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Biomedical subjects

P Nony

Publications and source records attributed to P Nony.

At least 19 recordsLinked to original sources
PubMed2005

Phosphodiesterase III inhibitors for heart failure.

BACKGROUND: In the treatment of chronic heart failure, vasodilating agents, ACE inhibitors and beta-blockers have shown an increase of life expectancy. Another strategy is to increase the inotropic state of the myocardium : phosphodiesterase inhibitors (PDIs) act by increasing intra-cellular cyclic AMP, thereby increasing the concentration of intracellular calcium, and lead to a positive inotropic effect. OBJECTIVES: This overview on summarised data aims to review the data from all randomised controlled trials of PDIs III versus placebo in symptomatic patients with chronic heart failure. The primary endpoint is total mortality. Secondary endpoints are considered such as cause-specific mortality, worsening of heart failure (requiring intervention), myocardial infarction, arrhythmias and vertigos. We also examine whether the therapeutic effect is consistent in the subgroups based on the use of concomitant vasodilators, the severity of heart failure, and the type of PDI derivative and/or molecule. This overview updates our previous meta-analysis published in 1994. SEARCH STRATEGY: Randomised trials of PDIs versus placebo in heart failure were searched using MEDLINE (1966 to 2004 January), EMBASE (1980 to 2003 December), Cochrane CENTRAL trials (The Cochrane Library Issue 1, 2004) and McMaster CVD trials registries, and through an exhaustive handsearching of international abstracting publications (abstracts published in the last 22 years in the "European Heart Journal", the "Journal of the American College of Cardiology" and "Circulation"). SELECTION CRITERIA: All randomised controlled trials of PDIs versus placebo with a follow-up duration of more than three months. DATA COLLECTION AND ANALYSIS: 21 trials (8408 patients) were eligible for inclusion in the review. 4 specific PDI derivatives and 8 molecules of PDIs have been considered. MAIN RESULTS: As compared with placebo, treatment with PDIs was found to be associated with a significant 17% increased mortality rate (The relative risk was 1.17 (95% confidence interval 1.06 to 1.30; p<0.001). In addition, PDIs significantly increase cardiac death, sudden death, arrhythmias and vertigos. Considering mortality from all causes, the deleterious effect of PDIs appears homogeneous whatever the concomitant use (or non-use) of vasodilating agents, the severity of heart failure, the derivative or the molecule of PDI used. AUTHORS' CONCLUSIONS: Our results confirm that PDIs are responsible for an increase in mortality rate compared with placebo in patients suffering from chronic heart failure. Currently available results do not support the hypothesis that the increased mortality rate is due to additional vasodilator treatment. Consequently, the chronic use of PDIs should be avoided in heart failure patients.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Impact of osmolality on burning sensations during and immediately after intramuscular injection of 0.5 ml of vaccine suspensions in healthy adults.

A randomised placebo controlled double-blind cross-over trial was performed on twenty healthy adults to assess the effect of osmolality (300,600,850 and 1100 mOsm) on local tolerance of an intramuscular injection (0.5 ml) of five suspensions containing the same components as the excipients of a combined Diphtheria-Tetanus-acellular Pertussis-inactivated Poliomyelitis-Haemophilus influenzae type b paediatric vaccine (DtacP-IPV-Hib, PENTAVAC). The results did not show any dose-effect relationship between burning or pain sensations and the different osmolalities tested. Although mild and not clinically relevant, these sensations seemed to occur more frequently following injection of an isotonic saline solution (P<0.05). Thus, the osmolality of vaccine like suspensions does not appear to be a potential cause of local pain or burning sensation after their administration.

Adolescent↗
PubMed2001

Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis.

