Sodium stibogluconate is a pentavalent antimony derivative that is highly active against Leishmania amastigotes in macrophages. Sodium stibogluconate has diverse effects on both this intracellular parasite and its host cell.
Sodium stibogluconate is a pentavalent antimony derivative that is highly active against Leishmania amastigotes in macrophages. Sodium stibogluconate has diverse effects on both this intracellular parasite and its host cell.
Sodium Stibogluconate is an intermediate used to prepare Dihydropyrido[2,3-d]pyrimidines as a new class of antileishmanial agents.
It has low activity against the extracellular promastigote stage
of Leishmania spp. in vitro, but is active against amastigotes
in macrophages. The trivalent form is considered to be the
toxophore, with metabolism of SbV to toxic SbIII in the host
cell macrophage and the parasite; the level of metabolism is
higher in amastigotes than promastigotes. Variation in the sensitivity
of different Leishmania species may contribute to differences
in clinical response. It is more active against visceral
than cutaneous leishmaniasis in animal models. Sodium stibogluconate
cures CNS infections with T. brucei in rodents.
Unresponsiveness and relapse of L. donovani infections in
Bihar State, India (over 60% of cases), is due to increasing
acquired resistance. In laboratory-generated and clinical
isolates,
resistant Leishmania promastigotes show increased
levels of intracellular thiols, for example trypanothione, to
which SbIII is conjugated and extruded by efflux pumps.
Lack of response is also reported in patients with mucosal
leishmaniasis caused by L. braziliensis. Relapse is common
in patients with visceral leishmaniasis who are immunosuppressed,
for example by HIV infection, but this is due to
pathogen interaction and the immune dependence of drug
activity and not acquired resistance. High mortality has been
reported in treatment of these co-infection cases.
Pharmaceutical Applications
A pentavalent antimonial of uncertain chemical composition; probably a complex mixture of polymeric forms. There is batchto- batch variation and solutions may contain 32–34% pentavalent antimony (SbV). The structural formula is conjectural as studies have identified a mixture of non-complexed SbV and large polymeric gluconate complexes. Chemical composition also depends on concentration and time. It is freely soluble in water.
Peak concentrations of about 12–15 mg antimony/L are
achieved in serum 1 h after a dose of 10 mg/kg. There is a slow
accumulation in the central compartment, and tissue concentrations
reach a maximum after several days. In contrast to trivalent
derivatives, pentavalent antimonials are not accumulated by
erythrocytes, but there is evidence of protein binding. Antimony
is detected in the skin for at least 5 days after treatment. Some
of the dose of SbV is converted to SbIII, possibly by the liver or
by macrophages. It is rapidly excreted into urine with a half-life
of about 2 h; 60–80% of the dose appears in the urine within
6 h of parenteral administration. In a study on structurally related
meglumine antimonate the pharmacokinetics of SbV
and SbIII were similar as measured by serum and urine levels.
Visceral, cutaneous and mucocutaneous leishmaniasis
The combination with paromomycin has been used in unresponsive
cases and in relapses of visceral and cutaneous
leishmaniasis.
Sodium antimony gluconate (Pentostam) is a pentavalent antimonialcompound intended primarily for the treatment ofvarious forms of leishmaniasis. It is available from the CDCas the disodium salt, which is chemically stable and freelysoluble in water. The 10% aqueous solution used for eitherintramuscular or intravenous injection has a pH of approximately5.5. Like all antimonial drugs, this drug has a lowtherapeutic index, and patients undergoing therapy with itshould be monitored carefully for signs of heavy metal poisoning.Other organic antimonial compounds are used primarilyfor the treatment of schistosomiasis and other flukes.The antileishmanial action of sodium stibogluconate requiresits reduction to the trivalent form, which is believedto inhibit phosphofructokinase in the parasite.
The toxic effects are limited by the rapid excretion, but cumulative
toxicity increases in proportion to dose. Myalgia, arthralgia,
anorexia and electrocardiographic changes have been
reported with high-dose regimens. In particular, development
of ventricular tachyarrhythmias associated with prolongation
of the QT interval has been recorded. Hepatocellular damage,
hepatic and renal functional impairment and pancreatitis
have also been reported. The changes are reversible on discontinuation
of treatment.
Poison by
intraperitoneal route. When heated to
decomposition it emits toxic fumes of Sb.
Veterinary Drugs and Treatments
Sodium stibogluconate is used for the treatment of leishmaniasis
in dogs.
otentially hazardous interactions with other drugs
P
Antifungals: possible increased risk of arrhythmias
with amphotericin - give 14 days apart.
No data on possible metabolic pathways.
Elimination occurs in two phases; a rapid initial phase, in
which the majority of a dose is excreted via the kidneys
within 12 hours, and a slower phase, possibly reflecting
reduction to trivalent antimony.
