Review articleColchicine in clinical medicine. A guide for internists
Introduction
Colchicine (COL) is a natural product which can be extracted from two plants of the lily family, i.e. from the genus Colchicum (usually called Colchicum autumnale) and from the Gloriosa superba. COL is frequently used in botany [1] and it is a tricyclic alkaloid (C22H25NO) which was isolated in 1820 and has a molecular mass of 399.437 [2].
The therapeutic value of COL is well established in the treatment of acute flares of gouty arthritis, familial Mediterranean fever (FMF), Behçet's disease, and recurring pericarditis with effusion. COL has also been used, mostly with limited role, in other disorders with inflammation prone to fibrosis.
The review discusses the use of COL in clinical medicine, i.e. the mechanism of action, pharmacology, dosage regimens, adverse effects, toxicity (poisoning), pharmacologic interactions, and clinical indications.
Section snippets
Mechanism of action
The pharmacotherapeutic mechanism of action of COL in diverse disorders is not fully understood [2], [3], [4], [5], [6], thought it is known that the drug accumulates preferentially in neutrophils [7], and this effect is useful in FMF. It is assumed that most therapeutic effects of the drug are related to its capacity to bind to β-tubulin, thus inhibiting self-assembly and polymerization of microtubules and interfering with several cellular functions. COL modulates the production of chemokines
Pharmacokinetics
After intravenous bolus injection of COL, the area under the concentration–time curve (AUC) is 61.2 ± 12.7 ng h/ml; the steady-state volume of distribution is 419 ± 95 l; the systemic clearance is 8.5 ± 1.8 l/h; and the terminal half-life (t½) is 58 ± 11 h [8].
COL is lipophilic and is promptly absorbed by the jejunum and ileum [8]. In healthy individuals the mean oral bioavailability of the drug is 45%, but with a range between 24 and 88% [8]. The large variations in bioavailability account for the
Parenteral use
Till 2007 COL could be used intravenously [16], [17] and for treating pericardial effusion also by intrapericardial injection [18]. However, 50 cases of serious adverse-events, including 23 fatalities have raised serious safety concerns about parenteral COL use [6], [19], [20], and since 2008 only oral route is used [6], [21].
Short term oral therapy
For treatment of acute flares of gouty arthritis usually COL is given as an oral dose of 1 mg, and thereafter 0.5 mg is given hourly until the acute gout flare subsides or
Adverse effects
Common adverse effects should not be confused with toxicity and poisoning. Side effects may be induced at the beginning of the therapy and also during the long term therapy.
Symptoms
Dose-dependent toxic side effects of COL are known from cases with acute poisoning, and COL poisoning has been compared to arsenic poisoning [4], [5], [19], [20]. Symptoms are listed in Table 1. Symptomatology starts 2 to 5 h after the toxic dose has been ingested, and includes burning in the mouth and throat, fever, vomiting, diarrhea, abdominal pain and kidney failure. These symptoms may set in as many as 24 h after the exposure. Doses between 0.5 and 0.8 mg/kg may induce bone marrow failure and
Drug interactions
COL undergoes intensive hepatic deacetylation through the CYP3A4 system [11], [19] and drugs interacting with the CYP3A4 system may increase/decrease the levels/effects of COL, increasing the toxicity of COL, and vice versa.
Severe clinical interactions have been reported in patients treated with COL and who received HMG-CoA reductase inhibitors[37], [38], [39], [40], [41], [42], [43], [44]. In most cases the initial symptom of toxicity was muscle weakness, and the symptom begun between 2 weeks
Historical use
In the 1st century AD Pedanius Dioscorides wrote “De Materia Medica” and stated that more than 3000 years ago Greek physicians used the plant from which COL is derived as a therapeutic agent for gout.
Middle age Arabic physicians also used the C. autumnale to treat acute flares of gout [51].
In Europe the Viennese physician Anton Stoerck (1731–1803) treated with COL extracts the Austrian Empress Maria Theresia who suffered of gout [52].
Especially in India and Africa various preparations of
Established medical use
Table 1 shows the medical use of COL. Benefit of COL has been well documented in the treatment of acute flares of gouty arthritis, of Adamantiades-Behçet disease, of FMF, and of recurring pericarditis with effusion.
Acute coronary syndromes
A Canadian university is studying the therapeutic value of COL in acute coronary syndromes [65].
Aphtous stomatitis
COL seems to be effective in the therapy of this pathology, which has some similarities with some complications of the Behçet disease [66], [67].
Chronic constipation, constipation-predominant irritable bowel syndrome
COL has been used for treating chronic constipation [5], [68].
The Australian company Giaconda has developed a combination therapy (COL and olsalazine) for treating constipation-predominant irritable bowel syndrome.
Chronic gouty arthritis
In some countries COL is used to treat
Conclusions
The therapeutic use of COL was described nearly 3000 thousand years ago. The drug has been used against acute flares of gout since Middle age, and in the therapy of FMF since almost 4 decades. Nonetheless, COL continues to surprise us.
Some uncertainties and perhaps controversy about the pharmacotherapeutic mechanism of action continue, but COL is a unique anti-inflammatory drug with respect to its clinical usefulness and it mode of action. Therefore, COL has an assured treatment place in the
Learning Points
* Multiple Choice Questions• Which of the following is true about the plasma half life (t½) of colchicine? A. The t½ is between 4.1 and 7.5 h B. The t½ is between 9.3 and 10.6 h. C. The t½ is between 11.3 and 14,5 h D. The t½ is between 18.2 and 27.4 h • Which of the following is true about the maximal concentration of colchicine? A. The plasma concentration is the same as leukocytes' concentration. B. The plasma concentration is up to 6 fold higher than leukocytes'' concentration. C. The leukocytes’
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