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Biomedical subjects

Philippe Lechat

Publications and source records attributed to Philippe Lechat.

At least 37 records · Page 2Linked to original sources
PubMed2005

Inhibition of catecholamine-induced cardiac fibrosis by an aldosterone antagonist.

In heart failure, the renin-angiotensin-aldosterone and the sympathetic systems are overactivated and lead to formation of cardiac fibrosis, which contributes to the aggravation of cardiac function. The aim of the present study was to evaluate the role of aldosterone and angiotensin II on formation of left ventricular fibrosis induced by chronic beta-adrenergic stimulation with isoproterenol (iso) in the rat heart failure model induced by myocardial infarction (MI). Rats were submitted to chronic treatment with either the aldosterone receptor antagonist potassium canrenoate (pc, 20 mg/kg/d) or both aldosterone and angiotensin II receptor antagonists with addition of losartan (los, 10 mg/kg/d). Isoproterenol induced cardiac hypertrophy, which was completely inhibited by potassium canrenoate alone in atria and by potassium canrenoate plus losartan in infarcted ventricles. Isoproterenol also induced cardiac fibrosis, which was completely inhibited in infarcted rats by potassium canrenoate alone in right and left ventricles. In left ventricle, extent of fibrosis was, for control MI, 1.30 +/- 0.34%; MI + iso, 2.50 +/- 0.27%; MI + iso + pc, 0.82 +/- 0.11%; and MI + iso + pc + los, 1.47 +/- 0.31%. The deleterious effects of beta-adrenoceptor stimulation on cardiac fibrosis seem therefore to involve aldosterone action. These results suggest a transregulation between the adrenergic and mineralocorticoid pathways, most likely at the nucleus level, with activation of profibrotic genes.

Adrenergic beta-Agonists↗
PubMed2005

A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination.

Human multidrug resistance protein 2 (MRP2, encoded by ABCC2) is involved in active efflux of anionic drugs such as methotrexate. MRP2 is expressed on the luminal side of hepatocytes and renal proximal tubular cells, indicating an important role in drug elimination. We postulated that loss-of-function mutations in ABCC2, which are involved in the Dubin-Johnson syndrome, may be associated with impaired methotrexate elimination and an increased risk of toxicity. We studied the biological phenotype and ABCC2 coding sequence in a patient receiving a high-dose methotrexate infusion for large B-cell lymphoma and who had an unusual pharmacokinetic profile, mainly characterized by a three-fold reduction in the methotrexate elimination rate. This resulted in severe methotrexate over-dosing and reversible nephrotoxicity. An inversion of the urinary coproporphyrin isomer I/III ratio (a specific biological marker of the Dubin-Johnson syndrome) was observed in this patient. Genetic analysis of ABCC2 identified a heterozygous mutation replacing a highly conserved arginine by glycine in the cytoplasmic part of the second membrane-spanning domain (position 412 of MRP2), a region associated with substrate affinity. This genetic variant was not found in a control population. Functional analysis in transiently transfected Chinese hamster ovary cells revealed a loss of transport activity of the G412 MRP2 mutant protein. An ABCC2 mutation altering MRP2-mediated methotrexate transport and resulting in impaired drug elimination and subsequent renal toxicity was identified. Candidates for methotrexate therapy should be considered for MRP2 functional testing.

Animals↗
PubMed2005

Anti-factor Xa kinetics after intravenous enoxaparin in patients undergoing percutaneous coronary intervention: a population model analysis.

AIM: Recent studies have suggested that intravenous (i.v.) enoxaparin could be used as antithrombotic therapy in patients ongoing percutaneous coronary intervention (PCI). However, anti-Xa pharmacokinetics following different i.v. dosing regimens is not clearly established. METHODS: A population pharmacokinetic analysis was developed using anti-Xa activities measured in 546 patients who received a single 0.5 mg kg(-1) i.v. dose of enoxaparin immediately before PCI. Effects of higher doses (0.75 mg kg(-1) and 1 mg kg(-1)) and/or additional bolus after the initial administration were similarly simulated. RESULTS: Enoxaparin anti-Xa time profiles were best described by a one-compartment model with zero-order kinetics. Mean population parameters (intersubject variability, %) were CL 1.2 l h(-1) (33), V 2.9 l (30) and zero-order input 0.25 h (24). With a single bolus of 0.5 mg kg(-1), the totality of the patients reached an effective anticoagulation level (anti-Xa >0.5 IU ml(-1)) and only 2.5% reached levels above 1.5 IU ml(-1). Simulations showed that greater doses (0.75 mg kg(-1) and 1 mg kg(-1)) prolonged the duration of anticoagulation (3.4 and 4.1 h, respectively) compared with the 0.5 mg kg(-1) bolus (2.7 h) and markedly increased the proportion (48% and 79%, respectively) of patients with anti-Xa levels >1.5 IU ml(-1). For delayed and/or prolonged procedures, patients could be administered a second bolus of half the initial dose in a time interval between 90 min to 2 h after in order to maintain similar anticoagulation profile levels. CONCLUSIONS: A single 0.5 mg kg(-1) i.v. dose of enoxaparin reached anticoagulation levels adequately and should be safer compared with greater doses for anticoagulation in patients undergoing an elective PCI. An additional second bolus could be proposed in patients with delayed or prolonged procedures.

