Galantamine chemical structure Scheme 1. Trost 2005 Galanthamine total synthesis:a bromine, sodium acetate, acetic acid, iron, rt b potassium carbonate, 2days c  Troc-Cl, DMAP, Pyridine, dichloromethane d palladium,Trost ligand, triethylamine, dichloromethane e 1.5 mol % TsOH, CH(OMe)3, methanol f DIBAL-H, toluene, -78 °C, 1 hr g  triphenylphosphine, acetonecyanohydrin, DIAD, diethyl ether h 2.20 mol % TsOH, THF, water i  15 mol % Palladium(II) acetate, 15 mol% dppp, 3 eq. Ag2CO3, toluene, 107 °C j selenium dioxide  disodium hydrogen phosphate dioxane, 150 °C 3 hrs k  methylamine ,methanol l 4 eq. DIBAL-H, m aqueous NaH2PO4 n NaCNBH3
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Galantamine

Galantamine (trade name Razadyne®, Reminyl®) is a medication used in the treatment of Alzheimer's disease. more...

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Galantamine is mostly used as hydrobromide salt. It is a centrally acting reversible cholinesterase inhibitor in the same class as donepezil. Galantamine has a much shorter half life than donepezil (there is a newer prolonged release version available in 2004) and it also has more nicotinic receptor activity and is potentially more stimulating but also probably because of this activity tends to cause worse gastrointestinal side effects.

Total synthesis

The natural source of galantamine are certain species of daffodil and because these species are scarce and because the isolation of galanthamine from daffodil is expensive (a 1996 figure specifies 50,000 US dollar per kilogram) alternative synthetic sources are under development by means of total synthesis. One recent publication details the enantioselective organic synthesis of galanthamine and also that of morphine from a single precursor .

The total synthesis of galanthamine (Trost 2005) is described as follows (see scheme 1): the sequence starts by bromination by electrophilic aromatic substitution of isovanillin 1 to bromophenol 2, then by synthesis of the second intermediate 5 by reacting dialdehyde 3 in a coupled aldol reaction and Horner-Wadsworth-Emmons reaction with trimethyl phosphonoacetate 4. The hydroxyl group is activated as a leaving group by acetylation with trichloroethyl carbonate (Troc) to 6. Next an enantioselective Trost AAA reaction takes place between bromophenol 2 and carbonate 6 to the allyl ether 7. Next the aldehyde group is protected as an acetal in 8 and this step enables the to organic reduction of the ester group to the alcohol 9 with DIBAH and subsequent conversion of this alcohol to a nitrile by nucleophilic displacement to 10 followed by aldehyde deprotection to 11. The intramolecular Heck reaction to 12 creates the dihydrofuran ring. Allylic oxidation by selenium dioxide provides allylic alcohol 13 with the correct stereochemistry. The aldehyde reacts with methylamine to the imine 14 and reduction of the imine and nitrile by DIBAL-H leading to ring-closure to the hemi-aminal 15 (not isolated) followed by acid quenching gives the alcohol 16. In the final step this alcohol group is reduced to give Galanthamine 17 together with 6% of the epi isomer 18.

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Pharmacologic treatment of Alzheimer's disease: an update - Clinical Pharmacology
From American Family Physician, 10/1/03 by Vincent W. Delagarza

The financial and social costs of Alzheimer's disease are staggering. In the United States, the disease accounts for about $100 billion per year in medical and custodial expenses, with the average patient requiring an expenditure of about $27,000 per year for medical and nursing care. In addition, 80 percent of caregivers report stress, and about 50 percent report depression. (1,2) This article reviews the pathophysiology of Alzheimer's disease, evidence for the efficacy of various pharmacologic treatments, and guidelines for the use of drug therapy in patients with this devastating disease.

Pathophysiology

Two microscopic changes occur in the brain in Alzheimer's disease: senile plaques develop between neurons, and neurofibrillary tangles develop within neurons. These changes are thought to be intricately related to the cause, development, and course of the disease.

