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151.
Josef S. Ozer Raj Chetty Gerry Kenna Joe Palandra Yiqun Zhang Anne Lanevschi Nandan Koppiker Bernard E. Souberbielle Shashi K. Ramaiah 《Regulatory toxicology and pharmacology : RTP》2010,56(3):237-246
Drug-induced liver injury (DILI) is the most frequent cause of discontinuation of new chemical entities during development. DILI can either be intrinsic/predictable or an idiosyncratic type. These two forms of DILI are contrasted in their manifestation and diagnosis. Even with regulatory guidance (FDA, 2009), there is still a gap in our ability to identify predictable DILI, both specifically and sensitively. Alanine aminotransferase (ALT) is the principal reference standard biomarker to diagnose DILI, yet its current application in preclinical to clinical translation for decision-making purposes has imperfections: (1) analytical ALT assay uniformity across industry would be aided by common analytical processes; (2) assessment of ALT toxicological performance in a large preclinical analysis would help to establish a true threshold of elevation for predictable DILI and improve translational use across various stages of pharmaceutical development and finally, (3) clinical evaluation of ALT elevations prospectively and retrospectively is recommended to define and manage variations in clinical study subjects including rising body mass index (BMI) range and ALT upper limit of normal (ULN) in the broader population over time. The emergence of new hepatotoxicity biomarkers necessitates a parallel and equivalent assessment to the aminotransferases in a regulatory qualification model. 相似文献
152.
目的 探索锡矿矿尘的致病强度和最低无害作用水平。方法 选择广西锡矿 1 960~1 974年期间接触矿尘至少 1年的男性矿工 4 471名建立回顾性接尘队列 ,并用以同一方法建立的瓷厂接尘队列与其进行比较 ;采用SAS中的生存检验分析软件进行非参数估算 ,评价锡矿矿尘致矽肺的危险度。结果 随访到 1 994年底 ,锡矿队列工人矽肺发病 971例 (2 1 .7% ) ,其中 81 %的病例为 1 958年前接尘对象 ,累积接触总粉尘量 (CTD)与矽肺危险度明显相关 :当CTD <50mg·m- 3·年 - 1 时 ,矽肺危险度为 0 .0 1 2 ;CTD >40 0mg·m- 3·年 - 1 时 ,矽肺危险度上升到 0 .971。瓷厂接尘工人CTD >40 0mg·m- 3·年 - 1 时 ,矽肺危险度仅为 0 .369。结论 锡矿接触矿尘工人的矽肺发病与CTD明显相关 ;锡矿矿尘导致矽肺的危险性远比瓷厂的陶瓷尘严重 相似文献
153.
The pharmacokinetic characteristics of a slow-release formulation of clonidine (150 micrograms) were compared with those of a conventional formulation (75 micrograms) after acute and chronic (2 week) administration to 12 hypertensive subjects. The Tmax of the slow-release formulation was significantly later than for the conventional formulation after both acute (8.3 +/- 6 hr vs. 2.1 +/- 2 hr) and chronic administration (4.0 +/- 3 hr vs. 2.5 +/- 2 hr). Although the Tmax did not change significantly with acute and chronic administration of the conventional preparation, it was significantly shorter after chronic administration of the slow-release formulation when acute and chronic administration were compared. The Cmax was approximately 60% lower for the slow-release formulation (1 x 150 micrograms; 0.42 +/- 0.09 ng/mL) compared with the conventional formulation (2 x 75 micrograms; 0.70 +/- 0.12 ng/mL) after acute administration, whereas in the steady state, in which the dose of the conventional preparation was halved (75 micrograms), the Cmax values were comparable: 1 x 150 micrograms-0.99 +/- 0.27 ng/mL, 1 x 75 micrograms-0.84 +/- 0.20 ng/mL and the dose-normalized interdose AUC were identical for the conventional (16.2 +/- 4.3 ng/mL.hr) and slow release (16.6 +/- 5.3 ng/mL.hr) products. T1/2 values for the conventional formulation of clonidine exceeded 20 hours in all but one subject and were considerably longer than those in previous reports, including those of the authors, in which a less sensitive assay was used.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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155.
S. N. Anavekar B. Jarrott M. Toscano W. J. Louis 《European journal of clinical pharmacology》1982,23(1):1-5
Summary The pharmacokinetics of clonidine and its relation to blood pressure response and side effects were studied after single oral doses of 75 µg, 150 µg and 250 µg in normotensive subjects. Following oral administration, the drug was absorbed rapidly after an initial lag time of 19–22 min and peak levels were reached between 2.4 and 2.9 h. Sampling over 48 h was necessary for accurate estimation of pharmacokinetic parameters. Post-peak plasma concentration declined in a monoexponential manner and the half-life of the elimination phase ranged from 9.0 to 15.1 h. Maximum plasma concentration (Cmax) and area under curve (AUC) increased proportionally with increasing doses. Clonidine produced significant reductions in the pulse rate and a dose dependent decrease in blood pressure. Clonidine (150 µg) also produced significant reductions in plasma catecholamine levels. 相似文献
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157.
Koppiker N 《IDrugs : the investigational drugs journal》2002,5(5):448-453
In addition to the classic roles that cyclic-3',5-guanosine monophosphate (cGMP) is thought to play in cell function regulation, such as smooth muscle regulation, inhibition of platelet aggregation, visual signal conduction and neutrophil degranulation, it is now understood to be involved with various physiological functions. The tissue levels and hence activity of cGMP are determined by the balance between production rates from guanosine triphosphate (GTP) through the guanylyl cyclase pathways, and degradation to GMP by specific cyclic nucleotide phosphodiesterases (PDEs). PDE5 inhibitors were initially developed for a possible role in cardiovascular disease; their role in the treatment of erectile dysfunction was brought to the forefront by the development of sildenafil. The focus of this article is the current patent literature around the use of PDE5 inhibitors for neuropathy. It also explores the possible hypotheses that may help to explain the mechanism(s) by which cGMP PDE5 inhibitors could have potential benefits in neuropathy. 相似文献
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