Pentavalent antimonials: new perspectives for old drugs

Abstract

Pentavalent antimonials, including meglumine antimoniate and sodium stibogluconate, have been used for more than half a century in the therapy of the parasitic disease leishmaniasis. Even though antimonials are still the first-line drugs, they exhibit several limitations, including severe side effects, the need for daily parenteral administration and drug resistance. The molecular structure of antimonials, their metabolism and mechanism of action are still being investigated. Some recent studies suggest that pentavalent antimony acts as a prodrug that is converted to active and more toxic trivalent antimony. Other works support the direct involvement of pentavalent antimony. Recent data suggest that the biomolecules, thiols and ribonucleosides, may mediate the actions of these drugs. This review will summarize the progress to date on the chemistry and biochemistry of pentavalent antimony. It will also present the most recent works being done to improve antimonial chemotherapy. These works include the development of simple synthetic methods for pentavalent antimonials, liposome-based formulations for targeting the Leishmania parasites responsible for visceral leishmaniasis and cyclodextrin-based formulations to promote the oral delivery of antimony.

Figure 1

Proposed structural formula for 364 Da and 365 Da ions identified by ESI(-)-MS in aqueous solutions of meglumine antimoniate and stibogluconate, respectively. Adapted from Ref. [23].

Figure 2

Two main models proposed for the mechanism of action of pentavalent antimonials against leishmaniasis. According to the “Prodrug model”, Sb(V) is reduced to Sb(III) in order to exert antileishmanial activity. According to the “Active Sb(V) model”, Sb(V) exhibits intrinsic antileishmanial activity.

Figure 3

Processes used for the preparation of meglumine antimoniate-containing liposomes of different size. Adapted from Ref. [84,85,86,87].

Figure 4

Influence of liposome encapsulation and of vesicle mean diameter on antimony level in the bone marrow of infected dogs, 96 h after intravenous bolus injection of meglumine antimoniate. Small liposomes (mean vesicle diameter of 400 nm) were given at 4 mg Sb/kg of body weight (n = 5). Large liposomes (mean vesicle diameter of 1,200 nm) were given at 5.5 mg Sb/kg of body weight (n = 10). Meglumine antimoniate was given at 100 mg Sb/kg of body weight (n = 5). Data are given as means ± standard deviation. *P <0.001 for One-way ANOVA followed by Bonferroni post-test. Adapted from Ref. [84].

Figure 5

Model proposed for the mechanisms involved in the enhanced absorption of Sb from oral meglumine antimoniate/β-CD composition. The meglumine antimoniate/β-CD nanoassemblies comprising high-molecular weight meglumine antimoniate/β-CD complexes, such as NMG-Sb-β-CD-Sb-NMG species, migrate along the gastrointestinal tract. These nanoassemblies then slowly release meglumine antimoniate in the form of 1:1 Sb-NMG complex which permeates by simple diffusion across the gastrointestinal epithelium. β-CD continue migrating up to the colon where it is degraded. Adapted from Ref. [102].