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Biomedical subjects

P Lechat

Publications and source records attributed to P Lechat.

At least 37 records · Page 2Linked to original sources
PubMed2000

Predictors of medical events in patients enrolled in the cardiac insufficiency bisoprolol study (CIBIS): a study of the interactions between beta-blocker therapy and occurrence of critical events using analysis of competitive risks.

BACKGROUND: The risk of occurrence of medical events in a clinical trial is competitive in nature; that is, in a given patient the risk of having a critical event depends on the amount of time elapsed since random assignment and on the previous events that may have occurred in the patient. The purpose of this study was to examine the relations between baseline variables, the interactions between treatment, bisoprolol, or placebo, and the occurrence of critical events during the CIBIS trial, a mortality and morbidity trial of beta-blockade in patients with heart failure. METHODS AND RESULTS: A Cox model for censored data was used to analyze the relations between baseline variables, total deaths, permanent treatment withdrawals, nonlethal cardiovascular events, and their interactions with bisoprolol or placebo. We examined the influence of treatment on the occurrence of deaths, permanent treatment withdrawals, and nonlethal cardiovascular events by using the technique of event history analysis, which takes into account competitive risks between events. Compared with placebo, bisoprolol reduced mortality rates in patients with a left ventricular ejection fraction < or =20% (relative risk [RR] 0.49; 95% confidence interval [CI] 0.27 to 0.88; P =.02). In patients whose baseline heart rate was in the upper tertile of distribution, permanent treatment withdrawals were less frequent in patients randomly assigned to bisoprolol than in patients randomly assigned to placebo (RR 0.50; 95% CI 0.28 to 0.88; P =.02). Bisoprolol reduced the incidence of nonlethal cardiac events in patients in whom heart failure was present for at least 4 years (RR 0.44; 95% CI 0.27 to 0.71; P <.01). Event history analysis revealed that among patients who died under treatment after having at least 1 nonlethal cardiovascular event, 20 patients were treated with placebo but only 7 patients were treated with bisoprolol (RR 0.41; 95% CI 0.17 to 0.98; P <.05). CONCLUSIONS: Some patients with heart failure derive more benefit from beta-blocker therapy than others. In the CIBIS trial, they are those patients with the lower left ventricular ejection fractions and those who have nonlethal cardiovascular events but in whom beta-blocker therapy is not permanently discontinued.

Adrenergic beta-Antagonists↗
PubMed2000

Effects of prolonged propranolol treatment on left ventricular remodeling and oxidative stress after myocardial infarction in rats.

Mechanisms determining the benefit of beta blockade in patients with heart failure remain incompletely understood but are assumed consequent to prevention of deleterious effects of catecholamines. Recent studies have demonstrated that oxidative stress in congestive heart failure may be related to increased catecholamine levels. The aim of this study was to examine effects of long-term treatment with propranolol on progression of left ventricular (LV) dysfunction, remodeling and oxidative stress on an experimental model of chronic heart failure. Six weeks after myocardial infarction by coronary ligation, Wistar rats were randomized to two groups: 10 weeks of therapy with propranolol (50 mg/kg/day in drinking water) and no treatment (infarcted controls). A third group was sham-operated rats without treatment. Animals were anesthetized for hemodynamic measurements, and hearts were then removed for histologic analysis, papillary muscle contractility study, and oxidative stress measurements using thiobarbituric acid reactive substance (TBARS) determination. Control infarcted rats demonstrated significant alterations of hemodynamic parameters and remodeling with increase of heart weight/body weight, of right ventricular lateral wall thickness, of LV circumference, LV septal area/body weight, and LV papillary muscle weight/body weight as compared with sham. In propranolol-treated rats, hypertrophy of the LV septum, papillary muscle, and right ventricle were similar to those of the infarcted control. Myocardial oxidative stress was significantly increased in control infarcted rats compared with sham, and propranolol prevented such oxidative stress increase. Papillary muscle isometric tension parameters were not significantly different among groups. Propranolol treatment prevented isoprenaline-induced spontaneous papillary muscle activity in vitro. Oxidative stress is increased in the rat model of heart failure secondary to coronary ligation. Long-term treatment with propranolol in vivo does not modify the compensatory process of hypertrophy but completely abolishes the oxidative stress increase and reduces the increased cardiac sensitivity to catecholamine-induced arrhythmias observed in this experimental model of heart failure.

