Article ; Online: Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
2023 Volume 20, Issue 6, Page(s) 1629–1640
Abstract: Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in experimental models. The heterogeneity of TBI, in terms of pathomechanisms and impacted brain ... ...
Abstract | Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in experimental models. The heterogeneity of TBI, in terms of pathomechanisms and impacted brain structures, likely contributes to these failures. Biomarkers have been recommended to identify patients with relevant pathology (predictive biomarkers) and confirm target engagement and monitor therapy response (pharmacodynamic biomarkers). Our group focuses on traumatic cerebrovascular injury as an understudied endophenotype of TBI and is validating a predictive and pharmacodynamic imaging biomarker (cerebrovascular reactivity; CVR) in moderate-severe TBI. We aim to extend these studies to milder forms of TBI to determine the optimal dose of sildenafil for maximal improvement in CVR. We will conduct a phase II dose-finding study involving 160 chronic TBI patients (mostly mild) using three doses of sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor. The study measures baseline CVR and evaluates the effect of escalating sildenafil doses on CVR improvement. A 4-week trial of thrice daily sildenafil will assess safety, tolerability, and clinical efficacy. This dual-site 4-year study, funded by the Department of Defense and registered in ClinicalTrials.gov (NCT05782244), plans to launch in June 2023. Biomarker-informed RCTs are essential for developing effective TBI interventions, relying on an understanding of underlying pathomechanisms. Traumatic microvascular injury (TMVI) is an attractive mechanism which can be targeted by vaso-active drugs such as PDE-5 inhibitors. CVR is a potential predictive and pharmacodynamic biomarker for targeted interventions aimed at TMVI. (Trial registration: NCT05782244, ClinicalTrials.gov ). |
---|---|
MeSH term(s) | Humans ; Phosphodiesterase 5 Inhibitors/therapeutic use ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Sildenafil Citrate/therapeutic use ; Cerebrovascular Circulation/physiology ; Brain Injuries, Traumatic/complications ; Brain Injuries, Traumatic/drug therapy ; Brain Injuries, Traumatic/pathology ; Biomarkers |
Chemical Substances | Phosphodiesterase 5 Inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 5 (EC 3.1.4.35) ; Sildenafil Citrate (BW9B0ZE037) ; Biomarkers |
Language | English |
Publishing date | 2023-09-11 |
Publishing country | United States |
Document type | Journal Article ; Review |
ZDB-ID | 2316693-9 |
ISSN | 1878-7479 ; 1933-7213 |
ISSN (online) | 1878-7479 |
ISSN | 1933-7213 |
DOI | 10.1007/s13311-023-01430-z |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
Full text online
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
Zs.A 6156: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.