Role of innovation in pharmaceutical regulation: A proposal for principles to evaluate EU General Pharmaceutical Legislation from the innovator perspective.

Because the EU General Pharmaceutical Legislation is under review, the EFPIA Innovation Board developed evaluation principles for the policy proposals and key considerations on how the regulatory framework can support innovation while ensuring only safe, efficacious and quality medicines are authorized. The evaluation principles are anchored on actions to promote: agile adoption of new methodologies with soft law tools; continued emphasis on regulatory science to inform policies; a cost/benefit assessment of the new regulation to ensure they have an overall positive impact; and mitigation of any negative externalities or unintended effects for any type of innovation or products. The evaluation principles are intended to guide the impact assessment of the pharmaceutical legislation in the EU but the principles can be applied globally.

Toward A Regulatory Pathway for the Use of in Silico Trials in the CE Marking of Medical Devices.

In Silico Trials methodologies will play a growing and fundamental role in the development and de-risking of new medical devices in the future. While the regulatory pathway for Digital Patient and Personal Health Forecasting solutions is clear, it is more complex for In Silico Trials solutions, and therefore deserves a deeper analysis. In this position paper, we investigate the current state of the art towards the regulatory system for in silico trials applied to medical devices while exploring the European regulatory system toward this topic. We suggest that the European regulatory system should start a process of innovation: in principle to limit distorted quality by different internal processes within notified bodies, hence avoiding that the more innovative and competitive companies focus their attention on the needs of other large markets, like the USA, where the use of such radical innovations is already rapidly developing.

[Cardiac lymphatic system]. / Le système lymphatique cardiaque.

The lymphatic system is a network of vessels and lymphoid tissues that maintain tissue fluid homeostasis, transport intestinal fat, and regulate immune surveillance. Despite a large body of evidence showing the importance of lymphatic vessels in cardiovascular diseases, the role of cardiac lymphatics has not been extensively investigated. This review highlights the chronology of key discoveries in cardiac lymphatic development and function. In physiology, the cardiac lymphatic system dynamically regulates interstitial fluid drainage to the mediastinal lymph nodes to maintain homeostasis and prevent edema. After myocardial infarction, lymphatic vessels in the ischemic heart become dysfunctional and contribute to the development of chronic myocardial edema that aggravates cardiac fibrosis and dysfunction. Stimulation of cardiac lymphangiogenesis, based on the delivery of lymphangiogenic growth factors, such as VEGF-C, may represent a novel therapeutic strategy to improve cardiac function.

[Ageing: a matter of heart?]. / Vieillissement - Une question de cœur ?

Ageing is considered as a major risk factor for the development of chronic diseases. Among these, heart failure seems to be particularly important for both triggering and accelerating pathological ageing. In the present review, we give a general overview of the most relevant results concerning the mechanism of normal and premature senescence of cardiomyocytes and cardiac stromal cells. In particular, we will address the role of telomere dysfunction, DNA damage response, impairment of mitochondrial function, miRNAs and secretome of senescent cells in cardiac ageing and failure.

Integrative knowledge management to enhance pharmaceutical R&D.

Information technologies already have a key role in pharmaceutical research and development (R&D), but achieving substantial advances in their use and effectiveness will depend on overcoming current challenges in sharing, integrating and jointly analysing the range of data generated at different stages of the R&D process.

Applying systems biology in drug discovery and development.

Translational research is a continuum between clinical and basic research where the patient is the center of the research process. It brings clinical research to a starting point for the drug discovery process, permitting the generation of a more robust pathophysiological hypothesis essential for a better selection of drug targets and candidate optimization. It also establishes the basis of early proof for clinical concept studies, preferably in phase I, for which biomarkers and surrogate endpoints can often be used. Systems biology is a prerequisite approach to translational research where technologies and expertise are integrated and articulated to support efficient and productive realization of this concept. The first component of systems biology relies on omics-based technologies and integrates the changes in variables, such as genes, proteins and metabolites, into networks that are responsible for an organism's normal and diseased state. The second component of systems biology is in the domain of computational methods, where simulation and modeling create hypotheses of signaling pathways, transcription networks, physiological processes or even cell- or organism-based models. The simulations aim to show the origin of perturbations of the system that lead to pathological states and what treatment could be achieved to ameliorate or normalize the system. This review discusses how translational research and systems biology together could improve global understanding of drug targets, suggest new targets and approaches for therapeutics, and provide a deeper understanding of drug effects. Taken together, these types of analyses can lead to new therapeutic options while improving the safety and efficacy of new and existing medications.

