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CBD Oil for Gout

Can CBD help with gout, and, if so, how?

Gout is the most common type of inflammatory arthritis. It causes sudden and severe joint pain that usually starts in the big toe.

However, other joints and areas around the joints can also be affected, such as the ankle, knee and foot.

According to the Arthritis Foundation, men are three times more likely than women to develop gout. It tends to impact men over 40 years old and women after their menopause (1).

What Causes Gout?

Gout is characterized by inflammation and intense pain that occur when urate crystals accumulate in the joints.  

Urate crystals form when an individual has high levels of uric acid in the blood. The body produces uric acid as a waste product when it digests purines.

Purines are a natural substance found in the body and some foods, such as seafood, steak, and organ meats.

Other foods may also lead to high levels of uric acid. These foods include alcoholic beverages, especially beer, and drinks sweetened with fructose (fruit sugar).

Uric acid usually dissolves in the blood and then passes through the kidneys into the urine. However, sometimes either the body produces too much uric acid, or the kidneys excrete too little uric acid, causing acid buildup.

When uric acid accumulates, it forms sharp, needle-like urate crystals in a joint or surrounding tissue that cause pain, inflammation, and swelling (2).

Why Some People Are Turning to CBD for Gout

Gout symptoms may come and go. However, there are ways to manage symptoms and prevent flares, says Mayo Clinic.

Symptoms include intense joint pain, lingering discomfort, inflammation and redness, and limited joint movements.

The Arthritis Foundation says that anecdotally, some people with arthritis who have tried CBD reported noticeable pain relief, sleep improvement, and anxiety reduction (3).

Several animal studies have suggested that CBD has pain-relieving and anti-inflammatory properties.

A 2015 study, which was published in the European Journal of Pain, examined the effects of CBD applied to the skin of a rat model of arthritis (4).

Results demonstrated that transdermal administration of CBD has long-lasting therapeutic effects without psychoactive side-effects.

With the given data, researchers found that the use of topical CBD has potential as an effective treatment of arthritic symptomatology.

The findings of the said study were not directly linked to humans. Still, the data is encouraging for individuals with gout and seeking pain and inflammation management through CBD oil.

A 2017 study provided significant support to the historical claims of CBD’s efficacy in treating inflammation, joint pain, gout, and other conditions (5).

A 2018 review published in Current Opinion in Pharmacology summarized how cannabinoids have the potential to treat pain associated with osteoarthritis.

Osteoarthritis, the most prevalent type of arthritis, is a condition that causes degeneration of cartilage and bones (6).

Researchers also noted in the report that the body's endocannabinoid system (ECS) plays an essential role in joint-related pain. This type of pain could pertain to gout patients who may experience high levels of pain in their joints.

Meanwhile, a study published in the Journal of Headache Pain reported positive findings from a group of medical cannabis patients (7).

The authors found that cannabis varieties high in the terpenes of caryophyllene and myrcene were the most successful in treating migraines, headaches, and specific pain disorders, including arthritis.

Such findings could be hopeful news for people with arthritis who are being explicitly treated to relieve gout-related pain (8).
Conclusion

Several studies have shown that cannabis and CBD oil are pain-relieving and anti-inflammatory, giving hope to individuals coping with gout (9).

However, more gout-specific, longitudinal research with human subjects is needed to verify the effectiveness of CBD oil for this condition.

Note that CBD cannot be a substitute for disease-modifying treatment for inflammatory arthritis or gout.

More importantly, those interested in trying CBD for the first time, or those who plan to include CBD as an adjunct gout therapy, should first consult with a doctor experienced in cannabis use.

References
  1. Arthritis Foundation. Gout. Retrieved from https://www.arthritis.org/diseases/gout.
  2. Mayo Clinic. (2019, March 1). Gout. Retrieved from https://www.mayoclinic.org/diseases-conditions/gout/symptoms-causes/syc-20372897.
  3. Arthritis Foundation. CBD for Arthritis Pain: What You Should Know. Retrieved from https://www.arthritis.org/health-wellness/healthy-living/managing-pain/pain-relief-solutions/cbd-for-arthritis-pain.
  4. Hammell DC, Zhang LP, Ma F, et al. Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. Eur J Pain. 2016;20(6):936–948. DOI:10.1002/ejp.818.
  5. Ryz NR, Remillard DJ, Russo EB. Cannabis Roots: A Traditional Therapy with Future Potential for Treating Inflammation and Pain. Cannabis Cannabinoid Res. 2017;2(1):210–216. Published 2017 Aug 1. DOI:10.1089/can.2017.0028.
  6. O'Brien M, McDougall JJ. Cannabis and joints: scientific evidence for the alleviation of osteoarthritis pain by cannabinoids. Curr Opin Pharmacol. 2018;40:104–109. DOI:10.1016/j.coph.2018.03.012.
  7. Baron EP, Lucas P, Eades J, Hogue O. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. J Headache Pain. 2018;19(1):37. Published 2018 May 24. DOI:10.1186/s10194-018-0862-2.
  8. Arthritis Foundation. CBD for Arthritis Pain: What You Should Know. Retrieved from https://www.arthritis.org/health-wellness/healthy-living/managing-pain/pain-relief-solutions/cbd-for-arthritis-pain.
  9. Ibid.

Jatropha macrorhiza

1. NAME
   1.1 Scientific name
   1.2 Family
   1.3 Common name(s)
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
   2.5 Poisonous parts
   2.6 Main toxins
3. CHARACTERISTICS
   3.1 Description of the plant
      3.1.1 Special identification features
      3.1.2 Habitat
      3.1.3 Distribution
   3.2 Poisonous parts of the plant
   3.3 The toxin(s)
      3.3.1 Name(s)
      3.3.2 Description, chemical structure, stability
      3.3.3 Other physico-chemical characteristics
   3.4 Other chemical contents of the plant
4. USES/CIRCUMSTANCES OF POISONING
   4.1 Uses
   4.2 High risk circumstances
   4.3 High risk geographical areas
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY
   7.1 Mode of action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL/TOXINOLOGICAL 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 Biochemcial 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
   8.5 Overall Interpretation of all toxicological analyses and
   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 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Hematological
      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
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses and other investigations
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological/toxinological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote/antitoxin treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes/antitoxins
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
   13.1 Clinical and toxicological
   13.2 Botanical
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)







    POISONOUS PLANTS

    1.  NAME

    1.1      Scientific name

             Jatropha macrorhiza

    1.2      Family

             Euphorbiaceae

    1.3      Common name(s)

             Arizona Desert potato

             Desert potato

             Physic nut

    2.  SUMMARY

    2.1      Main risks and target organs

             Dehydration and cardiovascular collapse as a result of 

             haemorrhagic   gastro-enteritis.  Central nervous system 

             depression. 

    2.2      Summary of clinical effects

             Symptoms are largely those associated with gastro-intestinal  

             irritation.  There is acute abdominal pain and a burning 

             sensation in the throat about half an hour after ingestion of 

             the seeds, followed by nausea, vomiting and diarrhoea.  The 

             vomitus and faeces may contain blood.  In severe intoxications 

             dehydration and haemorrhagic gastroenteritis can occur. There 

             may be CNS and cardiovascular depression and collapse; 

             children are  more susceptible. 

    2.3      Diagnosis

             Diagnosis by case history and presenting symptoms.  A definite  

             diagnosis  can only be made if there is a  history of 

             ingestion and the  ingested plant material has been positively 

             identified as Jatropha. 

    2.4      First-aid measures and management principles

             INGESTION:  Unless the patient is unconscious, convulsing, or 

             unable to swallow give fluids (milk or water) to dilute.  Seek 

             medical assistance.   In  hospital or a health care facility 

             induce vomiting unless the patient  has  already vomited, or 

             perform gastric lavage.  Administer activated  charcoal  and a 

             cathartic to hasten elimination, although in the presence of 

             diarrhoea  this is unecessary.

             SKIN:  Wash the affected area well with plenty of water and 

             use a mild soap.

             EYE:  Flush the eye with copious amounts of water for at least 

             15 minutes.   If irritation persists seek medical assistance. 



    2.5      Poisonous parts

             All parts are considered toxic but in particular the seeds.

    2.6      Main toxins

             Contains a purgative oil and a phytotoxin or toxalbumin 

             (curcin)  similar to ricin in Ricinis.  

    3.  CHARACTERISTICS

    3.1      Description of the plant

             3.1.1    Special identification features

                      Jatropha macrorhiza is perennial herb. It is a small 

                      shrub or tree up to 0.5m (2 feet) tall. It is easily 

                      identified  by the erect and tall stature arising 

                      from a tuber-like root (4-6cm  in diameter and 10-

                      30cm long)



                      Leaves:  up to 13cm (5 inches) across; dark green 

                      palmately lobed  leaves (10-15cm broad). 

                      Flowers: small, white to pinkish-purple in colour, 

                      borne in inconspicuous clusters. Usually bloom during 

                      May to October.

                      Fruit:  Round capsule, green when young turning dark 

                      brown to black when mature. Shell becomes dry and 

                      wrinkled when mature. Each capsule contains 3 seeds.

                      (Micromedex, 1974-1994) 



             3.1.2    Habitat

                      Prefers arid   environments.

             3.1.3    Distribution

                      Found in Arizona, Southern New Mexico and old Mexico 

                      at elevations of 3 500 to 7 500 feet. 

    3.2      Poisonous parts of the plant

    3.3      The toxin(s)

             3.3.1    Name(s)

                      MAIN TOXINS:

                      

                      Curcin - a phytotoxin (toxalbumin), found mainly in 

                      the seeds and   also in the fruit and sap. 

                      

                      Purgative oil - the seed yields 40% oil, known as 

                      hell oil,   pinheon oil, oleum infernale or oleum 

                      ricini majoris, which   contains small amounts of an 

                      irritant curcanoleic acid, which is   related to 

                      ricinoleic acid and crotonoleic acid, the principle   

                      active ingredients of castor oil and croton oil 

                      respectively   (Joubert et al., 1984). 

                      

                      OTHER TOXINS:

                      

                      This genera also may contain hydrocyanic acid (CRC 

                      Critical   Reviews in Toxicology 1977). 

                      There may be a dermatitis producing resin (Lampe & 

                      Fagerstrom,   1968). 

                      There may be an alkaloid, and a glycoside which 

                      produce   cardiovascular and respiratory depression. 

                      Tetramethylpyrazine   (TMPZ), an amide alkaloid has 

                      been obtained from the stem of J.  podagrica (Ojewole 

                      & Odebiyi, 1981). 

                      Atropine-like effects have also been reported 

                      following ingestion   of Jatropha multifida (Aplin 

                      1976). 



             3.3.2    Description, chemical structure, stability

                      Curcin:

                      Phytotoxins or toxalbumins are large, complex protein 

                      molecules of  high toxicity.  They resemble bacterial 

                      toxins in structure and   physiological effects.  

                      Phytotoxins are heat labile, and can be   positively 

                      identified by precipitin reactions with sera 

                      containing  known antibodies (Kingsbury 1964). Curcin 

                      is said to be highly   irritant and remains in the 

                      seed after the oil has been expressed.



                     

                      Tetramethylpyrazine (TMPZ):

                      CAS:  1124-11-4

                      MW:  136.22

                      Molecular formula:  C8-H12-N2



             3.3.3    Other physico-chemical characteristics

                      Curcin is unable to penetrate cell walls, this has 

                      been  indicated by the fact that these proteins do 

                      not affect protein  synthesis by Ehrlich ascites 

                      cells.  This is thought to be because  they lack a 

                      carrier moiety or at least the galactose-binding 

                      groups by which ricin binds to cell membranes.  This 

                      was discovered when it was found that the activity of 

                      curcin in cell-free systems is  not increased by 

                      treatment with 2-mercaptoethanol, which greatly  

                      enhances the inhibitory effect of ricin and abrin by 

                      splitting   their molecules into an effector and a 

                      carrier moiety (Stirpe et   al.,1976). 

    3.4      Other chemical contents of the plant

             No further information was available at the time of 

             preparation of the  monograph. 

