Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species.

Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer's disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors.

Objective: To determine whether the high potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans.

A Randomized, Double-Blind, Placebo- and Active-Controlled, Escalating Single-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Subcutaneous Eflapegrastim in Healthy Japanese and Caucasian Subjects.

Background: Eflapegrastim (Rolontis) is a novel long-acting pegylated recombinant human granulocyte colony-stimulating factor (G-CSF). Eflapegrastim has been developed to reduce the duration and incidence of chemotherapy-induced neutropenia in cancer patients using patient-friendly, less-frequent administration.

Objective: This phase I study aimed to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity of eflapegrastim following a single subcutaneous administration to healthy Japanese and Caucasian subjects.

A first-in-human study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of KM-819 (FAS-associated factor 1 inhibitor), a drug for Parkinson's disease, in healthy volunteers.

Background: KM-819 is a novel FAS-associated factor 1 (FAF1) inhibitor, and a neuroprotective agent, under clinical development for the treatment of Parkinson's disease as a disease-modifying drug.

Methods: This first-in-human, single and multiple ascending dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of KM-819 in healthy volunteers. Additionally, the effect of age on safety and pharmacokinetics were assessed.

Evaluation of the single-dose pharmacokinetics and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.

Purpose: This double-blind, placebo-controlled, intra-subject, dose-escalation study assessed single-dose safety, pharmacokinetics, and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.

Subjects And Methods: Sixteen healthy male Japanese and sixteen healthy male Caucasian subjects, matched for age, weight, and smoking status were randomized to receive four sequential single oral doses of either apixaban (2.5, 10, 25, and 50 mg) or matched placebo.

The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients.

β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that 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 (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys.

Effects of the glycine reuptake inhibitors bitopertin and RG7118 on glycine in cerebrospinal fluid: results of two proofs of mechanism studies in healthy volunteers.

Rationale: Hypofunction of NMDA receptors has been implicated in neuropsychiatric disorders including schizophrenia. NMDA receptor neurotransmission can be enhanced through inhibition of glycine reuptake by the glycine transporter type 1 (GlyT1).

Objectives: The primary objective of these studies was to explore the relationship between plasma exposure and glycine cerebrospinal fluid (CSF) concentrations following administration of bitopertin and RG7118 in healthy volunteers.

The effect of LCZ696 (sacubitril/valsartan) on amyloid-β concentrations in cerebrospinal fluid in healthy subjects.

Aims: LCZ696 (angiotensin receptor neprilysin inhibitor) is a novel drug developed for the treatment of heart failure with reduced ejection fraction. Neprilysin is one of multiple enzymes degrading amyloid-β (Aβ). Its inhibition may increase Aβ levels.

The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans.

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD.

Pharmacokinetic Profile of Orally Administered Scyllo-Inositol (Elnd005) in Plasma, Cerebrospinal Fluid and Brain, and Corresponding Effect on Amyloid-Beta in Healthy Subjects.

ELND005 (scyllo-inositol), an endogenous inositol stereoisomer, is being investigated as an oral treatment for Alzheimer's disease (AD). Pharmacokinetics of ELND005 in plasma, cerebrospinal fluid (CSF), and brain was characterized in healthy young subjects. Eight men received 2000 mg ELND005 every 12 hours for 10 days.

Clinically significant psychotropic drug-drug interactions in the primary care setting.

In recent years, the growing numbers of patients seeking care for a wide range of psychiatric illnesses in the primary care setting has resulted in an increase in the number of psychotropic medications prescribed. Along with the increased utilization of psychotropic medications, considerable variability is noted in the prescribing patterns of primary care providers and psychiatrists. Because psychiatric patients also suffer from a number of additional medical comorbidities, the increased utilization of psychotropic medications presents an elevated risk of clinically significant drug interactions in these patients.

Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor.

According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD.

Effect of human cerebrospinal fluid sampling frequency on amyloid-β levels.

Background: β-amyloid peptide (Aβ) is associated with neurodegeneration in Alzheimer's disease. Emerging evidence indicates that Aβ levels in cerebrospinal fluid (CSF) may serve as an early clinical biomarker for evaluating pharmacological activity of new drug candidates targeting Aβ production or Aβ clearance. Therefore, it is critical to understand whether intrasubject levels of CSF Aβ are consistent between sampling intervals to determine whether Aβ can be used as a pharmacodynamic biomarker for drug candidates.

Cerebrospinal fluid beta-amyloid and dynabridging in Alzheimer's disease drug development.

Cerebrospinal fluid (CSF) has become a matrix for biomarker discovery and development in recent years. A number of biomarkers for pathogenic processes in Alzheimer's disease have been identified. Studies have revealed the diagnostic potential of CSF amyloid-beta, tau and phosphorylated tau levels.

Identifying pharmacodynamic protein markers of centrally active drugs in humans: a pilot study in a novel clinical model.

Recognizing specific protein changes in response to drug administration in humans has the potential for significant utility in clinical research. In spite of this, many methodological and practical questions related to assessing such changes are unanswered. We conducted a series of clinical studies to assess the feasibility of measuring changes in proteins related to drug administration using a mass-spectrometry proteomics technique capable of quantifying hundreds of proteins simultaneously in cerebrospinal fluid (CSF) and plasma.

Antidepressant drug-drug interaction profile update.

Drug-drug interactions continue to be underappreciated and misunderstood by most clinicians. Although life-threatening drug interactions are rare, serious clinical consequences, including altered drug response, poor tolerability with reduced medication adherence, and increased costs for care tied to the increased complexity of therapy, are fairly commonplace. Drug interactions may be further complicated by genetic differences in metabolic capacity.

Delayed onset of oculogyric crisis and torticollis with intramuscular haloperidol.

Objective: To report a case of delayed-onset dystonic reactions, oculogyric crisis (OGC), and torticollis after treatment with intramuscular haloperidol lactate injection.

Case Summary: A 22-year-old Mexican American woman received intramuscular haloperidol lactate 7.5 mg followed 4 hours later by 10 mg.

Estimation of the absolute bioavailability of rivastigmine in patients with mild to moderate dementia of the Alzheimer's type.

Objective: To investigate the bioavailability of rivastigmine, an approved therapy for patients with mild to moderate dementia of the Alzheimer's type, at the highest approved single dose of 6 mg.

Design And Setting: Randomised, two-period crossover, single-centre, non-blinded, inpatient study.

Patients And Participants: Eleven patients (five females and six males) with mean age 69.

Brasofensine treatment for Parkinson's disease in combination with levodopa/carbidopa.

Objective: To investigate the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the dopamine transporter antagonist brasofensine (BMS-204756) in patients with Parkinson's disease receiving levodopa/carbidopa treatment.

Methods: A 4-period crossover study was performed in 8 men (mean age 66 y) with moderate Parkinson's disease (Hoehn-Yahr stage II-IV). A dose escalation study was used in which each patient was given a single oral dose of brasofensine 0.