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Biomedical subjects

G C Farrell

Publications and source records attributed to G C Farrell.

At least 91 records · Page 5Linked to original sources
PubMed1993

Eicosanoids released following inhibition of the endoplasmic reticulum Ca2+ pump stimulate Ca2+ efflux in the perfused rat liver.

In the isolated perfused rat liver 2,5-di(tert-butyl)hydroquinone (tBuHQ), a selective inhibitor of the endoplasmic reticulum Ca2+ pump, induces a prolonged glucose output and stimulates Ca2+ efflux. The present study shows that tBuHQ depleted the hormone-sensitive Ca2+ pool in the perfused liver, abolishing the vasopressin- or phenylephrine-induced Ca2+ efflux. The effects of tBuHQ were reversible, since the response to these agonists gradually returned within 1 hr of perfusion, and protein synthesis was not required for this recovery. Since tBuHQ does not cause Ca2+ efflux from isolated hepatocytes, we examined the mechanism responsible for the tBuHQ-induced Ca2+ efflux observed in the intact liver. The cyclooxygenase inhibitor indomethacin prevented the Ca2+ extrusion stimulated by tBuHQ, but not that induced by vasopressin. During infusion of tBuHQ there was a 9-fold increase in the concentration of thromboxane B2 in the perfusate. The Ca2+ efflux response to tBuHQ was inhibited by the thromboxane/prostaglandin endoperoxide receptor antagonist, L-655,240 (3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]2,2-dimethylpropa noic acid) in the absence of any effect on thromboxane B2 release. Thus, the inhibition of the endoplasmic reticulum Ca2+ pump by tBuHQ results in a rise in the cytosolic Ca2+ concentration in non-parenchymal cells, leading to the formation of cyclooxygenase products. The released eicosanoids, in turn, stimulate Ca2+ efflux from hepatocytes.

Animals↗
PubMed1993

Alpha-interferon 2b in the treatment of chronic hepatitis C: interim report of the first multicentre Australian trial.

Interferon has been shown to be effective in the treatment of chronic hepatitis C but the optimal treatment regime has not yet been defined. Studies using 3 million units (MU) of interferon thrice weekly (tiw) for 6 months have shown normalization of serum alanine aminotransferase (ALT) in about 50% of patients, but relapse occurs in at least 50% of responders after interferon is stopped. The aims of this study were to determine whether 5 MU of interferon tiw produces a higher response rate than 3 MU tiw and to examine if the higher dose results in more sustained remissions. In addition, factors that are associated with a more or less favourable response to interferon treatment were sought. Overall, 65% of patients responded and no advantage of the higher dose therapy was found, either in terms of response or relapse rate after treatment. The presence of cirrhosis on the pre-treatment liver biopsy was associated with a poor response rate to interferon and a trend towards a higher relapse rate. Risk factor for acquisition of disease was also related to likelihood of response but not relapse. We conclude that two thirds of Australian patients with chronic hepatitis C initially respond to interferon treatment. Positive predictors of response are intravenous drug use as a risk factor and histologically less severe liver disease. Relapse occurs in two thirds of all responders.

Australia↗
PubMed1993

Interferon suppresses erythromycin metabolism in rats and human subjects.

Interferon down-regulates expression of cytochrome P-450 3A in male rats. This study explored the hypothesis that interferon therefore decreases the metabolism of drugs catalyzed by cytochrome P-450 3A. Initial experiments in male rats used microsomal erythromycin N-demethylase activity as a probe for cytochrome P-450 3A catalytic activity. After administration of rat interferon-gamma, erythromycin metabolism was impaired (53% of control; p < 0.01). This change correlated with the decline in cytochrome P-450 3A-dependent androstenedione 6 beta-hydroxylase activity, indicating that the decrease in erythromycin N-demethylase activity could be attributed to interferon-mediated suppression of cytochrome P-450 3A. We then used the [14C]N-methyl erythromycin breath test to assess the activity of hepatic cytochrome P-450 3A in rats and human subjects before and after a single dose of interferon. In rats, rat interferon-gamma decreased erythromycin metabolism to 57% of control (p < 0.005). In the human study, six patients with chronic active hepatitis C and four healthy controls were examined 20 to 26 hr after receiving a subcutaneous injection of human interferon-alpha 2b. Interferon produced a small decrease (median = 15%; range = 3% to 35%) in erythromycin metabolism (p < 0.05), as determined by 2-hr excretion of 14CO2 in the breath. Thus interferon-mediated suppression of cytochrome P-450 3A is less strong in human subjects than in male rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Selectivity and sensitivity of changes in serum bile acids during induction of cirrhosis in rats.

