Colchicine

from Wikipedia, the free encyclopedia
Structural formula
Structure of (S) - (-) - colchicine
Colchicine, a natural product
General
Surname ( S ) - (-) - colchicine
other names
  • 7 α - H -colchicine
  • N - [(7 S ) -1,2,3,10-tetramethoxy-9-oxo-6,7-dihydro-5 H -benzo [ d ] heptalen-7-yl] acetamide
Molecular formula C 22 H 25 NO 6
Brief description

white to yellowish powder

External identifiers / databases
CAS number 64-86-8
EC number 200-598-5
ECHA InfoCard 100,000,544
PubChem 6167
ChemSpider 2731
DrugBank DB01394
Wikidata Q326224
Drug information
ATC code

M04 AC01

properties
Molar mass 399.43 g · mol -1
Physical state

firmly

Melting point

155-157 ° C

solubility

soluble in water (45 g l −1 at 20 ° C)

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling from  Regulation (EC) No. 1272/2008 (CLP) , expanded if necessary
06 - Toxic or very toxic 08 - Dangerous to health

danger

H and P phrases H: 300-340
P: 281-301 + 310-308 + 313-321-405-501
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Colchicine , and colchicine , is a toxic alkaloid from the group of colchicine alkaloids and is one of the tropolone - derivatives . It is considered to be mutagenic . Its name refers to the occurrence in the autumn crocus ( Colchicum autumnale ).

history

Medicines containing colchicine for the treatment of gout were already used in Mesopotamia and (documented in the Ebers Papyrus ) ancient Egypt. The discovery and isolation of colchicine in the 19th century is attributed to the Heidelberg pharmacist Philipp Lorenz Geiger .

The bloom of the autumn crocus contains 1.8% colchicine

Geiger made colchicine from seeds of Colchicum autumnale in 1833. At that time, preparations of the autumn crocus were already known as a medicinal drug and were used, for example, in gout (podagra). Today colchicine is only used for acute gout attacks or for intolerance to alternative drugs. In addition, colchicine is recommended in the current guideline on acute pericarditis as first-line therapy together with a non-steroidal anti-inflammatory drug (NSAID).

Occurrence

Colchicine is not only found in the seeds of the autumn crocus (0.5%), but also in their flowers (up to 1.8%), the tuber (approx. 0.2%) and the leaves (0.03%) . It occurs in the company of its alcohol (-) - colchiceine .

Stereochemistry

Colchicine has a stereocenter, so there are two enantiomers . If the name colchicine is not identified by a descriptor , the naturally occurring ( S ) - (-) - colchicine is meant.

( R ) - (+) - Colchicine is the enantiomer of ( S ) - (-) - Colchicine, does not occur in nature and is practically meaningless.

Enantiomers of colchicine
Surname ( S ) - (-) - colchicine ( R ) - (+) - colchicine
Structural formula (S) -Colchicine Structural Formula V1.svg (R) -Colchicine Structural Formula V1.svg
CAS number 64-86-8 75520-89-7
54192-66-4 (racemate)
EC number 200-598-5
ECHA info card 100,000,544
PubChem 6167 53278
2833 (racemate)
Wikidata Q326224 Q27122333
Q26998324 (racemate)

synthesis

Colchicine as a pure substance.

The chemist Albert Eschenmoser and coworkers at the ETH Zurich succeeded in a total synthesis of colchicine .

Analytics

The reliable qualitative and quantitative determination of colchicine in human plasma is achieved by coupling HPLC with mass spectrometry after adequate sample preparation . The analysis of urine samples is also possible with this method. Methods with special sample preparation are also available for forensic questions.

effect

Colchicine is a mitosis inhibitor that inhibits the formation of spindle fibers by binding to free microtubule subunits, which are no longer available for the spindle fiber structure during cell nucleus division. The processes of nuclear division are not interrupted by this, but the cells go through the mitotic phases as well as the cell division with different results. Because of the disturbed spindle apparatus , the correct equatorial alignment of the chromosomes in the metaphase is no longer possible . The sister chromatids are also not divided during the anaphase . During the process of division, therefore, unequal daughter cells with different chromosome content arise. A cell with missing chromosomes or without a set of chromosomes is not viable. The other cell with surplus chromatids doubles the chromosomes in the interphase . Animal cells with polyploidy usually die.

Botanical meaning

In plant cells, polyploidy causes the cells to enlarge. Colchicine was also used in the breeding of the genus hybrid triticale , as the plants that are created when wheat and rye are crossed are haploid and therefore sterile. Treatment with colchicine creates diploid, fertile plants. In addition, double haploid individuals can be generated when generating plants from microspore colonies by doubling the genome with colchicine. By doubling up, these are able to produce seeds for further breeding.

Medical importance

When creating karyograms , colchicine is used to stop mitosis in the metaphase and thus obtain chromosomes that can be easily assessed with a light microscope .

