Sodium Stibogluconate (DB05630): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Sodium stibogluconate (SSG) is a pentavalent antimonial compound that has served as a cornerstone in the treatment of the parasitic disease leishmaniasis for over half a century.[1] First introduced into medical use in the 1940s, it has been the historical mainstay for all three clinical forms of the disease: visceral, cutaneous, and mucosal leishmaniasis.[3] The drug is administered parenterally and functions as a prodrug, requiring reduction to its active trivalent antimony form within host macrophages and the parasite itself to exert its leishmanicidal effects.[4] Its mechanism of action, while not fully elucidated, is believed to be multifactorial, involving the critical disruption of the parasite's energy metabolism through the inhibition of glycolysis and the citric acid cycle, leading to the depletion of adenosine triphosphate (ATP) and guanosine triphosphate (GTP) pools, as well as the inhibition of DNA topoisomerase I.[3]

Despite its historical importance, the clinical utility of sodium stibogluconate has been significantly eroded by the global emergence of widespread drug resistance, particularly in key endemic areas for visceral leishmaniasis, such as the Indian subcontinent.[5] This has led to its replacement with alternative therapies like liposomal amphotericin B and miltefosine in many first-line treatment guidelines.[7] Furthermore, the drug is associated with a significant and challenging safety profile. Common adverse effects include musculoskeletal pain, gastrointestinal disturbances, and biochemical abnormalities, while severe, life-threatening toxicities such as pancreatitis and cardiotoxicity—manifesting as electrocardiogram changes and potentially fatal arrhythmias—require rigorous clinical monitoring.[1]

In a modern context, sodium stibogluconate is being re-examined for its potential as an antineoplastic agent. This new avenue of investigation is based on a distinct pharmacological property: its potent and selective inhibition of protein tyrosine phosphatases (PTPases), particularly SHP-1, which are key negative regulators of cellular signaling pathways implicated in cancer.[11] This has led to an orphan drug designation by the U.S. Food and Drug Administration for the treatment of acute myeloid leukemia (AML) and ongoing clinical trials.[14] Consequently, sodium stibogluconate represents a compound at a clinical crossroads—a legacy drug for a neglected tropical disease facing challenges of resistance, yet simultaneously a subject of modern pharmacological research with potential for repurposing in oncology.

Chemical Profile and Physicochemical Properties

Identification and Nomenclature

Sodium stibogluconate is a small molecule drug belonging to the pentavalent antimonial class of medicines.[3] It is identified by a range of synonyms and commercial names that reflect its chemical nature and history. The primary brand name is Pentostam, manufactured by GlaxoSmithKline and sold in the United Kingdom.[3] Other historical or regional brand names include Myostibin, Solustibosan, Stibanate, Stibanose, and Stibinol.[6] Common chemical synonyms include Antimony Sodium Gluconate, Stibogluconate Sodium, Natrii stibogluconas, and the Spanish equivalent, Estibogluconato sodico.[6] Its classification in the Anatomical Therapeutic Chemical (ATC) system is under the code P01CB02.[3]

Table 1: Key Identifiers and Chemical Properties of Sodium Stibogluconate

Identifier Type	Value / Property	Source(s)
Database Identifiers
DrugBank ID	DB05630	3
CAS Number	16037-91-5 (nonhydrate)	3
FDA UNII	APJ6285Y89 (nonhydrate)	5
PubChem CID	16685683	3
ATC Code	P01CB02	3
Chemical Structure
IUPAC Name (Idealized)	2,4:2',4'-O-(oxydistibylidyne)bis	3
Molecular Formula	Variable; examples include: $C_{12}H_{35}Na_{3}O_{26}Sb_{2}$, $C_{12}H_{17}O_{17}Sb_{2} \cdot 3Na \cdot 9H_{2}O$	3
Molecular Weight	Variable; reported values range from approx. 907.88 to 925.9 g/mol	5
Physicochemical Properties
Physical State	Solid; white to pale yellow powder	5
Solubility	Freely soluble in water; may require heating to ~75 °C for full dissolution	4
Stability	Hygroscopic; solutions are unstable and should be prepared just prior to use	5
Storage Conditions	2-8°C or -20°C; protect from light, keep desiccated	12
Formulation	Injectable solution; typically 100 mg pentavalent antimony per mL	1

