Does CBD Work for Gout? 

  • CBD may be an effective treatment for gout pain. This form of arthritis is incurable but manageable(1).
  • Over-the-counter and prescription medications are effective in gout treatment. However, these drugs may cause adverse side effects in some individuals(2).
  • A study in 2018 published in Molecules has shown that CBD might be a useful inflammation and pain treatment(3).
  • Another study conducted in mice with osteoarthritis reports that CBD may help attenuate inflammation and severe pain caused by the chronic condition(4).
  • There has been significant research showing CBD’s promise in treating gout symptoms. However, further studies need to be done on CBD’s effects on gout. 

Best CBD Oils for Gout

Editor's Pick

Spruce 750mg Lab Grade CBD Oil

Specifically formulated to be more palatable to CBD users
Spruce 750mg Lab Grade CBD Oil Bottle
  • Overall Clinical Score
    99%
    Editor's Pick
  • Score breakdown
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    Quality
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    Lab Testing Transparency
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  • Summary

    Each bottle of the 750mg CBD oil tincture contains 25mg of CBD per dropper full. The oil is peppermint flavor to mask any unpleasant tastes related to CBD.

    Pro's
    Cons's
    •  Mid-strength
    •  Natural peppermint flavor
    •  Made from 100% organic and natural ingredients
    •  No other flavors
  • Features
    Discount pricing available?20% Off Coupon Code: CBDCLINICALS
    Source
    Source of Hemp
    Kentucky, USA & North Carolina, USA
    FormOil Tincture
    IngredientsOrganic Hemp Seed Oil, Full Spectrum CBD Oil
    Type
    Type of CBD
    Full Spectrum
    Extraction
    Extraction Method
    Moonshine extraction method
    How to take itUnder tongue
    Potency
    Potency - CBD Per Bottle
    750 mg per bottle
    Carrier OilOrganic Hemp Seed Oil
    Concentration
    CBD Concentration Per Serving
    25mg of CBD per dropper full (1ml)
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursPeppermint
    Price Range$89 ($75.65 for subscriptions, 15% discount from regular price)
    $/mg CBD
    Price ($/mg)
    $0.12/mg ($0.10/mg with subscription)
    Shipping
    Shipping/Time to delivery
    2-4 business days (first class USPS)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsOrganic, Non-GMO, no pesticides, no herbicides, no solvents or chemical fertilizers, No preservatives or sweeteners
    AllergensVegan, Gluten free
    Refund policyWithin 30 days
    Recommended forNew CBD users
    Countries servedUSA only (all 50 states)
Check Latest Prices
Best Organic

Nuleaf Naturals 725mg Full Spectrum CBD Oil

Perfect for anyone who are looking for CBD products that promote a healthy body and mind.
Nuleaf Naturals 725mg Full Spectrum CBD Oil
  • Overall Clinical Score
    99%
    Best Organic
  • Score breakdown
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    Lab Testing Transparency
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  • Summary

    Natural remedy for various illnesses. There are approximately 300 drops in this 0.5 FL OZ bottle, where 1 drop = 2.4 mg of CBD.

    Pro's
    Cons's
    •  Pure CBD hemp
    •  All natural
    •  Approximately 300 drops total
    •  No other flavors
  • Features
    Discount pricing available?20% Off Coupon Code: CBDCLINICALS20
    Source
    Source of Hemp
    Colorado, USA
    FormOil Tincture
    IngredientsUSDA Certified Organic Hemp Oil, Full Spectrum Hemp Extract
    Type
    Type of CBD
    Full Spectrum CBD
    Extraction
    Extraction Method
    CO2 Method
    How to take itUnder the tongue for approximately 30 seconds before swallowing
    Potency
    Potency - CBD Per Bottle
    725mg of CBD per 0.5 FL OZ (15ml)
    Carrier OilOrganic Hemp Oil
    Concentration
    CBD Concentration Per Serving
    48.33mg to a max of 51.82mg per 1ml
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursNatural
    Price Range$99.00 - 1-pack, $434.00 - 6-pack
    $/mg CBD
    Price ($/mg)
    1-pack - $0.13, 6-pack - $0.59
    Shipping
    Shipping/Time to delivery
    2-3 Days via USPS
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsNo additives or preservatives, Non-GMO, NO herbicides, pesticides, or chemical fertilizers
    AllergensNot specified
    Refund policyWithin 30 days
    Recommended forHealth conscious
    Countries servedUSA (all 50 states) and over 40 countries including Australia, Azerbaijan, Beliza, Bosnia & Herzegovina, Brazil, Chile, China, Croatia, Czech Republic, Estonia, France, Hong Kong, Hungary, Ireland, Israel, Japan, Latvia, Lebanon, Lithuania, Macao, Malaysia, Malta, Netherlands, New Zealand, Oman, Parguay, Poland, Portugal, Saudi Arabia, Serbia, Singapore, South Korea, Sweden, Switzerland, United Arab Emirates, United Kingdom, Uruguay, and many more.
Check Latest Prices
Best Customer Service

Sabaidee Super Good Vibes CBD Oil

4x the strength of a regular cbd oil
Sabaidee Super Good Vibes CBD Oil
  • Overall Clinical Score
    99%
    Best Customer Service
  • Score breakdown
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
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  • Summary

    Super Good Vibes CBD Oil provides the purest and highest quality Cannabidiol (CBD) on the market as well as other high quality phytocannabinoids, terpenes, vitamins, omega fatty acids, trace minerals, and other beneficial for your health elements, which all work together to provide benefits.

