Thanks for your feedback, this will help us improve our content for you!
AAIC 2022 | PASTIS: investigating the impact of tadalafil on cerebral blood flow in small vessel disease
Atticus Hainsworth, St George’s University of London, London, UK, discusses the PASTIS trial (NCT02450253) – a double-blind, placebo-controlled, cross-over trial investigating tadalafil, a PDE5 inhibitor, as a potential therapeutic in small vessel disease. As small vessel disease is the main cause of vascular cognitive impairment in older adults, it was hoped the widely used vasodilator would impact cerebral blood flow (CBF). In total, 65 older people were recruited and administered one dose of tadalafil (20mg) or placebo on two visits, 7 days apart (randomized to order of treatment). The primary endpoint of the trial was a change in subcortical CBF. Dr Hainsworth explains that the observed treatment effects were not statistically significant. To detect treatment effects may require different dosing regimens. He suggests if they were to carry out the trial again to focus only on those aged 65 years and above, as the strongest indication of treatment effect was seen in this population. This interview took place at the Alzheimer’s Association International Conference (AAIC) 2022 in San Diego, CA.
Transcript (edited for clarity)
The PASTIS trial was a repurposing trial. It took an existing medication called tadalafil, that’s a PDE5 inhibitor, it’s widely used for erectile dysfunction mostly in men, in some women as well. Its mechanism is it’s a vasodilator, it increases blood flow. So our hypothesis was that it might increase brain blood flow. And so we recruited people who’d had a small stroke, who we knew had brain microvascular disease, what we call cerebral small vessel disease...
The PASTIS trial was a repurposing trial. It took an existing medication called tadalafil, that’s a PDE5 inhibitor, it’s widely used for erectile dysfunction mostly in men, in some women as well. Its mechanism is it’s a vasodilator, it increases blood flow. So our hypothesis was that it might increase brain blood flow. And so we recruited people who’d had a small stroke, who we knew had brain microvascular disease, what we call cerebral small vessel disease. And we picked those because that’s the disease process that we think leads to vascular cognitive impairment and contributes to dementia.
So we recruited 65 older people all through our one center in St. George’s Hospital and gave them one administration of the drug, of tadalafil, and compared that with placebo. The bottom line is it didn’t increase blood flow. It was a slight surprise. As I reported at the conference, it suggested that the brain’s regulation of its blood supply remained good, even in older people with small vessel disease. We had a hint that has encouraged us to think further about this. If we partition the age of the participants, if we look just at those over 65, there was an indication that there might have been a treatment effect. In other words, the tadalafil gave a hint of a small increase in blood flow, but that wasn’t a significant change, we weren’t powered to detect it. If we were doing it again, I think we’d do it slightly differently, and we’d focus on people over the age of 65. So that’s what I presented, it went over quite well, got a lot of good questions and some ideas for further work, further thoughts, how we might go forward. So that was great.
One of the really interesting takeaways I got from the AAIC in San Diego was a presentation by my friend and collaborator, Ottavio Arancio, who is based at Columbia University in New York. And he’s worked on PDE5 inhibitors for a long time, primarily in rodent models. And his data made me realize, I should have realized this a long time ago, that blood vessels aren’t the only things that have PDE5. PDE5 is in nerve cells as well. And if we were getting the brain concentrations of the tadalafil that we think we were, it’s very likely they would’ve inhibited the neuronal PDE5 enzyme as well.
Now, Ottavio’s data shows that – this is all in mice – if you chronically treat mice with the drug, with drugs like this, he used sildenafil and another agent that he’s invented himself, if you treat the mice for three weeks, it actually performs better on the sort of rudimentary cognitive tests that one can do on a mouse. Things like the Morris water maze, like a condition test where they’ve learned something and they remember it better if they’re on the drug. So that made me think, Well, we only tested one administration, one day, measuring three hours later. Is it possible if we gave the drug for longer, a few weeks or a few months, might we pick up a neuronal signal? Something that would suggest there was a benefit due to inhibiting that neuronal PDE5. I hasten to say that a mouse in a Morris water maze is not a human, is not a dementia situation, I’m not making that direct leap at all, but I came away from the conference thinking, I should think a bit more about that and how that potentially might help us to redesign a follow-up study with tadalafil.
AH Hainsworth has received honoraria from Eli-Lilly and NIA. He leads the MRC-Dementias-Platform UK Vascular Experimental Medicine group.