ispronicline and Memory-Disorders

Cognitive decline is a feature of ageing and can be defined as normal (age-associated memory impairment) or pathological (mild cognitive impairment/Alzheimer's disease). Stimulation of selective brain-specific neuronal nicotinic acetylcholine receptors might offer symptomatic treatment for normal ageing. The objective of this study was to assess the safety, tolerability and efficacy of TC-1734 (AZD3480), a selective α4β2 nicotinic agonist, in the treatment of age-associated memory impairment. A randomized placebo-controlled trial was conducted in 16 community-based centers within the USA. Subjects who met objective criteria for age-associated memory impairment were recruited between November 2004 and December 2005. Subjects were randomly assigned to receive orally 25 mg (n = 59), 50 mg (n = 68) TC-1734 (AZD3480) or placebo (n = 66) in a double-blind fashion for 16 weeks. Main outcome measures included routine clinical safety measures, tolerability, cognitive assessment via the Cognitive Drug Research computerized test battery and a Subject Global Impression Scale of Cognition (SCI-Cog). Two outcomes from the computerized test battery - a factor assessing attention and one assessing episodic memory, along with the SGI-Cog were defined as co-primary outcome variables. Baseline to Week 16 differences from placebo for 50 mg TC-1734 (AZD3480) were considered of primary importance. For 50 mg TC-1734 (AZD3480) attention factor the mean drug-placebo difference was 22.9 (95% confidence interval 4.8 to 41.4) p = 0.01 for episodic memory factor the difference was -7.6 (95% confidence interval -14.4 to -0.8), p = 0.029, and for the SGI-Cog the difference was 0.99 (95% confidence interval 0.2 to 1.8), p = 0.015. As all three co-primary outcomes were positive it can be concluded the compound likely had a beneficial effect on cognition. TC-1734 (AZD3480) appeared safe and well tolerated in this study.

Topics: Administration, Oral; Aged; Aged, 80 and over; Cognition Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Memory Disorders; Middle Aged; Pyridines; Treatment Outcome

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.

Topics: Aged; Cognition; Cross-Over Studies; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Humans; Male; Memory Disorders; Middle Aged; Nicotinic Agonists; Pyridines; Receptors, Nicotinic