Antivenoms for the treatment of spider envenomation

There are several groups of medically important araneomorph and mygalomorph spiders responsible for serious systemic envenomation. These include spiders from the genus Latrodectus (family Theridiidae), Phoneutria (family Ctenidae) and the subfamily Atracinae (genera Atrax and Hadronyche). The venom of these spiders contains potent neurotoxins that cause excessive neurotransmitter release via vesicle exocytosis or modulation of voltage-gated sodium channels. In addition, spiders of the genus Loxosceles (family Loxoscelidae) are responsible for significant local reactions resulting in necrotic cutaneous lesions. This results from sphingomyelinase D activity and possibly other compounds. A number of antivenoms are currently available to treat envenomation resulting from the bite of these spiders. Particularly efficacious antivenoms are available for Latrodectus and Atrax/Hadronyche species, with extensive cross-reactivity within each genera. In the case of Latrodectus antivenoms this is of considerable importance in countries where antivenom is unavailable or where certain antivenoms are associated with an unacceptably high risk of adverse reactions. Moreover, Latrodectus and Atrax antivenoms appear to be effective in the treatment of envenomation by closely related Steatoda spiders (family Theridiidae) or the unrelated spider Missulena bradleyi (family Actinopodidae), respectively. The effectiveness of Loxosceles antivenom in the treatment of the necrotic arachnidism resulting from the bite of recluse spiders is less clear mainly due to late presentation of victims. Antivenom is also available for Phoneutria envenomation but is reserved only for severe cases

Arachnid toxinology in Australia: From clinical toxicology to potential applications

The unique geographic isolation of Australia has resulted in the evolution of a distinctive range of Australian arachnid fauna. Through the pioneering work of a number of Australian arachnologists, toxinologists, and clinicians, the taxonomy and distribution of new species, the effective clinical treatment of envenomation, and the isolation and characterisation of the many distinctive neurotoxins, has been achieved. In particular, work has focussed on several Australian arachnids, including red-back and funnel-web spiders, paralysis ticks, and buthid scorpions that contain neurotoxins capable of causing death or serious systemic envenomation. In the case of spiders, species-specific antivenoms have been developed to treat envenomed patients that show considerable cross-reactivity. Both in vitro and clinical case studies have shown they are particularly efficacious in the treatment of envenomation by spiders even from unrelated families. Despite their notorious reputation, the high selectivity and potency of a unique range of toxins from the venom of Australian arachnids will make them invaluable molecular tools for studies of neurotransmitter release and vesicle exocytosis as well as ion channel structure and function. The venoms of funnel-web spiders, and more recently Australian scorpions, have also provided a previously untapped rich source of insect-selective neurotoxins for the future development of biopesticides and the characterisation of previously unvalidated insecticide targets. This review provides a historical viewpoint of the work of many toxinologists to isolate and characterise just some of the toxins produced by such a unique group of arachnids and examines the potential applications of these novel peptides. © 2006 Elsevier Ltd. All rights reserved

α-Elapitoxin-Aa2a, a long-chain snake α-neurotoxin with potent actions on muscle (α1)<inf>2</inf>βγδ nicotinic receptors, lacks the classical high affinity for neuronal α7 nicotinic receptors

In contrast to all classical long-chain α-neurotoxins possessing the critical fifth disulfide bond, α-elapitoxin-Aa2a (α-EPTX-Aa2a), a novel long-chain α-neurotoxin from the common death adder Acanthophis antarcticus, lacks affinity for neuronal α7-type nicotinic acetylcholine receptors (nAChRs) α-EPTX-Aa2a (8850 Da; 0.1-1 μM) caused a concentration-dependent inhibition of indirect twitches, and blocked contractures to cholinergic agonists in the isolated chick biventer cervicis nerve-muscle preparation, consistent with a postsynaptic curaremimetic mode of action. α-EPTX-Aa2a (1-10 nM) produced a potent pseudo-irreversible antagonism of chick muscle nAChRs, with an estimated pA2 value of 8.311 ± 0.031, which was not reversed by monovalent death adder antivenom. This is only 2.5-fold less potent than the prototypical long-chain α-neurotoxin, α-bungarotoxin. In contrast, α-EPTX-Aa2a produced complete, but weak, inhibition of 125I-α-bungarotoxin binding to rat hippocampal α7 nAChRs (pKI = 3.670), despite high sequence homology and similar mass to a wide range of long-chain α-neurotoxins. The mostly likely cause for the loss of α7 binding affinity is a leucine substitution, in loop II of α-EPTX-Aa2a, for the highly conserved Arg33 in long-chain α-neurotoxins. Arg 33 has been shown to be critical for both neuronal and muscle activity. Despite this substitution, α-EPTX-Aa2a retains high affinity for muscle (α1)2βγδ nAChRs. This is probably as a result of an Arg29 residue, previously shown to be critical for muscle (α1)2βγδ nAChR affinity, and highly conserved across all short-chain, but not long-chain, α-neurotoxins. α-EPTX-Aa2a therefore represents a novel atypical long-chain α-neurotoxin that includes a fifth disulfide but exhibits differential affinity for nAChR subtypes. Copyright © 2010 Published by Elsevier Inc. All rights reserved

