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Amatoxins

1. NAME
   1.1 Scientific name
   1.2 Family
   1.3 Common name(s)
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
   2.5 Poisonous parts
   2.6 Main toxins
3. CHARACTERISTICS
   3.1 Description of the plant
      3.1.1 Special identification features
      3.1.2 Habitat
      3.1.3 Distribution
   3.2 Poisonous parts of the plant
   3.3 The toxin(s)
      3.3.1 Name(s)
      3.3.2 Description, chemical structure, stability
      3.3.3 Other chemical constents
4. USES/CIRCUMSTANCES OF POISONING
   4.1 Uses
   4.2 High risk circumstances
   4.3 High risk geographical areas
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY
   7.1 Mode of action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL/TOXINOLOGICAL AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analysis
   8.2 Toxicological analyses and their interpretation
      8.2.3 Interpretation of toxicological analyses
9. CLINICAL EFFECTS
   9.1 Acute poisoning:
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning by:
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system.
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatologic
      9.4.9 Eyes, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunologic
      9.4.12 Metabolic
         9.4.12.1 Acid based disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks: pregnancy, breast feeding, enzyme
   9.5 Others
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses and other investigations
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological/Toxinological analysis
   10.3 Life supportive procedures and symptomatic treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
   10.7 Management discussion: alternatives and controversies, research
11. ILLUSTRATIVE CASES
   11.1 Case report from the literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes and antisera
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
   13.1 Clinical and toxicological
   13.2 Botanical
14. AUTHOR(S), REVIEWERS(S) DATES (INCLUDING EACH UPDATING), COMPLETE ADDRESSES
    1.   NAME

     1.1  Scientific name

          Amatoxins

     1.2  Family

          Agaricacae galerina lepiota
               Genera: Amanita, Galerina

          Other mushrooms

          Other mushrooms also contain amatoxins and/or may induce the same
          toxicity:

          Amanita:  verna, virosa, ocreata, bisporigera, suballiacae, 
                    tenuifolia, hygroscopica. 

          Galerina: autumnalis, marginata, venenata, fasciculata.

          Lepiota:  brunneo incarnata, bruneolillacae, castanea, felina, 
                    fuscovinacae, helveola bres.  huissman, helveola 
                    josseranda, locanensis, pseudohelveola, rufescens. 

     1.3  Common name(s)

          Amanita phalloides: English   Death cap, Deadly Agaric
                              French    Amanite phalloide
                              German    Knollenblätterpilz
                              Italian   Tignosa verdognala
     
          Amanita verna:      French    Amanite printaniere
                              German    Fruhlings Wulstling
                              Italian   Tignosa primavera
                              English   Destroying angel

          Amanita virosa:     French    Amanite vireuse
                              German    Spitzhutiger
                                        Knollenblätterpilz
                                        Kegeliger wustling

          Lepiota helveola:   French    Lepiote brune
                              German    Fleischröter
                                        Schirmling

    2.   SUMMARY

     2.1  Main risks and target organs

          Amatoxins are liver toxins.  The main risk is liver necrosis with 
          acute hepatic failure and subsequent complications, including 
          hepatic coma, coagulation disorders and renal failure. 



     2.2  Summary of clinical effects

          There are three phases:

          A latent phase of approximately 6 - 24 hours (mean 12.3 hours),
          rarely extending to 48 hours. 

          A gastrointestinal phase with abdominal pain, vomiting and 
          diarrhoea, leading to dehydration, hypovolaemia, electrolytes and 
          acid-base disorders. This phase usually lasts 2-3 days. 

          An hepatic phase which begins 36 - 48 hours after ingestion.  The 
          pre-icteric phase can only be detected by an increase in serum 
          transaminases. Hepatitis becomes clinically evident with the 
          onset of jaundice on the 3rd -4th day after ingestion.  In severe 
          poisoning, patients develop fulminant hepatitis with hepatic 
          coma, bleeding and anuria. When liver damage is reversible, 
          patients usually make a slow and steady recovery. Death occurs 
          within 6 to 16 days (mean 8 days). 

     2.3  Diagnosis

          Amatoxin analysis is not clinically useful for management.

          a)   Dehydration, and electrolyte disturbances may occur during 
               the gastrointestinal phase. 

          b)   Elevated transaminases and serum bilirubin are the first and 
               best indicators of liver damage and should be monitored. 

     2.4  First-aid measures and management principles

          All patients with suspected poisoning by amatoxin-containing 
          mushrooms should immediately be admitted to an intensive care 
          unit. 

          The following treatment is recommended when patients present 
          within 48 hours after ingestion:  immediate rehydration and 
          correction of hypovolaemia, gastric lavage (or emesis), 
          administration of cathartics and oral activated charcoal, forced 
          diuresis, high IV doses of penicillin and IV silibinin (if 
          available) 

          Emesis may be indicated in recent ingestion.  Gastric lavage is 
          indicated if the patient presents before onset of repeated 
          vomiting. 

          Activated charcoal is indicated and should be started during 
          rehydration. 

          Vigourous and immediate correction of dehydration and 
          hypovolaemia is indicated.  Monitor blood pressure, central 
          venous pressure and urinary output. 

          If silibinin is available, administer 20 - 50 mg/kg/day IV.


          Administer Penicillin G: 300,000 to 1,000,000 U/kg/day as an IV 
          infusion. 

          If hepatic failure occurs, supportive procedures including oral 
          mannitol or lactulose, low protein diet, vitamin K and fresh 
          frozen plasma should be instituted.  Artificial ventilation may 
          be necessary. 

          Haemodialysis is indicated only if the patient develops acute 
          renal failure. 

          Consider liver transplantation if the patient develops severe 
          hepatic failure with encephalopathy, marked jaundice, prothrombin 
          level below 10 per cent. 

     2.5  Poisonous parts

          All parts of amatoxin-containing mushrooms are poisonous.

     2.6  Main toxins

          Amatoxins

          Alpha, beta and gamma amanitins are the main toxins.

          Phallotoxins

          Amanita phalloides also contains phallotoxins but these toxins do 
          not seem to play a major role in human toxicity. 

    3.   CHARACTERISTICS

     3.1  Description of the plant
     
          3.1.1 Special identification features

               Identification

               Complete and precise identification of the mushroom (if 
               available) should be accomplished by a mycologist.  If no 
               mycologist is available, colour photographs may be helpful 
               for a first identification. Identification is difficult when 
               the mushrooms have been altered by cooking, eating or 
               storage. 