Adult↗
PubMed2005

Captopril-furosemide survival study in experimental heart failure.

The strategy of diuretic drug administration remains to be defined in heart failure as experimental and clinical evidence have clearly established the benefit of neurohormonal blockade. The impact of addition of diuretic treatment to angiotensin-converting enzyme inhibition on survival remains to be demonstrated. The objectives of the study were to evaluate cardiovascular and renal effects of addition of diuretic treatment to captopril (2 g/L, in drinking water), on survival, on the experimental model of heart failure. Rats were followed for 10 months after coronary ligation. Echocardiographic, hemodynamic, morphometry and renal function investigations were then performed on surviving rats. Survival (from 34 to 61%), diuresis and natriuresis were significantly improved compared to control group only in animals treated with a combination of captopril + furosemide. In treated group: cardiac dimensions were reduced with left ventricular fractional shortening significantly increased in combination group (from 22.4 to 28%); captopril + furosemide animals had highest heart rate and lowest systolic and diastolic blood pressures; body and heart weight were reduced, but kidney weight was significantly increased with furosemide (1.7 g in control vs. 2 g in capto + furo); plasma renin activity and angiotensin 1 were greatly increased, and moderately stimulated in control. In conclusion, this combination of drugs significantly improved cardiac remodeling and survival of animals, increased diuresis and natriuresis despite stimulation of plasma renin activity and kidney hypertrophy.

Animals↗
PubMed2004

Safety of hydroxychloroquine in pregnant patients with connective tissue diseases. Review of the literature.

Hydroxychloroquine (HCQ) is widely used in the treatment of systemic lupus erythematosus (SLE). Even if it is generally agreed that pregnancy per se increases disease activity in patients with SLE and that withdrawal of HCQ at the onset of pregnancy may result in exacerbation of SLE, use of HCQ during pregnancy has remained controversial for a long time. Parke was the first to propose continuation of HCQ throughout gestation. Currently, more than 250 pregnancies resulting in live births have been reported and no increase in the rate of birth defects have been demonstrated. When studied, no retinal toxicity and ototoxicity have been found. Data concerning lactation and HCQ treatment are rare. However, the amount of HCQ received by children through lactation seems very low. In conclusion, HCQ should probably be maintained throughout pregnancy in patients with SLE and it does not seem necessary to advise against breastfeeding.

Antirheumatic Agents↗
PubMed2004

Blockade of beta 1- and desensitization of beta 2-adrenoceptors reduce isoprenaline-induced cardiac fibrosis.

The aim of the present study was to analyse the role of beta(1)- and beta(2)-adrenoceptors in the catecholamine-induced myocardial remodeling, especially the interstitial fibrosis. Wistar rats were subjected to a 2-week chronic isoprenaline administration (30 microg/kg/h). Rats received a concomitant treatment with the selective beta(1)-adrenoceptor antagonist, bisoprolol (50 mg/kg/day p.o.) or were chronically pretreated with the selective beta(2)-adrenoceptor agonist salbutamol (40 microg/kg/h) for 1 week to induce beta(2)-adrenoceptor desensitization. The pretreatment with salbutamol induced a 59% down-regulation of left ventricular beta(2)-adrenoceptors compared to control. The extent of the isoprenaline-induced left ventricular fibrosis was significantly reduced in both the bisoprolol and salbutamol groups compared with the control isoprenaline-treated group especially in the apical region (1.7+/-0.6% and 1.4+/-0.3% versus 6.0+/-1.3%, respectively, P<0.005). beta(1)-adrenoceptor blockade and beta(2)-adrenoceptors down-regulation provided similar protection against isoprenaline-induced cardiac interstitial fibrosis suggesting that both beta-adrenoceptors are involved in such cardiac remodeling process.

