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 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 Xenon
133 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 mile-stones
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 cyto-protective
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 phosphodi-esterase
inhibitor sildenafil (Viagra). Dr Vane suggested that
the synergism could be related to the fact that silde-nafil
inhibits consumption of both cyclic GMP and cyclic AMP.
This could enhance the effect of prostacyclin in pulmonary
hypertension.
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