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Biomedical subjects

H L Elliott

Publications and source records attributed to H L Elliott.

At least 37 records · Page 2Linked to original sources
PubMed1998

How reproducible is bilateral forearm plethysmography?

AIMS: In studies using strain-gauge forearm plethysmography to measure changes in forearm blood flow (FBF) during intra-arterial infusions of vasoactive substances, measurements are often made in both arms simultaneously and the change in ratio of the infused and control arms used to express responses. However, the reproducibility of bilateral plethysmography in this setting has not been addressed in published studies. The unilateral technique remains in use, and forearm vascular resistance (FVR), an alternative method of expressing responses, is used by some investigators. We have assessed: (a) the intra-subject variability of bilateral FBF measurements (FBF ratios) at rest, after unilateral forearm exercise, and during intra-arterial infusions of vasoconstrictor substances; (b) whether bilateral plethysmography is more reproducible than unilateral plethysmography; and (c) the reproducibility of FVR (unilateral and bilateral). METHODS: Study 1 Nine healthy subjects attended 3 study days, 1 week apart. FBF was measured at rest and after 2 min of standardized unilateral forearm exercise; between-day intra-subject variability was expressed as coefficients of variation (CV) calculated using two-way analysis of variance (ANOVA). Study 2 Five healthy subjects attended 2 study days when FBF was measured during incremental infusions of noradrenaline (15, 30, 150, 300 pmol min[-1]) and angiotensin II (1, 5, 10, 50 pmol min[-1]); for each individual subject at each dose intra-subject variability was assessed using the difference between responses (percentage change from baseline) on days 1 and 2. RESULTS: Study 1 At rest, intra-subject variability (CV) of baseline FBF ratios was 19% compared with 31% (left) and 39% (right) for unilateral FBF measurements. After ipsilateral exercise, unilateral FBF measurements were more reproducible (32 vs 17%) than FBF ratios; by 20 min after exercise, the previous pattern had been re-established (19 vs 27%). Intra-subject variability (CV) of baseline FVR ratio and post-exercise FVR was 14%. Study 2 Inter-quartile ranges of the differences between responses on days 1 and 2 (FBF ratios vs FBF) were: angiotensin II 14 vs 18%; noradrenaline 16 vs 27%. CONCLUSIONS: FBF ratios are more reproducible than unilateral FBF measurements at rest (CV 19% vs 39%) and for measuring responses to intra-arterial infusions of vasoconstrictor substances. FVR may have a small reproducibility advantage. Non-experimental stimuli can cause significant and misleading changes in measured responses if unilateral measurements are used; it is therefore recommended that responses to intra-arterial infusions should be measured using bilateral forearm plethysmography with the results expressed as FBF ratios.

Angiotensin II↗
PubMed1998

Lacidipine: effects on vascular pressor responses throughout the dosage interval in normotensive subjects.

AIMS: To assess the duration and consistency of the pharmacological activity of the dihydropyridine calcium antagonist drug, lacidipine. METHODS: Eight healthy normotensive young males participated in a double-blind randomised crossover comparison of single and multiple doses (for 2 weeks) of lacidipine and placebo. The calcium antagonist effects were quantified at 2, 6 and 24 h post dose by the extent of the attenuation of the pressor responses to the intravenous administration of the vasoconstrictors angiotensin II and noradrenaline. RESULTS: After 2 weeks of treatment, lacidipine consistently and significantly attenuated the pressor responses to both agents at 2 h post dose. At 6 and 24 h post dose there was a significant and progressive decline in the effectiveness of lacidipine in attenuating the pressor responses and for the response to angiotensin II there was no statistically significant effect at either 6 or 24 h post dose. CONCLUSIONS: These results indicate that there is an obvious 'peak' in the pharmacological activity of lacidipine at about 2 h post dose and that this activity is not fully and consistently maintained throughout 24 h.

Adult↗
PubMed1998

Population pharmacokinetics of gentamicin in patients with cancer.

