Pharmacologic rationale for memantine
in chronic cerebral hypoperfusion, especially vascular dementia.
Mobius HJ.
Merz and Co.,
Frankfurt, Germany.
Alzheimer Dis Assoc Disord 1999 Oct-Dec;13 Suppl 3:S172-8
Abstract
Memantine
is a moderate-affinity, voltage-dependent, uncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors. In contrast to competitive NMDA antagonists,
memantine is well tolerated in humans and is being developed for the treatment of dementia. The pathogenesis of vascular dementia (VaD) is largely unknown, and is likely multifactorial, but it involves the impairment of blood circulation as a common denominator. There is broad evidence for the efficacy of
memantine in several animal models of
ischemia. Memantine also acts on several secondary, potentially contributing factors in VaD such as neuronal depolarization, removal of magnesium block of NMDA receptors, chronic overstimulation of these receptors, and, possibly, mitochondrial dysfunction. Among others, it also has additional positive effects on long-term potentiation and cognition in standard animal models of impaired synaptic plasticity. Recently, clinical efficacy of
memantine has been shown in an etiologically mixed population of severely demented patients, including those with VaD. Given the difficulties of diagnosing VaD in clinical practice, an optimal antidementive drug should be beneficial in both Alzheimer disease and VaD. Preclinical data presented in this paper indicate that such benefits can be achieved with
memantine. In addition, phase II clinical data in dementia are summarized, and two ongoing pivotal trials in VaD are described. Suggestions for VaD guideline development are made regarding clinical instruments, and etiologies and severity stages are considered.
