Therapeutic disasters that hastened safety testing of new drugs.

New drugs were not required to undergo premarket safety testing in the United States until 1938, when a therapeutic disaster-the Elixir Sulfanilamide tragedy-prompted Congress to pass a bill mandating this now-routine process. History repeated itself nearly 25 years later, when another therapeutic disaster-the thalidomide tragedy-led to passage of new amendments in 1962 to ensure drug efficacy and greater drug safety. As is typical with historical events, critical information was gained that led to novel approaches for understanding, predicting, diagnosing, and managing drug-induced toxicities. Continued refinement of current, along with development of new, approaches will mitigate future drug-related catastrophes, with the goal of avoiding them entirely.

Fred Loe, MD, and the history of trachoma.

Trachoma has been one of the most blinding diseases in the history of ophthalmology. From its initial description in antiquity until the late 1930s, no specific treatment or effective cure had been known, and the only expedient had been to destroy the diseased tissue containing the infectious agent, rendering the disease inactive. Virtually all medical, mechanical, and surgical treatments were unsatisfactory, with cure rates of approximately 20%. Therapy for trachoma had barely advanced from the measures used by the ancient Egyptian, Greek, and Roman physicians. All prior therapies became obsolete in 1938 when Fred Loe, MD, working on an American Indian reservation, introduced sulfanilamide as a treatment of trachoma, achieving a 90% cure rate. One of the most unusual aspects of Loe's career was that he had no formal training in ophthalmology and was completely self-taught as an ophthalmologist.

The last year before the dawn of antibiotics.

Pick up any bound volume of a general medical journal of 1934 (75 years ago - within the memory of old members of the profession), and there are likely to be papers concerning the dreaded effects of the Gram positive cocci. The pneumococcus, causing often fatal lobar pneumonia in previously fit young people, and the beta-haemolytic streptococcus, producing erysipelas, septicaemia and puerperal sepsis, were especially dangerous. Volume one of the Lancet for that year, for example, contains no less than four papers on different trials of treatment for streptococcal infection as well as a long and learned leading article.

Lobar pneumonia treated by Musgrave Park physicians.

In the decade 1935-45 the treatment of lobar pneumonia in the developed and warring world underwent a series of evolutions-anti-sera, specific anti-sera, refinement of sulpha drugs, sulpha and anti-sera, the introduction of penicillin for bacteriology, then ophthalmology, and then for penicillin-sensitive bacterial infections such as lobar pneumonia with its many Cooper types of Streptococcus pneumoniae. Penicillin for civilian use was essentially banned in World War II, a ban that early in 1941 two Musgrave Park physicians tried to circumvent. Strict secrecy on the details of penicillin production was enforced. The treatment option chosen by the Musgrave Park physicians in 1941, and the non-availability of penicillin led to sequelae affecting the post-Belfast careers of both patient and physicians.

Gonorrhea and the beginnings of clinical research ethics.

Research on ocular inflammation associated with gonorrhea began in conjunction with the entry of trachoma into Europe during the Napoleonic wars. The initial questions involved the cause of the contagiousness of gonorrhea and how the contagion spreads from the genitalia to other sites. Because efforts to infect animals with gonorrheal matter were unsuccessful, all experiments were conducted on human subjects. Once these two causes of blindness were tentatively differentiated, attempts to restore vision in an eye that had been blinded by a trachomatous membrane over the cornea by instilling gonorrheal pus began to be practiced. In 1841, Joseph Piringer described his use of this method to determine infectiousness decades before the discovery of pathogenic bacteria, as well as ethical concerns about the associated endangerment of patients. Beginning in the 1880s, research focused on the identification of the gonococcus and assessment of its pathogenicity. The ethical dilemma of inducing a disease with an unpredictable outcome persisted until the 1940s, when gonorrhea could be reliably cured by penicillin.

Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act.

The Elixir Sulfanilamide disaster of 1937 was one of the most consequential mass poisonings of the 20th century. This tragedy occurred shortly after the introduction of sulfanilamide, the first sulfa antimicrobial drug, when diethylene glycol was used as the diluent in the formulation of a liquid preparation of sulfanilamide known as Elixir Sulfanilamide. One hundred five patients died from its therapeutic use. Under the existing drug regulations, premarketing toxicity testing was not required. In reaction to this calamity, the U.S. Congress passed the 1938 Federal Food, Drug and Cosmetic Act, which required proof of safety before the release of a new drug. The 1938 law changed the drug focus of the Food and Drug Administration from that of a policing agency primarily concerned with the confiscation of adulterated drugs to a regulatory agency increasingly involved with overseeing the evaluation of new drugs. The Elixir Sulfanilamide tragedy, its effect on drug regulations, and the history of other diethylene glycol and diluent mass poisonings are discussed.

[Veterinary pharmacotherapy: from retrospect to future expectations]. / Veterinaire farmacotherapie: van terugblik naar toekomstverwachting.

To begin with, a review paper on apomorphine, published by J.J. Hinze in 1875, is discussed. Subsequently, the development of pharmacology and rational pharmacotherapy is described. The progress of veterinary pharmacotherapy during the sixties and seventies is recalled on the basis of instances, and recent additions such as aditoprim, florphenicol and flumazenil are also referred to. Finally, the possibilities of biotechnology, particularly polypeptides which are produced using the recombinant DNA technique, such as interferons, interleukins and somatotropins (which are of interest from the point of view of zootechnics) are discussed. The recombinant DNA technique also makes it possible to synthesise receptor proteins, and thus offers new and interesting possibilities for future pharmacological studies.