               Description

          Amanita Phalloides:

               Cap:  5 - 15 cm diameter, conical when young, then flat-
               topped. Surface colour olive green or yellow-green, 
               sometimes yellowish or white. 

               Gills: White

               Stem:  White, height 8 - 15 cm, diameter: 1 - 2.5 cm, filled
               with a cottony material when young, hollow at maturity.  
               Bulbous base. 

               Annulus: At a short distance beneath the cap, the stem bears 
               a downward-hanging membranous ring. 

               Volva: The upper extremity of the bulbous base of the stem 
               is prolonged upward in a free edge or membrane (volva) 
               encircling the stem (death's cup) 

          3.1.2 Habitat

               Phalloides:

               During summer and autumn under beach or oak trees (rarely 
               pine). 

          3.1.3 Distribution

               Phalloides:

               Frequently encountered throughout Europe

               Verna:

               Encountered throughout Europe; frequently encountered 
               throughout the United States and Canada. 
     
     3.2  Poisonous parts of the plant

          Amatoxins are found in all parts of the mushrooms.

     3.3  The toxin(s)

          3.3.1 Name(s) 

               Eight amatoxins have been isolated: alpha, beta, gamma, 
               epsilon amanitins, amanullin, amanullinic acid, proamanullin 
               and amanin. 
               
               Seven compounds have been isolated: phalloidin, phalloid, 
               prophalloin, phallisin, phallacin, phallacidin, phallisacin. 

          3.3.2 Description, chemical structure, stability

               Amatoxins

               Amatoxins are bicyclic octapeptides. The bicyclic structure 
               and a gamma hydroxyl group at the dihydroxy isoleucine 
               portion are necessary for toxicity. Amanitins are the most 
               toxic compounds. 

               Phallotoxins


               Phallotoxins are bicyclic heptapeptides. The bicyclic 
               structure and an allo-positioned hydroxyl functional group 
               at the pyrrolidine ring are necessary for toxicity.  
               (Wieland and Faulstich, 1978). 

               Formula




               Naturally occurring amatoxins:

               Structure and toxicity (LD50 mg/kg for the white mouse, i.p) 
               (Wieland & Faulstich, 1978). 

               a)   Amatoxins 

               b)   Phallotoxins

               Molecular weights
     
               Amatoxins contain 3 or 4 mol of water of crystallization.  
               Molecular weights are 990 for alpha, 373 for beta, and 974 
               for gamma amanitin. 

               Phallotoxins crystallize with 5 mol of water of 
               crystallization. Molecular weights are 879, 863 and 895 for 
               phalloidin, phalloid and philistine respectively (Wieland 
               and Faulstich, 1978). 

               Stability

               Amatoxins and phallotoxins are thermostable and are not 
               removed by boiling and discarding the water or by any form 
               of cooking.  Nor are they destroyed by drying and they have 
               been found to remain potent in mushrooms stored for over 10 
               years. 

          3.3.3 Other chemical constents

               Other chemical substances have been isolated.  Antamanide is 
               a decapeptide isolated from A. phalloides.  Experimentally 
               it prevents death in white mice from the lethal dose of 
               phalloidin. 

               Phallolysin has been isolated from A. Phalloides and other 
               Amanita species and has haemolytic activity in vitro. 

    4.   USES/CIRCUMSTANCES OF POISONING

     4.1  Uses

          Not relevant.

     4.2  High risk circumstances


          Amatoxin poisoning occurs mainly in the Summer and Autumn (the 
          growing period of the mushrooms).  However, cases of poisoning 
          may also be seen in Spring following ingestion of mushrooms such 
          as Amanita verna. 

     4.3  High risk geographical areas

          Beech and oak woods in Europe and North America.





    5.   ROUTES OF ENTRY

     5.1  Oral

          Amatoxin poisonings are always due to ingestion.

     5.2  Inhalation

          No data available.

     5.3  Dermal

          No data available.

     5.4  Eye

          No data available.

     5.5  Parenteral

          No data available.

     5.6  Others

          No data available.

    6.   KINETICS

     6.1  Absorption by route of exposure

          Oral

          Human:  Amatoxins are absorbed rapidly in humans; they can be 
          detected radioimmunologically in the urine as early as 90 - 120 
          minutes post-ingestion (Homann et al, 1986). 

          Animal:  Animal species differ in their ability to absorb 
          amatoxins from the gastrointestinal tract.  In the mouse and rat, 
          the poison is absorbed extremely slowly or not at all.  In the 
          guinea pig, cat and dog, doses of a few mg/kg cause death. 

          Phallotoxins are not absorbed from the gastrointestinal tract.


          Parenteral

          The kinetics of amatoxins have been studied in the dog after IV 
          administration, and in the mouse after intraperitoneal 
          administration (Faulstich et al, 1985; Fiume et al, 1975). 

     6.2  Distribution by route of exposure

          Protein binding

          Amatoxins are not bound to albumin (Faulstich et al, 1985; Fiume 
          et al, 1977) 

          Volume of distribution

          Human:  No data available.

          Animal:  Toxicokinetic study with labelled amatoxins in the dog 
          showed that the equilibrium distribution volume after intravenous 
          administration was identical with the extracellular space (160 - 
          290 ml/kg) (Faulstich et al, 1985). 

          
     6.3  Biological half-life by route of exposure

          Oral

          Human:  In a group of patients studied by Vesconi et al (1985), 
          serial determinations showed a rapid decrease of toxin levels in 
          all but one patient, with complete disappearance of detectable 
          concentrations by 48 hours after ingestion in all. 

          In a group of 32 patients studied by Jaeger et al (1988), 
          amatoxins disappeared rapidly from serum.  Amatoxins could be 
          detected in serum after 36 hours in only 2 patients. 

          Animal:  No data available.

          Parenteral

          Human:  No data available.
     
          Animal:  Amatoxins are eliminated very rapidly from serum.  After 
          intraperitoneal administration of amanitin in mice no toxin could 
          be detected in serum 4 hours after injection.  After intravenous 
          injection in dogs the plasma half lives ranged from 26.7 - 49.6 
          minutes and total body clearance were between 2.7 and 6.2 
          ml/min/kg (Faulstich et al, 1985). 

     6.4  Metabolism

          Human:  No data available.

          Animal:  In experimental studies, no metabolites could be 
          detected after administration of radioactive amanitin (Jahn et 
          al, 1980; Faulstich et al, 1985). 