AIMS: The purpose of this study was to describe the population pharmacokinetics of gentamicin in patients with cancer, to identify possible relationships between clinical covariates and population pharmacokinetic parameter estimates and to examine the relevance of existing dosage nomograms in light of the population model developed in these patients. METHODS: Data were collected prospectively from 210 patients with cancer and were analysed with package NONMEM. Data were split into two sets: a population data set and an evaluation set. Creatinine clearance was estimated using measured creatinine concentrations and using 'low' creatinines set to a minimum of 60 micromol l(-1), 70 micromol l(-1) or 88.4 micromol l(-1) RESULTS: A two compartment model was fitted to the concentration-time curve. Two best models were obtained, one that related clearance to estimated creatinine clearance (minimum creatinine value 60 micromol l(-1)) and the other that related clearance to age, creatinine concentration and body surface area. Volume of the central compartment was influenced by body surface area and albumin concentration. For both models 90% of measured concentrations lay within the 95% confidence interval of the simulated concentrations and the mean prediction errors were -7.2% and -6.6%, respectively. A final analysis performed in all patients identified the following relationship CL (1 h(-1))=0.88 x (1 + 0.043 x creatinine clearance) and central volume of distribution V1 (1)=8.59 x body surface area x (albumin/34)(-0.39). The mean population estimate of intercompartmental clearance (Q) was 1.301 h(-1) and peripheral volume of distribution (V2) was 9.801. Coefficient of variation was 18.5% on clearance and 28.2% on Q. Residual error expressed as a standard deviation was 0.36 mg l(-1) at 1.0 mg l(-1) and 1.32 mg l(-1) at 8.0 mg l(-1). The mean population estimate of clearance was 4.21 h(-1) and volume of distribution (Vss) was 24.61 (0.381 kg(-1)). The mean population estimates of half-lives were 1.8 h and 8.0 h. CONCLUSIONS: In the context of published nomograms this analysis indicated that both the traditional approach and the new, 'once daily' approach should achieve satisfactory concentrations in cancer patients although serum concentration monitoring is required to confirm optimal dosing in individual patients.

Adolescent↗
PubMed1998

Moxonidine: pharmacology, clinical pharmacology and clinical profile.

Management strategies in hypertension evolve in response to an increased understanding of underlying pathophysiological processes and developments and refinements in drug treatments. Recent research has identified the regulatory role of the imidazoline (I1) receptor in sympathetic outflow and blood pressure regulation and this has led to the development of moxonidine, a highly selective centrally acting antihypertensive agent. At a practical level, moxonidine is suitable for single daily dosing in hypertension. Furthermore, in comparative studies moxonidine has a low incidence of symptomatic adverse effects comparable, for example, to that of the ACE inhibitor drugs, captopril and enalapril. The antihypertensive efficacy of moxonidine has now been established in a series of comparative clinical trials against all other first-line antihypertensive drug classes but, in line with current concepts, it may be necessary to look beyond blood pressure reduction. For example, centrally acting agents are known to be effective for promoting the regression of LV hypertrophy and studies in hypertensive patients have shown that antihypertensive treatment with moxonidine successfully leads to significant reductions in LV mass indices. Furthermore, there is now evidence that moxonidine has a beneficial effect on insulin sensitivity such that there are likely to be improvements in the overall metabolic profile. Thus, the clinical characteristics of moxonidine indicate that it is well suited for consideration among the first-line antihypertensive treatment choices.

Antihypertensive Agents↗
PubMed1998

Renal and haemodynamic effects of amlodipine and nifedipine in hypertensive renal transplant recipients.

BACKGROUND: Immunosuppressive treatment with cyclosporin A (CsA) improves the survival of renal allografts, but is associated with renal vasoconstriction and hypertension. Previous reports suggest that the calcium-channel blockers nifedipine and amlodipine may improve graft function in CsA-treated patients. We have compared the effects of amlodipine (5-10 mg once daily) and nifedipine retard (10-40 mg twice daily) on renal function and blood pressure in renal transplant recipients treated with CsA. METHODS: This was a multicentre, two-way, crossover study in 27 evaluable hypertensive patients with renal insufficiency following renal transplantation, who were maintained on a stable dose of CsA. Patients received either amlodipine (5-10 mg once daily) or nifedipine retard (10-40 mg twice daily) for 8 weeks, and were then crossed over to the other treatment for a further 8 weeks. RESULTS: Trends were seen during amlodipine treatment towards larger improvements, in serum creatinine (by 8% of baseline on amlodipine vs 4% on nifedipine), lithium clearance (13% vs 2%), and glomerular filtration rate 11% vs 7%). Effective renal plasma flow was increased by 11% of baseline on nifedipine vs 9% on amlodipine. There were no significant differences between treatments. Amlodipine and nifedipine lowered systolic blood pressure to a similar extent (21 mmHg vs 15 mmHg respectively, P=0.25), but amlodipine was more effective than nifedipine in lowering diastolic blood pressure (13 mmHg vs 8 mmHg, P=0.006). Both treatments were well tolerated. CONCLUSION: Once-daily amlodipine is at least as effective as twice-daily nifedipine retard in controlling blood pressure and does not adversely affect graft function in hypertensive renal allograft recipients.

