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Biomedical subjects

H L Elliott

Publications and source records attributed to H L Elliott.

At least 73 records · Page 4Linked to original sources
PubMed1994

Antihypertensive treatment and trough: peak ratio: general considerations.

AIM: The proposed United States Food and Drug Administration guidelines on the trough: peak ratio were established to define the duration of action of an antihypertensive drug and to prevent the 'apparent' duration of action being extended by inappropriately large doses of drugs. Some studies have indicated that the trough:peak blood pressure response to some antihypertensive drugs is dose-dependent. The aim of the present investigation was to determine the relationship between drug concentration and its effect on the trough:peak ratio, particularly when the antihypertensive effect extends beyond the dose interval. LINEAR VERSUS SIGMOID RELATIONSHIP BETWEEN BLOOD PRESSURE FALL AND DRUG CONCENTRATION: Where the relationship between effect and concentration is linear the effect of the dose on the trough:peak ratio is minimal. In contrast, where the relationship is sigmoid (Hill equation), the value of the trough:peak blood pressure response is dose-dependent. Drugs with linear relationships between concentration and effect are more likely to sustain a useful antihypertensive response beyond the dose interval than sigmoid drugs. Published studies on the response to missed drug doses support this theoretical differentiation in drug type. CONCLUSIONS: We conclude that trough:peak blood pressure responses provide a useful arithmetic index of the duration of action of an antihypertensive drug. The nature of the relationship between concentration and effect determines the influence of the dose on the trough:peak ratio and whether the duration of action is extended beyond the dose interval.

Antihypertensive Agents↗
PubMed1994

Trough: peak ratio and twenty-four-hour blood pressure control.

DEFINITION OF TROUGH: PEAK RATIO: Applied to an antihypertensive drug, the term trough: peak ratio provides an index of how well the antihypertensive effect is sustained over the dose interval. This ratio is usually expressed as a percentage and is determined from the ratio of the blood pressure reduction at trough, i.e. at the end of the dose interval and before the next dose is administered, relative to the blood pressure reduction at the time of the peak drug effect. According to guidelines issued by the United States Food and Drug Administration, 50% is the minimum requirement for an acceptable trough: peak ratio. TIMING OF MEASUREMENT: Unfortunately, the Food and Drug Administration has not produced guidelines describing the methodology, required to define the trough: peak ratio, apart from the requirement that account be taken of placebo effects. However, although the timing of the trough measurement is defined, the response to an antihypertensive drug is influenced by intra- and interindividual variability, and to measure the peak response it is necessary to take multiple blood pressure measurements throughout the dose interval. This will take account not only of diurnal variations in an individual subject's blood pressure but also of interindividual variability in the timing and magnitude of the peak response to treatment. CONCLUSIONS: Assuming it is appropriately measured, the trough: peak ratio is a useful index of the consistency of the antihypertensive response throughout the dose interval and of the optimal dose frequency.

Antihypertensive Agents↗
PubMed1994

Therapeutic coverage: reducing the risks of partial compliance.

It is now apparent that the incidence of inadequate compliance is greater than had previously been recognised. The pattern of poor compliance is generally characterised by underdosing rather than overdosing and will usually involve interruptions in therapy of several days. There are many potentially important consequences of this, but therapeutically the most important is associated with the period without drug action. Establishing, for a range of antihypertensive agents, that there is a clear relationship between the circulating drug concentration and blood pressure-lowering effect it is possible to demonstrate that the pharmacodynamic characteristics of a drug will be well correlated with its pharmacokinetics. Thus, compared with other agents, amlodipine with its relatively smooth concentration-time profile and long elimination half-life will be superior in maintaining blood pressure control both with perfect compliance and when dosage regimens are perturbed due to missed drug doses.

Drug Administration Schedule↗
PubMed1994

Pharmacokinetics of spirapril in renal impairment.

