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Biomedical subjects

Philippe Lechat

Publications and source records attributed to Philippe Lechat.

48 records · Page 3Linked to original sources
PubMed2003

Comparative pharmacokinetics and pharmacodynamics of intravenous and oral nefopam in healthy volunteers.

To determine the pharmacokinetic, subjective effects of a single 20 mg dose of nefopam administered either intravenously or orally in healthy volunteers, twenty-four healthy Caucasian men received 20 mg nefopam orally+placebo intravenous infusion and placebo orally+intravenous infusion of 20 mg nefopam with one week interval, in a double-blind, double-dummy cross-over study. Nefopam and desmethyl-nefopam plasma concentrations were measured by HPLC with UV detection up to 48 hr after drug administration. Self-rating questionnaires (Mood and vigilance Visual Analogue Scales, Addiction Research Centre Inventory) and drug safety were investigated. The F value (bioavailability) of the parent drug was 0.36+/-0.13. The AUCoral/AUCiv ratio of nefopam+desmethyl-nefopam was 0.62+/-0.23. The half-life of nefopam was similar whether administered orally (5.1+/-1.3 hr) or intravenously (5.1+/-0.6 hr). The half-life of desmethyl-nefopam was two to three times longer than that of the parent molecule (orally: 10.6+/-3.0 versus 5.1+/-1.3 hr, P<10(-4) and intravenously: 15.0+/-2.4 versus 5.1+/-0.6 hr, P<10(-4)). As assessed by the Addiction Research Centre Inventory, no evidence of abuse liability in healthy, drug-naive volunteers was observed. On visual analogue scales, volunteers rated themselves as more drowsy, less alert, less energetic and less anxious after oral compared to intravenous administration. The AUC0-->24 hr of anxiety and energy parameters were not different after oral and intravenous administration: 90+/-142 versus 35+/-84 (P=0.27) and 66+/-74 versus 46+/-54 mm x hr (P=0.36), respectively. The AUC0-->24 hr of drowsiness and alertness parameters were significantly greater after oral than after intravenous administration: 68+/-65 versus 27+/-30 (P=0.005) and 54+/-63 versus 28+/-48 mm x hr (P=0.03), respectively. A clockwise hysteresis loop was observed for drowsiness in 16 out of 24 volunteers after oral administration. The results suggest that in healthy volunteers desmethyl-nefopam may contribute to the pharmacodynamic effects of single dose nefopam solution administered orally. This study shows a rather low bioavailability of nefopam given in intravenous solution when administered orally. Nevertheless, when the main metabolite desmethyl-nefopam is taken into account, the ratio of the areas under the curves is almost doubled.

Administration, Oral↗
PubMed2003

Planning and monitoring of placebo-controlled survival trials: comparison of the triangular test with usual interim analyses methods.

AIMS: For ethical and economic reasons, interim analysis of phase III clinical trials is essential. This study was conducted to compare the efficiency of two interim analysis procedures, which could be used to allow early termination of a clinical trial. METHODS: We made a post hoc application of two interim analysis methods (Lan & DeMets with O'Brien-Flemming modification, and the triangular test according to Whitehead) by using individual patient data from four published placebo-controlled survival trials. We determined the date the trial would have been stopped had each method been used, and we estimated consequent results in terms of events and patient numbers included in the trial, the duration of the trial, and on treatment effect. RESULTS: The triangular test provided the lowest number of events required to reach a conclusion of the trials while providing an accurate estimate of experimental treatment effects. The triangular test thus indicated the smallest number of patients that would have been enrolled, and the shortest trial duration. The difference between the methods was most important with a detrimental effect of experimental treatment: the number of required events was reduced by 75% and the trial duration was shortened by 48% with the triangular test compared to the Lan & DeMets method. CONCLUSIONS: Stopping a trial early must depend on the clinical context. It is most important to stop a placebo-controlled trial as soon as possible when the experimental treatment can be shown deleterious. In such a situation the triangular test is more appropriate than the Lan & DeMets method. When a treatment effect is no different from, or better than, placebo the triangular test is also superior but the importance of premature termination of the trial in such cases has to be balanced against the inevitable reduction of information that the trial can provide.

