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Objectives The aim of this study was to develop a risk score integrating cytochrome P450 2C19 loss-of-function genotypes with clinical risk factors influencing clopidogrel response that would allow the identification with more precision of subjects at risk for high platelet reactivity (HPR) and adverse clinical outcomes. Background Clopidogrel is the most broadly used platelet P2Y12 inhibitor. However, a considerable number of patients achieve inadequate platelet inhibition, with persistent HPR, an established marker of increased thrombotic risk, underscoring the need for tools to help identify these subjects. Although carriers of loss-of-function alleles of the cytochrome P450 2C19 enzyme have reduced clopidogrel metabolism leading to increased rates of HPR and thrombotic complications, this explains only a fraction of the pharmacodynamic response to clopidogrel, and a number of clinical factors have also been shown to have contributing roles. Methods Three prospective and independent studies were used to: 1) develop a risk score integrating genetic and clinical factors to identify patients with HPR while on clopidogrel; 2) investigate the external validity of the risk score; and 3) define clinical outcomes associated with the risk score in a cohort of patients with myocardial infarction treated with clopidogrel. Results A risk score ABCD-GENE (Age, Body Mass Index, Chronic Kidney Disease, Diabetes Mellitus, and Genotyping) was developed incorporating 5 independent predictors of HPR: 4 clinical (age >75 years, body mass index >30 kg/m2, chronic kidney disease [glomerular filtration rate Conclusions The ABCD-GENE score is a simple tool to identify patients with HPR on clopidogrel and who are at increased risk for adverse ischemic events, including mortality, following an acute myocardial infarction. In patients with a high ABCD-GENE score, long-term oral P2Y12 inhibitors other than clopidogrel should be considered.

Background: This study’s primary objective was to validate the routine use of S100B via a prospective study. The aim was a reduction of cranial computed tomography (CCT) scans by 30%. The secondary goal was to investigate the influence of age and associated risk factors on the reduction of CCT. Methods: S100B (sampling within 3 h postinjury) was used for patients with mild traumatic brain injury (mTBIs) presenting a medium risk of complications and requiring a CCT scan. Patients with negative S100B (S100B−) were discharged without a CCT scan. Results: Of the 1449 patients included in this study, 468 (32.3%) had S100B− with a sensitivity of 96.4% (95% CI: 87.5%–99.6%), a specificity of 33.4% (95% CI: 31%–36%) and a negative predictive value of 99.6% (95% CI: 98.5%–99.9%). No significant difference in serum levels or the S100B+ rate was observed if patients had retrograde amnesia (0.16 μg/L; 63.8%), loss of consciousness (0.13; 63.6%) or antiplatelet therapy (0.20; 77.9%). Significant differences were found between the S100B concentrations and S100B positivity rates in patients >65 years old and all the groups with patients 65 years old (n=504). Conclusions: The clinical use of S100B in mTBI management reduces the use of CCTs by approximately one-third; furthermore, the percentage of CCTs reduction is influenced by the age of the patient.

Article, see p 21 Despite progress in the diagnosis and treatment of stroke, it is estimated that >900 000 patients each year in the United States have a new stroke or transient ischemic attack (TIA) with an annual risk of 3% to 4% for recurrent events.1 The incidence of stroke or TIA is even higher in some countries such as China.2 Preventing stroke is therefore a major worldwide public health issue. Clopidogrel, in addition to 3 weeks of aspirin therapy, has been effective in reducing the risk of recurrence at 3 months in Chinese patients with TIA or a minor acute ischemic stroke, mainly by reducing the risk of recurrent ischemic stroke.3 To become active, clopidogrel needs to be metabolized via a 2-step oxidation process involving several hepatic cytochrome P450 isoenzymes, notably CYP2C19 , and irreversibly binds to P2Y12 receptors.4 Conversion of clopidogrel to its active metabolite depends on CYP2C19 genetic polymorphisms, with decreased platelet inhibition in carriers of 1 or 2 loss-of-function alleles (ie, intermediate or poor metabolizers). Several studies have shown that in patients with acute coronary syndromes treated by clopidogrel, carriers of at least 1 CYP2C19 loss-of-function allele, notably CYP2C19*2 , were at increased risk of major cardiovascular events and stent thrombosis, with a gene-dose relationship.5–8 Conversely, the CYP2C19*17 variant allele has been related to enhanced levels of active clopidogrel metabolites, greater inhibition of ADP-induced platelet aggregation, and increased risk of bleeding without an impact on ischemic events.9 The US Food and Drug Administration boxed warning in 2010 stated that CYP2C19 genotyping can be used as an aid in assessing the therapeutic safety and for considering alternative strategies to CYP2C19 poor metabolizers. From a clinical standpoint, however, the added value of assessing CYP2C19 polymorphisms depends on 3 factors: the …

