Tricaprilin (CER-0001) for the preventive treatment of migraine: A phase 2 randomised, double-blind, placebo-controlled pilot study.

Background: Increasing evidence indicates a metabolic etiology for migraines, with ketosis potentially rectifying metabolic and clinical features. We conducted a pilot study to evaluate CER-0001, a ketogenic agent, for migraine prevention without dietary changes.

Methods: This was a 2-part, double-blind, randomised, placebo-controlled study conducted in Australia.

Apathy as a Treatment Target in Alzheimer's Disease: Implications for Clinical Trials.

Apathy is one of the most prevalent, stable and persistent neuropsychiatric symptom across the neurocognitive disorders spectrum. Recent advances in understanding of phenomenology, neurobiology and intervention trials highlight apathy as an important target for clinical intervention. We conducted a comprehensive review and critical evaluation of recent advances to determine the evidence-based suggestions for future trial designs.

A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer's dementia.

Background: New therapies are urgently needed for Alzheimer's disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China.

An Open-Label, 8-Week Study of Safety and Efficacy of Pimavanserin Treatment in Adults with Parkinson's Disease and Depression.

Background: Many patients with Parkinson's disease (PD) experience depression.

Objective: Evaluate pimavanserin treatment for depression in patients with PD.

Methods: Pimavanserin was administered as monotherapy or adjunctive therapy to a selective serotonin reuptake inhibitor or serotonin/noradrenaline reuptake inhibitor in this 8-week, single-arm, open-label phase 2 study (NCT03482882).

Initial Clinical Experience of RP5063 Following Single Doses in Normal Healthy Volunteers and Multiple Doses in Patients with Stable Schizophrenia.

RP5063 is a multimodal dopamine (D)-serotonin (5-HT) stabilizer with a high affinity for D and 5-HT receptors and moderate affinity for the serotonin transporter. Single-dose (10 and 15 mg fasting, 15 mg fed) safety in healthy volunteers and multiple-dose (10, 20, 50, and 100 mg fed, 10 days) safety and pharmacodynamics in patients with stable schizophrenia were defined in two phase I studies. In the single-dose study, 32 treatment-emergent adverse events (TEAEs) were observed.

A Population Pharmacokinetic and Pharmacodynamic Analysis of RP5063 Phase 2 Study Data in Patients with Schizophrenia or Schizoaffective Disorder.

Background And Objective: RP5063 is a novel multimodal dopamine (D)-serotonin (5-HT) stabilizer possessing partial agonist activity for D and 5-HT, antagonist activity for 5-HT and moderate affinity for the serotonin transporter. Phase 2 trial data analysis of RP5063 involving patients with schizophrenia and schizoaffective disorder defined: (1) the pharmacokinetic profile; and (2) the pharmacokinetic/pharmacodynamic relationships.

Methods: Pharmacokinetic sample data (175 patients on RP5063; 28 doses/patient) were analyzed, utilized one- and two-compartment models, and evaluated the impact of covariates.

Evaluation of the effects of RP5063, a novel, multimodal, serotonin receptor modulator, as single-agent therapy and co-administrated with sildenafil, bosentan, and treprostinil in a monocrotaline-induced pulmonary arterial hypertension rat model.

Pulmonary arterial hypertension (PAH), a condition that is defined by pulmonary vasculature constriction and remodeling, involves dysfunctional signaling of the serotonin (5-HT) receptors, 5-HT. In a rat model of monocrotaline (MCT)-induced PAH, the effectiveness of RP5063 (RP), a dopamine and 5-HT receptor modulator, was evaluated as monotherapy and as an adjunct to standard PAH treatments. After a single 60 mg/kg dose of MCT, rats received vehicle (MCT+Veh; gavage twice-daily [b.

Pharmacokinetics of RP5063 Following Single Doses to Normal Healthy Volunteers and Multiple Doses Over 10 Days to Stable Schizophrenic Patients.

RP5063, a multimodal dopamine (D)-serotonin (5-HT) stabilizer, possesses high affinity for D and 5-HT receptors and moderate affinity for the serotonin transporter. Two phase I studies characterized the pharmacokinetics of a single dose (10 and 15 mg fasting, 15 mg fed/fasting) in healthy volunteers and multiple doses (10, 20, 50, and 100 mg fed) over 10 days in patients with stable schizophrenia. RP5063 displayed a dose-dependent C at 4 to 6 h, linear dose proportionality for both C and AUC, and a half-life between 40 and 71 h.

Affective and emotional dysregulation as pre-dementia risk markers: exploring the mild behavioral impairment symptoms of depression, anxiety, irritability, and euphoria.

Background: Affective and emotional symptoms such as depression, anxiety, euphoria, and irritability are common neuropsychiatric symptoms (NPS) in pre-dementia and cognitively normal older adults. They comprise a domain of Mild Behavioral Impairment (MBI), which describes their emergence in later life as an at-risk state for cognitive decline and dementia, and as a potential manifestation of prodromal dementia. This selective scoping review explores the epidemiology and neurobiological links between affective and emotional symptoms, and incident cognitive decline, focusing on recent literature in this expanding field of research.

Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects.

Istradefylline, a selective adenosine A inhibitor, is under development for the treatment of Parkinson's disease. The effect of oral steady-state rifampin 600 mg/day, a potent cytochrome P450 (CYP) 3A4 inducer, on the disposition of a single oral dose of istradefylline 40 mg was determined in a crossover study in 20 healthy subjects by measuring plasma concentrations of istradefylline and its M1 and M8 metabolites and their derived pharmacokinetic parameters. Based on the geometric mean ratio of log-transformed data, rifampin reduced istradefylline exposure: C , 0.

RP5063, a novel, multimodal, serotonin receptor modulator, prevents monocrotaline-induced pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension (PAH), a condition characterized by pulmonary vasculature constriction and remodeling, involves dysregulation of the serotonin (5-HT) receptors 5-HT and 5-HT. A rat model of monocrotaline (MCT)-induced PAH was used to examine the potential beneficial effects of RP5063, a 5-HT receptor modulator. After a single 60mg/kg dose of MCT, rats were gavaged twice-daily (b.

RP5063, a novel, multimodal, serotonin receptor modulator, prevents Sugen 5416-hypoxia-induced pulmonary arterial hypertension in rats.

RP5063, a multimodal dopamine (DA) and serotonin (5-HT) modulator with high affinity for DA and 5-HT receptors and moderate affinity for SERT, is a novel therapeutic of special interest in the treatment of pulmonary arterial hypertension (PAH). Evidence indicates that therapeutics targeting the 5-HT receptors can influence the pathogenesis of PAH. However, the therapeutic effect of RP5063 in humans has yet to be investigated.

RP5063, an atypical antipsychotic drug with a unique pharmacologic profile, improves declarative memory and psychosis in mouse models of schizophrenia.

Various types of atypical antipsychotic drugs (AAPDs) modestly improve the cognitive impairment associated with schizophrenia (CIAS). RP5063 is an AAPD with a diverse and unique pharmacology, including partial agonism at dopamine (DA) D, D, D, serotonin (5-HT), and 5-HT receptors (Rs), full agonism at αβ nicotinic acetylcholine (ACh)R (nAChR), and antagonism at 5-HT, 5-HT, and 5-HTRs. Most atypical APDs are 5-HT inverse agonists.

Dopamine serotonin stabilizer RP5063: A randomized, double-blind, placebo-controlled multicenter trial of safety and efficacy in exacerbation of schizophrenia or schizoaffective disorder.

The study objectives were to evaluate the efficacy, safety, tolerability, and pharmacokinetics of RP5063 versus placebo. The study was conducted in adults with acute exacerbation of schizophrenia or schizoaffective disorder. This 28-day, multicenter, placebo-controlled, double-blind study randomized 234 subjects to RP5063 15, 30, or 50mg; aripiprazole; or placebo (3:3:3:1:2) once daily.

Long-term safety and efficacy of preladenant in subjects with fluctuating Parkinson's disease.

Background: Preladenant is a selective adenosine A₂A receptor antagonist under investigation for Parkinson's disease treatment.

Methods: A phase 2 36-week open-label follow-up of a double-blind study using preladenant 5 mg twice a day as a levodopa adjunct in 140 subjects with fluctuating Parkinson's disease was conducted. The primary end point was adverse event (AE) assessment.

The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier).

Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders.

Frontotemporal degeneration, the next therapeutic frontier: molecules and animal models for frontotemporal degeneration drug development.

Frontotemporal degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade, there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug's success in treating FTD may predict efficacy in more common diseases such as Alzheimer's disease.

Patient self-report for evaluating mild cognitive impairment and prodromal Alzheimer's disease.

Patient-reported outcome (PRO) measures are used to evaluate disease and treatments in many therapeutic areas, capturing relevant aspects of the disorder not obtainable through clinician or informant report, including those for which patients may have a greater level of awareness than those around them. Using PRO measures in mild cognitive impairment (MCI) and prodromal Alzheimer's disease (AD) presents challenges given the presence of cognitive impairment and loss of insight. This overview presents issues relevant to the value of patient report with emphasis on the role of insight.

Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease.

Background: The promise of Alzheimer's disease biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging measure in Alzheimer's disease and thus represents the most rational target for an initial effort at standardization.

Rolapitant for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial.

Background: Postoperative nausea and vomiting (PONV) are common complications after surgery. Neurokinin-1 (NK(1)) receptor antagonists have been shown to be safe and effective for the prevention and treatment of PONV in humans. Rolapitant is a potent, selective NK1 receptor antagonist that is rapidly absorbed, has a remarkably long half-life (up to180 hours), and appears to have a low potential for drug-drug interactions.