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Dr. Geoffrey Isbister
Clinical Toxicology Research Group, University of Newcastle, Australia, New South Wales, Australia

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0 Antidotes
0 poisoning
0 Clinical toxicology and clinical Toxinology: toxins

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Journal article
Published: 30 July 2021 in Clinical Toxicology
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Snakebite-associated thrombotic microangiopathy (TMA) occurs in a subset of patients with venom-induced consumption coagulopathy (VICC) following snakebite. Acute kidney injury (AKI) is the commonest end-organ manifestation of TMA. The epidemiology, diagnostic features, outcomes, and effectiveness of interventions including therapeutic plasma-exchange (TPE), in snakebite-associated TMA are poorly understood. We reviewed all patients with suspected or confirmed snakebite recruited to the Australian Snakebite Project (2004-2018 inclusive), a prospective cohort study, from 202 participating Australian hospitals across the country. TMA was defined as anemia with schistocytosis. 2069 patients with suspected snakebite were enrolled, with 1158 (56.0%) systemically envenomed, of which 842 (72.7%) developed VICC, from which 104 (12.4%) developed TMA. Of those systemically envenomed, TMA occurred in 26% (13/50) taipan, 17% (60/351) brown, and 8% (16/197) tiger snakebites. Thrombocytopenia was present in 90% (94/104) of TMA cases, and a further eight (8%) had a > 25% decrease in platelets from the presentation. Patients with TMA were significantly older than non-TMA patients with VICC (53 [35–61] versus 41 [24–55] years, median [IQR], p < 0.0001). AKI developed in 94% (98/104) of TMA patients, with 34% (33/98) requiring dialysis (D-AKI). There were four deaths. In D-AKI TMA cases, eventual dialysis-free survival (DFS) was 97% (32/33). TPE was used in five D-AKI cases, with no significant difference in DFS or time to independence from dialysis. >90-day follow-up for 25 D-AKI cases (130 person-years) showed no end-stage kidney disease but 52% (13/25) had ≥ stage 3 chronic kidney disease (CKD). Our findings support a definition of snakebite-associated TMA as anemia with schistocytosis and either thrombocytopenia or >25% drop in platelet count. AKI occurring with snakebite-associated TMA varied in severity, with most achieving DFS, but with a risk of long-term CKD in half. We found no evidence of benefit for TPE in D-AKI.

ACS Style

Tina Noutsos; Bart J. Currie; Katherine Z. Isoardi; Simon G. A. Brown; Geoffrey K. Isbister. Snakebite-associated thrombotic microangiopathy: an Australian prospective cohort study [ASP30]. Clinical Toxicology 2021, 1 -9.

AMA Style

Tina Noutsos, Bart J. Currie, Katherine Z. Isoardi, Simon G. A. Brown, Geoffrey K. Isbister. Snakebite-associated thrombotic microangiopathy: an Australian prospective cohort study [ASP30]. Clinical Toxicology. 2021; ():1-9.

Chicago/Turabian Style

Tina Noutsos; Bart J. Currie; Katherine Z. Isoardi; Simon G. A. Brown; Geoffrey K. Isbister. 2021. "Snakebite-associated thrombotic microangiopathy: an Australian prospective cohort study [ASP30]." Clinical Toxicology , no. : 1-9.

Original article
Published: 27 July 2021 in British Journal of Clinical Pharmacology
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Aims The objectives are to determine the effect of NaHCO3 and/or mechanical ventilation on the biochemical profile and serum alkalinisation in tricyclic antidepressant (TCA) poisoning and investigate the impact of effective alkalinisation therapy on the QRS interval in TCA poisoning. Methods This was a retrospective review of TCA poisonings from three Australian toxicology units and a poisons information centre (Jan 2013-Jan 2019). We included patients with TCA toxicity who ingested>10mg/kg or had clinically significant toxicities consistent with TCA poisoning, and analysed patients’ clinical, electrocardiogram and biochemical data. Results Of 210 patients, 84 received NaHCO3 and ventilation (dual therapy), 12 NaHCO3, 46 ventilation and 68 supportive care treatment. When compared with single/supportive groups, patients who received dual therapy had taken a significantly higher median dose of TCA(1.5g vs.1.3g,p<0.001), a longer median maximum QRS interval(124ms,IQR:108-138 vs.106ms, IQR:98-115, p<0.001) and were more likely to have seizures(14% vs.3%,p=0.006) and arrhythmias(17% vs.1%,p<0.001). The dual therapy group demonstrated greater increases in serum pH (median:0.11,IQR:0.04-0.17) compared to the single/supportive therapy group (median:0.03,IQR:-0.01-0.09)(p<0.001). A greater proportion of patients reached target pH 7.45-7.55 in the dual therapy group(59%) compared to the single/supportive therapy group(10%)(p<0.001). For each 100mmol bolus of NaHCO3 given, the median increase in serum sodium was 2.5mmol/L (IQR:1.5-4.0). QRS narrowing occurred twice as quickly in the dual therapy vs. single/supportive therapy group. Conclusions A combination of NaHCO3 and mechanical ventilation was most effective in achieving serum alkalinisation and was associated with a more rapid narrowing of the QRS interval. We would advise the maximal dose of NaHCO3 should be <400 mmol(6 mmol/kg).

ACS Style

Kieran Pai; Nicholas A. Buckley; Katherine Z. Isoardi; Geoffrey K. Isbister; Therese Becker; Angela L. Chiew; Rose Cairns; Jared A. Brown; Betty S. Chan. Optimising Alkalinisation and its effect on QRS Narrowing in Tricyclic Antidepressant Poisoning. British Journal of Clinical Pharmacology 2021, 1 .

AMA Style

Kieran Pai, Nicholas A. Buckley, Katherine Z. Isoardi, Geoffrey K. Isbister, Therese Becker, Angela L. Chiew, Rose Cairns, Jared A. Brown, Betty S. Chan. Optimising Alkalinisation and its effect on QRS Narrowing in Tricyclic Antidepressant Poisoning. British Journal of Clinical Pharmacology. 2021; ():1.

Chicago/Turabian Style

Kieran Pai; Nicholas A. Buckley; Katherine Z. Isoardi; Geoffrey K. Isbister; Therese Becker; Angela L. Chiew; Rose Cairns; Jared A. Brown; Betty S. Chan. 2021. "Optimising Alkalinisation and its effect on QRS Narrowing in Tricyclic Antidepressant Poisoning." British Journal of Clinical Pharmacology , no. : 1.

