Neuropathic organophosphates: from Scrugham, Heim and Lorot to Jake leg paralysis

Henry Scrugham (1811-1898), the father of triphenyl-phosphate, was a student of Alexander Williamson (1824-1904), Professor of analytical and practical chemistry at the University College London. Williamson using the approach perfected by Scurgham reacted phosphorus pentachloride with cresol (a mixture of ortho, para and meta isomers) thus obtaining tricresyl phosphate (TCP). The triesters of phenol, cresol and naphtol were prepared with a higher yield by Rudolf Heim (1861-1919) by their respective reaction with phosphorus oxychloride (POCl3). Heim is also the first one to obtain pure tri-o-cresyl phosphate (TOCP). In the meantime French pharmacist Jules Brissonnet (1859-1915) synthesized creosote phosphate (containing i.a. TOCP) and popularized its use in the treatment of pulmonary phthisis (tuberculosis). Camille Lorot (1872-1951) and others in France and Germany recognized the ability of creosote phosphate to induce polyneuropathies but this knowledge did not prevent the Ginger Jake epidemic (Jake leg) of the 1930s in the US. The Jake induced neuropathy was first recognized and described in Oklahoma City by a General Practitioner, Ephraim Goldfain (1894-1983). Soon thereafter Maurice Isadore Smith (1887-1951), a pharmacologist, and chemist Elias Elvove (1883-1962) identified TOCP in Jamaican ginger extract as the causative agent. We attempt to shed some light on the life and family of the less known chemists, pharmacists and physicians associated with the synthesis of neuropathic organophosphates and with the recognition of their toxicity.