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F Pousset

Publications and source records attributed to F Pousset.

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

Population pharmacokinetic-pharmacodynamic analysis of fluindione in patients.

OBJECTIVE: Fluindione is a vitamin K antagonist with a long half-life. This study was designed to investigate the pharmacokinetics and pharmacodynamics of multiple doses of fluindione in patients. METHODS: In a learning group of 49 patients who began fluindione treatment, blood samples were taken 12, 18, or 24 hours after one, three, and five doses. Concentration of fluindione, activity of clotting factors II, VII, IX and X, prothrombin complex activity (PCA), and international normalized ratio (INR) were measured. An indirect-response pharmacodynamic model was used for each effect. A comprehensive analysis was performed with a nonparametric population approach. The model was evaluated in 24 other patients: blood samples were taken 24 hours after two, three, four, and six doses; and PCA and INR were observed. RESULTS: Analysis of concentrations and clotting factor activities showed notably that (1) fluindione has a long half-life (median, 69 hours), and (2) concentration that inhibits the synthesis of the clotting factors by 50% varied for each factor, with a median ranging from 0.25 to 2.05 mg.L-1 for factors VII and II, respectively. The results obtained for INR and PCA were validated in the 24 subsequent patients. CONCLUSION: The population approach allowed the comparison of several pharmacodynamic submodels. This first application of the indirect-response model to multiple oral anticoagulant doses in patients confirmed that both the pharmacokinetics and the pharmacodynamics of fluindione show substantial interindividual variability.

Anticoagulants↗
PubMed1998

Modeling INR data to predict maintenance fluindione dosage.

This study was designed to construct a pharmacokinetic/pharmacodynamic model describing the evolution of International Normalized Ratio (INR) under oral anticoagulation treatment by fluindione in patients and to develop a method for individualization of fluindione dosage. Three indirect response models describing the concentration-INR relationship were tested using a nonparametric estimation method. INR was modelled as a quantity being produced and eliminated. According to a log-likelihood ratio test, the evolution of INR was best modelled as an inhibition of its elimination by fluindione. The selected model was evaluated in 24 additional patients with INR measurements (after 2, 3, 4, 6, and 10 doses). Using a Bayesian method with data until day 4, INR was correctly predicted for days 6 and 10. The population characteristics of fluindione were estimated, pooling the two groups of patients. A Bayesian method for individualization of dosage regimen was developed, based on a risk function for INR at steady state. Prescription rules for fluindione were derived using this method retrospectively on the 73 patients in this study.

Anticoagulants↗
PubMed1998

[Endothelins in chronic cardiac insufficiency].

The endothelins are a family of three structurally related peptides. Endothelin-1 (ET-1) is formed from the big endothelin by the action of the endothelin converting enzyme. It acts on two types of receptor, ETA and ETB. ET-1 is a powerful vasoconstrictor but also has a number of other effects: positive inotropism and stimulation of cell growth, for example. Endothelin is found in the general circulation but its role is mainly local in maintaining vascular tone. The endothelin system is activated in cardiac failure and increased concentrations of plasma endothelin increased, ET-1 converting enzyme and increased density of endothelin receptors are observed. The action of the endothelin system and its relationships with other neuro-hormonal systems activated in cardiac failure are not fully understood but research is under way which should clarify these mechanisms in the next few years. In view of the properties of endothelin, inhibition of its action might be particularly useful in patients with cardiac failure. Its action can be blocked either by preventing its synthesis by inhibiting the endothelin converting enzyme or by blocking the endothelin receptor. Endothelin receptor blockade is associated with beneficial haemodynamic changes, an action on ventricular remodelling and possibly an improved prognosis. Many substances, either selective for ETA receptors or mixed ETA and ETB receptor blockers, are under development. The benefits of these products will require confirmation by large scale clinical trials.

Cardiac Output, Low↗
PubMed1997

Correlation between left ventricular hypertrophy and GAA trinucleotide repeat length in Friedreich's ataxia.

