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Effects of Xanomeline, a Selective Muscarinic Receptor Agonist, on Cognitive Function and Behavioral Symptoms in Alzheimer Disease

Effects of Xanomeline, a Selective Muscarinic Receptor Agonist, on Cognitive Function and... Abstract Objective: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an ml and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD). Design: A 6-month, randomized, double-blind, placebocontrolled, parallel-group trial followed by a 1-month, single-blind, placebo washout. Setting: Outpatients at 17 centers in the United States and Canada. Participants: A total of 343 men and women at least 60 years of age with mild to moderate AD. Interventions: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months. Outcome Measures: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER). Results: A significant treatment effect existed for ADAS-Cog (high dose vs placebo; P≤.05), and CIBIC+ (high dose vs placebo; P≤.02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P≤.002) dose-dependent reductions in vocal Out-bursts, bursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P≤.02). In the high-dose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group. Conclusions: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms. References 1. Reisberg B, Borenstein J, Salob S, Ferris SH, Franssen E, Georgotas A. Behavioral symptoms in Alzheimer's disease: phenomenology and treatment . J Clin Psychiatry . 1987;48( (suppl 5) ):9-15. 2. Drevets WC, Rubin EH. Psychotic symptoms and the longitudinal course of senile dementia of the Alzheimer type . Biol Psychiatry . 1989;25:39-48.Crossref 3. Teri L, Borson S, Kiyak HA, Yamagishi M. Behavioral disturbance, cognitive dysfunction, and functional skill: prevalence and relationship in Alzheimer's disease . J Am Geriatr Soc . 1989;37:109-116. 4. Wragg RE, Jeste DV. Overview of depression and psychosis in Alzheimer's disease . Am J Psychiatry . 1989;146:577-587. 5. Gilley DW, Wilson RS, Bennett DA, Bernard BA, Fox JH. Predictors of behavioral disturbance in Alzheimer's disease . J Gerontol B Psychol Sci Soc Sci . 1991;46:362-371. 6. Rosen J, Zubenko GS. Emergence of psychosis and depression in the longitudinal evaluation of Alzheimer's disease . Biol Psychiatry . 1991;29:224-232.Crossref 7. Deutsch LH, Bylsma FW, Rovner BW, Steele C, Folstein MF. Psychosis and physical aggression in probable Alzheimer's disease . Am J Psychiatry . 1991; 148:1159-1163. 8. Davies P. Neurotransmitter-related enzymes in senile dementia of the Alzheimer type . Brain Res . 1979;171:319-327.Crossref 9. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delong MR. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain . Science . 1982;215:1237-1239.Crossref 10. Wilcox GK, Esiri MM, Bowen DM, et al. Alzheimer's disease: correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities . J Neurol Sci . 1982;57:407-417.Crossref 11. Coyle JT, Price DL, Delong MR. Alzheimer's disease: a disorder of cortical cholinergic innervation . Science . 1983;219:1184-1190.Crossref 12. DeKosky ST, Harbaugh RE, Schmitt FA, et al. Cortical biopsy in Alzheimer's disease: diagnostic accuracy and neurochemical, neuropathological, and cognitive correlates . Ann Neurol . 1992;32:625-632.Crossref 13. Farlow M, Gracon SI, Hershey LA, Lewis KW, Sadowsky CH, Dolan-Ureno J. A controlled trial of tacrine in Alzheimer's disease . JAMA . 1992;268:2523-2529.Crossref 14. Davis KL, Thal LJ, Gamzu ER, et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease . N Engl J Med . 1992;327:1253-1259.Crossref 15. Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease . JAMA . 1994;271:985-991.Crossref 16. Growdon JH. Treatment for Alzheimer's disease? N Engl J Med . 