Pharmacokinetic investigation of sildenafil using positron emission tomography and determination of its effect on cerebrospinal fluid cGMP levels

Abstract

Sildenafil (Viagra) is a selective inhibitor of phosphodiesterase type 5 (PDE5), which degrades cyclic guanosine monophosphate to the linear nucleotide. Sildenafil is acutely used in erectile dysfunction and chronically in pulmonary hypertension. Evidence in the last decade shows that sildenafil may have potential as a therapeutic option for Alzheimer's disease or other neurodegenerative disorders. The purpose of this work was to explore whether sildenafil crosses the blood-brain barrier. Pharmacokinetic properties of sildenafil in rodents were investigated using 11 C-radiolabeling followed by in vivo positron emission tomography (PET) and ex vivo tissue dissection and gamma counting. PET results in rats suggest penetration into the central nervous system. Ex vivo data in perfused animals suggest that trapping of [ 11 C]sildenafil within the cerebral vascular endothelium limits accumulation in the

Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

“…In animal studies sildenafil is reported to pass the blood-brain barrier [51], though similar is not clearly evident in humans [52]. Muscle biopsies from the patients showed reduced nNOS protein expression and a corresponding reduction in PDE5 expression [23], which could cause the patients to be less sensitive to PDE5 inhibitors.…”

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

“…The synergistic effect should lead to achieve a degree of histone 3 acetylation that is not possible with HDAC6-selective inhibitors (eg, Ricolinostat) and, on the other hand, these new molecules will also achieve a degree of tubulin acetylation that has been impossible to obtain with the FDA-approved class I inhibitor, valproic acid (Gurvich et al, 2004). Moreover, the compounds proposed will have better brain permeability than the FDA-approved HDAC (Kazantsev and Thompson, 2008) and PDE5 inhibitors (eg, Sildenafil and Tadalafil, with a logBBo0) (Garcia-Barroso et al, 2013;Gomez-Vallejo et al, 2016).…”

A business of some heat: molecular imaging of phosphodiesterase 5

“…Gómez‐Vallejo et al . () cite several studies showing neuroprotective effects of PDE5 inhibition in brain injury and neurotoxicity models. Furthermore, PDE5 inhibition moderates cognitive decline in mouse models of Alzheimer′s disease.…”

“…This latter, procognitive, aspect of PDE5 is the motivation for the PET study by Gómez‐Vallejo et al . (), who proved a central action of sildenafil through increases in the cGMP content of cerebrospinal fluid from non‐human primates, measured using a very sensitive assay. However, their rat PET studies showed rather low cerebral uptake of [ 11 C]sildenafil (< 0.1% ID/g), and no evidence for displaceable binding in brain parenchyma (as distinct from the cerebrovascular lumen, which had some specific binding).…”

“…We hope that the report by Gómez‐Vallejo et al . () will inspire further quantitative PET studies of PDE5 and other elements of intracellular messaging pathways, bearing in mind the need for prior knowledge of the absolute concentration of the molecular target in tissue. Looking deeper than the membrane may bring new types of knowledge about the pathophysiology of psychiatric and neurological disorders, perhaps indiscernible to conventional molecular imaging studies of plasma membrane receptors and transporters.…”