The pharmacokinetics of spirapril and its active diacid metabolite spiraprilat were characterized in four groups of patients categorized on the basis of their renal function. No statistically significant effects of renal impairment upon the disposition of spirapril were detected. In contrast, there were significant perturbations in the pharmacokinetics of spiraprilat: The maximum plasma concentration (Cmax) values in the severely renally impaired group were 2-3 times those in the group of patients with normal renal function whereas the corresponding area under the curve (AUC) values were 5-6 times higher. However, there was no evidence of accumulation of spiraprilat in any of the groups as determined by the pharmacokinetic parameters derived after single and multiple doses. Thus, despite the evidence of a significant influence of renal impairment upon the disposition of spiraprilat, the lack of accumulation during the translation from single to multiple doses indicates that there is a considerable margin of safety for spirapril in renal impairment.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Clinical use of angiotensin-converting enzyme inhibitors in patients with renal impairment.

Angiotensin-converting enzyme (ACE) inhibitors are effective antihypertensive agents in a variety of patient groups, including those with chronic renal disease. In addition to their antihypertensive efficacy, there is recent evidence suggesting that ACE inhibitors may have renoprotective properties, particularly in cases of diabetic nephropathy wherein the glomerular filtration rate may be better preserved by ACE inhibitors than by other antihypertensive drugs. Although the potential benefits of ACE inhibitors are recognized, many physicians are concerned about their possible harmful effects in patients with renal disease as most ACE inhibitors are eliminated by the kidney; there is a perceived risk of progressive drug accumulation leading to toxic effects. Whether or not ACE inhibitors have a unique renoprotective effect remains to be clearly established by further long-term clinical studies. Nevertheless, in patients with hypertension and renal impairment (with the particular exception of renovascular disease), ACE inhibitors have an established efficacy and safety. If there is concern over drug accumulation in patients with impaired renal function, those ACE inhibitors (such as spirapril) with dual routes of elimination would then appear to be the agents of choice.

Aging↗
PubMed1994

Amlodipine--does the effect-time profile directly reflect the concentration-time profile throughout a 24-hour period?

Two studies were undertaken to investigate correlations between the time profile of plasma drug concentration and the time profile of hypotensive activity for the dihydropyridine calcium antagonist, amlodipine. The first study compared the concentration- and effect-time profiles for amlodipine and felodipine ER (extended release), and the second study characterized the concentration-effect relationship in hypertensive patients. The inter- and intra-subject variabilities in the disposition characteristics of amlodipine were less than for felodipine and there was correspondingly less variability in plasma drug concentrations; trough-to-peak ratios were calculated as 67 +/- 8% for amlodipine and 36 +/- 13% for felodipine ER. The characteristics of the plasma-concentration profiles appeared to be reflected in the profiles of hypotensive response such that, although the peak effect with felodipine ER was greater, there was less variability with amlodipine and the trough effect with amlodipine was consistently superior. Examination of the relationship between the plasma concentrations of amlodipine and the antihypertensive effect revealed that, although there was a temporal discrepancy between the two profiles, the two could be correlated using a linear-effect model. Results of this analysis indicated that the kinetic-dynamic model was most appropriately fitted simultaneously to the acute and steady-state data. Thus, the low inter- and intra-subject variabilities in the disposition characteristics of amlodipine are translated into a consistent and smoothly sustained 24-h antihypertensive response.

Aged↗
PubMed1993

Drug safety.

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Amlodipine↗
PubMed1993

Nifedipine GITS.

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Digestive System↗
PubMed1993

The pharmacodynamics and pharmacokinetics of the combination of nifedipine and doxazosin.

In a single-blind study 12 normotensive men took nifedipine 20 mg (Group 1, n = 6) or doxazosin 2 mg (Group 2, n = 6), followed by the combination. Each subject attended on four 9-h study days for evaluation of the effects of single and multiple doses of the monotherapy and the effects of adding single and multiple doses of the second drug. Measurements of BP, HR, plasma drug concentrations, and apparent liver blood flow were recorded. The combination was generally well tolerated. BP was consistently lower with the combination than with either monotherapy: for example, average erect BP was 108/61 (Group 1) and 112/62 mmHg (Group 2) compared with 122/66 and 116/68 during steady-state monotherapy. The introduction of nifedipine in Group 2 was associated with a significant increase in liver blood flow at 1.5 h: 1560 vs 1050 ml.min-1 during monotherapy with doxazosin. There was no significant kinetic interaction. In particular, the steady-state AUC of doxazosin was unaffected by the addition of nifedipine: 257, 307, 301, and 256 ng.ml-1.h for the 4 study days (Group 2).

