Erectile Dysfunction Drugs Linked to Lower Glaucoma Risk in Men

 Didn't your competent? doctor already prescribe this for stroke recovery and dementia risk reduction?

• Sildenafil (6 posts to November 2012)
• 16 posts on Viagra here.

Erectile Dysfunction Drugs Linked to Lower Glaucoma Risk in Men

Also from ARVO: HDL and AMD risk in women, statin use and glaucoma risk

DENVER -- Men using phosphodiesterase type 5 (PDE-5) inhibitors for erectile dysfunction (ED) had a modestly lower risk of glaucoma, according to a study reported here.

During 3 years of follow-up, men taking PDE-5 inhibitors had a reduced likelihood for glaucoma suspect (risk factors) and open-angle glaucoma (OAG). The absolute difference ranged from 1-3% for glaucoma suspect and about 1% for OAG. The relative risk differential achieved statistical significance each year for both conditions (P=0.04 to P<0.01).

"The association is likely vascular in origin, as PDE-5 inhibitors enhance [nitric oxide-cyclic guanosine monophosphate] signaling, improving ocular blood flow and optic nerve perfusion," concluded Abdelrahman M. Elhusseiny, MD, of the University of Miami, and colleagues in a poster presentation at the Association for Research in Vision and Ophthalmology (ARVO) meeting. "PDE-5 inhibitors do not produce sustained intraocular pressure reduction, suggesting the effect is not mediated by aqueous humor dynamics. Further prospective studies are needed to clarify mechanisms, evaluate long-term effects, and determine clinical implications."

PDE-5 inhibitors (such as sildenafil [Viagra], tadalafil [Cialis], and vardenafil [Levitra]) are prescribed primarily for ED and pulmonary hypertension, but the drugs' vascular and cryoprotective effects may have broader therapeutic implications, the investigators noted. To examine the issue, they queried the TriNetX clinical network for the years 2005-2025 to identify men at least 40 years old with diagnosed ED, and then grouped them according to history of PDE-5 inhibitor use.

The primary analysis included two propensity-matched groups of 23,603 men each (PDE-5 users and non-users). Mean follow-up in each group was almost 1,000 days. The primary endpoints were glaucoma suspect and OAG.

After a year of follow-up, rates of glaucoma suspect and OAG were 6.49% and 2.13% versus 9.73% and 3.22% for PDE-5 inhibitor users and non-users, respectively (P<0.01 for both comparisons). Rates of both conditions increased in both groups and between-group differences shrank during the next 2 years. At the end of follow-up, rates of glaucoma suspect and OAG were 11.17% and 3.88% among PDE-5 inhibitor users versus 12.06% (P=0.01) and 4.28% (P=0.04) among non-users.

Higher HDL Linked to Lower AMD Risk in Women

Higher levels of high-density lipoprotein (HDL) in women were associated with a small but statistically significant lower risk of developing neovascular age-related macular degeneration (nAMD), according to a study reported at ARVO.

Women with HDL levels ≥60 mg/dL had a 1% absolute difference in nAMD (10.2% vs 11.2%) with women who had low HDL (<50 mg/dL). The difference translated into a 9% reduction in relative risk (95% CI 0.83-0.99, P=0.03). However, the difference no longer remained significant in a time-to-event analysis (HR 0.93, 95% CI 0.85-1.02, P=0.11). A comparison of low versus normal HDL (50-59 mg/dL) showed no difference, and neither high nor low HDL levels altered nAMD risk in men.

"These findings suggest there may be sex-specific, lipid-related mechanisms involved in AMD progression, and highlight the need for further research into the role of HDL and retinal disease biology," said Adriana Kaganovski, of SUNY Downstate Health Sciences University in New York City, in a recorded summary of the study.

Lipid metabolism has been implicated in AMD pathogenesis but the influence of HDL on AMD risk remains unclear, said Kaganovski. To examine whether sex-specific HDL categories are associated with AMD risk, investigators searched the TriNetX network to identify adults with diagnosed nAMD and HDL measurements within 6 months of diagnosis. Men and women were stratified by sex-specific HDL levels for comparisons of high versus low and low versus normal levels.

