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Treatment Of Alzheimer’s Disease
Published in Zaven S. Khachaturian, Teresa S. Radebaugh, Alzheimer’s Disease, 2019
Lina Shihabuddin, Kenneth L. Davis
Xanomeline, an arecoline derivative, is a muscarinic agonist with selective affinity for central Ml receptors. It is orally bioavailable with a high degree of individual variability after first pass. In a study of approximately 300 patients with Alzheimer’s disease, xanomeline was shown to be safe and efficacious. In this study clinical efficacy was dose dependent. Baseline to end-point improvement in cognition with xanomeline 75 mg tid was superior to placebo on neuropsychological testing, CIBIC, and CGI (Tollefson et al., personal communications).
Psychotic symptoms in dementia
Published in Anne M. Hassett, David Ames, Edmond Chiu, Psychosis in the Elderly, 2005
A placebo-controlled trial of the cholinesterase inhibitor rivastigmine in DLB (McKeith et al, 2000) indicated a significant overall effect on neuropsy- chiatric symptoms, although no sub-analyses were undertaken examining psychosis specifically. Other trials of cholinesterase inhibitors have focused predominantly on cognitive outcome in patients with low levels of psychiatric symptoms. Although there is encouraging preliminary evidence of some effect on overall 'behavioral' scores (Birks and Harvey, 2004; Olin and Schneider, 2004), the potential efficacy on clinically significant psychotic symptoms has not been determined. A study of the muscarinic agonist xanomeline (Mirza et al, 2003) did suggest some benefit with respect to psychotic symptoms, which is consistent with the scientific studies, although poor tolerability limits potential clinical applications.
Vive la révolution! a paradigm shift in the pharmacological treatment of schizophrenia
Published in Current Medical Research and Opinion, 2023
Another novel agent in phase 3 of clinical development is a combination of xanomeline and trospium from Karuna Therapeutics, Inc.18. Xanomeline is a muscarinic M1 and M4 receptor agonist and is thought to reduce aberrantly high dopamine signaling to the striatum but is not well tolerated because of peripheral pro-cholinergic adverse effects19,20. These adverse effects can be attenuated with the use of trospium, a muscarinic receptor antagonist that does not cross the blood brain barrier. Prior attempts in the 1950s at using this strategy of combining muscarinic/antimuscarinic medications were limited by the choice of agents available at that time21. This newer approach of combining xanomeline and trospium has been more successful. Xanomeline-trospium combination appears reasonably well-tolerated and demonstrated efficacy for the treatment of schizophrenia in a phase 2 trial of which the results were published in 202122. A recently reported phase 3 trial demonstrated similar results23.
A patent review of pharmaceutical and therapeutic applications of oxadiazole derivatives for the treatment of chronic diseases (2013–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Abbas Hassan, Abid Hussain Khan, Faiza Saleem, Haseen Ahmad, Khalid Mohammed Khan
The muscarinic acetylcholine receptor M4 is also known as the cholinergic receptor M4 (M4mAChR). The M4mAChR is widely present in CNS, particularly in the striatum. They regulate dopaminergic neurotransmission. Since M4mAChR is the negative regulator of dopamine release, increased dopamine levels in the striatum are associated with psychotic symptom psychosis, hyperkinetic movement disorders, and cognitive dysfunctions, such as schizophrenia and Parkinson’s and Alzheimer’s diseases. The drug xanomeline (LY-246708) has shown selective M1 and M4 receptor agonists, which showed promise for the treatment of Alzheimer’s disease and schizophrenia. Calhoun et al. have synthesized 2-azaspiro[3.4]octane [126] and 5-oxa-2-azaspiro[3.4]octane [127] derived oxadiazoles and related compounds 194 for selective modulation of M4mAChR (Figure 57). The in vitro (10−3 molar and 10−9 molar concentrations) and in vivo (0.1–500 mg/kg) studies revealed that these compounds are effective for psychotic depression, Alzheimer’s disease, schizoaffective disorder, Parkinson’s disease, bipolar disorder, post-traumatic stress disorder, and frontotemporal dementia.
The modern role of antipsychotics for the treatment of agitation and psychosis in Alzheimer’s disease
Published in Expert Review of Neurotherapeutics, 2018
Byron Creese, Miguel Vasconcelos Da Silva, Iskandar Johar, Clive Ballard
The use of muscarinic receptor agonists in the treatment behavioral symptoms in AD shows some clinical promise. In an early phase III clinical trial, xanomeline, an M1, and M4 agonist, significantly reduced agitation and psychosis in AD in a dose-dependent manner. Despite the encouraging results around efficacy, the tolerability profile was poor with a discontinuation rate of >50% in the high-dose arm due to adverse events, with intolerable gastro-intestinal side effects at the main cause [36], More recently, a phase I pilot study in healthy adults assessing only the tolerability of a combination of xanomeline and trospium chloride (a peripheral muscarinic antagonist) showed a 46% reduction in cholinergic side-effects. There are now future plans to initiate a phase II study in schizophrenia [37] and given the previous efficacy data in AD, this novel combination may represent an important step toward re-evaluating the role of xanomeline in AD.