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    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

    REFERENCES

    ABPI/The Association of the British Pharmaceutical Industry.
    ABPI Compendium of Data Sheets and Summaries of Product
    Characteristics 1996-97.
    London: Datapharm Publications Ltd, 1996.

    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.

    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.]
    Gig Tr Prof Zabol 1967; 11: 32-7.

    Braconier JH, Miörner H.
    Recurrent episodes of thrombocytopenia during treatment with sodium
    stibogluconate (letter).
    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.
    Sudbury: Health and Safety Executive, 1994.

    Chulay JD, Spencer HC, Mugambi M.
    Electrocardiographic changes during treatment of leishmaniasis with
    pentavalent antimony (sodium stibogluconate).
    Am J Trop Med Hyg 1985; 34: 702-9.

    Chunge CN, Gachihi G, Chulay JD, Spencer HC.
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    East Afr Med J 1984; 61: 120-7.

    Davis A.
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    Domingo P, Ferrer S, Kolle L, Muńoz C, Rodriquez P.
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    Gasser RA Jr, Magill AJ, Oster CN, Franke ED, Grögl M, Berman JD.
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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.

    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.

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    Sodium stibogluconate (Pentostam) overdose during treatment of
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    Severe leucopenia during treatment of visceral leishmaniasis.
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