Arsenic Trioxide

(USAN)

💊 Chemical information

Acidum Arsenicosum Anhydricum; Arseni Trioxydum; Arsenic; Arsenic Oxide; Arsénico, trióxido de; Arsenicum Album; Arsénieux, anhydride; Arsenii trioxidum; Arsenious Acid; Arsenous Oxide; White Arsenic. Diarsenic trioxide.
Chemical formula: As2O3 = 197.8.
CAS — 1327-53-3 (arsenic trioxide); 7784-45-4 (arsenic triiodide).
ATC — L01XX27.
ATC Vet — QL01XX27.

Pharmacopoeias.

In Jpn. Eur. includes a form for homoeopathic preparations.

Ph. Eur. 6.2

(Arsenious Trioxide for Homoeopathic Preparations; Arsenii Trioxidum ad Praeparationes Homoeopathicae). A white or almost white powder. Practically insoluble to sparingly soluble in water; it dissolves in solutions of alkali hydroxides and carbonates.

💊 Adverse Effects

The toxicity of arsenic compounds varies according to chemical composition, solubility, and valency. Inorganic arsenic compounds are much more toxic than organic compounds and elemental arsenic is the least toxic. Toxicity increases with increasing solubility, and trivalent (arsenite) compounds are more toxic than pentavalent (arsenate) compounds. Arsenic exerts its effects through a variety of pathophysiological mechanisms such as induction of oxidative stress and binding to sulphydryl groups in enzymes, and it has the potential to affect most of the major organ systems in the body; it also induces alteration in gene expression.

Acute poisoning.

Estimates of lethal and toxic oral doses vary: the lethal dose of arsenic trioxide has been reported to be around 100 to 300 mg; a dose of 1 mg/kg of arsenic may be lethal in children; acute toxic doses of arsenic compounds have been reported to range from 1 mg to 10 g. Symptoms of acute poisoning occur within 30 minutes to several hours after ingestion and food delays the onset. Early features of acute arsenic poisoning following ingestion involve the gastrointestinal tract with common symptoms of a metallic or garlic taste, a burning sensation in the mouth, dysphagia, abdominal pain, severe nausea, projectile vomiting, haemorrhagic gastritis, and profuse ‘rice-water’ diarrhoea leading to hypovolaemic shock; the breath may have an odour of garlic. In the absence of adequate treatment, death can occur within 24 hours of a severely toxic dose. Absorption of arsenic may produce multisystem toxicity days or weeks later, which could include cardiomyopathy, anaemia, leucopenia, skin disorders, acute respiratory distress syndrome, hepatitis, renal failure, encephalopathy, and peripheral polyneuropathy. Arsenic compounds are irritant and corrosive when inhaled or in contact with the skin or eyes; acute systemic effects may occur after inhalation or skin contact.

Chronic poisoning.

Arsenic is widely distributed in the environment: the smelting industry (non-ferrous metals) is a major industrial source of arsenic contamination in the soil, water, and air; mining residues and arsenical pesticides and wood preservatives also contribute to soil and water contamination. Seafood is a source of organic arsenic. Occupational exposure is a potential cause of chronic arsenic toxicity but in the general population, food and drinking water is usually the source of arsenic. Chronic arsenic poisoning or occupational exposure typically produces varied skin disorders appearing over 1 to 10 years, particularly hyperkeratosis, especially affecting the palms and soles, and changes in skin pigmentation. Transverse white lines (Mee’s lines) may appear in the nails several weeks after absorption. Gastrointestinal disturbances may occur, although are less likely with chronic exposure. Hypertension, cardiovascular disorders, and diabetes mellitus have been associated with chronic arsenic poisoning. Jaundice may occur as a result of hepatomegaly and portal hypertension may eventually develop. Encephalopathy and peripheral neuropathies may also occur. Arsenic is toxic to the bone marrow and produces a wide range of blood disorders including leucopenia and aplastic anaemia. Chronic exposure to arsenic has been associated with neoplasms of the skin, lungs, bladder, liver, and kidney. Chronic inhalation of arsenic salts may result in perforation of the nasal septum.

Adverse effects of therapeutic use.