    Pro's
    Cons's
    •  Extra strong
    •  Significant benefits with just a few drops
    •  100% Natural ingredients
    •  No other flavors
  • Features
    Discount pricing available?15% Off Coupon Code: CBDCLINICALS15
    Source
    Source of Hemp
    Colorado, USA
    FormOil Tincture
    IngredientsCannabidiol (CBD), Coconut Medium-chain triglycerides (MCT) Oil, Peppermint oil
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2-extraction
    How to take itUsing 1-3 servings per day as needed is a good start to determine how much you need
    Potency
    Potency - CBD Per Bottle
    1000 mg per bottle
    Carrier OilCoconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    33.5 mg per dropper (1ml)
    Drug TestContains 0.3% THC but there is a chance you may test positive for marijuana
    FlavoursPeppermint
    Price RangeSingle Bottle - $119.95, 2-Pack - $109.97 each, 3-Pack - $98.31 each, 6-Pack - $79.99 each
    $/mg CBD
    Price ($/mg)
    Single bottle - $0.010, 2-Pack - $0.011, 3-Pack - $0.009, 6-Pack - $0.007
    Shipping
    Shipping/Time to delivery
    3-5 Business days
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    ContaminantsContaminant-free
    AllergensVegan and Gluten-free
    Refund policyWithin 30 days
    Recommended forPatients who are looking for serious CBD oil support
    Countries servedUSA only (all 50 states)
Check Latest Prices
Natural Alternative

cbdMD CBD Oil Tinctures

Uses USA hemp that is grown on non-GMO farms, and is both vegan and gluten-free
cbdMD CBD Oil Tinctures Products
  • Overall Clinical Score
    99%
    Natural Alternative
  • Score breakdown
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    Lab Testing Transparency
    Effectiveness
  • Summary

    cbdMD’s CBD oil tinctures are made using only CBD sourced from medical hemp and MCT oil as a carrier oil. Tinctures are offered in orange, mint, natural, and berry flavors. Safe for daily use, the oil tinctures are packaged with a built-in rubber dropper to adjust CBD dosage easily. The packaging is made to be easy to transport and discreet to use.

    Pro's
    Cons's
    •  Plenty of concentrations to choose from for all people with various kinds of needs
    •  Has vegan, organic, and gluten-free ingredients
    •  Affordable pricing
    •  Affordable pricing
    •  cbdMD uses MCT as its carrier oil so individuals who are allergic with coconuts should consider other brand options
  • Features
    Discount pricing available?15% Off Coupon Code: cbdMD15
    Source
    Source of Hemp
    Kentucky, USA
    FormOil Tincture
    IngredientsCannabidiol (CBD), MCT Oil, and Flavoring
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2 extraction method
    How to take itUnder tongue
    Potency
    Potency - CBD Per Bottle
    300 mg - 7500 mg / 30 ml bottle, 1000 mg - 1500 mg / 60 ml bottle
    Carrier OilOrganic Coconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    30 ml: 300 mg - 10 mg per dropper (1ml), 750 mg - 25 mg per dropper (1ml), 1500 mg - 50 mg per dropper (1ml), 3000 mg - 100 mg per dropper (1ml), 5000 mg - 166.6 mg per dropper (1ml), 7500 mg - 250 mg per dropper (1ml), 60 ml: 1000 mg - 16.6 mg per dropper (1ml), 1500 mg - 25 mg per dropper (1ml)
    Drug TestContaining less than 0.3% THC, there are still trace amounts
    FlavoursNatural, Berry, Orange and Mint
    Price Range30 ml Bottles: $29.99 for 300 mg, $69.99 for 750 mg, $99.99 for 1500 mg, $149.99 for 3000 mg, $239.99 for 5000 mg, $339.99 for 7500 mg 60 ml Bottles: $74.99 for 1000 mg, $99.99 for 1500 mg
    $/mg CBD
    Price ($/mg)
    30 ml - $0.05 - $0.10, 60 ml - $0.06 - $0.07
    Shipping
    Shipping/Time to delivery
    2-5 Business days (via Fedex)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants100% organic, non-GMO, and vegan-certified
    AllergensVegan, Gluten free
    Refund policyWithin 30 days
    Recommended forCBD users with different needs
    Countries servedUSA only (all 50 states)
Check Latest Prices

Why People Are Using CBD for Gout

According to the John Hopkins Arthritis Center, several drugs can be used to treat gout flare-ups(5). These include:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen and naproxen
  • Colchicine 
  • Corticosteroids

While the medications mentioned previously are effective, doctors often prescribe higher dosages to manage an acute attack of gout. These changes could cause side effects, which may be harmful to some people.

Mayo Clinic says side effects from using NSAIDs include high risks of developing stomach pain, bleeding, and ulcers(6). Meanwhile, colchicine use can result in vomiting, nausea, and diarrhea. 

The use of corticosteroids can lead to sudden mood changes, high blood pressure, and increased blood sugar levels(7). Corticosteroids are often prescribed to patients who cannot take NSAIDs and colchicine.

