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Biomedical subjects

H L Elliott

Publications and source records attributed to H L Elliott.

At least 55 records · Page 3Linked to original sources
PubMed1996

Post hoc analysis: use and dangers in perspective.

DANGERS AND ADVANTAGES OF POST HOC ANALYSIS: Post hoc analysis is of major importance in the generation of hypotheses. However, the hypothesis is created by the analysis and has not been proved by any "experiment'. In some circumstances the conclusion derived from a post hoc analysis is entirely appropriate. For example, it was the only method used by Crick and Watson for determining the structure of DNA. In other circumstances, however, the results will be misleading. NEED FOR CAUTION WITH INTERPRETATION: The results of a post hoc analysis should be viewed with considerable scepticism and, in advance of confirmation by other appropriately designed prospective studies, should not be regarded as definitive proof.

Analysis of Variance↗
PubMed1996

Mistyping of the human angiotensin-converting enzyme gene polymorphism: frequency, causes and possible methods to avoid errors in typing.

A polymorphism of the gene encoding the human angiotensin I-converting enzyme (ACE), which is defined by an insertion/deletion polymorphism in intron 16, has been identified as a candidate genetic locus in the development of cardiovascular and renal disease. We have demonstrated that the accuracy of ACE genotyping is critically dependent on the strategy of the PCR used in typing. Of 1238 individuals genotyped by a standard method, 335 were typed as DD, 645 as DI and 258 as II. However, when DD individuals were retyped using modified methods (including either 5% dimethyl sulphoxide, or a 'hot start') 35 of the original 335 samples (10.5%) were retyped as DI. In approximately half of these mistyped samples, PCR amplification was assessed as inefficient by the absence of a third faint heteroduplex band in a control ID sample: when the assay was repeated without any modifications, the mistyped samples were correctly genotyped. In the remainder, mistyping persisted. In these cases, the use of a third 'nested' PCR primer specific for the I allele was required for successful genotyping, providing a more reliable strategy without the need for further modification to the PCR technique. Our results suggest that the triple primer approach is the method of choice for accurate ACE genotyping.

Dimethyl Sulfoxide↗
PubMed1996

Review: the central role of calcium in the pathogenesis of cardiovascular disease.

Calcium-dependent processes play a central role in several different cells of the cardiovascular system including vascular smooth muscle and endothelial cells and also in monocytes, macrophages and platelets. In response to extracellular stimuli cytosolic calcium concentration increases. The increase is composed of two distinct phases. Firstly, calcium is released from intracellular stores via IP3. In the second phase calcium influx across the cell membrane is mostly responsible for the sustained rise in intracellular calcium concentration. This phase of the peak increase in cytosolic calcium is a prerequisite for sustained activation of the cell and the processes of vascular smooth muscle contraction and the activation of nuclear transcription factors for protein biosynthesis. Under ischemic conditions the regulatory systems which control the intracellular free calcium concentration consume a major portion of the cell's physiological energy supply (90%) and a decreased oxygen supply under ischemic conditions rapidly reduces the cell's capacity for intracellular calcium storage or outward transport across its membrane. Calcium antagonist drugs principally act on L-type calcium channels to reduce the influx of calcium into the the cells of the body. Since calcium antagonist drugs are able to influence a wide range of cellular processes which have been implicated in atherosclerosis, glomeruloscierosis, left ventricular hypertrophy and insulin resistance there are strong grounds for their use in a range of clinical disease states.

Calcium↗
PubMed1995

Clinical pharmacology of drugs acting on imidazoline and adrenergic receptors. Studies with clonidine, moxonidine, rilmenidine, and atenolol.

Centrally acting antihypertensive drugs are recognized to be safe and effective treatment for high blood pressure. Centrally mediated side effects, such as sedation, are commonly dose- and treatment-limiting events. Imidazoline-preferring receptors, while functionally similar to alpha 2 adrenoceptors, are distinguishable not only on the basis of in vitro radioligand binding but also in vivo in terms of side effects. Drugs with an imidazoline structure lower blood pressure but are less likely to impair psychomotor function. A placebo-controlled study compared moxonidine 0.1 mg with clonidine 0.1 mg orally in nine normal subjects. Both active drugs lowered blood pressure compared to placebo (clonidine more than moxonidine). However, psychomotor function and self-scored sedation and dry mouth were significantly affected only by clonidine. In a long-term (4 weeks) double-blind cross-over study in essential hypertension, rilmenidine was well tolerated and had similar effects to those of atenolol on erect and supine blood pressure. Rilmenidine had no effect on a wide range of autonomic and psychomotor tests or on responses to mental or physical stress. Atenolol, by contrast, had the predicted effects of a beta adrenoceptor antagonist on heart rate during exercise and the Valsalva maneuver. Imidazoline-preferring drugs offer a new and realistic approach to antihypertensive therapy with blood pressure reduction not limited by marked sedation within the therapeutic dose range.

