Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia.

Schizophrenia is a psychiatric disorder characterised by symptoms in three domains: positive (e.g. delusions, hallucinations), negative (e.

Efficacy and safety of the novel GlyT1 inhibitor BI 425809 in Alzheimer's dementia: a randomized controlled trial.

Background: This phase II proof-of-concept study assessed the efficacy and safety of BI 425809, a novel selective glycine transporter-1 inhibitor, for the treatment of cognitive impairment associated with probable Alzheimer's disease dementia.

Methods: This 12-week, multicenter, double-blind, placebo-controlled, parallel-group study randomized (1:1:1:1:1) patients with mild-to-moderate probable Alzheimer's disease dementia to BI 425809 2, 5, 10, and 25 mg or placebo once daily. The primary efficacy endpoint was the change from baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11-item total score after 12 weeks of treatment.

Pharmacokinetic-Interactions of BI 425809, a Novel Glycine Transporter 1 Inhibitor, With Cytochrome P450 and P-Glycoprotein Substrates: Findings From In Vitro Analyses and an Open-Label, Single-Sequence Phase I Study.

Purpose/background: Glycine transporter-1 inhibitors may ameliorate cognitive deficits in schizophrenia. This study evaluated potential drug-drug interactions with the glycine transporter-1 inhibitor BI 425809.

Methods/procedures: Interactions with cytochromes P450 (CYP) and P-glycoprotein (P-gp) were assessed in in vitro assays using human hepatocytes and Caco-2 cells, respectively.

The effect of BI 409306 on heart rate in healthy volunteers: a randomised, double-blind, placebo-controlled, crossover study.

Purpose: The potent, selective phosphodiesterase-9A inhibitor BI 409306 may be beneficial for patients with attenuated psychosis syndrome and could prevent relapse in patients with schizophrenia. Transient BI 409306-dependent increases in heart rate (HR) demonstrated previously necessitated cardiac safety characterisation. We evaluated cardiac effects of BI 409306 in healthy volunteers during rest and exercise.

The Absolute Bioavailability, Absorption, Distribution, Metabolism, and Excretion of BI 425809 Administered as an Oral Dose or an Oral Dose with an Intravenous Microtracer Dose of [C]-BI 425809 in Healthy Males.

Unlabelled: BACKGROUND AND OBJECTIVES: BI 425809, a novel glycine transporter-1 inhibitor, may ameliorate cognitive deficits in schizophrenia. The objectives of the studies were: to assess absolute bioavailability of oral BI 425809 compared with intravenous (IV) microtracer infusion (study 1), and to determine the mass balance, distribution, metabolism, and excretion of BI 425809 (study 2).

Methods: These were Phase I, open-label, non-randomized, single-period, single-arm studies in healthy males.

Effects of Cytochrome P450 3A4 Induction and Inhibition on the Pharmacokinetics of BI 425809, a Novel Glycine Transporter 1 Inhibitor.

Background And Objective: Increased glycine availability at the synaptic cleft may enhance N-methyl-D-aspartate receptor signalling and provide a promising therapeutic strategy for cognitive impairment associated with schizophrenia. These studies aimed to assess the pharmacokinetics of BI 425809, a potent glycine-transporter-1 inhibitor, when co-administered with a strong cytochrome P450 3A4 (CYP3A4) inhibitor (itraconazole) and inducer (rifampicin).

Methods: In vitro studies using recombinant CYPs, human liver microsomes, and human hepatocytes were conducted to determine the CYP isoforms responsible for BI 425809 metabolism.

Building clinically relevant outcomes across the Alzheimer's disease spectrum.

Demonstrating that treatments are clinically meaningful across the Alzheimer's disease (AD) continuum is critical for meeting our goals of accelerating a cure by 2025. While this topic has been a focus of several Alzheimer's Association Research Roundtable (AARR) meetings, there remains no consensus as to what constitutes a "clinically meaningful outcome" in the eyes of patients, clinicians, care partners, policymakers, payers, and regulatory bodies. Furthermore, the field has not come to agreement as to what constitutes a clinically meaningful treatment effect at each stage of disease severity.

Pharmacokinetics of Single Doses of BI 425809 in Healthy Chinese and Japanese Subjects: A Randomized Study.

Purpose: This study's primary goal was to evaluate the safety profile, tolerability, pharmacokinetics, and dose proportionality of BI 425809, a potent and selective inhibitor of glycine transporter 1, in healthy Chinese and Japanese subjects.

Methods: This single center, double-blind, single-rising dose study conducted in Korea randomly assigned (3:1) subjects within each ethnic subgroup (Chinese and Japanese) to receive a single dose of BI 425809 (10, 25, or 50 mg) or placebo. The primary end point was number (%) of subjects with drug-related adverse events (AEs).

Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer's disease.

Background: There are currently no approved treatments for the prodromal stage of Alzheimer's disease (AD). Approved symptomatic treatments for mild-to-moderate AD include acetylcholinesterase inhibitors and memantine, but more efficacious treatments are needed. BI 409306 is a potent and selective phosphodiesterase 9 inhibitor assessed for the symptomatic treatment of AD.

Evaluation of Pharmacokinetics and Pharmacodynamics of BI 425809, a Novel GlyT1 Inhibitor: Translational Studies.

BI 425809 is a potent and selective glycine transporter 1 (GlyT1) inhibitor being developed for the treatment of cognitive impairment in Alzheimer disease and schizophrenia. Translational studies evaluated the effects of BI 425809 on glycine levels in rat and human cerebrospinal fluid (CSF). Oral administration of BI 425809 in rats induced a dose-dependent increase of glycine CSF levels from 30% (0.

Multiple Rising Doses of Oral BI 425809, a GlyT1 Inhibitor, in Young and Elderly Healthy Volunteers: A Randomised, Double-Blind, Phase I Study Investigating Safety and Pharmacokinetics.

Background And Objective: Schizophrenia and Alzheimer's disease are characterised by abnormalities in glutamatergic pathways related to N-methyl-D-aspartate receptor hypofunction. Glycine is an N-methyl-D-aspartate receptor co-agonist; inhibition of glycine transporter 1 may improve N-methyl-D-aspartate receptor function. This phase I, randomised, two-part study evaluated the safety, tolerability and pharmacokinetic profile of BI 425809, a novel glycine transporter 1 inhibitor, in healthy male and female volunteers.

The safety, tolerability and pharmacokinetics of BI 409306, a novel and potent PDE9 inhibitor: Overview of three Phase I randomised trials in healthy volunteers.

Safety, tolerability and pharmacokinetics of BI 409306, a potent and selective phosphodiesterase 9A inhibitor, were assessed in healthy subjects in three Phase I, within-dose group, double-blind trials. Trial 1 randomised young and elderly subjects to receive BI 409306 25, 50, 100 mg, placebo once daily (OD) or BI 409306 50 mg twice daily (young) for 14 days. Trial 2 randomised young poor metabolisers (PM) of cytochrome P450 isoform 2C19 (CYP2C19) and elderly subjects to receive BI 409306 25, 50 mg or placebo OD for 14 days.

Safety, Tolerability and Pharmacokinetics of Oral BI 425809, a Glycine Transporter 1 Inhibitor, in Healthy Male Volunteers: A Partially Randomised, Single-Blind, Placebo-Controlled, First-in-Human Study.

Background And Objectives: Schizophrenia and Alzheimer's disease are characterised by glutamatergic pathway abnormalities related to N-methyl-D-aspartate (NMDA) receptor hypofunction and cognitive impairment. Glycine is an NMDA receptor co-agonist; inhibition of glycine transporter 1 (GlyT1) should improve NMDA receptor hypofunction. This study evaluated safety and pharmacokinetic properties of BI 425809-a potent and selective GlyT1 inhibitor.

A multicenter randomized placebo-controlled clinical trial of pramipexole for Tourette's syndrome.

Background: Dopamine agonists could theoretically normalize the suspected central dopamine hypersensitivity in Tourette's syndrome.

Methods: There was a multicenter randomized, placebo-controlled, double-blind clinical trial of pramipexole given for 6 weeks in 63 children and adolescents with Tourette's syndrome.

Results: There were no significant differences in the adjusted mean change in the Total Tic Score of the Yale Global Tic Severity Scale for patients treated with pramipexole (-7.

Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the VIOLET Study.

Introduction: Hypoactive sexual desire disorder (HSDD) is the most common form of female sexual dysfunction and is characterized by low sexual desire that causes distress.

Aim: The aim of this study was to assess the efficacy and safety of flibanserin, a postsynaptic 5-HT(1A) agonist/5-HT(2A) antagonist, in premenopausal women with HSDD.

Methods: North American premenopausal women with HSDD were randomized to 24 weeks' treatment with placebo (N = 295), flibanserin 50 mg (N = 295), or flibanserin 100 mg (N = 290), once daily at bedtime.

Impulse control disorders in Parkinson disease: a multicenter case--control study.

Objective: To assess factors associated with impulse control disorders (ICDs) in Parkinson disease (PD) using a multicenter case--control design.

