Toning Down a Treatment

• Report this Comment On April 03, 2009, at 7:23 PM, Georgejjll wrote:

  You said,"...thing. There's a reason why drugmakers choose the doses that they decide to use in phase 3 trials: The highest dose almost always has the highest effectiveness..." That is WRONG!!!

  Alzheimer's drugs generally have and inverted "U" shaped dose response, which means that too much is just as bad as too little" there is an optimum dose for drug effectiveness.

  For APOE4 non-carriers the optimum dose for Bapineuzumab may quite probably be 0.5 mg/kg.

  "Alzheimer's disease drugs: an application of the hormetic dose-response model.Calabrese EJ.

  Environmental Health Sciences Division, School of Public Health, University of Massachusetts, Amherst, Massachusetts 01003, USA. edwardc@schoolph.umass.edu

  This article provides an evaluation of the dose-response features of drugs that are intended to improve memory, some of which have been used in the treatment of Alzheimer's disease (AD). A common feature of these drugs is that they act via an inverted U-shaped dose response, consistent with the hormetic dose response model. This article assesses historical foundations that lead to the development of AD drugs, their dose-response features and how the quantitative features of such dose responses affected drug discovery and development, and the successes and possible failures of such agents in preclinical and clinical settings. This story begins about 150 years ago with the discovery of an active agent in the Calabar bean plant called physostigmine, its unfolding medical applications, and its implications for dose-response relationships, memory enhancement, and improved drug discovery activities. The article also demonstrates the occurrence of U-shaped dose responses for memory with numerous endogenous agonists including neurosteroids, various peptides (e.g., vasopressin, CCK-8, neuropeptide Y), and other agents (e.g., epinephrine, antagonists for platelet activity factor and nicotinic receptors), supporting the generalizability of the hormetic biphasic dose response. Finally, the significance of the U-shaped dose response is critical for successful clinical application, since it defines the therapeutic window."

  http://www.ncbi.nlm.nih.gov/pubmed/18568864?ordinalpos=1&...

  Look at pages 15 and 17 and tell me which doses you think prabably will prove to be most effective.

  http://library.corporate-ir.net/library/88/883/88326/items/3...

  Good luck and God bless,

  George

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