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Papers by Stephen Jackson
Journal of Psychopharmacology, 1999
Phenothiazines are widely used in older patients, but little experimental work has been carried o... more Phenothiazines are widely used in older patients, but little experimental work has been carried out in this age group. Two groups of healthy volunteers, a younger group (Y: six males and six females, aged 20-42 years) and an older group (0: six males and eight females, aged 65-77 years) took part in a randomized double-blind threeperiod crossover study in which they received by mouth single doses of thioridazine (Y: 50mg; 0: 25mg) remoxipride (Y: 100mg; 0: 50mg) or placebo. Measures of central nervous system (CNS) and haemodynamic function were carried out before drug administration and at 1.5-h intervals up to 9h post-dose, and blood samples were collected over a 24-h period. No significant differences in dose-corrected pharmacokinetic variables were found between the two groups. There was evidence of marked CNS depressant effects of thioridazine from both objective and subjective measures. The effects for remoxipride were similar, though generally less marked. After allowance was ...
Internal and emergency medicine, 2008
Journal of Internal Medicine, 2002
Cigarette smoking is associated with increased plasma homocysteine concentrations, endothelial dy... more Cigarette smoking is associated with increased plasma homocysteine concentrations, endothelial dysfunction and arterial stiffening. Homocysteine per se induces endothelial dysfunction and arterial stiffening and might account, at least partly, for the vascular abnormalities observed in smokers. We sought to determine whether folic acid supplementation, by reducing plasma homocysteine concentrations, enhanced endothelial function and reduced arterial stiffness in smokers. Double-blind, randomized controlled, parallel-group, trial. Academic medical centre. A consecutive sample of 24 healthy cigarette smokers (age 37.8 +/- 2.5 years, mean +/- SEM). Subjects were randomly assigned to 4-week folic acid 5 mg day-1 or placebo. The following were measured before and after treatment: (i) peripheral vasoreactivity (forearm arterial blood flow, FABF) during intra-arterial administration of endothelium-dependent (acetylcholine 1.5, 4.5 and 15 microg min-1) and endothelium-independent (sodium nitroprusside 1, 2 and 4 microg min-1) vasodilators; (ii) carotid-femoral pulse-wave velocity (PWV); (iii) blood pressure (BP). Folic acid reduced homocysteine concentrations (10.8 +/- 0.6 vs. 8.2 +/- 0.5 micromol L-1, P < 0.001) and enhanced endothelium-dependent vasodilatation during each acetylcholine infusion rate (ratio between the FABF in the infused and control arm during increasing infusion rates at baseline 1.09 +/- 0.03 vs. 1.41 +/- 0.09 after treatment, P < 0.01; 1.39 +/- 0.07 vs. 1.83 +/- 0.12, P < 0.01; 1.65 +/- 0.16 vs. 2.72 +/- 0.36, P < 0.05) whilst endothelium-independent vasodilatation was unaffected. A significant fall in BP was also observed (mean BP 88 +/- 2 vs. 83 +/- 1 mmHg, P < 0.01). By contrast, PWV did not significantly change (8.4 +/- 0.3 vs. 7.8 +/- 0.4 m s-1). No significant changes in plasma homocysteine concentrations, FABF, BP, and PWV were observed in the placebo group. A multiple regression analysis showed that changes in folic acid plasma concentrations independently predicted both FABF changes during maximal acetylcholine-mediated vasodilatation (P < 0.01) and BP changes (P = 0.01). Short-term folic acid supplementation significantly enhanced endothelial function and reduced BP in young chronic smokers. These effects were largely independent from the homocysteine lowering effects. Thus, a simple, nontoxic, and relatively inexpensive vitamin intervention might be useful in primary cardiovascular prevention in this high-risk group.
Journal of Hypertension, 2004
Journal of Bone and Mineral Research, 2002
Vitamin D and calcium supplementation significantly reduces the incidence of fractures. Evidence ... more Vitamin D and calcium supplementation significantly reduces the incidence of fractures. Evidence suggests vitamin D deficiency impairs neuromuscular function, causing an increase in falls and thereby fractures. The relationship between vitamin D, functional performance, and psychomotor function in elderly people who fall was examined in a prospective cross‐sectional study. Patients were recruited from a falls clinic and stratified according to serum 25‐hydroxyvitamin‐D levels (25OHD): group 1, 25OHD < 12 μg/liter; group 2 25OHD, 12‐17 μg/liter; and group 3, 25OHD > 17 μg/liter. Healthy elderly volunteers with 25OHD > 17 μg/liter comprised group 4 (n = 20/group). Measures included aggregate functional performance time (AFPT, seconds), isometric quadriceps strength (Newtons), postural sway (degrees), and choice reaction time (CRT, seconds). Serum bone biochemistry, 25OHD, and parathyroid hormone levels were measured. Patients who fell had significantly impaired functional per...
