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61.
Sebastián Videla Jesús Cebrecos Mounia Lahjou France Wagner Pascal Guibord Zhengguo Xu Anna Cabot Mercedes Encabo Gregorio Encina Eric Sicard Artur Sans 《Drugs in R&D》2013,13(2):129-135
Background
Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. No data on the dose proportionality of the pharmacokinetics of doxylamine are available, although this drug has been marketed in European countries for more than 50 years.Objective
The objective of this study was to evaluate and compare the dose proportionality between two marketed strengths (12.5 mg and 25 mg) of doxylamine hydrogen succinate after a single oral dose administration under fasting conditions in healthy human subjects.Study Design
This was a single-center, randomized, single dose, laboratory-blinded, two-period, two-sequence, crossover study.Setting
The study was conducted in a phase I clinical unit.Subjects and Methods
A single oral dose of doxylamine hydrogen succinate of 12.5 mg (equivalent to 8.7 mg of doxylamine base) or 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under fasting conditions in each study period. The drug administrations were separated by a wash-out period of 7 calendar days. Blood samples were collected for up to 60 h post-dose, and plasma doxylamine levels were determined by an ultra high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using non-compartmental analysis. Dose proportionality was assessed based on the parameter area under the concentration–time curve (AUCt normalized). Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs and 12-lead electrocardiogram (ECG).Results
In total, 12 healthy volunteers (3 male; 9 female) were included in the study. Mean maximum observed plasma concentration (Cmax) and area under the concentration–time curve from time zero to time t (AUCt) of doxylamine hydrogen succinate 12.5 mg and 25 mg tablets increased linearly and dose-dependently [12.5 mg: mean Cmax 61.94 ng/mL, coefficient of variation (CV) 23.2 %; mean AUCt 817.33 ng·h/mL, CV 27.4 %; and 25 mg: mean Cmax 124.91 ng/mL, CV 18.7 %; mean AUCt 1630.85 ng·h/mL, CV 22.8 %]. Mean AUCt normalized was 815.43 ng·h/mL, CV 22.8 % for 25 mg. The dose-normalized geometric mean ratio (%, 12.5 mg/25 mg) of AUCt was 98.92 (90 % CI: 92.46, 105.83). The most common adverse event was somnolence.Conclusions
Exposure to doxylamine was proportional over the therapeutic dose range of 12.5–25 mg in healthy volunteers. Based on the results, a predictable and linear increase in systemic exposure can be expected. Doxylamine hydrogen succinate was safe and well tolerated. 相似文献62.
63.
64.
Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease
María Carmona-Iragui Mircea Balasa Bessy Benejam Daniel Alcolea Susana Fernández Laura Videla Isabel Sala María Belén Sánchez-Saudinós Estrella Morenas-Rodriguez Roser Ribosa-Nogué Ignacio Illán-Gala Sofía Gonzalez-Ortiz Jordi Clarimón Frederick Schmitt David K. Powell Beatriz Bosch Albert Lladó Michael S. Rafii Juan Fortea 《Alzheimer's & dementia》2017,13(11):1251-1260
Introduction
We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]).Methods
Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid β (Aβ) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68).Results
CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aβ040 levels between groups or between subjects with and without CAA.Discussion
CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aβ40 levels are not a useful biomarker for CAA in AD. 相似文献65.
Marc Giménez‐Milà MD Carme Busquets MD Antonio Ojeda MD Adela Faulí MD PhD Luis Alfonso Moreno MD Sebastian Videla MD PhD 《Pain practice》2014,14(2):158-161
We report a case of a 73‐year‐old female who developed unbearable neuropathic pain after a herpes zoster episode. The pain persisted and could not be controlled despite multimodal analgesia. In addition to postherpetic neuralgia, myelitis and complex regional pain syndrome were diagnosed during the evolution of neuropathic pain. This complex neuropathic pain was resolved after sympathetic ganglion block. 相似文献
66.
Antioxidant properties of the alkaloid boldine in systems undergoing lipid peroxidation and enzyme inactivation 总被引:2,自引:0,他引:2
Boldine, in low micromolar concentrations, was able to prevent brain homogenate autooxidation, the 2,2'-azobis(2-amidinopropane)(AAP)-induced lipid peroxidation of red cell plasma membranes, and the AAP-induced inactivation of lysozyme. These results are indicative of a high reactivity of boldine towards free radicals. The analysis of the boldine effect as a function of incubation times suggests that a metabolite resulting from the interaction of boldine with free radicals also exhibits antioxidant activity, being more efficient than boldine in brain homogenate auto-oxidation and less efficient in lysozyme protection experiments. This behavior may be accounted for in terms of the relative location of the scavengers needed to afford maximal protection. 相似文献
67.
