A pilot study to explore the effect of udenafil on cerebral hemodynamics in older adults

Abstract

Objective Phosphodiesterase‐5 inhibitors (PDE5Is) enhance vasodilation. We investigated the effects of PDE5I on cerebral hemodynamics during cognitive tasks using functional near‐infrared spectroscopy (fNIRS). Methods This study used a crossover design. Twelve cognitively healthy men participants (mean age, 59 ± 3 years; range, 55–65 years) were recruited and randomly assigned to the experimental or control arm, then the experimental and control arm were exchanged after 1 week. Udenafil 100 mg was administered to participants in the experimental arm once daily for 3 days. We measured the fNIRS signal during the resting state and four cognitive tasks three times for each participant: at baseline, in the experimental arm, and in the control arm. Results Behavioral data did not show a significant difference between the experimental and control arms. The fNIRS signal showed significant decreases in the experimental arm compared to the control arm during several cognitive tests: verbal fluency test (left dorsolateral prefrontal cortex, T = −3.02, p = 0.014; left frontopolar cortex, T = −4.37, p = 0.002; right dorsolateral prefrontal cortex, T = −2.59, p = 0.027), Korean‐color word Stroop test (left orbitofrontal cortex, T = −3.61, p = 0.009), and social event memory test (left dorsolateral prefrontal cortex, T = −2.35, p = 0.043; left frontopolar cortex, T = −3.35, p = 0.01). Interpretation Our results showed a paradoxical effect of udenafil on cerebral hemodynamics in older adults. This contradicts our hypothesis, but it suggests that fNIRS is sensitive to changes in cerebral hemodynamics in response to PDE5Is.

Genetically proxied PDE5 inhibition and risk of dementia: a drug target Mendelian randomisation study

“…This may have been brought to light by the MR study design, which estimates a lifetime risk due to inherited differences in PDE5 inhibition compared to shorter-term use following diagnosis of ED or PAH. How relevant this is to pharmacological PDE5 inhibition compared its genetic proxy requires further investigation, but the aforementioned RCT showing negative effects on verbal fluency, memory tests, and prefrontal cortex activation suggests validity to the concerns highlighted in this study (38).…”

“…However, the PASTIS randomised controlled trial (RCT) did not show a difference in cerebral blood flow with taldafil compared to placebo in older people with symptomatic small vessel disease, a patient population at high risk for the development of VaD (37). Similarly, another RCT found that PDE5 inhibition had no positive effect on behavioural outcomes, along with negative effects on cerebral haemodynamics (38). Sustained PDE5 inhibition may counterintuitively reduce cAMP levels due to activation of PDE2 from chronically increased cGMP concentration, resulting in the harmful effects seen in those with genetic variants mimicking PDE5 inhibition (39).…”