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Prospects for Pharmacological Intervention in Alzheimer Disease

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Prospects for Pharmacological Intervention in Alzheimer Disease NEUROLOGICAL REVIEW SECTION EDITOR: DAVID E. PLEASURE, MD Prospects for Pharmacological Intervention in Alzheimer Disease Ge´rard Emilien, PhD; Konrad Beyreuther, PhD; Colin L. Masters, MD; Jean-Marie Maloteaux, MD, PhD lzheimer disease (AD) involves neuronal degeneration with impaired cholinergic trans- mission in the cerebral cortex and hippocampus in areas of the brain particularly as- sociated with memory and higher intellectual functioning. Other neurotransmitter defi- cits also occur, but the mechanisms underlying the widespread impairment of synaptic Afunctions remain uncertain. Research on the molecular basis of AD has elucidated a pathogenic pathway from which a range of rational pharmacological interventions has emerged. Although at least 3 cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine tartrate) are now available and provide patients with modest relief, the most promising strategy involves ap- proaches to retarding, halting, or preventing the formation or accumulation of b-amyloid (Ab) plaques. Estrogen is believed to have antioxidant or other anti-Ab effects, as hormonal replace- ment therapy in women with menopause is associated with a reduced risk or delayed onset of AD. The association between nonsteroidal anti-inflammatory drugs and a reduced risk of AD has not yet been confirmed, but these agents may protect the brain from the reactive glial and microglial responses associated with Ab deposition. Also, recent studies suggested that antioxidants, such as vitamin E taken alone or in combination with selegiline hydrochloride, can delay the progression of AD. Despite these encouraging results, no current therapy has been shown to halt or reverse the underlying disease process. The proof of the principle that anti-Ab drugs will work in the trans- genic models of AD is eagerly awaited with the expectation that they will eventually prove suc- cessful in humans. Arch Neurol. 2000;57:454-459 The accumulation of b-amyloid (Ab) effects of cholinergic-boosting strategies. plaques is the pathognomonic feature of In addition to the 3 licensed compounds Alzheimer disease (AD). How does this ac- (tacrine hydrochloride, donepezil, and ri- cumulation relate to the neuronal degen- vastigmine tartrate), there are many drugs eration that manifests as a progressive cog- awaiting approval or undergoing phase 3 nitive impairment with widespread trials (Table 1). While drugs specifi- neurological and neuropsychiatric distur- cally targeting the b-amyloidogenic path- bances? The slowly emerging answer is way only now are beginning to emerge in that Ab induces a variety of neurotoxic a preclinical setting, most other drugs are phenomena, including reactive oxygen directed at the cholinergic system. There species. However, to date only the sec- are many psychotropic agents available to ondary degenerative effects have been ame- treat the behavioral manifestations of nable to therapy, as seen in the beneficial AD, including antipsychotic, agitation- reducing , antidepressant, anxiolytic, and sedative-hypnotic drugs. Interventions in From the Laboratory of Pharmacology (Drs Emilien and Maloteaux) and Department of Neurology (Dr Maloteaux), Universite´ Catholique de Louvain Cliniques AD include treatment of the underlying Universitaires Saint Luc, Brussels, Belgium; the Centre for Molecular Biology, disease process and amelioration of neu- University of Heidelberg, Heidelberg, Germany (Dr Beyreuther); and the Department rochemical deficits produced by the cel- of Pathology, University of Melbourne, and the Mental Health Research Institute, lular changes. This review discusses cur- Parkville, Australia (Dr Masters). rent perspectives in the pharmacotherapy ARCH NEUROL / VOL 57, APR 2000 WWW.ARCHNEUROL.COM 454 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 of AD and examines how the different disciplinary ap- proaches are being incorporated into clinical research for Table 1. Relevant Drugs for Alzheimer Disease Awaiting effective drug treatments. Attention is drawn to new com- Approval or Undergoing Phase 3 Trials* pounds with novel mechanisms of action that could have a tremendous impact in the future treatment of AD. Drug Action Awaiting Approval Trichlorfon MODULATION OF THE CHOLINERGIC SYSTEM AChE inhibitor Physostigmine salicylate Different strategies have been developed to boost the cho- Idebenone Antioxidant linergic system, including increased acetylcholine pro- Nebracetam m1 Muscarinic receptor agonist duction with cholinergic precursors (choline and leci- Nefiracetam thin), prevention of synaptic acetylcholine destruction Propentofylline ACh agonist, calcium channel