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. 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