[Biosimilar medicines: Regulatory issues and medico-economic impacts]. / Médicaments biosimilaires : enjeux réglementaires et impacts médicoéconomiques.

The concept of biosimilar medicine was launched by 2001 and 2004 European Directives. First European marketing authorizations were delivered in 2006. They are "copies" of biologically manufactured medicines, mostly proteins. Taking into account the intrinsic variability related to the biological manufacture process, some variation of the chemical structure of the finished compound may be observed. They impact especially the glycosylation residues but not the amino-acid sequence (for proteins). For this reason, the marketing authorization application dossier has to involve, as opposed to the generic medicine procedure, the demonstration of the therapeutic equivalence in at least one clinical indication of the princeps medicine. Introduction of biosimilar medicines of monoclonal antibodies has represented a remarkable event in the domain of rheumatology, gastroenterology and dermatology with infliximab, etanercept and adalimumab biosimilars and in cancerology domains with rituximab, trastuzumab and bevacizumab biosimilars. Biosimilar medicines availability reduces the risk of drug supply rupture of princeps but their main impact is the economic one allowing cost reduction of costly princeps biological medicines. With the acquired clinical experience, the initial fears concerning switch form princeps to a biosimilar for a given patient has progressively disappeared.

[Introduction of Health technology assessment at hospital]. / Mise en place de l'évaluation des technologies de santé en milieu hospitalier.

INTRODUCTION: The Medical Devices Committee (CODIMS) of the Assistance publique-Hôpitaux de Paris (AP-HP) is responsible for deciding whether innovative and costly sterile medical devices (SMD) should be adopted for the AP-HP network and for issuing recommendations on their proper use. The aim of this study was to qualify retrospectively the level of evidence of clinical studies used for the device evaluations by the CODIMS in 2012 and 2013 and to analyze the relationship between levels of evidence and decisions. MATERIAL AND METHOD: Executive summaries written in 2012 and 2013 about studied SMD was analyzed and the level of evidence of clinical studies used was qualified in high/low levels of evidence according to the scale of Sackett et al. Then, levels of evidence were correlated to decisions published by the CODIMS. RESULTS: Sixty-one files of SMD (72.1% of implantable MD) have been evaluated (225 clinical studies). Among them, only 28% of clinical studies had a high level of evidence (and 28.6% of MD at-risk) and 18% did not have any clinical studies. The CODIMS delivered an unfavourable opinion for 16 SMD: only 28 clinicals studies were available for evaluation. Among these, only 6 studies had a high level of evidence. DISCUSSION ET CONCLUSION: The amount and level of evidence of clinical studies is naturally correlated to admittance of SMD. These findings suggest that the clinical evidence used to demonstrate safety and efficacy for high-risk medical devices is based on clinical studies with poor quality data, making more difficult the evaluation of SMD in hospital. The development of a multi-criteria tool to help decision-making would improve the process of SMD evaluation by the CODIMS.

Impact of ABCC2 polymorphisms on high-dose methotrexate pharmacokinetics in patients with lymphoid malignancy.

Human multidrug resistance-related protein 2 (MRP2, encoded by ABCC2) is involved in the transport of anionic drugs such as methotrexate (MTX). We prospectively investigated the influence of four common ABCC2 genetic variants (rs717620, rs2273697, rs8187694 and rs8187710) on MTX pharmacokinetics parameters. MTX concentrations were monitored in 50 patients with lymphoid malignancy (27 males; mean age: 53±17 years) receiving high-dose MTX (5.13±1.88 g m(-)(2) in a 4-h perfusion). The population pharmacokinetics modelling showed that ABCC2 -24T allele (rs717620) had a combined influence on both MTX elimination and distribution. The MTX clearance and distribution volume were significantly higher in carriers of at least one copy of the -24T allele as compared with noncarriers: 8.6±2.2 vs 6.7± 2.5 l h(-1), P<0.01 and 30.7±7.7 vs 22.1±8.8 l, P<0.001, respectively. Consequently, -24T allele carriers were more prone to reach MTX nontoxic levels, 48 h after administration.

Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice.

