In Vitro antileishmanial properties of neutron-irradiated meglumine antimoniate

Abstract

Pentavalent antimony, as meglumine antimoniate (Glucantime® ) or sodium stibogluconate (Pentostam® ), is the main treatment for leishmaniasis, a complex of diseases caused by the protozoan Leishmania, and an endemic and neglected threat in Brazil. Despite over half a century of clinical use, their mechanism of action, toxicity and pharmacokinetic data remain unknown. The analytical methods for determination of antimony in biological systems remain complex and have low sensitivity. Radiotracer studies have a potential in pharmaceutical development. The aim of this study was to obtain a radiotracer for antimony, with suitable physical and biological properties. Meglumine antimoniate was neutron irradiated inside the IEA-R1 nuclear reactor, producing two radioisotopes 122Sb and 124Sb, with high radionuclidic purity and good specific activity. This compound showed the same antileishmanial activity as the native compound. The use of the radiotracers, easily created by neutron irradiation, could be an interesting tool to solve important questions in antimonial pharmacology.<br>Os antimoniais pentavalentes, como o antimoniato de meglumina (Glucantime® ) ou estibogluconato de sódio (Pentostam® ), são o principal tratamento para a leishmaniose, um complexo de doenças causadas pelo protozoário parasita Leishmania, uma doença endêmica e negligenciada no Brasil. Apesar do seu uso clínico por mais de meio século, seu mecanismo de ação, toxicidade e dados de farmacocinética permanecem desconhecidos. Os métodos analíticos para determinação de antimônio em sistemas biológicos são complexos e apresentam baixa sensibilidade. Estudos utilizando radiotraçadores têm papel potencial no desenvolvimento farmacológico. O objetivo deste estudo foi desenvolver um radiotraçador de antimônio, com propriedades físicas e biológicas adequadas. O antimoniato de meglumina foi irradiado por nêutrons no reator nuclear IEA-R1, produzindo dois radioisótopos: 122Sb e 124Sb, com alta pureza radionuclídica e boa atividade específica. Este composto mostrou atividade antileishmania similar ao fármaco não irradiado. O uso de radiotraçadores, facilmente produzidos por irradiação por nêutrons pode ser um importante instrumento para elucidar questões sobre a farmacologia dos antimoniais

Biodistribution of meglumine antimoniate in healthy and Leishmania (Leishmania) infantum chagasi-infected BALB/c mice

“…Production and analysis of irradiated MA (IMA) - To produce the antimony radiotracer, 0.5-0.8 mL aliquots of MA were sealed in quartz ampoules and irradiated at the IEA-R1 nuclear reactor facility of Institute of Nuclear and Energy Research-National Commission of Nuclear Energy (SP) using a thermal neutron flux of 1.0 × 10 13 n 2 /cm/s for 7 min as previously described by Borborema et al (2005) . Antimony radioisotopes were produced by the following nuclear reactions: 121 Sb(n,γ) 122 Sb and 123 Sb(n,γ) 124 Sb.…”

Antileishmanial Activity of Medicinal Plants Used in Endemic Areas in Northeastern Brazil

“…Despite their extensive clinical use for several decades, the mechanism of action remains unclear [ 10 ]. Other drugs used to treat leishmaniasis include pentamidine and amphotericin B, but the use of these drugs has been limited due to their high toxicity and cost [ 11 ]. Recently, the oral drug miltefosine was approved for the treatment of human visceral Leishmania infections, and fluconazole taken orally is also effective against cutaneous leishmaniasis [ 12 ].…”

Pharmacokinetics of neutron-irradiated meglumine antimoniate in Leishmania amazonensis-infected BALB/c mice

“…Studying the biodistribution of MA is easier when the drug is radioactive, but there are no antimony radioisotopes commercially available. As we previously described, irradiating the MA was the best choice by which to support this goal in in vivo studies [21,22,24,25]. The advantage of this procedure is that neutron irradiation of the stable antimony isotopes present in the MA formulation enables the detection and quantification of total antimony, but without distinguishing between the pentavalent and trivalent antimony species.…”