A Randomized, Controlled Trial of Linopirdine in the Treatment of Alzheimer's Disease

Abstract

Objectives: We tested the efficacy and safety of linopirdine, a novel phenylindolinone, in the treatment of Alzheimer's disease. Methods: A multicentre, randomized, double-blind, parallel group, placebo-controlled trial of linopirdine (30 mg three times per day or placebo). Patients (n = 382, 55% male, 98% Caucasian, age range 51-95 years) with mild or moderate Alzheimer's disease, of whom 375 received at least one treatment dose were analysed. There were no important differences between the groups at baseline. Results: No difference was seen in Clinical Global Impression scores between patients receiving placebo and those receiving linopirdine (n = 189). Small differences in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores were seen throughout the study favouring linopirdine; at 6 months the ADAS-Cog scores were 20.2 (linopirdine) and 22

In Vivo Profile of ICA-27243 [N-(6-Chloro-pyridin-3-yl)-3,4-difluoro-benzamide], a Potent and Selective KCNQ2/Q3 (Kv7.2/Kv7.3) Activator in Rodent Anticonvulsant Models

“…The effects of KCNQ channels on neuronal excitability make KCNQ blockers potential targets for cognition enhancers, and a number of the earliest KCNQ blockers were developed as cognition-enhancing drugs (Gribkoff, 2003). The KCNQ blocker linopirdine has been shown to enhance cognition in a variety of animal models (Cook et al, 1990;Fontana et al, 1994), although the compound produced equivocal results in human clinical trials (Rockwood et al, 1997;Börjes-son et al, 1999). XE911, a potent blocker of KCNQ channels has also shown in vivo activity suggestive of cognition-enhancing ability (Zaczek et al, 1998).…”

K+ Channel Modulators for the Treatment of Neurological Disorders and Autoimmune Diseases

“…94 Linopirdine was regarded as a promising drug because it enhanced the release of acetylcholine in cholinergic nerve terminals in the brain only when its release was triggered and improved learning and memory in rodents and primates. Although clinical trials with linopirdine remained largely inconclusive 95 or showed that it did not improve memory performance in elderly subjects, 96 linopirdine became a valuable pharmacological tool. In 1995 Aiken et al reported that linopirdine blocks the M-current in rat CA1 pyramidal neurons and suggested that the I M blockade might be responsible for the enhancement of neurotransmitter release by linopirdine because the two effects had similar IC 50 /EC 50 values.…”

Cardiovascular KCNQ (Kv7) Potassium Channels: Physiological Regulators and New Targets for Therapeutic Intervention

“…Linopirdine was tested in clinical trials with the hope that it would reverse age-associated memory impairment or the cognitive deficit in patients with Alzheimer's disease (AD). Unfortunately, very little clinical benefit of linopirdine has been observed so far (Rockwood et al, 1997;Börjesson et al, 1999).…”