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Enantiomeric interaction of flurbiprofen in the rat 总被引:2,自引:0,他引:2
Flurbiprofen [FL, (+/-)-2-(2-fluoro-4-biphenylyl)propionic acid] is a 2-arylpropionic acid nonsteroidal anti-inflammatory drug which is commercially available as a racemate. The anti-inflammatory activity of FL, however, appears to be mainly due to the S enantiomer. Recently, it has been postulated that, in both humans and rats, the two enantiomers of FL may interact when racemic doses are given. This study examines the above postulate in the rat by administration of single iv doses of racemic FL (10 mg/kg), and R- and S-FL (5 mg/kg of each). Plasma concentrations (0-12 h) of the enantiomers were measured using a stereospecific HPLC assay. A significant interaction was noticed between the enantiomers: mean AUC +/- SD of R-FL was reduced from 115.3 +/- 21.3 to 49.0 +/- 10.4 mg/L.h as a result of S-FL coadministration. A trend towards reduced S-FL plasma concentration was also evident when the enantiomer was given as the racemate [mean AUC +/- SD; 176.8 +/- 37.7 racemate versus 241.4 +/- 86.2 mg/L.h alone]. The reduction in S-FL, however, was not significant due perhaps to the observed interanimal variation. While the enantiomeric interaction caused a significant enlargement of the volume of distribution of R-FL, it failed to alter the terminal half-life of the enantiomer. It is suggested that the interaction is a result of displacement from plasma protein binding sites of one enantiomer by the other. 相似文献
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Amir A Jamali Christopher Deuel Aimee Perreira Christopher J Salgado John C Hunter E Bradley Strong 《Computer aided surgery》2007,12(5):278-285
INTRODUCTION: Traditional advanced imaging modalities such as CT and MRI are limited in their ability to perform accurate linear distance and angular measurements regardless of anatomical orientation. The construction of 3D models has been used to perform anthropometric analyses as well as in the reconstruction of rapid prototypes. We hypothesized that such measurements would be precise to within 2 mm or 2 degrees of measurements performed with a coordinate measurement machine (CMM). We also hypothesized that there would be a high degree of interobserver reliability with these measurements. MATERIALS AND METHODS: Multiple aluminum screws were implanted in various positions in three foam pelvises which were subsequently scanned by CT and rendered as 3D models using a commercially available software package (Mimics). Linear and angular measurements were performed using a CMM machine, the software package, and a dial caliper or goniometer. The deviation of the measurements from the CMM data was compared using ANOVA. The interobserver reliability of both the manual and computer-generated measurements was calculated. RESULTS: The mean difference between the CMM distances and those measured manually and with the software was 2.12 +/- 1.20 mm and 1.57 +/- 1.05 mm, respectively. The mean difference between the CMM angular measurements and the angular measurements performed manually and with the software was 4.07 +/- 4.70 degrees and 1.62 +/- 1.32 degrees, respectively. In all cases, the manual measurements were significantly less accurate (p < 0.0001) and there was a high degree of interobserver reliability. CONCLUSIONS: Computer-generated measurements taken from three-dimensionally reconstructed models are more accurate than manual measurements and are within 2 mm and 2 degrees of measurements performed with a CMM. These measurements have high interobserver reliability. 相似文献
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Nonstereospecific studies have indicated that the pharmacokinetics of propranolol (PR) are altered in inflammatory conditions such as arthritis. However, as the kinetics and dynamics of PR are stereoselective, we examined the effect of adjuvant arthritis (AA) on the disposition of the individual enantiomers. A novel normal-phase stereospecific HPLC assay for PR was developed involving chiral derivatization with S-(naphthyl)ethyl isocyanate and fluorescence detection. Oral and iv doses of racemic PR were administered to control and AA rats (n = 6). AA had no significant effect on either clearance or S:R ratio after iv doses. On the other hand, after oral doses, clearance was significantly decreased in AA. Although significant for both enantiomers, this effect was more pronounced on the less active R-enantiomer. The AUC R:S ratio was, therefore, significantly altered (AA, 14 ± 3.0; control, 4.3 ± 1.2). Increased total (S + R) plasma concentrations of PR in AA, possibly due to a reduced intrinsic clearance, therefore, reflect mainly increased concentrations of the less active R-enantiomer. 相似文献
