A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M receptor agonist HTL0018318 in patients with mild-to-moderate Alzheimer's disease.

Introduction: This study examined the safety and pharmacodynamic effects of selective muscarinic M receptor orthosteric agonist HTL0018318 in 60 patients with mild-to-moderate Alzheimer's disease (AD) on background donepezil 10 mg/day.

Methods: A randomized, double-blind, placebo-controlled 4-week safety study of HTL0018318 with up-titration and maintenance phases, observing exploratory effects on electrophysiological biomarkers and cognition.

Results: Treatment-emergent adverse events (TEAEs) were mild and less frequently reported during maintenance versus titration.

From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects.

Safety and Pharmacokinetics of HTL0018318, a Novel M Receptor Agonist, Given in Combination with Donepezil at Steady State: A Randomized Trial in Healthy Elderly Subjects.

Introduction: HTL0018318 is a selective muscarinic M receptor partial agonist under development for the symptomatic treatment of dementias, including Alzheimer's disease. Clinically, HTL0018318 would likely be used alone or in conjunction with cholinesterase inhibitors (e.g.

Safety, pharmacokinetics and exploratory pro-cognitive effects of HTL0018318, a selective M receptor agonist, in healthy younger adult and elderly subjects: a multiple ascending dose study.

Background: The cholinergic system and M receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia's including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects.

First-in-man study to investigate safety, pharmacokinetics and exploratory pharmacodynamics of HTL0018318, a novel M -receptor partial agonist for the treatment of dementias.

Aims: HTL0018318 is a selective M receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses.

Methods: This randomized, double-blind, placebo-controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1-35 mg HTL0018318.

Cholinergic muscarinic M and M receptors as therapeutic targets for cognitive, behavioural, and psychological symptoms in psychiatric and neurological disorders.

Cholinergic dysfunction is involved in a range of neurological and psychiatric disorders, including schizophrenia, dementia and Lewy body disease (LBD), leading to widespread use of cholinergic therapies. However, such drugs have focused on increasing the availability of acetylcholine (ACh) generally, with relatively little work done on the muscarinic system and specific muscarinic receptor subtypes. In this review, we provide an overview of the major cholinergic pathways and cholinergic muscarinic receptors in the human brain and evidence for their dysfunction in several neurological and psychiatric disorders.

Treatment of elderly primary insomnia patients with EVT 201 improves sleep initiation, sleep maintenance, and daytime sleepiness.

Objective: Two doses of EVT 201, a partial positive allosteric modulator of the GABA(A) system, were evaluated in elderly primary insomnia patients with daytime sleepiness.

Patients And Methods: Participants were 149 elderly patients with DSM-IV primary insomnia including evidence of daytime sleepiness (53 males, 96 females; mean age 71.3yrs, range 65-86yrs).

The partial positive allosteric GABA(A) receptor modulator EVT 201 is efficacious and safe in the treatment of adult primary insomnia patients.

Objective: To evaluate polysomnographic (PSG) and self-reported measures of the efficacy and safety of EVT 201 in patients with primary insomnia.

Patients And Methods: Following clinical and PSG screening, 75 patients (mean age: 45.1+/-11.