dextromethorphan---quinidine-combination and Alzheimer-Disease

Agitation is common and distressing in patients with Alzheimer-type dementia, but safe, effective treatments remain elusive. Psychological treatments are first-line options, but they have limited efficacy. Off-label psychotropic medications are frequently used, but they also have limited effectiveness, and their use may have harmful side effects, including death. Areas covered: This review discusses the history leading to the conception of AVP-786 (deuterated (d6)-dextromethorphan/quinidine), its pharmacokinetic and pharmacodynamic profiles and safety issues, together with an overview of recent clinical trials. Data were found in the medical literature, in US and EU clinical trial registries and in information provided by the manufacturer. Expert opinion: AVP-786 is one of six investigational compounds in recent phase III clinical development for agitation in Alzheimer disease (AD). Quinidine and deuteration appear to prolong dextromethorphan's plasma half-life and facilitate brain penetration. The FDA granted fast-track designation to AVP-786 and allowed use of data generated on dextromethorphan-quinidine (AVP-923, Nuedexta®) for regulatory filings. AVP-923 reduced agitation in AD and was well tolerated in a phase II RCT that included more than 200 patients. A phase III clinical development program of AVP-786 for AD agitation was recently initiated. This program is expected to start generating results in July 2018.

Topics: Alzheimer Disease; Animals; Brain; Deuterium; Dextromethorphan; Drug Combinations; Humans; Psychomotor Agitation; Quinidine; Randomized Controlled Trials as Topic; Tissue Distribution; Treatment Outcome

Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks well-established long-term interventions that are both effective and safe. While non-pharmacological interventions are the suggested first-line treatment, it isn't effective in managing symptoms for every patient. In such cases, clinicians turn to the use of pharmacological interventions. Traditionally, these interventions consist of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine and antidepressants, where the efficacy doesn't necessarily outweigh the associated risks.. Gains made in understanding the neurobiological mechanisms underlying agitation have fueled several recent clinical trials. A comprehensive literature search for published articles evaluating pharmacologic interventions for agitation in AD was done. A review of some of these clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, dronabinol and citalopram show promise in treating agitation.. Neurobiological findings and enhanced trial designs have re-ignited the area of pharmacological treatment of NPS. Although further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to finding effective treatments for NPS such as agitation in patients with dementia is well underway.

Topics: Alzheimer Disease; Cannabinoid Receptor Agonists; Cannabinoids; Citalopram; Clinical Trials, Phase III as Topic; Dextromethorphan; Drug Combinations; Humans; Psychomotor Agitation; Quinidine; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

Dextromethorphan (DM)/quinidine (Q) is an approved treatment for pseudobulbar affect (PBA) based on trials in amyotrophic lateral sclerosis or multiple sclerosis. PRISM II evaluated DM/Q effectiveness and tolerability for PBA secondary to dementia, stroke, or traumatic brain injury; dementia cohort results are reported.. This was an open-label, multicenter, 90 day trial; patients received DM/Q 20/10 mg twice daily. Primary outcome was change in Center for Neurologic Study-Lability Scale (CNS-LS) score. Secondary outcomes included PBA episode count and Clinical and Patient/Caregiver Global Impression of Change scores with respect to PBA (CGI-C/PGI-C).. 134 patients were treated. CNS-LS improved by a mean (SD) of 7.2 (6.0) points at Day 90/Endpoint (P<.001) vs. baseline. PBA episodes were reduced 67.7% (P<.001) vs. baseline; global measures showed 77.5% CGI-C and 76.5% PGI-C "much"/"very much" improved. Adverse events included headache (7.5%), urinary tract infection (4.5%), and diarrhea (3.7%); few patients dropped out for adverse events (10.4%).. DM/Q significantly reduced PBA symptoms in patients with dementia; reported adverse events were consistent with the known safety profile of DM/Q. Trial Registration clinicaltrials.gov identifier: NCT01799941.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Dementia; Dementia, Vascular; Dextromethorphan; Diarrhea; Drug Combinations; Excitatory Amino Acid Antagonists; Female; Frontotemporal Dementia; Headache; Humans; Lewy Body Disease; Male; Middle Aged; Pseudobulbar Palsy; Quinidine; Urinary Tract Infections

Involuntary emotional expression disorder (IEED) is syndrome characterized with relatively stereotypical episodes of uncontrollable crying and/or laughing. Additionally, this syndrome can include irritability, anger and frustration. This syndrome is common among a number of neurologic diseases like patients with a stroke or traumatic brain injury (TBI), patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), as well as dementias such as Alzheimer's disease (AD), and motor disorders such as Parkinson's disease (PD). IEED is very common but misdiagnosed and consequently undertreated. Prevalence of IEED in AD is between 15-39%. Recent controlled clinical studies suggest that dextromethorphan (DM) and quinidine (Q) is an effective treatment for IEED. United States Food and Drug Administration (FDA) has accepted for filing and review its New Drug Application (NDA) for Zenvia (dextromethorphan hydrobromide and quinidine sulfate capsules) for the treatment of IEED. In Republic of Croatia current treatment involves antidepressants (tricyclic and selective serotonin reuptake inhibitors), antipsychotic agents, anxiolytics, antidementives and mood stabilizers. New promising treatment can reduce the frequency of episodes and improve the quality of life of patients and their families and caregivers.

Topics: Affective Symptoms; Alzheimer Disease; Clinical Trials as Topic; Combined Modality Therapy; Croatia; Crying; Dextromethorphan; Drug Approval; Drug Combinations; Expressed Emotion; Humans; Laughter; Psychotropic Drugs; Quinidine; United States