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991.
992.
目的设计并合成与环佐辛有类似的阿片受体亲和活性、在体内具有较长作用时间的3-四氢呋喃甲基苯并吗吩烷类似物。方法8-三氟甲磺酸酯-3-四氢呋喃甲基苯并吗吩烷经催化氨化制得目标物,对目标物进行受体亲和力测定。结果8-氨基及8-苯氨基化合物在体外与μ,δ和κ受体的亲和力均较相应的8-羟基化合物低。结论目标化合物的体外受体亲和力相对较低,但此结果尚不能完全说明其在体内的作用情况及其可否用于毒品成瘾的治疗。进一步研究正在进行。 相似文献
993.
Dale Miles Tarak D. Mody Lori I. Hatcher John Fiene Mark Stiles Patrick P. Lin J. W. Lee 《The AAPS journal》2003,5(3):1-16
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) methods were developed and validated for the evaluation of motexafin lutetium (MLu, lutetium texaphyrin, PCI-0123) pharmacokinetics in human plasma. The LC-MS/MS method was specific for MLu, whereas the ICP-AES method measured total elemental lutetium. Both methods were fast, simple, precise, and accurate. For the LC-MS/MS method, a closely related analogue (PCI-0353) was used as the internal standard (IS). MLu and the IS were extracted from plasma by protein precipitation and injected onto and LC-MS/MS system configured with a C18 column and an electrospray interface. The lower limit of quantitation was 0.05 μg MLu mL−1, with a signal-to-noise ratio of 15∶1. The response was linear from 0.05 to 5.0 μg MLu mL−1. For the ICP-AES method, indium was used as the IS. The sample was digested with nitric acid, diluted, filtered, and then injected onto the ICP-AES system. Two standard curve ranges were validated to meet the expected range of sample concentrations: 0.5 to 50, and 0.1 to 10 μg Lu mL−1. The LC-MS/MS and ICP-AES methods were validated to establish accuracy, precision, analyte stability, and assay robustness. Interday precision and accuracy of quality control samples were ≤6.3% coefficient of variation (CV) and within 2.2% relative error (RE) for the LC-MS/MS method, and ≤8.7% CV and within 4.9% RE for the ICP-AES method. Plasma samples from a subset of patients in a clinical study were analyzed using both methods. For a representative patient, over 90% of the elemental lutetium in plasma could be ascribed to intact MLu at early time points. This percentage decreased to 59% at 48 hours after dosing, suggesting that some degradation and/or metabolism of the drug may have occurred. 相似文献
994.
Arterial and venous thrombosis are a major cause of morbidity and mortality. Anticoagulants are a cornerstone of treatment in patients with these disorders. The two most frequently used anticoagulants, heparin and warfarin, have pharmacological and/or biophysical limitations that make them difficult to use in day-to-day clinical practice. Development of new anticoagulants, which were designed to overcome these limitations, has been facilitated by an increased understanding of the coagulation cascade, the advent of molecular modeling and structure-based drug design, and the realization that the treatment of thrombosis and its complications consumes billions of dollars in annual healthcare expenditures. New anticoagulants target various steps in the coagulation pathway. Coagulation is triggered by the factor VIIa/tissue factor complex and propagated by factors Xa and IXa, together with their activated cofactors, factor Va and VIIIa, respectively. Thrombin, the final effector in coagulation, then converts soluble fibrinogen into insoluble fibrin, the major matrix protein of the clot. New anticoagulation drugs that target each of these clotting enzymes have been developed. This review will focus on those drugs in more advanced stages of clinical evaluation. These include inhibitors of initiation of coagulation (tissue factor pathway inhibitor, nematode anticoagulant peptide and active-site blocked factor VIIa), inhibitors of propagation of coagulation (active-site blocked factor IXa, antibodies against factor IX/IXa, fondaparinux sodium, direct factor Xa inhibitors, protein C derivatives and soluble thrombomodulin), and thrombin inhibitors (hirudin, bivalirudin, argatroban and ximelagatran). 相似文献
995.