Editorial
Published: 17 June 2021 in PLOS Neglected Tropical Diseases
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ACS Style

José María Gutiérrez; Jean Philippe Chippaux; Geoffrey K. Isbister. PLOS Neglected Tropical Diseases broadens its coverage of envenomings caused by animal bites and stings. PLOS Neglected Tropical Diseases 2021, 15, e0009481 .

AMA Style

José María Gutiérrez, Jean Philippe Chippaux, Geoffrey K. Isbister. PLOS Neglected Tropical Diseases broadens its coverage of envenomings caused by animal bites and stings. PLOS Neglected Tropical Diseases. 2021; 15 (6):e0009481.

Chicago/Turabian Style

José María Gutiérrez; Jean Philippe Chippaux; Geoffrey K. Isbister. 2021. "PLOS Neglected Tropical Diseases broadens its coverage of envenomings caused by animal bites and stings." PLOS Neglected Tropical Diseases 15, no. 6: e0009481.

Clinical research
Published: 03 June 2021 in Clinical Toxicology
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Overdose with paracetamol modified-release (MR) formulation, a bilayer tablet containing 69% slow-release component, has been increasing since its introduction to the market. However, little evidence exists for the management of MR paracetamol overdose. We aimed to develop a population pharmacokinetic (PK) model for immediate-release (IR) and MR paracetamol and its major metabolism, and quantitatively understand the formulation difference in toxicity assessment based on the nomogram line. Data from a cross-over study design in nine healthy volunteers administered a single supratherapeutic oral dose (80 mg/kg) of either IR and MR paracetamol were available from a published study. Plasma concentrations for paracetamol and its metabolites glucuronide (APAPG) and sulfate conjugate (APAPS) for both formulations were measured and analysed with population pharmacokinetic (PK) method using NONMEM. Toxicity in both formulations was assessed by comparing the simulated paracetamol concentrations under different paracetamol dose levels with the 150 mg/L nomograms. The difference in the assessment was compared between the two formulations. Paracetamol concentrations for the IR formulation were described with a two-compartment model with first-order input and a lag time. The delayed time-course of MR paracetamol concentrations was best captured by a parallel absorption model in which the slow-release component was a serial zero-order then the first-order process. The formation of APAPG was linear, while APAPS concentrations were best fitted by a Michaelis-Menten process. The relative bioavailability of MR paracetamol compared to IR (FMR/IR) was estimated as 0.81. The simulated probability of making different toxicity assessments based on nomogram line was increased with dose levels and was as high as 14.6% after 22 g IR or MR paracetamol ingested. A joint parent-metabolite model to describe time-course profiles of both IR and MR paracetamol and its metabolites APAPG and APAPS concentrations was developed. Simulations from the model showed that toxicity assessment based on the 150 mg/L nomograms is not suitable in MR paracetamol overdoses.

ACS Style

Jingyun Li; Angela L. Chiew; Geoffrey K. Isbister; Stephen B. Duffull. Population pharmacokinetics of immediate-release and modified-release paracetamol and its major metabolites in a supratherapeutic dosing study. Clinical Toxicology 2021, 1 -8.

AMA Style

Jingyun Li, Angela L. Chiew, Geoffrey K. Isbister, Stephen B. Duffull. Population pharmacokinetics of immediate-release and modified-release paracetamol and its major metabolites in a supratherapeutic dosing study. Clinical Toxicology. 2021; ():1-8.

Chicago/Turabian Style

Jingyun Li; Angela L. Chiew; Geoffrey K. Isbister; Stephen B. Duffull. 2021. "Population pharmacokinetics of immediate-release and modified-release paracetamol and its major metabolites in a supratherapeutic dosing study." Clinical Toxicology , no. : 1-8.

Earth sciences
Published: 01 June 2021 in PLOS Neglected Tropical Diseases
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Background Snakebite incidence shows both spatial and temporal variation. However, no study has evaluated spatiotemporal patterns of snakebites across a country or region in detail. We used a nationally representative population sample to evaluate spatiotemporal patterns of snakebite in Sri Lanka. Methodology We conducted a community-based cross-sectional survey representing all nine provinces of Sri Lanka. We interviewed 165 665 people (0.8% of the national population), and snakebite events reported by the respondents were recorded. Sri Lanka is an agricultural country; its central, southern and western parts receive rain mainly from Southwest monsoon (May to September) and northern and eastern parts receive rain mainly from Northeast monsoon (November to February). We developed spatiotemporal models using multivariate Poisson process modelling to explain monthly snakebite and envenoming incidences in the country. These models were developed at the provincial level to explain local spatiotemporal patterns. Principal findings Snakebites and envenomings showed clear spatiotemporal patterns. Snakebite hotspots were found in North-Central, North-West, South-West and Eastern Sri Lanka. They exhibited biannual seasonal patterns except in South-Western inlands, which showed triannual seasonality. Envenoming hotspots were confined to North-Central, East and South-West parts of the country. Hotspots in North-Central regions showed triannual seasonal patterns and South-West regions had annual patterns. Hotspots remained persistent throughout the year in Eastern regions. The overall monthly snakebite and envenoming incidences in Sri Lanka were 39 (95%CI: 38–40) and 19 (95%CI: 13–30) per 100 000, respectively, translating into 110 000 (95%CI: 107 500–112 500) snakebites and 45 000 (95%CI: 32 000–73 000) envenomings in a calendar year. Conclusions/significance This study provides information on community-based monthly incidence of snakebites and envenomings over the whole country. Thus, it provides useful insights into healthcare decision-making, such as, prioritizing locations to establish specialized centres for snakebite management and allocating resources based on risk assessments which take into account both location and season.

ACS Style

Dileepa Senajith Ediriweera; Anuradhani Kasthuriratne; Arunasalam Pathmeswaran; Nipul Kithsiri Gunawardene; Shaluka Francis Jayamanne; Kris Murray; Takuya Iwamura; Geoffrey Isbister; Andrew Dawson; David Griffith Lalloo; Hithanadura Janaka de Silva; Peter John Diggle. Evaluating spatiotemporal dynamics of snakebite in Sri Lanka: Monthly incidence mapping from a national representative survey sample. PLOS Neglected Tropical Diseases 2021, 15, e0009447 .

