Combined Use of In Vitro Phototoxic Assessments and Cassette Dosing Pharmacokinetic Study for Phototoxicity Characterization of Fluoroquinolones

The present study aimed to develop an effective screening strategy to predict in vivo phototoxicity of multiple compounds by combined use of in vitro phototoxicity assessments and cassette dosing pharmacokinetic (PK) studies. Photochemical properties of six fluoroquinolones (FQs) were evaluated by UV spectral and reactive oxygen species (ROS) assays, and phototoxic potentials of FQs were also assessed using 3T3 neutral red uptake phototoxicity test (3T3 NRU PT) and intercalator-based photogenotoxicity (IBP) assay. Cassette dosing pharmacokinetics on FQs was conducted for calculating PK parameters and dermal distribution. All the FQs exhibited potent UV/VIS absorption and ROS generation under light exposure, suggesting potent photosensitivity of FQs. In vitro phototoxic risks of some FQs were also elucidated by 3T3 NRU PT and IBP assay. Decision matrix for phototoxicity prediction was built upon these in vitro data, taken together with outcomes from cassette dosing PK studies. According to the decision matrix, most FQs were deduced to be phototoxic, although gatifloxacin was found to be less phototoxic. These findings were in agreement with clinical observations. Combined use of in vitro photobiochemical and cassette dosing PK data will be useful for predicting in vivo phototoxic potentials of drug candidates with high productivity and reliability

Prevalence of amyloid-beta pathology in distinct variants of primary progressive aphasia

OBJECTIVE: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. RESULTS: Amyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-β positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-β positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-β biomarkers in PPA patients. Ann Neurol 2018;84:737-748