Animals↗
PubMed2000

Prediction of fluindione maintenance dosage hampered by large intraindividual variability.

In a previous study, the authors proposed a method to individualize fluindione dosage regimen, based on a pharmacokinetic/pharmacodynamic model describing the evolution of the International Normalized Ratio (INR). In this method, daily maintenance dosage for a target INR depends on the product of individual Cl and C50. The present work shows the results of a follow-up study in 50 patients for whom target INR was 2.5. INR measurements and dosage regimens were recorded both during hospital stay and during the 1st month of treatment. Patients were defined as equilibrated after 1 month if the last two INRs were in the range 1.5-3.5 under a stable dosage regimen. Actual maintenance dose was compared with the dose predicted using the three first INRs measured in the hospital. Intraindividual variability of Cl*C50 between hospital stay and after 1 month was evaluated. After 1 month, only 27 patients (54%) were equilibrated. Actual maintenance dose varied from 5 to 30 mg daily. There was no bias between predicted and actual maintenance dose (1.4 mg), but a large root mean squared error (8 mg) was found. The intraindividual variability in Cl*C50 between hospital and maintenance regimen was high (93%), which may explain the dispersion in the predicted maintenance dose.

Anticoagulants↗
PubMed1999

Different effects of bisoprolol on heart rate in patients with ischemic or idiopathic dilated cardiomyopathy (a 24-hour Holter substudy of the Cardiac Insufficiency Bisoprolol Study [CIBIS]).

The effect of beta blockade on heart rate in patients with either idiopathic or ischemic cardiomyopathy was studied. It was found that beta blockade reduced the early morning increase in heart rate to a greater extent in patients with idiopathic dilated cardiomyopathy than in those with ischemic dilated cardiomyopathy.

Adolescent↗
PubMed1998

Clinical effects of beta-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials.

BACKGROUND: beta-Blockers have improved symptoms and reduced the risk of cardiovascular events in studies of patients with heart failure, but it is unclear which end points are most sensitive to the therapeutic effects of these drugs. METHODS AND RESULTS: We combined the results of all 18 published double-blind, placebo-controlled, parallel-group trials of beta-blockers in heart failure. From this combined database of 3023 patients, we evaluated the strength of evidence supporting an effect of treatment on left ventricular ejection fraction, NYHA functional class, hospitalizations for heart failure, and death. beta-Blockers exerted their most persuasive effects on ejection fraction and on the combined risk of death and hospitalization for heart failure. beta-Blockade increased the ejection fraction by 29% (P<10(-9)) and reduced the combined risk of death or hospitalization for heart failure by 37% (P<0.001). Both effects remained significant even if >90% of the trials were eliminated from the analysis or if a large number of trials with a neutral result were added to the analysis. In contrast, the effect of beta-blockade on NYHA functional class was of borderline significance (P=0.04) and disappeared with the addition or removal of only 1 moderate-size study. Although beta -blockade reduced all-cause mortality by 32% (P=0.003), this effect was only moderately robust and varied according to the type of ss-blocker tested, ie, the reduction of mortality risk was greater for nonselective beta-blockers than for beta1-selective agents (49% versus 18%, P=0.049). However, selective and nonselective beta-blockers did not differ in their effects on other measures of clinical efficacy. CONCLUSIONS: These analyses indicate that there is persuasive evidence supporting a favorable effect of beta-blockade on ejection fraction and the combined risk of death and hospitalization for heart failure. In contrast, the effect of these drugs on other end points requires additional study.

Adrenergic beta-Antagonists↗
PubMed1998

Beta-blocker treatment in heart failure. Role of heart rate reduction.

The potential therapeutic effect of beta-blocker treatment in chronic heart failure is still actively being investigated through large scale clinical trials. The underlying cardioprotective mechanism relies upon protection against the deleterious consequences of cardiac sympathetic stimulation. Heart rate reduction induced by beta-blocker treatment may importantly contribute to such benefit especially by improving myocardial energetic balance and by inducing a less negative force-frequency relationship. Results from clinical trials such as CIBIS suggest that prognosis in chronic heart failure may partly depend on left ventricular function improvement, but additional data are needed to more precisely define the relationships between heart rate reduction, left ventricular function improvement, and survival.