    4.  USES/CIRCUMSTANCES OF POISONING

    4.1      Uses

             Jatropha is an ornamental plant naturalised in many tropical 

             areas.    The roots, stems, leaves seeds and fruits of the 

             plant have been widely used in traditional folk medicine in 

             many parts of West Africa.  The seeds of J. curcas have been 

             used as a purgative, antihelminthic and abortifacient as  well 

             as for treating ascites, gout, paralysis and skin diseases.  

             The seed  oil of the plant has been used as an ingredient in 

             the treatment of   rheumatic conditions, itch and parasitic 

             skin diseases, and in the treatment of fever, jaundice and 

             gonorrhoea, as a diuretic agent, and a mouth-wash.   The leaf 

             has been used  as a haemostatic agent and the bark as a fish  

             poison.  In certain African  countries people are accustomed 

             to chewing  these seeds when in need of a  laxative.

             J. curcas seeds have been found to be highly effective against 

             Strongyloides papillosus infection in goats (Adam & Magzoub, 

             in press).  It has also been   suggested that J. curcas seeds 

             could be a useful chemotherapeutic agent   provided that it is 

             active at a non-lethal dose (Adam, 1974).  This may be   

             because of it's reported antihelminthic activity. 



    4.2      High risk circumstances

             The very large tuber like root of J. macrorhiza resembles the 

             common potato and is often mistaken for such.

             As Jatropha plants are grown as an ornamental they will often 

             be found in   gardens and public areas and therefore will be 

             easily accessible.  As  Jatropha are fruit bearing and the 

             seeds have a pleasant taste, the plants  are particularly 

             attractive to children.

             This species of plant is not usually eaten by animals but 

             drought leading to an acute shortage of grass creates a 

             situation in which animals are forced to consume the plants 

             and their constituents in varying amounts. 



    4.3      High risk geographical areas

             This species are found in tropical countries throughout the 

             world; including tropical  America,  warmer parts of Australia 

             (Queensland and the Northern Territory),  Florida  (chiefly 

             south of Orlando), Hawaiian Islands and Africa (Mozambique,  

             Zambia,  Transvaal, Natal), Asia. 

    5.  ROUTES OF ENTRY

    5.1      Oral

             All cases of systemic poisoning have resulted from ingestion 

             of plant  material (in most cases the tubers and seeds). 

    5.2      Inhalation

             No relevant information at the time of preparation of the 

             monograph. 

    5.3      Dermal

             No relevant information at the time of preparation of the 

             monograph. 

    5.4      Eye

             No relevant information at the time of preparation of the 

             monograph. 

    5.5      Parenteral

             No relevant information at the time of preparation of the 

              monograph. 

    5.6      Others

             No relevant information at the time of preparation of the 

             monograph. 

    6.  KINETICS

    6.1      Absorption by route of exposure

             INGESTION:  Phytotoxins are well absorbed from the 

             gastrointestinal  tract. The onset of symptoms may be 

             developed one or more hours. 

    6.2      Distribution by route of exposure

             No relevant information at the time of preparation of the 

             monograph. 

    6.3      Biological half-life by route of exposure

             No relevant information at the time of preparation of the 

             monograph. 



    6.4      Metabolism

             Curcin - phytotoxins are partly metabolised in the digestive 

             tract. 

    6.5      Elimination by route of exposure

             No relevant information at the time of preparation of the 

             monograph. 

    7.  TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY

    7.1      Mode of action

             Phytotoxins (toxalbumins):  It has been suggested that in vivo   

             phytotoxins act as proteolytic enzymes, owing their toxicity 

             to the   breakdown of critical proteins and the accumulation 

             of ammonia (Kingsbury,   1964).

            

             Tetramethylpyrazine (TMPZ):  Has been found to possess a non-

             specific   spasmolytic and vasodilator activity (Ojewole & 

             Odebiyi, 1981).  These   actions may account,  at least in 

             part,  for the reported hypotensive   (depressor) effects of 

             the amide alkaloid in experimental animals.  TMPZ has also 



             been found to possess neuromuscular-blocking effects similar 

             to   d-tubocurarine (Ojewole & Odebiyi, 1980). 



    7.2      Toxicity

             7.2.1    Human data

                      7.2.1.1  Adults

                               Most cases of intoxication with J. 

                               macrorhiza are from mistaken ingesting the 

                               sweet tasting roots believing they are 

                               potatoes. In a male 3 pieces (about 2 inches 

                               diameter) caused symptoms.

                              

                               In some instances as few as three seeds have   

                               produced toxic symptoms. In others, 

                               consumption of as   many as 50 seeds has 

                               resulted in relatively mild symptoms.    

                               There is one report where the ingestion of 

                               only one seed   in an adult has produced 

                               toxic symptoms.  It has been   suggested 

                               that there may be two strains one with toxic   

                               seeds and one without (Kingsbury, 1964).  

                               Curcin, the   phytotoxin or toxalbumin found 

                               in  Jatropha curcas is   similar to ricin 

                               the phytotoxin found in the castor bean   

                               (Ricinis).  The minimum lethal dose of 

                               ricin, when   administered by injection, may 

                               be as small as 0.00000001%  of body weight, 

                               although oral toxicity is probably several   

                               hundred times less (Kingsbury, 1964). 

                      7.2.1.2  Children

                               Toxicity is thought to be the same as for 

                               adults, thus, as few as 1-3 seeds may 

                               produce toxic symptoms. 

             7.2.2    Animal data

                      Poisoning from ingestion of the seeds of the Jatropha 

                      plant  is well known in veterinary practice and 

                      autopsy findings include,  severe gastro-enteritis, 

                      nephritis, myocardial degeneration,   

                      haemagglutination, and subepicardial and 

                      subendocardial   haemorrhages as well as renal 

                      subcortical and subpleural bleeding.

                     

                      One study found a high mortality rate in mice fed 50% 

                      and 40% J.  curcas.  The important symptoms of 

                      poisoning included diarrhoea,   inability to keep 

                      normal posture, depression and lateral   recumbency.  

                      The degree of the pathological changes observed in 

                      the small intestines, liver, heart, kidneys, and 

                      lungs was related to the level of Jatropha in the 

                      diet.  The most marked pathological  changes were 

                      catarrhal enteritis, erosions of the intestinal 

                      mucosa, congestion and haemorrhages in small 

                      intestines, heart and lungs  and fatty changes in the 

                      liver and kidneys (Adam, 1974).

                     

                      Another oral dosing study undertaken using mice found 



                      that curcin,  as compared with crotin found in the 

                      seeds of croton tiglium, had a   slightly more rapid 

                      action with symptoms beginning at 12 hours and   most 

                      deaths occurring within 48 hours of poisoning.  An 

                      acute LD50   of 9.11mg/mouse was calculated at 48 

                      hours and a delayed LD50 of   5.83mg/mouse was 

                      calculated at 7 days.  The behaviour of the   animals 

                      was similar to that of mice treated with crotins, 

                      except   for some neurological symptoms (waddling, 

                      fine tremors, rocking,   occasionally convulsions), 

                      which were present especially among   animals 

                      poisoned with the highest doses of curcin.  Post-

                      mortem   examinations showed lesions in the liver, 

                      pancreas and spleen,   hyperaemia of the intestine, 

                      sometimes ascites; the whole picture  resembled that 

                      of rats poisoned with ricin. (Stirpe et al.,1976)

                     

                      In young ruminants oral doses of 0.5 to 10g/kg/day 

                      caused death  after dosing for periods ranging from 1 

                      day to 2 weeks.  The   clinical, haematological, and 

                      pathological changes indicated that   J. aceroides 

                      reduced the ability of the liver to synthesize 

                      protein, although there was no evidence of 

                      interference with the excretion   of bilirubin.  

                      Kidney dysfunction and haemoconcentration also   

                      occurred.  Postmortem and histological findings were 

                      similar to   those found above in studies with mice. 

                      (Barri et al., 1983)

                     

                      A study assessing the acute oral toxicity of J. 

                      curcas showed that  different ruminants had different 

                      susceptibilities to the effect of   J. curcas.  

                      Calves which received 0.25 or 1g/kg died within 19 

                      hours of administration, whilst goats given similar 

                      daily doses   were either killed or died within 7 to 

                      21 days.  It was not   established whether this 

                      species difference lies in direct   cytotoxic action 

                      or in the capacity with which the active   substances 

                      contained in J. curcas seed are converted in vivo to   

                      metabolites more or less toxic than the parent 

                      compounds. (Ahmed &  Adam, 1979)

                     

                      Feeding chicks seeds produced growth depression,  

                      hepatonephropathies, and haemorrhages. (Micromedex 

                      1974-1994) 



             7.2.3    Relevant in vitro data

                      In vitro phytotoxins cause agglutination of 

                      erythrocytes   (Joubert et al., 1984).  It has been 

                      observed that the seeds of J.  curcas contain 

                      proteins that are toxic to animals and inhibit   

                      protein synthesis in a cell-free system (lysate of 

                      rabbit   reticulocytes), but not in whole cells 

                      (Stirpe et al., 1976). 

    7.3      Carcinogenicity

             The seed oil of J. curcas was found to contain skin tumour 



             promoters in a two-stage mouse carcinogenesis experiment.  The 

             "irritant fraction"   contained in the methanol extract of the 

             seed oil when partially purified   induced ornithine 

             decarboxylase in mouse skin and inhibited the specific   

             binding of 3H-12-O-tetradecanoylphorbol-13-acetate to a 

             particulate fraction  of mouse skin.  After initiation with 7, 

             12-dimethylbenz[a]anthracene (DMBA),  this "irritant fraction" 

             induced  tumours in the skin of 36% of the mice  tested in 30 

             weeks (Horiuchi et al., 1987). 

    7.4      Teratogenicity

             No relevant information at the time of preparation of the 

             monograph. 

    7.5      Mutagenicity

             No relevant information at the time of preparation of the 

             monograph. 

    7.6      Interactions

             No relevant information at the time of preparation of the 

             monograph. 

    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

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.1.1.2  Biomedical analyses

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.1.1.3  Arterial blood gas analysis

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.1.1.4  Haematological analyses

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.1.1.5  Other (unspecified) analyses

                               No relevant information at the time of   

                               preparation of the monograph.

             8.1.2    Storage of laboratory samples and specimens

                      8.1.2.1  Toxicological analyses

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.1.2.2  Biomedical analyses

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.1.2.3  Arterial blood gas analysis

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.1.2.4  Haematological analyses

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.1.2.5  Other (unspecified) analyses

                               No relevant information at the time of   

                               preparation of the monograph.

             8.1.3    Transport of laboratory samples and specimens

                      8.1.3.1  Toxicological analyses

                               No relevant information at the time of   

                               preparation of the monograph.



                      8.1.3.2  Biomedical analyses

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.1.3.3  Arterial blood gas analysis

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.1.3.4  Haematological analyses

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.1.3.5  Other (unspecified) analyses

                               No relevant information at the time of   

                               preparation of the monograph.

    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)

                               No relevant information at the time of   

                               preparation of the monograph.  



                      8.2.1.2  Advanced Qualitative Confirmation Test(s)

                               Extraction of J. curcas seeds for the 

                               preparation of crude curcin has used 8 x 

                               250ml of ethyl ether.  The  ether has been 

                               removed by filtering.  The resulting powder 

                               is then dried and then extrated with 1L of 

                               cold   0.005M-sodium phosphate buffer, pH 

                               7.2, containing   0.2M-NaCl/100g of seeds.  

                               The mixture is stirred and left  overnight.  

                               After centrifugation the supernatant is   

                               brought to 100% saturation with solid 

                               (NH4)2SO4.  The   protein precipitate is 

                               then collected by centrifugation   and 

                               dissolved in a minimum amount of 

                               phosphate/NaCl buffer and then dialysed for 

                               24-48 hour against a continuous  flow  of 

                               the same buffer.  At the end of dialysis a 

                               brown  precipitate remains and is removed by 

                               centrifugation.  (Stirpe et al., 1976)

                              

                               Analysis of this crude preparation using a 

                               column of   Sephadex G-100 has eluted three 

                               peaks referred to as   curcin I, II and III. 

                               These proteins were found to have  different 

                               properties, curcin I is more toxic and 

                               brings  about different symptoms  and 

                               lesions in vivo, whereas  curcin II was much 

                               more  active on protein synthesis  (Stirpe 

                               et al., 1976). 

