MAY 2008


Could a drug deemed dangerous
actually heal?

Contraindicated beta-blockers appear to control, not exacerbate, asthma

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."

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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