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排序方式: 共有363条查询结果,搜索用时 15 毫秒
71.
G N Kumar J Dykstra E M Roberts V K Jayanti D Hickman J Uchic Y Yao B Surber S Thomas G R Granneman 《Drug metabolism and disposition》1999,27(8):902-908
ABT-378 is a potent in vitro inhibitor of the HIV protease and is currently being developed for coadministration with another HIV protease inhibitor, ritonavir, as an oral therapeutic treatment for HIV infection. In the present study, the effect of ritonavir, a potent inhibitor of cytochrome P-450 (CYP) 3A, on the in vitro metabolism of ABT-378 was examined. Furthermore, the effect of ABT-378-ritonavir combinations on several CYP-dependent monooxygenase activities in human liver microsomes was also examined. ABT-378 was found to undergo NADPH- and CYP3A4/5-dependent metabolism to three major metabolites, M-1 (4-oxo) and M-3/M-4 (4-hydroxy epimers), as well as several minor oxidative metabolites in human liver microsomes. The mean apparent K(m) and V(max) values for the metabolism of ABT-378 by human liver microsomes were 6.8 +/- 3.6 microM and 9.4 +/- 5.5 nmol of ABT-378 metabolized/mg protein/min, respectively. Ritonavir inhibited human liver microsomal metabolism of ABT-378 potently (K(i) = 0.013 microM). The combination of ABT-378 and ritonavir was much weaker in inhibiting CYP-mediated biotransformations than ritonavir alone, and the inhibitory effect appears to be primarily due to the ritonavir component of the combination. The ABT-378-ritonavir combinations (at 3:1 and 29:1 ratios) inhibited CYP3A (IC(50) = 1.1 and 4.6 microM), albeit less potently than ritonavir (IC(50) = 0.14 microM). Metabolic reactions mediated by CYP1A2, CYP2A6, and CYP2E1 were not affected by the ABT-378-ritonavir combinations. The inhibitory effects of ABT-378-ritonavir combinations on CYP2B6 (IC(50) = >30 microM), CYP2C9 (IC(50) = 13.7 and 23.0 microM), CYP2C19 (IC(50) = 28.7 and 38.0 microM), and CYP2D6 (IC(50) = 13.5 and 29.0 microM) were marginal and are not likely to produce clinically significant drug-drug interactions. 相似文献
72.
Epstein-Barr virus coopts lipid rafts to block the signaling and antigen transport functions of the BCR 总被引:6,自引:0,他引:6
The B cell antigen receptor (BCR) functions to initiate signaling and to internalize antigen for processing from within Lyn kinase-enriched membrane lipid rafts. The signaling function of the BCR is blocked by Epstein-Barr Virus (EBV) latent membrane protein 2A (LMP2A), which is constitutively phosphorylated by Lyn. Here, we show that LMP2A resides in lipid rafts and excludes the BCR from entering rafts by Lyndependent mechanisms, thus blocking both BCR signaling and antigen transport. Mutant LMP2A that permits BCR signaling and raft translocation still blocks antigen trafficking, indicating independent control of these BCR functions. Thus, EBV coopts the lipid rafts to disarm both the signaling and antigen-processing functions of the BCR by independent mechanisms. 相似文献
73.
Zhang J Wang P Dykstra M Gelebart P Williams D Ingham R Adewuyi EE Lai R McMullen T 《The Journal of pathology》2012,228(2):241-250
Lymph node metastases are common in papillary thyroid cancer (PTC) and can be resistant to surgical extirpation or radioiodine ablation. We examined the role of platelet‐derived growth factor receptor (PDGFR) in mediating lymph node metastases in PTC. Clinical specimens of PTC (n = 137) were surveyed in a tissue array and by western blots to examine the relationship between expression of the α and β subunits of PDGFR and lymph node metastases. PDGFR‐α was found at high levels in primary tumours with known lymphatic metastases but not in those tumours lacking nodal involvement (p < 0.0001). However, PDGFR‐β expression was not linked to metastatic disease (p = 0.78) as it was found in virtually all PTC specimens. A matching analysis in fresh PTC specimens (n = 13) confirmed that PDGFR‐α expression was strongly linked to metastatic spread (p = 0.0047). PDGFR‐α and ‐β were not found in normal thyroid tissue (p < 0.0001). PTC cell lines selectively expressing PDGFR‐α or ‐β were assessed for invasive potential and activation of downstream signal transduction pathways. PTC cell lines expressing PDGFR‐α responded to PDGF‐BB stimulation with increased invasive potential and this process can be blocked by the tyrosine kinase receptor inhibitor sunitinib (p < 0.009). Cell lines with only PDGFR‐β, or no PDGFR, did not show significant changes in invasive potential. Activation of PDGFR‐α led to downstream up‐regulation of both the MAPK/ERK and PI3K/Akt pathways and disruption of either pathway is sufficient to block PDGFR‐mediated increases in invasive potential. Thus, PDGFR‐α is associated with lymph node metastases in papillary thyroid carcinoma and PDGFR‐α promotes increased invasive potential in PTC cell lines. PDGFR‐α is a strong candidate for a diagnostic biomarker to identify patients at risk of nodal metastases. Our results also strengthen the rationale for selection of tyrosine kinase receptor inhibitors that target PDGFR in the treatment of progressive, metastatic PTC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
74.