BACKGROUND: The optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism remains controversial. METHODS AND RESULTS: We performed an open-label, randomized trial comparing a short oral anticoagulant course (3 months for proximal deep vein thrombosis [P-DVT] and/or pulmonary embolism [PE]; 6 weeks for isolated calf DVT [C-DVT]) with a long course of therapy (6 months for P-DVT/PE; 12 weeks for C-DVT). The outcome events were recurrences and major, minor, or fatal bleeding complications. A total of 736 patients were enrolled. There were 23 recurrences of venous thromboembolism in the short treatment group (6.4%) and 26 in the long treatment group (7.4%); the 2 treatment regimens had an equivalent effect. For the hemorrhage end point, the difference between the short and the long treatment groups was not significant: 15.5% versus 18.4% for all events (P=0.302), 1.7% versus 2.8% (P=0.291) for major events, and 13.9% versus 15.3% for minor bleeding. Subgroup analysis demonstrated that the rate of recurrence was lower for C-DVT than for P-DVT or PE. CONCLUSIONS: After isolated C-DVT, 6 weeks of oral anticoagulation is sufficient. For P-DVT or PE, we demonstrated an equivalence between 3 and 6 months of anticoagulant therapy. For patients with temporary risk factors who have a low risk of recurrence, 3 months of treatment seems to be sufficient. For patients with idiopathic venous thromboembolism or permanent risk factors who have a high risk of recurrence, other trials are necessary to assess prolonged therapy beyond 6 months.

Administration, Oral↗
PubMed2001

Characterization of adenovirus-induced inverted terminal repeat-independent amplification of integrated adeno-associated virus rep-cap sequences.

Stable packaging cell lines expressing the rep and cap genes for recombinant adeno-associated virus type 2 (rAAV-2) assembly constitute an attractive alternative to transient transfection protocols. We recently characterized a stable HeLa rep-cap cell clone (HeRC32) and demonstrated that upon vector transfection and adenovirus infection, efficient rAAV assembly correlated with a 100-fold amplification of the integrated rep-cap sequence with the inverted terminal repeats (ITRs) deleted. We now report a more detailed analysis of this phenomenon and highlight the key cellular and viral factors involved. Determination of the rep-cap copy number of HeRC32 cells indicated that maximum rep-cap amplification occurred between 24 and 48 h following adenovirus infection. Analysis by pulsed-field gel electrophoresis of adenovirus-infected HeRC32 cells indicated that amplified rep-cap sequences were found in an extrachromosomal form. Amplification of the rep-cap sequence with the ITRs deleted was not dependent on adenovirus replication and still occurred when the highly specific adenovirus polymerase was inactivated. In contrast, amplification was inhibited in the presence of aphidicolin, indicating that cellular polymerases were needed. Our study also documented that among the adenovirus gene products, the DNA-binding protein (DBP) was essential, since rep-cap amplification was severely abrogated when HeRC32 cells were infected at a nonpermissive temperature with an adenovirus mutant encoding a thermosensitive DBP. Furthermore, expression of DBP alone in HeRC32 cells was sufficient to induce a sustained level of rep-cap amplification. Finally, immunofluorescence analysis showed that HeRC32 cells expressing the DBP also simultaneously expressed the Rep proteins, suggesting a possible involvement of the latter in rep-cap amplification. Indeed, the lack of detectable amplification in an adenovirus-infected stable rep-cap HeLa cell clone unable to produce Rep proteins further supported that, among the viral gene products, both the DBP and Rep proteins are necessary to induce the targeted amplification of the integrated rep-cap sequences in the absence of the AAV ITRs.

Adenoviridae↗
PubMed2001

Novel cis-acting replication element in the adeno-associated virus type 2 genome is involved in amplification of integrated rep-cap sequences.

This study identifies a region of the adeno-associated virus type 2 (AAV-2) rep gene (nucleotides 190 to 540 of wild-type AAV-2) as a cis-acting Rep-dependent element able to promote the replication of transiently transfected plasmids. This viral element is also shown to be involved in the amplification of integrated sequences in the presence of adenovirus and Rep proteins.

Base Sequence↗
PubMed2000

In vivo measurement of myocardial oxidative metabolism and blood flow does not show changes in cancer patients undergoing doxorubicin therapy.