Molecular Structure and Compositional Ambiguity

A defining characteristic of sodium stibogluconate is the ambiguity of its precise chemical structure. It is not considered a discrete molecular entity but rather a complex and heterogeneous mixture of polymeric compounds.[3] The chemical composition is known to be variable, depending on factors such as concentration, time, and manufacturing batch.[5] Structures presented in chemical databases are therefore idealized or conjectural, based on the expected coordination of pentavalent antimony with D-gluconic acid.[3] The most commonly cited idealized structure involves two gluconate molecules complexed with two antimony atoms linked by an oxygen bridge, forming a 2,4:2',4'-O-(oxydistibylidyne)bis core.[3]

This inherent structural ambiguity is reflected in the inconsistent reporting of its molecular formula and weight across various sources. For example, formulas such as $C_{12}H_{35}Na_{3}O_{26}Sb_{2}$, $C_{12}H_{17}O_{17}Sb_{2} \cdot 3Na \cdot 9H_{2}O$, and $C_{12}H_{36}Na_{3}O_{26}Sb_{2}^{+}$ have all been reported, leading to calculated molecular weights that vary from approximately 907 to 925 g/mol.[3] This lack of a single, defined chemical structure is not merely a technical detail; it carries significant clinical implications. The potential for batch-to-batch variability in the proportion of different polymeric species or the presence of impurities can directly influence the drug's safety and efficacy profile. This was tragically illustrated in an outbreak of fatal cardiotoxicity in Nepal, which was linked to a specific generic batch of the drug, suggesting that manufacturing differences can result in clinically meaningful variations in toxicity.[21]

Physicochemical Characteristics

Sodium stibogluconate is supplied as a white or pale yellow, hygroscopic solid powder.[5] It is freely soluble in water, which facilitates its preparation as an injectable solution for parenteral administration.[4] However, some preparations may require heating to approximately 75°C or constant stirring overnight at room temperature to achieve complete solubilization.[5] Aqueous solutions are considered unstable and should be freshly prepared just prior to use to ensure potency and safety.[19]

The standard pharmaceutical formulation is an injectable solution containing the equivalent of 100 mg of pentavalent antimony ($Sb^{V}$) per mL.[1] These solutions also contain preservatives, such as m-chlorocresol, to maintain sterility.[1] Recommended storage conditions for the powder form are typically refrigeration (2-8°C) or freezing (-20°C), with the product kept in a desiccated environment and protected from light to prevent degradation.[12] Under these conditions, the drug is reported to be stable for at least four years.[24]

Pharmacology and Mechanism of Action

Pharmacodynamics

The pharmacodynamic profile of sodium stibogluconate is complex, with distinct mechanisms underlying its antileishmanial and potential antineoplastic activities. Although its mode of action against Leishmania parasites is not fully understood, it is known to be a multi-pronged assault on the parasite's fundamental biological processes.[3]

Antileishmanial Activity

Sodium stibogluconate is a prodrug. The administered pentavalent antimony ($Sb^{V}$) is relatively non-toxic and must undergo biological reduction to its pharmacologically active trivalent state ($Sb^{III}$) to exert its leishmanicidal effect.[4] This conversion occurs intracellularly, both within the host macrophage and within the amastigote form of the Leishmania parasite, which resides inside the macrophage.[5] The higher rate of metabolic reduction within the amastigote compared to the extracellular promastigote stage likely contributes to the drug's selective activity against the clinically relevant intracellular form of the parasite.[5] Once formed, the active $Sb^{III}$ toxophore disrupts parasite viability through several proposed mechanisms:

1. Disruption of Energy Metabolism: The primary mechanism is believed to be the inhibition of key parasite enzymes involved in energy production. $Sb^{III}$ interferes with both glycolysis and the citric acid cycle, leading to a profound reduction in the parasite's intracellular pools of ATP and GTP.[3] This energy crisis cripples the parasite's ability to function, resulting in a greater than 50% decrease in the synthesis of essential macromolecules, including DNA, RNA, and proteins.[6]
2. Inhibition of DNA Topoisomerase I: Sodium stibogluconate has been shown to be a direct inhibitor of DNA topoisomerase I.[6] This enzyme is crucial for relieving the torsional stress in DNA that occurs during replication and transcription. Its inhibition leads to DNA damage and further disrupts the synthesis of essential macromolecules, contributing to parasite death.[6]
3. Interaction with Thiol Groups: The active $Sb^{III}$ moiety is thought to bind to sulfhydryl (thiol) groups on parasite proteins and enzymes, disrupting their function.[11] The parasite's primary defense against this is the thiol-containing molecule trypanothione. Resistance to antimonials is associated with increased levels of intracellular trypanothione, which can conjugate with $Sb^{III}$ and facilitate its extrusion from the parasite via efflux pumps.[5]

