68-70 Similarly, some limited effects have been seen with glucose drinks, but again these effects are not robust.71,72 A more recent series of trials have identified oxygen as a cognition enhancer. Here, short (30 seconds to 3 minutes) administrations of pure oxygen have been shown to enhance performance on a wide range of tasks from the CDR system in healthy young73-80 and elderly81,82 volunteers. This wide-ranging work has shown that attention and working and episodic working memory can be enhanced by oxygen Inhibitors,research,lifescience,medical in normal

volunteers, and again supports the concept that enhancements can be made to nonimpaired cognitive function. Considering the work described above, it is not surprising that potential cognition enhancers are screened Inhibitors,research,lifescience,medical in phase 1 trials with young volunteers. NS2330, a compound that combines the inhibition of neuronal monoamine (noradrenaline, dopamine, and serotonin) reuptake with stimulation of the cholinergic system in the prefrontal cortex and hippocampus, was studied in a first-time-to-man safety and tolerability trial.83 At 1- and 2-mg doses, the compound produced a wide range of enhancements on CDR assessments,

including improvements in attention, working memory, and episodic memory, as well as increasing self-rated alertness. These effects were obtained despite the fact that only 6 volunteers Inhibitors,research,lifescience,medical received each active dose and 4 received placebo. The effects seemed particularly long-lasting, and, in a follow-up trial,84 higher doses were studied and effects were assessed up to 360 hours following a single dose. Benefits were seen which were of the same profile Inhibitors,research,lifescience,medical as those seen in the previous study and, remarkably, some benefits were seen at 360 hours. In another firsttime-to-man trial,

a range of doses of NS2359, a noradrenaline, dopamine, and serotonin reuptake inhibitor, was studied in 56 volunteers.85 The compound showed clear cognition-enhancing properties, Inhibitors,research,lifescience,medical particularly with regard to attention and episodic memory. These trials indicate that important Luminespib evidence on the potential of compounds to enhance cognitive function can be obtained simply by including cognitive testing in safety and tolerability trials, which need to be conducted Metalloexopeptidase as part of the drug development process. Further evidence of the utility of this approach comes from a multipledosing safety and pharmacokinetic trial in which CDR testing was introduced to evaluate the potential CNS actions of GTS-21, a selective agonist at the α7 nicotine receptor.86 Here, despite having only 12 volunteers on active medication and 4 on placebo, a clear profile of enhancements was seen for attention and working and secondary memory. This profile was unexpected, as the effects of nicotine are primarily limited to attention and information processing and no consistent effects have been seen in the world literature of beneficial effects of nicotine on memory.