In therapeutic doses paracetamol is a safe analgesic, but in overdosage it can cause severe hepatic necrosis. Following oral administration it is rapidly absorbed from the gastrointestinal tract, its systemic bioavailability being dose-dependent and ranging from 70 to 90%. Its rate of oral absorption is predominantly dependent on the rate of gastric emptying, being delayed by food, propantheline, pethidine and diamorphine and enhanced by metoclopramide. Paracetamol is also well absorbed from the rectum. It distributes rapidly and evenly throughout most tissues and fluids and has a volume of distribution of approximately 0.9L/kg. 10 to 20% of the drug is bound to red blood cells. Paracetamol is extensively metabolised (predominantly in the liver), the major metabolites being the sulphate and glucuronide conjugates. A minor fraction of drug is converted to a highly reactive alkylating metabolite which is inactivated with reduced glutathione and excreted in the urine as cysteine and mercapturic acid conjugates. Large doses of paracetamol (overdoses) cause acute hepatic necrosis as a result of depletion of glutathione and of binding of the excess reactive metabolite to vital cell constituents. This damage can be prevented by the early administration of sulfhydryl compounds such as methionine and N-acetylcysteine. In healthy subjects 85 to 95% of a therapeutic dose is excreted in the urine within 24 hours with about 4, 55, 30, 4 and 4% appearing as unchanged paracetamol and its glucuronide, sulphate, mercapturic acid and cysteine conjugates, respectively. The plasma half-life in such subjects ranges from 1.9 to 2.5 hours and the total body clearance from 4.5 to 5.5 ml/kg/min. Age has little effect on the plasma half-life, which is shortened in patients taking anticonvulsants. The plasma half-life is usually normal in patients with mild chronic liver disease, but its prolonged in those with decompensated liver disease.

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Marine fisheries are in crisis, requiring twice the fishing effort of the 1950s to catch the same quantity of fish, and with many fleets operating beyond economic or ecological sustainability. A possible consequence of diminishing returns in this race to fish is serious labour abuses, including modern slavery, which exploit vulnerable workers to reduce costs. Here, we use the Global Slavery Index (GSI), a national-level indicator, as a proxy for modern slavery and labour abuses in fisheries. GSI estimates and fisheries governance are correlated at the national level among the major fishing countries. Furthermore, countries having documented labour abuses at sea share key features, including higher levels of subsidised distant-water fishing and poor catch reporting. Further research into modern slavery in the fisheries sector is needed to better understand how the issue relates to overfishing and fisheries policy, as well as measures to reduce risk in these labour markets.

The plasma concentrations and urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates were measured in eight normal subjects, eight patients with mild liver disease and seven patients with severe liver disease following an oral dose of 1.5 g of paracetamol. The mean plasma paracetamol half-life was similar in normal subjects (2.43 h +/- 0.19) but was significantly prolonged in all patients with severe liver disease (4.25 h +/- 1.15:p = less than 0.001). Prolongation of the paracetamol half-life was related to reduced plasma albumin and increased prothrombin time. The mean ratios of plasma concentrations of unchanged paracetamol to paracetamol glucoronide and sulphate were significantly greater in patients with sever liver disease than the normal subjects. There were no significant differences in the overall 24-h urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates in the three groups. The glutathione conjugation of paracetamol did not seem to be impaired in patients with severe liver disease as evidence by the production of normal amounts of the cysteine and mercapturic acid conjugates. There is thus no evidence that they are at increased risk of hepatotoxicity when given a single therapeutic dose of paracetamol.

SUMMARY The effects of omeprazole, a substituted benzimidazole, on gastric acid and pepsin secretion have been studied in twelve healthy subjects. From six to eight hours after a single oral dose of 30 mg, there was a 66% reduction in basal acid output, and a 71*2% reduction in pentagastrin stimulated acid output. A single dose of 60 mg produced a 91.7% reduction in basal acid output and a 95-3% reduction in pentagastrin stimulated acid output. After seven days treatment with 30 or 60 mg daily, there was almost 100% inhibition of both basal and pentagastrin stimulated acid output. Omeprazole did not significantly affect pepsin secretion which is in keeping with its proposed mode of action, as an inhibitor of the H+/K+-ATPase enzyme on the secretory membrane of the parietal cell. There were no side effects after omeprazole either with single or repeated dosing.The substituted benzimidazoles are new agents which are potent inhibitors of gastric acid secretion. They act by selective, non-competitive inhibition of the H+/K+-ATPase enzyme in the parietal cell.' This enzyme is the active transport mechanism for hydrogen ion secretion in the stomach. Although one of these agents, omeprazole, has been shown to suppress basal and pentagastrin stimulated acid secretion after a single dose,2 little is known about its effects after repeated dosing. In addition, previous studies have used a buffered suspension of the drug2 as it is partially inactivated by gastric acid, or have looked at its acid inhibitory effect 24 hours after a dose.3We have studied the effects of two different doses of omeprazole on basal and pentagastrin stimulated acid and pepsin secretion after a single dose and after seven days of treatment. Capsules of entericcoated omeprazole granules were used, and the effects studied around the time of expected maximum acid inhibition. Methods SUBJECTSTwelve healthy male subjects, mean age 25-2 years

The pharmacokinetics of omeprazole were studied in a group of healthy male subjects after single and repeated oral doses of 30 and 60 mg. Absorption of omeprazole from its enteric-coated formulation was unpredictable. There was a highly significant increase in the area under the plasma concentration time curve (AUC) after repeated dosing. Omeprazole increases its own relative availability following repeated dosing. This may be due to inhibition of gastric acid secretion by omeprazole which is an acid-labile compound.

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