Researchers have speculated that inflammation around plaques destroys neighboring neurons. Plaques, which are composed of b-amyloid polypeptides, seem to form as a result of disorders in processing b-amyloid and its precursor protein. A combination of genetic predisposition and environmental influences is probably responsible. (3) One of these influences may be subclinical ischemia, because patients with high blood pressure and elevated cholesterol levels tend to have an increased risk for Alzheimer's disease. (4) Neurofibrillary tangles are made up partly of a protein called tau, which links together to form filaments. The density of these filaments within neurons in the brain is directly related to the severity of dementia. It is unclear why tangles form, but different alleles of a gene are known to create forms of tau that are more likely to tangle. (3) It is also unclear whether tangles are linked to plaque formation. The ultimate effect of the tangles, however, is compromise of microtubular function, with eventual destruction of the neuron. Involvement of cholinergic neurons causes levels of acetylcholine within synapses to decline. Levels of acetylcholinesterase also drop, perhaps to compensate for the loss of acetylcholine. Activity of another cholinesterase enzyme (butyrylcholinesterase) increases, and a significant portion of acetylcholine is metabolized by this enzyme as the disease progresses. Eventually, the neuron is destroyed.

Pharmacologic Therapy

While no drug has been shown to completely protect neurons, agents that inhibit the degradation of acetylcholine within the synapse are the mainstay of treatment for Alzheimer's disease. Cholinesterase/acetylcholinesterase inhibitors are the only agents approved by the U.S. Food and Drug Administration for the treatment of Alzheimer's disease. Other drugs have been studied, but their use remains controversial.

ACETYLCHOLINESTERASE INHIBITORS

The cholinesterase inhibitor tacrine (Cognex) is used rarely because of potential liver toxicity and the need for frequent laboratory monitoring. The acetylcholinesterase inhibitors donepezil (Aricept), rivastigmine (Exelon), and galantamine (Reminyl) have been proved effective in clinical trials. Table 1 (5-7) compares the pharmacologic characteristics of the three acetylcholinesterase inhibitors and provides dosing and cost information.

All three drugs have a low incidence of serious reactions, but they commonly have cholinergic side effects such as nausea, anorexia, vomiting, and diarrhea. Tolerance to these side effects often develops. However, if therapy with an acetylcholinesterase inhibitor is interrupted for more than several days, the drug should be restarted at the lowest dosage and retitrated, because of renewed susceptibility to side effects.

Instruments that measure cognition, behavior, and functional ability have shown that acetylcholinesterase inhibitors are beneficial in patients with Alzheimer's disease. While these instruments are discussed in greater detail elsewhere, (8) the most commonly used scales are summarized in Table 2. (9-15)

Although clinical trials have shown that treatment with acetylcholinesterase inhibitors delays nursing home placement and improves cognition and functional ability, these benefits may not apply to all patients with Alzheimer's disease. For example, patients might be excluded from a study if they have significant coexisting illnesses with symptoms that could be confused with drug side effects. Consequently, the study population might consist of patients who are more likely to respond to the drug.

Nonetheless, it is safe to conclude that patients who tolerate and respond to acetylcholinesterase inhibitors will experience modest cognitive improvements. In fact, deterioration of cognition will be delayed by one year in about 20 percent of treated patients (as measured by a seven-point improvement on the Alzheimer's Disease Assessment Scale, Cognitive Section). (5,6,16) [Reference 16--Evidence level A, randomized controlled trial] Table 3 (5-7,16-23) summarizes evidence for the benefits of acetylcholinesterase inhibitors.

