[History of the therapy of pernicious anemia]. / Az anaemia perniciosa terápiájának története.

Increased blood cell regeneration in exsanguinated experimental animals treated either with liver or with aqueous liver extracts was reported by Whipple and by Jeney and Jobling, respectively. These findings stimulated Minot and Murphy to provide evidence for the efficacy of liver against anaemia in clinical studies. After oral administration of liver (45-50 g per day) for 45 patients with anaemia perniciosa improvement of the hematological status was demonstrated. Consequently, for proving the therapeutic value of liver therapy Whipple, Minot and Murphy received Nobel price in 1934. The isolation of the antianemic factor from the liver has been succeeded in 1948 and designated as vitamin B12. At the same time Lucy Wills applied yeast for the treatment of pregnant women with anemia related to undernourishment. The conclusions of this study inspired the discovery of folate. The detailed investigation of the mode of action of vitamin B12 and folate enriched our knowledge in the area of pathophysiology and extended the clinical application of these two drugs.

Sidney Farber and the treatment of childhood acute lymphoblastic leukemia with a chemotherapeutic agent.

Acute lymphoblastic leukemia (ALL) is the most common malignancy affecting children accounting for approximately 30% of childhood cancers, which was uniformly fatal before the advent of effective chemotherapy. In this historical note, the fundamental contribution of Sidney Farber to the treatment of ALL by using, for the first time, aminopterin-a chemotherapeutic agent-has been recognized.

A short story of anti-rheumatic therapy. VIII. The immunodepressants.

The use of immunosuppressive drugs in rheumatology is fairly recent, starting just after the Second World War with the introduction of the first alkylating agents in oncohematology. When it became clear that some rheumatic diseases, particularly rheumatoid arthritis and systemic lupus erythematosus, showed an immune-mediated pathogenesis, including proliferation of immunocompetent cells, an application was soon found for immunosuppressive drugs in their treatment. This review outlines the historical milestones that led to the current use of drugs belonging to the major groups of immunosuppressants, i.e. alkylating agents (cyclophosphamide), folic acid (methotrexate) and purine (azathioprine) antagonists. We will also talk about the history of cyclosporin A, the first "selective" immunosuppressive agent, and that of some immunoactive drugs used more recently in rheumatology, such as mycophenolate mofetil, dapson and thalidomide, is briefly described.

The sulfonamide-diaminopyrimidine story.

This paper is devoted to chemotherapy in the sense that Paul Ehrlich (Nobel Prize winner in 1908) coined the word: to describe the cure of infectious diseases by chemical agents without injury to the organism infected. This approach, essentially that of selective toxicity, is applicable to the investigations performed by Gerhard Domagk (Nobel Prize winner in 1939), which resulted in the development of Prontosil rubrum. This agent was active in vivo but not in vitro. Tréfouël supposed that the in vivo action was due to a metabolite of the drug (sulfanilamide), a hypothesis later proved by Fuller in 1937. Sulfanilamide was a simple agent, easy to manufacture and free of patent rights. Thus, more than 5400 derivatives were synthesized and studied in the decades that followed. Research on the side-effects of sulfonamides resulted in the development of diuretics and antidiabetogenic agents. The resurgence of interest in sulfonamides in following years has been associated with the development of diaminopyrimidines by Hitchings (Nobel Prize winner in 1988). It soon became evident that combinations of these drugs produced potent synergistic effects. Trimethoprim, a potent antibacterial agent of this series, was selected for combining with sulfonamides such as sulfadiazine. This line is still continued and even recently new diaminopyrimidine derivatives such as aditoprim and baquiloprim have been synthesized having superior properties in farm animal species. Thus, even nowadays the principles of Ehrlich continue to have a major impact on the development of new veterinary drugs.

[Inhibitors of folic acid metabolism (author's transl)]. / Hemmstoffe des Folsäure-Stoffwechsels.

In contrast to antibiotic research, the study of folic acid metabolism and folic acid antagonists is conducted in the classical tradition of chemotherapy established by Paul Ehrlich. The elucidation of the mechanism of action of sulphonamides created an important prerequisite for the understanding of the biosynthesis of folic acid. The synthesis of inhibitors of dihydrofolate-reductase was guided on the one hand by the structure of dihydrofolate itself, and on the other hand by the fact that this substnce is essential for the growth of certain bacteria. Both approaches led to the synthesis of compounds which were effective and could be used therapeutically. The mechanism of selectivity of folic acid antagonists is described. A short account of the biochemical and genetic basis of resistance to folic acid antagonists is also given. The study of folic acid metabolism and folic acid antagonists provides a good example of the successful interaction of mechanistically inspired biochemical and chemical methods on the one hand, and an empirical approach characterised by the study of more complex biological phenomena on the other hand.