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an analgesic drug derived from the saffron plant and used to treat gout

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/07/12 20:26:13」(JST)

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Colchicine is a medication that treats gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum (autumn crocus, Colchicum autumnale, also known as "meadow saffron"). It was used originally to treat rheumatic complaints, especially gout, and still finds use for these purposes today despite dosing issues concerning its toxicity.^[1] It was also prescribed for its cathartic and emetic effects.

In addition to gout, colchicine is used to treat familial Mediterranean fever, pericarditis, and Behçet's disease.

1 History
- 1.1 FDA approval
2 Pharmacology
- 2.1 Mechanism of action
- 2.2 Indications
- 2.3 Use in cancer treatment
- 2.4 Off-label uses
- 2.5 Contraindications
- 2.6 Adverse effects
- 2.7 Toxicity
- 2.8 Biosynthesis
- 2.9 Botanical use
3 Marketing exclusivity in the United States
4 References
5 External links

History

The plant source of colchicine, the autumn crocus (Colchicum autumnale), was described for treatment of rheumatism and swelling in the Ebers Papyrus (ca. 1500 B.C.), an Egyptian medical papyrus.^[2] Colchicum extract was first described as a treatment for gout in De Materia Medica by Pedanius Dioscorides, in the first century AD. Use of the bulb-like corms of Colchicum to treat gout probably dates to ca. 550 AD, as the "hermodactyl" recommended by Alexander of Tralles. Colchicum corms were used by the Persian physician Avicenna and other Islamic physicians,^{[citation needed]} were recommended by Ambroise Pare in the sixteenth century, and appeared in the London Pharmacopoeia of 1618.^[3] Colchicum plants were brought to America by Benjamin Franklin, who suffered from gout himself and had written humorous doggerel about the disease during his stint as envoy to France.^[4]

Colchicine was first isolated in 1820 by the French chemists P.S. Pelletier and J.B.Caventou.^[5] In 1833, P.L. Geiger purified an active ingredient, which he named colchicine.^[6] The determination of colchicine's structure required decades, although in 1945 Michael Dewar made an important contribution when he suggested that, among the molecule's three rings, two were 7-member rings.^[7] Its pain-relieving and anti-inflammatory effects for gout were linked to its ability to bind with tubulin.

FDA approval

Oral colchicine had been used for many years as an unapproved drug with no prescribing information, dosage recommendations, or drug interaction warnings approved by the U.S. Food and Drug Administration (FDA).^[8] On July 30, 2009 the FDA approved colchicine as a monotherapy for the treatment of three different indications (familial Mediterranean fever, acute gout flares, and for the prophylaxis of gout flares^[8]), and gave URL Pharma a three-year marketing exclusivity agreement^[9] in exchange for URL Pharma doing 17 new studies and investing $100 million into the product, of which $45 million went to the FDA for the application fee. URL Pharma raised the price from $0.09 per tablet to $4.85, and the FDA removed the older unapproved colchicine from the market in October 2010 both in oral and IV form, but gave pharmacies the opportunity to buy up the older unapproved colchicine.^[10] Colchicine in combination with probenecid has been FDA approved prior to 1982.^[9]

Pharmacology

Mechanism of action

Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules. Availability of tubulin is essential to mitosis, and therefore colchicine effectively functions as a "mitotic poison" or spindle poison.^[11]

The mitosis inhibiting function of colchicine has been of great use in the study of cellular genetics. To see the chromosomes of a cell under a light microscope, it is important that they be viewed near the point in the cell cycle in which they are most dense. This occurs near the middle of mitosis (specifically metaphase), so mitosis must be stopped before it completes. Adding colchicine to a culture during mitosis is part of the standard procedure for doing karyotype studies.

Apart from inhibiting mitosis (a process heavily dependent on cytoskeletal changes), colchicine also inhibits neutrophil motility and activity, leading to a net anti-inflammatory effect. This has proven useful in the treatment of acute gout flares.