RhoA guanine exchange factor expression profile in arteries: evidence for a Rho kinase-dependent negative feedback in angiotensin II-dependent hypertension.

Sustained overactivation of RhoA is a common component for the pathogenesis of several cardiovascular disorders, including hypertension. Although activity of Rho proteins depends on Rho exchange factors (Rho-GEFs), the identity of Rho-GEFs expressed in vascular smooth muscle cells (VSMC) and participating in the control of Rho protein activity and Rho-dependent functions remains unknown. To address this question, we analyzed by quantitative RT-PCR the expression profile of 28 RhoA-GEFs in arteries of normotensive (saline-treated) and hypertensive (ANG II-treated) rats. Sixteen RhoA-GEFs were downregulated in mesenteric arteries of hypertensive rats, among which nine are also downregulated in cultured VSMC stimulated by ANG II (100 nM, 48 h), suggesting a direct effect of ANG II. Inhibition of type 1 ANG II receptors (losartan, 1 µM) or Rho kinase (fasudil, 10 µM) prevented ANG II-induced RhoA-GEF downregulation. Functionally, ANG II-induced downregulation of RhoA-GEFs is associated with decreased Rho kinase activation in response to endothelin-1, norepinephrine, and U-46619. This work thus identifies a group of RhoA-GEFs that controls RhoA and RhoA-dependent functions in VSMC, and a negative feedback of RhoA/Rho kinase activity on the expression of these RhoA-GEFs that may play an adaptative role to limit RhoA/Rho kinase activation.

The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure.

Hypertension is one of the most frequent pathologies in the industrialized world. Although recognized to be dependent on a combination of genetic and environmental factors, its molecular basis remains elusive. Increased activity of the monomeric G protein RhoA in arteries is a common feature of hypertension. However, how RhoA is activated and whether it has a causative role in hypertension remains unclear. Here we provide evidence that Arhgef1 is the RhoA guanine exchange factor specifically responsible for angiotensin II-induced activation of RhoA signaling in arterial smooth muscle cells. We found that angiotensin II activates Arhgef1 through a previously undescribed mechanism in which Jak2 phosphorylates Tyr738 of Arhgef1. Arhgef1 inactivation in smooth muscle induced resistance to angiotensin II-dependent hypertension in mice, but did not affect normal blood pressure regulation. Our results show that control of RhoA signaling through Arhgef1 is central to the development of angiotensin II-dependent hypertension and identify Arhgef1 as a potential target for the treatment of hypertension.

[The Innovative Medicine Initiative (IMI)]. / L'Initiative Médicaments Innovants : développement de l'innovation biomédicale en Europe.

The Innovative Medicine Initiative (IMI) is a joint technology initiative jointly implemented by the European Commission and by the European Federation of Pharmaceutical Industries and Associations (EFPIA). The objective of IMI, officially launched on April 30th 2008, is to identify and address the bottlenecks of the drug discovery and development process. IMI will reinforce the public-private partnerships and will be focused towards critical nodes of the drug discovery such as efficacy predictivity, safety predictivity, knowledge management and education and training. This initiative will also reinforce the attractivity of Europe for biomedical science and will then lead to the discovery of novel therapeutic strategies for the patients.

Implication of microRNAs in the cardiovascular system.

MicroRNAs (miRNAs) are endogenous, small, noncoding RNAs that regulate about 30% of protein-coding genes of the human genome. Thus far, more than 400 miRNAs have been cloned and sequenced in humans. Their biological importance, initially demonstrated in cancer, viral diseases and developmental processes, was more recently investigated in cardiovascular physiology and pathology. MiRNAs expression is tightly controlled in a tissue-specific and developmental stage-specific manner and some of them are highly and specifically expressed in cardiovascular tissues. Through the regulation of the expression of genes involved in cell growth, contractility and electrical conductance, cardiac miRNAs may play a major role in heart development and function. In vascular cells, miRNAs have been linked to vasculoproliferative conditions such as angiogenesis and neointimal lesion formation. Diagnostic use and therapeutic modulation of individual miRNAs or miRNA clusters in cardiovascular diseases will have to be further explored in the future. Molecules specifically regulating cardiovascular miRNAs, either mimicking or antagonizing miRNAs actions, will hopefully normalize dysfunctional gene networks and constitute a new therapy paradigm of cardiovascular diseases.