VITAMIN E

Vitamin E, an antioxidant, is thought to mitigate the inflammatory effects of plaque formation in the brain. In vitro, vitamin E protects nerve cells from the effects of b-amyloid, but it does not protect against other central nervous system diseases such as Parkinson's disease, in which oxidation is thought to play a part in neuronal destruction. (24)

The argument for the use of vitamin E comes from the Alzheimer's Disease Cooperative Study, (25) which evaluated the effects of 10 mg of selegiline once daily and/or 1,000 IU of vitamin E twice daily as treatments for Alzheimer's disease. The researchers concluded that these agents delayed disability and nursing home placement but not deterioration of cognitive function. The study population appeared to be highly selected: the subjects were younger but had more severe dementia than control patients and were not taking psychoactive medication. Consequently, there have been questions about whether the results of the study are applicable to a clinical setting.

A recent Cochrane review (26) concluded that after adjusting for differences between patient groups in the Alzheimer's Disease Cooperative Study, there was insufficient evidence to recommend vitamin E. The Cochrane review also found weak evidence of side effects associated with the use of vitamin E. The risks may be higher in the general population, in which many patients with Alzheimer's disease also have serious coexisting illnesses.

SELEGILINE

A number of studies have examined evidence for the use of selegiline (Eldepryl), a selective monoamine oxidase inhibitor, in the treatment of Alzheimer's disease. Most of these studies have shown some improvement in cognition, behavior, and mood, but little evidence of a global benefit in cognition, functional ability, and behavior. In 2000, the authors of a meta-analysis (27) of 15 clinical trials concluded that there was not enough evidence to recommend selegiline as a treatment for Alzheimer's disease.

Because of the risk of stupor, rigidity, severe agitation, and elevated temperature, selegiline therapy is contraindicated in patients who are taking meperidine (Demerol), and this precaution often is extended to other opioids. Concurrent use of selegiline with tricyclic antidepressants and selective serotonin reuptake inhibitors also should be avoided. (28) These restrictions may limit the use of selegiline in patients with Alzheimer's disease.

ESTROGEN

Several descriptive studies (29,30) have shown that postmenopausal women who take estrogen have a lower incidence of Alzheimer's disease. In addition, a recent review (31) of estrogen and neuroimaging studies demonstrated improved cerebral metabolism in women taking estrogen. Although estrogen may have a neuroprotective effect, (32) it does not appear to improve cognition or function in patients with Alzheimer's disease, (33) and the combination of estrogen and progestin actually may increase the risk for dementia and stroke. (34,35)

ANTI-INFLAMMATORY DRUGS

Inflammation surrounding b-amyloid plaques with resultant destruction of neurons is thought to be a key factor in the pathogenesis of Alzheimer's disease. Observational studies have found that persons who regularly use nonsteroidal anti-inflammatory drugs (NSAIDs) have a decreased incidence of Alzheimer's disease. (36,37) [Reference 37--Evidence level B, prospective cohort study] Thus, NSAIDs likely have some neuroprotective effect. However, several studies of anti-inflammatory drugs do not show a benefit for treatment. (38,39)

GINKGO BILOBA

Although a recent review (40) of four trials using ginkgo biloba in the treatment of Alzheimer's disease found a modest therapeutic benefit, there have been several reports of serious side effects associated with commercially available ginkgo, including coma, bleeding, and seizures. (41-43) One systematic review (44) provided evidence that ginkgo biloba was superior to placebo in improving cognitive function. Pharmaceutical-quality ginkgo is not available in the United States.

GUIDELINES FOR TREATMENT

A number of organizations have proposed guidelines for the treatment of dementia (Table 4), (45-50) and many insurers and managed-care organizations have developed criteria for the use of acetylcholinesterase inhibitors. All of the guidelines stress the importance of adherence to therapy, and many recommend the use of instruments to monitor response to treatment. Because of cost, most organizations recommend discontinuing therapy when dementia is severe. Some inferences drawn from a review of the literature and recommendations from drug manufacturers and specialty organizations can help guide physicians in treatment and in managing complications that occur in the course of Alzheimer's disease. An algorithm for the management of patients with Alzheimer's disease is presented in Figure 1.