BACKGROUND: Serotonin (5-hydroxytryptamine; 5-HT) overproduction is responsible for cardiac valvular disease in patients with carcinoid tumors. Reduced 5-HT inactivation is one proposed mechanism of the valvulopathy observed in individuals treated with the appetite suppressants fenfluramine and phentermine. One key protein limiting systemic availability of 5-HT is the 5-HT transporter (5-HTT) expressed by platelets and pulmonary vascular cells; 5-HTT is responsible for 5-HT uptake and subsequent inactivation of the amine passing through the lung. Here we investigated whether 5-HTT-deficient (5-HTT-KO) mice developed structural and/or functional cardiac abnormalities and valvulopathy. METHODS AND RESULTS: Cardiac endothelial cells expressed large amounts of 5-HTT in wild-type mice. 5-HTT deficiency appeared to be associated with marked interstitial, perivascular, and valvular fibrosis as evidenced by staining of cardiac collagen in 5-HTT-KO mice. Histological analysis provided evidence for valvulopathy characterized by valvular hyperplasia and prominent fibrosis at the attachment site and base of the leaflets. Echocardiography revealed an increase in left ventricular lumen diameter and a decrease in left ventricular diameter fractional shortening. Although 5-HT1B receptors mediated the 5-HT-induced collagen secretion by human cardiac myofibroblasts, the contribution of this receptor type to valvulopathy was ruled out because double-KO mice deficient in both 5-HTT and 5-HT1B receptors showed the same cardiac alterations as 5-HTT-KO mice. CONCLUSIONS: The present results establish a link between 5-HTT and the development of cardiac fibrosis and valvulopathy in vivo. 5-HTT-KO mice represent an especially relevant model for studying the mechanisms by which 5-HT induces valvulopathy.

[New insights and perspectives in the management of dyslipidemia]. / Avancées récentes et perspectives dans le traitement des dyslipidémies athérogènes.

PURPOSE: Recent end point trials of lipid-lowering drugs have shown that patients at very high-risk for coronary disease benefit from treatments that lowers low density lipoprotein cholesterol (LDL cholesterol) plasma levels< or =70 mg/dl and that patients with at least 2 risk factors benefit from LDL cholesterol levels< or =100 mg/dl. Epidemiologic studies have shown that the concentration of high density lipoprotein cholesterol (HDL cholesterol) is a strong, independent, inverse predictor of coronary disease risk. Innovative pharmacological approaches to raise low HDL cholesterol levels are currently of considerable interest, especially for patients with type 2 diabetes or metabolic syndrome. RESULTS: Rosuvastatin has shown superior efficacy in lowering LDL cholesterol, although evidence of clinical benefit is actually lacking. Ezetimibe is a lipid-lowering drug that inhibits absorption of dietary and biliary cholesterol. Its co-administration with statin has given very interesting results. Niacin is the most effective of currently available options for raising HDL cholesterol, although tolerability can be an issue, with serious side effects such as loss of glucose control and liver toxicity. Flushing may occur in 80% of treated patients. Two CETP inhibitors have shown therapeutical efficacy to raise HDL cholesterol, but clinical benefit remains uncertain.

Amoxicillin-clavulanic acid prescriptions at the Greater Paris University Hospitals (AP-HP).

OBJECTIVE: We aimed to document amoxicillin-clavulanic acid prescription to improve the proper use of antibiotics in hospital settings. We used three criteria: quality of medical charts, adequacy of indications, and adequacy of treatment duration. METHOD: This study was designed as a one-day point prevalence survey carried out by antibiotic lead specialists. RESULTS: We included 387 prescriptions from 32 hospitals. Immunodeficiency was recorded as a risk factor in 30% of patients. Computerized prescriptions were observed in 79% of cases. The indication was mentioned in 73% of cases and a 48/78-hour re-assessment of the antibiotic therapy was performed in 54% of cases. The antibiotic indication was primarily for pneumonia and was deemed appropriate in 75% of patients. Adult mean treatment duration was 11.1 days. Use of dual combination therapy and/or treatment duration exceeding two weeks accounted for the main reasons for an inappropriate use of antibiotics. Prescriptions recorded as having been made by senior physicians were of the shortest treatment duration (P=0.0163). CONCLUSION: Medical charts should be better filled in. Reinforcing the role of senior physicians in supervising antibiotic prescriptions is likely to result in a better control of treatment duration and ultimately in a reduced antibiotic consumption. By reinforcing the collaboration between pharmacists and antibiotic lead specialists, the improvement of computerized prescriptions at hospital level should help better detect the "at risk" prescriptions, namely those exceeding seven days or those combining antibiotics.

