The Physicochemical Basis of Clofazimine-Induced Skin Pigmentation

Murashov, Mikhail D.; LaLone, Vernon; Rzeczycki, Phillip; Keswani, Rahul K.; Yoon, Gi Sang; Sud, Sudha; Rajeswaran, W. G.; Larsen, Scott D.; Stringer, Kathleen A.; Rosania, Gus R.

doi:10.1016/j.jid.2017.09.031

Cited by 42 publications

(53 citation statements)

References 30 publications

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“…Prolonged use often leads to orange/yellow skin discoloration that develops during treatment through deposition in subcutaneous fat. 101 Clofazimine is an attractive addition to failing drug regimens, as it shows in vitro synergy with clarithromycin, amikacin, and tigecycline. 102 In a South Korean retrospective review of 42 patients with M. abscessus treated with clofazimine, 81% had symptomatic improvement, 31% had radiographic improvement, and 24% had sputum conversion.…”

Section: Clofaziminementioning

confidence: 99%

Nontuberculous Mycobacteria in Cystic Fibrosis

Richards

Olivier

2019

Semin Respir Crit Care Med

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Over the past decade, the incidence of nontuberculous mycobacterial (NTM) infection has been increasing in cystic fibrosis patients. Along with this have come a host of complications and burdens to patients that threaten longevity and quality of life. The two main constituents of NTM pulmonary disease, Mycobacterium avium complex (MAC) and M. abscessus, are notoriously difficult to treat with suboptimal clinical responses and are accompanied by high treatment burdens for patients. This review aims to summarize the current knowledge of NTM epidemiology, pathogenesis, professional society guidelines for diagnosis and treatment, and the efficacy of current management recommendations, with attention to cystic fibrosis patients. We go on to examine drugs of emerging but unknown efficacy in clinical use to provide a comprehensive assessment of the current state of management of NTM for cystic fibrosis patients.

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Section: Clofaziminementioning

confidence: 99%

Nontuberculous Mycobacteria in Cystic Fibrosis

Richards

Olivier

2019

Semin Respir Crit Care Med

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“…In terms of its toxicological properties, the major side effect of orally administered CFZ is a strong red skin pigmentation, observed in more than 94% of patients [17,18]. CFZ-induced skin pigmentation is attributed to the circulating, soluble free base form of CFZ that partitions into the subcutaneous fat layer of the skin rather than CLDI formation and accumulation [19]. Even though prolonged CFZ treatment is associated with massive drug biocrystal accumulation within resident tissue macrophages, there are no obvious toxicological manifestations from these biocrystals.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration

et al. 2018

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Clofazimine (CFZ) is a broad spectrum antimycobacterial agent recommended by the World Health Organization as a first line treatment for leprosy and second line treatment for multidrug resistant tuberculosis. Oral administration of CFZ leads to a red skin pigmentation side effect. Since CFZ is a weakly basic, red phenazine dye, the skin pigmentation side effect results from lipophilic partitioning of the circulating, free base (neutral) form of CFZ into the skin. Here, we developed a stable and biocompatible formulation of CFZ-HCl microcrystals that mimics the predominant form of the drug that bioaccumulates in macrophages, following long term oral CFZ administration. In mice, intravenous injection of these biomimetic CFZ-HCl microcrystals led to visible drug accumulation in macrophages of the reticuloendothelial system with minimal skin accumulation or pigmentation. In fact, no skin pigmentation was observed when the total amount of CFZ-HCl administered was equivalent to the total oral dose leading to maximal skin pigmentation. Thus, parenteral (injected or inhaled) biomimetic formulations of CFZ-HCl could be instrumental to avoid the pigmentation side effect of oral CFZ therapy.

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“…The cells were then centrifuged, and the media was removed. The cell pellet was suspended in 1 mL of DI water, and the drug was extracted and measured using a previously described spectrophotometric method(35–37). Drug accumulation is reported as fmol CFZ/xenobiotic sequestering cell.…”

Section: Methodsmentioning

confidence: 99%

An Expandable Mechanopharmaceutical Device (1): Measuring the Cargo Capacity of Macrophages in a Living Organism

et al. 2018

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Purpose: Clofazimine (CFZ) is an FDA-approved, poorly soluble small molecule drug that precipitates as crystal-like drug inclusions (CLDIs) which accumulate in acidic cytoplasmic organelles of macrophages. In this study, we considered CLDIs as an expandable mechanopharmaceutical device, to study how macrophages respond to an increasingly massive load of endophagolysosomal cargo. Methods: First, we experimentally tested how the accumulation of CFZ in CLDIs impacted different immune cell subpopulations of different organs. Second, to further investigate the mechanism of CLDI formation, we asked whether specific accumulation of CFZ hydrochloride crystals in lysosomes could be explained as a passive, thermodynamic equilibrium phenomenon. A cellular pharmacokinetic model was constructed, simulating CFZ accumulation driven by pH-dependent ion trapping of the protonated drug in the acidic lysosomes, followed by the precipitation of CFZ hydrochloride salt via a common ion effect caused by high chloride concentrations. Results: While lower loads of CFZ were mostly accommodated in lung macrophages, increased CFZ loading was accompanied by organ-specific changes in macrophage numbers, size and intracellular membrane architecture, maximizing the cargo storage capabilities. With increasing loads, the total cargo mass and concentrations of CFZ in different organs diverged, while that of individual macrophages converged. The simulation results support the notion that the proton and chloride ion concentrations of macrophage lysosomes are sufficient to drive the massive, cell type-selective accumulation and growth of CFZ hydrochloride biocrystals. Conclusion: CLDIs effectively function as an expandable mechanopharmaceutical device, revealing the coordinated response of the macrophage population to an increasingly massive, whole-organism endophagolysosomal cargo load.

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The Physicochemical Basis of Clofazimine-Induced Skin Pigmentation

Cited by 42 publications

References 30 publications

Nontuberculous Mycobacteria in Cystic Fibrosis

Nontuberculous Mycobacteria in Cystic Fibrosis

Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration

An Expandable Mechanopharmaceutical Device (1): Measuring the Cargo Capacity of Macrophages in a Living Organism

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