Large paracetamol overdose-Higher dose acetylcysteine is required.

Paracetamol poisoning continues to be a worldwide problem and, despite the availability of an effective antidote, acetylcysteine (NAC), the optimal way to use this antidote, particularly following very large doses of paracetamol, has not been established. Recent case series have shown an increased toxicity from high doses of paracetamol, even in those receiving prompt NAC therapy, particularly in patients above the 300 mg/L nomogram treatment line. Clinical trial evidence supporting shorter NAC dosing now allows the possibility for intensifying treatment without the risk of very high rates of ADRs. New biomarkers also show the possibility of early identification of patients at risk of liver injury who might also benefit from increased intensity treatment. This article discusses these data and proposes a logical therapy for increasing NAC dosing which now requires clinical trial testing.

Results of diagnostics and treatment of amanita phalloides poisoning in Slovakia (2004-2020).

The paper presents results of AI diagnostics and treatment across the period of 2004-2020 pointing to the efficacy of two particular protocols. METHOD: Quantitative determination of amanitins in blood (ATOs) and urine (ATOu) performed by the original ELISA kit, indicated upon mycological history and clinical symptoms of poisoning. ATOu positive cases were recommended our protocol; ATOu negative results excluded amanitin poisoning. RESULTS: out of 2876 fungal poisonings registered in Slovakia during the subjected period, were 698 AI suspected cases. In 557 of them, was AI reliably excluded, in 141 confirmed. Urinary ATOu correlated with the severity of poisoning in the range of 6-47 h after mushroom ingestion, without false negativity. Serum ATOs had no diagnostic value. 129 patients with confirmed AI received full treatment protocol with antidotes of penicillin plus silibinin. In this group died two patients of acute kidney injury in the early stages of poisoning and 127 patients were recovered. Silibinin without penicillin was used in 12 patients. One of them undergone liver transplantation and four patients died of fulminant liver failure, respectively intracranial hemorrhage. Treatment failure in the PNC + silibinin protocol was 1.5 % (2 of 127 patients), silibinin alone being 41.7 % (5 of 12 patients, p = 0.00058). CONCLUSION: Early diagnostics of amanitin intoxication based on mycological and clinical history and subsequent determination of urinary amanitin levels (ATOu) allows early initiation of treatment. The use of treatment protocol with antidotes of PNC and silibinin is of high therapeutic efficacy. The omission of PNC from the treatment protocol significantly worsens patients' prognosis.

Treatment of critical aluminum phosphide (rice tablet) poisoning with high-dose insulin: a case report.

BACKGROUND: Aluminum phosphide (rice tablet) is a highly efficient agent for preserving grains against rodents and insects. It accounts for a large number of poisoning cases. Aluminum phosphide poisoning has a high mortality rate of about 90%, and to date, no antidote is available. It releases phosphine gas after exposure to moisture, and this reaction is catalyzed by the acidity of the stomach. Phosphine is then absorbed throughout the respiratory or gastrointestinal tracts and causes toxicity through inhibition of cytochrome c oxidase and formation of highly reactive free radicals. Treatment of patients with aluminum phosphide poisoning is supportive, including mechanical ventilation and vasopressors. The usage of infusion of glucose-insulin-potassium in rice tablet poisoning has been suggested, after its positive beneficial cardiac inotropic effects in patients with beta-blocker and calcium channel blocker poisoning. CASE PRESENTATION: We report the case of a 30-year-old Iranian woman with critical aluminum phosphide poisoning, presented with hypotension and other signs of shock and severe metabolic acidosis, successfully treated with high-dose regular insulin and hypertonic dextrose and discharged from hospital in good condition. In contrast to our previous experiences, in which nearly all patients with critical aluminum phosphide poisoning died, this patient was saved with glucose-insulin-potassium. CONCLUSION: Aluminum phosphide poisoning has a high mortality rate, and to date, no antidote is available. Administration of high-dose intravenous regular insulin and dextrose is suggested as a potential life-saving treatment for patients with critical aluminum phosphide poisoning.

