The effects of CDP-choline treatment in Amanita phalloides mushroom toxicosis.

Amanita phalloides poisoning is known to be the most fatal case among mushroom poisoning cases. Its main mechanism of toxicity is that it leads to cell death by the irreversible binding of its toxins to the DNA-dependent RNA polymerase II enzyme. This study was planned to analyze the effects of the CDP-choline molecule on Amanita phalloides mushroom poisoning cases. The extract of the Amanita phalloides mushroom was taken and intraperitoneally administered to male Wistar Albino rats at a dose of 0.3 g/kg. In the experiment phase, the rats were divided into three groups of CDP-choline treatment according to the doses of 100 mg/kg, 250 mg/kg, and 500 mg/kg, and one control group was administered a 1 ml/kg dose of 0.9% isotonic NaCl solution. The treatments were then administered intraperitoneally at the 2nd hour, and at the 6th hour, the rats were sacrificed. The degree of damage in the liver and kidney tissues of the rats was evaluated histopathologically. It was concluded that CDP-choline reduced or prevented the damage that occurred in the liver significantly and dose-dependently in the toxicosis picture caused by Amanita phalloides, and it showed a tendency to lower or prevent the damage in the kidney, albeit not significantly.

Mechanism and treatment of α-amanitin poisoning.

Amanita poisoning has a high mortality rate. The α-amanitin toxin in Amanita is the main lethal toxin. There is no specific detoxification drug for α-amanitin, and the clinical treatment mainly focuses on symptomatic and supportive therapy. The pathogenesis of α-amanitin mainly includes: α-amanitin can inhibit the activity of RNA polymeraseII in the nucleus, including the inhibition of the largest subunit of RNA polymeraseII, RNApb1, bridge helix, and trigger loop. In addition, α-amanitin acts in vivo through the enterohepatic circulation and transport system. α-Amanitin can cause the cell death. The existing mechanisms of cell damage mainly focus on apoptosis, oxidative stress, and autophagy. In addition to the pathogenic mechanism, α-amanitin also has a role in cancer treatment, which is the focus of current research. The mechanism of action of α-amanitin on the body is still being explored.

Silibinin: a toxicologist's herbal medicine?

Silymarin is an herbal remedy, commonly called milk thistle, or St. Mary's Thistle, and has been used for over 2000 years. It has been available as a capsule of the plant extract in Europe since 1974 to treat hepatic disorders. To date toxicologists have relied on animal studies, human case series, or retrospective reviews to decide on its use. In the U.S. the ability to use IV silibinin, its pharmacologically active purified flavonolignan, is hindered by its lack of availability as a Food and Drug Administration approved pharmaceutical preparation. This commentary reviews the in vitro studies, animal studies, and human retrospective analyses which form the basis for its clinical use. Despite the numerous publications, summarized in this issue in a systematic review, the mortality rate from Amanita mushroom ingestion remains stubbornly the same over four decades of use, and hovers around 10%. Although in the retrospective systematic review the use of silibinin, or penicillin, compared to routine care is statistically significantly superior when the primary outcome is fatality. Despite this there is no quality randomized trial to definitively demonstrate its utility. While, intravenous silibinin has a low toxicity, unanswered is whether it is useful in protecting the liver in cases of amanitin-containing mushrooms toxicity, and whether earlier administration would likely improve outcomes.

Amanitin intoxication: effects of therapies on clinical outcomes - a review of 40 years of reported cases.

