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排序方式: 共有675条查询结果,搜索用时 15 毫秒
11.
Yi‐an Bi Xi Qiu Charles J. Rotter Emi Kimoto Mary Piotrowski Manthena V. Varma Ayman F. EI‐Kattan Yurong Lai 《Biopharmaceutics & drug disposition》2013,34(8):452-461
Hepatic uptake transport is often the rate‐determining step in the systemic clearance of drugs. The ability to predict uptake clearance and to determine the contribution of individual transporters to overall hepatic uptake is therefore critical in assessing the potential pharmacokinetic and pharmacodynamic variability associated with drug–drug interactions and pharmacogenetics. The present study revisited the interaction of statin drugs, including pitavastatin, fluvastatin and rosuvastatin, with the sodium‐dependent taurocholate co‐transporting polypeptide (NTCP) using gene transfected cell models. In addition, the uptake clearance and the contribution of NTCP to the overall hepatic uptake were assessed using in vitro hepatocyte models. Then NTCP protein expression was measured by a targeted proteomics transporter quantification method to confirm the presence and stability of NTCP expression in suspended and cultured hepatocyte models. It was concluded that NTCP‐mediated uptake contributed significantly to active hepatic uptake in hepatocyte models for all three statins. However, the contribution of NTCP‐mediated uptake to the overall active hepatic uptake was compound‐dependent and varied from about 24% to 45%. Understanding the contribution of individual transporter proteins to the overall hepatic uptake and its functional variability when other active hepatic uptake pathways are interrupted could improve the current prediction practice used to assess the pharmacokinetic variability due to drug–drug interactions, pharmacogenetics and physiopathological conditions in humans. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
12.
Eisenhauer EL Tew WP Levine DA Lichtman SM Brown CL Aghajanian C Huh J Barakat RR Chi DS 《Gynecologic oncology》2007,106(2):381-387
OBJECTIVE: Recent reports have suggested that only half of women age > or =65 with advanced ovarian cancer are treated with platinum-based chemotherapy. The objective of this study was to compare the response to platinum-taxane chemotherapy and subsequent outcomes between patients older and younger than 65 years of age with stages IIIC-IV epithelial ovarian cancer (EOC). PATIENTS AND METHODS: A cohort study was performed of all patients with stages IIIC-IV EOC who had their primary surgery at our institution from 1998 to 2004 and subsequently began platinum-taxane chemotherapy. Main outcomes were response to primary chemotherapy, platinum resistance and progression-free (PFS) and overall survival (OS). RESULTS: A total of 292 patients began primary platinum-taxane therapy after surgery and comprised our study group. Of these, 108 (37%) were > or =65 years old and 184 (63%) were <65. Stage of disease, optimal cytoreduction rate, number of chemotherapy cycles and chemotherapy regimen alterations were similar between groups. Patients > or =65 achieved a clinical complete response with a similar frequency to those <65 (70% vs. 79%) and had similar rates of platinum sensitivity at 6 months (61% vs. 65%). Patients > or =65 had equivalent PFS (P=0.99) and OS (P=0.36) to those <65. Age > or =65 years was not independently associated with impaired survival. CONCLUSIONS: Patients > or =65 years of age demonstrated similar rates of initial response, platinum resistance, PFS and OS to younger patients. Elderly women who can tolerate primary cytoreductive surgery should receive combination platinum-taxane chemotherapy. 相似文献
14.
