An open label randomized clinical trial comparing the safety and effectiveness of one, two or three weekly pentamidine isethionate doses (seven milligrams per kilogram) in the treatment of cutaneous leishmaniasis in the Amazon Region

Ellen Priscilla Nunes Gadelha, Rajendranath Ramasawmy, Bruna da Costa Oliveira, Nágila Morais Rocha, Jorge Augusto de Oliveira Guerra, George Allan Villa Rouco da Silva, Tirza Gabrielle Ramos de Mesquita, Carolina Chrusciak Talhari Cortez, Anette Chrusciak Talhari, Ellen Priscilla Nunes Gadelha, Rajendranath Ramasawmy, Bruna da Costa Oliveira, Nágila Morais Rocha, Jorge Augusto de Oliveira Guerra, George Allan Villa Rouco da Silva, Tirza Gabrielle Ramos de Mesquita, Carolina Chrusciak Talhari Cortez, Anette Chrusciak Talhari

Abstract

Background: American Cutaneous Leishmaniasis (ACL), a vector borne disease, is caused by various species of Leishmania and in the Amazonas, Leishmania guyanensis is predominant. The recommended drugs for treatment of cutaneous leishmaniasis (CL) in Brazil are pentavalent antimonials, pentamidine isethionate (PI) and amphotericin B. Pentamidine was initially used as metanolsulfonate or mesylate (Lomidine) at a dose of 4 mg/kg/daily, containing 2.3mg of base. This drug was withdrawn from the market in the eighties, and currently is available as PI. The PI dose required to achieve an equivalent dose of pentamidine base is 7 mg/kg, rather than the 4 mg/kg that is currently recommended in Brazil.

Objectives: The aim of this study was to evaluate the efficacy and safety of PI in a single dose, two or three doses of 7 mg/kg body weight, intramuscularly, with an interval of seven days between each dose.

Materials and methods: This study was conducted as a controlled, randomized, open-label clinical trial for a total number of 159 patients with CL. Individuals aged 16-64 years with one to six lesions of confirmed CL based on amastigotes visualization in direct examination of Giemsa stained of dermal scraping from the border of the lesion with no previous treatment for CL and no abnormal values for liver enzymes were eligible to participate in the study. Patients with history of diabetes, cardiac, renal, and hepatic disease as well as pregnant women were excluded. Cure was defined as complete healing in the diameters of the ulcers and lesions skin six months after the end of the treatment.

Results: From November 2013 to December 2015, 159 patients were screened and allocated in three groups for treatment with PI: i) 53 patients were treated with a single dose intramuscularly injection of 7 mg/kg body weight; ii) 53 received two doses of 7 mg/kg within an interval of seven days; and iii) 53 were treated with three doses of 7mg/kg with an interval of seven days between each dose. In 120 patients, L. guyanensis was identified. A cure rate of 45%, 81.1% and 96.2% were observed in the first, second and third group, respectively. The cure in the three PI dose group was higher compared to the single-dose (p<0.0001) and two-dose groups (p = 0.03). No serious adverse events occurred.

Conclusion: The present study shows that PI is a safe drug and its efficacy varied with the number of doses. The administration of PI in patients with ACL, predominantly caused by L. guyanensis, was mostly efficient in three or two doses of 7 mg/kg.

Trial registration: ClinicalTrials.gov NCT02919605.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Flow Diagram of the progress…
Fig 1. Flow Diagram of the progress through the phases: enrolment, intervention, allocation, follow-up and analysis.
Fig 2. Average of the capillary glycemia…
Fig 2. Average of the capillary glycemia reduction before and after half an hour of the applications between the treatments.