Change in neurocognitive functioning after treatment with cranial radiation in childhood. 总被引:7,自引:0,他引:7
Brenda J Spiegler Eric Bouffet Mark L Greenberg James T Rutka Donald J Mabbott 《Journal of clinical oncology》2004,22(4):706-713
PURPOSE: To evaluate the pattern of stability and change over time across multiple domains of neurocognitive function in radiated survivors of posterior fossa (PF) tumors. PATIENTS AND METHODS: Thirty-four children (25 males) treated for malignant PF tumors were observed with serial clinical neuropsychologic assessments. Thirty patients were treated for medulloblastoma and four patients were treated for ependymoma. Twelve patients were treated with reduced-dose and 21 patients were treated with standard-dose cranial radiation. All patients received an additional boost to the PF. One patient was treated with PF radiation only. Standardized neuropsychologic tests were administered at different times after diagnosis for each child. The rate of change in scores was determined using a mixed model regression. RESULTS: Results showed a 2- to 4-point decline per year in intelligence scores. For our relatively young sample, intellectual function declined quickly in the first few years after treatment, and then more gradually. Significant declines in visual-motor integration, visual memory, verbal fluency, and executive functioning were also documented. No decline was evident for verbal memory and receptive vocabulary. CONCLUSION: Cranial radiation is associated with a decline in multiple neurocognitive domains, with a few notable exceptions. Our results must be interpreted in the context of common limitations of clinical research, including patient variability, changes in test versions, small sample size, and clinical referral bias. 相似文献
996.
Joseph G Rajendran David A Mankoff Finbarr O'Sullivan Lanell M Peterson David L Schwartz Ernest U Conrad Alexander M Spence Mark Muzi D Greg Farwell Kenneth A Krohn 《Clinical cancer research》2004,10(7):2245-2252
PURPOSE: The aim of this study is to compare glucose metabolism and hypoxia in four different tumor types using positron emission tomography (PET). (18)F-labeled fluorodeoxyglucose (FDG) evaluates energy metabolism, whereas the uptake of (18)F-labeled fluoromisonidazole (FMISO) is proportional to tissue hypoxia. Although acute hypoxia results in accelerated glycolysis, cellular metabolism is slowed in chronic hypoxia, prompting us to look for discordance between FMISO and FDG uptake. EXPERIMENTAL DESIGN: Forty-nine patients (26 with head and neck cancer, 11 with soft tissue sarcoma, 7 with breast cancer, and 5 with glioblastoma multiforme) who had both FMISO and FDG PET scans as part of research protocols through February 2003 were included in this study. The maximum standardized uptake value was used to depict FDG uptake, and hypoxic volume and maximum tissue:blood ratio were used to quantify hypoxia. Pixel-by-pixel correlation of radiotracer uptake was performed on coregistered images for each corresponding tumor plane. RESULTS: Hypoxia was detected in all four patient groups. The mean correlation coefficients between FMISO and FDG uptake were 0.62 for head and neck cancer, 0.47 for breast cancer, 0.38 for glioblastoma multiforme, and 0.32 for soft tissue sarcoma. The correlation between the overall tumor maximum standardized uptake value for FDG and hypoxic volume was small (Spearman r = 0.24), with highly significant differences among the different tumor types (P < 0.005). CONCLUSIONS: Hypoxia is a general factor affecting glucose metabolism; however, some hypoxic tumors can have modest glucose metabolism, whereas some highly metabolic tumors are not hypoxic, showing discordance in tracer uptake that can be tumor type specific. 相似文献
997.
Raphael P Viscidi Mark Schiffman Allan Hildesheim Rolando Herrero Philip E Castle Maria C Bratti Ana Cecilia Rodriguez Mark E Sherman Sophia Wang Barbara Clayman Robert D Burk 《Cancer epidemiology, biomarkers & prevention》2004,13(2):324-327
Whether antibodies to human papillomavirus (HPV) capsids, elicited by natural infection, are protective is unknown. This question was addressed in a population-based cohort of 7046 women in Costa Rica by examining the association between baseline seroreactivity to HPV-16, HPV-18, or HPV-31 virus-like particles and the risk of subsequent HPV infection at a follow-up visit 5-7 years after enrollment. Seropositivity to HPV-16, HPV-18, or HPV-31 was not associated with a statistically significant decreased risk of infection with the homologous HPV type [relative risk (RR) and [95% confidence interval (CI)], 0.74 (0.45-1.2), 1.5 (0.83-2.7), and 0.94 (0.48-1.8), respectively]. Seropositivity to HPV-16 or HPV-31 was not associated with a decreased risk of infection with HPV-16 or its genetically related types [RR (95% CI), 0.82 (0.61-1.1) and 0.93 (0.68-1.2), respectively]. Seropositivity to HPV-18 was not associated with a decreased risk of infection with HPV-18 or its genetically related types (RR 1.3; 95% CI 1.0-1.8). Thus, we did not observe immunity, although a protective effect from natural infection cannot be excluded because of the limits of available assays and study designs. 相似文献
998.
