UKPID MONOGRAPH
SODIUM STIBOGLUCONATE
WN Harrison PhD CChem MRSC
SM Bradberry BSc MB MRCP
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service
(Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
SODIUM STIBOGLUCONATE
Toxbase summary
Type of product
Used in the treatment of visceral, cutaneous and mucocutaneous
leishmaniasis.
Toxicity
Toxic effects have been reported following parenteral administration
of antimony pharmaceuticals.
Features
There are no reports of ingestion, inhalation or topical exposure.
However, effects similar to those reported for other antimony
compounds may be expected (see antimony Toxbase entry).
Injection
- Parenteral sodium stibogluconate administration has been
associated with anorexia, nausea, vomiting, abdominal pain,
a metallic taste, diarrhoea, pancreatitis, reversible
elevations of liver enzyme activities, myalgia, arthralgia,
proteinuria, ECG changes (T wave inversion, Q-T interval
prolongation, S-T segment abnormalities), phlebitis,
uveitis, optic atrophy and rarely anaphylactic shock, acute
renal failure, hepatic necrosis and bone marrow hypoplasia.
Management
Injection
1. Discontinue therapy if significant adverse effects occur.
2. Symptomatic and supportive measures as dictated by the patient's
condition.
3. Monitor the ECG, biochemical and haematological profiles.
4. Collect urine and blood for antimony concentration measurements.
5. Chelation therapy with dimercaprol, DMSA or DMPS may be
considered, but discussion with a NPIS physician is recommended.
References
Bailly R, Lauwerys R, Buchet JP, Mahieu P, Konings J.
Experimental and human studies on antimony metabolism: their relevance
for the biological monitoring of workers exposed to inorganic
antimony.
Br J Ind Med 1991;48: 93-7.
Hepburn NC, Siddique I, Howie AF, Beckett GJ, Hayes PC.
Hepatotoxicity of sodium stibogluconate in leishmaniasis.
Lancet 1993; 342: 238-9.
Hepburn NC, Nolan J, Fenn L, Herd RM, Neilson JM, Sutherland GR,
Fox KA.
Cardiac effects of sodium stibogluconate: myocardial,
electrophysiological and biochemical studies.
QJM 1994; 87: 465-72.
Lauwers LF, Roelants A, Rosseel M, Heyndrickx B, Baute L.
Oral antimony intoxications in man.
Crit Care Med 1990; 18: 324-6.
Winship KA.
Toxicity of antimony and its compounds.
Adverse Drug React Acute Poisoning Rev 1987; 2: 67-90.
Substance name
Sodium stibogluconate
Origin of substance
NIF
Synonyms
Antimony sodium gluconate
Myostibin
Pentostam
Solustibosan
Solustin
Solusurmin
Solyusurmin
Stibanate
Stibanose
Stibatin
Stibinol (RTECS, 1997)
Chemical group
A pentavalent compound of antimony, a group V A element.
Reference numbers
CAS 16037-91-5 (RTECS, 1997)
12001-86-4 (RTECS, 1997)
RTECS CC7930000 (RTECS, 1997)
UN NIF
HAZCHEM CODE NIF
Physicochemical properties
Chemical structure
C6H9Na2O6Sb (MARTINDALE, 1996)
Molecular weight
1048.91 (RTECS, 1997)
Physical state at room temperature
Solid (MARTINDALE, 1996)
Colour
Colourless (MARTINDALE, 1996)
Odour
Odourless (MARTINDALE, 1996)
Viscosity
NA
pH
NIF
Solubility
Very soluble in water.
Practically insoluble in alcohol and ether.
(MARTINDALE, 1996)
Autoignition temperature
NIF
Chemical interactions
NIF
Major products of combustion
Antimony and sodium oxides. (SAX'S 1996)
Explosive limits
NIF
Flammability
NIF
Boiling point
NIF
Density
NIF
Vapour pressure
NIF
Relative vapour density
NIF
Flash point
NIF
Reactivity
NIF
Uses
In the treatment of visceral, cutaneous and mucocutaneous
leishmaniasis. (MARTINDALE, 1996)
Hazard/risk classification
Index no. (Antimony compounds) 051-003-00-9
Risk phrases
Xn; R20/22
Harmful by inhalation and if swallowed.
Safety phrases
S(2-) 22* (*If appropriate)
Keep out of reach of children. Do not breathe dust*.