Data analysis involved matched cohorts (4,347 to 8,911 participants each) to compare nAMD prevalence by HDL levels in men and women. For men, nAMD prevalence was 9-10% regardless of HDL level. Among women, nAMD prevalence was about 10-11%, and only the comparison of high versus low HDL produced a statistically significant difference.

Statin Use and Glaucoma Risk

Previously documented neuroprotective effects of statins may extend to glaucoma, according to a retrospective analysis involving more than 500,000 patients.

Statin use was modestly associated with the 5-year incidence of OAG (5.0% vs 5.3%, P<0.001). In a separate analysis of glaucoma-associated surgery, reflecting progressive disease, statin users had significantly lower hazards for incisional surgery, minimally invasive glaucoma surgery (MIGS), and selective laser trabeculoplasty (SLT).

"Our results are consistent with our hypothesis that statin use is associated with lower risk of glaucoma onset and progression," concluded Forest Lin, of the University of South Florida in Tampa, and colleagues in a poster presentation. "Prospective trials are needed to further elucidate the relationship between statin usage and glaucoma."

Statins' neuroprotective potential in glaucoma remains poorly understood, as previous studies have yielded inconsistent results, the investigators noted. To inform the issue, they tested the hypothesis that statin use would be associated with a decreased risk of OAG and progressive disease, as reflected in surgery and other interventions.

A search of the TriNetX database produced matched cohorts of 218,677 patients each for the analysis of glaucoma incidence and matched cohorts of 51,551 patients each for the analysis of progressive disease.

Over a 5-year period, 10,223 statin users and 10,801 non-users had new diagnoses of OAG, a difference that translated into a 9% reduction in the hazard ratio (95% CI 0.89-0.94). Statin use was associated with larger reductions in HRs for incisional surgery (HR 0.83, 95% CI 0.78-0.88), MIGS (HR 0.82, 95% CI 0.78-0.87), and SLT (HR 0.88, 95% CI 0.84-0.92). Statin users were more likely to be treated with ocular hypotensive agents (HR 1.39, 95% CI 1.37-1.41).

New Data Support Viagra for Alzheimer’s Prevention

 

But is it the drug or the amount of sex they are having? An easy piece of research to accomplish; WHOM will do that? What about for women?

Sex linked to better brain power in older age

 My doctor said it wasn't proven enough to do this.

But this for the negative view: Does Viagra really help prevent Alzheimer’s? Not so fast

The latest here:

New Data Support Viagra for Alzheimer’s Prevention

A new study provides more evidence that sildenafil (Viagra) which is used to treat erectile dysfunction (ED) may help protect against Alzheimer's disease (AD).

The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in AD among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.

This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).

"Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer's, which is in great need of new therapies," Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release. 

"We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil's potential against this devastating neurological disease," Cheng noted. 

The study was published online on March 1, 2024, in the Journal of Alzheimer's Disease. 

Neuroprotective?

Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities. 

They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of AD relative to the control drugs. 

For example, sildenafil use was associated with a 54% reduced incidence of AD in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of AD in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.

The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on AD risk, as previously reported by Medscape Medical News.

However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced AD risk.

The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient induced pluripotent stem cell (iPSC)-derived neurons. 

They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD.

"We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer's disease," Cheng said. 

The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Cheng had no relevant disclosures.

Sildenafil(Viagra) as a Candidate Drug for Alzheimer’s Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons

 

But is it the drug or the amount of sex they are having? An easy piece of research to accomplish; WHOM will do that?

Sex linked to better brain power in older age

 My doctor said it wasn't proven enough to do this.