AMA Style

Dileepa Senajith Ediriweera, Anuradhani Kasthuriratne, Arunasalam Pathmeswaran, Nipul Kithsiri Gunawardene, Shaluka Francis Jayamanne, Kris Murray, Takuya Iwamura, Geoffrey Isbister, Andrew Dawson, David Griffith Lalloo, Hithanadura Janaka de Silva, Peter John Diggle. Evaluating spatiotemporal dynamics of snakebite in Sri Lanka: Monthly incidence mapping from a national representative survey sample. PLOS Neglected Tropical Diseases. 2021; 15 (6):e0009447.

Chicago/Turabian Style

Dileepa Senajith Ediriweera; Anuradhani Kasthuriratne; Arunasalam Pathmeswaran; Nipul Kithsiri Gunawardene; Shaluka Francis Jayamanne; Kris Murray; Takuya Iwamura; Geoffrey Isbister; Andrew Dawson; David Griffith Lalloo; Hithanadura Janaka de Silva; Peter John Diggle. 2021. "Evaluating spatiotemporal dynamics of snakebite in Sri Lanka: Monthly incidence mapping from a national representative survey sample." PLOS Neglected Tropical Diseases 15, no. 6: e0009447.

Journal article
Published: 26 April 2021 in Toxins
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Bites by many Asiatic and African cobras (Genus: Naja) cause severe local dermonecrosis and myonecrosis, resulting in permanent disabilities. We studied the time scale in which two Indian polyvalent antivenoms, VINS and Bharat, remain capable of preventing or reversing in vitro myotoxicity induced by common cobra (Naja naja) venom from Sri Lanka using the chick biventer cervicis nerve-muscle preparation. VINS fully prevented while Bharat partially prevented (both in manufacturer recommended concentrations) the myotoxicity induced by Naja naja venom (10 µg/mL) when added to the organ baths before the venom. However, both antivenoms were unable to reverse the myotoxicity when added to organ baths 5 and 20 min post-venom. In contrast, physical removal of the venom from the organ baths by washing the preparation 5 and 20 min after the venom resulted in full and partial prevention of the myotoxicity, respectively, indicating the lag period for irreversible cellular injury. This suggests that, although the antivenoms contain antibodies against cytotoxins of the Sri Lankan Naja naja venom, they are either unable to reach the target sites as efficiently as the cytotoxins, unable to bind efficiently with the toxins at the target sites, or the binding with the toxins simply fails to prevent the toxin-target interactions.

ACS Style

Umesha Madhushani; Prabhani Thakshila; Wayne Hodgson; Geoffrey Isbister; Anjana Silva. Effect of Indian Polyvalent Antivenom in the Prevention and Reversal of Local Myotoxicity Induced by Common Cobra (Naja naja) Venom from Sri Lanka In Vitro. Toxins 2021, 13, 308 .

AMA Style

Umesha Madhushani, Prabhani Thakshila, Wayne Hodgson, Geoffrey Isbister, Anjana Silva. Effect of Indian Polyvalent Antivenom in the Prevention and Reversal of Local Myotoxicity Induced by Common Cobra (Naja naja) Venom from Sri Lanka In Vitro. Toxins. 2021; 13 (5):308.

Chicago/Turabian Style

Umesha Madhushani; Prabhani Thakshila; Wayne Hodgson; Geoffrey Isbister; Anjana Silva. 2021. "Effect of Indian Polyvalent Antivenom in the Prevention and Reversal of Local Myotoxicity Induced by Common Cobra (Naja naja) Venom from Sri Lanka In Vitro." Toxins 13, no. 5: 308.

Research article
Published: 09 April 2021 in Clinical Toxicology
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Understanding the time course of venom exposure in snakebite patients is important for the optimisation of treatment including antivenom dose and timing. We aimed to investigate the pharmacokinetics of red-bellied black snake (RBBS; Pseudechis porphyriacus) venom in envenomed patients. Timed venom concentration data were obtained from patients with RBBS envenomation recruited to the Australian Snakebite Project (ASP), including demographics and antivenom treatment. Venom concentrations were measured using an enzyme immunoassay. Data were modelled using NONMEM version 7.3. Uncertainty in venom “dose” was accounted for by arbitrarily fixing the average amount to 1 mg and incorporating between-subject variability on relative bioavailability. A scale parameter for venom clearance was implemented to account for the rapid venom clearance following antivenom dosing. A sensitivity analysis was performed to determine the magnitude of venom clearance amplification. There were 457 venom concentrations in 114 patients (median age 41, 2–90 y; 80 male). Antivenom was administered to 54 patients a median of 4.2 h post-bite (0.67 to 32 h). A one-compartment model with first-order absorption and elimination provided the best description of the data. The estimated clearance and volume of distribution were 5.21 L/h and 39.9 L, respectively. The calculated elimination half-life of P. porphyriacus venom from the final pharmacokinetic model was 5.35 ± 0.36 h. The variability in the relative dose of injected venom was 140%. Antivenom administration increased venom clearance by 40-fold. Ten patients showed evidence of a double peak in the absorption profile. The information on the exposure time of venom in the body following envenomation will help improve treatment and the timing of antivenom.

ACS Style

Suchaya Sanhajariya; Stephen B. Duffull; Geoffrey K. Isbister. Population pharmacokinetics of Pseudechis porphyriacus (red-bellied black snake) venom in snakebite patients. Clinical Toxicology 2021, 1 -7.

AMA Style

Suchaya Sanhajariya, Stephen B. Duffull, Geoffrey K. Isbister. Population pharmacokinetics of Pseudechis porphyriacus (red-bellied black snake) venom in snakebite patients. Clinical Toxicology. 2021; ():1-7.

Chicago/Turabian Style

Suchaya Sanhajariya; Stephen B. Duffull; Geoffrey K. Isbister. 2021. "Population pharmacokinetics of Pseudechis porphyriacus (red-bellied black snake) venom in snakebite patients." Clinical Toxicology , no. : 1-7.

Brief report
Published: 18 February 2021 in Proceedings of the National Academy of Sciences
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Acid-sensing ion channels (ASICs) are expressed in the nervous system, activated by acidosis, and implicated in pain pathways. Mambalgins are peptide inhibitors of ASIC1 and analgesic in rodents via inhibition of centrally expressed ASIC1a and peripheral ASIC1b. This activity has generated interest in mambalgins as potential therapeutics. However, most mechanism and structure–activity relationship work on mambalgins has focused on ASIC1a, and neglected the peripheral analgesic target ASIC1b. Here, we compare mambalgin potency and mechanism of action at heterologously expressed rat and human ASIC1 variants. Unlike the nanomolar inhibition at ASIC1a and rodent ASIC1b, we find mambalgin-3 only weakly inhibits human ASIC1b and ASIC1b/3 under severe acidosis, but potentiates currents under mild/moderate acidosis. Our data highlight the importance of understanding the activity of potential ASIC-targeting pharmaceuticals at human channels.