Herbal Compounds as an Antidote Against Snake Bite.

Snakebites have been declared a neglected health problem that is considered a national disease by the WHO (world health organisation). Asian countries like India have high snakebite death rates due to short antidotes and poorly equipped doctors. In today's scenario, local resources like herbs need to be used to prepare cheap antidotes and are often available to victims. Snake bites should be viewed as an emergency problem and require additional national guidelines, doctor training, expertise, and human concentration for effective and timely treatment-measures to be taken to ensure the availability and mass production of antidotes. Currently available, antidotes have problems with storage, manufacture, and aspects of the results. Attention should be paid to the natural compound Gedunin with antitoxic effects. To determine Gedunin's therapeutic efficacy, well-designed clinical research is required. This article emphasizes and proves the therapeutic effectiveness of the herbal plant active ingredient Gedunin against snakebites.

The Roles of Antidotes in Emergency Situations.

Management of the acutely poisoned patient requires supportive care and timely administration of antidotes to minimize ongoing toxicity and mortality. New applications for old antidotes include utilization of methylene blue and hydroxocobalamin in vasoplegia. Fomepizole is also being evaluated as a potential adjunct in acetaminophen toxicity. Other advancements include individualized acetylcysteine dosing regimens for acetaminophen toxicity and carnitine supplementation in valproic acid toxicity. Additional antidote considerations include administration of lipid emulsion in lipophilic xenobiotic exposure not responsive to standard resuscitative modalities. These expert recommendations provide guidance for providers caring for the acutely poisoned patient.

Pharmacological re-assessment of traditional medicinal plants-derived inhibitors as antidotes against snakebite envenoming: A critical review.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional healers have used medicinal plants to treat snakebite envenomation worldwide; however, mostly without scientific validation. There have been many studies on the therapeutic potential of the natural products against snake envenomation. AIM OF THE STUDY: This review has highlighted snake venom inhibitory activity of bioactive compounds and peptides from plants that have found a traditional use in treating snakebite envenomation. We have systematically reviewed the scenario of different phases of natural snake venom inhibitors characterization covering a period from 1994 until the present and critically analysed the lacuna of the studies if any, and further scope for their translation from bench to bedside. MATERIALS AND METHODS: The medicinal plant-derived compounds used against snakebite therapy were reviewed from the available literature in public databases (Scopus, MEDLINE) from 1994 till 2020. The search words used were 'natural inhibitors against snakebite,' 'natural products as therapeutics against snakebite,' 'natural products as antidote against snake envenomation,' ' snake venom toxin natural inhibitors,' 'snake venom herbal inhibitors'. However, the scope of this review does not include computational (in silico) predictions without any wet laboratory validation and snake venom inhibitory activity of the crude plant extracts. In addition, we have also predicted the ADMET properties of the identified snake venom inhibitors to highlight their valuable pharmacokinetics for future clinical studies. RESULTS: The therapeutic application of plant-derived natural inhibitors to treat snakebite envenomation as an auxiliary to antivenom therapy has been gaining significant momentum. Pharmacological reassessment of the natural compounds derived from traditional medicinal plants has demonstrated inhibition of the principal toxic enzymes of snake venoms at various extents to curb the lethal and/or deleterious effects of venomous snakebite. Nevertheless, such molecules are yet to be commercialized for clinical application in the treatment of snakebite. There are many obstacles in the marketability of the plant-derived natural products as snake envenomation antidote and strategies must be explored for the translation of these compounds from drug candidates to their clinical application. CONCLUSION: In order to minimize the adverse implications of snake envenomation, strategies must be developed for the smooth transition of these plant-derived small molecule inhibitors from bench to bedside. In this article we have presented an inclusive review and have critically analysed natural products for their therapeutic potential against snake envenomation, and have proposed a road map for use of natural products as antidote against snakebite.

Reducing the risk of death induced by aluminum phosphide poisoning: The new therapies.

