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Pilot randomized controlled study of a histamine receptor inverse agonist in the symptomatic treatment of AD


Egan, Michael, Yaari, Roy, Liu, Lian, Ryan, Michael, Peng, Yahong, Lines, Christopher, Michelson, David


Current Alzheimer Research, Volume: 9, No.: 4, Pages.: 481-490

Year of Publication



We performed a clinical trial to evaluate the effects of the histamine subtype-3 receptor inverse agonist MK- 0249 on cognition in AD patients. Mild-to-moderate AD patients were randomized 1:1 to 4 weeks of double-blind daily treatment with oral MK-0249 5-mg or placebo. Pharmacokinetic and PET data suggested that MK-0249 5-mg daily would achieve approximately 85% brain receptor occupancy at Cmax in elderly patients. Primary efficacy measures were the short Computerized-Neuropsychological-Test-Battery (CNTB) summary score and ADAS-Cog score. A secondary efficacy measure was a Cognition Summary Score summarizing results from 7 cognitive tests. Of 144 patients randomized, 132 completed 4 weeks (MK-0249 = 65, placebo = 67). Most patients (88.2%) were on concomitant symptomatic AD treatment. There were no significant differences between treatments on primary and secondary endpoints at week 4: short CNTB summary score = 0.89 (95% CI: -0.74,2.52); ADAS-Cog score s -0.25 (95% CI: -1.61,1.11); Cognition Summary Score = 1.38 (95% CI: -0.64,3.40). MK-0249 was generally well tolerated but was associated with an increased percentage of patients with adverse events (41/73; 56.2) versus placebo (18/70; 25.7%). Adverse events in > 5% of patients on MK-0249 were diarrhea (8.2% vs. 2.9%), headache (8.2% vs. 1.4%), muscle spasms (5.5% vs. 0%), insomnia (5.5% vs. 0%) and stomach discomfort (5.5% vs. 0%). MK-0249 5-mg once daily over 4 weeks was not effective in improving cognitive function in mild to moderate AD patients who were on concomitant symptomatic AD treatment. ( trial registration, NCT00420420).;


adverse, aged, aged, 80 and over, agonist, alzheimer disease, cognition disorders, complications, double-blind method, drug therapy, etiology, events, female, histamine, histamine agonists, humans, inverse, male, pilot projects, psychiatric status rating scales, quinazolinones, receptor, retrospective studies, subtype3, therapeutic use, time factors, treatment outcome

Countries of Study


Types of Dementia

Alzheimer’s Disease

Types of Study

Randomised Controlled Trial

Type of Outcomes

Cognition, Other

Type of Interventions

Pharmaceutical Interventions

Pharmaceutical Interventions