Adolescent↗
PubMed1998

Dietary sodium restriction impairs insulin sensitivity in noninsulin-dependent diabetes mellitus.

Dietary sodium restriction has a variety of effects on metabolism, including activation of the renin-angiotensin system. Angiotensin II has complex metabolic and cardiovascular effects, and these may be relevant to the effects of both nonpharmacological and pharmacological interventions in noninsulin-dependent diabetes mellitus (NIDDM). We have assessed the effect of dietary sodium restriction on insulin sensitivity and endogenous glucose production in eight normotensive patients with diet-controlled NIDDM who underwent hyperinsulinemic clamp studies in a randomized, double-blind, placebo-controlled cross-over protocol after two 4-day periods on sodium replete (160 mmol/day) and sodium deplete (40 mmol/day) diets. Mean +/- SD 24-h urinary sodium was 197 +/- 76.0 mmol (replete) and 67 +/- 19.5 mmol (deplete), P = 0.03. Insulin sensitivity was 42.0 +/- 11.3 mumol/kg.min (replete) and 37.0 +/- 11.6 mumol/kg.min (deplete), P = 0.04 (a reduction of 12%). Blood pressure was 130 +/- 21/78 +/- 11 mmHg (replete) and 128 +/- 12/73 +/- 10 mmHg (deplete). Dietary sodium restriction may result in a decrease in peripheral insulin sensitivity in normotensive patients with NIDDM, possibly via an elevation in prevailing angiotensin II concentrations.

Aged↗
PubMed1998

The vasodilating effect of insulin is dependent on local glucose uptake: a double blind, placebo-controlled study.

During systemic hyperinsulinemia in man, skeletal muscle vasodilation has consistently been demonstrated. However, most studies that have examined the vascular effect of local hyperinsulinemia have reported either no effect or only weak vasodilation, and all of these have been open in design. The present studies were designed in a double blind, placebo-controlled manner to evaluate the direct (local) vascular effect of insulin alone and in association with physiological concentrations of D-glucose. Forearm blood flow was measured in 17 healthy male volunteers by bilateral venous occlusion forearm plethysmography. Brachial artery infusions of 1 mU/min insulin, 5 mU/min insulin, or vehicle were administered for 90 min on 3 separate study days in random order. The higher dose of insulin was associated with weak (20%) vasodilation compared with placebo (F = 5.75 and P < 0.01, by ANOVA). When this protocol was repeated with intraarterial coinfusion of D-glucose, significant augmentation of the vascular effect was demonstrated (47% vasodilation). No augmentation of insulin-mediated vasodilation was observed with coinfusion of L-glucose, the metabolically inactive stereoisomer. These data suggest that local uptake of D-glucose by insulin-sensitive tissues is an important determinant of insulin-mediated vasodilation.

Adult↗
PubMed1998

Endothelial dysfunction in cardiovascular disease: risk factor, risk marker, or surrogate end point?

Endothelial dysfunction is a feature of the early stages of atherosclerotic cardiovascular disease. It also is almost invariably associated with recognized cardiovascular risk factors, including those that are irreversible (such as age and family history) and those that are reversible (such as hypertension and hypercholesterolemia). It remains the subject of debate whether endothelial dysfunction can be considered an independent risk factor or, perhaps more plausibly, an intermediate or surrogate end point. However, although the relevance to research into cardiovascular pathophysiology is not in dispute, there remains uncertainty about its relevance as a therapeutic target. Overall, the available evidence suggests that targeting of the conventional major risk factors remains the primary strategy, but an ancillary effect on intermediate end points, such as an improvement or reversal of endothelial dysfunction, constitutes an additional potential benefit.

