The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment

 Since post stroke we need lots of CBF(cerebral blood flow) along with extra oxygen delivery by our red blood cells. That should mean our stroke leadership should initiate research into both immediately. But without survivors in charge nothing will be done and your children and grandchildren will be screwed when they have strokes.

The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment

 

Mathilde M.H. Pauls, Lauren R. Binnie, Philip Benjamin, Shai Betteridge, Brian Clarke, Mohani-Preet K. Dhillon, Rita Ghatala, Fearghal A.H. Hainsworth … See all authors

First published: 08 February 2022

https://doi.org/10.1002/alz.12559

Clinical Trial Registration: . http://www.clinicaltrials.gov. Unique identifier: NCT02450253. https://eudract.ema.europa.eu. Unique identifier: 2015-001235-20.

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Abstract

Introduction

There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI.

Methods

In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling.

Results

Tadalafil increased CBF non-significantly in all subcortical areas(but maybe it will for stroke patients) (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (–7.8, –4.9 mmHg; P < .001). No serious adverse events were observed.

Discussion

This trial did not identify a significant treatment effect of single-administration tadalafil(will multiple administrations work better?) on subcortical CBF. To detect treatment effects may require different dosing regimens.

1 BACKGROUND

Small vessel disease (SVD) is a common cause of lacunar stroke and vascular contributions to cognitive impairment and dementia.^{1, 2} SVD is common in older people, seen on brain magnetic resonance imaging (MRI) as diffuse white matter hyperintensities (WMH), focal ischemic lesions, and micro-hemorrhages.² SVD is associated with reduced cerebral blood flow (CBF) particularly in subcortical areas, including deep grey nuclei, subcortical white matter, and within WMH.^3-7 There is currently no disease-modifying therapy for SVD.^{2, 8}

CBF is regulated by multiple factors, including nitric oxide (NO). Tonic endothelial NO activates guanylyl cyclase in overlying vascular myocytes, to drive cyclic guanosine monophosphate (cGMP) formation, leading to myocyte relaxation and vasodilation. Cytoplasmic cGMP is degraded by phosphodiesterase enzymes, in particular PDE5. Potent, selective PDE5 inhibitors (PDE5i) such as sildenafil (Viagra) and tadalafil (Cialis) are in routine use as vasodilators in erectile dysfunction and pulmonary arterial hypertension. PDE5i augment blood flow in peripheral tissues and are well tolerated across dosing regimens.^{9, 10} This study addressed the hypothesis that PDE5i increase CBF in older people, particularly in the subcortical regions affected by SVD.¹¹

PDE5 is present in human brain neurons¹² and in vascular myocytes within subcortical white matter.¹³ Among PDE5i, tadalafil has a relatively long plasma half-life (16 hours in healthy adults)^{14, 15} with evidence of brain penetration in rodents and primates.^{16, 17} Tadalafil is well tolerated and has been widely prescribed worldwide.^{9, 10, 14, 15} This article presents primary outcomes from a clinical trial with cross-over design^{8, 18} to determine whether a single administration of tadalafil increases subcortical CBF.

Drugs used for impotence could treat vascular dementia?

Would this be useful post-stroke to increase blood flow to the brain?  Or maybe to prevent your 33% chance of getting dementia post-stroke? Do not do this on your own without your doctors knowledge.
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Drugs used for impotence could treat vascular dementia?
Scientists are to explore whether drugs usually used to treat erectile problems by expanding blood vessels could become the next major way to tackle the dementia epidemic.
Experts led by Dr Atticus Hainsworth at St George’s, University of London, will explore whether tadalafil, which is a drug in the same class as Viagra, could help prevent vascular dementia by increasing blood flow to the brain.
Vascular dementia is the second most common form of dementia and accounts for around 110,000 cases of dementia in the UK.
Vascular dementia is often caused by damage to the small blood vessels of the brain leading to reduced blood flow to brain tissue. This blood vessel damage- known as small vessel disease- is seen in the brains of 50-70% of elderly people. The researchers hope that tadalafil’s blood-flow boosting properties can prevent the damage that leads to vascular dementia.
A major trans-Atlantic research partnership is to be launched to investigate this potential treatment, funded by the Alzheimer’s Society and the Alzheimer’s Drug Discovery Foundation.
Dr Atticus Hainsworth, the lead researcher, said: “The drug tadalafil is widely used to increase blood flow in penile tissue. Now we’re asking whether it can do the same for another vital organ, the brain.
“As there are very few drugs for the management of dementia, we want to know whether a well-known, well-tolerated drug can be used to help patients with this particular type of dementia.
 “My colleagues and I are very enthusiastic about this trans-Atlantic initiative.”
This new charity partnership is announced a year after the first G8 summit on dementia called for increased investment and global collaboration in dementia research in order to find a disease-modifying treatment by 2025. The research is part of a number of projects which have been announced by the Alzheimer’s Society.
Dr Doug Brown, Director of Research and Development at Alzheimer’s Society said: “Drug development can take decades and sadly, the path towards developing dementia treatments over the past decade is littered with drugs that have failed in clinical trials. As we learn more about the causes of dementia and its links to other conditions, there is hope that treatments we routinely use for other diseases may also work for people with dementia.
“These incredibly exciting studies could see existing treatments turned into drugs for the most common forms of dementia in a fraction of the time and at a fraction of the cost of developing new drugs from scratch. By next year 850,000 people in the UK will have dementia and we owe it to them to do everything we can to develop better treatments and ultimately a cure. Research like this is a huge part of that goal.”