Reported adverse effects of arsenic trioxide therapy in patients with acute promyelocytic leukaemia (APL) include leucocytosis, neutropenia, raised liver enzyme values, gastrointestinal disturbances, fatigue, oedema, hyperglycaemia, hypokalaemia, dyspnoea, cough, skin rashes, pruritus, pyrexia, headaches, paraesthesia, and dizziness. Prolongation of the QT interval and other cardiac arrhythmias have occurred. The so-called ‘leukocyte activation syndrome’ (‘APL differentiation syndrome’) similar to one that develops with tretinoin therapy has occurred in some patients. Sudden death has been reported in a few patients.
1. Health and Safety Executive. Inorganic arsenic compounds. Toxicity Revie
16. London: HMSO, 1986
2. Shannon RL, Strayer DS. Arsenic-induced skin toxicity. Hum Toxic ol 1989; 8: 99–104
3. Gebel T. Confounding variables in the environmental toxicology of arsenic. Toxicology 2000; 144: 155–62
4. WHO. Arsenic and arsenic compounds. Environmental Health Criteria 224. Geneva: WHO, 2001. Also available at: http:// www.inchem.org/documents/ehc/ehc/ehc224.htm (accessed 11/04/08
5. Borak J, Hosgood HD. Seafood arsenic: implications for human risk assessment. Regul Toxicol Pharmacol 2007; 47: 204–12
6. Flora SJ, et al. Arsenic induced oxidative stress and the role of antioxidant supplementation during chelation: a review. J Environ Biol 2007; 28 (2 suppl): 333–47
7. Islam LN, et al. Association of respiratory complications and elevated serum immunoglobulins with drinking water arsenic toxicity in human. J Environ Sci Health A Tox Hazard Subst Environ Eng 2007; 42: 1807–14
8. Guha Mazumder DN. Arsenic and non-malignant lung disease. J Environ Sci Health A Tox Hazard Subst Environ Eng 2007; 42: 1859–67.

Adulteration.

Arsenical compounds have reportedly been used to "cut" cocaine and symptoms of arsenic poisoning may occur in cocaine abusers.1 Toxicity due to the presence of arsenic in various ethnic remedies has also been reported.2-4
1. Lombard J, et al. Arsenic intoxication in a cocaine abuser. N Engl J Med 1989; 320: 869
2. Kew J, et al. Arsenic and mercury intoxication due to Indian ethnic remedies. BMJ 1993; 306: 506–7
3. Ernst E, Thompson Coon J. Heavy metals in traditional Chinese medicines: a systematic review. Clin Pharmacol Ther 2001; 70: 497–504
4. Ernst E. Heavy metals in traditional Indian remedies. Eur J Clin Pharmacol 2002; 57: 891–6.

Treatment of leukaemia.

References1-5 to and a review6 of adverse effects in patients receiving arsenic trioxide for the treatment of acute promyelocytic leukaemia, including a report of sudden death occurring in 3 patients in a dose-finding study.5
1. Huang SY, et al. Acute and chronic arsenic poisoning associated with treatment of acute promyelocytic leukaemia. Br J Haematol 1998; 103: 1092–5
2. Huang CH, et al. Complete atrioventricular block after arsenic trioxide treatment in an acute promyelocytic leukemic patient. Pacing Clin Electrophysiol 1999; 22: 965–7
3. Camacho LH, et al. Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide. J Clin Oncol 2000; 18: 2620–5
4. Ohnishi K, et al. Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med 2000; 133: 881–5
5. Westervelt P, et al. Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood 2001; 98: 266–71
6. Rust DM, Soignet SL. Risk/benefit profile of arsenic trioxide. Oncologist 2001; 6 (suppl 2): 29–32.

