title: Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI).
abstract: Cognitive decline seen in the normal elderly is associated with selective loss of neuronal nicotinic acetylcholine receptors (nAChRs). Nicotine given either by inhalation or transdermally helps cognition, but unacceptable side effects limit its utility. The present study assessed the safety, tolerability and effect on cognition of ispronicline, a highly selective partial agonist at the 4beta2 nAChR, in elderly subjects (n =76) with age associated memory impairment (AAMI). This double-blind, placebo-controlled cross-over study explored ascending oral doses of ispronicline in the range 50-150 mg given as a single morning dose for a period of 3 weeks. Pharmacokinetics (PK) were assessed, as well as cognitive function measured by means of the Cognitive Drug Research (CDR) computerized test battery. Ispronicline had a favourable safety profile and was well tolerated at doses below 150 mg. No effect of clinical importance was seen on biochemistry, haematology, urine analysis, vital signs, electrocardiogram (ECG) or Holter monitoring. The most frequent drug induced adverse event was light-headedness (dizziness). A beneficial effect was seen on cognition across the dose range. This was most marked at 50 mg on factors measuring attention and episodic memory. PK analysis indicated a plasma Cmax range of 5-25/35 ng/ml ispronicline was associated with the most beneficial effect. These early results demonstrate ispronicline was well tolerated and did not display the side effects typical of nicotine. Ispronicline also had a beneficial effect on cognition in subjects with AAMI. This was seen most strongly in a Cmax range that had been predicted from pre-clinical animal studies.
authors.affiliation: Clinical Development and Regulatory Affairs, Targacept Inc, Winston Salem, NC 27101, USA. geoffrey.dunbar@targacept.com
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Dunbar
authors.forename: Fraser
authors.initials: F
authors.lastname: Inglis
authors.forename: Ramana
authors.initials: R
authors.lastname: Kuchibhatla
authors.forename: Tonmoy
authors.initials: T
authors.lastname: Sharma
authors.forename: Mark
authors.initials: M
authors.lastname: Tomlinson
authors.forename: James
authors.initials: J
authors.lastname: Wamsley
mesh_terms: D000368:Aged; D003071:Cognition / Q000187:drug effects*; D018592:Cross-Over Studies; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy*; D008875:Middle Aged; D018722:Nicotinic Agonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011978:Receptors, Nicotinic / Q000187:drug effects
chemical_list: D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C490152:ispronicline