Gout is an incurable type of arthritis that affects joints, particularly the big toe joint. However, with medications and self-management, it can be treated(8)

To avoid the side effects of gout medications, more patients are turning to cannabidiol (CBD). It has been shown to have analgesic (pain-relieving) and anti-inflammatory properties that may be beneficial to gout patients.

CBD comes from the Cannabis Sativa plant. Unlike tetrahydrocannabinol (THC), it is non-psychoactive. 

THC is the other primary ingredient of medical marijuana and also comes from the Cannabis Sativa plant. Like CBD, THC can be used medicinally. 

However, THC is often used recreationally and sometimes abused(9). Because of THC’s addictive nature, it is likely that users may develop a dependence on it. 

How CBD Oil Works to Alleviate Symptoms of Gout

Findings from the Centers for Disease Control and Prevention (CDC) report that gout is caused by hyperuricemia, the excessive uric acid buildup in the body(10).

Individuals who have increased chances of developing hyperuricemia are usually obese males who have health problems, like hypertension, diabetes, and reduced kidney function(11).

Certain diets may increase the likelihood of people developing gout. These consumption behaviors include drinking large quantities of alcohol and fructose-rich beverages.

Also at risk are those who often eat food high in purines, which the body breaks down into uric acid. Such foods include organ meats, red meats, and seafood, like sardines, tuna, and anchovies.

Gout has been dubbed as the “disease of kings” because it is generally caused by overindulgence in food and drinks(12)

In the affected joints, gout may be detected when the following symptoms are observed: intense pain, redness, swelling, and heat(13).

Gout may come in the form of acute gout or chronic gout. Acute gout only affects one joint, while chronic gout may occur repeatedly and affect more than one joint(14).

CBD for Inflammation

Further research needs to be done on CBD’s therapeutic effects on gout symptoms. However, a significant number of studies conducted on CBD have suggested its anti-inflammatory properties. 

A study published in Future Medicinal Chemistry concludes that cannabinoids have anti-inflammatory effects that may help treat several types of arthritis and inflammation-related diseases(15). The primary cannabinoids are CBD and THC.

Cannabinoids are compounds that may come from the body, from plants, or laboratories. They interact with the endocannabinoid system (ECS) and activate cannabinoid receptors, known as CB1 and CB2 receptors. 

Cannabinoids help the ECS with several functions, like immune responses, mood, appetite, and memory.

Cannabinoids have been shown to help suppress cytokines at inflammatory sites in the body, reducing symptoms of inflammatory diseases(16).

Cytokines are a group of proteins that can be classified as pro-inflammatory or anti-inflammatory(17). Their modulation can balance the initiation and resolution of inflammation(18)

CBD is a cannabinoid that is known to have anti-inflammatory properties(19).

Another study in 2019 has found that CBD has anti-inflammatory and antioxidant properties. These therapeutic benefits may help treat several conditions, like arthritis, diabetes, cardiovascular diseases, psychosis, among others(20).

CBD for Pain Relief

A 2018 study states that cannabinoids, like CBD, may be useful in treating inflammation and pain(21).

Research conducted in rodents that have osteoarthritis showed that CBD reduced inflammation and blocked osteoarthritis pain signals(22)

The study suggested that CBD might be a safe and effective therapy for osteoarthritis. The researchers believe that they have discovered CBD’s neuroprotective properties.

Another study, this time on CBD as a topical pain reliever, has shown that the use of CBD gel on rat models markedly attenuated joint swelling and pain, without causing psychoactive side effects in the test subjects(23)

In the study, the application of 6.2 mg and 62 mg of CBD gel per day, for four consecutive days after arthritis pain began, helped treat arthritis in rats.

The results of the animal study showed CBD as a promising treatment for pain relief in humans.

The Pros and Cons of CBD Oil for Gout

The Pros

  • Animal and human studies have reported the benefits of CBD in treating symptoms of gout.
  • CBD is safe for use because it has an excellent safety profile(24)
  • CBD is non-addictive(25). Thus, gout patients may not have to worry about developing a dependence on it. 

The Cons

  • While there are studies on CBD’s potential in alleviating gout symptoms, research on CBD’s effectiveness in treating gout itself is lacking. 
  • The United States Food and Drug Administration (US FDA) has not approved CBD use aside from the treatment of epilepsy. 
  • There is no standard dosage for CBD when used for the treatment of gout. 
  • CBD products are unregulated, resulting in a proliferation of mislabeled CBD products online(26).  

How CBD Oil Compares to Alternative Treatments for Gout

Although gout cannot be cured completely, patients’ lifestyle changes help manage their symptoms. These modifications include weight loss, diet changes, hypertension control, and change in medication regimens(27)

A study has found that cherry consumption helps lower the risk of gout attacks(28).

Studies have also been made on whether vitamin C intake helps in the attenuation of gout. However, the results of these studies are conflicting.

A study reports that vitamin C reduces uric acid levels and prevents gout recurrences(29). Another study, meanwhile, concludes that vitamin C reduces the risk of gout development but does not significantly reduce uric acid in gout patients(30).

Meanwhile, the use of CBD has minimal risk factors, as common side effects include tiredness, diarrhea, and changes in appetite or weight(31). CBD use may also help complement the alternative treatments mentioned previously.

