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31.
Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV. 总被引:5,自引:0,他引:5
Don K Walker Samantha Abel Pierre Comby Gary J Muirhead Angus N R Nedderman Dennis A Smith 《Drug metabolism and disposition》2005,33(4):587-595
UK-427,857 (4, 4-difluoro-N-[(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl]cyclohexanecarboxamide) is a novel CCR5 antagonist undergoing investigation for use in the treatment of human immunodeficiency virus (HIV) infection. Pharmacokinetic and metabolism studies have been performed in mouse, rat, dog, and human after single and multiple administration by oral and intravenous routes. The compound has physicochemical properties that are borderline for good pharmacokinetics, being moderately lipophilic (log D(7.4) 2.1) and basic (pK(a) 7.3), possessing a number of H-bonding functionalities, and with a molecular weight of 514. The compound was incompletely absorbed in rat (approximately 20-30%) but well absorbed in dog (>70%). Based on in vitro studies in Caco-2 cells, UK-427,857 has relatively poor membrane permeability, and transcellular flux is enhanced in the presence of inhibitors of P-glycoprotein. Further evidence for the involvement of P-glycoprotein in restricting the oral absorption of UK-427,857 was obtained in P-glycoprotein null mice (mdr1a/mdr1b knockout). In these animals, AUC after oral administration was 3-fold higher than in control animals. In oral dose escalation studies in humans, the compound demonstrated nonlinear pharmacokinetics, with increased dose-normalized exposure with increased dose size, consistent with saturation of P-glycoprotein. The oral dose-exposure relationship of UK-427,857 in humans was not reflected in either rat or dog. In animal species and humans, UK-427,857 undergoes some metabolism, with parent compound the major component present in the systemic circulation and excreta. Elimination of radioactive dose was primarily via the feces. In rat, parent compound was secreted via bile and directly into the gastrointestinal tract. Metabolites were products of oxidative metabolism and showed a high degree of structural consistency across species. 相似文献
32.
Sonia Galván-Arzate José Pedraza-Chaverrí Omar N Medina-Campos Perla D Maldonado Beatriz Vázquez-Román Camilo Ríos Abel Santamaría 《Food and chemical toxicology》2005,43(7):1037-1045
Thallium (Tl+) toxicity has been related with the generation of reactive oxygen species (ROS) and oxidative stress (OS) in the central nervous system. Since changes in endogenous antioxidant systems might contribute to acute Tl+-induced OS and neurotoxicity, in this study we measured the metal concentration and the levels of lipid peroxidation (LP) in different brain regions (hypothalamus (Ht); cerebellum (Ce); striatum (S); hippocampus (Hc) and frontal cortex (Cx)) in possible correlation with the content of reduced glutathione (GSH), the activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD), and the animal performance in behavioral tests, all evaluated after a single administration of thallium acetate (8 or 16 mg/kg, i.p.) to rats. Seven days after Tl+ administration, the metal was homogeneously and dose-dependently accumulated in all regions evaluated. LP was increased in Ht, Ce and S, while GSH was depleted in S. Cu,Zn-SOD activity was also decreased in Ht and S. All these changes occurred with 16 mg/kg dose and at 7 days after treatment, but not at 1 or 3 days. In addition, Tl+-treated animals exhibited general hypokinesis, but no changes were observed in spatial learning. Our findings suggest that a delayed response of the brain to Tl+ may be the result of its residual levels. Also, despite the regional alterations produced by Tl+ in LP and the limited changes in endogenous antioxidants, there is a correlation between the Tl+-induced oxidative damage and the affected behavioral tasks, suggesting that, although still moderate, Tl+ evokes neurotoxic patterns under the experimental conditions tested. 相似文献
33.
Puntis JW Thwaites R Abel G Stringer MD 《Developmental medicine and child neurology》2000,42(2):97-99
Whether antireflux surgery should be routinely performed at the time of gastrostomy in children with neurological disorders is debatable because of the risk of gastroesophageal reflux. Some argue that these children should be screened for occult gastroesophageal reflux as this will determine the need for fundoplication. This study retrospectively examines outcome in 29 children with neurological disorders who underwent percutaneous endoscopic gastrostomy (PEG) without concomitant fundoplication. Children were included if they had no clinical evidence of severe gastroesophageal reflux before PEG insertion. The median age of children at PEG insertion was 5.6 years (range 1.1 to 18.0). The children were followed for a median of 2.6 years (range 0.4 to 4.9). Insertion of PEG was technically impossible in two children; and an asymptomatic gastrocolic fistula in another child led to subsequent tube removal. Fourteen of the 26 remaining children developed symptomatic gastroesophageal reflux after PEG; five of these showed no reflux on pH monitoring prePEG. Control of symptoms was achieved by medical intervention in 12, but two required fundoplication. Our findings indicate that in the child with neurological disabilities without symptoms indicating severe gastroesophageal reflux, fundoplication is unlikely to be necessary as a consequence of PEG insertion. We conclude that routine investigation for gastroesophageal reflux in the child without severe vomiting can be avoided and the number of antireflux procedures reduced. 相似文献
34.
35.
