"Inadvertently inserted" Sildenafil - the unexpected joy of side effects research

In the 1980s, Pfizer wanted to find new treatments for several cardiovascular diseases, including angina
.
At that time, nitrates were effective drugs for short-term treatment of angina pectoris, but these drugs had the disadvantage of developing drug tolerance in a short time
.
Nitrates can be used as exogenous donors of NO, which are catalyzed by glutathione transferase in smooth muscle cells and then release NO.
NO binds to guanylate cyclase (GC) and activates the enzyme activity, catalyzing three Guanosine phosphate (GTP) is converted into cyclic guanosine monophosphate (cGMP) and increases the content of intracellular second messenger cGMP, reduces intracellular Ca2+ release and extracellular Ca2+ influx, thereby relaxing vascular smooth muscle and reducing cardiac preload and afterload , improve myocardial blood supply
.
In addition, NO produced by nitrate compounds can also inhibit platelet aggregation and adhesion, and is also beneficial to the treatment of angina pectoris
.
At that time researchers had already discovered that cyclic nucleotides were degraded by phosphodiesterase (PDE)
.
Francis et al.
first isolated and purified PDE5 from rat lungs in 1980
.
PDE5 is concentrated in vascular smooth muscle and platelets, and selective inhibition of PDE5 can play the role of vasodilation and anti-platelet aggregation at the same time
.
Therefore, PDE5 becomes a potential ideal target for the treatment of angina attacks
.
In 1986, Pfizer formed a research group to try to find selective PDE5 inhibitors
.
The world's first reported PDE5 inhibitor was zaprinast
.
Zaprinast was originally developed as an anti-allergic drug, and was subsequently screened with PDE5 isolated from rabbit platelets and found to have vasodilatory effects
.
The study found that zaprinast has a weak affinity with PDE5 and has a certain selectivity
.
Therefore, Pfizer took the drug as the research object, carried out a series of transformation and screening, and finally successfully screened out a relatively excellent compound, which was later sildenafil
.
In its citrate form, sildenafil was advanced into full preclinical studies in 1989 and into clinical studies in 1991 for the treatment of hypertension and angina pectoris
.
Preclinical studies have shown that sildenafil can indeed dilate arterial and venous vessels at the same time and inhibit platelet aggregation
.
Clinical studies conducted between 1991 and 1992 found that sildenafil was rapidly absorbed orally, reaching peak plasma concentrations (Cmax) about 1 hour after administration, and the absolute oral bioavailability was only 41% due to a significant first-pass effect
.
The area under the drug-time curve (AUC) increased approximately proportionally with increasing doses from 25 to 200 mg, with simple linear pharmacokinetic properties
.
After the drug enters the human body, it is metabolized by demethylation of cytochrome P450 isoenzymes CYP2C9 and CYP3A4.
The average half-life of oral administration is 4 hours.
The plasma protein binding rate of sildenafil and its metabolites is about 67%.
It is mainly excreted in the form of its metabolites through urine and feces
.
In addition, sildenafil was found to have some vasodilatory effect and mildly lower blood pressure in healthy subjects, but the effect was weak compared to nitroglycerin
.
Compared with nitroglycerin, the first-line drug for the treatment of angina pectoris, sildenafil has obvious efficacy and pharmacokinetic properties.
defect
.
Therefore, in 1993, the clinical study of sildenafil as a drug for the treatment of cardiovascular disease officially failed
.
However, one side effect caught the researchers' attention
.
Some volunteers who took relatively high doses experienced more frequent or longer erections than before the drug
.
Members of the Pfizer research team hypothesized that if PDE5 plays an important role in the physiology of corpus cavernosum smooth muscle, it is likely that administration of sildenafil may promote erectile responses to sexual stimulation
.
In the state of sexual arousal, NO is released from the penile nerve and vascular endothelium, and then diffuses into the cavernosal smooth muscle cells, increasing the level of cGMP
.
At the time, many doctors believed that ED (erectile dysfunction) was a relatively difficult condition to treat, mainly due to psychological reasons
.
However, some urologists working on ED have begun to inject vasodilators into the cavernosa to treat ED by modulating cAMP levels
.
Although these methods are feasible, the disadvantages are also obvious.
The injection method of administration will inevitably cause physical damage to the body.
Artificially induced erections often last for a long time after sexual intercourse, which will increase local bleeding and stasis.
Risk of injury and priapism
.
So in late 1993, Pfizer launched a preliminary clinical trial of the drug for the treatment of ED
.
At the outset, they encountered a difficult problem that needed to be solved: how to scientifically measure the effect of the drug in the case of sexual stimulation
.
The team consulted with Clive Gingell, a urologist at Southmeads Hospital in Bristol, England, who has been working on ED for a long time.
Ultimately, they decided to use the Rigiscan tester to monitor erections
.
They used a randomized, double-blind, crossover protocol to give patients with psychogenic ED a single dose of 10 mg, 25 mg, 50 mg of sildenafil or placebo
.
The results showed that after visual and auditory stimulation, taking different doses of sildenafil all had the effect of promoting erection, and there was an obvious dose-effect relationship
.
In subsequent studies, it was found that patients who took the drug did improve their quality of sexual life.