J. David Leander C. Ray Wood Dennis M. Zimmerman Linda A. Dykstra 《Drug development research》1986,7(1):75-85
Chen [1965] described a specific form of catalepsy produced by phencyclidine and related arylcyclohexylamine analogues in pigeons. The present study expanded those observations to a variety of compounds identified as having phencyclidine-like subjective effects in man or in drug discrimination experiments in laboratory animals. Besides phencyclidine and ketamine, etoxacrol, dexoxadrol, dextrorphan, cyclazocine, and a series of benz(f)isoquinolines produced phencyclidine-like catalepsy, thus correlating with drug discrimination data from pigeons using phencyclidine-like drugs. A variety of opioid agonists and mixed agonists/antagonists, along with nefopam, amantadine, baclofen, and THIP, did not produce phencyclidine-like catalepsy. Opioid antagonists, haloperidol, and α-methylparatyrosine did not antagonize the phencyclidine-like catalepsy. These results emphasize the specificity of phencyclidine-like catalepsy as a test for determining the presence or absence of phencyclidine-like activity in compounds during drug development. 相似文献
75.
The value of urodynamic testing in the management of neonates with myelodysplasia: a prospective study 总被引:5,自引:0,他引:5
We report the results of a prospective study conducted to identify neonates with myelomeningocele at risk for changes in the upper urinary tract. Thirty newborns underwent full urological evaluation and were followed for a mean period of 18.2 months. The initial studies included voiding cystourethrography, excretory urography and urodynamic tests. Followup consisted of periodic radiographic studies and repeat urodynamic testing if any changes were observed. According to urodynamic findings the patients were divided into 2 groups: group 1 consisted of 9 neonates (30 per cent) with detrusor-sphincter dyssynergia and high pressure, decreased-compliance bladders, and group 2 consisted of 21 children (70 per cent) with atonic bladders and low pressure, reduced-compliance bladders without dyssynergia. In group 1, 55 per cent of the patients had initially abnormal radiographic findings in contrast with 28.5 per cent in group 2. Anticholinergic drugs and clean intermittent catheterization or vesicostomy reversed the changes in 40 per cent of the children in group 1, 40 per cent remained stable and 20 per cent showed signs of deterioration. Four children in group 1 with normal neonatal radiographs were treated expectantly and at followup they all showed signs of deterioration. The neonates in group 2 with normal radiographic findings remained normal at followup. Of those who initially had changes 67 per cent reversed to normal without treatment, 17 per cent remained stable and 17 per cent had deterioration. Newborns with detrusor-sphincter dyssynergia or high pressure, reduced-compliance bladders are at high risk of having upper urinary tract changes and require preventive decompressive treatment. Children with atonic or low pressure, reduced-compliance bladders and those with a coordinated bladder and sphincter are at low risk and need only close followup. 相似文献
76.
77.
78.
Improving liver allocation: MELD and PELD 总被引:8,自引:4,他引:4
Richard B. Freeman Jr Russell H. Wiesner John P. Roberts Suzanne McDiarmid Dawn M. Dykstra Robert M. Merion 《American journal of transplantation》2004,4(S9):114-131
On February 27, 2002, the liver allocation system changed from a status-based algorithm to one using a continuous MELD/PELD severity score to prioritize patients on the waiting list. Using data from the Scientific Registry of Transplant Recipients, we examine and discuss several aspects of the new allocation, including the development and evolution of MELD and PELD, the relationship between the two scoring systems, and the resulting effect on access to transplantation and waiting list mortality. Additional considerations, such as regional differences in MELD/PELD at transplantation and the predictive effects of rapidly changing MELD/PELD, are also addressed.
Death or removal from the waiting list for being too sick for a transplant has decreased in the MELD/PELD era for both children and adults. Children younger than 2 years, however, still have a considerably higher rate of death on the waiting list than adults.
A limited definition of ECD livers suggests that they are used more frequently for patients with lower MELD scores. 相似文献
Death or removal from the waiting list for being too sick for a transplant has decreased in the MELD/PELD era for both children and adults. Children younger than 2 years, however, still have a considerably higher rate of death on the waiting list than adults.
A limited definition of ECD livers suggests that they are used more frequently for patients with lower MELD scores. 相似文献
79.
80.