title: Primum nil cocere – risk benefit evaluation of early synthetic drugs
title: Primum nil nocere –Zur Nutzen-Risiko-Bewertungfrüher synthetischerArzneistoffe
Creators: name: Schneider, Axel
Publisher: name: Philipps-Universität Marburg
Year: 2014
Subjects: Baruch Spitz
Toxisch-Epidermale-Nekrolyse
Phenazon
Sulfonal
Antipyrin
Chloroform Antipyrin Sulfonal Phenazon Nutzen Risiko Bewertung
Chloroform
Risiko
TEN
Bewertung
Nutzen
Lyel syndrom
risk benefit evaluation
Medizin, Gesundheit

description: Während für traditionelle
      pflanzliche Arzneimittel Informationen über deren Toxizität
      und Wirksamkeit vorhanden waren, konnten man über die ersten
      synthetischen Substanzen noch keine Aussagen treffen. Am
      Beispiel von Phenazon und Sulfonal konnte gezeigt werden,
      dass zum Ende des 19. Jh. Substanzen noch vor der Vermarkung
      an einer validen Anzahl von Patienten getestet wurde. Die
      Anzahl genügte, um Aussagen über häufige vorkommende
      Nebenwirkungen treffen zu können. Im Verlaufe von drei Jahren
      konnten so schon selten vorkommende Nebenwirkungen
      nachgewiesen werden. Einhergehen mit den Nutzen, den die
      Substanzen für die Therapie in der damaligen Zeit bedeuteten,
      wurden risikominimierende Maßnahmen getroffen, um das Nutzen
      Risiko-Verhältnis positiv zu beeinflussen. Überdies konnte
      gezeigt werden, dass die Toxisch-Epidermale-Nekrolyse (ICD-10
      L51.20-L51.21) bereits 1887 durch den Arzt Baruch Spitz
      beschrieben wurde.
description: The purpose of this study was to
      determine if, and how far, risk-benefit-evaluations were
      already performed at the time of the introduction of the
      first synthetic drugs in the 19th century. While for natural
      products or compounds derived therefrom more or less
      information about toxicity and even efficacy was available.
      But the totally new synthetic entities were not related to
      anything formerly known. This led to new challenges of drug
      safety evaluation. Exploring the three examples chloroform
      introduced as an inhalation narcoritc in 1847, antipyrin
      introduced as an antipyretic and analgesic in 1883 and
      sulfonal a completely new sedative available from 1888. It
      could be shown that the physicians of the 19th century
      already followed a quite sophisticated system for testing new
      substances. It comprised practical testing with a realistic
      patient collective and a broad reporting in trade
      publications and conference presentations. The primary aim
      was to investigate the real benefit for practical therapies
      and their associated risks. The first uses of new synthetic
      compounds in clinics were restrained and always took place in
      full awareness that serious unexpected adverse drug reactions
      (ADR) could occur. New substances were just administered in
      cases where conventional therapies had failed, or diseases
      were very severe. Antipyrin and sulfonal were tested even
      before a wide marketing of these drugs started. Manufactures
      sponsored studies with the new products by providing drugs
      free of charge. Physicians used them in their daily practice
      approximately for one year. Within this time it was possible
      to treat around 300 patients which are, according to modern
      stistics, enough to make statements about common (1/100 to
      &lt;1/10) ADRs. After almost three years the number of
      patients was sufficient to detect even rare (1/10,000 to
      &lt;1/1,000) ADRs. A prominent example is the toxic epidermal
      necrolysis (TEN) under antipyrin treatment. Toxic epidermal
      necrolysis (TEN) is a rare but serious drug adverse reaction.
      It is also known as Lyell syndrome (ICD-10 L51.20–L51.21),
      named after the British dermatologist Alan Lyell (1917–2007),
      who described the syndrome in 1956 and some
      followingpublications. However, it could be shown that TEN
      has already been described in the medical literature in 1887
      by the Jewish physician Baruch Spitz (1818–1897), i.e.
      several decades earlier than Lyell. Consequently, the eponym
      “Lyell syndrome” was assigned incorrectly. To justify the
      treatment with synthetic agents the risk of the illness had
      to be greater than that of the drug administration. So in
      mild disease patterns, synthetic agents were rarely used. To
      determine the risk to human health, animal tests,
      self-experiments, multicentre clinical trials,
      side-effect-reports, but also statistical surveys were
      conducted. Early attitudes towards balancing benefits and
      risks are also reflected by recommendations of risk reducing
      methods of administration or dose limitations. Thus, some
      form of benefit-risk evaluation clearly existed in the early
      days of synthetic drug substances. Physicians in the late
      19th century obviously acted with considerable care using the
      new substances keeping in mind the obligation of “primum nil
      nocere”, which dates back to the times of
      Hippokrates.