However, it is not recommended to use CBD alongside traditional gout medications, such as corticosteroids(32). The liver enzyme cytochrome P450 metabolizes these medications. 

CBD may inhibit the P450 enzyme system and increase the risk of amplifying the side effects of gout medications(33).

How to Choose the Right CBD for Gout

There are three types of CBD oils: full-spectrum CBD oil, broad-spectrum CBD oil, and isolates.

Full-spectrum oils make use of all the ingredients of cannabis plants, including less than 0.30% THC, fatty acids, flavonoids, terpenes, and essential oils.

The main advantage of using a full-spectrum oil is that its active ingredients synergize to produce an entourage effect. This mechanism is believed to generate maximum therapeutic benefits from the ingredients of the cannabis plant.

Full-spectrum oils contain THC, which may be detected via drug tests. THC may also cause mild psychoactive effects in some individuals.

Gout patients who want to avoid these potential risks may choose to buy broad-spectrum CBD oil. This type of oil has all the ingredients of a full-spectrum oil sans the THC.

Those who are looking for a CBD oil made of pure cannabidiol may purchase CBD isolates. 

CBD Dosage for Gout

The rule when using CBD for gout is to begin with a low dosage. Patients can start with a few milligrams of CBD and increase the dosage in small increments if no adverse effects are observed.

The dosage amounts may be increased until significant improvements are noted

Body weight should be considered when choosing a CBD dosage. The heavier the patient, the larger their required dose.

Average adults can take a maximum of around 5 mg of CBD daily.

Before adding CBD to one’s gout medication regimen, always consult with a doctor first.

How to Take CBD for Gout

There are various ways to take CBD in the treatment of gout. One way is through ingestion via CBD oil, CBD tinctures (droppers), CBD pills, CBD gummies, or CBD gel caps. 

When a CBD product goes through the digestive tract, it takes effect in one to two hours. When taken sublingually (under the tongue) through tinctures, CBD may take effect in 15 to 45 minutes. 

CBD can also be applied topically, on body parts affected by gout, as it is available in lotion, salve, or balm format. 

There are CBD oil massages available, which may be beneficial to gout patients. CBD oil may help alleviate pain associated with gout(34).

Another format is CBD vape or pen. When CBD is inhaled, effects may be observed instantaneously. 

However, taking CBD by vaping is not recommended. There have been incidents that suggest that vaping may cause lung problems(35).

Conclusion

Medical cannabis-related products, like CBD, may help in the treatment of gout symptoms. Further research, however, needs to be made on the therapeutic effects of CBD on gout itself. 

Compared to most gout medications, CBD has been shown to have a more favorable safety profile. It is a treatment worth exploring as an added therapy for gout relief.

Before using CBD, patients should inform their doctors first. 


