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Effect of the addition of pentoxifylline on the therapeutic and inflammatory response in patients with cutaneous leishmaniasis: A Randomized Placebo Controlled Trial

Alexandra Cossio1, Maria Del Mar Castro1, Adriana Navas1, Liliana Valderrama1, Lyda Cuervo-Pardo1, Ricardo Marquez1, Sandra J. Jojoa1, Ruth M. Castillo1, Maria A. Gómez1 and Nancy Gore Saravia1*
  • 1 Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Colombia

Introduction: The inflammatory response is an important factor in the therapeutic response of cutaneous leishmaniasis (CL). Co-adjuvant use of immunomodulators may improve the efficacy or outcome of treatment. This study sought to determine whether the addition of pentoxifylline (PTX) to meglumine antimonite (MA) treatment improves therapeutic response in CL patients and to determine the effect of PTX on the inflammatory response. Methods: A randomized, double-blind, "Add on" placebo-controlled trial was conducted in 2 centers in Colombia. The protocol was approved and monitored by the institutional ethical committee. Seventy-five parasitologically diagnosed patients were randomly allocated by computer. Inclusion criteria: age 18-65 years, lesion >1 month evolution, multiple lesions or single lesion ≥ 3 cm. Intervention: intramuscular MA (20 mg/ kg /day x 20 days) plus oral PTX 400 mg thrice daily (n=36). Control: MA plus placebo (n=37). Expression of inflammatory genes cxcl10,cxcl5,ccl2, IL1b, ptgs2 and csf1 was evaluated by qRT-PCR in peripheral blood mononuclear cells from CL patients, before and after antimonial treatment, in combination with either PTX (n=12) or placebo (n=12). Therapeutic response and adverse events were assessed at the end of treatment 5, 7, 13 and 26 weeks. Results: Seventy participants (93%) were analyzed by intention to treat (ITT) and forty-eight (64%) per protocol (PP). Treatment failure was 12/34 (35.3%) for PTX vs. 9/36 25% placebo; (OR: 1.63; 95% CI: 0.58 – 4.5). PP failure rate was 6/20 (30%) for PTX and 5/28 (17.8%) for placebo (OR: 1.97; 95% CI: 0.50 – 7.68). No differences between overall frequency and severity of adverse events were found (PTX=142 vs. placebo=140). Expression of inflammatory mediators at the end of treatment was not altered by addition of PTX to MA. However, therapeutic failure was associated with significant overexpression of IL1β and Ptgs2 (p<0.05) irrespective of the study group. Conclusion: Addition of PTX to standard treatment of CL did not modify the therapeutic response in this population with early mild to moderate CL, or alter the gene expression of the evaluated inflammatory mediators.

Acknowledgements

We acknowledge the devoted work of the health personnel in the municipality of Tumaco and to the Department of Valle del Cauca, and the research staff of the Centro Internacional de Entrenamiento e Investigaciones Medicas-CIDEIM. Thanks to TECNOQUÍMICAS® whom donated the pentoxifylline and placebo, and to the Ministry of Health of Colombia and Secretaría de Salud of Cali.
Financial support: Support for this study was provided by COLCIENCIAS Contracts 253 - 2010.

References

Brito G, Dourado M, Polari L, Celestino D, Carvalho LP, Queiroz A, Carvalho E, Machado P, Passos S. Treatment with Pentoxifylline in CL patients. Short Report: Clinical and Immunological Outcome in Cutaneous Leishmaniasis Patients Treated with Pentoxifylline. Available at: http://ajtmh.org/cgi/doi/10.4269/ajtmh.12-0729.(Accessed Frebruary 24, 2014).

Bruynzeel I, Stoof T.J, Willemze R. Pentoxifylline and skin inflammation. Clinical and Experimental Dermatology 1998; 23(4): 168–172.

Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03, June 2010. National Institutes of Health, National Cancer Institute. Available at: http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf. (Accessed October 22, 2013).

Cooper A, Mikhail A, Lethbridge MW, Kemeny DM, Macdougall IC. Pentoxifylline improves hemoglobin levels in patients with erythropoietin-resistant anemia in renal failure. J Am Soc Nephrol. 2004 Jul;15(7):1877-82.

Fergusson D, Aaron SD, Guyatt G, Hébert P. Post­randomisation exclusions: the intention to treat principle and excluding patients from analysis. BMJ 2002;325:652–4.

Gonzales-Fajardo L, Fernandez O, MacMahon D, Saravia N. Ex vivo host and parasite response to antileishmanial drugs and immunomodulators. Plos Neglected Tropical Diseases. Manuscript Number PNTD-D-14-01279R1. In press.