Modulation of in vitro eosinophil progenitors by hydrocortisone: role of accessory cells and interleukins 总被引:1,自引:0,他引:1
The growth of human eosinophil progenitors (CFU-Eo) and the modulation of growth by hydrocortisone were studied as functions of the presence of lymphocytes and monocytes in marrow cells under study; and the source of colony-stimulating factors, specifically, media conditioned by macrophage-like cell line, GCT; phytohemagglutinin-stimulated mononuclear cells (PHA-LCM); or the T cell line, MO. CFU-Eo growth was greatest in marrow containing accessory cells as compared to marrow depleted of accessory cells; and in marrow treated with phytohemagglutinin-stimulated leukocyte conditioned media (PHA-LCM) or MO (T cell line)-conditioned medium (MO-CM) as compared with GCT cell- conditioned medium (GCT-CM). Hydrocortisone reproducibly inhibited eosinophil progenitor growth in unfractionated marrow stimulated by GCT- CM. This effect was abrogated by admixing irradiated mononuclear cells or T lymphocytes with the target marrow or by adding interleukin 1 or interleukin 2 (IL-1, IL-2). Inhibition by hydrocortisone did not occur when monocyte and T lymphocyte depleted marrow was studied. Unlike GCT- CM, MO-CM and PHA-LCM stimulated equal proportions of eosinophil progenitors in nondepleted and accessory cell-depleted marrow and demonstrated less hydrocortisone inhibition. However, both GCT-CM and PHA-LCM produced in the presence of hydrocortisone stimulated significantly fewer CFU-Eos in both unfractionated and accessory cell- depleted marrow target populations. These results indicate that the growth of CFU-Eo and inhibition of growth by hydrocortisone is a direct function of a monocyte-T cell interaction and probably is mediated through effects on the production/release of eosinophil colony stimulating factor (Eo-CSF). 相似文献
15.
Aron H. Lichtman Eberhard Albert Lux Robert McQuade Sandro Rossetti Raymond Sanchez Wei Sun Stephen Wright Elena Kornyeyeva Marie T. Fallon 《Journal of pain and symptom management》2018,55(2):179-188.e1
Context
Prior Phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain.Objectives
To assess adjunctive nabiximols (Sativex®), an extract of Cannabis sativa containing two potentially therapeutic cannabinoids (Δ9-tetrahydrocannabinol [27 mg/mL] and cannabidiol [25 mg/mL]), in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy.Methods
Phase 3, double-blind, randomized, placebo-controlled trial in patients with advanced cancer and average pain Numerical Rating Scale scores ≥4 and ≤8 despite optimized opioid therapy. Patients randomized to nabiximols (n = 199) or placebo (n = 198) self-titrated study medications over a two-week period, followed by a three-week treatment period at the titrated dose.Results
Median percent improvements in average pain Numerical Rating Scale score from baseline to end of treatment in the nabiximols and placebo groups were 10.7% vs. 4.5% (P = 0.0854) in the intention-to-treat population (primary variable) and 15.5% vs. 6.3% (P = 0.0378) in the per-protocol population. Nabiximols was statistically superior to placebo on two of three quality-of-life instruments at Week 3 and on all three at Week 5. In exploratory post hoc analyses, U.S. patients, but not patients from the rest of the world, experienced significant benefits from nabiximols on multiple secondary endpoints. Possible contributing factors to differences in nabiximols efficacy include: 1) the U.S. participants received lower doses of opioids at baseline than the rest of the world and 2) the subgroups had different distribution of cancer pain types, which may have been related to differences in pathophysiology of pain. The safety profile of nabiximols was consistent with earlier studies.Conclusions
Although not superior to placebo on the primary efficacy endpoint, nabiximols had benefits on multiple secondary endpoints, particularly in the U.S. patients. Nabiximols might have utility in patients with advanced cancer who receive a lower opioid dose, such as individuals with early intolerance to opioid therapy. 相似文献16.