  1. Gout. (28 Jan 2019). Retrieved from https://www.cdc.gov/arthritis/basics/gout.html
  2. Mayo Clinic Staff. (2019 March 1). Gout Diagnosis and Treatment. Retrieved from https://www.mayoclinic.org/diseases-conditions/gout/diagnosis-treatment/drc-20372903
  3. Bruni, N., Della Pepa, C., Oliaro-Bosso, S., Pessione, E., Gastaldi, D., & Dosio, F. (2018). Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules (Basel, Switzerland), 23(10), 2478. https://doi.org/10.3390/molecules23102478
  4. Philpott, H. T., OʼBrien, M., & McDougall, J. J. (2017). Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain, 158(12), 2442–2451. https://doi.org/10.1097/j.pain.0000000000001052
  5. Treatment of Gout. (n.d). Retrieved from https://www.hopkinsarthritis.org/arthritis-info/gout/gout-treatment/
  6. Mayo Clinic Staff. op. cit. 
  7. Ibid.
  8. Gout. (28 Jan 2019). op. cit.  
  9. Zehra, A., Burns, J., Liu, C. K., Manza, P., Wiers, C. E., Volkow, N. D., & Wang, G. J. (2018). Cannabis Addiction and the Brain: a Review. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 13(4), 438–452. https://doi.org/10.1007/s11481-018-9782-9
  10. Gout. (28 Jan 2019). op. cit.  
  11. Ibid. 
  12. Hendricks, M. (n.d.). Defining What Causes the ‘Disease of Kings’. Retrieved from https://www.hopkinsmedicine.org/institute_basic_biomedical_sciences/news_events/articles_and_stories/cysticfibrosis/2010_03_Disease_of_Kings.html
  13. Gout. (28 Jan 2019). op. cit.  
  14. Gout. Retrieved from https://medlineplus.gov/ency/article/000422.htm
  15. Nagarkatti, P., Pandey, R., Rieder, S. A., Hegde, V. L., & Nagarkatti, M. (2009). Cannabinoids as novel anti-inflammatory drugs. Future medicinal chemistry, 1(7), 1333–1349. https://doi.org/10.4155/fmc.09.93
  16. Ibid.
  17. Zhang, J. M., & An, J. (2007). Cytokines, inflammation, and pain. International anesthesiology clinics, 45(2), 27–37. https://doi.org/10.1097/AIA.0b013e318034194e 
  18. Nagarkatti, P. op. cit. 
  19. Russo E. B. (2008). Cannabinoids in the management of difficult to treat pain. Therapeutics and clinical risk management, 4(1), 245–259. https://doi.org/10.2147/tcrm.s1928
  20. Atalay, S., Jarocka-Karpowicz, I., & Skrzydlewska, E. (2019, December 25). Antioxidative and Anti-Inflammatory Properties of Cannabidiol. Retrieved from https://www.mdpi.com/2076-3921/9/1/21/htm
  21. Bruni, N., Della Pepa, C., Oliaro-Bosso, S., Pessione, E., Gastaldi, D., & Dosio, F. (2018). Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules (Basel, Switzerland), 23(10), 2478. https://doi.org/10.3390/molecules23102478
  22. Philpott, H.T. op. Cit.
  23. Hammell, D. C., Zhang, L. P., Ma, F., Abshire, S. M., McIlwrath, S. L., Stinchcomb, A. L., & Westlund, K. N. (2016). Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. European journal of pain (London, England), 20(6), 936–948. https://doi.org/10.1002/ejp.818 
  24. Iffland, Kerstin, and Franjo Grotenhermen. “An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies.” Cannabis and cannabinoid research vol. 2,1 139-154. 1 Jun. 2017, doi:10.1089/can.2016.0034
  25.  “CANNABIDIOL (CBD) Critical Review Report.” World Health Organization, 2018.Parkinson’s Foundation. op. cit. 
  26. Freedman, Daniel A, and Anup D Patel. “Inadequate Regulation Contributes to Mislabeled Online Cannabidiol Products.” Pediatric neurology briefs vol. 32 3. 18 Jun. 2018, doi:10.15844/pedneurbriefs-32-3
  27. Saag, K. G., & Choi, H. (2006). Epidemiology, risk factors, and lifestyle modifications for gout. Arthritis research & therapy, 8 Suppl 1(Suppl 1), S2. https://doi.org/10.1186/ar1907
  28. Zhang, Y., Neogi, T., Chen, C., Chaisson, C., Hunter, D. J., & Choi, H. K. (2012). Cherry consumption and decreased risk of recurrent gout attacks. Arthritis and rheumatism, 64(12), 4004–4011. https://doi.org/10.1002/art.34677
  29. Juraschek, S. P., Miller, E. R., 3rd, & Gelber, A. C. (2011). Effect of oral vitamin C supplementation on serum uric acid: a meta-analysis of randomized controlled trials. Arthritis care & research, 63(9), 1295–1306. https://doi.org/10.1002/acr.20519
  30. Stamp, L. K., O’Donnell, J. L., Frampton, C., Drake, J. M., Zhang, M., & Chapman, P. T. (2013, May 30). Clinically Insignificant Effect of Supplemental Vitamin C on Serum Urate in Patients With Gout: A Pilot Randomized Controlled Trial. Retrieved from https://onlinelibrary.wiley.com/doi/full/10.1002/art.37925
  31. Iffland, K. op. cit. 
  32. Cabrera, M. A., Dip, R. M., Furlan, M. O., & Rodrigues, S. L. (2009). Use of drugs that act on the cytochrome P450 system in the elderly. Clinics (Sao Paulo, Brazil), 64(4), 273–278. https://doi.org/10.1590/s1807-59322009000400002
  33. Yamaori, Satoshi, et al. Potent Inhibition of Human Cytochrome P450 3A Isoforms by Cannabidiol: Role of Phenolic Hydroxyl Groups in the Resorcinol Moiety. 10 Feb. 2011, www.medicinalgenomics.com/wp-content/uploads/2013/11/Potent-inhibition-of-CYP3A-with-CBD.pdf.
  34. Gamble, L. J., Boesch, J. M., Frye, C. W., Schwark, W. S., Mann, S., Wolfe, L., Brown, H., Berthelsen, E. S., & Wakshlag, J. J. (2018). Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs. Frontiers in veterinary science, 5, 165. https://doi.org/10.3389/fvets.2018.00165
  35. “Outbreak of Lung Injury Associated with the Use of E-Cigarette, or Vaping Products.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 25 Feb. 2020, www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html

More Info

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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

 

Presentation

 

Tablets 100mg bottle of 100 tablets

Tablets 300mg calendar pack of 2×14 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).

 

  1. 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).

 

  1. 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.

 

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

 

  1. British National Formulary. Number 32 (September 1996). British

Medical Association and Royal Pharmaceutical Society.

 

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

 

  1. Ellenhorn MJ. Ellenhorn’s Medical Toxicology: Diagnosis and

Treatment of Human Poisoning. 2nd Edition 1997. Williams &

Wilkins.

 

  1. 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.

 

  1. Potter JL and Silvidi AA. Xanthine lithiasis, nephrocalcinosis,

and renal failure in a leukaemia patient treated with

allopurinol. Clin Chem 1987; 33: 2314-6.

 

  1. 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.

 

  1. Reprotox System(R), Micromedex inc., Denver Colorado, Edition

Expires 3/97.

