British anti-Lewisite

Ravindra Kumar Garg DM FRCP

General Neurology

Updated 01.08.2024
Released 11.30.2006
Expires For CME 01.08.2027

British anti-Lewisite

Author: Ravindra Kumar Garg DM FRCP

See Contributor Disclosures

Editor: Matthew Lorincz MD PhD

British anti-Lewisite

In This Article

Quick Link

Introduction

Overview

British anti-Lewisite was developed in 1941 as an antidote to lewisite, an arsenic-based chemical warfare agent. British anti-Lewisite is used in arsenic, gold, and mercury (soluble inorganic compounds) poisoning. This drug is not indicated in patients with iron, cadmium, selenium, silver, or uranium poisoning. British anti-Lewisite is occasionally used for both acute heavy metal intoxication and Wilson disease. Parenteral British anti-Lewisite can be successfully used in lead poisoning if oral therapy fails. Dimercaprol compound is useful for the treatment of potentially life-threatening acute arsenic poisoning as well. Mobilization of cerebral deposits of mercury is difficult to achieve. A combination of low-dose British anti-Lewisite plus dimercaptopropane sulfonic acid can help in mobilizing the intracerebral mercury into the circulation, thus, facilitating urinary excretion. In in vitro testing, it has been observed that dimercaprol has potential to treat snakebite. Dimercaprol, a metal ion chelator, acts against Zn2+-dependent snake venom metalloproteinases, which mediates procoagulant property of snake venom. Unfortunately, dimercaprol and DMPS in murine models failed to demonstrate sufficient potency against Dispholidus typus (boomslang) venom-induced consumption coagulopathy. An innovative chelator composed of hyaluronic acid and British anti-Lewisite reduces cobalt toxicity from joint implants, improving safety and avoiding complex surgeries.

Key points

	• British anti-Lewisite is a chelating agent.
	• British anti-Lewisite has a greater affinity for metal than for body proteins, and, thus, reverses the functioning of these proteins.
	• British anti-Lewisite is used in arsenic, gold, and mercury (soluble inorganic compounds) poisoning.
	• British anti-Lewisite is not indicated in iron, cadmium, selenium, silver, or uranium poisoning.
	• British anti-Lewisite is administered by deep intramuscular injections of 2 to 5 mg/kg, one to four times per day for up to 10 days.
	• It is no longer the preferred chelating agent.

Historical note and terminology

Lewisite (2-chlorovinyldichoroarsine) is an arsenic-based vesicant chemical warfare agent that was initially developed, although not used, by the United States during World War I. It was believed to have much greater toxicity than mustard gas, with some animal data suggesting that as little as one-third teaspoon on the skin would result in human death (30). During the period between World Wars I and II, all major countries developed lewisite production facilities and, as World War II loomed, both Great Britain and the U.S. initiated research projects designed to develop an antidote to lewisite. On July 21, 1940, an Oxford University group of chemists reported the successful development of British anti-Lewisite (22). On first arrival in the United States in 1941, a series of studies was initiated to determine British anti-Lewisite’s biochemistry, pharmacology, experimental therapeutics, and clinical applications (36). Improvements in synthesis resulted in the development of effective therapeutic ointments and solutions. British anti-Lewisite was produced during World War II by DuPont. Plans for the possible production of 200,000 pounds per year were developed (36). During and after the war, nonmilitary uses for the heavy metal chelating action of British anti-Lewisite became apparent. Eagle and Magnuson found that 48 patients with severe or mild symptoms of arsenical encephalopathy were effectively treated with British anti-Lewisite (13). By 1947, 32 articles had been published or were in press on the therapeutic value of British anti-Lewisite (22). British anti-Lewisite was the drug of choice for treatment of intoxication with arsenic, antimony, mercury, and gold. It was also considered effective in cases of intoxication with bismuth, copper, and nickel (11).

