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Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor
TLDR
The magnitude and duration of central Aβ reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.
The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients
TLDR
Verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ after acute and chronic administration to rats and monkeys.
Pharmacokinetics and Pharmacodynamics of the Novel Daily Rivastigmine Transdermal Patch Compared With Twice‐daily Capsules in Alzheimer's Disease Patients
TLDR
Plasma butyrylcholinesterase inhibition rose slowly after patch administration, whereas two distinct peaks were seen after capsule administration, and average exposure with the 10 cm2 patch was comparable to the highest capsule dose.
The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Aβ Pharmacodynamic Responses in Mice, Dogs, and Humans
TLDR
Nonclinical and early clinical development of LY2886721 is reported, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD and has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models.
The effect of LCZ696 (sacubitril/valsartan) on amyloid‐β concentrations in cerebrospinal fluid in healthy subjects
TLDR
LCZ696 did not cause changes in CSF levels of aggregable Aβ isoforms (1–42 and 1–40) compared with placebo, despite achieving CSF concentrations of LBQ657 sufficient to inhibit neprilysin.
Effects of the glycine reuptake inhibitors bitopertin and RG7118 on glycine in cerebrospinal fluid: results of two proofs of mechanism studies in healthy volunteers
TLDR
The mechanism of action of bitopertin and RG7118, i.e. inhibition of glycine reuptake in the brain, was confirmed and the maximal increase observed in healthy volunteers was similar to the one observed in animals showing the good translatability of this biomarker.
Dose‐dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer's disease
TLDR
Rapid, sustained, dose‐dependent inhibition of CSF AChE suggests that SDZ ENA 713 has therapeutic potential in AD patients.
Low Penetration of Oseltamivir and Its Carboxylate into Cerebrospinal Fluid in Healthy Japanese and Caucasian Volunteers
TLDR
Emerging data support the idea that oseltamivir and OC have limited potential to induce or exacerbate CNS adverse events in individuals with influenza and demonstrate that the CNS penetration of oselTamivIR and OC is low in Japanese and Caucasian adults.
Pharmacokinetics and Pharmacodynamics of the Triptan Antimigraine Agents
TLDR
The pharmacological properties of the triptans (time to peak plasma concentration, half-life, bioavailability and receptor binding) are reviewed and related to efficacy and time of onset and the effects of concomitant medication, food, age and disease are considered.
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