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In the Pantheon of PH Research,
Tim Higenbottam Sets the Pace
 He
vividly remembers the first patient - a woman about 30
years old with primary pulmonary hypertension (PH) and
unstable angina, "very blue," and hardly any
measurable cardiac output. She was among the patients
seen in the early 1980s at a Cambridge, United Kingdom,
hospital who were dying, the focus of frenetic activity
by Tim Higenbottam, MD, FRCP, and his colleagues in a
lung transplantation program.
Unable to find a donor soon enough, they turned to protacyclin,
an investigational drug at that time for peripheral vascular
disease. The woman consented to its being used experimentally
over the long term for her primary PH, and soon after
its initiation she showed dramatic improvement. Dr Higenbottam
and a colleague devised an infusion pump through a subclavian
line to continue the delivery of prostacyclin and they
monitored her progress for the next 13 months. At that
point they decided other patients with primary PH deserved
a similar trial of prostacyclin, and this pioneering experience
with the drug is among the major achievements establishing
Dr Higenbottam as one of the giants among researchers
into the disease. After more than two years the woman
chose to receive a lung transplant, but the remarkable
turnaround with prostacyclin had set the stage for the
worldwide use of the drug in subsequent trials in the
United States.
Building up a cohort of patients and generously supported
by the Wellcome Company, Dr Higenbottam expanded on their
observational work that paved the way for the larger randomized
controlled trials of prostacyclin. In a career that has
spanned the introduction of lung transplantation medicine,
Dr Higenbottam has exerted a profound influence on colleagues
worldwide. Among his achievements:
- Discovery of the benefits of inhaled nitric oxide
in PH.
- Introduction of the 6-minute walking test as a noninvasive
technique to assess improvement in PH.
- Authorship of the International Guidelines for Lung
Transplantation and for PH.
- Introduction of transbronchial lung biopsy for diagnosing
lung rejection.
- Development of inhaler devices and the application
of mathematical modeling and simulation of breathing
to optimize inhaled drug delivery.
Currently Senior Principal Scientist and Associate Director
of Global Clinical Science at Astra Zeneca R&D in
the United Kingdom, Dr Higenbottam described how his initial
studies of prostacyclin led to further approaches of using
the drug. "We used prostacyclin to protect the lung
in the donor when the donor had died and was going to
undergo an operation to obtain the graft. That process
has enabled us to go from doing the operation on the donor
and recipient in the same hospital to actually extending
the ischemic time to about 2.5 hours."
The discovery of the efficacy of nitric oxide was based
on Dr Higenbottam's work in physiology. "We were
using inhaled nitric oxide to measure the lung diffusion
capacity alongside carbon monoxide. We had PH patients
inhale the same concentrations that we had used for the
gas diffusion studies and we were able to show that nitric
oxide is a selective pulmonary vasodilator. We then developed
a device for use in ambulatory patients because prior
to that they could not use it except through a ventilator.
The new technique involved a pulsing device delivering
nitric oxide every time they breathed."
In his new role at Astra Zeneca, Dr Higenbottam remains
on the frontier of new approaches to lung disease. "My
job is to apply some of these thoughts on disease and
make the final link between the molecule and affecting
the disease process itself." In PH, "the major
problem is how to restore function to the chronically
damaged lung, enhancing the reparative process. This will
lead us to the next generations of treatments - looking
at growth factors and various signaling systems that work
not only in the exogenous stem cells nut on endogenous
stem cells in the organ. Growth and repair are the main
issues in chronic lung disease. The current generation
of treatments is beneficial in terms of the horrendous
pathophysiology. The treatments are improving the circulation
of the blood through the lung, but we need to move beyond
that. We need to ask, how we can restore some compromised
vessels back to normal."
The introduction of bosentan has been a major advance.
"It has profound effects, and the approach of endothelin-1
antagonism is a very strong one, clearly addressing a
persistent abnormality present in all forms of PH. Bosentan
in this regard is probably the best, because it is oral,
but it's the same category as other agents - it's just
better.
"We need to think in terms of real function, not
just vessels where there's a narrowing as a result of
a particular deficiency, but actually restoring the stricture
and architecture of the vessels to normal. I believe that
in the next five to ten years we will have that therapy.
The key will be restoring the blood vessel and airway
back to normal."
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