opener, and with acetylcholinesterase (AChE) inhibitors, such as phosphodiesterase inhibitor tacrine (9-amino-1, 2, 3, 4-tetrahydroacridine, Cognex; Undergoing Phase 3 Trials Parke-Davis, Morris Plains, NJ), donepezil (developed un- Amiridin Eptastigmine AChE inhibitor der the code E2020, Aricept; Pfizer Inc, New York, NY), Galantamine rivastigmine (developed under the code SDZ ENA 713, Cevimeline m1 Muscarinic receptor agonist Exelon; Novartis Pharmaceuticals, East Hanover, NJ), phy- hydrochloride sostigmine salicylate, and galantamine, or direct stimu- Talsaclidine lation of postsynaptic muscarinic receptors with recep- Dehydroepiandrosterone Neurosteroid tor agonists. However, tacrine and donepezil are the only Montirelin hydrate ACh release stimulator, protirelin agonist NS-105 Nootropic agent and ACh and drugs that have been approved by the Food and Drug Ad- GABA modulator ministration (FDA). Selegiline hydrochloride Monoamine oxidase B inhibitor Evidence now indicates that some AChE inhibitors Taltirelin hydrate Protirelin agonist also may provide neuroprotective effects, perhaps through the activation of nicotinic receptors, and may even en- *AChE indicates acetylcholinesterase; ACh, acetylcholine; and GABA, hance neurotrophic regeneration. Other possible ac- g-aminobutyric acid. tions include the effect of cholinergic agonists on the pro- cessing and secretion of the amyloid precursor protein Donepezil and Ab.1,2 In November 1996, donepezil (a piperidine-based AChE Tacrine inhibitor with specificity for AchE) was approved by the FDA as a symptomatic therapy for mild to moderate AD. After the initial positive and overly optimistic reports in The bioavailability of donepezil is approximately 100%, 1986 on the efficacy of tacrine, it was subsequently noted with peak plasma concentrations occurring between 2 and to be an even stronger inhibitor of the butyrylcholines- 4 hours after an oral dose. Food appears to have no sig- terase family of enzymes. More recently, apart from AChE nificant effect on the drug absorption. Donepezil has a mean inhibition, tacrine has been shown to possess a much elimination half-life of 70 hours, with significant interin- broader pharmacological profile, such as blockage of po- dividual variation; a daily dose is recommended. Done- tassium channels, inhibition of the neuronal mono- pezil is bound highly (93%-96%) to the proteins albumin amine uptake processes, and inhibition of monoamine and a1-acid glycoprotein. The drug is metabolized in the oxidase.3 The heightened efficacy of tacrine in alleviat- liver by CYP2D6 and CYP3A3/4 and by glucuronidation. ing some of the behavioral symptoms of AD compared A dosage of 5 mg/d yields steady-state AChE inhibition with other AChE inhibitors might be related to these other of approximately 64% as determined by cholinesterase in- pharmacological actions. The purported cognitive- hibition in human red blood cell samples.10 In a 30-week enhancing effects of tacrine and the AChE inhibitors are phase 3 clinical trial of donepezil, both the 5- and 10-mg often difficult to disentangle from their nonspecific arousal treatment groups had ADAS-Cog (Alzheimer’s Disease As- and behavioral effects, which can be expected from all sessment Scale-Cognitive subscale) scores superior to the classes of cholinergic stimulants. Serious adverse effects placebo group throughout the 6-month trial. Moreover, of tacrine, including hepatotoxic effects,4 have weak- more than 80% of the patients in the treatment group ened its position as a drug of choice. showed either improvement or no decline during the Tacrine has a mean bioavailability of 17%, with in- 6-month trial. The long-term efficacy of donepezil treat- terindividual variability from 2% to 36% (Table 2).10 ment has not been evaluated yet. However, the efficacy for This low bioavailability is thought to be secondary to large up to 2 years was evaluated in patients who completed the presystemic clearance. Food appears to decrease the rate 30-week phase 3 trial and who underwent a long-term, but not the extent of absorption. Tacrine hydrochloride open-label study with donepezil. For a mean of 40 weeks, is rapidly metabolized, with mean half-lives of 1.6 and patients maintained performance levels better than their 2.1 hours after single doses of 25 mg and 50 mg, respec- original baseline scores. The ADAS-Cog scores collected tively, which must be taken 4 times a day. Tacrine me- for more than 2 years suggested that patients receiving tabolism appears to be mediated through cytochrome donepezil maintained the same magnitude of benefit as in P-450 1A 2 isoenzyme. Clinical dosages of 80 to 160 mg/d the beginning of the study, indicating that long-term use usually achieve approximately 30% AChE inhibition. of donepezil may be beneficial.11 ARCH NEUROL / VOL 57, APR
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