SAR216471, an alternative to the use of currently available P2Y12 receptor inhibitors?

P2Y12 antagonism is a key therapeutic strategy in the management and prevention of arterial thrombosis. The objective of this study was to characterize the pharmacodynamic (PD) and pharmacokinetic (PK) properties of SAR216471, a novel P2Y12 receptor antagonist. SAR216471 blocks the binding of 2MeSADP to P2Y12 receptors in vitro (IC50=17 nM). This inhibition was shown to be reversible. It potently antagonized ADP-induced platelet aggregation in human and rat platelet-rich plasma (IC50=108 and 62 nM, respectively). It also inhibited platelet aggregation when blood was exposed to collagen or thromboxane A2. Its high selectivity was demonstrated against a large panel of receptors, enzymes, and ion channels. Despite its moderate bioavailability in rats, oral administration of SAR216471 resulted in a fast, potent, and sustained inhibition of platelet aggregation where the extent and duration of platelet inhibition were directly proportional to its circulating plasma levels. Pre-clinical study of SAR216471 in a rat shunt thrombosis model demonstrated a dose-dependent antithrombotic activity after oral administration (ED50=6.7 mg/kg). By comparison, ED50 values for clopidogrel, prasugrel and ticagrelor were 6.3, 0.35 and 2.6 mg/kg, respectively. Finally, the anti-hemostatic effect of SAR216471 and its competitors was investigated in a rat tail bleeding model, revealing a favorable safety profile of SAR216471. Together, these findings have established a reliable antiplatelet profile of SAR216471, and support its potential use in clinical practice as an alternative to currently available P2Y12 receptor antagonists.

[Implementing a pluridisciplinary network of intimate partner violence prevention]. / La création d'un réseau pluridisciplinaire de prévention de la violence conjugale.

INTRODUCTION: The victims of a spouse's violence have a high risk of developing mental and physical health symptoms. The efforts aimed at preventing the consequences of domestic violence are encouraged by the current literature as well as the national and international recommendations. They highlight the fact that intervention and treatment programs have more or less failed. BACKGROUND: This publication introduces the main stages of the implementation of a network, the main goals of which are to improve the knowledge and professional practices aimed at the victims of domestic violence, and to enhance the continuation and quality of health and social care (screening, assessment and addressing). After relating the developments and the methodology of the victims' consultations carried out, we will show how such a network device enables one to exceed the usual practice limits. First, we point out certain specificities pertaining to postimmediate psychological care (psychological debriefing) of victims of intimate partner violence. METHODOLOGY: After presenting a specific methodology of assessment of the global situation of the victim, three illustrations of the specific consequences of domestic violence will be made, in order to highlight the interest of collaborating between professionals who are used to tackling this issue. First, is the way to empower women and help them to avoid assaults and thus prevent victimisation. The overall goal of this specific intervention is to teach women that they can end the cycle of perpetuating of intimate partner violence by learning safety factors, such as what to do if more violence occurs and where and how to seek assistance if it were to recur. Second, is to prevent the consequences of domestic violence on a child's development. It is based on the fact that children who witness domestic violence are negatively affected, as children who witness abuse are likely to experience a number of psychological symptoms. So the network proposes preventive measures and specific addressing to reduce the impact of violence. The third example relates to the high proportion of sexual assault among the nature of violence women suffer from. Victims of marital rape experience significant levels of negative mental and physical health symptoms. Network professionals have improved the screening of sexual assault in order to propose to the victims specific addressing, in terms of gynaecologic and psychological care. DISCUSSION: As a consequence, we deal with the professional and deontological positioning that the medical professionals have towards this device. The network device aims at going beyond the limits of the usual care, both through a pooling of knowledge and multidisciplinary practices. The establishment of common models of intervention (working groups), also suggests a best practice in relation to complex issues: the establishment of a network is a means of establishing the link between professionals. However, professionals in a network should routinely question their practice and ethics and to avoid "confusion of roles" - the risk of multidisciplinary and standard practices. Differences and professional specialisation are essential components of a care offer tailored to the clinical complexity of victims of domestic violence. It now appears necessary to assess the impact of this care at the social, health and psychological levels of victims of domestic violence.

Genotype phenotype correlation of 30 patients with Smith-Magenis syndrome (SMS) using comparative genome hybridisation array: cleft palate in SMS is associated with larger deletions.

BACKGROUND: Smith-Magenis syndrome (SMS) is rare (prevalence 1 in 25 000) and is associated with psychomotor delay, a particular behavioural pattern and congenital anomalies. SMS is often due to a chromosomal deletion of <4 Mb at the 17p11.2 locus, leading to haploinsufficiency of numerous genes. Mutations of one of these gemes, RAI1, seems to be responsible for the main features found with heterozygous 17p11.2 deletions. METHODS: We studied DNA from 30 patients with SMS using a 300 bp amplimers comparative genome hybridisation array encompassing 75 loci from a 22 Mb section from the short arm of chromosome 17. RESULTS: Three patients had large deletions (10%). Genotype-phenotype correlation showed that two of them had cleft palate, which was not found in any of the other patients with SMS (p<0.007, Fisher's exact test). The smallest extra-deleted region associated with cleft palate in SMS is 1.4 Mb, contains <16 genes and is located at 17p11.2-17p12. Gene expression array data showed that the ubiquitin B precursor (UBB) is significantly expressed in the first branchial arch in the fourth and fifth weeks of human development. CONCLUSION: These data support UBB as a good candidate gene for isolated cleft palate.