Christina R Maxwell Yuling Liang Bryanne D Weightman Stephen J Kanes Ted Abel Raquel E Gur Bruce I Turetsky Warren B Bilker Robert H Lenox Steven J Siegel 《Neuropsychopharmacology》2004,29(4):739-746
Auditory evoked potentials have been used in a variety of animal models to assess information-processing impairments in schizophrenia. Previous mouse models have primarily employed a paired click paradigm to assess the transient measures of auditory gating. The current study uses stimulus trains at varied interstimulus intervals (ISI) between 0.25 and 8 s in mice to assess the effects of chronic olanzapine and haloperidol on auditory processing. Data indicate that olanzapine increases the amplitude of the N40, P80, and P20/N40 components of the auditory evoked potential, whereas haloperidol had no such effect. The ISI paradigm also allowed for an evaluation of several components of the mouse evoked potential to assess those that display response properties similar to the human P50 and N100. Data suggest that the mouse N40 displays an ISI response relationship that shares characteristics with the human N100, whereas the P20 appears more consistent with the human P50 across the ISI range evaluated in this task. This study suggests that olanzapine may help improve N100 impairments seen in schizophrenia, while haloperidol does not. 相似文献
36.
37.
Vasopressin receptor mediated contraction and [3H]inositol metabolism in rat tail artery 总被引:1,自引:0,他引:1
Inositol phosphates (IP) production and contraction in isolated but otherwise intact rat tail artery were measured in response to stimulation by vasopressin agonists. We have previously studied similar alpha-adrenoceptor responses. Identical rank orders of vasopressin agonists' potency were found for IP accumulation and contraction. The vasopressin analogue [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid)-2-(O-methyl)tyrosine,D-arginine8] vasopressin, was shown to be a specific, reversible antagonist for both IP accumulation and contraction by all vasopressin agonists tested. No antagonism of vasopressin induced increases in IP accumulation or contraction were found using phenoxybenzamine. Therefore, in this tissue vasopressin receptors mediate both contraction and IP accumulation; and vasopressin mediated responses appear to be direct effects not mediated via the activation of alpha-adrenoceptors. Demonstration of two entirely different receptors, mediating the same functional response, and which both promote IP production, is consistent with a general obligatory role for phosphoinositide catabolism in receptor mediated vascular smooth muscle contraction. 相似文献
38.
Markus Wertz Michael Benno Schmidt Hieronymus Hoelzig Maximilian Wagner Bernd Abel Gert Kloess Sebastian Hahnel Andreas Koenig 《Materials》2022,15(13)
In the study the influence of different dental technical tools on the surface temperature and phase composition of fixed dental prostheses (FDPs) made of yttria-partially stabilized zirconia polycrystals (3Y-/4Y-/5Y-PSZ) was investigated. FDPs were fabricated by using computer-aided manufacturing (CAM). The FDPs were treated with a contra-angle handpiece equipped with different burs and polishers. The resulting surface temperatures were measured with a thermographic camera, and the resulting phase transformations were investigated by X-ray diffraction and quantified by Rietveld refinement. Processing with burs resulted in no phase transformation, but a preferred orientation shift. Using coarse polisher induced a phase transformation to the rhombohedral phase, while fine polishers produced no relevant phase transformations and no preferred orientation shift. Compared to the monoclinic phase (ca. 9% theoretical volume increase), which is associated with low-temperature degradation (LTD), the rhombohedral phase is much more voluminous (ca. 15% theoretical volume increase) and distorted and, therefore, has a greater degradation potential. 相似文献
39.
Ken L. Abel Sebastian Weber David Poppitz Juliane Titus Thomas L. Sheppard Roger Glser 《RSC advances》2022,12(26):16875
Thermally stable, highly mesoporous Si-stabilized ZrO2 was prepared by sol–gel-synthesis. By utilizing the surfactant dodecylamine (DDA), large mesopores with a pore width of ∼9.4 nm are formed. Combined with an NH3-treatment on the hydrogel, a high specific surface area of up to 225 m2 g−1 and pore volume up to 0.46 cm3 g−1 are obtained after calcination at 973 K. The individual contributions of Si-addition, DDA surfactant and the NH3-treatment on the resulting pore system were studied by inductively coupled plasma with optical emission spectrometry (ICP-OES), X-ray diffraction (XRD), N2 sorption, and transmission electron microscopy (TEM). Electron tomography was applied to visualize and investigate the mesopore network in 3D space. While Si prevents the growth of ZrO2 crystallites and stabilizes the t-ZrO2 phase, DDA generates a homogeneous mesopore network within the zirconia. The NH3-treatment unblocks inaccessible pores, thereby increasing specific surface area and pore volume while retaining the pore width distribution.Schematic representation of ZrO2 crystallites; (a) monoclinic ZrO2, (b) tetragonal ZrO2 following Si-stabilization, (c) mesoporous t-ZrO2 following Si-stabilization and use of surfactant dodecylamine. 相似文献
40.
E L Abel 《Drug and alcohol dependence》1986,18(3):253-257
A retrospective study of homicide victims in Erie County, NY was conducted for 1973-1984 to determine the association of blood alcohol levels among homicide victims slain by guns and other weapons. Most victims of gunshot or beating had negative blood alcohol levels (BALs) at time of death whereas most stabbing victims had positive BALs, especially black victims. Gunshot victims were more likely to be killed in a private home compared to a street or building. Location of homicide did not relate significantly to BAL. Younger victims were less likely to be shot to death compared to middle-aged victims. These results do not support previous contentions that alcohol is a major contributor to gun-related homicides. 相似文献