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Colchicum autumnale L.

1. NAME
   1.1 Scientific name
   1.2 Family
   1.3 Common name(s) and synonyms
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 physico-chemical characteristics
   3.4 Other chemical contents of the plant
4. USES/CIRCUMSTANCES OF POISONING
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstances
   4.3 High risk geographical areas
5. ROUTES OF EXPOSURE
   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 and excretion
7. TOXINOLOGY
   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 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
   8.6 References
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
      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 Central nervous system (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 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base 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
   9.5 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote/antitoxin treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventative measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES):



    COLCHICUM AUTUMNALE

    International Programme on Chemical Safety
    Poisons Information Monograph 142
    Plant

    1.  NAME

        1.1  Scientific name

             Colchicum autumnale L.

        1.2  Family

             Colchicaceae

        1.3  Common name(s) and synonyms

             Common names:

             Autumn crocus (UK); 
             azafran silvestre;
             colchico (Italy); 
             colchico autumnale (Italy); 
             colchico comun colchicum;
             colchique (France); 
             dame nue; 
             fall crocus (USA); 
             Herbstblume (Germany);
             Herbstzeitlose (Germany); 
             meadow crocus; 
             meadow saffron (UK);
             Michelwurz (Germany); 
             mysteria;
             Nackte Jungfer (Germany); 
             naked boys;
             naked ladies (UK); 
             purple crocus; 
             safran des prés; 
             tue-chien;
             veilleuse; 
             Wiesensafran (Germany);
             Winterhauch (Germany); 
             wonder bulb;
             zafferano bastorda (Italy); 
             zafferano salvatico (Italy); 
             Zeitlose (Germany).

             Latin synonyms:

             C. autumnale subspecies pannonicum (Griseb. & Schenk) Nyman; 
             C. autumnale var. bulgaricum (Velen.) Domin;
             C. borisii Stef.; 
             C. bugaricum Velen.; 
             C. commune Neck.;
             C. drenowskii Degen & Rech.f.; 
             C. haynaldii Heuff.; 
             C. pannonicum Griseb. & Schenk; 
             C. polyanthon Ker Gawl.; 
             C. praecox Spenn.; 
             C. rhodopaeum Kov.;
             C. transsilvanicum Schur; 
             C. vernale Hoffm.; 
             C. vernum Kunth; (Strid & Tan, 1991; Tutin et al., 1980).

    2.  SUMMARY

        2.1  Main risks and target organs

             Colchicine exerts multi-organ toxicity.  The main toxic
             effects are related to the effects of colchicine on mitosis
             and account for diarrhoea, bone marrow depression,
             cardiotoxicity, central nervous system disturbances and
             alopecia.  Other acute effects are hypovolemia, shock and
             coagulation disturbances, which may lead to death.

        2.2  Summary of clinical effects

             Toxic manifestations appear after a delay of 2 to 12
             hours following ingestion or parenteral administration. 
             Symptomatology progresses in three stages:
    
             Stage I  (Days 1-3)  Gastrointestinal and circulatory
             phase:
    
             -Severe gastrointestinal irritation:  nausea, vomiting,
             abdominal cramps, severe diarrhoea.
             Central nervous system excitation and/or depression.
    
             -Dehydration, hypovolemia, shock.  Cardiogenic shock may
             occur and may result in death within the 72 hours.
    
             -Hypoventilation, acute respiratory distress syndrome.
    
             Stage II  (Days 3-10) Bone marrow aplasia phase:
    
             -Bone marrow aplasia with agranulocytosis.
    
             -Coagulation disorders with diffuse haemorrhages.
    
             -Rhabdomyolysis.
    
             -Polyneuritis, myopathy, ascending paralysis.
    
             -Acute renal failure.
    
             -Infectious complications.
    
             Stage III  (After 10 days) Recovery phase:
    
             -Alopecia.

        2.3  Diagnosis

             Colchicine levels are not clinically useful:  biological
             samples must be stored in airtight conditions and protected
             from light.
    

             Monitor the following:
    
             -Electrolytes, particularly potassium, calcium.
    
             -Acid-base balance.
    
             -Full blood count and platelets.
    
             -Coagulation parameters and fibrin/fibrinogen degradation
             products.
    
             -Creatinine phosphokinase and transaminases.

        2.4  First-aid measures and management principles

             Patients with C. autumnale poisoning should always be
             admitted as soon as possible in an intensive care unit (and
             monitored for at least 48 hours).
    
             Treatment may include:

             -Early gastric emptying.
             Activated charcoal in repeated doses.
    
             -Rehydration, plasma expander infusion, inotropic and
             vasopressor drugs.
    
             -Artificial ventilation.
    
             -Correction of electrolyte and acid-base disorders.Early
             forced diuresis.
    
             -Prevention of infectious complications.
             Monitor vital signs (ECG, blood pressure, respiration,
             central venous pressure), fluid and electrolyte balance,
             haematological and coagulation parameters.

        2.5  Poisonous parts

             The active principles are contained in all parts of the
             plant, especially in the seeds and bulbs.

        2.6  Main toxins

             The main toxin is colchicine.  Several other less toxic
             principles have been isolated (Gessner & Orzechowski,
             1974).

