Synergy between medicinal chemistry and biological research.

Salvador Moncada studied medicine at the University of El Salvador (El Salvador) before coming to the UK in 1971 to work on a PhD with Professor John Vane at the Institute of Basic Medical Sciences, Royal College of Surgeons (UK). After a short period of research at the University of Honduras (Honduras), he joined the Wellcome Research Laboratories (UK) where he became Head of the Department of Prostaglandin Research and later, Director of Research. He returned to academic life in 1996 as founder and director of the Wolfson Institute for Biomedical Research at University College London (UK). Moncada played a role in the discovery of the mechanism of action of aspirin-like drugs and later led the teams which discover prostacyclin and identified nitric oxide as a biological mediator. In his role as a Director of Research of the Wellcome Laboratories, he oversaw the discovery and development of medicines for epilepsy, migraine, malaria and cancer. Currently, he is working on the regulation of cell proliferation as Director of the Institute of Cancer Sciences at the University of Manchester (UK). Moncada has won numerous awards from the international scientific community and in 2010, he received a knighthood from Her Majesty Queen Elizabeth II for his services to science.

Attempts to make sense of the antiphospholipid syndrome.

Many investigators have been intrigued by the paradoxical association of a circulating anticoagulant, first called lupus anticoagulant by Feinstein and Rapaport [1], with a tendency to develop thrombosis, as initially described by Walter Bowie [2]. Work in Leuven on this topic started when Luis Carreras, an Argentinian hematologist, joined the laboratory of blood coagulation at this university in 1979. At that time, the head of the laboratory was Marc Verstraete. Luis had a particular interest in antibody-mediated coagulation disorders, and had prepared reviews on thrombosis and thrombocytopenia induced by heparin [3] and on the lupus inhibitor [4]. In Leuven, he joined Jos Vermylen, senior member of the laboratory, and an internist with particular interest in hemostasis, thrombosis and vascular disease. As such, Professor Vermylen was involved in both laboratory research and patient care.

Prostaglandins, bioassay and inflammation.

The formation of the British Pharmacological Society coincided almost exactly with a series of ground-breaking studies that ushered in an entirely new field of research--that of lipid mediator pharmacology. For many years following their chemical characterisation, lipids were considered only to be of dietary or structural importance. From the 1930s, all this changed--slowly at first and then more dramatically in the 1970s and 1980s with the emergence of the prostaglandins (PGs), the first intercellular mediators to be clearly derived from lipids, in a dynamic on-demand system. The PGs exhibit a wide range of biological activities that are still being evaluated and their properties underlie the action of one of the world's all-time favourite medicines, aspirin, as well as its more modern congeners. This paper traces the development of the PG field, with particular emphasis on the skillfull utilisation of the twin techniques of bioassay and analytical chemistry by U.K. and Swedish scientists, and the intellectual interplay between them that led to the award of a joint Nobel Prize to the principal researchers in the PG field, half a century after the first discovery of these astonishingly versatile mediators.

Vascular prostaglandin synthesis: the early days.

Prostacyclin (PGI2) and thromboxane (TxA2) labile cyclooxygenase (COX) products via PGH2 were identified in biological fluids by the ingenious application of the principle of parallel pharmacological assays developed by John Vane. Either organ perfusates or circulating blood superfuse bioassay tissues arranged in a cascade. Tissues were selected based on specificity of responses to targeted eicosanoids. Additionally, PGI2 inhibited platelet aggregation, a finding that led to discovery of its critical anti-thrombotic activity at the blood-endothelial interface. The biological activities of PGI2 and TxA2 were the fingerprints for tracking their isolation and ultimate chemical identification. These studies were responsible for opening the modern era of vascular biology that has facilitated the development of a rational approach to the treatment of diabetic and hypertensive complications involving the arterial circulation.

The eicosanoids: a historical overview.

Eicosanoids are biologically active compounds derived from 20 carbon unsaturated fatty acids, among which arachidonic acid is a substrate of particular importance. The history of the eicosanoids dates back to the thirties, when new biologically active compounds were found in human seminal plasma. These "prostaglandins" were purified, and their structures and mechanisms of biosynthesis were elucidated in the early sixties. Other eicosanoids, including thromboxane A2, a potent platelet aggregating agent, and prostacyclin, an antagonist to thromboxane A2, were discovered in the seventies. The inhibitory actions of acetylsalicylic acid on eicosanoid synthesis were also uncovered at this time. In 1979, a new metabolic sequence leading to the synthesis of a new group of eicosanoids, called leukotrienes, was reported. The leukotrienes have several biological activities, including the mediation of bronchoconstriction in allergic response. The eicosanoids comprise a diverse group of biologically active compounds; many of these arise from arachidonic acid, and are associated with injury, allergic responses, and platelet aggregation.