E A Lissi M Salim-Hanna M Fauré L A Videla 《Xenobiotica; the fate of foreign compounds in biological systems》1991,21(8):995-1001
1. 2,2'-Azo-bis-amidinopropane (ABAP) thermal decomposition produces free radicals that initiate the lipid peroxidation of erythrocyte ghost membranes. 2. Addition of 6-n-propyl-2-thiouracil decreases the rate of the process, both by decreasing consumption of the natural antioxidants of the membranes and by direct interaction with the free radicals involved in the lipid peroxidation. 3. Peroxyl radicals produced in ABAP thermal decomposition inactivate lysozyme, horseradish peroxidase (HRP) and glucose oxidase, in that order. The number of enzyme molecules inactivated per radical introduced into the system increases with enzyme concentration. 4. Competitive studies employing mixtures of enzymes show that the order of reactivity of these enzymes towards the peroxyl radicals is the opposite to that obtained for the rate of enzyme inactivation. It is concluded that inactivation efficiency is determined mainly by the average number of free radicals that must react with an enzyme molecule to produce its inactivation, and that this number is directly related to the molecular weight of the enzyme. 相似文献
68.
Protein oxidation in thyroid hormone-induced liver oxidative stress: relation to lipid peroxidation. 总被引:3,自引:0,他引:3
The influence of thyroid hormone administration (daily doses of 0.1 mg of 3,3',5-triiodothyranine (T3)/kg for 1-3 consecutive days) on rat liver protein oxidation was investigated in relation to the calorigenic and lipid peroxidative actions of the hormone. T3 treatment elicited a progressive enhancement in the serum levels of the hormone, the rectal temperature of the animals, and in the rate of O2 uptake of the liver, changes that are significantly correlated and evidence the development of thyroid calorigenesis. Liver lipid peroxidation was augmented by T3 administration as determined by the tissue content of thiobarbituric acid reactants, with a maximal effect (3.1-fold increase) being found at 2 days after treatment, whereas protein oxidation measured by the content of protein hydrazone derivatives exhibited a maximal 88% increase at 3 days. Maximal rates of lipid peroxidation occur at 1 day after the administration of T3, whereas those of protein oxidation are attained after treatment with three daily doses of T3, time at which the former levels off. It is concluded that T3 administration induces a substantial enhancement in hepatic protein oxidation, in addition to lipid peroxidation, that seems to be due to the higher oxidative stress status conditioned in the liver by thyroid calorigenesis. Both processes exhibit a differential time course of changes, that may represent differences in the susceptibility of target molecules to free radical attack and/or in the efficiency of repair mechanisms. 相似文献
69.
Specific Preferences in Lineage Choice and Phenotypic Plasticity of Glioma Stem Cells Under BMP4 and Noggin Influence 下载免费PDF全文
Guillermo Agustín Videla Richardson Carolina Paola Garcia Alejandro Roisman Irma Slavutsky Damián Darío Fernandez Espinosa Leonardo Romorini Santiago Gabriel Miriuka Naomi Arakaki Horacio Martinetto María Elida Scassa Gustavo Emilio Sevlever 《Brain pathology (Zurich, Switzerland)》2016,26(1):43-61
Although BMP4‐induced differentiation of glioma stem cells (GSCs) is well recognized, details of the cellular responses triggered by this morphogen are still poorly defined. In this study, we established several GSC‐enriched cell lines (GSC‐ECLs) from high‐grade gliomas. The expansion of these cells as adherent monolayers, and not as floating neurospheres, enabled a thorough study of the phenotypic changes that occurred during their differentiation. Herein, we evaluated GSC‐ECLs’ behavior toward differentiating conditions by depriving them of growth factors and/or by adding BMP4 at different concentrations. After analyzing cellular morphology, proliferation and lineage marker expression, we determined that GSC‐ECLs have distinct preferences in lineage choice, where some of them showed an astrocyte fate commitment and others a neuronal one. We found that this election seems to be dictated by the expression pattern of BMP signaling components present in each GSC‐ECL. Additionally, treatment of GSC‐ECLs with the BMP antagonist, Noggin, also led to evident phenotypic changes. Interestingly, under certain conditions, some GSC‐ECLs adopted an unexpected smooth muscle‐like phenotype. As a whole, our findings illustrate the wide differentiation potential of GSCs, highlighting their molecular complexity and paving a way to facilitate personalized differentiating therapies. 相似文献
70.
Hormone resuscitation therapy for brain‐dead donors – is insulin beneficial or detrimental? 下载免费PDF全文
Hormonal replacement therapy to brain‐dead potential organ donors remains controversial. A retrospective study was carried out of hormonal therapy on procurement of organs in 63 593 donors in whom information on thyroid hormone therapy (triiodothyronine or levothyroxine [T3/T4]) was available. In 40 124 donors, T3/T4 and all other hormonal therapy were recorded. The percentage of all organs procured, except livers, was greater when T3/T4 had been administered. An independent beneficial effect of antidiuretic hormone (ADH) was also clear. Corticosteroids were less consistently beneficial (most frequently when T3/T4 had not been administered), although never detrimental. Insulin was almost never beneficial and at times was associated with a reduced yield of organs, particularly of the pancreas and intestine, an observation that does not appear to have been reported previously. In addition, there was reduced survival at 12 months of recipients of pancreases from T3/T4‐treated donors, but not of pancreas grafts. The possibly detrimental effect observed following insulin therapy is discussed. 相似文献