Opposite Approach To Asthma Treatment
ironjustice
ScienceDaily (Jan. 27, 2009) — Just when the Food and Drug
Administration is reconsidering the use of stimulants to treat asthma,
a new research study offers further evidence to support a University
of Houston professor's theory that an opposite approach to asthma
treatment may be in order.
Richard A. Bond, professor of pharmacology at the University of
Houston College of Pharmacy (UHCOP), has been investigating whether
beta-2 adrenoreceptor antagonist drugs (or beta blockers) ultimately
might be a safer, more effective strategy for long-term asthma
management than the currently used beta-2 adrenoreceptor agonists (or
stimulants).
The beta-2 adrenoreceptor is a receptor found in many cells, including
the smooth muscle lining the airways, and has long been a target for
asthma drugs. However, a recent study shows the absence of asthma-like
symptoms in a mouse model that lacks the key gene that produces the
receptor. This lends further evidence to Bond's theory that questions
whether the pharmaceutical industry should be working to block or
inhibit the receptor instead of the current approach of chronically
stimulating it to reduce asthma symptoms.
The study, "Beta2-Adrenoreceptor Signaling is Required for the
Development of an Asthma Phenotype in a Murine Model," is in the
current online issue of the journal Proceedings of the National
Academy of Sciences (PNAS), one of the world's most-cited
multidisciplinary scientific serials. A follow-up commentary by an
independent scientist in the field also will be published in the print
issue of PNAS in February.
The timely release of this study comes on the heels of the FDA
considering a renewed look at the use of long-acting beta agonist
drugs (LABAs) – at least those used alone, without a steroidal
component – for the management of asthma symptoms. In an FDA report
released in December, an analysis of more than 100 trials on four
drugs (two LABAs alone and two LABA/corticosteroid combinations) found
an increased risk of hospitalization and asthma-related deaths with
the LABA-only therapy. During the same month, an FDA advisory panel
urged the FDA to ban the LABA-only drugs and strengthen warnings on
the combination drugs.
Bond and his colleagues propose an alternative to stimulants, using
antagonists (or beta blockers) instead. This approach, termed
paradoxical pharmacology, suggests patients may be treated with
medication that initially worsens their symptoms before eventually
improving their overall health.
Beta blockers currently are contraindicated for asthma because they
typically trigger bronchoconstriction, decreasing the flow of air to
the lungs. Bond has suggested, however, that although beta blockers
would not replace the need for emergency inhalers for acute episodes,
the negative effects associated with beta blockers eventually taper
off to provide long-term relief from asthma symptoms. In addition,
several studies have shown chronic use of the beta-2 agonists (or
stimulants) can negatively affect asthma control and airway
hyperresponsiveness by desensitizing the beta-2 adrenoreceptor through
regular stimulation.
In this latest study, the research team was unable to trigger the
development of asthma-like symptoms in a mouse model in which the
beta-2 adrenoreceptor gene had been removed as compared to the mouse
model with the intact receptor gene.
"The study indicates that, with regard to developing asthma-like
features, the mouse is better off without the beta-2 adrenoreceptor at
all," Bond said. "It means that whether we block receptor signaling
pharmacologically by using beta blockers or genetically by 'removing'
the receptor, we get the same answer. The research shows that blocking
or inhibiting the receptor with antagonists, instead of stimulating it
with agonists, reduces the asthma-like features of the mouse model."
Bond's co-authors come from a multi-institutional research team that
include current UH pharmacology graduate student Long P. Nguyen; UH
pharmacology Ph.D. graduate Rui Lin; former UH post-doc fellow Sergio
Parra; UH biology graduate student Ozozoma Omoluabi; Baylor College of
Medicine's Dr. Nicola A. Hanania; M.D. Anderson Cancer Center's
Michael J. Tuvim and Dr. Burton F. Dickey; and fellow UHCOP faculty
researcher Brian J. Knoll.
With support from the Strategic Program for Asthma Research of the
American Asthma Foundation, a second human clinical trial based on
Bond's research is under way using the beta-blocker drug nadolol in
patients with mild asthma. In the first clinical trial, sponsored by
San Francisco-based Inverseon Inc., eight of 10 patients had less
airway hyperresponsiveness on beta-blocker therapy at the end of the
trial, although some did experience an initial negative response.
Commenting on the results of the first clinical trial, two U.K.
researchers wrote in the Jan. 10 issue of the British journal The
Lancet that the use of beta-blocker therapy for asthma warrants
serious, but careful, consideration and further investigation,
including the use of specific alternative types of beta blockers.
To those ends, Inverseon, of which Bond is scientific founder, has
filed U.S. patent applications for using beta blockers to treat airway
disease. Dr. William Garner, chairman of Inverseon, said the company
recently received a notice of allowance – one of several procedural
steps on the path to patent approval – from the U.S. Patent Office.
"The comment in The Lancet on Inverseon's human asthma study, combined
with the notice of allowance from the U.S. Patent Office, represents
important external validation of Inverseon's approach to asthma,"
Garner said. "We believe that our oral therapy has the potential to be
a significant product for the chronic treatment of asthma."
Adapted from materials provided by University of Houston, via
EurekAlert!, a service of AAAS.
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