Enzymatic Inhibition and Antineoplastic Potential

Separate from its antiprotozoal effects, sodium stibogluconate possesses a distinct pharmacological activity as a potent and selective inhibitor of protein tyrosine phosphatases (PTPases), a family of enzymes that act as key negative regulators in cellular signaling pathways.[11] This property forms the scientific basis for its investigation as an anti-cancer agent.

The drug covalently modifies sulfhydryl groups in the cysteine residues of the PTPase active site, leading to irreversible inhibition.[11] It exhibits high selectivity for the Src homology 2 (SH2) domain-containing tyrosine phosphatase-1 (SHP-1), causing 99% inhibition at concentrations of approximately 10-11 µM.[12] It also inhibits SHP-2 and PTP1B, but at concentrations roughly ten times higher (~110 µM).[12] By inhibiting these phosphatases, which normally act as brakes on signaling pathways, sodium stibogluconate can augment cytokine-induced signaling. For example, it has been shown to enhance IL-3-induced phosphorylation of Jak2 and Stat5 and to augment proliferation in response to IL-3 and GM-CSF.[19] In the context of cancer, this PTPase inhibition is hypothesized to restore apoptotic signaling pathways that are suppressed in tumor cells, potentially overcoming resistance to apoptosis. This is the rationale for its investigation in combination with agents like interferon-alpha (IFN-alpha) in cancer therapy.[11]

Pharmacokinetics

The pharmacokinetic profile of sodium stibogluconate is characterized by its parenteral route of administration, rapid renal clearance, and notable inter-individual variability.

Absorption, Distribution, Metabolism, and Excretion (ADME)

Due to poor gastrointestinal absorption, sodium stibogluconate must be administered parenterally, either via intramuscular (IM) injection or slow intravenous (IV) infusion.[3] Following IM administration, peak blood concentrations of antimony are reached in approximately 1.3 hours.[26] The drug does not appear to accumulate significantly in tissues with daily dosing.[3] Its volume of distribution ($V_{d}$) has been reported to be approximately 45.7 L, suggesting distribution beyond the plasma volume.[26]

The metabolism of sodium stibogluconate is not well characterized, but the critical metabolic step is the intracellular reduction of $Sb^{V}$ to the active $Sb^{III}$ form.[4] The primary route of elimination for the parent compound is via the kidneys.[1] The majority of an administered dose is excreted in the urine within 24 hours, with a reported renal clearance of approximately 12.7 L/hr.[1] The elimination half-life is relatively short, estimated to be around 6 hours in humans, which necessitates daily dosing to maintain therapeutic concentrations.[18]

Population Variability

A significant finding in the pharmacokinetics of sodium stibogluconate is the evidence of a bimodal distribution pattern of drug exposure among patients.[26] A study analyzing the area-under-the-curve (AUC) after IM administration identified two distinct populations: "rapid eliminators," who exhibited low drug exposure (low AUC), and "slow eliminators," who had significantly higher drug exposure (high AUC).[26]

This pharmacokinetic variability may provide a crucial mechanistic explanation for the wide range of clinical outcomes observed with the drug. Patients who are rapid eliminators may be at higher risk of achieving sub-therapeutic drug concentrations, potentially leading to treatment failure and the development of drug resistance. Conversely, patients who are slow eliminators would experience higher and more prolonged exposure to the drug, placing them at a substantially increased risk for dose-dependent toxicities, particularly the severe adverse events of pancreatitis and cardiotoxicity. This suggests that individual differences in drug handling could be a key determinant of both efficacy and safety, and that therapeutic drug monitoring, though not standard practice, could potentially be used to optimize dosing and improve patient outcomes.

