ALZHEIMER'S DISEASE (AD)

Currently approved therapies do not directly address disease mechanisms related to the amyloid hypothesis. Drugs in use intend to normalize the regulation of substances mediating signals from one nerve cell to another (so-called neurotransmitters). Diseased nerve cells may release either insufficient or excessive amounts of specific neurotransmitters. Therefore, therapies are aimed at either increasing or suppressing neurotransmitter availability. Although these therapies appear to lack in specificity and may not halt long-term nerve cell deterioration, they may produce significant temporary improvements in functioning and facilitate patient care.

Brain nerve cell degeneration may involve a lack of stimulation mediated by the neurotransmitter acetylcholine. Acetylcholine-esterase inhibitors prevent the degradation of acetylcholine and therefore increase its availability for signaling between cells. Drugs in this category include tacrine (Cognex®], donepezil [Aricept®], rivastigmine [Exelon®], and galantamine [Reminyl®]. The latter agent may also act as a modulator of nicotinic acetylcholine receptor-ion channels. Acetylcholine esterase inhibitors are effective mainly in mild cases of Alzheimer's disease.

Another FDA approved substance is ergoloid mesylate [various preparations] that appears to act as a replacement for deficient activity of the neurotransmitter dopamine.

Many neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington, multiple sclerosis, seizure disorders) may contrarily involve an excess stimulation of nerve cells by neurotransmitters, glutamate in particular. Excessive stimulation may accelerate nerve cell deterioration, a phenomenon known as excitotoxicity. Abnormalities in glutamate receptor function in dementia syndromes appear to have the desired distribution to explain the nerve cell pathology of Alzheimer's dementia (see above, preferential involvement of cortico-cortical connections and hippocampal projections). Memantine, synthetized by Lilly (USA) in 1963 as a postulated hypoglycemic agent (no blood sugar-lowering activity found, however) was recognized by the Merz Co. (Germany) in 1972 to be active on the central nervous system. Memantine was then demonstrated to act by blocking glutamate receptors (more precisely, to act as a low-affinity noncompetitive antagonist of N-methyl-D-aspartate [NMDA] receptors). The well-tolerated drug has been used over 10 years in Germany for the treatment of dementia and was approved for this purpose by the European Medicines Evaluation Agency in February 2002. Compared with acetylcholine-esterase inhibitors, memantine may be beneficial not only for mild but also advanced Alzheimer's dementia (New England Journal of Medicine 2003; vol. 348, pages 1333-1341). Approval by the FDA is overdue.