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Colchicine: An Old Wine in a New Bottle?

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Send Orders of Reprints at [email protected] Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2013, 12, 000-000 1 1871-5230/13 $58.00+.00 © 2013 Bentham Science Publishers Colchicine: An Old Wine in a New Bottle? François Roubille 1,2,3,* , Ekaterini Kritikou 1 , David Busseuil 1 , Stéphanie Barrère-Lemaire 2,3 and Jean-Claude Tardif 1 1 Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada; 2 Cardiology Department, University Hospital of Montpellier, Montpellier, France; 3 Inserm, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, IN- SERM, U661; Universités de Montpellier 1 and 2; France Abstract: Although colchicine, a natural product, is one of the oldest drugs still currently available, its possible functions seem to be surprisingly not well-known. Beyond its present medicinal use (gout, familial Mediterranean fever, Behcet’s disease, chondrocalcinosis and other crystal arthritis), numerous other conditions have been recently proposed for the use of this drug, including pericardial diseases. However, colchicine appears as a double-edged sword, with underestimated toxicity and frequent side effects. In this review, we present the main pharmacologic features of this drug, with an empha- sis on toxicity and highlight its possible applications in the cardiovascular field. Keywords: Colchicine, pericardial diseases, pericarditis, gout, tubulin, inflammation, cardiovascular diseases. 1. INTRODUCTION Colchicine has been used for centuries for the treatment and prevention of gouty attacks and rheumatic complaints and it is one of the oldest drugs still currently available. The active compound was initially extracted from the plant autumn crocus (Colchicum autumnale; Fig. 1). The term colchicum derives from the Greek word “” (an an- cient country on the eastern shore of the Black Sea) which indicates the origin of the plant. Colchicine was first de- scribed for the treatment of rheumatism and swelling in the Ebers Papyrus (1500 BC). The use of the bulb-like corms of Colchicum for gout traces back to 550 AD, as the "hermo- dactyl" (that is the fingers of Hermes) was recommended by Alexander of Tralles to treat gout [1]. It was then men- tioned later [2], especially by the Persian physician ibn Sina (Avicenna, eleventh century) and by the French surgeon Ambroise Paré in the sixteenth century. The drug appeared in the London Pharmacopoeia (a drug-making book) of 1618. From the first description of colchicine and until the eighteenth century, this drug was recommended or not [1], following trends and because of its toxicity, as underlined by Sydenham (1624-1689). In 1763, Störck popularized the use of colchicine [1, 3] by precisely using the root extracts in various diseases. He tested them on himself and found that the volume of urine was increased. However, treatment with the whole root led to diarrhea, abdominal pains and tenes- mus. Higher doses of the whole root in dogs caused a similar syndrome, which rapidly led to death. In the eighteenth and nineteenth century, colchicine was one of the rare efficient drugs available, with noticeable side effects, prompting phy- sicians to propose it as a sort of panacea [3], especially for Nicholas d’Husson who recommended it as “Eau Médicinale”. *Address correspondence to this author at the Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada; Tel: 514-376-3330; Fax: 514-593-2500; E-mail: [email protected] Fig. (1). Left. Photograph. The plant from which colchicine is de- rived (color version available on the online version). Right. The drawing is taken from the Laborde and Houde textbook referenced in the bibliography.
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Send Orders of Reprints at [email protected]

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2013, 12, 000-000 1

1871-5230/13 $58.00+.00 © 2013 Bentham Science Publishers

Colchicine: An Old Wine in a New Bottle?

François Roubille1,2,3,*, Ekaterini Kritikou1, David Busseuil1, Stéphanie Barrère-Lemaire2,3 and Jean-Claude Tardif1

1Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada;

2Cardiology Department, University

Hospital of Montpellier, Montpellier, France; 3Inserm, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, IN-

SERM, U661; Universités de Montpellier 1 and 2; France

Abstract: Although colchicine, a natural product, is one of the oldest drugs still currently available, its possible functions

seem to be surprisingly not well-known. Beyond its present medicinal use (gout, familial Mediterranean fever, Behcet’s

disease, chondrocalcinosis and other crystal arthritis), numerous other conditions have been recently proposed for the use

of this drug, including pericardial diseases. However, colchicine appears as a double-edged sword, with underestimated

toxicity and frequent side effects. In this review, we present the main pharmacologic features of this drug, with an empha-

sis on toxicity and highlight its possible applications in the cardiovascular field.

Keywords: Colchicine, pericardial diseases, pericarditis, gout, tubulin, inflammation, cardiovascular diseases.

1. INTRODUCTION

Colchicine has been used for centuries for the treatment and prevention of gouty attacks and rheumatic complaints and it is one of the oldest drugs still currently available. The active compound was initially extracted from the plant autumn crocus (Colchicum autumnale; Fig. 1). The term colchicum derives from the Greek word “ ” (an an-cient country on the eastern shore of the Black Sea) which indicates the origin of the plant. Colchicine was first de-scribed for the treatment of rheumatism and swelling in the Ebers Papyrus (1500 BC). The use of the bulb-like corms of Colchicum for gout traces back to 550 AD, as the "hermo-dactyl" (that is the fingers of Hermes) was recommended by Alexander of Tralles to treat gout [1]. It was then men-tioned later [2], especially by the Persian physician ibn Sina (Avicenna, eleventh century) and by the French surgeon Ambroise Paré in the sixteenth century. The drug appeared in the London Pharmacopoeia (a drug-making book) of 1618. From the first description of colchicine and until the eighteenth century, this drug was recommended or not [1], following trends and because of its toxicity, as underlined by Sydenham (1624-1689). In 1763, Störck popularized the use of colchicine [1, 3] by precisely using the root extracts in various diseases. He tested them on himself and found that the volume of urine was increased. However, treatment with the whole root led to diarrhea, abdominal pains and tenes-mus. Higher doses of the whole root in dogs caused a similar syndrome, which rapidly led to death. In the eighteenth and nineteenth century, colchicine was one of the rare efficient drugs available, with noticeable side effects, prompting phy-sicians to propose it as a sort of panacea [3], especially for Nicholas d’Husson who recommended it as “Eau Médicinale”.

*Address correspondence to this author at the Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada; Tel: 514-376-3330; Fax: 514-593-2500; E-mail: [email protected]

Fig. (1). Left. Photograph. The plant from which colchicine is de-

rived (color version available on the online version). Right. The

drawing is taken from the Laborde and Houde textbook referenced

in the bibliography.

2 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2013, Vol. 12, No. 1 Roubille et al.

The active drug was first isolated in 1820 by the French chemists P.S. Pelletier and J. Caventon [4]. In 1833, P.L. Geiger purified an active ingredient and proposed the name colchicine [1]. Colchicum plants were brought to America by Benjamin Franklin, who suffered from gout himself and had written a humorous poem about the disease [5]. Pernice, an Italian pathologist, published in 1889 [6] the first observation of the molecular changes observed in two dogs injected with a large dose of tincture of Colchicum. He described the ab-sence of ana-telophases during mitosis, indicating that col-chicine was functioning as a mitotic spindle poison. The structure of the active compound was elucidated in 1955 (Fig. 2) [7]. In 2009, the FDA approved colchicine for the treatment of gout and familial Mediterranean fever (FMF).

Fig. (2). Chemical structure of colchicine.

The history of the drug enlightens its efficacy but also its toxicity at high doses (that can even lead to death). Extensive experimental work with colchicine has led to the understand-ing of its mechanism of action by binding to tubulin and thereby inhibiting microtubule polymerization, and it has also provided important insights into the mechanisms under-lying the mitotic process. Over the past decade, colchicine

has been proposed as a treatment for various conditions, opening new chapters in its long history as a medication. In

this mini-review, we focus on its possible applications in cardiovascular diseases; current indications for colchicine are summarized in Table 1A.

2. MECHANISM OF ACTION

Colchicine is known as a powerful spindle poison. Its efficacy, particularly in gout, could be explained by this ac-tion. Furthermore, colchicine could exert anti-inflammatory effects independent of its impact on spindle.

2.1. Colchicine Inhibits the Polymerization of Tubulin

In 1968, tubulin was identified as the biological target of colchicine [8]. The identification of tubulin as the basic subunit of microtubules paved the way for molecular analy-sis and highlighted that microtubules from different struc-tures had the same composition; colchicine played an impor-tant role in this discovery [9, 10]. The name “tubulin” was coined by Mohri, who was the first to determine its amino-acid composition [11]. In 2000, the first structure-based ap-proach for compounds that interact with the colchicine site described more precisely the sites of interaction with tubulin, through biochemical and molecular modeling techniques. The colchicine binding site was finally identified in 2004 [12].

Even when used at low doses, colchicine can be found in white blood cells, blocking tubulin polymerization and sub-sequently microtubule generation and stability. Through its action on tubulin, colchicine can interfere with many func-tions of white blood cells including migration and degranula-tion. Direct inhibition of the migration of neutrophils is con-sidered colchicine’s main mechanism of action in gout [13]. Nevertheless, it could exert other effects. Colchicine func-tions as a spindle poison by inhibiting tubulin polymeriza-tion, which might explain its impact on all dividing or mi-grating cells, as the spindle is of crucial importance for both these biological functions (Fig. 3).

Table 1A. Main indications of colchicine (except cardiovascular diseases).

Main clinical indications (dif-

ferences could exist among

countries)

• Gout (flare-ups and prevention)

• Familiar Mediterranean Fever (FMF)

• Behcet disease

• Chondrocalcinosis and other microcrystalline arthritis

• [7, 43]

• [52, 53, 81]

• [82]

• [83]

Potential indications

• Primary biliary cirrhosis

• Psoriasis

• Amyloidosis

• [84, 85]

• [86]

• [87, 88]

Case reports of efficiency

• Dermatitis herpetiformis

• Relapsing polychondritis

• Necrotizing vasculitis

• Sweet’s syndrome

• Leukocytoclastic vasculitis

• Various dermatitis

• Reviewed in [7]

Colchicine: An Old Wine in a New Bottle? Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2013, Vol. 12, No. 1 3

2.2. Possible Anti-Inflammatory Properties

Colchicine could have direct anti-inflammatory effects (reviewed in [14]) by inhibiting key inflammatory signaling networks known as the inflammasome and proinflammatory cytokines. Importantly, gout and chondrocalcinosis are char-acterized by deposition of monosodium urate or calcium pyrophosphate dihydrate crystals, respectively, in joints and periarticular tissues. These crystals have been shown to en-gage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome [15], resulting in the production of active interleukin-1 (IL-1 ) and IL-18. Macrophages from mice deficient in various components of the inflammasome such as caspase-1, ASC and NALP3 are defective in crystal-induced IL-1 activation. Moreover, impaired neutrophil influx is observed in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or IL-1 -receptor-deficient mice [15]. Although the most important effect of colchicine in gouty inflammation is inhibition of neutrophil migration [16], these data suggest an alternative mechanism for the effectiveness of colchicine at preventing an attack of gout through anti-inflammatory functions, such as preventing the release of IL1 by the neutrophils [17, 18], independently from the impact on cell migration. As part of its putative anti-inflammatory impact, the inhibition of pore formation induced by activation of P2X receptors has been proposed to explain the diminution of IL1 release [17]. In another model, colchicine was unable to inhibit ATP-driven IL-1 release [15] but did diminish ureate-stimulated in-flammasome recruitment. Taken together, these data show that the mechanism by which colchicine prevents crystal-induced activation of the inflammasome is not known. Whether colchicine-mediated inhibition of microtubules may prevent the crystals from entering the cell or prevent the crystals from interacting with NALP3 remains to be investi-gated.

3. PHARMACOKINETICS FEATURES OF COLCHI-

CINE

Colchicine is lipophilic and quickly absorbed in the jeju-num and ileum [7, 19-21]. Peak in plasma levels is obtained about 2 hours (0.5-3 h) after oral administration [22], and half-time is roughly 4 hours. The bioavailability ranges from 25% to 50% [7, 23, 24], because of a hepatic first-passage. It can be detected in leukocytes for up to 10 days after oral administration. Although intravenous colchicine has a much shorter half-life than orally administered, its use is not rec-ommended due to toxicity. The drug is eliminated mainly by hepatic metabolism via oxidative demethylation by the cyto-chrome P450 system (isoform CYP 3A4) with production of 2- and 3-demethylcolchicine [25]. Enterohepatic recircula-tion may lead to a second peak in plasma levels within 6 hours of ingestion. The excretion is largely dependent on P-glycoprotein, an ATP-dependent phosphor glycoprotein lo-cated in the cell membrane. This is of great importance, as P-glycoprotein-mediated excretion could explain toxicity ob-served due to drug-drug interactions [26], as all compounds that inhibit CYP 3A4 can potentially lead to toxicity (for example, clarithromycin, erythromycin, ketoconazole). Pro-tein interactions could explain the interactions with cy-closporine. Rhabdomyolysis has been reported during con-comitant use of statins. Colchicine's half-life is prolonged by 100% in renal failure and by 10 times in the presence of cir-rhosis. Importantly, colchicine can enter all tissues [24] and is also excreted in breast milk [27]. Furthermore, the drug is able to accumulate in leukocytes [22, 28], where colchicine exerts marked effects: the concentration in neutrophils may be more than 16 times higher than the peak concentration in plasma [29]. Importantly, colchicine can accumulate in monocytes, reaching concentrations higher than the plasma levels [19, 20]. This intracellular accumulation depends on the abundance of the P-glycoprotein (also named ABCB1) [21], which makes difficult to predict, based on plasma levels,

Fig. (3). Impact of colchicine in pathological situations.

4 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2013, Vol. 12, No. 1 Roubille et al.

which concentration of colchicine could be achieved in spe-cific cell types such as inflammatory cells. This finding could explain why some patients suffering from familial Mediterranean fever do not respond to the drug, because of polymorphisms in the gene encoding for P-glycoprotein [22].