European Journal of Clinical Pharmacology, 1983
Indomethacin 100 rag/day or matching placebo was given for 2.5 days to 9 healthy volunteers in a ... more Indomethacin 100 rag/day or matching placebo was given for 2.5 days to 9 healthy volunteers in a double-blind cross-over study, followed by an intravenous injection of 0.2 mg/kg of hydralazine. Compared to placebo, indomethacin produced no statistically significant change in pulse rate or blood pressure in both standing and supine positions. Hydralazine injection was followed by a statistically significant fall in lying and standing diastolic pressure and a rise in lying and standing pulse after both indomethacin and placebo pretreatments. There were no significant differences in these effects following indomethacin compared to placebo pretreatment. These results do not support the hypothesis that endogenous prostaglandins are involved in the mechanism of action of hydralazine.
European Journal of Clinical Pharmacology, 1983
Theophylline concentrations were measured in a clinical setting in 15 patients given a slow relea... more Theophylline concentrations were measured in a clinical setting in 15 patients given a slow release theophylline preparation (Theo-Dur) every 12 h for reversible obstructive airways disease. Doses of 300-600 mg (464 +/- 134), 12 hourly, resulted in mean serum concentrations which increased from 11.2 +/- 2.9 micrograms/ml at 0 h to a peak of 15.5 +/- 4.6 micrograms/ml at 6 h and decreased again to 10.4 +/- 2.9 micrograms/ml at 12 h. The mean percentage fluctuation of serum concentrations (maximum minus minimum expressed as a % of the maximum) was 38.6 +/- 10.1%, range 20.3% to 54.9%. There was a significant positive correlation between % fluctuation and theophylline steady-state clearance determinations. Excluding a single heavy smoker, theophylline clearance also showed a significant inverse relationship with age. These data suggest that when this slow release preparation is given 12 hourly, satisfactorily sustained serum theophylline concentrations will be achieved in most adults.
Journal of the American Geriatrics Society, 2000
To elucidate the pathophysiological mechanism of the vasodepressor form (VD) of carotid sinus syn... more To elucidate the pathophysiological mechanism of the vasodepressor form (VD) of carotid sinus syndrome (CSS) by maneuvers designed to induce generalized sympathetic activation after baroreceptor unloading (lower body negative pressure, LBNP) or direct peripheral adrenoreceptor stimulation via local administration of norepinephrine (NA). DESIGN: Subjects were identified with VD of CSS through diagnostic testing. SETTING: Research laboratory. PARTICIPANTS: Eleven young controls (YC) (mean age Ϯ standard error of mean ϭ 22.8 Ϯ 0.7), eight elderly controls (EC) (72.6 Ϯ 0.6), and eight elderly patients with VD (78.7 Ϯ 1.7). MEASUREMENTS: Forearm arterial blood flow (FABF) was measured in the left and right arms by venous occlusion plethysmography. Measurements were performed during baseline conditions, LBNP ( Ϫ 20 mmHg), and intraarterial NA infusion in the left brachial artery at three progressively increasing rates (60, 120, and 240 pmol/min). RESULTS: During LBNP, FABF significantly decreased in YC (baseline 3.61 Ϯ 0.30 vs Ϫ 20 mmHg 2.96 Ϯ 0.24 mL/ 100 g/min, P ϭ .030) and EC (4.05 Ϯ 0.74 vs 3.69 Ϯ 0.65 mL/100 g/min, P ϭ .033) but increased in elderly patients with VD (3.65 Ϯ 0.60 vs 4.54 Ϯ 0.80 mL/100 g/min, P ϭ .020). During NA infusion, a significant forearm vasoconstriction occurred in YC (FABF left:right ratio 1.00 Ϯ 0.05 at baseline; 0.81 Ϯ 0.08 at 60 pmol/min, P ϭ .034; 0.81 Ϯ 0.05 at 120 pmol/min, P Ͻ .001; 0.72 Ϯ 0.04 at 240 pmol/ min, P Ͻ .001), whereas no significant FABF changes were observed in EC (1.04 Ϯ 0.06; 0.96 Ϯ 0.07, P ϭ .655; 0.89 Ϯ 0.10, P ϭ .401; 0.94 Ϯ 0.10, P ϭ .590) or elderly patients with VD (1.04 Ϯ 0.06; 1.16 Ϯ 0 .10, P ϭ .117; 1.04 Ϯ 0.08, P ϭ .602; 1.11 Ϯ 0.10, P ϭ .305). CONCLUSION: VD of CSS is associated with a paradoxical vasodilatation during LBNP and an impairment of peripheral ␣ -adrenergic responsiveness, which may be agerelated. J Am Geriatr Soc 51:853-857, 2003.
