A Randomized Trial for Mucosal Leishmaniasis: Oral Pentoxifylline Combined with Pentavalent Antimony
Abstract & Commentary
By Michele Barry, MD, FACP
Professor of Medicine, Co-Director Tropical Medicine and International Travelers' Clinic, Yale University School of Medicine.
Dr. Barry is a consultant for the Ford Foundation, and receives funds from Johnson & Johnson.
Synopsis: Mucosal leishmaniasis is associated with intense tissue damage and high tumor necrosis factor production. Patients who experience treatment failure often will require greater than one pentavalent antimony (Sbv) course or alternative drugs to achieve a cure.
Source: Machado PR, et al. Oral Pentoxifylline Combined with Pentavalent Antimony: A Randomized Trial for Mucosal Leishmaniasis. Clin Infect Dis. 2007 Mar 15;44(6):788-793.
This publication describes a double-blind, placebo-controlled trial evaluating the efficacy of adding pentoxifylline to Sbv treatment of 23 patients with mucosal leishmaniasis caused by L. brasiliensis. Eligible patients were between ages 18-65 and had severe mucosal leishmaniasis, defined as the presence of deep mucosal ulcers or nasal septal perforation. A clinical diagnosis was confirmed by either a positive intradermal skin test with leishmania antigen, parasite culture or characteristic histopathological findings. Patients were randomized to parenteral Sbv (meglumine antimony) at a dosage of 20 mg per kg per day plus oral pentoxifylline (Pentox) at a dosage of 400 mg 3 times daily for 30 days. Controls received Sbv treatment plus identical placebo pills.
All patients in the pentoxifylline group experienced a cure with one course of Sbv whereas 5 (41.6%) of 12 patients in the placebo group required a second course of Sbv (P = 0.037). The mean healing time, ± standard deviation, was 83 ± 36 days compared with 145 ± 99 days in the placebo group, P = 0.049. No relapses were documented in either group at a 2-year follow-up visit.
Commentary
In Central and South America, cutaneous leishmaniasis is a major health problem with mucosal disease occurring in 3% of all patients with cutaneous disease caused by Leishmania braziliensis. Mucosal disease is observed either concomitantly or months to years following cutaneous disease, and is characterized by the presence of destructive lesions that predominantly affect the nose and vocal cord. Standard treatment has been high dose pentavalent antimony, but with clinical treatment failures noted up to 19% of the time.1 Pentoxifylline is a methylxanthine that was originally licensed for use in peripheral artery disease associated with claudication. Its putative mechanism of action for ischemic claudication was as a rheologic modifier that increased red cell deformity and decreased whole blood viscosity. It has recently been shown to have a role in down-regulating TNF-α production. There is evidence that mucos-al lesions in leishmaniasis are related to an unmodulated immune response in the host with increased production of pro-inflammatory cytokines and TNF-α production.2
This study demonstrated enhanced resolution of mucosal disease using combination therapy. Previously, these authors had demonstrated in an open label study that Sbv and pentoxifylline significantly decreased TNF-α levels and resulted in a cure in 9 out of 10 patients refractory to three courses of Sbv.3 However, in both this study and the previous one, the numbers were small and statistical significance was not achieved. Thus, these papers present intriguing results that are not quite ready for prime time treatment. As we await larger numbers, pentoxifylline remains a relatively benign off-label consideration for refractory cases needing retreatment.
References:
- Netto EM, et al. Long-term follow-up of patients with leishmania (Viannia) Braziliensis infection and treated with glucantime. Trans R Soc Trop Med Hyg. 1990;84: 367-370.
- Bacellar O, et al. Up-regulation of Th-1 responses in mucosal leishmaniasis patients. Infect Immun. 2002; 70:6734-6740.
- Lessa HA, et al. Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony. Am J Trop Med Hyg. 2001;65:87-89.
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