     6.5  Elimination by route of exposure
     
          Oral
     
          Amatoxins can be detected in urine as early as 90 - 120 minutes 
          after ingestion of an amatoxin-containing mushroom (Homann et al, 
          1986). In a group studied by Vesconi et al (1985) amatoxins were 
          detected in urine up to 24 - 66 hour after ingestion. In 15 cases 
          studied by Jaeger et al (1988), alpha and beta amanitin 
          concentrations in urine were 20 - 40 times higher than those 
          found in serum.  The highest concentrations were observed during 
          the first 24 - 48 hours but in some cases amatoxins were detected 
          up to 72 - 96 hours after ingestion. Concentrations as high as 
          4,800 mg/l alpha amanitin and 4,300 mg/l beta amanitin were 
          observed.  Total mean amounts of 950 mg alpha amanitin and 1,700 
          mg beta amanitin were excreted in the urine of these patients. 

          In 5 patients reported by Busi et al (1979), amanitin was 
          detected by radioimmunoassay in gastroduodenal fluids at 12 - 72 
          hours after ingestion. In 4 cases, Jaeger et al (1988) found high 
          concentrations of alpha and beta amanitin (HPLC analysis) in 
          gastroduodenal fluids up to 120 hours after ingestion. The 
          amatoxins eliminated in bile may be reabsorbed via the 
          enterohepatic circulation (Vesconi et al, 1985; Faulstich et al, 
          1985). 

          Jaeger et al (1988) studied alpha and beta amanitin elimination 
          in 4 patients. In all cases high concentrations of alpha (mean 
          1.05 mg/L) and beta amanitin (3.56 mg/L) were detected in 
          diarrhoea fluids between the 24 and 96 hours post ingestion.  In 
          one case 6.3 mg alpha amanitin was eliminated over a period of 24
          hours.  The high rate of excretion of amatoxin in the presence of 
          diarrhoea seems due to non absorption of ingested amatoxins 
          rather than to excretion of amatoxins by the gastrointestinal 
          tract. 

          Animal:  No data available.

          Parenteral

          Human:  No data available.

          Animal:  After administration of labelled amatoxins in dogs, 83 - 
          89% is eliminated in urine and less than 10% is excreted in the 
          bile. 

    7.   TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY

     7.1  Mode of action

          Amatoxins

          The amatoxins, particularly the amanitins, have been shown
          to impair transcription of both DNA and RNA by interfering
          with RNA polymerase II.  Cells with the highest rate of

          multiplication, such as the intestinal mucosa, are injured first,
          followed by the liver and kidney. Amanitins cause necrosis of
          hepatocytes and of the cells in the proximal tubules of the
          kidney (Fiume and al., 1965).  However, direct toxicity on the
          kidney has not been confirmed in human poisoning
          (Constantino et al, 1978).

          Phallotoxins

          It is probable that the phallotoxins play no role in human 
          poisoning. Phallotoxins are not absorbed from the 
          gastrointestinal tract in the experimental animals investigated, 
          and probably not in man.  When given parenterally to laboratory 
          animals, phallotoxins destroy the endoplasmic reticulum and 
          mitochondria of the liver cells and induce necrosis of 
          hepatocytes.  Phalloidin binds to the actin G of the plasma 
          membranes, polymerizes all actin G irreversibly and hence 
          increases the permeability of the plasma membranes of 
          hepatocytes. 

     7.2  Toxicity

          7.2.1 Human data

               7.2.1.1   Adults

                    Amatoxins are among the most lethal poisons known.   As 
                    little as 0.1 mg/kg may be a lethal dose for an adult 
                    (Vesconi et al, 1985).  Concentrations of 5 - 15 mg 
                    amatoxin per 40 gram fresh mushroom have been found.  
                    This means that one amanita cap or 15 - 20 Galerina 
                    caps could kill a healthy adult. 

                    In a collaborative study of 205 cases of intoxications 
                    recorded throughout Europe from 1971 to 1980, the 
                    overall mortality was 22.4% (Floersheim et al, 1982).  
                    A significant difference between adults and children 
                    was observed. Mortality was 51.3% in children under 10 
                    years of age, and 16.5% in the patients older than 10 
                    years.  Prognosis seems to be determined by the 
                    quantity of mushroom eaten (dose of toxins per kg body 
                    weight). 

                    Mortality is 50% if untreated and less than 5% with 
                    intensive care (Lampe, 1978).  This group of mushrooms 
                    accounts for over 95% of all cases of fatal mushroom 
                    poisoning in the U.S. 

                    A literature review suggests that the incidence of 
                    mortality has gradually decreased during the last 
                    decades probably due to hospitalisation and intensive 
                    care, with early rehydration (Constantino et al, 1978; 
                    Vesconi et al, 1985). 

                    No data are available on the maximum tolerated dose in
                    man.

               7.2.1.2   Children

                    In the study of Floersheim et al (1982), the mortality 
                    in children under 10 years of age was 51.3% 

          7.2.2 Animal data

               There is significant variation betwen animal species 
               (Wieland et Faulstich, 1978). 

               Dogs

               The symptoms of amanitin intoxication have been studied in 
               beagle dogs.  Early symptoms are hyperglycaemia followed by 
               hypoglycaemia which caused death in most dogs after 1 - 2 
               days.  If given glucose, the dogs developed acute liver 
               damage with death after 2 - 3 days.  Severe haemorrhage in 
               various organs were the main cause of death in several 
               cases.  A late symptom was kidney failure from which a few 
               dogs died after 7 days (Wieland and Faulstich, 1978). 

               Toxic dose

               Amatoxins:

               In the white mouse, the LD50 after intraperitoneal 
               administration is 300 mg/kg and death occurs in 2 - 5 days.  
               The rat is more resistant: the LD50 is about 4 mg/kg after 
               intraperitoneal administration. The LD50 in dogs is 0.1 
               mg/kg after intravenous injection (Wieland and Faulstich, 
               1978). 

               Phallotoxins:

               Phallotoxins are less toxic than amatoxins.  In the white 
               mouse the LD50 is 2.5 mg/kg after intraperitoneal
               administration.  Rats are more susceptible to phallotoxins 
               than mice (Wieland and Faulstich, 1978). 

          7.2.3 Relevant in vitro data

     7.3  Carcinogenicity

          No data available.

     7.4  Teratogenicity

          No data available.

     7.5  Mutagenicity

          No data available. 

     7.6  Interactions


          No data available.

    8.   TOXICOLOGICAL/TOXINOLOGICAL AND BIOMEDICAL INVESTIGATIONS

     To be completed.