Clinical Trials, Phase III as Topic↗
PubMed2002

Toxic cardiac effects of catecholamines: role of beta-adrenoceptor downregulation.

The aim of our study was to analyse the mechanisms underlying cardiac toxicity caused by beta-adrenoceptor stimulation and the relationships with their associated downregulation during heart failure. We used the experimental model of coronary artery ligation-induced myocardial infarction in male Wistar rats. In order to increase beta-adrenergic stimulation, rats were subjected to a 15-day chronic isoprenaline administration (30 microg/kg/h). Isoprenaline administration induced haemodynamic inotropic compensation, almost abolished in vitro inotropic response to isoprenaline on papillary muscle (P<0.005) but promoted fibrosis. Isoprenaline treatment markedly reduced the B(max) of beta(2)-adrenoceptors (by 53% in sham and 44% in infarcted rats) but not that of beta(1)-adrenoceptors. These results suggest that beta(1)-adrenoceptors rather than beta(2)-adrenoceptors underlie the deleterious effects of chronic beta-adrenergic stimulation on cardiac fibrosis and are in agreement with the demonstrated benefit induced in human heart failure by beta(1)-adrenoceptor antagonists.

Adrenergic beta-Agonists↗
PubMed2002

The mechanism of the angiotensin-converting enzyme inhibitor quinapril is not related to bradykinin level in heart tissue.

In order to examine the effect of the angiotensin-converting enzyme inhibitor (ACEi) quinapril, we performed a sensitive and specific radioimmunoassay (RIA) to quantify bradykinin, BK-(1-9), in heart and kidney tissues. The BK-(1-9) level was unaffected in the heart of sham and water-deprived rats treated for 2h with quinapril (10mg/kg), but was significantly higher in the kidneys in the two groups. In these conditions, circulating and tissue angiotensin II (Ang II) levels were significantly decreased by quinapril. Moreover, our results indicated that acute treatment with this dose of quinapril induced kinin-mediated effects which were not related to its action on bradykinin degradation in rat hearts.

Angiotensin I↗
PubMed2002

Relationships between the antihypertensive effects of bisoprolol and levels of plasma atrial natriuretic peptide in hypertensive patients.

Previous studies have demonstrated that beta-blockade increases the levels of plasma atrial natriuretic peptide (ANP), but relationships between this effect and the antihypertensive action of beta-blockade remain unknown. In this study we investigated the amplitude and determinants of bisoprolol-induced ANP increase and the relationships between this increase and the antihypertensive effect of bisoprolol. Nineteen patients with mild to moderate hypertension were included in the study. In the first phase of the study (cross-over, placebo controlled, randomized phase), the effects of 10 mg bisoprolol on plasma ANP at rest and during exercise were compared to placebo. The antihypertensive action of bisoprolol was then evaluated after a 2-week period of treatment (10 mg/day) using ambulatory blood pressure monitoring. Bisoprolol significantly increased plasma ANP level at rest (from 30.6 +/- 20.5 to 42.8 +/- 35.6; P < 0.05) and also during exercise (from 54.7 +/- 44.3 to 119.1 +/- 159.9; pg/mL +/- SD; P < 0.05). Plasma ANP at rest was not significantly correlated with left ventricular mass. After the 15 days of treatment, the bisoprolol-induced daytime diastolic blood pressure reduction was significantly correlated to the initial bisoprolol-induced plasma ANP increase (r = 0.49, P = 0.035). These results suggest that the antihypertensive effect of beta-blocking agents could be partly mediated by an increase of ANP release.

Adolescent↗
PubMed2002

Bisoprolol for the treatment of chronic heart failure: a meta-analysis on individual data of two placebo-controlled studies--CIBIS and CIBIS II. Cardiac Insufficiency Bisoprolol Study.