Adult↗
PubMed1993

A comparative assessment of amlodipine and felodipine ER: pharmacokinetic and pharmacodynamic indices.

This study investigated potential therapeutic differences between Amlodipine 5 mg and Felodipine ER 10 mg in 12 normotensive/borderline hypertensive subjects by comparison of the plasma drug concentration-time profiles and the blood pressure and heart rate responses. There was significantly less trough-to-peak variability in plasma drug concentrations with amlodipine with a ratio of 67%, compared to 37% for felodipine. Correspondingly there was less variability with amlodipine in the blood pressure reductions across the dosage interval. Overall, amlodipine displayed a more consistent hypotensive effect across 24 hours and lower blood pressure values at trough, i.e. 24 hours post-dose.

Aged↗
PubMed1993

Pharmacodynamic modeling of the antihypertensive response to amlodipine.

The distinctive pharmacokinetic characteristics of amlodipine, particularly the long half-life, are presumed to translate directly to a prolonged duration of action, but the concentration-effect relationship for the antihypertensive response has not been clearly established. In this study of 12 patients with essential hypertension, treatment with 5 mg amlodipine once daily has been evaluated with use of an integrated pharmacokinetic-pharmacodynamic model to calculate individual patient responsiveness for the decrease in blood pressure per unit change in drug concentration. Amlodipine concentrations were well correlated with the placebo-corrected reductions in blood pressure in individual patients and responsiveness, for example, for erect systolic blood pressure was -3.1 +/- 0.9 mm Hg/ng/ml. By characterizing the concentration-effect relationships in individual patients, this study has confirmed that the plasma concentration-time profile is an appropriate index of the effect-time profile, as reflected by an antihypertensive response that is sustained throughout 24 hours with relatively little trough-to-peak variability.

Adult↗
PubMed1993

A comparative assessment of the duration of action of amlodipine and nifedipine GITS in normotensive subjects.

1 This study in normotensive subjects compared the duration and consistency of action of amlodipine (5 mg) and nifedipine GITS (60 mg) by assessment of the attenuation of pressor responses to noradrenaline and angiotensin II. 2 Both drugs significantly attenuated pressor responses to both vasoconstrictors at 6 and 24 h post-dose with rightward shifts of up to 2.3-fold in the dose-response curves. 3 There was significantly less pharmacokinetic variability with amlodipine: for example, intra-subject variability was 33% with amlodipine and 59% with nifedipine GITS. 4 There were no significant differences in the pressor dose ratios up to 48 h post-dose with amlodipine whereas there was a significant and progressive reduction in the pressor dose ratios with nifedipine. 5 These results suggest that both drugs are broadly comparable as once daily treatments but amlodipine displayed less intra- and inter-subject variability and provided a significantly more sustained effect with a reserve of pharmacological activity up to 48 h post-dose.

Adult↗
PubMed1993

A clinical pharmacological assessment of doxazosin and enalapril in combination.

This study in 12 normotensive males investigated potential pharmacokinetic and pharmacodynamic interaction mechanisms resulting from the combination of enalapril and doxazosin. Blood pressure reductions were consistently greater with the combination but there was no evidence of a significant pharmacodynamic interaction (as determined by heart rate changes, renal function tests or by pressor responsiveness indices) and there was no evidence of a pharmacokinetic interaction with either drug. Responsiveness to each drug i.e. blood pressure reduction per unit drug concentration was not significantly altered in the combination regimen. In conclusion, these results suggest that the combination of enalapril and doxazosin produces a usefully additive hypotensive effect but there was no evidence of synergism i.e an effect which was more than additive.