PURPOSE: The aim was to investigate in patients receiving doxorubicin whether any alteration in myocardial oxidative metabolism or blood flow as assessed by positron emission tomography (PET) could be observed either after the first dose of the drug, or during its chronic administration. METHODS: Six female non-heart-failure cancer patients treated with doxorubicin were included in a longitudinal study. Resting radionuclide cineangiography and PET scanning with carbon-11 acetate were performed the day before the initiation of doxorubicin treatment at a dosage of 50 mg/m2 every 3 weeks, and 3 weeks after the cumulative administration of 300 mg/m2 (chronic toxicity). In addition, PET was performed 24 h after the first administration of doxorubicin (evaluation of acute toxicity). Myocardial oxidative metabolism and blood flow were assessed by PET (acute and chronic toxicity), and left ventricular ejection fraction was measured by radionuclide angiography (chronic toxicity). RESULTS: Using PET for both acute and chronic toxicity evaluations, no significant effect of doxorubicin was observed either on the flux through the tricarboxylic acid (TCA) cycle or on myocardial blood flow. However, systolic left ventricular function showed a small but significant impairment after the administration of 300 mg/m2 of doxorubicin. CONCLUSIONS: Other hypotheses should be explored to better explain the predominant mechanisms of the cardiotoxicity of anthracyclines in humans.

Aged↗
PubMed2000

A pharmacokinetic simulation model for ivabradine in healthy volunteers.

Ivabradine is a novel bradycardic agent that has been developed for the prevention of angina. Ivabradine has an active metabolite S-18982. The aim of this study is to develop a pharmacokinetic simulation model. Pharmacokinetic data from two studies were pooled and included data from a total of 66 healthy male volunteers. The data were collected following single dose intravenous and multiple dose oral administration of ivabradine. The multiple dose regimens were administered every 12 h and there were seven active dosing levels. The modelling was performed using the NONMEM software. The model was assessed in terms of its ability to describe the original data set used in its construction and also data arising from a different clinical pharmacology study involving 12 additional subjects. The pharmacokinetics of ivabradine and S-18982 were best described by two linked two compartment intravenous bolus and first-order input, with first-pass loss, and first-order output model. When the model was used for simulation it produced an adequate description of both the original data and data arising from a different clinical pharmacology study.

Benzazepines↗
PubMed1999

An insulator element and condensed chromatin region separate the chicken beta-globin locus from an independently regulated erythroid-specific folate receptor gene.

We have identified a folate receptor gene upstream of the chicken beta-globin locus and separated from it by a 16 kbp region of silent chromatin. We find that this receptor is expressed only at a stage of erythroid differentiation (CFU-E) preceding the activation of beta-globin genes, consistent with the role of folate receptors in proliferation. This discovery raises the question of how these two loci are regulated during erythropoiesis. Our data suggest that the folate receptor gene and the beta-globin locus are regulated independently. We show that a 3.3 kbp DNA region upstream of the folate receptor gene is sufficient to induce strong expression of a transgene in CFU-E stage cells. We also find that the region between the beta-globin locus and the folate receptor gene is fully methylated and condensed at this stage of differentiation. Its 3' boundary coincides with the 5' beta-globin insulator. We speculate that the 5' beta-globin boundary element might be important for the proper regulation of two adjacent domains activated at two different stages during differentiation.

Amino Acid Sequence↗
PubMed1999

Implication of evidence-based medicine in prescription guidelines taught to French medical students: current status in the cardiovascular field.

OBJECTIVES: To study how satisfactory the contents of introductory courses in cardiovascular therapeutics, given to medical students in France, are with respect to the concepts of evidence-based medicine. METHODS: Medical school lecturers were asked to provide written course material used as part of medical school courses. Best-available evidence was classified as existent (including two therapeutic subclasses: indicated and contraindicated), and nonexistent. Four scores (from 0 to 10) were given, according to conformity with best-available evidence, and citation of randomized clinical trials (RCT), meta-analyses and therapeutic objectives. RESULTS: Thirty-four written documents were obtained from 43 faculties. Although the score (mean +/- SEM) of conformity with best-available evidence was 5.43 +/- 0.28 for the existent best-available evidence class, the corresponding scores for the citation of RCT, meta-analyses, and therapeutic objectives were, respectively, 1 +/- 0.2, 0.16 +/- 0.07, and 2.7 +/- 0.3. The four scores were highest when the best-available evidence belonged to the indicated class, intermediate when best-available evidence was nonexistent, and lowest for the contraindicated class (P < .05). These scores were significantly higher when the printed material was intended for specialists. CONCLUSION: Despite some limitations, the extent of agreement with the best-available evidence is only moderate. Pathophysiologic reasoning is largely preferred to justify the choice of therapeutics recommended to medical students.

