Metrifonate treatment of the cognitive deficits of Alzheimer's disease

Abstract

The efficacy and safety of metrifonate, an acetylcholinesterase inhibitor, was evaluated clinically in patients diagnosed with mild to moderate Alzheimer's disease (AD). This was a prospective, 30-week, multicenter, double-blind, randomized, parallel group, dose-finding study, which included a 2-week screening period, a 12-week treatment period, and follow-up visits at 8 and 16 weeks post-treatment. Patients received placebo or metrifonate once daily. Metrifonate-treated patients received a loading dose of 0.5 mg/kg (25 to 45 mg), 0.9 mg/kg (45 to 80 mg), or 2.0 mg/kg (100 to 180 mg) for 2 weeks, followed by a maintenance dose of 0.2 mg/kg (10 to 20 mg), 0.3 mg/kg (15 to 25 mg), or 0.65 mg/kg (30 to 60 mg) for 10 weeks. Four hundred eighty patients were enrolled. Percentages of patients completing double-blind treatment were 96% in the placebo group and 89 to 94% in the metrifonate group. Metrifonate significantly improved cognitive ability, as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and enhanced global function, as assessed the Clinicians's Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus). At 3 months, in the intent-to-treat patients, the treatment difference for the change in ADAS-Cog score in favor of metrifonate was 2.94 points (95% CI, 1.61 to 4.27; p = 0.0001). These patients also exhibited a 0.35-point improvement on the CIBIC-Plus relative to the placebo patients (95% CI, 0.15 to 0.54; p = 0.0007). Patients receiving lower drug doses had scores intermediate to those of the placebo and the 0.65 mg/kg metrifonate groups on both performance scales. The drug was well tolerated; side effects were predominantly gastrointestinal in nature, and no hepatic toxicity was observed. Therefore, in this study, metrifonate safely improved the cognitive deficits and benefited the global function of AD patients.

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

“…Metrifonate is a acetylcholinesterase inhibitor (AChEI) and increases ACh availability in the synapse in a more direct manner than 5-HT 6 antagonists (Cummings et al, 1998;Ringman and Cummings, 1999). Preclinical studies demonstrated that metrifonate improved age-impaired memory functions (spatial and nonspatial) (Dachir et al, 1997;Scali et al, 1997;van der Staay et al, 1996a) and scopolamine-induced impairments in water maze and passive avoidance tasks (Itoh et al, 1997;Riekkinen et al, 1996).…”

Memory deficits are associated with impaired ability to modulate neuronal excitability in middle-aged mice

“…Activation of cholinergic receptors shape neuronal excitability and synaptic throughput (Tai et al 2006) through multiple Ca 2+ -dependent processes (Gahwiler and Brown 1987;Tai et al 2006). Restoration of cholinergic function has been shown to rescue deficits on hippocampal-dependent tasks in aged rodent and mouse models of Alzheimer's disease (AD) (Disterhoft and Oh 2006), as well as in human AD patients (Cummings et al 1998;Morris et al 1998;Pettigrew et al 1998), and therefore is a potential target aimed at the rescue of early agerelated cognitive decline. …”

Practice parameter: Management of dementia (an evidence-based review) [RETIRED]

“…Development of controlled-release physostigmine, 19,20 metrifonate, [21][22][23] velnacrine, 24,25 and eptastigmine [26][27][28] were discontinued because of unacceptable toxicities.…”