.
At the same time, it was also found that after taking sildenafil, the subjects would have adverse reactions such as headache, dizziness, indigestion, abnormal vision, etc.
These adverse reactions originate from its inhibitory effect on PDE in other parts of the human body, most of which are related to the corresponding smooth muscle.
Diastole is related, but the duration is relatively short
.
For the follow-up study and drug approval, the researchers invited external experts as consultants to develop a scientific, credible questionnaire and diary record format
.
The most representative of them is the International Index of Erectile Function (IIEF) with 15 questionnaires
.
Not only is the IIEF accepted and recognized by regulatory agencies for its reliability in assessing treatment effects, it has also become the gold standard for evaluating efficacy in ED clinical research
.
In order to study whether sildenafil is effective for ED caused by different causes, Pfizer has conducted several clinical trials
.
The results of the study show that sildenafil has a good therapeutic effect on ED caused by different causes
.
As of 1997, 21 independent clinical trials with more than 4500 subjects have been conducted and the results have shown that sildenafil is effective in different patient populations, with the main dose-related side effects including transient headaches , flushing, indigestion and visual disturbances
.
Pfizer has simultaneously submitted registration applications to the U.
S.
Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA)
.
In March 1998 and in September of the same year, the FDA and EMEA respectively approved the listing of sildenafil citrate, with the trade name Viagra, for the treatment of ED
.
The recommended dose of sildenafil is 50 mg orally one hour before sex
.
After Viagra was launched, it immediately set off a storm in the field of ED treatment, aroused people's awareness and attention to sexual health, and quickly became the first-line drug for ED treatment.

.
The role of NO is in almost every system of the body, and the cGMP produced by it plays an important role in regulating the physiological functions of the body
.
The great success of sildenafil in the clinical application of ED and PAH has further stimulated the research enthusiasm of other pharmacological effects of sildenafil, and obtained encouraging results
.
The results of the study show that sildenafil has a certain therapeutic effect on a variety of cardiovascular diseases, neurodegenerative diseases, and digestive tract diseases
.
The development process of sildenafil can inspire everyone involved in drug development
.
First, animal models can be very different from the reality of human disease
.
Especially if there are differences in some key targets, it is likely to greatly affect the actual therapeutic effect of the drug
.
Second, even if the drug has certain problems in clinical trials, don't deny it prematurely, maybe some other therapeutic effects can be found
.
At the same time, we must also recognize that the theoretical basis and clinical data can promote each other
.
Because of some basic theories, we carry out some experiments, and the experimental results can help us perfect or discover new theories
.
In the process of drug development, both should be done equally
.
Finally, I would like to thank Mr.
Wu and Assistant Professor Xu for their guidance and help.
We spent a full semester and learned all aspects of new drug research and development and benefited a lot
.
About the author Drug-seeking truth group They are students of the new drug research and development strategy course of Nanjing University
.
They are full of vigor, their fighting spirit is high, they are down-to-earth to learn the knowledge of new drug research and development, and they firmly believe that I love my teacher and I love the truth more
.
They are the successors of the new generation of pharmaceutical industry, and they are the future light in the field of new drug research and development! *This article is only for academic content exchange and does not constitute any medication advice! References: 1.
Francis, SH, T.
Lincoln, and J.
Corbin, Characterization of a novel cGMP binding protein from rat lung.
J.
Biol.
Chem.
1980, 255 (2), 620.
2.
Terrett, NK, AS Bell, D.
Brown, and P.
Ellis, Sildenafil (Viagra), a potent and selective inhibitor of type 5 CGMP phosphodiesterase with utility for the treatment of male erectile dysfunction.
Bioorg.
Med.
Chem.
Lett.
1996, 6 (15 ), 1819.
3.
Osterloh, IH, The discovery and development of Viagra(sildenafil citrate), in Sildenafil, U.
Dunzendorfer, Editor 2004, Birkhaeuser Verlag.
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1.
4.
Ghofrani, HA, IH Osterloh, and F.
Grimminger, Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond.
Nat.
Rev.
Drug Discovery 2006, 5 (8), 689.
5.
Jackson, G.
,