Numerous people suffer from accidental or deliberate exposure to different pesticides when poisoning with aluminum phosphate (AlP) is increasing in the eastern countries. Aluminum phosphate is a conventional insecticide that quickly reacts with water or the moistures in the atmosphere and produces fatal phosphine gas, which absorbs quickly by the body. Oral consumption or inhalation of AlP leads to excessive reaction of the body such as fatigue, vomiting, fever, palpitation, vasodilatory shock, increasing blood pressure, cardiac dysfunction, pulmonary congestion, shortness of breath, and death. The garlic smell from the patient's mouth or exhale is one of the methods to recognize the positioning. Due to the lack of individual antidotes, several supportive treatments are required. The present study focused on the available and new therapies that help reduce the effect of AlP poisoning and the mortality rate. The therapies are divided into the antioxidant-related agent and the other agents. The impacts of each agent on the experimental cases are reported.

Toxicity assessment of gelsenicine and the search for effective antidotes.

BACKGROUND: Gelsenicine, one of the most toxic alkaloids of Gelsemium elegans Benth (G. elegans), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available. OBJECTIVE: This study aimed to analyse the toxicity characteristics of gelsenicine. METHODS: Both acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened. RESULTS: In the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD50 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood-brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice. CONCLUSIONS: Gelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicine-related poisoning and its toxicity mechanisms.

A suicide attempt by ingestion of oleander leaves and treatment with digoxin-specific Fab antibody fragments.

Natural cardiac glycosides have positive inotropic heart effects but at high, toxic doses they can cause life-threatening cardiac arrhythmias. Here we present the first Croatian case of a 16-year-old girl who attempted suicide by eating dried oleander leaves, which contain natural cardiac glycosides, and her treatment with a specific antidote. The girl presented with an oedema of the uvula indicating local toxicity, severe bradycardia, first-degree atrioventricular block, drowsiness, and vomiting. Having taken her medical history, we started treatment with atropine, intravenous infusion of dextrose-saline solution and gastroprotection, but it was not successful. Then we introduced digoxin-specific Fab antibody fragments and within two hours, the patient's sinus rhythm returned to normal. Cases of self-poisoning with this oleander are common in South-East Asia, because it is often used as a medicinal herb, and digoxin-specific Fab fragments have already been reported as effective antidote against oleander poisoning there. Our case has taught us that it is important to have this drug in the hospital pharmacy both for digitalis and oleander poisoning.

Study of the cardioprotective effects of crocin on Human Cardiac Myocyte cells and reduction of oxidative stress produced by aluminum phosphide poisoning.

OBJECTIVES: The effects of Crocin as a cardioprotective material against Aluminum phosphide poisoning by reducing the oxidative stress is investigated. METHODS: The level of biomarkers of oxidative stress (Catalase, Superoxide dismutase, Malondialdehyde and Protein carbonyl) were measured in the cell culture model on Human Cardiac Myocyte cells to detect the protective effect of crocin. Initially, to define the pure impact of aluminum phosphide poison and crocin on the heart cells, their effects on the biomarkers quantity in cell line were measured, separately, using the standard related kits. Later the effect of crocin with different concentration as a treatment on the oxidative stress biomarkers of the poisoned heart cells were monitored. Note that in pre-treatment case, the crocin was initially added to the cells before poisoning them. Data were analyzed using the analysis of variance method. KEY FINDINGS: Results showed that crocin treatment reduced the aluminum phosphide (AlP) poisoning effect significantly. The treatment resulted in substantial deviation in the biomarkers of oxidative stress at the pre- and post-treatment phases for all groups. The oxidative markers values of the poisoned cells were recovered by crocin treatment. CONCLUSIONS: Crocin is proposed as a potentially powerful antioxidant to treat the cardiotoxicity caused by aluminum phosphide poisoning.

Intravenous lipid emulsion as an adjuvant therapy of acute clozapine poisoning.

