sildenafil-citrate and Brain-Injuries--Traumatic

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 ).

Topics: Biomarkers; Brain Injuries, Traumatic; Cerebrovascular Circulation; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

To investigate the acute effects of sildenafil citrate in an experimental model of severe head trauma, and to compare it with the efficacy of mannitol, which is an osmotically active agent frequently used in clinical treatment of traumatic brain injury (TBI).. Twenty-eight Wistar-derived albino strain female rats were randomized into four groups comprising seven rats each. These groups were designated as follows: Group I: sham; Group II: TBI; Group III: TBI + mannitol (20% 1 gr/ kg, intraperitoneal); and Group IV: TBI + sildenafil citrate (10 mg/kg, intraperitoneal). Sections prepared following the tissue processing of samples obtained from the right prefrontal cortex and right hippocampal regions of the brains of sacrificed rats were histopathologically evaluated. Fractionator method via the Stereo Investigator software program (Micro Bright Field) was used to count the neurons. Pyknotic neuron count and pyknotic / total neuron count were compared between the groups.. In the comparison of Group II and IV, pyknotic neuron count (prefrontal; group II: 116.00 ± 30.50, group IV: 80.00 ± 19.47) and pyknotic/ total neuron count (prefrontal; group II: 0,30 ± 0.08, group IV: 0.21 ± 0.02) were significantly lower in Group IV in both regions (p < 0.05). Similarly, in the comparison of Group II and III, the values in Group III were lower in both regions (p < 0.05).. Sildenafil citrate decreases neuronal death in the acute phase and produces similar results with mannitol. Therefore, we believe that sildenafil citrate can be a useful adjunct or alternative agent for the clinical treatment of patients with acute TBI.

Topics: Animals; Brain; Brain Injuries, Traumatic; Cell Death; Disease Models, Animal; Female; Mannitol; Neurons; Neuroprotective Agents; Phosphodiesterase 5 Inhibitors; Rats; Rats, Wistar; Sildenafil Citrate

Sexual dysfunction is common after traumatic brain injury (TBI) but evaluation of treatment interventions have been sparse.. To report on the treatment of sexual dysfunction for two males with severe TBI.. Case one was treated for erectile dysfunction (ED). After a medical examination which found no underlying physiological problems, Sildenafil was prescribed. Scores on the Golombok Rust Inventory of Sexual Satisfaction Impotence subscale found that scores had improved from the dysfunction range at baseline to the functional range at 6 weeks follow-up. There was some reduction in this improvement at 3 months follow-up, maybe associated with a co-morbid deterioration of emotional state. Case two was treated for idiopathic delayed ejaculation (DE). A standard sex therapy intervention was employed that resulted in the resolution of the problem, documented on the Sex Behavior sub-scale of the Derogatis Inventory for Sexual Functioning-Self Report (comparing baseline to post intervention and follow-up scores).. The case reports show promise for the treatment of sexual dysfunction after severe TBI using standard medical and sex therapy treatments. In the future, controlled evaluations are required to demonstrate the efficacy of such interventions.

Topics: Adult; Behavior Therapy; Brain Injuries, Traumatic; Erectile Dysfunction; Humans; Male; Middle Aged; Sexual Dysfunction, Physiological; Sildenafil Citrate; Urological Agents; Young Adult