Adrenergic beta-1 Receptor Agonists↗
PubMed2004

Potassium canrenoate, an aldosterone receptor antagonist, reduces isoprenaline-induced cardiac fibrosis in the rat.

The purpose of the present study was to determine whether the administration of an antagonist of aldosterone could prevent the fibrosis induced by an acute injection of isoprenaline. Male Wistar rats were submitted to one subcutaneous injection of isoprenaline (400 mg/kg) and were simultaneously treated with potassium canrenoate in drinking water (20 mg/kg/day) started 5 days before the injection of isoprenaline. Two months later, echocardiographic and hemodynamic measurements were performed. Then, the heart was prepared for morphometric histology and quantification of fibrosis in the left ventricle. Heart and left ventricular weights were increased significantly by isoprenaline. Potassium canrenoate attenuated this increase. The administration of isoprenaline increased significantly end diastolic diameter and end systolic volume compared with control. These changes were increased further with the addition of potassium canrenoate. In contrast, the fibrosis induced by isoprenaline was reduced significantly by potassium canrenoate at the three section levels. Potassium canrenoate attenuated the fibrosis but not the enhanced dilatation of the left ventricle induced by isoprenaline.

Animals↗
PubMed2004

Comparison of treatment initiation with bisoprolol vs. enalapril in chronic heart failure patients: rationale and design of CIBIS-III.

BACKGROUND: Angiotensin-converting-enzyme (ACE) inhibitors and beta-blockers are standard therapy for chronic heart failure (CHF). beta-blockers are recommended to be initiated after ACE-inhibitors, but this order is not evidence based. The initiation order may be important since many, especially elderly CHF patients cannot tolerate target doses of both. Data suggest that beta-blockers may be more important to CHF patients than ACE-inhibitors, especially in early stages of CHF. AIMS: To compare the effect on combined death or hospitalisation of initial monotherapy with either bisoprolol or enalapril, followed by combination therapy. METHODS: One-thousand CHF patients without ACE-inhibitor, beta-blocker or angiotensin-receptor-blocker therapy will be randomised 1:1 to monotherapy with either enalapril or bisoprolol for 6 months, followed by combined therapy for 6-18 months. The primary objective is to show non-inferiority for bisoprolol-first vs. enalapril-first regarding combined death or hospitalisation. If that is shown, superiority for bisoprolol-first will be tested. CONCLUSIONS: If the trial shows non-inferiority for bisoprolol-first vs. enalapril-first, the first CHF therapy may be chosen based on individual judgement in each patient. If bisoprolol-first is superior to enalapril-first, a beta-blocker should be given prior to an ACE-inhibitor in CHF, and the paradigm of testing CHF compounds against a background of ACE-inhibitor therapy will be challenged.

Adrenergic beta-Antagonists↗
PubMed2004

Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects.

As dronedarone a new noniodinated antiarrhythmic agent structurally related to amiodarone could inhibit CYP2D6 and is planned to be associated with beta-blockers, interactions with CYP2D6 metabolized beta-blockers such as metoprolol, have to be studied. Forty-nine healthy male subjects genotyped for CYP2D6 were included in a randomized, double-blind, placebo-controlled study. Metoprolol was administrated during 13 days (200 mg/day). After the initial 5 days, subjects received placebo (n = 12), 800 mg (n = 6), 1200 mg (n = 9), or 1600 mg (n = 17) of dronedarone daily during eight additional days. Pharmacokinetic parameters of metoprolol were investigated at day 5 and at day 13 in 44 subjects, 39 extensive metabolizers and five poor metabolizers for CYP2D6. Cardiac contractility function was evaluated by the rate-corrected electromechanical systole duration (QS2i) and the mean velocity of endocardial circumferential fiber shortening (Vcfmean). Cmax and AUC0--24 h of metoprolol increased from days 5 to 13 in proportion to dronedarone dose only in CYP2D6 extensive metabolizers genotyped subjects (P < 0.001). In all subjects, from days 5 to 13, Vcfmean decreased and QS2i significantly increased in dronedarone groups. The Vcfmean changes were however significant only with the 1600 mg dronedarone dose compared with placebo while QS2i changes induced by addition of dronedarone were significant compared with placebo at all dose levels. Between days 5 and 13, QS2i and Vcfmean changes were significantly correlated with both dronedarone concentrations at day 13 and with metoprolol concentration changes between days 5 and 13. Plasma metoprolol concentrations were highest in poor metabolizer subjects and dronedarone did not further increase their level but increased QS2i in the two subjects receiving the 1600 mg dose. Addition of dronedarone (800-1600 mg daily) to metoprolol (200 mg daily) increases bioavailability of metoprolol in CYP2D6 extensive metabolizers and induces an additive dronedarone dose-dependent negative inotropic effect. Nevertheless at 800 mg daily (anticipated therapeutic dose) these effects were modest.

