Phosphodiesterase-5 (PDE-5) Inhibitors as Therapy for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury

被引:2
|
作者
Kalyani, Priyanka [1 ]
Lippa, Sara M. [2 ,3 ]
Werner, J. Kent [2 ,3 ]
Amyot, Franck [2 ]
Moore, Carol B. [3 ]
Kenney, Kimbra [3 ]
Diaz-Arrastia, Ramon [1 ]
机构
[1] Univ Penn, Dept Neurol, 3400 Spruce St, Philadelphia, PA 19104 USA
[2] Walter Reed Natl Mil Med Ctr, Natl Intrepid Ctr Excellence, Palmer Rd S, Bethesda, MD 20814 USA
[3] Uniformed Serv Univ Hlth Sci, Dept Neurosci, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA
关键词
Cerebrovascular reactivity; Dose-finding study; Hypercapnia; MRI-BOLD; Sildenafil citrate;
D O I
10.1007/s13311-023-01430-z
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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).
引用
收藏
页码:1629 / 1640
页数:12
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