Temporal variations in plasma vitamin K and lipid concentrations and clotting factor activity in humans.

There is no information available on temporal variability in plasma vitamin K concentrations and its relationship to coagulation processes. We investigated the possible existence of temporal changes in plasma vitamin K and lipid concentrations and activity of clotting factors II, VII, IX, and X and relationships between these variables. Plasma vitamin K and lipid concentrations and clotting factor activity were measured at four-hour intervals for 28 hours in a group of healthy volunteers. Temporal variations existed in plasma vitamin K concentrations, with a mean maximum at 22:00 hr and a mean minimum (32% of the maximum) at 10:00 hr. Plasma triglycerol concentrations mirrored the changes in vitamin K concentrations. Mean factor VII activity was positively correlated with mean total plasma cholesterol concentrations (r = 0.714; P < 0.0001) and with mean plasma low density lipoprotein (LDL) cholesterol concentrations (r = 0.461; P < 0.0001). No distinct correlations were found between plasma vitamin K concentrations and either high density lipoprotein (HDL) or LDL cholesterol concentrations, or between triglycerol, HDL, or LDL cholesterol concentrations and functional activity of factors II, IX, and X. Plasma vitamin K concentrations did not correlate with the functional activity of any of the clotting factors. The presence of a correlation between plasma cholesterol concentrations and factor VII activity for blood samples collected at four-hour intervals suggests that plasma cholesterol concentrations may have a more acute effect on factor VII activity. Temporal variations in plasma vitamin K concentrations indicate that a single time point measurement may be an inappropriate method of establishing vitamin K status in an individual.

The influence of (R)- and (S)-warfarin, vitamin K and vitamin K epoxide upon warfarin anticoagulation.

The contribution of (R)- and (S)-warfarin enantiomers, vitamin K and vitamin K epoxide and patient factors to inter-individual variability in daily warfarin requirements were examined in a group of 73 patients. Simple correlation analysis showed a significant positive relationship between INR values and plasma (S)-warfarin concentrations (r = 0.25; p = 0.038). Multivariate analysis for relationships with INR demonstrated a highly significant positive relationship between INR and (S)-warfarin (p = 0.004) and plasma vitamin K epoxide concentrations (p = 0.028), and a significant negative relationship between INR and plasma vitamin K concentrations (p = 0.034). Twenty five percent of variation in INR could be explained by these variables (adjusted R2 = 0.25). Correlation analysis of data showed that warfarin dosage was significantly and negatively correlated with patient age (r = -0.42; p <0.0001). Patient age accounted for 25% of variation in warfarin dosage requirements (R2 = 0.25). The combined effects of age and vitamin K appear to account for much of the inter-individual variability in warfarin dosage requirements.

Are altered pharmacokinetics of non-steroidal anti-inflammatory drugs (NSAIDs) a risk factor for gastrointestinal bleeding?

AIMS: We hypothesised that pharmacokinetic factors might go some way to explaining the risk of major gastrointestinal haemorrhage with non-steroidal anti-inflammatory drugs (NSAIDs), with bleeders exhibiting a reduced clearance of NSAIDs compared with non-bleeders and set out to investigate this. METHODS: Fifty patients presenting to hospital with acute gastrointestinal bleeding while taking piroxicam, indomethacin, diclofenac or naproxen and age, sex, musculoskeletal disease and drug matched community dwelling controls, up to two for each index case, who had not bled were recruited. Clinical details including duration of therapy were recorded. Bleeders discontinued the implicated NSAID at presentation, controls at least five half-lives before the study. Bleeders were contacted by letter 1 month after discharge and invited to take part and were studied after a median delay of 5 months. Subjects received an oral dose of their respective NSAID and venous blood was sampled, over a period determined by the half-life of the NSAID. Plasma concentrations were determined by high performance liquid chromatography. RESULTS: The median length of treatment for the index patients was 1 year (range 2 weeks--28 years) and for the control patients 2 years (1 month--25 years), P<0.0005. There were no significant differences in peak plasma concentration, time to peak plasma concentration or area under the plasma concentration-time curve between bleeders or controls for any of the NSAIDs studied, apart from piroxicam Cmax being lower in bleeders at 2.07 mg l(-1) than in controls at 3.21 mg l(-1), mean difference (95% CI) -1.14 (-1.83 - -0.48), P<0.005. CONCLUSIONS: The data failed to support the hypothesis that reduced clearance of NSAIDs, which results in higher plasma concentrations, is a risk factor for acute gastrointestinal haemorrhage.

