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排序方式: 共有395条查询结果,搜索用时 15 毫秒
101.
BENGT REDFORS GUDRUN BRAGADOTTIR JOHAN SELLGREN KRISTINA SWÄRD SVEN‐ERIK RICKSTEN 《Acta anaesthesiologica Scandinavica》2010,54(2):183-190
Background: Imbalance of the renal medullary oxygen supply/demand relationship can cause ischaemic acute renal failure (ARF). The use of dopamine for prevention/treatment of ischaemic ARF has been questioned. It has been suggested that dopamine may increase renal oxygen consumption (RVO2) due to increased solute delivery to tubular cells, which may jeopardise renal oxygenation. Information on the effects of dopamine on renal perfusion, filtration and oxygenation in man is, however, lacking. We evaluated the effects of dopamine on renal blood flow (RBF), glomerular filtration rate (GFR), RVO2 and renal O2 demand/supply relationship, i.e. renal oxygen extraction (RO2Ex). Methods: Twelve uncomplicated, mechanically ventilated and sedated post‐cardiac surgery patients with pre‐operatively normal renal function were studied. Dopamine was sequentially infused at 2 and 4 ug/kg/min. Systemic haemodynamics were evaluated by a pulmonary artery catheter. Absolute RBF was measured using two independent techniques: by the renal vein thermodilution technique and by infusion clearance of paraaminohippuric acid (PAH), with a correction for renal extraction of PAH. The filtration fraction (FF) was measured by the renal extraction of 51Cr‐EDTA. Results: Neither GFR, tubular sodium reabsorption nor RVO2 was affected by dopamine, which increased RBF (45–55%) with both methods, decreased renal vascular resistance (30–35%), FF (21–26%) and RO2Ex (28–34%). The RBF/CI ratio increased with dopamine. Dopamine decreased renal PAH extraction, suggestive of a flow distribution to the medulla. Conclusions: In post‐cardiac surgery patients, dopamine increases the renal oxygenation by a pronounced renal pre‐and post‐glomerular vasodilation with no increases in GFR, tubular sodium reabsorption or renal oxygen consumption. 相似文献
102.
Ackler S Xiao Y Mitten MJ Foster K Oleksijew A Refici M Schlessinger S Wang B Chemburkar SR Bauch J Tse C Frost DJ Fesik SW Rosenberg SH Elmore SW Shoemaker AR 《Molecular cancer therapeutics》2008,7(10):3265-3274
ABT-263 is a potent, orally bioavailable inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-x(L), and Bcl-w, which is currently in phase I clinical trials. Previous work has shown that this compound has low nanomolar cell-killing activity in a variety of lymphoma and leukemia cell lines, many of which overexpress Bcl-2 through a variety of mechanisms. Rapamycin is a macrolide antibiotic that inhibits the mammalian target of rapamycin complex, leading to cell cycle arrest and inhibition of protein translation. Rapamycin (and its analogues) has shown activity in a variety of tumor cell lines primarily through induction of cell cycle arrest. Activity has also been shown clinically in mantle cell lymphoma and advanced renal cell carcinoma. Here, we show that treatment of the follicular lymphoma lines DoHH-2 and SuDHL-4 with 100 nmol/L rapamycin induces substantial G(0)-G(1) arrest. Addition of as little as 39 nmol/L ABT-263 to the rapamycin regimen induced a 3-fold increase in sub-G(0) cells. Combination of these agents also led to a significant increase in Annexin V staining over ABT-263 alone. In xenograft models of these tumors, rapamycin induced a largely cytostatic response in the DoHH-2 and SuDHL-4 models. Coadministration with ABT-263 induced significant tumor regression, with DoHH-2 and SuDHL-4 tumors showing 100% overall response rates. Apoptosis in these tumors was significantly enhanced by combination therapy as measured by staining with an antibody specific for cleaved caspase-3. These data suggest that combination of ABT-263 and rapamycin or its analogues represents a promising therapeutic strategy for the treatment of lymphoma. 相似文献
103.
Bruncko M Oost TK Belli BA Ding H Joseph MK Kunzer A Martineau D McClellan WJ Mitten M Ng SC Nimmer PM Oltersdorf T Park CM Petros AM Shoemaker AR Song X Wang X Wendt MD Zhang H Fesik SW Rosenberg SH Elmore SW 《Journal of medicinal chemistry》2007,50(4):641-662
Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide. 相似文献
104.
Martins PS Brunialti MK Martos LS Machado FR Assunçao MS Blecher S Salomao R 《Critical care (London, England)》2008,12(1):R25
Background
Infection control depends on adequate microbe recognition and cell activation, yet inflammatory response may lead to organ dysfunction in sepsis. The aims of this study were to evaluate cell activation in the context of sepsis and its correlation with organ dysfunction. 相似文献105.
S Slater MJ Crawford MA Kabbouche SL LeCates S Cherney P Vaughan A Segers P Manning D Burdine SW Powers & AD Hershey 《Cephalalgia : an international journal of headache》2009,29(9):969-973
The aim of this study was to evaluate the impact of gender and age on headache characteristics and disability. Headache characteristics were assessed at an initial visit to a paediatric specialty care centre and five follow-up visits. A total number of 4121 patients were evaluated. Fifty-eight per cent of the sample was female. Boys were younger at their first headache and initial visit. They more frequently described headache pain as squeezing and location as top of the head. Girls reported more frequent and longer headaches. Girls more often described headache pain as sharp and location as back of the head. Age accounted for more variance than gender in headache severity, duration, frequency and disability. Gender differences exist in headache characteristics. Age is also an important factor in the variability in characteristics and disability. Longitudinal studies are needed to describe further the natural history of headaches in childhood and compare outcome between genders. 相似文献
106.