Adult↗
PubMed1993

R-verapamil: pharmacokinetics and effects on PR interval, blood pressure and heart rate.

1. This study in healthy normotensive male volunteers investigated the pharmacokinetics and the effects on electrocardiographic PR interval, blood pressure and heart rate of single oral doses of the single isomer R-verapamil (250, 500 and 1000 mg) in comparison to placebo and 240 mg racemic verapamil. 2. After 500 and 1000 mg R-verapamil there were significant prolongations in PR interval, maximal at 1-2 h after dosing and coincident with peak plasma drug concentrations, but these were not significantly different from the maximum prolongation obtained with 240 mg racemic verapamil. 3. After 1000 mg R-verapamil there was a significant hypotensive effect, particularly on standing. 4. Single doses of 500 and 1000 mg R-verapamil produced peak plasma drug concentrations in the range 1000-3000 ng ml-1. If this concentration range is appropriate for adjuvant cancer chemotherapy it can be predicted that similar steady state concentrations will occur with a dosage regimen of 300 mg 3 times daily.

Administration, Oral↗
PubMed1993

A comparison in young and elderly subjects of the pharmacokinetics and pharmacodynamics of single and multiple doses of benazepril.

1. The pharmacokinetics and pharmacodynamics of single and multiple oral doses of the ACE inhibitor benazepril were investigated in young and elderly normotensive subjects. 2. Following multiple doses the trough concentrations were significantly higher in the elderly and the areas under the plasma concentration-time curves (AUC0-24) were significantly greater, by approximately 23%. 3. The fall in blood pressure tended to be greater in the elderly subjects but this is likely to be attributable to their higher initial blood pressures, although it may reflect the small differences in pharmacokinetics. 4. The age related differences in kinetics and dynamics following multiple dosing are quantitatively similar to those obtained with single doses. However, there appears to be a quantitative difference between benazepril and other ACE inhibitors in that the age related increases were of a relatively smaller magnitude.

Administration, Oral↗
PubMed1993

The effects of age on the pharmacokinetics and pharmacodynamics of single oral doses of benazepril and enalapril.

1. Eighteen healthy, normotensive subjects (nine young and nine elderly) participated in a double-blind, 3-way, crossover study to compare aspects of the pharmacokinetics and pharmacodynamics of single oral doses of 10 mg benazepril, 10 mg enalapril and placebo. 2. The hypotensive effect was similar after both drugs but the absolute reductions were greater in the elderly who had higher initial levels of blood pressure. 3. The AUCs for both benazeprilat and enalaprilat were higher in the elderly but by a significantly greater amount for enalaprilat (+ 113% vs 40%; P < 0.01). 4. The AUCs for both drugs tended to be highest in subjects with the lowest creatinine clearance. 5. The changes in kinetics and dynamics observed in the elderly after benazepril are qualitatively similar to those with other ACE inhibitors. The clinical significance of the quantitative differences requires further investigation.

Administration, Oral↗
PubMed1993

Haemodynamic and hormonal responses to oral enalapril in salt depleted normotensive man.

A combination of dietary sodium restriction (40 mmol day-1) and frusemide pretreatment has been used to activate the renin angiotensin system (RAS) in order to characterise the haemodynamic and hormonal responses to enalapril in young normotensives. Enalapril significantly reduced supine blood pressure with a mean maximum fall of 19 +/- 7.6, compared with 6.5 +/- 6.8 mm Hg with placebo. Similar but greater responses were seen in erect blood pressure. Mean maximal plasma ACE inhibition (78 +/- 5.7%) was associated with a significant increase in PRA from 5.2 +/- 2.1 ngAI ml-1 h-1 to a peak of 29.1 +/- 6 ngAI ml-1 h-1. This simple well tolerated regimen produced consistent RAS activation and gave readily measurable falls in blood pressure following enalapril. This model may be used to undertake detailed assessments of ACE inhibition, renin inhibition and angiotensin receptor blockade.

Analysis of Variance↗