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.

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 This drug was withdrawn from the market in the eighties, and currently is available as PI.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.

Efficacy and safety of a single dose pentamidine (7mg/kg) for patients with cutaneous leishmaniasis caused by L. guyanensis: a pilot study

Abstract: BACKGROUND: There have been few studies on pentamidine in the Americas; and there is no consensus regarding the dose that should be applied. OBJECTIVES: To evaluate the use of pentamidine in a single dose to treat cutaneous leishmaniasis. METHODS: Clinical trial of phase II pilot study with 20 patients. Pentamidine was used at a dose of 7 mg/kg, in a single dose. Safety and adverse effects were also assessed. Patients were reviewed one, two, and six months after the end of treatments. RESULTS: there was no difference between the treatment groups in relation to gender, age, number or location of the lesions. Pentamidine, applied in a single dose, obtained an effectiveness of 55%. Mild adverse events were reported by 17 (85%) patients, mainly transient pain at the site of applications (85%), while nausea (5%), malaise (5%) and dizziness (5%) were reported in one patient. No patient had sterile abscess after taking medication at a single dose of 7mg/kg. CONCLUSIONS: Clinical studies with larger samples of patients would enable a better clinical response of pent amidine at a single dose of 7mg, allowing the application of more powerful statistical tests, thus providing more evidences of the decrease in the effectiveness of that medication. Hence, it is important to have larger studies with new diagrams and/or new medications.

Efficacy and safety of a single dose pentamidine (7mg/kg) for patients with cutaneous leishmaniasis caused by L. guyanensis: a pilot study.

BACKGROUND: There have been few studies on pentamidine in the Americas; and there is no consensus regarding the dose that should be applied. OBJECTIVES: To evaluate the use of pentamidine in a single dose to treat cutaneous leishmaniasis. METHODS: Clinical trial of phase II pilot study with 20 patients. Pentamidine was used at a dose of 7 mg/kg, in a single dose. Safety and adverse effects were also assessed. Patients were reviewed one, two, and six months after the end of treatments. RESULTS: there was no difference between the treatment groups in relation to gender, age, number or location of the lesions. Pentamidine, applied in a single dose, obtained an effectiveness of 55%. Mild adverse events were reported by 17 (85%) patients, mainly transient pain at the site of applications (85%), while nausea (5%), malaise (5%) and dizziness (5%) were reported in one patient. No patient had sterile abscess after taking medication at a single dose of 7mg/kg. CONCLUSIONS: Clinical studies with larger samples of patients would enable a better clinical response of pent amidine at a single dose of 7mg, allowing the application of more powerful statistical tests, thus providing more evidences of the decrease in the effectiveness of that medication. Hence, it is important to have larger studies with new diagrams and/or new medications.

Estudo clínico randomizado comparando antimoniato de meglumina, pentamidina e anfotericina B para o tratamento da leishmaniose cutânea ocasionada por Leishmania guyanensis / A randomized clinical trial comparing meglumine antimoniate, pentamidine and amphotericin B for the treatment of cutaneous leishmaniasis by Leishmania guyanensis

FUNDAMENTOS: O tratamento da leishmaniose tegumentar americana (LTA) ainda constitui desafio, pois a maioria dos medicamentos é injetável e têm-se poucos ensaios clínicos randomizados comparando a eficácia das drogas. Além disso, é provável que as espécies de Leishmania tenham influência nas respostas terapêuticas. OBJETIVOS: Avaliar e comparar a eficácia e a segurança dos esquemas de tratamento na LTA, ocasionada por Leishmania (Viannia) guyanensis. MÉTODOS: 185 pacientes foram selecionados, conforme critérios de elegibilidade, e distribuídos, aleatoriamente, em 3 grupos - 2 com 74 enfermos e outro com 37 - que receberam, respectivamente, antimoniato de meglumina, isotionato de pentamidina e anfotericina B em doses, períodos e vias de administração padronizados. Os enfermos foram reexaminados um, dois e seis meses após o final dos tratamentos. RESULTADOS: Não houve diferença entre os grupos terapêuticos em relação ao sexo, idade, número ou local das lesões. A análise por intenção de tratar (ITT) mostrou eficácias de 58,1 por cento para a pentamidina e 55,5 por cento para o antimoniato (p=0,857). O grupo da anfotericina B foi analisado separadamente, pois 28 (75,7 por cento) pacientes negaram-se a continuar no estudo após a randomização. Eventos adversos leves ou moderados foram relatados por 74 (40 por cento) pacientes, principalmente artralgia (20,3 por cento), para o grupo do antimoniato, e dor (35,1 por cento) ou enduração (10,8 por cento) no local das injeções para a pentamidina. CONCLUSÕES: A pentamidina tem eficácia similar ao antimonial pentavalente para o tratamento da LTA ocasionada por L. guyanensis. Face aos baixos resultados de eficácia apresentados por ambas as drogas, necessita-se, com urgência, investigar novas opções terapêuticas para esta enfermidade.