Characteristics of frequent emergency department presenters to an Australian emergency medicine network

<p>Abstract</p> <p>Background</p> <p>To describe the characteristics of emergency department (ED) patients defined as frequent presenters (FP) presenting to an Australian emergency department network and compare these with a cohort of non-frequent presenters (NFP).</p> <p>Method</p> <p>A retrospective chart review utilising an electronic emergency medicine patient medical record database was performed on patients presenting to Southern Health EDs from March 2009 to March 2010. Non-frequent presenters were defined as patients presenting less than 5 times and frequent presenters as presenting 8 or more times in the study period. Characteristics of both groups were described and compared.</p> <p>Results</p> <p>During the 12-month study period there were 540 FP patients with 4549 admissions and 73,089 NFP patients with 100,943 admissions. FP patients were slightly older with a significant increase in frequency of patients between the ages of 70 to 79 years and they were more likely to be divorced or separated than NFP patients. Frequent presenters to the emergency department were more likely to utilise the ambulance service to arrive at the hospital, or in the custody of police than NFP patients. FPs were more likely to be admitted to hospital, more likely to have an admission to a mental health bed than NFP patients and more likely to self-discharge from the emergency department while waiting for care.</p> <p>Conclusions</p> <p>There are major implications for the utilisation of limited ED resources by frequent presenters. By further understanding the characteristics of FP we may be able to address the specific health care needs of this population in more efficient and cost effective ways. Further research analysing the effectiveness of targeted multidisciplinary interventions aiming to reduce the frequency of ED attendances may be warranted.</p

A retrospective descriptive study of the characteristics of deliberate self-poisoning patients with single or repeat presentations to an Australian emergency medicine network in a one year period

Background - A proportion of deliberate self-poisoning (DSP) patients present repeatedly to the emergency department (ED). Understanding the characteristics of frequent DSP patients and their presentation is a first step to implementing interventions that are designed to prevent repeated self-poisoning. Methods - All DSP presentations to three networked Australian ED’s were retrospectively identified from the ED electronic medical record and hospital scanned medical records for 2011. Demographics, types of drugs ingested, emergency department length of stay and disposition for the repeat DSP presenters were extracted and compared to those who presented once with DSP in a one year period. Logistic regression was used to analyse repeat versus single DSP data. Results - The study determined 755 single presenters and 93 repeat DSP presenters. The repeat presenters contributed to 321 DSP presentations. They were more likely to be unemployed (61.0% versus 39.9%, p = 0.008) and have a psychiatric illness compared to single presenters (36.6% versus 15.5%, p < 0.001). Repeat presenters were less likely to receive a toxicology consultation (11.5% versus 27.3%, p < 0.001) and were more likely to abscond from the ED (7.5% versus 3.4%, p = 0.004). Repeat presenters were more likely to ingest paracetamol and antipsychotics than single presenters. The defined daily dose for the most common antipsychotic ingested, quetiapine, was less in the repeat presenter group (median 1.9 [IQR: 1.3-3.5]) compared with the single presenter group (4 [1.4-9.5]), (OR 0.85, 95% CI 0.74-0.99). Conclusion - Patients who present repeatedly to the ED with DSP have pre-existing disadvantages, with increased likelihood of being unemployed and having a mental illness. These patients are also more likely to have health service inequities given the greater likelihood to abscond from the ED and lower likelihood of receiving toxicology consultation for their DSP. Early recognition of repeat DSP patients in the ED may facilitate the development of individualised care plans with the aim to reduce repeat episodes of self-poisoning and subsequent risk of successful suicide