    3.  CHARACTERISTICS

        3.1  Description of the plant

             3.1.1  Special identification features

                    Colchicum autumnale is a small herbaceous
                    perennial plant 10 to 40 cm high, flowering typically
                    in the autumn after the leaves have disappeared.
    
                    Leaves: lanceolate, dark green, shiny (15 to 35 cm x 2
                    to 7 cm).  They appear in the spring, then die back
                    before the flowers appear.
    
                    Flowers: showy pink, purple to white flowers in groups
                    of 1 to 6 are produced from an underground bulb.  Each
                    petal is about 3 to 4.5 cm long and is fused below
                    into a pale stalk-like tube 5-20 cm long.
    
                    Fruit: an oblong to ovoid green then brown capsule
                    containing many seeds (180 to 200).
    
                    Bulb: thickened, vertical, underground stem, 2.5 to 6
                    x 2 to 4 cm, covered in a brown tunic.
    
                    Different aspects of C. autumnale may be seen
                    throughout the year:
    
                    -in spring: leaves with fruit (April to July)
                    -in autumn: flowers. (August to October)
    
                    (Huxley, 1992).

             3.1.2  Habitat

                    C. autumnale grows in wet meadows, woodland
                    clearings and shady rocky habitats on non calcareous
                    substrates.  It may be found up to an altitude of
                    2,000 metres.

             3.1.3  Distribution

                    C. autumnale is a native plant of south, west
                    and central Europe, extending to the eastern banks of
                    the Black Sea, in Georgia (Bruneton, 1995; Tutin et
                    al., 1980).  The plant is cultivated throughout much
                    of the world, primarily as an outdoor
                    ornamental.

        3.2  Poisonous parts of the plant

             All parts of the plant contain toxins.  The greatest
             concentration of toxins is found in the seeds and the bulb
             (corm) (Cooper & Johnson, 1984; Frohne & Pfänder, 1983). 
             Colchicine is present in the flowers (0.1 to 0.8% in fresh
             flowers; up to 1.8% in dried flowers), in the seeds (0.2 to
             0.8%) in the bulb (corm) (0.4 to 0.6%).  The leaves contain
             very low amounts of colchicine (Gessner & Orzechowski,
             1972).

        3.3  The toxin(s)

             3.3.1  Name(s)

                    C. autumnale contains several active
                    principles.  Colchicine, the major toxin, is an
                    alkaloid which was isolated by Pelletier and Caventou
                    in 1820 but at the time was thought to be veratrine
                    which is similar in effect.  It was Geiger in 1833
                    that identified the toxin as colchicine (Neuwinger,
                    1994).  The other toxins present, which are closely
                    related to colchicine, include:
                    desacetylmethylcolchicine, desacetylthiocolchicine,
                    colchicoside, demethyl desacetylcolchicine.

             3.3.2  Description, chemical structure, stability

                    CAS number:
    
                    colchicine: 64-86-6
                    desacetylmethylcolchicine: 477-30-5
                    desacetylthiocolchicine: 2731-16-0
    
                    Molecular weight:
    
                    colchicine: 399.48
                    desacetylmethylcolchicine: 371.47
                    desacetylthiocolchicine: 373.50
    
                    Chemical structure:
    
                    colchicine:  C22H25NO6
                    desacetylmethylcolchicine: CHNO5
                    desacetylthiocolchicine: CH23NO4S
    
                    The biological activity of colchicine is due to a
                    portion of its tricyclic molecule, a seven-membered
                    aromatic cyclopentatrieolone ring (tropolene)
                    (Neuwinger, 1994).

             3.3.3  Other physico-chemical
             characteristics

                    Colchicine is freely soluble in alcohol or
                    chloroform and slightly soluble in petroleum ether. 
                    Solubility in water is 1/25.  On exposure to light,
                    colchicine is transformed to lumicolchicine. 
                    Colchicine is not altered by desiccation of the plant
                    and it is thermostable.

        3.4  Other chemical contents of the plant

             No data available.

    4.  USES/CIRCUMSTANCES OF POISONING

        4.1  Uses

             4.1.1  Uses

                    Miscellaneous pharmaceutical product
                    Other therapeutic preparation
                    Other drug; veterinary

             4.1.2  Description

                    Medical:
    
                    Several extracts of C. autumnale have been used in
                    therapeutics: powder of seeds, tincture of seeds or
                    bulb, alcoholic extracts.
    
                    2.5 g of seeds and 25 g of tincture contain 10 mg
                    colchicine.  Although colchicine has been used for
                    several diseases including neoplastic and allergic
                    diseases, and as a diuretic, it is currently almost
                    exclusively used as a pharmaceutical in the treatment
                    of gout attack and familial Mediterranean Fever.
    
                    Homeopathic medicine:
    
                    C. autumnale is used for gout and polyarthritis.
    
                    Veterinary medicine:
    
                    C. autumnale is used for arthritis and as a
                    diuretic.

        4.2  High risk circumstances

             Poisoning by C. autumnale is a rare event.  Several
             circumstances of poisoning have been reported (Gessner &
             Orzechowski, 1974).
    
             Accidental poisoning:
    
             -ingestion of seeds by children using the dried seed parts as
             rattles;
    
             -ingestion of leaves as "salad";
    
             -ingestion of bulbs in mistake for onions;
    
             -ingestion of powder of seeds;
    
             -ingestion in order to induce abortions;
    
             -poisoning of nursing animals or of human beings after use of
             milk from poisoned animals (goats, sheep).
    
