The evil of the unknown--risk-benefit evaluation of new synthetic drugs in the 19th century.

In the 19th century, synthetic chemistry discovered completely new chemical entities for medicinal use, which dramatically enriched the therapeutic armamentarium. However, no information was available regarding the safety of these new drugs, which were unrelated to most of the medicinal agents formerly known. Therefore, the question arises, if and how far, considerations regarding the relationship between benefit and risks were made. In this study, chloroform, phenazone (antipyrine) and sulfonal, were investigated as examples for drugs newly introduced in the 19th century. The results revealed that these drugs were provided by the manufacturer, tested by the physicians in a multicentre pattern and side effects were published in the medical literature soon after. Within a few years, several hundred cases were reported but the data were rarely summarized statistically. Therefore, physicians needed to stay updated with the medical literature because neither systematic industrial research nor regulatory authorities existed. The number of case reports within the first years were sufficient to detect common (> 1/100 to < 1/10) side effects but rare events were also reported. An extraordinary example is the drug-induced toxic epidermal necrolysis, which is commonly known as the Lyell syndrome or its less severe form, the Stevens-Johnson syndrome. This reaction has been clearly described by Baruch Spitz (1854-1932) as a side effect of antipyrine in 1887, several decades before Stevens, Johnson and particularly Lyell.