicis nerve-muscle preparation. Both toxins inhibited contractile responses to exogenous ACh and CCh, but not KCl, suggesting a post-synaptic mode of action at the nicotinic acetylcholine receptor (nAChR). CCh concentration–response curves obtained in the presence or absence of α-elapitoxin-Ppr1 or α-elapitoxin-Pc1 indicated pA2 values of 6.97 ± 0.03 and 7.04 ± 0.07, respectively. Neither α-elapitoxin-Ppr1 (0.1 μM) nor α-elapitoxin-Pc1 (0.1 μM) had a significant effect on the electrically-induced twitches of the rat isolated phrenic nerve-diaphragm preparation. When the venom with the toxin removed (10 μg/ml) was added to both the rat and chick preparations, the inhibition was significantly less than that caused by the intact whole venoms (10 μg/ml). The current study shows that α-elapitoxin-Ppr1 and α-elapitoxin-Pc1 act as pseudo-irreversible antagonists at the nAChR of the skeletal neuromuscular junction and that the avian preparation is more sensitive to the neurotoxic effects of these toxins than the mammalian preparation.
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In vitro neurotoxic effects of Pseudechis spp. venoms: A comparison of avian and murine skeletal muscle preparations
Toxicon : official journal of the International Society on Toxinology, 2012Co-Authors: Andrew Hart, Geoffrey K. Isbister, Wayne C. HodgsonAbstract:Two common in vitro skeletal muscle preparations used for the study of venom neurotoxicity are the indirectly stimulated chick isolated biventer cervicis nerve-muscle preparation and the rat isolated phrenic nerve-diaphragm preparation. The aim of the current study was to compare the in vitro neurotoxicity of six Pseudechis spp. (Black snakes) venoms in both avian (chicken) and mammalian (rat) skeletal muscle preparations to determine differences in sensitivity. All Pseudechis spp. venoms significantly inhibited indirect twitches, in both preparations, indicating the presence of post synaptic neurotoxins. The inhibitory effects of all venoms were more rapid in the avian preparation, except for Pseudechis colletti venom where no significant difference was seen between the murine and avian muscles. Time taken to produce 50% reduction in stimulated twitches (i.e. t(50)) was markedly shorter in the avian preparation. We have shown that the avian in vitro preparation is more sensitive to the neurotoxic activity of Pseudechis spp. than the murine preparation. This difference is likely to be due to species differences in the interaction between the neurotoxins and the nicotinic receptor binding sites as well as differences in the 'safety factor' between the preparations.
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Neuromuscular toxicology of the venom of Collett's snake ( Pseudechis colletti ): A histopathological study
Muscle & nerve, 2011Co-Authors: Andrew Hart, Wayne C. Hodgson, Tracey Scott-davey, John HarrisAbstract:A bite by Collett's snake, (Pseudechis colletti) can cause rhabdomyolysis in human victims but no signs of neurotoxicity. The pathology of muscle and peripheral nerve has not been described previously. In this study we investigated neuromuscular toxicity in rats. The venom was inoculated subcutaneously into the anterolateral aspect of one hindlimb of adult rats at a dose replicating that inoculated into an adult human male during an envenoming bite. The venom caused edema, an increase in muscle wet weight, and the degeneration of 20-35% of the underlying soleus muscle. Muscle fiber regeneration began at 4 days and was complete by 8 weeks. There was little evidence of either post- or presynaptic toxicity. The dominant effect of this venom in mammals is myotoxicity. Copyright © 2010 Wiley Periodicals, Inc.
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Isolation and pharmacological characterisation of papuantoxin-1, a postsynaptic neurotoxin from the venom of the Papuan black snake (Pseudechis papuanus).
Biochemical pharmacology, 2005Co-Authors: Sanjaya Kuruppu, Shane Reeve, A. Ian Smith, Wayne C. HodgsonAbstract:The Papuan black snake (Pseudechis papuanus) is found throughout the southern coastal regions of Papua New Guinea and is thought to occur in the adjacent region of Iriyan Jaya. Neurotoxicity is a major symptom of envenomation by this species. This study describes the isolation of the first neurotoxin papuantoxin-1 from the venom of P. papuanus. Papuantoxin-1 (6738Da), which accounts for approximately 5% of the whole venom, was purified to homogeneity using successive steps of RP-HPLC. The toxin (0.3-1.0 microM) caused concentration dependent inhibition of indirect twitches (0.1 Hz, 0.2 ms and supramaximal V) and inhibited the responses to nicotinic agonists in the chick biventer cervicis nerve-muscle preparation, indicating a postsynaptic mode of action. However, papuantoxin-1 displayed no signs of myotoxicity. Papuantoxin-1 displayed pseudo-irreversible antagonism of cumulative concentration-response curves to carbachol at the skeletal muscle nicotinic receptors with an estimated pA2 value of 6.9+/-0.3. CSL black snake antivenom, which is raised against the venom of the Australian black snake Pseudechis australis, appears to be effective in reversing the effects of papuantoxin-1. Thus, black snake antivenom should be considered for the treatment of the neurotoxic effects following envenomation by the Papaun black snake.