             (Cooper & Johnson, 1984; Gessner & Orzechowski, 1974;
             Kingsbury, 1964).
    
             Voluntary intoxication:
    
             -Ellwood and Robb (1971) reported a case of a 16-year-old
             girl who had eaten a dozen flowers.
    
             Criminal intoxication:
    
             -by alcoholic extract has been reported (Gessner &
             Orzechowski, 1974).

        4.3  High risk geographical areas

             See section 3.1.3.

    5.  ROUTES OF EXPOSURE

        5.1. Oral

             Intoxication is always due to oral absorption of parts
             of the plant or extracts.

        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:
    
             Rapidly absorbed from the gastrointestinal tract.  Peak
             plasma concentration is reached 0.5 to 2 hours after
             ingestion (Wallace & Ertel, 1973).
    
             Half time of absorption is 15 minutes (Galliot, 1979).
    
             Absorption may be modified by pH, gastric contents,
             intestinal motility (Wallace et al., 1990)
    
             Colchicine is not totally absorbed.  There is an important
             hepatic first pass effect.

        6.2  Distribution by route of exposure

             Protein binding is 10 to 20% (Bennett et al., 1980).
    
             Colchicine distributes in a space larger than that of the
             body.  The apparent volume of distribution is 2.2 L/kg
             (Wallace et al., 1970).  In severe renal or liver diseases
             the volume of distribution is smaller (1.8 L/kg).
    
             Colchicine accumulates in the kidney, liver, spleen,
             gastrointestinal wall and leukocytes but not in heart, brain,
             skeletal muscle.
    
             Colchicine crosses the placenta and has also been found in
             maternal milk.

        6.3  Biological half-life by route of exposure

             a) Parenteral:
    
             After a single 2 mg intravenous dose the average plasma half-
             life is 20 minutes (Wallace et al., 1970).  Plasma half-life
             is increased in severe renal disease (40 minutes) and
             decreased in severe hepatic disease (9 min) (Wallace et al.,
             1970).
    
             b) Oral:
    
             After oral administration plasma concentrations reach a peak
             within 0.5 to 2 hours and afterwards decrease rapidly within
             2 hours (Wallace & Ertel, 1973).  The plasma half-life is 60
             minutes (Galliot, 1979).  Colchicine may remain in tissues
             for as long as 10 days.

        6.4  Metabolism

             Colchicine undergoes some hepatic metabolism. 
             Colchicine is partially deacetylated in the liver (Naidus et
             al., 1977).  Large amounts of colchicine and of its
             metabolites undergo enterohepatic circulation.  This may
             explain the occurrence of a second plasma peak concentration
             observed 5 to 6 hours after ingestion (Galliot, 1979;
             Walaszek et al., 1960).

        6.5  Elimination and excretion

             Colchicine is excreted unchanged (10 to 20%) or as
             metabolites.
    
             Kidney:
    
             Urinary excretion amount to 16 to 47% of an administered dose
             (Heaney et al., 1976).  50 to 70% of colchicine is excreted
             unchanged and 30 to 50% as metabolites.  20% of the dose
             administered is excreted in urine in the first 24 hours and
             27.5% in the first 28 hours.  Colchicine is detected in urine
             up to 7 to 10 days after ingestion.  Urinary excretion is
             increased in patients with impaired hepatic function (Wallace
             et al., 1970).
    
             Bile:
    
             10 to 25% of colchicine is excreted in the bile (Heaney et
             al., 1976).
    
             Faeces:
    
             Large amounts of the drug are excreted in the faeces.  After
             intravenous administration 10 to 56% is excreted in the
             faeces within the first 48 hours (Walaczek et al., 1960).
    
             Breast Milk:
    
             Colchicine may be eliminated in breast milk.

    7.  TOXINOLOGY

        7.1  Mode of action

             Colchicine binds to tubulin and this prevents its
             polymerization into microtubules.  The binding is reversible
             and the half-life of the colchicine-tubulin complex is 36
             hours.  Colchicine impairs the different cellular functions
             of the microtubule: separation of chromosome pairs during
             mitosis (because colchicine arrests mitosis in metaphase),
             amoeboid movements, phagocytosis.
    
             Toxicodynamics
    
             Mitosis blockade accounts for diarrhoea, bone marrow
             depression and alopecia.  Colchicine may have a direct toxic
             effect on muscle, including heart muscle, central and
             peripheral nervous system and liver.  Inhibition of cellular
             function does not, however, account for all the organ
             failures seen in severe overdose.
    
             Pharmacodynamics
    
             Gout inflammation is initiated by urate crystals within
             tissues.  The crystals are ingested by neutrophils but this
             leads to the release of enzymes and the destruction of the
             cells.  Chemotactic factors are released and attract more
             neutrophils.  Colchicine may act by preventing phagocytosis,
             the release of chemotactic factors and the response of
             neutrophils.
    
             Colchicine, in therapeutic doses, has other properties such
             as antipyretic effects, respiratory depression,
             vasoconstriction and hypertension.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             5 g seeds = 50 g tincture = 20 mg
                             colchicine is a lethal dose.