BACKGROUND: Friedreich's ataxia (FA), the most common inherited ataxia, is associated frequently with cardiac hypertrophy, and death is often cardiac related. Recently, the disease has been associated with a mutation that consists of an unstable expansion of GAA repeats in the first intron of the gene encoding frataxin on chromosome 9. METHODS AND RESULTS: We studied 44 consecutive patients with FA, determined the size of GAA expansions in the frataxin gene, and examined the relation between the genotype and cardiac phenotype assessed by M-mode and two-dimensional echocardiography. All the patients were homozygous for the mutation. The size of the GAA expansion on the smaller allele varied from 270 to 1200. We found a correlation between the size of GAA expansion and the left ventricular wall thickness (r = .51, P < .001) and the left ventricular mass index (r = .45, P = .002). Left ventricular hypertrophy was observed in 81% of patients with a number of GAA repeats above the median value of 770 compared with only 14% in the other group (P = .002). CONCLUSIONS: These data demonstrate that in FA, the severity of left ventricular hypertrophy is related to the number of GAA repeats. These results suggest that abnormalities of the gene encoding frataxin, a protein of unknown function highly expressed in the normal heart, may play an important role in the modulation of cardiac hypertrophy.

Adult↗
PubMed1997

Prognostic value of plasma endothelin-1 in patients with chronic heart failure.

AIMS: Endothelin-1 is a potent vasoconstrictive and multifunctional peptide. Elevated concentrations have been reported in congestive heart failure. We hypothesized that the level of endothelin-1 in plasma is a prognostic marker in congestive heart failure. METHODS AND RESULTS: Plasma levels of endothelin-1 were measured by radioimmunoassay in 120 congestive heart failure patients with ischaemic or non-ischaemic cardiomyopathy (mean ejection fraction 28 +/- 11%, in New York Heart Association (NYHA) functional class I:21, class II 35, class III: 61, class IV: 3). During a median follow-up of 361 +/- 338 days, 14 cardiac deaths occurred. In the univariate Cox model, endothelin-1 was the most powerful prognostic marker among the variables tested (P = 0.0001). A multivariate model, including plasma atrial natriuretic peptide and noradrenaline, NYHA class, age, and echocardiographic left ventricular end-diastolic diameter index was highly predictive of mortality (P = 0.00008), but only endothelin-1 remained significantly associated with outcome (P = 0.02). Patients with plasma endothelin-1 > or = 5 pg. ml-1 had a higher mortality rate than those with endothelin-1 < 5 pg. ml-1 (21% vs 4%, P = 0.001). CONCLUSION: Our results suggest that elevated endothelin-1 plasma levels are associated with a poor prognosis and routine plasma endothelin-1 determination provides important prognostic information in mild to moderate heart failure.

Atrial Natriuretic Factor↗
PubMed1997

Hemodynamic and neurohormonal effects of flosequinan in patients with heart failure.

In a double-blind, placebo-controlled study, the central and peripheral hemodynamic effects of 100 mg oral flosequinan and the impact of this drug on neurohormonal activation were noninvasively evaluated in 18 patients with congestive heart failure, after the first administration and after 10 days of treatment. No significant hemodynamic and neurohormonal changes were observed after acute administration. After 10 days, flosequinan produced central and peripheral hemodynamic improvement characterized by an increase in left ventricular circumferential fiber shortening velocity (+12%), a decrease in total systemic resistance (-36%), and an increase in leg blood flow (+37%). No significant changes were observed in heart rate and arterial pressure in patients receiving flosequinan, though a slight increase in heart rate (+17%) was recorded. Despite these favorable hemodynamic effects, flosequinan significantly increased plasma norepinephrine (+38%) and plasma renin activity (+13%) after 10 days of treatment. Thus, the beneficial central and peripheral hemodynamic effects of flosequinan are accompanied by activation of the sympathetic and reninangiotensin systems. This might be related to the unfavorable effects of the drug on survival in patients with heart failure.