ACS Style

Ben Cristofori-Armstrong; Elena Budusan; Lachlan D. Rash. Mambalgin-3 potentiates human acid-sensing ion channel 1b under mild to moderate acidosis: Implications as an analgesic lead. Proceedings of the National Academy of Sciences 2021, 118, 1 .

AMA Style

Ben Cristofori-Armstrong, Elena Budusan, Lachlan D. Rash. Mambalgin-3 potentiates human acid-sensing ion channel 1b under mild to moderate acidosis: Implications as an analgesic lead. Proceedings of the National Academy of Sciences. 2021; 118 (8):1.

Chicago/Turabian Style

Ben Cristofori-Armstrong; Elena Budusan; Lachlan D. Rash. 2021. "Mambalgin-3 potentiates human acid-sensing ion channel 1b under mild to moderate acidosis: Implications as an analgesic lead." Proceedings of the National Academy of Sciences 118, no. 8: 1.

Journal article
Published: 11 January 2021 in Toxins
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Bungarus multicinctus, the Chinese krait, is a highly venomous elapid snake which causes considerable morbidity and mortality in southern China. B. multicinctus venom contains pre-synaptic PLA2 neurotoxins (i.e., β-bungarotoxins) and post-synaptic neurotoxins (i.e., α-bungarotoxins). We examined the in vitro neurotoxicity of B. multicinctus venom, and the efficacy of specific monovalent Chinese B. multicinctus antivenom, and Australian polyvalent elapid snake antivenom, against venom-induced neurotoxicity. B. multicinctus venom (1–10 μg/mL) abolished indirect twitches in the chick biventer cervicis nerve-muscle preparation as well as attenuating contractile responses to exogenous ACh and CCh, but not KCl. This indicates a post-synaptic neurotoxic action but myotoxicity was not evident. Given that post-synaptic α-neurotoxins have a more rapid onset than pre-synaptic neurotoxins, the activity of the latter in the whole venom will be masked. The prior addition of Chinese B. multicinctus antivenom (12 U/mL) or Australian polyvalent snake antivenom (15 U/mL), markedly attenuated the neurotoxic actions of B. multicinctus venom (3 μg/mL) and prevented the inhibition of contractile responses to ACh and CCh. The addition of B. multicinctus antivenom (60 U/mL), or Australian polyvalent snake antivenom (50 U/mL), at the t90 time point after the addition of B. multicinctus venom (3 μg/mL), did not restore the twitch height over 180 min. The earlier addition of B. multicinctus antivenom (60 U/mL), at the t20 or t50 time points, also failed to prevent the neurotoxic effects of the venom but did delay the time to abolish twitches based on a comparison of t90 values. Repeated washing of the preparation with physiological salt solution, commencing at the t20 time point, failed to reverse the neurotoxic effects of venom or delay the time to abolish twitches. This study showed that B. multicinctus venom displays marked in vitro neurotoxicity in a skeletal muscle preparation which is not reversed by antivenom. This does not appear to be related to antivenom efficacy, but due to the irreversible/pseudo-irreversible nature of the neurotoxins.

ACS Style

Qing Liang; Tam Minh Huynh; Yen Zhi Ng; Geoffrey K. Isbister; Wayne C. Hodgson. In Vitro Neurotoxicity of Chinese Krait (Bungarus multicinctus) Venom and Neutralization by Antivenoms. Toxins 2021, 13, 49 .

AMA Style

Qing Liang, Tam Minh Huynh, Yen Zhi Ng, Geoffrey K. Isbister, Wayne C. Hodgson. In Vitro Neurotoxicity of Chinese Krait (Bungarus multicinctus) Venom and Neutralization by Antivenoms. Toxins. 2021; 13 (1):49.

Chicago/Turabian Style

Qing Liang; Tam Minh Huynh; Yen Zhi Ng; Geoffrey K. Isbister; Wayne C. Hodgson. 2021. "In Vitro Neurotoxicity of Chinese Krait (Bungarus multicinctus) Venom and Neutralization by Antivenoms." Toxins 13, no. 1: 49.

Review
Published: 08 December 2020 in PLOS Neglected Tropical Diseases
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Snakebite is a neglected tropical disease with significant morbidity and mortality. Thrombotic microangiopathy (TMA) is an important but poorly understood complication of snakebite associated with acute kidney injury (AKI). Numerous treatments have been attempted based on limited evidence. We conducted a systematic review of TMA following snakebite using a pre-determined case definition of blood film red cell schistocytes or histologically diagnosed TMA. The search strategy included major electronic databases and grey literature. We present a descriptive synthesis for the outcomes of AKI, dialysis free survival (DFS), other end-organ damage, overall survival, and interventions with antivenom and therapeutic plasmapheresis (TPE). This study was prospectively registered with PROSPERO (CRD42019121436). Seventy-two studies reporting 351 cases were included, predominantly small observational studies. Heterogeneity for study selection, design, reporting and outcomes were observed. The commonest envenoming species were hump-nosed vipers (Hypnale spp.), Russell’s viper (Daboia russelii) and Australian brown snakes (Pseudechis spp.). The prevalence of TMA was at least 5.4% in proven and probable Hypnale bites, and 10–15% of Australian elapid envenomings, AKI occurred in 94% (293/312) of TMA cases, excluding case reports. The majority of cases with AKI required dialysis. Included prospective and retrospective cohort studies reporting interventions and renal outcomes showed no evidence for benefit from antivenom or TPE with respect to DFS in dialysis dependant AKI. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment for quality of accumulated evidence for interventions was low. The major complication of TMA following snakebite is AKI. AKI improves in most cases. We found no evidence to support benefit from antivenom in snakebite associated TMA, but antivenom remains the standard of care for snake envenoming. There was no evidence for benefit of TPE in snakebite associated TMA, so TPE cannot be recommended. The quality of accumulated evidence was low, highlighting a need for high quality larger studies.