                      8.2.1.3  Simple Quantitative Method(s)

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.2.1.4  Advanced Quantitative Method(s)

                               No relevant information at the time of   

                               preparation of the monograph.

             8.2.2    Tests for biological specimens

                      8.2.2.1  Simple Qualitative Test(s)

                               No relevant information at the time of   



                               preparation of the monograph.

                      8.2.2.2  Advanced Qualitative Confirmation Test(s)

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.2.2.3  Simple Quantitative Method(s)

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.2.2.4  Advanced Quantitative Method(s)

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.2.2.5  Other Dedicated Method(s)

                               No relevant information at the time of   

                               preparation of the monograph.

             8.2.3    Interpretation of toxicological analyses

                      No relevant information at the time of preparation of 

                      the   monograph. 

    8.3      Biomedical investigations and their interpretation

             8.3.1    Biochemcial analysis

                      8.3.1.1  Blood, plasma or serum

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.3.1.2  Urine

                               No relevant information at the time of   

                               preparation of the monograph.

                      8.3.1.3  Other fluids

                               No relevant information at the time of   

                               preparation of the monograph.

             8.3.2    Arterial blood gas analyses

                      No relevant information at the time of preparation of 

                      the   monograph. 

             8.3.3    Haematological analyses

                      No relevant information at the time of preparation of 

                      the   monograph. 

             8.3.4    Interpretation of biomedical investigations

                      No relevant information at the time of preparation of 

                      the   monograph. 

    8.4      Other biomedical (diagnostic) investigations and their 

             interpretation 

             No relevant information at the time of preparation of the 

             monograph. 

    8.5      Overall Interpretation of all toxicological analyses and 

             toxicological investigations 

             No relevant information at the time of preparation of the 

             monograph. 

    8.6      References

             No relevant information at the time of preparation of the 

             monograph. 

    9.  CLINICAL EFFECTS

    9.1      Acute poisoning

             9.1.1    Ingestion

                      Symptoms of poisoning are likely to be similar for 

                      species  of Jatropha. There is usually a delay of an 

                      hour or more between  consumption of  the plant and 

                      the occurrence of symptoms.  Symptoms are largely  

                      those associated with gastro-intestinal irritation.  

                      There is acute abdominal pain and a burning sensation 



                      in the throat about half an hour after  ingestion of 

                      the seeds followed by nausea,  vomiting and profuse  

                      watery diarrhoea.  In severe poisoning,  these 

                      symptoms progress to haemorrhagic gastroenteritis and  

                      dehydration.  Polydipsia can be  extreme.  Salivation 

                      and sweating  may occur.  There may be skeletal  

                      muscle spasm.  Intense hyperpnoea or a quick panting 

                      respiration is  seen together with  hypotension and 

                      electrocardiographic  abnormalities.  There may be  

                      CNS and cardiovascular depression,  children are more 

                      susceptible;  this may be either a direct effect  of 

                      toxins or secondary to  dehydration. 

                      

                      In one report, as well as gastrointestinal symptoms, 

                      atropine-like  effects developed eight hours after 

                      ingestion of Jatropha multifida   (Aplin, 1976).  

                      Symptoms included sweating, dry skin and mouth,   

                      slight mydriasis, mild tachycardia and flushing of 

                      facial skin and   persisted for four hours. 



             9.1.2    Inhalation

                      No relevant information at the time of preparation of 

                      the   monograph. 



             9.1.3    Skin exposure

                      Primary chemical irritation from  mechanical and/or 

                      chemical injury (Lampe & Fagerstrom, 1968). 



             9.1.4    Eye contact

                      Primary chemical irritation from mechanical and/or 

                      chemical  injury.

             9.1.5    Parenteral exposure

                      No relevant information at the time of preparation of 

                      the   monograph. 

             9.1.6    Other

                      No relevant information at the time of preparation of 

                      the   monograph. 

    9.2      Chronic poisoning

             9.2.1    Ingestion

                      No relevant information at the time of preparation of 

                      the   monograph. 

             9.2.2    Inhalation

                      No relevant information at the time of preparation of 

                      the   monograph. 

             9.2.3    Skin exposure

                      No relevant information at the time of preparation of 

                      the   monograph.

             9.2.4    Eye contact

                      No relevant information at the time of preparation of 

                      the   monograph. 

             9.2.5    Parenteral exposure

                      No relevant information at the time of preparation of 

                      the   monograph. 

             9.2.6    Other

                      No relevant information at the time of preparation of 

                      the   monograph. 



    9.3      Course, prognosis, cause of death

             In non-fatal cases the course of intoxication is short; the 

             patient may become asymptomatic within 24 hours.  Recovery 

             seems to be the rule. 

    9.4      Systematic description of clinical effects

             9.4.1    Cardiovascular

                      Hypotension with a fast weak pulse. Shock due to 

                      fluid and  electrolyte loss may occur.

                      Electrocardiographic abnormalities. 

             9.4.2    Respiratory

                      Hyperpnoea.

             9.4.3    Neurological

                      9.4.3.1  CNS

                               There may be CNS depression either as a 

                               direct   result of toxins or secondary to 

                               hypotension. Seizures have been mentioned in 

                               association with  toxalbumin poisoning, but 

                               generally in animal cases or in  symptom 

                               summaries rather than actual case reports  

                               (Micromedex, 1974-1994). 

                      9.4.3.2  Peripheral nervous system

                               No relevant information at the time of   

                               preparation of the monograph.



                      9.4.3.3  Autonomic nervous system

                               There have been reports of salivation, 

                               sweating   and abdominal cramping occurring 

                               in human intoxications of Jatropha 

                               macrorhiza root (Consroe and Glow, 1975). 

                               This suggests some cholinergic activity.

                              

                               Contrary to this, atropine-like effects have 

                               been reported (Aplin, 1976); thus diminished 

                               cholinergic stimulation  may  be evident.  

                               Mydriasis, dry mouth, flushed hot dry  skin,  

                               tachycardia, etc.. 



                      9.4.3.4  Skeletal and smooth muscle

                               The muscles and extremities may be 

                               contracted by  spasms.  Intestinal spasm can 

                               be severe. 

             9.4.4    Gastrointestinal

                      Acute abdominal pain and a burning sensation in the  

                      throat  about half an hour after ingestion of the 

                      seeds.  This is  followed by nausea, vomiting and 

                      profuse watery diarrhoea.  The  vomitus and  faeces 

                      may contain blood.   Lesions  are those of 

                      haemorrhagic gastro-intestinal inflammation.  



             9.4.5    Hepatic

                      Liver damage may occur in serious cases of toxalbumin  

                      poisoning. There may be increases ALT, total 

                      bilirubin, and AST.  (Micromedex, 1974-1994) 

             9.4.6    Urinary

                      9.4.6.1  Renal

                               Oliguria, probably secondary to hypotension   



                               rather than direct renal toxicity. 

                               Urinalysis may reveal  haemoglobinuria and 

                               albuminuria. 

                      9.4.6.2  Others

                               No relevant information at the time of   

                               preparation of the monograph.

             9.4.7    Endocrine and reproductive systems

                      No relevant information at the time of preparation of 

                      the   monograph. 

             9.4.8    Dermatological

                      Dermatitis as a result of primary chemical irritation   

                      possibly in conjunction with mechanical injury can 

                      occur in most,  if not all, individuals.  Reactions 

                      occur soon after exposure.  The severity of the 

                      reaction is dependent on the extent and duration  of 

                      contact.  Hypersensitisation may also develop. 

             9.4.9    Eye, ears, nose, throat:  local effects

                      Retinal haemorrhages, optic nerve injury have been 

                      reported  in toxalbumin poisoning (Micromedex, 1974-

                      1994). 

             9.4.10   Hematological

                      Haemoconcentration secondary to fluid loss.

                      Toxalbumins are haemagluttinating. Effects in 

                      poisoning are minimal even though the effect is 

                      prominent in vitro.  (Micromedex,  1974-1994) 

             9.4.11   Immunological

                      No relevant information at the time of preparation of 

                      the   monograph. 

             9.4.12   Metabolic

                      9.4.12.1 Acid base disturbances

                               Acid base disturbances are not typical in  

                               toxalbumin poisoning (Micromedex, 1974-1994)

                      9.4.12.2 Fluid and electrolyte disturbances

                               Dehydration which is often severe.

                               Electrolyte  disturbances. 

                      9.4.12.3 Others

                               No relevant in formation at the time of  

                               prparation of the monograph.

             9.4.13   Allergic reactions

                      Stated as being a primary chemical irritant (Lampe &   

                      Fagerstrom, 1968), but hypersensitivity reactions may 

                      occur in   susceptible individuals.  The inflammation 

                      resulting from primary  chemical irritant effects of 

                      Jatropha is a predisposing factor to   the 

                      development of contact allergy. 

             9.4.14   Other clinical effects

                      Toxoalbumin poisoning may produce fever (Micromedex,  

                      1974-1994).

             9.4.15   Special risks

                      No relevant information at the time of preparation of 

                      the   monograph. 

    9.5      Others

             Oedematous swelling of several organs.

    10. MANAGEMENT

    10.1     General principles

             The management of Jatropha poisoning is similar to that for 



             the castor bean (Ricinis).  Decontamination is indicated for 

             all known or suspected  poisonings.  There is no antidote.  

             Rehydration, either voluntary water  ingestion or i.v. fluid 

             administration, to counteract fluid lost due to  vomiting and 

             diarrhoea is critical.  Treatment is essentially  symptomatic  

             and supportive.  The more critical analyses and investigations  

             are fluid  and electrolytes, acid-base status, full blood 

             count, and renal  and hepatic function.  Monitor level of 

             consciousness.  Specific therapy may  be  indicated for 

             haemorrhagic gastrointestinal damage, skeletal muscle and   

             gastrointesinal spasm, excessive salivary secretions and 

             haemoglobinuria.  After substantial exposures to toxalbumin 

             containing plants, an observation  period of up to 8 hours is 

             advised. 



    10.2     Relevant laboratory analyses and other investigations

             10.2.1   Sample collection

                      Blood and urine sample collection.

             10.2.2   Biomedical analysis

                      Complete blood count, electrolytes, blood urea 

                      nitrogen,   creatinine, acid-base status, glucose, 

                      prothrombin time, liver   enzymes, amylase, and 

                      urinalysis. 

             10.2.3   Toxicological/toxinological analysis

                      No relevant information at the time of preparation of 

                      the   monograph. 

             10.2.4   Other investigations

                      Monitor hepatic, renal, pancreatic, and red blood 

                      cell   function. 

    10.3     Life supportive procedures and symptomatic treatment

             Fluid and electrolyte status may deteriorate suddenly and 

             severely.  Give IV fluids and electrolyte as necessary to 

             restore and maintain fluid  and electrolyte balance.   Monitor 

             renal function and alkalinize urine to  minimize effects of 

             haemoglobinuria.  Treat haemorrhagic gastro-intestinal  damage 

             as for peptic ulceration.  Observe for signs of CNS depression 

             and  initiate assisted  ventilation if necessary. 



    10.4     Decontamination

             In all cases of ingestion or suspected ingestion, if the 

             patient is  seen sufficiently soon (within 1-2 hours of 

             ingestion), induce emesis with  Ipecac Syrup or perform 

             gastric lavage unless vomiting has been extensive. 

    10.5     Elimination

             Administer activated charcoal and a cathartic to enhance and 

             hasten  elimination, although severe diarrhoea may make this 

             unnecessary. Cathartic  administration must be cautious due to 

             the risk of exacerbating purgation  and fluid loss.

            

             Phytotoxins are non dialysable.  However, methods for 

             eliminating the toxins from the blood (haemodialysis, 

             peritoneal dialysis, charcoal haemoperfusion   etc.) have been 

             suggested as useful, whether this removes plant toxins  other 

             than phytotoxins from the blood and therefore improves the 

             prognosis  and  hastens the recovery, is yet to be 

             demonstrated.  A possible indication  for  this would be life-



             threatening CNS or respiratory depression (not  secondary  to 

             hypovolaemia) which is unresponsive to other supportive  

             measures. 