Antihypertensive Agents↗
PubMed1995

Enhanced pressor response to angiotensin I in normotensive men with the deletion genotype (DD) for angiotensin-converting enzyme.

The insertion (I)/deletion (D) polymorphism of the human angiotensin-converting enzyme gene has emerged as a genetic risk factor for ischemic heart disease. However, the functional consequences of this polymorphism in humans are not known. Ten normotensive men with the DD genotype and 10 with the II genotype participated in a study in which pressor responses to stepwise infusions of incremental doses of angiotensin I (Ang I) and Ang II and Ang II production during Ang I infusion were measured. Pressor responses were expressed as PD20, which reflects the angiotensin dose required to raise mean blood pressure by 20 mm Hg. The PD20 for Ang I in subjects with the DD genotype was significantly lower than that in II genotype subjects (8.8 versus 14.8 ng/kg per minute, P = .0091), whereas the PD20 for Ang II between the two groups did not differ significantly. The ratio of PD20 for Ang I and Ang II in DD subjects was significantly lower than that in II subjects (0.85 versus 0.96, P = .0452), and the venous levels of Ang II during Ang I infusion in DD subjects were significantly higher than those in II subjects (P < .01). Our study has shown increased pressor responsiveness to Ang I, probably as a consequence of the generation of increased Ang II levels, in subjects homozygous for the DD allele of the angiotensin-converting enzyme gene. This result may be relevant to the reported adverse cardiovascular risk conferred by the D allele, as it provides a mechanistic rationale for the association between this polymorphism and cardiovascular disease.

Adult↗
PubMed1995

Analysis of trough:peak ratio and the assessment of anti-hypertensive drug action.

The conventional blood pressure (BP) measurement is essentially a 'snapshot' at a single time point in any given 24 h period. In the clinical management of the hypertensive patient, however, it is assumed that this snapshot is representative of the BP throughout 24 h and indicative of the consistency of the control produced by anti-hypertensive drug treatment. However, anti-hypertensive drugs vary in the duration and consistency of their anti-hypertensive effect and a single measurement of BP can only be reliably indicative if the drug effect is known to be consistently maintained throughout the 24 h. Following the deliberations of the Food and Drug Administration in the USA, the calculation of a trough:peak ratio has been proposed as an index of the consistency of the anti-hypertensive response and the suitability of an anti-hypertensive drug for its chosen dose and dose interval. In brief, to confirm that the magnitude of the BP is relatively consistent throughout 24 h it is recommended that the magnitude of the BP reduction at the end of the dose interval (at trough) should be at least 50% of the BP reduction measured at peak, namely a trough:peak of 50%. The trough:peak ratio provides a clinically relevant index for assessing whether an anti-hypertensive drug is likely to provide a consistent anti-hypertensive effect throughout the 24 h.

Antihypertensive Agents↗
PubMed1995

Vascular reactivity: a measurement of calcium channel blockade.

Clinical studies have shown that calcium antagonist drugs interfere with the reactivity of vascular smooth muscle and thereby attenuate the pressor responses to adrenergic and non-adrenergic vasoconstrictor agents. It is, therefore, possible to explore the extent and duration of calcium channel blockade by studying the magnitude and time course of the attenuation of pressor responses. The effects of three long-acting calcium antagonists, amlodipine, lacidipine and nifedipine GITS (gastrointestinal therapeutic system), on vascular reactivity were assessed over 24h and 48h dosage intervals. It was shown that all three agents attenuate the vasoconstrictor responses to both adrenergic and non-adrenergic stimuli. However, amlodipine and nifedipine GITS were found to suppress vascular reactivity more consistently than lacidipine over 24h. Extending the analysis to 48h after dosing showed that amlodipine had the most consistent effect.

