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991.
992.
Randolph JT Waid P Nichols C Sauer D Haviv F Diaz G Bammert G Besecke LM Segreti JA Mohning KM Bush EN Wegner CD Greer J 《Journal of medicinal chemistry》2004,47(5):1085-1097
The design and synthesis of a series of 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A that are novel, nonpeptide LHRH antagonists, is described. The macrolide antagonist 1, discovered during a screen of our chemical repository, was compared to a macrocyclic peptide antagonist 2 using molecular modeling, thus providing a model for the design of more potent antagonists. Medicinal chemistry efforts to find a replacement for cladinose at position 3 of the erythronolide core provided a series of oxazolidinone carbamates that were equally as active as the cladinose-containing parent macrolides. The descladinose LHRH antagonist 14 has 1-2 nM affinity for both rat and human LHRH receptors and is a potent inhibitor of LH release (pA2 = 8.76) in vitro. In vivo, 14 was found to produce a dose-dependent suppression of LH in male castrate rats via both i.v. and p.o. dosing. 相似文献
993.
Davis JW Goodsaid FM Bral CM Obert LA Mandakas G Garner CE Collins ND Smith RJ Rosenblum IY 《Toxicology and applied pharmacology》2004,200(1):16-26
Gene expression patterns using microarrays have been described for rodent models of nephrotoxicity. To determine if significant gene expression changes previously identified have application across multiple species, we studied quantitative gene expression changes in the kidneys of female cynomolgus monkeys after exposure to two nephrotoxicants. Animals were dosed with the aminoglycoside gentamicin (10 mg/kg), the experimental oligosaccharide antibiotic everninomicin (30 or 60 mg/kg), or a combination of gentamicin (10 mg/kg) and everninomicin (30 mg/kg) for 7 days. Monkeys receiving these drugs in combination developed renal lesions as early as Day 1. By Day 7, monkeys dosed with 60 mg/kg everninomicin alone also developed renal lesions, while the group exposed to both compounds had more extensive renal damage. The modulation of several genes previously reported to be associated with nephrotoxicity in rodent models was confirmed using quantitative real-time PCR. Among these, waf-1, matrix metalloproteinase-9, and vimentin exhibited changes consistent with the definition of a genomic indicator of toxicity. In addition, we identified three early gene biomarkers that may be predictive of drug-induced nephrotoxicity: clusterin, osteopontin, and hepatitis A virus cellular receptor-1. Logistic regression demonstrated a high degree of correlation between changes in gene expression and the probability of the development of histopathologic lesions. These results are the first confirming rodent gene expression changes associated with nephrotoxicity in a nonhuman primate model and provide preliminary evidence for identifying early gene expression changes predicting the onset of drug-induced renal tubular damage in cynomolgus monkeys. 相似文献
994.
Pharmacokinetics of etoricoxib in patients with renal impairment 总被引:1,自引:0,他引:1
Agrawal NG Matthews CZ Mazenko RS Kline WF Woolf EJ Porras AG Geer LA Wong PH Cho M Cote J Marbury TC Moncrief JW Alcorn H Swan S Sack MR Robson RA Petty KJ Schwartz JI Gottesdiener KM 《Journal of clinical pharmacology》2004,44(1):48-58
The effect of renal insufficiency on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, was examined in 23 patients with varying degrees of renal impairment (12 moderate [creatinine clearance between 30 and 50 mL/min/1.73 m2], 5 severe [creatinine clearance below 30 mL/min/1.73 m2], and 6 with end-stage renal disease requiring hemodialysis) following administration of single 120-mg oral doses of etoricoxib. Even the most severe renal impairment was found to have little effect on etoricoxib pharmacokinetics. The low recovery of etoricoxib in dialysate (less than 6% of the dose) supports that hemodialysis also has little effect on etoricoxib pharmacokinetics, and binding of etoricoxib to plasma proteins was generally unaffected by renal disease. Single doses of etoricoxib were generally well tolerated by patients with renal impairment. Based on pharmacokinetic considerations, dosing adjustments are not necessary for patients with any degree of renal impairment. However, because patients with advanced renal disease (creatinine clearance below 30 mL/min/1.73 m2) are likely to be very sensitive to any further compromise of renal function, and there is no long-term clinical experience in these patients, the use of etoricoxib is not recommended in patients with advanced renal disease. 相似文献
995.