    10.6     Antidote/antitoxin treatment

             10.6.1   Adults

                      No antidote. Many antidotes have been investigated 

                      for  toxalbumin poisoning, but no specific treatments 

                      are available.  (Micromedex, 1974-1994) 

             10.6.2   Children

                      No antidote. Many antidotes have been investigated 

                      for  toxalbumin poisoning, but no specific treatments 

                      are available.  (Micromedex, 1974-1994) 

    10.7     Management discussion

             In cases of poisoning where dehydration has been severe close 

             follow  up of renal function is imperative. 

    11. ILLUSTRATIVE CASES

    11.1     Case reports from literature

             Case History:  A 3-year-old Hawaiian-Caucasian boy was 

             admitted to   Kauikeoani Children's Hospital on September 20, 

             1958, because of persistent  vomiting and diarrhoea.  The 

             episodes were of sudden onset following the   ingestion of 

             several large black seeds gathered from an over-hanging branch  

             of a neighbour's tree (later identified as Jatropha curcas).  

             He was unable to retain any ingested food or water.  Each 

             intake was vomited almost   immediately after ingestion.  The 

             vomitus was said to contain the white   granulated material 

             and the particles of the black shells.  After several   bouts 

             of vomiting, the child started to have watery bowel movements.  

             The   stools contained seed particles also.  Three and a half 

             hours following the  ingestion of the seeds, the child 

             appeared lethargic.  His skin felt cold   and clammy.  The 

             child was admitted to the hospital in severe dehydration.  The 

             family and past history were non-contributory.

             Blood pressure was 100/70; pulse 130; respiration 40; 

             temperature 99.8°F   (rectal).  The patient appeared 

             lethargic, cyanotic, and acutely ill.  The   peripheral 

             vessels were constricted.  Severe dehydration was indicated by   

             the poor skin turgor, sunken eyeballs, and deepening 

             periorbital shadows.    The bowel sounds were hyperactive.  

             The remainder of the physical   examination was within normal 

             limits.  The haemoglobin was 14.2gm/100mL, the red blood cell 

             count , 5.4 million, and the platelets were normal.  The 

             white blood cell count was 27,000 per cu mm, and the 

             differential was   normal.  The urine showed a trace of 

             albumin, and elements consisting of 2-4 white blood cells per 

             high power field and many granular and some hyaline  casts.  

             The carbon oxide level was 17mEq/L; chlorides, 101mEq/L; and   

             potassium, 4.4mEq/L.  The stool cultures were negative for 

             pathogens.

            

             The child was given 1000mL of isotonic electrolyte solution.  

             Blood was   drawn for type and cross matching.  The patient 

             was oliguric for the first   24 hours.  He responded to 

             treatment, and twenty hours after admission he   was able to 

             tolerate oral feedings without any vomiting or diarrhoea, and   



             was voiding well.  He was discharged from the hospital after 3 

             days without  complication.  (Ho 1960).

            

             Case History:  Two sisters aged 5 and 3 years respectively 

             were rushed to   Ahmadu Bello University Teaching Hospital, 

             Zaria, Nigeria, with a history of vomiting and drowsiness 

             about 5 hours after ingesting unspecified  quantities  of ripe 

             seeds of J. curcas.  They had each vomited between 6 and 10 

             times  within the hour preceding their arrival.  There had 

             been no  diarrhoea and  the vomitus consisted of a whitish 

             material mixed with the  food they had  taken 2 hour 

             previously.  On examination they were well-fed  children,  

             afebrile, not pale, jaundiced or cyanosed but moderately  

             dehydrated.  There  was neither abdominal tenderness nor any 

             abnormal  finding on rectal  examination.  They were both 

             restless, drowsy but  rousable and their pupils  were normal 

             and reactive.  Laboratory  investigations revealed normal  

             haemoglobin, normal liver-function tests and mild alkalosis. 

             Treatment  consisted of rehydration with intravenous fluids 

             and sedation with small  doses of promethazine hydrochloride.  

             They  recovered rapidly and were both  discharged some 48 

             hours after admission.   (Abdu-Aguye et al.,1986).

            

             Case History:  An 18 year old, well developed Caucasian male 

             was admitted to hospital at 11:45 p.m. because of persistent 

             vomiting, diarrhoea and   drowsiness.  The patient had 

             ingested 3 pieces (about 2 inches in diameter)  of a plant 

             root (identified as Jatropha macrorhiza) about 4 hours 

             earlier;  symptoms emerged about 1 hour after ingestion.  

             Except for drowsiness and   tenderness of all quadrants of the 

             abdomen, physical examination and   haematologic and urinary 

             laboratory values of the patient showed no striking 

             abnormalities.  Bed rest was prescribed and tap water was 

             given ad libitum to quench the paitients extreme polydipsia.  

             After an uneventful nights   sleep, the patient was discharged 

             at 10:30 the next morning without   complications.  (Consroe 

             and Glow, 1975).

            

             Case History:  A 48 year old, well developed Caucasian male 

             was admitted to  hospital at 3 p.m. because of persistent 

             diarrhoea after ingesting an   unknown quantity of a sweet 

             tasting potato-like plant root (identified as   Jatropha 

             macrorhiza) at 8 a.m.  Bouts of severe vomiting and diarrhoea 

             about every 3 minutes appeared 45 to 60 minutes after 

             ingestion and persisted   throughout most of the afternoon.  

             The patient also complained of drowsiness, perspiration, 

             salivation, polydipsia, cramps in the legs and abdomen and  of  

             feeling cold and clammy.  Physical examination revealed a poor 

             skin  turgor,  sunken eyeballs excessive salivary secretions 

             and no lesions of  mouth or  throat.  there was tenderness in 

             all quadrants of the abdomen and  deep  tendon reflexes were 

             hyperactive and intermittent muscle spasms in  toes and  calfs 

             were apparent.  Vital signs and urinary and haematological  

             values were  normal except for elevations in haematocrit (60%) 

             and  haemoglobin  (20.2gm/100ml).  Initially, 1 litre of 5% 

             dextrose in water,  atropine (0.5mg  im.) and diazepam (5mg, 



             im.) every 6-8 hours as needed were prescribed.   After a 

             restful night, the patient was discharged at 9 a.m.,  the 

             following  morning without complications.  (Consroe and Glow, 

             1975). 



    11.2     Internally extracted data on cases

             No relevant information at the time of preparation of the 

             monograph. 

    11.3     Internal cases

             No relevant information at the time of preparation of the 

             monograph. 

    12. ADDITIONAL INFORMATION

    12.1     Availability of antidotes/antitoxins

    12.2     Specific preventive measures

    12.3     Other

    13. REFERENCES

    13.1     Clinical and toxicological

             Abdu-Aguye I, A Sannusi, R A Alafiya-Tayo, S R Bhusnurmath. 

             (Jul 1986) Acute Toxcity Studies with Jatropha curcas L.  

             Human Toxicology,   5(4):269-274. 

             

             Adam S E I.  (Mar 1974)  Toxic effects of Jatropha Curcas in 

             mice.    Toxicology, 2(1):67-76. 

             

             Adam S E I, M Magzoub.  Preliminary observations on the 

             anthelmintic   activity of Jatropha curcas against 

             strongyloides and Haemonchus infections  in goats and sheep.  

             Topical Animal Health Production 25: (in press).  Cited   in 

             Ahmed & Adam, 1979. 

             

             Ahmed O M M, S E I Adam. (Jul 1979)  Effects of Jatropha 

             curcas on Calves.   Veterinary Pathology 16(4):476-482. 

             

             Aplin T E H. (May 1976)  Poisonous Garden Plants and Other 

             Plants Harmful to Man in Australia.  Western Australia 

             Department of Agriculture, Bulletin   3964. 

             

             Barri M E S, T O Onsa, A A Elawad, N Y Elsayed, I A Wasfi, E M 

             Abdul Bari, S E I Adam.  (1983)  Toxicity of Five Sudanese 

             Plants to Young Ruminants.    Journal of Comparative 

             Pathology, 93:559-575. 

             

             Consroe P F, Glow D E.  (1975).  Clinical Toxicology of the 

             Desert Potato :  Two Case Reports of Acute Jatropha Macrorhiza 

             Root Ingestion.  Arizona   Medicine, 23(6):475-477. 

             

             CRC Critical Review in Toxicology.  (Nov 1977).  Higher Plant 

             Genera and   their toxins,  pp 213-237 

             

             Ho Richard K B.  (March-April 1960).  Acute Poisoning From the 

             Ingestion of  Seeds of Jatropha Curcas.  Medical Journal of 

             Hawaii, 19(4):421-423.  

             

             Horiuchi T, H Fujiki, M Hirota, M Suttajit, M Suganuma, A 

             Yoshioka, V   Wongchai, E Hecker, T Sugimura.  (Mar 1987)  

             Presence of tumor promoters in  the seed oil of Jatropha 



             curcas L. from Thailand.  Japanese Journal of   Cancer 

             Research, 78(3):223-236. 

             

             Joubert P H, J M M Brown, I T Hay, P D B Sebata.  (May 1984).  

             Acute   poisoning with Jatropha curcas (purging nut tree) in 

             children.  South   African Medical Journal, 65:729-730. 

             

             Kingsbury J M.  Poisonous Plants of the United States and 

             Canada, 1964. 

             

             Lampe and Fagerstrom.  (1968).  Plant Toxicity and Dermatitis 

             - A Manual for Physicians.  The Williams and Wilkins Company, 

             Baltimore. 

             

             Ojewole J A O, O O Odebiyi. (1980)  Neuromuscular and 

             Cardiovascular Actions of Tetramethylpyrazine from the Stem of 

             Jatroha Podagrica.  Planta Medica, 38:332-338. 

             

             Ojewole J A O, O O Odebiyi. (1981)  Mechanism of the 

             Hypotensive Effect of   Tetramethylpyrazine, an Amide Alkaloid 

             from the Stem of Jatropha podagrica. 

             

             Stirpe F, A Pession-Brizzi, E Lorenzoni, P Strocchi, L 

             Montanaro, S Sperti.  (Apr 1976)  Studies on the Proteins from 

             the Seeds of Croton tiglium and of Jatropha curcas.  Toxic 

             properties and inhibition of protein synthesis in  vitro.  

             Biochemistry Journal, 156(1):1-6. 



    13.2     Botanical

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

    ADDRESS(ES)

    June 1994

    Juliette Begg and Tania Gaskin

    National Toxicology Group

    P.O. Box 913

    Dunedin

    NEW ZEALAND











See Also:

        Jatropha curcas L. (PIM 570)

        Jatropha gossypiifolia (PIM 643)

        Jatropha hastafa (PIM 644)

        Jatropha multifida (PIM 646)

        Jatropha podagrica (PIM 647)

	Summary for UKPID

    Allopurinol

    Kathryn Pughe, BSc (Hons) MRPharmS

    National Poisons Information Service (Newcastle Centre)
    Regional Drug & Therapeutics Centre
    Wolfson Building
    Claremont Place
    Newcastle upon Tyne
    NE1 4LP
    UK


    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information
    Service.


    Name

         Proprietary    Zyloric(R), Zyloric-300(R)
         Generic        Allopurinol

    Chemical group / family

         Antigout agents - xanthine oxidase inhibitor
         BNF 10.1.4

    Reference number

         CAS 315-30-3
         CAS 17795-21-0

    Manufacturer / supplier

         Wellcome UK
         The Wellcome Foundation Ltd
         Hale Court Greencourts Business Park
         Styal Road
         Manchester
         M22 5LQ

         Tel:      0161 435 9372
                   01707 398085 (24hr emergencies)
         Fax:      0161 435 9363

    Presentation

         Tablets 100mg bottle of 100 tablets
         Tablets 300mg calendar pack of 2x14 tablets
         Also available from generic drug companies in various pack sizes.

    Physico-chemical properties:

    Chemical structure
         1H-Pyrazolo[3,4-d]pyrimidin-4-ol, C5H4N4O

    Physical state at room temp
         white / almost white crystalline powder, odourless

    Molecular weight
         136.1

    pKa
         10.2

    Solubility
         in alcohol  >1 in 10 000
         in water    >1 in 10 000

    Uses

    Indications

         Prophylaxis of gout and of uric acid and calcium oxalate renal
         stones.

    Therapeutic Dosage

         Initially 100mg daily as a single dose, after food, gradually
         increased over 1-3 weeks according to the plasma or urinary uric
         acid concentration to about 300mg daily. Usual maintenance dose
         200-600mg, rarely 900mg daily, divided into doses of not more
         than 300mg.
         Child (in neoplastic conditions, enzyme disorders) 10-20mg/kg
         daily.

