Winner of the Nobel Prize in medicine. The researcher who discovered prostacyclin, the most widely prescribed drug in pulmonary hypertension. The pioneer who uncovered the mode of action of aspirin. Knighted in 1984 for his contributions to medical research. These achievements of Sir John Vane and the accolades received for them tend to dwarf those of even the most highly respected investigators in pulmonary hypertension.
It's been 20 years since Dr Vane shared the Nobel Prize for his studies of prostaglandins, and his discovery of one of them, prostacyclin, eventually ushered in a new era in the treatment of pulmonary hypertension. Ironically, the initial research involving the drug took a different direction.
“The first clinical trials on prostacyclin were not in pulmonary hypertension. They were in peripheral vascular disease,” recalled Dr Vane during a recent interview from his office in the United Kingdom. Dr Vane was cited by the Nobel committee for his “discovery of the prostaglandin known as prostacyclin in 1976, and for analyzing its biological effects and function.” Yet it was years before the drug epoprostenol (Flolan) was first used in pulmonary hypertension after Timothy Higenbottam, MD, documented its efficacy in the disease in 1987. Initially, however, Polish researchers who spent time with Dr Vane in his UK laboratory took a different track with prostacyclin when they returned to Poland.
“They reported striking and prolonged benefits following intra-arterial infusion of prostacyclin in five patients with advanced atherosclerotic lower-limb peripheral vascular disease. Rest pain disappeared, previously refractory ulcers healed, and muscle blood flow as measured by Xenon133 clearance was significantly increased for at least 6 weeks after prostacyclin infusion. They later reported striking improvements in some of 55 patients with advanced peripheral artery disease of the lower extremities.”
With the benefits also observed in pulmonary hypertension and Dr Vane later serving as Group Research and Development Director of the Wellcome Foundation, the path was cleared for the introduction of Flolan. Since the introduction of the drug, longer lasting analogs have been introduced, but no one has produced a compound with a half-life of more than 2 hours and this remains a barrier still to be overcome with the use of such agents.
Addressing this problem, Dr Vane said, “the answer must be that the prostacyclin molecule is unstable, and no matter what you do to it to try to add stability, you can't add all that much. Since the analogs have to be based on the original structure of prostaglandin, they are going to have relatively short half-lives.”
Dr Vane's research on other medications are also milestones in the development of more effective treatment for a wide range of disorders. These include his discovery of the mode of action of aspirin, for example. As a pharmaceutical consultant, Dr Vane initiated the program in inhibiting angiotensin-converting enzyme (ACE) that led to the development of the ACE inhibitor captopril (Capozide). He also oversaw the development of atracurium (Tracrium), acyclovir (Zovirax), and lamotrigine (Lamictal). After achieving knighthood, Dr Vane founded the William Harvey Research Institute in 1986 and has built the Institute to more than 100 members. In 1971 Dr Vane and his associates discovered that aspirin and similar drugs produced their effects because they inhibit the biosynthesis of prostaglandins. This paved the way for further discovery implicating the cyclooxygenases as being responsible for producing prostaglandins. This, in turn, has led the way for additional research into the COX-2 inhibitor used to treat such inflammatory diseases as rheumatoid arthritis.
Dr Vane has also explored other avenues of research into the mechanisms of prostaglandin, including its cytoprotective effects. “In models of myocardial infarction, it will reduce the infarct size. It will reduce oxygen demand and enzyme release from the infarcted areas. Other prostaglandins also share similar cytoprotective activity, distinct from the activity on platelet aggregation or vasodilatation.”
One of the intriguing questions still unresolved is the possibly synergistic relationship between prostacyclin—essentially a cyclic AMP agonist—and the phosphodiesterase inhibitor sildenafil (Viagra). Dr Vane suggested that the synergism could be related to the fact that sildenafil inhibits consumption of both cyclic GMP and cyclic AMP. This could enhance the effect of prostacyclin in pulmonary hypertension.