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R Callaghan

Publications and source records attributed to R Callaghan.

47 records · Page 3Linked to original sources
PubMed1993

The effect of a nutritional model of chronic liver injury on the hepatic glucuronidation of morphine in rats.

The effect of a choline-deficient diet on the hepatic glucuronidation of morphine was investigated using a rat perfused liver system. Rats fed a choline-deficient diet developed a fatty liver with minimal necrosis. Despite the morphological changes, neither hepatic extraction ratio (0.51 +/- 0.02 in control; 0.45 +/- 0.04 in the choline-deficient rats) nor intrinsic clearance (0.85 +/- 0.05 in control; 0.77 +/- 0.09 in choline-deficient rats) were affected by this injury model. This finding suggests that glucuronidation is relatively resistant to this chronic liver injury.

Animals↗
PubMed1993

Hepatic enzyme activity is the major factor determining elimination rate of high-clearance drugs in cirrhosis.

The relative importance of alterations in hepatic enzyme activity, blood flow and drug binding to drug elimination in patients with liver disease remains controversial. In addition, liver disease appears to selectively impair drug oxidation pathways while leaving glucuronidation preserved. These studies using isolated perfused rat livers were designed to examine the effects of liver disease on the hepatic extraction and clearance and intrinsic clearance of morphine, a glucuronidated drug, and meperidine, an oxidized drug, under controlled blood flow and drug-binding conditions. We chose chronic carbon tetrachloride-induced cirrhosis as the liver disease. At a flow rate of 12 ml/min, the extraction of meperidine was reduced from 0.91 +/- 0.02 ml/min in controls to 0.76 +/- 0.04 ml/min (p < 0.05) in cirrhosis, hepatic clearance was reduced from 10.9 +/- 0.3 ml/min in controls to 9.15 +/- 0.48 ml/min (p < 0.05) in cirrhosis and intrinsic hepatic clearance was reduced from 179 +/- 35 ml/min in controls to 69 +/- 14 ml/min (p < 0.05) in cirrhosis. In contrast, for morphine we saw no significant changes: extraction ratio, 0.59 +/- 0.02 in controls and 0.49 +/- 0.04 in cirrhosis; hepatic clearance, 7.02 +/- 0.26 ml/min in controls and 6.04 +/- 0.42 ml/min in cirrhosis; and hepatic intrinsic clearance, 15.4 +/- 1.2 ml/min in controls and 13.9 +/- 2.3 ml/min in cirrhosis. Regression analysis of hepatic clearance vs. hepatic blood flow and hepatic clearance vs. hepatic intrinsic clearance demonstrate that in normal livers the elimination of both morphine and meperidine is mainly dependent on blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

A comparison of membrane properties and composition between cell lines selected and transfected for multi-drug resistance.

Cell lines selected (CHRC5) and transfected (LR-73-1A) for multi-drug resistance have total lipid compositions which are indistinguishable between resistant and parental cells. Lipid composition was evaluated by 1H NMR and the total fatty acid content by GLC. No change in surface hydrophobicity, as measured with the fluorescent probe dansyl-PE, was observed as a result of transfection of CHO cells with the mdr1 gene. However, the selected cell line, CHRC5, showed a decreased surface hydrophobicity. This decreased surface hydrophobicity was indicated by an 8 nm increase in the fluorescence emission of dansyl-PE in the CHRC5 cell line compared with the AB1. Both resistant cell lines showed an increase in the polarisation of the fluorescent probe, TMA-DPH in the plasma membranes corresponding to a 14% and a 24% change in fluorescence polarisation for the selected and transfected cell lines, respectively. This is indicative of reduced mobility of the acyl chains in the resistant cell lines. Both the CHRC5 and the transfected cell lines showed almost a 2-fold increase in the initial rate of membrane cycling. The membrane cycling could be inhibited by a known bilayer stabiliser, the N-carbobenzoxy-D-Phe-L-Phe-Gly. These results indicate that the properties of the plasma membrane from resistant cells are altered compared with their parental cell line.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1988

Morphometric and cytophotometric nuclear analysis of altered hepatocyte foci induced by N-nitrosomorpholine (NNM) and aflatoxin B1 (AFB1) in liver of Wistar rats.

The progressive morphological changes in the liver during neoplastic transformation have been studied by histological, cytophotometric and morphometric methods in male Wistar rats treated with two carcinogens: N-nitrosomorpholine (NNM) and aflatoxin B1 (AFB1). Cytophotometric and morphometric analysis of hepatocyte nuclei using Feulgen-stained tissue sections were performed in morphologically normal hepatic parenchyma and in early preneoplastic foci composed of altered hepatocytes. Foci of clear cells, mixed cells and large basophilic cells possessed a ploidy distribution similar to the surrounding non-transformed parenchyma, while the small hyperbasophilic cell foci were predominantly diploid. These findings confirm that the foci composed of PAS-negative, small hyperbasophilic cells with an unique diploid content may represent one of the earliest stages in the neoplastic transformation.

Aflatoxin B1↗
PubMed1985

Prostaglandin synthesis inhibition reverses the gastric antisecretory activity of somatostatin in anaesthetized rats.

The inhibitory action on somatostatin (ST) on the spontaneous and stimulated (pentagastrin 18 micrograms/kg/h i.v. and histamine 5 mg/kg/h i.v.) gastric acid secretion and its modification after pretreatment with an inhibitor of endogenous prostaglandins biosynthesis (indomethacin 5 mg/kg i.v.) has been studied in the anaesthetized rat. ST 30 micrograms/kg/h i.v. inhibits basal and stimulated gastric acid secretion. In the presence of indomethacin the inhibition elicited by ST on basal and pentagastrin induced gastric acid secretion was partially attenuated, whereas in the histamine group the inhibitory action was totally abolished. The antagonism elicited by indomethacin was not surmounted by increasing (X 3.3) the dose of ST. These findings suggest that endogenous prostaglandins may be involved in the mechanism by which ST exerts its antisecretory effect in this model.

Anesthesia↗
PubMedDate not supplied

Association of chromosome 7, chromosome 10 and EGFR gene amplification in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is characterized by intratumoral heterogeneity in both histomorphological and genetic changes, displaying a wide variety of numerical chromosome aberrations, the most common of which are trisomy 7 and monosomy 10. The amplification of the epidermal growth factor receptor (EGFR) gene is the most frequently reported genetic abnormality. The associations between these parameters and their implication in the tumoral progression are poorly understood. We performed simultaneous fluorescence in situ hybridization (FISH) with centromeric DNA probes for chromosomes 7 and 10 in smear preparations, and EGFR gene amplification by PCR from 25 cases of GBM. Trisomy/ polysomy for chromosome 7 was present in 76% of cases and monosomy 10 in 68%. Both alterations were associated in 56% of cases. The EGFR gene was amplified in 52% of tumors; in 44% associated with trisomy/ polysomy 7, and in 36% with monosomy 10. The three parameters were associated together in 28% of cases. Kaplan-Meier survival rate analysis demonstrated lower survival rates in patients with monosomy 10, trisomy 7, and monosomy associated with trisomy 7. The other combinations were not different in frequency in relation to survival. In the present study, trisomy/polysomy 7 and monosomy 10 have been found to be frequently associated. The combination of both anomalies is probably important in the tumorigenesis of glioblastoma. Moreover, this association is apparently independent of EGFR gene amplification, which could be a later event in this process.

Adult↗