Efficacy and Safety of a Transdermal Donepezil Patch in Patients with Mild to Moderate Alzheimer's Disease: Open-Label, Extension Study.

BACKGROUND: In Japan, only oral formulation of donepezil hydrochloride is approved for the treatment of Alzheimer's disease. OBJECTIVE: To evaluate safety and efficacy of a donepezil patch 27.5 mg application for 52 weeks in patients with mild-to-moderate Alzheimer's disease; and to evaluate safety on switching from donepezil hydrochloride tablets. METHODS: This 28-week, open-label study (jRCT2080224517) is an extension of a 24-week double-blind (donepezil patch 27.5 mg versus donepezil hydrochloride tablet 5 mg) noninferiority study. The patch group (continuation group) continued administration of the patch and the tablet group (switch group) switched to the patch in this study. RESULTS: A total of 301 patients participated (156 patients continued using patches; 145 patients switched). Both groups showed similar course on the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog) and ABC dementia scales. At weeks 36 and 52, changes in ADAS-Jcog from week 24 [mean (standard deviation)] were 1.4 (4.8) and 2.1 (4.9) in the continuation group, and 1.0 (4.2), and 1.6 (5.4) in the switch group. The incidence of adverse events at application site in the continuation group over 52 weeks was 56.6% (98/173). Erythema, pruritus, and contact dermatitis at application site were observed in more than 10 patients each. There was no additional adverse event of clinical concern, and no increase in their incidence from the double-blind study. During the four weeks following switching, no patient discontinued or suspended administration due to adverse events. CONCLUSION: Application of the patch for 52 weeks was well tolerated and feasible, including switching from tablets.

Inhibition of astrocytic adenosine receptor A2A attenuates microglial activation in a mouse model of Sandhoff disease.

Astrocyte-microglia communication influences the onset and progression of central nervous system (CNS) disorders. In this study, we determined how chronic inflammation by activated astrocytes affected and regulated CNS functions in Sandhoff disease (SD), a CNS lysosomal storage disorder. SD triggers intense CNS inflammation such as microglial activation and astrogliosis. It is caused by mutation of the HEXB gene, which reduces ß-hexosaminidase (Hex) enzymatic activity in lysosomes, leading to accumulation of the substrate GM2 ganglioside in neuronal cells. Hexb-/- mice display a phenotype similar to human patients that suffer from chronic inflammation characterized by activation of astrocytes and microglia. In Hexb-/- mice, tremors and loss of muscle coordination begins at ~12 weeks. Interestingly, we found that reactive astrocytes expressed adenosine A2A receptor in the cerebral cortices of Hexb-/- mice at the later inflammatory phase. In cultured astrocytes, expression of A2A receptor could be induced by astrocyte defined medium, and then the activation of the A2A receptor induced ccl2 expression. In Hexb-/- mice, inhibition of the A2A receptor antagonized by istradefylline decreased the number of activated microglial cells and inflammatory cytokines/chemokines at 13 weeks. Thus, the astrocytic A2A receptor is an important sensor that regulates microglial activation in the late phase of inflammation.