     8.1  Material sampling plan

     8.1.1 Sampling and specimen collection

     8.1.1.1 Toxicological analysis

          a)   Radioimmunoassay

          Radioimmunoassay methods for detecting amatoxins in biological 
          fluids have been developed by Faultisch et al (1987), Fiume et al 
          (1975), Andres et al (1987).  Antibodies against amanitin were 
          obtained in rabbits (Faultisch, Andres) or in rats (Fiume).  The 
          test used either 3H tracer (Faulstich, Fiume) or 125 I tracer 
          (Andres).  The sensitivity of radioimmunoassay is 0.1 ng/mL for 
          serum and 0.25 ng/mL for urine (Vesconi et al, 1985; Fiume, 
          1980); 0.1 ng/mL for serum and 1 mg/mL for urine (Andres et al, 
          1987). 

          b)   High Performance Liquid Chromatography

          HPLC assays have been developed for detection of alpha and beta 
          amanitins in human serum, urine or gastrointestinal fluids 
          (Pastorello et al, 1982, Jehl et al, 1985, Caccialanza et al, 
          1985).  Sensitivity is 6 - 10 ng/mL (Jehl et al, 1985; 
          Caccialanza et al, 1985). 



     8.2  Toxicological analyses and their interpretation

     8.2.3 Interpretation of toxicological analyses


               Serum/blood

               a)  In a group of 29 patients studied by Vesconi et al 
               (1985), serum amatoxin levels were detectable in 65% of 
               patients (Vesconi et al 1985) even as late as 30 hours post 
               ingestion.  Concentrations were 0.5 - 24 mg/L.  Only 4 of 19 
               had levels greater than 3 mg/l. 

               b)   Pastorello et al (1982) found serum levels of alpha 
               amanitin between 70 and 90 mg/l in patients with Amanita 
               phalloides intoxication. 

               c)  Jaeger et al 1988 (unpublished data) found alpha and 
               beta amanitin in serum only in one third of patients.  Mean 
               concentrations were 73 +/- 69 mg/l for alpha amanitin (range 
               8 - 190 mg/l). Amanitin was found in serum in only one case 

               after 48 hours. 

               d)  Busi et al (1977) found amatoxin in the serum of 
               intoxicated patients up to 36 hours post-ingestion. 

               e)  Velvaert et al (1982) detected amatoxin in the serum of 
               poisoned patients in 70% of cases before the 12th hour and 
               in 50% of cases by 24 hours. 

          
               Urine

               Urine amatoxin levels in a group of patients studied by 
               Vesconi et al (1985) ranged from 0.5 to 56 mg/l.  Initial 
               catheterization to obtain concentrated urine found levels as 
               high as 180 mg/l.  In serial determinations, urinary levels 
               were found 24 - 66 hours post ingestion.  Total urinary 
               output of amatoxins in this period ranged from 12 - 23 mg. 

               In a group of patients studied by Jaeger et al (1988), 
               amatoxins were detected in urine in 15 of 24 patients.  
               Alpha amanitin was present in 14 and beta amanitin in 10 
               patients.  In some cases serial determinations showed that 
               amanitins were excreted for up to 72 - 96 hours post-
               ingestion.  Concentrations as high as 4,800 mg/l alpha 
               amanitin and 4,300 mg/l beta amanitin were observed.  Mean 
               total amounts of 950 mg alpha amanitin and mean 1,700 mg 
               beta amanitin were excreted in urine in these patients. 

               Velvaert et al (1982)  detected amatoxins in urine (by 
               radioimmunoassay) in all cases before 24 hours and in 80% of 
               cases by 48 hours post-ingestion. 

               Bile

               In 4 cases, Jaeger et al (1988) found amanitin 
               concentrations in gastroduodenal fluid ranging between 44 
               and 4,950 mg/l between the 44th and 108th hour post-
               ingestion. 

               Faeces

               In 4 patients, Jaeger et al (1988) found concentrations of 
               alpha amanitin (mean 1.05 mg/l) and beta amanitin (mean 3.5 
               mg/l) in diarrhoeal faeces. 



    9.   CLINICAL EFFECTS

     9.1  Acute poisoning:

          9.1.1 Ingestion

               Amanitin intoxication has 3 chronological phases:  


               a symptomless latent phase, 6 - 24 hours post-ingestion 

               a gastrointestinal phase, starting 6 - 24 hours post-
               ingestion and lasting for 2 - 3 days, with abdominal pain, 
               nausea, vomiting and diarrhoea 

               an hepatic phase, which begins 36 - 48 hours post-ingestion, 
               with jaundice, hepatitis and coma; death occurs within 6 - 
               15 days of ingestion. 

          9.1.2 Inhalation

               No data available.

          9.1.3 Skin exposure

               No data available.

          9.1.4 Eye contact

               No data available.

          9.1.5 Parenteral exposure

               No data available.

          9.1.6 Other

               No data available.

     9.2  Chronic poisoning by:

          9.2.1 Ingestion

               No data available.

          9.2.2 Inhalation
     
               No data available.

          9.2.3 Skin exposure

               No data available.

          9.2.4 Eye contact

               No data available.

          9.2.5 Parenteral exposure

               No data available.

          9.2.6 Other

               No data available.


     9.3  Course, prognosis, cause of death

          The course of amanitin intoxication has 3 chronological 3 phases:

          a)  A latent phase of approximately 6 - 24 hours (mean 12.3
          hours), rarely extending to 48 hours. 

          b)  A gastrointestinal phase with abdominal pain, vomiting and 
          diarrhoea causing dehydration, hypovolaemia, electrolyte and 
          acid-base disorders. This phase usually lasts 2-3 days. 

          c)  An hepatic phase which begins 36 - 48 hours after ingestion.  
          The pre-icteric phase can only be detected by an increase in 
          serum transaminases. Hepatitis becomes clinically evident with 
          the onset of jaundice on the 3rd -4th day after ingestion.  In 
          severe intoxications, patients develop fulminant hepatitis with 
          hepatic coma, bleeding and anuria.  When liver damage is 
          reversible, patients usually make a slow and steady recovery.  In 
          fatal cases death occurs within 6 - 16 days (mean 8 days). 

          Prognosis: An analysis of the literature shows that the factors 
          most likely to indicate a poor prognosis in Amanita hepatitis are 
          peak prothrombin time > 100 sec; factor V < 10%; lactic 
          acidosis; gastrointestinal bleeding; and age < 12 years.  Other 
          criteria, such as the duration of the latency period; the peak 
          serum concentration of aminotransferases; and amanitin analysis 
          are not useful for prognosis.  Orthotopic liver transplantation 
          should be considered in patients with poor prognosis criteria. 

