Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of flutamide, a potent nonsteroidal antiandrogen, on the metabolism of iv tracers of [3H]estradiol was studied in five patients with advanced prostate cancer. The drug produced no change in the percentage of the injected radioactivity recovered in urine or in the glucuronide or nonglucuronide conjugate fractions. Of the five individual metabolites that were quantitated, estrone, estradiol, and estriol were unaffected by flutamide, but the drug caused striking decreases in conversion of estradiol to 2-hydroxyestrone (4.0% vs. 7.4%) (P less than 0.005) and 2-methoxyestrone (1.1% vs. 2.6%; P less than 0.05); every one of the patients showed a marked fall in recovery of both of these compounds. This depression of the formation of 2-oxygenated metabolites is reminiscent of the findings in liver disease; the same abnormality occurs regularly in cirrhosis and frequently in extrahepatic biliary obstruction. Taken together with our previous studies of the effects of flutamide on testosterone and cortisol metabolism, this study demonstrates that flutamide produces multiple functional, reversible, cirrhosis-like disturbances of steroid metabolism. Because these disturbances are universal in the patients studied regardless of whether they had clinical responses to flutamide, we doubt that the steroid metabolic changes play a role in the therapeutic effect of the drug.
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PMID:Effect of flutamide on estradiol metabolism. 46 81

Nafcillin, a semisynthetic penicillin effective against penicillinase-producing staphylococci, is eliminated largely in man via the liver. This study assessed the effect of cirrhosis and extrahepatic biliary obstruction in man on the pharmacokinetics of nafcillin. The plasma clearance of nafcillin controls was 583 +/- 144.2 ml per min (mean +/- SD) and fell strikingly to 291 +/- 147.6 and 163 +/- 56.3 ml per min in patients with cirrhosis and extrahepatic obstruction, respectively (P less than 0.001). In the latter two groups nafcillin excreted in urine increased from about 30 to 50% of administered dose (P less than 0.02), suggesting that renal disease superimposed on hepatic disease would further decrease over-all nafcillin clearance. The depression of nafcillin clearance with hepatobiliary disease did not correlate with any conventional liver laboratory test. The initial volume of distribution of nafcillin (V1) was unaltered but at steady state (Vd()) there was a significant reduction in the distribution volume in the patients with liver disease. Accordingly, the impairment in drug elimination, as assessed by its clearance from plasma, was underestimated by the prolongation of the nafcillin elimination half-life (t1/2(beta)) which was 1.02 +/- 0.20 hr in controls, and 1.23 +/- 0.31 (P greater than 0.05) and 1.73 +/- 0.44 hr (P less than 0.03), respectively, in patients with cirrhosis and extrahepatic obstruction.
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PMID:Disposition of nafcillin in patients with cirrhosis and extrahepatic biliary obstruction. 91 79

Imparied cell-mediated immunity has been described in obstructive jaundice and has been attributed to depressant serum factors or to depressed intrinsic T-cell function. The authors studied lymphocyte responsiveness to phytohemagglutinin stimulation, the in-vitro correlate of T-cell function, in 11 patients with biliary obstruction. Peripheral-blood mononuclear cells and serum were obtained before (mean serum bilirubin level 302 mumol/L) and after (mean serum bilirubin level 23 mumol/L) treatment of the biliary obstruction. Simultaneous cell culture of all samples disclosed no evidence of a serum depressant factor in patients with obstructive jaundice, and crossover incubation studies failed to suggest that there is a depression of intrinsic T-cell responsiveness that can be reversed by biliary drainage.
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PMID:Human lymphocyte responsiveness is not enhanced by relief of biliary obstruction: an in-vitro study. 202 1