P P Muldoon J Chen J L Harenza R A Abdullah L J Sim-Selley B F Cravatt M F Miles X Chen A H Lichtman M I Damaj 《British journal of pharmacology》2015,172(3):869-882
Background and Purpose
Abrupt discontinuation of nicotine, the main psychoactive component in tobacco, induces a withdrawal syndrome in nicotine-dependent animals, consisting of somatic and affective signs, avoidance of which contributes to drug maintenance. While blockade of fatty acid amide hydrolase, the primary catabolic enzyme of the endocannabinoid arachidonoylethanolamine (anandamide), exacerbates withdrawal responses in nicotine-dependent mice, the role of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of a second endocannabinoid 2-arachidonylglycerol (2-AG), in nicotine withdrawal remains unexplored.Experimental Approach
To evaluate the role of MAGL enzyme inhibition in nicotine withdrawal, we initially performed a genetic correlation approach using the BXD recombinant inbred mouse panel. We then assessed nicotine withdrawal intensity in the mouse after treatment with the selective MAGL inhibitor, JZL184, and after genetic deletion of the enzyme. Lastly, we assessed the association between genotypes and smoking withdrawal phenotypes in two human data sets.Key Results
BXD mice displayed significant positive correlations between basal MAGL mRNA expression and nicotine withdrawal responses, consistent with the idea that increased 2-AG brain levels may attenuate withdrawal responses. Strikingly, the MAGL inhibitor, JZL184, dose-dependently reduced somatic and aversive withdrawal signs, which was blocked by rimonabant, indicating a CB1 receptor-dependent mechanism. MAGL-knockout mice also showed attenuated nicotine withdrawal. Lastly, genetic analyses in humans revealed associations of the MAGL gene with smoking withdrawal in humans.Conclusions and Implications
Overall, our findings suggest that MAGL inhibition maybe a promising target for treatment of nicotine dependence. 相似文献17.
18.
Chemical mediators of granulopoiesis: a review 总被引:2,自引:0,他引:2
19.
Cravatt BF Saghatelian A Hawkins EG Clement AB Bracey MH Lichtman AH 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(29):10821-10826
Fatty acid amides (FAAs) constitute a large class of endogenous signaling lipids that modulate several physiological processes, including pain, feeding, blood pressure, sleep, and inflammation. Although FAAs have been proposed to evoke their behavioral effects through both central and peripheral mechanisms, these distinct signaling pathways have remained experimentally challenging to separate. Here, we report a transgenic mouse model in which the central and peripheral FAA systems have been functionally uncoupled. Mice were generated that express the principle FAA-degrading enzyme FAA hydrolase (FAAH) specifically in the nervous system (FAAH-NS mice) by crossing FAAH(-/-) mice with transgenic mice that express FAAH under the neural specific enolase promoter. FAAH-NS mice were found to possess wild-type levels of FAAs in the brain and spinal cord, but significantly elevated concentrations of these lipid transmitters in peripheral tissues. This anatomically restricted biochemical phenotype correlated with a reversion of the reduced pain sensitivity of FAAH(-/-) mice, consistent with the FAA anandamide producing this effect by acting on cannabinoid receptors in the nervous system. Interestingly, however, FAAH-NS mice still exhibited an antiinflammatory phenotype similar in magnitude to FAAH(-/-) mice, indicating that this activity, which was not blocked by cannabinoid receptor antagonists, was mediated by peripherally elevated FAAs. These data suggest that the central and peripheral FAA signaling systems regulate discrete behavioral processes and may be targeted for distinct therapeutic gain. 相似文献
20.
Lichtman SM 《Critical reviews in oncology/hematology》2000,33(2):119-128
Persons 65 years of age and older are the fastest growing segment of the United States population. Over the next 30 years they will comprise approximately 20% of the population. There will be a parallel rise in the number of patients with non-Hodgkin's lymphoma. Age has long been known to be an adverse prognostic factor. Clinical trials of older patients are complicated by the effect of comorbid illness, particularly its effect on overall survival. CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) remains the standard therapy for all patients with aggressive non-Hodgkin's lymphoma. There are a number of regimens which may be beneficial for older patients with significant comorbidity and poor performance status. The randomized trials in the elderly has reaffirmed CHOP and emphasize the need for adequate dosing, maintaining schedule and anthracyclines. Relapsed patients have a poor prognosis but selected fit older patients may benefit from aggressive reinduction regimens and possibly bone marrow transplantation. Future research should include defining the role of comorbidity, measurement of organ dysfunction and assessment of performance status with geriatric functional scales. New drug treatments should also be explored. 相似文献