INTRODUCTION: Clozapine is a frequently prescribed atypical antipsychotic drug. Various case reports documented the successful recovery of acute antipsychotics toxicity in association with the administration of intralipid emulsion (ILE). AIM: This study aimed to assess the adjuvant therapeutic role of SMOF Lipid administration on the outcomes of acute clozapine poisoning. METHODS: Forty patients with acute clozapine poisoning were randomly allocated into two equal groups. The control group received the standard supportive treatment only, whereas the intervention group received the standard supportive treatment plus SMOF Lipid 20% infusion. All patients were subjected to history taking, full clinical examination, and laboratory investigations. The study outcomes were evaluated. RESULTS: The mean Glasgow Coma Scale (GCS) at 6 hours (13.1 ± 2.3 vs 9.2 ± 2, p < 0.001) and 12 hours (14.3 ± 1.5 vs 9.6 ± 2, p < 0.001) after admission was significantly higher in the intervention group compared to the control group. The intervention group showed a significantly lower frequency of prolonged QTc interval 12 hours after admission (p = 0.003), as well as a significantly shorter hospital stay (p < 0.001). CONCLUSIONS: SMOF Lipid infusion seemed to have improved GCS, the prolonged QTc interval, and shortened the length of hospital stay. Furthermore, there were no adverse effects related to its administration.

Paracetamol overdose in the newborn and infant: a life-threatening event.

PURPOSE: Paracetamol is the only drug recommended to treat fever in neonates. At recommended doses, paracetamol has not been associated with liver injury in neonates, while hepatotoxicity may occur after intake of a single high dose or multiple excessive doses. The aim of this narrative review is to critically analyze and summarize the available literature on newborns and infants exposed to supratherapeutic doses of paracetamol, with special focus on their clinical features, outcome, and management. METHODS: The PubMed, SCOPUS, and Google Scholar search engines were used to collect data, without time limitation. The following keywords were used: paracetamol/acetaminophen, overdose, hepatotoxicity, N-acetylcysteine, newborn, infant. RESULTS: The literature search identified a total of 27 case reports, a number of review articles, and few other relevant publications. Neonatal poisoning from paracetamol resulted from transplacental drug transfer after maternal overdose in some published cases, while it was the consequence of medication errors in other cases. Newborns and infants who have received a single overdose and have paracetamol concentrations below the Rumack-Matthew nomogram limits are at low risk of serious hepatic damage, while those who have recently ingested more than one supratherapeutic dose of paracetamol should be managed with caution. The treatment of choice for paracetamol poisoning is N-acetylcysteine, a specific antidote which reduces paracetamol hepatotoxic effects. N-Acetylcysteine should be given according to specific regimens through weight-based dosing tables. CONCLUSIONS: Caution should be used when paracetamol is administered to the newborn. In the event of an overdose, careful patient monitoring and personalization of post-overdose procedures are recommended.

How to rescue high-dose methotrexate induced nephrotoxicity and literature review about hemodiafiltration?

Methotrexate (MTX) is a highly renal and liver toxicity drug used in hematological malignancy treatment in children and adults. High-dose methotrexate (HD-MTX) therapy may cause impairment of kidney and decrease the elimination of MTX, at the same time, the serum concentration of MTX increased. Today the treatment for preventing MTX toxicity after renal shutdown is Carboxypeptidase. We report a patient who experienced nephrotoxicity after the HD-MTX infusions during the treatment for non-Hodgkin lymphoma (NHL) and received hemodiafiltration (HDF) with large dose of leucovorin (LV) to treat MTX intoxication. LV is very potent in the prevention of neurotoxicity and administration of LV could protect the normal cells, but the dosage and duration of LV should be according to the MTX concentration. Although a large dose of LV was applied, the patient's condition did not improve. It was found that the HDF with large dose of LV to save the patient and steadily improved the patient's clinical condition.

Position paper on the safety/efficacy profile of direct oral anticoagulants in patients with chronic kidney disease. Consensus document from the SIN, FCSA and SISET.