British Journal of Pharmacology, 2002
The Pharmaceutical Journal, 1997
Clinical Science, 1981
The oxygen contents of 64 blood samples were determined in duplicate by both methods. The values ... more The oxygen contents of 64 blood samples were determined in duplicate by both methods. The values of the [Hb!, So" Po, and of the directly measured oxygen contents ranged from 9•2 to 13•3 g/dl, 30 to 99%, 22 to 126 mmHg and 4•5 to 17•4 vol.% respectively. There was a significant correlation between the two methods (r = 0•99; P < 0•001) but the calculated method gave
Clinical Pharmacology & Therapeutics, 2007
The vasoconstrictive action of angiotensin II (AII) is partly, sympathetically mediated and angio... more The vasoconstrictive action of angiotensin II (AII) is partly, sympathetically mediated and angiotensin-converting enzyme (ACE) inhibitors appear to exert a sympatholytic effect. We examine the effect of an orally administered, selective AT(1) receptor antagonist (losartan 50 mg) on sympathetically mediated vasoconstriction in healthy volunteers in an observer blind crossover study. Seven healthy, normotensive volunteers (21-32 years), were studied on two occasions at the end of each 6-week treatment period (losartan or placebo). Forearm blood flow (FABF) (ml/dl forearm/min) was measured by venous occlusion plethysmography during the application of lower body negative pressure (LBNP) (-20 cm H(2)O) and at the end of each incremental infusion of norepinephrine (60, 120, and 240 pmol/min). Comparison of blood flow changes was by repeated measures analysis of variance; P&amp;lt;0.05 was taken as statistically significant. Losartan did not alter blood pressure compared to placebo. It did significantly enhance LBNP-induced vasoconstriction in both the left arm compared to placebo (-36.6+/-3.4 vs -23.5+/-3.3%; P=0.017) and the right arm compared to placebo (-39.5+/-3.8 vs -21.0+/-3.6%; P=0.005). The FABF response to all doses of infused norepinephrine (60, 120, and 240 pmol/min) was also enhanced by losartan compared to placebo (-35.0+/-2.7 vs -18.2+/-6.0%; -43.6+/-4.3 vs -28.6+/-5.8%, and -53.9+/-3.2 vs -42.5+/-6.8%; P=0.057, respectively. Losartan enhances locally mediated sympathetic vasoconstriction in the forearm circulation of man, probably through its effect on circulating AII concentrations and we postulate that the adrenergic sympathetic constrictor action of AII is not mediated by the AT(1) receptor or is surmountable at this receptor.
Ernst Schering Research Foundation workshop, 2007
The increasing size of the elderly population means that both the relative and absolute numbers o... more The increasing size of the elderly population means that both the relative and absolute numbers of prescriptions for elderly patients are increasing. Depending on the age group, between 60% and 80% of elderly people are taking medication, and between 20% and 30% are taking at least three drugs. Prescribing for elderly patients as opposed to younger patients is thus ever more important. This has inevitably meant that the drug development process must increasingly recognise the importance of identifying and developing therapeutic targets relevant to older patients. Clearly, the scientific ethical and regulatory principles that determine conduct of clinical trials in younger individuals apply equally to older people. In addition, the development of drugs to be used in older patients requires an awareness of a number of physiological, pathophysiological and sociological considerations.
Clinical Risk, 2012
Drug-related problems are prevalent in older people admitted to hospital and may be the reason fo... more Drug-related problems are prevalent in older people admitted to hospital and may be the reason for admission. Lindley et al. showed adverse drug events to be higher for older people in hospital receiving inappropriate medication. In an observational cross-sectional study of patients aged 70 years and over admitted to general medical wards in the Netherlands, Mannesse et al. showed that about 24% experienced a severe adverse drug reaction (ADR) and in 12% the admission was probably caused by an ADR. In an earlier study in Scotland one in 20 admissions for older people were thought probably to be related to a drug-related problem. Standard 4 of The National Service Framework for Older People relates to General Hospital Care and use of medicines is a fundamental component of this standard as outlined in the Medicines Management supplement. The standard requires that all people over 75 years should have their medicines reviewed at least annually and those taking four or more medicines should have a review six monthly. The purpose of medication review should be to ensure that there is evidence of some sort to support the treatments an older person is receiving (appropriate medication) and to identify potentially inappropriate medications (PIMs) that are being taken. Appropriate prescribing includes use of medicines with evidence-based indications even if the evidence falls short of randomized controlled trials. Appropriate prescribing also means non-use of medicines with no clear indications or medicines that are contraindicated. This definition applies across all age-groups both in hospital and in the community. In the latest National Patient Safety Agency patient safety incident reports, medication errors were the third most common cause of patient safety incidents in hospital settings (the first and second being patient accident and treatment procedure, respectively). An Audit Commission report estimated that medication errors may have been associated with more than 150 fatalities each year in England and Wales between 1996 and 2000. Medication errors can occur at any stage of the medicines process including the prescribing, dispensing or administration of a drug. Safe prescribing entails appropriate choice as well as avoiding making errors when actually prescribing. This article will focus on reducing medication errors by optimizing prescribing quality. We will describe tools that can be used in hospitals to identify suboptimal prescribing and suggest how to use audit to improve and maintain good quality prescribing.