ACS Style

Tina Noutsos; Bart J. Currie; Rachel A. Lek; Geoffrey K. Isbister. Snakebite associated thrombotic microangiopathy: a systematic review of clinical features, outcomes, and evidence for interventions including plasmapheresis. PLOS Neglected Tropical Diseases 2020, 14, e0008936 .

AMA Style

Tina Noutsos, Bart J. Currie, Rachel A. Lek, Geoffrey K. Isbister. Snakebite associated thrombotic microangiopathy: a systematic review of clinical features, outcomes, and evidence for interventions including plasmapheresis. PLOS Neglected Tropical Diseases. 2020; 14 (12):e0008936.

Chicago/Turabian Style

Tina Noutsos; Bart J. Currie; Rachel A. Lek; Geoffrey K. Isbister. 2020. "Snakebite associated thrombotic microangiopathy: a systematic review of clinical features, outcomes, and evidence for interventions including plasmapheresis." PLOS Neglected Tropical Diseases 14, no. 12: e0008936.

Comment
Published: 08 December 2020 in Toxins
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We read with interest the article by Manuwar et al

ACS Style

Theo Tasoulis; Tara L. Pukala; Geoffrey K. Isbister. Comments on Proteomic Investigations of Two Pakistani Naja Snake Venoms Species Unravel the Venom Complexity, Posttranslational Modifications, and Presence of Extracellular Vesicles. Toxins 2020, 12, 669. Toxins 2020, 12, 780 .

AMA Style

Theo Tasoulis, Tara L. Pukala, Geoffrey K. Isbister. Comments on Proteomic Investigations of Two Pakistani Naja Snake Venoms Species Unravel the Venom Complexity, Posttranslational Modifications, and Presence of Extracellular Vesicles. Toxins 2020, 12, 669. Toxins. 2020; 12 (12):780.

Chicago/Turabian Style

Theo Tasoulis; Tara L. Pukala; Geoffrey K. Isbister. 2020. "Comments on Proteomic Investigations of Two Pakistani Naja Snake Venoms Species Unravel the Venom Complexity, Posttranslational Modifications, and Presence of Extracellular Vesicles. Toxins 2020, 12, 669." Toxins 12, no. 12: 780.

Research article
Published: 30 November 2020 in PLOS Neglected Tropical Diseases
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Delays in treatment seeking and antivenom administration remain problematic for snake envenoming. We aimed to describe the treatment seeking pattern and delays in admission to hospital and administration of antivenom in a cohort of authenticated snakebite patients. Adults (> 16 years), who presented with a confirmed snakebite from August 2013 to October 2014 were recruited from Anuradhapura Hospital. Demographic data, information on the circumstances of the bite, first aid, health-seeking behaviour, hospital admission, clinical features, outcomes and antivenom treatment were documented prospectively. There were 742 snakebite patients [median age: 40 years (IQR:27–51; males: 476 (64%)]. One hundred and five (14%) patients intentionally delayed treatment by a median of 45min (IQR:20-120min). Antivenom was administered a median of 230min (IQR:180–360min) post-bite, which didn’t differ between directly admitted and transferred patients; 21 (8%) receiving antivenom within 2h and 141 (55%) within 4h of the bite. However, transferred patients received antivenom sooner after admission to Anuradhapura hospital than those directly admitted (60min [IQR:30-120min] versus 120min [IQR:52-265min; p

ACS Style

Anjana Silva; Jiri Hlusicka; Nipuna Siribaddana; Subodha Waiddyanatha; Senaka Pilapitiya; Prasanna Weerawansa; Niroshan Lokunarangoda; Sujeewa Thalgaspitiya; Sisira Siribaddana; Geoffrey K. Isbister. Time delays in treatment of snakebite patients in rural Sri Lanka and the need for rapid diagnostic tests. PLOS Neglected Tropical Diseases 2020, 14, e0008914 .

AMA Style

Anjana Silva, Jiri Hlusicka, Nipuna Siribaddana, Subodha Waiddyanatha, Senaka Pilapitiya, Prasanna Weerawansa, Niroshan Lokunarangoda, Sujeewa Thalgaspitiya, Sisira Siribaddana, Geoffrey K. Isbister. Time delays in treatment of snakebite patients in rural Sri Lanka and the need for rapid diagnostic tests. PLOS Neglected Tropical Diseases. 2020; 14 (11):e0008914.

Chicago/Turabian Style

Anjana Silva; Jiri Hlusicka; Nipuna Siribaddana; Subodha Waiddyanatha; Senaka Pilapitiya; Prasanna Weerawansa; Niroshan Lokunarangoda; Sujeewa Thalgaspitiya; Sisira Siribaddana; Geoffrey K. Isbister. 2020. "Time delays in treatment of snakebite patients in rural Sri Lanka and the need for rapid diagnostic tests." PLOS Neglected Tropical Diseases 14, no. 11: e0008914.

Original research
Published: 17 November 2020 in Emergency Medicine Australasia
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Objective Rapidly and safely managing severe acute behavioural disturbance (ABD) in the prehospital setting is important for the welfare of both patient and prehospital clinician alike. We investigated the safety and effectiveness of ketamine as rescue sedation in patients with severe ABD. Methods This prospective observational study investigated ketamine use by a state ambulance service as rescue sedation for patients with severe ABD who remained agitated following droperidol administration. The primary outcome was the proportion of adverse events (vomiting, hypersalivation, emergence, over‐sedation, airway obstruction, laryngospasm, hypoxia, bradypnoea and intubation). Secondary outcomes included time to sedation, requirement for additional sedation and rate of successful sedation. Results There were 105 presentations (males 69/102 [69%]; median age 31 years (16–83 years). The commonest causes of ABD were illicit drug (39%) and alcohol (33%) intoxication. The median total dose of intramuscular ketamine was 200 mg (interquartile range [IQR] 150–200 mg). There were 64 adverse events in 40 (38%) patients. Four had vomiting, two had hypersalivation, two had emergence, 15 were oversedated, four had hypoxia, three had bradypnoea and 16 were intubated. Sedation was achieved in 103 (98%) patients at a median time post‐ketamine of 8 min (IQR 5–13 min). Additional sedation was administered to 41 patients (nine prehospital and 37 within 1 h of arriving to hospital). In 44 (42%) patients, ketamine successfully sedated the patient with no adverse effects and no ongoing sedation requirement. Conclusion The use of ketamine as rescue sedation in prehospital patients with severe ABD is effective. Adverse events are common but can be managed supportively.

