Selective AT1 receptor antagonism enhances sympathetically mediated vasoconstriction in man.

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<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.

Effect of methionine loading on pulse wave analysis in elderly volunteers.

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. Simultaneously, systolic blood pressure increased significantly by 4.9% (p<0.02). CONCLUSION: In elderly volunteers, acute hyperhomocysteinaemia induced by methionine loading resulted in no overall significant delayed reduction in peripheral arterial distensibility. A significant deterioration in the lipid profile and increased blood pressure was seen during acute hyperhomocysteinaemia.

Premedication for bronchoscopy in older patients: a double-blind comparison of two regimens.

INTRODUCTION: Older patients are the most prevalent age cohort requiring bronchoscopy. Prior sedation should be offered to improve patient comfort and operator technical ease. Older patients have increased sensitivity to centrally acting drugs increasing the procedural risk. This perceived risk may limit access to bronchoscopy in older patients. There have been no systematic prospective placebo-controlled studies in older patients. We compared a novel premedication regimen-oral temazepam plus nebulised Lignocaine (new treatment) to an established regimen of intravenous alfentanyl (control). METHODS: Consecutive patients 75 years and older referred for bronchoscopy were considered. Twenty-five patients were randomly assigned to each group. The primary outcome measure was the lowest oxygen saturation recorded from the administration of IV drugs and for 30 min post-bronchoscopy. RESULTS: The lowest mean oxygen saturation in the new treatment group was 92.2% (90.3-94.2) and in the control group 91.1% (89.2-93.1). This was not statistically different (P = 0.370). There were no adverse events. CONCLUSION: This is the largest prospective study to date on an older population undergoing bronchoscopy supporting previous retrospective findings regarding the safety of this procedure. Determined by oxygen saturations there is no difference in safety between premedication regimens comprising oral temazepam/nebulised lignocaine or intravenous alfentanyl.

Neuromuscular and psychomotor function in elderly subjects who fall and the relationship with vitamin D status.

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 microg/liter; group 2 25OHD, 12-17 microg/liter; and group 3, 25OHD > 17 microg/liter. Healthy elderly volunteers with 25OHD > 17 microg/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 performance, psychomotor function, and quadriceps strength compared with healthy subjects (AFPT: 51.0 s vs. 32.8 s,p < 0.05; CRT: 1.66 s vs. 0.98 s,p < 0.05; strength: 223N vs. 271N, t = 2.35, p = 0.02). Group 1 had significantly slower AFPT (66.0 s vs. 44.8 s, t = 4.15, p < 0.05) and CRT (2.37 s vs. 0.98 s, t = 3.59, p < 0.05) than groups 2 and 3. Group 1 had the greatest degree of postural sway and the weakest quadriceps strength, although this did not reach significance. Multivariate analysis revealed 25OHD as an independent variable for AFPT, CRT, and postural sway. PTH was an independent variable for muscle strength. Older people who fall have impaired functional performance, psychomotor function, and muscle strength. Within this group, those with 25OHD < 12 microg/liter are the most significantly affected.

The effects of age on the response to caffeine.

Twelve healthy subjects, six young and six elderly, of either sex, took part in this two-period crossover study. In each session, a dose of trial drug--either 200 mg caffeine or a matching placebo--was given orally at 0900 hours. A battery of psychomotor tests and visual analogue scales was administered before treatment and at 1, 2 and 3 h post-treatment. The objective tests showed a significant increase in tapping rate in the young, while the elderly showed improved attention, faster choice-reaction time, and greater body sway on caffeine. The visual analogue scales showed that the young subjects felt more alert, calmer, more interested, and steadier on caffeine, while no significant changes were seen in the elderly. These results show that caffeine produces changes predominantly in the direction of improved performance and feeling of well-being, and suggest that the elderly are more sensitive to the objective effects of the drug, while reporting less subjective effect than the young.

"First-dose" response to mianserin: effects of age.