Xenobiotica, 2003
1. The stereoselective metabolism and pharmacokinetics of the enantiomers of flurbiprofen were in... more 1. The stereoselective metabolism and pharmacokinetics of the enantiomers of flurbiprofen were investigated following the oral administration of the racemic drug (100 mg) to four young and four elderly healthy volunteers (two males and two females per group). 2. The stereochemical composition of the drug and the 4&amp;#39;-hydroxy- metabolite in serum and the drug, 4&amp;#39;-hydroxy- and 3&amp;#39;-hydroxy-4&amp;#39;-methoxy- metabolites, both free and conjugated, in urine were determined by a direct chromatographic method of enantiomeric analysis. 3. Modest enantioselectivity in clearance (CL S/R: young, 0.86; elderly, 0.88) was largely responsible for the apparent elimination half-life of (S)-flurbiprofen being significantly greater (p&amp;lt;0.01) than that of the R-enantiomer in both age groups (young, S: 5.2 +/- 0.7 versus R: 4.5 +/- 0.6 h; elderly, S: 9.6 +/- 1.2 versus R: 7.1 +/- 1.0 h). The serum concentrations of 4&amp;#39;-hydroxyflurbiprofen were five- to 20-fold lower than those of the corresponding drug enantiomers, stereoselective disposition being evident in the significantly greater (p&amp;lt;0.05) apparent half-lives of the S- compared with the R-enantiomer in both groups (young, S: 10.6 +/- 2.4 versus R: 6.7 +/- 1.1 h; elderly, S: 13.7 +/- 1.7 versus R: 10.2 +/- 1.2 h). 4. Some 60 and 72% of the dose was excreted in 24-h urine in elderly and young volunteers, respectively, a significantly greater (p&amp;lt;0.05) proportion of which was of the R-configuration in both age groups (S/R: young, 0.87; elderly, 0.81). The major urinary excretion products were flurbiprofen and 4&amp;#39;-hydroxyflurbiprofen, and their acyl-conjugates in both groups. 5. Age-associated differences in the pharmacokinetics of flurbiprofen occurred in a non-stereoselective manner and were primarily as a consequence of a significant approximately 40% decrease (p&amp;lt;0.01) in clearance of both enantiomers in the elderly due to reduced metabolic activity. Consequently, the elderly had greater exposure to both enantiomers, as reflected by the AUCs(0-inf) being significantly higher (p&amp;lt;0.05), by 60%, in this age group compared with the young. 6. The findings suggest that age-related alterations in the disposition of flurbiprofen could have significant implications for the use of the drug in the elderly.
Xenobiotica, 2002
1. The stereoselective metabolism and pharmacokinetics of the enantiomers of ibuprofen have been ... more 1. The stereoselective metabolism and pharmacokinetics of the enantiomers of ibuprofen have been investigated following the oral administration of the racemic drug (400 mg) to 12 healthy volunteers.2. The stereochemical composition of the drug in serum, both total and unbound, and drug and metabolites, both free and conjugated, in urine were determined by a combination of the direct and indirect chromatographic procedures to enantiomeric analysis. 3. The oral clearance of (S)-ibuprofen was significantly greater than that of the R-enantiomer (74.5 +/- 18.1 versus 57.1 +/- 11.7 ml min(-1); p &amp;lt; 0.05) and the clearance of (R)-ibuprofen via inversion was ca two fold that via alternative pathways. 4. Some 74.0 +/- 9.6% of the dose was recovered in urine over 24 h as ibuprofen, 2-hydroxyibuprofen and carboxyibuprofen, both free and conjugated with glucuronic acid. Analysis of the stereochemical composition of the urinary excretion products indicated that 68% of the dose of (R)-ibuprofen had undergone chiral inversion. 5. Metabolism via glucuronidation and both routes of oxidation, showed enantio-selectivity for (S)-ibuprofen, the enantiomeric ratios (S/R) in partial metabolic clearance being 7.1, 4.8 and 3.4 for formation of ibuprofen glucuronide, 2-hydroxyibuprofen and carboxyibuprofen respectively.6. Modest stereoselectivity was observed in the formation of (2&amp;#39;R, 2R)- and (2&amp;#39;S, 2S)-carboxyibuprofen in comparison to the alternative diastereoisomers, the ratios in formation clearance being 1.6 and 1.2 respectively.
Postgraduate Medical Journal, 2006
Objective To test the hypothesis that an acute increase in plasma homocysteine produced by methio... more Objective To test the hypothesis that an acute increase in plasma homocysteine produced by methionine is associated with an acute increase in pulse wave velocity. Design A double blind, cross over, placebo controlled design was used and pulse wave velocity, plasma homocysteine, total cholesterol: high density lipoprotein ratio, plasma triglyceride, oxidised low density lipoprotein cholesterol concentrations, apolipoproteins A1 and B, and C reactive protein were measured between 12.5 and 20 hours after methionine loading or placebo. Results Between 12.5 and 20 hours after exposure to a methionine loading test, arterial pulse wave velocity showed no significant difference compared with placebo. At 12 hours after exposure to the methionine loading test, in the presence of a controlled diet, triglyceride concentration significantly increased by 32.6% (p<0.02), cholesterol: high density lipoprotein ratio increased significantly by 22.5% (p<0.05) compared with placebo. Simultaneousl...