4. EFFICACY IN CARDIOVASCULAR DISEASES

In the past decade, considerable work has highlighted the interest of colchicine in cardiovascular diseases, especially in acute pericarditis. Although the guidelines of the European Society of Cardiology did not recommend strongly the drug in 2004 [30], further studies showed the efficacy and safety of the drug in this clinical setting. Indeed, Imazio et al. first demonstrated that colchicine was effective for the treatment and the prevention of recurrent pericarditis in a prospective, randomized, open-label designed study of 120 patients (mean age 56.9+/-18.8 years, 54 males) with a first episode of acute pericarditis (idiopathic, viral, postpericardiotomy syndromes, and connective tissue diseases) [31], who were randomly assigned to conventional treatment with aspirin or conventional treatment plus colchicine (1.0 to 2.0 mg for the first day and then 0.5 to 1.0 mg/day for 3 months). The pri-mary end point was recurrence rate, which was significantly reduced from 32.3% down to 10.7% at 18 months in the col-chicine group (p=0.004). Surprisingly, colchicine was dis-continued only in 5 cases (8.3%) because of diarrhea and no other serious adverse effects were observed.

In a second study, Imazio and colleagues showed that colchicine could be efficient after conventional treatment failure to manage acute pericarditis [32]. In a prospective, randomized, open-label design, 84 consecutive patients with a first episode of recurrent pericarditis were randomly as-signed to receive conventional treatment with aspirin alone or conventional treatment plus colchicine (1.0-2.0 mg the first day and then 0.5-1.0 mg/d for 6 months). The primary end point was the recurrence rate, which was significantly decreased in the colchicine group (actuarial rates at 18 months were 24.0% vs 50.6% with conventional treatment; p=0.02) with no serious adverse effects observed. The authors further demonstrated that colchicine was safe and effective for secondary prevention of recurrent pericarditis [33]. Recently, colchicine was proposed to reduce post-pericardiotomy reactions revealed as pericarditis [34, 35] or acute atrial fibrillation [36]. Colchicine is now considered as one of the conventional treatments for acute pericarditis, irrespective of its cause. Whether this approach will soon be validated in updated guidelines remains to be confirmed. The place of colchicine among other anti-inflammatory drugs for cardiac disorders is more extensively described in the paper of Algalarrondo et al. elsewhere in this special topic issue.

Nevertheless, the very low rate of side effects in these trials is surprising, given the side effects reported in the lit-erature in other clinical settings. This discrepancy might be explained by the clinical management that differs among countries, with doses of 0.5 mg per day often recommended, especially in case of intolerance. Further lowering of the dose could be sufficient to improve the tolerability of colchi-cine. Also, patients with acute pericarditis are often young and comorbidities are relatively uncommon in clinical stud-ies, particularly because renal failure represents an exclusion

criterion. For example, in the COPE trial, patients with se-rum creatinine higher than 2.5 mg/dL were not included [31], which could explain the low rate of side effects and drug discontinuation. However, colchicine is not always well tol-erated in real life. Registries about patients admitted for peri-carditis and treated with colchicine could help us to further elucidate this point.

Colchicine is therefore an old drug which offers new benefits in pericardial diseases [31, 37-40] and might be of interest for other cardiovascular diseases. For example, col-chicine was suspected to exert anti-atherosclerotic actions demonstrated both by macroscopic and microscopic investi-gation of the aorta in rabbits [41] and was proposed to reduce inflammation in patients with stable coronary disease [42]. However, it was ineffective to prevent restenosis after stent implantation. The value of colchicine in these clinical set-tings deserves to be clarified.

5. TOLERABILITY

The tolerability of colchicine can be improved by avoid-ing the use of loading doses and utilizing weight-adjusted doses (i.e. 0.5 mg twice daily for patients >=70 kg, but only 0.5 mg daily for patients <70 kg). Colchicine seems to be efficient in treating gout at low doses [43] and the dosage should be adapted in case of concomitant administration with other medications [44] (see also Table 1B). In a multicenter, double-blind, placebo-controlled study, two regimens (low-dose colchicine (1.8 mg over 1 hour) and high-dose colchi-cine (4.8 mg over 6 hours)) were compared with placebo in gout flare-up, with the primary endpoint evaluated on the first day after administration. The trial included 184 patients and the response rates were as follow: 28 of 74 patients (37.8%) in the low-dose group, 17 of 52 patients (32.7%) in the high-dose group, and 9 of 58 patients (15.5%) in the pla-cebo group (respectively p=0.005 and p=0.034, versus pla-cebo). Rescue medication was taken within the first 24 hours by 23 patients (31.1%) in the low-dose group (p=0.027 ver-sus placebo), 18 patients (34.6%) in the high-dose group (p=0.103 versus placebo), and 29 patients (50.0%) in the placebo group. Patients in the low-dose group had an adverse event profile similar to that of the placebo group. High-dose colchicine was associated with significantly more diarrhea, vomiting, and other adverse events compared to low-dose colchicine or placebo. With high-dose colchicine, 40 patients (76.9%) had diarrhea (OR 21.3 [95% CI 7.9-56.9]), 10 (19.2%) had severe diarrhea, and 9 (17.3%) had vomiting. With low-dose colchicine, 23.0% of the patients had diarrhea (OR 1.9 [95% CI 0.8-4.8]), none had severe diarrhea, and none had vomiting. The safety and tolerability of colchicine were therefore improved by using low but effective doses, taking into account comorbidities such as renal impairment [45, 46] and advanced age [47, 48]. Furthermore, colchicine is sometimes associated to drugs avoiding GI adverse drug reactions, the main side-effects, in several drugs. Special attention is then mandatory to take into account specific side-effects of these concomitant drugs (for instance tiemonium, opium …).

Altogether, these considerations urged to propose contra-indications presented in Table 1B, as well as simple ad-vices to monitor colchicine in routine use (see Table 1c).

Colchicine: An Old Wine in a New Bottle? Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2013, Vol. 12, No. 1 5

Table 1B. Main contraindications of colchicine in routine use.

1) Concomitant treatments with Macrolide (télithromycine, azithromycine, clarithromycine, dirithromycine, érythromycine, josamycine, midécamycine,

roxithromycine, troléandomycine, spiramycine), pristinamycine, verapamil,

2) Concomitant treatments (to avoid if possible): protease inhibitor, statins, cyclosporine, anticoagulants

3) Creatinine clearance < 30 mL/min (recent dosage)

4) Severe hepatic dysfunction

5) Anemia, thrombocytopenia, leucopenia without explanation or uncontroled

6) (if possible) Pregnancy, lactating woman and women at risk of pregnancy

7) History of an allergic reaction or significant sensitivity to constituents of study drug (rare).

Table 1C. How to monitor (simply) colchicine in routine use.