Amlodipine↗
PubMed1995

Haemodynamics, cardiac conduction and pharmacokinetics of mibefradil (Ro 40-5967), a novel calcium antagonist.

OBJECTIVES: Mibefradil (Ro40-5967) is a chemically novel non-dihydropyridine calcium antagonist. In this phase II study we compared its acute and chronic effects on blood pressure, heart rate and atrioventricular conduction (electrocardiographic PQ interval) with those of verapamil and diltiazem. PATIENTS AND METHODS: After a 4-week placebo run-in, 18 patients with mild to moderate essential hypertension were given single doses of mibefradil (150 mg), slow-release (SR) verapamil (240 mg), diltiazem (240 mg) and placebo at weekly intervals; pharmacokinetics and the effects on blood pressure, heart rate and PQ interval were studied on four 10-h study days. Seventeen of the same patients subsequently underwent 4 weeks of treatment with either mibefradil (100 mg daily; n = 10) or verapamil SR (240 mg daily; n = 7), and on the last day, they attended a further 10-h study day. Two studies were conducted: an acute, single-dose, double-blind, randomly allocated, placebo-controlled, crossover study and a chronic, open-label, randomly allocated, parallel-group study. RESULTS: Mibefradil was well tolerated. In the acute study, the antihypertensive effect (difference from placebo) of mibefradil 150 mg was of slower onset than that of verapamil or diltiazem, but comparable blood pressure reductions had been achieved by 6 h. The mean +/- SD maximal PQ prolongation (difference from placebo) was 15.6 +/- 16.1 ms, compared with 44.0 +/- 22.6 ms for verapamil and 56.0 +/- 48.9 ms for diltiazem (P<0.05 mibefradil versus verapamil; P<0.01 mibefradil versus diltiazem). In the chronic study there were no significant differences during steady-state conditions between mibefradil at 100 mg and verapamil SR at 240 mg in their effects on blood pressure, PQ and heart rate. The mean +/- SD elimination half-life (t1/2) of mibefradil under steady-state conditions was 26.8 +/- 5.5 h (versus an apparent t1/2 of 16.9 +/- 11.1 h for verapamil SR, P<0.05). CONCLUSIONS: Mibefradil is a well-tolerated and efficacious antihypertensive agent well suited to single daily dosing because of its intrinsic long plasma half-life. The effects on both blood pressure and PQ interval are of more gradual onset than those of unmodified verapamil and diltiazem after single doses.

Adolescent↗
PubMed1994

Methodological considerations in calculation of the trough: peak ratio.

AIM: The Food and Drug Administration in the United States has published guidelines which indicate that a minimum trough: peak ratio of 50-66% is required for the efficacy of an antihypertensive drug to be considered satisfactory in relation to its proposed dosage interval. However, these guidelines do not give any definition of the most appropriate methodology, and published data contain widely disparate values which often reflect methodological inconsistencies. This article attempts to define the principal methodological requirements for the accurate and reproducible measurement of trough and peak antihypertensive effects and for calculation of the trough: peak ratio. PROBLEMS IN CALCULATING THE TROUGH:PEAK RATIO: It is essential to take account of the antihypertensive effect of placebo, otherwise the results may be spurious. Similarly, account must be taken of the closely related circadian variability in blood pressure, which is particularly likely to compromise the interpretation of the peak effect. While the incorporation of placebo in a randomly allocated, crossover design is ideal, there are practical (and ethical) difficulties with this approach. CONCLUSIONS: Provided there is an adequate placebo run-in period (of not less than 4 weeks) and individual patients are studied under carefully standardized conditions, with multiple blood pressure recordings throughout the dose interval, it is possible by means of a sequential, placebo-active treatment design to calculate the trough: peak ratio with acceptable accuracy and reproducibility.

Antihypertensive Agents↗
PubMed1994

Concentration-effect analysis of antihypertensive drug response. Focus on calcium antagonists.