1992:327:1306-1308.Crossref 17. Cummings JL, Kaufer D. Neuropsychiatric aspects of Alzheimer's disease: the cholinergic hypothesis revisited . Neurology . 1966;47:876-883.Crossref 18. Raskind MA, Peskind ER. Neurobiologic bases of noncognitive behavioral problems in Alzheimer disease . Alzheimer Dis Assoc Disord . 1994;8( (suppl 3) ):54-60.Crossref 19. Bonner TI, Buckley NJ, Young AC, Brann MR. Identification of a family of muscarinic acetylcholine receptor genes . Science . 1987;237:527-532.Crossref 20. Hulme EC, Birdsall NJM, Buckley NJ. Muscarinic receptor subtypes . Annu Rev Pharmacol Toxicol . 1990;30:633-673.Crossref 21. McKinney M, Coyle JT. Subject review: the potential for muscarinic receptor subtype-specific pharmacotherapy for Alzheimer's disease . Mayo Clinic Proc . 1991;66:1225-1237.Crossref 22. Fisher A, Barak D. Promising therapeutic strategies in Alzheimer's disease based on functionally selective m1 muscarinic agonists: progress and perspectives in new muscarinic agonists . Drug News Perspect . 1994;7:453-464. 23. Mrzljak L, Levey Al, Goldman-Rakic PS. Association of ml and m2 muscarinic receptor proteins with asymmetric synapses in the primate cerebral cortex: morphological evidence for cholinergic modulation of excitatory neurotransmission . Proc Natl Acad Sci U S A . 1993;90:5194-5198.Crossref 24. Levey AI, Kitt CA, Simonds WF, Price DL, Brann MR. Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies . J Neurosci . 1991;11:3218-3226. 25. Flynn DD, Ferrari-DiLeo G, Mash DC, Levey Al. Rapid communication: differential regulation of molecular subtypes of muscarinic receptors in Alzheimer's disease . J Neurochem . 1995;64:1888-1891.Crossref 26. Winkler J, Suhr ST, Gage FH, Thai LJ, Fisher LJ. Essential role of neocortical acetylcholine in spatial memory . Nature . 1995;375:484-487.Crossref 27. Giacobini E. Cholinergic receptors in human brain: effects of aging and Alzheimer's disease . J Neurosci Res . 1990;27:548-560.Crossref 28. Sversson AL, Alufusoff I, Nordberg A. Characterization of muscarinic receptor subtypes in Alzheimer and control brain cortices by selective muscarinic antagonists . Brain Res . 1992;396:142-148.Crossref 29. Mash DC, Flynn DD, Potter LT. Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation . Science . 1985;228:1115-1117.Crossref 30. Davis R, Raby C, Callahan MJ, et al. Subtype selective muscarinic agonists: potential therapeutic agents for Alzheimer's disease . Prog Brain Res . 1993;98:439-445. 31. Yasuda RP, Ciesla W, Flores LR, et al. Development of antisera selective for m4 and m5 muscarinic cholinergic receptors: distribution of m4 and m5 receptors in rat brain . Mol Pharmacol . 1993;43:149-157. 32. Bernard V, Normand E, Bloch B. Phenotypical characterization of the rat striatal neurons expressing muscarinic receptor genes . J Neurosci . 1992;12:3591-3600. 33. Selkoe DJ. Alzheimer's disease: a central role for amyloid . J Neuropathol Exp Neurol . 1994;43:438-447.Crossref 34. Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by Congo red . Proc Natl Acad Sci U S A . 1994;91:12243-12247.Crossref 35. Nitsch RM, Slack BE, Wurtman RJ, Growdon JH. Release of Alzheimer's amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors . Science . 1992;258:304-307.Crossref 36. DeLapp NW, Eckols K, Bymaster FP, Mitch CH, Shannon HE, Ward JS. The muscarinic M1 agonist xanomeline increases soluble amyloid precursor protein release from Chinese hamster ovary-m1 cells . Life Sci . 1995;57:1183-1190.Crossref 37. Bymaster FP, Wong DT, Mitch CH, et al. Neurochemical effects of the M1 muscarinic agonist xanomeline (LY246708/NNC11-0232) . J Pharmacol Exp Ther . 1994;269:282-289. 38. Shannon HE, Bymaster FP, Calligaro DO, et al. Xanomeline: a novel muscarinic receptor agonist with functional selectivity for m1 receptors . J Pharmacol Exp Ther . 1994;269:271-281. 39. Bymaster FP, Whitesitt CA, Shannon HE. Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer's disease. Drug Dev Res. In press. 40. Farde L, Suhara T, Halldin C, et al. New radioligands for PET-examination of central muscarinic receptors. Presented at the Alzheimer's and Parkinson's Diseases Recent Developments Third International Conference; November 1-6,1993; Chicago, Ill. 41. Bodick NC, DeLong AF, Bonate PL, Gillespie T, Henry DP, Satterwhite JH. Xanomeline, a specific m1 agonist: early clinical studies . In: Giacobini E, Becker R, eds. Alzheimer Disease: Therapeutic Strategies . Cambridge, Mass: Birkhauser Boston Inc; 1994:234-238. 42. Sramek JJ, Hurley DJ, Wardle TS, et al. The safety and tolerance of xanomeline tartrate in patients with Alzheimer's disease . J Clin Pharmacol . 1995:35:800-806.Crossref 43. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease . Neurology . 1984;34:939-944.Crossref 44. Folstein MF, Folstein SE, McHugh PR. 'Mini-Mental State': a practical method for grading the cognitive state of patients for the clinician . J Psychiatr Res . 1975;12:189-198.Crossref 45. Mohs RC, Cohen L. Alzheimer's Disease Assessment Scale (ADAS) . Psychopharmacol Bull . 1988;24:627-628. 46. Veroff AE, Cutler NR, Sramek JJ, et al. A new assessment tool for neuropsychopharmacologic research: the computerized neuropsychological test battery . J Geriatr Psychiatry Neurol . 1991;3:211-217.Crossref 47. Knopman DS, Knapp MJ, Gracon SI, Davis CS. The Clinician Interview-Based Impression (CIBI): a clinician's global change rating scale in Alzheimer's disease . Neurology . 1994;44:2315-2321.Crossref 48. Spiegel R, Brunner C, Ermini-Fünfschilling D, et al. A new behavioral assessment scale for geriatric out- and in-patients: the NOSGER (Nurses' Observation Scale for Geriatric Patients) . J Am Geriatr Soc . 1991;39:339-447. 49. Ferris SH, Steinberg G, Shulman E, et al. Institutionalization of Alzheimer's patients: reducing precipitating factors through family counseling . Arch Found Thanatol . 1985;12:7. 50. Reisberg B, Borenstein J, Franssen E, Shulman E, Steinberg G, Ferris SH. Remediable behavioral symptomatology in Alzheimer's disease . Hosp Community Psychiatry . 1986;37:1199-1201. 51. Teri L, Rabins P, Whitehouse P, et al. Management of behavior disturbance in Alzheimer disease: current knowledge and future directions . Alzheimer Dis Assoc Disord . 1992;6:77-88.Crossref 52. Platt JE, Campbell M, Green WH, Perry R, Cohen IL. Effects of lithium carbonate and haloperidol on cognition in aggressive hospitalized school-age children . J Clin Psychopharmacol . 1981;1:8-13.Crossref 53. Cummings JL, Gorman DG, Shapira J. Physostigmine ameliorates the delusions of Alzheimer's disease . Biol Psychiatry . 1993;33:536-541.Crossref 54. Chiodo LA, Buney BS. Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons . J Neurosci . 1983;3:1607-1619. 55. White FJ, Wang RY. Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons . Science . 1983;221:1054-1057.Crossref 56. Stockton ME, Rasmussen K. Electrophysiological effects of olanzapine, a novel atypical antipsychotic, on A9 and A10 dopamine neurons . Neuropsychopharmacology . 1994;14:97-104.Crossref 57. Lipsitz L, Bodick N, Goldberger AL, MacMahon M, Medina A. Effects of central muscarinic-1 receptor stimulation on blood pressure regulation. Hypertension. In press. 58. Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer's disease . Neurology . 1996;46:130-135.Crossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Neurology American Medical Association

Effects of Xanomeline, a Selective Muscarinic Receptor Agonist, on Cognitive Function and Behavioral Symptoms in Alzheimer Disease

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Publisher
American Medical Association
Copyright
Copyright © 1997 American Medical Association. All Rights Reserved.