          In a study of 205 amanita intoxications, the gastrointestinal 
          syndrome was present in 199 patients and hepatitis in 198;  52 
          patients developed hepatic coma and the overall mortality was 
          22.4% (Floersheim et al, 1982) 

     9.4  Systematic description of clinical effects

          9.4.1 Cardiovascular

               In the gastrointestinal phase, vomiting and diarrhoea can 
               produce severe fluid losses resulting in hypovolaemic shock 
               with tachycardia and a fall in central venous pressure. 
               Functional reversible renal failure often accompanies 
               hypovolaemic shock secondary to gastrointestinal fluid loss. 

               When shock occurs in the hepatitic phase, it is mainly due 
               to haemorrhage secondary to severe coagulation disorders. 
               Cardiovascular collapse also accompanies severe hepatic 
               failure in the terminal phase. 

          9.4.2 Respiratory

               Respiration is usually normal but hyperventilation 
               accompanies fulminant hepatitis.  Respiratory failure with 
               hyperventilation or apnoea may occur in patients presenting 
               with hepatic coma and has a poor prognosis. 


          9.4.3 Neurological

               9.4.3.1   CNS

                    Neurologic symptoms are related to hepatic 
                    encephalopathy which usually occurs 5 - 6 days after 
                    ingestion.  Somnolence and confusion are the first 
                    signs, and coma usually follows.  Convulsions may be 
                    observed in hepatic coma. 

                    In severe hepatic failure, coma may also be due to
                    hypoglycaemia secondary to disordered glucose 
                    metabolism. 

               9.4.3.2   Peripheral nervous system.

                    No data available.

               9.4.3.3   Autonomic nervous system

                    No data available.

               9.4.3.4   Skeletal and smooth muscle

                    No data available.

          9.4.4 Gastrointestinal

               Gastrointestinal symptoms appear after a latent period of 6 
               - 24 hours (mean 12.3 hours).  In a study of 205 Amanita
               intoxications, gastrointestinal symptoms were present in 199 
               patients (Floersheim et al, 1982). 

               a)  Nausea, vomiting, colic.

               There is a sudden onset of colicky abdominal pain rapidly 
               followed by nausea, frequent vomiting and diarrhoea. 

               b)  Diarrhoea

               In most cases, diarrhoea is severe, watery and cholera-like.  
               In the absence of fluid replacement, diarrhoea rapidly 
               induces dehydration, haemoconcentration and hypovolaemic 
               shock.  Diarrhoea may persist for 2 - 4 days. 

          9.4.5 Hepatic

               Clinical signs of hepatocellular damage usually develop on 
               the 3rd to 4th day after ingestion.  Clinical presentation 
               may only include a mild jaundice and a mild hepatomegaly. 

               In severe cases, hepatitis follows a fulminant course with 
               marked jaundice and hepatic coma and may be accompanied by 
               renal failure and cardiovascular collapse.  In fatal cases, 
               death occurs within 6 - 16 days (mean 8 days). 


          9.4.6 Urinary

               9.4.6.1   Renal

                    Two types of renal failure may be observed.  During the 
                    gastrointestinal phase a functional renal failure is 
                    frequent.  It is associated with hypovolaemia and is 
                    secondary to fluid loss and to hypoperfusion of the 
                    kidneys.  It may improve if dehydration and 
                    hypovolaemia are corrected aggressively. 

                    Anuria and renal failure may occur during the third 
                    phase of poisoning together with severe hepatitis, 
                    hepatic coma and haemorrhage. 

                    Serious kidney complications may be avoided by 
                    administration of fluids (Constantino et al, 1978, 
                    Vesconi et al, 1985).  A direct nephrotoxic effect of 
                    amatoxins has not been proven in human intoxication. 

               9.4.6.2   Others

                    No data available.

          9.4.7 Endocrine and reproductive systems

               No data available.

          9.4.8 Dermatologic

               Mild jaundice with icteric sclerae is present in the hepatic 
               phase. 

          9.4.9  Eyes, ear, nose, throat:  local effects

               Eyes:Scleral icterus occurs.

               Nose:Nasal haemorrhage may occur in patients with 
                    coagulation disorders secondary to severe 
                    hepatocellular damage.  If intubation is necessary, the 
                    nasal route should be avoided because it may induce 
                    severe local haemorrhage. 

          9.4.10 Haematological

               Severe hepatocellular damage may result in severe 
               haemorrhage. 

               Usually the earliest indication of coagulopathy is 
               persistent bleeding from IV puncture sites (Bivins et al, 
               1985).  Other bleeding, epistaxis and gastrointestinal 
               haemorrhage may occur. 

               These are due to marked coagulation defects secondary to 
               impaired synthesis of clotting factors.  This indicates a 

               poor prognosis. (Floersheim, 1987). 


          9.4.11 Immunologic

               No data available.

          9.4.12 Metabolic

               9.4.12.1  Acid based disturbances

                    In the gastrointestinal phase, metabolic acidosis may 
                    occur as the result of bicarbonate loss in diarrhoea; 
                    in later stages, acidosis may be due to hepatic 
                    failure. 
     
               9.4.12.2  Fluid and electrolyte disturbances

                    Dehydration and hypovolaemia
     
                    The gastrointestinal syndrome often results in marked 
                    dehydration and hypovolaemia with haemoconcentration 
                    and functional renal failure. 

                    Electrolyte disturbances

                    Hypokalaemia is particularly common in the 
                    gastrointestinal phase. 
     
               9.4.12.3  Others

                    Glucose

                    Glucose metabolism is often disturbed in severe hepatic 
                    failure.  Spontaneous hypoglycaemia results from 
                    impaired glycogenolysis and gluconeogenesis (Bivins et 
                    al, 1985).  

                    Hepatic enzymes

                    Elevated serum transaminase, LDH and serum bilirubin 
                    are the first and best indicators of liver damage and 
                    should be monitored throughout the course of the 
                    illness.  Hepatic enzymes usually reach a peak after 60 
                    - 72 hours and then decrease.  Enzyme levels may be 
                    relatively low in massive liver necrosis (Bivins et al, 
                    1985). 

                    Coagulation parameters

                    Coagulation disorders indicate hepatic insufficiency.  
                    Levels of clotting factors synthesized by the liver, 
                    such as fibrinogen and prothrombin, may be decreased.  
                    A prothrombin level below 10 per cent indicates a poor 
                    prognosis (Floersheim 1987) 


          9.4.13 Allergic reactions

               No data available.


          9.4.14 Other clinical effects

               Amatoxin does not affect temperature regulation directly but 
               temperature disorder may occur in severe hepatic failure 
               with encephalopathy. 