    Contra-indications

         Known intolerance of allopurinol.
         Not for treatment of the acute attack of gout.

    Hazard / risk classification

         None

    Pharmacokinetics

    Absorption               80-90%
    Volume of distribution   1.6 Lkg-1
    Metabolism               approx 80%
    Elimination              10% excreted in urine unchanged, 70% excreted
                             as allopurinol
    Plasma half-life         allopurinol    0.5-2h
                             oxypurinol     10-40h

    Special populations

    Pregnancy - little data available, avoid use.

    Hepatic disease - patients may have a higher risk of adverse reactions

    Renal disease - Reduce dose in renal impairment as increased risk of
    adverse reactions. Reduced rate of elimination and possible
    precipitation of oxypurinol or xanthine calculi. Reduce risks of
    calculi by maintaining sufficient hydration to maintain daily urinary
    output above 2l and ensuring that the urine remains slightly alkaline.

    Breast milk - Allopurinol and oxypurinol are excreted in breast milk.
    The effects on the infant are unknown.

    Toxicokinetics

         NK

    Adverse effects

         Skin rashes are the most common side-effect. These are generally
         maculopapular or pruritic, but more serious hypersensitivity
         reactions may occur and include exfoliative rashes, the
         Stevens-Johnson syndrome, and toxic epidermal necrolysis.

         Further symptoms of hypersensitivity include fever, chills,
         leucopenia or leucocytosis, eosinophilia, arthralgia, and
         vasculitis leading to renal and hepatic damage. These
         hypersensitivity reactions may be severe, even fatal, and
         patients with hepatic or renal impairment are at special risk.

    Interactions

         ACE Inhibitors                Increased risk of toxicity with
                                       captopril, especially in patients
                                       with renal impairment.

         Adenine arabinoside           Enhanced toxic effects as half-life
                                       increased.

         Salicylates and               Decreased therapeutic activity of
         uricosuric agents             allopurinol.

         Chlorpropamide                Increased risk of prolonged
                                       hypoglycaemic activity in patients
                                       with poor renal function.

         Coumarin anticoagulants       Effects of anticoagulants possibly
                                       enhanced.

         Cyclosporin                   Plasma levels possibly increased -
                                       risk of nephrotoxicity.

         Cytotoxics                    Effects of azathioprine and
                                       mercaptopurine enhanced with
                                       increased toxicity.

         Phenytoin                     Inhibition of hepatic oxidation may
                                       occur, but may not be clinically
                                       significant.

         Theophylline                  No clinical reports of
                                       interactions.

    Mechanism of action / toxicity

    Acute ingestion

    Accidental or deliberate ingestion of up to 5g (Manufacturer's data
    sheet), and in one case 22.5g (Ferner et al, 1988), has been reported,
    with low toxicity.

    Chronic ingestion

    Toxicity on therapeutic doses is more common in patients with renal
    failure.

    Features

    Nausea, vomiting, diarrhoea, dizziness, headache, somnolence and
    abdominal pain. Rarely renal insufficiency and hepatitis.

    Management

    Unlikely to be required. Recovery follows general supportive measures.
    In cases of massive overdose the patient's renal and hepatic function
    should be evaluated. Adequate hydration to maintain optimum diuresis
    facilitates excretion of allopurinol and its metabolites.

    Case data

    1.   A 15 year old girl ingested 22.5g (416mg/kg) of allopurinol,
    received gastric lavage within 3 hours of ingestion and 50g of
    activated charcoal. No signs of toxicity developed. Minor increases in
    plasma phosphate (to 1.43 mmol/L) and alkaline phosphatase (to 129 IU)
    were noted over the next 4 days. The half-life of allopurinol was 3.6
    hours, and oxypurinol 26 hours. (Ferner et al, 1988).

    2.   An 11 year old boy with acute lymphoblastic leukaemia presented
    in renal failure    after having been treated with allopurinol
    900mg/day for 3 months. He failed to respond to peritoneal dialysis,
    and died on the seventh day post-admission. Autopsy revealed an
    obstructive uropathy, focal ephrocalcinosis, and multiple small stones
    in the calyces of both kidneys. The stones were found to contain 82%
    xanthine, 15% oxypurinol, and 3% hypoxanthine. Uric acid and
    allopurinol were not detected (Potter & Silvidi, 1987).

    3.   A 79 year old man taking allopurinol of unknown dosage and
    duration developed general malaise, weakness and anorexia. The initial
    impression was acute hepatitis. Liver function tests revealed the
    following: Total bilirubin 1.3mg/dL, LDH 1957 IU/L, SGOT 1487 IU/L,
    SGPT 535 IU/L, and alkaline phosphatase 331 IU/L. Despite aggressive
    treatment, the patient died on the third hospital day. Autopsy showed
    hepatic toxic centrilobular necrosis. An antemortum blood sample was
    found to contain allopurinol 230.8mcg/ml; normal peak serum levels
    after a typical 300mg dose are 3 to 9mcg/ml ( Tam & Carroll, 1989).

    Other toxicological data

    Carcinogenicity     Longterm studies in rodents showed no
                        carcinogenicity.

    Mutagenicity        No mutagenicity showed in human lymphocytes

    Teratogenicity      There are no controlled studies on the use of
                        allopurinol in human pregnancy or possible effects
                        on fertility / male reproduction. There are 2
                        published reports of normal outcomes following
                        exposure during pregnancy.
                        Animal studies: Facial clefts and minor skeletal
                        defects have been reported in mice exposed to
                        allopurinol, but no teratogenic effects were
                        reported after administration of high doses in
                        rats and rabbits.

    Author

    Kathryn Pughe, BSc (Hons) MRPharmS

    National Poisons Information Service (Newcastle Centre)
    Regional Drug & Therapeutics Centre
    Wolfson Building
    Claremont Place
    Newcastle upon Tyne
    NE1 4LP
    UK

    This monograph was produced by the staff of the Newcastle Centre of
    the National Poisons Information Service in the United Kingdom. The
    work was commissioned and funded by the UK Departments of Health, and
    was designed as a source of detailed information for use by poisons
    information centres.

    Peer review was undertaken by the Directors of the UK National Poisons
    Information Service.

    Last updated January 1997

    References:

    Books:

    1.   ABPI Compendium of Data Sheets and Summaries of Product
         Characteristics. Datapharm Publications Ltd. 1996-97.

    2.   AHFS Drug Information. McEvoy GK (Ed.) 1996.

    3.   British National Formulary. Number 32 (September 1996). British
         Medical Association and Royal Pharmaceutical Society.

    4.   Dollery C. Therapeutic Drugs. Churchill Livingstone. 1991.

    5.   Ellenhorn MJ. Ellenhorn's Medical Toxicology: Diagnosis and
         Treatment of Human Poisoning. 2nd Edition 1997. Williams &
         Wilkins.

    6.   Martindale : The Extra Pharmacopoeia. 31st Edition. Reynolds JEF
         (Ed.) Pharmaceutical Press. 1996.

    Papers:

    1.   Ferner RE, Simmonds HA, Bateman DN. Allopurinol kinetics after
         massive overdosage. Hum Toxicol 1988; 7: 293-4.

    2.   Potter JL and Silvidi AA. Xanthine lithiasis, nephrocalcinosis,
         and renal failure in a leukaemia patient treated with
         allopurinol. Clin Chem 1987; 33: 2314-6.

    3.   Tam S and Carroll W. Allopurinol hepatotoxicity. Am J Med 1989;
         86:357-8.

    Computer databases

    1.   Poisindex System(R), Micromedex inc., Denver Colorado, Edition
         Expires 3/97.

    2.   Reprotox System(R), Micromedex inc., Denver Colorado, Edition
         Expires 3/97.

    3.   TOXBASE, National Poisons Information Service, 1996.
    

See Also:
        Allopurinol (PIM 020F, French)




INTOX Home Page
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.

    13. REFERENCES

        Bismuth C and Sebag C (1981)  Cardiogenic shock during acute
        poisoning with colchicine.  Nouv Presse Med, 10(13): 1073.
    
        Bourdon R and Galliot M (1976)  Determination of colchicine in
        biological fluids.  Ann Biol Clin (Paris), 34(6): 393-401.
    
        Bruneton J (1995)  Pharmacognosy, phytochemistry, medicinal
        plants.  Paris, Lavoisier.
    
        Caplan YH, Orloff KG and Thompson BC (1980)  A fatal overdose with
        colchicine.  J Anal Toxicol, 4: 153-155.
    
        Cooper MR and Johnson AW (1984)  Poisonous plants in Britain and
        their effects on animals and man.  London, HMSO, Ministry of
        Agriculture Fisheries and Food, reference book 161.
    
        Crabie P, Pollet J and Pebay-Peyroula F (1970)  Blood coagulation
        during acute colchicine poisoning.  Eur J Toxicol, 3(6): 373-
        385.
    
        Ellenhorn MJ, Schonwald S, Ordog G and Wasserberger J (1996) 
        Ellenhorn's medical toxicology: diagnosis & treatment of human
        poisoning, 2nd ed.  USA, Baltimore, Williams & Wilkins.
    
        Ellwood MG and Robb GH (1971)  Self-poisoning with colchicine. 
        Postgraduate Medical Journal, 47: 129-138.
    
        Frayha RA, Tabbara Z and Berbir N (1984)  Acute colchicine
        poisoning presenting as symptomatic hypocalcaemia.  Br J
        Rheumatol, 23(4): 292-295.
    
        Frohne D and Pfänder HJ (1983)  A colour atlas of poisonous
        plants.  Stuttgart, Wolfe.
    
        Gessner O and Orzechowski G (1974)  Colchicum autumnale,
        Hebstzeitlose.  In: C Winter. (1974)  Gift-und Arzneipflanzen von
        Mitteleuropa.  Heidelberg, Universitätsverlag,  pp 388-391.
    
        Goodman LS and Gilman A (1985)  The pharmacological basis of
        therapeutics, 6th ed.  London, MacMillan.
    
        Gooneratne BWM (1966)  Massive generalized alopecia after
        poisoning by Gloriosa superba.  Br Med J, 1 (5494): 1023-1024.
    
        Habermehl G (1985)  Colchicum autumnale. In: Mitteleuropäische
        Giftpflanzen und ihre Wirkstoffe. Springer Verlag, Berlin, pp
        6-8.
    

        Heaney D, Derghazarian CB, Pineo GF and Ali MA (1976)  Massive
        colchicine overdose: a report on the toxicity.  Am J Med Sci,
        271(2): 233-238.
    
        Hillemand B, Joly JP, Membrey-Maheo E and Ouvry D (1977) 
        Transitory diabetes with regressive hyperlipemia and hyperuricemia
        during acute colchicine poisoning. Report of a case.  Ann Med
        Interne (Paris), 128(4): 379-385.
    
        Huxley AH ed-in-chief (1992)  The new Royal Horticultural Society
        dictionary of Gardening, vol 1.  London, MacMillan.
    
        Jarvie D, Park J and Stewart MJ (1979)  Estimation of colchicine
        in a poisoned patient by using high performance liquid
        chromatography.  Clin Toxicol, 14(4): 375-381.
    
        Jean-Blain C and Grisvard M (1973)  Colchique. In: Plantes
        vénéneuses.  Paris, La Maison Rustique. pp 36-37.
    
        Kingsbury JM (1964)  Poisonous plants of the United States and
        Canada.  USA, New Jersey, Prentice-Hall.
    
        Lhermitte M, Bernier JL, Mathieu JL, Mathieu-Nolf M, Erb F and
        Roussel, P (1985)  Colchicine quantitation by high-performance
        liquid chromatography in human plasma and urine.  J Chromatogr,
        342(2): 416-423.
    
        Naidus RM, Rodvien R and Mielke CH Jr (1977)  Colchicine toxicity:
        a multisystem disease.  Arch Intern Med, 137(3): 394-396.
    
        Nagaratnam N, De Silva DPKM and De Silva N (1973)  Colchicine
        poisoning following ingestion of Gloriosa superba tubers.  Trop
        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) 
        Haemodynamic studies in eight cases of acute colchicine poisoning. 
        Hum Toxicol, 2(2): 169-173.
    