In 1949, Porter found a seven-fold increase in copper excretion in two patients with Wilson disease and some decrease in neurologic signs after treatment with British anti-Lewisite (23). In 1951, Cummings at the National Hospital, Queen Square, and Denny-Brown and Porter at Boston City Hospital conducted studies on the long-term effects of British anti-Lewisite in four and five, respectively, patients with Wilson disease. The effects were definitive and dramatic; the patients exhibited great improvement in accordance with marked increases in urinary copper excretion (10; 12). British anti-Lewisite’s use as the primary treatment for Wilson disease was short-lived because Walshe, in 1956, showed the value of the less toxic chelating agent, penicillamine (34). Other agents have been developed since (06). Nevertheless, British anti-Lewisite may still have some therapeutic value in patients who do not respond well to more modern agents (25). It has been postulated that, because British anti-Lewisite is nonpolar, it may accelerate the removal of copper from within the brain compared to more modern agents (25; 33).

British anti-Lewisite is not generally recommended for use today because more efficient and safer chelators for oral or parenteral administration have been developed (02; 05; 03). In the United States it is marketed by Akorn as British anti-Lewisite in Oil® in 3 mL 100 mg/mL single-use ampoules (the solute is peanut oil).

Indications

FDA-approved uses of British anti-Lewisite are for treatment of mild and severe arsenic toxicity, mild and severe gold toxicity, mild and severe lead poisoning (when used concomitantly with EDTA injection), and acute mercury toxicity. Chelating treatment should be started as quickly as possible, as efficacy declines rapidly as the time interval between metal poisoning and treatment increases (16).

Mückter and colleagues, in 1997, published an intriguing article titled, “Are we ready to replace dimercaprol (BAL) as an arsenic antidote?” (21). The authors concluded that whereas two hydrophilic British anti-Lewisite derivatives (2,3,dimercaptopropane-1-sulphonate sodium [DMPS] and meso-2-3-dimercaptosuccinic acid [DMSA]) are less toxic than British anti-Lewisite and approved in several countries, in time-critical situations British anti-Lewisite may be more effective than these two compounds in restoring cellular function.

A 2004 report described the use of British anti-Lewisite in acute lead poisoning in a 4-year-old boy following ingestion of a lead-containing toy medallion. The child was treated with British anti-Lewisite and EDTA, which rapidly reduced his blood lead levels from 123 µg/dL to 57 µg/dL. He was then switched to other chelators to reduce his blood lead level still further (29). A report described using British anti-Lewisite for intentional arsenic trioxide ingestion and for intentional mercuric chloride ingestion (35). In the first case, British anti-Lewisite (5 mg/kg) was given every 6 hours for 48 hours by deep intramuscular injection. After the first dose the patient complained of a burning sensation in the lips, throat, and mouth; lacrimation; rhinorrhea; sweating; and nausea. After a dose adjustment to 3 mg/kg every 6 hours and later to every 12 hours, there were no further adverse effects. The second patient was treated by 3 mg/k British anti-Lewisite every 4 hours for 5 days. The patient developed a rash that was thought to be related to a peanut allergy and not directly to British anti-Lewisite. Both of these patients purchased their metal powders on the internet. It was concluded that the knowledge of aggressive decontamination, presumably using British anti-Lewisite, is essential. British anti-Lewisite is still being successfully used in patients with lead poisoning. Vossoughinia and colleagues treated a 19-year-old woman with severe abdominal pain, icterus, and anemia (32). The patient did not respond to oral chelators, so parenteral dimercaprol and calcium ethylenediaminetetraacetic acid (EDTA) was given. The patient responded dramatically after 5 days of treatment.

British anti-Lewisite is also a third-line alternative in the treatment of Wilson disease in patients intolerant to penicillamine and trientine. British anti-Lewisite has been reported effective in controlling unilateral rubral tremors in patients with Wilson disease refractory to 1-year therapy with penicillamine and anti-tremor medications. The tremors decreased considerably after adding dimercaprol (09).

Retained shrapnel is an uncommon cause of systemic lead toxicity. Lead foreign bodies in joint spaces may be a source of systemic lead absorption, causing elevated blood lead levels. In such patients, chelation therapy with dimercaprol can bring significant clinical improvement. Dimercaprol (British anti-Lewisite) crosses the blood-brain barrier, and chelate central nervous system lead as well (14; 18; 37).