Journal of Psychopharmacology, 1999
Phenothiazines are widely used in older patients, but little experimental work has been carried o... more Phenothiazines are widely used in older patients, but little experimental work has been carried out in this age group. Two groups of healthy volunteers, a younger group (Y: six males and six females, aged 20-42 years) and an older group (0: six males and eight females, aged 65-77 years) took part in a randomized double-blind threeperiod crossover study in which they received by mouth single doses of thioridazine (Y: 50mg; 0: 25mg) remoxipride (Y: 100mg; 0: 50mg) or placebo. Measures of central nervous system (CNS) and haemodynamic function were carried out before drug administration and at 1.5-h intervals up to 9h post-dose, and blood samples were collected over a 24-h period. No significant differences in dose-corrected pharmacokinetic variables were found between the two groups. There was evidence of marked CNS depressant effects of thioridazine from both objective and subjective measures. The effects for remoxipride were similar, though generally less marked. After allowance was ...
Internal and emergency medicine, 2008
Journal of Internal Medicine, 2002
Cigarette smoking is associated with increased plasma homocysteine concentrations, endothelial dy... more Cigarette smoking is associated with increased plasma homocysteine concentrations, endothelial dysfunction and arterial stiffening. Homocysteine per se induces endothelial dysfunction and arterial stiffening and might account, at least partly, for the vascular abnormalities observed in smokers. We sought to determine whether folic acid supplementation, by reducing plasma homocysteine concentrations, enhanced endothelial function and reduced arterial stiffness in smokers. Double-blind, randomized controlled, parallel-group, trial. Academic medical centre. A consecutive sample of 24 healthy cigarette smokers (age 37.8 +/- 2.5 years, mean +/- SEM). Subjects were randomly assigned to 4-week folic acid 5 mg day-1 or placebo. The following were measured before and after treatment: (i) peripheral vasoreactivity (forearm arterial blood flow, FABF) during intra-arterial administration of endothelium-dependent (acetylcholine 1.5, 4.5 and 15 microg min-1) and endothelium-independent (sodium nitroprusside 1, 2 and 4 microg min-1) vasodilators; (ii) carotid-femoral pulse-wave velocity (PWV); (iii) blood pressure (BP). Folic acid reduced homocysteine concentrations (10.8 +/- 0.6 vs. 8.2 +/- 0.5 micromol L-1, P &amp;lt; 0.001) and enhanced endothelium-dependent vasodilatation during each acetylcholine infusion rate (ratio between the FABF in the infused and control arm during increasing infusion rates at baseline 1.09 +/- 0.03 vs. 1.41 +/- 0.09 after treatment, P &amp;lt; 0.01; 1.39 +/- 0.07 vs. 1.83 +/- 0.12, P &amp;lt; 0.01; 1.65 +/- 0.16 vs. 2.72 +/- 0.36, P &amp;lt; 0.05) whilst endothelium-independent vasodilatation was unaffected. A significant fall in BP was also observed (mean BP 88 +/- 2 vs. 83 +/- 1 mmHg, P &amp;lt; 0.01). By contrast, PWV did not significantly change (8.4 +/- 0.3 vs. 7.8 +/- 0.4 m s-1). No significant changes in plasma homocysteine concentrations, FABF, BP, and PWV were observed in the placebo group. A multiple regression analysis showed that changes in folic acid plasma concentrations independently predicted both FABF changes during maximal acetylcholine-mediated vasodilatation (P &amp;lt; 0.01) and BP changes (P = 0.01). Short-term folic acid supplementation significantly enhanced endothelial function and reduced BP in young chronic smokers. These effects were largely independent from the homocysteine lowering effects. Thus, a simple, nontoxic, and relatively inexpensive vitamin intervention might be useful in primary cardiovascular prevention in this high-risk group.
Journal of Hypertension, 2004
Journal of Bone and Mineral Research, 2002
Vitamin D and calcium supplementation significantly reduces the incidence of fractures. Evidence ... more Vitamin D and calcium supplementation significantly reduces the incidence of fractures. Evidence suggests vitamin D deficiency impairs neuromuscular function, causing an increase in falls and thereby fractures. The relationship between vitamin D, functional performance, and psychomotor function in elderly people who fall was examined in a prospective cross‐sectional study. Patients were recruited from a falls clinic and stratified according to serum 25‐hydroxyvitamin‐D levels (25OHD): group 1, 25OHD < 12 μg/liter; group 2 25OHD, 12‐17 μg/liter; and group 3, 25OHD > 17 μg/liter. Healthy elderly volunteers with 25OHD > 17 μg/liter comprised group 4 (n = 20/group). Measures included aggregate functional performance time (AFPT, seconds), isometric quadriceps strength (Newtons), postural sway (degrees), and choice reaction time (CRT, seconds). Serum bone biochemistry, 25OHD, and parathyroid hormone levels were measured. Patients who fell had significantly impaired functional per...