        Stapczynski JS, Rothstein RJ, Gaye WA and Niemann JT (1981) 
        Colchicine overdose: report of two cases and review of the
        literatature.  Ann Emerg Med, 10(7): 364-369.
    
        Strid A and Tan Kit eds (1991)  Mountain flora of Greece, vol. 2. 
        UK, Edinburgh University.
    
        Tutin TG, Heywood VH, Burges NA, Moore DM, Valentine DH, Walters
        SM and Webb DA eds (1980)  Flora Europaea, vol 5.  UK, Cambridge,
        Cambridge University Press.

    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
    


    


INTOX Home Page
Colchicine
1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
   1.7 Presentation, Formulation
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
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
         3.3.1.1 Colour
         3.3.1.2 State/Form
         3.3.1.3 Description
      3.3.2 Properties of the locally available formulation(s)
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation(s)
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalational
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   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
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Methods
   8.2 Therapeutic and toxic concentration
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 contact
      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 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)



    1.  NAME
 
        1.1  Substance 
 
             Colchicine (USAN) 
 
             (Fleeger,1993) 
 
        1.2  Group
 
              ATC classification index 
 
             Antigout preparations (M04) 
             Preparations with no effect on uric acid metabolism (M04AC) 
 
             (WHO, 1992) 
 
        1.3  Synonyms
 
             Colchicina (Italian)
             Colchicin (German)
             Colchicum
             Colchique (French)
             NSC 757
 
             (To be completed by each Centre using local data) 
 
        1.4  Identification numbers
 
             1.4.1  CAS number
 
                    64-86-8
 
             1.4.2  Other numbers
 
                    UPDT                  8211
                    NIOSH/RTECS           GH 0700000
                    NSC                   757
 
        1.5  Brand names, Trade names
 
              Colchicine (monocomponent)
             
             Australia       Colgout (Protea); Colchicine (Medical
                             Research); Colcin (Knoll); Coluric (Nelson).
             
             Canada          Colchicine (Abbott).
             
             France          Colchicine (Houde ISH); Colchineos
                             (Houde ISH).
             
 
 
 
             Germany         Colchicum-Dispert (Kali-Chemie).
             
             South Africa    Colchicine Houdse (Roussel).
             
             USA             Colchicine (Abbott, Barr Lab., Danbury,
                             Lilly, Rugby, Towne, United Research
                             Laboratories)
             
              Colchicine plus probenecid
             
             UK              ColBenemid (Merck Sharpe & Dohme)
             
             USA             ColBenemid (Merck Sharpe & Dohme);
                             Col-Probencid (Danbury, Goldline, Interstate,
                             Parmed, United Research Lab.,) Proben-C
                             (Rugby)
             
              Colchicine associated with other compounds
             
             France          Colchimax - contains colchicine,
                             phenobarbitone and opium tincture
                             (Houde ISH).
             
             Generic products are also available.
             
             (To be completed by each Centre using local data)
 
        1.6  Manufacturers, Importers
 
             Biogen Laboratories, Columbia, Ethical Pharmaceuticals, 
             Fisher Scientific, Purepac, Regal Laboratories, Rondex, 
             Schein, Tourne- Paulsen, Westward, Zenith.
             
             (To be completed by each Centre using local data)
 
        1.7  Presentation, Formulation
 
             Colchicine is available as tablets and, in some 
             countries, as injectable solutions.
             
             Tablets contain mostly 0.5 to 0.65 mg.  Formulations with 1 
             mg per tablet are also available.
             
             Sterile solutions containing 0.5 mg/ml are also available for 
             intravenous injection.
             
             (To be completed by each Centre using local data)
 
 
 
    2.  SUMMARY
 
        2.1  Main risks and target organs
 
             Colchicine exerts a multiorgan toxicity.  The main toxic 
             effects are related to the effects of colchicine on cellular 
             division and account for diarrhoea, bone marrow depression, 
             alopecia.  Other acute effects are hypovolaemia, 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 (Day 1 to 3) gastrointestinal and circulatory phase
             
             Severe gastrointestinal irritation: Nausea, vomiting, 
             abdominal cramps, severe diarrhoea.
             
             Dehydration, hypovolaemia, shock.  Cardiogenic shock may 
             occur and may result in death within the first 72 hours.
             
             Hypoventilation, acute respiratory distress syndrome.
             
              Stage II (Day 3 to 10) bone marrow aplasia phase
             
             Bone marrow aplasia with agranulocytosis.
             
             Coagulation disorders with diffuse haemorrhages.
             
             Rhabdomyolyis.
             
             Polyneuritis, myopathy.
             
             Acute renal failure.
             
             Infectious complications.
             
              Stage III: (After 10 day) recovery phase
             
             Alopecia.
 
 
 
        2.3  Diagnosis
 
             Clinical diagnosis is difficult because of the 
             multiorgan toxicity.
             
             Colchicine levels are not clinically useful.
             
             Note: 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 profile and fibrin/fibrinogen degradation 
             products.
             
             Creatinine phosphokinase and transaminases.
 
        2.4  First aid measures and management principles
 
             Patients with colchicine overdose should always be 
             admitted as soon as possible to an intensive care unit for a 
             minimum of 48 hours.
             
             Monitor vital signs (ECG, blood pressure, respiration, 
             central venous pressure), fluid and electrolyte balance, and 
             blood cells.
             
             Treatment may include the following:
             
             Rehydration, plasma expander infusion, inotropic and 
             vasopressor drugs,
             
             Artificial ventilation.
             
             Early gastric lavage.
             
             Correction of electrolytes and acid-base disorders.
             
             Early forced diuresis.
             
             Correction of coagulation disorders.
             
             Prevention of infectious complications.
 
 
 
    3.  PHYSICO-CHEMICAL PROPERTIES
 
        3.1  Origin of the substance
 
             Colchicine is an alkaloid of Colchicum autumnale (autumn 
             crocus, meadow saffron).  It was isolated in 1820 by 
             Pelletier and Caventou. Colchicum is also present in Gloriosa 
             superba (Glory Lily) (Gooneratne, 1966; Nagaratnam et al., 
             1973).  For more information see the PIM on Colchicum 
             autumnale.
             
             The chemical structured was described by Dewar in 1945.  The 
             chemical synthesis was first realised by Woodward.
 
        3.2  Chemical structure
 
              Structural formula
 
             STRUCTURAL FORMULA
 
             Molecular formula
             
             C22H25NO6
             
             Molecular weight
             
             399.4
             
             Structural Chemical names
             
              (S)-N-(5,6,7,9-Tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo 
             [alpha] heptalen-7-yl)acetamide.
             
              N-(5,5,7,9-Tetrahydro-1,2,3,10-tetramethoxy-9- 
             oxobenzo[alpha]heptalen-7-yl)acetamide.
             
             (Budavari, 1989; Reynolds, 1993)
             
              Derivatives
             
             Different compounds have been isolated from Colchicum 
             autumnal. Colchicine has the most important biological 
             activity which is related to the tropolonic cycle (C).
             
 
 
 
                                                                             
    
    Biological   Substance                    R1        R2       R3      R3
    activity     name
                                                                             
    
    +++          Colchicine                   CH3       COCH3    0       OCH3
    
    
    ++           Desacetyl                    CH3       CH3      0       OCH3
    
                 methylcolchicine             CH3       H        0       SCH3
    
    ++           Desacetylthiocolchicine      C6H1105   COCH3            OCH3
    
    ++           Colchicoside                 CH3       H        0       OH
    
    +            Trimethylcolchicinic acid    CH3       COCH3    0       0
    
    0            Colchiceine                                     0H
                                                                             
     
        3.3  Physical properties
 
             3.3.1  Properties of the substance
 
                    3.3.1.1  Colour 
 
                             Pale yellow. It darkens on exposure to light.
 
                    3.3.1.2  State/Form
 
                             Odourless powder or scales. 
 
 
                    3.3.1.3  Description 
 
                             Melting point 153-157°C
                             
                             pH of 0.5% solution is 5.9
                             
                             Freely soluble in alcohol or chloroform, 
                             slightly soluble in ether (1/220) and 
                             insoluble in petroleum ether.  Solubility in 
                             water is 1/25.
 
 
 
             3.3.2  Properties of the locally available formulation(s)
 
                    To be completed by each Centre using local 
                    data.
 
        3.4  Other characteristics
 
             3.4.1  Shelf-life of the substance
 
                    Shelf-life of the substance is three to five years.
 
             3.4.2  Shelf-life of the locally available formulation(s)
 
                    To be completed by each Centre using local data.
 
             3.4.3  Storage conditions
 
                    Store in airtight conditions and protect from light.
 
             3.4.4  Bioavailability
 
                    To be completed by each Centre using local data.
 
             3.4.5  Specific properties and composition
 
                    To be completed by each Centre using local data.
 
    4.  USES
 
        4.1  Indications
 
             4.1.1  Indications
 
                    Not relevant
 
             4.1.2  Description
 
                    Gout
                    
                    Colchicine is used for acute gout attacks to reduce 
                    pain and inflammation.  It may be used on long-term 
                    basis to prevent or reduce the frequency of 
                    attacks.
                    
                    Familial Mediterranean Fever
                    
                    Colchicine is used on long-term basis to prevent fever 
                    and recurrent polyserositis.  Colchicine is effective 
                    in preventing the amyloidosis in this condition.
                    
                    Behcet's disease
                    
                    Colchicine has been showed to be effective in the 
                    treatment of articular, cutaneous and mucosal 
                    symptoms.
 
 
 
                    
                    Other
                    
                    Colchicine has been used in the treatment of 
                    scleroderma and sarcoidosis.
 
        4.2  Therapeutic dosage
 
             4.2.1  Adults
 
                    Acute Gout Attack
                    
                    Oral
                    
                    1 or 1.3 mg initial dose, followed by 0.5 to 0.65 mg 
                    every 1 to 2 hours (or 1 to 1.3 mg every 2 hours) 
                    until the pain is relieved or nausea and diarrhoea 
                    appear. The total dose should not exceed 10 mg over 3 
                    days.
                    
                    A course should not be repeated within three days.
                    
                    Tolerance is usually 4 to 8 mg.
                    
                    Parenteral
                    
                    Intravenous injection.   Initial dose is 1 to 2 mg. 
                    The total dose is 4 mg in 24 hours or in an 
                    attack.
                    
                    Prophylaxis of recurrent gout
                    
                    Oral
                    
                    0.5 mg to 0.65 mg once weekly or up to three times 
                    daily, depending on the frequency of prior acute 
                    attacks.
                    
                    (Reynolds 1993)
 
             4.2.2  Children
 
                    No dosage is available for use in young 
                    children (Levy, 1977).
                    
                    A dose of 0.5 mg daily has been used in children  with 
                    familial mediterranean fever from the age of 5 years 
                    of age or under, and 1 mg daily for older children 
                    (Reynolds 1993).
 
 
 
        4.3  Contraindications
 
             Underlying disease.
             
             Pregnancy: There is a risk of foetal chromosomal damage 
             (Reynolds, 1989).
 
    5.  ROUTES OF ENTRY
 
        5.1  Oral
 
             Oral absorption is the most frequent cause of 
             intoxication.
 
        5.2  Inhalational
 
             Not relevant.
 
        5.3  Dermal
 
             Not relevant.
 
        5.4  Eye
 
             Not relevant.
 
        5.5  Parenteral
 
             Intoxications after parenteral administration are rare, 
             (Benoit et al., 1974, Jaeger et al., 1980, Liu et al., 1978), 
             however, the toxic dose appears to be lower than the oral 
             toxic dose.
             
             Five fatal outcomes after intravenous colchicine: the daily 
             dose was 3 to 6 mg and the total dose was 9 to 21 mg over 2 
             to 8 days.(Jaeger et al., 1980)
             
             A fatal bone marrow aplasia in a 70 year-old man after 10 mg 
             intravenous colchicine over 5 days (Liu et al., 1978).
 
        5.6  Other
 
             Intoxication with multisystemic reactions after 
             instillation of 50 mg colchicine into the penile urethra for 
             treatment of condyloma acuminata (Naidus et al., 1977).
 
 
 
    6.  KINETICS
 
        6.1  Absorption by route of exposure
 
             Oral
             
             Rapidly absorbed from the gastro-intestinal 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., 1970).
             