Indications

Colchicine has a relatively low therapeutic index. In August 2009, colchicine won Food and Drug Administration (FDA) approval in the United States as a stand-alone drug for the treatment of acute flares of gout and familial Mediterranean fever.^[12]^[13] It had previously been approved as an ingredient in an FDA-approved combination product for gout. The approval was based on a study in which two doses an hour apart were effective at combating the condition.^[12]

It is also used as an anti-inflammatory agent for long-term treatment of Behçet's disease.^[14]

Use in cancer treatment

Since one of the defining characteristics of cancer cells is a significantly increased rate of mitosis,^{[citation needed]} this means that cancer cells are significantly more vulnerable to colchicine poisoning than are normal cells. However, the therapeutic value of colchicine against cancer is (as is typical with chemotherapy agents) limited by its toxicity against normal cells.

Off-label uses

The British drug development company Angiogene is developing a prodrug of a colchicine congener, ZD6126^[15] (also known as ANG453) as a treatment for cancer.

Colchicine is used for constipation-predominant irritable bowel syndrome in women,^[16] and for treatment of severe or persistent aphthous stomatitis (canker sores).^[17]

Colchicine is also used as adjunct to conventional therapy in the treatment of pericarditis.

An Australian randomized trial found low-dose colchicine substantially reduced the risk of heart attack, stroke, and sudden death in people with coronary heart disease.^[18]

Contraindications

Long-term (prophylactic) regimens of oral colchicine are absolutely contraindicated in patients with advanced renal failure (including those on dialysis). Ten to 20% of a colchicine dose is excreted unchanged by the kidneys. Colchicine is not removed by hemodialysis. Cumulative toxicity is a high probability in this clinical setting. A severe neuromyopathy may result. The presentation includes a progressive onset of proximal weakness, elevated creatine kinase, and sensorimotor polyneuropathy. Colchicine toxicity can be potentiated by the concomitant use of cholesterol-lowering drugs (statins, fibrates). This neuromuscular condition can be irreversible (even after drug discontinuation). Accompanying dementia has been noted in advanced cases. It may culminate in hypercapnic respiratory failure and death. (Minniti-2005)

Adverse effects

Side-effects include gastrointestinal upset and neutropenia. High doses can also damage bone marrow and lead to anemia and also cause hair loss. All of these side-effects can result from hyperinhibition of mitosis.^{[citation needed]}

A main side-effect associated with all mitotic inhibitors is peripheral neuropathy, which is a numbness or tingling in the hands and feet due to peripheral nerve damage that can become so severe that reduction in dosage or complete cessation of the drug may be required. Microtubules are involved in vesicular transport. Peripheral nerves are among the longest in the body. Brownian motion is not significant enough in these peripheral nerves to allow vesicles to reach their destination. Thus, they are susceptible to microtubule toxins.^{[citation needed]}

Toxicity

Colchicine poisoning has been compared to arsenic poisoning. Symptoms start 2 to 5 hours after the toxic dose has been ingested and include burning in the mouth and throat, fever, vomiting, diarrhea, abdominal pain, and kidney failure. These symptoms may set in as many as 24 hours after exposure. Onset of multiple-system organ failure may occur within 24 to 72 hours. This includes hypovolemic shock due to extreme vascular damage and fluid loss through the GI tract, which may cause death. In addition, sufferers may experience kidney damage that causes low urine output and bloody urine, low white blood cell counts (persisting for several days), anemia; muscular weakness, and respiratory failure. Recovery may begin within six to eight days.

There is no specific antidote for colchicine, though various treatments exist.^[19] Certain common inhibitors of CYP3A4 and/or P-gp, including grapefruit juice, may increase the risk of colchicine toxicity.^[1]

Biosynthesis

Several experiments show that the biosynthesis of colchicine involves the amino acids phenylalanine and tyrosine as precursors. Indeed, the feeding of Colchicum autumnale with radioactive amino acid, tyrosine-2-C14, caused the latter to partially incorporate in the ring system of colchicine. The induced absorption of radioactive phenylalanine-2-C14 by Colchicum byzantinum, another plant of the Colchicaceae family, resulted in its efficient absorption by colchicine.^[20] However, it was proven that the tropolone ring of colchicine resulted, in essence, from the expansion of the tyrosine ring. Further radioactive feeding experiments of Colchicum autumnale revealed that Colchicine can be synthesized biosynthetically from (S)-Autumnaline. That biosynthesic pathway occurs primarily through a para-para phenolic coupling reaction involving the intermediate isoandrocymbine. The resulting molecule undergoes O-methylation directed by S-Adenosylmethionine (SAM). Two oxidation steps followed by the cleavage of the cyclopropane ring leads to the formation of the tropolone ring contained by N-formyldemecolcine. N-formyldemecolcine hydrolyzes then to generate the molecule demecolcine, which also goes through an oxidative demethylation that generates deacetylcolchicine. The molecule of colchicine appears finally after addition of acetyl-Coenzyme A to deacetylcolchicine.^[21]^[22]