Biomarkers↗
PubMed1997

The euglycaemic hyperinsulinaemic clamp: an evaluation of current methodology.

1. The recognition of the role of insulin resistance in disease states and the recent development of new drugs that modify insulin-dependent metabolism has led to increased use of the euglycaemic hyperinsulinaemic clamp to measure in vivo insulin sensitivity, but several key aspects of the technique are poorly documented in the literature. 2. We have evaluated the reproducibility and intersubject variation of measurements of insulin sensitivity in groups of insulin-sensitive and insulin-resistant subjects and assessed the effects of hand warning on haemodynamic and metabolic responses. 3. Subjects participated in one of two protocols: (i) 18 healthy male volunteers and 18 patients with hypertension and glucose intolerance were clamped on two occasions, 1 week apart with measurements of insulin sensitivity (M) derived after 120 and 180 min of hyperinsulinaemia; and (ii) six healthy volunteers were clamped on one occasion with simultaneous sampling of antecubital and 'arterialized' (dorsal hand) venous blood for comparison of plasma glucose concentrations and oxygen saturation and a further six volunteers were clamped on two occasions with and without the use of hand warming. 4. Measurements of M derived after 120 min (M120) and 180 min (M180) of hyperinsulinaemia were reproducible: the coefficients of repeatability (mg/kg per min) of M120 and M180 were 1.0 and 0.9 for volunteers and 1.0 and 1.0 for the patient group, respectively. The intersubject variation in insulin stimulus was high: coefficients of variation for M180 were 22% for volunteers compared with 38% for the patient group. In volunteers compared with the patient group, hand warming significantly increased venous oxygen saturations (95 +/- 2 vs 79 +/- 18%, respectively) and glucose concentrations (5.2 +/- 0.2 vs 4.5 +/- 0.4 mmol/L, respectively) and measurements of M were significantly higher using arterialized compared with antecubital venous blood. However, local hand warming was associated with systemic vasodilatation: blood pressure decreased (e.g. 6 mmHg diastolic; P < 0.05) with a compensatory increase in heart rate (8 b.p.m.). 5. In conclusion, clamps of 120 and 180 min duration yielded measurements of M that were reproducible. The technique is much more robust when used in the context of a crossover design because of the significant (20-40%) intersubject variation in M, even among apparently homogeneous male volunteers. Hand warming effectively arterializes venous blood and gives significantly higher M values, but induces systemic vasodilation, which may confound measurements of M.

Adult↗
PubMed1997

Clinical pharmacokinetics of nifedipine. Implications for the care of the elderly.

Nifedipine, the prototype for the dihydropyridine class of calcium antagonists, has been available for 20 years and its efficacy as a vasodilator and an antihypertensive agent is well recognised. The development of the so-called nifedipine gastrointestinal therapeutic system (GITS), which allows once-daily administration, has modified and improved the overall therapeutic profile of nifedipine to such a significant extent that it might almost be considered a new drug entity. The nifedipine GITS is associated with distinct improvements in terms of patient compliance and convenience, and a reduced incidence of adverse effects. With regard to the care of the elderly, this 'new' drug offers the prospect of a well tolerated and effective treatment without major cost implications.

Aged↗
PubMed1997

Evaluation of endpoints in hypertension: blood pressure.

The benefits of antihypertensive therapy in reducing both cerebrovascular and cardiac events have been clearly demonstrated in the meta-analysis of randomised outcome trials. Whilst the use of diuretics and beta-blockers have tended to predominate in these trials, other agents were also included and thus it is reasonable to suggest that the benefit of treatment is not attributable to any particular class of agent but rather to a reduction in blood pressure per se. It may therefore, be reasonably argued that blood pressure itself is the only validated surrogate marker of cardiovascular outcome. In routine clinical practice evaluation has indicated that in treated hypertensives not only is blood pressure not lowered to normotensive levels but also that control of pressure was not consistent over a 24 hour period. Finally epidemiological evidence suggests that blood pressure control should be based upon treatment strategies that lower blood pressure to normotensive levels in a smooth and consistent fashion.

