Biomedical subjects
Publications and source records attributed to H Wynne.
Glucuronidation and sulphation were studied in vitro in human liver samples from 22 subjects aged 40-89 years using paracetamol as substrate. There was no significant correlation with age for the activity of either enzyme pathway. These results provide further evidence that age per se does not have a major effect on the activities of hepatic metabolising enzymes.
Aging in humans is associated with marked declines in the disposition of numerous drugs and other xenobiotics that require hepatic biotransformation before elimination. Considerable pharmacokinetic evidence in humans, coupled with data on in vitro liver microsomal monooxygenase functions generated in inbred male rodent models, has implicated impaired liver phase I drug metabolism (i.e., diminished efficacy of microsomal monooxygenases) in reduced drug clearance in the elderly. This study (1) assessed the in vitro activities and amounts of liver microsomal monooxygenases as a function of donor age and gender in healthy humans and (2) provides the most extensive and comprehensive data to date demonstrating the absence of significant age- and gender-dependent differences in the activities and contents of human liver monooxygenases.
This study was designed to investigate the susceptibility of the parthenogenetic eggs of Daphnia magna to cadmium, zinc, copper, and lead. Early life stages of D. magna proved to be highly tolerant to heavy metal toxicity in comparison with later stages. This relatively high tolerance might be explained by the structural constitution of the eggs.
Plasma aspirin esterase activity, expressed as nmol salicylate formed/ml plasma/min, was found to be similar in a group of healthy elderly adults, a group of young adults and a group of frail young adults, but was lower in a sample of frail elderly subjects. This was associated with reduced plasma albumin levels in healthy elderly subjects compared with young subjects and levels were lower still in the frail elderly group. Plasma cholinesterase also showed a trend towards reduced activity in the frail elderly subjects. As plasma aspirin esterase activity may influence the amount of circulating aspirin, these changes may have implications for the use of aspirin in frail elderly people.
1. Benorylate (4-acetamido phenyl-O-acetylsalicylate) hydrolysis in vitro by human plasma and by human liver microsomes and cytosol has been investigated. 2. Benorylate was hydrolysed by a route involving initial hydrolysis of the acetyl group to yield phenetsal followed by hydrolysis to paracetamol and salicylate. Hydrolysis via acetylsalicylate was minor. 3. Benorylate was more actively hydrolysed by liver cytosol than microsomes and about 10 times faster than plasma. 4. Following a single oral dose benorylate (4 g) to volunteers only salicylate and paracetamol were detected in the plasma. 5. The therapeutic effects of benorylate appear to be mediated by salicylate and paracetamol.
The plasma, in addition to the liver, is a major site of hydrolysis of aspirin. Human plasma and liver aspirin esterase activities in samples from a group of patients varied over a two fold range and there was a significant correlation between individual plasma and liver activities. Human liver aspirin esterase was present in the cytosolic and microsomal fractions. Cytosolic and microsomal enzymes had different activities and apparent affinities for aspirin.
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The clearance of many oxidized drugs falls with age. Whilst factors such as reduced liver size, blood flow and specific enzyme activity may be important, the possibility that reduced enzyme affinity for substrate contributes to this fall has not hitherto been investigated. Using liver microsomes from 12 young adult and 12 elderly male Norwegian Brown rats we defined the kinetics of ethoxyresorufin-O-de-ethylation and aldrin epoxidation, specific substrates for the 3-methylcholanthrene inducible and phenobarbitone inducible forms of cytochrome P450, respectively. Our results show a marked fall in the maximal activity of both enzymes in advanced age whether expressed in terms of microsomal protein or unit of cytochrome P450, but with no change in apparent enzyme affinity (Km). Since Km is unchanged, we feel that qualitative age-related changes in cytochrome P450 are unlikely. Reduced metabolism may be due to age-related alterations in coenzymes or smooth endoplasmic reticulum lipid membranes.
The epidemiology of 737 consecutive self-poisoning admissions to Freeman Hospital, Newcastle upon Tyne, has been investigated with reference to age in young (less than 35), mid-aged (35-64) and elderly (greater than or equal to 65 year) patients. The most important differences were increased formal psychiatric illness in the elderly, demonstrated by increased likelihood of admission to psychiatric units; less likelihood of overdose with multiple agents in the elderly, and less use of alcohol. There were also differences in the types of drugs used. The youngest patients took more paracetamol and less psychoactive drugs and more of their drugs were prescribed for a relative than the other two groups. The elderly were much less likely to receive gastric lavage or emesis and more likely to receive supportive treatment only than younger patients. This difference may, in part, be explained by the more frequent occurrence of benzodiazepine poisoning in those over 65 years.
The elderly often suffer from chronic musculoskeletal disease, and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to control symptoms. The aged have been shown to be particularly at risk of adverse effects from these drugs, of which gastrointestinal irritation and bleeding are both common and potentially serious. Because of this, a comparison of NSAID pharmacokinetics in young and elderly subjects is of particular importance. In general, protein binding tends to decrease with age; volumes of distribution may undergo a small increase; and clearance, especially of renally eliminated drugs, may fall. However, these changes are relatively minor, and the increased propensity of the elderly to suffer adverse reactions to NSAIDs cannot readily be explained on a pharmacokinetic basis.
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