From an experiment onanginato the most famous drug for erectile dysfunctioncommonly called impotence: the history of sildenafildeveloped by Pfizer and known by the trade name of Viagra®is a common story in scientific research, made of in-depth study, but also of timing and intuition of researchers. While looking for an alternative to the drugs commonly used for angina, a cardiovascular disease characterized by a reduced blood flow to the heartstudy subjects began reporting “erections” as a side effect. Having understood the potential of the drug, the researchers changed the direction of their studies, evaluating its usefulness in the treatment of erectile dysfunction. Those studies not only gave rise to the myth of “blue pill”, but also new research methodologies, an entire class of drugs and today sildenafil is rediscovering a new life thanks to research on various diseases characterized by a poor local blood supply.
Looking for a new drug for angina
It is the Eighties, precisely 1986. In the Sandwich plants in the United Kingdom, Pfizer begins testing new drugs forangina pectorisa coronary heart disease caused by poor blood flow to the heart and characterized by intense chest pain.
First choice drugs, i nitratesact as an exogenous source of nitrogen monoxide (NO), an important mediator of various reactions in our body. In fact, NO stimulates the formation of a second mediator, cGMP (cyclic guanosine monophosphate). In turn, cGMP induces relaxation of the smooth muscles surrounding arteries and veins, leading to vasodilation, which results in a greater blood supply to the myocardium e lowering of heart pressure.
The problem with these drugs is that they can give a particular type of tolerance called tachyphylaxisi.e. the body quickly gets used to the drug, which therefore has less effect. Pfizer researchers were looking for drugs that could act on phosphodiesterases (PDE), the enzymes that degrade cGMP, so that it remains in circulation for longer and prolongs its vasodilation action.
Promising in the laboratory, disappointing in humans
From in vitro and in vivo studies the researchers obtained a promising molecule: UK -92,480better known as sildenafilwith which they continued the studies and moved on to the next phase of clinical trials on healthy volunteers. Unfortunately, the transition from laboratory to man was not so exciting.
Sildenafil did reduce blood pressure, but very moderately. Furthermore, he had a half-life very short: it means that once taken and arrived in the bloodstream, it was quickly metabolised, so that it would have been necessary to take multiple doses, even quite high ones, during the day. Furthermore, it interacted with the nitrates themselves, ultimately making it not very suitable for further development of the drug.
Interesting side effects of sildenafril
It was during a clinical study, lo study 148-207that the patients (or according to some stories, the nurses) began to report a strange side effect: taking sildenafil 3 times a day, after a few days they had an erection!
At first, the idea of a drug for erectile dysfunction was discarded because this effect only developed after a few days of taking ita little inconvenient for the intended use. Only when the physiology of erection was clearer, which involves the same NO-cGMP mechanism as angina, did we glimpse the potential of sildenafil, taken as needed, to support and improve the erection process.
As with angina, in fact, cGMP causes vasodilation and therefore increases the blood flow to the penis, allowing erection. Inhibiting phosphodiesterase, in particular the PDE-5 isoform, could be a winning strategy. In those years, they were used to treat erectile dysfunction vasodilators injected locally (particularly painful) at the level of the cavernous bodies of the penis, an understandably uncomfortable therapy, invasive and with serious side effects, because it led to priapisma condition of persistent erection (over 4 hours), painful and with risk of bleeding and bruising.
Have a medication you could take orallyas needed, with few transient side effects (headache, indigestion and redness) and which took effect quickly was very attractive to researchers. In vitro studies confirmed that sildenafil inhibited PDE-5 and in 1993 the first clinical study (study 148-350) was held to evaluate the efficiency of the sildenafil on erectile dysfunction. There were no tools to evaluate the effects of the drug, so researchers had to develop a questionnaire to submit to patients and partners. It is about theInternational Index of Erectile Function (IIEF, International Index of Erectile Function), which has become the standard still used today for the evaluation of erectile dysfunction.
The marketing and new uses of sildenafil
The trials continued for another five years, confirming the effectiveness of sildenafil in promoting and supporting erection during sexual intercourse: it was revolutionary. In 1998, the Food and Drug Administration (FDA) first and a few months later the EMEA (European Medicines Evaluation Agency, currently EMA) approved themarketing of sildenafil citratetrade name Viagra®. The blue pill was recommended for any type of erectile dysfunction, whether secondary to other pathologies (such as diabetes, spinal cord injuries or even prostatectomy), or type psychologicalachieving immediate success and diffusion.
A few years later, in 2002, studies also began for use in another pathology,pulmonary arterial hypertensioncharacterized by an increase in blood pressure in the lungs. In 2005, FDA and EMEA approve the marketing of sildenafil as Revatio® for the treatment of this pathology.
Since then, even after the advent of generic drugs, the fortune of sildenafil has not stopped, as demonstrated by the studies currently underway for various pathologies, from COVID-19 to Alzheimer’s, from the treatment of pain to Raynaud’s syndrome related to multiple sclerosis. In general, these are disorders that have one thing in common reduced blood supply in specific districtsthewhere the particular mechanism of action of sildenafil could be useful.
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