European Journal of Clinical Pharmacology, 1983
Indomethacin 100 rag/day or matching placebo was given for 2.5 days to 9 healthy volunteers in a ... more Indomethacin 100 rag/day or matching placebo was given for 2.5 days to 9 healthy volunteers in a double-blind cross-over study, followed by an intravenous injection of 0.2 mg/kg of hydralazine. Compared to placebo, indomethacin produced no statistically significant change in pulse rate or blood pressure in both standing and supine positions. Hydralazine injection was followed by a statistically significant fall in lying and standing diastolic pressure and a rise in lying and standing pulse after both indomethacin and placebo pretreatments. There were no significant differences in these effects following indomethacin compared to placebo pretreatment. These results do not support the hypothesis that endogenous prostaglandins are involved in the mechanism of action of hydralazine.
European Journal of Clinical Pharmacology, 1983
Theophylline concentrations were measured in a clinical setting in 15 patients given a slow relea... more Theophylline concentrations were measured in a clinical setting in 15 patients given a slow release theophylline preparation (Theo-Dur) every 12 h for reversible obstructive airways disease. Doses of 300-600 mg (464 +/- 134), 12 hourly, resulted in mean serum concentrations which increased from 11.2 +/- 2.9 micrograms/ml at 0 h to a peak of 15.5 +/- 4.6 micrograms/ml at 6 h and decreased again to 10.4 +/- 2.9 micrograms/ml at 12 h. The mean percentage fluctuation of serum concentrations (maximum minus minimum expressed as a % of the maximum) was 38.6 +/- 10.1%, range 20.3% to 54.9%. There was a significant positive correlation between % fluctuation and theophylline steady-state clearance determinations. Excluding a single heavy smoker, theophylline clearance also showed a significant inverse relationship with age. These data suggest that when this slow release preparation is given 12 hourly, satisfactorily sustained serum theophylline concentrations will be achieved in most adults.
Journal of the American Geriatrics Society, 2000
To elucidate the pathophysiological mechanism of the vasodepressor form (VD) of carotid sinus syn... more To elucidate the pathophysiological mechanism of the vasodepressor form (VD) of carotid sinus syndrome (CSS) by maneuvers designed to induce generalized sympathetic activation after baroreceptor unloading (lower body negative pressure, LBNP) or direct peripheral adrenoreceptor stimulation via local administration of norepinephrine (NA). DESIGN: Subjects were identified with VD of CSS through diagnostic testing. SETTING: Research laboratory. PARTICIPANTS: Eleven young controls (YC) (mean age Ϯ standard error of mean ϭ 22.8 Ϯ 0.7), eight elderly controls (EC) (72.6 Ϯ 0.6), and eight elderly patients with VD (78.7 Ϯ 1.7). MEASUREMENTS: Forearm arterial blood flow (FABF) was measured in the left and right arms by venous occlusion plethysmography. Measurements were performed during baseline conditions, LBNP ( Ϫ 20 mmHg), and intraarterial NA infusion in the left brachial artery at three progressively increasing rates (60, 120, and 240 pmol/min). RESULTS: During LBNP, FABF significantly decreased in YC (baseline 3.61 Ϯ 0.30 vs Ϫ 20 mmHg 2.96 Ϯ 0.24 mL/ 100 g/min, P ϭ .030) and EC (4.05 Ϯ 0.74 vs 3.69 Ϯ 0.65 mL/100 g/min, P ϭ .033) but increased in elderly patients with VD (3.65 Ϯ 0.60 vs 4.54 Ϯ 0.80 mL/100 g/min, P ϭ .020). During NA infusion, a significant forearm vasoconstriction occurred in YC (FABF left:right ratio 1.00 Ϯ 0.05 at baseline; 0.81 Ϯ 0.08 at 60 pmol/min, P ϭ .034; 0.81 Ϯ 0.05 at 120 pmol/min, P Ͻ .001; 0.72 Ϯ 0.04 at 240 pmol/ min, P Ͻ .001), whereas no significant FABF changes were observed in EC (1.04 Ϯ 0.06; 0.96 Ϯ 0.07, P ϭ .655; 0.89 Ϯ 0.10, P ϭ .401; 0.94 Ϯ 0.10, P ϭ .590) or elderly patients with VD (1.04 Ϯ 0.06; 1.16 Ϯ 0 .10, P ϭ .117; 1.04 Ϯ 0.08, P ϭ .602; 1.11 Ϯ 0.10, P ϭ .305). CONCLUSION: VD of CSS is associated with a paradoxical vasodilatation during LBNP and an impairment of peripheral ␣ -adrenergic responsiveness, which may be agerelated. J Am Geriatr Soc 51:853-857, 2003.
