November 2, 2021

Why did 11 babies die in a generic Viagra trial?

The story goes that Viagra started out as a chest pain medication. It didn’t work out very well. But the men in these clinical trials noticed a curious side effect of erections – and voila, a successful drug was born.

Since then, the uses of Viagra, or its unbranded counterpart, sildenafil, have continued to transform. Clinicaltrials.gov currently lists 60 planned and ongoing sildenafil trials, and it is already a common treatment for high blood pressure in the lungs. Until this week, one of many ongoing trials involved pregnant women in the Netherlands whose babies were growing too slowly in the womb. But after 11 of those babies died of lung problems after birth, the trial was quickly completed, as was a similar trial in Canada.

Why has a drug best known for treating erectile dysfunction been tested in pregnant women? There is one answer rooted in biology and one rooted in economics.

On the basic biology: Sildenafil works by relaxing blood vessels and increasing blood flow, hence its effectiveness against erectile dysfunction and high blood pressure in the lungs. In the 2000s, when Viagra worked wonders for men, scientists became interested in how it could help fetuses. In a condition called intrauterine growth restriction, the fetus does not receive enough blood and does not develop. Fetuses that do not grow may die. The only real treatment barely resembles treatment: inducing a premature labor before the fetus dies. If sildenafil could increase blood flow to the fetus, the doctors thought, the drug might be able to help it grow in the womb.

In 2004, promising animal data led doctors in Canada to pilot a small study on sildenafil in 10 women. The drug appeared to increase fetal growth slightly, so they made plans for a larger international trial covering Canada, New Zealand, Australia, the UK and the Netherlands. “It was buzzing at the conferences,” Wessel Ganzevoort, lead investigator of the Dutch trial told the Dutch newspaper. By Volksrant. “Foreign colleagues let it slip that they sometimes prescribe [sildenafil], with good results. (The Dutch trial used a generic version of sildenafil that was not manufactured by Pfizer, the pharmaceutical company that makes Viagra.)

The arms of the trial in New Zealand, Australia and the UK have already been completed, and UK investigators have actually published their results in The Lancet in December. The results were not promising. The drug did not prolong the pregnancy or improve the results. But the trial showed no serious side effects related to sildenafil either, so the Dutch and Canadian trials continued until 11 deaths were announced this week. In a statement, Kenneth Lim, principal investigator of the Canadian trial, said he was not aware of the adverse results in Canada but suspended the trial.

It’s too early to say exactly what happened, but one specific detail emerges. The Amsterdam University Medical Center, which led the Dutch trial, noted in a press release that 93 pregnant women had taken sildenafil as part of the trial and that 19 babies had died, including 11 possibly of a “form of pulmonary arterial hypertension”. because sildenafil is actually approved to treat high blood pressure in the lungs in adults.

But sildenafil can have the perverse effect of causing the exact problem it is supposed to solve if patients suddenly stop the drug, says Robert Tulloh, who studies the disease (pulmonary hypertension) at Bristol University Hospitals. The body can acclimatize to the drug over time, in the same way that taking steroids can cause the body to produce fewer natural steroids. Now imagine that the fetuses are growing inside the women on sildenafil. At birth, their lungs must suddenly start to function and they are cut off from sildenafil. In addition, says Tulloh, sildenafil affects a very basic cellular pathway in the human body involving nitric oxide. “Even amoeba has nitric oxide capacity,” he says. Use of the drug during fetal development can have other unexpected side effects. (The Amsterdam UMC did not immediately respond to questions about the cause of infant deaths.)

Sildenafil is approved for pulmonary hypertension in adults, but its use in newborns and children is controversial. In 2012, the FDA actually issued a warning regarding the use of sildenafil for pulmonary hypertension in children between the ages of 1 and 17. lower doses. But it’s still in use – frequently enough that the FDA had to issue a clarification in 2014 that its warning was not intended to discourage sildenafil in children in all cases. Its use in newborns, in particular premature babies, is also off-label.

Viagra is now sold as a generic, and its popularity as an erectile dysfunction drug means that a ready supply is available. “Because it’s so cheap that people use it in all kinds of situations,” says Tulloh.

The high cost of drug development has led scientists to reuse drugs previously approved for all diseases. Current sildenafil trials include everything from cancer to concussions to urinary incontinence. The biology and economics of sildenafil are linked.

When a drug can potentially have so many different effects, it also has a lot of side effects, some of which, unfortunately, are even fatal.


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