             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 kidney, liver, spleen, gastro- 
             intestinal wall and leucocytes and is apparently excluded 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
 
             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 min) and decreased 
             in severe hepatic disease (9 min) (Wallace et al., 1970).
             
             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 by route of exposure
 
             Colchicine is excreted unchanged (10 to 20 percent) or 
             as metabolites.
             
             Oral
             
              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 48 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.
             
              Breast Milk
             
             Colchicine may be eliminated in breast milk (White & White, 
             1980).
             
             Intravenous
             
              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.  PHARMACOLOGY AND TOXICOLOGY
 
        7.1  Mode of action
 
             7.1.1  Toxicodynamics
 
                    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.
                    
                    Mitosis blockade accounts for diarrhoea, bone marrow 
                    depression and alopecia.  Colchicine may have a direct 
                    toxic effect on muscle, peripheral nervous system and 
                    liver. Inhibition of cellular function does not, 
                    however, account for all the organ failures seen in 
                    severe overdose.
 
             7.1.2  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 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
 
                             Oral
                             
                             Fatalities have been reported after ingestion 
                             of 7 to 12 mg (Stapczynski et al., 1981).
                             
                             The severity and the mortality rate of the 
                             poisoning is directly related to the dose 
                             ingested (Gaultier & Bismuth, 1978; Bismuth 
                             et al., 1977; Lambert et al., 1981).
                             
 
 
 
                                                                         
    
            Dose              Symptoms                       Mortality
            absorbed                                         Rate
            mg/kg
                                                                         
    
            <0.5             Gastrointestinal symptoms      0%
                              decrease of coagulation
                              factors
    
            0.5-0.8           + Bone marrow aplasia          10-50%
                              + alopecia
    
            > 0.8            + circulatory failure          100%
                                                                         
    
 
                             Intravenous
                             
                             Fatal outcomes in five patients who had 
                             received a total dose of 9 to 21 mg over two 
                             to eight days (daily dose 3 to 6 mg) (Jaeger 
                             et al., 1980).
                             
                             A fatal bone marrow aplasia in a 70-year-old 
                             patient who had received 10 mg of intravenous 
                             colchicine over 5 days (Liu et al., 
                             1978).
                             
                             The enhanced toxicity of intravenous 
                             colchicine is probably due to the higher 
                             bioavailability of colchicine after 
                             parenteral administration.
 
                    7.2.1.2  Children
 
                             Oral
                             
                             The toxic dose is about 0.1 mg/kg and the 
                             lethal dose is between 0.5 and 0.8 mg/kg 
                             (Besson-Leaud et al., 1977).
 
 
 
             7.2.2  Relevant animal data
 
                                                                        
             
             Species      Route              Effect    Dose (mg/kg)
                                                                        
             
             Rat          Intravenous        LD 50         1.6
             
             Rat          Intraperitoneal    LD 50         6.1
             
             Rat          Subcutaneous       LD Lo         4
             
             Mouse        Intravenous        LD 50         4.13
             
             Mouse        Intraperitoneal    LD 50         2
             
             Dog          Oral               LD Lo         0.125
             
             Dog          Subcutaneous       LD Lo         0.571
             
             Cat          Oral               LD Lo         0.125
             
             Cat          Subcutaneous       LD Lo         0.5
             
             Cat          Intravenous        LD 50         0.25
                                                                        
             
             (RTECS, 1979)
 
             7.2.3  Relevant in vitro data
 
                    No data available.
 
        7.3  Carcinogenicity
 
             No data available.
 
        7.4  Teratogenicity
 
             Colchicine is contraindicated in pregnancy as Down's 
             syndrome and spontaneous abortion have been reported. 
             Colchicine should be discontinued three months prior to 
             conception (Drugdex, 1989).
 
        7.5  Mutagenicity
 
             See section 9.4.7.
 
 
 
        7.6  Interactions
 
             Menta et al. (1987) reported a case of acute cyclosporin 
             nephrotoxicity induced by colchicine administration. 
             Colchicine may interfere with cyclosporin pharmacokinetics by 
             increasing cyclosporin plasma levels either by enhancing 
             cyclosporin absorption or by reducing its hepatic 
             metabolism.
 
        7.7  Main adverse effects
 
             Gastrointestinal symptoms are a common complication of 
             chronic colchicine therapy.  Thus the dose of colchicine is 
             usually limited by gastrointestinal toxicity. 
             
             About 80 per cent of the patients treated with colchicine at 
             a dose of 3 to 4 mg per day develop gastrointestinal 
             disturbances (Wallace, 1980).
             
             Fatal outcomes have been reported after intravenous 
             colchicine therapy (see section 7.2.1.1).
             
             The following adverse reactions have been reported during 
             colchicine treatment (Dukes, 1983):
             
             Gastrointestinal
             
             Vomiting, diarrhoea, abdominal discomfort, paralytic ileus, 
             malabsorption syndrome with steatorrhoea.
             
             Haematological
             
             Bone marrow depression with agranulocytosis, acute 
             myelomonocytic leukaemia, multiple myeloma, 
             thrombocytopenia.
             
             Neurological
             
             Peripheral neuritis, myopathy, rhabdomyolysis (Riggs et al., 
             1986).
             
             Dermatological
             
             Allergic reactions are rare urticaria; oedema may be seen. 
             Alopecia has been reported after chronic treatment.
             
             Reproductive system
             
             A reversible, complete azoospermia has been reported (Merlin 
             1972).
             
 
 
 
             Metabolic
             
             Colchicine is capable of producing a reversible impairment of 
             vitamin B12 absorption (Webb et al, 1968).  Porphyria cutanea 
             tarda has been reported (Gossweiler, 1985).
 
    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
 
        8.1  Methods
 
             Colchicine may be analysed in biological fluids by 
             different methods:
             
             Fluorometric method:  Fluorescence of organometallic 
             (Gallium) complexes (Bourdon & Galliot, 1976).
             
             Radioimmunoassay:  (Ertel et al., 1979; Scherrman et al., 
             1980).
             
             High performance liquid chromatography: (Jarvie et al, 1979, 
             Caplan et al., 1980; Harzer, 1984; Lhermitte et al., 
             1985).
             
             Liquid chromatography (Thompson, 1985).
 
        8.2  Therapeutic and toxic concentration
 
             Colchicine may be measured in biological fluids but 
             levels are not useful or necessary for the management of 
             colchicine poisoning.
             
              Serum/Plasma/Blood
             
              Plasma
             
             Plasma levels lower than 20 ng/ml at the 6th hour in severe 
             intoxications have been reported (Bourdon & Galliot 
             1976).
             
             In an overdose with 7.5 mg, plasma levels of 21 ng/ml at the 
             6th hour and below 5 mg/ml at the 24th hour were noted 
             (Jarvie et al., 1979).
             
             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).
             
             Post-mortem serum blood levels of 170 and 240 ng/mL (at the 
             4th and 8th hour) in 2 heroin addicts following intravenous 
             injection were reported (Harzer, 1984) .
             
 
 
 
             The following plasma levels were noted in an overdose with 31 
             mg orally: 720, 212, 132 and 120 ng/mL at the 20, 125, 305, 
             605 minutes respectively (Lhermitte et al., 1985).
             
              Blood
             
             Colchicine levels in blood are higher than those in 
             plasma.
             
             In an overdose with 20 mg colchicine orally a blood level of 
             250 ng/ml at the second hour was noted (Caplan et al. 1980). 
             No colchicine could be detected at the 40th hour.
             
              Urine
             
             Colchicine levels in urine range between 200 and 2500 ng/ml 
             over the first 24 hours (Bismuth et al., 1977; Lambert et al, 
             1981, Jaeger et al. 1985).
             
             Information was available on urinary excretion in 5 cases. 
             Concentrations in urine are 10 to 80 fold higher than those 
             in plasma. Four to 25 per cent of the dose ingested was 
             excreted in urine over three to ten days.  Excretion was 
             specially high during the first 24 hours following ingestion. 
             Colchicine is eliminated in urine up to the tenth day (Jaeger 
             et al., 1985).
             
              Gastric lavage fluid
             
             In four cases, gastric lavage performed 3 to 6 hours post 
             ingestion removed 7 to 25 per cent 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).
 
    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 gastro-intestinal 
                    motility have also been ingested (phenobarbitone, 
                    psychotropic drugs, opium derivatives). Symptomatology 
                    progresses in three stages and may include:
                    
 
 
 
                    Stage I (Day 1 to 3) Gastrointestinal and circulatory 
                    phase:
                    
                    Severe gastrointestinal irritation: Nausea, vomiting, 
                    abdominal cramps, severe diarrhoea.
                    
                    Dehydration, hypovolemia, shock.  Cardiogenic shock 
                    may occur and may result in death within the first 72 
                    hours.
                    
                    Hypoventilation, acute respiratory distress 
                    syndrome.
                    
                    Stage II (Day 3 to 10) Bone marrow aplasia phase:
                    
                    Bone marrow aplasia with agranulocytosis.
                    
                    Coagulation disorders with diffuse haemorrhages.
                    
                    Rhabdomyolyis.
                    
                    Polyneuritis, myopathy.
                    
                    Acute renal failure.
                    
                    Infectious complications.
                    
                    Stage III: (After ten days) Recovery phase:
                    
                    Alopecia
                    
                    (Gaultier & Bismuth, 1978, Ellenhorn & Barceloux, 
                    1988, Stapczynski et al., 1981).
 
             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
 
                    The clinical course after intravenous injection 
                    is similar to that observed after ingestion.  The time 
                    to onset of symptoms depends on the dose and rate of 
                    injection but gastro-intestinal symptoms usually 
                    appear two to six days after the beginning of 
                    colchicine therapy.
                    
                    Two cases of lethal overdose after a single 
                    intravenous injection of 30 mg colchicine were 
                    reported; gastro-intestinal symptoms appeared 2 hours 
                    after injection (Michaux et al., 1972) .
 
             9.1.6  Other
 
                    An intoxication with multisystemic reactions 
                    after instillation of 50 mg colchicine into the penile 
                    urethra for treatment of condyloma acuminata has been 
                    reported. (Naidus et al., 1977)
 
        9.2  Chronic poisoning
 
             9.2.1  Ingestion
 
                    Chronic administration of colchicine may induce 
                    similar toxicity to that seen in acute poisoning: 
                    gastro-intestinal symptoms (vomiting, diarrhoea), 
                    agranulocytosis, aplastic anaemia, myopathy (Gilman et 
                    al., 1985)
 
             9.2.2  Inhalation
 
                    No data available.
 
             9.2.3  Skin contact
 
                    No data available.
 
             9.2.4  Eye contact
 
                    No data available.
 
             9.2.5  Parenteral exposure
 
                    Similar to acute poisoning.
 
             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).
             
             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) of the intoxication, death is 
             due to cardiogenic 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
 
                    Cardiovascular shock is always present in 
                    severe intoxications. Most deaths result from shock 
                    within the first 72 hours.
                    
                    Hypotension is usually the result of hypovolaemia due 
                    to gastrointestinal fluid loss.  Hypovolaemia 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 of 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 (Hill et al., 1975; Corbin et al., 1989; 
                    Maurizi et al., 1986; Davies et al., 1988; Hobson & 
                    Rankin, 1986).
 
             9.4.3  Neurological
 
                    9.4.3.1  Central nervous system (CNS)
 
                             In severe cases hypotension and/or 
                             hypoxaemia 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 (Carr, 1965; 
                             Favarel-Garrigues et al., 1975; Kuncl, 1987; 
                             Bismuth et al., 1977; Mouren et al., 1969; 
                             Kontos, 1962). Ascending paralysis may be 
                             responsible for respiratory failure (Carr, 
                             1965). Polyneuritis usually recovers within 
                             one month (Bismuth et al., 1977).
 
                    9.4.3.3  Autonomic nervous system
 
                             None described.
 
                    9.4.3.4  Skeletal and smooth muscle
 
                             Rhabdomyolysis may occur with an 
                             increase in muscle enzymes and myoglobinuria 
                             (Murray et al., 1983; Kontos et al., 1962; 
                             Letellier et al., 1979). A case of 
                             rhabdomyolysis was reported in a 58-year-old 
                             patient treated with 3 mg colchicine daily 
                             over 6 days (Letellier et al., 1979).  The 
                             patient developed proximal scapular weakness 
                             with muscle oedema and increase in muscle 
                             enzymes.
 