BACKGROUND: Despite the available evidence from randomized clinical trials, beta-blockers are often not used optimally in patients with congestive heart failure (CHF). This meta-analysis aims at providing a precise and quantitative estimate of the benefit and risks of long-term bisoprolol on major clinical events in patients with CHF, both overall and in selected subgroups. This may help clinicians in their decisions as to whether to prescribe bisoprolol for their individual patients. METHODS: Meta-analysis was performed of results from the 2 randomized, controlled clinical studies in which bisoprolol was compared with placebo (Cardiac Insufficiency Bisoprolol Study [CIBIS and CIBIS II]), which included 3288 patients with proven CHF. The main outcomes were total death, cardiovascular death, sudden death, hospitalization for heart failure, and myocardial infarction. RESULTS: A highly significant 29.3% relative reduction of death (17%, 40%; P =.00003) was observed, as well as significant risk reduction in cardiovascular death and sudden death in favor of bisoprolol. Also, a highly significant relative reduction of 18.4% (25%, 11%; P =.00001) in hospital admission or death was observed. A similar relative reduction of death was consistently observed in selected subgroups of patients. CONCLUSIONS: Bisoprolol prevents major cardiovascular events in patients with CHF with a high benefit-to-risk ratio and can be recommended for these patients.

Adrenergic beta-Antagonists↗
PubMed2002

Catecholamine effects on cardiac remodelling, oxidative stress and fibrosis in experimental heart failure.

The aim of the study was to assess the relationships between oxidative stress, cardiac remodelling and fibrosis on an experimental model of heart failure with adrenergic stimulation. Large myocardial infarction (approximately 50% of the left ventricle myocardium) was obtained by ligation of the left coronary artery of normotensive male Wistar rats. Sham animals were submitted to left thoracotomy without coronary ligation. In order to perform cardiac stimulation by catecholamines, mini-osmotic pumps were implanted in animals 10 weeks after surgery to deliver noradrenalin for a 2-week period. At the end of this period, the following investigations were performed: haemodynamics, morphometry, fibrosis quantification, plasma and tissue catecholamine assay and oxidative stress status. Coronary ligation induced dilatation of left ventricle with compensatory hypertrophy of the right ventricle and of the remaining left ventricle myocardium. This remodelling process was associated in non-infarcted myocardium with increased collagen infiltration and increased oxidative stress. Ten weeks after surgery, the chronic administration of noradrenalin for 2 weeks did not increase oxidative stress. Noradrenalin, however, induced inotropic stimulation and myocardial hypertrophy, but to a lesser extent in infarcted rats compared to sham rats. Our results suggest that noradrenalin infusion to levels in excess of those seen post-infarction is associated with fibrosis and oxidative stress. Moreover, noradrenalin in infarcted animals caused additional fibrosis without further increasing oxidative stress. The mechanism of catecholamine-induced fibrosis may thus involve different processes such as ischaemia, increased mechanical stress, cytokines and neurohormones.

Animals↗
PubMedDate not supplied

[Antilipemics and prevention of cerebrovascular accidents. Meta-analysis].

BACKGROUND: Previous overviews have suggested that the HMG-CoA reductase inhibitors (statins), but not other lipid lowering therapies (LLTs), may reduce stroke incidence in coronary patients. Our objective was to investigate the amplitude and sources of heterogeneity of LLT effects on stroke prevention. METHODS: A literature search was performed from 1966-2001 to identify all English-language published trials testing LLT. We then conducted a meta-analysis including randomised primary and secondary coronary heart disease prevention trials, which tested statins, nonstatins, diet or other interventions, and providing data on stroke incidence. RESULTS: The overall meta-analysis (38 individual trials, 83,161 patients, mean follow-up of 4.7 years) showed a significant relative risk reduction (RRR) of strokes by LLTs of 17% (p < 0.001), without significant heterogeneity between trials and between subgroups according to either the type of prevention (primary or secondary prevention) or type of LLT. Most demonstrative effects was obtained however with statins (RRR = 26%). Effect model analysis showed that the treatment benefits appeared constant whatever the risk of stroke, suggesting that LLTs may be effective in a population with a higher risk of stroke. Weighted regression showed a significant correlation between the RRR of stroke and total cholesterol levels (baseline, final, and change). Only final cholesterol level allowed a clear separation between benefit (RRR > 0) and no effect (RRR < 0) of LLTs on stroke incidence, with a cut-off for benefit of 6.0 mmol/L. CONCLUSION: LLTs reduce stroke incidence in coronary patients, especially when total cholesterol is under 6.0 mmol/L, this explains the better results obtained with statins.