International audience; Although kidney transplantation remains the best treatment for end-stage renal failure, it is limited by chronic humoral aggression of the graft vasculature by donor-specific antibodies (DSAs). The complement-independent mechanisms that lead to the antibody-mediated rejection (ABMR) of kidney allografts remain poorly understood. Increasing lines of evidence have revealed the relevance of natural killer (NK) cells as innate immune effectors of antibody-dependent cellular cytotoxicity (ADCC), but few studies have investigated their alloreactive potential in the context of solid organ transplantation. Our study aimed to investigate the potential contribution of the antibody-dependent alloreactive function of NK cells to kidney graft dysfunction. We first conducted an observational study to investigate whether the cytotoxic function of NK cells is associated with chronic allograft dysfunction. The NK-Cellular Humoral Activation Test (NK-CHAT) was designed to evaluate the recipient and antibody-dependent reactivity of NK cells against allogeneic target cells. The release of CD107a/Lamp1(+) cytotoxic granules, resulting from the recognition of rituximab-coated B cells by NK cells, was analyzed in 148 kidney transplant recipients (KTRs, mean graft duration: 6.2 years). Enhanced ADCC responsiveness was associated with reduced graft function and identified as an independent risk factor predicting a decline in the estimated glomerular filtration rate over a 1-year period (hazard ratio: 2.83). In a second approach, we used the NK-CHAT to reveal the cytotoxic potential of circulating alloantibodies in vitro. The level of CD16 engagement resulting from the in vitro recognition of serum-coated allogeneic B cells or splenic cells was further identified as a specific marker of DSA-induced ADCC. The NK-CHAT scoring of sera obtained from 40 patients at the time of transplant biopsy was associated with ABMR diagnosis. Our findings indicate that despite the administration of immunosuppressive treatments, robust ADCC responsiveness can be maintained in some KTRs. Because it evaluates both the Fab recognition of alloantigens and Fc-driven NK cell activation, the NK-CHAT represents a potentially valuable tool for the non-invasive and individualized evaluation of humoral risk during transplantation.

International audience; PURPOSE:Results of previous studies assessing the risk of bleeding associated with prescription of antiplatelet (AP) and/or oral anticoagulant (AC) therapy to hemodialysis patients are conflicting. Our purpose was to describe practices for prescription of AP and AC in hemodialysis patients in the Lorraine region, and to assess their effect on the risk of major bleeding events.METHODS:All adults with chronic kidney disease who began a first renal replacement therapy by hemodialysis in 2009 or 2010 in one of the 12 dialysis centers in Lorraine were included in the Thrombosis and Hemorrhage in HemoDialysis patients (T2HD) study and followed up until 30 June 2013. The association of each treatment (AP, AC, AP + AC) with the risk of major bleeding was estimated by three Cox proportional hazard models with an inverse probability of treatment weighting on a propensity score, considering the untreated patients as the reference.RESULTS:Among 502 patients included, 227 (45.2%) received an AP, 68 (13.5%) an AC, 81 (16.1%) a combination AP + AC, and 126 (25.1%) were untreated. As compared with untreated patients, those given AP (HR 5.52, 95% CI [3.11-9.80]), AC (HR: 4.15, 95% CI: [3.46-4.99]), and AP + AC (HR: 5.59, 95% CI [2.62-11.91]) were at greater risk of major bleeding events.CONCLUSIONS:The risk of major bleeding is higher in patients receiving an oral AC compared with untreated patients and those receiving an AP agent. A combination of the two drugs does not seem to increase the risk.

