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 4β2 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 50–150mg 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 150mg. 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 50mg on factors measuring attention and episodic memory. PK analysis indicated a plasma Cmax range of 5–25/35ng/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.

Keywords

ispronicline age associated memory impairment cognition neuronal nicotinic acetylcholine receptor

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References

Buccafusco J , Letchworth S , Bencherif M , Lippiello P M (2005) Long lasting cognitive improvement with nicotinic receptor agonists: mechanisms of pharmacokinetic-pharmacodynamic discordance. Trends in Pharmacological Research, 26: 352–360

Court J A , Lloyd S , Johnson M , Griffiths M , Birdsall N J , Piggott M A , Oakley A E , Ince P G , Perry E K , Perry R H (1997) Nicotinic and muscarinic cholinergic receptor binding in the human hippocampal formation during development and aging. Developmental Brain Research 101: 93–105

Crook T , Bartus T , Ferris S , Whitehouse P , Cohen G , Gershon S (1986) Age-associated memory impairment: proposed diagnostic criteria and measures of clinical change. Report of a National Institute of Mental Health work group. Developmental Neurobiology 2: 261–276

Dunbar G C (2005) Ispronicline: safety, tolerability, pharmacokinetic and Pharmaco EEG changes in volunteer studies. In Fisher A , Hanin I , Memo M , Stocchi F (eds), New Trends in Alzheimer and Parkinson Related Disorders: ADPD 2005. International Proceedings, Medimondi, Bologna, Italy, pp. 235–241

Dunbar G C , Kuchibhatla R V (2006) Cognitive enhancement in man with ispronidine, a nicotinic partial agonist. Journal Molecular Neuro science (In press)

Fratiglioni L , Wang H X (2000) Smoking and Parkinson's and Alzheimer's disease: review of the epidemiology studies. Behavioral Brain Research 113:117–120

Gatto G J , Andrees Bohme G , Caldwell W S , Letchworth S R , Traina V M , Obinu M C , Laville M , Reibaud M , Pradier L , Dunbar G , Bencherif M (2004) TC-1734: an orally active neuronal nicotinic acetylcholine receptor modulator with antidepressant neuroprotective and long lasting cognitive effects. CNS Drugs Review 10: 147–166

Levin E D (1992) Nicotinic systems and cognitive function. Special issue: nicotine. Psychopharmacology, 108: 417–431

Levin E D , Rezvani A H (2000) Development of nicotinic drug therapy for cognitive disorders. European Journal of Pharmacology, 393: 141–146

10.

Min S K , Moon I W , Ko R W , Shin H S (2001) Effects of transdermal nicotine on attention and memory in healthy elderly non-smokers. Psychopharmacology 159: 83–88

11.

Perry E K , Perry R H , Gibson P , Blessed G , Tomlinson B (1977) A cholinergic connection between normal aging and senile dementia in human hippocampus. Neuroscience Letters 6: 85–89

12.

Warburton D M (1990) Psychopharmacological aspects of nicotine. In Wonnacot S , Russell M A H , Stolerman I P , (eds), Nicotine Psychopharmacology: Molecular, Cellular and Behavioral Aspects. Oxford University Press, Oxford, pp. 77–111

13.

Wechsler D (1987) The Wechsler Memory Scale – Revised. Harcourt, Sidcup Wesnes K A (2000) The value of assessing cognitive function in drug development. Dialogues in Clinical Neuroscienc, 2: 183–202

14.

Wesnes K A , Ward T , McGinty A , Petrino O (2000) The memory enhancing effects of a Ginkgo biloba/Panax ginseng combination in healthy middle–aged volunteers. Psychopharmacology 152: 353–361

15.

White H K , Levin E D (1999) Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer's disease. Psychopharmacology 143: 158–165

16.

White H K , Levin E D (2004) Chronic transdermal nicotine patch treatment: effects on cognitive performance in age-associated memory impairment. Psychopharmacology 171: 465–471