Rho exchange factors in the cardiovascular system.

Increasing evidence has accumulated to implicate overactivation of Rho protein as a common component for the pathogenesis of several cardiovascular disorders including hypertension, coronary and cerebral vasospasm, atherosclerosis, and diabetes. Recent advances in Rho protein signaling research indicate that the Rho exchange factors (Rho GEFs) which activate Rho proteins by catalyzing the exchange of GDP for GTP are major regulators of Rho protein activity. In addition, linkage analysis and association studies have recently identified Rho GEFs as susceptibility genes for cardiovascular diseases. All of these data are converging to suggest that as upstream activators of Rho proteins, Rho GEFs expressed in cardiovascular cells are good candidate targets for the treatment of cardiovascular disorders.

Quantitative mRNA analysis of serotonin 5-HT4 receptor isoforms, calcium handling proteins and ion channels in human atrial fibrillation.

Serotonin 5-HT(4) receptors are present in human atrial myocytes and have been proposed to contribute to the generation of atrial fibrillation (AF). Here, we quantified 5-HT(4) receptors as well as other key genes involved in cardiac rhythm and contraction in right atrial appendages of patients with chronic AF (CAF) and acute AF (AAF). Right atrial appendages were obtained from eleven patients in sinus rhythm (SR), five with AAF and six with CAF (>12 months). TaqMan real time quantitative RT-PCR was performed on total RNA. Results were normalised to the average of three housekeeping genes, cyclophilin, GADPH and RL-19. The rank order of expression of h5-HT(4) receptors variants was (b)>(a)>(g)>(c) in the group of patients in SR. In AAF, we found a strong decrease in h5-HT(4(b)), h5-HT(4(c),) and h5-HT(4(g)) transcripts. In CAF patients, the mRNA expression level of the h5-HT(4(b)) isoform significantly increased two fold versus SR. A similar increase was reported for beta(1)-adrenergic receptor, connexin 43 and the L-type Ca(2+) channel CaCNA1C subunit. Interestingly, CAF was associated with a strong increase in the expression of Na(+)/Ca(2+) exchanger and the voltage-dependent Na(+) channel SCN5A subunit. Our results indicate that h5-HT(4(b)) is the dominant cardiac isoform of human 5-HT(4) receptors and its expression is increased in CAF. These data support the involvement of 5-HT(4) receptors in atrial arrhythmia.

Beneficial effects of direct call to emergency medical services in acute myocardial infarction.

OBJECTIVES: We investigated the impact of an emergency medical services call on the management of acute myocardial infarction, considering time intervals for intervention and revascularization procedures. METHODS: Data were prospectively collected from January 2001 to October 2002 from 531 patients hospitalized for myocardial infarction with ST segment elevation and a pre-hospital delay of less than 24 h. RESULTS: Only 26% of patients called the emergency medical services at the onset of symptoms (n=140). Other patients (n=391, 74%) called another medical contact. Baseline characteristics and cardiovascular history were similar in the two groups, except for the percutaneous coronary intervention history (10% in the emergency medical services group versus 4% in the other medical contact group, P<0.05). Time intervals from the onset of symptoms of myocardial infarction to call or to medical intervention, as well as the time interval from medical intervention to hospital admission were significantly shorter in the emergency medical services group. The early reperfusion rate was also significantly greater in the emergency medical services group (77%) compared with the other medical contact group (64%), mainly because of a greater incidence of primary percutaneous coronary intervention (36 versus 26%, P<0.03, respectively). Multivariate analysis adjusted for sex and age showed that less than three medical care providers [odds ratio (OR) 5.042, P<0.001], percutaneous coronary intervention history (OR 2.462, P<0.05), as well as rhythmic disorders (OR 2.105, P<0.05) and complete atrioventricular block (OR 2.757, P<0.05) were independent predictors of emergency medical services care. CONCLUSION: This study demonstrated that a call to the emergency medical services is underutilized by patients with symptoms of myocardial infarction, and documented the beneficial effects of an emergency medical services call by reducing pre-hospital delays and increasing early revascularization therapies.