Clinical Applications and Efficacy

Treatment of Leishmaniasis

For over five decades, sodium stibogluconate has been a primary therapeutic agent for all three major clinical syndromes of leishmaniasis: visceral, cutaneous, and mucosal.[1] Treatment protocols have evolved over time to combat increasing unresponsiveness, with current international guidelines generally recommending a higher daily dose than was used historically.[2]

General Dosing Principles

The standard recommended dose, supported by the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC), is 20 mg/kg/day of pentavalent antimony ($Sb^{V}$), administered as a single daily dose.[1] While older guidelines and package inserts often cited a maximum daily dose of 850 mg, extensive clinical experience has led to the conclusion that this restriction should be removed, as a full weight-based dose (without an upper cap) is more efficacious and not substantially more toxic.[2] Treatment is administered via slow intravenous infusion (over at least five minutes with cardiac monitoring) or deep intramuscular injection.[3]

Table 2: Recommended Dosing Regimens for Leishmaniasis

Form of Leishmaniasis	Recommended Regimen (Systemic)	Duration of Therapy	Key Considerations	Source(s)
Visceral Leishmaniasis (VL)	20 mg/kg/day $Sb^{V}$ IV or IM	28 days	First-line only in regions with low antimony resistance. Combination with paromomycin is recommended in East Africa.	2
Cutaneous Leishmaniasis (CL)	20 mg/kg/day $Sb^{V}$ IV or IM	20 days	Systemic therapy is recommended for New World CL (L. Viannia subgenus) to prevent mucosal spread, or for complex/multiple lesions.	2
Mucocutaneous Leishmaniasis (ML)	20 mg/kg/day $Sb^{V}$ IV or IM	28 days	Requires a longer course of therapy due to the destructive nature of the disease.	2
Intralesional (for CL)	0.1 mL/cm² (0.2–5 mL total) injected into lesion(s)	Repeated every 3–7 days until healing	An option for single or few small, uncomplicated lesions. Not for use on sensitive areas (e.g., face, digits). Very painful.	18

Visceral Leishmaniasis (Kala-azar)

For visceral leishmaniasis, the standard regimen is 20 mg/kg/day for 28 days.[2] Historically, this regimen achieved high cure rates, often exceeding 90-95%, in endemic regions such as East Africa, Brazil, and the Mediterranean.[31] However, its efficacy is now highly dependent on the geographic region due to resistance. In East Africa, a 17-day combination therapy of sodium stibogluconate (20 mg/kg/day) and paromomycin (15 mg/kg/day) is now the WHO-recommended first-line treatment for HIV-negative patients.[28]

Cutaneous Leishmaniasis (CL)

Systemic treatment for cutaneous leishmaniasis typically involves a 20-day course of 20 mg/kg/day.[2] This approach is particularly important for New World cutaneous leishmaniasis caused by the Leishmania Viannia subgenus to reduce the risk of late-onset mucosal disease.[30] It is also indicated for patients with multiple, large, or cosmetically sensitive lesions.[29]

For patients with a single lesion or a few small, uncomplicated lesions, intralesional administration is an alternative.[18] This involves injecting the drug directly into the skin lesion at a dose of approximately 0.1 mL/cm², repeated at intervals of 3 to 7 days until the lesion heals.[18] While this method minimizes systemic toxicity, it is reported to be exceedingly painful.[3] Studies in pediatric populations, including children under the age of two, have shown intralesional therapy to be safe and highly effective, with one study reporting a 100% cure rate.[32]

Mucocutaneous Leishmaniasis (ML)

Mucocutaneous leishmaniasis, a destructive metastatic complication of certain New World Leishmania species, requires aggressive and prolonged systemic therapy. The recommended regimen is the same as for visceral leishmaniasis: 20 mg/kg/day for 28 days.[2]

Pediatric Use

There are no distinct, formally established pediatric guidelines for sodium stibogluconate; treatment regimens are largely extrapolated from adult data.[32] The standard weight-based dose of 20 mg/kg/day is used for systemic therapy in children.[27] As noted, intralesional therapy has been successfully and safely used in very young children.[32]

Impact of Resistance

The most significant challenge to the continued use of sodium stibogluconate is the dramatic rise in drug resistance.[6] This problem is most acute in the treatment of visceral leishmaniasis on the Indian subcontinent, particularly in the state of Bihar, where unresponsiveness rates have been reported in over 60% of cases.[5] This high level of resistance has rendered antimonials effectively obsolete as first-line agents in this region and has driven the widespread adoption of alternative drugs.[6] The primary mechanism of resistance involves the up-regulation of the parasite's thiol metabolism, particularly the synthesis of trypanothione, which binds to and facilitates the efflux of the active $Sb^{III}$ from the parasite cell.[5]