The effects of single 10 mg oral doses of the antidepressant mianserin on psychomotor performance, subjective sedation and supine and standing blood pressure were compared in ten young and nine elderly healthy volunteers. Immediate and residual sedation following this subtherapeutic dose was readily detected in both groups. In contrast to previous studies with benzodiazepines, the sedation effect was not accentuated in the older subjects. Subjective awareness of sedation was significant in the young but not, however, in the elderly. "First-dose" postural hypotension, presumably due to post-synaptic alpha-blockade also occurred in young subjects only. Caution may be needed on initial dosage of mianserin in young individuals who drive or undertake skilled tasks and in the elderly who may be unaware of psychomotor impairment. The reported alpha 2 receptor selectivity of mianserin might explain the lack of postural effects in the elderly, and might constitute a potentially useful characteristic in the development of new compounds.

Functional magnetic resonance imaging of odor identification: the effect of aging.

BACKGROUND: Sense of smell declines with age and impairment in olfaction has been observed in some neurodegenerative disorders such as Alzheimer's disease. Functional neuroimaging techniques enable researchers to observe brain regions activated by olfactory stimuli. METHODS: We gave three mainly olfactory-mediated odors (limonene, methylsalicylate, and eugenol) to six young and six elderly subjects and observed the areas activated by using blood oxygen level dependent contrast functional magnetic resonance imaging. RESULTS: The group mapping of young subjects showed extensive activation in the orbitofrontal cortex, commonly believed to be the olfactory cortex, some limbic areas (the hippocampus and the thalamus), regions involved with gustatory sensation (the anterior insula and the inferior postcentral gyrus), superior and inferior temporal gyri, and cerebellum. In the elderly group, only the left inferior temporal gyrus and the primary visual cortex reached accepted significance levels. CONCLUSIONS: We have therefore confirmed previous reports of brain regions involved in olfactory processing in young volunteers and demonstrated decreased activation in elderly volunteers.

Psychomotor performance in elderly hypertensive patients.

The psychomotor performance of 25 elderly patients with mild to moderate hypertension (aged 62-78 years, SBP = 162-212 mmHg; DBP = 98-124 mmHg) was compared with 25 age-matched controls (SBP = 110-160 mmHg; DBP = 64-92 mmHg). The hypertensive subjects did not have evidence of target-organ damage and were on no antihypertensive treatment at the time of assessment. Performance on a range of tests: symbol/digit substitution test (SDST) (34.3 vs. 39.5, P < 0.01), continuous attention test (CAT) (33 vs. 36.2, P < 0.01), choice reaction time (CRT) (270 ms vs. 320 ms, P < 0.01), paired word association test (PWAT) (4.1 vs. 7.0, P < 0.001) and inspection time threshold (INSP) (158 ms vs. 52 ms, P < 0.001), showed significant impairment in the hypertensive group compared with controls. These differences did not correlate with the duration of hypertension or degree of BP elevation. The impairment in hypertensive subjects was stable over a four week period. These results suggest the occurrence of a functional and possibly reversible impairment of psychomotor performance in elderly hypertensive patients which may have implications for antihypertensive treatment.

Effect of antihypertensive treatment on psychomotor performance in the elderly.

The psychomotor effects of control of hypertension were studied in a parallel group comparison of 25 elderly hypertensives (aged 61-79 years; SBP = 192 (range 162-212) mmHg; DBP = 112 (range 98-124) mmHg) shown to have psychomotor impairment when not on antihypertensive treatment. Single blind treatment was commenced with placebo or a diuretic: atenolol, nifedipine or captopril (5 x n = 5). A range of tests using an automated psychomotor test battery showed a significant improvement compared with placebo in tests of attention and psychomotor speed in subjects rendered normotensive (n = 18) after treatment for one week (SDST + 3.8, P < 0.001; CAT + 1.2, P < 0.03; PWAT + 1.9, P < 0.004; INSP -49.5 ms, P < 0.001). Subgroup analysis suggested greater improvement in psychomotor performance with captopril, but this was equivocal because of the small sample size in each group. Hence, the psychomotor effects of treatment with nifedipine and captopril were compared in a further 13 hypertensives (aged 62-76 years; SBP = 178 (range 169-193) mmHg; DBP = 106 (range 97-117) mmHg) in a double-blind crossover study. With both drugs, control of hypertension was associated with a significant and comparable improvement in several psychomotor performance measures. The results suggest that impaired psychomotor performance due to hypertension improves with antihypertensive treatment. The improvement appears to be related to control of hypertension rather than to the direct CNS effects of antihypertensive drugs.