But this for the negative view: Does Viagra really help prevent Alzheimer’s? Not so fast

The latest here:

Sildenafil as a Candidate Drug for Alzheimer’s Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons

Article type: Research Article

Authors: Gohel, Dhruv^{a; 1} | Zhang, Pengyue^{b; 1} | Gupta, Amit Kumar^{a; 1} | Li, Yichen^a | Chiang, Chien-Wei^c | Li, Lang^c | Hou, Yuan^a | Pieper, Andrew A.^{d; e; f; g; h} | Cummings, Jeffreyⁱ | Cheng, Feixiong^{a; j; k; *}

Affiliations: [a] Genomic Medicine Institute,Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA | [b] Department of Biostatistics and Health Data Science, Indiana University, Indianapolis, Indiana, USA | [c] Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH, USA | [d] Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA | [e] Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA | [f] Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA | [g] Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA | [h] Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, OH, USA | [i] Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA | [j] Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA | [k] Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

Correspondence: [*] Correspondence to: Feixiong Cheng, PhD, Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Tel.: +1 216 4447654; Fax: +1 216 6361609; E-mail: chengf@ccf.org.

Note: [1] These authors contributed equally to this work.

Abstract: 

 Background: 

Alzheimer’s disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD. Objective: To investigate the potential therapeutic benefit of sildenafil on AD. 

Methods: 

We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil’s mechanism-of-action. 

Results:

We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32– 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49– 1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD. 

Conclusions:

These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.

Keywords: KeywordsAlzheimer’s disease, induced pluripotent stem cells, phosphodiesterase-5 (PDE5), real-world patient data, RNA-sequencing, sildenafil, tau phosphorylation

DOI: 10.3233/JAD-231391

Journal: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2024

Accepted 18 January 2024

|

Published: 01 March 2024

Price: EUR 27.50

Erectile Dysfunction Drugs Tied to Less Alzheimer's Risk

But is it the drug or the amount of sex they are having? An easy piece of research to accomplish; WHOM will do that?

Sex linked to better brain power in older age

 My doctor said it wasn't proven enough to do this.

But this for the negative view: Does Viagra really help prevent Alzheimer’s? Not so fast

The latest here:

Erectile Dysfunction Drugs Tied to Less Alzheimer's Risk

Large U.K. study tracked health records of 270,000 men

by Judy George, Deputy Managing Editor, MedPage Today February 7, 2024

Erectile dysfunction drugs were associated with reduced risk of Alzheimer's disease, electronic health record (EHR) data from 270,000 men in the U.K. suggested.

Over a median follow-up of about 5 years, men who started taking phosphodiesterase type 5 (PDE5) inhibitors were less likely to have an Alzheimer's diagnosis than nonusers (adjusted HR 0.82, 95% CI 0.72-0.93), reported Ruth Brauer, PhD, of the University College London, and co-authors.

Alzheimer's risk dropped further for men who had more than 20 prescriptions for PDE5 inhibitors, the researchers wrote in Neurology. For those issued 21-50 prescriptions, the HR was 0.56; for those with more than 50 prescriptions, the HR was 0.65.

PDE5 inhibitors are anti-hypertensive agents. Four -- sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra) -- are approved to treat erectile dysfunction because of their vasodilatory effects on the corpus cavernosum. Sildenafil also is approved to treat pulmonary arterial hypertension (PAH).

In rodents, sildenafil has been shown to improve memory and cognitive function, help synaptic plasticity and learning, and reduce amyloid burden. Tadalafil also has improved memory and lowered amyloid in animal studies. "However, evidence of neuroprotective effects in humans is not conclusive," Brauer and colleagues wrote.

The findings conflict with ones reported from a recent NIH DREAM study, which showed no difference in Alzheimer's and dementia diagnosis rates with PDE5 inhibitors compared with other PAH drugs among Medicare recipients.

But they're in line with a previous case-control analysis of insurance claims data that suggested sildenafil users were 69% less likely to develop Alzheimer's disease than non-users, noted Sevil Yasar, MD, PhD, and Lolita Nidadavolu, MD, PhD, both of the Johns Hopkins University School of Medicine in Baltimore, in an accompanying editorial.

"One major limitation of all three studies is that they have all used insurance claims or EHR data, which relies heavily on diagnosis by providers, which may lead to underdiagnosis or misdiagnosis of dementia, thus leading to misclassification bias," Yasar and Nidadavolu wrote.