ISSN
0003-9942
eISSN
1538-3687
DOI
10.1001/archneur.1997.00550160091022
Publisher site
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Abstract

Abstract Objective: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an ml and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD). Design: A 6-month, randomized, double-blind, placebocontrolled, parallel-group trial followed by a 1-month, single-blind, placebo washout. Setting: Outpatients at 17 centers in the United States and Canada. Participants: A total of 343 men and women at least 60 years of age with mild to moderate AD. Interventions: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months. Outcome Measures: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER). Results: A significant treatment effect existed for ADAS-Cog (high dose vs placebo; P≤.05), and CIBIC+ (high dose vs placebo; P≤.02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P≤.002) dose-dependent reductions in vocal Out-bursts, bursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P≤.02). In the high-dose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group. Conclusions: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms. References 1. Reisberg B, Borenstein J, Salob S, Ferris SH, Franssen E, Georgotas A. Behavioral symptoms in Alzheimer's disease: phenomenology and treatment . J Clin Psychiatry . 1987;48( (suppl 5) ):9-15. 2. Drevets WC, Rubin EH. Psychotic symptoms and the longitudinal course of senile dementia of the Alzheimer type . Biol Psychiatry . 1989;25:39-48.Crossref 3. Teri L, Borson S, Kiyak HA, Yamagishi M. Behavioral disturbance, cognitive dysfunction, and functional skill: prevalence and relationship in Alzheimer's disease . J Am Geriatr Soc . 1989;37:109-116. 4. Wragg RE, Jeste DV. Overview of depression and psychosis in Alzheimer's disease . Am J Psychiatry . 1989;146:577-587. 5. Gilley DW, Wilson RS, Bennett DA, Bernard BA, Fox JH. Predictors of behavioral disturbance in Alzheimer's disease . J Gerontol B Psychol Sci Soc Sci . 1991;46:362-371. 6. Rosen J, Zubenko GS. Emergence of psychosis and depression in the longitudinal evaluation of Alzheimer's disease . Biol Psychiatry . 1991;29:224-232.Crossref 7. Deutsch LH, Bylsma FW, Rovner BW, Steele C, Folstein MF. Psychosis and physical aggression in probable Alzheimer's disease . Am J Psychiatry . 1991; 148:1159-1163. 8. Davies P. Neurotransmitter-related enzymes in senile dementia of the Alzheimer type . Brain Res . 1979;171:319-327.Crossref 9. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delong MR. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain . Science . 1982;215:1237-1239.Crossref 10. Wilcox GK, Esiri MM, Bowen DM, et al. Alzheimer's disease: correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities . J Neurol Sci . 1982;57:407-417.Crossref 11. Coyle JT, Price DL, Delong MR. Alzheimer's disease: a disorder of cortical cholinergic innervation . Science . 1983;219:1184-1190.Crossref 12. DeKosky ST, Harbaugh RE, Schmitt FA, et al. Cortical biopsy in Alzheimer's disease: diagnostic accuracy and neurochemical, neuropathological, and cognitive correlates . Ann Neurol . 1992;32:625-632.Crossref 13. Farlow M, Gracon SI, Hershey LA, Lewis KW, Sadowsky CH, Dolan-Ureno J. A controlled trial of tacrine in Alzheimer's disease . JAMA . 1992;268:2523-2529.Crossref 14. Davis KL, Thal LJ, Gamzu ER, et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disease . N Engl J Med . 1992;327:1253-1259.Crossref 15. Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease . JAMA . 1994;271:985-991.Crossref 16. Growdon JH. Treatment for Alzheimer's disease? N Engl J Med . 