The same holds for the new compound studied and for its interaction with the challenge. As a selleck inhibitor consequence, a positive result (ie, reversal or prevention of the challenge’s

effects by the new drug) is undoubtedly a clue to efficacy, but. a negative result can hardly be taken as the basis for a “no-go” decision. This often makes pharmaceutical companies reluctant to add a POC study in HVs to their development plan, arguing that, in case of negative results, it could merely delay it. and increase costs. In fact, introducing POC studies in HVs implies further enhancing the global phase 1 scheme (Table I). In this “enhanced development plan,” Inhibitors,research,lifescience,medical the single-dose study has the same design and goals as the regular Inhibitors,research,lifescience,medical one. The repeated-dose study merges the former repeated-dose and PD HV studies, ie, it. is conducted according to a crossover (per dose), placebo-controlled design. Provided that a single administration study has shown good tolerability in an HV group close to the target population (eg, elderly HVs for cognitive enhancers), this study can be conducted in such a group. A model, if available, can also be used in this study,

Inhibitors,research,lifescience,medical by adding an administration the day after the classic PK and PD assessments. This avoids wasting HVs and resources, and maximizes the chances of positive results; however, it requires paying close attention to tolerability and safety, which must, be verified before a challenge is added to a repeated-administration study. Models at FORENAP Few models are available for routine use in drug development. We have launched a program to adapt existing models Inhibitors,research,lifescience,medical for this purpose (Table III), following the principles described above. Below we discuss the rationale for each of these models, as well as preliminary results when available, at. least those which are not covered by confidentiality agreements. Table III Models available or in development at FORENAP. AD, Alzheimer’s disease; Inhibitors,research,lifescience,medical CCK-4, cholecystokinin tetrapeptide; EEG, electroencephalography;

ERP, event-related potential; fMRI, functional magnetic resonance imaging; MEG, magnetoencephalography. Alzheimer’s disease and age-related cognitive impairment The scopolamine model The scopolamine model because is based on the cholinergic hypothesis of aging and Alzheimer’s disease (AD). Its theoretical drawback is that scopolamine is a nonselective muscarinic blocker, whereas selective muscarinic Mr blockade could be considered to better modelize the status of the cholinergic system in AD.12 Nevertheless, it is a well-established model, producing cognitive defects close to those observed in mild AD and FRG changes consisting of an increase in 5 and – to a lesser extent – 6 bands, and a decrease in a and p power.