Brauer and colleagues studied 269,725 men in U.K. primary care records with a new diagnosis of erectile dysfunction between 2000 and 2017. Patients with a history of cognitive impairment or dementia were excluded. Those who had a prescription for a PDE5 inhibitor (sildenafil, tadalafil, vardenafil, or avanafil) were compared with those who didn't.

The mean age at cohort entry was 58.5 years. Median follow-up was 5.1 years, during which 1,119 men were newly diagnosed with Alzheimer's disease.

Overall, 749 men exposed to PDE5 inhibitors developed Alzheimer's, which corresponded to a crude incident rate of 8.1 per 10,000 person-years at risk. Among unexposed men, 370 developed Alzheimer's, corresponding to a crude incident rate of 9.7 per 10,000 person-years.

The primary result was consistent in a sensitivity analysis that included a 1-year lag period to partly account for prodromal Alzheimer's, but not one with a 3-year lag.

In subgroup analyses, Alzheimer's risk was lower than those who started on sildenafil compared with men who didn't use PDE5 inhibitors (adjusted HR 0.81, 95% CI 0.71-0.93). PDE5 inhibitor exposure in men ages 70 and older, and in those with a history of hypertension or diabetes, also was associated with a lower risk of Alzheimer's.

Additional data from in vitro and in vivo studies could strengthen analyses that examine links between PDE5 inhibitors and Alzheimer's, the editorialists noted. "These include in vitro studies exploring the role of inflammation and clearance of beta-amyloid," Yasar and Nidadavolu wrote. Blood and cerebrospinal fluid biomarkers of inflammation and endothelial function or imaging to assess neuroinflammation and vascular changes also could help evaluate potential mechanisms associated with PDE5 inhibitor use.

"In the end, however, further observational studies exploring mechanisms will not prove a causal association," they emphasized. "A well-designed randomized controlled trial is needed before [PDE5 inhibitors] can be prescribed for Alzheimer's disease prevention."

• Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

This study had no targeted funding.

Brauer and co-authors reported no disclosures.

The editorialists had no disclosures.

Primary Source

Neurology

Source Reference: Adesuyan M, et al "Phosphodiesterase type 5 inhibitors in men with erectile dysfunction and the risk of Alzheimer disease: a cohort study" Neurology 2024; DOI: 10.1212/WNL.0000000000209131.

Secondary Source

Neurology

Source Reference: Yasar S, Nidadavolu L "Repurposing erectile dysfunction medication for Alzheimer disease prevention" Neurology 2024; DOI: 10.1212/WNL.0000000000209180.

Can Erectile Dysfunction Drugs Reduce Dementia Risk?

But all this earlier research, isn't your doctor already prescribing Viagra?

So inconsistencies, WHOM  is going to do the followup research to get a definitive answer?  Ask your doctor what is the downside of doing this prior to complete results?  I'd do almost anything to reduce the chances of dementia after seeing my Dad have it.

For your stroke edification. And for the women:

FDA Approves 'Female Viagra' Amid Cheers and Jeers August 2015.

18 posts on Viagra here.

Impotence medicine associated with reduced long-term risk of death after heart attack March 2017 

Drugs used for impotence could treat vascular dementia?  December 2014 

This made it sound helpful, even though it was just in rats and during the first week:  viagra and stroke rehab March 2011

Sildenafil Enhances Neurogenesis and Oligodendrogenesis in Ischemic Brain of Middle-Aged Mouse November 2012

 

 

Viagra may one day help treat heart disease. Here’s why March 2019

The latest here.

 

Can Erectile Dysfunction Drugs Reduce Dementia Risk?

— DREAM study findings conflict with other recent data

by Judy George, Deputy Managing Editor, MedPage Today October 4, 2022

Last Updated October 5, 2022

New research failed to support the hypothesis that phosphodiesterase-5 (PDE5) inhibitors like sildenafil (Viagra) and tadalafil (Cialis) are promising drug repurposing candidates for Alzheimer's disease and dementia.