[FIGURE 1 OMITTED]

The patient who is selected for acetylcholinesterase inhibitor therapy should have stable medical or psychiatric illnesses. An unstable illness will cause deterioration of functional ability and predispose the patient to delirium, which will minimize the benefits of therapy and complicate the assessment of a drug's effectiveness. Age should not be the only factor in patient selection; comorbid diseases and functional ability may be more important factors.

Acetylcholinesterase inhibitors must be taken regularly and in a dosage sufficient to benefit the patient. Prolonged interruptions of therapy will result in sustained and irreversible cognitive decline. (5-7) A patient who is unlikely to adhere to therapy or who has an illness that frequently interrupts therapy will not benefit from treatment and will be exposed to cholinergic side effects.

The manufacturers of the acetylcholinesterase inhibitors recommend slow titration (Table 1) (5-7) to avoid cholinergic side effects. If a target dosage cannot be achieved with one drug, it may be worthwhile to try a different medication. Antiemetics may alleviate some of the gastrointestinal side effects associated with acetylcholinesterase inhibitors, but frail patients taking medications with anticholinergic actions may be predisposed to delirium. If significant weight loss occurs, an appetite stimulant may be taken temporarily, although no clinical evidence supports this use.

Acetylcholinesterase inhibitors do not necessarily have to be withdrawn if a patient develops disturbed behavior. Treatment with nonpharmacologic strategies or even psychotropic medication may be required if the behavior upsets the patient or causes potential harm to family, caregivers, or others. Disturbed behaviors are common in patients with Alzheimer's disease and often precede the diagnosis of dementia. (51) Clinical trials do not suggest that acetylcholinesterase inhibitors worsen or precipitate such behaviors.

Periodic monitoring and assessment of a patient's functional ability and Mini-Mental State Examination score are useful. The results may encourage the patient's family, and the rate of change can guide the physician, patient, and family in future planning. The assessments also can help in deciding whether to continue therapy or change to another acetylcholinesterase inhibitor.

The author indicates that he does not have any conflicts of interest. Sources of funding: none reported.

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(20.) Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, et al. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 2001;57:481-8.

(21.) Knopman D, Schneider L, Davis K, Talwalker S, Smith F, Hoover T, et al. Long-term tacrine (Cognex) treatment: effects on nursing home placement and mortality, Tacrine Study Group. Neurology 1996;47:166-77.

(22.) Reuters Health News. Donepezil delays nursing home placement. Accessed April 2003 at: http://www.druginfozone.org/docs/pcjw_51st_edition_in. pdf.

(23.) Feldman H, Gauthier S, Hecker J, Vellas B, Subbiah P, Whalen E. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology 2001;57:613-20.

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(25.) Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 1997;336:1216-22.

(26.) Tabet N, Birks J, Grimley Evans J, Orrel M, Spector A. Vitamin E for Alzheimer's disease. Cochrane Database Syst Rev 2003: CD002854.

(27.) Birks J, Flicker L. Selegiline for Alzheimer's disease. Cochrane Database Syst Rev 2003:CD000442.

(28.) Physicians' desk reference. Accessed May 2003 (with password) at: www.pdr.net.

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(30.) Baldereschi M, Di Carlo A, Lepore V, Bracco L, Maggi S, Grigoletto F, et al. Estrogen-replacement therapy and Alzheimer's disease in the Italian Longitudinal Study on Aging. Neurology 1998;50:996-1002.

(31.) Maki PM, Resnick SM. Effects of estrogen on patterns of brain activity at rest and during cognitive activity: a review of neuroimaging studies. Neuroimage 2001;14:789-801.

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(34.) Shumaker SA, Legault C, Thal L, Wallace RB, Ockene JK, Hendrix SL, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651-62.

(35.) Wassertheil-Smoller S, Hendrix S, Limacher M, Heiss G, Kooperberg C, Baird A, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: The Women's Health Initiative: a randomized trial. JAMA 2003;289:2673-84.