[Prevention of major ischemic events in lower limb arterial disease: does aspirin play a role?]. / Prévention des évènements ischémiques majeurs au cours de l'artériopathie oblitérante des membres inférieurs: l'aspirine a-t-elle un rôle?

OBJECTIVE: To determine the effect of aspirin among patients with lower limb occlusive arterial disease. DESIGN: Meta-analysis of trials issuing from a collaborative meta-analysis of randomized trials of anti-platelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Five trials were identified as comparing aspirin (with or without dipyridamole) to placebo, in 1 029 patients with lower limb occlusive arterial disease. There was no new publication found comparing aspirin and placebo in lower limb occlusive arterial disease. MAIN OUTCOME MEASURE: As in the main meta-analysis, "serious vascular event": non fatal myocardial infarction, non fatal stroke or vascular death. RESULTS: Among these 1 029 patients, allocation to aspirin did not reduce the outcome of serious vascular event, nor of any of the individual events. This result, as opposed to the enhancement of 23% +/- 8% announced in the main meta-analysis, clearly demonstrate that the beneficial effect cannot be attributable to aspirin. DISCUSSION: In the collaborative meta-analysis, aspirin was the most widely used product (75% of the trials) and it showed its beneficial effect when administered at doses ranging from 75 to 150 mg/day, as compared to placebo. Among the other anti-platelet treatments analyzed, clopidogrel was the only product for which large scale randomized evidence versus aspirin was available. Various national health institutions, in the United States as well as in Europe, show a major concern regarding the use of anti-platelet treatments, in peripheral arterial occlusive disease as well as in other manifestations of cardiovascular disease. Their guidelines take of course the patient's health into account but the economical aspect of this prevention is increasingly hard to circumvent. Based on the results of the collaborative meta-analysis, these guidelines all recommend a lifetime use of low doses of aspirin, reserving clopidogrel for patients intolerant to aspirin, mainly because they do not consider the additional benefit recognized with clopidogrel as important enough to counterbalance the cost of the treatment. While aspirin as a first choice antiplatelet therapy cannot be discussed in coronary disease, after a myocardial infarction, or in cerebrovascular disease, its use in lower limb occlusive arterial disease does not enable a reduction in morbi-mortality. From an economical point of view, the use of a cheap but inefficient preventive treatment could also lead to an increased cost for curing the complications expected with an uncontrolled widely spread disease as chronic lower limb ischemia.

Effect of sodium cis-beta-4-methoxybenzoyl-beta-bromacrylate (Cytembena) on HeLa cell kinetics.

The treatment of HeLa cells with various concentrations of sodium beta-4-methoxybenzoyl-beta-bromacrylate (Cytembena) results in inhibition of growth and modification of cell cycle distribution. These phenomena were observed at concentrations between 7.5 x 10(-5) and 2.5 x 10(-5) M. The estimation of DNA content by flow cytometry showed an important shift in the distribution of cycling cells with a relative decrease of G0 + G1 cells and a striking accumulation of G2 + M cells. According to our experimental conditions, the blocking up in G2 + M is irreversible at 7.5 and 5 x 10(-5) M.

Transfer for primary angioplasty versus immediate thrombolysis in acute myocardial infarction: a meta-analysis.

