Sildenafil (Viagra) is the most well-known treatment for men's diseases, and it was born out of an accident in a trial to treat heart disease. As its mechanism was discovered, scientists discovered its other indications, such as pulmonary hypertension. Recently, several studies have shown that sildenafil can reduce the risk of Alzheimer's disease, but can it really prevent this disease that affects human cognitive function?
Written by | Barking
Figure 1 Sildenafil (Viagra®) Image source: Internet
Sildenafil (Viagra®), you must have heard of its other, more well-known name: Viagra. It is a best-selling drug developed by Pfizer in the United States for the treatment of male erectile dysfunction (ED). In addition to the treatment of ED, several recent studies have shown that sildenafil is associated with a reduced risk of Alzheimer's disease. This article will introduce you to the slightly legendary research and development process of sildenafil, and at the same time introduce you to the current research progress - how far is it to treat Alzheimer's disease, sildenafil?
Treatment ED: Lost East Harvest Mulberry Elm
Sildenafil was developed to treat ED after an accident. As a phosphodiesterase type 5 inhibitor (PDE5-I), sildenafil can inhibit PDE5 from breaking down cyclic guanosine monophosphate (cGMP), causing blood vessels to dilate, thereby lowering blood pressure, so it was initially developed to treat cardiovascular diseases such as angina and hypertension [1].
Fig.2 Mechanism of action of sildenafil[2]
In April 1991, early clinical trials failed due to unsatisfactory treatment of cardiovascular diseases. In the course of clinical studies, researchers unexpectedly discovered the side effects of sildenafil: in some male volunteers with relatively high oral doses, the frequency of penile erections and the prolongation of erections appeared. Nurses also often observe male patients covering their abdomen to hide their embarrassment. However, after the failure of the clinical trial, the subjects refused to return the remaining drugs, and the researchers found it strange that sildenafil had improved their sex life [1].
The discovery sparked the interest of scientists, who began to study the potential of sildenafil in the treatment of erectile dysfunction. After numerous clinical trials and studies, in 1998, the U.S. Food and Drug Administration (FDA) approved sildenafil as a drug for the treatment of erectile dysfunction in men[3]. This approval opens up a whole new treatment modality that is a boon for men with ED.
The mechanism of action of sildenafil in the treatment of ED has also been elucidated, and consistent with the previous conclusions, sildenafil can highly selectively inhibit the activity of PDE5 in the human body, and the expression level of PDE5 in the body cavernosa is extremely high, but the expression level of PDE5 in other tissues and organs of the human body is very high, so the therapeutic effect for cardiovascular diseases is not ideal, but it is suitable for the treatment of ED [4]. After taking sildenafil, the vascular smooth muscle of the penile cavernous corpus in men relaxes under the action of the drug, blood flow increases, the cavernous body becomes congested, and the penis becomes erect, thus acting as a therapeutic effect[2].
After being approved by the FDA in 1998, sildenafil reached $400 million in market sales in the first quarter of the United States, with more than 300,000 prescriptions issued in just one week in May 1998. Pfizer also contributed to this, sending a large number of sales representatives to instruct doctors on how to bring up the topic of impotence, which was still sensitive at the time, and to distribute pill samples to treat the disease, which had plagued men since ancient times. In the time that followed, sildenafil's influence continued to expand, bringing about a revolution in sexual medicine on a global scale, bringing in more than $1 billion in revenue for Pfizer worldwide each year [1].
Viagra's® patents outside the U.S. expired in 2012 and in the U.S. in 2020, creating a new wave of market for generic anti-ED drugs. In China, sildenafil is still far ahead in the sales list of chemical drugs every year, and in 2021, the total sales of sildenafil in mainland China will be at least 4 billion yuan. It is worth mentioning that among the top 20 terminal chemical drugs in China's online pharmacies in 2021, sildenafil citrate tablets (Viagra) ranked first with a high growth rate of 61.04% [5].
The launch and best-selling of sildenafil marks a new era of medical treatment in sexual medicine. It's about opening the door for men to talk about the frustrations they once were ashamed to talk about, and that questions they once couldn't talk about to doctors could be a sign of other, more serious health problems, including heart disease.