          9.4.15 Special risks:  pregnancy, breast feeding, enzyme 
                 deficiency 

               Pregnancy:  Kauffmann et al, (1978) reported a Amanita 
               phalloides poisoning in a 25 year old woman at 9 weeks 
               gestation.  The patient developed a toxic hepatitis 
               (transaminase 1800 U/l).  After life threatening maternal 
               illness was overcome, a therapeutic abortion was carried out 
               at 12 weeks gestation.  Histologic examination of the foetal 
               liver showed cellular damage related to amanitin toxicity. 
               Amatoxins therefore cross the placenta barrier in 
               concentrations sufficient to affect the foetus. 

               Breast-feeding:  Because amatoxins are excreted in breast 
               milk, nursing mothers who have ingested Amanita, whether 
               they are symptomatic or not, should be told to stop nursing 
               until it is determined whether or not they have been 
               poisoned (Bivins et al, 1985). 

     9.5  Others

          No data available.

    10.  MANAGEMENT

     10.1 General principles

          Management depends on the length of time since ingestion and on
          symptoms.

          Supportive treatment includes:

          Gastrointestinal phase:  maintenance of fluid and electrolyte 
          balance.  

          Hepatic phase: correction of coagulation disorders, serum glucose 
          disorders, treatment of respiratory and renal failure.

          Prevention of absorption:

          By emesis or gastric lavage in cases of recent ingestion; by 
          repeated oral activated charcoal. 

          Several antidotes have been proposed for the management of 
          amatoxin poisoning, including thioctic acid, high-dose 

          penicillin, silibinin, steroids, cytochrome C and hyperbaric 
          oxygen (Parisch and Doehring 1986, Floersheim 1987).  None of 
          these has been clearly proven to be of clinical efficacy (Bivins 
          et al, 1985).  However, penicillin and silibinin apparently have 
          some antitoxic effects in vitro and therefore should be included 
          tentatively in the management. 


          Enhanced elimination

          According to recent toxicokinetic studies (Vesconi et al, 1985, 
          Jaeger et al, 1988) only forced diuresis appears substantially to 
          enhance the elimination of amatoxins.  This should be instituted 
          as early as possible. 

     10.2 Relevant laboratory analyses and other investigations

          10.2.1 Sample collection

               Collect samples of mushroom material, vomitus, lavage fluid 
               and diarrhoea for toxicological identification. 

          10.2.2 Biomedical analysis

               Monitor hepatic enzymes: LDH and serum transaminases 
               bilirubin. they are the first and the best indicators of 
               liver damage and should be monitored throughout the course 
               of the illness. 

               Monitor serum electrolytes, blood gases, BUN, serum 
               creatinine in order to detect hypokalaemia, metabolic 
               acidosis and renal failure. 

               Monitor coagulation parameters especially the clotting 
               factors fibrinogen and prothrombin synthesized by the liver. 
               A prothrombin level below 10% indicates a poor prognosis 
               (Floersheim, 1987). 

               Monitor serum glucose levels hourly at the bedside in order 
               to detect and correct hypoglycaemia (Bivins et al, 1985). 

          10.2.3 Toxicological/Toxinological  analysis

               Analysis of amatoxins in biological fluids is not clinically 
               useful in the early management of poisoning.  However, 
               amatoxin determination may be useful to confirm the 
               diagnosis before the onset of hepatic failure. 

     10.3 Life supportive procedures and symptomatic treatment

          On admission insert a central venous catheter and an urinary 
          catheter. Frequently monitor blood pressure, central venous 
          pressure, urinary output and vital signs. 

          Give supportive treatment for dehydration and electrolyte 
          disorders. 

          Vigorous and immediate correction of dehydration and hypovolaemia 
          is essential to prevent renal failure. Start forced diuresis 
          (Vesconi et al, 1985, Bivins et al, 1985).  Administration of 
          plasma expanders and fluids should be guided by monitoring of 
          blood pressure, central venous pressure and urinary output. 

          Correct hypokalaemia (by KCl diluted in solutions of dextrose 5 
          %, or NaCl 0.9 %) and metabolic acidosis (by sodium bicarbonate 
          solution 1.4%) according to the results of repeated laboratory 
          analyses. 

          Supportive treatment of hepatic failure

          1.  Hypoglycaemia

               Serum glucose levels should be measured hourly at the 
               bedside (Bivins et al, 1985).  Give IV solution of 10 % 
               dextrose by continuous infusion and additional boluses of 
               glucose as indicated by laboratory tests. 

          2.  Coagulation Disorders

               Monitor coagulation (prothrombin and fibrinogen).  If 
               hypoprothrombinaemia and hypofibrinogenaemia or clinical 
               haemorrhage are present give vitamin K (10 - 30 mg/day IV) 
               and fresh frozen plasma. 

          3.   Hepatic encephalopathy and renal failure require standard 
               management, including protein restriction, bowel cleansing, 
               artificial ventilation, haemodialysis. 

          4.   Liver transplantation

               Liver transplantation should be considered in poisoning with 
               severe hepatic failure.  Criteria for severe hepatic failure 
               and a poor prognosis are: hepatic encephalopathy, marked 
               jaundice, oliguria or anuria, bleeding, hypoglycaemia, and a 
               prothrombin level < 10%. 

     10.4 Decontamination

          Indications:  Treatment depends on the length of time since 
          ingestion and on the symptoms. 

          1.  Prior to development of symptoms, emptying the stomach by 
          gastric lavage or emesis and inducing diarrhoea with cathartics. 
          Then administer oral activated charcoal and perform intermittent 
          gastroduodenal aspiration. 

          2.  After the onset of the gastrointestinal phase, administer 
          repeated oral activated charcoal and perform intermittent 
          gastroduodenal aspiration. Diarrhoea should not be treated except 
          by fluid replacement. 

          The advantage of gastric lavage is that charcoal which may be

          administered through the lavage tube immediately after gastric 
          emptying (Bivins et al, 1985). 

     10.5 Elimination

          Cathartics:  indicated if the patient is seen before the 
          gastrointestinal phase or if diarrhoea is not severe. 

          Gastroduodenal aspiration:  Intermittent gastroduodenal 
          aspiration (between charcoal administrations) is indicated in 
          order to remove toxins eliminated in the bile (Busi et al, 1979; 
          Jaeger et al, 1988). 

          Forced diuresis:  Toxicokinetic studies (Vesconi et al, 1985, 
          Jaeger et al, 1988)  indicate that significant amounts of 
          amatoxins are eliminated in urine especially during the 48 hours 
          following ingestion. Early forced diuresis is therefore indicated 
          and should be instituted immediately after admission of the 
          patient to hospital during correction of dehydration. 

