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      Treatments for Latrodectism—A Systematic Review on Their Clinical Effectiveness

      review-article
      1 , * , 2 , 3
      Toxins
      MDPI
      red-back spider, widow spider, envenomation, antivenom, treatment

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          Abstract

          Latrodectism or envenomation by widow-spiders is common and clinically significant worldwide. Alpha-latrotoxin is the mammalian-specific toxin in the venom that results in toxic effects observed in humans. Symptoms may be incapacitating and include severe pain that can persist for days. The management of mild to moderate latrodectism is primarily supportive while severe cases have variously been treated with intravenous calcium, muscle relaxants, widow-spider antivenom and analgesic opioids. The object of this systematic review is to examine the literature on the clinical effectiveness of past and current treatments for latrodectism. MEDLINE, EMBASE and Google Scholar were searched from 1946 to December 2016 to identify clinical studies on the treatment of latrodectism. Studies older than 40 years and not in English were not reviewed. There were only two full-publications and one abstract of placebo-controlled randomised trials on antivenom use for latrodectism. Another two randomised comparative trials compared the route of administration of antivenom for latrodectism. There were fourteen case series (including two abstracts), fourteen case reports and one letter investigating drug treatments for latrodectism with the majority of these also including antivenom for severe latrodectism. Antivenom with opioid analgesia is often the major treatment reported for latrodectism however; recent high quality evidence has cast doubt on the clinical effectiveness of this combination and suggests that other treatments need to be investigated.

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          Most cited references58

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          Validation of a verbally administered numerical rating scale of acute pain for use in the emergency department.

          Verbally administered numerical rating scales (NRSs) from 0 to 10 are often used to measure pain, but they have not been validated in the emergency department (ED) setting. The authors wished to assess the comparability of the NRS and visual analog scale (VAS) as measures of acute pain, and to identify the minimum clinically significant difference in pain that could be detected on the NRS. This was a prospective cohort study of a convenience sample of adults presenting with acute pain to an urban ED. Patients verbally rated pain intensity as an integer from 0 to 10 (0 = no pain, 10 = worst possible pain), and marked a 10-cm horizontal VAS bounded by these descriptors. VAS and NRS data were obtained at presentation, 30 minutes later, and 60 minutes later. At 30 and 60 minutes, patients were asked whether their pain was "much less," "a little less," "about the same," "a little more," or "much more." Differences between consecutive pairs of measurements on the VAS and NRS obtained at 30-minute intervals were calculated for each of the five categories of pain descriptor. The association between VAS and NRS scores was expressed as a correlation coefficient. The VAS scores were regressed on the NRS scores in order to assess the equivalence of the measures. The mean changes associated with descriptors "a little less" or "a little more" were combined to define the minimum clinically significant difference in pain measured on the VAS and NRS. Of 108 patients entered, 103 provided data at 30 minutes and 86 at 60 minutes. NRS scores were strongly correlated to VAS scores at all time periods (r = 0.94, 95% CI = 0.93 to 0.95). The slope of the regression line was 1.01 (95% CI = 0.97 to 1.06) and the y-intercept was -0.34 (95% CI = -0.67 to -0.01). The minimum clinically significant difference in pain was 1.3 (95% CI = 1.0 to 1.5) on the NRS and 1.4 (95% CI = 1.1 to 1.7) on the VAS. The findings suggest that the verbally administered NRS can be substituted for the VAS in acute pain measurement.
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            Alpha-latrotoxin receptor, latrophilin, is a novel member of the secretin family of G protein-coupled receptors.

            alpha-Latrotoxin (LTX) stimulates massive exocytosis of synaptic vesicles and may help to elucidate the mechanism of regulation of neurosecretion. We have recently isolated latrophilin, the synaptic Ca2+-independent LTX receptor. Now we demonstrate that latrophilin is a novel member of the secretin family of G protein-coupled receptors that are involved in secretion. Northern blot analysis shows that latrophilin message is present only in neuronal tissue. Upon expression in COS cells, the cloned protein is indistinguishable from brain latrophilin and binds LTX with high affinity. Latrophilin physically interacts with a Galphao subunit of heterotrimeric G proteins, because the two proteins co-purify in a two-step affinity chromatography. Interestingly, extracellular domain of latrophilin is homologous to olfactomedin, a soluble neuronal protein thought to participate in odorant binding. Our findings suggest that latrophilin may bind unidentified endogenous ligands and transduce signals into nerve terminals, thus implicating G proteins in the control of synaptic vesicle exocytosis.
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              Pharmacokinetic-pharmacodynamic relationships of immunoglobulin therapy for envenomation.