Geoffrey K. Isbister - One of the best experts on this subject based on the ideXlab platform.
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Australian snakebite myotoxicity (ASP-23).
Clinical toxicology (Philadelphia Pa.), 2020Co-Authors: Chris Johnston, Geoffrey K. IsbisterAbstract:Myotoxicity is a recognised but poorly characterised effect of snake envenoming worldwide. We aimed to describe the clinical effects, complications and effectiveness of antivenom in myotoxicity from Australian snake envenoming. Patients were recruited to the Australian Snakebite Project (ASP), a prospective, observational study of patients with suspected or proven snakebite countrywide. After informed consent data is collected and stored in a dedicated database and blood samples are taken and stored. We included patients with envenoming and biochemical evidence of myotoxicity (peak creatine kinase [CK] > 1000 U/L). Snake species was determined by expert identification or venom specific enzyme immunoassay. Analysis included patient demographics, clinical findings, pathology results, treatment and outcomes (length of hospital stay, complications). 1638 patients were recruited January 2003-December 2016, 935 (57%) were envenomed, 148 developed myotoxicity (16%). Snake species most commonly associated with myotoxicity were Notechis spp. (30%), Pseudechis porphyriacus (20%) and Pseudechis australis (13%). Bite site effects occurred in 19 patients. Non-specific systemic symptoms occurred in 135 patients (91%), specific signs and symptoms in 83. In 120 patients with early serial CK results, the median peak CK was 3323 U/L (IQR;1050-785100U/L), the median time to first CK >500 U/L was 11.1 h and median time to peak CK of 34.3 h. White cell count was elevated in 136 patients (93%; median time to elevation, 4.9 h). 37 patients had elevated creatinine, six were dialysed. Two patients died from complications of severe myotoxicity. Antivenom given before the first abnormal CK (>500 U/L) was associated with less severe myotoxicity (2976 versus 7590 U/L). Non-envenomed patients with elevated CK had rapid rise to abnormal CK (median 3.5 h) and less had elevated WCC (32%). Myotoxicity from Australian snakes is relatively common and has systemic effects, with significant associated morbidity and mortality. CK is not a good early biomarker of mytoxicity. Early antivenom may play a role in reducing severity.
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Severe rhabdomyolysis from red-bellied black snake (Pseudechis porphyriacus) envenoming despite antivenom.
Toxicon : official journal of the International Society on Toxinology, 2016Co-Authors: Adeline Y.l. Lim, Puneet N. Singh, Geoffrey K. IsbisterAbstract:Envenoming by the Australian red-bellied black snake (Pseudechis porphyriacus) causes non-specific systemic symptoms, anticoagulant coagulopathy, myotoxicity and local effects. Current management for systemic envenoming includes administration of one vial of tiger snake antivenom within 6 h of the bite to prevent myotoxicity. We present a case of severe rhabdomyolysis in a 16 year old male which developed despite early administration of one vial of tiger snake antivenom. Free venom was detected after the administration of antivenom concurrent with rapidly decreasing antivenom concentrations. The case suggests that insufficient antivenom was administered and the use of larger doses of antivenom need to be explored for red-bellied black snake envenoming.
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pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis mulga snake in the anesthetised rat
Clinical Toxicology, 2014Co-Authors: Andrew Hart, Wayne C. Hodgson, Margaret A Oleary, Geoffrey K. IsbisterAbstract:Context. Myotoxicity is a common clinical effect of snake envenoming and results from either local or systemic myotoxins in snake venoms. Although numerous myotoxins have been isolated from snake venoms, there has been limited study on the relationship between the time course of venom concentrations (pharmacokinetics) and the time course of muscle injury measured as a rise in creatine kinase (CK) (pharmacodynamics). Objective. The aim of this study was to develop an in vivo model of myotoxicity to investigate the time course of myotoxicity and the effect of antivenom. Materials and methods. Anesthetised rats were administered Pseudechis australis (mulga snake) venom either through i.v., i.m. or s.d. route, including a range of doses (5–100 μg/kg). Serial blood samples were collected for measurement of venom using enzyme immunoassay and measurement of CK and creatinine. Antivenom was administered before, 1 and 6 h after venom administration to investigate its effect on muscle injury. Plots of venom and CK ...
