Clofazimine: A Review of its Use in Leprosy and <i>Mycobacterium Avium</i> Complex Infection

Garrelts, James C.

doi:10.1177/106002809102500513

Cited by 53 publications

(34 citation statements)

References 23 publications

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“…This discoloration is evident within weeks of beginning treatment, fades months to years after the cessation of treatment, and occurs in a significant percentage of patients (16,33,42). CFM-induced skin discoloration has also been observed during treatment of M. avium complex and MDR TB infections, as well as during clinical trials to investigate the usefulness of CFM in inflammatory diseases, suggesting that this phenomenon is not leprosy specific (9,16,24,43). The reports available suggest that the intensity, duration, and prevalence of skin discoloration are dependent on the dose and duration of treatment.…”

Section: Discussionmentioning

confidence: 99%

“…However, the very physicochemical properties selected by its inventors to allow for accumulation in macrophages lead to suboptimal pharmacokinetic properties and consequent side effects that may limit its use. An excessively long half-life (Ͼ70 days in humans) and the propensity for accumulation and crystallization within fatty tissues and the tissues of the MPS cause gastrointestinal and ocular harm; moreover, these pharmacokinetic properties of the drug, together with its dye properties, lead to unwelcome skin discoloration (13,14,16,21,25,26,41).…”

mentioning

confidence: 99%

“…One such compound is clofazimine (CFM), a riminophenazine and marketed antimycobacterial drug used since 1962 in the treatment of leprosy (16,17) and, more recently, in the treatment of Mycobacterium avium complex infection (16) and MDR-TB (43). CFM, a redox active compound, with dye properties, was specifically designed as an antitubercular to accumulate within cells of the mononuclear phagocyte system (MPS) and kill intracellular bacteria (6)(7)(8).…”

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confidence: 99%

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Clofazimine Analogs with Efficacy against Experimental Tuberculosis and Reduced Potential for Accumulation

Zheng

Wang

et al. 2011

Antimicrob Agents Chemother

158

149

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The global tuberculosis crisis urgently demands new, efficacious, orally available drugs with the potential to shorten and simplify the long and complex treatments for drug-sensitive and drug-resistant disease. Clofazimine, a riminophenazine used for many years to treat leprosy, demonstrates efficacy in animal models of tuberculosis via a novel mode of action. However, clofazimine's physicochemical and pharmacokinetic properties contribute to side effects that limit its use; in particular, an extremely long half-life and propensity for tissue accumulation together with clofazimine's dye properties leads to unwelcome skin discoloration. We recently conducted a systematic structure-activity study of more than 500 riminophenazine analogs for antiMycobacterium tuberculosis activity. We describe here the characteristics of 12 prioritized compounds in more detail. The new riminophenazine analogs demonstrated enhanced in vitro activity compared to clofazimine against replicating M. tuberculosis H37Rv, as well as panels of drug-sensitive and drug-resistant clinical isolates. The new compounds demonstrate at least equivalent activity compared to clofazimine against intracellular M. tuberculosis and, in addition, most of them were active against nonreplicating M. tuberculosis. Eleven of these more water-soluble riminophenazine analogs possess shorter half-lives than clofazimine when dosed orally to mice, suggesting that they may accumulate less. Most importantly, the nine compounds that progressed to efficacy testing demonstrated inhibition of bacterial growth in the lungs that is superior to the activity of an equivalent dose of clofazimine when administered orally for 20 days in a murine model of acute tuberculosis. The efficacy of these compounds, along with their decreased potential for accumulation and therefore perhaps also for tissue discoloration, warrants further study. Despite global efforts, tuberculosis (TB) remains responsible for the second greatest number of deaths due to an infectious disease with 1.7 million deaths reported due to TB in 2009 (45). Of particular concern, the increasing prevalence of TB caused by multidrug-resistant (MDR) and extensively drugresistant (XDR) strains of Mycobacterium tuberculosis puts at risk hard-won gains to public health. MDR-TB treatment regimens, where available, comprise multiple expensive drugs with limited efficacy and significant toxicity that must be administered by both oral and parenteral routes for up to 24 months (30). Treatment of drug-sensitive TB is also long and complex, requiring at least 6 months of a four-drug regimen to achieve a stable cure. The first-line TB drugs are poorly tolerated, reducing compliance and increasing the risk of resistance development. New TB drugs that are safe, orally available, have novel modes of action and efficacy sufficient to simplify and shorten the regimen required to cure TB would impact both patients and TB control by providing improved treatment for drug-resistant TB and by providing a faster, more tolerable cure for dr...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Clofazimine Analogs with Efficacy against Experimental Tuberculosis and Reduced Potential for Accumulation