BACKGROUND AND AIMS: Amanita phalloides poisoning causes severe liver damage which may be potentially fatal. Several treatments are available, but their effectiveness has not been systematically evaluated. We performed a systematic review to investigate the effect of the most commonly used therapies: N-acetylcysteine (NAC), benzylpenicillin (PEN), and silibinin (SIL) on patient outcomes. In addition, other factors contributing to patient outcomes are identified. METHODS: We searched MEDLINE and Embase for case series and case reports that described patient outcomes after poisoning with amanitin-containing Amanita mushrooms. We extracted clinical characteristics, treatment details, and outcomes. We used the liver item from the Poisoning Severity Score (PSS) to categorize intoxication severity. RESULTS: We included 131 publications describing a total of 877 unique cases. The overall survival rate of all patients was 84%. Patients receiving only supportive care had a survival rate of 59%. The use of SIL or PEN was associated with a 90% (OR 6.40 [3.14-13.04]) and 89% (OR 5.24 [2.87-9.56]) survival rate, respectively. NAC/SIL combination therapy was associated with 85% survival rate (OR 3.85 [2.04, 7.25]). NAC/PEN/SIL treatment group had a survival rate of 76% (OR 2.11 [1.25, 3.57]). Due to the limited number of cases, the use of NAC alone could not be evaluated. Additional analyses in 'proven cases' (amanitin detected), 'probable cases' (mushroom identified by mycologist), and 'possible cases' (neither amanitin detected nor mushroom identified) showed comparable results, but the results did not reach statistical significance. Transplantation-free survivors had significantly lower peak values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total serum bilirubin (TSB), and international normalized ratio (INR) compared to liver transplantation survivors and patients with fatal outcomes. Higher peak PSS was associated with increased mortality. CONCLUSION: Based on data available, no statistical differences could be observed for the effects of NAC, PEN or SIL in proven poisonings with amanitin-containing mushrooms. However, monotherapy with SIL or PEN and combination therapy with NAC/SIL appear to be associated with higher survival rates compared to supportive care alone. AST, ALT, TSB, and INR values are possible predictors of potentially fatal outcomes.

Intravenous rifampicin use in the management of amanita phalloides toxicity.

Context: Amanita phalloides related toxicity from amatoxins can result in acute liver and multi-organ failure and is responsible for 90% of all mushroom poisoning death. However, more evidence is needed in regards to different management strategies.Case details: We present two cases of amanita mushroom ingestion who were treated with intravenous rifampicin.Discussion: Further study is needed to establish the efficacy and role of rifampicin in amatoxin related mushroom poisoning.

Successful treatment with tumor necrosis factor-α blockers for poison-induced liver injury: case report and literature review.

Acute poisoning could result in hepatic dysfunction which is potentially life threatening. We reviewed three cases of poison-induced liver injury with gastrointestinal disorder on admission. Two cases were poisoned by mushroom α-Amanitin while the other was poisoned by acetaminophen (APAP). They were cured under the close monitor of laboratory examinations and other supportive therapies, as well as the off-label medication of etanercept, a kind of tumor necrosis factor-α (TNF-α) blockers with written informed consent. Among them, case1 was given the first dose doubling of TNF-α blockers for higher liver enzyme levels. There is a lack of effective and safe treatments for poison-induced liver injury. TNF-α has been proved to play an important role in the aggravation of liver injury and the start-up of inflammatory cascade reaction. Therapy with TNF-α blockers shown potential therapeutic efficacy in hepatic dysfunction by some researches. Anyway, no strong recommendation could be drawn from these small sample size studies. On the other side, TNF-α could also mediate an opposing effect for hepatocytes since the hepatic toxicity of TNF-α blockers has generated attentions. The safety for the off-label medication of TNF-α blockers in liver injury, however, still lacks strong evidences. More experimental and clinical researches are needed to focus on potential mechanisms.

A Comparison of the Effectiveness of Silibinin and Resveratrol in Preventing Alpha-Amanitin-Induced Hepatotoxicity.

Amanita phalloides species mushrooms containing alpha-amanitin (α-AMA) are responsible for the majority of fatal mushroom intoxications and can lead to severe poisonings resulting in hepatotoxicity and acute hepatic failure. Existing antidotes, such as silibinin, are not sufficiently effective in the prevention and/or resolution of α-AMA-induced hepatotoxicity. We investigated the effects of resveratrol on α-AMA-induced hepatotoxicity and compared with silibinin, a known antidote using in vivo and in vitro toxicity models. In the in vivo protocol, resveratrol (30 mg/kg) was given simultaneously with α-AMA (α-AMA + SR) or 12 (α-AMA + 12R) or 24 (α-AMA + 24R) hr after α-AMA administration. Silibinin (5 mg/kg) (α-AMA + Sil) and normal saline (α-AMA + NS) were given simultaneously with α-AMA. We found that liver transaminase levels in α-AMA + SR and α-AMA + 12R groups and histomorphologic injury score in the α-AMA + SR, α-AMA + 12R, α-AMA + 24R and α-AMA + Sil groups were significantly lower than that of the α-AMA + NS group. Resveratrol decreased mononuclear cell infiltration, necrosis and active caspase-3 immunopositivity in the liver. In the in vitro protocol, the effects of resveratrol and silibinin were evaluated in a reduction in cell viability induced by α-AMA in THLE-2 and THLE-3 hepatocytes. Neither resveratrol nor silibinin was found to be effective in increasing cell viability decreased by α-AMA + NS. As a conclusion, resveratrol was found to be effective in α-AMA-induced hepatotoxicity with its anti-inflammatory properties in in vivo conditions. It is a promising compound with the potential for use in the treatment of hepatotoxicity associated with Amanita phalloides type mushroom poisonings.