Donnelly KC Lingenfelter R Cizmas L Falahatpisheh MH Qian Y Tang Y Garcia S Ramos K Tiffany-Castiglioni E Mumtaz MM 《Environmental toxicology and pharmacology》2004,18(2):135-141
One of the initial steps in remediating contaminated environments is to assess the human and ecological health risk associated with exposure to contaminants in a specific medium. Presented here are the results of a five-year study investigating the toxicity of simple and complex mixtures. A series of model compounds and simple mixtures including polycyclic aromatic hydrocarbons (PAHs), pentachlorophenol (PCP), and halogenated aliphatic hydrocarbons (HAHs) were analyzed. Mixture toxicity was studied using microbial genotoxicity assays and cytotoxicity assays with renal and neural cells. The majority of binary mixtures described here induced additive responses. A limited number of samples were identified where binary mixtures induced inhibitory effects. For example, benzo(a)pyrene (BAP) alone induced 30% renal cell death, whereas an equimolar dose of chrysene and BAP only produced 1.6% cellular death. In none of the mixtures tested did the mixture toxicity results deviate from the predicted results by an order of magnitude. The results from testing binary mixtures in this study indicate that the results did not deviate significantly from additivity. Complex mixture results were more difficult to interpret. The toxicity of complex mixtures could not be accurately predicted based on chemical analysis. This could be due to chemical interactions or due to the presence of unidentified chemicals, such as alkyl PAHs or high molecular weight PAHs that are not included in the standard risk assessment procedure. Even though the results from these in vitro studies indicate that additive assumptions will generally be appropriate for binary mixtures similar to the ones tested here, the risk associated with complex mixtures remains a challenge to predict. Before the results of toxicity testing can be used to adjust risk assessment calculations, it is important to fully appreciate the chemical composition and to understand the mechanism of observed chemical interactions in animals chronically exposed to low doses of chemical mixtures. This research was supported by ATSDR Grant no. ATU684505 and NIEHS SBRP Grant no. P42 ES04917. 相似文献
996.
The increase in risk of diabetes mellitus from exposure to second-generation antipsychotic agents 总被引:7,自引:0,他引:7
Citrome LL 《Drugs of today (Barcelona, Spain : 1998)》2004,40(5):445-464
This is a review of the evidence for a link between exposure to second-generation antipsychotic agents and the development of type 2 diabetes mellitus. Most of this evidence comes from case series and retrospective pharmacoepidemiological studies. Exposure to second-generation antipsychotic agents increases the risk for diabetes mellitus compared to no exposure to antipsychotic drugs. The risk with second-generation antipsychotic agents compared to exposure to first-generation antipsychotics is smaller and not consistent. The differential risk among the second-generation antipsychotic agents has not yet been adequately established. Other risk factors for diabetes mellitus, such as advancing age, non-White ethnicity, family history, obesity, lack of physical activity and the diagnosis of schizophrenia, probably contribute more to the risk than exposure to any single antipsychotic drug. Clinicians are urged to manage risk by regularly monitoring all patients receiving second-generation antipsychotic agents for the emergence of diabetes mellitus. 相似文献
997.
The process for continuous improvement of the TNM classification 总被引:17,自引:0,他引:17
The TNM classification is a worldwide benchmark for reporting the extent of malignant disease and is a major prognostic factor in predicting the outcome of patients with cancer. The objectives for cancer staging were defined by the International Union Against Cancer (UICC) TNM Committee almost 50 years ago and are still broadly applicable today. To keep pace with the modern demands of evidence-based practice, the UICC introduced a structured process for introducing changes to the TNM classification. The elements of the TNM process were determined to include the development of unambiguous criteria for the information and documentation required to consider changes in the classification, establishment of a well-defined process for the annual review of relevant literature, formation of site-specific expert panels, and the participation of experts from all over the world in the TNM review process. Communication between the oncology community and those involved in the TNM classification was established as being essential to the success of the process. The process, which was introduced in 2002, will be tested over the next 3-4 years and evaluated. In addition to the formal process, individual initiative, involvement by the national staging committees, and group consensus are required. Furthermore, increased involvement by the experts should improve the understanding and dissemination of the TNM classification. 相似文献
998.