Gastrointestinal decontamination in the acutely poisoned patient

ObjectiveTo define the role of gastrointestinal (GI) decontamination of the poisoned patient.Data sourcesA computer-based PubMed/MEDLINE search of the literature on GI decontamination in the poisoned patient with cross referencing of sources.Study selection and data extractionClinical, animal and in vitro studies were reviewed for clinical relevance to GI decontamination of the poisoned patient.Data synthesisThe literature suggests that previously, widely used, aggressive approaches including the use of ipecac syrup, gastric lavage, and cathartics are now rarely recommended. Whole bowel irrigation is still often recommended for slow-release drugs, metals, and patients who "pack" or "stuff" foreign bodies filled with drugs of abuse, but with little quality data to support it. Activated charcoal (AC), single or multiple doses, was also a previous mainstay of GI decontamination, but the utility of AC is now recognized to be limited and more time dependent than previously practiced. These recommendations have resulted in several treatment guidelines that are mostly based on retrospective analysis, animal studies or small case series, and rarely based on randomized clinical trials.ConclusionsThe current literature supports limited use of GI decontamination of the poisoned patient

Spider-Venom Peptides as Bioinsecticides

Over 10,000 arthropod species are currently considered to be pest organisms. They are estimated to contribute to the destruction of ~14% of the world’s annual crop production and transmit many pathogens. Presently, arthropod pests of agricultural and health significance are controlled predominantly through the use of chemical insecticides. Unfortunately, the widespread use of these agrochemicals has resulted in genetic selection pressure that has led to the development of insecticide-resistant arthropods, as well as concerns over human health and the environment. Bioinsecticides represent a new generation of insecticides that utilise organisms or their derivatives (e.g., transgenic plants, recombinant baculoviruses, toxin-fusion proteins and peptidomimetics) and show promise as environmentally-friendly alternatives to conventional agrochemicals. Spider-venom peptides are now being investigated as potential sources of bioinsecticides. With an estimated 100,000 species, spiders are one of the most successful arthropod predators. Their venom has proven to be a rich source of hyperstable insecticidal mini-proteins that cause insect paralysis or lethality through the modulation of ion channels, receptors and enzymes. Many newly characterized insecticidal spider toxins target novel sites in insects. Here we review the structure and pharmacology of these toxins and discuss the potential of this vast peptide library for the discovery of novel bioinsecticides

Spiders of medical importance in the Asia-Pacific: Atracotoxin, latrotoxin and related spider neurotoxins

1. The spiders of medical importance in the Asia-Pacific region include widow (family Theridiidae) and Australian funnel-web spiders (subfamily Atracinae). In addition, cupboard (family Theridiidae) and Australian mouse spiders (family Actinopodidae) may contain neurotoxins responsible for serious systemic envenomation. Fortunately, there appears to be extensive cross-reactivity of species-specific widow spider antivenom within the family Theridiidae. Moreover, Sydney funnel-web antivenom has been shown to be effective in the treatment of mouse spider envenomation. 2. α-Latrotoxin (α-LTx) appears to be the main neurotoxin responsible for the envenomation syndrome known as 'latrodectism' following bites from widow spiders. This 120 kDa protein binds to distinct receptors (latrophilin 1 and neurexins) to induce neurotransmitter vesicle exocytosis via both Ca2+-dependent and -independent mechanisms, resulting in vesicle depletion. This appears to involve disruption to a process that normally inhibits vesicle fusion in the absence of Ca2+. Precise elucidation of the mechanism of action of α-LTx will lead to a major advancement in our understanding of vesicle exocytosis. 3. δ-Atracotoxins (δ-ACTX) are responsible for the primate-specific envenomation syndrome seen following funnel-web spider envenomation. These peptides induce spontaneous repetitive firing and prolongation of action potentials in excitable cells. This results from a hyperpolarizing shift of the voltage-dependence of activation and a slowing of voltage-gated Na+ channel inactivation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 on insect and mammalian voltage-gated Na+ channels in a manner similar, but not identical, to scorpion α-toxins and sea anemone toxins. δ-Atracotoxins provide us with highly specific tools to study Na+ channel structure and function. 4. ω- and Janus-faced ACTX, from funnel-web spider venom, are novel neurotoxins that show selective toxicity to insects. In particular ω-ACTX define a new insecticide target due to a specific action to block insect voltage-gated Ca2+ channels. Both these ACTX show promise for the development of baculoviral recombinant biopesticides expressing these toxins for the control of insecticide-resistant agricultural pests. In addition, they should provide valuable tools for the pharmacological and structural characterization of insecticide targets