1992:327:1306-1308.Crossref 17. Cummings JL, Kaufer D. Neuropsychiatric aspects of Alzheimer's disease: the cholinergic hypothesis revisited . Neurology . 1966;47:876-883.Crossref 18. Raskind MA, Peskind ER. Neurobiologic bases of noncognitive behavioral problems in Alzheimer disease . Alzheimer Dis Assoc Disord . 1994;8( (suppl 3) ):54-60.Crossref 19. Bonner TI, Buckley NJ, Young AC, Brann MR. Identification of a family of muscarinic acetylcholine receptor genes . Science . 1987;237:527-532.Crossref 20. Hulme EC, Birdsall NJM, Buckley NJ. Muscarinic receptor subtypes . Annu Rev Pharmacol Toxicol . 1990;30:633-673.Crossref 21. McKinney M, Coyle JT. Subject review: the potential for muscarinic receptor subtype-specific pharmacotherapy for Alzheimer's disease . Mayo Clinic Proc . 1991;66:1225-1237.Crossref 22. Fisher A, Barak D. Promising therapeutic strategies in Alzheimer's disease based on functionally selective m1 muscarinic agonists: progress and perspectives in new muscarinic agonists . Drug News Perspect . 1994;7:453-464. 23. Mrzljak L, Levey Al, Goldman-Rakic PS. Association of ml and m2 muscarinic receptor proteins with asymmetric synapses in the primate cerebral cortex: morphological evidence for cholinergic modulation of excitatory neurotransmission . Proc Natl Acad Sci U S A . 1993;90:5194-5198.Crossref 24. Levey AI, Kitt CA, Simonds WF, Price DL, Brann MR. Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies . J Neurosci . 1991;11:3218-3226. 25. Flynn DD, Ferrari-DiLeo G, Mash DC, Levey Al. Rapid communication: differential regulation of molecular subtypes of muscarinic receptors in Alzheimer's disease . J Neurochem . 1995;64:1888-1891.Crossref 26. Winkler J, Suhr ST, Gage FH, Thai LJ, Fisher LJ. Essential role of neocortical acetylcholine in spatial memory . Nature . 1995;375:484-487.Crossref 27. Giacobini E. Cholinergic receptors in human brain: effects of aging and Alzheimer's disease . J Neurosci Res . 1990;27:548-560.Crossref 28. Sversson AL, Alufusoff I, Nordberg A. Characterization of muscarinic receptor subtypes in Alzheimer and control brain cortices by selective muscarinic antagonists . Brain Res . 1992;396:142-148.Crossref 29. Mash DC, Flynn DD, Potter LT. Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation . Science . 1985;228:1115-1117.Crossref 30. Davis R, Raby C, Callahan MJ, et al. Subtype selective muscarinic agonists: potential therapeutic agents for Alzheimer's disease . Prog Brain Res . 1993;98:439-445. 31. Yasuda RP, Ciesla W, Flores LR, et al. Development of antisera selective for m4 and m5 muscarinic cholinergic receptors: distribution of m4 and m5 receptors in rat brain . Mol Pharmacol . 1993;43:149-157. 32. Bernard V, Normand E, Bloch B. Phenotypical characterization of the rat striatal neurons expressing muscarinic receptor genes . J Neurosci . 1992;12:3591-3600. 33. Selkoe DJ. Alzheimer's disease: a central role for amyloid . J Neuropathol Exp Neurol . 1994;43:438-447.Crossref 34. Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by Congo red . Proc Natl Acad Sci U S A . 1994;91:12243-12247.Crossref 35. Nitsch RM, Slack BE, Wurtman RJ, Growdon JH. Release of Alzheimer's amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors . Science . 1992;258:304-307.Crossref 36. DeLapp NW, Eckols K, Bymaster FP, Mitch CH, Shannon HE, Ward JS. The muscarinic M1 agonist xanomeline increases soluble amyloid precursor protein release from Chinese hamster ovary-m1 cells . Life Sci . 1995;57:1183-1190.Crossref 37. Bymaster FP, Wong DT, Mitch CH, et al. Neurochemical effects of the M1 muscarinic agonist xanomeline (LY246708/NNC11-0232) . J Pharmacol Exp Ther . 1994;269:282-289. 38. Shannon HE, Bymaster FP, Calligaro DO, et al. Xanomeline: a novel muscarinic receptor agonist with functional selectivity for m1 receptors . J Pharmacol Exp Ther . 