1. Before treatment:

a. Renal function has to be evaluated

b. If the patient is likely to present hepatic dysfunction, biology has to be checked

c. Blood cell count

2. During the first month:

a. Blood cell count

b. Renal function

3. In case of new drug likely to induce interactions, or in case of any clinica events involving hepatic dysfunction or renal impairment:

a. Blood cell count

b. Renal function

4. In case of toxicity or poisoning suspicion:

Nausea, vomiting

Severe diarrhea in spite of the drug discontinuation

a. Blood cell count

b. Renal function

6. TOXICITY

Toxicity of colchicine is usually underestimated with signs that could mislead the practitioner. It is often believed to target mainly pregnant women and the fetus, whereas few cardiologists fear life-threatening toxicity (see Table 2, for main known toxicities on other tissues). Toxicity of colchi-cine in animal models was suspected early because of its mechanism of action. Indeed, colchicine was likely to inter-fere with the mitotic spindle and to affect cell division, and this action was proposed to account for possible adverse ef-fects on fertility, pregnancy, breastfeeding or childhood. Colchicine significantly increased the proportion of ane-uploid oocytes in pregnant mice [49]; however, the potential risk for fertility and pregnancy remained low [50]. By con-trast, no adverse events on fertility [51], pregnancy, and fetal or childhood development have been reported in patients with familial Mediterranean fever (FMF) with prolonged exposure to the drug, as demonstrated in 350 children receiv-

ing continuous prophylactic treatment with colchicine (1-2 mg/day) for 6-13 years [52]. Furthermore, the prolonged use of colchicine therapy in 45 women with FMF [53] was safe and effective in preventing flares of FMF and amyloidosis with an acceptable adverse effect profile. Colchicine discon-tinuation predisposed patients to acute FMF flares. A large study compared the effect of the drug in 179 pregnancies in a group of women with FMF taking colchicine, 197 pregnan-cies in women with FMF who did not take colchicine during pregnancy, and 312 pregnancies from another cohort of healthy women of similar age and ethnicity [54]. Surpris-ingly, there was no difference in the 3 groups regarding early abortions, late abortions, or congenital malformations. Moreover, a mild trend towards a better outcome for the col-chicine-treated group was observed (albeit without statistical significance). Taken together, these findings support the safety of colchicine, which might benefit women in control-ling FMF without affecting pregnancy outcomes. The drug

6 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2013, Vol. 12, No. 1 Roubille et al.

seems the best option to control this disease (it cuts the re-currences by half in primary or secondary prevention [31]) and to limit fertility issues in patients with FMF [55]. On the other hand, in the general population, the possible effects on pregnancy outcomes are not well studied. Potential terato-genicity cannot be entirely excluded from the animal and currently available clinical data, leading to the recommenda-tion of amniocentesis with karyotyping when colchicine is used for long periods during pregnancy [56]. Colchicine was even shown to heifer oocytes treated with colcemid [57] to enhance nuclear transfer, embryonic development, estab-lishment of pregnancy and development to term.

Specific precautions should be taken for diagnostic and therapeutic approaches when pericarditis occurs during pregnancy (reviewed in [58]). Ideally, pregnancy should be planned in a phase of disease quiescence. However, this is not possible in case of acute pericarditis. Nonselective cy-clooxygenase inhibitors and aspirin can be used safely dur-ing the first and second trimesters of pregnancy, but should be withdrawn later and particularly at gestational week 32, because of the possible effects on ductus arteriosus and renal function. Low to medium doses of prednisone are allowed during pregnancy and breastfeeding. Colchicine is usually contraindicated during pregnancy, except in women with FMF.

Azoospermia is a possible rare adverse event reported in men (<1%), based upon a few case reports [59-61] Although colchicine may arrest mitosis at high concentrations, there were no significant effects on sperm count, plasma testoster-one, luteinizing hormone and follicle-stimulating hormone in healthy volunteers after 3–6 months of therapy [62].

7. POISONING

Life-threatening poisoning, although rare, is a serious concern. Colchicine can indeed be highly harmful at high doses, as demonstrated in animals. A dose of 40 mg can be lethal, and there is no antidote to this spindle poisoning. In

1887, an overdose was described in guinea pigs as follows: “in guinea pigs weighing 300 g, subcutaneous injection of 50 mg induces characteristic effects comprising: agitation, (…) and vomiting. Secondly, the animal becomes sad and pros-trate (…). (The authors described in details digestive, muscu-lar and neurologic disorders). The animal dies in roughly 4 to 6 hours” [63]. One of the first suspected cases of poisoning with colchicine was reported in 1902 [64].

Fatal poisoning in humans, although unusual, has been described (recently reviewed in [65]). The first symptoms include gastrointestinal disorders, not easily distinguishable from the typical side effects of colchicine, with the next step however leading to multi-organ failure [66, 67] between a day and a week. Death could occur between one and two days after massive ingestion, due to collapsus [68, 69] car-diac arrhythmias [70] or extracardiac complications such as massive hemorrhages or infections. Colchicine toxicity can be largely underestimated in vulnerable patients, for example those who are hospitalized, potentially leading to death [71]. This could be explained by comorbidities, such as renal im-pairment. Although relatively uncommon [72], colchicine poisoning may produce life-threatening systemic effects comprising nausea and vomiting, bone-marrow suppression often leading to sepsis, hypocalcemia, adult respiratory dis-tress syndrome, and direct cardiotoxic effects. Treatment requires early recognition and supportive care including fluid and electrolyte replacement and occasionally blood compo-nent replacement therapy. Colchicine-specific antibodies have demonstrated beneficial effects [73] on colchicine in-toxication, but they are not currently commercially available [26, 73, 74].

8. COST CONSIDERATIONS

The recent decision of the FDA to approve a “new” ver-sion of colchicine, Colcrys®, has generated a lot of criticism. As new studies had been requested to test the drug’s safety and efficacy [43], Colcrys® became more expensive, raising controversies [75, 76]. Indeed, Colcrys® costs approximately

Table 2. Clinical features of intoxication with colchicine [26].

Main Pathological Process Main Biological Effect Main Clinical Presentation

Microtubular disruption

Impaired protein assembly in the Golgi apparatus

Inhibition of endocytosis, exocytosis

Altered cell shape

Decreased cellular motility

Inhibition of mitosis

High turnover rate cells

gastro-intestinal

bone marrow

hair follicles

Nausea, diarrhea, vomiting, abdominal pain (up to

10%)

Agranulocytosis, aplastic anemia (less than 1%)

Alopecia (about 1%)

Direct myocardial toxicity

Microtubules in heart – problems of conduction and

contractility

Problems in rate of contraction [89]

Problems in cellular contraction [90]

Problems in cell basic functions [91, 92]

Inhibition of extracellular secretion Multi-organ failure (in case of overdose) Death

Colchicine: An Old Wine in a New Bottle? Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2013, Vol. 12, No. 1 7

$5US per pill – roughly 10 to 50 times higher than tradi-tional formulations of colchicine [76] – and it is specifically designed for long-term treatments, resulting in a heavy global cost. Nevertheless, in the case of gout, comparison of different treatment options including colchicine, non-steroidal anti-inflammatory drugs (NSAIDs) and corticoster-oids underlined that colchicine was associated with a very low risk of adverse events, even in patients with gastrointes-tinal disorders [77]. On the contrary, NSAIDS were contra-indicated in patients with gastrointestinal disorders, renal insufficiency, and heart failure. The monthly cost of treating 100 patients with Colcrys® was estimated to $33,100, com-pared with $3,000 for NSAIDs. Taking into account the fact that hospitalizations for gastrointestinal complications (1.8%) and heart failure (1.9%) are common with NSAIDs, the monthly cost of treating 100 patients with NSAIDs could increase to $161,000. These pharmacoeconomic considera-tions were in favor of Colcrys® when chronic therapy was considered (e.g. for treatment of FMF). Importantly, despite higher cost per dose, Colcrys® might be more cost effective for management of gout flare-ups than NSAIDs. Duration of treatment is also relatively short for acute pericarditis and it represents a situation similar to that of gout flare-ups.