Adrenergic beta-Antagonists↗
PubMed2004

Effect of renal function on the pharmacokinetics of enoxaparin and consequences on dose adjustment.

The use of weight-adjusted enoxaparin dosage in patients with renal failure results in increased bleeding complications. The authors investigated the impact of patient-related factors such as renal function on the pharmacokinetics of enoxaparin. Anti-Xa activity was measured in the blood of 60 patients (74 +/- 10 years, body weight 72 +/- 15 kg, men 60%, creatinine clearance 56 +/- 24 mL/min) with acute coronary syndromes receiving subcutaneous administration of enoxaparin. A population-based approach with limited sampling strategy was used. A 1-compartment model with first-order absorption and elimination best fitted the data. The mean clearance (CL/F) and distribution volume (V/F) were 0.72 L/h and 6.65 L, respectively. V/F was influenced by body weight. CL/F was mainly related to the renal function, decreasing with increasing levels of serum creatinine, and lower in women than in men. The elimination half-life was thus estimated to be 6.4 and 9.2 hours in male and female patients, respectively. The final covariate submodel was then: [Equation included in full-text article]. Maximal anti-Xa activity was predicted to rise above 1.5 IU/mL in case of mild elevation of serum creatinine according to gender and body weight. Renal function is the main factor affecting enoxaparin pharmacokinetics. In patients with decreased renal function, enoxaparin dose should be adjusted on the basis of body weight, serum creatinine, and gender to reach a target anticoagulation level assessed by maximal anti-Xa activity in steady-state conditions.

Acute Disease↗
PubMed2003

Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function.

Serotonin (5-HT) controls a wide range of biological functions. In the brain, its implication as a neurotransmitter and in the control of behavioral traits has been largely documented. At the periphery, its modulatory role in physiological processes, such as the cardiovascular function, is still poorly understood. The rate-limiting enzyme of 5-HT synthesis, tryptophan hydroxylase (TPH), is encoded by two genes, the well characterized tph1 gene and a recently identified tph2 gene. In this article, based on the study of a mutant mouse in which the tph1 gene has been inactivated by replacement with the beta-galactosidase gene, we establish that the neuronal tph2 is expressed in neurons of the raphe nuclei and of the myenteric plexus, whereas the nonneuronal tph1, as detected by beta-galactosidase expression, is in the pineal gland and the enterochromaffin cells. Anatomic examination of the mutant mice revealed larger heart sizes than in wild-type mice. Histological investigation indicates that the primary structure of the heart muscle is not affected. Hemodynamic analyses demonstrate abnormal cardiac activity, which ultimately leads to heart failure of the mutant animals. This report links loss of tph1 gene expression, and thus of peripheral 5-HT, to a cardiac dysfunction phenotype. The tph1-/- mutant may be valuable for investigating cardiovascular dysfunction observed in heart failure in humans.

Alleles↗
PubMed2003

Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials.

BACKGROUND: Previous overviews suggested that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), but not other lipid-lowering therapy (LLT), may reduce stroke incidence in coronary patients. OBJECTIVE: To investigate the amplitude and sources of heterogeneity of LLT effects on stroke prevention. METHODS: We searched the literature from 1966 to 2001 and then conducted a meta-analysis including randomized trials of primary and secondary coronary heart disease prevention, testing statins, nonstatin drugs, diet, or other interventions and providing data on stroke incidence. RESULTS: The meta-analysis (38 trials, 83 161 patients, mean follow-up of 4.7 years) showed a significant relative risk reduction (RRR) of strokes by LLT of 17% (P<.001), without significant heterogeneity between trials and between subgroups according to either the type of prevention (primary or secondary) or the type of LLT. The most substantial effects were obtained, however, with statins (RRR, 26%). Effect model analysis showed that treatment benefit appeared constant whatever the risk of stroke, suggesting that LLT may be effective in a population with a higher risk of stroke. Weighted regression showed a significant correlation between RRR of stroke and total cholesterol levels (baseline, final, and change). Only final cholesterol allowed clear separation between benefit (RRR>0) and no effect (RRR<0) of LLT on stroke incidence, with a cutoff for benefit of 232 mg/dL (6.0 mmol/L). CONCLUSION: Lipid-lowering therapy reduces stroke incidence in coronary patients, especially when total cholesterol level is lowered to less than 232 mg/dL (6.0 mmol/L), which explains the best results being obtained with statins.