Hajduk PJ Gomtsyan A Didomenico S Cowart M Bayburt EK Solomon L Severin J Smith R Walter K Holzman TF Stewart A McGaraughty S Jarvis MF Kowaluk EA Fesik SW 《Journal of medicinal chemistry》2000,43(25):4781-4786
A strategy is described for designing high-affinity ligands using information derived from the NMR-based screening of fragments. The method involves the fragmentation of an existing lead molecule, identification of suitable replacements for the fragments, and incorporation of the newly identified fragments into the original scaffold. Using this technique, novel substituents were rapidly identified and incorporated into lead inhibitors of adenosine kinase that exhibited potent in vitro and in vivo activities. This approach is a valuable strategy for modifying existing leads to improve their potency, bioavailability, or toxicity profile and thus represents a useful technique for lead optimization. 相似文献
107.
Miller R Ewy W Corrigan BW Ouellet D Hermann D Kowalski KG Lockwood P Koup JR Donevan S El-Kattan A Li CS Werth JL Feltner DE Lalonde RL 《Journal of pharmacokinetics and pharmacodynamics》2005,32(2):185-197
The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy
and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development
and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical
model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation
between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate
potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second
example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer’s disease (AD). The issue was how
to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression,
and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify
an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning
experiences as well as extensive financial savings. The motivation for this case in point was the “Learn-Confirm” paradigm
described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and
simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled
clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the
treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the
drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug Application was applied
to confirm the evidence of efficacy across these dose levels. Modeling and simulation analyses showed that the two studies
corroborate each other with respect to the pain relief profiles. The use of PK/PD information confirmed evidence of efficacy
across the three studied doses, eliminating the need for additional clinical trials and thus supporting the approval of the
product. It can be speculated that the work by Lewis Sheiner reflected in the FDA document titled “Innovation or Stagnation:
Challenge and Opportunity on the Critical Path to New Medical Products” made this scientific approach to the drug approval
process possible. 相似文献
108.
A new knowledge-based scoring function (PMF-score), implemented into the DOCK4 program, was used to screen a database of 3247 small molecules for binding to the FK506 binding protein (FKBP). The computational ranking of these compounds was compared to the binding affinities measured by NMR. It was demonstrated that small, weakly binding molecules have, on average, higher computational scores than nonbinders and are enriched in the upper ranks of the computational scoring lists. In addition, the results obtained with the PMF scoring function were superior (by 30-120% larger enrichment factors) to those obtained with the standard force field score of DOCK4. The reliable ranking of small, weakly binding molecules offers new ways of designing building blocks in combinatorial libraries as well as SAR by NMR libraries with the increased chance of identifying suitable lead compounds for drug design. 相似文献
109.
P J Hajduk T Gerfin J M Boehlen M H?berli D Marek S W Fesik 《Journal of medicinal chemistry》1999,42(13):2315-2317
A high-throughput screening strategy is described that involves the acquisition of two-dimensional 15N/1H correlation spectra in less than 10 min on 50 microM protein samples using cryogenic NMR probe technology. By screening at these concentrations, small organic molecules can be tested in mixtures of 100, which dramatically increases the throughput of the NMR-based assay. Using this strategy, libraries of more than 200 000 compounds can be tested in less than 1 month. There are many advantages of high-throughput NMR-based screening compared to conventional assays, such as the ability to identify high-affinity ligands for protein targets with no known function. This suggests that the method will be extremely useful for screening the large number of targets derived from genomics research. 相似文献
110.
Carcinogenic polycyclic aromatic hydrocarbons increase intracellular Ca2+ and cell proliferation in primary human mammary epithelial cells 总被引:1,自引:1,他引:1
Previous studies have shown that polycyclic aromatic hydrocarbons (PAHs)
mobilize intracellular Ca2+ in human T cells by inositol
trisphosphate-dependent mechanisms resulting from activation of
phospholipase C-gamma by SRC-related protein tyrosine kinases, thereby
mimicking antigen-receptor activation. Ca2+ appears to play an important
second messenger role in growth factor control of cell proliferation in
human mammary epithelial cells (HMEC), such as the epidermal growth factor
receptor pathway. The purpose of the present studies was to determine if
PAHs are able to increase intracellular Ca2+ in primary cultures of HMEC
and increase cell proliferation. Two carcinogenic and two non-carcinogenic
PAHs were tested for their ability to increase intracellular Ca2+ in HMEC.
The carcinogenic PAHs dimethylbenz[a]anthracene (DMBA) and benzo[a] pyrene
(BaP) were able to cause Ca2+ elevation in HMEC at early time points (2 h)
and caused sustained alterations in Ca2+ homeostasis (18 h). DMBA showed
maximal effects at early time points (2 h), while BaP showed maximal
effects on sustained Ca2+ (18 h). 2,3,7,8-Tetrachlorodibenzo-p-dioxin
(TCDD), a potent dioxin and tumor promoter, produced maximal Ca2+ elevation
at 2 h, with a return to near baseline levels by 6 h. The non-carcinogenic
PAHs benzo[e]pyrene and anthracene did not significantly alter
intracellular Ca2+ at any time point. alpha-Naphthoflavone significantly
reduced the Ca2+ response induced by BaP treatment, but not by DMBA or
TCDD, suggesting that P450 1A or 1B metabolism of BaP may be important in
the sustained Ca2+ elevating response. In evaluating the effects of BaP on
HMEC proliferation, BaP was found to increase the number of cells recovered
after 4 days in culture in the absence or presence of various
concentrations of epidermal growth factor. These studies provide initial
evidence that Ca2+ signaling may be associated with mitogenesis in HMEC,
which may play a role in tumor promotion and progression produced by PAHs.
相似文献