Botanical use

Since chromosome segregation is driven by microtubules, colchicine is also used for inducing polyploidy in plant cells during cellular division by inhibiting chromosome segregation during meiosis; half the resulting gametes, therefore, contain no chromosomes, while the other half contain double the usual number of chromosomes (i.e., diploid instead of haploid, as gametes usually are), and lead to embryos with double the usual number of chromosomes (i.e., tetraploid instead of diploid). While this would be fatal in most higher animal cells, in plant cells it is not only usually well tolerated but in fact frequently results in plants that are larger, hardier, faster-growing, and in general more desirable than the normally diploid parents; for this reason, this type of genetic manipulation is frequently used in breeding plants commercially.

When such a tetraploid plant is crossed with a diploid plant, the triploid offspring will usually be sterile (unable to produce fertile seeds or spores), although many triploids can be propagated vegetatively. Growers of annual triploid plants not readily propagated must buy fresh seed from a supplier each year. Many sterile triploid plants, including some tree and shrubs, are becoming increasingly valued in horticulture and landscaping because they do not become invasive species. In certain species, colchicine-induced triploidy has been used to create "seedless" fruit, such as seedless watermelons (Citrullus lanatus). Since most triploids do not produce pollen themselves, such plants usually require cross-pollination with a diploid parent to induce fruit production.

Colchicine's ability to induce polyploidy can be also exploited to render infertile hybrids fertile, for example in breeding triticale (× Triticosecale) from wheat (Triticum spp.) and rye (Secale cereale). Wheat is typically tetraploid and rye diploid, with their triploid hybrid infertile; treatment of triploid triticale with colchicine gives fertile hexaploid triticale.

When used to induce polyploidy in plants, colchicine cream is usually applied to a growth point of the plant, such as an apical tip, shoot, or sucker. Also, seeds can be presoaked in a colchicine solution before planting. Another way to induce polyploidy is to chop off the tops of plants and carefully examine the regenerating lateral shoots and suckers to see if any look different.^[23] If no visual difference is evident, flow cytometry can be used for analysis.

Doubling of plant chromosome numbers also occurs spontaneously in nature, with many familiar plants being fertile polyploids. Natural hybridization between fertile parental plants of different levels of polyploidy can produce new plants at an intermediate level, such as a triploid produced by crossing between a diploid and a tetraploid, or a hexaploid produced by crossing between a diploid and an octoploid.

Marketing exclusivity in the United States

As a drug predating the FDA, colchicine was sold in the United States for many years without having been reviewed by the FDA for safety and efficacy. In 2009, the FDA reviewed an NDA submitted by URL Pharma and approved colchicine for gout flares, awarding Colcrys a three-year term of market exclusivity, prohibiting generic sales, and increasing the price of the drug from $0.09 to $4.85 per tablet.^[24]^[25]^[26]

Numerous consensus guidelines, and previous randomized controlled trials, had concluded that colchicine is effective for acute flares of gouty arthritis. However, as of 2006, the drug was not formally approved by the FDA, owing to the lack of a conclusive randomized control trial (RCT). That year, the FDA started an Unapproved Drugs Initiative, through which they sought more rigorous testing of efficacy and safety of colchicine and other unapproved drugs.^[27] In exchange for paying for the costly testing, the FDA gave URL Pharma three years of market exclusivity for its Colcrys brand,^[28] under the Hatch-Waxman Act, based in part on URL-funded research in 2007, including pharmacokinetic studies and a randomized control trial with 185 patients with acute gout. URL Pharma also received seven years of market exclusivity for Colcrys in treatment of familial Mediterranean fever, under the Orphan Drug Law. URL Pharma then raised the price per tablet from $0.09 to $4.85 and sued to remove other versions from the market, increasing annual costs for the drug to U.S. state Medicaid programs from $1 million to $50 million. Medicare also paid significantly higher costs—making this a direct money-loser for the government. (In a similar case, thalidomide was approved in 1998 as an orphan drug for leprosy and in 2006 for multiple myeloma.)^[29]

