title: The scopolamine model as a pharmacodynamic marker in early drug development.
abstract: BACKGROUND
  Drug development is a high-risk and high failure enterprise, and studies that provide an early read on the pharmacodynamic activity of novel compounds could save time and money, increasing the efficiency of the drug development process.
  
  
  OBJECTIVE
  Preclinical and clinical experiments were designed to examine the utility of the scopolamine-induced cognitive impairment model in predicting pharmacodynamic signals of putatively procognitive compounds, utilizing the acetylcholinesterase inhibitor donepezil for illustration.
  
  
  RESULTS
  In normal healthy rats, scopolamine (0.3 mg/kg) significantly impaired performance on the two-platform water maze and on the T-maze. The deficits in water maze performance were reversed by donepezil at 0.5 and 1.0 mg/kg. There was a trend towards reversal of scopolamine-induced deficits in performance on the T-maze with 1.0 mg/kg donepezil. In normal healthy humans, scopolamine (0.3 and 0.5 mg) reliably impaired performance on the Cognitive Drug Research test battery composite scores (power of attention, continuity of attention, quality of working memory, quality of episodic secondary memory, and speed of memory) in a dose- and time-dependent manner. Donepezil (10 mg) significantly attenuated the scopolamine-induced impairment in cognition on power of attention, continuity of attention, quality of working memory, and speed of memory.
  
  
  CONCLUSIONS
  These findings suggest that reversal of scopolamine-induced cognitive impairment is a viable model for predicting pharmacodynamic signals of procognitive compounds in both animals and humans. The utility of the scopolamine-induced cognitive impairment model is discussed and illustrated at various decision points in drug development, with a focus on Go/No Go decisions.
authors: Global Pharmaceutical Research and Development, Neuroscience, Abbott Laboratories, 100 Abbott Park Rd, Dept R48B, Bldg AP4, Abbott Park, IL 60064, USA. robert.lenz@abbott.com
authors: Robert A
authors: RA
authors: Lenz
authors: Jeffrey D
authors: JD
authors: Baker
authors: Charles
authors: C
authors: Locke
authors: Lynne E
authors: LE
authors: Rueter
authors: Eric G
authors: EG
authors: Mohler
authors: Keith
authors: K
authors: Wesnes
authors: Walid
authors: W
authors: Abi-Saab
authors: Mario D
authors: MD
authors: Saltarelli
mesh_terms: D000328:Adult; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000633:toxicity; D018697:Nootropic Agents / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D012601:Scopolamine / Q000008:administration & dosage / Q000633:toxicity*; D016037:Single-Blind Method; D013045:Species Specificity; D013997:Time Factors; D055815:Young Adult
chemical_list: D007189:Indans; D018727:Muscarinic Antagonists; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil; D012601:Scopolamine