Because some patients with cirrhosis have serum transaminase levels within the normal range, a prospective study was undertaken to determine whether the concentration of individual serum bile acids would be a sensitive indicator of development of cirrhosis. The choline-deficient rat has been used as a model for study of these changes. Using high-performance liquid chromatography, we measured the concentrations of individual serum bile acids at 3, 6, 10, 20 and 30 wk of dietary intake. Serum levels of total glycine- and taurine-conjugated bile acids were elevated at all stages tested as compared with levels in control groups (choline supplemented). Similarly, unconjugated bile acids and, particularly, cholic acid showed significantly higher levels at all stages except with the occurrence of cirrhosis at 30 wk, at which time there was a significantly lower level for unconjugated bile acids (0.48 +/- 0.11 vs. 1.40 +/- 0.36 in controls) and for cholic acid (0.17 +/- 0.05 vs. 0.91 +/- 0.39 in controls). The ratio of serum cholic acid to serum chenodeoxycholic acid changed in temporal relationship to progression in the histological lesions in livers of these rats. The ratio was at its highest at 78 +/- 3 at 3 wk (no histological change) and decreased with increasing time and changes in histological appearance until 30 wk, at which time it was down to 1.6 +/- 0.6. The routinely used markers of liver injury (serum ALT, alkaline phosphatase and bilirubin), however, did not match the progression of hepatic histological changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1993

Induction of cytochrome P450 2B1 in rat liver by the aromatase inhibitor aminoglutethimide.

Aminoglutethimide (AG) is an inhibitor of P450 aromatase and is in clinical use for the treatment of estrogen-dependent breast cancer in postmenopausal women. AG produces adrenal insufficiency by inhibition of the adrenal P450 cholesterol side chain cleavage enzyme, but a number of serious pharmacokinetic interactions have been reported between AG and coadministered drugs. The present study was undertaken in the rat to assess the modulatory capacity of AG toward P450 enzyme activities in vitro and in vivo and to identify the P450 subject to such effects. In vivo administration of AG produced a dose-related increase in activities attributable to the hepatic P450 enzyme 2B1. Thus, AG administration (25 and 50 mg/kg, i.p., on 3 consecutive days) resulted in 85 and 100% increases in testosterone 16 beta-hydroxylation and 3.3- and 7.4-fold increases in 7-pentylresorufin O-depentylation (both mediated by P450 2B1) in rat liver; at a dose of 5 mg/kg, no effect on these activities was noted. In addition, microsomes from rats administered high-dose AG catalyzed increased rates of androst-4-ene-3,17-dione 16 beta-hydroxylation (from 0.72 +/- 0.10 nmol/min/mg in control to 3.51 +/- 0.47 nmol/min/mg protein). These findings were confirmed by direct immunoquantification of P450 2B1 in hepatic microsomes, by which it was found that the content of the enzyme in control fractions (2.4 +/- 0.7 micrograms/mg microsomal protein) was increased 2.9- and 6.5-fold by the respective doses of AG. In contrast, there was no evidence for increases in two other similarly inducible proteins, P450 3A or P450 2C6.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoglutethimide↗
PubMed1992

Hepatotoxicity from paracetamol self-poisoning in western Sydney: a continuing challenge.