          Other techniques:  Toxicokinetic studies (Vesconi et al, 1985, 
          Jaeger et al, 1988) showed that amatoxins were present in serum 
          only during the first 24 - 48 hours and at very low 
          concentrations compared with concentrations found in urine.  
          Extracorporeal elimination (plasmapheresis, peritoneal dialysis, 
          haemodialysis and haemoperfusion) is not indicated. Haemodialysis 
          or haemoperfusion in order to remove amatoxins would only be 
          indicated if a patient with previous renal failure develops 
          Amanita intoxication. 

     10.6 Antidote treatment

          Currently no specific antidote for amatoxins is available.  
          However it has been suggested that some drugs may have some 
          "antidotal" effect. 

          Penicillin G

          Experimental studies have shown that penicillin G reduced or 
          inhibited hepatic uptake of amatoxins and protected mice and rats 
          against lethal doses of amatoxins (Floersheim, 1987).  Moreover, 
          in a retrospective study administration of penicillin was 
          significantly more often associated with survival (Floersheim et 
          al, 1982).  Early treatment with high doses of penicillin G is 
          recommended using 300,000 - 1,000,000 U/kg/day as an IV infusion 
          (Floersheim, 1987) 

          Silibinin

          The antidotal effects of silibinin against amatoxins has been 
          confirmed in experimental models.  Silibinin is thought to 
          inhibit the penetration of the amatoxins into liver cells (Jahn 
          et al, 1980, Floersheim, 1987). Administration of silibinin is 
          recommended if the patient is seen within 48 hours of ingestion.  
          The doses are 20 - 50 mg/kg/day IV and treatment should be 
          continued for 48 - 96 hours. 

          Silimaryn (Legalon R 70) capsules, 1.4 - 4.2 g/day for 4 days,
          may also be given but this treatment may be useless if the 
          patient presents with vomiting or is treated by oral charcoal. 

          Thioctic Acid

          The clinical efficacy of this agent has not been proved and 
          experimentally thioctic acid was ineffective as an antidote 
          against amatoxins in mice and dogs (Floersheim, 1987).  There is 
          no reason to continue its use. 

          Cimetidine

          Cimetidine has been investigated as a possible antidote.  In an 
          experimental study, Schneider et al (1987) noted decreased liver 
          fatty changes in mice treated by high doses of cimetidine.  
          However, much work needs to be done before cimetidine can be 
          recommended as a standard therapy. 

          Cytochrome C

          The clinical efficacy of cytochrome C has not been proven 
          (Floersheim et al, 1982). 

     10.7 Management discussion: alternatives and controversies, research 
          needs 

          Hospitalisation Criteria

          If a patient develops gastroenteritis 6 - 24 hours after 
          ingestion of mushrooms,  poisoning by amatoxin-containing 
          mushrooms shouldbe considered.  The patient should be admitted 
          immediately to an intensive care unit and appropriate treatment 
          should be started. 

          If a group of people ate the same type of mushroom and one 
          presents with symptoms, consider the possibility that the others 
          who are not yet symptomatic also may have been poisoned and will 
          require treatment (Bivins et al, 1985). 

          Mixed intoxication

          If patients who have eaten several kinds of unidentified 
          mushrooms develop early gastrointestinal symptoms, additional 
          amatoxin intoxication should be considered if gastrointestinal 
          symptoms last for more than 24 hours. 

    11.  ILLUSTRATIVE CASES

     11.1 Case report from the literature

          a)   Floersheim et al (1982) studied 205 cases of Amanita 
          phalloides poisoning.  The mortality was 22.4%.  Death rate was 
          51.3% in children below 10 years of age but only 16.5% in 
          patients older than 10 years. 

          84% of patients with thromboplastin time below 10% died while all 
          patients with minimum values greater than 40% survived.  
          Treatment with a combination of penicillin and silibinin was 
          associated with an increased survival. 

          b)   Vesconi et al (1985) reported 53 cases of Amanita phalloides 
          poisoning inpatients aged from 4 - 72 years; the mortality was 
          11.3%.  All deaths were due to acute liver failure and occurred 6 
          - 12 days after admission.  In 19 of 29 patients, amatoxins were 
          detected in serum (0.5 -24 mg/l).  Amatoxins were detected in 
          urine in all 19 patients studied (0.5 -56 mg/l).  The authors 
          recommend the following treatment: 

          Immediate and vigorous rehydration, gastroduodenal lavage, 
          laxatives and adsorbent agents, forced diuresis, high doses of 
          penicillin and silimaryn. 

          c)   Woodle et al (1985) reported a 3 year-old girl who had 
          ingested Amanita phalloides.  She developed abdominal pain, 
          vomiting, diarrhoea and then hepatitis.  Laboratory data showed 
          marked cytolysis (SGOT 16,648 U/l; SGPT 9,844 U/l) and 
          coagulation disorders (prothrombin time 34.2. sec).  Serum 
          bilirubin was 23 mg/L and ammonia was 122 mg/dL. Despite 
          supportive treatment the patient deteriorated rapidly and 
          developed Grade III encephalopathy. An orthotopic liver 
          transplant was performed on the 5th day.  After transplantation 
          the patient improved rapidly but showed neurological sequelae. 

          d)   Genser et Marcus (1987) reported a group of 10 patients who 
          ingested Amanita virosa mushrooms.  All were treated with gastric 
          lavage, insertion of a tube into the second portion of the 
          duodenum for suction, charcoal hemoperfusion, and high dose 
          intravenous penicillin G.  Despite these treatment, 3 of the 10 
          developed moderate to severe hepatotoxicity and renal injury.  
          One of these three developed hepatic coma and a severe 
          coagulopathy.  The remaining 7 patients had gastrointestinal 
          toxicity and mild to moderate organ toxicity.  All 10 patients 
          recovered fully. 

     11.2 Internally extracted data on cases  
     
          Jaeger et al (1988) studied amatoxin kinetics in 32 cases.  
          Amatoxins were found in serum in only 10 patients.  Mean 
          concentrations were 73 mg/l for alpha amanitin and 55.6 mg/l for 
          beta amanitin.  Amatoxins were present in urine in all 15 cases 
          studied at concentrations as high as 4,800 mg/l for apha amanitin 
          and 4,300 mg/l beta amanitin.  Mean total amounts of  0.95 mg 
          alpha amanitin and mean 1.7 mg beta amanitin were excreted in
          urine over 32 hours.  High amatoxin concentrations were also 
          found in gastroduodenal fluids and in faeces.  The authors 
          recommend early and vigorous rehydration and early forced 
          diuresis. 