EEC No:
NIF (CHIP2, 1994)
INTRODUCTION AND EPIDEMIOLOGY
Sodium stibogluconate is a pentavalent antimony compound. It is used
in the treatment of visceral, cutaneous and mucocutaneous
leishmaniasis. Adverse effects from pentavalent antimony drugs are
reportedly less frequent and less severe than from trivalent antimony
preparations (Reynolds, 1996). Pentostam, an aqueous solution of
sodium stibogluconate, is the treatment of choice for visceral
leishmaniasis. Most reports of adverse effects occur during
therapeutic use.
MECHANISM OF TOXICITY
The mechanism of toxicity of antimony compounds is unclear but may
involve disruption of thiol proteins via binding to sulphydryl groups
(de Wolff, 1995).
TOXICOKINETICS
Absorption
Antimony compounds may be absorbed by inhalation and ingestion, though
gastrointestinal absorption in man is poor necessitating parenteral
administration of antimony pharmaceuticals.
Distribution and Excretion
Following intravenous or intramuscular sodium stibogluconate
administration, antimony is excreted rapidly via the kidneys. Rees et
al (1980) demonstrated that some 80-90 per cent of an intramuscular
dose of sodium stibogluconate was recovered in the urine within six
hours of administration. Rapid renal elimination is reflected by a
marked fall in the serum or whole blood antimony concentration to
approximately one to four per cent of the peak concentration eight
hours after an intravenous dose. However, even some 6-24 months after
parenteral antimony therapy, Mansour et al (1967) reported increased
urine antimony concentrations (range 5.8-145.3 µg/L) compared to
untreated controls (range 2.9-9.1 µg/L). During daily administration
there is slow distribution to the central compartment so that tissue
concentrations reach a theoretical maximum after some seven days
(ABPI, 1996).
Small amounts of antimony appear in faeces via bile after conjugation
with glutathione. A significant amount of antimony excreted in bile
undergoes enterohepatic circulation (Bailly et al, 1991).
CLINICAL FEATURES: ACUTE EXPOSURE
There are no reports of acute ingestion, inhalation or topical
exposure to sodium stibogluconate. However, effects similar to those
reported for other antimony compounds may be expected (see antimony
monograph).
Injection
Hepatotoxicity
A 27 year-old woman with cutaneous leishmaniasis developed a transient
rise in alanine aminotransferase activity (to 2.4 times the upper
limit of normal) when she was inadvertently given ten times the
intended dose of parenteral pentavalent sodium stibogluconate
(Herwaldt et al, 1992). However, more typically hepatotoxicity is
observed during prolonged therapy with antimony pharmaceuticals.
Cardiovascular toxicity
No cardiovascular complications arose in a patient who accidentally
was given ten times the intended intravenous dose of sodium
stibogluconate (Herwaldt et al, 1992).
Gastrointestinal and pulmonary toxicity
Coughing, nausea, vomiting, diarrhoea or substernal pain may occur
rarely during intravenous injection (ABPI, 1996).
CLINICAL FEATURES: CHRONIC EXPOSURE
There are no reports of chronic ingestion, inhalation or topical
exposure to sodium stibogluconate. However, effects similar to other
antimony compounds may be expected (see antimony monograph).
Injection
Dermal toxicity
Davis (1968) reported antimony dermatitis in some four per cent of 160
patients treated with antimony-containing drugs.
Gastrointestinal toxicity
Patients treated for some one to two weeks with parenteral antimony
compounds frequently reported anorexia, nausea and vomiting with some
complaints of abdominal pain, a metallic taste and diarrhoea (Davis,
1968).
Pancreatitis also has been reported as a complication of parenteral
therapy with stibogluconate or meglumine antimonate (de Lalla et al,
1993; McCarthy et al, 1993; Gasser et al, 1994; Domingo et al, 1996).
Hepatotoxicity
Parenteral treatment with antimony compounds has caused hepatic
necrosis although reversible elevations of liver enzyme activities are
more typical (Winship, 1987; Saenz et al, 1991; Hepburn et al, 1993).
Nephrotoxicity
Sodium stibogluconate therapy has caused acute tubular necrosis
(Balzan and Fenech, 1992; Rai et al, 1994a; Rai et al, 1994b).
Renal tubular acidosis has also been described (Horber et al, 1991).
In a review of 92 patients with visceral leishmaniasis (kala-azar)
treated with sodium stibogluconate, two showed evidence of renal
toxicity with casts and proteinuria although these patients also were
receiving intramuscular pentamidine, another recognized renal toxin
(Chunge et al, 1984).