Although individualised antihypertensive therapy is widely recommended, prospective methods for optimising treatment are hampered by the paucity of basic information about dose-plasma concentration-response relationships for commonly used drugs. Concentration-effect analysis has been applied to a number of therapeutic areas. With antihypertensive drugs this approach has clearly identified direct relationships between pharmacokinetic and pharmacodynamic profiles within individual patients. Thus, either a linear or nonlinear model can be used to quantify the antihypertensive drug response in terms of parameters that incorporate pharmacokinetic and pharmacodynamic information. Furthermore, these models take account of placebo effects and time-dependent changes in blood pressure and drug concentrations during a dosage interval. Concentration-effect analysis has been used to characterise the responses to a range of calcium antagonist drugs. These studies have demonstrated that these analyses are useful for optimising dosage schedules, identifying determinants of blood pressure response, and predicting steady-state profiles of blood pressure (including peak/trough effects) after administration of a single ('test') dose. This mode of analysis warrants early inclusion in the clinical development of any new antihypertensive agent, so that the familiar difficulties in identifying the optimum dosage range are avoided.

Antihypertensive Agents↗
PubMed1994

Pressor and subpressor doses of angiotensin II increase insulin sensitivity in NIDDM. Dissociation of metabolic and blood pressure effects.

There is evidence that the renin-angiotensin system may be involved in the metabolic as well as the cardiovascular features of diabetes and that pressor doses of angiotensin II (ANG II) increase insulin sensitivity in parallel with blood pressure (BP) in healthy subjects, but the effects of ANG II on insulin sensitivity have not been previously reported in patients with non-insulin-dependent diabetes mellitus (NIDDM). In a randomized, double-blind, placebo-controlled, crossover study, 11 patients with NIDDM attended 3 study days to evaluate the effects of a 3-h infusion of subpressor and pressor doses of ANG II on whole body insulin sensitivity using the euglycemic hyperinsulinemic clamp. BP and heart rate were recorded, and blood samples were collected for serum insulin, C-peptide, potassium, catecholamines, plasma renin activity, and plasma ANG II concentrations. Plasma levels of ANG II (means +/- SD) were 9 +/- 4, 29 +/- 9, and 168 +/- 47 pmol/ml after placebo, low dose infusion, and high dose infusion, respectively. The higher dose of ANG II was associated with significant increases in BP (e.g., 18 mmHg systolic BP at 150 min) and plasma aldosterone. Whole body insulin sensitivity was 23.8 +/- 12.7 mumol glucose.kg-1.min-1 after placebo and 30.6 +/- 12.7 and 27.2 +/- 13.3 following low and high dose ANG II infusions, respectively (P < 0.05, analysis of variance). In summary, acute infusion of ANG II, with or without an increase in BP, increases insulin sensitivity in normotensive patients with NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Prediction and optimisation of the antihypertensive response to nifedipine.

The predictability of the long term antihypertensive response to nifedipine in individual patients has been assessed by an analysis based upon the concentration-effect parameters defined following the first dose administration of 20 mg nifedipine (Retard). The predicted and measured reductions in blood pressure during steady state nifedipine treatment were compared for the trough and peak responses and there was reasonable agreement for the group of patients as a whole. However, when the measured and predicted blood pressure profiles were compared for each individual patient there was close agreement for the majority of patients but there were significant discrepancies in a few cases. Further analysis of the steady state concentrations in these cases revealed that there was no change in their responsiveness to nifedipine and that discrepancies were directly attributable to inappropriate compliance with the drug regimen. The analysis was further extended to simulate the blood pressure responses to alternative fixed dosage regimens. Assessment of these simulations suggests that blood pressure control with nifedipine Retard is significantly improved by three times daily drug administration.

Blood Pressure↗
PubMed1994

FDA guidelines on trough: peak ratios in the evaluation of antihypertensive agents. United States Food and Drug Administration.

The proposed guidelines for antihypertensive drugs from the United States Food and Drug Administration (FDA) suggest that a trough: peak ratio (placebo corrected) of at least 50% should be a requisite for approval in the United States. It is apparent that many existing antihypertensive agents fail to meet this criterion. In contrast, the newer dihydropyridine calcium antagonist lacidipine has a trough:peak ratio greater than 60% which, combined with its other properties, indicates that it is suitable for once-daily administration in hypertension. There is evidence to suggest that a favorable trough:peak ratio may be beneficial in patients who are not fully compliant with the dosage regimen. In addition, a high ratio is indicative of small pharmacologically induced variability in blood pressure: indeed, lacidipine significantly reduces both systolic and mean blood pressure variability. Because blood pressure variability, independent of absolute pressure, is an important determinant of target-organ damage, there is reason to believe that agents that reduce variability may improve the morbidity associated with hypertension.

Antihypertensive Agents↗