Cancer Drug Might Fight Lethal Lung Hypertension

Gleevec, a medication experts have hailed as a wonder drug in the fight against certain cancers, may also come to the rescue of patients battling lethal pulmonary hypertension.

According to a case study in the Sept. 29 issue of the New England Journal of Medicine, a 61-year-old man suffering from an advanced case of the disease saw his condition improve and stabilize after taking Gleevec (imatinib) -- even though all other medications had failed.

"Only the addition of Gleevec was able to prevent further deterioration, and even improved his condition," said co-researcher Dr. Hossein A. Ghofrani, of University Hospital Giessen, in Germany.

Although a single case report does not warrant widespread use of Gleevec for pulmonary hypertension, the German researchers who wrote the report said they are now planning a large clinical trial.

"I think a trial is a wonderful idea," said Dr. Richard Stein, a professor of clinical cardiology at Albert Einstein Medical College in New York City, and a spokesman for the American Heart Association. "Hopefully, we'll be able to make a real difference for these people."

According to Stein, pulmonary hypertension occurs when blood pressure mounts to dangerously high levels in the pulmonary artery, which carries blood from the right side of the heart to the lungs. The relatively common condition can occur for many reasons, but most often arises as a byproduct of other pathologies, such as heart disease and various lung ailments. Under the strain of these conditions, the pulmonary artery thickens and stiffens, causing blood pressure to rise.

"Right now, we have two classes of drugs that seem to be improving outcomes," Stein said. These include prostaglandin-linked compounds such as prostacyclin, and, more recently, another potent vasodilator -- Viagra (sildenafil). Both drugs work by relaxing and opening narrowed vessels.

"None of these medications cure the disease or give the patient a normal life back," Stein noted. "But most can prolong quality-of-life time before they get very sick." Patients with very high pulmonary blood pressures usually don't live past a year, he said.

In the German case report, the patient was diagnosed with just such a case of advanced pulmonary hypertension, this time a rarer, "primary" form of unknown origin. Standard therapies such as prostacyclin and Viagra proved useless, and the man's condition continued to deteriorate.

"In this desperate situation, we decided to initiate compassionate treatment with daily administration of 200 milligrams of oral imatinib mesylate (Gleevec)," given on top of the other medications, the researchers explained.

The change in the man's condition was dramatic.

By three months, his condition had improved "impressively," the researchers said, allowing him to become much stronger and more mobile than before Gleevec. That improvement has continued to the six-month point, they add.

The therapy appears to be working in other patients, too. "We have [successfully] treated more than 20 patients so far, all of which had no other therapeutic options or who were waiting on the transplant list for a new organ but appeared to run out of time," noted co-researcher Dr. Friedrich Grimminger, also of Univerity Hospital Giessen.

How did a drug best known for curing chronic myelogenous leukemia beat back hypertension?

Unlike the other drugs, Gleevec does not appear to work by dilating blood vessels, according to the researchers. Instead, the key to its effect lies in a phenomenon shared by both cancer and pulmonary hypertension.

"In cancer, tissue proliferation is uncontrolled and leads to the spreading of the tumor," Grimminger explained. "In pulmonary hypertension, also, uncontrolled growth of the vascular wall is the underlying mechanism of the disease."

"Gleevec is a drug which suppresses uncontrolled growth of tissue by specific blockade of the so-called tyrosine kinase pathway," he added. "We have proven that this pathway also plays an important role in the course of pulmonary hypertension. Due to these similarities, the anticancer drug Gleevec also works in progressive pulmonary hypertension."

This mechanism made sense to Dr. Norman Edelman, chief medical officer at the American Lung Association.

"What happens in response to hypertension is that vessels get thicker," he said. "The assumption is that [Gleevec] reverses that. So this treatment does have biologic validity, it's plausible."

In fact, because tissue proliferation is a hallmark of other serious illness, Gleevec's uses might expand even further, according to researcher Ghofrani. "Our current findings might open the door to a completely new therapeutic field of targeted treatment for chronic proliferative diseases such as atherosclerosis, COPD, lung emphysema or lung fibrosis," he said.

Right now, the emphasis is on pulmonary hypertension, however. "A large worldwide clinical trial is about to be conducted under our scientific lead," Ghofrani said. Besides testing Gleevec's safety and effectiveness, "we also hope to answer the question [of] whether the drug also works in earlier stages of the disease," he noted.

Stein stressed that, right now, experts have "just one report of the drug being effective." But he's hopeful that the results seen in this patient will be repeated in the upcoming trial. If that's the case, "Gleevec may turn out to be a valuable third product that we can use for these people," he said.

