A.R. Tanner

Oxygen-derived free radicals promote hepatic injury in the rat

We have investigated the possible protective effect of superoxide dismutase and allopurinol in a rat model of mild and severe hepatic necrosis produced by Corynebacterium parvum with or without endotoxin. Histology showed a sinusoidal mononuclear cell infiltrate with multiple granulomata but variable degrees of hepatic necrosis. In the severe hepatic injury model there was a reduction in mortality, associated with a decrease in histologic and biochemical evidence of hepatic necrosis, after treatment with superoxide dismutase. This protective effect was not demonstrated with partially heat-inactivated superoxide dismutase. In the mild hepatic injury model similar trends in reduction of serum levels of hepatic enzymes were observed after treatment with both superoxide dismutase and allopurinol. These results indicate that oxygen-derived free radicals may play an important role in the pathogenesis of hepatic injury in the rat.

Pharmacology of propranolol in patients with cirrhosis and portal hypertension.

Ten patients with cirrhosis and protal hypertension received an initial 20 mg oral test dose of propranolol and subsequently 160 mg of a slow release preparation, orally, each day for seven days. Protein binding, serial plasma propranolol concentrations and effects on heart rate were studied. Protein binding was slightly reduced (mean 85%, range 78.9-88.1%) compared with four normals (mean 87.9%). In patients with severe liver disease (serum albumin less than 30 g/l) propranolol remained detectable in plasma 24 hours after the single 20 mg dose and high steady state concentrations (mean 266.5 ng/ml, range 84-406) were observed during regular dosing. At steady state there was a significant correlation between log total plasma propranolol concentrations and the percentage fall in heart rate (r = 0.659, p less than 0.05). We suggest that in patients with severe liver chronic disease (serum albumin less than 30 g/l), propranolol therapy should be initiated in hospital. The starting dose should be low (20 mg of the conventional formulation tds or 80 mg of the slow release preparation daily) and that regular monitoring of the heart rate should be carried out.

Monocyte function in Crohn's disease and ulcerative colitis.

Monocyte function as reflected by phagocytosis of Candida albicans and chemotaxis towards zymosan-activated serum has been assessed in Crohns disease and ulcerative colitis. Phagocytosis and random movement were significantly increased to a similar degree in both diseases when compared with controls (p less than 0.001). There was no significant difference in chemotaxis between the disease and control groups, although there was a trend towards its being increased in ulcerative colitis. There was no correlation between the results obtained and disease activity or medication.

Drug influences on rat hepatic macrophage enzyme production and release in vitro

Abstract. Drug influences on hepatic macrophage enzyme release have been investigated using a rat model of macrophage recruitment and activation. N‐acetyl‐glucosaminidase (NAG), a lysosomal enzyme, and plasminogen activator (PA), a cytosolic enzyme, have been measured in both cell lysates and supernatants after 24 h in culture. 6‐mercaptopurine (6‐MP) and azathioprine significantly decreased (P < 0·03) the enhanced production of NAG by recruited macrophages following stimulation in vitro (total NAG activity, nmol substrate hydrolysed/μg cell protein; recruited macrophages exposed to endotoxin, no drug exposure 0·63 ± 0·08, azathioprine 0·44 ± 0·08, 6MP 0·36 ± 0·06). Prednisolone, azathioprine and 6MP significantly reduced (P < 0·05) the supernatant release of PA in response to endotoxin exposure in vitro by both cell types (supernatant PA values after 24 h in culture, recruited macrophages exposed to endotoxin, no drug 26·0 ± 2·9 units, prednisolone 18·5 ± 1·7 units, levamisole 27·3 ± 4·7 units, azathioprine 18·1 ± 2·3 units, 6MP 17·3 ± 1·5 units). The results from this study indicate that certain drugs used in human liver disease are able to modify the secretory activity of rat hepatic macrophages.