Dimercaprol compounds are helpful in treatment of mercury and arsenic toxicities as well (15). A patient with altered mental status, hyponatremia, and abnormal thyroid functions was diagnosed to have mercury poisoning (07). Blood Hg level was greater than 9 ng/mL. Following chelating therapy with 2,3-dimercaptopropane-1-sulfonate of 8 months duration, the patient improved remarkably. Another patient ingested 37.5 g of arsenic for suicide, but prompt chelating therapy with 2,3-dimercaptopropane-1-sulphonate resulted in complete recovery (17). With early treatment, development of peripheral neuropathy was prevented.

Mobilization of cerebral deposits of mercury in chronic toxicities is difficult to achieve. Newer information indicates that a combination of low-dosed British anti-Lewisite plus dimercaptopropane sulfonic acid can help in mobilizing cerebral mercury into the blood circulation, which can result in prompt removal from body via urinary excretion (04).

In an isolated case, dimercaprol was found effective in a pregnant patient with bismuth intoxication (08). In an adolescent pregnant girl who developed acute kidney injury due to an overdose of colloidal bismuth subcitrate administration of parenteral chelating agent dimercaprol for 14 days resulted in complete clinical reversal. She gave birth to a healthy baby as well.

Cobalt-containing alloys in orthopedic implants, such as hip replacements, release cobalt ions causing local and systemic toxicity. This leads to complications requiring complex revision surgeries. To address this, a synovial fluid-mimicking chelator composed of hyaluronic acid functionalized with British anti-Lewisite (BAL-HA), was developed. BAL-HA effectively binds cobalt, improving cell vitality and accelerating cobalt clearance. This biocompatible chelator, injectable into the joint, shows promise in reducing cobalt toxicity from metal-on-metal implants without risking kidney failure (28).

In in vitro testing, it has been observed that dimercaprol has a potential to treat snakebite. Viper snake envenomation leads to a profound coagulopathy and systemic hemorrhage. Coagulopathy is mediated by Zn2+-dependent metalloproteinases. Dimercaprol, a metal ion chelator, has an in vitro activity against this enzyme. Administration of dimercaprol also provided survival benefits in murine preclinical models of viper snakebites (01; 38). Unfortunately, dimercaprol and 2,3-Dimercapto-1-propanesulfonic acid (DMPS) in preclinical murine models failed to demonstrate sufficient potency against Dispholidus typus (boomslang) venom-induced consumption coagulopathy (19).

Experimental observations revealed that dimercaprol may be an effective neuroprotective agent. Acrolein is a toxic byproduct of lipid peroxidation, and it has been shown to be associated with neuropathogenesis in spinal cord injury, multiple sclerosis, and Alzheimer disease. Suppressing acrolein using acrolein scavengers has been noted as a novel strategy of neuroprotection. Dimercaprol, when administered through intraperitoneal injection, significantly reduces acrolein contents in spinal cord following a spinal cord injury in rats. Spinal cord injury in rats is a condition known to produce increased acrolein concentration (27). In another experimental study, a combination of arsenic trioxide and dimercaprol has been found a promising enhancer of radiosensitivity in mice with pancreatic cancer xenografts (26).