Gutierrez-Reyes G, Lopez-Ortal P, Sixtos S, Cruz S, Ramirez-Iglesias MT, Gutierrez-Ruiz MC, Sanchez-Avila F, Roldan E, Vargas-Vorackova F, Kershenobich D.Effect of pentoxifylline on levels of pro-inflammatory cytokines during chronic hepatitis C. Scandinavian Journal of Immunology. 2006; 63:461–467.

Lance S. The all randomized/full analysis Set (ich e9)—may patients be Excluded from the analysis?. Drug Information Journal. 2001;35 :881–891.

Lessa, H. A., Machado, P., Lima, F., Cruz, A. A., Bacellar, O., Guerreiro, J. and Carvalho, E. M., Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony. Am J Trop Med Hyg 2001. 65: 87-89.

Llanos-Cuentas A, Araujo-Castillo T R, Miranda-Verastegui C, Santamaria-Castrellon G, Ramirez L, Lazo M, De Doncker S, Boelaert M, Robays J, Dujardin JC, Arevalo J, Chappuis F. Clinical and parasite species risk factors for pentavalent antimonial treatment failure in cutaneous leishmaniasis in Peru. Clin Infect Dis. 2008 Jan 15;46(2):223-31.

Machado P, Araújo C, Da Silva AT, Almeida RP, D'Oliveira Jr A, Bittencourt A, Carvalho EM. Failure of early treatment of cutaneous leishmaniasis in preventing the development of an ulcer. Clin Infect Dis. 2002 Jun 15;34(12):E69-73. Epub 2002 May 17.

Machado, P. R., Lessa, H., Lessa, M., Guimaraes, L. H., Bang, H., Ho, J. L. and Carvalho, E. M., Oral pentoxifylline combined with pentavalent antimony: a randomized trial for mucosal leishmaniasis. Clin Infect Dis 2007. 44: 788-793.

Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ.A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981 Aug; 30(2):239-45.

Netea MG, Simon A, van de Veerdonk F, Kullberg BJ, Van der Meer JW, Joosten LA. IL-1beta processing in host defense: beyond the inflammasomes. PLoS Pathog. 2010 Feb 26;6(2):e1000661. doi: 10.1371/journal.ppat.1000661. Review.

Neuner P, Klosner G, Schauer E, Pourmojib M, Macheiner W, Grünwald C, Knobler R, Schwarz A, Luger TA, Schwarz T. Pentoxifylline in vivo down-regulates the release of IL-1 beta, IL-6, IL-8 and tumour necrosis factor-alpha by human peripheral blood mononuclear cells. Immunology. 1994 Oct; 83(2):262-7.

Nicklasson M, Björkman S, Roth B, Jönsson M, Höglund P. Stereoselective metabolism of pentoxifylline in vitro and in vivo in humans. Chirality. 2002 Aug;14(8):643-52.

Ojha R, Cervantes C, Fischbach L. Oral Pentoxifylline and Pentavalent Antimony for Treatment of Leishmaniasis: Promising but Inconclusive Evidence of Superiority, Compared with Antimony Monotherapy. CID 2007:45 (15 October).

Schandené L, Vandenbussche P, Crusiaux A, Alègre ML, Abramowicz D, Dupont E, Content J, Goldman M. Differential effects of Pentoxifylline on the production of tumour necrosis factor-alpha (TNF-alpha) and Interleukin-6 (IL-6) by monocytes and T cells. Immunology. 1992 May;76(1):30-4.

Sadeghian G, Nilforoushzadeh MA.Effect of combination therapy with systemic glucantime and pentoxifylline in the treatment of cutaneous leishmaniasis. Int J Dermatol. 2006 Jul;45(7):819-21.

Smith AH, Bates MN. Confidence Limit Analyses Should Replace Power Calculations in the Interpretation of Epidemiologic Studies. Epidemiology, Vol. 3, No. 5 (Sep., 1992), pp. 449-452. Available at: http://www.jstor.org/stable/3702639. (Accesseed January 27, 2015).

Keywords: cutaneous leishmaniasis, Pentoxifylline, Inflammatory Response, Leishmaniasis, Treatment

Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015.

Presentation Type: Oral Presentation

Topic: Infectious and parasitic diseases

Citation: Cossio A, Castro M, Navas A, Valderrama L, Cuervo-Pardo L, Marquez R, Jojoa SJ, Castillo RM, Gómez MA and Gore Saravia N (2015). Effect of the addition of pentoxifylline on the therapeutic and inflammatory response in patients with cutaneous leishmaniasis: A Randomized Placebo Controlled Trial. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00318

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Received: 21 May 2015; Published Online: 15 Sep 2015.

* Correspondence: PhD. Nancy Gore Saravia, Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, Please Select, 760001, Colombia, saravian@cideim.org.co