Adrenergic beta-Antagonists↗
PubMed1998

Modifications of myocardial Na+,K(+)-ATPase isoforms and Na+/Ca2+ exchanger in aldosterone/salt-induced hypertension in guinea pigs.

OBJECTIVE: The aim of this study was to determine whether changes in cardiac Na+,K(+)-ATPase subunits and Na+/Ca2+ exchanger expression are regulated in aldosterone-salt hypertensive guinea pigs. METHODS: Guinea pigs (GP) were unilaterally nephrectomized and randomized into three groups (aldosterone-salt; control-salt; control). After 90 days of treatment, echocardiographic M-mode assessment and right carotid arterial catheterization were performed in vivo, and plasma hormones and electrolytes were measured. mRNA and protein levels were studied by Northern and Western blot analysis. RESULTS: Aldosterone-salt treatment induced, (1) arterial hypertension (+40%) and LV hypertrophy (+60%) without altering LV-fractional shortening, (2) an increase in plasma norepinephrine levels (+262%) and suppression of renin activity. Northern blot analysis showed the presence of the mRNA encoding the three alpha isoforms and the beta 1 subunit of Na+,K(+)-ATPase in GP myocardium. In the aldosterone-salt group, levels of alpha 1 and beta 1 mRNAs were unchanged. alpha 2 mRNA was increased in both ventricles, whereas alpha 3 mRNA was increased in hypertrophied LV only. Furthermore, levels of the Na+/Ca2+ exchanger mRNA were decreased in both ventricles. At protein level, the two major transcripts (alpha 1 and alpha 2) were detected but alpha 3 isoform was not. Parallel changes in protein and mRNA accumulation of alpha 1 and alpha 2 isoforms were observed in hypertrophied LV. CONCLUSION: These results show that alpha 1 and alpha 2 isoforms are expressed in GP heart and that they are independently regulated in aldosterone-salt hypertension. Like the alpha 1 isoform in renal tissue, alpha 2 isoform is the main target of aldosterone-salt. Reciprocal expression of the Na+/Ca2+ exchanger and Na+,K(+)-ATPase suggests an adaptational mechanism which maintains an appropriate sodium gradient and calcium concentration in hypertensive myocardium.

Aldosterone↗
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

A cost-minimization of heart failure therapy with bisoprolol in the French setting: an analysis from CIBIS trial data. Cardiac Insufficiency Bisoprolol Study.

Beta-blocker-induced benefit in heart failure is under intense evaluation. Several large-scale mortality trials are currently being performed, with CIBIS II evaluating bisoprolol. The economic impact of beta-blocker therapy in heart failure has not been previously determined. The present study is a cost-effectiveness evaluation of bisoprolol treatment based on CIBIS I data. It considers direct costs, that is, the bisoprolol medication cost and the cost of hospitalization related to heart failure and its complications. Hospitalization costs were calculated from the French system of classification (PMSI), which provides costs according to homogeneous groups of patients (GHM). The cost difference between bisoprolol and placebo in the entire CIBIS population and the trial duration result from an increase in cost caused by bisoprolol treatment (+ 2018 Frs/patient) and a decrease in cost related to reduced hospitalization (6349 Frs/patient). A total savings per patient of about 4330 Frs was produced by bisoprolol. Cost reduction is still more pronounced in patients not having a history of myocardial infarction. We conclude that heart failure therapy with bisoprolol lowers medical healthcare costs, mainly due to the reduced rate of hospital admissions for heart failure.

Adrenergic beta-Antagonists↗
PubMed1998

In vivo left ventricular function and collagen expression in aldosterone/salt-induced hypertension.