                    7.2.1.2  Children

                             The lethal dose for child is said to
                             be c. 1 to 1.5g (Frohne & Pfänder, 1983).
    
                             Ellwood & Robb (1971) reported a fatal
                             outcome in a 16-year-old girl who had eaten a
                             dozen flowers of C. autumnale (for details
                             see section 11.1).

             7.2.2  Relevant animal data

                    Livestock loss due to C. autumnale has been
                    reported in Europe. In oxen, ingestion of 8 to 10 g/kg
                    fresh leaves or 2-3 g/kg dried leaves (in hay) was
                    lethal (Kingsbury, 1964).
    
                    Poisonings in dogs have also been reported.

             7.2.3  Relevant in vitro data

                    No data available.

        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 ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                             Colchicine may be analysed in
                             biological fluids by different methods:
    
                             -Fluorometric method:  Fluorescence of
                             organometallic (Gallium)  complexes (Bourdon
                             & Galliot, 1976).
    

                             -Radioimmunoassay:  (Ertel et al., 1976;
                             Scherrman et al., 1980)
    
                             -High performance liquid chromatography: 
                             (Jarvie et al., 1979; Caplan et al., 1980;
                             Haizer, 1984; Lhermitte et al.,
                             1985).

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             Plasma
    
                             -Bourdon and Galliot (1976) reported plasma
                             levels lower than 20 ng/mL at the 6th hour in
                             severe intoxications.
    
                             -Jarvie et al. (1979) in an overdose with 7.5
                             mg, noted plasma levels of 21 ng/mL at the
                             6th hour and below 5 mg/mL at the 24th
                             hour.
    
                             -In severe intoxications plasma levels
                             usually range between 20 to 50 ng/mL during
                             the 24 first hours.  After the 24th hour only
                             small amounts of colchicine (< 20 ng/mL) are
                             detected in plasma (Bismuth et al., 1977;
                             Lambert et al., 1981; Jaeger et al.,
                             1985).
    
                             -Haizer (1984) reported post-mortem serum
                             blood levels of 170 and 240 ng/mL (at the 4th
                             and 8th hour) in 2 heroin addicts following
                             intravenous injection.
    
                             -Lhermitte et al. (1985) noted the following
                             plasma levels in an overdose with 31 mg
                             orally:  720, 212, 132, and 120 ng/mL at the
                             20, 125, 305, 605 minutes respectively.
    
                             Blood
    
                             Colchicine levels in blood are higher than
                             those in plasma.
    

                             -In an overdose with 20 mg colchicine orally
                             Caplan et al. (1980) noted a blood level of
                             250 ng/mL at the 2nd hour.  No colchicine
                             could be detected at the 40th hour.

                    8.3.1.2  Urine

                             Colchicine levels in urine range
                             between 200 and 2500 ng/mL over the first 24
                             hours (Bismuth et al., 1977; Jaeger et al.,
                             1985; Lambert et al., 1981).
    
                             Jaeger et al. (1985) studied urinary
                             excretion in 5 cases.  Concentrations in
                             urine are 2 to 80 fold higher than those in
                             plasma.  4 to 25 of the dose ingested was
                             excreted in urine over 3 to 10 days. 
                             Excretion was specially high during the first
                             24 hours following ingestion.  Colchicine is
                             eliminated in urine up to the 10th
                             day.

                    8.3.1.3  Other fluids

                             Gastric lavage fluid:
    
                             In 4 cases, gastric lavage performed 3 to 6
                             hours post ingestion removed 7 to 25% of the
                             dose ingested (Jaeger et al., 1985).
    
                             Diarrhoea:
    
                             In an overdose with 25 mg colchicine orally,
                             1.4 mg were eliminated in diarrhoea on the
                             2nd day (Jaeger et al., 1985).

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

             Colchicine may be measured in biological fluids but
             levels are not useful or necessary for the management of
             colchicine poisoning.
    
             Sample collection
             Blood samples for colchicine should be drawn in plastic tubes
             with heparin.  Colchicine may be analysed in whole blood or
             plasma.  Biological samples (blood, plasma, urine...) should
             be stored in airtight conditions and protected from light. 
             Concentrations in whole blood are markedly higher than those
             in plasma.  Concentrations in urine are 10 to 80 fold higher
             than those in plasma.
    
             Biomedical analysis 
             A biochemical profile with glucose, BUN, electrolytes,
             creatinine, blood cell count, coagulation parameters, liver
             and muscle enzymes, and blood gases should be obtained on
             admission and repeated every 12 hours.  Samples for
             bacteriological analysis should be obtained at the stage of
             aplasia or when fever occurs.
    
             Toxicological analysis
             Colchicine analysis in biological fluids is not necessary or
             useful for the management of the poisoning.
    
             Other investigations
             No other specific investigations are required.  Bone marrow
             biopsy may be indicated but it is not performed
             routinely

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Toxic manifestations appear after a delay of 2
                    to 12 hours following ingestion.  The delay may be
                    increased if other drugs decreasing gastrointestinal
                    motility have also been ingested (phenobarbitone,
                    psychotropic drugs, opium derivatives). 
                    Symptomatology progresses in 3 stages and may
                    include:
    
                    Stage I (Day 1-3)  Gastrointestinal and circulatory
                    phase:
    
                    -Severe gastrointestinal irritation:  Nausea,
                    vomiting, abdominal cramps, severe diarrhoea.
    
