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
相关论文
共 50 条
  • [11] Determination of Phosphodiesterase Type-5 Inhibitors (PDE-5) in Dietary Supplements
    Gheorghiu, Oana Ramona Catalina
    Ciobanu, Anne Marie
    Gutu, Claudia Maria
    Chitescu, Carmen Lidia
    Costea, Giorgiana Valentina
    Anghel, Daniela Madalina
    Vlasceanu, Ana Maria
    Baconi, Daniela Luiza
    MOLECULES, 2023, 28 (10):
  • [12] Phosphodiesterase type 5 (PDE-5) inhibitors in controlling symptomatic esophageal hypercontractility
    Agrawal, A
    Hila, A
    Tatuian, R
    Mainie, I
    Freeman, J
    Castell, DO
    AMERICAN JOURNAL OF GASTROENTEROLOGY, 2004, 99 (10): : S19 - S19
  • [13] EFFICACY OF PDE-5 INHIBITORS IN ERECTILE DYSFUNCTION AFTER SPINAL CORD INJURY
    Konstantinidis, C.
    Kratiras, Z.
    Alexandros, T.
    Panagiotis, K.
    Thomas, C.
    Konstantinos, S.
    JOURNAL OF SEXUAL MEDICINE, 2016, 13 (05): : S145 - S145
  • [14] Safety and efficacy of phosphodiesterase-5 (PDE-5) inhibitors in fetal growth restriction: a systematic literature review and meta-analysis
    Liu, Ying
    Un, Ella Man-Wai
    Bai, Ying
    Chan, Man Keong
    Zeng, Luo Xin
    Lei, Sut Leng
    Li, Junjun
    Ung, Carolina Oi Lam
    JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, 2024, 27
  • [15] Conversion of phosphodiesterase-5 (PDE5) catalytic site to higher affinity by PDE5 inhibitors
    Blount, Mitsi A.
    Zoraghi, Roya
    Bessay, Emmanuel P.
    Beasley, Alfreda
    Francis, Sharron H.
    Corbin, Jackie D.
    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2007, 323 (02): : 730 - 737
  • [16] Cardiovascular localization of phosphodiesterase type 5 (PDE-5)
    Parums, DV
    Charlton, RG
    Ridden, J
    Cindrova, T
    Johnson, N
    Burslem, F
    Phillips, S
    JOURNAL OF PATHOLOGY, 2001, 193 : 38A - 38A
  • [17] Effect of Phosphodiesterase-5 (PDE-5) Inhibitors on Clinical Outcomes in Patients With Pulmonary Hypertension: A Meta-Analysis of Randomized Control Trials
    Karedath, Jithin
    Dar, Hassaan
    Ganipineni, Vijay Durga Pradeep
    Gorle, Sri Anjali
    Gaddipati, Sarvani
    Bseiso, Anan
    Pizzorno, Guiomarly
    Shaik, Tanveer Ahamad
    CUREUS JOURNAL OF MEDICAL SCIENCE, 2023, 15 (01)
  • [18] The clinical pharmacokinetics of phosphodiesterase-5 inhibitors for erectile dysfunction
    Gupta, M
    Kovar, A
    Meibohm, B
    JOURNAL OF CLINICAL PHARMACOLOGY, 2005, 45 (09): : 987 - 1003
  • [19] Clinical evaluation of erectile dysfunction in the era of PDE-5 inhibitors
    Lobo, JR
    Nehra, A
    UROLOGIC CLINICS OF NORTH AMERICA, 2005, 32 (04) : 447 - +
  • [20] An update on the PDE-5 inhibitors (PDE-5i)
    McCullough, AR
    JOURNAL OF ANDROLOGY, 2003, 24 (06): : S52 - S58