Adult↗
PubMed1996

Parasympathetic activity in Friedrich's ataxia.

We compared 19 patients with Friedreich's ataxia, a progressive hereditary neuromuscular disorder, with 19 healthy age-matched subjects. During nighttime, patients had shorter mean RR and decreased heart rate variability parameters related to parasympathetic activity than healthy subjects, whereas no difference occurred during daytime.

Adult↗
PubMed1996

Effects of bisoprolol on heart rate variability in heart failure.

Analysis of heart rate variability (HRV) provides a non-invasive index of autonomic nervous system activity. HRV has been shown to be reduced in heart failure. Preliminary data indicate that beta blockers improve clinical status in patients with heart failure, but HRV improvement remains to be demonstrated. Fifty-four patients from the randomized double-blind, placebo-controlled Cardiac Insufficiency Bisoprolol Study were included in the HRV study. The bisoprolol daily dose was 5 mg once daily. We assessed HRV during 24-hour Holter recordings before randomization and after 2 months of treatment. HRV as measured in the time domain by root-mean-square successive differences (rMSSD), the percentage of adjacent RR differences >50 ms (pNN50), and the SD of RR intervals (SDNN), and in the frequency domain by high-frequency (0.16 to 0.40 Hz) and low-frequency (0.04 to 0.15 Hz) power. Most patients were in New York Heart Association functional class III. The mean left ventricular ejection fraction was 27 +/- 7%, and heart failure was idiopathic or ischemic. After 2 months, the patients receiving bisoprolol had a reduced mean heart rate compared with that in placebo patients (p=0.0004). Bisoprolol increased 24-hour rMSSD (p=0.04) and 24-hour pNN50 (p=0.04), daytime SDNN (p=0.05), and daytime high-frequency power (p=0.03) power. Bisoprolol induced a significant increase in HRV parameters related to parasympathetic activity in heart failure. Increased vagal tone may contribute to the protective effect of beta blockers and may have prognostic implications.

Adrenergic beta-Antagonists↗
PubMed1996

Captopril does not acutely modulate plasma endothelin-1 concentration in human congestive heart failure.

Congestive heart failure (CHF) is a syndrome characterized by increased levels of angiotensin II (Ang II) and endothelin-1 (ET-1). In vitro, Ang II stimulates ET-1 release. The purpose of the study was to assess the effect of a single dose of an angiotensin-converting enzyme inhibitor (ACEI) captopril versus placebo on plasma endothelin concentration in human congestive heart failure. Captopril (25 mg, given orally) was compared with placebo in a group of 20 patients with systolic dysfunction in a double-blind randomized study. Plasma irET concentration was significantly increased in CHF patients compared with normal subjects (5.59 pg/ml +/- 0.35 vs. 3.58 pg/ml +/- 0.99, p < 0.0002). Despite the decrease in systolic blood pressure and the increase in plasma renin activity, suggesting a significant blockade of the renin-angiotensin system, no difference in plasma irET-1 was observed between captopril and placebo. Our results suggest that captopril does not acutely influence irET-1 plasma concentration in human CHF. These data do not support the hypothesis that the acute vasodilator effect of a single dose of 25 mg of captopril given daily orally involves modulation of the increased plasma concentration of endothelin observed in CHF.

Adult↗
PubMed1996

Effect of serotonin on cytokine mRNA expression in rat hippocampal astrocytes.

Serotonin is a widely distributed neurotransmitter which elicits a range of central activities. We examined the effect of serotonin on cytokine mRNA expression by rat hippocampal astrocytes in primary cultures. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis shows that interleukin-6 (IL6) mRNA is expressed after 10(-12) M serotonin stimulation whereas transforming growth factor-beta (TGF beta) and tumor necrosis factor (TNF alpha) are induced by 10(-10) M serotonin. These inductions appeared after 1 h stimulation for IL6 and TNF alpha, whereas that of TGF beta appeared after 4 h. The present results provide the first evidence that serotonin can influence astrocyte cytokine production, and thus this neurotransmitter may be considered a potential neuroimmunomodulator.

