Again, theoretically, this may provide a selective effect in the brain

areas most deficient in intrasynaptic ACh. Conceivably, in areas where acetylcholine is high, a competitive agent may have little effect, and a noncompetitive acetylcholinesterase inhibitor may further increase acetylcholine levels and contribute to central cholinergic side effects. Two other characteristics of galantamine are its 10- to 50-fold greater selectivity for AChE than BChE,33 and its allosteric modulation of nicotinic receptor sites, thus possibly enhancing cholinergic transmission.34 Galantamine has been approved in Austria and Sweden. A new drug application (NDA) Inhibitors,research,lifescience,medical has been filed, with possible FDA approval before September 2000. Summary The ChEIs differ from Inhibitors,research,lifescience,medical each other in their selectivity for AChE] and BChE, mechanism of inhibition, reversibility, and competition for binding. There are also differences in pharmacokinetics. An unresolved question is whether or not these differences result in differential ZD6474 mouse Clinical efficacy. Pharmacokinetic and pharmacodynamic differences will certainly be used in promoting these drugs to physicians. Clinical evidence Inhibitors,research,lifescience,medical This section describes the evidence for the clinical efficacy of the ChEIs described above, based on published or available phase 3 and 4 trials. The significant trials are summarized by drug, below, and in Table I, with respect to methodological

parameters and outcome. It is important to consider that most of these trials were designed with the main objective of obtaining marketing approval from the FDA or the European Agency for the Inhibitors,research,lifescience,medical Evaluation of Medicinal Products (EMEA). As such, the protocols were fairly similar to each other, generally selecting outpatients with mild-to-moderate AD, usually with Mini-Mental

State Examination (MMSE) scores between 10 and 26, inclusively (galantamine trials used a narrower range). Patients in these trials were generally physically healthy, usually treated for 6 months or less, and had a mean age of 72 years, Inhibitors,research,lifescience,medical a decade lower than the median age of AD patients in the US.35 Tacrine Two multicenter trials have demonstrated tacrine’s significant effect, on the Alzheimer’s Disease Assessment. Scale (ADAS) Cognitive Subscale (ADASc) assessment, and on measures of daily function. In one 12-wcck trial,8 patients receiving 80 mg of tacrine improved significantly on the ADAS and clinical global about rating compared with the groups that received smaller doses or placebo. In another 30-week study,9 663 patients were randomized to treatments with three different dosages or placebo. Statistically significant treatment effects for the 1 20-mg and 160-mg daily dosage groups were found on the ADAS and a clinician interview-based impression of change. Tacrine’s FDA-approved dosing regimen is an artifact of the forced titration study design of the 30-week multicenter trial.