First, do some harm. It's not everybody's
idea of how to practise medicine, but it might just
hold the key to a better, more lasting asthma treatment,
according to an international group of pulmonologists
who decided to turn conventional thinking on its head.
Far from proposing a new drug for asthma, they treated
the disease with an old drug whose label says it shouldn't
be used in asthmatics.
Nadolol, a beta-blocker, has the
opposite biological effect to the beta-agonists that
are the mainstay of asthma therapy today. Instead of
providing relief from asthma symptoms, it's likely to
exacerbate them in the short term. But get beyond the
very short term, its advocates argue, and nadolol will
start to bring lasting improvement to asthmatics' breathing.
One of the originators of this
thesis, Dr Richard Bond, associate professor of pharmacology
at the University of Houston, has dubbed it "paradoxical
pharmacology." He notes that asthma is not the only
disease in which drugs that seem to do all the wrong
things can actually help. Hyperactive children are given
stimulants. Acne is treated with the skin irritant retinoic
acid. Some current Alzheimer's research focusses on
depressing the dopamine system with antipsychotics,
when logic suggests it should be stimulated.
But the best example, he says,
concerns beta-blockers themselves, and how they came
to revolutionize congestive heart failure (CHF) treatment
after long being considered dangerous and counter-productive.
Giving beta-blockers to CHF patients would immediately
reduce the heart's pumping ability. So instead, physicians
used drugs that stimulated the heart to pump more. But
while this brought short-term benefit, it wore out the
heart.
About 10 years ago, researchers
discovered that after taking beta-blockers for a few
months, patients' hearts actually began to pump more
strongly. The harm done by beta-blockers was transitory,
but the benefit was lasting. It produced a revolution
in the treatment of congestive heart failure, with mortality
rates falling by more than half.
"Decades of conventional wisdom
were overturned, and beta blockers replaced stimulants
as the top drug for CHF patients," says Dr Bond. "For
30 years, intellect told us that beta blockers wouldn't
work to treat these patients, and unfortunately millions
of heart patients died prematurely. It would be a tragedy
to not have learned from that lesson."
TESTING
THE THEORY
No-one would be thinking like this, of course, if current
asthma therapy were a success story. Experimenting with
contraindicated drugs doesn't seem so reckless when
gold-standard asthma drugs like salmeterol and formoterol
themselves carry an FDA 'black box' label, warning that
they "may increase the chance of severe asthma episodes
and death when those episodes occur." That's not exactly
a sign of an ideal asthma medication.
Studies like the UK's Serevent
Nationwide Surveillance study showed higher death rates
in asthma patients taking long-acting beta-agonists
than in those taking short-acting rescue medication
like albuterol. So, if stimulating the beta-adrenoreceptors
over a period can worsen asthma, why not try blockading
them and see if it improves asthma?
That has now been done, in mice
and to a small extent in adult humans. Two recent papers
present the results. The mouse study, led by Dr Bond,
is reported in the American Journal of Respiratory
Cell and Molecular Biology. What it shows is that
mucin content in the airway of asthmatic-model mice
treated with salbuterol for 28 days actually increased
slightly. But asthmatic mice given 28 days' chronic
treatment with the non-selective beta-blocker nadolol
had almost no mucin in the airway at 28 days. Even by
seven days, mucin and inflammatory markers were sharply
reduced in these mice.
The human study, reported in the
journal Pulmonary Pharmacology and Therapeutics,
followed 10 patients taking oral nadolol. It was not
double-blinded or placebo-controlled. Dosage started
at 10mg and was increased in patients who tolerated
it. The main cause of stopping dose increases was falling
blood pressure, a known effect of this drug class. Ultimately,
three patients stayed on 10 mg, four reached 20 mg,
and three reached 40 mg.
The drug effect was quantified
with the standard asthma test of methacholine challenge,
measuring the amount of methacholine required to produce
a 20% drop in forced expiratory volume (FEV). Eight
of the 10 saw highly significant improvements on this
test after nine weeks on their final dose. Two saw deterioration.
Overall, the average amount of methacholine needed in
all 10 patients to achieve a 20% drop in FEV at nine
weeks was more than double what it had been at study
outset.
The only side effect apart from
lowered blood pressure was a 5% drop in FEV when not
being challenged, which was seen in three patients.
None of these effects were large enough to be felt by
the patients, though they were measured by the researchers.
It might be that a more selective beta-blocker, which
targets only the beta2 adrenoreceptor, would sidestep
the issue of hypotension. The study was small, and the
patients only suffered from mild asthma. But the proof
of concept seems real enough.
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