Animals↗
PubMed1996

Effects of beta-blockade with bisoprolol on heart rate variability in advanced heart failure: analysis of scatterplots of R-R intervals at selected heart rates.

The effect of beta-blockade on heart-rate variability was assessed at different heart rates in 52 patients with heart failure included in the randomized, placebo-controlled, Cardiac Insufficiency Bisoprolol Study (CIBIS). Scatterplots of R-R intervals display beat-to-beat variability by plotting each R-R interval against the preceding interval. Scatterplot dispersion at different R-R intervals provides a measure of beat-to-beat heart-rate variability at different heart rates. A 24-hour Holter tape was performed at baseline and after 2 months of treatment with bisoprolol or matched placebo. Geometric measurements of scatterplots were used to determine beat-to-beat dispersion for different R-R intervals. Bisoprolol and placebo groups were well matched at base-line. After 2 months of treatment, bisoprolol significantly increased beat-to-beat variability at the longest R-R intervals (p < 0.05); however, there was no change in scatterplot dispersion at the shortest R-R intervals. This suggests that beta-blockade increases parasympathetic or decreases sympathetic tone or both in heart failure patients only at the slowest heart rates.

Adrenergic beta-Antagonists↗
PubMed1996

Correlation between time-domain measures of heart rate variability and scatterplots in postinfarction patients.

Heart rate variability (HRV) is usually measured in time or frequency domains. Beat-to-beat variability, which cannot be assessed by frequency-domain analysis, and can only be assessed globally by time-domain analysis, provides information concerning the nonlinear behavior of heart rate. This beat-to-beat variability can be displayed on scatterplots, where each RR interval is plotted against the preceding RR interval. However, the relationship between scatterplots and other measures of HRV is unknown. We studied the correlations between time-domain measures and scatterplot length, width, and area in 50 postinfarction patients. Scatterplot length and width were measured after printing. Scatterplot area was calculated from length and width, assimilating the plot to an ellipse. Long-term variability indexes (SDNN and SDANN) were strongly correlated with scatterplot length (r > 0.9, P < 0.0001), and short-term variability parameters (pNN50 and variability index) with scatterplot width (r > 0.9; P < 0.0001). Scatterplots are, therefore, a simple way of providing information concerning long- and short-term HRV. Furthermore, measurement of scatterplot width at different given RR intervals could be an approach to the evaluation of short-term HRV for different heart rates. This could provide a simple way of assessing cardiac parasympathetic modulation at different heart rates.

Adult↗
PubMed1996

Plasma levels and molecular forms of proatrial natriuretic peptides in healthy subjects and in patients with congestive heart failure.

A specific and sensitive radioimmunoassay (RIA) for the N-terminal fragment of proatrial natriuretic peptide (NproANP) was developed. Antiserum raised in rabbits against a mixture enriched with prohormone was 100% cross-reactive with human proANP(1-30). Plasma concentrations of proANP(1-30) and ANP immunoreactivities (ir-) were simultaneously measured in healthy subjects and patients with congestive heart failure (CHF; 26 dilated cardiomyopathy and 5 ischemic heart disease). High plasma levels of both ir-proANP(1-30) and ir-ANP were detected in CHF patients. Circulating ir-ANP levels were elevated in New York Heart Association functional Classes II and III patients but not in Class I patients. However, plasma levels of ir-proANP(1-30) were higher in asymptomatic patients than in healthy subjects, and markedly increased in patients of Classes II and III. Analysis of ir-proANP(1-30) by gel filtration chromatography or reverse-phase high pressure liquid chromatography revealed a 10 kDa peptide circulating as a distinct entity. These findings indicate that: (i) the most probable form of NproANP in human plasma is a 10 kDa peptide and (ii) in CHF patients the rise in plasma ir-proANP(1-30) levels is more pronounced than the variation in plasma ir-ANP. Thus, NproANP plasma levels may prove to be a more sensitive marker of left ventricular dysfunction than ANP.

