Autopsy Findings in a Case of Lepromatous Leprosy Treated with Clofazimine

Kv, Desikan; Ramanujam, K; Ramu, G; Balakrishnan, S

doi:10.5935/0305-7518.19750019

Cited by 16 publications

(21 citation statements)

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“…Our results provide evidence that an inducible xenobiotic sequestration response mediated by a subpopulation of cells of the immune system is profoundly impacting the distribution and bioaccumulation of clofazimine. This is consistent with human autopsy reports (5,15,46) indicating the presence of clofazimine crystals in lymphatic tissues. Furthermore, our results suggest that these "crystals" are not accidental or haphazard.…”

Section: Discussionsupporting

confidence: 81%

“…Qualitatively (12)(13)(14), clofazimine is known to form crystal-like drug inclusions (CLDIs) inside cells of the mononuclear phagocyte system. However, the extent to which clofazimine accumulates in these intracellular inclusions has not been quantitatively established (12,15,16). Because it is a lipophilic, weakly basic molecule (17), clofazimine is likely to accumulate inside acidic organelles by a pH-dependent ion trapping mechanism (18).…”

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confidence: 99%

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Multiscale Distribution and Bioaccumulation Analysis of Clofazimine Reveals a Massive Immune System-Mediated Xenobiotic Sequestration Response

Baik

Stringer

Mane

et al. 2013

Antimicrob Agents Chemother

135

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Chronic exposure to some well-absorbed but slowly eliminated xenobiotics can lead to their bioaccumulation in living organisms. Here, we studied the bioaccumulation and distribution of clofazimine, a riminophenazine antibiotic used to treat mycobacterial infection. Using mice as a model organism, we performed a multiscale, quantitative analysis to reveal the sites of clofazimine bioaccumulation during chronic, long-term exposure. Remarkably, between 3 and 8 weeks of dietary administration, clofazimine massively redistributed from adipose tissue to liver and spleen. During this time, clofazimine concentration in fat and serum significantly decreased, while the mass of clofazimine in spleen and liver increased by >10-fold. These changes were paralleled by the accumulation of clofazimine in the resident macrophages of the lymphatic organs, with as much as 90% of the clofazimine mass in spleen sequestered in intracellular crystal-like drug inclusions (CLDIs). The amount of clofazimine associated with CLDIs of liver and spleen macrophages disproportionately increased and ultimately accounted for a major fraction of the total clofazimine in the host. After treatment was discontinued, clofazimine was retained in spleen while its concentrations decreased in blood and other organs. Immunologically, clofazimine bioaccumulation induced a local, monocyte-specific upregulation of various chemokines and receptors. However, interleukin-1 receptor antagonist was also upregulated, and the acutephase response pathways and oxidant capacity decreased or remained unchanged, marking a concomitant activation of an antiinflammatory response. These experiments indicate an inducible, immune system-dependent, xenobiotic sequestration response affecting the atypical pharmacokinetics of a small molecule chemotherapeutic agent.

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Section: Discussionsupporting

confidence: 81%

mentioning

confidence: 99%

Multiscale Distribution and Bioaccumulation Analysis of Clofazimine Reveals a Massive Immune System-Mediated Xenobiotic Sequestration Response

Baik

Stringer

Mane

et al. 2013

Antimicrob Agents Chemother

135

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“…Clofazimine was withdrawn and the symptoms cleared up in 8 to lO weeks. Desikan et al , (1975) have reported autopsy findings in a young Indian woman who had suffered from lepromatous leprosy complicated by severe lepra reaction and nephrotic syndrome. The story was that prednisolone had failed to control the reaction so clofazimine was added to her treatment, 300 mg daily, but had to be stopped after 4 months because of diarrhoea which had not responded to reduced dosage.…”

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confidence: 99%

Complications of Treatment With Clofazimine (Lamprene: B663)

Wh¹

1976

Leprosy Review

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Much has been written on the subject of this dye since Browne and Hogerzeil (1962) first reported its good effect in the treatment of leprosy, and, as regards its side effects, most are by now well known. These include red-brown pigmentation of skin and conjunctiva with darkening of skin lesions; red colouration of urine, stools, sputum and sweat; dryness of skin, particularly of forearms and lower legs,

