Facteurs influençant la prescription de la médication cardioprotectrice recommandée chez les patients avec une maladie artérielle périphérique

Introduction : Les guides de pratique recommandent que les patients avec une maladie artérielle périphérique (MAP) soient traités médicalement afin de réduire la survenue d’évènements cardiovasculaires majeurs. Objectif : Identifier les facteurs associés à la prescription des thérapies préventives recommandées. Méthode : Les patients avec une MAP (n=362) traités consécutivement par angiodilatation fémoropoplitée entre 2008 et 2010 dans un centre tertiaire (CHU de Québec, Canada) ont été inclus dans l’étude. L’issue clinique primaire était la prescription de trois thérapies combinées. Résultats : Au total, 52% des patients recevaient la thérapie combinée. La présence d’au moins trois facteurs de risque cardiovasculaire (Rapport de cotes (RC)=4,51; IC 95% : 2,76-7,37) était le facteur le plus fortement associé à la prise des thérapies combinées. Conclusion : La prise en charge du risque cardiovasculaire des patients avec une MAP est encore sous-optimale. Une meilleure compréhension des barrières et des facilitateurs à l’application des recommandations est toujours nécessaire.Introduction: Guidelines recommend that patients with peripheral arterial disease (PAD) should be medically treated to reduce the occurrence of serious cardiovascular events. Objective: To identified factors associated with the prescription of preventive therapies in patients with PAD. Methods: Consecutive patients with PAD (n=362) who underwent peripheral percutaneous transluminal angioplasty between 2008 and 2010 in one tertiary care center (CHU de Quebec, Canada) were considered for the study. Data were collected from the medical charts. The main outcome was the combined prescription of three therapies. Results: A total of 52% of the patients received the three combined therapies. Having at least three cardiovascular risk factors (Odds Ratio (OR)=4.51; 95% CI: 2.76-7.37) was the factor most strongly associated with the prescription of the combined therapies. Conclusion: Canadian patients with PAD are still not optimally managed. We still need to better understand the barriers and facilitators to the application of the guidelines in PAD patients

Molecular imaging of the human pulmonary vascular endothelium using an adrenomedullin receptor ligand.

Presented at the Sixth Annual Scientific Workshops and Debates of the Pulmonary Vascular Institute, Istanbul, January 24, 2013. An abstract was published in Pulmonary Circulation 2013;3:706.International audienceThis phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99mTc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans (N = 20) were included into escalating groups of 5 mCi (n = 5), 10 mCi (n = 5), or 15 mCi (n = 10) 99mTc-PulmoBind. SPECT imaging was serially performed, and 99mTc-PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% ± 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99mTc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension

Update on the urotensinergic system: new trends in receptor localization, activation, and drug design.

International audienceThe urotensinergic system plays central roles in the physiological regulation of major mammalian organ systems, including the cardiovascular system. As a matter of fact, this system has been linked to numerous pathophysiological states including atherosclerosis, heart failure, hypertension, diabetes as well as psychological, and neurological disorders. The delineation of the (patho)physiological roles of the urotensinergic system has been hampered by the absence of potent and selective antagonists for the urotensin II-receptor (UT). Thus, a more precise definition of the molecular functioning of the urotensinergic system, in normal conditions as well as in a pathological state is still critically needed. The recent discovery of nuclear UT within cardiomyocytes has highlighted the cellular complexity of this system and suggested that UT-associated biological responses are not only initiated at the cell surface but may result from the integration of extracellular and intracellular signaling pathways. Thus, such nuclear-localized receptors, regulating distinct signaling pathways, may represent new therapeutic targets. With the recent observation that urotensin II (UII) and urotensin II-related peptide (URP) exert different biological effects and the postulate that they could also have distinct pathophysiological roles in hypertension, it appears crucial to reassess the recognition process involving UII and URP with UT, and to push forward the development of new analogs of the UT system aimed at discriminating UII- and URP-mediated biological activities. The recent development of such compounds, i.e. urocontrin A and rUII(1-7), is certainly useful to decipher the specific roles of UII and URP in vitro and in vivo. Altogether, these studies, which provide important information regarding the pharmacology of the urotensinergic system and the conformational requirements for binding and activation, will ultimately lead to the development of potent and selective drugs

Presence of urotensin-II receptors at the cell nucleus: specific tissue distribution and hypoxia-induced modulation.