Other formulations of colchicine are available, especially generic ones. First, in Europe many are prescribed, 1 mg daily cost is roughly 0.15 euros (0.20 US dollars), so that pharmacoeconomic considerations are not really important

there. By analogy, in most of the countries, traditional for-mulations are available at low cost, providing to the physi-cians a powerful drug in various clinical situations (see Ta-bles 1, 3, 4). Future work could aim at improving colchi-cine’s bioavailability [78], minimizing its side effects as well as investigating other classes of potent antimitotic agents acting through the colchicine binding site of tubulin [79].

9. CONCLUSION

In this review, we aimed at summarizing large amounts of data on colchicine. Several aspects have not been specifi-cally described, such as resistance or non-responsiveness to colchicine, how to stop the treatment… as little is clearly established on these points. Although colchicine is an old drug, its therapeutic window is narrow, an issue which is often ignored. The mechanism of action of this powerful and somewhat promising drug deserves to be better understood, as colchicine has recently gained interest of the medical community for the treatment of various diseases.

Colchicine could be of interest in new fields of cardio-vascular diseases, as inflammation increasingly appears as an important factor in their pathophysiology. The value of col-chicine in the management of patients with acute coronary syndromes (ACS) should probably be assessed. Indeed, only one clinical trial testing colchicine and targeting ACS [80] in 80 heterogeneous patients showed a moderate inflammatory

Table 3. Currently registered studies with colchicine*.

Countries Disease of Interest Treatment Reference

Pericardial disease

France

200 patients at high risk of tamponade because

of moderate to large persistent pericardial

effusion more than 7 days after cardiac surgery.

Colchicine oral form, 1 mg, once a day during 14 days versus

placebo.NCT 01266694

Italy 360 patients with surgical pericardiotomyColchicine 0.5 mg BID or colchicine 0.5mg (<70kg) every 48 to

72 hours before surgery for 1 month after surgery versus placeboNCT01552187

Cancer

USA40 men with castrate-resistant prostate cancer

with failed taxotere-based chemotherapy

Continuous low dose oral colchicine 0.6 mg bid to a maximum of

1.2 mg bidNCT01481233

Rheumatology

Israel80 patients with chronic shoulder pain related

to calcific tendonitisColchicine (0.5 mg twice daily for 4 months) versus placebo NCT00983177

USA 80 patients on allopurinol therapy with gout Once-daily treatment with colchicine versus placebo NCT01451645

USA76 patients with gout (magnetic resonance

imaging study)Substudy comparing colchicine and febuxostat NCT01112982

Others

Israel12 patients with diabetic nephropathy and

proteinuria2 mg once daily for 6 months NCT01005121

IranPatients with established proliferative

vitreoretinopathy

Colchicine combined with intraoperative infusion of dexamethasone,

low molecular weight heparin and 5-FU during vitrectomyNCT00370760

*Although there are currently 20 ongoing studies with colchicine, only interventional clinical trials (7 in total) are listed. Drug interaction studies and pharmacodynamic studies are

not included.

8 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2013, Vol. 12, No. 1 Roubille et al.

syndrome and a biological delayed primary endpoint. Fi-nally, chemical improvements could lead to a less toxic but more efficient compound, offering new perspectives for that venerable drug.

CONFLICT OF INTEREST

The authors confirm that this article content has no con-flicts of interest.

ACKNOWLEDGEMENTS

Dr Roubille received research grants from the Fédération Française de Cardiologie.

APPENDIX

Methodology Applied to Write this Review

The words “colchicine” and “heart” have been used to perform search in pubmed. Only English texts have been studied with special focus on each chapter of this paper, leading to 351 papers. 112 have been discarded as consid-ered out of the topic. “Toxicity, poisoning, pharmacological features, pregnancy, pericarditis, myocarditis, acute coronary syndrome” have been also search in association with colchi-cine. About 50 other manuscripts have then been rad as ref-erenced in the previous papers. No date limitations have been applied. Basic or clinical articles have been taken into account.

ABBREVIATIONS

ABCB1 = ATP-binding cassette sub-family B member 1

ACS = Acute coronary syndromes

CI = Confidence intervalle

IL = Interleukin

FDA = Food and drug administration

FMF = Familial Mediterranean fever

NALP3 = NAcht Leucine-rich repeat Protein 3

NSAID = Non-steroidal anti-inflammatory drugs

OR = Odds Ratio

RR = Relative Risk

REFERENCES

[1] Rodnan, G. P.; Benedek, T. G. The early history of antirheumatic drugs. Arthritis Rheum, 1970, 13 (2), 145-65.

[2] Roberts, W. N.; Liang, M. H.; Stern, S. H. Colchicine in acute gout. Reassessment of risks and benefits. JAMA, 1987, 257 (14), 1920-1922.

[3] Wallace, S. L., Colchicum: the panacea. Bull. N Y Acad. Med.,

1973, 49 (2), 130-135. [4] Pelletier, P.S, C. J. Ann. Chim. Phys. 1820. [5] Wallace, S. Benjamin Franklin and the introduction of colchicum

into the United States. Bull. Hist. Med., 1968, 42 (4), 312-320. [6] Dustin, P. The centennial of the discovery of the antimitotic

properties of colchicine. Rev. Med. Brux., 1989, 10 (9), 385-390. [7] Bhat, A.; Naguwa, S. M.; Cheema, G. S.; Gershwin, M. E.

Colchicine revisited. Anns. N. Y. Acad. Sci., 2009, 1173, 766-773. [8] Weisenberg, R. C.; Borisy, G. G.; Taylor, E. W. The colchicine-

binding protein of mammalian brain and its relation to microtubules. Biochemistry, 1968, 7 (12), 4466-4479.

[9] Adelman, M. R.; Borisy, G. G.; Shelanski, M. L.; Weisenberg, R. C.; Taylor, E. W. Cytoplasmic filaments and tubules. Fed. Proc., 1968, 27 (5), 1186-1193.

[10] Shelanski, M. L.; Taylor, E. W. Properties of the protein subunit of central-pair and outer-doublet microtubules of sea urchin flagella. J. Cell Bbiol., 1968, 38 (2), 304-315.

[11] Mohri, H. Amino-acid composition of "Tubulin" constituting microtubules of sperm flagella. Nature, 1968, 217 (5133), 1053-1054.

[12] Ravelli, R. B.; Gigant, B.; Curmi, P. A.; Jourdain, I.; Lachkar, S.; Sobel, A.; Knossow, M. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature, 2004, 428 (6979), 198-202.

[13] Matsukawa, A.; Yoshimura, T.; Maeda, T.; Takahashi, T.; Ohkawara, S.; Yoshinaga, M. Analysis of the cytokine network among tumor necrosis factor alpha, interleukin-1beta, interleukin-8, and interleukin-1 receptor antagonist in monosodium urate crystal-induced rabbit arthritis. Lab. Investig. J. Tech.Methods Pathol., 1998, 78 (5), 559-569.

[14] Pope, R. M.; Tschopp, J. The role of interleukin-1 and the inflammasome in gout: implications for therapy. Arthritis

Rheumat., 2007, 56(10), 3183-3188. [15] Martinon, F.; Petrilli, V.; Mayor, A.; Tardivel, A.; Tschopp, J.

Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature, 2006, 440 (7081), 237-241.

[16] Cronstein, B. N.; Molad, Y.; Reibman, J.; Balakhane, E.; Levin, R. I.; Weissmann, G. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J. Clin. Investig., 1995, 96 (2), 994-1002.

[17] Marques-da-Silva, C.; Chaves, M. M.; Castro, N. G.; Coutinho-Silva, R.; Guimaraes, M. Z. Colchicine inhibits cationic dye uptake induced by ATP in P2X2 and P2X7 receptor-expressing cells: implications for its therapeutic action. Brit. J. Pharmacol., 2011, 163 (5), 912-926.

[18] Ferrua, B.; Manie, S.; Doglio, A.; Shaw, A.; Sonthonnax, S.; Limouse, M.; Schaffar, L. Stimulation of human interleukin 1 production and specific mRNA expression by microtubule-disrupting drugs. Cellular Immunol., 1990, 131 (2), 391-397.

[19] Cerquaglia, C.; Diaco, M.; Nucera, G.; La Regina, M.; Montalto, M.; Manna, R. Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update. Curr. Drug Targets. Inflamm. Allergy 2005, 4 (1), 117-124.

[20] Sabouraud, A.; Rochdi, M.; Urtizberea, M.; Christen, M. O.; Achtert, G.; Scherrmann, J. M. Pharmacokinetics of colchicine: a

Table 4. Recent directions for research

• Acute coronary syndrome or stroke

• Hidrosadenitis suppurativa

• Recurrent aphthous stomatitis

• Mixed cryoglobulinemia syndrome in hepatitis C virus-infection

• “Chronic liver disease”

• [80] (negative study)

• [93] (negative study)

• [94]

• [95] (low level of proof)

• [96]

Colchicine: An Old Wine in a New Bottle? Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2013, Vol. 12, No. 1 9

review of experimental and clinical data. Zeitschrift fur

Gastroenterologie, 1992, 30 (Suppl 1), 35-39. [21] Cocco, G.; Chu, D. C.; Pandolfi, S. Colchicine in clinical medicine.

A guide for internists. Eur. J. Intern. Med., 2010, 21 (6), 503-508. [22] Wallace, S. L.; Ertel, N. H. Plasma levels of colchicine after oral

administration of a single dose. Metabolism: Clin. Exp., 1973, 22 (5), 749-753.

[23] Achtert, G.; Scherrmann, J. M.; Christen, M. O. Pharmacokinetics/bioavailability of colchicine in healthy male volunteers. Euro. j. Drug Metab. Ph., 1989, 14 (4), 317-322.

[24] Ferron, G. M.; Rochdi, M.; Jusko, W. J.; Scherrmann, J. M. Oral absorption characteristics and pharmacokinetics of colchicine in healthy volunteers after single and multiple doses. J. Clin.

Pharmacol., 1996, 36 (10), 874-883. [25] Tateishi, T.; Soucek, P.; Caraco, Y.; Guengerich, F. P.; Wood, A. J.

Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation. Biochem. Pharmacol., 1997, 53 (1), 111-116.

[26] Finkelstein, Y.; Aks, S. E.; Hutson, J. R.; Juurlink, D. N.; Nguyen, P.; Dubnov-Raz, G.; Pollak, U.; Koren, G.; Bentur, Y. Colchicine poisoning: the dark side of an ancient drug. Clin. Toxicol., 2010, 48 (5), 407-414.

[27] Ben-Chetrit, E.; Scherrmann, J. M.; Levy, M. Colchicine in breast milk of patients with familial Mediterranean fever. Arthritis

Rheum., 1996, 39 (7), 1213-7. [28] Wallace, S. L.; Omokoku, B.; Ertel, N. H. Colchicine plasma

levels. Implications as to pharmacology and mechanism of action. Am. J. Med., 1970, 48 (4), 443-448.

[29] Fordham, J. N.; Kirwan, J.; Cason, J.; Currey, H. L. Prolonged reduction in polymorphonuclear adhesion following oral colchicine. Ann. Rheum. Dis., 1981, 40 (6), 605-608.

[30] Maisch, B.; Seferovic, P. M.; Ristic, A. D.; Erbel, R.; Rienmuller, R.; Adler, Y.; Tomkowski, W. Z.; Thiene, G.; Yacoub, M. H.; Task Force on the, D. Management of Pricardial Diseases of the European Society of, C., Guidelines on the diagnosis and management of pericardial diseases executive summary; The Task force on the diagnosis and management of pericardial diseases of the European society of cardiology. Euro. Heart J., 2004, 25 (7), 587-610.

[31] Imazio, M.; Bobbio, M.; Cecchi, E.; Demarie, D.; Demichelis, B.; Pomari, F.; Moratti, M.; Gaschino, G.; Giammaria, M.; Ghisio, A.; Belli, R.; Trinchero, R. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation, 2005, 112 (13), 2012-2016.

[32] Imazio, M.; Bobbio, M.; Cecchi, E.; Demarie, D.; Pomari, F.; Moratti, M.; Ghisio, A.; Belli, R.; Trinchero, R. Colchicine as first-choice therapy for recurrent pericarditis: results of the CORE (COlchicine for REcurrent pericarditis) trial. Arch, InternMed,

2005, 165 (17), 1987-91. [33] Imazio, M.; Brucato, A.; Cemin, R.; Ferrua, S.; Belli, R.;

Maestroni, S.; Trinchero, R.; Spodick, D. H.; Adler, Y.; Investigators, C. Colchicine for recurrent pericarditis (CORP): a randomized trial. Ann. Intern. Med., 2011, 155 (7), 409-14.

[34] Imazio, M.; Brucato, A.; Rovere, M. E.; Gandino, A.; Cemin, R.; Ferrua, S.; Maestroni, S.; Zingarelli, E.; Barosi, A.; Simon, C.; Sansone, F.; Patrini, D.; Vitali, E.; Belli, R.; Ferrazzi, P.; Trinchero, R.; Spodick, D. H.; Adler, Y. Colchicine prevents early postoperative pericardial and pleural effusions. Am. Heart J. 2011, 162 (3), 527-532 e1.

[35] Meurin, P.; Tabet, J. Y. Colchicine in acute pericarditis: a new standard? Arch. Cardiovasc. Dis., 2011, 104 (8-9), 425-427.

[36] Imazio, M.; Brucato, A.; Ferrazzi, P.; Rovere, M. E.; Gandino, A.; Cemin, R.; Ferrua, S.; Belli, R.; Maestroni, S.; Simon, C.; Zingarelli, E.; Barosi, A.; Sansone, F.; Patrini, D.; Vitali, E.; Trinchero, R.; Spodick, D. H.; Adler, Y.; Investigators, C. Colchicine reduces postoperative atrial fibrillation: results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) atrial fibrillation substudy. Circulation, 2011, 124 (21), 2290-2295.

[37] Adler, Y.; Finkelstein, Y.; Guindo, J.; Rodriguez de la Serna, A.; Shoenfeld, Y.; Bayes-Genis, A.; Sagie, A.; Bayes de Luna, A.; Spodick, D. H. Colchicine treatment for recurrent pericarditis. A decade of experience. Circulation, 1998, 97 (21), 2183-2185.

