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New Drug Treats Newborn Respiratory Failure

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Duke Health News 919-660-1306

DURHAM, N.C. -- Investigators from Duke University
Neonatal-Perinatal Research Institute and the Howard Hughes
Medical Institute (HHMI) have developed a new drug that appears
in preliminary testing to be successful in treating newborns
whose lungs are unable to properly oxygenate their blood. The
researchers also believe that the drug -- called
O-nitrosoethanol (ENO) -- will prove effective in improving
oxygenation in patients with such disorders as asthma, chronic
obstructive pulmonary disease (COPD), cystic fibrosis and
sickle cell disease.

The researchers tested ENO on seven Duke newborns with
persistent pulmonary hypertension, or high blood pressure
within the lungs. In this potentially life-threatening
disorder, blood vessels within the lungs constrict, severely
limiting the amount of blood flowing through the lungs, leaving
the body starved of oxygen-rich blood.

"Our study showed that this new drug improved the
oxygenation of seven babies with persistent pulmonary
hypertension, without the adverse side effects of currently
used drugs," said Jonathan Stamler, M.D., HHMI investigator and
principal investigator of the team who published the results of
their study in the July 13, 2002, issue of the journal Lancet.
"It's an encouraging start."

"While larger trials will need to be conducted to confirm
the results, we are very hopeful that this drug will not only
help babies with persistent pulmonary hypertension, but can
possibly play an important role in treating other diseases of
improper oxygenation, such as asthma and cystic fibrosis," said
Ronald Goldberg, M.D., chief of neonatal-perinatal medicine at
Duke University Medical Center and a co-author of the
paper.

Persistent pulmonary hypertension occurs when a newborn's
body does not respond properly immediately after birth. While
inside the womb, a fetus does not use its lungs to oxygenate
its blood. Rather, a passage between the two pumping chambers
of its heart allows the blood oxygenated by the mother and
delivered through the umbilical cord to be pumped directly
throughout the fetus's body, bypassing the lungs. At birth,
when the baby begins breathing air for the first time, this
passage closes naturally, forcing the baby's heart to pump
blood to the lungs to pick oxygen.

However, constricted pulmonary arteries in some newborns
prevent the passage from closing, so the physician must
immediately provide oxygenation for the newborn. One
oxygenation method is the use of extracorporeal membrane
oxygenation (ECMO), a smaller version of the heart-lung machine
used in surgery, which adds oxygen and removes carbon dioxide
from the blood. The second approach is the use of inhaled
nitric oxide (NO), a gas that is known to help relax blood
vessels. Without either or both of these therapies, most babies
die.

"Other than ECMO, which is a very invasive therapy, inhaled
NO is the only other treatment for these babies," Stamler said.
"However, while it can be quite effective in relaxing vessels,
it is by no means perfect. NO therapy is cumbersome to
administer, has similar rates of mortality as ECMO, it is
relatively impotent (most of the NO gets trapped in the lung)
and its use is complicated by a rebound effect in which after
therapy is stopped, the problems return, and sometimes even
worse than before. In addition, NO therapy has not proven
effective in many adult diseases."

The key discovery of the HHMI group is that a class of
molecules called S-nitrosothiols (SNO) within airways of the
lung regulate vessel and airway relaxation in response to the
needs of tissues. SNOs are more effective than NO in this
process.

The researchers also found that SNO is depleted from the
lungs of hypoxemic babies. Previously, it had been thought that
NO alone relaxed the vessels. Inhaled NO gas can produce SNOs,
but it does so very inefficiently and in the process toxic free
radicals are produced, Stamler said, adding that is why nature
exploits SNO, not NO.

"These free radicals are extremely reactive atoms implicated
in the rebound phenomenon, as well as in the potential damage
to other tissues and organs," Stamler said. "This problem has
limited the use and efficacy of inhaled NO. It is still unclear
how long the drug can be given safely."

The challenge facing the research team was to find an agent
that would not produce the toxic free radicals and could
replete SNO. Additionally, any potential drug would have to be
able to be transformed into a gas for administration, in order
reach the distant airways within the lungs.

The team searched through data banks of known molecules and
found that ENO had the ideal chemical characteristics and in
test tubes produced SNOs. Through a complex and novel
preparatory process, the group turned the ENO into gas.

"This drug was designed in the laboratory to replenish SNO
in the airways, which are more potent than NO without creating
the free radicals that cause damage," Stamler said. "In
animals, ENO successfully lowered pulmonary pressures, improved
oxygenation, and just as importantly, prevented the
cardiovascular and respiratory deterioration commonly seen
after the discontinuation of inhaled NO therapy. It also seemed
to preserve heart function better than NO."

Based on these findings, the Food and Drug Administration
(FDA) permitted the use of ENO in babies with persistent
pulmonary hypertension. For the study, the researchers enrolled
seven consecutive newborns admitted to Duke's intensive care
nursery. The babies were on average 40 weeks gestational age
and weighed an average of 8.9 pounds.

The newborns received the ENO therapy during a four-hour
period, and were taken off the drug for 15-minute intervals.
During these "off" periods, the improvements were sustained,
leading the researchers to feel confident that ENO is more
efficient than NO. Immediately after discontinuation of NO
therapy, the rebound effect begins.

"We are the first neonatal intensive care unit to use this
new drug, and we are quite excited about it so far," said
Goldberg. "These findings are just as dramatic as the original
nitric oxide studies, but this new agent appears to be safer.
Because the features of ENO are different from NO, the side
effects and properties may be different as well.

"This summer, we are planning to start additional trials
with a larger group of babies," Goldberg continued. "Based on
what we have seen so far, ENO has a great potential to help
this group of very sick babies."

Stamler believes that ENO will also prove to be effective in
diseases in which the depletion of SNOs is the hallmark, such
as asthma, cystic fibrosis, and adult pulmonary hypertension,
as well as in diseases where NO-generated radicals may even
promote damage, such as adult respiratory distress syndrome
(ARDS), chronic obstructive pulmonary disease (COPD), sickle
cell disease and lung transplantation. Trials are now ongoing
at Duke in some of the diseases.

"This drug seems to do many good things, but we need larger
trials," Stamler continued. "We are beginning to think that
almost any disease or disorder of the heart, lung or blood that
involves oxygen deficiencies should be rigorously studied using
this drug."

Other members of the Duke team were, Martin Moya, M.D., a
pediatric fellow who enrolled the patients and administered the
ENO; Robert Califf, M.D., of the Duke Clinical Research
Institute, and Andrew Gow, Ph.D.

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