Table 4: Comparative Analysis of Antileishmanial Therapies

Feature	Sodium Stibogluconate	Liposomal Amphotericin B	Miltefosine
Route of Administration	Intravenous (IV), Intramuscular (IM), Intralesional	Intravenous (IV)	Oral
Typical Regimen (VL)	20 mg/kg/day for 28 days	3 mg/kg on days 1-5, 14, 21 (immunocompetent)	2.5 mg/kg/day for 28 days
Efficacy	High in sensitive regions; very low in resistant regions (e.g., Bihar, India)	Very high efficacy globally, including in antimony-resistant areas. Treatment of choice for VL in the U.S.	Good efficacy, especially for VL in South Asia. Variable efficacy for CL depending on species/region.
Major Toxicities	Cardiotoxicity (QTc prolongation), pancreatitis, myalgia, arthralgia, phlebitis	Infusion-related reactions (fever, chills), nephrotoxicity (less than conventional amphotericin B), hypokalemia	Gastrointestinal (vomiting, diarrhea), hepatotoxicity. Teratogenic (contraindicated in pregnancy).
Regulatory Status (U.S.)	Investigational New Drug (IND) available via CDC	FDA-approved for Visceral Leishmaniasis	FDA-approved for VL, ML, and CL caused by specific species

Sources: [6]

Investigational Use in Oncology

Beyond its role as an antiparasitic agent, sodium stibogluconate is being actively investigated for its potential in cancer therapy, specifically for hematologic malignancies.

Orphan Drug Designation

On June 5, 2017, the U.S. Food and Drug Administration (FDA) granted orphan drug designation to sodium stibogluconate for the treatment of acute myeloid leukemia (AML).[15] This designation, sponsored by BioXcel Corporation, is intended to facilitate the development of drugs for rare diseases. While it has received this designation, the drug is not yet FDA-approved for this indication.[8]

Clinical Trials and Rationale

The basis for its use in oncology stems from its activity as a PTPase inhibitor, particularly of SHP-1 and SHP-2.[11] These phosphatases are critical negative regulators of cytokine signaling pathways that are often dysregulated in cancer. By inhibiting them, sodium stibogluconate can potentially restore pro-apoptotic signals and enhance the efficacy of other cancer therapies. Clinical investigations are underway, including a Phase 2 trial evaluating its use in patients with myelodysplastic syndrome (MDS) or AML harboring specific p53 mutations.[14]

Safety, Tolerability, and Risk Management

The clinical use of sodium stibogluconate is frequently limited by its extensive and potentially severe toxicity profile. Adverse effects are common, and rigorous monitoring is required to mitigate the risk of serious complications.[1]

Adverse Effect Profile

Adverse events are a frequent occurrence during treatment with sodium stibogluconate.[3]

• Common Adverse Effects: The most frequently reported side effects are musculoskeletal complaints, including muscle pain (myalgia) and joint pain (arthralgia), which can affect over half of patients.[1] Gastrointestinal symptoms are also very common and include loss of appetite (anorexia), nausea, vomiting, abdominal pain, and a metallic taste.[3] Constitutional symptoms such as headache, fatigue, lethargy, fever, and sweating are also frequently observed.[3]
• Biochemical Abnormalities: Asymptomatic elevations in liver and pancreatic enzymes are extremely common. Reversible increases in serum transaminases (AST, ALT) occur in over 60% of patients.[1] Elevations in pancreatic enzymes (amylase and lipase) are even more frequent, seen in 84-97% of patients, though clinical pancreatitis is less common.[1]
• Severe Adverse Events: Although less common, severe and life-threatening reactions can occur. These include severe allergic reactions and anaphylaxis (rare), bone marrow suppression leading to leucopenia or thrombocytopenia, and acute renal failure.[8] Clinical pancreatitis, while less frequent than asymptomatic enzyme elevation, is a serious and potentially fatal complication.[3]

Cardiotoxicity: A Special Focus

The most serious dose-limiting toxicity of sodium stibogluconate is cardiotoxicity.[22]