References

    1. Ministério da Saúde (Brasil). Secretaria de Vigilância em Saúde Manual de Vigilância da Leishmaniose Tegumentar Americana. 2. ed Brasília: Editora do Ministério da Saúde, 2017
    1. Benício EA, Santos MCC, Oliveira CMC, Talhari C, Talhari S, Schriefer A, et al. Combining diagnostic procedures for the management of leishmaniasis in areas with high prevalence of Leishmania guyanensis. An Bras Dermatol. 2011;86(6):1141–1142.
    1. Ministério da Saúde (Brasil). Secretaria de Vigilância em Saúde. Doenças negligenciadas: estratégias do Ministério da Saúde. Rev Saúde Pública 2010;44(1):200–2
    1. Lainson R, Shaw JJ, Silveira FT, de Souza AA, Braga RR, Ishikawa EA. The dermal leishmaniases of Brazil, with special reference to the eco-epidemiology of the disease in Amazonia. Memorias do Instituto Oswaldo Cruz. 1994; 89(3):435–43. .
    1. Paes MG. Estudo de quatro espécies de Lutzomyia França 1924 (Diptera Psychodidae) em área endêmica de Leishmaniose Tegumentar Americana na periferia de Manaus [dissertação]. Manaus(AM): Instituto Nacional de Pesquisas da Amazônia/Fundação Universidade do Amazonas; 1991.
    1. Naiff MF, Cupolillo E, Naiff RD, Momen H, Barret TV, Grimaldi G. Jr. Leishmaniose tegumentar americana na Amazônia: distribuição geográfica dos agentes etiológicos na região. Rev Soc Bras Med Trop 1999; 32 Suppl 1:243.
    1. Romero GA, Guerra MV, Paes MG, Macedo VO. Comparison of cutaneous leishmaniasis due to Leishmania (Viannia) braziliensis and L. (V.) guyanensis in Brazil: therapeutic response to meglumine antimoniate. The American Journal of Tropical Medicine and Hygiene. 2001; 65(5):456–65. .
    1. Chrusciak-Talhari A, Dietze R, Chrusciak Talhari C, da Silva RM, Gadelha Yamashita EP, de Oliveira Penna G, et al. Randomized controlled clinical trial to access efficacy and safety of miltefosine in the treatment of cutaneous leishmaniasis Caused by Leishmania (Viannia) guyanensis in Manaus, Brazil. Am J Trop Med Hyg. 2011; 84(2):255–60. 10.4269/ajtmh.2011.10-0155
    1. Machado PR, Ampuero J, Guimarães LH, Villasboas L, Rocha AT, Schriefer A, Souza RS, Talhari A, Penna G, Carvalho EM. Miltefosine in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in Brazil:a randomized and controlled trial. Plos Negl Trop Dis. 2010. December 21;4(12):e912 10.1371/journal.pntd.0000912
    1. Lainson R & Shaw JJ. Evolution, classification and geographical distribution In: Peters W, Killick-Kendrick eds. The Leishmaniasis in Biology and Medicine. London: Academic Press; 1987:1–120.
    1. Talhari S, Arias JR, Cunha MGS, Naiff RD, Naiff MF, Freitas RA, Barrett T. Leishmaniose no estado do Amazonas—aspectos epidemiológicos, clínicos e terapêuticos. An Bras Dermatol 1988; 63(6):433–38.
    1. Guerra JAO, Barros MLB, Guerra MVF, Talhari S, Paes MG. Leishmaniose Tegumentar no município de Manaus–Aspectos epidemiológicos. Rev Soc Bras Med Trop 2003: 31: supl. 1: 172.
    1. Reithinger R, Dujardin JC, Louzir H, Pirmez C, Alexander B, Brooker S. Cutaneous leishmaniasis. Lancet Infect Dis. 2007;7:581–596. 10.1016/S1473-3099(07)70209-8
    1. World Health O. Leishmaniasis—Epidemiological situation 2015 (accessed July 28, 2018).
    1. SisLeish-OPAS/WHO. 2017. Data recorded by Programas Nacionais de Leishmaniose/Vigilância. Assessed February 23, 2018.
    1. Guerra JA, Prestes SR, Silveira H, Coelho LI, Gama P, Moura A, et al. Mucosal Leishmaniasis caused by Leishmania (Viannia) braziliensis and Leishmania (Viannia) guyanensis in the Brazilian Amazon. PLoS neglected tropical diseases. 2011; 5(3):e980 10.1371/journal.pntd.0000980 .
    1. Guerra JAO, Ribeiro JAS, Coelho LIARC, Barbosa MGV, Paes MG. Epidemiologia da leishmaniose tegumentar na Comunidade São João, Manaus, Amazonas, Brasil. Cad Saude Publ. 2006; 22:2319–27
    1. Neves LO, Talhari AC, Gadelha EP, Silva RM Junior, Guerra JA, Ferreira LC, et al. A randomized clinical trial comparing meglumine antimoniate, pentamidine and amphotericin B for the treatment of cutaneous leishmaniasis by Leishmania guyanensis. Anais brasileiros de dermatologia. 2011; 86(6):1092–101.
    1. Nacher M, Carme B, Sainte Marie D, Couppié P, Clyti E, Guibert P, et al. Influence of clinical presentation on the efficacy of a short course of pentamidine in the treatment of cutaneous leishmaniasis in French Guiana. Ann Trop Med Parasitol. 2001;95:331–6. 10.1080/00034980120064355
    1. Pradinaud R. Le traitement de la leishmaniose tégumentaire par la pentamidine en Guyane française. Med Trop. 1994;54:418–22.
    1. Dorlo TPC, and Kager PA. Pentamidine dosage: a base/salt confusion. PLoS neglected tropical diseases, 2008: vol. 2 p. 225
    1. Bourreau Eliane et al. Presence of Leishmania RNA Virus 1 in Leishmania guyanensis Increases the Risk of First-Line Treatment Failure and Symptomatic Relapse. Journal of Infectious Diseases, p. jiv355, 2015
    1. Hu RVPF, Straetemans M, Kent AD, Sabajo LOA, de Vries HJC, Lai A Fat RFM. Randomized single-blinded non-inferiority trial of 7 mg/kg pentamidine isethionate versus 4 mg/kg pentamidine isethionate for cutaneous leishmaniaisis in Suriname. PLoS Negl Trop Dis, 2015
    1. Gadelha EPN, Guerra JAO, Talhari CC, da Silva RM, Talhari S, Ourives-Neves L, Gontijo B, Chrusciak-Talhari A. Efficacy and safety of a single dose pentamidine (7mg/kg) for patients with cutaneous leishmaniasis caused by L. guyanensis: a pilot study. Anais Brasileiros de Dermatologia (Online), 2015. v. 90, p. 807 10.1590/abd1806-4841.20153956
    1. Naafs B. Pentamidine-induced diabetes mellitus. Transactions of the Royal Society of Tropical Medicine and Hygiene, v. 79.1 (1985):141.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren