Prescription Patterns of Medications for Alzheimer's Disease in Japan from 2010 to 2015: A Descriptive Pharmacy Claims Database Study.

INTRODUCTION: Although four kinds of Alzheimer's disease (AD) drugs are available at present there was only one drug until 2011 in Japan. This study aimed to elucidate prescription trends of these medications for AD in Japanese outpatients before and after the new drug releases in 2011. METHODS: This descriptive study of pharmacy claims databases analyzed outpatient prescription data from community pharmacies across Japan. The study patients were 20 years or older and first administered medications for AD (donepezil, memantine, rivastigmine, or galantamine) between January 2010 and September 2014. They were grouped on the basis of the year of their initial medications for AD administration into the 2010-2011 and 2012-2014 groups (1 and 2, respectively) and their characteristics and AD treatments were summarized by group. The subanalyses used a multivariable logistic regression model to examine the relationship between patient characteristics and discontinuation or change to combination therapy within a year. RESULTS: A total of 103,592 patients (group 1 and 2, 28,581 and 75,011, respectively) were prescribed medications for AD during the study period. The group 1 and 2 mean ± standard deviation (SD) ages were 79.6 ± 7.4 and 80.9 ± 7.3 years while female patients constituted 64.0% and 64.5%, respectively. Furthermore, in groups 1 and 2 patients, 99.0% and 94.3% received a medication for AD monotherapy, 92.3% and 59.6% were prescribed donepezil, and 40.5% and 41.5% discontinued treatment within a year, respectively. The subanalyses suggest that being at least 85 years old strongly correlated with treatment discontinuation and change to combination therapy within a year. CONCLUSION: Although the prescription proportions of the various medications for AD have changed since 2011, no apparent changes occurred in the patient characteristics of those who initiated AD treatment between 2010-2011 and 2012-2014.

Caspase-8 mediates mitochondrial release of pro-apoptotic proteins in a manner independent of its proteolytic activity in apoptosis induced by the protein synthesis inhibitor acetoxycycloheximide in human leukemia Jurkat cells.

The cysteine protease caspase-8 plays an essential role in apoptosis induced by death receptors. The protein synthesis inhibitor acetoxycycloheximide (Ac-CHX) has been previously shown to induce rapid apoptosis mediated by the release of cytochrome c in human leukemia Jurkat cells. In this study, the novel molecular mechanism that links caspase-8 to the mitochondrial release of pro-apoptotic proteins has been identified. Jurkat cells deficient in caspase-8 were more resistant to Ac-CHX than wild-type Jurkat cells and manifested decreased apoptosis induction and caspase activation as well as inefficient release of cytochrome c, Smac/DIABLO, and AIF into the cytosol. In contrast to Fas ligand stimulation, the general caspase inhibitor barely prevented the mitochondrial release of these pro-apoptotic proteins in Ac-CHX-treated cells, suggesting that caspase-8 activity is dispensable for triggering the mitochondrial pathway in Ac-CHX-induced apoptosis. Consistent with this notion, caspase-8-deficient Jurkat cells reconstituted with catalytically inactive caspase-8 became sensitive to Ac-CHX and exhibited apoptosis, caspase activation, the liberation of pro-apoptotic proteins into the cytosol, and Bak conformational change as efficiently as wild-type Jurkat cells. Unlike caspase-3, -6, -7, and -9, a small but significant portion of caspase-8 was found to localize in mitochondria before and after exposure to Ac-CHX. These results clearly demonstrate that caspase-8 is able to mediate the mitochondrial release of pro-apoptotic proteins in a manner independent of its proteolytic activity in Ac-CHX-induced apoptosis.

Acetoxycycloheximide (E-73) rapidly induces apoptosis mediated by the release of cytochrome c via activation of c-Jun N-terminal kinase.

Cycloheximide (CHX) is an inhibitor of protein synthesis and commonly used to modulate death receptor-mediated apoptosis or to induce apoptosis in a number of normal and transformed cells. In this study we show that a close structural derivative of CHX, acetoxycycloheximide (E-73) induced rapid processing of procaspases and subsequent apoptosis with much higher efficacy than CHX in human leukemia Jurkat T cells. E-73 induced the release of cytochrome c from mitochondria even in the presence of the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone. The Bcl-2 family protein Bcl-x(L) suppressed cytochrome c release as well as processing of procaspases-3, -8, and -9 in E-73-treated cells. In Jurkat T cells transfected with the caspase-8 modulator FLIP(L), E-73 still induced activation of procaspase-3 and subsequent apoptosis, suggesting that the caspase-8 activity is dispensable for apoptosis. In contrast to CHX, E-73 drastically induced activation of extracellular signal-regulated kinase, c-Jun N-terminal kinase (JNK), and p38 MAP kinase. Inhibitory profiles of small-molecular kinase inhibitors revealed that JNK activation was critical for induction of cytochrome c release in E-73-induced apoptosis. Thus, our present results demonstrate that E-73, unlike CHX, induces strong activation of the JNK pathway and triggers rapid apoptosis mediated by the release of cytochrome c.