Preclinical AD

Schmitt FA, Davis DG, Wekstein DR, Smith CD, Ashford JW, Mai kesbery WR (2000) Preclinical AD revisited Neuropathology of cognitively normal older adults. Neurology 55 370-376. 

Chetelat G. Alzheimer disease Abeta-independent processes-rethinking preclinical AD. Nat Rev Neurol. 

Incorporation of fluorine at a site adjacent to a "metabolic soft spot" has also been used as a strategy to increase duration of action. Linopir-dine (24) was among the first clinical compounds that enhanced potassium-evoked release of acetylcholine in preclinical models of AD [22]. Linopirdine showed no clinical efficacy and its human pharmacokinetic profile was suggested as the reason for this lack of clinical efficacy. Specifically noted was the molecule s poor brain exposure and short half-life due to formation of the N-oxides 25 and 26 (Table 3) [23,24]. Optimization of 24 resulted in replacement of the indolone core by the anthracenone 27, which had improved in vitro activity, but still exhibited a short duration of action. To improve the metabolic stability, fluorine... 

Dayan AD Rifaximin (Normix ) Preclinical Expert Report. London, submitted to Medicines and Healthcare Products Regulatory Agency, 1997. 

Currently the only specific pharmacological therapeutic option available for AD patients is treatment with cholinesterase inhibitors, which provide moderate benefits in a subset of patients for a limited period [7]. More efficient future therapeutic strategies may be directed at the metabolic events resulting in Ap accumulation, for example by inhibition of P- or y-sec-retase [7], or at the prevention of neuronal loss by neurotrophin therapy [6]. The availability of transgenic mouse models of the disease, such as mice overexpressing APP mutants [8], and the utilization of primate models of cerebral amyloid [9] permits preclinical testing of novel diagnostic and therapeutic approaches. 

Because of the preclinical observations, Nemunaitis et al. completed a Phase I trial of Ad-p53 gene transfer in sequence with cisplatin in 24 NSCLC patients (23). Intravenous cisplatin was administered on d 1 and the Ad-p53 (INGN 201) vector was administered on d 4 by intratumoral CT or bronchoscopic injection. Up to a total of six monthly courses... 

Another important advance adding to the value of PBPK modeling in the pharmaceutical industry are physiological, mechanistic models developed to describe oral absorption in humans and preclinical species. Oral absorption is a complex process determined by the interplay of physiological and biochemical processes, physicochemical properties of the compound and formulation factors. Physiologically based models to predict oral absorption in animals and humans have recently been reviewed [18, 19] and several models are now commercially available. The commercial models have not been published in detail because of proprietary reasons but in essence they are transit models segmenting the gastrointestinal tract... 

For common preclinical laboratory specimens such as mouse and rat, it is possible to image the skeletal features associated with different developmental stages of serial end-point harvested specimens (Fig. 1). Additionally, with the use of radio-opaque contrast agents, it is possible to image capture the soft tissue features of these specimens (Fig. 2). The combined imaging can be used to illustrate various anatomical features of interest within the same specimen (Fig. 3). This imaging technique therefore has an added potential of conferring multi-modality to an individual micro-CT machine. 

Donepezil HC1, a piperidine, is a highly selective inhibitor of the enzyme AChE [3,4] that is chemically unique from other AChE inhibitors [5, 6]. In vitro and preclinical studies have demonstrated that donepezil is approximately 1200 times more selective for AChE in the brain than for butyrylcholinesterase (BuChE) in the periphery [3, 4, 7]. Phase II and III studies conducted in the United States have shown that donepezil (5 or 10 mg once daily) produces statistically significant improvements in cognition and global function in patients with AD [8-10]. Its clinical efficacy and minimal side-effect profile are thought to be related to its specific inhibition of AChE in the areas of the brain affected by the cholinergic deficit that typifies this disease [3, 4, 7],... 

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