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Biomedical subjects

E Bellissant

Publications and source records attributed to E Bellissant.

64 records · Page 4Linked to original sources
PubMed1991

Arterial vasodilating profile and biological effects of pinacidil in healthy volunteers.

1. The effects of pinacidil (25 mg, sustained release formulation) a) on systemic (arterial pressure, cardiac output) and regional (brachial and carotid arteries' diameters and flows) haemodynamics (pulsed Doppler techniques), b) on sympathetic (plasma noradrenaline) and renin-angiotensin (plasma renin activity) systems, and c) on atrial natriuretic factor have been investigated and compared with those of a placebo during the 12 h period following oral administration in a randomized, double-blind and cross-over study performed in six healthy volunteers. Simultaneously, the plasma levels of pinacidil and of its active metabolite, pinacidil N-oxide, were determined. 2. As compared with placebo, pinacidil decreased systemic vascular resistance and arterial blood pressure but cardiac output was not modified. 3. Pinacidil significantly increased brachial and carotid arteries' diameters (by 7 and 8% respectively) and flows (by 60 and 17% respectively) and decreased forearm vascular resistance (by 43%). Thus, pinacidil dilates both large and small arteries, increases large vessels' compliance and redistributes blood flow towards the muscular vascular bed. These effects peaked at 4 h and their duration at the brachial level was 8 h. 4. Pinacidil administration resulted in a stimulation of both sympathetic (increases in heart rate and plasma noradrenaline) and renin-angiotensin systems, and induced a transient increase in atrial natriuretic factor. 5. The duration of pinacidil haemodynamic effects at the brachial level is consistent with the pharmacokinetic data which show that pinacidil and pinacidil N-oxide plasma levels almost plateaued between 3 and 8, and 2 and 8 h respectively after oral administration of the sustained release formulation used.

Adult↗
PubMed1990

Application of the triangular test to phase II cancer clinical trials.

Phase II cancer clinical trials are primarily designed to determine whether the response rate p to the treatment under study is greater than a specified value p0, that is to test the null hypothesis H0: p less than or equal to p0 against an alternative hypothesis H1 : p greater than p0 specified by p = p1. As an alternative to the single and multistage procedures and to Wald's continuous sequential probability ratio test (SPRT), we applied the group sequential methods proposed by Jones and Whitehead, namely the triangular test (TT) and the discrete SPRT, to the comparison of p with p0, and we expressed H0 and H1 in terms of the log odds-ratio statistic log [p(1 - p0)/p0(1 - p)]. A stimulation study showed that both the TT and the discrete SPRT had type I error and power close to the nominal values, and they compared favourably with multistage methods in terms of the average sample size.

Clinical Trials as Topic↗
PubMed1990

[Role of the enoximone-dobutamine combination in the treatment of congestive cardiac insufficiency].

Theoretically, there are two reasons for using the association of dobutamine and enoximone in patients with acute cardiac failure; the powerful vasodilator effect of enoximone and the different biochemical actions of the two drugs on the myocardial fibre affecting the production (dobutamine) or the degradation (enoximone) of cyclic AMP. The combined effects of beta adrenergic agonists and phosphodiesterase III inhibitors in vitro and in vivo have been previously reported. An increased contractile response to dobutamine has been demonstrated with enoximone on isolated human ventricle obtained during cardiac transplantation. We confirmed the additive effect of dobutamine (5 to 10 micrograms/kg/min) and enoximone (1 mg/kg/bolus IV) in 8 patients with acute cardiac failure with each molecule used alone. Mild changes in heart rate (+19 bpm) and in systolic blood pressure (-3 mmHg) were observed simultaneously. The absence of an increase in SvO2 compared to the use of each molecule in monotherapy is probably related to a tendency to increase myocardial oxygen consumption which may be potentially deleterious in terms of gas exchange. Having demonstrated the additive effects of the association of dobutamine and enoximone, there is probably a place for this therapeutic association in the management of acute cardiac failure. However, the potential risk of inducing an atrial and/or ventricular tachyarrhythmia and the consequences of lowering ventricular filling pressures and systemic vascular resistances should be born in mind; when using this therapeutic association, the authors suggest starting treatment with low doses of dobutamine (5/kg/min) and enoximone (0.5 - 1 mg/kg) with haemodynamic control and steadily increasing the doses, depending on the results obtained.

Cardiotonic Agents↗
PubMed1990

[Modeling of the relation between plasma concentration of the active metabolite of perindopril and inhibition of the activity of plasma converting enzyme in healthy volunteers].

UNLABELLED: The purpose of this study was to investigate the relationship between plasma concentration (Cp) of perindoprilat (P), the active metabolite of perindopril, and plasma converting enzyme activity (CEA) after a single oral administration of perindopril. CEA and Cp were investigated before, and, 1, 2, 3, 4, 6, 8, 10, 24 and 48 hours after a random administration of a placebo or 4, 8, 16 mg perindopril in a double-blind and crossover study performed in 6 healthy male volunteers. Effect on CEA was expressed as the percentage of inhibition of pretreatment value (CEA0): CEI = 100 (CEA0 = CEA)/CEA0. The CEI-Cp relationship was non linear and displayed an hysteresis loop. Following Sheiner et al. (Clin Pharmacol Ther, 1979; 25: 358-71), we used an effect compartment in which drug dissipation is governed by a first-order rate constant keo. Concentration of P in the effect compartment (Ce) was related to CEI by the Hill equation CEI = 100 Emax Cen/(EC50n + Cen), where Emax (expressed as a percentage) is the theoretical maximum effect, EC50 the Ce which produces 50 p. 100 of Emax, and n the Hill coefficient. Pharmacodynamic parameters were estimated by the non parametric approach proposed by Unadkat et al. (Clin Pharmacol Ther, 1986; 40: 86-93). The Hill equation was fitted to the data for 3 different values of n: 1, 2, and 3. RESULTS: for all the 3 doses, the best curve fitting was achieved for n = 1 or 2. We obtained keo = 0.60 +/- 0.30 h-1 (mean +/- s.d.), Emax = 90 +/- 10 p. 100, EC50 = 1.30 +/- 0.95 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

[Non-invasive regional and cardiac output determination in healthy volunteers. Predictive value].

