King of poisons or ‘magic bullet’?

A potent poison purportedly behind the death of a king, arsenic has also served numerous, less-sinister, medicinal purposes.

In fact, the terms ‘magic bullet’ and the ‘arsenic that saved’ were popularly used to describe the ability of an organic arsenical compound drug, Salvarsan (arsphenamine), to cure syphilis.

The first modern chemotherapeutic, Salvarsan was discovered in 1909 by Nobel Prize-winning immunologist Paul Ehrlich, along with Japanese student bacteriologist Sahachiro Hata.

Ehrlich’s earlier magic bullet theory had posited that selective drugs were needed ‘which, like antitoxins aimed specifically at their corresponding toxins, would have affinity for pathogens and act as “magic bullets” without affecting the host’s cells’.¹

The theory was borne out with Salvarsan, which was found to be toxic to the bacterium Treponema pallidum, the spirochete that causes syphilis. It was a vast improvement on the previous standard treatment for syphilis – years of mercury injections.

However, severe side effects, including convulsions and death, led to the development of a less toxic but less effective compound – Neosalvarsan, which was released in 1913.²

Other therapeutic uses
As early as Hippocratic times, arsenic was used to treat ulcers and abscesses.³

By the late 1700s, a solution of arsenic trioxide in potassium bicarbonate was developed by British physician Thomas Fowler and used as an alternative to quinine in malaria treatment and for trypanosomiasis.³

The solution was also variously prescribed for asthma, chorea, eczema, pemphigus, psoriasis, anaemia, hypertension, heartburn, rheumatism and tuberculosis.³

By the end of the 19th century, ‘Fowler’s Solution’ was proven to significantly decrease white blood cell counts in patients with chronic myelogenous leukaemia. It went onto become the dominant treatment for leukaemia.⁴

Toxicity
Despite arsenic’s therapeutic benefits, time and again formulations have been abandoned due to concerns around toxicity and carcinogenicity.⁵ In the treatment of syphilis, it was replaced in the 1940s with the advent of penicillin.³

Applications in leukaemia treatment were largely abandoned following the development of radiation in the 20th century.⁵

Today, injectable arsenic trioxide is approved only for the treatment of relapsed or refractory acute promyelocytic leukaemia, where it works by converting immature cancerous white blood cells into normal white blood cells.³

References:
1. Boscha F and Rosicha L. The Contributions of Paul Ehrlich to Pharmacology: A Tribute on the Occasion of the Centenary of His Nobel Prize. Pharmacology. 2008 Oct;82(3):171-179. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790789/.

2. Tan SY and Grimes S. Paul Ehrlich (1854-1915): man with the magic bullet. Singapore Med J. 2010;51(11):842-843. Available from: http://smj.sma.org.sg/5111/5111ms1.pdf

3. Frith J. Arsenic – the “Poison of Kings” and the “Saviour of Syphilis”. Journal of Military and Veterans’ Health. 2013 Dec;21(4);11-17. Available from: http://jmvh.org/article/arsenic-the-poison-of-kings-and-the-saviour-of-syphilis/

4. Antman KH. Introduction: the history of arsenic trioxide in cancer therapy. Oncologist.
2001;6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11331433

5. Adams S. Arsenic: medicinal double-edged sword. Available from: healio.com/hematology-oncology/news/print/hemonc-today/%7B130e1d7d-ebd2-48b3-9546-158a630fa71b%7D/arsenic-medicinal-double-edged-sword