Cardiovascular and peripheral vascular toxicity
ECG changes following exposure to antimony compounds are seen
typically in patients with leishmaniasis or schistosomiasis who have
been treated with parenteral antimony compounds. Typical features
include T wave inversion or amplitude reduction, Q-T interval
prolongation and S-T segment abnormalities (Davis, 1968; Chulay et al,
1985; Henderson and Jolliffe, 1985). These effects usually reverse
when treatment is discontinued.
In 12 soldiers with cutaneous leishmaniasis treated with sodium
stibogluconate Hepburn et al (1994) found that although a reversible
decrease in T-wave amplitude occurred during treatment there were no
significant changes in echocardiographic indices of left ventricular
function, arrhythmia frequency or heart-rate variability. The authors
concluded that 20 mg/kg/day sodium stibogluconate for 20 days had no
cardiac side-effects in most fit, young patients.
Gupta (1990) similarly noted that T-wave changes induced by antimony
therapy were not associated with a deterioration in cardiac function.
In a review of 160 patients with schistosomiasis treated with
antimony-containing drugs (Davis, 1968) retrosternal chest pain was
reported by 27 individuals. In three cases this was associated with
acute vascular collapse immediately after intravenous drug
administration (after the first dose in one case) suggesting an
anaphylactic-type response.
Phlebitis occurred in 31 patients receiving intravenous sodium
stibogluconate in the treatment of visceral leishmaniasis (Chunge et
al, 1984) and in one patient administered antimony sodium tartrate in
the treatment of urinary schistosomiasis (Davis, 1968).
Neurotoxicity
Rai et al (1994b) described combined ninth and tenth cranial nerve
palsies in a patient with kala-azar treated with parenteral
stibogluconate. There was significant improvement within two weeks of
cessation of treatment.
Reversible peripheral neuropathy associated with sodium stibogluconate
therapy has been reported also (Brummitt et al, 1996).
Acute hydrocephalus in association with significant ocular toxicity
(see below) occurred in a child following 23 antimony potassium
tartrate injections (Grant and Schuman, 1993).
Haemotoxicity
Mallick (1990) described bone marrow hypoplasia as a complication of
sodium stibogluconate administration. Haematological indices improved
significantly following treatment withdrawal and steroid therapy.
Other authors have described leucopenia (Hiēsönmez et al, 1988; Saenz
et al, 1991) or recurrent episodes of thrombocytopenia (Braconier and
Miörner, 1993) during parenteral antimonial therapy though no bone
marrow biopsies were performed.
Chunge et al (1984) reported epistaxis in 13 patients receiving
parenteral antimony-containing drugs, in three cases associated with
pancytopenia.
Musculoskeletal toxicity
Myalgia and arthralgia are reported frequently by patients with
leishmaniasis or schistosomiasis treated with parenteral antimony
compounds (Davis, 1968; Winship, 1987; Castro et al, 1990; Saenz et
al, 1991). This effect is not necessarily dose-related (Gastro et al,
1990).
Ocular toxicity
In a review of 92 patients with visceral leishmaniasis treated with
parenteral stibogluconate, six developed uveitis and two retinal
haemorrhages after completion of treatment and apparent cure (Chunge
et al, 1984).
In an early case report cited by Grant and Schuman (1993) a child
developed acute onset bilateral blindness with fixed dilated pupils
following 23 antimony tartrate injections. There was clinical evidence
of optic neuritis with papilloedema and subsequent permanent optic
atrophy.
Forsyth (1958) reported one patient who developed transient retinal
haemorrhages and exudates and another in whom the fundus was described
as 'granular' following parenteral sodium antimony tartrate therapy
for schistosomiasis. Visual acuity was diminished in both cases but
returned to normal within six months.
Three children who received repeated courses of parenteral tartar
emetic in the treatment of schistosomiasis developed optic atrophy
(Kassem et al, 1976).
MANAGEMENT
Management following ingestion or inhalation of antimony compounds are
discussed in the antimony monograph.
Injection
If serious adverse effects develop discontinuation of antimony therapy
is a priority.
Treatment is symptomatic and supportive. Monitor cardiac rhythm and
biochemical and haematological profiles.
In cases of overdose, if an increased antimony body burden is
suspected antidotal therapy may be considered following analytical
confirmation of antimony concentrations (see antimony monograph).