Antihypertensive Agents↗
PubMed1996

White-coat hypertension as a cause of cardiovascular dysfunction.

BACKGROUND: The increasing use of 24 h ambulatory blood pressure monitoring has allowed diagnosis of white-coat hypertension, in which blood pressures are higher on clinic measurements than on ambulatory monitoring. Treatment is not generally thought to be necessary for this disorder. However, there is evidence that patients with white-coat hypertension develop renal impairment and left ventricular hypertrophy. We undertook this study to assess whether white-coat hypertension, in the absence of cardiovascular structural abnormalities, is associated with cardiovascular functional abnormalities. METHODS: Cardiovascular function was assessed by ultrasonography in three groups of patients classified as normotensive, persistently hypertensive, or white-coat hypertensive (23, 20, and 22 patients, respectively) on the basis of ambulatory blood pressure monitoring, carried out for 28 h with recordings taken every 15 min during the day and every 20 min during the night, and clinic measurements, made with a semi-automatic oscillometric device. RESULTS: Similar abnormalities of diastolic left ventricular function were identified in the patients with persistent hypertension and those with white-coat hypertension; both groups differed in these indices from the normotensive group (E/A ratios 0.94 [SD 0.23], 1.06 [0.21], and 1.24 [0.31] respectively; ANOVA p < 0.005). In addition, the white-coat and persistently hypertensive groups, when compared with the normotensive group, showed similar abnormalities of elasticity, compliance, and stiffness (stiffness index 4.32 [1.90], 4.53 [1.38], and 3.27 [0.95] respectively; ANOVA p < 0.05) of the large arteries. INTERPRETATION: Functional cardiovascular abnormalities were identified in white-coat hypertensive patients who had no identifiable structural abnormalities. Such functional abnormalities can be reversed by antihypertensive treatment. We propose that patients with white-coat hypertension might benefit from antihypertensive treatment as well as those with persistent hypertension. This hypothesis should be addressed in prospective clinical trials.

Aged↗
PubMed1996

Endothelial nitric oxide production and insulin sensitivity. A physiological link with implications for pathogenesis of cardiovascular disease.

BACKGROUND: Insulin sensitivity varies up to threefold in apparently healthy individuals, but the mechanism for this is unknown. We have examined the hypothesis that vascular endothelial nitric oxide production and insulin sensitivity are directly related in humans. METHODS AND RESULTS: Nineteen healthy male subjects were studied on 3 separate days 1 week apart during which time they underwent measurement of insulin sensitivity by the euglycemic hyperinsulinemic clamp technique (soluble insulin 1.5 mU . kg-1 . min-1) and measurement of in vivo basal and stimulated endothelial nitric oxide production by forearm venous occlusion plethysmography. There was a correlation between insulin sensitivity and forearm vasoconstrictor responses to NG-monomethyl-L-arginine, the substrate inhibitor of nitric oxide synthase (r = .52, P < .05). No correlations were observed between insulin sensitivity and noradrenaline, acetylcholine, or sodium nitroprusside responses. CONCLUSIONS: Endothelial nitric oxide synthesis and insulin sensitivity are positively related in healthy humans, which suggests a direct physiological link.

Acetylcholine↗
PubMed1996

Concentration-effect relationships and implications for trough-to-peak ratio.

The guidelines on trough-to-peak ratio identified an index of the duration of action of an antihypertensive drug (relative to its dosage interval) to prevent the use of inappropriately large doses of drug simply to extend the apparent duration of action. In some instances, however, trough-to-peak ratio may be dose-dependent and this analysis examines the contribution that the underlying concentration-antihypertensive effect relationship makes to the dose dependency of trough-to-peak ratio. Where this concentration-effect relationship is essentially linear the trough-to-peak ratio is almost invariably dose-independent. In contrast, where the relationship is identified as being of a sigmoid-Emax type the trough-to-peak ratio is likely to be dose-dependent. The nature of the concentration-effect relationship also influences the duration of action beyond the dosage interval whereby "linear" drugs are superior to "Emax" drugs by virtue of the greater persistence of the antihypertensive effect.

Antihypertensive Agents↗
PubMed1996

Calculation of trough-to-peak ratio in the research unit setting. Advantages and disadvantages.

