Potent Medicine

The test for the boys and girls was simple: to cover as much ground as they could in 6 minutes. But these children, ages 5 to 18, had pulmonary hypertension—high blood pressure in their lungs from constricted blood vessels. Such kids “don’t have a lot of energy,” explains pediatric cardiologist Tilman Humpl. “They can’t exercise at all. They may not be able to walk up from the basement to the first floor.”

During the test, the 14 children walked, on average, 278 meters, about half of what a healthy young person would walk at a comfortable pace. But 6 months later, after treatment with an experimental drug, the same kids averaged 443 meters during the time. “That’s a huge increase for a patient with that disorder,” says Humpl, of the Hospital for Sick Children in Toronto.

What’s more, the treatment seemed to extend the children’s lives.

The drug that Humpl credits with making the difference is just now making its debut in children, but it’s already been used by some 20 million adult men. Named sildenafil citrate, it’s better known as Viagra.

The major use of sildenafil—and other drugs known as phosphodiesterase-5 (PDE-5) inhibitors, including vardenafil (Levitra) and tadalafil (Cialis)—is treating erectile dysfunction. While that sexual disorder has various causes, limited blood flow to the penis can be a contributing factor. Compounds that inhibit PDE-5 block that enzyme’s constricting effect on blood vessel cells, thereby easing blood flow.

Because impotence is generally regarded as an annoyance rather than a threat to health, the medications that treat it are frequently called “lifestyle drugs.” However, potential new applications could give these compounds lifesaving medical roles.

In June, the Food and Drug Administration cleared Viagra’s maker, New York–based Pfizer, to market the sildenafil drug called Revatio for the treatment of pulmonary hypertension.

Other research teams, many of them supported by Pfizer, are testing PDE-5 inhibitors against additional cardiovascular diseases. Some scientists are also exploring the drugs in conditions as varied as liver disease and complications of pregnancy.

Although there’s concern about potential side effects, including heart attacks (SN: 1/18/03, p. 38: http://sciencenews.org/articles/20030118/fob8.asp), vision impairment, and even blindness, some scientists are confident that these drugs will be valuable for a wide range of medical treatments.

Transcending impotence

The drug that was to become Viagra germinated, in the late 1980s, in a laboratory where Pfizer scientists were striving to develop a medication for high blood pressure. While the compound didn’t appear to work for that purpose, it was sufficiently promising in other ways that Pfizer launched a trial to test it against angina, chest pains that signal a dangerous heart condition.

But the drug didn’t pan out for that use either, and it might well have been scrapped altogether if some male study participants hadn’t reported that the drug reversed their impotence.

Given that history, it’s sweetly ironic that investigators wielding sildenafil are once again taking aim at cardiovascular problems. The condition most thoroughly studied is pulmonary hypertension. However, studies that have examined other potential benefits hint at a role for the drug in conditions including chronic heart failure and fetal-growth restriction, according to cardiac surgeon Shahzad G. Raja of the Royal Hospital for Sick Children in Glasgow, Scotland.

FDA’s decision to approve sildenafil for pulmonary hypertension took into account several studies, including one with 277 patients who had, as adults, developed pulmonary hypertension for various reasons. Another recent study found that sildenafil benefited 12 volunteers with pulmonary hypertension that resulted from sickle-cell anemia (SN: 1/1/05, p. 14: Available to subscribers at http://sciencenews.org/articles/20050101/note20.asp). The formulation used to treat pulmonary hypertension contains a lower dose of sildenafil than Viagra does, but patients are expected to take it three times each day.

Humpl says that his recent study is the first to extend sildenafil’s use to children with the blood pressure disorder. Hypertension, whether in the lungs or elsewhere, puts a strain on the heart, which may then enlarge abnormally and eventually fail. None of the young volunteers died during the yearlong study, even though their disease was so severe at the start that the researchers had not expected most of the participants to live until its end, Humpl and his colleagues report in the June 21 Circulation.

With the new drug, “we can keep them alive for more than 12 months, and not only keep them alive but improve their quality of life,” says Humpl.

Another study found that sildenafil improved several symptoms of chronic heart failure, a disease in which a stressed heart enlarges until it can no longer pump blood. In Milan, Italy, 16 men with that ailment received an oral dose of the drug. An hour later, their peak oxygen consumption during exercise—an indicator of how vigorously the body can work—had increased by nearly 20 percent, Marco Guazzi of San Paolo Hospital and his colleagues reported in the Dec. 21, 2004 Journal of the American College of Cardiology.

Sildenafil’s effects on blood vessels within the heart probably explain that finding, Guazzi says.

In the majority of people, PDE-5 inhibitors probably protect the heart, says cardiologist David A. Kass of the Johns Hopkins Medical Institutions in Baltimore. He and his fellow investigators made an animal model of heart failure by surgically constricting the main artery leading out of a mouse’s heart. This forced the organ to work extra hard to squeeze blood through the narrowed vessel.

After 3 weeks in this condition, mice receiving no other treatment were pumping only about 40 percent of the blood out of their hearts with each beat, whereas healthy animals pump out more than 60 percent of the heart’s blood. Mice that had been receiving sildenafil daily for at least a week showed no reduction in their hearts’ pumping.

Furthermore, the researchers reported in the February Nature Medicine, sildenafil prevented or reversed the enlargement of the heart that followed the operation in untreated mice.