Effect of ageing upon warfarin dose requirements: a longitudinal study.

This longitudinal study was designed to establish the rate of age-related change in warfarin dose requirements. Warfarin dosage was recorded retrospectively in 104 patients who had been stabilized on warfarin for a median period of 10 years (range 6-24 years) for prophylaxis of thromboembolic disease. There was a significant negative correlation between dosage and age at the start of therapy (p = 0.002, r = -0.30). Warfarin requirements fell over time, dosage difference being significantly correlated with age difference (p = 0.01, r = 0.25). Use of regression equation derived from these data suggests a 21% fall in warfarin requirements in this population over a 15-year period. The relationship between change in warfarin dose requirements and ageing established in this longitudinal study is in good agreement with that established by cross-sectional studies, suggesting that no major birth cohort effect is influencing requirements in our warfarin-treated population.

Patient awareness of the adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs).

We set out to determine the extent to which two groups of patients reported having been informed about the adverse effects of NSAIDs. These consisted of 50 patients who had suffered an acute gastrointestinal bleed while taking a NSAID, and 100 age, sex and drug matched controls who had not. Eight (16%) of the index patients, and 41 (41%) of the control patients remembered having been informed of potential adverse effects, an odds ratio of 3.65 (95% CI 1.55-8.58, P < 0.002). Two (4%) of the index patients recalled having been advised what to do should adverse symptoms develop, whereas 21 (21%) of the control patients did so, an odds ratio of 6.38 (95% CI 1.4-28.4, P < 0.01). Eighteen (36%) of patients who bled had experienced gastrointestinal pain prior to the bleed, but of these only two (11%) admitted reduced compliance with NSAID therapy. In contrast, 10 (67%) of the 15 control patients who had suffered epigastric discomfort admitted reduced compliance, an odds ratio of 16.0 (95% CI 2.6-98.8, P < 0.001). Our results suggest that patients who report not having been informed of adverse effects of NSAIDs are less likely to reduce intake in response to epigastric pain than patients who report having received such information. If the patients who bled had reduced their intake of NSAIDs to the same extent as apparently better informed control patients in response to epigastric pain, it is possible that some episodes of acute gastrointestinal bleeding would have been avoided.

An audit of meal provision in an elderly care hospital.

OBJECTIVES: To estimate the nutritional provision to elderly patients, to compare with United Kingdom (UK) Government dietary reference values (DRV), to modify food provision to correct any major deficiencies, and to evaluate these modifications for their acceptability and consumption. METHODS: Energy, principal macro nutrients, vitamins, minerals and non-starch polysaccharide (NSP) and dietary fibre provision were measured prospectively throughout the menu cycle in a 72-bedded hospital for patients over 65 years before and after dietary supplementation with both energy-rich foods and high-fibre cakes. RESULTS: At baseline, mean energy provision was 1472(320) kcal, 6153(1340) kJ, representing less than the estimated average requirement (EAR) for elderly males and females. Fat provided 49% of total energy, daily protein provision exceeded the EAR for males and females (16% energy) and provision of the micro nutrients thiamine, riboflavin, vitamins B12, C, A, calcium and iron met or exceeded these recommendations. Vitamin B6 provision was only adequate for females. Provision of niacin, folate, vitamin D, NSP and dietary fibre was also below recommendations. Supplementation allowed energy provision to reach the target EAR and fibre provision the reference nutrient intake. CONCLUSIONS: Nutritional provision in hospital is meeting some, but not all, available Government standards for nutritional guidelines in elderly people. Increased fibre provision was poorly tolerated, but dietary supplementation with energy-rich foods was well tolerated.

The association of age and frailty with the pharmacokinetics and pharmacodynamics of metoclopramide.

We have investigated the association of age and frailty with the pharmacokinetics and pharmacodynamics of the conjugated drug, metoclopramide. Six healthy young, six healthy elderly (> 65 years), and six frail elderly (> 65 years) subjects were studied on two occasions, receiving 10 mg metoclopramide by intravenous bolus and orally, in random order. Blood and urine were collected for measurement of pharmacokinetic parameters. Liver volume was measured by ultrasound. Sedation and contentment were self-recorded on visual analogue scales. Liver volume was not significantly different in the three groups, nor was bio-availability of metoclopramide. Clearance was similar in the young and fit elderly but reduced in the frail elderly subjects when compared with the young (p < 0.05), both when expressed in absolute terms and per unit liver volume. There were no differences in percentages cleared as the free drug or as the sulphate or glucuronide metabolite within or between groups, suggesting that frailty can produce a general impairment of conjugation pathways. The frail elderly subjects reported more sedation after intravenous dosage than the other subjects, whilst only young subjects reported akathisia. This did not relate to pharmacokinetic differences and seemed therefore to reflect associated pharmacodynamic changes in specific receptor or target sites.