British Journal of Pharmacology, 2002
The Pharmaceutical Journal, 1997
Clinical Science, 1981
The oxygen contents of 64 blood samples were determined in duplicate by both methods. The values ... more The oxygen contents of 64 blood samples were determined in duplicate by both methods. The values of the [Hb!, So" Po, and of the directly measured oxygen contents ranged from 9•2 to 13•3 g/dl, 30 to 99%, 22 to 126 mmHg and 4•5 to 17•4 vol.% respectively. There was a significant correlation between the two methods (r = 0•99; P < 0•001) but the calculated method gave
Clinical Pharmacology & Therapeutics, 2007
The vasoconstrictive action of angiotensin II (AII) is partly, sympathetically mediated and angio... more The vasoconstrictive action of angiotensin II (AII) is partly, sympathetically mediated and angiotensin-converting enzyme (ACE) inhibitors appear to exert a sympatholytic effect. We examine the effect of an orally administered, selective AT(1) receptor antagonist (losartan 50 mg) on sympathetically mediated vasoconstriction in healthy volunteers in an observer blind crossover study. Seven healthy, normotensive volunteers (21-32 years), were studied on two occasions at the end of each 6-week treatment period (losartan or placebo). Forearm blood flow (FABF) (ml/dl forearm/min) was measured by venous occlusion plethysmography during the application of lower body negative pressure (LBNP) (-20 cm H(2)O) and at the end of each incremental infusion of norepinephrine (60, 120, and 240 pmol/min). Comparison of blood flow changes was by repeated measures analysis of variance; P&amp;lt;0.05 was taken as statistically significant. Losartan did not alter blood pressure compared to placebo. It did significantly enhance LBNP-induced vasoconstriction in both the left arm compared to placebo (-36.6+/-3.4 vs -23.5+/-3.3%; P=0.017) and the right arm compared to placebo (-39.5+/-3.8 vs -21.0+/-3.6%; P=0.005). The FABF response to all doses of infused norepinephrine (60, 120, and 240 pmol/min) was also enhanced by losartan compared to placebo (-35.0+/-2.7 vs -18.2+/-6.0%; -43.6+/-4.3 vs -28.6+/-5.8%, and -53.9+/-3.2 vs -42.5+/-6.8%; P=0.057, respectively. Losartan enhances locally mediated sympathetic vasoconstriction in the forearm circulation of man, probably through its effect on circulating AII concentrations and we postulate that the adrenergic sympathetic constrictor action of AII is not mediated by the AT(1) receptor or is surmountable at this receptor.
Ernst Schering Research Foundation workshop, 2007
The increasing size of the elderly population means that both the relative and absolute numbers o... more The increasing size of the elderly population means that both the relative and absolute numbers of prescriptions for elderly patients are increasing. Depending on the age group, between 60% and 80% of elderly people are taking medication, and between 20% and 30% are taking at least three drugs. Prescribing for elderly patients as opposed to younger patients is thus ever more important. This has inevitably meant that the drug development process must increasingly recognise the importance of identifying and developing therapeutic targets relevant to older patients. Clearly, the scientific ethical and regulatory principles that determine conduct of clinical trials in younger individuals apply equally to older people. In addition, the development of drugs to be used in older patients requires an awareness of a number of physiological, pathophysiological and sociological considerations.
Clinical Risk, 2012
Drug-related problems are prevalent in older people admitted to hospital and may be the reason fo... more Drug-related problems are prevalent in older people admitted to hospital and may be the reason for admission. Lindley et al. showed adverse drug events to be higher for older people in hospital receiving inappropriate medication. In an observational cross-sectional study of patients aged 70 years and over admitted to general medical wards in the Netherlands, Mannesse et al. showed that about 24% experienced a severe adverse drug reaction (ADR) and in 12% the admission was probably caused by an ADR. In an earlier study in Scotland one in 20 admissions for older people were thought probably to be related to a drug-related problem. Standard 4 of The National Service Framework for Older People relates to General Hospital Care and use of medicines is a fundamental component of this standard as outlined in the Medicines Management supplement. The standard requires that all people over 75 years should have their medicines reviewed at least annually and those taking four or more medicines should have a review six monthly. The purpose of medication review should be to ensure that there is evidence of some sort to support the treatments an older person is receiving (appropriate medication) and to identify potentially inappropriate medications (PIMs) that are being taken. Appropriate prescribing includes use of medicines with evidence-based indications even if the evidence falls short of randomized controlled trials. Appropriate prescribing also means non-use of medicines with no clear indications or medicines that are contraindicated. This definition applies across all age-groups both in hospital and in the community. In the latest National Patient Safety Agency patient safety incident reports, medication errors were the third most common cause of patient safety incidents in hospital settings (the first and second being patient accident and treatment procedure, respectively). An Audit Commission report estimated that medication errors may have been associated with more than 150 fatalities each year in England and Wales between 1996 and 2000. Medication errors can occur at any stage of the medicines process including the prescribing, dispensing or administration of a drug. Safe prescribing entails appropriate choice as well as avoiding making errors when actually prescribing. This article will focus on reducing medication errors by optimizing prescribing quality. We will describe tools that can be used in hospitals to identify suboptimal prescribing and suggest how to use audit to improve and maintain good quality prescribing.