In April 2010, in an editorial in the New England Journal of Medicine (NEJM), A.S. Kesselheim and D.H. Solomon said that the rewards of this legislation are not calibrated to the quality or value of the information produced, that there is no evidence of meaningful improvement to public health, that it would be much less expensive for the FDA, the National Institutes of Health or large insurers like medicare and medicaid or coalitions of private insurers to pay for trials themselves. Furthermore, the cost burden of this subsidy falls primarily on patients or their insurers.^[29] URL Pharma posted a detailed rebuttal of the NEJM editorial.^[30]

In September 2010, the FDA ordered a halt to marketing unapproved single-ingredient oral colchicine.^[31]

The patents for colchicine will expire on February 17, 2029.^[32]

References

^ ^a ^b "Colchicine for acute gout: updated information about dosing and drug interactions". National Prescribing Service. 14 May 2010. Retrieved 14 May 2010.
^ Wallace Graham and James B. Roberts (1953). "Intravenous colchicine in the treatment of gouty arthritis". Ann Rheum Dis 12 (1): 16–19. doi:10.1136/ard.12.1.16. PMC 1030428. PMID 13031443.
^ Edward F. Hartung (1954). "History of the Use of Colchicum and related Medicaments in Gout". Ann Rheum Dis 13 (3): 190–200. doi:10.1136/ard.13.3.190. (free BMJ registration required)
^ Manuchair S. Ebadi (2007). Pharmacodynamic basis of herbal medicine. ISBN 978-0-8493-7050-2.
^ Pelletier and Caventou (1820) "Examen chimique des plusieurs végétaux de la famille des colchicées, et du principe actif qu'ils renferment. [Cévadille (veratrum sabadilla) ; hellébore blanc (veratrum album) ; colchique commun (colchicum autumnale)]" (Chemical examination of several plants of the meadow saffron family, and of the active principle that they contain.) Annales de Chimie et de Physique, 14 : 69-81.
^ Geiger, Ph. L. (1833) "Ueber einige neue giftige organische Alkalien" (On some new poisonous organic alkalis) Annalen der Pharmacie, 7 (3) : 269-280; colchicine is discussed on pages 274-276.
^ Dewar, Michael J.S. (February 3, 1945) "Letters to Editor: Structure of colchicine," Nature 155 : 141-142. Note: Dewar did not prove the structure of colchicine; he merely suggested that it contained two 7-membered rings. Colchicine's structure was determined by X-ray crystallography in 1952 [Murray Vernon King, J. L. de Vries, and Ray Pepinsky (July 1952) "An x-ray diffraction determination of the chemical structure of colchicine," Acta Crystallographica, 5 : 437-440]. Its total synthesis was first accomplished in 1959 [Albert Eschenmoser (1959) "Synthese des Colchicins," Angewandte Chemie, 71 : 637-640.]
^ ^a ^b "FDA Approves Colchicine With Drug Interaction and Dose Warnings". July 2009.
^ ^a ^b [1] FDA Orange Book; search for colchicine
^ Questions and Answers for Patients and Healthcare Providers Regarding Single-ingredient Oral Colchicine Products
^ Cyberbotanica: Colchicine
^ ^a ^b FDA Approves Gout Treatment After Long Years of Use, an August 2009 article from MedPage Today
^ Cerquaglia C, Diaco M, Nucera G, La Regina M, Montalto M, Manna R (February 2005). "Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update". Current drug targets: inflammation and allergy 4 (1): 117–24. doi:10.2174/1568010053622984. PMID 15720245.
^ Cocco, Giuseppe; Chu, David C.C.; Pandolfi, Stefano (2010). "Colchicine in clinical medicine. A guide for internists". European Journal of Internal Medicine 21 (6): 503. doi:10.1016/j.ejim.2010.09.010. PMID 21111934.
^ Description of ZD6126 on US National Cancer Institute website retrieved 26th April 2008
^ Verne, GN; Davis et al (May 1998). "Treatment of chronic constipation with colchicine: randomized, double-blind, placebo-controlled, crossover trial.". Am J Gastroenterology 98 (5): 1112–6.
^ Porter, S; Scully (June 2005). "Aphthous Ulcers (recurrent)". Clin Evid 13: 1687–1694.
^ Nidorf, SM (2012). "Low-dose colchicine for secondary prevention of cardiovascular disease.". J Am Coll Cardiol 61: 404–410. doi:10.1016/j.jacc.2012.10.027.
^ Colchicine. National Institute for Occupational Safety and Health. Emergency Response Safety and Health Database, August 22, 2008. Retrieved December 23, 2008.
^ Leete, E. The biosynthesis of the alkaloids of Colchicum: The incorporation of phenylalaline-2-C14 into colchicine and demecolcine. J. Am. Chem. Soc. 1963, 85, 3666-3669.
^ Dewick, P. M.(2009).Medicinal Natural Products: A biosynthetic Approach. Wiley. p.360-362.
^ Maier, U. H.; Meinhart, H. Z. Colchicine is formed by para para phenol-coupling from autumnaline. Tetrahedron Lett. 1997, 38, 7357-7360.
^ Deppe, Carol (1993). Breed Your own Vegetable Varieties. Little, Brown & Company. p.150-151. ISBN 0-316-18104-8
^ Kurt R. Karst (2009-10-21). "California Court Denies Preliminary Injunction in Lanham Act Case Concerning Unapproved Colchicine Drugs".
^ Harris Meyer (2009-12-29). "The High Price of FDA Approval". Kaiser Health News and the Philadelphia Inquirer.
^ Colcrys vs. Unapproved Colchicine Statement from URL Pharma
^ "FDA Unapproved Drugs Initiative".
^ "About Colcrys". Colcrys. URL Pharma. Retrieved 11 September 2011.
^ ^a ^b Kesselheim AS, Solomon DH (June 2010). "Incentives for drug development--the curious case of colchicine". N. Engl. J. Med. 362 (22): 2045–7. doi:10.1056/NEJMp1003126. PMID 20393164.
^ Response from URL Pharma
^ "FDA orders halt to marketing of unapproved single-ingredient oral colchicine". 30 Sep 2010.
^ [2]