 

  1. 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

  1. 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

  1. 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

  1. 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

  1. ROUTES OF EXPOSURE

5.1. Oral

5.2 Inhalation

5.3 Dermal

5.4 Eye

5.5 Parenteral

5.6 Others

  1. 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

  1. 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

  1. 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

  1. 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

  1. 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

  1. ILLUSTRATIVE CASES

11.1 Case reports from literature

  1. ADDITIONAL INFORMATION

12.1 Specific preventative measures

12.2 Other

  1. REFERENCES
  2. 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:

 

  1. autumnale subspecies pannonicum (Griseb. & Schenk) Nyman;
  2. autumnale var. bulgaricum (Velen.) Domin;
  3. borisii Stef.;
  4. bugaricum Velen.;
  5. commune Neck.;
  6. drenowskii Degen & Rech.f.;
  7. haynaldii Heuff.;
  8. pannonicum Griseb. & Schenk;
  9. polyanthon Ker Gawl.;
  10. praecox Spenn.;
  11. rhodopaeum Kov.;
  12. transsilvanicum Schur;
  13. vernale Hoffm.;
  14. vernum Kunth; (Strid & Tan, 1991; Tutin et al., 1980).

 

  1. 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).

 

  1. 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

 

  1. 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

 

  1. 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)

 

  1. 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.

 

  1. 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:

 

  1. autumnale is used for gout and polyarthritis.

 

Veterinary medicine:

 

  1. 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.

 

  1. 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.

 

  1. 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

 

  1. 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).

 

  1. 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.

 

  1. 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.

 

  1. 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

 

  1. 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

 

  1. 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.

 

  1. 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

 

  1. 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).

 

  1. 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

 

  1. 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

 

  1. 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.

 

  1. 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.

 

  1. 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).

 

  1. 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.

 

  1. 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

 

  1. a) Emesis:

 

Emesis may be useful in recent ingestion if there are no

contraindications.

 

  1. 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).

 

  1. 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.

 

  1. 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

 

  1. 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.

 

  1. 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.

 

  1. 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.

 

  1. ADDITIONAL INFORMATION

 

12.1 Specific preventative measures

 

Not available for human use.

 

12.2 Other

 

No data available.

 

  1. 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.

 

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

ADDRESS(ES):

 

Authors: A. Jaeger, F. Flesch

Service de Réanimation et

 

Date: 26 April 1990

 

General edit and botanical review:

 

Christine Leon

Medical Toxicology Unit

 

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

  1. 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

  1. 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

  1. 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

  1. ROUTES OF ENTRY

5.1 Oral

5.2 Inhalational

5.3 Dermal

5.4 Eye

5.5 Parenteral

5.6 Other

  1. 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

  1. 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

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

8.1 Methods

8.2 Therapeutic and toxic concentration

  1. 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

  1. 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

  1. ILLUSTRATIVE CASES

11.1 Case reports from literature

11.2 Internally extracted data on cases

11.3 Internal cases

  1. ADDITIONAL INFORMATION

12.1 Availability of antidotes

12.2 Specific preventive measures

12.3 Other

  1. REFERENCES
  2. 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)

 

 

 

  1. 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.

 

  1. 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.

 

  1. 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).

 

  1. 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).

 

 

 

  1. 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.

 

 

 

  1. 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).

 

  1. 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).

 

  1. 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

 

  1. 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.

 

  1. 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

  1. 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.

 

  1. ADDITIONAL INFORMATION

 

12.1 Availability of antidotes

 

Not relevant

 

12.2 Specific preventive measures

 

Not relevant

 

12.3 Other

 

Unknown

 

  1. REFERENCES

 

Bennet WF & Glenn KC (1980) Hypersensitivity of platelets to

thrombin: formation of stable thrombin-receptor complexes and the

role of shape-change. Cell 22(2): 621-627.

 

Benoit JP, Leveque M, Carli PM (1974) Aplasie médullaire mortelle

au cours d’un bref traitement de colchicine. Rev Méd Dijon, 9:

485-488.

 

Besson-Leaud M (1977) De quelques intoxications chez l’enfant.

Ann Pédiatr, 24: 363-371.

 

Bismuth C, Gaultier M, & Conso F (1977). Aplasie médullaire aprés

intoxication aiguë à la colchicine. Nouv Presse Med, 6: 1625-

1629.

 

Bismuth C & Sebag C (1981) Choc cardiogénique lors d’une

intoxication aigue par la colchicine. Nouv Presse Méd, 10:

1073.

 

Bourdon R & Galliot M (1976) Dosage de la colchicine dans les

liquides biologiques. Ann Biol Clin, 34: 393-401.

 

Budavari S ed. (1989) The Merck index, an encyclopedia of

chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey,

Merck and Co Inc, pp 386- 387.

 

Caplan YH, Orloff KG & Thompson BC (1980) A fatal overdose with

colchicine. J Anal Toxicol 4(3): 153-5

 

Carr AA (1965) Colchicine toxicity. Arch Intern Med, 115: 29-

33.

 

Corbin JC, Duval G, Plane M, & Chuet C (1989) Syndrome de

détresse respiratoire aigue de l’adulte au cours d’une

intoxication par la colchicine. Rean Soins Intens Med Urg, 2: 187-

189.

 

Crabie P., Pollet J., Pebay-Peyroula F. (1970). Etude de l’

hémostase au cours des intoxications aiguës par la colchicine.

J.E.T., 3: 374-385.

 

Davies H.O., Hyland R.H., Morgan C.D. (1988) Massive overdose of

colchicine. Can Med Assoc J, 138: 335-336.

