OBJECTIVE:Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE) inhibitors are hypothesized to improve cognition in schizophrenia and Alzheimer disease by increasing cGMP levels in certain brain regions. This phase I, randomized, parallel-group, double-blind, placebo-controlled study provides proof-of-mechanism evidence for BI 409306, a novel, oral PDE9A inhibitor. METHODS: In healthy males, exposure of BI 409306 (25-, 50-, 100-, and 200-mg single dose) and placebo was assessed in plasma and cerebrospinal fluid (CSF). Effect of BI 409306 on CSF cGMP levels was evaluated, and adverse events (AEs) were monitored. RESULTS: In all enrolled subjects (N = 20), plasma BI 409306 concentration increased rapidly (median tmax : 0.75-1.25 hr) followed by rapid increases in CSF (median tmax : 1.5-2.0 hr). Maximum CSF cGMP concentrations were achieved within 2 to 5 hr, declining to baseline levels 10 to 14 hr after dosing. Dose-dependent increases in plasma and CSF exposure and CSF cGMP were shown. BI 409306 was safe and well tolerated. Most AEs were mild to moderate in intensity and study procedure-related. CONCLUSIONS:BI 409306 increased rapidly in plasma and was subsequently detected in CSF, resulting in dose-dependent increases in cGMP levels in CSF. Results indicate BI 409306 efficiently crosses the blood-CSF barrier, with an acceptable level of AEs.
RCT Entities:
OBJECTIVE:Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE) inhibitors are hypothesized to improve cognition in schizophrenia and Alzheimer disease by increasing cGMP levels in certain brain regions. This phase I, randomized, parallel-group, double-blind, placebo-controlled study provides proof-of-mechanism evidence for BI 409306, a novel, oral PDE9A inhibitor. METHODS: In healthy males, exposure of BI 409306 (25-, 50-, 100-, and 200-mg single dose) and placebo was assessed in plasma and cerebrospinal fluid (CSF). Effect of BI 409306 on CSF cGMP levels was evaluated, and adverse events (AEs) were monitored. RESULTS: In all enrolled subjects (N = 20), plasma BI 409306 concentration increased rapidly (median tmax : 0.75-1.25 hr) followed by rapid increases in CSF (median tmax : 1.5-2.0 hr). Maximum CSF cGMP concentrations were achieved within 2 to 5 hr, declining to baseline levels 10 to 14 hr after dosing. Dose-dependent increases in plasma and CSF exposure and CSF cGMP were shown. BI 409306 was safe and well tolerated. Most AEs were mild to moderate in intensity and study procedure-related. CONCLUSIONS:BI 409306 increased rapidly in plasma and was subsequently detected in CSF, resulting in dose-dependent increases in cGMP levels in CSF. Results indicate BI 409306 efficiently crosses the blood-CSF barrier, with an acceptable level of AEs.
Authors: Neema S Patel; Jennifer Klett; Katy Pilarzyk; Dong Ik Lee; David Kass; Frank S Menniti; Michy P Kelly Journal: Neurobiol Aging Date: 2018-02-05 Impact factor: 4.673
Authors: Ryan P Ceddia; Dianxin Liu; Fubiao Shi; Mark K Crowder; Sumita Mishra; David A Kass; Sheila Collins Journal: Diabetes Date: 2021-10-07 Impact factor: 9.461
Authors: Susana S Correia; Rajesh R Iyengar; Peter Germano; Kim Tang; Sylvie G Bernier; Chad D Schwartzkopf; Jenny Tobin; Thomas W-H Lee; Guang Liu; Sarah Jacobson; Andrew Carvalho; Glen R Rennie; Joon Jung; Paul A Renhowe; Elisabeth Lonie; Christopher J Winrow; John R Hadcock; Juli E Jones; Mark G Currie Journal: Front Pharmacol Date: 2021-05-24 Impact factor: 5.810
Authors: David Brown; Kazuyuki Nakagome; Joachim Cordes; Ronald Brenner; Gerhard Gründer; Richard S E Keefe; Robert Riesenberg; David P Walling; Kristen Daniels; Lara Wang; Jennifer McGinniss; Michael Sand Journal: Schizophr Bull Date: 2019-03-07 Impact factor: 9.306