 
 
             9.4.4  Gastrointestinal
 
                    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 
                    hypovolaemia 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.
                    
                    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 includes 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.  Histological 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 electrolytes losses or hypovolaemia. 
                             Acute renal failure may occur following 
                             cardio-vascular or septic shock.
 
 
 
                    9.4.6.2  Other
 
                             Proteinuria and haematuria have been 
                             reported.
 
             9.4.7  Endocrine and reproductive systems
 
                    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 
                    (Gauthier et al., 1975).
                    
                    Reproductive
                    
                     Acute
                    
                    A case of colchicine poisoning (40 mg) has been 
                    reported in a 18 year old pregnant woman (Lambert et 
                    al., 1981).  The patient developed severe poisoning 
                    with coagulopathy, 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).  2 cases of Down's syndrome babies 
                    have been reported (Ehrenfeld et al., 1987). The 
                    obstetric histories of 36 women with familial 
                    Mediterranean fever on long-term colchicine treatment 
                    between 3 and 12 years have been reported (Ehrenfeld 
                    et al., 1987).  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.
 
             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.
                    
 
 
 
                    Cutaneous and subcutaneous haemorrhages are frequent 
                    in severe poisoning.  They are due to coagulation 
                    disturbances and may be induced by venous or arterial 
                    punctures.
 
             9.4.9  Eye, ear, nose, throat: local effects
 
                    Eye
                    
                    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 (Wallace, 1974; Lambert et 
                    al., 1981).
 
             9.4.10 Haematological
 
                    At toxic doses, colchicine induces marked bone 
                    marrow depression.
                    
                    Leucocytes
                    
                    At the initial stage a peripheral leucocytosis occurs 
                    frequently.  a leucopenia with agranulocytosis begins 
                    at the third day and reaches a maximum at day 5 to 7. 
                    WBC return to normal values at about the 10 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 toward bleeding is always present in severe 
                    cases. It appears two to three days following 
                    ingestion and may last for eight to ten days.
                    
                    Usually the earliest indication 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 consumptive 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; Lambert et al., 1981; Crabie et 
                    al.,1970)
 
             9.4.11 Immunological
 
                    No data available.
 
             9.4.12 Metabolic
 
                    9.4.12.1 Acid-base disturbances
 
                             Metabolic acidosis due to diarrhoea 
                             and/or shock may be seen.
 
                    9.4.12.2 Fluid and electrolyte disturbances
 
                             The gastro-intestinal 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
                             
                             A 58-year-old woman who ingested 25 mg and 
                             developed transient diabetes mellitus has 
                             been reported (Hillemand et al., 1977).
                             
                             Hyperlipaemia
                             
                             A transient hyperlipaemia has been reported 
                             (Hillemand et al. 1977).
                             
                             Hyperuricaemia
                             
                             A transient hyperuricaemia has also been 
                             noted (Hillemand et al. 1977).
                             
                             Hyperthermia-fever
                             
                             Occurrence of fever may be relate 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. The obstetric histories of 36 women with 
                    familial Mediterranean fever on long-term colchicine 
                    treatment between 3 and 12 years have been reported 
                    (Ehrenfeld et al. 1987).  Seven of 28 pregnancies 
                    ended in miscarriage. Thirteen 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  Other
 
             No data available.
 
        9.6  Summary
 
             Not relevant
 
    10. MANAGEMENT
 
        10.1 General principles
 
             Patients with colchicine overdose should always be 
             admitted in an intensive care unit.  Treatment depends on the 
             dose ingested, the symptomatology and the delay following 
             ingestion.  It includes gastric lavage, early forced 
             diuresis, and supportive treatment with correction of the 
             shock, artificial ventilation, treatment and prevention of 
             haemorrhagic 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 Relevant laboratory analyses
 
             10.2.1 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. 
                    Concentration in urine are 10 to 80 fold higher than 
                    those in plasma.
 
 
 
             10.2.2 Biomedical analysis
 
                    A biochemical profile with glucose, BUN, 
                    electrolytes, creatinine, blood cells, coagulation 
                    parameters, 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.
 
             10.2.3 Toxicological analysis
 
                    Colchicine analysis in biological fluids is 
                    not necessary or useful for the management of the 
                    poisoning.
 
             10.2.4 Other investigations
 
                    No other specific investigations are 
                    required.
 
        10.3 Life supportive procedures and symptomatic/specific treatment
 
             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.
             
             Insert a venous catheter for rehydration and drug 
             injection.
             
             If shock is present, insertion of a pulmonary artery (Swan- 
             Ganz) catheter for monitoring of haemodynamic parameters may 
             be useful for guiding the treatment. 
             
             The patient remains at risk until at least 48 hours after 
             exposure.
             
             Diarrhoea
             
             Diarrhoea should not be treated because some colchicine is 
             eliminated in faeces.
             
             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/hr).
             
 
 
 
             Hypotension, shock
             
             Hypotension should be anticipated and treated with adequate 
             fluid replacement and vasoactive drugs.  Monitor blood 
             pressure.  Early institution of hemodynamic 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. 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/min).
             
              Vasodilators
             
             Vasodilators e.g. glyceryl trinitrate may be useful in the 
             case of cardiogenic shock with increased systemic arterial 
             resistance (personal observation).
             
             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.
             
             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).
             
             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 only if 
             haemorrhages develop.  According to biological parameters, 
             treatment may include infusion of fresh-frozen plasma, 
             platelet units, fibrinogen and coagulation factors 
             (PPSB).
             
             Prevention of Infectious Complications
             
             In severe cases with shock and/or aplasia a prophylactic 
             antibiotic treatment should be given. Prophylactic 
             antibiotherapy 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).
 
        10.4 Decontamination
 
             Gastric Lavage
             
             Early gastric lavage is indicated because it may remove 7 to 
             25 per cent of the dose ingested if it is performed within 6 
             hours of ingestion (Jaeger et al., 1985).
             
             Emesis
             
             Emesis may be useful in recent ingestion if there are no 
             contraindications.
             
             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.
             
             Cathartics
             
             The usefulness of cathartics has not been established and is 
             not recommended.
 
 
 
        10.5 Elimination
 
             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.
             
             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 is not useful.
 
        10.6 Antidote treatment
 
             10.6.1 Adults
 
                    Currently no antidote for colchicine is 
                    available.
 
             10.6.2 Children
 
                    No antidote available.
 
        10.7 Management discussion
 
             Gastrointestinal symptoms may be overshadowed if 
             psychotropic drugs or drugs decreasing gastrointestinal 
             motility have also been ingested.
             
             Institute prophylactic antibiotic therapy.
 
    11. ILLUSTRATIVE CASES
 
        11.1 Case reports from literature
 
              Case report 1
             
             In 69 reported cases of colchicine poisoning (Bismuth et al., 
             1977) thirty eight patients (dose ingested <0.5 mg/kg) 
             developed gastro- intestinal symptoms and coagulation 
             disturbances; all survived. Twenty patients (dose ingested 
             0.5 to 0.8 mg/kg) developed bone marrow aplasia:  mortality 
             was 10 per cent. Eleven patients (dose ingested > 0.8 mg/kg) 
             died within 72 hours from cardiovascular shock.
             
 
 
 
              Case report 2
             
             In another reported 22 cases (Lambert et al., 1981), 
             according to the doses ingested (DI), mortality rates were: 
             100% for DI > 1 mg/kg; 50% for DI = 0.5 to 0.9 mg/kg; 10% 
             for DI < 0.5 mg/kg.  Clinical features included: 
             gastrointestinal symptoms (22 cases), leucopenia, aplasia (11 
             cases), disseminated intravascular coagulation (9 cases), 
             shock (9 cases), acute respiratory distress syndrome (8 
             cases), polyneuropathy (4 cases).
             
              Case report 3
             
             Two cases were reported (Gaultier et al., 1969) who developed 
             inappropriate antidiuresis following ingestion of about 40 
             mg. Both patients recovered.
             
              Case report 4
             
             A 18-year-old woman developed an acute respiratory distress 
             syndrome (ARDS) following ingestion of 150 mg.  The patient 
             died at the 42nd hour (Hill et al., 1975).
             
              Case report 5
             
             An acute respiratory distress syndrome was reported in a 17- 
             year-old woman who had ingested 0.37 mg/kg (Corbin et al., 
             1989).  Pulmonary capillary wedge pressure was 7 mm Hg.  The 
             patient died (72nd hour), despite mechanical ventilation 
             (PEEP), from shock any hypoxaemia.
             
              Case report 6
             
             Two cases with ARDS have been reported (Maurizi et al., 
             1986).  A 25- year-old woman who had ingested 80 mg died on 
             the 7th day from septic shock with acute renal failure; a 21 
             year old man who had ingested 15 to 20 mg also developed 
             aplasia and recovered.
             
              Case report 7
             
             A fatal overdose in a 15-year-old boy who had ingested 18 mg 
             colchicine and developed cardiovascular shock, ARDS, 
             metabolic acidosis, hypocalcaemia, hypokalaemia, 
             hypophosphotaemia, bone marrow suppression and coagulopathy 
             has been reported (Hobson & Rankin, 1986).
             
 
 
 
              Case report 8
             
             Report of an overdose with about 24 mg in a 15 year old girl 
             (Murray et al., 1983). The clinical picture showed:
             
             *      myocardial injury with cardiogenic shock
             *      ventilatory insufficiency with ARDS
             *      rhabdomyolysis
             *      metabolic acidosis
             *      agranulocytosis
             *      coagulopathy
             *      alopecia.
             
             The patient recovered without sequelae.
 
        11.2 Internally extracted data on cases
 
             Jaeger et al. (1980) reported five fatal outcomes in 
             five patients after intravenous colchicine treatment for 
             gout. The total dose ranged between 9 to 21 mg administered 
             over two to eight days.  During the treatment the patients 
             developed gastro-intestinal symptoms and thereafter (on about 
             the 7th day) agranulocytosis, thrombocytopenia and shock with 
             acute renal failure.  Death occurred between the 7th and 15th 
             day after beginning of the treatment.
             
             Sauder et al. (1983) performed haemodynamic studies in eight 
             cases of colchicine poisoning. The doses ingested ranged 
             between 9 and 160 mg.  Haemodynamic studies performed between 
             the 6th and 72nd hour following ingestion showed:
             
             Hypovolemia in all cases,
             
             A hyperkinetic state with increased cardiac index and 
             decreased systemic vascular resistance in the 4 patients who 
             recovered.
             
             Cardiogenic shock with decreased cardiac index and increased 
             systemic vascular resistances in the 4 patients who died.
             
             An initial decrease of cardiac performance is an index of 
             severity and poor prognosis.
             
             Jaeger et al, (1985) performed a toxicokinetic study in 5 
             cases (dose ingested 19 to 60 mg).  Plasma concentrations 
             ranged between 20 and 54 ng/mL during the 24 first hours. 
             Gastric lavage removed 7.1 to 25% of the dose ingested.  In 
             one case 1.4 mg colchicine was excreted in diarrhoea on the 
             second day.  Four to 25 per cent of the dose ingested was 
             eliminated in urine over 3 to 10 days.
             
 
 
 
             Urinary colchicine excretion was especially high during the 
             first day following ingestion (2 to 10 per cent of the dose 
             ingested). Colchicine levels in urine were 10 to 80 times 
             higher than those in plasma.  This study emphasizes the 
             usefulness of early gastric lavage, of early diuresis and of 
             colchicine elimination in diarrhoea.
 
        11.3 Internal cases
 
             To be completed by each Centre using local data.
 
    12. ADDITIONAL INFORMATION
 
        12.1 Availability of antidotes
 
             Not relevant
 
        12.2 Specific preventive measures
 
             Not relevant
 
        12.3 Other
 
             Unknown
 
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    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
        ADDRESS(ES)
 
        Authors     A. Jaeger, F. Flesch, Ph. Sauder, J Kopferschmitt
                    Poison Control Center
                    Strasbourg
                    France
        
                    Tel: 33-88161144
                    Fax: 33-88161930
        
        Date        28 March 1989
        
        Peer Review          London, United Kingdom, March 1990
                             Berlin, Germany, October 1995