Donepezil, the most widely used drug for the treatment of Alzheimer's disease (AD), is an acetylcholinesterase (AChE) inhibitor and is thought to improve cognition by stimulating cholinergic neurotransmission. However, no correlation has yet been established between the inhibitory role of AChE inhibitors and their therapeutic effects when used in AD patients. The cleavage pathway of amyloid precursor protein (APP) includes amyloidgenic (β, γ-cleavage) and non-amyloidgenic (α-cleavage) pathways. The intracellular transportation of APP is important in determining these cleavage pathways. It has been suggested that sorting nexin (SNX) family proteins regulates the intracellular transport of APP, thereby enhancing α-cleavage. In this study, we examined the effects of donepezil on SNX33 expression changes and APP processing in primary cultures of fetal rat cortical neurons. While donepezil treatment increased the levels of SNX33 expression and soluble APPα (sAPPα) in culture media, no changes were observed regarding full-length APP expression in the cell lysate. Donepezil also reduced the release of amyloid β (Aβ) into culture media in a concentration- and time-dependent manner. This reduction was not affected by acetylcholine receptor antagonists. The membrane surface expression of APP was elevated by donepezil. Furthermore, SNX knockdown by antisense morpholino oligos prevented the effects of donepezil. These results indicated that donepezil increased APP expression at the surface of the plasma membrane by decreasing APP endocytosis through upregulation of SNX33, suggesting donepezil might stimulate the non-amyloidogenic pathway. This new mechanism of action for the currently used anti-AD drug may provide a valuable basis for future drug discovery.

Management of chemotherapy-induced adverse effects and the associated pharmaceutical interventions as well as supportive care evidence creation are the most important responsibilities of oncology pharmacists. We have evaluated the (1) efficacy of long-term and successive pharmaceutical care in outpatient chemotherapy and (2) nephroprotective effects of magnesium (Mg) against cisplatin-induced nephrotoxicity (CIN). The results revealed that the adoption rate of pharmaceutical proposals was 98%, and that approximately 70% of the proposals attenuated painful symptoms. Moreover, approximately 60% of pharmaceutical interventions were established after the third visit; in particular, approximately 20% were suggested after the tenth visit. These results have shown that long-term and successive pharmaceutical care by oncology pharmacists in outpatient chemotherapy contributes to a safe and less onerous chemotherapy implementation. CIN frequency and serum creatinine elevation were significantly attenuated by Mg premedication during the cisplatin, docetaxel, and fluorouracil regimen, without changes in adverse effects and response rate. Mg premedication has been suggested to exert a protective effect against CIN without influencing on adverse effects and anti-tumor efficacy. The nephroprotective effect of Mg against CIN was evaluated using Wistar rats. Cisplatin (2.5 mg/kg) was administered once or three times weekly with or without 40 mg/kg MgSO4. The results revealed that Mg regulates the expression of organic cation transporter 2, multidrug and toxin extrusion protein 1, and copper transporter 1, leading to reduced renal platinum accumulation, which results in CIN attenuation. In conclusion, evaluation of pharmaceutical care and supportive care by oncology pharmacists is necessary for advanced care of cancer patients.