For the “gout therapeutic agent” colchicine, there are increasing indications for successful applications in a multitude of other very different clinical pictures.

Taken in the appropriate dose , cell division processes are prevented in the body. This leads to the formation of non-functional cells everywhere in the body, the elimination of which overloads the immune system. This leads to severe symptoms of poisoning and can be life-threatening. When taking Colchicum medicines, a maximum dose must not be exceeded. The drug falls under the prescription drugs and should never be taken without supervision by a doctor, as children, the elderly and pregnant women can be at risk.

The use of colchicine in food-producing animals is generally prohibited in the European Union in accordance with the EU maximum residue limit regulation for food of animal origin .

gout

Colchicine can be taken as a tablet or drops and eliminates the often extreme joint pain associated with gout very reliably. Due to the narrow therapeutic range , a single dose of 2 mg and a daily dose of 6 mg should not be exceeded. There have already been deaths at 12 mg. A lower dose is now recommended to reduce side effects (especially diarrhea). Colchicine must not be used during pregnancy and men should also not father children during therapy (up to 6 months after discontinuing treatment). The effect is probably based on an inhibition of the migration of inflammatory cells into the joints . Excretion is partly unchanged via the kidneys , but also via the bile with enterohepatic circulation ( half-life : 4–5 h).

Familial Mediterranean fever

In patients with familial Mediterranean fever , lifelong use of colchicine can prevent the development of amyloidosis .

cancer

Attempts have also been made to use the cell division inhibiting effect of colchicine for cancer therapy . However, colchicine is too toxic for therapeutic use (narrow therapeutic index ), so there are no approved medicinal products containing colchicine for this indication. With a similar mode of action (, spindle poison 'with inhibition of mitosis) will be in the oncology the vinca alkaloids used.

cirrhosis

Even if the fiber formation in the liver can be inhibited by the administration of colchicine in animal experiments, no significant improvement compared to a placebo group was found in a clinical study on 55 patients with histologically confirmed alcoholic liver cirrhosis . The observation time was more than 40 months. The side effects were tolerable.

Behçet's disease

When Behçet positive results could be obtained in various studies, particularly in children. Compared to steroids or immunosuppressants , colchicine appears to be advantageous due to its better long-term tolerance.

(Acute) pericarditis

Colchicine also relieves inflammation in serous mucous membranes, such as in pericarditis . Therapy with colchicine is particularly effective in acute pericarditis.

Colchicine lowers the recurrence rate of acute and recurrent pericarditis, according to a Cochrane meta-analysis.

Side effects

Severe diarrhea is a common side effect , because the epithelial cells of the intestine are also very active in dividing and reacting sensitively. In the event of an overdose, the kidney may be irreparably damaged. Long-term use can damage the bone marrow and cause hair loss. Furthermore, nausea, abdominal pain and vomiting can occur.

Uncommon side effects include: skin discomfort such as itching; Burning skin and / or bleeding, changes in the blood count with a drop in white blood cells, anemia, nerve and muscle weakness, drowsiness, kidney damage, nail growth disorders and various hypersensitivity reactions.

Today other pain relievers such as indomethacin from the group of non-steroidal anti-inflammatory drugs (NSAIDs) are preferred because of the known side effects .

literature

Web links

Wiktionary: Colchicine  - explanations of meanings, word origins, synonyms, translations