OBJECTIVE: To determine the annual incidence of admissions for paracetamol overdosage in the years 1985 to 1990, morbidity and mortality rates, predictors of poor prognosis and the most appropriate use of N-acetylcysteine (NAC). DESIGN: A retrospective review of case records of all patients with a discharge diagnosis of paracetamol overdosage. SETTING: A 900-bed tertiary referral teaching hospital in western Sydney with a busy accident and emergency department. PATIENTS: 306 patient records were reviewed and details of the overdose and admission were recorded. INTERVENTIONS: NAC infusion in patients with possible paracetamol hepatotoxicity. MAIN OUTCOME MEASURES: Blood paracetamol levels; elevated alanine aminotransferase levels; prolonged prothrombin time; severe liver injury; and NAC side effects. RESULTS: Annual admission rate was constant at circa 55 per annum. Female to male ratio was 2:1. Predictors of liver injury included paracetamol dose over 10 g, presentation more than 10 hours after the overdose and chronic ingestion of more than 80 g alcohol per day. There were no deaths. Fifty-five patients (18%) had toxic paracetamol levels, 51% received treatment with NAC, including 40% of those with non-toxic levels, and 11% of those treated with NAC experienced side effects. CONCLUSION: Paracetamol overdosage continues to be a significant cause of hospital admissions in western Sydney. Severe hepatic damage occurs infrequently and the prognosis for liver injury, when it occurs, is good. Treatment with NAC should be reserved for patients with definite indications for the drug.

Acetaminophen↗
PubMed1992

Interferon suppresses the isoform-specific activities of hepatic cytochrome P450 in female rats.

The results from the present study indicate that rat IFN-gamma decreases hepatic P450 levels and catalytic activities in female rats. The magnitude of the down-regulation of P450 is similar to that found in male rats. Furthermore, the activities of specific P450 isoforms (P4502A1 and P4502C6 and possibly P4502C12, and P4502B1 and 2) are decreased by IFN. Hence, the effect of IFN in female rats appears to involve several, but not all, hepatic P450 isoforms. Both hormone-dependent and hormone-independent isoforms are suppressed by IFN. The mechanism for this effect does not, however, appear to be mediated by changes in serum levels of sex steroids.

Animals↗
PubMed1992

The effects of partial hepatectomy on serum sex steroids in humans.

In both rats and humans, partial hepatectomy results in a substantial increase in serum estradiol concentrations. Because mammalian liver of both sexes contains estrogen receptor, it has been suggested that this surge in serum estrogen concentration may initiate or facilitate liver regeneration. We have reexamined the potential role of sex steroids in human liver regeneration by measuring serum estradiol and testosterone concentrations in men and postmenopausal women before and after hepatic resection. The results were compared with those obtained in patients subjected to other forms of major surgery. In both men and postmenopausal women, serum estradiol levels increased after partial hepatectomy. However, the magnitude of increase was not related to the amount of liver removed. Moreover, similar increases occurred in patients undergoing other major surgical procedures not involving the liver. Serum testosterone concentrations decreased in men and increased in postmenopausal women undergoing all forms of surgery. It is concluded that effects of partial hepatectomy on serum sex steroid levels are nonspecific and probably related to stress. These observations diminish the likelihood that such changes are an important factor in the control of liver regeneration in humans.

Abdomen↗
PubMed1992

Impaired expression of microsomal cytochrome P450 2C11 in choline-deficient rat liver during the development of cirrhosis.

The microsomal content and activity of the principal male-specific cytochrome P450 2C11 are reduced in cirrhotic rat liver. In order to define the pathophysiological mechanism for such changes, the present study was undertaken to determine the time course of impaired P450 2C11 expression in relation to the development of cirrhosis during intake of a choline-deficient diet. Fatty infiltration of the liver was evident after 6 weeks of intake but hepatic fibrosis was not present until 10 weeks, when fine fibrotic bands in a perisinusoidal distribution were observed. Fibrotic bands were progressively more prominent at 20 and 25 weeks and cirrhosis was established by 30 weeks of dietary intake. Portal pressure, as measured by saline manometry and indicated by splenomegaly, appeared to increase gradually after 6 weeks and by 25 weeks values were significantly greater than controls. The microsomal content of P450 2C11 and its associated steroid 16 alpha-hydroxylase activity were unchanged at 6 weeks but were decreased to around 30% of control from 10 weeks of intake of the choline-deficient diet to the end of the experimental period (30 weeks). Serum bile acids were approximately 2-fold greater in choline-deficient rats from 10 weeks. Similarly, serum estradiol concentrations were elevated (to 2.5-fold of control) in male rats after 10 weeks intake of the choline-deficient diet; this increase was sustained in 30-week cirrhotic rats. On the other hand, there was no evidence of altered serum testosterone until 30 weeks of dietary deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1991