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Comparative sensitivity of commercially available aPTT reagents to mulga snake (Pseudechis australis) venom
Pathology, 2014Co-Authors: Lisa F. Lincz, Margaret A. O'leary, Chris Johnston, Fiona E. Scorgie, Ritam Prasad, Michael Seldon, Emmanuel J. Favaloro, Geoffrey K. IsbisterAbstract:This study aimed to determine the relative sensitivity of activated partial thromboplastin time (aPTT) reagents to the anticoagulant effects of phospholipases in mulga snake (Pseudechis australis) venom.Twenty-one haematology laboratories participating in the Royal College of Pathologists of Australasia Quality Assurance Programs were sent human plasma samples spiked with mulga venom (n=25 total results). Results for 17 patients with mulga snake envenoming were available through the Australian Snakebite Project.Only 12 of 25 venom spiked samples returned an abnormally prolonged aPTT. Tests performed with Dade Actin FS (n=7) did not identify any of the spiked samples as abnormal. Although clotting times were significantly prolonged using the lupus anticoagulant sensitive Actin FSL (n=5, p=0.043), only one was reported as abnormal. Only laboratories using TriniCLOT aPTT S (n=6), HemosIL APTT SP (n=2) and Stago PTT-A (n=1) consistently recorded the spiked sample as being above the upper normal reference interval. Abnormally prolonged aPTTs were recorded for four of eight patients whose tests were performed with Actin FSL, five of eight patients with TriniCLOT aPTT HS, and three of three patients using TriniCLOT aPTT S.We conclude that some reagents used for routine aPTT testing are relatively insensitive to the anticoagulant effects of mulga snake venom. Tests performed with these reagents should be interpreted with caution.
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Mulga snake (Pseudechis australis) envenoming: a spectrum of myotoxicity, anticoagulant coagulopathy, haemolysis and the role of early antivenom therapy – Australian Snakebite Project (ASP-19)
Clinical toxicology (Philadelphia Pa.), 2013Co-Authors: Chris Johnston, Margaret A. O'leary, Julian White, Simon G A Brown, Bart J. Currie, Randall Greenberg, Michael A. Taylor, Casey Barnes, Geoffrey K. IsbisterAbstract:Context. Mulga snakes (Pseudechis australis) are venomous snakes with a wide distribution in Australia. Objective. The objective of this study was to describe mulga snake envenoming and the response of envenoming to antivenom therapy. Materials and methods. Definite mulga bites, based on expert identification or venom-specific enzyme immunoassay, were recruited from the Australian Snakebite Project. Demographics, information about the bite, clinical effects, laboratory investigations and antivenom treatment are recorded for all patients. Blood samples are collected to measure the serum venom concentrations pre- and post-antivenom therapy using enzyme immunoassay. Results. There were 17 patients with definite mulga snake bites. The median age was 37 years (6–70 years); 16 were male and six were snake handlers. Thirteen patients had systemic envenoming with non-specific systemic symptoms (11), anticoagulant coagulopathy (10), myotoxicity (7) and haemolysis (6). Antivenom was given to ten patients; the media...
David J Williams - One of the best experts on this subject based on the ideXlab platform.