Cardiac fibrosis is linked to aldosterone-induced hypertension, but the effects on in vivo left ventricular (LV) function are not established. We studied the relations between in vivo LV function and aldosterone/salt cardiac fibrosis. Adult guinea pigs (GPs) were treated for 3 months with an aldosterone infusion and high-salt diet. This treatment induced arterial hypertension (+35%) and moderate LV hypertrophy (LVH; +60%) without right ventricular (RV) hypertrophy. Echo-Doppler LV assessment demonstrated unaltered cardiac output, stroke volume, or LV relaxation. Type I collagen messenger RNA (mRNA) was significantly increased in both ventricles (LV, +48%; RV, +77%) and accompanied by a significant increase in total collagen deposition (LV, from 0.52% in controls to 4.4% in treated GPs; RV, from 0.82 to 5.5% in treated GPs). Plasma norepinephrine levels increased 2.6-fold (p < 0.01) and correlated with the increase in collagen deposition in both ventricles. Collagen content was not correlated with hypertension or LVH. We conclude that aldosterone administration induces cardiac collagen accumulation and a sympathetic stimulation, which might preserve systolic and diastolic function.

Aldosterone↗
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

Prevention of heart failure progression: current approaches.

Heart failure results from damage and stress to the myocardium whatever the aetiology. An increase in stress by cardiac overload is initially overcome by compensatory mechanisms that maintain blood pressure through a combination of the sympathetic nervous system and the renin-angiotensin-aldosterone system. These mechanisms may also alter myocyte function and induce progressive cell death and replacement by fibrous tissue. Disease therapy must reduce cardiac loading and avoid blood pressure control by mechanisms that have deleterious effects. Therapy includes diuretics, vasodilators and alpha- and beta-adrenergic blockade. Complete blockade of all receptors involved in the adverse effects of neurohormonal stimulation might represent an ultimate therapy objective, and improve subsequent prognosis. Large clinical trials are in progress to determine the therapy of choice in the prevention of progression of heart failure.

Adaptation, Physiological↗
PubMed1997

[Beta-blockers and new drugs for cardiac failure].

Intensive investigations are currently performed in the treatment of cardiac failure, based on the hypothesis of the potentially deleterious effects of compensatory neurohormonal mechanisms. Administration of beta-adrenergic blockers at progressively increasing doses appears well tolerated in most cases, improves left ventricular function and symptoms, and reduces the frequency of hospitalisations for heart failure worsening in patients already receiving a background treatment combining diuretics and an angiotensin converting enzyme inhibitor. Survival improvement remains to be established by the ongoing large scale multicentric trials of beta-blockers. Other therapeutic strategies are investigated, mainly inhibition of angiotensin II and endothelin effects by specific antagonists.

Adrenergic beta-Antagonists↗
PubMed1997

Prognostic value of bisoprolol-induced hemodynamic effects in heart failure during the Cardiac Insufficiency BIsoprolol Study (CIBIS).

BACKGROUND: To further evaluate the mechanism of beta-blocker-induced benefits in heart failure, the relationships between bisoprolol-induced hemodynamic effects and survival were studied during the Cardiac Insufficiency BIsoprolol Study (CIBIS). METHODS AND RESULTS: In 557 patients studied, bisoprolol significantly reduced heart rate (-16.3+/-15.3 versus -1.6+/-13.4 bpm, respectively; P<.001) compared with placebo at 2 months after inclusion in the study. Heart rate change over time had the highest predictive value for survival (P<.01). Left ventricular fractional shortening (LVFS) significantly increased in the bisoprolol group compared with the placebo group 5 months after inclusion (+0.04+/-0.06 versus -0.001+/-0.05, respectively; P<.001; n=160). LVFS change over time was also significantly correlated with further survival (P<.02 by Cox analysis). Using a nonparametric approach, we demonstrated a significant interaction between study treatment group and LVFS over time. Patients who demonstrated improvement of LVFS over time (82% and 51% of patients in the bisoprolol and the placebo groups, respectively; P<.02) were at lower risk, but the hazard did not further decrease with a further increase of fractional shortening, and there was no significant difference between study treatment groups. Finally, it could be demonstrated that each of the three factors (heart rate change over time, LVFS change over time, and bisoprolol treatment) made a specific contribution to mortality rate. CONCLUSIONS: Preservation of left ventricular function appears to play a key role in the bisoprolol-induced beneficial effects on prognosis in heart failure. Short-term beta-blocker-induced cardiac effects could provide a means to identify those patients who will experience improved survival over the long term.

