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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in a poisoned patient by using high performance liquid
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Roussel, P (1985) Colchicine quantitation by high-performance
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Geogr Med, 25: 15-17.
Neuwinger HD (1994) African ethnobotany; poisons and drugs.
Chemistry, pharmacology, toxicology. London, Chapman & Hall.
Sauder P, Kopferschmitt J, Jaeger A and Mantz JM (1983)
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Hum Toxicol, 2(2): 169-173.
Stapczynski JS, Rothstein RJ, Gaye WA and Niemann JT (1981)
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literatature. Ann Emerg Med, 10(7): 364-369.
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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