💊 Treatment of Adverse Effects

Acute poisoning due to the ingestion of arsenic compounds should be treated by immediate gastric lavage if the patient presents within 1 hour and has not already vomited. Activated charcoal has been used to reduce absorption but is unlikely to be of benefit unless a significant amount of arsenic has been ingested. Intravenous replacement of fluids and electrolytes should be undertaken as necessary to correct dehydration and electrolyte imbalance; pressor agents may be required. Chelation therapy should start immediately the cause of arsenic poisoning is suspected. The therapy of choice for acute poisoning is unithiol given intravenously in cases of gastrointestinal toxicity. Dimercaprol given intramuscularly is the second choice therapy if unithiol is unavailable. Oral therapy with unithiol or succimer should be substituted when gastrointestinal disturbances are no longer a problem. Oral penicillamine has also been used, including in conjunction with dimercaprol in severely ill patients, but its use in arsenic poisoning has been superseded by unithiol and succimer. Patients suffering from chronic arsenic poisoning should be removed from the source of contamination as soon as possible. Initiation of oral chelation therapy with unithiol or succimer will depend on the patient’s clinical condition and laboratory results of arsenic in urine, hair, and nails. Chelation therapy should be continued until arsenic concentrations in urine have fallen to acceptable levels, although the therapeutic end-points of chelation therapy are poorly defined. If renal failure occurs haemodialysis may be required.

Poisoning.

The treatment of 3 patients who had ingested massive doses of arsenic has been described.1,2 An adult survived after ingesting 54 g of arsenic trioxide:1 in addition to standard supportive measures, attempts to remove the arsenic from his gastrointestinal tract included lavage, endoscopic removal, manual removal after gastrotomy, and cleansing enemas, plus chelation therapy. Of 2 siblings who ingested solubilised inorganic arsenic in a pesticide solution,2 one child (aged 4 months) was estimated to have ingested 428 mg/kg arsenic and died despite aggressive attempts at removal of the arsenic, including chelation therapy, extracorporeal membrane oxygenation, exchange transfusion, and haemodialysis. The other child, aged 2 years, was estimated to have ingested 14.6 mg/kg arsenic, and survived following standard chelation therapy.
1. Dueñas-Laita A, et al. Acute arsenic poisoning. Lancet 2005; 365: 1982
2. Lai MW, et al. Acute arsenic poisoning in two siblings. Pediatrics 2005; 116: 249–57.

💊 Precautions

Patients receiving arsenic trioxide for acute promyelocytic leukaemia should have their ECG, blood sugar, electrolytes, blood count, and coagulation monitored at least twice weekly during induction and at least weekly during consolidation. More frequent monitoring may be needed in clinically unstable patients. Arsenic trioxide should be used with caution in renal impairment since renal excretion is the main route of elimination.

💊 Pharmacokinetics

Water-soluble arsenic acids and their salts are more rapidly absorbed from the gastrointestinal tract than poorly soluble arsenicals such as arsenic trioxide. The absorption of arsenic trioxide is dependent upon the physical form of the compound and coarsely powdered material may be eliminated in the faeces before significant dissolution and absorption can occur. Soluble arsenic salts may also be absorbed following inhalation and through skin. Once absorbed, arsenic is stored mainly in the liver, kidneys, heart, and lungs, with smaller amounts in the muscles and nervous tissue. About 2 weeks after ingestion, arsenic is deposited in the hair and nails and remains fixed to the keratin for years. It is also deposited in the bones and skin. Although pentavalent arsenic is reduced to some degree in vivo to the more toxic trivalent form, trivalent arsenic is slowly and extensively oxidised to pentavalent arsenic. Both forms are methylated and excreted in the urine, mainly as dimethylarsinic acid, with smaller amounts appearing as monomethylarsonic acid and inorganic arsenic compounds. Although about 60% of a dose may be eliminated in the urine within 8 days, small amounts may continue to be excreted for several weeks after a single dose. Less significant amounts of arsenic are excreted in the faeces and sweat and via the lungs and skin. It is also distributed into breast milk and readily crosses the placenta.

💊 Uses and Administration

Arsenic trioxide is used for induction of remission and consolidation in acute promyelocytic leukaemia (see below). It is given as an intravenous infusion over 1 to 2 hours to patients who are refractory to, or who have relapsed from, conventional therapy with retinoids and antineoplastics; if acute vasomotor reactions occur, the rate of infusion may be slowed and up to 4 hours may be taken. For induction, a dose of 150 micrograms/kg is given once daily until remission occurs; no more than 50 doses should be given (in the USA, the maximum number of induction doses allowed is 60). Treatment for consolidation must begin 3 to 4 weeks after completion of induction (or 3 to 6 weeks in the USA). The dose for consolidation is 150 micrograms/kg once daily given for 25 doses spread over a period of up to 5 weeks; the regimen suggested in the UK is to give the daily dose for 5 days each week followed by 2 days without dosing. Arsenic trioxide is used in certain Asian herbal remedies. Arsenic anhydride has also been used. Arsenic trioxide has been widely used as a constituent of weedkillers and sheepdips and as a rodenticide. Arsenic trioxide and arsenic triiodide were formerly used internally as solutions or externally as ointments in the treatment of various skin diseases, but such use is generally no longer recommended. Externally, arsenic trioxide has a caustic action.

