Sodium Stibogluconate

Toxicity

The main symptoms of antimony overdosage are gastro-intestinal disturbances (nausea, vomiting and severe diarrhoea). Haemorrhagic nephritis and hepatitis may also occur.

Description

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.

Description

Sodium stibogluconate (Na3Sb2C12H38O26), also known as sodium antimony(V) gluconate, is a solid ionic compound that is freely soluble in water. Its precise structure is unknown; the one shown here is idealized based on the atomic formula.
Workers in India prepared sodium stibogluconate in the late 1940s via the reaction of antimony pentoxide with sodium hydroxide. It has been used since then as an injectable drug for treating visceral leishmaniasis, a fatal insect-borne microbial disease.
Visceral leishmaniasis is the most virulent form of the disease, which is caused by protozoa of the genus Leishmania. The parasite is transported by several genera of flying insects and introduced into the skin by insect bites. The initial symptom is skin ulcers, followed by fever, low red blood count, and enlarged internal organs. It is a prevalent disease among poor, malnourished populations.
Over the years, Indian scientists observed that in areas where the drinking water is contaminated with As(III), Individuals not only suffer from arsenic toxicity, but they do not respond well to the leishmaniasis treatment. The Sb(V) in stibogluconate is reduced to Sb(III) by the Leishmania parasite before the antimony disrupts the bug’s defenses; As(III) works the same way. Researchers now believe that Leishmania mutations may have caused the microbe to become resistant to As(III) and Sb(III).
In 2005, the Indian government stopped recommending the use of antimony-based drugs, but sodium stibogluconate and others continue to be used because alternatives are significantly more expensive. As a result, cure rates plunged by ≈60% between 2006 and 2010.

The Uses of Sodium Stibogluconate

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.

The Uses of Sodium Stibogluconate

Sodium Stibogluconate is an intermediate used to prepare Dihydropyrido[2,3-d]pyrimidines as a new class of antileishmanial agents.

Background

Sodium stibogluconate is a medicine used to treat leishmaniasis and is only available for administration by injection. It belongs to the class of medicines known as the pentavalent antimonials. Sodium stibogluconate is sold in the UK as Pentostam (manufactured by GlaxoSmithKline). Widespread resistance has limited the utility of sodium stibogluconate, and in many parts of the world, amphotericin or miltefosine are used instead. It is also being investigated as an anti-tumor agent.

Indications

For the treatment of various types of a protozoal infection called leishmaniasis, which may result from sandfly bites in tropical and temperate parts of the world. Also investigated for use/treatment in cancer/tumors (unspecified) and solid tumors.

What are the applications of Application

Sodium stibogluconate is a robust inhibitor of PTPases, including PTPase1 (SHP-1), SHP-2, and PTP1B

Antimicrobial activity

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 Sb^V to toxic Sb^III 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.

Acquired resistance

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 Sb^III 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 (Sb^V). The structural formula is conjectural as studies have identified a mixture of non-complexed Sb^V and large polymeric gluconate complexes. Chemical composition also depends on concentration and time. It is freely soluble in water.

Pharmacokinetics

The mode of action of sodium stibogluconate is not clearly understood. In vitro exposure of amastigotes to 500 mg pentavalent antimony/ml results in a greater than 50% decrease in parasite DNA, RNA protein and purine nucleoside triphosphate levels. It has been postulated that the reduction in ATP (adenosine triphosphate) and GTP (guanosine triphosphate) synthesis contributes to decreased macromolecular synthesis.

Pharmacokinetics

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 Sb^V is converted to Sb^III, 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 Sb^V and SbIII were similar as measured by serum and urine levels.

Clinical Use

Visceral, cutaneous and mucocutaneous leishmaniasis
The combination with paromomycin has been used in unresponsive cases and in relapses of visceral and cutaneous leishmaniasis.

Clinical Use

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.

Side Effects

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.

Safety Profile

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.

Drug interactions

otentially hazardous interactions with other drugs
P Antifungals: possible increased risk of arrhythmias with amphotericin - give 14 days apart.

Metabolism

Not Available

Metabolism

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.