(36.) Stewart WF, Kawas C, Corrada M, Metter EJ. Risk of Alzheimer's disease and duration of NSAID use. Neurology 1997;48:626-32.

(37.) in t' Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med 2001;345:1515-21.

(38.) Scharf S, Mander A, Ugoni A, Vajda F, Christophidis N. A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease. Neurology 1999;53:197-201.

(39.) Aisen PS, Davis KL, Berg JD, Schafer K, Campbell K, Thomas RG, et al. A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study. Neurology 2000; 54:588-93.

(40.) Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 1998; 55:1409-15.

(41.) Miwa H, Iijima M, Tanaka S, Mizuno Y. Generalized convulsions after consuming a large amount of gingko nuts. Epilepsia 2001; 42:280-1.

(42.) Fessenden JM, Wittenborn W, Clarke L. Gingko biloba: a case report of herbal medicine and bleeding postoperatively from a laparoscopic cholecystectomy. Am Surg 2001;67:33-5.

(43.) Galluzzi S, Zanetti O, Binetti G, Trabucchi M, Frisoni GB. Coma in a patient with Alzheimer's disease taking low dose trazodone and gingko biloba. J Neurol Neurosurg Psychiatry 2000;68:679-80.

(44.) Ernst E, Pittler MH. Ginkgo biloba for dementia: a systematic review of double-blind, placebo-controlled trials. Clin Drug Invest 1999;17:301-8.

(45.) Practice guideline for the treatment of patients with Alzheimer's disease and other dementias of late life. American Psychiatric Association. Am J Psychiatry 1997;154(5 suppl):1-39.

(46.) Fillit H, Cummings J. Practice guidelines for the diagnosis and treatment of Alzheimer's disease in a managed care setting: Part II--Pharmacologic therapy. Alzheimer's Disease (AD) Managed Care Advisory Council. Manag Care Interface 2000;13:51-6.

(47.) Patterson C, Gauthier S, Bergman H, Cohen C, Feightner JW, Feldman H, et al. The recognition, assessment and management of dementing disorders: conclusions form the Canadian Consensus Conference on Dementia. Can J Neurol Sci. 2001;28(suppl 1):S3-16.

(48.) NICE issues guidance on drugs for Alzheimer's disease. National Institute for Clinical Excellence. Accessed April 2003 at: www. nice.org.uk/article.asp?a=14406.

(49.) Doody RS, Stevens JC, Beck C, Dubinsky RM, Kaye JA, Gwyther L, et al. Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:1154-66.

(50.) Cummings JL, Frank JC, Cherry D, Kohatsu ND, Kemp B, Hewett L, et al. Guidelines for managing Alzheimer's disease: Part II. Treatment. Am Fam Physician 2002;2525-34.

(51.) Jost BC, Grossberg GT. The evolution of psychiatric symptoms in Alzheimer's disease: a natural history study. J Am Geriatr Soc 1996;44:1078-81.

VINCENT W. DELAGARZA, M.D., is associate professor of family medicine at West Virginia University School of Medicine, Morgantown, and medical director of two nursing homes associated with the university's family medicine program. Dr. DeLaGarza received his medical degree from the University of Maryland School of Medicine, Baltimore, and completed a family medicine residency at Andrews Air Force Base, Washington, D.C., and a geriatric fellowship at Johns Hopkins University School of Medicine, Baltimore. He is certified by the American Academy of Family Physicians in family medicine and geriatrics, by the American Medical Directors Association in long term care, and by the American Board of Hospice and Palliative Medicine.

Address correspondence to Vincent W. DeLaGarza, M.D., West Virginia University School of Medicine, Department of Family Medicine, Robert C. Byrd Health Sciences Center, Box 9152, Morgantown, WV 26506 (e-mail: vdelagarza@pol.net or delagarzav@rcbhsc.wvu.edu). Reprints are not available from the author.

Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.

COPYRIGHT 2003 American Academy of Family Physicians
COPYRIGHT 2003 Gale Group

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