Homoeopathy.

Arsenic trioxide has been used in homoeopathic medicines under the following names: Arsenious trioxide; Arsenici trioxidum; Arsenicum album; Acidum arsenicosum; Ars. alb.

Acute myeloid leukaemias.

The use of arsenic trioxide in the management of patients with acute promyelocytic leukaemia has been reviewed.1-4 Remission was achieved in patients who had relapsed despite conventional therapy with retinoids and antineoplastics.5,6 Arsenic trioxide is also being investigated for postremission therapy and in conjunction with transplantation.4 Treatment was also successful in newly-diagnosed patients but severe liver toxicity occurred in some cases.5 For references to adverse effects occurring in patients receiving arsenic trioxide for acute promyelocytic leukaemia, see under Adverse Effects, above.
1. Soignet SL. Clinical experience of arsenic trioxide in relapsed acute promyelocytic leukemia. Oncologist 2001; 6 (suppl 2): 11–6
2. Murgo AJ. Clinical trials of arsenic trioxide in hematologic and solid tumors: overview of the National Cancer Institute Cooperative Research and Development Studies. Oncologist 2001; 6 (suppl 2): 22–8
3. Slack JL, et al. Advances in the management of acute promyelocytic leukemia and other hematologic malignancies with arsenic trioxide. Oncologist 2002; 7 (suppl 1): 1–13
4. Douer D, Tallman MS. Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies. J Clin Oncol 2005; 23: 2396–2410
5. Niu C, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999; 94: 3315–24
6. Soignet SL, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001; 19: 3852–60.

Multiple myeloma.

Arsenic trioxide is under investigation for the treatment of relapsed or refractory multiple myeloma.
1. Munshi NC. Arsenic trioxide: an emerging therapy for multiple myeloma. Oncologist 2001; 6 (suppl 2): 17–21
2. Munshi NC, et al. Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia 2002; 16: 1835–7
3. Bahlis NJ, et al. Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clin Cancer Res 2002; 8: 3658–68
4. Berenson JR, Yeh HS. Arsenic compounds in the treatment of multiple myeloma: a new role for a historical remedy. Clin Lymphoma Myeloma 2006; 7: 192–8.

Myelodysplastic syndromes.

The use of arsenic trioxide for the treatment of myelodysplastic syndromes is also under investigation.
1. List A, et al. Opportunities for Trisenox (arsenic trioxide) in the treatment of myelodysplastic syndromes. Leukemia 2003; 17: 1499–1507
2. Vey N. Arsenic trioxide for the treatment of myelodysplastic syndromes. Expert Opin Pharmacother 2004; 5: 613–21
3. Schiller GJ, et al. Phase II multicenter study of arsenic trioxide in patients with myelodysplastic syndromes. J Clin Oncol 2006; 24: 2456–64
4. Vey N, et al. Arsenic trioxide in patients with myelodysplastic syndromes: a phase II multicenter study. J Clin Oncol 2006; 24: 2465–71
5. Sekeres MA. New data with arsenic trioxide in leukemias and myelodysplastic syndromes. Clin Lymphoma Myeloma 2007; 8 (suppl 1): S7–S12.

💊 Preparations

Proprietary Preparations

Austria: Tr isenox; Belg.: Trisenox; Cz.: Trisenox; Fr.: Tr is enox; Gr.: Tr is enox; Ital.: Trisenox; Jpn: Tr is en ox; Neth.: Tr is en ox; Spain: Tr isenox; UK: Tr is enox; USA: Tr is en ox . Multi-ingredient: Ital.: Pasta Arsenicale.
Published December 28, 2018.