Old Tree Flowering: A New Use for the Prevention of Alzheimer's Disease
In recent years, it is not uncommon to reuse old drugs, and "repurposing old drugs" refers to the study of drugs that are already on the market or in clinical trials, discovering new indications for them, and using them for the treatment of diseases [6]. For the characteristics of high R&D cost, long R&D cycle and high R&D risk of new drug R&D, the development of new uses for old drugs that have been tested at all levels can undoubtedly greatly accelerate the R&D progress.
There are many well-known cases, such as aspirin, a century-old antipyretic and analgesic drug, which has recently been found to have a very good role in the prevention and treatment of cardiovascular diseases [7], metformin, which has been widely used as an oral hypoglycemic drug since its introduction in 1957, has also been found to have unique advantages in cardiovascular and cerebrovascular protection, and recent studies have also shown that the treatment of metformin is associated with a reduced risk of lung cancer, prostate cancer, rectal cancer, breast cancer, and other cancers [8].
The most well-known use of sildenafil, the protagonist of this article, is the treatment of ED, and after its successful marketing, research on its other indications has not stopped. Pulmonary hypertension is one of them, as a fatal cardiovascular disease, patients will suffer from heart failure and eventually death in severe cases, and subsequent studies have found that sildenafil has a good therapeutic effect on pulmonary hypertension. After years of clinical trials, the FDA approved sildenafil as a drug for the treatment of pulmonary hypertension under the trade name "Revatio" in 2005. The launch of Revatio has changed the pattern of high prices for pulmonary hypertension treatment drugs and reduced the financial burden on patients.
Nowadays, sildenafil is gradually discovering new uses, and several articles have reported that Viagra may have the effect of reducing the risk of Alzheimer's disease.
In 2021, a study published in the journal Nature Aging showed that people who took sildenafil had a 69% lower risk of Alzheimer's disease compared to those who did not. The study covered more than 7 million people in the United States with an average age of around 71 years, of whom 116,000 took sildenafil[9].
A new study of nearly 670,000 men in the United Kingdom, published in the journal Neurology on Feb. 7, 2024, shows that people who take PDE5I have a lower chance of developing Alzheimer's disease than those who don't. Among them, men who took sildenafil or similar drugs had an 18% lower risk of developing Alzheimer's disease compared with men who did not take these drugs. In contrast, those who used it more frequently (21 to 50 prescriptions were issued) had a 44 percent lower risk of developing Alzheimer's [10].
Figure 3 Study published in the journal Neurology on February 7 [10]
Another study, published March 19 in the Journal of Alzheimer's Disease, found that people who took sildenafil were 30 to 54 percent less likely to be diagnosed with Alzheimer's disease compared with those who did not take sildenafil, further confirming the Neurology article [11].
Figure 4 Study published in the Journal of Alzheimer's Disease on March 9 [11]
However, this is not the first time that these drugs have been linked to a reduced risk of Alzheimer's disease – since the late 90s, studies at the animal level have shown that PDE5I drugs have a positive effect on cognitive performance [12].
As mentioned above, the mechanism by which sildenafil treats ED has been well studied, but how the drug affects brain diseases such as Alzheimer's is unknown. Scientists have proposed several potential mechanisms. For example, targets such as PDE5 are also found in other parts of the body, including the brain, so increasing blood flow in the brain may reduce the likelihood of Alzheimer's disease to some extent [13].
In the 2021 Nature Aging study, Feixiong Cheng, principal investigator of the Cleveland Clinic, and his colleagues further explored the mechanism of sildenafil's impact on Alzheimer's disease, in addition to the conclusions that sildenafil use is associated with a reduced risk of Alzheimer's disease. They found that sildenafil could promote neuronal growth and reduce the expression of phospho-tau from neuronal models of induced pluripotent stem cells in AD patients, and phosphorylated tau protein, a class of proteins that is closely associated with Alzheimer's disease - accumulates in the brains of Alzheimer's patients, which mechanistically supports the potential benefits of sildenafil for AD. However, the authors also show that the association between the use of sildenafil and a reduction in the incidence of AD does not establish a causal relationship, which requires more experimental validation [14].