Hawksley random zero sphygmomanometer versus the standard sphygmomanometer: an investigation of mechanisms.

There has been recent controversy over the accuracy of the Hawksley random zero sphygmomanometer (RZS). In most instances, there has been a bias towards lower recordings with the RZS. In an attempt to identify the mechanism, we designed a study to test the hypothesis that biased error is due to: (1) the magnitude of the random zero; and (2) the magnitude of the pressure being recorded. A RZS (60 mm Hg zero UK version) was connected via a Y-tube to a standard mercury sphygmomanometer (SMS). The circumference of the cam responsible for the variable reservoir size in the RZS was marked into quarters. Within each 10 mm Hg band from 300 to 60 mm Hg, 12 paired readings were taken randomly: three within each of the four quarters of the cam circumference. The mean SMS value was 148.8 vs. 148.2 mm Hg for the RZS. Although of minimal biological significance this difference was highly significant (t = 6.2; p < 0.0001). Our findings fail to confirm the difference between RZS and SMS previously reported and we did not find any evidence of a relation in the difference between SMS and RZS and either the random zero value or the height of the blood pressure. Our findings suggest that if the RZS does under record BP versus the SMS it may relate to a patient-machine interaction not detectable in our system.

Investigation of ambulatory blood pressure monitoring data editing criteria.

Ambulatory blood pressure monitoring (ABPM) allows multiple measurements of BP over a 24h period but often produces a proportion of measurements which are distant from the mean and unlikely to be genuine. The software which accompanies the SpaceLabs 90207 monitor requires criteria to be set which excludes outliers (autoediting) but there is no published data evaluating at what levels these autoediting criteria should be set. This study set out to ascertain whether outlying BP measurements represent true blood pressures or machine error, the determinants of machine error and appropriate autoedit criteria. Twenty subjects, both normotensive and hypertensive, were studied by ABPM with a blinded observer recording BP using a standard mercury sphygmomanometer (SMS) connected via a T-tube during three activity phases: sitting with cuffed arm still, walking but keeping arm still during measurement and sitting but gently moving the arm during measurement. The results show that a high ABPM/SMS discrepancy is associated with arm movement. After studying different autoediting criteria which aimed to eliminate the maximum number of conflicting readings while excluding the minimum number of unconflicting readings, an autoediting threshold of between 1.75 and 2 s.d.s from the mean based separately on sleep and awake measurements is suggested.

Effects of caffeine on vigilance and other performance tests in normal subjects.

In two randomized double-blind crossover studies, 8 and 10 healthy volunteers took either 200 mg caffeine or placebo. Objective and subjective measures of caffeine effects were carried out over the following 1-3.5 h. Auditory vigilance, a test lasting 1 h, showed significantly better performance on caffeine than on placebo. In the second study, this effect was only apparent in the second half of the test. Of the shorter objective tests used, only finger tapping showed a significant effect of caffeine, the rate of tapping over 1 min being increased. The subjective assessments showed increased interest and alertness in the caffeine session. Reliable detection of the effects of mild stimulant drugs using objective measures may require the use of tests of long duration.

Single dose pharmacodynamics of thioridazine and remoxipride in healthy younger and older volunteers.

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 (O: six males and eight females, aged 65-77 years) took part in a randomized double-blind three-period crossover study in which they received by mouth single doses of thioridazine (Y: 50 mg; O: 25 mg) remoxipride (Y: 100 mg; O: 50 mg) 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 9 h 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 made for dose, there was little indication of any difference in degree of CNS depression between the two age groups. Haemodynamic measures showed orthostatic reductions in blood pressure with thioridazine which were particularly marked in the older group, who also showed lower compensatory increases in pulse rate. These results indicate potential problems with orthostatic hypotension with thioridazine in older patients. CNS depression may also be a problem, especially in patients with compromised cholinergic function.

