Colchicine for dermatologic diseases

Journal of Drugs in Dermatology, March-April, 2005 by Roberta Bibas, Neide Kalil Gaspar, Marcia Ramos-e-Silva

Abstract

The authors review all aspects related to colchicine from its pharmacology to its usage in several skin diseases.

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Introduction

Colchicine has been prescribed in dermatology for many diseases with good results, without any formal indication for its dermatologic use. The objective of this review is to discuss all aspects related to this drug from its pharmacology to its usage in several skin diseases.

History

Colchicine is an alkaloid extracted from the seeds and tubes of Colchicum autumnale (meadow saffron). (1) It is light yellow and oxidizes into a dark color when exposed to ultraviolet radiation. (2) It is also transformed into different photoisomers when exposed to ultraviolet light. (3) It was not used for treating patients until after the 6th century A.D., although there was an idea of its therapeutic use long before.

Storck, in 1763, began prescribing colchicine for the treatment of acute gout crisis, and it is believed that its use was introduced in the United States by Benjamin Franklin, a gout sufferer himself. Colchicine alcaloid was only isolated from Colchicum autumnale in 1820, by Pelletier and Caventou. (4)

There are two non-dermatologic absolute indications of colchicine: acute gout crisis and familial Mediterranean fever. Colchicine is the drug of choice in the prevention and treatment of the amyloidosis associated with familial Mediterranean fever. (5)

Pharmacological Properties

Colchicine is rapidly absorbed when taken orally, and its blood concentration peak occurs 0.5 to 2 hours after ingestion. Fifty percent of the drug circulates and links to plasmatic proteins. (6) A great quantity of this substance and its metabolites collect in the intestinal tract through bile and intestinal secretions. Colchicine users have increased intestinal epithelium turnover, which is responsible for the majority of its adverse effects. There is also a large concentration in the liver, kidneys, and spleen, while other organs, such as the heart, striated muscles, and brain, do not contain large amounts of the drug. Almost all colchicine is excreted in feces, while only 10% to 20% is excreted in urine. (4) It is presented as tablets of 0.5 or 0.6 mg, which must be kept from light (1) because of the oxidation with ultraviolet exposure.

Cellular, Anti-inflammatory, and Pharmacological Effects

In vivo and in vitro cellular division of plants and animals can be interrupted by colchicine. Its capacity to interrupt mitosis is due to its linkage to dimers of tubulin, preventing the transformation of tubulin in microtubules. (1) The microtubular toxicity will cause cessation of mitosis in metaphase and interference in cellular mobility. The interruption of the mitosis occurs because there is no formation of the mitotic spindles. Cells with high division indexes are the first to be affected. High concentrations of the drug can interrupt mitosis and promote cell death. This action is also performed by vinca alkaloids (vincristine, vinblastine, podophilotoxin, and griseofulvin).

In fact, an anti-mitotic and also anti-inflammatory effect will occur because colchicine reduces mobility, adhesiveness, and chemotaxis of polimorphonuclear cells along with interfering in lysosome degranulation. Because of its cytogenetic effects, colchicine is considered highly teratogenic to animals; however, studies in humans did not demonstrate increased risk of teratogenicity in newborns. (7) Studies have shown that it can be taken while breastfeeding. (8)

Colchicine interferes with intercellular adhesion molecules, selectins, thus inhibiting T-lymphocyte activation and its adhesion to endothelial cells. (9, 10) An adhesion molecule's up-regulation is an important factor in inflammation, and colchicine alters the quantity and quality of expression and topography of a variety of cellular glycoproteins. Even in low concentration, it also inhibits neutrophil endothelial adhesiveness in response to TNF-alpha and IL-1. Colchicine may exert its prophylactic effects on cytokine-provoked inflammation by diminishing the qualitative expression of E-selectin on endothelium, and its therapeutic effects by diminishing the quantitative expression of L-selectin on neutrophils. (9)

Furthermore, Asahina et al (11) noticed that colchicine inhibits the expression of VCAM-1 in dermal cells stimulated by TNF-alpha and IL-1 alpha-stimulated human umbilical vein endothelial cells (HUVEC). This action is even more efficient than with griseofulvin, another microtubule blocker.

Serum xylosyltransferase, a marker for chondroitin biosynthesis, has its activity inhibited by colchicine, which also suppresses the basal level of RNA for collagen 1. (12) Chung et al (13) observed that only colchicine suppressed the basal level of type 1 collagen mRNA, induced by TGF-beta when comparing its activity with D-penicillamine.

The ability of colchicine to link to proteins contributes to its in vitro activity of inhibiting the liberation of histamine granules of mastocytes, inhibiting parathormone and insulin liberation, and also the melanosomes' movement in melanocytes. (1) All those alterations are related to the translocation of granules in the microtubular system, but there still is great controversy over whether or not those actions would happen with the clinically used dosage. (4)