Adult↗
PubMed1996

[Epidemiology of cardiac failure and current prognosis of the most seriously ill patients].

The lack of consensus concerning the diagnostic criteria of cardiac failure explains the relative paucity of epidermiological data. Most of the available information comes from American health registers and the Framingham study: in the United States, there are more than 3 million people with cardiac failure (over 1% of the population) and over 400,000 new patients each year. Cardiac failure is the main cause of death in 40,000 deaths and an associated cause in a further 250,000 deaths. In the Framingham study (1948-1988) the mean survival time after diagnosis is 1.7 year in men and 3.2 years in women, corresponding to 1 and 5 year survival rates of 57% and 25% in men and 64% and 38% in women. These figures are worse than those of the large scale therapeutic trials of the last 10 years and represent survival of the most severe cases. Although not strictly epidemiological data, analysis of the large scale trials allows evaluation of the clinical features and survival of patients under optimal medical treatment (ACE inhibitors associated with other treatments): these results are important to bear in mind when considering alternative therapies (transplantation, mechanical assist devices), the accessibility of which may be limited for reasons of availability or cost. In terms of public health, it is important that accurate epidemiological data concerning cardiac failure. In particular severe cardiac failure, is made available in France.

Adolescent↗
PubMed1995

Evaluation of cardiac beta 1-adrenergic sensitivity with dobutamine in healthy volunteers.

1. Evaluation of cardiac beta 1-adrenergic sensitivity in heart failure should provide instructive therapeutic as well as prognostic information. We set up a non-invasive test in healthy volunteers to evaluate beta 1-adrenergic reactivity using dobutamine as a preferential agonist. 2. The range of i.v. bolus doses was 3.2 to 12.2 micrograms kg-1. The test was well tolerated. The parameters that were most sensitive and best correlated to dobutamine doses were systolic blood pressure and the rate-corrected electromechanical systole (QS2i). The reproducibility of the test over 48 h and over 1 month was satisfactory for most parameters, with a mean variation coefficient ranging from 9 to 26%, and was better for QS2i than for heart rate. 3. Slope of log dose-response for heart rate and QS2i was similar with dobutamine and with isoprenaline, corresponding to stimulation of the same type of beta-adrenergic receptors (beta 1-subtype). This result was obtained despite a higher vagal stimulation with dobutamine. We conclude that the left ventricular contractile response assessed by QS2i provided the best parameter for evaluation of beta 1-adrenergic cardiac effects either with dobutamine or with isoprenaline. 4. In heart failure patients such a dobutamine test should allow separation of altered contractility and beta-adrenergic desensitization, since alteration of inotropic response to dobutamine should depend on both altered contractile function and adrenergic desensitization but heart rate response should only depend on the latter phenomenon.

Adult↗
PubMed1995

[Changes in heart rate variability after myocardial infarction. Value of Poincareé's diagram].

The variability of the heart rate is reduced after myocardial infarction. It then progressively increases, to return to near normal values after several months. However, these changes in heart rate variability occur at the same time as slowing of the heart rate which makes interpretation difficult. Poincaré's diagram is constructed from a Holter recording plotting each RR interval against the preceding RR interval. The authors have developed a geometric approach to this diagram to evaluate parasympathetic tone for a given heart rate. By measuring the dispersion in height of the Poincaré's diagram, the authors evaluate the shor-term variability for a given RR interval. Two 24 hr Holter recordings were performed in 52 patients at one and two weeks after a myocardial infarction. The dispersion in the height of the Poincaré's diagrams was measured at the 10th, 25th, 50th, 75th and 90th percentiles of the total dispersion. The authors have shown an increase in the short-term variability of the shortest RR intervals (1th, 25th and 50th percentiles) which is not observed in the longer RR intervals (75th and 90th percentiles). In conclusion, theres is an increase in the heart rate variability at the shortest RR intervals. This suggests that the recovery of parasympathic tone after myocardial infarction occurs mainly at the fastest heart rates.

Aged↗