Adrenergic beta-Antagonists↗
PubMed1997

Effect of the oxidation state of LDL on the modulation of arterial vasomotor response in vitro.

Although it is established that highly oxidized LDL modify both vasodilator and vasoconstrictor responses in normal and atherosclerotic arterial tissue, there is a paucity of data on the relationship between the degree of the oxidative modification of LDL and vasomotor response. We therefore compared the impact of native LDL (Nat-LDL), and of partially (P-oxLDL), of moderately (M-oxLDL) and of highly oxidized LDL (H-oxLDL) on the vasomotor response of isolated human internal mammary artery and of rat thoracic aorta. Copper-mediated oxidative modification for up to 24 h at 37 degrees C was characterised by a progressive increase in the net negative electrical charge of LDL, and in the content of oxysterols; by contrast, lipid hydroperoxide and TBARS content peaked in M-oxLDL at 6 h. Neither basal vascular tone nor vasoconstriction induced by KCl (100 mmol/l) were modified significantly in arterial segments in relation to the degree of LDL oxidation. While Nat-LDL did not modify the contractile response of rat aorta to norepinephrine, increase in the degree of oxidative modification of LDL progressively and significantly shifted the norepinephrine response curve to the right (EC50 values for Nat-LDL, M-oxLDL and H-oxLDL: 1.2+/-0.5x10(-8), 3.5+/-1x10(-7), 1.3+/-0.4x10(-6) mol/l respectively) with reduction in the maximal effect (74.5+/-12.2 and 100.1+/-6.2% for H-oxLDL and M-oxLDL respectively, P < 0.05 versus controls). Similar findings were made in human arteries treated with H-oxLDL (P < 0.05 for EC50 and maximal response versus controls). The acetylcholine-induced, endothelial-dependent relaxation of rat aortic segments was significantly and progressively impaired with increase in the degree of LDL oxidation, maximal relaxation with H-oxLDL being 3-fold less (P < 0.05) than Nat-LDL at the same protein concentration (100 microg/ml). Acetylated LDL was without effect. Our data indicate that the increase in the degree of copper-mediated, oxidative modification of LDL parallels progressive reduction in the vasomotor response of the arterial wall to norepinephrine-induced contraction and to acetylcholine-induced relaxation subsequent to precontraction. Our data are consistent with the hypothesis that the major oxysterols (7-ketocholesterol, 7beta-hydroxycholesterol) present in Ox-LDL underlie such effects.

Animals↗
PubMed1997

Is chlormethiazole neuroprotective in experimental global cerebral ischemia? A microdialysis and behavioral study.

Chlormethiazole, an anticonvulsive agent, has been shown to have a possible neuroprotective effect against cerebral ischemia. In addition, chlormethiazole inhibits methamphetamine-induced release of dopamine, protecting against this neurotransmitter's neurotoxicity. The aim of this work was to ascertain whether, in experimental cerebral ischemia, chlormethiazole administration attenuated the ischemia-induced rise of the extracellular concentration of aminergic neurotransmitters and whether it reduces ischemia-induced deficits in memory and learning. Histology for assessment of ischemic damage was a so included. The four-vessel occlusion rat model was used to induce global cerebral ischemia. Aminergic neurotransmitters and their metabolites in the striatal extracellular fluid obtained by microdialysis were assayed by high-performance liquid chromatography-electrochemical detection. The drug was administered either IP (50 mg/kg-1) or directly through the dialysis probe (30 microM) 80 min before ischemia. For the behavioral test and histology, the drug was given IP (100 mg/kg-1) 1 h postischemia. The results obtained did not demonstrate any statistically significant evidence that chlormethiazole has an effect on the ischemia-induced rise in extracellular dopamine and serotonin levels. There was also no variation in metabolite levels. Behavioral measures (learning, recall) were not changed appreciably by the treatment. We observed no significant cell protection in the hippocampus (CA1, CA1), striatum, and entorhinal cortex in animals treated with chlormethiazole. We conclude that, under our experimental conditions, chlormethiazole has little or no effect on the neurochemical, neurobehavioral, and histological consequences of global cerebral ischemia.

Animals↗