Using four analytic approaches designed to address potential biases, PDE5 inhibitors did not reduce the risk of Alzheimer's and related dementia compared with other drugs used for pulmonary arterial hypertension (PAH), showed Rishi Desai, MS, PhD, of Brigham and Women's Hospital and Harvard Medical School in Boston, and colleagues.

The findings, published in Brain Communications, are part of the ongoing NIH DREAM (Drug Repurposing for Effective Alzheimer's Medicines) initiative.

PDE5 inhibitors work by relaxing smooth muscle cells. Sildenafil and tadalafil are approved treatments for erectile dysfunction and PAH.

The new DREAM study findings conflict with a recent analysis in Nature Aging that suggested sildenafil users were 69% less likely to develop Alzheimer's disease than non-sildenafil users.

"Major differences in the design of these two investigations likely explain this inconsistency," co-author Madhav Thambisetty, MD, PhD, of the National Institute on Aging, told MedPage Today.

In the Nature Aging analysis, Feixiong Cheng, PhD, of the Cleveland Clinic Genomic Medicine Institute, and colleagues compared the risk of incident Alzheimer's disease in sildenafil users against people who used antihypertensive agents or type 2 diabetes drugs.

"This design choice is likely to result in comparison of individuals with erectile dysfunction -- which is by far the most common indication for sildenafil -- to generally older individuals with diabetes or hypertension," Thambisetty observed.

"Since worse cardiometabolic health is a well-recognized risk factor for Alzheimer's disease, and seeking treatment for erectile dysfunction is likely reflective of a certain level of preserved physical and cognitive function, we believe that results from [Cheng's group] can be at least partly explained by severe confounding by indication," he pointed out.

"We restricted our analyses to an alternative indication for PDE5 inhibitors -- PAH -- and selected an equivalent comparator drug that is used for the same indication to minimize confounding by indication," Thambisetty stated.

In rodents, sildenafil has been shown to improve memory and cognitive function, help synaptic plasticity and learning, and reduce amyloid burden. Tadalafil also has improved memory and learning and lowered amyloid in rodents. "However, results in human studies have been inconsistent," Desai and colleagues noted.

Using Medicare fee-for-service claims data from 2007 through 2018, DREAM study researchers matched 2,888 patients with PAH on PDE5 inhibitors (73.6% sildenafil, 26.4% tadalafil) with 2,888 comparable people on endothelin receptor antagonists.

Mean age of the cohort was 74, and 69% were women. Overall, 90% had hypertension, 72% had heart failure, and 43% had atrial fibrillation.

The research group used four analytic approaches to counter possible biases like informative censoring, reverse causality, and outcome misclassification:

• An as-treated follow-up approach
• An as-started follow-up approach with a 6-month induction period
• An approach that incorporated a 6-month symptoms-to-diagnosis period
• An approach using a high-specificity outcome definition of dementia

In all four analyses, PDE5 inhibitors were not associated with reduced risk for Alzheimer's and dementia. Hazard ratios were 0.99 (95% CI 0.69–1.43), 1.00 (95% CI 0.71–1.42), 0.67 (95% CI 0.43–1.06), and 1.15 (95% CI 0.57–2.34), respectively.

The researchers also tested whether sildenafil had effects on cell culture-based Alzheimer's models and found no evidence that the drug corrected molecular abnormalities associated with Alzheimer's disease.

The study may have been underpowered to detect differences of small magnitude, Desai and colleagues noted. Evaluating people with PAH allowed for unbiased comparisons of treatment effects, but this population is atypical with a high underlying cardiometabolic disease burden, they acknowledged.

Nonetheless, "electronic health records in large real-world clinical datasets are important tools to test hypotheses about plausible drug targets in Alzheimer's disease and related dementias," Thambisetty said.

Previous results from the DREAM initiative have shown that tumor necrosis factor inhibitors for rheumatoid arthritis were linked with a lower risk of Alzheimer's and dementia in people with cardiovascular disease.

• Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

The DREAM study is funded by the intramural program of the National Institute on Aging.

