Historical Review: Problematic Malaria Prophylaxis with Quinine.

Quinine, a bitter-tasting, short-acting alkaloid drug extracted from cinchona bark, was the first drug used widely for malaria chemoprophylaxis from the 19th century. Compliance was difficult to enforce even in organized groups such as the military, and its prophylaxis potential was often questioned. Severe adverse events such as blackwater fever occurred rarely, but its relationship to quinine remains uncertain. Quinine prophylaxis was often counterproductive from a public health viewpoint as it left large numbers of persons with suppressed infections producing gametocytes infective for mosquitoes. Quinine was supplied by the first global pharmaceutical cartel which discouraged competition resulting in a near monopoly of cinchona plantations on the island of Java which were closed to Allied use when the Japanese Imperial Army captured Indonesia in 1942. The problems with quinine as a chemoprophylactic drug illustrate the difficulties with medications used for prevention and the acute need for improved compounds.

Autoimmunity: from black water fever to regulatory function.

Autoimmunity is a field that has only been around for a little over a century. Initially, it was thought that autoimmunity could not happen, that the body would never turn on itself (i.e. "horror autotoxicus"). It was only around the First World War that autoimmunity was recognized as the pathogenesis of various diseases, including rheumatoid arthritis. The discovery of Compound E led to successful treatment of patients with autoimmune diseases, but it was not till later that the adverse effects of this class of drugs were elucidated. The "modern" age of autoimmunity began around 1945 with the description of blackwater fever, and most of the subsequent research on hemolytic anemia and the role of an autoantibody in its pathogenesis led to a description of the anti-globulin reaction. The lupus erythematous (LE) cell was recognized in the mid-1940s by Hargreaves. His research carried on into the 1960s. Rheumatoid factor was also first described in the 1940s as yet another serum factor with activity against globulin-coated sheep red blood cells. The concept of autoimmunity really gained a foothold in the 1950s, when autoimmune thyroid disease and idiopathic thrombocytopenia were first described. Much has happened since then, and our understanding of autoimmunity has evolved now to include mechanisms of apoptosis, signaling pathway derangements, and the discovery of subsets of T cells with regulatory activity. The modern day study of autoimmunity is a fascinating area of research, and full understanding of the pathogenesis of autoimmune diseases is far from being completely elucidated.

Blackwater fever: the rise and fall of an exotic disease.

After several descriptions by Hippocrates and a single possible medieval description by Gilles de Corbeil, a severe febrile illness accompanied by the passage of dark urine burst upon the medical scene in West Africa in 1819, described by an English surgeon named Tidlie. Most of his patients died within a few days. Further reports appeared from tropical regions until the turn of the century, J. Farrell Easmon having given the condition the name blackwater fever in 1884. Controversy raged about its relationship to malaria, as well as over its treatment with cinchona bark and quinine. Evidence evolved that it was a complication of falciparum malaria in which hemoglobinuria causing acute renal failure resulted from massive quinine-induced lysis of red blood cells. People with red cell abnormalities such as glucose-6-phosphate dehydrogenase deficiency proved particularly prone to developing it. Its incidence fell as more mildly acting antimalarial drugs replaced quinine. Several enigmatic issues bedeviled understanding of it, but a careful analysis of its historical development has enabled resolution of each of these.

[Blackwater fever: a French episode drawn from the research of Alexandre Yersin]. / La fièvre bilieuse hémoglobinurique: un épisode français tiré d'une recherche d'Alexandre Yersin.

This article discusses the research on blackwater fever that was undertaken by Alexandre Yersin in 1895. It shows with the help of the three-fold light of the laboratory notes, the published articles, and the private correspondence of Yersin, how historical, political, scientific and personal factors interact.