Obstructive jaundice causes depression of immune system function but it is unclear at present how rapidly immune function recovers after relief of biliary obstruction. To address this issue, we studied 218 Sprague-Dawley rats with common bile duct obstruction. Mononuclear phagocyte function, cell mediated immune function, portal-systemic shunt fraction, liver function tests, and liver histology were evaluated in normal (sham) rats, obstructed rats, and at weekly intervals after relief of biliary obstruction. Hepatic uptake of radiolabelled bacteria was 82 per cent in sham rats and 66 per cent in rats 21 days after CBD obstruction (P less than 0.05). Phagocytic activity returned to normal within 7 days after choledochoduodenostomy. Cell mediated immunity, measured by skin graft rejection, was significantly prolonged in the obstructed group (P less than 0.05) but had returned to normal 7 days after biliary diversion. Return of hepatocellular function, as measured by liver function tests, paralleled recovery of immune function. This study demonstrates prompt recovery of the immune system after internal biliary drainage for obstructive jaundice. This finding is in contrast to previous studies that demonstrated persistent immune suppression months after biliary diversion. These data may have implications concerning the usefulness of internal biliary drainage before surgery in patients with obstructive jaundice.
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PMID:Effects of relief of biliary obstruction on mononuclear phagocyte system function and cell mediated immunity. 181 Feb 99

The increased susceptibility to infections after surgery in jaundiced patients is considered to be caused by an impairment of cellular immunity and/or nutritional status. Endotoxins are suggested to play a role in the pathogenesis. However, the mechanism of action is unknown. Germ-free rats were used to study the effect of biliary obstruction in a model with negligible amounts of endotoxin. Cellular immunity, production of tumor necrosis factor (as a mediator of endotoxin toxicity) by peritoneal macrophages, and the nutritional status were assessed. Significant suppression of cellular immunity was found in conventional rats with obstructive jaundice. In contrast, cellular immunity was not suppressed in jaundiced germ-free rats. Large amounts of tumor necrosis factor were spontaneously secreted by peritoneal macrophages of jaundiced conventional rats, whereas macrophages from jaundiced germ-free rats did not. Moreover macrophage activation (expressed in tumor necrosis factor production) was significantly related to suppression of cellular immunity. Weight changes and depression of albumin levels were not different in germ-free and conventional rats after bile duct ligation. The data presented indicate that suppression of cellular immunity in obstructive jaundice is caused by endotoxins, whereas the impaired nutritional status seems to not be affected by the presence of endotoxins.
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PMID:Suppression of cellular immunity in obstructive jaundice is caused by endotoxins: a study with germ-free rats. 229 4

High surgical mortality in patients with obstructive jaundice and sepsis have been attributed to reticuloendothelial system (RES) depression. The purpose of this study was to clarify the effects of mechanical biliary obstruction on RES clearance of pathogenic bacteria by comparing the phagocytic index (K) with the directly measured hepatic uptake of indium 111-labeled bacteria injected into the portal vein of normal dogs and dogs with partial (PBO) or complete biliary obstruction (CBO). No significant difference was observed between the K in normal dogs (0.19 +/- 0.08; n = 6) and that in dogs with PBO (0.24 +/- 0.06; n = 5) or CBO (0.21 +/- 0.03; n = 4). There was no significant difference in uptake of radiolabel by the liver among the three groups of dogs. In our model, biliary obstruction had no effect on hepatic RES function and may not represent a significant determinant of mortality in patients with obstructive jaundice.
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PMID:Effects of biliary obstruction on hepatic clearance of bacteria. 250 73

Acute respiratory failure after hepatic resection, especially in case of concomitant liver dysfunction, is the most troublesome postoperative complication. In order to clarify the pathophysiological mechanism of acute respiratory failure, EVLW (extravascular lung water) was measured by double indicator dilution method in canine model. Mongrel dogs underwent laparotomy and the common bile duct was ligated and divided. After 6 weeks, EVLW was significantly elevated compared with that of normal dogs (p less than 0.05). From 4 hours after 70% hepatic resection dextran-40 was loaded to increase PWP (pulmonary wedge pressure). EVLW was increased accompanying the elevation of PWP in all groups, but in the group with biliary obstruction EVLW was significantly increased for the same elevation of PWP. These results suggest that permeability of pulmonary capillary was highly increased after hepatic resection in biliary obstruction group. Pulmonary edema in this canine model seems to resemble ARDS in human and the pathophysiological mechanism was thought to be related with depression of RES phagocytic function, activation of complement system and pulmonary vascular plugging by aggregates of degenerating granulocytes and endothelial injury. Gabexate mesilate blocked the increase of the lung vascular permeability and was thought to be effective to protect the lung from postoperative acute respiratory failure.
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PMID:[Acute respiratory failure after hepatic resection in canine biliary obstruction model]. 314 48