[38] Adler, Y.; Spodick, D. H.; Shabetai, R.; Brucato, A. Can colchicine prevent recurrence of new-onset acute pericarditis? Nat. Clin. Pract. Cardiovasc. Med., 2006, 3 (2), 78-79.

[39] Flather, M.; Collinson, J. First line treatment with colchicine reduced recurrent pericarditis. Evidence-Based Med., 2006, 11 (2), 44.

[40] Imazio, M.; Brucato, A.; Trinchero, R.; Spodick, D.; Adler, Y. Colchicine for pericarditis: hype or hope? Euro. Heart J., 2009, 30 (5), 532-539.

[41] Wojcicki, J.; Hinek, A.; Jaworska, M.; Samochowiec, L. The effect of colchicine on the development of experimental atherosclerosis in rabbits. Polish J. Pharmacol. Pharm., 1986, 38 (4), 343-348.

[42] Nidorf, M.; Thompson, P. L. Effect of colchicine (0.5 mg twice daily) on high-sensitivity C-reactive protein independent of aspirin and atorvastatin in patients with stable coronary artery disease. Am.

J. Cardiol., 2007, 99 (6), 805-7. [43] Terkeltaub, R. A.; Furst, D. E.; Bennett, K.; Kook, K. A.; Crockett,

R. S.; Davis, M. W. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis

Rheum.,2010, 62 (4), 1060-8. [44] Terkeltaub, R. A.; Furst, D. E.; Digiacinto, J. L.; Kook, K. A.;

Davis, M. W. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis Rheum., 2011, 63 (8), 2226-2237.

[45] Curiel, R. V.; Guzman, N. J. Challenges Associated with the Management of Gouty Arthritis in Patients with Chronic Kidney Disease: A Systematic Review. Semin. Arthritis Rheum., 2012.

[46] Marwah, R. K. Comorbidities in gouty arthritis. J. investig. med.

2011, 59 (8), 1211-1220. [47] Fravel, M. A.; Ernst, M. E. Management of gout in the older adult.

Am. J. Geriatric Pharmacother., 2011, 9 (5), 271-285. [48] Stamp, L. K.; Jordan, S. The challenges of gout management in the

elderly. Drugs Aging, 2011, 28 (8), 591-603. [49] Mailhes, J. B.; Yuan, Z. P. Differential sensitivity of mouse oocytes

to colchicine-induced aneuploidy. Environ. Mol. Mutagen., 1987, 10 (2), 183-188.

[50] Mijatovic, V.; Hompes, P. G.; Wouters, M. G. Familial Mediterranean fever and its implications for fertility and pregnancy. Eur. J. Obstetrics, Gynecol. Reproduc. Biol., 2003, 108 (2), 171-176.

[51] Ben-Chetrit, E.; Levy, M. Reproductive system in familial Mediterranean fever: an overview. Ann. Rheum. Dis., 2003, 62 (10), 916-919.

[52] Zemer, D.; Livneh, A.; Danon, Y. L.; Pras, M.; Sohar, E. Long-term colchicine treatment in children with familial Mediterranean fever. Arthritis Rheum., 1991, 34 (8), 973-977.

[53] Ben-Chetrit, E.; Levy, M. Colchicine prophylaxis in familial Mediterranean fever: reappraisal after 15 years. Semin. Arthritis

Rheum., 1991, 20 (4), 241-246. [54] Ben-Chetrit, E.; Ben-Chetrit, A.; Berkun, Y.; Ben-Chetrit, E.

Pregnancy outcomes in women with familial Mediterranean fever receiving colchicine: is amniocentesis justified? Arthritis Care

Res., 2010, 62 (2), 143-148. [55] Zayed, A.; Nabil, H.; State, O.; Badawy, A. Subfertility in women

with familial Mediterranean fever. J. Obst. Gynaecol. Res., 2012. 38(10), 1240-1244.

[56] Ehrenfeld, M.; Brzezinski, A.; Levy, M.; Eliakim, M. Fertility and obstetric history in patients with familial Mediterranean fever on long-term colchicine therapy. Brit. J. Obst. Gynaecol., 1987, 94 (12), 1186-1191.

[57] Li, G. P.; White, K. L.; Aston, K. I.; Bunch, T. D.; Hicks, B.; Liu, Y.; Sessions, B. R. Colcemid-treatment of heifer oocytes enhances nuclear transfer embryonic development, establishment of pregnancy and development to term. Mol. Reproduc. Dev., 2009, 76 (7), 620-628.

[58] Imazio, M.; Brucato, A.; Rampello, S.; Armellino, F.; Trinchero, R.; Spodick, D. H.; Adler, Y. Management of pericardial diseases during pregnancy. J. Cardiovasc. Med., 2010, 11 (8), 557-562.

[59] Merlin, H. E. Azoospermia caused by colchicine--a case report. Fertil. Steril., 1972, 23 (3), 180-181.

[60] Kirchin, V. S.; Southgate, H. J.; Beard, R. C. Colchicine: an unusual cause of reversible azoospermia. BJU int., 1999, 83 (1), 156.

10 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2013, Vol. 12, No. 1 Roubille et al.

[61] Ben-Chetrit, E.; Backenroth, R.; Haimov-Kochman, R.; Pizov, G. Azoospermia in familial Mediterranean fever patients: the role of colchicine and amyloidosis. Ann. Rheum. Dis., 1998, 57 (4), 259-260.

[62] Bremner, W.J.; Paulsen, C. A., Colchicine and testicular function in man. N. Engl. J. Med., 1976, 294 (25), 1384-5.

[63] Laborde, J. V. H., A. Le colchique et la colchicine. Paris. G. Steinheil, 1887.

[64] Brouardel, P. Les empoisonnements criminels et accidentels. Ed Baillières, Paris. 1902.

[65] Finkelstein, Y.; Aks, S. E.; Hutson, J. R.; Juurlink, D. N.; Nguyen, P.; Dubnov-Raz, G.; Pollak, U.; Koren, G.; Bentur, Y. Colchicine poisoning: the dark side of an ancient drug. Clin. Toxicol., 48 (5), 407-414.

[66] Ozdemir, R.; Bayrakci, B.; Teksam, O. Fatal poisoning in children: acute colchicine intoxication and new treatment approaches. Clin.

Toxicol., 2011, 49 (8), 739-743. [67] Nagesh, K. R.; Menezes, R. G.; Rastogi, P.; Naik, N. R.;

Rasquinha, J. M.; Senthilkumaran, S.; Fazil, A. Suicidal plant poisoning with Colchicum autumnale. J. Forensic Legal Med.,

2011, 18 (6), 285-7. [68] van Heyningen, C.; Watson, I. D. Troponin for prediction of

cardiovascular collapse in acute colchicine overdose. EMJ, 2005, 22 (8), 599-600.

[69] Mullins, M. E.; Carrico, E. A.; Horowitz, B. Z. Fatal cardiovascular collapse following acute colchicine ingestion. Journal of

toxicology. Clin. Toxicol., 2000, 38 (1), 51-54. [70] Milne, S. T.; Meek, P. D. Fatal colchicine overdose: report of a

case and review of the literature. Am. J. Emer. Med., 1998, 16 (6), 603-608.