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proteomics and antivenomics of papuan black snake Pseudechis papuanus venom with analysis of its toxicological profile and the preclinical efficacy of australian antivenoms
Journal of Proteomics, 2017Co-Authors: Davinia Pla, Alvaro Segura, Owen Paiva, Benjamin W. Bande, R Welton, Libia Sanz, Christine E. Wright, Juan J. Calvete, José María Gutiérrez, David J WilliamsAbstract:Abstract The Papuan black snake ( Pseudechis papuanus Serpentes: Elapidae) is endemic to Papua New Guinea, Indonesian Papua and Australia's Torres Strait Islands. We have investigated the biological activity and proteomic composition of its venom. The P . papuanus venom proteome is dominated by a variety (n ≥ 18) of PLA 2 s, which together account for ~ 90% of the venom proteins, and a set of low relative abundance proteins, including a short-neurotoxic 3FTx (3.1%), 3–4 PIII-SVMPs (2.8%), 3 cysteine-rich secretory proteins (CRISP; 2.3%) 1–3 l -amino acid oxidase (LAAO) molecules (1.6%). Probing of a P . papuanus cDNA library with specific primers resulted in the elucidation of the full-length nucleotide sequences of six new toxins, including vespryn and NGF not found in the venom proteome, and a calglandulin protein involved in toxin expression with the venom glands. Intravenous injection of P . papuanus venom in mice induced lethality, intravascular haemolysis, pulmonary congestion and oedema, and anticoagulation after intravenous injection, and these effects are mainly due to the action of PLA 2 s. This study also evaluated the in vivo preclinical efficacy of Australian black snake and polyvalent Seqirus antivenoms. These antivenoms were effective in neutralising the lethal, PLA 2 and anticoagulant activities of P . papuanus venom in mice. On the other hand, all of the Seqirus antivenoms tested using an antivenomic approach exhibited strong immunorecognition of all the venom components. These preclinical results suggest that Australian Seqirus 1 antivenoms may provide paraspecific protection against P . papuanus venom in humans. Significance paragraph The toxicological profile and proteomic composition of the venom of the Papuan black snake, Pseudechis papuanus , a large diurnal snake endemic to the southern coast of New Guinea and a handful of close offshore islands, were investigated. Intravenous injection of P . papuanus venom in mice induced intravascular hemolysis, pulmonary congestion and edema, anticoagulation, and death. These activities could be assigned to the set of PLA 2 molecules, which dominate the P . papuanus venom proteome. This study also showed that Australian Seqirus black snake or polyvalent antivenoms were effective in neutralising the lethal, PLA 2 and anticoagulant activities of the venom. These preclinical results support the continued recommendation of these Seqirus antivenoms in the clinical management of P . papuanus envenoming in Australia, Papua New Guinea or Indonesian Papua Province.
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Proteomics and antivenomics of Papuan black snake (Pseudechis papuanus) venom with analysis of its toxicological profile and the preclinical efficacy of Australian antivenoms.
Journal of proteomics, 2016Co-Authors: Davinia Pla, Alvaro Segura, Owen Paiva, Benjamin W. Bande, R Welton, Libia Sanz, Christine E. Wright, Juan J. Calvete, José María Gutiérrez, David J WilliamsAbstract:The Papuan black snake (Pseudechis papuanus Serpentes: Elapidae) is endemic to Papua New Guinea, Indonesian Papua and Australia's Torres Strait Islands. We have investigated the biological activity and proteomic composition of its venom. The P. papuanus venom proteome is dominated by a variety (n≥18) of PLA2s, which together account for ~90% of the venom proteins, and a set of low relative abundance proteins, including a short-neurotoxic 3FTx (3.1%), 3-4 PIII-SVMPs (2.8%), 3 cysteine-rich secretory proteins (CRISP; 2.3%) 1-3 l-amino acid oxidase (LAAO) molecules (1.6%). Probing of a P. papuanus cDNA library with specific primers resulted in the elucidation of the full-length nucleotide sequences of six new toxins, including vespryn and NGF not found in the venom proteome, and a calglandulin protein involved in toxin expression with the venom glands. Intravenous injection of P. papuanus venom in mice induced lethality, intravascular haemolysis, pulmonary congestion and oedema, and anticoagulation after intravenous injection, and these effects are mainly due to the action of PLA2s. This study also evaluated the in vivo preclinical efficacy of Australian black snake and polyvalent Seqirus antivenoms. These antivenoms were effective in neutralising the lethal, PLA2 and anticoagulant activities of P. papuanus venom in mice. On the other hand, all of the Seqirus antivenoms tested using an antivenomic approach exhibited strong immunorecognition of all the venom components. These preclinical results suggest that Australian Seqirus1 antivenoms may provide paraspecific protection against P. papuanus venom in humans. The toxicological profile and proteomic composition of the venom of the Papuan black snake, Pseudechis papuanus, a large diurnal snake endemic to the southern coast of New Guinea and a handful of close offshore islands, were investigated. Intravenous injection of P. papuanus venom in mice induced intravascular hemolysis, pulmonary congestion and edema, anticoagulation, and death. These activities could be assigned to the set of PLA2 molecules, which dominate the P. papuanus venom proteome. This study also showed that Australian Seqirus black snake or polyvalent antivenoms were effective in neutralising the lethal, PLA2 and anticoagulant activities of the venom. These preclinical results support the continued recommendation of these Seqirus antivenoms in the clinical management of P. papuanus envenoming in Australia, Papua New Guinea or Indonesian Papua Province. Copyright © 2016 Elsevier B.V. All rights reserved.
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Multi-locus phylogeny and species delimitation of Australo-Papuan blacksnakes (Pseudechis Wagler, 1830: Elapidae: Serpentes).
