The Safety and Tolerance of Xanomeline Tartrate, an M1-Specific Cholinergic Agonist, in Patients with Alzheimer’s Disease

  • N. R. Cutler
  • J. J. Sramek
  • R. D. Seifert
  • J. J. Conrad
  • T. S. Wardle
Part of the Advances in Behavioral Biology book series (ABBI, volume 44)

Abstract

Xanomeline tartrate [3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)-1,2,5,6-tetrahydro-l-methylpyridine tartrate], also known as LY246708 tartrate, is a potent and selective M1 agonist that crosses the blood brain barrier in animals and is orally bioavailable (Eli Lilly, unpublished data). Safety trials of xanomeline tartrate in healthy young adults did not determine a maximum tolerated dose. At the highest dose tested in a single dose trial, 150 mg, one volunteer experienced moderate nausea, while no adverse effects were observed at doses up to 75 mg bid in a multiple dose trial. A study of healthy elderly subjects reported moderate diarrhea, nausea, vomiting, diaphoresis and hypotension at the maximum dose of 50 mg tid. However, higher dosages were not tested. Clinical trials of other cholinergic compounds have shown that the AD patient population frequently tolerates drugs quite differently from healthy volunteers (Cutler et al., 1992). “Bridging studies” which determine the safety and tolerance of a drug in the target population aid in the selection of appropriate doses for Phase II efficacy tests (Cutler et al., 1993). We report the results of two double-blind, placebo controlled bridging studies of the safety and tolerance of xanomeline tartrate in AD patients.

Keywords

Cholinergic Agonist Healthy Elderly Subject Orthostatic Blood Pressure Moderate Nausea Moderate Diarrhea 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Cutler, N.R., Sramek, J.J., Murphy, M.F., and Nash, R.J., 1992, Implications of the study population in the early evaluation of anticholinesterase inhibitors for Alzheimer’s disease, Ann. Pharmacother. 26: 1118–1122.PubMedGoogle Scholar
  2. Cutler, N.R., Sramek, J.J., Seifert, R.D., and Sawin, S.F., 1993, The target population in phase I trials of acetylcholinesterase inhibitors in dementia: the role of the “bridging study.” in: Alzheimer’s Disease: Advances in Clinical and Basic Research, Corain, B., Iqbal, K., Nicolini, M., Winblad, B., Wisniewski, H., and Zatta, P., eds., Sussex, England, John Wiley Sons, Ltd. pp. 559–562.Google Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • N. R. Cutler
    • 1
  • J. J. Sramek
    • 1
  • R. D. Seifert
    • 1
  • J. J. Conrad
    • 1
  • T. S. Wardle
    • 1
  1. 1.California Clinical TrialsBeverly HillsUSA

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