BACKGROUND AND PURPOSE Positive allosteric modulation of a4 beta 2 nicotinic acetylcholine (nACh) receptors could add a new dimension to the pharmacology and therapeutic approach to these receptors. The novel modulator NS9283 was therefore tested extensively. EXPERIMENTAL APPROACH Effects of NS9283 were evaluated in vitro using fluorescence-based Ca2+ imaging and electrophysiological voltage clamp experiments in Xenopus oocytes, mammalian cells and thalamocortical neurons. In vivo the compound was tested in models covering a range of cognitive domains in mice and rats. KEY RESULTS NS9283 was shown to increase agonist-evoked response amplitude of (a4)3(beta 2)2 nACh receptors in electrophysiology paradigms. (a2)3(beta 2)2, (a2)3(beta 4)2 and (a4)3(beta 4)2 were modulated to comparable extents, but no effects were detected at a3-containing or any 2a : 3 beta stoichiometry nACh receptors. Native nACh receptors in thalamocortical neurons similarly displayed DH beta E-sensitive currents that were receptive to modulation. NS9283 had favourable effects on sensory information processing, as shown by reversal of PCP-disrupted pre-pulse inhibition. NS9283 further improved performance in a rat model of episodic memory (social recognition), a rat model of sustained attention (five-choice serial reaction time task) and a rat model of reference memory (Morris water maze). Importantly, the effects in the Morris water maze could be fully reversed with mecamylamine, a blocker of nACh receptors. CONCLUSIONS AND IMPLICATIONS These results provide compelling evidence that positive allosteric modulators acting at the (a4)3(beta 2)2 nACh receptors can augment activity across a broad range of cognitive domains, and that a4 beta 2 nACh receptor allosteric modulation therefore constitutes a promising therapeutic approach to symptomatic treatment of cognitive impairment.

OBJECTIVE: The Diabetes Prevention Program (DPP) is a 27-center randomized clinical trial designed to evaluate the safety and efficacy of interventions that may delay or prevent development of diabetes in people at increased risk for type 2 diabetes. RESEARCH DESIGN AND METHODS: Eligibility requirements were age > or = 25 years, BMI > or = 24 kg/m2 (> or = 22 kg/m2 for Asian-Americans), and impaired glucose tolerance plus a fasting plasma glucose of 5.3-6.9 mmol/l (or < or = 6.9 mmol for American Indians). Randomization of participants into the DPP over 2.7 years ended in June 1999. Baseline data for the three treatment groups--intensive lifestyle modification, standard care plus metformin, and standard care plus placebo--are presented for the 3,234 participants who have been randomized. RESULTS: Of all participants, 55% were Caucasian, 20% were African-American, 16% were Hispanic, 5% were American Indian, and 4% were Asian-American. Their average age at entry was 51 +/- 10.7 years (mean +/- SD), and 67.7% were women. Moreover, 16% were < 40 years of age, and 20% were > or = 60 years of age. Of the women, 48% were postmenopausal. Men and women had similar frequencies of history of hypercholesterolemia (37 and 33%, respectively) or hypertension (29 and 26%, respectively). On the basis of fasting lipid determinations, 54% of men and 40% of women fit National Cholesterol Education Program criteria for abnormal lipid profiles. More men than women were current or former cigarette smokers or had a history of coronary heart disease. Furthermore, 66% of men and 71% of women had a first-degree relative with diabetes. Overall, BMI averaged 34.0 +/- 6.7 kg/m2 at baseline with 57% of the men and 73% of women having a BMI > or = 30 kg/m2. Average fasting plasma glucose (6.0 +/- 0.5 mmol/l) and HbA1c (5.9 +/- 0.5%) in men were comparable with values in women (5.9 +/- 0.4 mmol/l and 5.9 +/- 0.5%, respectively). CONCLUSIONS: The DPP has successfully randomized a large cohort of participants with a wide distribution of age, obesity, and ethnic and racial backgrounds who are at high risk for developing type 2 diabetes. The study will examine the effects of interventions on the development of diabetes.

The Diabetes Prevention Program is a randomized clinical trial testing strategies to prevent or delay the development of type 2 diabetes in high-risk individuals with elevated fasting plasma glucose concentrations and impaired glucose tolerance. The 27 clinical centers in the U.S. are recruiting at least 3,000 participants of both sexes, approximately 50% of whom are minority patients and 20% of whom are > or = 65 years old, to be assigned at random to one of three intervention groups: an intensive lifestyle intervention focusing on a healthy diet and exercise and two masked medication treatment groups--metformin or placebo--combined with standard diet and exercise recommendations. Participants are being recruited during a 2 2/3-year period, and all will be followed for an additional 3 1/3 to 5 years after the close of recruitment to a common closing date in 2002. The primary outcome is the development of diabetes, diagnosed by fasting or post-challenge plasma glucose concentrations meeting the 1997 American Diabetes Association criteria. The 3,000 participants will provide 90% power to detect a 33% reduction in an expected diabetes incidence rate of at least 6.5% per year in the placebo group. Secondary outcomes include cardiovascular disease and its risk factors; changes in glycemia, beta-cell function, insulin sensitivity, obesity, diet, physical activity, and health-related quality of life; and occurrence of adverse events. A fourth treatment group--troglitazone combined with standard diet and exercise recommendations--was included initially but discontinued because of the liver toxicity of the drug. This randomized clinical trial will test the possibility of preventing or delaying the onset of type 2 diabetes in individuals at high risk.