Cancer-induced cachexia is a common manifestation observed in patients with malignancies. Elevated levels of circulating,glucocorticoids and interleukin-6 (IL-6) hare been observed in cancer patients with cachexia and...
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Cancer-induced cachexia is a common manifestation observed in patients with malignancies. Elevated levels of circulating,glucocorticoids and interleukin-6 (IL-6) hare been observed in cancer patients with cachexia and are implicated as major mediators in this process. The purpose of this study was to investigate the role of circulating glucocorticoid levels as primary mediators in cancer-induced cachexia. We evaluated whether inhibition of glucocorticoids with the receptor antagonist RU-486 could abrogate the detrimental wasting of muscle and adipose tissues seen in a well-characterized murine tumor-induced cachexia model. Mice (12/group) were randomized to control, tumor-bearing, control + vehicle, or tumor-bearing + glucocorticoid receptor antagonist groups. Circulating serum glucocorticoid and IL-6 levels were measured in addition to multiple body composition parameters, such as total body weight lean body mass, and adipose content. The results of this study indicate a significant physiological alteration in the tumor-bearing host that causes severe and detrimental changes in body composition parameters. Regression analysis demonstrated a significant correlation between increased circulating glucocorticoid levels and alterations in body composition parameters. These observed defects were not abrogated with the administration of a glucocorticoid receptor antagonist. We therefore conclude that the untoward effects of tumor-induced cachexia are not mediated primarily by the peripheral effects of high circulating glucocorticoid levels but may involve a complex interaction with IL-6.
Purpose: The aims of these experiments were to determine the effect of a therapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers;and the concentration-effect relationship bet...
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Purpose: The aims of these experiments were to determine the effect of a therapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers;and the concentration-effect relationship between dexamethasone and CYP3A4 activity in primary human hepatocyte cultures. Methods: The effect of dexamethasone (8 mg administered by mouth two times a day for 5 days) on CYP3A4 activity in 12 healthy volunteers was assessed with the erythromycin breath test and urinary ratio of dextromethorphan to 3-methoxymorphinan. Concentration-effect of dexamethasone on CYP3A4-dependent testosterone 6-beta -hydroxylation was determined in human hepatocytes treated with 2 to 250 mu mol/L dexamethasone. Results: The percent of erythromycin metabolized per hour increased from 2.20% +/- 0.60% (mean +/- SD) at baseline to 2.67% +/- 0.55% on day 5 of dexamethasone (mean increase in hepatic CYP3A4 activity 25.7% +/- 24.6%;P = .004). The mean urinary ratio of dextromethorphan to 3-methoxymorphinan was 28 (4.8 to 109) and 7 (1 to 23) at baseline and on day 5 of dexamethasone (mean decrease = 49%;P = .06). Substantial intersubject variability was observed in the extent of CYP3A4 induction. The extent of CYP3A4 induction was inversely correlated with baseline erythromycin breath test (r(2) = 0.58). In hepatocytes, dexamethasone 2 to 250 mu mol/L resulted in an average 1.7-fold to 6.9-fold increase in CYP3A4 activity respectively. The extent of CYP3A4 induction with dexamethasone in hepatocyte preparations was inversely correlated with baseline activity (r(2) = 0.59). Conclusions: These data demonstrate that dexamethasone at doses used clinically increased CYP3A4 activity with extensive intersubject variability and that the extent of CYP3A4 induction was, in part, predicted by the baseline activity of CYP3A4 in both healthy volunteers and human hepatocyte cultures.
The glucocorticoid uptake in vitro by human periferal leukocytes was studied. The uptake showed 2 main components, 1 saturable and 1 non-saturable. The saturable component was compared with the uptake by the specific ...
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The glucocorticoid uptake in vitro by human periferal leukocytes was studied. The uptake showed 2 main components, 1 saturable and 1 non-saturable. The saturable component was compared with the uptake by the specific glucocorticoid receptor in rabbit granulocytes. The similarities with the rabbit receptor in structural specificity, time course of uptake at ***. C, sensitivity to metabolic inhibition by PCMS [p-chloro-mercuribenzene sulfonic acid] and the physiological concentration for half saturation indicate that the saturable component corresponds to a specific glucocorticoid receptor. Cells from chronic lymphatic leukemia and chronic myeloid leukemia were also studied. Only the former had a saturable glucocorticoid uptake.
The relation between immunity, plasm glucocorticoid (GC) and Lymphocyte glucocorticoid receptor (GCR) number were studied in 4 patients with hemorrhagic fever with nephrntic syndrome (HFNS) by using radioimmune assay ...
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The relation between immunity, plasm glucocorticoid (GC) and Lymphocyte glucocorticoid receptor (GCR) number were studied in 4 patients with hemorrhagic fever with nephrntic syndrome (HFNS) by using radioimmune assay and radioligand binding technique. We found that there was increasing of plasm GC and lymphocyte GCR number with the developing of specific immune response in HFRS. This result caused immune inhibitory effect. It may be a reason that HFNS patients occur rarely immune disease after convalescence.
It is necessary to further study the relation of immunity and endocrine during immunity diseases.
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