Prognostic impact of ANX7-GTPase in metastatic and HER2-negative breast cancer patients. 总被引:4,自引:0,他引:4
Meera Srivastava Lukas Bubendorf Mark Raffeld Christoph Bucher Jochen Torhorst Guido Sauter Cara Olsen Olli P Kallioniemi Ofer Eidelman Harvey B Pollard 《Clinical cancer research》2004,10(7):2344-2350
PURPOSE: ANX7-GTPase located on chromosome 10q21 is significantly altered and associated with hormone-refractory metastatic prostate cancers. Therefore, we investigated whether levels of ANX7 correlate with breast cancer progression and survival EXPERIMENTAL DESIGN: A diagnostic tumor tissue microarray containing 525 human breast tissue specimens at different stages of the disease was assayed for ANX7 using immunocytochemical methods with ANX7 monoclonal antibody. A separate prognostic tumor tissue microarray containing 553 human breast tissue specimens annotated with clinicopathological parameters was assayed for ANX7, HER2, estrogen receptor, progesterone receptor, and p53 protein. RESULTS: We report here for the first time that the expression of ANX7-GTPase is significantly enhanced and associated with the presence of metastatic disease (P < 0.0001) in the 525 human breast tissue specimens analyzed. Furthermore, using a separate 553 case retrospective prognostic tumor tissue microarray, we found that increased ANX7 expression is also significantly associated with poor overall patient survival (P < 0.014). This is particularly true when restricted to patients in whom the BRE clinical grade is 2 (P < 0.001) or for whom there is a lack of HER2 expression (P < 0.002). Finally, Cox regression analysis shows that as the expression of ANX7 rises, the probability of survival decreases by more than 10-fold for those patients with HER2-negative tumors. These latter patients represented 66% of the population affected with breast cancer in this study. CONCLUSIONS: High levels of ANX7 in tumor correlate strongly with poor survival of HER2-negative patients and the most aggressive forms of breast cancer. This is the first study to demonstrate that ANX7 antibody has the potential for development into an in vivo diagnostic and therapeutic tool. This simple and reliable immunohistochemical assay may therefore become an important biomarker for metastatic breast cancer diagnosis and management of HER2-negative breast tumor patients. 相似文献
999.
Francesco Izzo Paolo Marra Gerardo Beneduce Giuseppe Castello Paolo Vallone Vincenzo De Rosa Franco Cremona C Mark Ensor Frederick W Holtsberg John S Bomalaski Mike A Clark Chaan Ng Steven A Curley 《Journal of clinical oncology》2004,22(10):1815-1822
PURPOSE: Recently, we reported that a large number of human hepatocellular cancer (HCC) cell lines were auxotrophic for arginine. Here we report the results obtained with the amino acid-degrading enzyme arginine deiminase (ADI) conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw) as a means of lowering plasma arginine to treat HCC. The study was a cohort dose-escalation phase I/II study. PATIENTS AND METHODS: Pharmacodynamic studies indicated an ADI-SS PEG 20,000 mw dose level of 160 U/m(2) was sufficient to lower plasma arginine from a resting level of approximately 130 micromol/L to below the level of detection (< 2 micromol/L) for more than 7 days, a dose later defined as the optimal biologic dose. All patients were to receive three cycles at the optimum biologic dose. RESULTS: This therapy was well tolerated, even in patients who had no detectable plasma arginine for 3 continuous months of therapy. Of the 19 patients enrolled, two had a complete response, seven had a partial response, seven had stable disease, and three had progressive disease. The median survival for the 19 patients enrolled on this study was 410 days, with four patients still alive at present (> 680 days). CONCLUSION: Elimination of all detectable plasma arginine in patients with HCC was well tolerated and seemed to be effective in the treatment of some patients with HCC. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with HCC as well as other human tumors auxotrophic for arginine is warranted. 相似文献
1000.
Polymorphisms in interleukin -2, -6, and -10 are not associated with gastric cardia or esophageal cancer in a high-risk chinese population. 总被引:7,自引:0,他引:7