Molecular phylogenetics and evolution, 2016Co-Authors: Simon T. Maddock, David J Williams, Bryan G. Fry, Aaron Childerstone, Axel Barlow, Wolfgang WüsterAbstract:Genetic analyses of Australasian organisms have resulted in the identification of extensive cryptic diversity across the continent. The venomous elapid snakes are among the best-studied organismal groups in this region, but many knowledge gaps persist: for instance, despite their iconic status, the species-level diversity among Australo-Papuan blacksnakes (Pseudechis) has remained poorly understood due to the existence of a group of cryptic species within the P. australis species complex, collectively termed “pygmy mulga snakes”. Using two mitochondrial and three nuclear loci we assess species boundaries within the genus using Bayesian species delimitation methods and reconstruct their phylogenetic history using multispecies coalescent approaches. Our analyses support the recognition of 10 species, including all of the currently described pygmy mulga snakes and one undescribed species from the Northern Territory of Australia. Phylogenetic relationships within the genus are broadly consistent with previous work, with the recognition of three major groups, the viviparous red-bellied black snake P. porphyriacus forming the sister species to two clades consisting of ovoviviparous species.
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antivenomic characterization of two antivenoms against the venom of the taipan oxyuranus scutellatus from papua new guinea and australia
American Journal of Tropical Medicine and Hygiene, 2014Co-Authors: Maria Herrera, Guillermo León, Mauren Villalta, Alvaro Segura, Mariangela Vargas, Owen Paiva, S Jensen, Ana Helena Pagotto, Solange M T Serrano, David J WilliamsAbstract:Antivenoms manufactured by bioCSL Limited (Australia) and Instituto Clodomiro Picado (Costa Rica) against the venom of the taipan snakes (Oxyuranus scutellatus) from Australia and Papua New Guinea (PNG), respec- tively, were compared using antivenomics, an analytical approach that combines proteomics with immunoaffinity chro- matography. Both antivenoms recognized all venom proteins present in venom from PNG O. scutellatus, although a pattern of partial recognition was observed for some components. In the case of the Australian O. scutellatus venom, both antivenoms immunorecognized the majority of the components, but the CSL antivenom showed a stronger pattern of immunoreactivity, which was revealed by the percentage of retained proteins in the immunoaffinity column. Antivenoms interacted with taipoxin in surface plasmon resonance. These observations on antivenomics agree with previous neutralization studies. are responsible for the majority of cases: Acanthophis laevis (smooth-scaleddeathadder),Micropechisikaheka(NewGuinea small-eyed snake), and Oxyuranus scutellatus (Papuan taipan). Lower numbers of cases are induced by other Acanthophis species, Pseudechis papuanus (Papuan blacksnake), and Pseudonaja textilis (New Guinea brownsnake). 3 In southern PNG and southern Papua, the vast majority of snakebites are inflicted by O. scutellatus. 3 Envenomings by this large elapid snake are characterized by minor local effects and severe sys- temic manifestations, including irreversible flaccid paralysis, coagulopathy associated with systemic spontaneous bleeding, myotoxicity, acute kidney injury, and cardiac damage. 2-6 The therapy for envenomings by O. scutellatus in PNG is based on the intravenous administration of either CSL Poly- valent Antivenom or CSL Taipan Antivenom (both manufac- tured by bioCSL Limited in Melbourne, Victoria, Australia; CSL). They are F(ab')2 antivenoms generated by pepsin diges- tion and ammonium sulphate precipitation of plasma of hyperimmunized horses. 3 Both of these antivenoms, when administered early, have been shown to be effective in halting coagulopathy and bleeding and reduce the incidence of respi- ratory paralysis. CSL Polyvalent Antivenom is a polyspecific mixture of immunoglobulins (Igs) raised against the venom of Australian elapid species from five genera (Acanthophis, Notechis, Oxyuranus, Pseudechis ,a ndPseudonaja). Although CSL Taipan Antivenom is therapeutically indicated only for treating envenoming by snakes of the genus Oxyuranus ,t his antivenom is also the result of hyperimmunizing horses with venom from the same five genera of Australian elapid snakes used in production of CSL Polyvalent Antivenom. 7 Recently, a
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Snakes across the Strait: trans-Torresian phylogeographic relationships in three genera of Australasian snakes (Serpentes: Elapidae: Acanthophis, Oxyuranus, and Pseudechis).