Humans↗
PubMedDate not supplied

[From ischaemia to heart failure: heart rate--actor or stamper?].

The heart rate in sinus rhythm depends on If current-induced automaticity of sinus node cells. Such a current is activated by hyperpolarisation and is modulated by influences from sympathetic and para-sympathetic tones. There are established prognostic values for the baseline heart rate and its variability in coronary heart disease and heart failure. However, heart rate per se directly modulates myocardial oxygen consumption and cardiac contractility by interfering with the excitation-contraction coupling. The therapeutic implications of pharmacological modulation of the heart rate are important mainly for slowing the heart rate, as illustrated by the use of calcium antagonists in coronary heart disease and beta-blockers in both coronary heart disease and heart failure. The possibility of a direct action on sinusal automaticity by drugs such as ivabradine, an If channel blocker, reveals new therapeutic perspectives. Indeed, a benefit of combination therapy with these drugs and beta-blockers should be lower heart rate values than can be attained with maximally tolerated doses of beta-blockers.

Autonomic Nervous System↗
PubMedDate not supplied

[Clinical trials of beta-blockers in heart failure: history, overview and future prospects].

Although beta-blockers have been classically contraindicated in heart failure patients, their administration at progressively increasing doses provides long-term benefit in such patients with altered left ventricular function, and prevents the direct and indirect deleterious cardiac effects of catecholamines. By improving left ventricular function and preventing severe arrhythmias, beta-blockade improves survival, reduces the occurrence of sudden death and hospital admissions for worsening heart failure. The degree of benefit is dose dependent, although few prospective data confirm this fact. Among tested compounds, bisoprolol, metoprolol and carvedilol have produced similar improvements in survival with a 34% reduction in mortality in large-scale clinical trials. Bucindolol, however, did not significantly improve survival in the BEST trial. Different hypotheses may explain such results. In terms of therapeutic strategy, beta-blocker treatment must be initiated in stabilised patients already receiving diuretics and an angiotensin-converting enzyme inhibitor. Ongoing studies are evaluating the potential benefit of starting treatment first with beta-blockers in order to better prevent sudden death, particularly as this most often occurs in the early stages of the disease.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Cell cycle arrest and apoptosis induced by oxaliplatin (L-OHP) on four human cancer cell lines.

BACKGROUND: The effects of oxaliplatin (L-OHP) on cell cycle and apoptosis were examined. MATERIALS AND METHODS: The HT29, MCF7, Hela and A549 cell lines were treated and dual parameter flow cytometry BrdU/PI was then performed to monitor cell cycle modifications. Annexin V-FITC and PI probes were used for the detection of apoptosis. RESULTS: The cells were treated for 3 h followed or not by 24 and 72 h of post-incubation. No changes were observed after 3 h of treatment, while after 24 h of post-incubation, all the cells except A549 were predominantly accumulated in the G2/M-phase; this accumulation was time-dependent. Apoptosis induction was late and moderate and was observed only after 12 h of treatment and 24 h of post-incubation. CONCLUSION: L-OHP induced cell cycle arrest and moderate apoptosis; these two activities were time-dependent. These findings warrant further investigation into the potential antitumour activity of L-OHP in MCF7 and Hela cells and in lengthening the infusion duration in order to achieve the acquired cellular modifications.

Antineoplastic Agents↗