Increased expression of cytochrome P450 IIIA2 in male rat liver after dietary vitamin A supplementation.

In this study dietary vitamin A supplementation (25 IU/g diet) was assessed for its effect on hepatic microsomal P450 content and on P450 enzyme-specific drug oxidase activities in rats. Intake of the supplemented diet by male rats over a 15-week period resulted in a fivefold increase in hepatic vitamin A stores over those measured in control liver from rats that received a balanced diet without vitamin A supplementation. Serum retinol was unchanged and there was no evidence of hepatocellular injury in any of the animals. There was a 26% increase in P450 content in vitamin A-supplemented rat liver and regioselective androst-4-ene-3,17-dione (androstenedione) and progesterone hydroxylation revealed changes in several P450 pathways. Thus, androstenedione 16 alpha-hydroxylation (P450 IIC11-mediated) and progesterone 21-hydroxylation (P450 IIC6-mediated) were decreased slightly to 80 and 74% of respective control activities while P450 IIA1/2-dependent androstenedione 7 alpha-hydroxylation was slightly increased. In contrast, the 6 beta-hydroxylations of androstenedione and progesterone were increased to 169 and 152% of control following dietary supplementation. Kinetic analysis of androstenedione 6 beta-hydroxylation revealed an increase in maximal reaction velocity (Vmax 4.00 +/- 0.47 vs 2.20 +/- 0.10 nmol/min/mg protein) but the Km was unchanged, suggesting an increase in enzyme concentration. Consistent with this assertion, immunoquantitation of the steroid 6 beta-hydroxylase, P450 IIIA2, revealed a 158% increase in the microsomal expression of this enzyme (9.8 +/- 2.7 vs 6.2 +/- 1.3 ng/micrograms microsomal protein). From these studies it now seems clear that vitamin A, as a dietary additive in nontoxic doses, has the capacity to alter the activity of hepatic microsomal drug oxidases by modulating the expression of P450 enzymes.

Androstenedione↗
PubMed1991

Prediction of response to interferon in patients with chronic active hepatitis C, and evidence that this improves hepatic metabolic function.

We sought to ascertain whether response to alpha interferon treatment could be predicted among patients with chronic active hepatitis C, and whether antipyrine clearance estimations would determine changes in liver function with this disease. The patients came from a randomized controlled trial, with patients who were initially untreated eventually being offered interferon treatment. Among 28 patients treated with interferon 18 (64%) responded with normalization of serum aminotransferase levels. Responders were less likely to have acquired hepatitis C by blood transfusion and more likely to have acquired it by intravenous drug abuse (P less than 0.05). All 13 patients with less severe chronic active hepatitis responded to interferon but only 5 of 15 patients with progressive fibrosis or cirrhosis responded (P less than 0.01). During 8-39 (median 19) months of observation of 16 untreated patients, there was a significant fall in antipyrine clearance (Cl-Ap) but no change in serum albumin. Among interferon-treated patients, Cl-Ap improved in 9 of 16 compared with 1 of 14 controls observed for the same time period (P less than 0.02). It is concluded that Cl-Ap is a sensitive test for detecting changes in liver function during chronic hepatitis. Without treatment, deterioration is evident at 18 months in 50% of patients with chronic active hepatitis C. Conversely, normalization of serum aminotransferase levels by interferon is associated with improvement of Cl-Ap.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Can the response to interferon treatment be predicted in patients with chronic active hepatitis C?