Nicotinic acid treatment for Paralepistopsis acromelalga intoxication: assessment using magnetic resonance imaging.

CONTEXT: Paralepistopsis acromelalga, formerly known as Clitocybe acromelalga, is a rare poisonous mushroom. The mycotoxins in this mushroom cause symptoms resembling those of erythromelalgia; however, its pathogenesis remains unclear. In this report, a patient who received nicotinic acid treatment for P. acromelalga poisoning and radiological evaluation for erythromelalgia has been presented. Case detail: A 59-year-old woman was hospitalized for redness, swelling, and burning pain in her extremities that rendered difficulty in walking, and a diagnosis of P. acromelalga poisoning was made by detailed interview and mushroom identification. She was treated with intravenous nicotinic acid for 17 days followed by oral nicotinic acid amide for 2 months. She exhibited rapid symptomatic improvement and walked independently after 11 days of initial treatment. Initial MRI of her feet revealed toe-dominated subcutaneous thickening. After nicotinic acid treatment, those radiological findings improved dramatically. DISCUSSION: The subcutaneous thickening evident on MRI indicated P. acromelalga poisoning-induced erythromelalgia involved subcutaneous inflammatory edema. The typical duration of edema without treatment is more than a month. The improvement on MRI after nicotinic acid treatment indicated that the adequate vasodilation induced by nicotinic acid contributed to resolution of the symptoms. Nicotinic acid was associated with the improvement of the edematous changes caused by the P. acromelalga intoxication.

Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: Silibinin in suspected amatoxin-containing mushroom poisoning.

A shortcut review was carried out to establish whether silibinin is better than conservative management at reducing liver transplantation and death after poisoning with amatoxin-containing mushrooms. Thirty-eight papers were found in Medline and 86 in EMBASE using the reported searches. Of these, five presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that the evidence is limited, but given the lack of alternative treatments in patients with suspected amatoxin-containing mushroom poisoning and the relatively few adverse effects, silibinin should be considered in some patients.

Co-ingestion of amatoxins and isoxazoles-containing mushrooms and successful treatment: A case report.

Mushroom poisonings occur when ingestion of wild mushrooms containing toxins takes place, placing the consumers at life-threatening risk. In the present case report, an unusual multiple poisoning with isoxazoles- and amatoxins-containing mushrooms in a context of altered mental state and poorly controlled hypertension is presented. A 68-year-old female was presented to São João hospital (Portugal) with complaints of extreme dizziness, hallucinations, vertigo and imbalance, 3 h after consuming a stew of wild mushrooms. The first observations revealed altered mental state and elevated blood pressure. The examination of cooked mushroom fragments allowed a preliminary identification of Amanita pantherina. Gas chromatography-mass spectrometry (GC-MS) showed the presence of muscimol in urine. Moreover, through high-performance liquid chromatography-ultraviolet detection (HPLC-UV) analysis of the gastric juice, the presence of α-amanitin was found, showing that amatoxins-containing mushrooms were also included in the stew. After 4 days of supportive treatment, activated charcoal, silybin and N-acetylcysteine, the patient recovered being discharged 10 days post-ingestion with no organ complications. The prompt and appropriate therapy protocol for life-threatening amatoxins toxicity probably saved the patient's life as oral absorption was decreased and also supportive care was immediately started.

Survival following investigational treatment of amanita mushroom poisoning: thistle or shamrock?

We report the first case, to our knowledge, of amatoxin hepatotoxicity in Iowa and explore the ethical and decisional challenges of offering an investigational treatment of a rare disease. Acute liver failure due to ingestion of amatoxin-containing mushrooms is a relatively rare entity. Once amatoxin poisoning is identified, there is no clearly effective treatment, leading to a broad range of theoretically beneficial, anecdotally successful, or investigational options. The evolution of hepatotoxicity led us to offer investigational treatment with silibinin, an extract of Mediterranean milk thistle. We explore the pitfalls in medical decision-making experienced by both the patient and the physician in the face of ambiguity. The patient did well following silibinin infusion, but we are left uncertain as to whether the patient truly responded to treatment or was simply destined to recover.

