{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T06:47:46Z","timestamp":1792219666912,"version":"4.4.0"},"reference-count":44,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T00:00:00Z","timestamp":1647820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007637","name":"Colciencias","doi-asserted-by":"publisher","award":["222951928964"],"award-info":[{"award-number":["222951928964"]}],"id":[{"id":"10.13039\/100007637","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI093775-01"],"award-info":[{"award-number":["AI093775-01"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1U19AI129910-01"],"award-info":[{"award-number":["1U19AI129910-01"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Addition of the immunomodulator pentoxifylline (PTX) to antimonial treatment of mucosal leishmaniasis has shown increased efficacy. This randomized, double-blind, placebo-controlled trial evaluated whether addition of pentoxifylline to meglumine antimoniate (MA) treatment improves therapeutic response in cutaneous leishmaniasis (CL) patients. Seventy-three patients aged 18\u201365 years, having multiple lesions or a single lesion \u2265 3 cm were randomized to receive: intramuscular MA (20 mg\/kg\/day \u00d7 20 days) plus oral PTX 400 mg thrice daily (intervention arm, n = 36) or MA plus placebo (control arm, n = 37), between 2012 and 2015. Inflammatory gene expression was evaluated by RT-qPCR in peripheral blood mononuclear cells from trial patients, before and after treatment. Intention-to-treat failure rate was 35% for intervention vs. 25% for control (OR: 0.61, 95% CI: 0.21\u20131.71). Per-protocol failure rate was 32% for PTX, and 24% for placebo (OR: 0.50, 95% CI: 0.13\u20131.97). No differences in frequency or severity of adverse events were found (PTX = 142 vs. placebo = 140). Expression of inflammatory mediators was unaltered by addition of PTX to MA. However, therapeutic failure was associated with significant overexpression of il1\u03b2 and ptgs2 (p &lt; 0.05), irrespective of study group. No clinical benefit of addition of PTX to standard treatment was detected in early mild to moderate CL caused by Leishmania (V.) panamensis.<\/jats:p>","DOI":"10.3390\/pathogens11030378","type":"journal-article","created":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T21:48:42Z","timestamp":1647899322000},"page":"378","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Pentoxifylline in the Treatment of Cutaneous Leishmaniasis: A Randomized Clinical Trial in Colombia"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0485-2919","authenticated-orcid":false,"given":"Maria del Mar","family":"Castro","sequence":"first","affiliation":[{"name":"Centro Internacional de Entrenamiento e Investigaciones M\u00e9dicas (CIDEIM), Cali 760031, Colombia"},{"name":"Universidad Icesi, Cali 760031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2247-5459","authenticated-orcid":false,"given":"Alexandra","family":"Cossio","sequence":"additional","affiliation":[{"name":"Centro Internacional de Entrenamiento e Investigaciones M\u00e9dicas (CIDEIM), Cali 760031, Colombia"},{"name":"Universidad Icesi, Cali 760031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Navas","sequence":"additional","affiliation":[{"name":"Centro Internacional de Entrenamiento e Investigaciones M\u00e9dicas (CIDEIM), Cali 760031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Centro Internacional de Entrenamiento e Investigaciones M\u00e9dicas (CIDEIM), Cali 760031, Colombia"},{"name":"Universidad Icesi, Cali 760031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Valderrama","sequence":"additional","affiliation":[{"name":"Centro Internacional de Entrenamiento e Investigaciones M\u00e9dicas (CIDEIM), Cali 760031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyda","family":"Cuervo-Pardo","sequence":"additional","affiliation":[{"name":"Centro Internacional de Entrenamiento e Investigaciones M\u00e9dicas (CIDEIM), Cali 760031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Marquez-O\u00f1ate","sequence":"additional","affiliation":[{"name":"Centro Internacional de Entrenamiento e Investigaciones M\u00e9dicas (CIDEIM), Cali 760031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Adelaida","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Centro Internacional de Entrenamiento e Investigaciones M\u00e9dicas (CIDEIM), Cali 760031, Colombia"},{"name":"Universidad Icesi, Cali 760031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy Gore","family":"Saravia","sequence":"additional","affiliation":[{"name":"Centro Internacional de Entrenamiento e Investigaciones M\u00e9dicas (CIDEIM), Cali 760031, Colombia"},{"name":"Universidad Icesi, Cali 760031, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,21]]},"reference":[{"key":"ref_1","unstructured":"WHO (2021, December 12). Fact Sheet on Leishmaniasis. Available online: https:\/\/www.who.int\/en\/news-room\/fact-sheets\/detail\/leishmaniasis."},{"key":"ref_2","first-page":"CD004834","article-title":"Interventions for American cutaneous and mucocutaneous leishmaniasis","volume":"8","author":"Pinart","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Reveiz, L., Maia-Elkhoury, A.N., Nicholls, R.S., Romero, G.A., and Yadon, Z.E. (2013). Interventions for American cutaneous and mucocutaneous leishmaniasis: A systematic review update. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061843"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Castro, M.D.M., Cossio, A., Velasco, C., and Osorio, L. (2017). Risk factors for therapeutic failure to meglumine antimoniate and miltefosine in adults and children with cutaneous leishmaniasis in Colombia: A cohort study. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0005515"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"187","DOI":"10.4269\/ajtmh.2001.64.187","article-title":"Treatment failure in children in a randomized clinical trial with 10 and 20 days of meglumine antimonate for cutaneous leishmaniasis due to Leishmania viannia species","volume":"64","author":"Palacios","year":"2001","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_6","unstructured":"PAHO (2013). Leishmaniasis en las Am\u00e9ricas. Recomendaciones Para el Tratamiento, Organizaci\u00f3n Panamericana de la SaludL(OPS\/OMS)."},{"key":"ref_7","unstructured":"(2010). Control of the Leishmaniases: Report of a Meeting of the WHO Expert Commitee on the Control of Leishmaniases, WHO."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nri.2016.72","article-title":"Cutaneous leishmaniasis: Immune responses in protection and pathogenesis","volume":"16","author":"Scott","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1097\/01.TA.0000096642.54111.E8","article-title":"Effects of phosphodiesterase inhibition on the inflammatory response after shock: Role of pentoxifylline","volume":"56","author":"Coimbra","year":"2004","journal-title":"J. Trauma"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1111\/j.1365-3083.2006.001761.x","article-title":"Effect of pentoxifylline on levels of pro-inflammatory cytokines during chronic hepatitis C","volume":"63","author":"Sixtos","year":"2006","journal-title":"Scand. J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"87","DOI":"10.4269\/ajtmh.2001.65.87","article-title":"Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony","volume":"65","author":"Lessa","year":"2001","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1086\/511643","article-title":"Oral pentoxifylline combined with pentavalent antimony: A randomized trial for mucosal leishmaniasis","volume":"44","author":"Machado","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/path.1711590406","article-title":"Histological analysis and the pathogenesis of mucocutaneous leishmaniasis","volume":"159","author":"Ridley","year":"1989","journal-title":"J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"617","DOI":"10.4269\/ajtmh.12-0729","article-title":"Clinical and immunological outcome in cutaneous leishmaniasis patients treated with pentoxifylline","volume":"90","author":"Brito","year":"2014","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"510","DOI":"10.4103\/2229-5178.142528","article-title":"Pentoxifylline and its applications in dermatology","volume":"5","author":"Hassan","year":"2014","journal-title":"Indian Derm. Online J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.4269\/ajtmh.16-0435","article-title":"Oral Pentoxifylline Associated with Pentavalent Antimony: A Randomized Trial for Cutaneous Leishmaniasis","volume":"96","author":"Brito","year":"2017","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1093\/infdis\/jir816","article-title":"Noninferiority of miltefosine versus meglumine antimoniate for cutaneous leishmaniasis in children","volume":"205","author":"Rubiano","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e2809","DOI":"10.1136\/bmj.e2809","article-title":"Potential impact on estimated treatment effects of information lost to follow-up in randomised controlled trials (LOST-IT): Systematic review","volume":"344","author":"Akl","year":"2012","journal-title":"BMJ"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1046\/j.1365-2230.1998.00316.x","article-title":"Pentoxifylline and skin inflammation","volume":"23","author":"Bruynzeel","year":"1998","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e00764-19","DOI":"10.1128\/IAI.00764-19","article-title":"Profiles of Local and Systemic Inflammation in the Outcome of Treatment of Human Cutaneous Leishmaniasis Caused by Leishmania (Viannia)","volume":"88","author":"Navas","year":"2020","journal-title":"Infect. Immun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1007\/s15010-007-6279-5","article-title":"Post-kala-azar dermal Leishmaniasis and uveitis in an HIV-positive patient","volume":"36","author":"Ramos","year":"2008","journal-title":"Infection"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"422","DOI":"10.2174\/187152812803590028","article-title":"Pentoxifylline use in dermatology","volume":"11","author":"Cakmak","year":"2012","journal-title":"Inflamm. Allergy Drug. Targets"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"392","DOI":"10.4269\/ajtmh.19-0139","article-title":"In Situ Cellular Response Underlying Successful Treatment of Mucosal Leishmaniasis with a Combination of Pentavalent Antimonial and Pentoxifylline","volume":"101","author":"Faria","year":"2019","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/j.2042-7158.1998.tb03307.x","article-title":"Circadian variations in the pharmacokinetics of pentoxifylline in man","volume":"50","author":"Srinivasu","year":"1998","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1177\/0091270011433435","article-title":"Pharmacokinetics of pentoxifylline and its main metabolites in patients with different degrees of heart failure following a single dose of a modified-release formulation","volume":"53","author":"Nisi","year":"2013","journal-title":"J. Clin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"805108","DOI":"10.1155\/2013\/805108","article-title":"Mucosal leishmaniasis: An underestimated presentation of a neglected disease","volume":"2013","author":"Strazzulla","year":"2013","journal-title":"Biomed. Res. Int."