External links

Feature on colchicine, by Matthew J. Dowd at vcu.edu
NIOSH Emergency Response Database
Eugene E. Van Tamelen, Thomas A. Spencer Jr., Duff S. Allen Jr., Roy L. Orvis (1959). "The Total Synthesis of Colchicine". J. Am. Chem. Soc. 81 (23): 6341–6342. doi:10.1021/ja01532a070.

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Related Pictures

★リンクテーブル★

リンク元	「薬理学」「コルヒチン」「痛風治療薬」「無顆粒球症」

「薬理学」

Colchicine
Systematic (IUPAC) name
	N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide
Clinical data
Trade names	Colcrys
AHFS/Drugs.com	monograph
MedlinePlus	a682711
Pregnancy cat.	D (AU) C (US)
Legal status	Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	45%
Protein binding	34-44%
Metabolism	Metabolism, partly by CYP3A4
Half-life	26.6-31.2 hours
Excretion	Faeces (65%)
Identifiers
CAS number	64-86-8
ATC code	M04AC01
PubChem	CID 6167
IUPHAR ligand	2367
DrugBank	DB01394
ChemSpider	5933
UNII	SML2Y3J35T
KEGG	D00570
ChEBI	CHEBI:27882
ChEMBL	CHEMBL107
Chemical data
Formula	C22H25NO6
Mol. mass	399.437
	SMILES O=C(N[C@@H]3C\1=C\C(=O)C(\OC)=C/C=C/1c2c(cc(OC)c(OC)c2OC)CC3)C;
	InChI InChI=1S/C22H25NO6/c1-12(24)23-16-8-6-13-10-19(27-3)21(28-4)22(29-5)20(13)14-7-9-18(26-2)17(25)11-15(14)16/h7,9-11,16H,6,8H2,1-5H3,(H,23,24)/t16-/m0/s1 ; Key:IAKHMKGGTNLKSZ-INIZCTEOSA-N ;
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英: pharmacology
関: drug entries

定義

生物系と化学物質の選択的な相互作用を研究する学問 (SPC.2)

