Abstract
Previous studies have shown that the association of the drug meglumine antimoniate (MA) with β-cyclodextrin can improve its bioavailability by the oral route. In this work, ribose and maltose were investigated for their ability to form mixed or association complexes with MA, release MA and modulate the serum levels of Sb after oral administration in mice. Analysis of the MA/ribose composition by high performance liquid chromatography coupled to mass spectrometry (LCMS-IT-TOF) revealed the presence of mixed meglumine-Sb-ribose and Sb-ribose complexes. Analysis of the MA/maltose composition suggested the formation of MA-maltose association compounds. Circular dichroism characterization of these compositions following dilution in water at 37 °C suggested a partial and slow dissociation of the association compounds. When the MA/ribose composition was administered orally and compared to MA, the serum concentration of Sb was significantly lower after 1 h and greater after 3 h. On the other hand, the MA/maltose composition showed similar serum Sb concentration after 1 h and higher level of Sb after 3 h, when compared to MA. In conclusion, the present study has demonstrated the formation of mixed or association complexes of MA with sugars, such as maltose and ribose, which promoted sustained serum level of Sb after oral administration.
Highlights
Leishmaniases are infective tropical parasitic diseases, which are endemic in 98 countries, reaching up to 1.2 million new cases per year, affecting mainly poor and marginalized populations, with 90% of cases ocurring in just six countries: India, Bangladesh, Sudan, South Sudan, Brazil and Ethiopia [1].The clinical manifestations of the complex of diseases can involve the skin, with local, diffuse or disfiguring lesions, or the viscera, leading to death if untreated
The results indicate that meglumine antimoniate (MA)/maltose and MA/ribose compositions act as sustained drug release systems, prolonging the serum level of Sb after oral administration in mice
Evidence for the interaction of MA with ribose or maltose was first obtained by circular dichroism
Summary
Leishmaniases are infective tropical parasitic diseases, which are endemic in 98 countries, reaching up to 1.2 million new cases per year, affecting mainly poor and marginalized populations, with 90% of cases ocurring in just six countries: India, Bangladesh, Sudan, South Sudan, Brazil and Ethiopia [1]. Even though pentavalent antimonials are still the first-line drugs against all forms of leishmaniasis in several countries, their use in the clinical setting shows several limitations [2]. These compounds have to be given parenterally, daily, for at least three weeks (typically, 20 mg of Sb/kg/day for 20–30 days). Its long half-life (~150 h) and the 28-days treatment duration make the drug critically prone to low compliance and emergence of drug resistance [4] In this context, new drugs must be developed that are capable of being administered orally with minimal medical supervision, at an affordable price. MA/β-CD compositions was attributed to the formation of a NMG-Sb-β-CD complex that maintains the antimonial compound depolymerized and sustainedly releases the low molecular-weight 1:1. The results indicate that MA/maltose and MA/ribose compositions act as sustained drug release systems, prolonging the serum level of Sb after oral administration in mice
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