},{"key":"ref_27","first-page":"CD001733","article-title":"Pentoxifylline for treating venous leg ulcers","volume":"12","author":"Jull","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"269","DOI":"10.2147\/TCRM.S1458","article-title":"Factors affecting therapeutic compliance: A review from the patient\u2019s perspective","volume":"4","author":"Jin","year":"2008","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.actatropica.2011.02.007","article-title":"Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World","volume":"118","author":"Oliveira","year":"2011","journal-title":"Acta Trop."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1111\/j.1365-4632.2006.02867.x","article-title":"Effect of combination therapy with systemic glucantime and pentoxifylline in the treatment of cutaneous leishmaniasis","volume":"45","author":"Sadeghian","year":"2006","journal-title":"Int. J. Dermatol."},{"key":"ref_31","unstructured":"Instituto Nacional de Salud (2020). Informe de Evento Leishmaniasis Cutanea, INS."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e000122","DOI":"10.1136\/bmjgh-2016-000122","article-title":"It is time to revise the international Good Clinical Practices guidelines: Recommendations from non-commercial North-South collaborative trials","volume":"1","author":"Ravinetto","year":"2016","journal-title":"BMJ Glob. Health"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1097\/00001648-199209000-00011","article-title":"Confidence limit analyses should replace power calculations in the interpretation of epidemiologic studies","volume":"3","author":"Smith","year":"1992","journal-title":"Epidemiology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1136\/bmj.325.7365.652","article-title":"Post-randomisation exclusions: The intention to treat principle and excluding patients from analysis","volume":"325","author":"Fergusson","year":"2002","journal-title":"BMJ"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"290","DOI":"10.7326\/0003-4819-154-4-201102150-00016","article-title":"CONSORT 2010 statement: Updated guidelines for reporting parallel group randomized trials","volume":"154","author":"Bian","year":"2011","journal-title":"Ann. Intern. Med."},{"key":"ref_36","unstructured":"Instituto Nacional de Salud (2010). Gu\u00eda Para la Atenci\u00f3n Cl\u00ednica Integral del Paciente con Leishmaniasis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"926","DOI":"10.4049\/jimmunol.129.3.926","article-title":"Monoclonal antibodies that distinguish subspecies of Leishmania braziliensis","volume":"129","author":"Bennett","year":"1982","journal-title":"J Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/291581a0","article-title":"Monoclonal antibodies that distinguish between New World species of Leishmania","volume":"291","author":"Pratt","year":"1981","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"270","DOI":"10.4269\/ajtmh.1987.36.270","article-title":"Identification and distribution of New World Leishmania species characterized by serodeme analysis using monoclonal antibodies","volume":"36","author":"Grimaldi","year":"1987","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"738","DOI":"10.4269\/ajtmh.2002.66.738","article-title":"Heterogeneity, geographic distribution, and pathogenicity of serodemes of Leishmania viannia in Colombia","volume":"66","author":"Saravia","year":"2002","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_41","unstructured":"National Cancer Institute (2021, December 14). Common Terminology Criteria for Adverse Events (CTCAE) v 4.03: U.S. Department of Health and Human Services; 2010 [cited 2021], Available online: https:\/\/evs.nci.nih.gov\/ftp1\/CTCAE\/CTCAE_4.03\/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2872","DOI":"10.1128\/IAI.01133-13","article-title":"Chronicity of dermal leishmaniasis caused by Leishmania panamensis is associated with parasite-mediated induction of chemokine gene expression","volume":"82","author":"Navas","year":"2014","journal-title":"Infect. Immun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0166-6851(00)00270-X","article-title":"Episomal and stable expression of the luciferase reporter gene for quantifying Leishmania spp. infections in macrophages and in animal models","volume":"110","author":"Roy","year":"2000","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1086\/510860","article-title":"Pharmacokinetics of antimony in children treated for leishmaniasis with meglumine antimoniate","volume":"195","author":"Cruz","year":"2007","journal-title":"J. Infect. Dis."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/11\/3\/378\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:40:18Z","timestamp":1760136018000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/11\/3\/378"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,21]]},"references-count":44,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["pathogens11030378"],"URL":"https:\/\/doi.org\/10.3390\/pathogens11030378","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,21]]}}}