[71] Mullins, M.; Cannarozzi, A. A.; Bailey, T. C.; Ranganathan, P. Unrecognized fatalities related to colchicine in hospitalized patients. Clin. Toxicol., 49 (7), 648-652.

[72] Hood, R. L. Colchicine poisoning. J. Emerg. Med., 1994, 12 (2), 171-177.

[73] Baud, F. J.; Sabouraud, A.; Vicaut, E.; Taboulet, P.; Lang, J.; Bismuth, C.; Rouzioux, J. M.; Scherrmann, J. M. Brief report: treatment of severe colchicine overdose with colchicine-specific Fab fragments. N. Eng. J. Med., 1995, 332(10), 642-645.

[74] Flanagan, R. J.; Jones, A. L. Fab antibody fragments: some applications in clinical toxicology. Drug safety : Intern. J. Med. Toxicol. Drug Exp., 2004, 27 (14), 1115-1133.

[75] Grody, W. W.; Getzug, T., Colchicine's other indication--effect of FDA action. N. Eng. J. Med., 2010, 363 (23), 2267-2268.

[76] Kesselheim, A. S.; Solomon, D. H. Incentives for drug development--the curious case of colchicine. N. Eng. J. Med., 2010, 362 (22), 2045-2047.

[77] Wertheimer, A. I.; Davis, M. W.; Lauterio, T. J. A new perspective on the pharmacoeconomics of colchicine. Curr. Med. Res. Opin. 2011, 27 (5), 931-937.

[78] Shen, Q.; Wang, Y.; Zhang, Y. Improvement of colchicine oral bioavailability by incorporating eugenol in the nanoemulsion as an oil excipient and enhancer. Intern. J. Nanomed., 2011, 6, 1237-1243.

[79] Lai, M. J.; Kuo, C. C.; Yeh, T. K.; Hsieh, H. P.; Chen, L. T.; Pan, W. Y.; Hsu, K. Y.; Chang, J. Y.; Liou, J. P. Synthesis and structure-activity relationships of 1-benzyl-4,5,6-trimethoxyindoles as a novel class of potent antimitotic agents. ChemMedChem 2009, 4 (4), 588-593.

[80] Raju, N. C.; Yi, Q.; Nidorf, M.; Fagel, N. D.; Hiralal, R.; Eikelboom, J. W. Effect of colchicine compared with placebo on high sensitivity C-reactive protein in patients with acute coronary

syndrome or acute stroke: a pilot randomized controlled trial. J.

Thromb. Thrombolysis., 2012, 33 (1), 88-94. [81] Wright, D. G.; Wolff, S. M.; Fauci, A. S.; Alling, D. W. Efficacy of

intermittent colchicine therapy in familial Mediterranean fever. Ann. Intern. Med., 1977, 86 (2), 162-165.

[82] Masuda, K.; Nakajima, A.; Urayama, A.; Nakae, K.; Kogure, M.; Inaba, G. Double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behcet's disease. Lancet, 1989, 1 (8647), 1093-1096.

[83] Nuki, G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr. Rheumatol. Reports., 2008, 10 (3), 218-227.

[84] Kaplan, M. M.; Alling, D. W.; Zimmerman, H. J.; Wolfe, H. J.; Sepersky, R. A.; Hirsch, G. S.; Elta, G. H.; Glick, K. A.; Eagen, K. A. A prospective trial of colchicine for primary biliary cirrhosis. N.

Eng. J. Med., 1986, 315 (23), 1448-1454. [85] Gong, Y.; Gluud, C. Colchicine for primary biliary cirrhosis: a

Cochrane Hepato-Biliary Group systematic review of randomized clinical trials. Am. J. Gastroenterol., 2005, 100 (8), 1876-1885.

[86] McKendry, R. J.; Kraag, G.; Seigel, S.; al-Awadhi, A. Therapeutic value of colchicine in the treatment of patients with psoriatic arthritis. Ann. Rheum. Dis., 1993, 52 (11), 826-828.

[87] Kyle, R. A.; Gertz, M. A.; Greipp, P. R.; Witzig, T. E.; Lust, J. A.; Lacy, M. Q.; Therneau, T. M. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N. Eng. J. Med., 1997, 336 (17), 1202-1207.

[88] Arik, N.; Yuksel, H.; Adam, B.; Akpolat, T.; Ozdemir, O. May colchicine therapy be of value in the prevention of dialysis amyloidosis? Nephron, 1996, 73 (2), 365-366.

[89] Klein, I. Colchicine stimulates the rate of contraction of heart cells in culture. Cardiovasc. Res. 1983, 17 (8), 459-465.

[90] Nath, K.; Shay, J. W.; Bollon, A. P. Relationship between dibutyryl cyclic AMP and microtubule organization in contracting heart muscle cells. Proc. Natl. Acad. Sci. USA, 1978, 75 (1), 319-323.

[91] Crie, J. S.; Ord, J. M.; Wakeland, J. R.; Wildenthal, K. Inhibition of cardiac proteolysis by colchicine. Selective effects on degradation of protein subclasses. Biochem. J., 1983, 210 (1), 63-71.

[92] Limas, C. J. Myocardial colchicine-binding proteins: possible relation to DNA synthesis initiation. J. Mol. Cellular Cardiol., 1979, 11 (11), 1137-1150.

[93] van der Zee, H. H.; Prens, E. P. The anti-inflammatory drug colchicine lacks efficacy in hidradenitis suppurativa. Dermatology,

2011, 223 (2), 169-173. [94] Altenburg, A.; Abdel-Naser, M. B.; Seeber, H.; Abdallah, M.;

Zouboulis, C. C. Practical aspects of management of recurrent aphthous stomatitis. J. Euro. Acad. Dermatol. Venereol., 2007, 21 (8), 1019-1026.

[95] Pietrogrande, M.; De Vita, S.; Zignego, A. L.; Pioltelli, P.; Sansonno, D.; Sollima, S.; Atzeni, F.; Saccardo, F.; Quartuccio, L.; Bruno, S.; Bruno, R.; Campanini, M.; Candela, M.; Castelnovo, L.; Gabrielli, A.; Gaeta, G. B.; Marson, P.; Mascia, M. T.; Mazzaro, C.; Mazzotta, F.; Meroni, P.; Montecucco, C.; Ossi, E.; Piccinino, F.; Prati, D.; Puoti, M.; Riboldi, P.; Riva, A.; Roccatello, D.; Sagnelli, E.; Scaini, P.; Scarpato, S.; Sinico, R.; Taliani, G.; Tavoni, A.; Bonacci, E.; Renoldi, P.; Filippini, D.; Sarzi-Puttini, P.; Ferri, C.; Monti, G.; Galli, M. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. Autoimmunity Rev., 2011, 10 (8), 444-454.

[96] Muntoni, S.; Rojkind, M.; Muntoni, S. Colchicine reduces procollagen III and increases pseudocholinesterase in chronic liver disease. World J. Gastroenterol., 2010, 16 (23), 2889-2894.

Received: June 21, 2012 Revised: September 07, 2012 Accepted: December 07, 2012


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