Zheng

Wang

et al. 2011

Antimicrob Agents Chemother

158

149

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“…After administration for more than 10 to 22 weeks, however, drug resistance and rebound bacteremia were seen in some patients. Clarithro (167,239,416). While clofazimine crystals are found in the tears of 32% of leprosy patients receiving long-term therapy (273), ocular effects, such as cornealconjunctival pigmentation and a "bull's-eye" retinopathy, are unusual (112,273,429).…”

Section: Therapeutic Agents and Treatmentmentioning

confidence: 99%

The Mycobacterium avium complex

1993

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Mycobacterium avium complex (MAC) disease emerged early in the epidemic of AIDS as one of the common opportunistic infections afflicting human immunodeficiency virus-infected patients. However, only over the past few years has a consensus developed about its significance to the morbidity and mortality of AIDS. M. avium was well known to mycobacteriologists decades before AIDS, and the MAC was known to cause disease, albeit uncommon, in humans and animals. The early interest in the MAC provided a basis for an explosion of studies over the past 10 years largely in response to the role of the MAC in AIDS opportunistic infection. Molecular techniques have been applied to the epidemiology of MAC disease as well as to a better understanding of the genetics of antimicrobial resistance. The interaction of the MAC with the immune system is complex, and putative MAC virulence factors appear to have a direct effect on the components of cellular immunity, including the regulation of cytokine expression and function. There now is compelling evidence that disseminated MAC disease in humans contributes to both a decrease in the quality of life and survival. Disseminated disease most commonly develops late in the course of AIDS as the CD4 cells are depleted below a critical threshold, but new therapies for prophylaxis and treatment offer considerable promise. These new therapeutic modalities are likely to be useful in the treatment of other forms of MAC disease in patients without AIDS. The laboratory diagnosis of MAC disease has focused on the detection of mycobacteria in the blood and tissues, and although the existing methods are largely adequate, there is need for improvement. Indeed, the successful treatment of MAC disease clearly will require an early and rapid detection of the MAC in clinical specimens long before the establishment of the characteristic overwhelming infection of bone marrow, liver, spleen, and other tissue. Also, a standard method of susceptibility testing is of increasing interest and importance as new effective antimicrobial agents are identified and evaluated. Antimicrobial resistance has already emerged as an important problem, and methods for circumventing resistance that use combination therapies are now being studied.

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“…several inflammatory disorders including psoriasis and autoimmune disease [1,4,6,8,14]. Its use is, however, limited by its toxicity [15].…”

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confidence: 99%

Clofazimine Induced Suicidal Death of Human Erythrocytes

Officioso

Alzoubi

Manna

et al. 2015

Cell Physiol Biochem

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Background/Aims: The antimycobacterial riminophenazine clofazimine has previously been shown to up-regulate cellular phospholipase A₂ and to induce apoptosis. In erythrocytes phospholipase A₂ stimulates eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Phospholipase A₂ is in part effective by fostering formation of prostaglandin E₂, which triggers Ca²⁺ entry. Stimulators of Ca²⁺ entry and eryptosis further include oxidative stress and energy depletion. The present study tested, whether and how clofazimine induces eryptosis. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, hemolysis from hemoglobin release, cytosolic Ca²⁺ activity ([Ca²⁺]_i) from Fluo3-fluorescence, reactive oxygen species (ROS) from 2′, 7′-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, and cytosolic ATP level utilizing a luciferin-luciferase assay kit. Results: A 24-48 hours exposure of human erythrocytes to clofazimine (≥1.5 µg/ml) significantly increased the percentage of annexin-V-binding cells without appreciably modifying forward scatter. Clofazimine significantly increased [Ca²⁺]_i, significantly decreased cytosolic ATP, but did not significantly modify ROS. The effect of clofazimine on annexin-V-binding was significantly blunted, but not fully abolished by removal of extracellular Ca²⁺, and by phospholipase A₂ inhibitor quinacrine (25 µM). Clofazimine further augmented the effect of Ca²⁺ ionophore ionomycin (0.1 µM) on eryptosis. The clofazimine induced annexin-V-binding was, however, completely abrogated by combined Ca²⁺ removal and addition of quinacrine. Conclusion: Clofazimine stimulates phospholipid scrambling of the erythrocyte cell membrane, an effect in part dependent on entry of extracellular Ca²⁺, paralleled by cellular energy depletion and sensitive to phospholipase A₂ inhibitor quinacrine.

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Clofazimine: A Review of its Use in Leprosy and Mycobacterium Avium Complex Infection

Cited by 53 publications

References 23 publications

Clofazimine Analogs with Efficacy against Experimental Tuberculosis and Reduced Potential for Accumulation

Clofazimine Analogs with Efficacy against Experimental Tuberculosis and Reduced Potential for Accumulation

The Mycobacterium avium complex

Clofazimine Induced Suicidal Death of Human Erythrocytes

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