Xenobiotica, 2003
1. The stereoselective metabolism and pharmacokinetics of the enantiomers of flurbiprofen were in... more 1. The stereoselective metabolism and pharmacokinetics of the enantiomers of flurbiprofen were investigated following the oral administration of the racemic drug (100 mg) to four young and four elderly healthy volunteers (two males and two females per group). 2. The stereochemical composition of the drug and the 4&amp;#39;-hydroxy- metabolite in serum and the drug, 4&amp;#39;-hydroxy- and 3&amp;#39;-hydroxy-4&amp;#39;-methoxy- metabolites, both free and conjugated, in urine were determined by a direct chromatographic method of enantiomeric analysis. 3. Modest enantioselectivity in clearance (CL S/R: young, 0.86; elderly, 0.88) was largely responsible for the apparent elimination half-life of (S)-flurbiprofen being significantly greater (p&amp;lt;0.01) than that of the R-enantiomer in both age groups (young, S: 5.2 +/- 0.7 versus R: 4.5 +/- 0.6 h; elderly, S: 9.6 +/- 1.2 versus R: 7.1 +/- 1.0 h). The serum concentrations of 4&amp;#39;-hydroxyflurbiprofen were five- to 20-fold lower than those of the corresponding drug enantiomers, stereoselective disposition being evident in the significantly greater (p&amp;lt;0.05) apparent half-lives of the S- compared with the R-enantiomer in both groups (young, S: 10.6 +/- 2.4 versus R: 6.7 +/- 1.1 h; elderly, S: 13.7 +/- 1.7 versus R: 10.2 +/- 1.2 h). 4. Some 60 and 72% of the dose was excreted in 24-h urine in elderly and young volunteers, respectively, a significantly greater (p&amp;lt;0.05) proportion of which was of the R-configuration in both age groups (S/R: young, 0.87; elderly, 0.81). The major urinary excretion products were flurbiprofen and 4&amp;#39;-hydroxyflurbiprofen, and their acyl-conjugates in both groups. 5. Age-associated differences in the pharmacokinetics of flurbiprofen occurred in a non-stereoselective manner and were primarily as a consequence of a significant approximately 40% decrease (p&amp;lt;0.01) in clearance of both enantiomers in the elderly due to reduced metabolic activity. Consequently, the elderly had greater exposure to both enantiomers, as reflected by the AUCs(0-inf) being significantly higher (p&amp;lt;0.05), by 60%, in this age group compared with the young. 6. The findings suggest that age-related alterations in the disposition of flurbiprofen could have significant implications for the use of the drug in the elderly.
Xenobiotica, 2002
1. The stereoselective metabolism and pharmacokinetics of the enantiomers of ibuprofen have been ... more 1. The stereoselective metabolism and pharmacokinetics of the enantiomers of ibuprofen have been investigated following the oral administration of the racemic drug (400 mg) to 12 healthy volunteers.2. The stereochemical composition of the drug in serum, both total and unbound, and drug and metabolites, both free and conjugated, in urine were determined by a combination of the direct and indirect chromatographic procedures to enantiomeric analysis. 3. The oral clearance of (S)-ibuprofen was significantly greater than that of the R-enantiomer (74.5 +/- 18.1 versus 57.1 +/- 11.7 ml min(-1); p &amp;lt; 0.05) and the clearance of (R)-ibuprofen via inversion was ca two fold that via alternative pathways. 4. Some 74.0 +/- 9.6% of the dose was recovered in urine over 24 h as ibuprofen, 2-hydroxyibuprofen and carboxyibuprofen, both free and conjugated with glucuronic acid. Analysis of the stereochemical composition of the urinary excretion products indicated that 68% of the dose of (R)-ibuprofen had undergone chiral inversion. 5. Metabolism via glucuronidation and both routes of oxidation, showed enantio-selectivity for (S)-ibuprofen, the enantiomeric ratios (S/R) in partial metabolic clearance being 7.1, 4.8 and 3.4 for formation of ibuprofen glucuronide, 2-hydroxyibuprofen and carboxyibuprofen respectively.6. Modest stereoselectivity was observed in the formation of (2&amp;#39;R, 2R)- and (2&amp;#39;S, 2S)-carboxyibuprofen in comparison to the alternative diastereoisomers, the ratios in formation clearance being 1.6 and 1.2 respectively.
Postgraduate Medical Journal, 2006
Objective To test the hypothesis that an acute increase in plasma homocysteine produced by methio... more Objective To test the hypothesis that an acute increase in plasma homocysteine produced by methionine is associated with an acute increase in pulse wave velocity. Design A double blind, cross over, placebo controlled design was used and pulse wave velocity, plasma homocysteine, total cholesterol: high density lipoprotein ratio, plasma triglyceride, oxidised low density lipoprotein cholesterol concentrations, apolipoproteins A1 and B, and C reactive protein were measured between 12.5 and 20 hours after methionine loading or placebo. Results Between 12.5 and 20 hours after exposure to a methionine loading test, arterial pulse wave velocity showed no significant difference compared with placebo. At 12 hours after exposure to the methionine loading test, in the presence of a controlled diet, triglyceride concentration significantly increased by 32.6% (p<0.02), cholesterol: high density lipoprotein ratio increased significantly by 22.5% (p<0.05) compared with placebo. Simultaneousl...