                    -Dehydration, hypovolemia, shock, prolongation of
                    prothrombin time, leucocytosis.  Cardiogenic shock may
                    occur and may result in death within the first 72
                    hours.
    
                    -Hypoventilation, acute respiratory distress
                    syndrome.
    
                    Central nervous system excitation and/or
                    depression.
    
                    -Hypoventilation, acute respiratory distress
                    syndrome.
    
                    Stage II (Day 3-10) Bone marrow aplasia phase:
    
                    -Bone marrow aplasia with agranulocytosis.
    
                    -Coagulation disorders with diffuse haemorrhages.
    
                    -Rhabdomyolysis.
    
                    -Polyneuritis, myopathy, ascending paralysis.
    
                    -Acute renal failure.
    
                    -Infectious complications.
    
                    Stage III:  (After 10 days) Recovery phase:
    
                    -Alopecia.

             9.1.2  Inhalation

                    Not relevant.

             9.1.3  Skin exposure

                    Not relevant.

             9.1.4  Eye contact

                    Not relevant.

             9.1.5  Parenteral exposure

             9.1.6  Other

                    (Ellenhorn et al., 1996; Gaultier & Bismuth,
                    1978; Stapczynski et al., 1981).

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Chronic administration of colchicine may induce
                    similar toxicity to that seen in acute poisoning:
                    gastrointestinal symptoms (vomiting, diarrhoea),
                    agranulocytosis, aplastic anaemia, myopathy (Goodman &
                    Gilman, 1985).

             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

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             Course:
    
             (see section 9.1.1.)
    
             Prognosis:
    
             Prognosis is related to the dose ingested (see section 7.2.1)
             and therapeutic measures (especially early intervention).
    
             Occurrence of cardiogenic shock indicates a poor prognosis
             (Sauder et al., 1983).
    
             If the patient has recovered from aplasia and has not
             developed acute respiratory distress syndrome or systemic
             infectious complications, prognosis is usually good.
    
             Cause of death:
    
             At the early stage (day 1 to 3), cause of death will be due
             to cardiovascular shock and/or acute respiratory distress
             syndrome.
    
             Death due to haemorrhagic or infectious complications may
             occur at the stage of bone marrow aplasia (day 3 to
             10).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Shock:
    
                    Cardiovascular shock is always present in severe
                    intoxications.  Most deaths result form shock within
                    the first 72 hours.
    
                    Hypotension is usually the result of hypovolemia due
                    to gastrointestinal fluid loss.  Hypovolemia with
                    decreased central venous pressure is initially always
                    present but some patients may develop cardiogenic
                    shock (Sauder et al., 1983; Bismuth & Sebag,
                    1981).
    
                    Haemodynamic studies showed two different profiles: 
                    patients with a hyperkinetic state (increased cardiac
                    index and decreased systemic vascular resistances);
                    patients with cardiogenic shock (decreased cardiac
                    index and increased systemic vascular resistances)
                    (Sauder et al., 1983).  Occurrence of cardiogenic
                    shock indicates a poor prognosis.  Septic shock may
                    occur during the phase of aplasia.

             9.4.2  Respiratory

                    Acute respiratory failure is usually
                    concomitant with circulatory failure, although Murray
                    et al., 1983, reported a case with ascending paralysis
                    occurring more than 4 hours post-exposure.
    
                    Acute respiratory distress syndrome due to diffuse
                    interstitial and alveolar oedema has been reported in
                    severe cases (Davies et al., 1988; Hill et al., 1986;
                    Hobson et al., 1986).

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             In severe cases, hypotension and/or
                             hypoxemia can lead to confusion, agitation,
                             and mental depression.  Coma and seizures are
                             observed.  Profound coma may be due to
                             cerebral complications such as
                             haemorrhages.

                    9.4.3.2  Peripheral nervous system

                             Peripheral neuritis, neuromyopathy
                             and myopathy have been reported
                             (Bertrand,1979; Bismuth, 1977; Carr, 1965;
                             Favarel-Garrigues et al., 1975; Kontos, 1962;
                             Mouren et al., 1969).  Ascending paralysis
                             may be responsible for respiratory failure
                             (Carr, 1965; Murray et al., 1983. 
                             Polyneuritis usually recovers within one
                             month (Bertrand, 1979; Bismuth et al., 1977)
                             but may last longer (Mouren et al.,
                             1969).

                    9.4.3.3  Autonomic nervous system

                             No data available.

                    9.4.3.4  Skeletal and smooth muscle

                             Rhabdomyolysis may occur with an
                             increase in muscle enzymes and myoglobinuria
                             (Kontos et al., 1962; Letellier et al., 1979;
                             Murray et al., 1983).

                             Letellier et al. (1979) reported a case of
                             rhabdomyolysis in a 58-year-old patient
                             treated with 3 mg colchicine daily over 6
                             days.  The patient developed proximal
                             scapular weakness with muscle oedema and
                             increase in muscle enzymes.

             9.4.4  Gastrointestinal

                    a) Acute:
    
                    Gastrointestinal symptoms develop after a delay of 2
                    to 12 hours following ingestion and include nausea,
                    vomiting, abdominal pain and severe diarrhoea. 
                    Usually diarrhoea lasts for 48 hours and may induce

                    hypovolemia and electrolyte disturbances. 
                    Gastrointestinal symptoms also occur after colchicine
                    overdose by the intravenous route.  Paralytic ileus
                    may develop (Heaney et al., 1976).
    
