Drug developed at Duke appears effective in treating respiratory failure in newborns

July 11, 2002

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.

Duke University Medical Center

Related Asthma Articles from Brightsurf:

Breastfeeding and risks of allergies and asthma
In an Acta Paediatrica study, exclusive breastfeeding for the first 3 months was linked with a lower risk of respiratory allergies and asthma when children reached 6 years of age.

Researchers make asthma breakthrough
Researchers from Trinity College Dublin have made a breakthrough that may eventually lead to improved therapeutic options for people living with asthma.

Physics vs. asthma
A research team from the MIPT Center for Molecular Mechanisms of Aging and Age-Related Diseases has collaborated with colleagues from the U.S., Canada, France, and Germany to determine the spatial structure of the CysLT1 receptor.

New knowledge on the development of asthma
Researchers at Karolinska Institutet in Sweden have studied which genes are expressed in overactive immune cells in mice with asthma-like inflammation of the airways.

Eating fish may help prevent asthma
A scientist from James Cook University in Australia says an innovative study has revealed new evidence that eating fish can help prevent asthma.

Academic performance of urban children with asthma worse than peers without asthma
A new study published in Annals of Allergy, Asthma and Immunology shows urban children with poorly controlled asthma, particularly those who are ethnic minorities, also suffer academically.

Asthma Controller Step Down Yardstick -- treatment guidance for when asthma improves
The focus for asthma treatment is often stepping up treatment, but clinicians need to know how to step down therapy when symptoms improve.

Asthma management tools improve asthma control and reduce hospital visits
A set of comprehensive asthma management tools helps decrease asthma-related visits to the emergency department, urgent care or hospital and improves patients' asthma control.

Asthma linked to infertility but not among women taking regular asthma preventers
Women with asthma who only use short-acting asthma relievers take longer to become pregnant than other women, according to research published in the European Respiratory Journal.

What are the best ways to diagnose and manage asthma?
A team of experts from The University of Texas Medical Branch at Galveston examined the current information available from many different sources on diagnosing and managing mild to moderate asthma in adults and summarized them.

Read More: Asthma News and Asthma Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.