W. G. E. Cooksley

Reticuloendothelial phagocytic function in human liver disease and its relationship to haemolysis

Summary. This study was undertaken to examine the hypothesis that enhanced reticuloendothelial (RE) phagocytosis and splenic sequestration of red blood cells are important aetiological factors in the haemolysis accompanying liver disease. RE phagocytic capacity (REPC) was measured by the rate of plasma disappearance of radio‐iodinated microaggregated human serum albumin (125I‐MAA) in 57 patients with acute or chronic liver disease, and its relationship to splenic size, RBC survival and splenic sequestration of RBC was analysed. In addition, RE perfusion was measured using a tracer dose of 125I‐MAA, and the RE phagocytic index (REPI), an index of the individual cellular RE activity, independent of perfusion, was calculated.

INFLUENCE OF ALCOHOL AND CAFFEINE CONSUMPTION ON CAFFEINE ELIMINATION

1. Ten healthy male volunteers were each studied on four separate occasions to assess the role of regular caffeine and alcohol intake on caffeine elimination. Antipyrine disappearance was also studied as an established quantitative test of hepatic microsomal function.

The Effect of Smoking On Caffeine Elimination - Implications for its Use as a Semiquantitative Test of Liver-Function

1. The effects of caffeine ingestion and cigarette smoking on caffeine and antipyrine pharmacokinetics were studied using normal subjects as their own controls before and after cessation of smoking in an attempt to minimize genetic and other environmental influences.

Regulation of Plasma Ferritin by the Isolated Perfused Rat Liver

Summary. The isolated perfused rat liver has been used to investigate the regulation of plasma ferritin in normal, iron‐deficient and iron‐overloaded states. Both 125I‐labelled and non‐labelled rat liver ferritins were rapidly cleared from the perfusion circuit with a half‐life of approximately 30 min. Perfusion of livers from normal, iron‐loaded or iron‐deficient rats with blood obtained from normal, iron‐loaded or iron‐deficient rats showed that the liver takes up plasma ferritin, and releases ferritin into the perfusate to achieve a perfusate ferritin level appropriate to the iron stores of the animal from which the liver was taken. It is concluded that the liver is capable of both uptake and release of ferritin and that within the liver there resides a mechanism which maintains circulating ferritin concentrations at a level appropriate to body iron stores.

Mononuclear cell factors that inhibit fibroblast collagen synthesis. I. In vitro conditions determining their production and expression

Peripheral blood mononuclear cells (PBMC) incubated either with phytohaemagglutinin‐P (PHA) under serum‐free conditions or with tuberculin purified protein derivative in the presence of 5% human blood group AB serum released into the culture medium factors that decreased collagen synthesis by dermal fibroblasts. These factors were first detected after incubation of PBMC with PHA for 24 h and were produced by non‐adherent cells. The decrease in collagen synthesis was observed despite changes in conditions of fibroblast culture, the addition of a cross‐linking inhibitor, and the use of different fibroblast cell lines.

Enhancement of hepatic drug metabolism by glutethimide in patients with liver disease

SummaryA controlled study of the effects of glutethimide on antipyrine metabolism was performed to ascertain how patients with varying degrees of liver damage responded to microsomal enzyme inducing agents. The administration of 250 mg glutethimide daily for one week resulted in significant enhancement of antipyrine metabolism in 4 patients with compensated cirrhosis and 5 patients with features of hepatic failure as well as 7 control subjects without liver disease. Even patients with very severe liver disease did undergo microsomal enzyme induction. Changes in antipyrine half-life after glutethimide were directly proportional to the original antipyrine half-life so that the greatest absolute alterations due to enzyme induction occurred in patients with the most severely impaired hepatic function. These results indicate that not only is antipyrine metabolism severely impaired in patients with liver failure, but elimination rates are markedly altered by enzyme inducing agents. Thus, although these results cannot be extrapolated to all inducers of hepatic microsomal enzymes nor to all drugs metabolized by microsomal oxidases, it is suggested that safe and effective management of drug therapy in these patients requires measurement of plasma levels.

Mononuclear cell factors that inhibit fibroblast collagen synthesis. II. Properties of the factors

Supernatants harvested from peripheral blood mononuclear cells (PBMC) incubated either with the non‐specific mitogen phytohaemagglutinin‐P (PHA) or with the specific antigen tuberculin purified protein derivative for 72 h decreased collagen synthesis by dermal fibroblasts. PHA‐induced mononuclear cell factors (PHA‐MCF) responsible for decreases in collagen synthesis by dermal fibroblasts were localized by column chromatography on Sephacryl S‐200 to fractions of 30,000‐60,000 daltons. Proteolytic enzymes destroyed the activity of PHA‐MCF, but after incubation with neuraminidase some activity of these factors remained, The activity of PHA‐MCF was not inhibited by incubation with the monosaccharides L‐fucose, L‐rhamnose. N‐acetylglucosamine, and α‐melhyl‐D‐mannoside but was partially destroyed by heating at 80°C for 10 min. The factors were not mitogenic to PBMC. These factors did not appear to resemble any previously characterized factors produced by non‐adherent mononuclear cells. The mechanism by which these factors decreased fibroblast collagen synthesis appeared complex. There was no detectable increase in the release of collagenasc by fibroblasts, nor was a cytotoxic effect apparent. Increased PGE2 production by fibroblasts could not be related to the factor‐induced decrease in fibroblast collagen synthesis.

The interaction of cigarette smoking and chronic drug ingestion on human drug metabolism

1. Drug metabolism was assessed by the disappearance rate of antipyrine as measured in saliva. Results were expressed in terms of both clearance and half life.