                    Gastrointestinal disturbances may be lacking or
                    decreased if drugs decreasing gastrointestinal
                    motility (atropine, phenobarbitone, opium tincture)
                    have also been ingested.
    
                    b) Chronic:
    
                    Gastrointestinal symptoms are a common feature during
                    colchicine treatment.  Paralytic ileus has been
                    reported after intravenous colchicine
                    treatment.

             9.4.5  Hepatic

                    Colchicine may exert direct hepatic toxicity. 
                    Hepatomegaly has been reported.  Hepatic damage may
                    occur in severe poisoning and include cytolysis and
                    hepatocellular insufficiency, increase in glutamic
                    pyruvic transaminase (SGOT) (alanine amino
                    transferase, ALT) and glutamic oxaloacetic
                    transaminase (SGOT) (aspartate amino transferase, AST)
                    and in alkaline phosphatase, a decrease in coagulation
                    factors.  Histologic examination has shown necrosis
                    and steatosis of hepatocytes.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             No direct nephrotoxic effect has
                             been reported.  Functional renal
                             insufficiency is usually observed and is
                             secondary to fluid and electrolyte losses or
                             hypovolemia.
    
                             Acute renal failure may occur following
                             cardiovascular or septic shock.  Proteinuria
                             and haematuria have been reported.

                    9.4.6.2  Other

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    a) Endocrine
    
                    Transient diabetes mellitus has been reported by
                    Hillemand et al. (1977) in a 58 year old woman after
                    an overdose with 25 mg.
    
                    Inappropriate antidiuretic syndrome has been reported
                    by Gauthier et al. (1975).
    
                    b) Reproductive
    
                    Acute
    
                    Lambert et al. (1981) reported a case of colchicine
                    poisoning (40 mg) in a 18-year-old pregnant woman. 
                    The patient developed severe poisoning with
                    coagulopathy, acute respiratory distress syndrome
                    (ARDS) and abortion on day 7 following ingestion.  The
                    patient recovered.
    
                    Chronic
    
                    A reversible complete azoospermia has been reported in
                    a 36-year- old man treated with colchicine for gout
                    (Merlin, 1972).  Two cases of Down's syndrome babies
                    have been reported.  Ehrenfeld et al. (1987) reported
                    the obstetric histories of 36 women with familial
                    Mediterranean fever on long-term colchicine treatment
                    between 3 and 12 years.  Seven of 28 pregnancies ended
                    in miscarriage. 13 women had periods of infertility. 
                    All 116 infants born to mothers who had taken
                    colchicine during pregnancy were healthy.  The authors
                    do not advise discontinuation of colchicine before
                    planned pregnancy but recommend amniocentesis for
                    karyotyping and reassurance.

             9.4.8  Dermatological

                    Acute
    
                    Alopecia begins at about the 12th day and is complete
                    by 3 weeks after ingestion.  Hair regrowth begins
                    after the first month.  Sometimes the colour of the
                    hair may change.
    
                    Cutaneous and subcutaneous haemorrhages are frequent
                    in severe poisoning.  They are due to coagulation
                    disturbances.

             9.4.9  Eye, ear, nose, throat: local effects

                    Eyes: Subconjunctival haemorrhage may
                    occur.
    
                    Ear: Definitive unilateral deafness due to an inner
                    ear haemorrhage has been observed (personal
                    experience).
    
                    Nose: Nasal haemorrhages may occur especially after
                    local trauma due to insertion of tracheal or gastric
                    tubes.
    
                    Throat: Stomatitis may also occur (Lambert et al.,
                    1981; Wallace, 1974).

             9.4.10 Haematological

                    At toxic doses, colchicine induces marked bone
                    marrow depression.
    
                    Leukocytes:
    
                    At the initial stage, a peripheral leukocytosis occurs
                    frequently.  However, the leucocytes seem at this
                    stage to be functionally deficient.  A leucopenia with
                    agranulocytosis begins at the third day and reaches a
                    maximum at day 5 to 7.  White blood cells (WBC) return
                    to normal values at about the 10th to 12th day.
    
                    Erythrocytes
    
                    Anaemia is frequent in severe cases and may be due to
                    different factors:
    
                    -Hypoplastic anaemia due to bone marrow suppression
                    may be observed but is rarely important.
    
                    -Haemolytic anaemia with Heinz body has been rarely
                    reported (Heaney et al., 1976).
    
                    -Acute intravascular haemolysis with haemoglobinemia
                    and haemoglobinuria has been observed in 6 severe
                    cases (Lambert et  al., 1981).
    
                    -Severe anaemia is mostly secondary to multiple
                    diffuse haemorrhages.
    
                    Bleeding diatheses and coagulopathy:
    
                    -A tendency towards bleeding is always present in
                    severe cases.  It appears 2 to 3 days following
                    ingestion and may last for 8 to 10 days.
    

                    -Usually the earliest clinical sign of coagulopathy is
                    persistent bleeding from venous or arterial puncture
                    sites and subcutaneous haemorrhages.
    