999.
Rajendra A Spinella PC Drott HR Dominguez TE Sutton L Helfaer M 《Journal of neuro-oncology》2004,67(3):345-349
OBJECTIVE: To determine if serum S-100beta levels are elevated in children with brain neoplasms and if it can be used as a tumor marker for children with brain neoplasms. DESIGN: Prospective cohort study. SETTING: Urban, tertiary care, children's teaching hospital. PATIENTS: 136 healthy children and 27 children with brain neoplasms. METHODS: Serum levels of S-100beta were measured in 136 healthy children to serve as controls and 27 children with brain neoplasms, who underwent biopsy or resection of the mass. Patients were then classified into astrocytoma or non-astrocytoma groups. MEASUREMENTS AND MAIN RESULTS: The median serum S-100beta level for the control group was 0.27 mcg/l (range, 0.06-2.6 mcg/l), and for the brain neoplasm group was 0.2 mcg/l (range, 0.01-2.1 mcg/l), (p = 0.09). There were 13 children with astrocytomas and 14 with non-astrocytomas. The S-100beta levels for the astrocytoma group was 0.25 mcg/l (range, 0.05-1.1 mcg/l) and for the non-astrocytoma group 0.17 mcg/l (range, 0.01-2.1 mcg/l), (p = 0.47). CONCLUSIONS: Serum S-100beta levels are not elevated in children with brain neoplasms compared to healthy children, nor are they elevated in children with astrocytomas compared to non-astrocytomas. The S-100beta protein does not appear to be useful as a serum tumor marker in children with brain neoplasms. 相似文献
1000.
Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer 总被引:1,自引:0,他引:1
Turner PK Houghton JA Petak I Tillman DM Douglas L Schwartzberg L Billups CA Panetta JC Stewart CF 《Cancer chemotherapy and pharmacology》2004,53(3):253-260
Purpose The study objectives were to define subcutaneous (s.c.) interferon gamma (IFN-) disposition in patients with gastrointestinal malignancies receiving 5-fluorouracil (5-FU) and leucovorin (LV) and to examine the relationship between IFN- exposures and Fas upregulation in vivo and in vitro.Methods Patients received IFN- (10, 25, 50, 75, and 100 g/m2) with LV and 5-FU, and serial samples were collected after the first dose. IFN- concentrations were measured by ELISA. A linear one-compartment model with a lag was fitted to the IFN- plasma concentration-time data. To examine the relationship between IFN- systemic exposure and biological activity in vivo, cell surface Fas upregulation was assessed in peripheral blood mononuclear cell (PBMC) subcompartments.Results The median (range) apparent IFN- clearance was 46 l/m2 per hour (2.6–92 l/m2 per hour). With increasing IFN- dosages, the area under the concentration-time curve (AUC0) and Cmax increased; however, significant interpatient variability was observed. IFN- AUC0 and time above 33.3 pg/ml significantly correlated with Fas upregulation in several PBMC compartments, but dosage was significantly correlated with this pharmacodynamic marker only in CD4+ and CD56+ cells. In vitro studies in HT29 cells demonstrated that clinically relevant IFN- concentrations (1 to 10 U/ml for 6.5 h) with 5-FU/LV upregulated Fas expression 3.5-fold, similar to that in PBMC in vivo.Conclusions We characterized IFN- disposition and developed a limited sampling model for use in future pharmacokinetic studies. Our results showed that IFN- upregulates Fas in PBMC in vivo and in HT29 cells in vitro at tolerable, clinically relevant exposures and that monitoring IFN- pharmacokinetics/pharmacodynamics may be warranted in IFN- clinical use.This work was supported in part by US Public Health Service awards CA23099, CA32613 and CA23944, the Wings Cancer Foundation, and American Lebanese Syrian Associated Charities (ALSAC). 相似文献