Twenty-one of 40 patients with chronic non-A, non-B hepatitis (37 anti-HCV positive) were randomised to receive interferon alpha 2b (3 million units subcutaneously thrice weekly for 24 weeks) and then to be observed for six months. Among the other 19 patients (controls) randomised to be observed without treatment for 12 months, eight have subsequently been treated with interferon for six months. One treated patient and three controls were lost to follow-up. A return to normal serum alanine aminotransferase levels which lasted until the end of the treatment period occurred in 18 (64%) of the 28 patients given interferon (and in 13 of 21 (62%) randomised to treatment), but only in one of the 16 untreated controls (p less than 0.001). Multivariant analysis indicated that, compared with the ten nonresponders, the 18 patients who responded to interferon were more likely to have acquired infection by intravenous drug abuse than by blood transfusion (p less than 0.05), and were more likely to have histologically less severe chronic liver disease (p less than 0.01). Thus, all 13 patients with less severe liver disease histologically responded to interferon, but only five of 15 patients with cirrhosis or bridging fibrosis responded. Among 17 responders followed for more than four months, five (28%) are still in remission a median of 13 months (range four months to 24 months) after stopping interferon. The characteristics which favoured a response during treatment also appeared to distinguish those who experienced sustained post-treatment remission.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Does hepatitis C virus play a role in "non-viral" chronic liver disease?

It has recently been suggested that the hepatitis C virus may play a significant role in chronic liver diseases, such as autoimmune chronic active hepatitis, which are usually attributed to non-viral causes. We tested for antibodies to hepatitis C virus (anti-HCV) in sera from 140 patients with well characterised "non-viral" chronic liver diseases as well as sera from 51 patients thought to have chronic non-A, non-B (NANB) hepatitis (acting as positive controls) and 25 patients with non-hepatic autoimmune disorders. As expected, 45 of 51 patients (88%) diagnosed as having chronic NANB hepatitis were anti-HCV seropositive. Among 26 patients with cryptogenic cirrhosis, 8 were anti-HCV seropositive; in 5 patients (22%) there was no apparent risk factor for parenteral transmission. In the remaining 114 patients with chronic liver disease, 10 patients (9%) were seropositive for anti-HCV. However, 5 of these patients had a significant risk factor for parenteral transmission of hepatitis C virus, leaving only 5 of 106 (4.7%) with unexplained positive anti-HCV test results. Among patients with high titres of circulating autoantibodies but no liver disease, no positive results occurred. It is concluded that hepatitis C virus infection may account for some cases of cryptogenic cirrhosis. Although anti-HCV occurs more commonly in patients with other "non-viral" chronic liver diseases than has been reported in the community (0.5%-1.2%), the low prevalence of the antibodies indicates that hepatitis C virus infection is unlikely to be important in the aetiology or pathogenesis of autoimmune chronic active hepatitis and other poorly understood chronic liver diseases.

Autoimmune Diseases↗
PubMed1990

Hepatitis C virus in intravenous drug users.

Sera from 172 intravenous drug users were tested for the presence of antibodies to hepatitis C virus (anti-HCV). The results were analysed in relation to aspects of the history of drug use and evidence of liver disease. The presence of anti-HCV was strongly associated with duration of intravenous drug use. Two-thirds of patients were anti-HCV seropositive within two years of commencing regular intravenous drug use, and there was 100% seropositivity among people injecting drugs for more than eight years. Seropositivity for hepatitis C virus closely paralleled exposure to hepatitis B virus, which was also endemic in this population. In contrast, only one patient tested positive for antibodies to the human immunodeficiency virus. The presence of anti-HCV correlated poorly with biochemical markers of hepatitis. About half the patients with anti-HCV had normal serum levels of alanine aminotransferase, whereas an abnormal liver biochemistry was frequently observed in anti-HCV seronegative subjects. Previous studies of non-A, non-B hepatitis that have used abnormal liver biochemistry as a marker have underestimated the prevalence of chronic hepatitis among intravenous drug users; the use of a specific screening test reveals that infection with hepatitis C virus is very common in this population.

Adult↗