 

Drugdex (1989) February issue.

 

Dukes MNG (1983) Side effects of Drugs. Annual 7, Excerpta

Medica.

 

Ehrenfeld M, Levy M, Margalioth EJ, Eliakim M (1986) The effects

of long- term colchicine therapy on male fertility in patients

with familial mediterranean fever. Andrologia, 18: 420-426.

 

Ehrenfeld M, Brzezinski A, Levy M, & Eliakim M (1987) Fertility

and obstetric history in patients with familial mediterranean

fever on long-term colchicine therapy. Br J Obstet Gynaecol, 94:

1186-1191.

 

Ellenhorn M.J., Barceloux D.G. (1988) Medical Toxicology –

Diagnosis and Treatment of Human poisoning, 1st ed. New York,

Elsevier.

 

Ertel NH, Mittler JC, Akgun S, & Wallace SL (1976)

Radioimmunoassay for colchicine in plasma and urine. Science, 193:

233-234.

 

Favarel-Garrigues JC, Bony D, & Poisot D (1975) Intoxications

aiguës par la colchicine. Concours Med, 97: 5183-5197.

 

Fleeger CA ed. (1993) USAN 1994: USAN and the USP dictionary of

drug names. Rockville, MD, United States Pharmacopeial Convention,

Inc., p 171.

 

Frayha RA, Tabbara Z, & Berbir N (1984) Acute colchicine poisoning

presenting asymptomatic hypocalcaemia. Br J Rheumatol, 23: 292-

295.

 

Galliot M (1979) Complexes metaliques dérivés de la colchicine.

Application au dosage biologique dans le médicaments et les

liquides biologiques. Thése, Paris, p 134.

 

Gaultier M, Kanfer A, Bismuth C, Crabie P, & Frejaville JP (1969)

Données actuelles sur l’ intoxication aiguë par la colchicine. A

propos de 23 observations. Ann Med Interne, 120: 605-618.

 

Gaultier M, Bismuth C, Autret A, & Pillon M (1975) Antidiurése

inapproprieée après intoxication aigue par la colchicine. Nouv

Presse Méd, 4: 3132-3134.

 

Gaultier M & Bismuth C (1978) Intoxication aiguë par la

colchicine. Revue du Praticien 28(57): 4545-4554.

 

Goodman LS, Gilman AG, Rall TW, & Murad F eds. (1985) Goodman and

Gilman’s Pharmacological Basis of Therapeutics. 7th Ed. New York,

Macmillan.

 

Gooneratne BWM (1966) Massive generalized alopecia after poisoning

by Gloriosa superba. Br Med J, 1(5494): 1023-1024.

 

Gossweiler B (1985) Kolchizinvergiftung Schweiz. Rundschau Med,

74: 1443-1449.

 

Heaney D, Derghazarian CB, Pineo GF (1976) Massive colchicine

overdose. A report on the toxicity. Am J Med Sci, 271: 233-

238.

 

Harzer K (1984)Tödliche Vergiftugh mit Colchicin. Z Rechtsmed, 93:

181-185.

 

Heath DA, Palmer JS, Aurbach D (1972) The hypocalcaemic action of

colchicine. Endocrinology, 90(6): 1589-1593.

 

Hill RN, Spragg RG, Wedel MK, & Moser KM (1975) Adult respiratory

distress syndrome associated with colchicine intoxication.

 

Hillemand B, Joly JP, Membrey-Maheo E, & Ouvry D (1977) Diabète

transitoire avec hyperlipidémie et hyperuricémie régressives au

cours d’ une intoxication aiguë par la colchicine. Relation d’un

cas. Ann Med Interne, 128: 379-385.

 

Hobson CH & Rankin AP (1986) A fatal colchicine overdose. Anaesth

Intensive Care, 14(4): 453-455.

 

Jaeger A, Simon CH, Tempe JD, Mantz JM, Bismuth C, Conso F,

Mathiot C, Baumelou A, Bavoux F, Jouanjean X, & Toulet R (1980)

Accidents thérapeutiques mortels après colchicine intraveineuse.

Nouvelle Presse Med, 9: 1587.

 

Jaeger A, Galliot M, Zaehringer M, Sauder PH, Bourdon R,

Kopferschmitt J, Jaegle ML, & Mantz JM (1985) Elimination

digestive et excrétion rénale de la colchicine au cours des

intoxications aiguës. In: “Pharmacocinétique appliquée en

réanimation” Monographie de la Société de Réanimation de Langue

Française, Ed Expansion Scientifique, pp 257-262.

 

Jarvie D, Park J, & Stewart MJ (1979) Estimation of colchicine in

a poisoned patient by using high performance liquid

chromatography. Clin Toxicol, 14: 375-381.

 

Kontos HA (1962) Myopathy associated with chronic colchicine

toxicity. N Engl J Med, 266: 38.

 

Kuncl RW (1987) Colchicine myopathy and neuropathy. New Engl J

Med, 316: 1562-1568.

 

Lambert H, Laprevote-Heully MC, Manel J, Gilgenkrantz S, & Larcan

A (1981) Les intoxications aiguës par la colchicine. A propos de

22 observations. Ann Med Nancy et de l’Est, 20: 891-900.

 

Letellier PH., Langeard M., Agullo M. (1979). Rhabdomyolyse

secondaire à une série d’injections intra-veineuses de colchicine.