Direct oral anticoagulants (DOAC) are mostly prescribed to prevent cardioembolic stroke in patients with non-valvular atrial fibrillation (AF). An increasing number of guidelines recommend DOAC in AF patients with preserved renal function for the prevention of thromboembolism, and an increased use of DOAC in daily practice has been recorded also in elderly patients. Ageing is associated with a reduction in glomerular filtration rate, and impaired renal function, regardless of the cause, increases the risk of bleeding. Multiple medication use (polypharmacy) for treating superimposed co-morbidities is common in both elderly and chronic kidney disease (CKD) patients and drug-drug interaction may cause accumulation of DOAC, thereby increasing the risk of bleeding. The safety profile of DOAC in patients with CKD has not been defined with any certainty, particularly in those with severely impaired renal function or end stage renal disease. This has been due to the heterogeneity of studies and the relative paucity of data. This document reports the position of three Italian scientific societies engaged in the management of patients with atrial fibrillation who are treated with DOAC and present with CKD.

Metabolic and mitochondrial treatments for severe paracetamol poisoning: a systematic review.

BACKGROUND: Paracetamol (acetaminophen) remains a leading cause of poisoning in Europe, North America, and Australia. For over four decades, acetylcysteine has been the antidote of choice. However, despite the use of acetylcysteine, some patients who ingest very large doses of paracetamol or who reach hospital late in the course of their poisoning, develop acute liver failure. Some will develop metabolic acidosis indicating mitochondrial toxicity. OBJECTIVE: We review the experimental and clinical data reported with the use of cimetidine, fomepizole, and calmangafodipir in the treatment of paracetamol toxicity to determine if these treatments alone or in combination with acetylcysteine might be of benefit. METHODS: We searched Ovid Medline 1946-2020, Embase 1947-2020, Scopus 2004-2020, Cochrane Databases of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov 1997-2020 for records including the concepts of paracetamol poisoning and cimetidine, fomepizole, calmangafodipir, and acetylcysteine. We included basic science studies in animals and all available study types in humans. We reviewed the reference lists of included articles to search for references missed in the original search. We registered the protocol in PROSPERO. RESULTS: We completed all search strategies on 20 August 2019, 27 January 2020, and 15 June 2020. These produced 6,826 citations. We identified and deleted 2,843 duplicate resulting in a total of 3,856 unique citations. After applying inclusion and exclusion criteria, 89 studies remained. The largest numbers of studies described the past use of cimetidine, and the more recent use of fomepizole.Cimetidine: There is good animal evidence that cimetidine blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. Early case reports were inconclusive regarding the benefit to humans in paracetamol poisoning. Two comparative trials found no benefit of cimetidine in paracetamol poisoning, but few patients had severe poisoning.Fomepizole: There is good animal evidence that fomepizole blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. There are no comparative trials of fomepizole for acute paracetamol poisoning. Case reports are inconclusive due to multiple other interventions including the use of acetylcysteine in all cases. The benefit of fomepizole as adjunct treatment has not been demonstrated.Calmangafodipir: Calmangafodipir, a drug mimicking superoxide dismutase, has emerged as a potential treatment for severe paracetamol toxicity because the formation of superoxide free radicals appears to explain part of the mitochondrial toxicity of extremely large paracetamol overdoses. Calmangafodipir has reached Phase I/II trial of safety in humans with acute paracetamol overdose. Planning for a Phase III study of efficacy is currently underway. CONCLUSIONS: The vast majority of patients with acute paracetamol overdose enjoy excellent outcomes with acetylcysteine alone. Although cimetidine and fomepizole inhibit CYP 2E1 in animals, there is insufficient evidence to recommend their use either as a primary treatment or adjunct therapy in paracetamol poisoning. Calmangafodipir remains investigational.

Arsenic intoxication: general aspects and chelating agents.