• Electrocardiogram (ECG) Changes: The most common manifestation of cardiotoxicity is abnormalities on the ECG. These typically include T-wave inversion or a reduction in T-wave amplitude, and more critically, prolongation of the corrected QT (QTc) interval.[3] These changes are generally dose-dependent and are often reversible upon discontinuation of the drug or a reduction in the infusion rate.[3]
• Clinical Significance: Prolongation of the QTc interval is a well-documented risk factor for life-threatening ventricular arrhythmias, including Torsades de Pointes, ventricular tachycardia, and ventricular fibrillation, which can lead to syncope and sudden cardiac death.[10]
• Formulation-Dependent Risk: The risk of cardiotoxicity may not be uniform across all formulations of the drug. An outbreak of fatal cardiotoxicity was reported in Nepal among patients treated with a specific batch of generic sodium stibogluconate.[21] In this incident, 36% of patients treated with the new generic died, with 23% of deaths directly attributed to cardiotoxicity, a rate dramatically higher than the 0.8% cardiotoxic death rate seen with the previously used generic.[21] This event underscores how the chemical ambiguity and potential for manufacturing variability of sodium stibogluconate can translate into significant and unpredictable clinical risks, making quality control a paramount safety concern.

Administration-Related Complications

Sodium stibogluconate is described as being "exceedingly toxic to veins".[3] Intravenous administration is frequently complicated by pain at the injection site and chemical phlebitis, which can progress to venous thrombosis.[3] After several doses, it can become extremely difficult to maintain venous access. The use of a peripherally inserted central catheter (PICC) does not necessarily prevent this complication and can sometimes exacerbate it, leading to inflammation and thrombosis along the entire course of the vein containing the catheter.[3] A practical strategy to mitigate this local toxicity is to dilute the daily dose in a large volume of fluid and administer it as a slow infusion over a longer period.[3] Intramuscular injection is also an option but is noted to be exceedingly painful.[3]

Contraindications and Precautions

Given its toxicity profile, sodium stibogluconate is contraindicated in several patient populations.

• Absolute Contraindications: The drug should not be used in patients with a known hypersensitivity to any of its components, those with significant pre-existing renal impairment, or in women who are breastfeeding.[8]
• Precautions: Caution is strongly advised in patients with underlying cardiac disease (particularly arrhythmias), hepatic disease, or severe malnutrition.[16]
• Pregnancy: The safety of sodium stibogluconate in pregnancy has not been established. It is generally considered less safe than other available options and should be used only when the potential benefits to the mother are judged to outweigh the potential risks to the fetus.[3]

Clinical Monitoring and Management

Rigorous clinical and laboratory monitoring is essential for any patient receiving sodium stibogluconate to ensure early detection and management of toxicity.

Table 3: Comprehensive Safety Profile and Monitoring Requirements

System/Organ Class	Associated Adverse Events	Recommended Monitoring & Management Actions	Source(s)
Cardiac	T-wave inversion, QTc interval prolongation, ventricular arrhythmias, sudden death	Obtain baseline ECG. Monitor ECG at least weekly during therapy. Interrupt or discontinue treatment if significant QTc prolongation (e.g., >0.5 s) or arrhythmia occurs.	3
Pancreatic	Asymptomatic elevation of amylase and lipase, acute pancreatitis	Monitor serum amylase and lipase at least twice weekly. Interrupt treatment if amylase rises >4-5 times the upper limit of normal (ULN) or if clinical signs of pancreatitis develop.	3
Hepatic	Elevation of serum transaminases (AST, ALT), jaundice (rare)	Monitor liver function tests (LFTs) at baseline and weekly. Interrupt treatment if AST or ALT rises >3-4 times ULN.	1
Hematologic	Leucopenia, thrombocytopenia	Monitor complete blood count (CBC) at baseline and weekly.	18
Renal	Proteinuria, renal failure (rare)	Monitor renal function tests (serum urea and creatinine) at baseline and weekly. Contraindicated in significant renal impairment.	8
Injection Site (IV)	Pain, chemical phlebitis, venous thrombosis	Monitor IV site daily. Administer as a slow, dilute infusion to minimize irritation. Rotate infusion sites.	3

Global Regulatory Status and Public Health Context

The regulatory status of sodium stibogluconate is unique and fragmented, reflecting its position as a legacy drug for a neglected tropical disease. It does not hold widespread commercial approval in many developed nations but remains accessible through specific pathways due to its essential role in treating leishmaniasis.

