Current Awareness in Clinical Toxicology Editors: Damian Ballam MSc and Allister Vale MD June 2017 CONTENTS General Toxicology 9 Metals 34 Management 17 Pesticides 35 Drugs 19 Chemical Warfare 36 Chemical Incidents & 28 Plants 36 Pollution Chemicals 29 Animals 37 CURRENT AWARENESS PAPERS OF THE MONTH Is mannitol the treatment of choice for patients with ciguatera fish poisoning? Mullins ME, Hoffman RS. Clin Toxicol 2017; online early: doi: 10.1080/15563650.2017.1327664: Context Ciguatera fish poisoning arises primarily from consumption of carnivorous reef fish caught in tropical and sub-tropical waters. Ciguatoxins, a class of tasteless, heat-stable, polycyclic toxins produced by dinoflagellates, accumulate through the food chain and concentrate in various carnivorous fish, such as groupers, barracudas, wrasses, amberjack, kingfishes, and eels. Characteristics of ciguatera fish poisoning include early nausea, vomiting, and diarrhea in the first one to two days post ingestion, followed by the appearance of sensory disturbances. The classic dysaesthesia is cold allodynia, often described as reversal of hot and cold sensation, but a more accurate description is burning pain on exposure to cold. Objective To discuss and appraise the evidence regarding the use of mannitol or other drugs in treating ciguatera framed in the historical context of the last four decades. Current Awareness in Clinical Toxicology is produced monthly for the American Academy of Clinical Toxicology by the Birmingham Unit of the UK National Poisons Information Service, with contributions from the Cardiff, Edinburgh, and Newcastle Units. The NPIS is commissioned by Public Health England 2 Methods We searched PubMed and Embase for all years from 1966 to March 31, 2017 with search terms "ciguatera", "mannitol", and "treatment". These searches identified 85 articles, of which 36 were relevant to the review question. We searched Google Scholar to supplement the primary search and reviewed the references of articles for sources overlooked in the original searches. These secondary searches identified another 23 references. We excluded six clinical reports (two case series and four case reports) which did not clearly describe ciguatera or which lacked information on treatment or outcome. Fifty-three clinical articles remained for review. We searched PubMed using "ciguatera" AND "treatment" NOT "mannitol" to better identify reports describing other treatments. The search identified 128 articles, of which nine described specific pharmacological treatments and their outcomes. We combined our findings into a consensus review of the evidence both for and against the use of mannitol or other medications for ciguatera fish poisoning. Early human evidence of effectiveness of mannitol A 1988 report described an unexpected discovery that intravenous mannitol could rapidly and effectively treat ciguatera fish poisoning. Several other uncontrolled case series and case reports appeared to support the use of mannitol. In 2002, a small randomized, controlled trial reported no significant difference between mannitol and normal saline. Subsequent case reports have cited this study as the reason for or to withhold mannitol. Thus, some controversy exists regarding whether mannitol is useful or not for treating ciguatera fish poisoning. Basic science and animal research on ciguatera and mannitol In vitro experiments of isolated neurons demonstrate that ciguatoxins produce neuronal edema, open certain sodium channels, block potassium channels, cause uncontrolled and repetitive action potentials after a stimulus. Addition of mannitol decreases the edema and reduces the uncommanded action potentials. However, intraperitoneal injection of ciguatoxin in rats increases neuronal refractory period and slows nerve conduction velocity. Treatment with mannitol fails to correct these effects. Comparative trials of mannitol Evidence supporting mannitol for ciguatera fish poisoning includes four uncontrolled case series, one prospective, unblinded comparative trial and several case reports. Evidence against mannitol consists of one RCT, which has a small sample size and several potential limitations. Empirical human experience with other treatments Evidence regarding other treatments consists only of ten case reports and three overlapping case series that describe using amitriptyline, fluoxetine, duloxetine, gabapentin, pregabalin, or tocainide. For each of these, a long duration of treatment appears to be necessary to maintain symptomatic improvement. None of these treatments has been shown to be superior to mannitol. Conclusions It is reasonable to consider using intravenous mannitol in cases of acute ciguatera fish poisoning. Medications used in other neuropathic syndromes appear