Arsenic (As) is widely used in the modern industry, especially in the production of pesticides, herbicides, wood preservatives, and semiconductors. The sources of As such as contaminated water, air, soil, but also food, can cause serious human diseases. The complex mechanism of As toxicity in the human body is associated with the generation of free radicals and the induction of oxidative damage in the cell. One effective strategy in reducing the toxic effects of As is the usage of chelating agents, which provide the formation of inert chelator-metal complexes with their further excretion from the body. This review discusses different aspects of the use of metal chelators, alone or in combination, in the treatment of As poisoning. Consideration is given to the therapeutic effect of thiol chelators such as meso-2,3-dimercaptosuccinic acid, sodium 2,3-dimercapto-1-propanesulfonate, 2,3-dimercaptopropanol, penicillamine, ethylenediaminetetraacetic acid, and other recent agents against As toxicity. The review also considers the possible role of flavonoids, trace elements, and herbal drugs as promising natural chelating and detoxifying agents.

Management of epistaxis in patients on novel oral anticoagulation therapy.

BACKGROUND: Individuals on anticoagulation therapy are at increased risk of bleeding, including epistaxis. There is a lack of available reversal agents for novel oral anticoagulation therapy. OBJECTIVE: This paper reviews the current literature on epistaxis in the context of novel oral anticoagulation use, in order to recommend guidelines on management. METHOD: A comprehensive search of published literature was conducted to identify all relevant articles published up to April 2019. RESULTS: Patients on oral anticoagulation therapy are over-represented in individuals with epistaxis. Those on novel oral anticoagulation therapy were more likely to relapse compared to patients on classic oral anticoagulants or non-anticoagulated patients. Idarucizumab is an effective antidote for bleeding associated with dabigatran use. Recommendations for epistaxis management in patients on novel oral anticoagulation therapy are outlined. CONCLUSION: Clinicians need to be aware of the potential severity of epistaxis and the increased likelihood of recurrence. High-quality studies are required to determine the efficacy and safety of andexanet alfa and ciraparantag, as well as non-specific reversal agents.

Latrodectism in Italy: First report of successful treatment of L. tredecimguttatus envenomation using L. mactans antivenom from North America.

INTRODUCTION: Latrodectism is a rare, but potentially severe, clinical syndrome caused by spider of the genus Latrodectus. L. tredecimguttatus is widespread in Italy and its bite cause the injection of α-latrotoxin that cause depletion of acetylcholine at motor nerve endings and release of catecholamines at adrenergic nerve endings. We describe the first clinical case of L. tredecimguttatus poisoning successfully treated with L. mactans antivenom from North America. CASE REPORT: A healthy 60-year-old patient was admitted to the emergency department after unknown insect sting or arachnid/snake bite. In the early morning, the patient was working in the countryside when he felt a sting-like pain in the medial area of the right lower leg, associated with an intense burning sensation. An hour later he developed agitation, hoarseness, sweating, abdominal distress and intense pain in his right leg. In the emergency room vital signs showed a hypertensive crisis, tachycardia and peripheral oxygen desaturation. ECG was normal and ABE showed mixed acid-base disorder. Blood tests showed leukocytosis with neutrophilia, high levels of myoglobin, with normal coagulation and normal plasmatic cholinesterase. Neck, thorax and abdomen CT scan, with and without contrast medium, was negative. Four hours after admission hypertension worsened with board like rigid abdomen and onset of fasciculations, tremors, miosis and intense regional sweating. The definitive diagnosis of poisoning by L tredecimguttatus was based on the clinical picture. Within short time the antidote was provided by the Poison Centre and administered. A marked improvement of the symptomatology was noted after 30 minutes, and 1 hour later all symptoms were under control. The patient was discharged after 2 days. CONCLUSIONS: The clinical presentation of a patient suffering from latrodectism places the clinician in front of a challenging differential diagnosis. Following the suspicion, the first-line doctor is invited to discuss the case with a toxicologist, in order to confirm or exclude the diagnosis and implement all therapeutic measures. In our clinical case, the absence of organic lesions, laboratory tests not suggestive for other causes, and the presence of typical clinical feature suggested the diagnosis of L tredecimguttatus poisoning. This hypothesis was then supported by the close temporal relation between antivenom administration and symptoms improvement. With this case, we report the first use of L mactans antivenom from North America to treat L.tredecimguttatus poisoning and we confirm its effectiveness in counteracting latrodectism caused by this spider.