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S. M. Mirbod Hideyo Yoshida Marjan Jamali Kazuhito Masamura Ryoichi Inaba Hirotoshi Iwata 《International archives of occupational and environmental health》1997,70(1):22-28
The aims of this study were (1) to evaluate subjective symptoms in the hand-arm system of all traffic police motorcyclists
of a city located in the central part of Japan and (2) to assess their hand-arm vibration exposure associated with traffic
police motorcycle riding. The study population consisted of 119 motorcycling traffic policemen and 49 male controls. By means
of a questionnaire, information on the occupational history and the presence of subjective symptoms in the hand-arm system
of all subjects was obtained. Vibration was measured on the handlebars of the representative motorcycles and on the hands
of the riders. The 4- and 8-h energy-equivalent frequency-weighted acceleration as well as the lifetime vibration dose were
calculated for all police motorcyclists. The prevalence of finger blanching in the traffic police motorcyclists was 4.2%,
but none of the controls had this symptom. The rates of finger numbness (19.3%), finger stiffness (16.0%), shoulder pain (13.4%),
and shoulder stiffness (45.4%) were significantly higher among police motorcyclists as compared with controls. The root-mean-square
(rms) frequency-weighted acceleration on the handlebars of police motorcycles was in the range of 2.2–4.9 m/s2 rms. The computed 4- and 8-h energy-equivalent frequency-weighted acceleration values were 2.8– 4.5 and 2.0 –3.2 m/s2 rms, respectively. A pattern of increasing percentage prevalence with increasing cumulative vibration dose was noticed. The
subjects with a lifetime vibration dose of more than 20.1 m2 h 3 s-4 (ln scale) showed significantly higher prevalence rates for symptoms in the fingers and shoulders as compared with the control
group. As occupational vibration exposure of traffic police motorcyclists might be considered a risk factor for the development
of symptoms in the hand-arm system of the riders, its evaluation and control is needed for prevention methodology evolution.
Received: 15 April 1996/Accepted: 8 November 1996 相似文献
10.
M. Abdellah Alaoui Jamali Ming-biao Yin Alessandra Mazzoni Issam Bankusli Youcef M. Rustum 《Cancer chemotherapy and pharmacology》1989,25(2):77-83
Summary The effect ofN-(3,4-dimethoxyphenyl)N-methyl-2-(naphthyl)-m-dithiane-2-propylamine hydrochloride (RO11-2933), an analog of the calcium channel blocker tiapamil, on doxorubicin (DOX)-induced cytotoxicity and DNA damage in human ovarian cancer cells sensitive and resistant to DOX was investigated. A2780-DX2, A2780-DX3, and A2780-DX6 cell sublines were characterized by 7-, 26-, and 48-fold resistance after 2 h DOX exposure and 30-, 50-, and 500-fold resistance after 72 h DOX exposure, respectively. Increased drug efflux resulting in a lower intracellular drug accumulation, decreased DOX-induced DNA single-strand breaks (DNA SSBs), and rapid DNA repair correlated with the degree of resistance. In addition, DNA SSBs were rapidly repaired within 8 h in A2780-DX3 cells, whereas no significant repair of DNA SSBs was observed in sensitive cells. In comparison with verapamil, RO11-2933 was found to reverse DOX resistance at lower and nontoxic concentrations (2 M as compared with 10 M verapamil). This reversion was complete in cells with a low degree of resistance (A2780-DX1 and A2780-DX2) but partial in highly resistant cells (A2780-DX3 and A2780-DX6), and continuous exposure to RO11-2933 was essential for optimal reversal of drug resistance. Interestingly, RO11-2933 was found to inhibit the repair of DNA SSBs induced by DOX but not those induced by X-ray. These results suggest that the potentiation of DNA SSBs and the specific inhibition of DNA repair by RO11-2933 in multidrug-resistant cells could be of particular value in overcoming MDR in the clinic.Abbreviations RO11-2933
N-(3,4-dimethoxyphenethyl)-N-methyl-2-(2-naphthyl)-m-dithiane-2-propylamine hydrochloride
- DOX
doxorubicin-HCl
- SSBs
single-strand breaks
- MDR
multidrug resistance
This work was supported in part by CA 18420 and CA 21071 相似文献