to suppress the paresthesiae of persistent ciguatera cases. However, the human evidence is of low quality for all treatments. Full text available from: http://dx.doi.org/10.1080/15563650.2017.1327664 3 A review of vilazodone exposures with focus on serotonin syndrome effects Heise CW, Malashock H, Brooks DE. Clin Toxicol 2017; online early: doi: 10.1080/15563650.2017.1332369: Background Vilazodone is an antidepressant with selective serotonin reuptake inhibition and partial 5HT1A agonism. Serotonin syndrome is believed to be due to excessive stimulation of 5- HT2A and 5-HT1A receptors, resulting in the clinical triad of altered mentation, autonomic instability and neuromuscular abnormalities. The goal of this study is to define serotonergic effects after vilazodone exposure. Methods A retrospective review of two databases: the American Association of Poison Controls Centers' National Poison Data System (NPDS) and the American College of Medical Toxicology's Toxicology Investigators Consortium (ToxIC Registry). A case series of four patients from one medical toxicology service is also presented. Results During the 52-month study period, a total of 3192 vilazodone human exposures were reported to NPDS. Of these, 1734 (54%) were isolated vilazodone cases. The clinical effects of vilazodone toxicity included drowsiness (20%), vomiting (14%), tachycardia (11%) and agitation (10%). Most patients (71%) had symptoms for between 2 and 24 h, though some (14%) remained symptomatic for more than 24 h. The most common treatment was intravenous fluids (15%) and the most serious intubation (2%). From the ToxIC Registry, a total of 23 cases of vilazodone exposures were identified. Of these, 17 (74%) had vilazodone listed as the first (primary) agent and 10 (43%) involved vilazodone-only ingestions. Nine (39%) cases documented serotonin syndrome; and most (8/9; 89%) listed vilazodone as the primary agent. All (n = 4) subjects in the case series with acute vilazodone toxicity had serotonin syndrome. Conclusions Vilazodone overdose, including vilazodone-only ingestions, are associated with serotonin syndrome. Serotonergic toxicity and appropriate treatments should be considered when caring for patients with vilazodone ingestions. Full text available from: http://dx.doi.org/10.1080/15563650.2017.1332369 Hepatotoxicity evaluation of traditional Chinese medicines using a computational molecular model Zhao P, Liu B, Wang C, Acute Liver Failure Study Team (ALFST). Clin Toxicol 2017; online early: doi: 10.1080/15563650.2017.1333123: Background Liver injury caused by traditional Chinese medicines (TCMs) is reported from many countries around the world. TCM hepatotoxicity has attracted worldwide concerns. Objective This study aims to develop a more applicable and optimal tool to evaluate TCM hepatotoxicity. Methods A quantitative structure-activity relationship (QSAR) analysis was performed based on published data and U.S. Food and Drug Administration's Liver Toxicity Knowledge Base (LTKB). 4 Results Eleven herbal ingredients with proven liver toxicity in the literature were added into the dataset besides chemicals from LTKB. The finally generated QSAR model yielded a sensitivity of 83.8%, a specificity of 70.1%, and an accuracy of 80.2%. Among the externally tested 20 ingredients from TCMs, 14 hepatotoxic ingredients were all accurately identified by the QSAR model derived from the dataset containing natural hepatotoxins. Conclusions Adding natural hepatotoxins into the dataset makes the QSAR model more applicable for TCM hepatotoxicity assessment, which provides a right direction in the methodology study for TCM safety evaluation. The generated QSAR model has the practical value to prioritize the hepatotoxicity risk of TCM compounds. Furthermore, an open-access international specialized database on TCM hepatotoxicity should be quickly established. Full text available from: http://dx.doi.org/10.1080/15563650.2017.1333123 Relationship between blood toxin level and clinical features in patients with grayanotoxin poisoning – six clinical cases Choi HL, Park KH, Park JS, Choi HY, Kim H, Kim SM. Clin Toxicol 2017; online early: doi: 10.1080/15563650.2017.1331448: Background The purpose of this study was to investigate grayanotoxin (GTX) levels in the blood of patients with GTX intoxication and in the consumed Rhododendron liqueur, and to determine whether there was an association between blood GTX level and the patient's clinical status. Methods In September 2015, six patients were concurrently presented to the emergency department with various toxicity symptoms, which occurred after the consumption of Rhododendron liqueur at the same toxin concentration. Liquid chromatography-tandem mass spectrometry analysis was conducted on blood samples