ACS Style

Katherine Z Isoardi; Lachlan E Parker; Colin B Page; Michael A Humphreys; Keith Harris; Stephen Rashford; Geoffrey K Isbister. K etamine as a rescue treatment for severe acute behavioural disturbance : A prospective prehospital study. Emergency Medicine Australasia 2020, 33, 610 -614.

AMA Style

Katherine Z Isoardi, Lachlan E Parker, Colin B Page, Michael A Humphreys, Keith Harris, Stephen Rashford, Geoffrey K Isbister. K etamine as a rescue treatment for severe acute behavioural disturbance : A prospective prehospital study. Emergency Medicine Australasia. 2020; 33 (4):610-614.

Chicago/Turabian Style

Katherine Z Isoardi; Lachlan E Parker; Colin B Page; Michael A Humphreys; Keith Harris; Stephen Rashford; Geoffrey K Isbister. 2020. "K etamine as a rescue treatment for severe acute behavioural disturbance : A prospective prehospital study." Emergency Medicine Australasia 33, no. 4: 610-614.

Journal article
Published: 12 November 2020 in IUPHAR/BPS Guide to Pharmacology CITE
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Acid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [43, 2, 3]) are members of a Na+ channel superfamily that includes the epithelial Na+ channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabitis elegans, channels in Drosophila melanogaster and 'orphan' channels that include BLINaC [62] and INaC [64] that have also been named BASICs, for bile acid-activated ion channels [81]. ASIC subunits contain two TM domains and assemble as homo- or hetero-trimers [41, 38, 7] to form proton-gated, voltage-insensitive, Na+ permeable, channels that are activated by levels of acidosis occurring in both physiological and pathophysiological conditions with ASIC3 also playing a role in mechanosensation (reviewed in [40, 80, 43, 61, 21]) . Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [75], ASIC1b (ASICβ, BNaC2β) [17] and ASIC1b2 (ASICβ2) [70]; note that ASIC1a is also permeable to Ca2+] and ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [59, 76, 37] and ASIC2b (MDEG2, BNaC1β) [51]] have been cloned and differ in the first third of the protein. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H+-gated currents. A third member, ASIC3 (DRASIC, TNaC1) [74] is one of the most pH-sensitive isoforms (along with ASIC1a) and has the fastest activation and desensitisation kinetics, however can also carry small sustained currents. ASIC4 (SPASIC) evolved as a proton-sensitive channel but seems to have lost this function in mammals [52]. Mammalian ASIC4 does not support a proton-gated channel in heterologous expression systems but is reported to downregulate the expression of ASIC1a and ASIC3 [1, 39, 31, 49]. ASIC channels are primarily expressed in central (ASIC1a, -2a, 2b and -4) and peripheral neurons including nociceptors (ASIC1-3) where they participate in neuronal sensitivity to acidosis. They have also been detected in taste receptor cells (ASIC1-3)), photoreceptors and retinal cells (ASIC1-3), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and -3), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1-3), immune cells (ASIC1,-3 and -4) and bone (ASIC1-3) (ASIC distribution is well reviewed in [50, 25]). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [32, 45, 87], responses to focal ischemia [82] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [36], as well as seizures [88] and pain [80, 26, 27, 13, 29]. Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones [51, 5, 35, 11]. In general, the known small molecule inhibitors of ASICs are non-selective or partially selective, whereas the venom peptide inhibitors have substantially higher selectivity and potency. Several clinically used drugs are known to inhibit ASICs, however they are generally more potent at other targets (e.g. amiloride at ENaCs, ibuprofen at COX enzymes) [60, 56]. The information in the tables below are for the effects of inhibitors on homomeric channels, for information of known effect on heteromeric channels see the comments below.

ACS Style

Stephan Kellenberger; Lachlan D. Rash. Acid-sensing (proton-gated) ion channels (ASICs) (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database. IUPHAR/BPS Guide to Pharmacology CITE 2020, 2020, 1 .

AMA Style

Stephan Kellenberger, Lachlan D. Rash. Acid-sensing (proton-gated) ion channels (ASICs) (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database. IUPHAR/BPS Guide to Pharmacology CITE. 2020; 2020 (5):1.

Chicago/Turabian Style

Stephan Kellenberger; Lachlan D. Rash. 2020. "Acid-sensing (proton-gated) ion channels (ASICs) (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database." IUPHAR/BPS Guide to Pharmacology CITE 2020, no. 5: 1.

Short report
Published: 11 November 2020 in British Journal of Clinical Pharmacology
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Paracetamol‐induced hepatotoxicity is the leading cause of acute liver failure in many countries, including North America and the United Kingdom. Among the three dominant paracetamol metabolism pathways (i.e. glucuronidation, sulfation and oxidation), the importance of sulfation is often underestimated because of the general thinking that the sulfation pathway is saturated at therapeutic doses and ultimately accounts for a limited proportion of the fate of a paracetamol dose. We illustrate that insufficient sulfation leads to a shift in biotransformation of paracetamol to toxic oxidation pathways and patients with low sulfate reserves are at higher risk of paracetamol toxicity. Here, we propose that sulfation is of critical importance in understanding the risk of liver toxicity secondary to paracetamol overdose. Serum inorganic sulfate, a measurable substrate on the causal path of paracetamol‐induced liver toxicity, should be considered a biomarker for potential toxicity as well as a target for treatment.

ACS Style

Jingyun Li; Angela L. Chiew; Geoffrey K. Isbister; Stephen B. Duffull. Sulfate conjugation may be the key to hepatotoxicity in paracetamol overdose. British Journal of Clinical Pharmacology 2020, 87, 2392 -2396.

AMA Style

Jingyun Li, Angela L. Chiew, Geoffrey K. Isbister, Stephen B. Duffull. Sulfate conjugation may be the key to hepatotoxicity in paracetamol overdose. British Journal of Clinical Pharmacology. 2020; 87 (5):2392-2396.

Chicago/Turabian Style

Jingyun Li; Angela L. Chiew; Geoffrey K. Isbister; Stephen B. Duffull. 2020. "Sulfate conjugation may be the key to hepatotoxicity in paracetamol overdose." British Journal of Clinical Pharmacology 87, no. 5: 2392-2396.

Journal article
Published: 06 November 2020 in Clinical Toxicology
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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.

ACS Style

Christopher I. Johnston; Geoffrey K. Isbister. Australian snakebite myotoxicity (ASP-23). Clinical Toxicology 2020, 1 -8.

