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Donepezil (DPZ) is an acetylcholine-esterase inhibitor currently used as the frontline drug to treat Alzheimer's disease. The aim of this study was to investigate the possibility of postmortem redistribution (PMR) of DPZ, which could complicate the determination of cause of death in medico-legal cases. Additionally, metabolic enzyme DNA polymorphism, drug-drug interaction and the presence of lesions in metabolic and egestion organs were examined to eliminate the possibility of a high antemortem DPZ concentration. Subsequently, the average DPZ concentration of four sites of peripheral blood (right and left femoral artery and vein) was compared with central blood and liver DPZ concentrations in seven postmortem cases. DPZ concentrations ranged from 0.02 to 0.45 μg/mL in the peripheral blood, 0.09-0.4 μg/mL in central blood, and from 1.2 to 6.7 μg/kg in the liver. In most specimens, the concentrations were higher than the therapeutic range (approximately 0.030-0.075 μg/mL). DPZ central blood to peripheral blood (C/P) ratios averaged 1.73 ± 1.02 (±standard deviation) while liver to peripheral blood (L/P) ratios were higher and averaged 17.5 ± 7.25. It is documented that a C/P ratio of less than (or about) 1.0 and an L/P ratio less than 5 are not indicative of PMR, whereas a C/P ratio exceeding 2 and L/P ratio exceeding 20 highlight a propensity for significant PMR. Our data suggest that DPZ exhibits a moderate degree of PMR. Additionally, a lowered pH was found in all blood specimens (<6-6.75 in the peripheral blood and <6-6.66 in the central blood). This postmortem reduction in blood pH may increase the ionic forms of DPZ, resulting in a high blood DPZ concentration. [ABSTRACT FROM AUTHOR]

In this study, the genes expressed in response to low pH stress were identified in the unicellular cyanobacterium Synechocystis sp. PCC 6803 using DNA microarrays. The expression of slr0967 and sll0939 constantly increased throughout 4-h acid stress conditions. Overexpression of these two genes under the control of the trc promoter induced the cells to become tolerant to acid stress. The Δslr0967 and Δsll0939 mutant cells exhibited sensitivity to osmotic and salt stress, whereas the trc mutants of these genes exhibited tolerance to these types of stress. Microarray analysis of the Δslr0967 mutant under acid stress conditions showed that expression of the high light-inducible protein ssr2595 ( HliB ) and the two-component response regulator slr1214 ( rre15 ) were out of regulation due to gene inactivation, whereas they were upregulated by acid stress in the wild-type cells. Microarray analysis and real-time quantitative reverse transcription-polymerase chain reaction analysis showed that the expression of sll0939 was significantly repressed in the slr0967 deletion mutant. These results suggest that sll0939 is directly involved in the low pH tolerance of Synechocystis sp. PCC 6803 and that slr0967 may be essential for the induction of acid stress-responsive genes. [ABSTRACT FROM AUTHOR]