                    -Other types of bleeding include epistaxis, gingival,
                    conjunctival and gastrointestinal haemorrhages. 
                    Bleeding may be due to thrombocytopenia or a
                    intravascular coagulopathy.
    
                    -A consumptive coagulopathy with prolongation of
                    coagulation time, hypoprothrombinaemia, a decrease in
                    fibrinogen, elevated fibrin degradation products and
                    thrombocytopenia is observed in severe intoxication
                    (Bismuth et al., 1977; Crabie et al., 1970; Lambert et
                    al., 1981).

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Metabolic acidosis due to
                             dehydration and/or shock may be
                             seen.

                    9.4.12.2 Fluid and electrolyte disturbances

                             The gastrointestinal syndrome often
                             results in marked dehydration and
                             hypovolaemia with haemoconcentration and
                             functional renal failure.
    
                             Hypokalaemia due to gastrointestinal losses
                             is also frequent at the initial stage.
    
                             Hypocalcaemia may be seen and can persist for
                             several days.  Frayha et al. (1984) reported,
                             in a 20-year-old girl who had ingested 20 mg,
                             convulsions and paralytic ileus which were
                             related to a hypocalcaemia (1.25 mmol/L). 
                             Hypocalcaemia may be due to a direct toxic
                             effect of colchicine (Heath et al.,
                             1972).

                    9.4.12.3 Others

                             Hyperglycaemia: Hillemand et al.
                             (1977) reported a 58-year-old woman who
                             ingested 25 mg and developed transient
                             diabetes mellitus.
    

                             Hyperlipaemia:  A transient hyperlipaemia has
                             been reported (Hillemand et al., 1977).
    
                             Hyperuricaemia:  A transient hyperuricaemia
                             as also been noted (Hillemand et al.,
                             1977).
    
                             Hyperthermia-fever:  occurrence of fever may
                             be related to an infectious complication,
                             especially during the stage of
                             aplasia.

             9.4.13 Allergic reactions

                    No data available.

             9.4.14 Other clinical effects.

                    No data available.

             9.4.15 Special risks

                    Pregnancy
    
                    Two cases of Down's syndrome babies have been
                    reported.  Ehrenfeld et al. (1987) reported the
                    obstetric histories of 36 women with familial
                    Mediterranean fever on long-term colchicine treatment
                    between 3 to 12 years.  Seven of 28 pregnancies ended
                    in miscarriage.  13 women had periods of infertility. 
                    All 16 infants born to mothers who had taken
                    colchicine during pregnancy were healthy.  The authors
                    do not advise discontinuation of colchicine before
                    planned pregnancy but recommend amniocentesis for
                    karyotyping and reassurance.
    
                    Breast-feeding
    
                    As colchicine is eliminated in the breast milk breast-
                    feeding should be avoided.

        9.5  Others

             No data available.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Patients with C. autumnale poisoning should always be
             admitted to an intensive care unit.  Treatment depends on the
             dose ingested, the symptomatology and the delay following
             ingestion.  It includes gastric emptying, activated charcoal,
             early forced diuresis, and supportive treatment with
             correction of the shock, artificial ventilation, treatment
             and prevention of haemorrhagic coagulation and infectious
             complications.  Vital signs (ECG, blood pressure, central
             venous pressure, respiration) should be monitored.  Be
             careful  about venous and arterial punctures if there is a
             severe coagulopathy.

        10.2 Life supportive procedures and symptomatic/specific treatment

             a) Observation and monitoring:
    
             Monitor systematically vital signs, ECG, blood pressure and
             central venous pressure.  Repeated monitoring of central
             venous pressure is essential to avoid circulatory overload
             during plasma expander infusion.
    
             If shock is present, insertion of a pulmonary artery catheter
             for monitoring of haemodynamic parameters may be useful for
             guiding the treatment in the initial phase.
    
             The patient remains at risk until at least 48 hours after
             exposure.
    
             b) Diarrhoea:
    
             Diarrhoea should not be treated because some colchicine is
             eliminated in faeces.
    
             c)Dehydration - Electrolyte disturbances - Acidosis:
    
             Give intravenous fluids and electrolytes according to
             clinical and biological status.  If metabolic acidosis is
             present give intravenous bicarbonate.  Monitor potassium
             levels and blood gases.  Maintain adequate urinary output
             (>100 mL/hour).
    
             d)Hypotension, shock:
    
             Hypotension should be anticipated and treated with adequate
             fluid replacement and vasoactive drugs.  Monitor blood
             pressure.  Early institution of haemodynamic monitoring is
             very helpful for adequate treatment of shock.
    

             Hypotension and shock are due primarily to hypovolaemia. 
             Cardiogenic shock may occur.
    
             -Plasma expanders:
    
             Infuse plasma expander solutions (e.g. albumin or modified
             gelatine fluids) under control of haemodynamic parameters
             e.g. central venous pressure, pulmonary arterial pressure. 
             Very large amounts of plasma expanders may be necessary:  3
             to 4 litres over 24 hours (personal observation).
    
             -Inotropic and vasoconstrictor drugs:
    
             If the patient is unresponsive to these measures administer
             inotropic and vasoconstrictor drugs e.g. dopamine or
             dobutamine in doses sufficient to cause vasoconstriction (10
             to -20 mcg/kg/minute).
    