生物系と薬の相互作用

薬の生物系に対する相互作用：薬理作用 <-化学の視点
生物系の薬に対する相互作用：薬物動態 <-生物の視点

薬品の命名

Ending of the drug name	Category	Example
～afil	Erectile dysfunction	sildenafil
～ane	Inhalatinal general anesthetic	halothane
～azepam	Benzodiaizepine	diazepam
～azine	Phenothiazine (neuroleptic, antiemetic)	chlorpromazine
～azole	Ailtifungal	ketoconazole
～barbital	Barbiturate	phenobarbital
～caine	Local anesthetic	lidocaine
～cillin	Penicillin	methicillin
～cycline	Antibiotic, protein syntlesis inhibitor	tetracycline
～ipramine	TCA	iimipramine
～navir	Protease inhibitor	saquinavir
～olol	β-antagonist	propranolol
～operidol	Butyrophenone ( neuroleptic )	haloperidol
～oxin	Cardiac glycoside ( inotropic agent )	digoxin
～phylline	Methylxanthine	theophylline
～pril	ACE inhibitor	captopril
～terol	β₂ agonist	albuterol
～tidine	H₂ antagonist	cimtidine
～triptyline	TCA	amitriptyline
～tropine	Pituitary hormone	somatotropine
～zosin	a₁ antagonist	prazosin

薬一覧

薬物代謝

薬理動態

神経伝達物質

貧血治療薬

甲状腺関連物質

甲状腺ホルモン製剤

レボチロキシン levothyroxine
リオチニシン liothyronine

抗甲状腺薬

痛風治療薬

痛風発作予防薬

コルヒチン colchicine

尿酸排泄促進薬

尿酸生成抑制薬

アロプリノール allopurinol

「コルヒチン」

　　[★]

英: colchicine
ラ: colchicinum
商: コルヒチン
関

痛風治療薬

痛風発作予防薬

　　　尿酸発作の特効薬、尿酸合成、排泄に関与しない
　　　好中球の走化因子(LTB4,IL-8)に対する走化性低下
　　　→炎症部位への遊走を妨げる
　　　尿酸血症の貪食による脱顆粒の抑制
　　副作用
　　　再生不良貧血、脱毛、下痢
　　服用
　　　発作が起こりそうなときに飲む

微小管、チューブリンの重合をさまげる。

禁忌

本剤の成分に対し過敏症の既往歴のある患者
肝臓又は腎臓に障害のある患者で、肝代謝酵素CYP3A4を強く阻害する薬剤又はP糖蛋白を阻害する薬剤を服用中の患者
妊婦又は妊娠している可能性のある婦人

「痛風治療薬」

　　[★]

英: arthrifuge, gout suppressant, drug for treatment of gout, antipodagric
同: 抗痛風薬
関: 薬理学、痛風

痛風発作予防薬

コルヒチン colchicine

尿酸排泄促進薬

尿酸生成抑制薬

アロプリノール allopurinol
フェブキソスタット febuxostat (PPC.846)

「無顆粒球症」

　　[★]

英: agranulocytosis
ほぼ同: 好中球減少症
関

first aid step1 2006 p.

clozapine, carbamazepine, colchicine(first aid step1 2006 p.207)

[nps1-1] "Colchicine for acute gout: updated information about dosing and drug interactions". National Prescribing Service. 14 May 2010. Retrieved 14 May 2010.

[2] Wallace Graham and James B. Roberts (1953). "Intravenous colchicine in the treatment of gouty arthritis". Ann Rheum Dis 12 (1): 16–19. doi:10.1136/ard.12.1.16. PMC 1030428. PMID 13031443.

[3] Edward F. Hartung (1954). "History of the Use of Colchicum and related Medicaments in Gout". Ann Rheum Dis 13 (3): 190–200. doi:10.1136/ard.13.3.190. (free BMJ registration required)

[4] Manuchair S. Ebadi (2007). Pharmacodynamic basis of herbal medicine. ISBN 978-0-8493-7050-2.

[5] Pelletier and Caventou (1820) "Examen chimique des plusieurs végétaux de la famille des colchicées, et du principe actif qu'ils renferment. [Cévadille (veratrum sabadilla) ; hellébore blanc (veratrum album) ; colchique commun (colchicum autumnale)]" (Chemical examination of several plants of the meadow saffron family, and of the active principle that they contain.) Annales de Chimie et de Physique, 14 : 69-81.