Desai disclosed relationships with Bayer, Vertex, and Novartis. Co-authors dislcosed relationships with Bristol-Myers Squibb, Merck, Pfizer, Lilly, Intra-Cellular Therapies, Eisai, Boehringer Ingelheim, Aetion, Roche, AbbVie, Danisco, and Med Tech Epi.

Primary Source

Brain Communications

Source Reference: Desai RJ et al "No association between initiation of phosphodiesterase-5 inhibitors and risk of incident Alzheimer's disease and related dementia: Results from the Drug Repurposing for Effe

Can Viagra Prevent Alzheimer's?

For your stroke edification, you want neurite outgrowth. And for the women:

FDA Approves 'Female Viagra' Amid Cheers and Jeers August 2015.

18 posts on Viagra here.

Impotence medicine associated with reduced long-term risk of death after heart attack March 2017 

Drugs used for impotence could treat vascular dementia?  December 2014 

This made it sound helpful, even though it was just in rats and during the first week:  viagra and stroke rehab March 2011

Sildenafil Enhances Neurogenesis and Oligodendrogenesis in Ischemic Brain of Middle-Aged Mouse November 2012

 

 

Viagra may one day help treat heart disease. Here’s why March 2019

The latest here.

Can Viagra Prevent Alzheimer's?

— Sildenafil shows potential for drug repurposing

by Judy George, Senior Staff Writer, MedPage Today December 6, 2021

Sildenafil (Viagra, Revatio) may be a candidate drug to prevent or treat Alzheimer's disease, new research suggested.

Across 6 years of follow-up, sildenafil users were 69% less likely to develop Alzheimer's disease than non-sildenafil users (HR 0.31, 95% CI 0.25-0.39, P<1 × 10^-8), a large case-control analysis of insurance claims showed.

Sildenafil also emerged as a potential disease risk modifier in an analysis of drugs that might be repurposed for Alzheimer's, reported Feixiong Cheng, PhD, of the Cleveland Clinic Genomic Medicine Institute, and co-authors.

Moreover, the phosphodiesterase 5 inhibitor, which is approved to treat erectile dysfunction and pulmonary arterial hypertension, increased neurite growth and decreased phospho-tau expression in neuron models derived from induced pluripotent stem cells, Cheng and colleagues wrote in Nature Aging.

Understanding endophenotypes may uncover common underlying mechanisms and lead to drugs that could be repurposed for diseases like Alzheimer's, the researchers noted.

"Recent studies show that the interplay between amyloid and tau is a greater contributor to Alzheimer's than either by itself," Cheng said in a statement. "Therefore, we hypothesized that drugs targeting the molecular network intersection of amyloid and tau endophenotypes should have the greatest potential for success."

The researchers integrated genetic and other data to determine which of over 1,600 FDA-approved drugs might be effective in treating Alzheimer's disease, zeroing in on drugs that targeted both amyloid and tau. As the investigators narrowed the list of candidates, they looked for drugs with ideal brain penetration, positive in vivo findings in Alzheimer's mouse models, and sufficient patient data.

"Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate," Cheng said.

The team then looked at diagnostic codes and pharmacy claims for 7.23 million people in the MarketScan Medicare Claims database from 2012 to 2017 to identify relationships between sildenafil and Alzheimer's disease in a case-control analysis.

To reduce the likelihood of confounding by indication, the researchers also evaluated four comparator drugs: losartan (Cozaar), an antihypertensive agent, metformin (Glucophage), a biguanide used to treat type 2 diabetes, diltiazem (Cartia), an antihypertensive and calcium channel blocker, and glimepiride (Amaryl), a sulfonylurea used to treat type 2 diabetes. Of the four comparators, losartan and metformin currently are in clinical trials for Alzheimer's disease.

Sildenafil showed a 55% reduced risk of Alzheimer's compared with losartan, 63% compared with metformin, 65% compared with diltiazem, and 64% compared with glimepiride, after adjusting for age, sex, race, and disease comorbidities.

Across all comparator drug groups, people with coronary artery disease, hypertension, and type 2 diabetes had reduced likelihood of Alzheimer's disease. The results remained consistent when people with these comorbidities were excluded.