International audienceUrotensin II (UII) and its receptor UT, are widely expressed in the cardiovascular and central nervous system, where they exert regulatory actions under both physiological and pathological conditions. Our study, aimed at investigating the presence of functional nuclear UT in various rat and monkey tissues as well as in human cell lines, demonstrated for the first time by Western blot analysis and confocal immunofluorescence a tissue-specific nuclear expression of this receptor (heart and central nervous system). This nuclear UT was further characterized pharmacologically through radioligand binding studies using specific ligands of the urotensinergic system, as well as somatostatin. In 2D-gel experiments, we observed the presence of different post-translational modifications between membrane and nuclear UT receptors in brain extracts. Transcription initiation assays showed de novo RNA synthesis caused by UII and Urotensin-related peptide (URP) which were inhibited by an UT antagonist urantide. In hypoxic/ischemic conditions, UT receptors were differentially modulated in regard to subcellular localization. Thus, the unique regiospecificity of the nuclear UT receptor along with its particular modulation under hypoxic conditions could indicate a specific and complementary physiological role that could be correlated with pro-angiogenic and/or neuromodulatory actions of UII, both in the cardiovascular and central nervous system

Urocontrin, a novel UT receptor ligand with a unique pharmacological profile.

International audienceIn recent years, several studies have demonstrated that urotensin II (UII) and urotensin II-related peptide (URP) can exhibit differential biological activity. So far, known antagonists of the urotensin II receptor (UT) are of limited usefulness for investigating the specific pathophysiological role of UII or URP. Therefore, identification of new compounds able to discriminate UII- and URP-associated biological activities is crucially needed. In the present study, we report preliminary data regarding the pharmacological properties of a novel UT ligand termed urocontrin, i.e. [Bip(4)]URP, that is able to reduce the ex vivo efficacy of hUII- but not URP-induced vasoconstriction in rat aortic rings. In vivo studies support the pharmacological profile described above. Although urocontrin exert some residual agonist activity, this compound should be useful for the rational design of potent molecules that would allow discriminating specific biological action mediated by UII or URP

Lipophilicity-antiproliferative activity relationship study leads to the preparation of a ruthenium(II) arene complex with considerable in vitro cytotoxicity against cancer cells and a lower in vivo toxicity in zebrafish embryos than clinically approved cis-platin.

International audienceRu(II)-arene complexes are attracting increasing attention due to their considerable antitumoral activity. However, it is difficult to clearly establish a direct relationship between their structure and antiproliferative activity, as substantial structural changes might not only affect their anticancer activity but also tightly control their activation site(s) and/or their biological target(s). Herein, we describe the synthesis and characterization of four ruthenium(II) arene complexes bearing bidentate N,O-donor Schiff-base ligands ([Ru(η(6)-benzene)(N-O)Cl]) that display a significantly distinct antiproliferative activity against cancer cells, despite their close structural similarity. Furthermore, we suggest there is a link between their respective antiproliferative activity and their lipophilicity, as the latter affects their ability to accumulate into cancer cells. This lipophilicity-cytotoxicity relationship was exploited to design another structurally related ruthenium complex with a much higher antiproliferative activity (IC50 > 25.0 μM) against three different human cancer cell lines. Whereas this complex shows a slightly lower activity than that of clinically approved cis-platin against the same human cancer cell lines, it displays a lower toxicity in zebrafish (Danio rerio) embryos at concentrations up to 20 μM

PulmoBind, an adrenomedullin-based molecular lung imaging tool.