1994;269:271-281. 39. Bymaster FP, Whitesitt CA, Shannon HE. Xanomeline: a selective muscarinic agonist for the treatment of Alzheimer's disease. Drug Dev Res. In press. 40. Farde L, Suhara T, Halldin C, et al. New radioligands for PET-examination of central muscarinic receptors. Presented at the Alzheimer's and Parkinson's Diseases Recent Developments Third International Conference; November 1-6,1993; Chicago, Ill. 41. Bodick NC, DeLong AF, Bonate PL, Gillespie T, Henry DP, Satterwhite JH. Xanomeline, a specific m1 agonist: early clinical studies . In: Giacobini E, Becker R, eds. Alzheimer Disease: Therapeutic Strategies . Cambridge, Mass: Birkhauser Boston Inc; 1994:234-238. 42. Sramek JJ, Hurley DJ, Wardle TS, et al. The safety and tolerance of xanomeline tartrate in patients with Alzheimer's disease . J Clin Pharmacol . 1995:35:800-806.Crossref 43. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease . Neurology . 1984;34:939-944.Crossref 44. Folstein MF, Folstein SE, McHugh PR. 'Mini-Mental State': a practical method for grading the cognitive state of patients for the clinician . J Psychiatr Res . 1975;12:189-198.Crossref 45. Mohs RC, Cohen L. Alzheimer's Disease Assessment Scale (ADAS) . Psychopharmacol Bull . 1988;24:627-628. 46. Veroff AE, Cutler NR, Sramek JJ, et al. A new assessment tool for neuropsychopharmacologic research: the computerized neuropsychological test battery . J Geriatr Psychiatry Neurol . 1991;3:211-217.Crossref 47. Knopman DS, Knapp MJ, Gracon SI, Davis CS. The Clinician Interview-Based Impression (CIBI): a clinician's global change rating scale in Alzheimer's disease . Neurology . 1994;44:2315-2321.Crossref 48. Spiegel R, Brunner C, Ermini-Fünfschilling D, et al. A new behavioral assessment scale for geriatric out- and in-patients: the NOSGER (Nurses' Observation Scale for Geriatric Patients) . J Am Geriatr Soc . 1991;39:339-447. 49. Ferris SH, Steinberg G, Shulman E, et al. Institutionalization of Alzheimer's patients: reducing precipitating factors through family counseling . Arch Found Thanatol . 1985;12:7. 50. Reisberg B, Borenstein J, Franssen E, Shulman E, Steinberg G, Ferris SH. Remediable behavioral symptomatology in Alzheimer's disease . Hosp Community Psychiatry . 1986;37:1199-1201. 51. Teri L, Rabins P, Whitehouse P, et al. Management of behavior disturbance in Alzheimer disease: current knowledge and future directions . Alzheimer Dis Assoc Disord . 1992;6:77-88.Crossref 52. Platt JE, Campbell M, Green WH, Perry R, Cohen IL. Effects of lithium carbonate and haloperidol on cognition in aggressive hospitalized school-age children . J Clin Psychopharmacol . 1981;1:8-13.Crossref 53. Cummings JL, Gorman DG, Shapira J. Physostigmine ameliorates the delusions of Alzheimer's disease . Biol Psychiatry . 1993;33:536-541.Crossref 54. Chiodo LA, Buney BS. Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons . J Neurosci . 1983;3:1607-1619. 55. White FJ, Wang RY. Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons . Science . 1983;221:1054-1057.Crossref 56. Stockton ME, Rasmussen K. Electrophysiological effects of olanzapine, a novel atypical antipsychotic, on A9 and A10 dopamine neurons . Neuropsychopharmacology . 1994;14:97-104.Crossref 57. Lipsitz L, Bodick N, Goldberger AL, MacMahon M, Medina A. Effects of central muscarinic-1 receptor stimulation on blood pressure regulation. Hypertension. In press. 58. Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer's disease . Neurology . 1996;46:130-135.Crossref

Journal

Archives of NeurologyAmerican Medical Association

Published: Apr 1, 1997

References

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