The researchers further tested sildenafil in a model based on human microglia cells and neurons derived from induced pluripotent stem cells from Alzheimer's patients and found the drug increased neurite growth and decreased p-tau 181 expression.

"There is some data to date that suggests sildenafil treatment is associated with increased neurogenesis and decreased inflammation, but more research is needed," noted Claire Sexton, DPhil, of the Alzheimer's Association in Chicago, who wasn't involved with the study.

"More than ever before, Alzheimer's researchers understand that a variety of approaches will be needed -- most likely used in combination -- for effective treatment of the disease," Sexton told MedPage Today.

"Scientists are more extensively testing the potential benefits of drugs approved for other diseases for the treatment of dementia," she pointed out. "Repurposing existing drugs for new uses can speed up the research process. Since scientists are building on previous research, much is already known about the drugs' potential side effects, it may take less time for the drugs to be tested, and the clinical trials may be less expensive."

A subgroup analysis showed sildenafil was linked to a decreased risk of Alzheimer's across all comparator drugs for men, but only compared with diltiazem for women. This may be because there were not enough women to power a study for statistical significance since sildenafil is prescribed primarily to men, Cheng and co-authors noted.

The study has other limitations, the team acknowledged. Potential literature bias and data incompleteness may have influenced the network analysis. In addition, Alzheimer's disease was defined using ICD codes, which may be inaccurate.

"The association between sildenafil use and decreased incidence of Alzheimer's disease does not establish causality, which will require a randomized controlled trial," the researchers added.

• Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

This work was primarily supported by the National Institute on Aging and Translational Therapeutics Core of the Cleveland Alzheimer's Disease Research Center. It was supported in part by the Brockman Foundation, Allen Initiative in Brain Health and Cognitive Impairment, the Elizabeth Ring Mather & William Gwinn Mather Fund, S. Livingston Samuel Mather Trust, the Louis Stokes VA Medical Center and the Alzheimer's Disease Drug Discovery Foundation.

Cheng had no disclosures. One co-author disclosed relationships with Acadia, Actinogen, Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, BioXcel, Cassava, Cerecin, Cerevel, Cortexyme, Cytox, EIP Pharma, Eisai, Foresight, GemVax, Genentech, Green Valley, Grifols, Karuna, Merck, Novo Nordisk, Otsuka, Resverlogix, Roche, Samumed, Samus, Signant Health, Suven, Third Rock, United Neuroscience, ADAMAS, MedAvante, and Bioasis; other co-authors declared no competing interests.

Primary Source

Nature Aging

Source Reference: Fang J, et al "Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer's disease" Nat Aging 2021; DOI: 10.1038/s43587-021-00138-z.

 

Sildenafil Enhances Neurogenesis and Oligodendrogenesis in Ischemic Brain of Middle-Aged Mouse

Sounds good to me, get those clinical trials going. Viagra to you. Ask your doctor for a prescription - Monty Python Nudge Nudge Wink Wink

 

Sildenafil Enhances Neurogenesis and Oligodendrogenesis in Ischemic Brain of Middle-Aged Mouse

Abstract 

Adult neural stem cells give rise to neurons, oligodendrocytes and astrocytes. Aging reduces neural stem cells. Using an inducible nestin-CreER^T2/R26R-yellow fluorescent protein (YFP) mouse, we investigated the effect of Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, on nestin lineage neural stem cells and their progeny in the ischemic brain of the middle-aged mouse. We showed that focal cerebral ischemia induced nestin lineage neural stem cells in the subventricular zone (SVZ) of the lateral ventricles and nestin expressing NeuN positive neurons and adenomatous polyposis coli (APC) positive mature oligodendrocytes in the ischemic striatum and corpus callosum in the aged mouse. Treatment of the ischemic middle-aged mouse with Sildenafil increased nestin expressing neural stem cells, mature neurons, and oligodendrocytes by 33, 75, and 30%, respectively, in the ischemic brain. These data indicate that Sildenafil amplifies nestin expressing neural stem cells and their neuronal and oligodendrocyte progeny in the ischemic brain of the middle-aged mouse.