AMA Style

Christopher I. Johnston, Geoffrey K. Isbister. Australian snakebite myotoxicity (ASP-23). Clinical Toxicology. 2020; ():1-8.

Chicago/Turabian Style

Christopher I. Johnston; Geoffrey K. Isbister. 2020. "Australian snakebite myotoxicity (ASP-23)." Clinical Toxicology , no. : 1-8.

Journal article
Published: 31 October 2020 in Toxins
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Coastal taipan (Oxyuranus scutellatus) envenoming causes life-threatening neuromuscular paralysis in humans. We studied the time period during which antivenom remains effective in preventing and arresting in vitro neuromuscular block caused by taipan venom and taipoxin. Venom showed predominant pre-synaptic neurotoxicity at 3 µg/mL and post-synaptic neurotoxicity at 10 µg/mL. Pre-synaptic neurotoxicity was prevented by addition of Australian polyvalent antivenom before the venom and taipoxin and, reversed when antivenom was added 5 min after venom and taipoxin. Antivenom only partially reversed the neurotoxicity when added 15 min after venom and had no significant effect when added 30 min after venom. In contrast, post-synaptic activity was fully reversed when antivenom was added 30 min after venom. The effect of antivenom on pre-synaptic neuromuscular block was reproduced by washing the bath at similar time intervals for 3 µg/mL, but not for 10 µg/mL. We found an approximate 10–15 min time window in which antivenom can prevent pre-synaptic neuromuscular block. This time window is likely to be longer in envenomed patients due to the delay in venom absorption. Similar effectiveness of antivenom and washing with 3 µg/mL venom suggests that antivenom most likely acts by neutralizing pre-synaptic toxins before they interfere with neurotransmission inside the motor nerve terminals.

ACS Style

Umesha Madhushani; Geoffrey K. Isbister; Theo Tasoulis; Wayne C. Hodgson; Anjana Silva. In-Vitro Neutralization of the Neurotoxicity of Coastal Taipan Venom by Australian Polyvalent Antivenom: The Window of Opportunity. Toxins 2020, 12, 690 .

AMA Style

Umesha Madhushani, Geoffrey K. Isbister, Theo Tasoulis, Wayne C. Hodgson, Anjana Silva. In-Vitro Neutralization of the Neurotoxicity of Coastal Taipan Venom by Australian Polyvalent Antivenom: The Window of Opportunity. Toxins. 2020; 12 (11):690.

Chicago/Turabian Style

Umesha Madhushani; Geoffrey K. Isbister; Theo Tasoulis; Wayne C. Hodgson; Anjana Silva. 2020. "In-Vitro Neutralization of the Neurotoxicity of Coastal Taipan Venom by Australian Polyvalent Antivenom: The Window of Opportunity." Toxins 12, no. 11: 690.

Journal article
Published: 29 October 2020 in Biomedicines
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Early diagnosis of snake envenomation is essential, especially neurotoxicity and myotoxicity. We investigated the diagnostic value of serum phospholipase (PLA2) in Australian snakebites. In total, 115 envenomated and 80 non-envenomated patients were recruited over 2 years, in which an early blood sample was available pre-antivenom. Serum samples were analyzed for secretory PLA2 activity using a Cayman sPLA2 assay kit (#765001 Cayman Chemical Company, Ann Arbor MI, USA). Venom concentrations were measured for snake identification using venom-specific enzyme immunoassay. The most common snakes were Pseudonaja spp. (33), Notechis scutatus (24), Pseudechis porphyriacus (19) and Tropidechis carinatus (17). There was a significant difference in median PLA2 activity between non-envenomated (9 nmol/min/mL; IQR: 7–11) and envenomated patients (19 nmol/min/mL; IQR: 10–66, p < 0.0001) but Pseudonaja spp. were not different to non-envenomated. There was a significant correlation between venom concentrations and PLA2 activity (r = 0.71; p < 0.0001). PLA2 activity was predictive for envenomation; area under the receiver-operating-characteristic curve (AUC-ROC), 0.79 (95% confidence intervals [95%CI]: 0.72–0.85), which improved with brown snakes excluded, AUC-ROC, 0.88 (95%CI: 0.82–0.94). A cut-point of 16 nmol/min/mL gives a sensitivity of 72% and specificity of 100% for Australian snakes, excluding Pseudonaja. PLA2 activity was a good early predictor of envenomation in most Australian elapid bites. A bedside PLA2 activity test has potential utility for early case identification but may not be useful for excluding envenomation.

ACS Style

Geoffrey Isbister; Nandita Mirajkar; Kellie Fakes; Simon Brown; Punnam Veerati. Phospholipase A2 (PLA2) as an Early Indicator of Envenomation in Australian Elapid Snakebites (ASP-27). Biomedicines 2020, 8, 459 .

AMA Style

Geoffrey Isbister, Nandita Mirajkar, Kellie Fakes, Simon Brown, Punnam Veerati. Phospholipase A2 (PLA2) as an Early Indicator of Envenomation in Australian Elapid Snakebites (ASP-27). Biomedicines. 2020; 8 (11):459.

Chicago/Turabian Style

Geoffrey Isbister; Nandita Mirajkar; Kellie Fakes; Simon Brown; Punnam Veerati. 2020. "Phospholipase A2 (PLA2) as an Early Indicator of Envenomation in Australian Elapid Snakebites (ASP-27)." Biomedicines 8, no. 11: 459.