Reticulo-endothelial function was evaluated by measuring the biokinetics of a standardized 99mTc-sulphur colloid using scintillation camera technique in rats with biliary obstruction. There was no difference in the uptake of the colloid in the liver (K1) between sham operation and biliary obstruction at 1 week and 3 weeks. However, when corrected for changes in liver volume, the corrected colloidal uptake rate (cK1) of the liver was significantly decreased in 1 week's biliary obstruction (P less than 0.005 compared with sham operation) and 3 weeks' biliary obstruction (P less than 0.025 compared with 1 week obstruction). Colloidal uptake rate of the extrahepatic reticulo-endothelial system (K2) was significantly increased (P less than 0.005) in rats with 3 weeks' biliary obstruction. Activity distribution of 99mTc-sulphur colloid in 3 weeks' biliary obstruction was significantly decreased in both total organ basis and per gram basis (P less than 0.005). The results demonstrated a depression of RE activity of the liver in biliary obstruction.
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PMID:Reticulo-endothelial function in rats with obstructive jaundice. 408 49

Using CD series monoclonal antibody indirect immune fluorescent assay and LDH enzyme-release assay, we investigated lymphocyte subsets and natural killer cells (NKC) activity in the peripheral blood of 30 patients with obstructive jaundice. The results showed that the percentage of CD3+, CD4+, B cells and that of CD8+ was high. The ratio of CD4/CD8 was low at the first 10 days of jaundice when the serum bilirubin level was less than 171 mumol/L. Our studies suggested that obstructive jaundice might cause depression and impairment of host cellular and humoral immunity. Further studies showed that impaired immune function of jaundiced patients returned to normal 30 days after the disappearance of the jaundice by external or internal biliary drainage. Immune function recovered 30 days after relief of biliary obstruction and external or internal biliary drainage. External or internal biliary drainage was useful in improving host immunity.
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PMID:[Effects of obstructive jaundice on immunocompetence in jaundiced patients]. 822 24

To determine if disturbances of the liver microcirculation may be of pathophysiological relevance for liver damage during acute biliary obstruction, we studied the effects of bile duct ligation (BDL) on hepatic microhemodynamics and leukocyte adhesion in rat liver in vivo. Male Wistar rats were subjected to BDL for 3 days and 7 days, respectively. Sham-operated controls underwent laparotomy without BDL. After 3 days, intravital fluorescence microscopy (IVM) and hydrogen gas (H2) clearance were performed to study hepatic microvascular perfusion. Furthermore, leukocyte-endothelial cell interactions were assessed by IVM. Intercellular adhesion molecule 1 (ICAM-1) protein expression was studied by Western blot analysis and tissue immunofluorescence after 3 and 7 days, respectively. Analysis of microvascular perfusion by IVM revealed a marked impairment of sinusoidal perfusion after 3 days. Assessment of H2 clearance confirmed that overall hepatic microvascular perfusion was decreased. In addition, increased leukocyte adhesion in sinusoids and venules could be observed. A concomitant increase of ICAM-1 expression in liver tissue was also noted within the first week after BDL. Our results show that BDL is followed by a marked depression of the hepatic microcirculation and increased leukocyte adhesion in vivo within 3 to 7 days. Together, these findings suggest that deficits in microvascular perfusion and increased neutrophil infiltration may represent a potential source of liver injury during acute biliary obstruction.
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PMID:Extrahepatic biliary obstruction impairs microvascular perfusion and increases leukocyte adhesion in rat liver. 936 46


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