Regulatory Landscape

• United States (FDA): Sodium stibogluconate is not commercially licensed or approved by the Food and Drug Administration (FDA).[8] It is classified as an Investigational New Drug (IND) and is made available for the treatment of leishmaniasis through a protocol managed by the Centers for Disease Control and Prevention (CDC).[1] The U.S. Department of Defense also uses it under an IND protocol for military personnel.[1] The drug has also received two orphan drug designations from the FDA: one for cutaneous leishmaniasis (designated in 2009, status withdrawn in 2023) and an active designation for the treatment of acute myeloid leukemia (designated in 2017).[15]
• Europe and United Kingdom (EMA/MHRA): The drug is commercially available in the United Kingdom under the brand name Pentostam.[6] Its regulatory approval appears to be at the national level via the UK's Medicines and Healthcare products Regulatory Agency (MHRA), as it is not listed as a centrally authorized product by the European Medicines Agency (EMA).[45]
• Australia (TGA): Sodium stibogluconate is not registered on the Australian Register of Therapeutic Goods (ARTG) and is therefore not a commercially available medicine in Australia.[18] However, it can be accessed for individual patients through the Therapeutic Goods Administration's (TGA) Special Access Scheme (SAS). TGA documents confirm that "Stibogluconate - Pentostam injection" has been approved for supply under this scheme.[48] The SAS allows for the importation and supply of unapproved therapeutic goods for patients with specific medical needs.[49]

This varied regulatory landscape highlights the challenges of providing access to essential medicines for rare or geographically concentrated diseases. In non-endemic countries like the U.S. and Australia, where the commercial market is limited, special investigational or access pathways are used to make the drug available to the small number of patients who need it, such as travelers or military personnel returning from endemic areas.

World Health Organization (WHO) Designation

Sodium stibogluconate holds a significant place in global public health and is included on the WHO Model List of Essential Medicines in the category of "Antileishmaniasis medicines".[3] The WHO has played a pivotal role in establishing treatment guidelines for the drug. Notably, in 1984, the WHO recommended increasing the daily dose to 20 mg/kg/day to overcome growing therapeutic unresponsiveness, a recommendation that remains the standard of care today.[1] In certain regions, such as East Africa, the WHO now recommends sodium stibogluconate as part of a first-line combination therapy with paromomycin for visceral leishmaniasis in HIV-negative individuals, demonstrating its continued, albeit evolving, role in public health strategies.[28]

Synthesis and Future Perspectives

Sodium stibogluconate occupies a complex and evolving position in the therapeutic armamentarium. For over half a century, it was the indispensable treatment for leishmaniasis, a debilitating neglected tropical disease. Its history is one of immense public health value, providing a life-saving therapy for a condition affecting the world's most vulnerable populations. However, its legacy is now defined by a dual challenge: the erosion of its efficacy due to widespread parasite resistance and a significant toxicity profile that demands careful patient management. In many parts of the world, particularly for visceral leishmaniasis in South Asia, it has been superseded by safer and more reliably effective agents like liposomal amphotericin B and miltefosine.

Yet, sodium stibogluconate is not an obsolete relic. It remains a WHO-listed essential medicine and a recommended therapy in regions where antimonial resistance is not yet rampant. Furthermore, modern scientific inquiry has unveiled a novel mechanism of action—the potent inhibition of protein tyrosine phosphatases—that has opened an entirely new and unexpected therapeutic avenue. This has led to its repurposing as an investigational agent in oncology, with an orphan drug designation for acute myeloid leukemia.

The future of sodium stibogluconate is therefore likely to proceed along two parallel tracks. The first involves mitigating its limitations in the treatment of leishmaniasis. Research into novel drug delivery systems, such as nano-deformable liposomes, aims to create formulations that can be applied topically, thereby concentrating the drug at the site of infection in cutaneous leishmaniasis, improving efficacy, and dramatically reducing the systemic toxicities associated with parenteral administration.[50] The second, and perhaps more transformative, track involves the rigorous clinical investigation of its antineoplastic properties. Validating its efficacy in AML and MDS, either as a monotherapy or in combination with other agents, will require carefully designed clinical trials that can harness its unique mechanism of PTPase inhibition while managing its considerable safety concerns in a fragile patient population.[13] Ultimately, the story of sodium stibogluconate is a compelling example of a legacy drug's life cycle: from a frontline therapy to a challenged incumbent, and potentially, to a repurposed agent in a completely different field of medicine.

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