Early Development of Sildenafil for Pulmonary Hypertension: A Retrospective Account

Ghazwan Butrous

https://doi.org/10.1002/pul2.70188 

Abstract

In 1999, I was asked by Pfizer to investigate the potential use of sildenafil, commonly known today as Viagra, for indications beyond its initial approval for erectile dysfunction. After conducting thorough research, I discovered studies published by the May and Baker pharmaceutical company that suggested a type 5 phosphodiesterase (PDE5) inhibitor could reduce pulmonary pressure in experimental animals [1-3]. However, the drug from these studies (mainly Zaprinast or E4021) had been discontinued for unknown reasons.

Upon further investigation, I realized that Pfizer chemists had developed sildenafil as a precursor to Zaprinast. I recognized its potential and presented several suggestions to Pfizer's medical director, Dr. Steve Felstead. One of the suggestions was that sildenafil could be used to treat pulmonary hypertension. Following a comprehensive conversation, I proposed the use of intravenous sildenafil, which was accessible to Pfizer, in cooperation with specialists in pulmonary hypertension. Unfortunately, the initial efforts were hampered by a lack of funding.

Steve contacted a senior director, and by chance, there were unallocated funds available—approximately $500,000—due to the cancellation of another study. This unexpected opportunity allowed us to start developing protocols for the study.

I wasn′t well-acquainted with the key opinion leaders in pulmonary hypertension at that time. My research led me to Professor Tim Higginbottom, a pioneer and professor at Sheffield. He had started his work in pulmonary hypertension during his previous time at Papworth Hospital in Cambridge. I arranged for him to meet with me at the Royal Society of Medicine in London in 1999 to talk about the potential of sildenafil.

During our meeting, Professor Higginbottom was initially sceptical. He questioned the appropriateness of using a drug primarily known as a lifestyle medication for patients with pulmonary hypertension, especially since these patients were typically at very high risk, even during standard catheterization sessions. At that time, most patients diagnosed with pulmonary hypertension were in advanced stages, which added to the potential risks.

I emphasized that existing evidence suggested sildenafil could reduce pulmonary pressure. Though not entirely convinced, Professor Higginbottom agreed to try the medication, considering the risk. The investigator's study was started in 1999 (I shall write another vignette on this study later).

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