Individual evidence

  1. ↑ Colchicine data sheet at Sigma-Aldrich , accessed on October 7, 2014 ( PDF ).
  2. ↑ a b c d Entry on colchicine. In: Römpp Online . Georg Thieme Verlag, accessed on June 22, 2014.
  3. ↑ a b Entry on colchicine in the GESTIS substance database of the IFA , accessed on July 23, 2016(JavaScript required) .
  4. ↑ Entry on Colchicine in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on February 1, 2016. Manufacturers or distributors can expand the harmonized classification and labeling .
  5. ↑ Entry on colchicine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
  6. ^ Brockhaus ABC chemistry. FA Brockhaus Verlag, Leipzig 1965, p. 704.
  7. ↑ Attila Dunky, Rudolf Eberl: Gout and hyperuricemia. G. Braun, Karlsruhe 1981 (= Rheuma-Forum. Volume 11), ISBN 3-7650-1632-2 , pp. 11 and 13 f.
  8. ↑ M. Huebler: About Colchicine. In: Arch. Pharm. 171, 1865, pp. 193-216, doi: 10.1002 / ardp.18651710302 .
  9. ^ Geiger, Philipp Lorenz. In: Edward Kremers, George Urdang, Glenn Sonnedecker: Kremers and Urdang's History of Pharmacy. American Institute of the History of Pharmacy, Madison WI 1986, ISBN 0-931292-17-4 , p. 459.
  10. ↑ P. Geiger: About some new poisonous organic alkalis. In: Annals of Pharmacy. Volume 7, 1833, pp. 274f.
  11. ↑ ESC Guideline for the Diagnosis and Management of pericardial Diseases 2015 (www.escardio.org)
  12. ↑ J. Schreiber, W. Leimgruber, M. Pesaro, P. Schudel, A. Eschenmoser: Synthesis of Colchicine . In: Angew. Chem. Band 71 , no. 20 , 1959, pp. 637-640 , doi : 10.1002 / anie.19590712002 . ; J. Schreiber, W. Leimgruber, M. Pesaro, P. Schudel, T. Threlfall, A. Eschenmoser: Synthesis of Colchicine . In: Helv. Chim. Acta. tape 44 , no. 2 , 1961, p. 540–597 , doi : 10.1002 / hlca.19610440225 .
  13. ↑ Y. Jiang, J. Wang, Y. Wang, H. Li, JP Fawcett, J. Gu: Rapid and sensitive liquid chromatography-tandem mass spectrometry method for the quantitation of colchicine in human plasma. In: J Chromatogr B Analyt Technol Biomed Life Sci. 850 (1-2), May 1, 2007, pp. 564-568. PMID 17236823
  14. ↑ M. Lhermitte, JL Bernier, D. Mathieu, M. Mathieu-Nolf, F. Erb, P. Roussel: Colchicine quantitation by high-performance liquid chromatography in human plasma and urine. In: J Chromatogr. 342 (2), Aug 9, 1985, pp. 416-423. PMID 4055966
  15. ↑ SW Ng, CK Ching, AY Chan, TW Mak: Simultaneous detection of 22 toxic plant alkaloids (aconitum alkaloids, solanaceous tropane alkaloids, sophora alkaloids, strychnos alkaloids and colchicine) in human urine and herbal samples using liquid chromatography-tandem mass spectrometry. In: J Chromatogr B Analyt Technol Biomed Life Sci. 942-943, Dec 30, 2013, pp. 63-69. PMID 24216273
  16. ↑ M. Chèze, M. Deveaux, G. Pépin: Liquid chromatography-tandem mass spectrometry for the determination of colchicine in postmortem body fluids. Case report of two fatalities and review of the literature. In: J Anal Toxicol. 30 (8), Oct 2006, pp. 593-598. PMID 17132257
  17. ^ J. Graw, W. Hennig: Genetics. 5th edition. Verlag Springer, 2010, ISBN 978-3-642-04998-9 , p. 404.
  18. ↑ a b U. Lange et al.: Current Aspects of Colchicine Therapy, Part 2: Further classic indications and new therapeutic approaches. In: Z. medical training. Qual. Yourself. (ZaeFQ). 96/2002, pp. 115–119, accessed on May 10, 2014.
  19. ↑ RED LIST , main group: 44.A.1.
  20. ^ EJ Nathaniel, NB Friedman, H. Rychuk: Electron microscopic observations on cells of Harding-Passey melanoma following colchicine administration. In: Cancer Res. 28 (6), Jun 1968, pp. 1031-1040.
  21. ↑ Colchicine ineffective in cirrhosis of the liver. In: Ärzteblatt. 99/2002, p. 2631.
  22. ^ H. Cortez-Pinto et al.: Lack of effect of colchicine in alcoholic cirrhosis: final results of a double blind randomized trial. In: Eur J Gastroenterol Hepatol. 14/2002, pp. 377-381.
  23. ↑ A. Lonardo, P. Loria: Of liver, whiskey and plants; a requiem for colchicine in alcoholic cirrhosis? In: Eur J Gastroenterol Hepatol. 14/2002, pp. 355-358.
  24. ↑ HM Sander, HW Randle: Use of Colchicine in Behçet's syndrome. In: Cutis. 37/1986, pp. 344-348.
  25. ↑ Massimo Imazio, Antonio Brucato, Roberto Cemin, Stefania Ferrua, Stefano Maggiolini, Federico Beqaraj, Daniela Demarie, Davide Forno, Silvia Ferro, Silvia Maestroni, Riccardo Belli, Rita Trinchero, David H. Spodick, Yehuda Adler: A Randomized Trial of Colchicine for acute pericarditis. In: New England Journal of Medicine. 2013, p. 130831233005005, doi: 10.1056 / NEJMoa1208536 .
  26. ↑ Samer Alabed, Juan B Cabello, Greg J Irving, Mohammed Qintar, Amanda Burls: Colchicine for pericarditis . In: Cochrane Database of Systematic Reviews . John Wiley & Sons, August 28, 2014, doi : 10.1002 / 14651858.cd010652.pub2 .
  27. ↑ Onmeda: Colchicine: Side Effects ( Memento of the original from June 4, 2012 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. . @1@ 2Template: Webachiv / IABot / medikamente.onmeda.de