RESUMEN
BACKGROUND: Few studies have investigated treatment options for patients with Alzheimer's disease (AD) showing a poor response to oral cholinesterase inhibitors (ChEIs) in Japan. OBJECTIVE: To investigate the efficacy and safety of switching from oral ChEIs to rivastigmine transdermal patch in patients with AD. METHODS: In this multicenter, open-label, phase IV study in outpatient clinics in Japan, patients with mild-moderate AD who had a poor response to or experienced difficulty in continuing donepezil or galantamine were switched to rivastigmine transdermal patch (5 cm2; loaded dose 9 mg, delivery rate 4.6 mg/24 h) with a 1-step titration in week 4 (10 cm2; loaded dose 18 mg, delivery rate 9.5 mg/24 h), which was continued for 4 weeks in the titration period and 16 weeks in a maintenance period. The primary endpoint was the change in Mini-Mental State Examination (MMSE) total score from baseline to week 24. RESULTS: A total of 118 patients were enrolled and switched to rivastigmine, of which 102 completed the 24-week study. The MMSE total score was essentially unchanged during the study, with a least-square mean change (SD) of -0.35 (2.64) at week 24 (p = 0.1750). Exploratory analysis with a mixed-effect model comparing changes in MMSE between the pre- and post-switch periods suggested that switching to rivastigmine prevented a worsening of MMSE. Application site skin reactions/irritations occurred in 30.5% of patients overall, in 22.0% in the 8-week titration period, and in 10.2% in the 16-week maintenance period. CONCLUSION: Within-class switching from an oral ChEI to rivastigmine transdermal patch might be an efficacious and tolerable option for AD patients showing a poor or limited response to a prior oral ChEI.
RESUMEN
Novel ratiometric, near-infrared fluorescent pH probes with various pK(a) values have been designed and synthesized on the basis of aminocyanine bearing a diamine moiety, and their photochemical properties were evaluated. Under acidic conditions, these pH probes showed a 46- to 83-nm red shift of the absorption maximum. This change is sufficiently large to permit their use as ratiometric pH probes, and is reversible, whereas monoamine-substituted aminocyanines showed irreversible changes because of their instability under acidic conditions. Furthermore, the pK(a) values of these probes can be predicted from the calculated pK(a) values of the diamine moieties, obtained from the SciFinder database. This design strategy is very simple and flexible, and should be applicable to develop NIR pH probes for various applications.
Asunto(s)
Diaminas/química , Colorantes Fluorescentes/química , Espectroscopía Infrarroja Corta/métodos , Colorantes Fluorescentes/síntesis química , Células HeLa , Humanos , Concentración de Iones de HidrógenoRESUMEN
PURPOSE: Hydrodynamic injection has been shown to reactivate silenced transgene expression in mouse liver. In this study, the roles of inflammatory cytokines and reactive oxygen species (ROS) in the reactivation were examined. METHODS: Production of inflammatory cytokines and ROS by hydrodynamic injection of saline was examined in mice that had received a hydrodynamic injection of a plasmid expressing Gaussia luciferase. The level of reporter gene expression was used as an indicator of the reactivation. The involvement of cytokines and ROS was examined by depleting Kupffer cells or by pre-administration of antioxidants, respectively. RESULTS: A hydrodynamic injection of saline induced a significant production of interleukin (IL)-6. Depleting Kupffer cells using clodronate liposomes markedly reduced the IL-6 production but had no significant effect on the transgene expression. On the other hand, an injection of catalase or N-acetylcysteine significantly inhibited the hydrodynamic injection-induced reactivation of silenced transgene expression. The silenced expression was also reactivated by carbon tetrachloride, an inducer of oxidative stress in the liver, in a dose-dependent manner, and this reactivation was significantly inhibited by catalase. CONCLUSIONS: These findings show a positive correlation between the generation of ROS and the reactivation of silenced transgene expression after hydrodynamic injections.
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Expresión Génica , Silenciador del Gen/efectos de los fármacos , Técnicas de Transferencia de Gen , Hígado/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transgenes , Animales , Tetracloruro de Carbono/farmacología , Ácido Clodrónico/farmacología , ADN/administración & dosificación , ADN/genética , Ensayo de Inmunoadsorción Enzimática , Expresión Génica/efectos de los fármacos , Hidrodinámica , Inyecciones Intravenosas , Interleucina-6/sangre , Interleucina-6/inmunología , Soluciones Isotónicas/administración & dosificación , Soluciones Isotónicas/farmacología , Macrófagos del Hígado/efectos de los fármacos , Macrófagos del Hígado/patología , Liposomas , Hígado/inmunología , Hígado/patología , Luciferasas/genética , Masculino , Ratones , Ratones Endogámicos ICR , Microscopía Fluorescente , Plásmidos/administración & dosificación , Plásmidos/genética , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Based on the findings that the azo functional group has excellent properties as the hypoxia-sensor moiety, we developed hypoxia-sensitive near-infrared fluorescent probes in which a large fluorescence increase is triggered by the cleavage of an azo bond. The probes were used for fluorescence imaging of hypoxic cells and real-time monitoring of ischemia in the liver and kidney of live mice.
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Compuestos Azo/química , Transferencia Resonante de Energía de Fluorescencia/métodos , Colorantes Fluorescentes/química , Hipoxia/diagnóstico , Isquemia/diagnóstico , Espectroscopía Infrarroja Corta/métodos , Enfermedad Aguda , Animales , Línea Celular Tumoral , Fluorescencia , Humanos , Ratones , Oxígeno/químicaRESUMEN
In spite of the wide availability of various near-infrared (NIR) fluorophores as labeling reagents, there are few functional NIR fluorescent probes for which change in the absorption and/or fluorescence spectra upon specific reaction with biomolecules is seen. The widely used photoinduced electron-transfer mechanism is unsuitable for NIR fluorophores, such as tricarbocyanines, because their long excitation wavelength results in a small singlet excitation energy. We have reported the unique spectral properties of amine-substituted tricarbocyanines, which were utilized to develop two design strategies. One approach was based on control of the absorption wavelength by using the difference in electron-donating ability before and after a specific reaction with a biomolecule, and the other approach was based on control of the fluorescence intensity by modulating the Förster resonance energy-transfer efficiency through a change in the overlap integral that arises from the change in absorption under acidic conditions. These strategies were validated by obtaining tricarbocyanine-based ratiometric NIR fluorescent probes for esterase and for pH level.
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Carbocianinas/química , Colorantes Fluorescentes/química , Esterasas/metabolismo , Colorantes Fluorescentes/síntesis química , Concentración de Iones de Hidrógeno , Estructura Molecular , Espectroscopía Infrarroja CortaRESUMEN
Novel ratiometric fluorescent probes for Zn2+ in the near-infrared region, based on a tricarbocyanine chromophore, have been designed, synthesized, and evaluated. Upon addition of Zn2+, a 44 nm red shift of the absorption maximum was observed, which indicates that this probe could work as a ratiometric probe for Zn2+. This change is due to the difference in the electron-donating ability of the amine substituent before and after reaction with Zn2+. This fluorescence modulation of amine-substituted tricarbocyanines should be applicable to dual-wavelength measurement of various biomolecules or enzyme activities.