International audiencePrevious studies showed that adrenomedullin (AM) could be a promising agent for molecular imaging of the pulmonary circulation, with abundant specific binding sites at the pulmonary vascular endothelium. The purpose of this work was to design an AM-based compound that encompasses the desired imaging properties without posing safety issues for clinical applications. AM analogs were synthesized through solid-phase peptide synthesis. They were evaluated for (99m)Tc labeling efficiency and in vivo lung uptake. Biodistribution and hemodynamic characteristics of the lead compound were determined in anesthetized dogs as well as by a dosimetric analysis. Lung perfusion was evaluated in the monocrotaline model of pulmonary arterial hypertension in rats. A cyclic AM (residues 22-52) analog encompassing a polyethylene glycol spacer and a tetrapeptide chelating moiety was found to possess the desired characteristics, with 90.7% ± 0.3% (mean ± SD) labeling efficiency, 40% lung uptake at 10 min after injection, and a favorable safety profile. Lung uptake of the (99m)Tc-labeled compound was markedly reduced in rats with pulmonary arterial hypertension. This lead compound could be a suitable clinical imaging agent for the molecular diagnosis of disorders of the pulmonary circulation

Characterization of the adrenomedullin receptor acting as the target of a new radiopharmaceutical biomolecule for lung imaging.

International audienceDirect labeling of linear adrenomedullin (AM) with (99m)Tc ([(99m)Tc]AM) displayed excellent selectivity for imaging the pulmonary circulation system in dogs. Hence, we investigated this particular selectivity and characterized the binding sites found in dog lungs. AM and other peptides belonging to the calcitonin peptide family, including calcitonin-gene related peptide (CGRP), adrenomedullin-2 (AM2), amylin and pro-adrenomedullin N-terminal peptide (PAMP), were prepared by solid-phase peptide synthesis. Receptor binding assays were performed by using [(125)I]AM as a radioligand on dog lung homogenates. It was found that AM bound with potent affinity, displaying in fact a high and a low affinity binding site. Moreover, competition binding assays using peptide ligands showed the following ranking for displacement: AM>AM(13-52)>CGRP approximately AM2> or =AM(22-52)> or =AM2(16-47)>CGRP(8-37)>amylin approximately PAMP. Thus, these results strongly suggested that the AM binding site found in dog lungs and acting as a clearance receptor is mainly the adrenomedullin AM(1) receptor subtype. The pharmacophores underlying AM(1) binding affinity and specificity were studied by determining the key amino acids, the minimal peptide fragment, and some aspects of the secondary structures. So far, it appeared that the C-terminal segment of human AM is an essential feature for binding. Also, the alpha-helix secondary structure found in the AM molecule would facilitate the ligand recognition process with the AM receptor in dog lungs. Our results demonstrated that AM or some analogs or fragments could be suitable radiopharmaceutical agents for lung imaging

Receptor-independent cellular uptake of pituitary adenylate cyclase-activating polypeptide.

International audiencePituitary adenylate cyclase-activating polypeptide (PACAP), a hypophysiotropic neurohormone, participates in the regulation of pleiotropic functions. The recent discovery of intracellular PACAP receptors in the brain and the testis as well as the physico-chemical characteristics of PACAP, i.e. extended α-helix containing basic residues, prompted us to evaluate the propensity of PACAP to cross the plasma membrane in a receptor-independent manner. Using confocal microscopy and flow cytometry, we demonstrated the ability of FITC-conjugated PACAP to efficiently penetrate into the internal cell compartment by direct translocation and endocytosis through clathrin-coated pits and macropinocytosis. Our study also revealed that, once inside the cells, PACAP38 is not entirely degraded by intracellular enzymes and that a significant amount of intact PACAP38 is also able to exit cells. Moreover, using binding assay on rat nuclear fractions from various tissues, PACAP nuclear receptors were identified. We also found that PACAP stimulates calcium release in rat testis nuclei. Interestingly, PACAP27 and PACAP38 but not VIP were able to upregulate de novo DNA synthesis in testis nuclei and that this effect was abolished by PACAP(6-38). These results support the presence of PAC1 receptors at the nuclear membrane and raise questions about their role in the biological activity of the peptide. These findings contribute to the characterization of PACAP as an intracrine factor and suggest that these intracellular PAC1 binding sites, probably associated with specific biological activities, should be taken into account during the development of PACAP-based drugs