References

01: Albulescu LO, Xie C, Ainsworth S, et al. A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite. Nat Commun 2020;11(1):6094. PMID 33323937
02: Andersen O. Principles and recent developments in chelation treatment of metal intoxication. Chem Rev 1999;99(9):2683-710. PMID 11749497
03: Archer SL. Dilated cardiomyopathy and left bundle branch block associated with ingestion of colloidal gold and silver is reversed by British antiLewisite and vitamin E: the potential toxicity of metals used as health supplements. Can J Cardiol 2008;24(5):397-9. PMID 18464946
04: Bjorklund G, Mutter J, Aaseth J. Metal chelators and neurotoxicity: lead, mercury, and arsenic. Arch Toxicol 2017;91(12):3787-97. PMID 29063135
05: Blanusa M, Varnai VM, Piasek M, Kostial K. Chelators as antidotes of metal toxicity: therapeutic and experimental aspects. Curr Med Chem 2005;12(23):2771-94. PMID 16305472
06: Brewer GJ. The treatment of Wilson disease. Adv Exp Med Biol 1999;448:115-26. PMID 10079820
07: Carter M, Abdi A, Naz F, Thabet F, Vyas A. A mercury toxicity case complicated by hyponatremia and abnormal endocrinological test results. Pediatrics 2017;140(2). PMID 28701428
08: Çelebi-Tayfur A, Yaradılmış RM, Ulus F, et al. Bismuth intoxication resulting in acute kidney injury in a pregnant adolescent girl. Turk J Pediatr 2019;61(2):292-6. PMID 31951346
09: Chakor RT, Bharote H, Eklare N, Tamboli K. Unilateral rubral tremors in Wilson's disease treated with dimercaprol. Ann Indian Acad Neurol 2015;18(1):115-6. PMID 25745328
10: Cummings JN. The effects of B.A.L. in hepatolenticular degeneration. Brain 1951;74:10-22. PMID 14830662
11: Deichmann WB, Gerarde HW. Symptomatology and Therapy of Toxicological Emergencies. New York: Academic, 1964:1-605.
12: Denny-Brown D, Porter H. The effect of BAL (2,3-dimercaptopropanol) on hepatolenticular degeneration (Wilson disease). N Engl J Med 1951;245(24):917-25. PMID 14882450
13: Eagle H, Magnuson HJ. The systemic treatment of 227 cases of arsenic poisoning (encephalitis, dermatitis, blood dyscrasias, jaundice, fever) with 2,3-dimercaptopropanol (BAL). Am J Syph Gonorrhea Venereal Dis 1946;30:420-41. PMID 21000085
14: Grasso IA, Blattner MR, Short T, Downs JW. Severe systemic lead toxicity resulting from extra-articular retained shrapnel presenting as jaundice and hepatitis: a case report and review of the literature. Mil Med 2017;182(3):e1843-8. PMID 28290970
15: Kamensky OL, Horton D, Kingsley DP, Bridges CC. A case of accidental mercury intoxication. J Emerg Med 2019;56(3):275-8. PMID 30718027
16: Kosnett MJ. The role of chelation in the treatment of arsenic and mercury poisoning. J Med Toxicol 2013;9(4):347-54. PMID 24178900
17: Lu PH, Tseng JC, Chen CK, Chen CH. Survival without peripheral neuropathy after massive acute arsenic poisoning: treated by 2,3-dimercaptopropane-1-sulphonate. J Clin Pharm Ther 2017;42(4):506-8. PMID 28547870
18: McAninch SA, Adkison J, Meyers R, Benham M. Bullet fragment-induced lead arthropathy with subsequent fracture and elevated blood lead levels. Proc (Bayl Univ Med Cent) 2017;30(1):88-91. PMID 28127147
19: Menzies SK, Clare RH, Xie C, et al. In vitro and in vivo preclinical venom inhibition assays identify metalloproteinase inhibiting drugs as potential future treatments for snakebite envenoming by Dispholidus typus. Toxicon X 2022;14:100118. PMID 35321116
20: Merck. The Merck Index: An Encyclopedia of Chemicals and Drugs, eighth edition. Rahway, NJ: Merck & Co., 1968:1-1713.
21: Mückter H, Liebl B, Franz-Xaver R, Hunder G, Walther U, Fichti B. Are we ready to replace dimercaprol (BAL) as an arsenic antidote? Hum Exper Toxicol 1997;16:460-5. PMID 9292286
22: Ord MG, Stocken LA. A contribution to chemical defence in World War II. Trends Biochem Sci 2000;25(5):253-6. PMID 10782099
23: Porter H. Amino acid excretion in degenerative diseases of the nervous system. J Lab Clin Med 1949;34:1623-6.
24: Rafati-Rahimzadeh M, Rafati-Rahimzadeh M, Kazemi S, Moghadamnia AA. Current approaches of the management of mercury poisoning: need of the hour. Daru 2014;22:46. PMID 24888360
25: Scheinberg IH, Sternlieb I. Wilson’s Disease. Philadelphia: Saunders, 1984:1-171.
26: Tang R, Zhu J, Liu Y, Wu N, Han J. Formulation comprising arsenic trioxide and dimercaprol enhances radiosensitivity of pancreatic cancer xenografts. Technol Cancer Res Treat 2021;20:15330338211036324. PMID 34433326
27: Tian R, Shi R. Dimercaprol is an acrolein scavenger that mitigates acrolein-mediated PC-12 cells toxicity and reduces acrolein in rat following spinal cord injury. J Neurochem 2017;141(5):708-20. PMID 28301040
28: Ude CC, Schmidt SJ, Laurencin S, et al. Hyaluronic acid-British anti-Lewisite as a safer chelation therapy for the treatment of arthroplasty-related metallosis. Proc Natl Acad Sci U S A 2023;120(45):e2309156120. PMID 37903261
29: VanArsdale JL, Horowitz BZ, Merritt TA, et al. Brief Report: Lead Poisoning From Ingestion of a Toy Necklace–Oregon, 2003. JAMA 2004;292(4):430.
30: Vilensky, J. Dew of Death: The Story of Lewisite, America’s World War I Weapon of Mass Destruction. Bloomington: Indiana University Press, 2005:1-213.
31: Vilensky JA, Redman K. British anti-Lewisite (dimercaprol): an amazing history. Ann Emerg Med 2003;41(3):378-83. PMID 12605205
32: Vossoughinia H, Pourakbar A, Esfandiari S, Sharifianrazavi M. Severe abdominal pain caused by lead toxicity without response to oral chelators: a case report. Middle East J Dig Dis 2016;8(1):67-72. PMID 26933485
33: Walshe JM. Penicillamine: the treatment of first choice for patients with Wilson’s disease. Mov Disord 1999;14(4):545-50. PMID 10435489
34: Walshe JM. The conquest of Wilson’s disease. Brain 2009;132:2289-95. PMID 19596747
35: Wang EE, Mahajan N, Willis B, Leiken J. Successful treatment of potentially fatal heavy metal poisonings. J Emerg Med 2007;32(3):289-94. PMID 17394994
36: Waters LL, Stock C. BAL (British anti-lewisite). Science 1945;102:601-6. PMID 17818184
37: Weiss D, Lee D, Feldman R, Smith KE. Severe lead toxicity attributed to bullet fragments retained in soft tissue. BMJ Case Rep 2017;2017. PMID 28275014
38: Xie C, Albulescu LO, Bittenbinder MA, et al. Neutralizing effects of small molecule inhibitors and metal chelators on coagulopathic Viperinae snake venom toxins. Biomedicines 2020;8(9):297. PMID 32825484