             -Vasodilators:
    
             Vasodilators e.g. glyceryl trinitrate may be useful in the
             case of cardiogenic shock with increased systemic arterial
             resistance (personal observation).
    
             e)Respiratory disturbances:
    
             Respiratory depression or ARDS should be treated by
             artificial ventilation.  The early institution of mechanical
             ventilation is indicated in patients with severe intoxication
             and shock.
    
             f) Bone Marrow Depression:
    
             Isolate the patient if there is evidence of bone marrow
             depression.  Infusion of white blood cell units is usually
             not necessary because aplasia is transient.  However, it may
             be useful in patients who develop concomitant infection
             (Gauthier & Bismuth, 1978).
    
             g) Coagulation Disorders:
    
             Prevent haemorrhagic complications due to local trauma: avoid
             insertion of endotracheal tube by the nasal route, avoid
             femoral arterial puncture.
    
             Coagulation disorders require specific treatment, moreover if
             haemorrhages develop.  According to biological parameters,
             treatment may include infusion of fresh-frozen plasma,
             platelet units, fibrinogen and coagulation factors.
    
             h) Prevention of Infectious Complications:
    
             In severe cases with shock and/or aplasia a prophylactic
             antibiotic treatment should be given.  Prophylactic
             antibiotic therapy may be directed towards gram positive
             (e.g. staphylococcal) and negative bacteria and also
             anaerobic bacteria.  Preventative treatment for fungal
             infections should also be given because fungal septicaemia
             may develop (personal observation).

        10.3 Decontamination

             a) Emesis:
    
             Emesis may be useful in recent ingestion if there are no
             contraindications.
    
             b) Gastric lavage:
    
             Gastric lavage is indicated with colchicine ingestion because
             it may remove 7 to 25% of the dose ingested if it is
             performed within 6 hours of ingestion (Jaeger et al.,
             1985).
    
             c) Oral activated charcoal:
    
             The efficacy of oral activated charcoal has not been
             established.  However, because colchicine undergoes
             enterohepatic circulation, oral activated charcoal may be
             indicated:  one dose at the end of the gastric lavage and
             repeated every 4 to 6 hours.
    
             d) Cathartics:
    
             The usefulness of cathartics has not been established.  Most
             patients have diarrhoea and thus cathartics are not
             indicated.  Cathartics may be useful if drugs decreasing
             gastrointestinal motility have been ingested with colchicine. 
             In any case, diarrhoea should not be treated.

        10.4 Enhanced elimination

             a) Forced diuresis:
    
             Toxicokinetic studies (Jaeger et al., 1985) indicate that
             significant amounts of colchicine are eliminated in urine,
             especially during the first 24 hours following ingestion.
    
             Thus early forced diuresis should be instituted after
             correction of dehydration and/or shock (Jaeger et al., 1985). 
             Continue forced diuresis until the third or fourth day
             provided there are no contraindications.
    
             b) Haemoperfusion, Haemodialysis:
    
             No data about haemoperfusion or haemodialysis clearances have
             been reported.  However, the low colchicine plasma
             concentrations reported in acute poisonings and the large
             volume of distribution indicate that haemoperfusion or
             haemodialysis are not useful.

        10.5 Antidote/antitoxin treatment

             10.5.1 Adults

                    Currently no antidote for colchicine is
                    available.  Experimental studies have shown that anti-
                    colchicine antibodies were able to neutralize toxic
                    effects of colchicine after acute intoxication in
                    rabbits and mice (Scherrmann et al., 1986).  Until
                    now, immunotoxicotherapy has not been used in a human
                    case.

             10.5.2 Children

                    Currently no antidote for colchicine is
                    available.  Experimental studies have shown that anti-
                    colchicine antibodies were able to neutralize toxic
                    effects of colchicine after acute intoxication in
                    rabbits and mice (Scherrmann et al., 1986).  Until
                    now, immunotoxicotherapy has not been used in a human
                    case.

        10.6 Management discussion

             Gastrointestinal symptoms may be lacking if
             psychotropic drugs or drugs decreasing gastrointestinal
             motility have also been ingested.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Ellwood and Robb (1971) reported self-poisoning in a
             16-year-old girl who ate more than a dozen flowers of C.
             autumnale.  A few hours later she developed profuse
             diarrhoea and then a severe shock and respiratory failure
             which led to death.  Necropsy showed engorged oedematous
             lungs and some fatty infiltration in the liver.

    12. ADDITIONAL INFORMATION

        12.1 Specific preventative measures

             Not available for human use.

        12.2 Other

             No data available.

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    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES):

        Authors: A. Jaeger,  F. Flesch
        Service de Réanimation et 
        Centre Anti-Poisons,
        CHU, Pavillon Pasteur
        1 place de l'Hopital
        67091 Strasbourg
        France
    
        Tel:  33-88161144
        Fax:  33-88161330
    
        Date: 26 April 1990
    
        General edit and botanical review:
    
        Christine Leon
        Medical Toxicology Unit
        Guy's & St Thomas Hospital Trust
        c/o Royal Botanic Gardens, Kew
        Richmond
        Surrey
        TW9 3AB
        United Kingdom
    
        Tel: +44 (0) 181 332 5702
        Fax: +44 (0) 181 332 5768
        e-mail: c.leon@rbgkew.org.uk
    
        July 1997