Early Development of Sildenafil for Pulmonary Hypertension: A Retrospective Account

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). Several months passed without any communication from Professor Higginbottom until, unexpectedly, he called to inform me that he had administered sildenafil to a patient with secondary pulmonary hypertension secondary to COPD. To our surprise, this patient responded dramatically well to intravenous sildenafil. This was significant because such patients with pulmonary hypertension often did not respond well to vasodilators. In scientific research, unexpected results usually lead to groundbreaking discoveries, challenging existing theories and opening new horizons for exploration, innovation, and maybe a new therapeutic approach. The study continued, expanding to other centers in Europe, although I received little information beyond the involvement of these additional sites. Professor Higginbottom got in touch with me again about 6 months later to ask for oral sildenafil for another patient. This time, the request concerned an old friend of his—a professor from Iceland visiting England—who had pulmonary hypertension. The patient had been reluctant to use prostacyclin, a standard treatment at the time, and responded well to sildenafil. However, the commercial version of sildenafil was not readily available in Iceland, which explained Professor Higginbottom's request. I was unable to consider this request, especially at that time, when there had been some severe side effects with sildenafil reported. This led to some health advisories not to give sildenafil to patients with any heart problems (which were revised later) [4]. Despite my concerns about the off-label use of sildenafil for an unestablished indication, this patient continues to take oral sildenafil. This case represented one of the earliest long-term use of sildenafil to treat pulmonary hypertension. I later learned from Tim that one of his graduate students, Dr Tom Siddons, included several patients treated with sildenafil in his PhD thesis, where he also compared it with long-term inhaled nitric oxide (iNO), which improves cardiac output and walking distance. The unofficial use of sildenafil in its early stages was crucial. Sildenafil′s potential to improve pulmonary hypertension was slowly made known to physicians through word of mouth and subsequent case studies and letters to medical journals [5]. The author has nothing to report. The author has nothing to report. The author declares no conflicts of interest.