Journal article
Published: 06 October 2020 in Clinical Toxicology
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Amlodipine, a dihydropyridine calcium channel blocker (CCB), is the leading cause of cardiovascular drug-related overdose deaths in the USA. In contrast, angiotensin-II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) cause minimal toxicity in overdose. ACEIs/ARBs are often combined with dihydropyridines in hypertension treatment. Co-ingested ARBs/ACEIs may significantly contribute to the toxicity of dihydropyridine, but this has not been investigated. To investigate the clinical outcomes from dihydropyridine overdoses with ARBs/ACEIs versus dihydropyridine overdoses alone. This was a retrospective study of patients reported to the New South Wales Poisons Information Centre (NSW PIC) and 3 toxicology units (Jan 2016 to Jun 2019) in Australia. Patients >14 years who took an overdose of dihydropyridines (amlodipine, felodipine, lercanidipine, nifedipine) were included. Concurrent overdoses with non-dihydropyridine CCBs, alpha-blockers and beta-blockers were excluded. Patient demographics, drugs exposure details, serial vital signs, treatments and outcome were collected. There were 100 patients. 68 took mixed overdoses of dihydropyridines with ARBs/ACEIs and 32 took single overdoses of dihydropyridines without ARBs/ACEIs. The mixed group had lower median nadir mean arterial pressures (62 vs 75 mmHg, p < 0.001), more frequently had hypotension (OR 4.5, 95%CI: 1.7-11.9) or bradycardia (OR 8.8, 95%CI: 1.1-70). Multivariable analysis indicated the mixed overdoses had an 11.5 mmHg (95%CI: 4.9-18.1) lower minimum systolic blood pressure (SBP) compared with the single group; other factors associated with a lower minimum SBP were higher doses [2.3 mmHg (95%CI: 1.1-3.5) lower per 10 defined daily doses] and younger age [2.2 mmHg (95%CI: 0.3-4.2) higher per decade]. A larger proportion of the mixed ingestion group received intravenous fluids (OR 5.7, 95%CI: 1.8-18.6) and antidotes and/or vasopressors (OR 2.9, 95%CI: 1.004-8.6). Combined overdoses of dihydropyridines with ARBs/ACEIs caused more significant hypotension and required more haemodynamic support than overdoses of dihydropyridines alone.

ACS Style

Jessica Huang; Nicholas A. Buckley; Katherine Z. Isoardi; Angela L. Chiew; Geoffrey K. Isbister; Rose Cairns; Jared A. Brown; Betty S. Chan. Angiotensin axis antagonists increase the incidence of haemodynamic instability in dihydropyridine calcium channel blocker poisoning. Clinical Toxicology 2020, 59, 464 -471.

AMA Style

Jessica Huang, Nicholas A. Buckley, Katherine Z. Isoardi, Angela L. Chiew, Geoffrey K. Isbister, Rose Cairns, Jared A. Brown, Betty S. Chan. Angiotensin axis antagonists increase the incidence of haemodynamic instability in dihydropyridine calcium channel blocker poisoning. Clinical Toxicology. 2020; 59 (6):464-471.

Chicago/Turabian Style

Jessica Huang; Nicholas A. Buckley; Katherine Z. Isoardi; Angela L. Chiew; Geoffrey K. Isbister; Rose Cairns; Jared A. Brown; Betty S. Chan. 2020. "Angiotensin axis antagonists increase the incidence of haemodynamic instability in dihydropyridine calcium channel blocker poisoning." Clinical Toxicology 59, no. 6: 464-471.

Journal article
Published: 25 September 2020 in Biomedicines
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The Chinese Cobra (Naja atra) is an elapid snake of major medical importance in southern China. We describe the in vitro neurotoxic, myotoxic, and cytotoxic effects of N. atra venom, as well as examining the efficacy of three Chinese monovalent antivenoms (N. atra antivenom, Gloydius brevicaudus antivenom and Deinagkistrodon acutus antivenom) and an Australian polyvalent snake antivenom. In the chick biventer cervicis nerve-muscle preparation, N. atra venom (1–10 µg/mL) abolished indirect twitches in a concentration-dependent manner, as well as abolishing contractile responses to exogenous acetylcholine chloride (ACh) and carbamylcholine chloride (CCh), indicative of post-synaptic neurotoxicity. Contractile responses to potassium chloride (KCl) were also significantly inhibited by venom indicating myotoxicity. The prior addition of Chinese N. atra antivenom (0.75 U/mL) or Australian polyvalent snake antivenom (3 U/mL), markedly attenuated the neurotoxic actions of venom (3 µg/mL) and prevented the inhibition of contractile responses to ACh, CCh, and KCl. The addition of Chinese antivenom (0.75 U/mL) or Australian polyvalent antivenom (3 U/mL) at the t90 time point after the addition of venom (3 µg/mL), partially reversed the inhibition of twitches and significantly reversed the venom-induced inhibition of responses to ACh and CCh, but had no significant effect on the response to KCl. Venom (30 µg/mL) also abolished direct twitches in the chick biventer cervicis nerve-muscle preparation and caused a significant increase in baseline tension, further indicative of myotoxicity. N. atra antivenom (4 U/mL) prevented the myotoxic effects of venom (30 µg/mL). However, G. brevicaudus antivenom (24 U/mL), D. acutus antivenom (8 U/mL) and Australian polyvalent snake antivenom (33 U/mL) were unable to prevent venom (30 µg/mL) induced myotoxicity. In the L6 rat skeletal muscle myoblast cell line, N. atra venom caused concentration-dependent inhibition of cell viability, with a half maximal inhibitory concentration (IC50) of 2.8 ± 0.48 μg/mL. N. atra antivenom significantly attenuated the cytotoxic effect of the venom, whereas Australian polyvalent snake antivenom was less effective but still attenuated the cytotoxic effects at lower venom concentrations. Neither G. brevicaudus antivenom or D. acutus antivenom were able to prevent the cytotoxicity. This study indicates that Chinese N. atra monovalent antivenom is efficacious against the neurotoxic, myotoxic and cytotoxic effects of N. atra venom but the clinical effectiveness of the antivenom is likely to be diminished, even if given early after envenoming. The use of Chinese viper antivenoms (i.e., G. brevicaudus and D. acutus antivenoms) in cases of envenoming by the Chinese cobra is not supported by the results of the current study.

ACS Style

Qing Liang; Tam Minh Huynh; Nicki Konstantakopoulos; Geoffrey K. Isbister; Wayne C. Hodgson. An Examination of the Neutralization of In Vitro Toxicity of Chinese Cobra (Naja atra) Venom by Different Antivenoms. Biomedicines 2020, 8, 377 .

AMA Style

Qing Liang, Tam Minh Huynh, Nicki Konstantakopoulos, Geoffrey K. Isbister, Wayne C. Hodgson. An Examination of the Neutralization of In Vitro Toxicity of Chinese Cobra (Naja atra) Venom by Different Antivenoms. Biomedicines. 2020; 8 (10):377.

Chicago/Turabian Style

Qing Liang; Tam Minh Huynh; Nicki Konstantakopoulos; Geoffrey K. Isbister; Wayne C. Hodgson. 2020. "An Examination of the Neutralization of In Vitro Toxicity of Chinese Cobra (Naja atra) Venom by Different Antivenoms." Biomedicines 8, no. 10: 377.