Pharmacology and human toxicology of antimony drugs

No effective vaccine for Leishmania has yet been developed; chemotherapy remains the only way at present of treating the disease. Dosage of antimony drugs is based on the amount of metal (antimony) administered per body weight. The early trial of treatment of visceral leishmaniasis by sodium stiboglu-conate was recommended to be 10 mg kg-1 day-1 for the period of 6-10 days. Despite a high cure rate, increasing resistance and relapses have been reported.44 46 Currently, the optimum overall dosage of the drug is roughly 20 mg kg-May-1 with maximum 850 mg of antimony per day for 20 30 days.47,48

Antimony compounds have been known for their much lower toxicity in humans compared with arsenic. Generally, SbIII is more toxic than its penta-valent analogue (SbV),49 with 50% of a lethal dose (LD50) ranging from 172 to 4000 mg kg- in mice and rats (for SbIII), in contrast to the highly toxic arsenic compound (e.g. Me2AsCl ~5mgkg-1).15 Nevertheless, side-effects of SbIn such as nausea, vomiting, weakness and myalgia, abdominal colic, diarrhea and skin rashes, together with the most important cardiotoxicity, have been observed.50

It was also reported that when 10 times of the daily recommended sodium stibogluconate was accidentally administered in a case of cutaneous leishman-iasis treatment (8500 mg per day), no serious toxicity was observed and the overdose was tolerated.51 This suggests that although not recommended, a single high dose of SbV has little side-effect on patients.

Genotoxicity has been shown in SbCl3 and Sb2O3 by inducing sister chro-matid exchange (SCE) in V79 cells and human lymphocytes.52 54 In contrast, no significant SCE activity was found in their pentavalent analogues.52 In addition to elevating the SCE activity, SbCl3 also triggers DNA damage and induces apoptosis in Chinese hamster and human cells after short-term exposure (>50 mM). This again suggests the limited toxicity of SbV is preferable to the trivalent form. SbIn compounds have also been found to inhibit the repair of DNA damage. The inhibition of repair of radiation-induced DNA doublestrand breaks was observed to be dose dependent when SbCl3 or PAT was incubated with Chinese hamster ovary cells.55

Antimony-induced oxidative stress and cardiotoxicity have been reported previously. PAT induces cell death and decrease of spontaneous beat rate;

reduced intracellular glutathione (GSH) levels and increased lipid pre-oxidation were also observed in cardiac myocytes.56 Detailed studies on the mechanisms of PAT on cardiac myocytes revealed that depletion of cellular ATP levels due to inhibition of pyruvate dehydrogenase and disruption of cellular thiol homeostasis due to inhibition of glutathione peroxidase to cardiac myocytes conferred antimony cardiotoxicity.57

In spite of the relatively low toxicity of antimony, SbV and/or Sb111 administered for treatment dosage still places a heavy load on the parasite-weakened body. One study on the meglumine antimonate treatment of visceral leishmaniasis patients co-infected with human immunodeficiency virus (HIV) type-1 showed that severe side-effects and even fatality could occur at the dosing schedule recommended by the centers for disease control and prevention (CDCP) (Atlanta, GA).58

Since the mid-1980s, visceral leishmaniasis has been increasingly reported as a complication of AIDS. In 1999, more than 1400 cases of HIV-Leishmania co-infection were reported. Therefore pentavalent antimonials have been frequently used in co-infected patients. The treatment with 20 mg of antimonial compounds kg_1day_1, with a maximum daily dose of 850 mg in adults, seemed to be ineffective for most HIV-infected patients. Higher antimonial doses (>20 mg of SbVkg-1 day-1), with no upper-limited daily dose, have been recommended for immunocompetent patients, and some reports have shown that this treatment could be more effective in HIV-related visceral leishmaniasis.59

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