Arsphenamine

Lore & Background

Arsphenamine was first synthesized in 1907 in Paul Ehrlich's lab by Alfred Bertheim. The antisyphilitic activity of this compound was discovered by Sahachiro Hata in 1909, during a survey of hundreds of newly synthesized organic arsenical compounds. Ehrlich had theorized that by screening many compounds, a drug could be discovered that would have anti-microbial activity but not kill the human patient. Ehrlich's team began their search for such a 'magic bullet' among chemical derivatives of the dangerously toxic drug atoxyl.

Arsphenamine was originally called '606' because it was the sixth in the sixth group of compounds synthesized for testing. It was marketed by Hoechst AG under the trade name 'Salvarsan' in 1910. Salvarsan was the first organic antisyphilitic, and a great improvement over the inorganic mercury compounds that had been used previously. It was distributed as a yellow, crystalline, hygroscopic powder that was highly unstable in air. This significantly complicated administration, as the drug had to be dissolved in several hundred milliliters of distilled, sterile water with minimal exposure to air to produce a solution suitable for injection.

Ehrlich's laboratory developed a more soluble (but slightly less effective) arsenical compound, Neosalvarsan (neoarsphenamine), which was easier to prepare, and it became available in 1912. Less severe side-effects such as nausea and vomiting were still common. An additional problem was that both Salvarsan and Neosalvarsan had to be stored in sealed vials under a nitrogen atmosphere to prevent oxidation. These arsenical compounds were supplanted as treatments for syphilis in the 1940s by penicillin.

Reader's Guide

Arsphenamine holds a pivotal place in medical history as the first modern antimicrobial agent and the first effective treatment for syphilis, relapsing fever, and African trypanosomiasis. Its development by Paul Ehrlich's lab, based on screening many compounds for selective toxicity, embodied the 'magic bullet' concept. The drug's introduction in 1910 marked a major advance over toxic inorganic mercury compounds. However, its use was complicated by its instability in air, requiring careful preparation and administration. Side effects such as rashes, liver damage, and risks of life and limb were partly attributed to improper handling, prompting Ehrlich to standardize practices. The later development of Neosalvarsan in 1912 offered easier preparation but slightly reduced efficacy. Both drugs were eventually replaced by penicillin in the 1940s. In 2005, mass spectrometric analysis revealed that Salvarsan's structure, long thought to contain As=As double bonds, actually consists of cyclic species with single arsenic–arsenic bonds, which slowly release an oxidized species likely responsible for its antisyphilis properties.

Did You Know?

• The antisyphilitic activity of arsphenamine was discovered by Sahachiro Hata in 1909.
• Salvarsan had to be dissolved in distilled, sterile water with minimal exposure to air because it was highly unstable in air.
• In 2005, mass spectrometric analysis showed that Salvarsan actually contains cyclic species with single arsenic–arsenic bonds, not double bonds.