Analysis of Variance↗
PubMed1998

Alternate promoters and developmental modulation of expression of the chicken GATA-2 gene in hematopoietic progenitor cells.

We have isolated and characterized the chicken GATA-2 (cGATA-2) gene. We show that, as in the case of some other members of the GATA gene family, the gene is expressed from alternative first exons. One of the resulting mRNAs represents only a minor form of the GATA-2 mRNA in the cells and tissues we analyzed; the other is ubiquitously expressed. We have defined the minimal promoter that controls expression of this most abundant mRNA and that is necessary for full activity in hematopoietic progenitor cells. The activity of this promoter in transient assays is consistent with developmental differences of expression levels in these cells. We identify within the promoter a previously unrecognized extended CCAAT motif essential for its activity. The organization of the cGATA-2 gene, with alternative first exons and a CCAAT box in the proximal promoter, is similar to that recently described for mouse GATA-2, and the proximal promoter also resembles the only promoter so far described in Xenopus. Nonetheless, the roles of the promoters in development and tissue-specific expression are quite different in these organisms, most strikingly in the mouse, which assigns developmental roles to its proximal and distal promoters that are quite different from those in the chicken. We suggest that although the overall organization may remain the same, the role assigned to each promoter varies among organisms. We identify distant upstream regulatory elements in the cGATA-2 gene that modulate expression from the proximal promoter and that may be responsible for this variation.

Animals↗
PubMed1998

Revisiting the effect compartment through timing errors in drug administration.

The variations in the pharmacological effects induced by timing errors in drug intake are compared for two drugs, one acting by way of an effect compartment and the other directly from the central compartment. A simulation was performed for two drugs having the same concentration-effect relationship at the receptor site, the same mean effect at equilibrium and identical concentrations in the central compartment. In this article. Patrice Nony, Michel Cucherat and Jean-Pierre Boissel discuss how, for the same variability of concentrations in the central compartment, the variations in mean effects are different. When there is a large variability in the interval separating two consecutive doses, the model that includes an effect compartment dampens the pharmacokinetic variability present in the central compartment. Such an approach may be useful for the prescription recommendations of drugs, especially those with narrow therapeutic indices.

Dose-Response Relationship, Drug↗
PubMed1998

The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0.

Vitamin K antagonists are most commonly used in long-term thrombosis prophylaxis and the use in patients with cardiovascular disease seems to be increasing. By interfering with the normal hemostatic mechanism, an increased risk of bleeding will arise and administration of human plasma or prothrombin complex concentrates may be necessary. It can be difficult to normalize hemostasis using plasma and prothrombin complex concentrates, because these may be associated with thromboembolic side-effects. The level of factor VII, one of the vitamin-K-dependent coagulation factors, decreases during oral anticoagulant therapy and the administration of recombinant factor VIIa normalizes the prolonged prothrombin time in warfarin-treated rats. After administration of acenocoumarol (International Normalized Ratio > 2), decreased levels of factor X and factor IX (19-46%), protein C (2-20%) and factor VII (4-17%) were found in 28 healthy volunteers. After one dose of recombinant factor VIIa (5, 10, 20, 40, 80, 120, 160, 240, or 320 microg/kg) the International Normalized Ratio and prothrombin time normalized, which may imply an effect on bleeding in individuals receiving oral anticoagulant therapy. The lowest dose (5 microg/kg) normalized the International Normalized Ratio for 12 h and doses > 120 microg/kg normalized it for 24 h. Fragment 1+2 stayed within its normal range in all dose groups, indicating that no systemic coagulation occurred.

Acenocoumarol↗
PubMed1998

Population pharmacokinetics of recombinant factor VIIa in volunteers anticoagulated with acenocoumarol.