              Parenteral administration of horse- and sheep-derived antivenoms constitutes the cornerstone in the therapy of envenomations induced by animal bites and stings. Depending on the type of neutralising molecule, antivenoms are made of: (i) whole IgG molecules (150 kDa), (ii) F(ab')(2) immunoglobulin fragments (100 kDa) or (iii) Fab immunoglobulin fragments (50 kDa). Because of their variable molecular mass, these three types of antivenoms have different pharmacokinetic profiles. Fab fragments have the largest volume of distribution and readily reach extravascular compartments. They are catabolised mainly by the kidney, having a more rapid clearance than F(ab')(2) fragments and IgG. On the other hand, IgG molecules have a lower volume of distribution and a longer elimination half-life, showing the highest cycling through the interstitial spaces in the body. IgG elimination occurs mainly by extrarenal mechanisms. F(ab')(2) fragments display a pharmacokinetic profile intermediate between those of Fab fragments and IgG molecules. Such diverse pharmacokinetic properties have implications for the pharmacodynamics of these immunobiologicals, since a pronounced mismatch has been described between the pharmacokinetics of venoms and antivenoms. Some venoms, such as those of scorpions and elapid snakes, are rich in low-molecular-mass neurotoxins of high diffusibility and large volume of distribution that reach their tissue targets rapidly after injection. In contrast, venoms rich in high-molecular-mass toxins, such as those of viperid snakes, have a pharmacokinetic profile characterised by a rapid initial absorption followed by a slow absorption process from the site of venom injection. Such delayed absorption has been linked with recurrence of envenomation when antibody levels in blood decrease. This heterogeneity in pharmacokinetics and mechanism of action of venom components requires a detailed analysis of each venom-antivenom system in order to determine the most appropriate type of neutralising molecule for each particular venom. Besides having a high affinity for toxicologically relevant venom components, an ideal antivenom should possess a volume of distribution as similar as possible to that of the toxins being neutralised. Moreover, high levels of neutralising antibodies should remain in blood for a relatively prolonged time to assure neutralisation of toxins reaching the bloodstream later in the course of envenomation, and to promote redistribution of toxins from extravascular compartments to blood. Additional studies are required on different venoms and antivenoms in order to further understand the pharmacokinetic-pharmacodynamic relationships of antibodies and their fragments and to optimise the immunotherapy of envenomations.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Toxins (Basel)
                Toxins (Basel)
                toxins
                Toxins
                MDPI
                2072-6651
                21 April 2017
                April 2017
                : 9
                : 4
                : 148
                Affiliations
                [1 ]Clinical Toxicology Research Group, School of Medicine and Public Health, The University of Newcastle, Newcastle 2298, Australia
                [2 ]Sydney Medical School, University of Sydney, Sydney 2006, Australia; nicholas.buckley@ 123456sydney.edu.au
                [3 ]Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne 3800, Australia; Andis.Graudins@ 123456monashhealth.org
                Author notes
                [* ]Correspondence: Nicole.Ryan@ 123456newcastle.edu.au ; Tel.: +61-249-211-312
                Article
                toxins-09-00148
                10.3390/toxins9040148
                5408222
                28430165
                871fbb2f-33be-4a45-a98c-a721a115508d
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 21 February 2017
                : 10 April 2017
                Categories
                Review

                Molecular medicine
                red-back spider,widow spider,envenomation,antivenom,treatment
                Molecular medicine
                red-back spider, widow spider, envenomation, antivenom, treatment

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