Are systemic levels of non steroidal anti inflammatory drugs relevant to acute upper gastrointestinal haemorrhage?

It is uncertain as to the extent which gastrointestinal (GI) haemorrhage related to NSAIDs is due to a local, topical effect or to an action related to systemic absorption. We hypothesised that, should systemic drug concentrations be of importance, plasma levels of NSAIDs might be higher in patients who had developed GI haemorrhage, from controls who had not. Ten patients with GI haemorrhage, who had ingested piroxicam (and no other NSAID), within the preceding 64 h, at the same dosage and on no new medication for the past 14 days, had blood taken at presentation for measurement of piroxicam concentrations. Plasma piroxicam concentrations were measured in 19 community dwelling controls, matched for age +/- 8 years, gender, daily piroxicam dosage, and time from last dose as their respective index case. All had been taking piroxicam for at least 3 months, and none had experienced GI adverse effects. Median plasma piroxicam concentrations in patients at 8.27 micrograms/l, was higher than in controls at 5.06 micrograms/l. These results suggest that a systemic component, at least with piroxicam, may play a significant (though not necessarily exclusive) role in causing major gastrointestinal haemorrhage.

Is caffeine a factor in subjective insomnia of elderly people?

Subjective insomnia is more prevalent in elderly than in young populations. In order to examine the relationship between caffeine and sleep quality we studied 181 community-dwelling subjects over a wide age range and 53 elderly patients receiving continuing hospital care. Subjects completed a sleep questionnaire and data concerning smoking, alcohol, use of hypnotics and caffeine-containing substances were recorded. Late afternoon plasma caffeine concentrations were measured in a sub-group of 87 of the community-dwelling subjects and in the hospitalized patients. For the group as a whole, there was a significant negative correlation between age and coffee but not tea consumption (p < 0.001). A global score of sleep quality was significantly inversely related to age (p < 0.001). For the community-dwelling population, the median plasma caffeine concentration was 1.71 micrograms/ml (range 0.10-6.74) and showed a significant correlation with sleep quality (p < 0.05). In contrast, for the hospital dwelling population, median caffeine concentration was higher in patients reporting sleep problems than in those without (p < 0.05). Self-reported consumption of coffee and tea did not correlate with plasma caffeine concentrations. It is possible that people with poor sleep quality, residing in the community, are aware of the stimulatory effects of caffeine and lower their intake accordingly, whereas hospitalized elderly patients, who have less control over their environment, do not.

Pharmacoeconomics of nonsteroidal anti-inflammatory drugs (NSAIDs).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the relief of the symptoms of osteoarthritis (OA), rheumatoid arthritis (RA), sprains and strains, sports injuries and menstrual disorders, and have a small role in the management of patent ductus arteriosus in the neonate. In patients with RA, symptom relief through use of NSAIDs is firmly established, although it remains unclear whether they influence the course and outcome of the disease. For the average patient with RA taking NSAIDs, the attributable risk of hospitalisation with gastrointestinal problems related to NSAIDs is 1.3 to 1.6% annually and risk of death is 0.15%. Associations of therapy with risk are greatest with age, corticosteroid use and previous NSAID-related gastrointestinal adverse effects, and less marked with disability and high NSAID dose. These are important data in attempting to balance risk of therapy with clinical efficacy in an individual patient, and assessing the cost-effectiveness of prophylaxis. Although half of all NSAID consumption is for control of pain associated with degenerative conditions, their superiority over simple analgesics in osteoarthritis is poorly documented. This finding supports the use of the simple analgesic paracetamol (acetaminophen) as the preferred therapy of osteoarthritis, especially when its lower cost and low incidence of adverse effects are taken into consideration. Consistent differences in clinical effectiveness of individual NSAIDs have not been demonstrated, although unpredictable interpatient variation in response to individual agents is of considerable clinical importance, and a more expensive NSAID may prove cost effective for some patients. Cost effectiveness can be improved by a self-adjusted dosage regime which also leads to lower overall drug consumption. The adverse gastrointestinal effects of these drugs account for about 30% of the overall cost of arthritis treatment, and although studies to date have been too limited to assess the relative risk of gastrointestinal toxicity of the different NSAIDs reliably, ibuprofen appears to be one of the least hazardous, and azapropazone one of the most hazardous. Although the effectiveness of prophylaxis with H 2-antagonists and with prostaglandin E 1 analogues (prostaglandin-E 1 analogues) has been established, estimates of cost-benefit ratios are widely divergent. To establish the most cost-effective therapy with NSAIDs, more data are required to establish multivariable risk profiles for identification of patients at particular risk, the optimal drug, and its optimal dosage and duration of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