The trough-to-peak ratio for the response to an antihypertensive drug is a clinically meaningful parameter but only when the calculation has been derived from an appropriate and scientifically robust study. Since the methodological details have not been defined by any regulatory authority, several possible approaches have developed. The major apparent advantages of the intensive study of individual patients in the research unit setting are that the conditions of measurement can be standardized and an accurate account can be taken of the circadian variations in the responses to placebo and active drug treatment. The principal disadvantage is that it is an "artificial" environment that may, or may not, be directly relevant to routine clinical circumstances. Nevertheless, the values obtained with this approach to date are directly comparable to values obtained by the alternative approaches, such as ambulatory blood pressure measurements (provided that those are also well-conducted studies). Thus, using the trough-to-peak ratio not only appears valid but also permits the detailed study of individual patients and also lends itself to the incorporation of additional and confirmatory clinical pharmacological assessments.

Antihypertensive Agents↗
PubMed1996

Potential confounding effect of hand-warming on the measurement of insulin sensitivity.

1. Hand-warming is employed during metabolic studies to "arterialize' venous blood, but also has systemic haemodynamic effects. Study 1 aimed to determine if hand-warming affects the value for whole-body insulin sensitivity derived from the hyperinsulinaemic euglycaemic clamp technique. Study 2 was designed to assess the effect of hand-warming on contralateral forearm blood flow. 2. In study 1, eight healthy male subjects attended for four modified euglycaemic clamp studies, during which the right hand was placed in a heated-air hand box (55 degrees C), and the glucose infusion rate was adjusted according to blood samples from a cannula in either an ipsilateral dorsal hand vein or a contralateral antecubital vein with the box switched either on or off. In study 2, five healthy subjects attended two study days when the effect of 2 h of hand-warming (or control) on contralateral forewarm blood flow was measured. 3. Study 1; when clamps were performed according to samples taken from the contralateral antecubital vein, insulin sensitivity values were significantly lower during box-on versus box-off clamps (mean +/- SD 10.2 +/- 3.0 versus 13.0 +/- 3.8 mg min-1 kg-1, P < 0.05, 95% confidence interval -0.2, -5.3). When clamps were performed according to samples taken from the ipsilateral hand, there was no difference in insulin sensitivity during box-on versus box-off clamps (9.2 +/- 2.1 versus 9.0 +/- 1.7 mg min-1 kg-1, P not significant, 95% confidence interval -0.5, +0.9). There was a mean increase in heart rate of 6 beats/min in the box-on conditions (P < 0.05, analysis of variance). Study 2; forearm blood flow in the contralateral arm during hand-warming was significantly higher than in the control condition (P < 0.05, analysis of variance), although heart rate was similar on both study days. 4. Hand-warming had a detectable effect on insulin sensitivity when clamps were performed according to samples withdrawn from the contralateral arm, but no measurable effect when clamps were performed in the conventional manner. In addition, hand-warming increased heart rate during hyperinsulinaemia and contralateral FBF under basal conditions. These findings raise concern about unwanted (potentially confounding) systemic haemodynamic effects of hand-warming on the measurement of insulin sensitivity and insulin-mediated vasodilation.

Blood Glucose↗
PubMed1996

Benefits of twenty-four-hour blood pressure control.

BACKGROUND: Despite the clear recognition that blood pressure does not remain at the same level over a 24-h period, normally falling during sleep and rising during times of physical or mental activity, a single blood pressure measurement gained during the working day is conventionally used to classify a patient as normotensive or hypertensive. ANTIHYPERTENSIVE TREATMENT AND 24-H BLOOD PRESSURE CONTROL: There is still no definitive proof that antihypertensive drugs providing full 24-h blood pressure control will lead to improved outcomes compared with drugs that provide incomplete 24-h blood pressure control. However, there is a large body of evidence showing that cardiovascular target-organ damage is correlated with 24-h blood pressure measurements and supportive evidence that a fall in these 24-h measurements can predict a likely reduction in cardiovascular target-organ damage. CONCLUSIONS: In deciding which antihypertensive agent to use, physicians should select, where possible, those agents that provide blood pressure control through the 24-h period.

Blood Pressure↗