BACKGROUND: The benefit of primary percutaneous coronary intervention (PCI) over thrombolysis has been clearly demonstrated in acute myocardial infarction (AMI). However, the best therapeutic strategy for a patient with AMI presenting to acute care services without catheterization facilities remains under debate. Our objective was to gather all available information from clinical trials comparing transfer of patients experiencing AMI for angioplasty versus immediate thrombolysis. METHODS AND RESULTS: We performed a meta-analysis of all data available from published randomized trials and from presentations in scientific sessions of major cardiology congresses comparing the 2 strategies. The primary end point was the combined criteria (CC) of death/reinfarction/stroke as defined in each trial. Relative risk (RR) evaluated the treatment effect. We identified 6 clinical trials including 3750 patients. Transfer time was always <3 hours. The CC was significantly reduced by 42% (95% confidence interval [CI] 29% to 53%, P<0.001) in the group transferred for primary PCI compared with the group receiving on-site thrombolysis. When CC parameters were considered separately, reinfarction was significantly reduced by 68% (95% CI, 34% to 84%; P<0.001) and stroke by 56% (95% CI, -15% to 77%; P=0.015). There was a trend toward reduction in all-cause mortality of 19% (95% CI, -3% to 36%; P=0.08) with transfer for PCI. CONCLUSIONS: Even when transfer to an angioplasty center is necessary, primary PCI remains superior to immediate thrombolysis. Organization of ambulance systems, prehospital management, and adequate PCI capacity appear now to be the key issues in providing reperfusion therapy for AMI.

Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial.

BACKGROUND: beta-Blockade-induced benefit in heart failure (HF) could be related to baseline heart rate and treatment-induced heart rate reduction, but no such relationships have been demonstrated. METHODS AND RESULTS: In CIBIS II, we studied the relationships between baseline heart rate (BHR), heart rate changes at 2 months (HRC), nature of cardiac rhythm (sinus rhythm or atrial fibrillation), and outcomes (mortality and hospitalization for HF). Multivariate analysis of CIBIS II showed that in addition to beta-blocker treatment, BHR and HRC were both significantly related to survival and hospitalization for worsening HF, the lowest BHR and the greatest HRC being associated with best survival and reduction of hospital admissions. No interaction between the 3 variables was observed, meaning that on one hand, HRC-related improvement in survival was similar at all levels of BHR, and on the other hand, bisoprolol-induced benefit over placebo for survival was observed to a similar extent at any level of both BHR and HRC. Bisoprolol reduced mortality in patients with sinus rhythm (relative risk 0.58, P:<0.001) but not in patients with atrial fibrillation (relative risk 1.16, P:=NS). A similar result was observed for cardiovascular mortality and hospitalization for HF worsening. CONCLUSIONS: BHR and HRC are significantly related to prognosis in heart failure. beta-Blockade with bisoprolol further improves survival at any level of BHR and HRC and to a similar extent. The benefit of bisoprolol is questionable, however, in patients with atrial fibrillation.

Persistent transient myocardial ischemia despite beta-adrenergic blockade predicts a higher risk of adverse cardiac events in patients with coronary artery disease.

OBJECTIVES: We evaluated the prevalence and prognostic significance of transient myocardial ischemia despite beta-adrenergic blockade in patients with coronary artery disease. BACKGROUND: Persistence of transient ischemia despite therapy may correspond to a subset of high risk patients with coronary disease. The impact of beta-blocker withdrawal in these patients remains unknown. METHODS: Patients (n = 313) with documented coronary artery disease and beta-blocker therapy, with (group I, n = 84) or without (group II, n = 229) transient ischemia on ambulatory electrocardiographic monitoring, were followed up during 21 +/- 9 months for cardiac events (death, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass surgery and worsening angina). Occurrence of events was compared by log-rank test. RESULTS: The number of coronary stenoses did not differ significantly between groups I and II. Beta-blocker therapy was discontinued more frequently during follow-up in group II (25% vs. 14% in group I, p = 0.04). Cumulative percentage of death or myocardial infarction, or both, tended to be higher in group I a 30 months (17% vs. 5% in group II, p = 0.09). Coronary angioplasty and bypass surgery were significantly more frequent in group I (p = 0.01 and 0.0008, respectively). Transient ischemia was associated with a higher cumulative probability of adverse events (p = 0.004). The number of coronary stenoses, presence of transient ischemia and beta-blocker withdrawal were the only significant prognostic factors of cardiac events in the Cox model. In group I patients, the relative hazard of cardiac events was increased threefold when beta-blocker therapy was interrupted. CONCLUSIONS: These data suggest that 1) the occurrence of transient ischemia despite beta-blocker therapy identifies a subset of high risk patients with coronary artery disease, and 2) the interruption of beta-blocker therapy increases the risk of adverse cardiac events.

Studies on in vitro colony formation by mouse bone marrow cells using different inflammatory pleural exudates. Relation to colony stimulating factor (CSF).