Comparative assessment of enprofylline and theophylline for chronic obstructive airways disease in the elderly.

Enprofylline, a recently developed xanthine derivative, is a more potent bronchodilator than theophylline. This study compares the efficacy and safety of enprofylline with theophylline for chronic obstructive airways disease (COAD) in elderly subjects. The study was of a randomized double-blind parallel design and commenced with a 1-week reference period when oral bronchodilators were withdrawn. Patients were then treated with either enprofylline or theophylline 150 mg bd for 2 weeks (period 1) followed by 300 mg bd for a further 3 weeks (period 2). Patients recorded peak expiratory flow rate (PEFR) and adverse experiences, if any, in a diary, daily. Of 111 patients recruited for the study, 85 entered active treatment (theophylline, n = 44; enprofylline, n = 41). Mean age was 72 years and mean bronchodilator reversibility was 22%. Enprofylline increased mean morning PEFR by 11% (period 1) and 19% (period 2) whereas theophylline increased PEFR by 13% and 19%, respectively. From the enprofylline group 29% were withdrawn from the study due mainly to headache and nausea/vomiting and from the theophylline group 7% were withdrawn due mainly to nausea/vomiting. Mean plasma concentrations of enprofylline were 2.0 mg l-1 and 3.4 mg l-1, and with theophylline 5.4 mg l-1 and 10.0 mg l-1 at the end of periods 1 and 2, respectively. Enprofylline and theophylline produced similar improvements in lung functions and symptoms of chronic obstructive airways disease, but enprofylline was less well tolerated than theophylline.

Predictors of falls in a high risk population: results from the prevention of falls in the elderly trial (PROFET).

OBJECTIVES: The prevention of falls in the elderly trial (PROFET) provides evidence of the benefits of structured interdisciplinary assessment of older people presenting to the accident and emergency department with a fall. However, the service implications of implementing this effective intervention are significant. This study therefore examined risk factors from PROFET and used these to devise a practical approach to streamlining referrals from accident and emergency departments to specialist falls services. METHODS: Logistic regression analysis was used in the control group to identify patients with an increased risk of falling in the absence of any intervention. The derived predictors were investigated to see whether they also predicted loss to follow up. A second regression analysis was undertaken to test for interaction with intervention. RESULTS: Significant positive predictors of further falls were; history of falls in the previous year (OR 1.5 (95%CI 1.1 to 1.9)), falling indoors (OR 2.4 (95%CI 1.1 to 5.2)), and inability to get up after a fall (OR 5.5 (95%CI 2.3 to 13.0)). Negative predictors were moderate alcohol consumption (OR 0.55 (95%CI 0.28 to 1.1)), a reduced abbreviated mental test score (OR 0.7 (95%CI 0.53 to 0.93)), and admission to hospital as a result of the fall (OR 0.26 (95%CI 0.11 to 0.61)). A history of falls (OR 1.2 (95%CI 1.0 to 1.3)), falling indoors (OR 3.2 (95%CI 1.5 to 6.6)) and a reduced abbreviated mental test score (OR 1.3 (95%CI 1.0 to 1.6)) were found to predict loss to follow up. CONCLUSIONS: The study has focused on a readily identifiable high risk group of people presenting at a key interface between the primary and secondary health care sectors. Analysis of derived predictors offers a practical risk based approach to streamlining referrals that is consistent with an attainable level of service commitment.

Pharmacokinetics and prescribing in the elderly.

The use of prescribed medication in general is higher in the elderly than in the young and it is possible that existing patterns of antimicrobial agent prescribing may predispose to suboptimal response, certain adverse drug reactions (ADR) and the emergence of resistant strains of organisms. Age is an important variable affecting the pharmacokinetics of drugs, including many antimicrobials. Changes which may affect Cmax/MIC ratios and/or the time above MIC include reduced first-pass metabolism, altered distribution volume, reduced binding to albumin, reduced metabolic biotransformation and reduced renal elimination. Application of a knowledge of antimicrobial agent pharmacokinetic changes with age and their implications for response may enable more precise determination of dose regimens for older patients, which is probably desirable for the prevention of both ADR and bacterial resistance.