Antihistamines.

The discovery of histamine, its physiological role and reversal of its pharmacological effects by antihistamines takes us on a journey through the origins of modern physiology and the rising understanding of pharmacology at the end of the 19th and the early part of the 20th centuries. This journey, which has been traced in the excellent historical review by Michael Emanuel [Clin Exp Allergy 1999;29:1-11], is populated by some of the greatest scientists of the era, including six Nobel laureates - Bovet, Dale, Ehrlich, Richet, Windaus and Black. In addition, it laid the basis of medicinal chemistry not only for antihistamines, but also for the discovery of a plethora of drugs still in use today.

Antihistamine therapy in allergic rhinitis.

Antihistamines have long been a mainstay in the therapy for allergic rhinitis. Many different oral antihistamines are available for use, and they are classified as first generation or second generation based on their pharmacologic properties and side-effect profiles. The recent introduction of intranasal antihistamines has further expanded the role of antihistamines in the treatment of allergic rhinitis. Certain patient populations, such as children and pregnant or lactating women, require special consideration regarding antihistamine choice and dosing as part of rhinitis therapy.

Personal reflections on Sir James Black (1924-2010) and histamine.

Sir James Black, Nobel laureate (1988), became interested in the role of histamine in gastric acid secretion in the early 1950s. In 1964, he joined the pharmaceutical company Smith Kline and French Laboratories at their English subsidiary to seek a new type of antagonist that would block those actions of histamine that were not blocked by mepyramine. No such compound was known and working with medicinal chemists it took four years to discover a lead compound. Further work provided the compound burimamide, which was used to define histamine H(2) receptors in 1972 for the first time, and to verify the action in human volunteers. Subsequent work led to the drug metiamide, which was withdrawn during early clinical trials. This was replaced by cimetidine, which was launched in 1977, as the first histamine H(2)-receptor antagonist and which revolutionized the treatment of peptic ulcer disease. The characterisation of a second type of histamine receptor revitalised interest in histamine and led to many later studies on the role of histamine in inflammation.

Histamine and its receptors.

This article reviews the development of our knowledge of the actions of histamine which have taken place during the course of the 20th century. Histamine has been shown to have a key physiological role in the control of gastric acid secretion and a pathophysiological role in a range of allergic disorders. The synthesis of, and pharmacological studies on, selective agonists and antagonists has established the existence of four types of histamine receptor and histamine receptor antagonists have found very important therapeutic applications. Thus, in the 1940s, H(1)-receptor antagonists ('the antihistamines') yielded and still provide valuable treatment for allergic conditions such as hay fever and rhinitis. In the late 1970s and 1980s, H(2)-receptor antagonists (in the discovery of which the two authors were personally involved) revolutionised the treatment of peptic ulcer and other gastric acid-related diseases. The H(3)-receptor antagonists, although available since 1987, have been slower to find a therapeutic role. However, the discovery of nonimidazole derivatives such as brain-penetrating H(3) antagonists has provided drugs that are in early-phase clinical trials, possibly for application in obesity, and a variety of central nervous system disorders, such as memory, learning deficits and epilepsy. Finally, the most recently (1999) discovered H(4) receptor promises the potential to provide drugs acting on the immunological system with possible applications in asthma and inflammation.

Histamine and the antiallergic antihistamines: a history of their discoveries.

The paper provides a historical overview of the discovery of both histamine and the H1 antihistamines. The context of these discoveries is provided in relation to the development of medicinal chemistry during the 19th century. Background is provided on the history of discovery of mechanisms of anaphylaxis and allergy and the immunology of hypersensitivity at the end of the 19th and early 20th century. The discovery of histamine and the antihistamines is then discussed in relation to the development of pharmacological receptor theory culminating in the discovery of the first antihistamines in the 1930s and their widespread clinical introduction in the 1940s.