This study establishes a population PK model for FVII clotting activity (FVII:C) after injection of recombinant activated factor VII (rFVIIa) to healthy volunteers. Twenty eight volunteers, anticoagulated with acenocoumarol, received one or two rFVIIa injections, with dose ranging from 5 to 320 microg/kg. The FVII:C kinetic was fitted to a 2 compartment model, with continuous "endogenous perfusion" mimicking endogenous activity. Estimated clearance was 2.4 1/h (20% inter-individual variability and 9% inter-period variability). The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses < or = 20 microg/kg and 88 ml/kg for doses > 20 microg/kg respectively, with 16% inter-individual variability. The dose producing 50% of the maximum drop of INR was estimated to be 2.2 microg/kg. The model will be used to better define the dosage regimen for future clinical developments.

Acenocoumarol↗
PubMed1997

The N-terminal fingers of chicken GATA-2 and GATA-3 are independent sequence-specific DNA binding domains.

The GATA family of vertebrate DNA binding regulatory proteins are expressed in diverse tissues and at different times of development. However, the DNA binding regions of these proteins possess considerable homology and recognize a rather similar range of DNA sequence motifs. DNA binding is mediated through two domains, each containing a zinc finger. Previous results have led to the conclusion that although in some cases the N-terminal finger can contribute to specificity and strength of binding, it does not bind independently, whereas the C-terminal finger is both necessary and sufficient for binding. Here we show that although this is true for the N-terminal finger of GATA-1, those of GATA-2 and GATA-3 are capable of strong independent binding with a preference for the motif GATC. Binding requires the presence of two basic regions located on either side of the N-terminal finger. The absence of one of these near the GATA-1 N-terminal finger probably accounts for its inability to bind. The combination of a single finger and two basic regions is a new variant of a motif that has been previously found in the binding domains of other finger proteins. Our results suggest that the DNA binding properties of the N-terminal finger may help distinguish GATA-2 and GATA-3 from GATA-1 and the other GATA family members in their selective regulatory roles in vivo.

Amino Acid Sequence↗
PubMed1997

Standardization of terminology in meta-analysis: a proposal for working definitions.

In this paper we present a brief overview of the growing concern to standardize definitions and terminology in meta-analysis. This tool has become inescapable in both drug research and therapeutic evaluation. The performed and published meta-analyses are increasing, as well as the variation in the meaning of the terms used in meta-analysis. In the second part of the paper we propose glossary of the most common terms used in reports of meta-analyses. The glossary has been written by only one group of scientists, the definitions are therefore proposed to the scientific community as working definitions, to be subject to reactions from leaders in meta-analysis.

Clinical Trials as Topic↗
PubMed1997

Differential binding of the Bombyx silk gland-specific factor SGFB to its target DNA sequence drives posterior-cell-restricted expression.

The gene encoding the silk protein P25 in Bombyx mori is expressed in the posterior silk gland (PSG) cells and repressed in the middle silk gland (MSG) cells. To identify the factors involved in this transcription-dependent spatial restriction, we examined the P25 chromatin in PSG and MSG nuclei by DNase I-aided ligation-mediated PCR and analyzed the expression of various P25-lacZ constructs in biolistically treated silk glands. P25 promoter activation depends on two cis-acting elements. One coincides with the target sequence of SGFB, a silk gland-specific factor present in all silk gland nuclei, but bound to its target DNA sequence in only PSG cells. The interaction of the other element with a factor that we named PSGF is also exclusive to PSG cells. Placed ahead of a non-P25-related basal promoter, the SGFB and PSGF elements are sufficient to drive posterior-cell transcription. Collectively, our data support the hypothesis that the spatial restriction of P25 expression is driven by the stabilization of SGFB onto its target sequence by the action of PSGF.

Animals↗
PubMed1996

Interactive and dynamic ECG analysis. Is it just an IDEA or a clinically relevant approach?

The idea that it is possible to increase the overall electrocardiographic (ECG) diagnostic performance is developed in this paper, provided that different programs or methods and various data sources are combined and that the dynamicity of the patients' record is considered. This dynamicity consists of the following three dimensions: beat-to-beat changes within continuous recordings, changes between serial records, and clinical events. Data integration should be time- or event-related, and multisources data should interact. Interactive and dynamic ECG analysis (IDEA), however, can only be achieved if powerful clinical workstations are developed that access the right information, when and where needed, a challenge that the IDEA workstation intends to accomplish.

Clinical Laboratory Information Systems↗