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Ravindra Kumar Garg DM FRCP

Dr. Garg of King George's Medical University in Lucknow, India, has no relevant financial relationships to disclose.
See Profile

Editor

Matthew Lorincz MD PhD

Dr. Lorincz of the University of Michigan has no relevant financial relationships to disclose.
See Profile

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

British anti-Lewisite

Other Pertinent Drugs

meso-2,3-dimercaptosuccinic acid (succimer, meso-DMSA)
2,3-dimercaptopropane-1-sulfonic acid (unithiol, DMPS)
D-penicillamine (DPA) and N-acetyl-D-penicillamine (NAPA)
ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DPTA)
deferoxamine (DFO)
- deferiprone (L1)
- triethylenetetraamine (trientine)
- N-acetyl-L-cysteine (NAC)
- iron hexacyanoferrate – Prussian blue (PB)

Also Relevant

Arsenic neuropathy
Chelation therapy
Childhood lead poisoning
Lead neuropathy
Mercury neuropathy
- Metal neurotoxicity
- Wilson disease

Clinical Categories

Patient Handouts

Bioterrorism: biological diseases/agents

British anti-Lewisite

British anti-Lewisite

Introduction

Overview

Key points

Historical note and terminology

Pharmacology

Indications

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

Editor

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Brain death/death by neurologic criteria

Hepatic encephalopathy

Bowel dysfunction in neurologic disorders

Coma due to primary brainstem and diencephalic lesions

Transient visual loss

Neuroimaging in acute stroke

Sports activities: neurologic complications

Neurotechnology: brain-computer and brain-machine interfaces

British anti-Lewisite

Introduction

Overview

Key points

Historical note and terminology

Pharmacology

Indications

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

Editor

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Brain death/death by neurologic criteria

Hepatic encephalopathy

Bowel dysfunction in neurologic disorders

Coma due to primary brainstem and diencephalic lesions

Transient visual loss

Neuroimaging in acute stroke

Sports activities: neurologic complications

Neurotechnology: brain-computer and brain-machine interfaces

This is an article preview.
Start a Free Account
to access the full version.