Other researchers believe that PDE5I drugs can strengthen the connections between neurons and synapses in the brain, because this process relies in part on cGMP, and the brain stores memories by strengthening synaptic connections to help connected neurons "talk" to each other. This could explain the link between the PDE5I drug and a reduced risk of Alzheimer's, as one of the symptoms of Alzheimer's is memory loss [13].
In addition, a 2019 study in the American Journal of Human Genetics revealed that people with genetic risk factors for type 2 diabetes are more likely to develop erectile dysfunction (ED) than those without these risk factors [14]. High blood pressure or type 2 diabetes is associated with a risk of developing Alzheimer's. However, it is unclear whether drugs such as PDE5I have been associated with improving cognition by controlling these disorders [15].
At present, none of these theories have been clearly confirmed, and the effect of PDE5I drugs on Alzheimer's disease still needs to be explored. There are also studies that come to different conclusions, for example, a 2022 study in patients with pulmonary hypertension (pulmonary hypertension can be treated with PDE5I drugs) found that this drug was not associated with a reduction in the risk of Alzheimer's [16].
Figure 5 Studies in patients with pulmonary hypertension have shown that PDE5I is not associated with a reduced risk of Alzheimer's [16].
All of these studies have the same limitations: although the surveys covered very large populations, they were observational, meaning that they only retrospectively compared prevalence in different populations and did not delve into other factors that may affect the risk of Alzheimer's. Therefore, it is not possible to draw a definitive conclusion that PDE5I drugs affect the risk of AD. For example, the results of the 2024 Alzheimer's Disease study were noted that the authors did not take into account genetic or socioeconomic factors in their analysis, as well as the effects of the dose of the drug they used in the experiment.
Treatment of AD, where is the way forward?
In the past big data retrospective studies, the people covered are often people with good cognitive function, who can have sex and have the need to take drugs, especially the majority of sildenafil users are men, and whether sildenafil can improve women's cognitive ability has not been considered, which will bias the research results. To prove that sildenafil is indeed effective in preventing Alzheimer's disease, or even to use it in the clinic to help people in need, scientists need to conduct clinical trials according to strict standards, not just the big data that proves the relevance of the above-mentioned data. More stringent clinical trial criteria can include recruiting subjects who meet the criteria, setting up control and dosing groups in parallel, and matching the age and sex of the two groups to the population to be treated in the future, all of which can help to obtain more accurate results.
Several clinical trials have evaluated the potential effects of PDE5I drugs on human cognition. However, the size of these trials was limited; for example, one trial included only 10 participants. Some trials only tested the short-term effects of the treatment—measuring the cognitive effects of a single dose over the course of one day [17].
To further demonstrate that drugs like Cidiafia can help prevent Alzheimer's, future trials may need to be conducted for longer periods, say three to five years, and include patients with clinically diagnosed Alzheimer's, which would be more convincing than previous studies.
At the same time, it is also important to find clues about the treatment mechanism of Alzheimer's disease in the process of clinical trials, at present, there are many theories about the pathogenesis of Alzheimer's disease, and the pathology is complex, if some new technologies are used in the treatment process to explore the changes in patient indicators during the treatment process, such as using brain imaging technology to measure the changes in blood flow after taking PDE5I drugs, these data may be helpful for the treatment of Alzheimer's disease in the future.
Long-term trials also allow scientists to observe the side effects of long-term use of these drugs. For example, for brain diseases such as Alzheimer's disease, the ability of the drug to penetrate the blood-brain barrier is important, and the drug molecule can only exert a better effect if there is enough accumulation in the brain, so in subsequent studies, scientists may be able to optimize this aspect to achieve better treatment results [13].
If these drugs are ultimately proven to be effective in preventing Alzheimer's disease, then as with other older drugs that have been found to have new uses, it will be pushed to clinical use much faster and more patients will benefit as safety data are already available at the human level.
For these little blue pills, it still has a long way to go before it becomes a prescription drug that can really prevent Alzheimer's disease.
bibliography
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This article is supported by the Science China Star Program
Producer: Science Popularization Department of China Association for Science and Technology
Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd
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