FUNDAMENTALS: American tegumentary leishmaniasis (ATL) treatment remains a challenge, since most available drugs are injectable and only a small number of comparative, randomized clinical trials have been performed to support their use. Moreover, treatment outcome may depend on the causative species of Leishmania. OBJECTIVES: To evaluate and compare the efficacy and tolerability of meglumine antimoniate, pentamidine isethionate, and amphotericin B in the treatment of ATL caused by Leishmania (Viannia) guyanensis. METHODS: 185 patients were selected according to the eligibility criteria and randomly allocated into three groups - two groups with 74 patients each, and one group with 37 patients, which underwent meglumine, pentamidine and amphotericin B treatment, respectively. Doses, mode of administration and time periods of treatment followed the current recommendations for each drug. Patients were re-examined one, two and six months after completion of treatment. RESULTS: No differences were observed among the therapeutic groups in relation to gender, age, number or site of lesions. Intention-to-treat (ITT) analysis showed efficacy of 58.1 percent for pentamidine and 55.5 percent for meglumine (p=0.857). The amphotericin B group was analyzed separately, since 28 patients (75.7 percent) in this group refused to continue participating in the study. Mild or moderate adverse effects were reported by 74 (40 percent) patients, especially arthralgia (20.3 percent) in the meglumine group, and pain (35.1 percent) or induration (10.8 percent) at the site of injection in the pentamidine group. CONCLUSION: Pentamidine and meglumine show similar efficacy in the treatment of ATL caused by L. guyanensis. Given the low efficacy of both drugs, there is an urgent need for new therapeutical approaches.

A randomized clinical trial comparing meglumine antimoniate, pentamidine and amphotericin B for the treatment of cutaneous leishmaniasis by Leishmania guyanensis.

FUNDAMENTALS: American tegumentary leishmaniasis (ATL) treatment remains a challenge, since most available drugs are injectable and only a small number of comparative, randomized clinical trials have been performed to support their use. Moreover, treatment outcome may depend on the causative species of Leishmania. OBJECTIVES: To evaluate and compare the efficacy and tolerability of meglumine antimoniate, pentamidine isethionate, and amphotericin B in the treatment of ATL caused by Leishmania (Viannia) guyanensis. METHODS: 185 patients were selected according to the eligibility criteria and randomly allocated into three groups - two groups with 74 patients each, and one group with 37 patients, which underwent meglumine, pentamidine and amphotericin B treatment, respectively. Doses, mode of administration and time periods of treatment followed the current recommendations for each drug. Patients were re-examined one, two and six months after completion of treatment. RESULTS: No differences were observed among the therapeutic groups in relation to gender, age, number or site of lesions. Intention-to-treat (ITT) analysis showed efficacy of 58.1% for pentamidine and 55.5% for meglumine (p=0.857). The amphotericin B group was analyzed separately, since 28 patients (75.7%) in this group refused to continue participating in the study. Mild or moderate adverse effects were reported by 74 (40%) patients, especially arthralgia (20.3%) in the meglumine group, and pain (35.1%) or induration (10.8%) at the site of injection in the pentamidine group. CONCLUSION: Pentamidine and meglumine show similar efficacy in the treatment of ATL caused by L. guyanensis. Given the low efficacy of both drugs, there is an urgent need for new therapeutical approaches.