Molecular phylogenetics and evolution, 2005Co-Authors: Wolfgang Wüster, David J Williams, Alex J. Dumbrell, Chris Hay, Catharine E. Pook, Bryan G. FryAbstract:We analyze the phylogeny of three genera of Australasian elapid snakes (Acanthophis—death adders; Oxyuranus—taipans; Pseudechis—blacksnakes), using parsimony, maximum likelihood, and Bayesian analysis of sequences of the mitochondrial cytochrome b and ND4 genes. In Acanthophis and Pseudechis, we find evidence of multiple trans-Torresian sister-group relationships. Analyses of the timing of cladogenic events suggest crossings of the Torres Strait on several occasions between the late Miocene and the Pleistocene. These results support a hypothesis of repeated land connections between Australia and New Guinea in the late Cenozoic. Additionally, our results reveal undocumented genetic diversity in Acanthophis and Pseudechis, supporting the existence of more species than previously believed, and provide a phylogenetic framework for a reinterpretation of the systematics of these genera. In contrast, our Oxyuranus scutellatus samples from Queensland and two localities in New Guinea share a single haplotype, suggesting very recent (late Pleistocene) genetic exchange between New Guinean and Australian populations.
Bryan G. Fry - One of the best experts on this subject based on the ideXlab platform.
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Anticoagulant activity of black snake (Elapidae: Pseudechis) venoms: Mechanisms, potency, and antivenom efficacy.
Toxicology letters, 2020Co-Authors: Christina N. Zdenek, Chris Hay, Nicholas J. Youngman, James Dobson, Nathan Dunstan, Luke Allen, Leontina Milanovic, Bryan G. FryAbstract:Abstract Venoms from Pseudechis species (Australian black snakes) within the Elapidae family are rich in anticoagulant PLA2 toxins, with the exception of one species (P. porphyriacus) that possesses procoagulant mutated forms of the clotting enzyme Factor Xa. Previously the mechanism of action of the PLA2 toxins’ anticoagulant toxicity was said to be due to inhibition of Factor Xa, but this statement was evidence free. We conducted a series of anticoagulation assays to elucidate the mechanism of anticoagulant action produced by P. australis venom. Our results revealed that, rather than targeting FXa, the PLA2 toxins inhibited the prothrombinase complex, with FVa—alone or as part of the prothrombinase complex—as the primary target; but with significant thrombin inhibition also noted. In contrast, FXa, and other factors inhibited only to a lesser degree were minor targets. We quantified coagulotoxic effects upon human plasma caused by all nine anticoagulant Pseudechis species, including nine localities of P. australis across Australia, and found similar anticoagulant potency across all Pseudechis species, with greater potency in P. australis and the undescribed Pseudechis species in the NT. In addition, the northern localities and eastern of P. australis were significantly more potent than the central, western, and southern localities. All anticoagulant venoms responded well to Black Snake Antivenom, except P. colletti which was poorly neutralised by Black Snake Antivenom and also Tiger Snake Antivenom (the prescribed antivenom for this species). However, we found LY315920 (trade name: Varespladib), a small molecule inhibitor of PLA2 proteins, exhibited strong potency against P. colletti venom. Thus, Varespladib may be a clinically viable treatment for anticoagulant toxicity exerted by this species that is not neutralised by available antivenoms. Our results provide insights into coagulotoxic venom function, and suggest future in vivo work be conducted to progress the development of a cheaper, first-line treatment option to treat PLA2-rich snake venoms globally.
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Multi-locus phylogeny and species delimitation of Australo-Papuan blacksnakes (Pseudechis Wagler, 1830: Elapidae: Serpentes).
Molecular phylogenetics and evolution, 2016Co-Authors: Simon T. Maddock, David J Williams, Bryan G. Fry, Aaron Childerstone, Axel Barlow, Wolfgang WüsterAbstract:Genetic analyses of Australasian organisms have resulted in the identification of extensive cryptic diversity across the continent. The venomous elapid snakes are among the best-studied organismal groups in this region, but many knowledge gaps persist: for instance, despite their iconic status, the species-level diversity among Australo-Papuan blacksnakes (Pseudechis) has remained poorly understood due to the existence of a group of cryptic species within the P. australis species complex, collectively termed “pygmy mulga snakes”. Using two mitochondrial and three nuclear loci we assess species boundaries within the genus using Bayesian species delimitation methods and reconstruct their phylogenetic history using multispecies coalescent approaches. Our analyses support the recognition of 10 species, including all of the currently described pygmy mulga snakes and one undescribed species from the Northern Territory of Australia. Phylogenetic relationships within the genus are broadly consistent with previous work, with the recognition of three major groups, the viviparous red-bellied black snake P. porphyriacus forming the sister species to two clades consisting of ovoviviparous species.
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Snakes across the Strait: trans-Torresian phylogeographic relationships in three genera of Australasian snakes (Serpentes: Elapidae: Acanthophis, Oxyuranus, and Pseudechis).
Molecular phylogenetics and evolution, 2005Co-Authors: Wolfgang Wüster, David J Williams, Alex J. Dumbrell, Chris Hay, Catharine E. Pook, Bryan G. FryAbstract:We analyze the phylogeny of three genera of Australasian elapid snakes (Acanthophis—death adders; Oxyuranus—taipans; Pseudechis—blacksnakes), using parsimony, maximum likelihood, and Bayesian analysis of sequences of the mitochondrial cytochrome b and ND4 genes. In Acanthophis and Pseudechis, we find evidence of multiple trans-Torresian sister-group relationships. Analyses of the timing of cladogenic events suggest crossings of the Torres Strait on several occasions between the late Miocene and the Pleistocene. These results support a hypothesis of repeated land connections between Australia and New Guinea in the late Cenozoic. Additionally, our results reveal undocumented genetic diversity in Acanthophis and Pseudechis, supporting the existence of more species than previously believed, and provide a phylogenetic framework for a reinterpretation of the systematics of these genera. In contrast, our Oxyuranus scutellatus samples from Queensland and two localities in New Guinea share a single haplotype, suggesting very recent (late Pleistocene) genetic exchange between New Guinean and Australian populations.
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Neurotoxic effects of venoms from seven species of australasian black snakes (Pseudechis): Efficacy of black and tiger snake antivenoms
Clinical and experimental pharmacology & physiology, 2005Co-Authors: Sharmaine Ramasamy, Bryan G. Fry, Wayne C. HodgsonAbstract:SUMMARY 1. Pseudechis species (black snakes) are among the most widespread venomous snakes in Australia. Despite this, very little is known about the potency of their venoms or the efficacy of the antivenoms used to treat systemic envenomation by these snakes. The present study investigated the in vitro neurotoxicity of venoms from seven Australasian Pseudechis species and determined the efficacy of black and tiger snake antivenoms against this activity. 2. All venoms (10 µg/mL) significantly inhibited indirect twitches of the chick biventer cervicis nerve–muscle preparation and responses to exogenous acetylcholine (ACh; 1 mmol/L), but not to KCl (40 mmol/L), indicating activity at post-synaptic nicotinic receptors on the skeletal muscle. 3. Prior administration of either black or tiger snake antivenom (5 U/mL) prevented the inhibitory effects of all Pseudechis venoms. 4. Black snake antivenom (5 U/mL) added at t90 (i.e. the time-point at which the original twitch height was reduced by 90%) significantly reversed the effects of P. butleri (28 ± 5%), P. guttatus (25 ± 8%) and P. porphyriacus (28 ± 10%) venoms. Tiger snake antivenom (5 U/mL) added at the t90 time-point significantly reversed the neurotoxic effects of P. guttatus (51 ± 4%), P. papuanus (47 ± 5%) and P. porphyriacus (20 ± 7%) venoms. 5. We show, for the first time, the presence of neurotoxins in the venom of these related snake species and that this activity is differentially affected by either black snake or tiger snake antivenoms.
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pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis mulga snake in the anesthetised rat
Clinical Toxicology, 2014Co-Authors: Andrew Hart, Wayne C. Hodgson, Margaret A Oleary, Geoffrey K. IsbisterAbstract:Context. Myotoxicity is a common clinical effect of snake envenoming and results from either local or systemic myotoxins in snake venoms. Although numerous myotoxins have been isolated from snake venoms, there has been limited study on the relationship between the time course of venom concentrations (pharmacokinetics) and the time course of muscle injury measured as a rise in creatine kinase (CK) (pharmacodynamics). Objective. The aim of this study was to develop an in vivo model of myotoxicity to investigate the time course of myotoxicity and the effect of antivenom. Materials and methods. Anesthetised rats were administered Pseudechis australis (mulga snake) venom either through i.v., i.m. or s.d. route, including a range of doses (5–100 μg/kg). Serial blood samples were collected for measurement of venom using enzyme immunoassay and measurement of CK and creatinine. Antivenom was administered before, 1 and 6 h after venom administration to investigate its effect on muscle injury. Plots of venom and CK ...
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Species differences in the neuromuscular activity of post-synaptic neurotoxins from two Australian black snakes (Pseudechis porphyriacus and Pseudechis colletti).
Toxicology letters, 2013Co-Authors: Andrew Hart, Geoffrey K. Isbister, Paul O'donnell, Nicholas A. Williamson, Wayne C. HodgsonAbstract:Abstract Bites by Australian black snakes (Pseudechis spp.) do not cause neurotoxicity in human envenoming. This is unusual as in vitro neurotoxicity has been reported for all Pseudechis spp. venoms. The present study aimed to identify, isolate and characterise neurotoxins from the venoms of Pseudechis porphyriacus and Pseudechis colletti to elucidate the reason for the lack of neurotoxicity in humans. α-Elapitoxin-Ppr1 and α-elapitoxin-Pc1 were isolated from P. porphyriacus and P. colletti, respectively, using reverse-phase high performance liquid chromatography. Each toxin consisted of 62 amino acids with molecular weights of 6746.5 Da and 6759.6 Da, respectively. α-Elapitoxin-Ppr1 and α-elapitoxin-Pc1 caused concentration-dependent (0.1–0.3 μM) inhibition of indirect twitches in the chick biventer cervicis nerve-muscle preparation. Both toxins inhibited contractile responses to exogenous ACh and CCh, but not KCl, suggesting a post-synaptic mode of action at the nicotinic acetylcholine receptor (nAChR). CCh concentration–response curves obtained in the presence or absence of α-elapitoxin-Ppr1 or α-elapitoxin-Pc1 indicated pA2 values of 6.97 ± 0.03 and 7.04 ± 0.07, respectively. Neither α-elapitoxin-Ppr1 (0.1 μM) nor α-elapitoxin-Pc1 (0.1 μM) had a significant effect on the electrically-induced twitches of the rat isolated phrenic nerve-diaphragm preparation. When the venom with the toxin removed (10 μg/ml) was added to both the rat and chick preparations, the inhibition was significantly less than that caused by the intact whole venoms (10 μg/ml). The current study shows that α-elapitoxin-Ppr1 and α-elapitoxin-Pc1 act as pseudo-irreversible antagonists at the nAChR of the skeletal neuromuscular junction and that the avian preparation is more sensitive to the neurotoxic effects of these toxins than the mammalian preparation.
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In vitro neurotoxic effects of Pseudechis spp. venoms: A comparison of avian and murine skeletal muscle preparations
Toxicon : official journal of the International Society on Toxinology, 2012Co-Authors: Andrew Hart, Geoffrey K. Isbister, Wayne C. HodgsonAbstract:Two common in vitro skeletal muscle preparations used for the study of venom neurotoxicity are the indirectly stimulated chick isolated biventer cervicis nerve-muscle preparation and the rat isolated phrenic nerve-diaphragm preparation. The aim of the current study was to compare the in vitro neurotoxicity of six Pseudechis spp. (Black snakes) venoms in both avian (chicken) and mammalian (rat) skeletal muscle preparations to determine differences in sensitivity. All Pseudechis spp. venoms significantly inhibited indirect twitches, in both preparations, indicating the presence of post synaptic neurotoxins. The inhibitory effects of all venoms were more rapid in the avian preparation, except for Pseudechis colletti venom where no significant difference was seen between the murine and avian muscles. Time taken to produce 50% reduction in stimulated twitches (i.e. t(50)) was markedly shorter in the avian preparation. We have shown that the avian in vitro preparation is more sensitive to the neurotoxic activity of Pseudechis spp. than the murine preparation. This difference is likely to be due to species differences in the interaction between the neurotoxins and the nicotinic receptor binding sites as well as differences in the 'safety factor' between the preparations.
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Neuromuscular toxicology of the venom of Collett's snake ( Pseudechis colletti ): A histopathological study
Muscle & nerve, 2011Co-Authors: Andrew Hart, Wayne C. Hodgson, Tracey Scott-davey, John HarrisAbstract:A bite by Collett's snake, (Pseudechis colletti) can cause rhabdomyolysis in human victims but no signs of neurotoxicity. The pathology of muscle and peripheral nerve has not been described previously. In this study we investigated neuromuscular toxicity in rats. The venom was inoculated subcutaneously into the anterolateral aspect of one hindlimb of adult rats at a dose replicating that inoculated into an adult human male during an envenoming bite. The venom caused edema, an increase in muscle wet weight, and the degeneration of 20-35% of the underlying soleus muscle. Muscle fiber regeneration began at 4 days and was complete by 8 weeks. There was little evidence of either post- or presynaptic toxicity. The dominant effect of this venom in mammals is myotoxicity. Copyright © 2010 Wiley Periodicals, Inc.