Kass’ study adds to growing evidence that sildenafil has the potential to mend hearts, says Michael E. Mendelsohn of Tufts–New England Medical Center in Boston.

Another rodent study hints that sildenafil could protect the heart against injuries caused by chemotherapy. The drug doxorubicin, which is used to treat both tumors and blood cancers, can damage heart cells.

To see whether they could blunt the cancer drug’s harmful effect, researchers at Virginia Commonwealth University Medical Center in Richmond treated groups of mice with a saline solution or a solution containing either doxorubicin or sildenafil or both drugs.

Mice receiving only the anticancer agent lost a substantial number of heart-muscle cells, while little damage occurred in animals that got both compounds, cardiologist Rakesh C. Kukreja and his colleagues reported in the April 5 Circulation.

PDE-5 inhibitors may also have important applications in illnesses unrelated to the heart. For example, researchers in Valencia, Spain, are testing sildenafil to counteract neurological problems that are sometimes associated with liver disease. Elevated ammonia concentrations in the blood, which arise in many people with cirrhosis, appear to contribute to mental deficits and other neurological abnormalities.

The scientists added sildenafil to the drinking water of some rats with high ammonia concentrations or blocked liver function. Within 2 days, the drug-treated animals easily outperformed the others on a navigational test in a maze, neurobiologist Vicente Felipo of the Valencian Foundation of Biomedical Investigations and his colleagues reported in the February Hepatology.

Another study found preliminary evidence that PDE-5 inhibition might relieve a rare kidney condition called nephrogenic diabetes insipidus. In the disease, cells fail to assemble a protein necessary for concentrating waste products, a condition that results in copious production of abnormally dilute urine. Injecting sildenafil into rats that had a condition resembling the disease partially circumvents that problem by activating a backup mechanism for building the essential protein. Researchers led by Dennis Brown of Massachusetts General Hospital East in Charlestown report the work in the June American Journal of Physiology–Renal Physiology.

Women and children next

Ironically, medicines that have been widely used to treat a condition unique to men may someday be applied to disorders affecting only women and infants. Animal research presented at the Experimental Biology meeting in San Diego last April suggests that sildenafil could combat preeclampsia, a disorder of rising blood pressure during pregnancy (SN: 4/16/05, p. 254: Available to subscribers at http://sciencenews.org/articles/20050416/note13.asp).

The sometimes life-threatening illness, which affects about 1 in 20 pregnancies, develops when arteries that feed the uterus don’t grow large enough to meet the organ’s burgeoning demand for blood.

George Osol of the University of Vermont College of Medicine in Burlington and his colleagues tested pregnant rats with preeclampsia-like circulatory problems. The team found that daily sildenafil treatments improved the growth of uterine blood vessels and produced healthier pups.

Fetal-growth restriction is another problem of pregnancy that’s associated with limited uterine blood flow. The condition affects about 1 in 12 pregnancies and can produce complications at birth and long-term developmental disorders in a child.

To test the potential of sildenafil against this disorder, Mark Wareing and his colleagues at the University of Manchester in England set aside small samples of tissue taken from the wombs of 39 women during deliveries by cesarean section. A dozen of the women had had pregnancies complicated by fetal-growth restriction.

The researchers used chemicals to stimulate small arteries in the tissues to alternately narrow and widen. They then exposed the tissues to sildenafil and again prodded the arteries to narrow and widen. Wide vessels increase blood flow and lower blood pressure.

Sildenafil produced a “striking improvement” in the arteries’ widening response, but only in tissues from women whose fetuses experienced restricted growth, Wareing’s team reports in the May Journal of Clinical Endocrinology & Metabolism. Their findings, the researchers say, suggest that sildenafil can relieve at least one cause of fetal-growth restriction.

Other babies might also eventually benefit from PDE-5 inhibitors, says Kukreja. He’s considering children born with congenital heart defects requiring prompt surgery. The slightest wrinkle in these delicate procedures can momentarily cut off the blood supply to the heart, causing a heart attack with potentially disastrous consequences.

To test whether sildenafil might brace infants’ hearts against that possibility, Kukreja and his colleagues used young rabbits. The researchers injected sildenafil into some of the animals but not others. Half an hour later, the team clamped an important heart artery for 30 minutes in all the rabbits to simulate the sort of heart attacks that children sometimes suffer during the corrective surgery.

In animals that hadn’t received sildenafil, about a third of the heart tissue fed by the obstructed artery died. In pretreated animals, however, only about a sixth of the tissue perished. The drug treatment also delayed an injury-related decline in the heart’s output of pumped blood, the Virginia cardiologists reported in the January Pediatric Research.

Cardiac surgeon Raja says sildenafil treatment is “promising for patients who are to undergo any kind of heart surgery.”

For occasional use, at least in adults, sildenafil and similar drugs are relatively safe, says Raja. Although numerous side effects have been reported, they’re uncommon and can be minimized through screening, he says.

For treatment day after day, as in heart disease and fetal growth restriction, sildenafil’s potential risks are less well-established. Judging from the trials so far, “it’s got a good safety profile,” says Raja. But for such conditions, he says, “we don’t have enough clinical evidence [to] safely start prescribing.”

If further studies bear out at least some of the promising new research, the PDE-5 inhibitors could take on assignments far more critical than aiding activities in the bedroom. Though Viagra may enhance lifestyles, says Johns Hopkins’ Kass, “it isn’t really marketed as a medicine. Now, we find out it could be a medicine.”