More information

To learn more about pulmonary hypertension, head to the American Lung Association.

New Warning Issued on Paxil

U.S. health officials have issued a warning about possible birth defects in infants born to women who take the antidepressant Paxil during the first trimester of pregnancy.

A study sponsored by GlaxoSmithKline, the drug's maker, suggested that infants born to women taking Paxil were at about double the risk of birth defects compared with women taking other antidepressants. The most common defects were cardiovascular. The risks were about 50 percent higher than they were in the general population.

GlaxoSmithKline, which first alerted the U.S. Food and Drug Administration of the problems around Sept. 6, anticipates labeling changes to the drug, said company spokeswoman Mary Ann Rhyne.

"We've also taken this information to regulatory bodies around the world to voluntarily add this to the label," she said. "That discussion, as I understand it, is how to handle it."

Glaxo has also sent a letter to physicians alerting them to the findings.

Dr. Mary Jo O'Sullivan, a professor of obstetrics and gynecology at the University of Miami School of Medicine, said the findings do raise some concerns. "One cannot deny with absolute certainty that there's nothing related to Paxil and an increased risk of malformations, but we dont have a truly controlled population," she said.

"One has to be cautious and if there's a way to get a patient off Paxil prior to pregnancy and substitute another drug, then that would be the ideal way to go," O'Sullivan advised. "But just because she's on Paxil does not necessarily mean that her risk of congenital malformation is overwhelming. This needs more work."

Paxil (paroxetine) belongs to a group of drugs called selective serotonin reuptake inhibitors (SSRIs), which first hit the market in 1988 and are widely used today to treat depression, anxiety and other mood and behavioral disorders in adults as well as children.

This class of popular drugs has been the subject of much recent controversy.

In February, Spanish researchers reported that babies born to women taking SSRIs during pregnancy may experience neonatal withdrawal syndrome in the first few days of life. The association seemed to be highest among women using Paxil.

And last year, reports of suicidal thinking among adolescents using SSRIs led to the FDA ordering a "black box" warning be placed on SSRI labels. There has also been concern that SSRIs triggers manic behavior in 10- to 14-year-olds.

The data on SSRIs and birth defects is inconclusive, with some studies showing a higher risk and other research showing no increased problem.

GlaxoSmithKline undertook this study because a British pregnancy registry turned up a possible signal for cardiovascular defects in women using bupropion (Wellbutrin) and Paxil.

For this study, the researchers relied on a database affiliated with UnitedHealthcare, a national managed-care plan covering the Northeast, Southeast, Midwest and Western United States. They focused on women taking bupropion in the first trimester of pregnancy and compared them with infants born to women who took bupropion before or after the first trimester, as well as women taking other antidepressants during the first trimester.

When all analyses were completed, there appeared to be no increased risk associated with bupropion. A secondary analysis to investigate the risk associated with other antidepressants, including Paxil, was carried out at the request of the FDA.

That analysis found about double the risk of general birth defects in Paxil compared to other antidepressants, when taken in the first trimester. The prevalence of birth defects as a whole among infants born to women in this group was 4 percent, or 43.6 per 1,000 births.

The risk for cardiovascular defects was slightly more than double. The more common of these were ventricular septal defects, where one or more holes are present in the muscular wall separating the right and left ventricles of the heart. This is the most common congenital heart defect.

The overall rate of birth defects in the general population is about 3 percent, and the rate of heart defects about 1 percent. The overall rate among infants of women taking Paxil in the first trimester was about 4 percent and, for women taking other antidepressants during this time, about 2 percent. "I wished I had an explanation," Rhyne said of the discrepancy.

Researchers still do not know if the relationship is a causal one and there is, in general, a paucity of research on the subject. Data from the Swedish Birth Registry, for instance, found no increased risk of major malformations associated with SSRIs. But other small studies have found risks.

"There's not a whole lot of detail there," Rhyne said. "We're trying to drill down on information that we have to see exactly what is going on."

And for women who are on Paxil or considering taking it, GlaxoSmithKline said it is sticking by previous recommendations.

"This medicine already has a pregnancy precaution. That means that physicians should be talking with patients about potential benefits and potential risks and we recommend that this study be a part of that discussion," Rhyne said. "The label already has a category C pregnancy caution, which means no adequate, well-controlled studies have been done to determine the effect on the fetus. This is a medicine doctors should already be talking with patients about."

"Like everything else, it's a risk-and-benefit ratio," O'Sullivan said.

More information

The U.S. Food and Drug Administration has more on the recent information regarding Paxil.