          A 26 month-old child was admitted with acute hepatitis following 
          amanita phalloides ingestion.  Transaminase levels reached a peak 

          of 17,400 IU/l for GOT and 14,300 IU/l for GPT.  On the 3rd day 
          she developed severe coma with hepatocellular insufficiency 
          (prothrombin level lower than 10%). On the 4th day an orthotopic 
          liver transplant was performed.  Clinical and biological status 
          improved rapidly.  Immunosuppressive treatment included 
          cyclosporin, azathioprine and methylprednisolone (case to be 
          published by Butscher et al). 

     11.3 Internal cases

          To be added by PCC.

    12.  ADDITIONAL INFORMATION

     12.1 Availability of antidotes and antisera

     12.2 Specific preventive measures

     12.3 Other


    13.  REFERENCES

     13.1 Clinical and toxicological

          Andres RY, Frei W (1987).  Amatoxin and Anti-Amatoxin for 
          radioimmunoassay prepared by a novel chemical approach. Toxicon 

          Bonneti E, Derenzini M, Fiume L (1976).  Increased penetration of 
          amanitine into hepatocytes when conjugated with albumin. Arch 
          Toxicol 35:69-73 

          Busi C, Fiume L, Costantino D, Langer M, Vesconi F (1979). 
          Amanita Toxins in gastroduodenal fluid of patients poisoned by 
          the mushroom Amanita phalloides. New England J Med 300:800 

          Caccialanza G, Gandini C, Ponci R (1985). Direct simultaneous 
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          179-185 

          Faulstich H, Fauser U (1973).  Unterschungen zur Frage der 
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          Faulstich H, Trischmann H, Zobeley S (1975). A radioimmunoassay 
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          Faulstich H, Jahn W, Wieland Th (1980). Silybin inhibition of 
          amotoxin uptake in the perfused rat liver. Arzneim Forsch (Drug 
          Res) 30:452-454 

          Faulstich H, Talas A, Wellhoner HH (1985).  Toxicokinetics of 
          labelled amatoxins in the dogs. Arch Toxicol 56: 190-194 

          Fiume I, Busi C, Campadelli-Fiume G, Franceschi C (1975). 

          Production of antibodies to amanitins as the basis for their 
          radioimmunoassay. Experientia 1233-4 

          Floersheim GL Weber O, Tschumi P, Ulbrich M (1982). Die klinische 
          knollenblaterpilzvergiftung (Amanita Phalloides): prognostische 
          faktoren und therapeutische massnahmen. Schweiz Med Wschr 112: 
          1164-1177 

          Floersheim GL (1983). Diagnose der Knolleblatter-pilzvergiftung. 
          Deutsch Med Wschr 112:1164-1177 

          Hanrahan JP, Gordon MA (1984). Mushroom poisoning. J Am Med Assoc 
          251:1057-1061 

          Homann J, Heinrich D, Wizemann V, Matthes KJ (1983). Soll die 
          Therapie bei knollenblatterpilzvergiftung wirklich qeandert 
          werden? Deutsch Med Wschr 108: 1455-1456 

          Jahn W, Faulstich H, Wieland T.  Pharmacokinetics of {3H}-methyl-
          dehydroxymethyl-amanitin in the isolated perfused rat liver, and 
          the influence of several drugs.  In: Faulstich H;, Kommerell B;, 
          Wieland T (eds) Amanita toxins and poisoning.  Witzstrock, Baden-
          Baden, pp. 80-85 

          Jehl F, Gallion C, Birckel P, Jaeger A, Flesch F, Minck R (1985). 
          Determination of alpha-amanitin and beta-amanitin in human 
          biological fluids by high-performance liquid chomatography. Anal 
          Biochem 149: 35-42 

          Johnson BEC, Preston JF, Kimbrough JW (1976). Quantitation of 
          amanitins in Galerina Autumnalis. Mycologia 67: 1248-1253 

          Kaufmann M, Muller A, Paweletz N, Haller U, Kubli F (1978). 
          Fetale Schadigung bei einer knollenblatter-pilzvergifting der 
          mutter in der Fruhschwangerschaft. Geburtsh Frauenheilk 38: 122-
          124 

          Larcan A, Lambert H, Laprevote-Heully MC, Patret JL (1976). 
          Reflexion sur le traitement d'urgence et la reanimation de 
          l'intoxication phalloidienne. GM de France 83: 1319-1333 

          Larcan A, Lambert H (1980).  Intoxications phalloidiennes.  Une 
          mortalite de 8, 4% au Centre Anti-Poisons de Nancy. Quot Medecin 
          12 

          Marra F, D'Aiuto G, Fasano C, Russo N, Fratello U (1977).  
          Epatite tossica da amanita phalloides. Min Anest 43: 357-366 

          Pastorello L, Tolentino D (1982).  Determination of alpha 
          amanitin by high-performance liquid chromatography.  J 
          Chromatography 233: 398-403 

          Preston JF, Stark HJ, Kimbrough JW (1974).  Quantitation of 
          amanitins in Amanita Verna with calf thymus RNA polymerase. B 
          Lloydia 38: 153-161 

          Seeger R, Stijve T (1979).  Amanitin content and toxicity of 
          Amanita. Verna bull Z Naturforsch 34: 1133-1138 

          Woodle ES, Moody RR, Cox KL, Cannon RA, Ward RE (1985). 
          Orthotopic liver transplantation in a patient with Amanita 
          poisoning. J Am Med Assoc 253: 69-70 

     13.2 Botanical

          Bivins HG, Bivins R, Lammers R, McMicken DB, Wolowodiuk O (1985). 
          Mushroom ingestion. Ann Emergency Med 14: 101-106 

          Jaeger A, Flesch F, Jehl F, Sauder Ph, Kopferschmitt J (1980). 
          Les intoxications par champignons. Personal cases. 

          Yocum RR, Simons DM (1977).  Amatoxins and phallotoxins in 
          Amanita species of the North-Eastern United State. Lloydia 40: 
          178-190 

    14.  AUTHOR(S), REVIEWERS(S) DATES (INCLUDING EACH UPDATING),
     COMPLETE ADDRESSES

     Authors:  A Jaeger , F Flesch, Ph Sauder, J Kopferschmitt
               Centre Anti-Poisons
               Hospices Civils de Strasbourg
               67091 Strasbourg Cédex
               France

               Tel: 33-88161114 (direct)
               Fax: 33-88161930

     Date:     25 April 1989

     Peer Review: London, March 1990













    See Also:
       Toxicological Abbreviations