MEDICAL SURVEILLANCE
Sodium stibogluconate should not be administered to patients with
significantly impaired renal function and used with caution in
patients with heart or liver disease (ABPI, 1996).
OCCUPATIONAL DATA
Maximum exposure limit
Antimony and compounds: Long-term exposure limit (8 hour TWA reference
period) 0.5 mg/m3 (Health and Safety Executive, 1997).
OTHER TOXICOLOGICAL DATA
Carcinogenicity
There are no data regarding the carcinogenicity of sodium
stibogluconate.
There is some evidence that occupational antimony exposure is
associated with an increased risk of lung cancer although frequent
concomitant exposure to arsenic and other heavy metals precludes a
definitive conclusion about its carcinogenic potential (Gerhardsson et
al, 1982; McCallum, 1989; Gerhardsson and Nordberg, 1993; Jones, 1994;
Schnorr et al, 1995).
Antimony also has been implicated in the aetiology of bladder tumours
in patients with schistosomiasis who have been treated with antimony
compounds (Winship, 1987).
Reprotoxicity
There are no data regarding the reprotoxicity of sodium
stibogluconate.
Women occupationally exposed to antimony aerosols were reported to
have a higher incidence of spontaneous abortion, premature births and
menstrual disorders. Antimony was present in the blood, urine,
placenta, amniotic fluid and breast milk of these women (Belyaeva,
1967).
Genotoxicity
NIF
Fish toxicity
NIF
EC Directive on Drinking Water Quality 80/778/EEC
Antimony: Maximum admissible concentration 10 µg/L (DOSE, 1992).
WHO Guidelines for Drinking Water Quality
Antimony: Provisional guideline value 0.005 mg/L (WHO, 1993).
AUTHORS
WN Harrison PhD CChem MRSC
SM Bradberry BSc MB MRCP
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service (Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
UK
This monograph was produced by the staff of the Birmingham Centre of
the National Poisons Information Service in the United Kingdom. The
work was commissioned and funded by the UK Departments of Health, and
was designed as a source of detailed information for use by poisons
information centres.
Date of last revision
28/1/98
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London: Datapharm Publications Ltd, 1996.
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Experimental and human studies on antimony metabolism: their relevance
for the biological monitoring of workers exposed to inorganic
antimony.
Br J Ind Med 1991;48: 93-7.
Balzan M, Fenech F.
Acute renal failure in visceral leishmaniasis treated with sodium
stibogluconate.
Trans R Soc Trop Med Hyg 1992; 86: 515-6.
Belyaeva AP.
[The effect produced by antimony on the generative function.]
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Braconier JH, Miörner H.
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J Antimicrob Chemother 1993; 31: 187-8.
Brummitt CF, Porter JA, Herwaldt BL.
Reversible peripheral neuropathy associated with sodium stibogluconate
therapy for American cutaneous leishmaniasis.
Clin Infect Dis 1996; 22: 878-9.
Castro C, Sampaio RN, Marsden PD.
Severe arthralgia, not related to dose, associated with pentavalent
antimonial therapy for mucosal leishmaniasis.
Trans R Soc Trop Med Hyg 1990; 84: 362.
CHIP2/Chemicals (Hazard Information and Packaging for Supply)
Regulations 1994.
Health and Safety Commission.
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Chulay JD, Spencer HC, Mugambi M.
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pentavalent antimony (sodium stibogluconate).
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Chunge CN, Gachihi G, Chulay JD, Spencer HC.
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Davis A.
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de Lalla F, Pellizzer G, Gradoni L, Vespignani M, Franzetti M, Stecca
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Acute pancreatitis associated with the administration of meglumine
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Antimony in lung, liver and kidney tissue from deceased smelter
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Gupta P.
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Henderson A, Jolliffe D.
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Hepburn NC, Siddique I, Howie AF, Beckett GJ, Hayes PC.
Hepatotoxicity of sodium stibogluconate in leishmaniasis.
Lancet 1993; 342: 238-9.
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Fox KA.
Cardiac effects of sodium stibogluconate: myocardial,
electrophysiological and biochemical studies.
QJM 1994; 87: 465-72.
Herwaldt BL, Kaye ET, Lepore TJ, Berman JD, Baden HP.
Sodium stibogluconate (Pentostam) overdose during treatment of
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Severe leucopenia during treatment of visceral leishmaniasis.
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Acute renal failure and 9th, 10th nerve palsy in patient of kala-azar
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