THE ROLE OF BRIDGING STUDIES IN THE DEVELOPMENT OF CHOLINESTERASE-INHIBITORS FOR ALZHEIMERS-DISEASE

The impairment of cognitive function that is seen in patients with Alz heimer's disease is widely considered to be a consequence of cortical deficiencies in cholinergic transmission. Numerous cholinesterase inhi bitors have been investigated for treatment of the disease, aiming to bolster the cholinergic system by blocking the degradation of acetylch oline and prolonging its ability to transmit a signal. The improvement of cognitive impairment that is achieved with cholinesterase inhibito rs is dose dependent; however, the administration of clinically benefi cial doses is sometimes associated with the development of intolerable cholinergic adverse effects. The poor tolerability of efficacious dos es creates a narrow therapeutic index for some cholinesterase inhibito rs, posing a difficult obstacle in both the development and clinical u se of these agents. Bridging studies, in which the maximum tolerated d ose of the compound is determined in a patient population in the early stages of development, can significantly reduce the time and cost of developing new cholinesterase inhibitors. This is achieved by identify ing the upper limit of the dose range in the target population before phase II efficacy studies are initiated. Bridging studies accelerate a nd facilitate the process of development of new compounds by obviating the need for repeated redesign of phase II studies in the search fur an optimal dose.