  1. Med. Caen, 14, 4: 157-159.

 

Levy M & Eliakim M (1977) Long-term prophylaxis in familial

Mediterranean fever. Br Med J, 2(6090): 808

 

Lhermitte M, Bernier JL, Mathieu D, Mathieu-Nolf M, Erb F, &

Roussel P (1985) Colchicine quantitation by high-performance

liquid chromatography in human plasma and urine. J Chromatogr,

342:416-423.

 

Liu YK, Hymowitz R, & Carroll MG (1978) Marrow aplasia induced by

colchicine. Arthritis, Rheumatism, 21: 731-735.

 

Maurizi M, Delorme N, Laprevote-Heully MC, Lambert H, & Larcan A

(1986) Syndrome de détresse respiratorie aiguë de l’ adulte au

cours des intoxications par la colchicine. Ann Fr Anesth Reanim,

5: 530-532.

 

Menta R, Rossi E, Guariglia A, David S, & Cambi V (1987)

Reversible acute cyclosporin nephrotoxicity induced by colchicine

administration. Nephrol Dial Transplant 2:380-382.

 

Merlin HE (1972) Azoospermia caused by colchicine. A case report.

Fertil and Steril. 23: 180-191.

 

Michaux P, Curtes JP, & Lejeune (1972) Responsabilité médicale et

pharmaceutique à la suite de l’ administration intraveineuse d’

une préparation contenant de la colchicine. Méd Lég Dommage Corp,

5: 248-250.

 

Mouren P, Tatossian A, Poiso Y, Giudicelli S, Jouglard J, Dufour

H, & Poyen D (1969) L’ intoxication aiguë par la colchicine.

Presse Med, 77, 14: 505-508.

 

Murray SS, Kramlinger KG, & McMichan JC (1983) Acute toxicity

after excessive ingestion of colchicine. Mayo Clin Proc, 58: 528-

532.

 

Nadius RM, Rodvien R, & Mielke CH Jr. (1977 Colchicine toxicity –

a multisystem disease. Arch Intern Med, 137: 394-396.

 

Nagaratnam N, De Silva DP, & De Silva N (1973) Colchicine

poisoning following ingestion of Gloriosa superba tubers. Trop

Geogr Med, 25: 15-17.

 

Registry OF Toxic Effects OF Chemical Substances (1979) Volume

One. US Department of Health and Human Services. Ed. Richard J.

Lewis Sr. and Rodger L. Tatken.

 

Reynolds JEF ed.(1989) Martindale, the extra pharmacopoeia, 29th

  1. London, The Pharmaceutical Press. pp 438-439.

 

Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 30th

  1. London, The Pharmaceutical Press. pp 335-337.

 

Riggs JE, Schochet SS, Gutmann L, Crosby TW, & Dibartolomeo AG

(1986) Chronic human colchicine neuropathy and myopathy. Arch

Neurol, 43: 521-523.

 

Sauder PH, Kopferschmitt J, Jaeger A, & Mantz JM (1983)

Haemodynamic studies in eight cases of acute colchicine poisoning.

Human Toxicol, 2: 169-173.

 

Scherrmann JM, Boudet L, Pontikis R, Nguyen HN, & Fournier E

(1980) A sensitive radioimmunoassay for colchicine. J Pharm

Pharmacol 32(11): 800-802.

 

Stapczynski JS, Rothstin RJ, Gaye WA (1981) Colchicine overdose:

report of two cases and review of the literature. Ann Emerg Med,

10: 364.

 

Thompson RD (1985) Liquid chromatographic determination of

colchicine in pharmaceuticals: collaborative study. J Assoc Off

Anal Chem, 68: 1051-1055.

 

Walaszek EJ, Kocsis JJ, Leroy GV, & Geiling EMK (1960) Studies on

the excretion of radioactive colchicine. Arch Int Pharmacodyn

Ther, 125: 371-382.

 

Wallace SL & Ertel NH (1970) Occupancy approach to colchicine

dosage. Lancet, 2: 1250-1251.

 

Wallace SL, Omokoku B & Ertel NH (1970) Colchicine plasma levels.

Am J Med, 48: 443-448.

 

Wallace SL (1974) Colchicine. Senin Arthritis Rheum 3(4): 369-

81

 

Wallace SL (1980) Colchicine. In: WN Kelley, Ed. Harris, S.

Ruddy, CB. Sledge. Textbook of Rheumatology, Philadelphia, W.B.

Saunders Company, 878-884.

 

Webb DI (1968) Mechanism of vitamin B12 malabsorption in patients

receiving colchicine. N Engl J Med, 279: 845.

 

White GJH & White MK (1980) Breast feeding and drugs in human

milk. Vet Human Toxicol, 22: 1-43.

 

WHO (1992) Anatomical Therapeutic Chemical (ATC) classification

index. Oslo, WHO Collaborating Centre for Drug Statistics

Methodology, p 73.

 

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

ADDRESS(ES)

 

Authors   A. Jaeger, F. Flesch, Ph. Sauder, J Kopferschmitt

Poison Control Center

 

Date    28 March 1989

 

Peer Review     London, United Kingdom, March 1990

Berlin, Germany, October 1995

 

 

 

 

 

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