Anticholesteremic Agents↗
PubMed2003

Pharmacokinetic comparison of fast-disintegrating and conventional tablet formulations of risperidone in healthy volunteers.

BACKGROUND: Difficulties with and resistance to tablet-taking are common in all patient groups and can exacerbate compliance problems and undermine treatment efficacy. In recent years, rapidly dissolving oral drug formulations have been developed to overcome problems related to swallowing difficulties. OBJECTIVE: The goal of this study was to evaluate the bioequivalence of a fast-disintegrating oral tablet of risperidone and the conventional oral tablet. METHODS: This was a randomized, open-label, 2-way crossover trial in which healthy volunteers received two 0.5-mg tablets of a fast-disintegrating oral risperidone formulation and two 0.5-mg tablets of conventional oral risperidone, each in a single administration. Blood samples for pharmacokinetic analysis of the active moiety (risperidone + 9-hydroxy-risperidone), risperidone, and its active metabolite 9-hydroxy-risperidone were obtained during a 96-hour period after dosing. Safety assessments included monitoring of adverse events, hematology and biochemistry tests of the sampled blood, urinalysis, blood pressure measurements, and electrocardiography. RESULTS: The bioequivalence assessment was based on pharmacokinetic and statistical analysis of data from 37 subjects who completed both treatment periods. The plasma concentration-time profiles of the active moiety, risperidone, and 9-hydroxy-risperidone were similar after intake of the 2 formulations. The fast-disintegrating tablet and the conventional tablet showed bioequivalence with respect to the active moiety, risperidone, and 9-hydroxy-risperidone. The 90% CIs for the mean treatment ratios of the log-transformed peak plasma concentration, area under the plasma concentration-time curve (AUC) to the last quantifiable time point, and AUC extrapolated to infinity were all within the predefined equivalence range from 80% to 125%. Twenty-eight of 50 (56%) subjects originally randomized reported adverse events, with a similar incidence for both treatments. All adverse events were mild, with somnolence and headache being the most frequently reported. No clinically relevant changes were observed in physical, biochemical, hematologic, or urinalysis variables during the study. CONCLUSION: In this study in healthy subjects, a single administration of two 0.5-mg fast-disintegrating risperidone tablets was bioequivalent to a single administration of two 0.5-mg conventional risperidone tablets.

Adult↗
PubMed2003

Beta-blocker benefit according to severity of heart failure.

BACKGROUND AND AIMS: Beta-blockers are an established treatment for chronic heart failure. However, the relationship between their benefit and the severity of the disease remains to be determined. METHODS AND RESULTS: We studied the relationship between amplitude of benefit of beta-blockers and severity of chronic heart failure, based on data for mortality and hospitalizations for worsening heart failure, using a meta-analysis of randomized controlled trials, complementary subgroup analyses and analysis of individual data from the CIBIS II trial. In the meta-analysis, mortality was reduced by 22% (95%CI: 16 to 28) and hospitalizations for worsening heart failure by 24% (95%CI: 20 to 29). Benefit was similar with metoprolol, bisoprolol and carvedilol. After exclusion of bucindolol trials, due to the heterogeneity of results for mortality, the reduction in mortality was similar according to the severity of heart failure, assessed either by left ventricular ejection fraction or by New York Heart Association classification. In CIBIS II, beta-blockers induced a significant reduction in mortality of 45% (95%CI: 9 to 66), 41% (95%CI: 17 to 59) and 23% (95%CI: 1 to 40) in the low, intermediate and high risk groups, respectively. Hospitalizations were reduced by 35% (95%CI: 2 to 57), 41% (95%CI: 18 to 58) and 23% (95%CI: 0 to 41), there was no significant difference between the three score groups. CONCLUSION: We conclude that the amplitude of benefit of the beta-blockers carvedilol, metoprolol and bisoprolol on mortality and morbidity is similar, regardless of the severity of chronic heart failure.

Adrenergic beta-Antagonists↗