The effects of nifedipine (20 mg), propranolol (80 mg), the nifedipine (20 mg) + propranolol (80 mg) combination and a placebo on cardiac [heart rate (HR), cardiac output (CO, Doppler determination)] and systemic [mean arterial pressure (MAP), systemic vascular resistance (SVR)] and regional hemodynamic [brachial blood flow (BBF) and arterial diameter (BAD) (pulsed Doppler), forearm vascular resistance (FVR)] parameters were investigated during the 3 hours following their random administration in a double blind and cross over study performed in 6 healthy subjects. At their peak effects, (a) nifedipine decreased SVR (-17 p. 100, p less than 0.01), increased HR (+ 12p. 100, p less than 0.001) and CO (+ 18 p. 100, p less than 0.001), did not change MAP and increased BBF (+31 p. 100, p less than 0.001) with a vasodilating effect which affected both large and small arteries; (b) propranolol decreased HR (-14 p. 100, p less than 0.05) and CO (-25 p. 100, p less than 0.01), increased SVR (+25 p. 100, p less than 0.01), did not change MAP and decreased BBF (-28 p. 100, p less than 0.05) with a vasoconstrictor effect which affected both large and small arteries; (c) in the nifedipine-propranolol combination, nifedipine neutralized propranolol-induced systemic and regional vasoconstrictor effects while propranolol antagonized nifedipine-induced increases in HR and CO. Thus, the favorable synergistic effects of the nifedipine-propranolol combination in hypertensive patients could be demonstrated in healthy subjects inasmuch as MAP was decreased and peripheral vascular blood flows were preserved.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

[Role of pharmacokinetic-pharmacodynamic relationships in drug development].

An important part of drug development relies on the analysis of the relationships between drug doses and therapeutic and/or side effects. This analysis implies an in-depth understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug and of the relationship which links them (PK-PD relationship). The aim of this round table was to define the place of the study of PK-PD relationships in drug development. After reviewing the definitions of PK models, PD models, and of integrated PK-PD models, the article highlights the importance of studying the PK-PD relationship during the successive phases of drug development (pre-clinical, phase I/II, phase III) and in specific populations (children, elderly people). A number of examples taken from pharmaceutical development or international literature are given. They show the methodology used and the type of information which can be drawn at each step of drug development. The article also presents the difficulties which prevent a more systematic application of this kind of approach during drug development. Scientific limits, problems in relation with the misunderstanding of the approach both in academic institutions and in pharmaceutical companies, and difficulties related to the lack of specific guidelines are discussed. The conclusion emphasizes the importance of using PK-PD modeling all along drug development and presents a number of actions which could further broaden its use.

Clinical Trials as Topic↗
PubMedDate not supplied

[Monitoring of clinical trials and interim analysis. 1. Monitoring committee].

In order to fulfil the ethical principles linked to the protection of patients randomized in a controlled clinical trial, monitoring procedures need to be set up. In this context, a committee of experts, called the data monitoring committee is in charge of reviewing regularly unblinded data to assess the quality and the relevance of the trial, to evaluate the evidence of an emerging treatment difference and to control the rate of occurrence of serious adverse events. After each meeting, the monitoring committee reports to the steering committee its recommendation to continue or to stop the trial prematurely. Protocol modifications might be proposed as well. Illustrated with several examples, this article reviews different situations a monitoring committee might have to tackle with.

Clinical Protocols↗
PubMedDate not supplied

[Monitoring of clinical trials and interim analysis. 2. Statistic methods].

Although the decision to continue or to stop prematurely a clinical trial is not solely based on statistical tests, they bring useful objective arguments to the data monitoring board. However, the multiple use of statistical tests leads to increase the risk of false positive conclusions in favor of one of the treatments, and several methods have been developed to address this problem. This article presents the four major strategies that are being used for monitoring clinical trials, as well as the rationale for planning and using such statistical monitoring procedures.

Bayes Theorem↗
PubMedDate not supplied

[Design and analysis of phase II trials in oncology with a group sequential method, the triangular test].

In cancer, phase II clinical trials are most of the time non comparative trials, the purpose of which is to determine whether a new chemotherapy is effective enough to warrant further study in phase III. So, it is necessary, at this stage, to dispose of decision methods which allow, for ethical reasons, for early stopping when inefficacy or efficacy is evident. In a previous work, we have extended to these phase II trials two group sequential methods initially proposed in phase III, and we have demonstrated the advantages of these methods (type I error alpha and power close to the nominal values, reduction of the sample size) as compared to the main methods proposed in the literature. The aim of this paper is to present the method which appears to be the best suited to phase II clinical trials, the triangular test. After a first part, focused on its theoretical aspects, the second part, more practical, presents its use for the design of a cancer trial and its analysis.

Breast Neoplasms↗