The association of age with the activity of alcohol dehydrogenase in human liver.

Ethanol is principally oxidized in the liver by the cytosolic enzyme alcohol dehydrogenase (ADH). We have examined the effect of age and sex on alcohol dehydrogenase activities in human liver obtained from 16 healthy subjects, age range 45-88 years. There was no correlation between ADH activity, whether expressed as activity per mg cytosolic protein or per gram wet weight liver, and age. Activities were similar in men and women. These results suggest that, in common with activities of other hepatic drug metabolizing enzymes, age has no effect upon the activity of ADH in human liver.

Age-related changes in hepatic function. Implications for drug therapy.

An age-related decrease in the hepatic clearance of many drugs has been reported. Several mechanisms have been proposed, but only some are supported by hard evidence. Liver volume declines with age, as does hepatic blood flow--changes which may largely account for the reduced clearance of capacity- and flow-limited drugs, respectively. Age-related histological changes in the liver are minor and of uncertain significance; standard liver function tests do not change significantly with aging. There is, as yet, no direct evidence of a generalised fall in hepatic drug-metabolising enzyme activities in aging humans measured in vitro, but some in vivo studies suggest that certain very specific cytochrome P450 isoenzymes may be affected by aging, especially in men. Finally, there may be an age-related decline in the response to environmental influences.

The association of age with the induction of drug-metabolizing enzymes in human monocytes.

In vivo studies in man suggest that the enzyme-inducing effect of environmental influences such as drugs or smoking may be reduced in elderly people. We have investigated the basal activity and response to induction of the oxidative enzyme, aryl hydrocarbon hydroxylase (AHH) in human monocytes. Three groups were studied: ten fit young, ten fit elderly and eight frail elderly subjects. Significant induction of AHH activity in response to the hydrocarbon benz(a)anthracene was achieved in all three groups. No impairment of basal AHH activity or in the synthesis of new enzyme protein was noted with age or frailty. There is still no direct evidence of an age-associated fall in drug metabolizing enzyme activities in man.

The association of age and frailty with paracetamol conjugation in man.

The association of age, physical frailty and liver size upon hepatic conjugation reactions was studied using paracetamol as a model drug. Nineteen fit subjects (mean age 26 years), 20 fit subjects (mean age 73 years), and eight frail, hospitalized subjects (mean age 82 years) were recruited. Paracetamol clearance expressed in terms of body weight was significantly lower in the fit elderly than in the fit young subjects, and was lowest in the frail elderly subjects (p less than 0.01). There was no difference in paracetamol clearance expressed per unit volume of liver between the fit young and fit elderly subjects but it was significantly reduced in the frail subjects. Although the partial metabolic clearance to paracetamol sulphate was preserved per unit volume of liver with ageing and frailty, the partial metabolic clearance to paracetamol glucuronide per unit volume of liver was markedly reduced in the frail elderly (p less than 0.01) when compared with the fit subjects. These results show that age-associated changes in paracetamol clearance are attributable to both changes in liver volume and in general health. The findings underline the important influences of the elderly person's physical state upon drug clearance.

Hepatic drug clearance: the effect of age using indocyanine green as a model compound.

The hepatic extraction ratio and clearance of indocyanine green (ICG) were determined and used to derive apparent liver blood flow in nine subjects between the ages of 22 and 83 years. There was no correlation between the hepatic extraction ratio of ICG and age (rs = -0.435, NS). There was a significant negative correlation between both ICG clearance and age (rs = -0.710, P less than 0.05) and apparent liver blood flow and age (rs = -0.750, P less than 0.05). These results validate the comparison of liver blood flow values derived from ICG clearance in humans over a wide age range and confirm that liver blood flow does fall with age.