An inflammatory exudate obtained in Swiss mice 3 hours after intrapleural injection of dextran was able to increase the number of cultivated peritoneal macrophages in S phase. This exudate was also able to stimulate the formation of colonies from mice bone marrow progenitors of macrophages and granulocytes in methylcellulose culture. The stimulating activity of this acute inflammatory exudate was compared with that of colony stimulating factor (GM.CSF). The qualitative and quantitative results showed that the biological activity of the mitogenic factor of this inflammatory exudate, inflammatory mitogenic factor (IMF) was very close to GM.CSF at optimal concentration, but when used at the same concentration, the exudate was less active than GM.CSF. A stimulating activity was also found with another inflammatory pleural exudate induced by calcium pyrophosphate. The comparative kinetics of the action of the two exudates on CFUc appeared alike but the rise was earlier with calcium pyrophosphate. These results suggest the release of a growth factor for monocyte-macrophage in different acute inflammatory exudates.

Effect of in vitro treatment with indomethacin on mouse granulocyte-macrophage colony-forming cells in culture (CFUC). Possible role of prostaglandins.

The effect of indomethacin (6 mg/kg daily orally for 2, 3 or 4 days) on myelopoiesis was studied in mice by estimating 1) differential cell counts of bone marrow, 2) proliferation of the CFUC in presence of GM-CSF, 3) proliferative state of CFUC after tritiated thymidine suicide. After 4 days of treatment, a rise in the recognizable myeloid precursors, an increase of both the colony forming capacity and the number of CFUC in S-phase were observed. These data suggest that indomethacin produced an hyperplasia of the committed stem cell compartment. The decrease of PGE2 amounts in bone marrow cells following treatment with indomethacin could explain the hyperplasia observed. These in vivo results are in accordance with the in vitro data which show that PG could control the proliferation and differentiation of myeloid progenitor cells.

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.

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.

Effects of donor's age on growth kinetics of rabbit articular chondrocytes in culture.

The in vitro proliferative capacity of articular chondrocytes derived from young and old rabbits was investigated to examine if the modifications incurred can be related to the in vivo aging. Determinations were made of the cartilage cell density, cell volume, cell number at confluency, plating efficiency, growth curve and DNA content distributions. The old donor cells were characterized by a decline in all the parameters of cartilage growth studied: cell number at confluency, cell replication rate (from 20 h to 45 h) as well as an increase in cell volume. The mean cycle time in vitro increased from 17.5 h compared to 27 h during in vivo aging, essentially because of an elongation of the G1 phase. Chondrocytes derived from young and old donors may be an appropriate model system for studying the in vitro effects of drugs on rheumatoid diseases as a function of in vivo aging.

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.

Prognostic value of neurohormonal activation and cardiopulmonary exercise testing in patients with chronic heart failure.

We compared the value of plasma neurohormones and cardiopulmonary exercise testing for predicting long-term prognosis in patients with moderate congestive heart failure (CHF). We studied 264 consecutive patients with CHF due to left ventricular systolic dysfunction. Plasma atrial natriuretic peptide (ANP), norepinephrine, and endothelin-1 were measured at rest in all patients, who also underwent a symptom-limited maximal exercise with oxygen consumption (VO(2)) determination. After a median follow-up of 789 days, 52 deaths and 31 heart transplantations occurred, of which 4 were urgent. In an univariate analysis, New York Heart Association functional class, systolic blood pressure at rest, left ventricular end-diastolic diameter, left ventricular ejection fraction, peak VO(2), percent of predicted peak VO(2), plasma ANP, plasma norepinephrine, and plasma endothelin-1 were associated with survival without urgent heart transplantation. In a multivariate stepwise regression analysis, only plasma ANP (p = 0.0001), left ventricular ejection fraction (p = 0.007), and plasma norepinephrine (p = 0.035), but neither peak VO(2) nor percentage of predicted peak VO(2), were independent predictors of death or urgent heart transplantation. Determination of plasma ANP and norepinephrine provides additional independent information for long-term prognostic determination compared with exercise testing alone. Measurement of plasma neurohormones should therefore be considered routinely as a complementary or alternative tool for identifying high-risk patients with moderate CHF.

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.