Oiling the wheels of discovery.

LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.

A history of glaucoma pharmacology.

The history of glaucoma pharmacology begins in 1862 with the isolation of physostigmine from the calabar bean. The discovery of epinephrine's intraocular pressure lowering capacity came along some 40 years later. During the 20th century, drug discovery and development accelerated, with the introduction of carbonic anhydrase inhibitors, beta blockers, and prostaglandin analogs. This survey of the history of glaucoma medications reviews some of the pivotal stories behind the development of the drugs that we use daily to manage our patients with glaucoma. In addition, some unmet needs that persist in glaucoma pharmacology are discussed.

Gastric cytoprotection 30 years after its discovery by André Robert: a personal perspective.

It is generally accepted that the development of gastric mucosal injury and protection is a consequence of an imbalance between the existing aggressive and defensive factors in the gastric mucosa. The excess secretion of gastric acid and increased production of pepsin have been considered as the main etiological factors in the development of peptic ulcer diseases in humans. André Robert and his coworkers (Kalamazoo, Michigan, USA) identified a new pathway for the gastric mucosal protection against the gastric mucosal damage injury (e.g. from HCl, NaOH, NaCl, ethanol, or thermal injury) by small doses of prostaglandins (1-5 µg/kg given ig or sc), without presence of any gastric acid secretory properties in rats. This phenomenon was termed "gastric cytoprotection" (1979). The results of this basic research offered a lot of new possibilities to test this hypothesis in different experimental models under different experimental conditions, in both human healthy subjects as well as in patients with various gastrointestinal disorders (acute and chronic gastrointestinal inflammatory conditions in the stomach and intestines, as well as GI precancerous states, i.e., oesophageal, stomach, pancreatic, liver and colon cancers). An international symposium on "gastric cytoprotection: 30 years after André Robert's concept" was organized at Split (Croatia) on September 13, 2009, at which invited experts from China, Croatia, Italy, Japan, Poland, and USA gave presentations and discussed the studies performed in the field of cytoprotection between 1979 and 2009. This paper provides a short critical summary of this meeting in the context of an "official historic background" of the events underlying the discovery of "gastric cytoprotection" which originated from the pioneering work of André Robert.

Prostacyclin among prostanoids.

Prostanoids are cyclic lipid mediators which arise from enzymic cyclooxygenation of linear polyunsaturated fatty acids, e.g. arachidonic acid (20:4 n 6, AA). Biologically active prostanoids deriving from AA include stable prostaglandins (PGs), e.g. PGE(2), PGF(2alpha), PGD(2), PGJ(2) as well as labile prostanoids, i.e. PG endoperoxides (PGG(2), PGH(2)), thromboxane A(2) (TXA(2)) and prostacyclin (PGI(2)). A "Rabbit aorta Contracting Substance" (RCS) played important role in discovering of labile PGs. RCS was discovered in the Vane's Cascade as a labile product released along with PGs from the activated lung or spleen. RCS was identified as a mixture of PG endoperoxides and thromboxane A(2). Stable PGs regulate the cell cycle, smooth muscle tone and various secretory functions; they also modulate inflammatory and immune reactions. PG endoperoxides are intermediates in biosynthesis of all prostanoids. Thromboxane A(2) (TXA(2)) is the most labile prostanoid (with a half life of 30 s at 37 degrees C). It is generated mainly by blood platelets. TXA(2) is endowed with powerful vasoconstrictor, cytotoxic and thrombogenic properties. Again the Vane's Cascade was behind the discovery of prostacyclin (PGI(2)) with a half life of 4 min at 37 degrees C. It is produced by the vascular wall (predominantly by the endothelium) and it acts as a physiological antagonist of TXA(2). Moreover, prostacyclin per se is a powerful cytoprotective agent that exerts its action through activation of adenylate cyclase, followed by an intracellular accumulation of cyclic-AMP in various types of cells. In that respect PGI(2) collaborates with the system consisting of NO synthase (eNOS)/nitric oxide free radical (NO)/guanylate cyclase/cyclic-GMP. Both cyclic nucleotides (c-AMP and c-GMP) act in synergy as two energetic fists which defend the cellular machinery from being destroyed by endogenous or exogenous aggressors. Recently, a new partner has been recognized in this endogenous defensive squadron, i.e. a system consisting of heme oxygenase (HO-1)/carbon monoxide (CO)/biliverdin/biliverdin reductase/bilirubin. The expanding knowledge on the pharmacological steering of this enzymic triad (PGI(2)-S/eNOS/HO-1) is likely to contribute to the rational therapy of many systemic diseases such as atherosclerosis, diabetes mellitus, arterial hypertension or Alzheimer diseases. The discovery of prostacyclin broadened our pathophysiological horizon, and by itself opened new therapeutic possibilities. Prostacyclin sodium salt and its synthetic stable analogues (iloprost, beraprost, treprostinil, epoprostenol, cicaprost) are useful drugs for the treatment of the advanced critical limb ischemia, e.g. in the course of Buerger's disease, and also for the treatment of pulmonary artery hypertension (PAH). In this last case a synergism between prostacyclin analogues and sildenafil (a selective phosphodiesterase 5 inhibitor) or bosentan (an endothelin ET-1 receptor antagonist) points our to complex mechanisms controlling pulmonary circulation. At the Jagiellonian University we have demonstrated that several well recognised cardiovascular drugs, e.g. ACE inhibitors (ACE-I), statins, some of beta-adrenergic receptor antagonists, e.g. carvedilol or nebivolol, anti-platelet thienopyridines (ticlopidine, clopidogrel) and a metabolite of vitamin PP--N(1)-methyl-nicotinamide--all of them are endowed with the in vivo PGI(2)-releasing properties. In this way, the foundations for the Endothelial Pharmacology were laid.

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.

Sir John Robert Vane: 29 March 1927 - 19 November 2004.

Sir John Robert Vane, who died on 19 November 2004, will be remembered as one of the most influential British pharmacologists. During his distinguish career he published more than 700 scientific papers and wrote or editing 20 books. His many awards include the Nobel Prize in Physiology or Medicine (1982) and a knighthood in 1984.

The development of prostaglandins.

The past 30 years has seen increasing application of prostaglandins and their analogues to the practice of reproductive medicine. This chapter outlines the evolution of their use in obstetrics.