Dog intoxication by lizard's claw mushroom, Lysurus cruciatus (higher Basidiomycetes) in southern Brazil.

A case of mushroom poisoning of a dog caused by a phalloid fungus is reported for the first time. The phalloid caused gastrointestinal syndrome in a 1-year-old dog, and was identified as Lysurus cruciatus, a common phalloid fungus in southern Brazil.

Antioxidant treatment and outcome of Cortinarius orellanus poisoning: a case series.

OBJECTIVES: To study the frequency, severity, and long-term outcome of renal injury in Cortinarius orellanus poisoning, to evaluate the association between the ingested amount of C. orellanus and outcome, and to evaluate the effect of N-acetylcysteine and corticosteroid treatment on outcome. METHODS: Case series of eight patients. Diagnosis and severity of acute kidney injury (AKI) and chronic kidney disease (CKD) were classified according to current AKI and CKD definitions. N-acetylcysteine and corticosteroids were administered to six patients, former according to the standard for paracetamol poisoning. MAIN FINDINGS: All patients developed AKI, six in the most severe stage and four required renal replacement therapy (RRT). After 12 months, seven patients presented with CKD, of whom three required chronic RRT and further two were in advanced CKD. AKI and CKD severity highly correlated with the consumed amounts of Cortinarius orellanus (r = 0.98, p < 0.001 and r = 0.78, p = 0.02, respectively) but not with N-acetylcysteine and corticosteroid treatment. CONCLUSIONS: AKI and CKD by current definitions and classifications are frequent and severe after Cortinarius orellanus poisoning. The ingested amount of Cortinarius orellanus correlates with the severity of both AKI and CKD. N-acetylcysteine and corticosteroid treatment do not seem to have a beneficial effect on either AKI or CKD.

Erythromelalgia associated with Clitocybe acromelalga intoxication.

CONTEXT: Erythromelalgia is a rare disorder characterized by reddening, severe burning pain, and swelling of the extremities. Food poisoning by Clitocybe acromelalga, a poisonous mushroom, is known to induce erythromelalgia; however, its treatment protocol remains unclear. We describe here three cases of erythromelalgia following the consumption of C. acromelalga with varying clinical courses. CASE DETAILS: Of the three patients, the first patient presented 22 days after the onset of erythromelalgia; although he was treated with aspirin, numbness in the limbs persisted as sequela. Patient 2 presented at 3 days after the symptomatic onset and was immediately treated with high-dose intravenous nicotinic acid, with a dramatic symptomatic improvement. Patient 3, who had milder symptoms, spontaneously recovered within a week without any treatment. DISCUSSION: The clinical manifestations and varying clinical courses associated with C. acromelalga toxicity are discussed here, with the pathogenesis of this mycotoxin and a potential treatment. Detailed interviews of such patients are important, particularly because of the remarkably slow course of this mycotoxin as compared with common food poisonings. Treatment with intravenous nicotinic acid was associated with improvement in one patient. We believe that this painful disorder might thus be treatable, although the mechanism underlying the treatment remains unclear.

Amanita phalloides poisoning and treatment with silibinin in the Australian Capital Territory and New South Wales.

OBJECTIVES: To report the frequency and clinical outcomes of Amanita phalloides poisoning in the Australian Capital Territory and New South Wales, and the treatments used (including silibinin). DESIGN, SETTING AND PATIENTS: Retrospective case series of patients admitted to public hospitals in Canberra and Sydney for suspected A. phalloides poisoning between 1999 and 2012 (identified from hospital records and calls to the New South Wales Poisons Information Centre). MAIN OUTCOME MEASURES: Frequency of poisoning and the clinical outcomes. RESULTS: Twelve patients presented with a history suggesting A. phalloides poisoning, 10 with probable poisoning and two with possible poisoning. Eight of those with probable poisoning developed significant hepatotoxicity and four died. Silibinin was administered to nine of those with probable poisoning (the other presented before 2005). Maintaining silibinin supply became a challenge during two clusters of poisoning. Eight of the patients with probable poisoning were not long-term residents of the ACT, and six were immigrants from Asia. CONCLUSIONS: The mortality rate due to A. phalloides poisoning in this case series was high despite treatment according to current standards, including use of silibinin, and the frequency of hepatotoxicity was more than double that for the previous decade. Ongoing public health campaigns are required.