Methods: Patients enrolled in the DOMINION study, a multicenter study assessing the cross-sectional frequency of ICDs in PD, were eligible to participate in the case--control study. PD patients with and without an ICD (n = 282 each) (compulsive gambling, buying, sexual behavior, and eating) were matched individually on age, gender, and dopamine agonist treatment.

Amantadine use associated with impulse control disorders in Parkinson disease in cross-sectional study.

A recent controlled clinical trial suggested a role for amantadine as a treatment for pathological gambling in patients with Parkinson disease (PD). Analyzing data from a large cross-sectional study of impulse control disorders (ICDs) in PD, amantadine use (n = 728), vs no amantadine use (n = 2,357), was positively associated with a diagnosis of any ICD (17.6% vs 12.

eDiary and Female Sexual Distress Scale(©) in evaluating distress in hypoactive sexual desire disorder (HSDD).

Sex-related distress is integral to the diagnosis of hypoactive sexual desire disorder (HSDD). This article describes the results of three prospective, non-treatment validation studies (two North American and one European), each testing over 200 participants with HSDD, other types of female sexual dysfunction (FSD), or no FSD in which the 12-item Female Sexual Distress Scale(©) (FSDS(©)), the 13-item FSDS-Revised(©)(FSDS-R(©)), and a single question asked using a daily electronic diary (the eDiary For HSDD Trials(©); eDiary) were used to measure sex-related distress. FSDS results with 30- and seven-day recall were equivalent.

Cutoff score of the sexual interest and desire inventory-female for diagnosis of hypoactive sexual desire disorder.

Objective: To determine the most appropriate cutoff value for the Sexual Interest and Desire Inventory-Female (SIDI-F) score to discriminate between women with hypoactive sexual desire disorder (HSDD) and those with no female sexual dysfunction (FSD). The SIDI-F is a clinician-rated instrument consisting of 13 items designed to assess HSDD severity in women. The total score ranges from 0 to 51, with higher scores indicating better sexual function.

Validation of the sexual interest and desire inventory-female in hypoactive sexual desire disorder.

Introduction: The Sexual Interest and Desire Inventory-Female (SIDI-F) is a 13-item scale developed as a clinician-administered assessment tool to measure hypoactive sexual desire disorder (HSDD) severity in women.

Aim: To estimate the reliability and validity of the SIDI-F as a measure of HSDD severity.

Methods: Women, aged 18-65 years, with primary HSDD, Female Sexual Arousal Disorder (FSAD), or no Female Sexual Dysfunction (no FSD) participated in two nontreatment studies (in North America and Europe).

Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients.

Context: An association between dopamine-replacement therapies and impulse control disorders (ICDs) in Parkinson disease (PD) has been suggested in preliminary studies.

Objectives: To ascertain point prevalence estimates of 4 ICDs in PD and examine their associations with dopamine-replacement therapies and other clinical characteristics.

Design: Cross-sectional study using an a priori established sampling procedure for subject recruitment and raters blinded to PD medication status.

Validation of the female sexual distress scale-revised for assessing distress in women with hypoactive sexual desire disorder.

Introduction: The concept of sexually related personal distress is currently central to the diagnosis of all female sexual dysfunctions (FSD). In the current study, we have focused on validating a slightly revised version of the Female Sexual Distress Scale (FSDS), the FSDS-Revised (FSDS-R), to enhance the sensitivity of the instrument with patients suffering from hypoactive sexual desire disorder (HSDD). In addition, we have attempted to extend the validation generalizability of the scale by demonstrating that both instruments possess reliability and discriminative validity in premenopausal women with HSDD.

The Sexual Interest and Desire Inventory-Female (SIDI-F): item response analyses of data from women diagnosed with hypoactive sexual desire disorder.

Introduction: Hypoactive sexual desire disorder (HSDD) is the most common sexual complaint in women. Currently there are no validated instruments for specifically assessing HSDD severity, or change in HSDD severity in response to treatment, in premenopausal women. The Sexual Interest and Desire Inventory-Female (SIDI-F) is a clinician-administered instrument that was developed to measure severity and change in response to treatment of HSDD.

Reliability and validity of the Sexual Interest and Desire Inventory-Female (SIDI-F), a scale designed to measure severity of female hypoactive sexual desire disorder.

The Sexual Interest and Desire Inventory-Female (SIDI-F) is a 13-item scale developed as a clinician-administered assessment tool to quantify the severity of symptoms in women diagnosed with hypoactive sexual desire disorder (HSDD). The present investigation assessed the reliability and validity of the SIDI-F as a measure of HSDD severity. Results show that the SIDI-F exhibits excellent internal consistency, with Cronbach's alpha of 0.