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“…En la laparotomía ha llamado la atención el color pardusco, rojizo o ladrillo del peritoneo y de la pared intestinal, que presenta engrosamiento focal en el yeyuno, cuya Eritema nudoso leproso y enteropatía letal mucosa aparece rojiza y edematosa (7,(18)(19)(20)(21)(22)(23)(24). La lesión puede llegar a la obstrucción intestinal, parcial o completa (10,11).…”

Section: Discussionunclassified

“…En el estudio histológico no hay atrofia de las vellosidades intestinales sino infiltración de la mucosa, de la submucosa y aun de la capa muscular, por macrófagos y plasmocitos, con pocos eosinófilos (7,(19)(20)(21)(22). Pocas veces hay enteritis con eosinófilos y eosinofilia sanguínea (18,19,21).…”

Section: Discussionunclassified

Eritema nudoso leproso persistente y enteropatía letal por clofazimina

et al. 2009

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Introducción. La enteropatía por clofazimina es una complicación grave de este fármaco, cuando se usa a dosis altas para la reacción leprosa tipo 2 y otras enfermedades. Objetivo. Presentar una mujer de 31 años con síntomas de lepra, incluidos episodios de eritema nudoso leproso, agravados durante el embarazo, sin diagnóstico médico preciso. Relatar la evolución de su enteropatía letal por clofazimina. Materiales y métodos. Entrevista con la paciente y sus familiares, revisión de la historia clínica y de la literatura pertinente. Resultados. La paciente presentó lesiones cutáneas anestésicas y varios episodios de eritema nudoso, agravados durante sus embarazos. Luego de epistaxis repetidas y perforación del tabique nasal, se diagnóstico lepra lepromatosa, 12 años después de numerosas consultas médicas. Su esposo y su hija de 12 años presentaron signos de lepra para la cual se trataron. La paciente tuvo episodios de reacción tipo 2 durante la poliquimioterapia, para los cuales recibió 400 mg diarios de clofazimina. A los dos meses de este tratamiento comenzó a presentar dolor abdominal persistente durante más de un año, muy serio y episódicamente exacerbado, manejado con analgésicos y antiespasmódicos, incluida la morfina. Tuvo, además, diarrea, estreñimiento, náuseas, pérdida de peso y adenopatías mesentéricas. Falleció sin diagnóstico de su afección intestinal. No se hizo autopsia. Conclusiones. La clínica final de la paciente sugiere que se trata de un caso de enteropatía letal por clofazimina, una complicación que no se había reconocido previamente en nuestros pacientes. Es necesario aumentar el conocimiento de la lepra entre los médicos.Palabras clave: lepra lepromatosa/complicaciones, quimioterapia, eritema nudoso, clofazimina, agentes antibacterianos/efectos adversos, abdomen agudo. Persistent type 2 lepra reaction and clofazimine-induced lethal enteropatyIntroduction. Clofazimine enterophathy is a serious complication of clofazimine when used at high doses for treatment of type 2 lepra or or erythema nodosum leprosum. Objective. A woman is presented who had a delayed diagnosis of leprosy, persistent type 2 lepra reaction and lethal clofazimine enteropathy. Materials and methods. A 31-year-old woman presented leprosy symptoms over a 16-year period without medical diagnosis of her disease. During this period, type 2 lepra episodes occurred, but were not accurately diagnosed. These episodes became more severe during her second pregnancy. The patient and her family were interviewed, and her clinical history reviewed. Results. After twelve years of medical consults, lepromatous leprosy was diagnosed, based on perforation of her nasal septum, with a bacterial index of 5. Her husband and a 12-year-old daughter have leprosy symptoms. During multidrug therapy, she presented with repeated type 2 lepra reaction episodes for which she received daily clofazimine 400 mg doses. Two months after this treatment, severe and frequent episodes of intense abdominal pain began to occur. These persisted for more than a year and...

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Autopsy Findings in a Case of Lepromatous Leprosy Treated with Clofazimine

Cited by 16 publications

References 0 publications

Multiscale Distribution and Bioaccumulation Analysis of Clofazimine Reveals a Massive Immune System-Mediated Xenobiotic Sequestration Response

Multiscale Distribution and Bioaccumulation Analysis of Clofazimine Reveals a Massive Immune System-Mediated Xenobiotic Sequestration Response

Complications of Treatment With Clofazimine (Lamprene: B663)

Eritema nudoso leproso persistente y enteropatía letal por clofazimina

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