[6] Geiger, Ph. L. (1833) "Ueber einige neue giftige organische Alkalien" (On some new poisonous organic alkalis) Annalen der Pharmacie, 7 (3) : 269-280; colchicine is discussed on pages 274-276.

[7] Dewar, Michael J.S. (February 3, 1945) "Letters to Editor: Structure of colchicine," Nature 155 : 141-142. Note: Dewar did not prove the structure of colchicine; he merely suggested that it contained two 7-membered rings. Colchicine's structure was determined by X-ray crystallography in 1952 [Murray Vernon King, J. L. de Vries, and Ray Pepinsky (July 1952) "An x-ray diffraction determination of the chemical structure of colchicine," Acta Crystallographica, 5 : 437-440]. Its total synthesis was first accomplished in 1959 [Albert Eschenmoser (1959) "Synthese des Colchicins," Angewandte Chemie, 71 : 637-640.]

[MSJuly2009-8] "FDA Approves Colchicine With Drug Interaction and Dose Warnings". July 2009.

[accessdata.fda.gov-9] [1] FDA Orange Book; search for colchicine

[10] Questions and Answers for Patients and Healthcare Providers Regarding Single-ingredient Oral Colchicine Products

[11] Cyberbotanica: Colchicine

[medpage-12] FDA Approves Gout Treatment After Long Years of Use, an August 2009 article from MedPage Today

[13] Cerquaglia C, Diaco M, Nucera G, La Regina M, Montalto M, Manna R (February 2005). "Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update". Current drug targets: inflammation and allergy 4 (1): 117–24. doi:10.2174/1568010053622984. PMID 15720245.

[14] Cocco, Giuseppe; Chu, David C.C.; Pandolfi, Stefano (2010). "Colchicine in clinical medicine. A guide for internists". European Journal of Internal Medicine 21 (6): 503. doi:10.1016/j.ejim.2010.09.010. PMID 21111934.

[15] Description of ZD6126 on US National Cancer Institute website retrieved 26th April 2008

[16] Verne, GN; Davis et al (May 1998). "Treatment of chronic constipation with colchicine: randomized, double-blind, placebo-controlled, crossover trial.". Am J Gastroenterology 98 (5): 1112–6.

[17] Porter, S; Scully (June 2005). "Aphthous Ulcers (recurrent)". Clin Evid 13: 1687–1694.

[18] Nidorf, SM (2012). "Low-dose colchicine for secondary prevention of cardiovascular disease.". J Am Coll Cardiol 61: 404–410. doi:10.1016/j.jacc.2012.10.027.

[19] Colchicine. National Institute for Occupational Safety and Health. Emergency Response Safety and Health Database, August 22, 2008. Retrieved December 23, 2008.

[20] Leete, E. The biosynthesis of the alkaloids of Colchicum: The incorporation of phenylalaline-2-C14 into colchicine and demecolcine. J. Am. Chem. Soc. 1963, 85, 3666-3669.

[21] Dewick, P. M.(2009).Medicinal Natural Products: A biosynthetic Approach. Wiley. p.360-362.

[22] Maier, U. H.; Meinhart, H. Z. Colchicine is formed by para para phenol-coupling from autumnaline. Tetrahedron Lett. 1997, 38, 7357-7360.

[23] Deppe, Carol (1993). Breed Your own Vegetable Varieties. Little, Brown & Company. p.150-151. ISBN 0-316-18104-8

[24] Kurt R. Karst (2009-10-21). "California Court Denies Preliminary Injunction in Lanham Act Case Concerning Unapproved Colchicine Drugs".

[25] Harris Meyer (2009-12-29). "The High Price of FDA Approval". Kaiser Health News and the Philadelphia Inquirer.

[26] Colcrys vs. Unapproved Colchicine Statement from URL Pharma

[27] "FDA Unapproved Drugs Initiative".

[URL_Colcrys-28] "About Colcrys". Colcrys. URL Pharma. Retrieved 11 September 2011.

[Kesselheim-29] Kesselheim AS, Solomon DH (June 2010). "Incentives for drug development--the curious case of colchicine". N. Engl. J. Med. 362 (22): 2045–7. doi:10.1056/NEJMp1003126. PMID 20393164.

[30] Response from URL Pharma

[31] "FDA orders halt to marketing of unapproved single-ingredient oral colchicine". 30 Sep 2010.

[32] [2]

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案内

colchicine