International audience; Osteochondroma is a non-rare benign osseous neoplasm[1] that is often observed within the posterior arch of vertebrae.Vascular compression may be observed because of thisexuberant bone formation [2]. Vertebral artery compressionin transverse canal is exceptional. We report on a case ofvertebral artery occlusion related to compressive osteochondroma,responsible for acute stroke in the vertebrobasilarsystem.

International audience; OBJECTIVE: To summarise and compare the efficacy and safety of various oral anticoagulants (dabigatran, rivaroxaban, apixaban, and vitamin K antagonists) and antiplatelet agents (acetylsalicylic acid) for the secondary prevention of venous thromboembolism. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Literature search using Medline (1950 to present), Embase (1980 to present), and the Cochrane Register of Controlled Trials using the OVID interface. Publications from potentially relevant journals were also searched by hand. REVIEW METHODS: Randomised controlled trials of patients receiving anticoagulants, antiplatelet drugs, or placebo or observation for secondary prevention of venous thromboembolism. Selected outcomes were rates of recurrent venous thromboembolism and major bleeding. Two reviewers independently extracted data onto standardised forms. RESULTS: 12 articles met our inclusion criteria, with 11,999 patients evaluated for efficacy and 12,167 for safety. All treatments reduced the risk of recurrent venous thromboembolism. Compared with placebo or observation, vitamin K antagonists at a standard adjusted dose (target international normalised ratio 2.0-3.0) showed the highest risk difference (odds ratio 0.07; 95% credible interval 0.03 to 0.15) and acetylsalicylic acid showed the lowest risk difference (0.65; 0.39 to 1.03). Risk of major bleeding was higher with a standard adjusted dose of vitamin K antagonists (5.24; 1.78 to 18.25) than with placebo or observation. Fatal recurrent venous thromboembolism and fatal bleeding were rare. Detailed subgroup and individual patient level data were not available. CONCLUSIONS: All oral anticoagulants and antiplatelet agents investigated in this analysis were associated with a reduced recurrence of venous thromboembolism compared with placebo or observation, although acetylsalicylic acid was associated with the lowest risk reduction. Vitamin K antagonists given at a standard adjusted dose was associated with the greatest risk reduction in recurrent venous thromboembolism, but also the greatest risk of major bleeding.

BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS:At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P

International audience; Docosahexaenoic acid (DHA), an important component of marine lipids, exhibits anti-inflammatory activity related to some of its oxygenated metabolites, such as neuroprotectin/protectin D1 [NPD1/PD1; 10(R),17(S)-dihydroxy-docosa-4Z,7Z, 11E,13E,15Z,19Z-hexaenoic acid] produced through the 15-lipoxygenase pathway. However, other metabolites from DHA can be produced through this pathway, and other polyunsaturated fatty acids (PUFAs) of nutritional value may be oxygenated as well. Their biological activities remain unknown. Isomers of protectin D1 were synthesized using soybean lipoxygenase and tested for their ability to inhibit human blood platelet aggregation. A geometric isomer called PDX, previously described with the 11E,13Z,15E geometry, instead of 11E,13E,15Z in PD1, inhibited platelet aggregation at submicromolar concentrations when induced by either collagen, arachidonic acid, or thromboxane. The inhibition occurred at the level of both the cyclooxygenase activity and thromboxane receptor site. Interestingly, all the metabolites tested exhibiting the E,Z,E-conjugated triene were active, whereas E,E,Z trienes (as in PD1) or all-trans (E,E,E) trienes were inactive. We conclude that PDX and other oxygenated products from PUFAs of nutritional interest, having the E,Z,E-conjugated triene motif and collectively named poxytrins (PUFA oxygenated trienes), might have antithrombotic potential.

International audience; Docosahexaenoic acid (DHA), an important component of marine lipids, exhibits anti-inflammatory activity related to some of its oxygenated metabolites, such as neuroprotectin/protectin D1 [NPD1/PD1; 10(R),17(S)-dihydroxy-docosa-4Z,7Z, 11E,13E,15Z,19Z-hexaenoic acid] produced through the 15-lipoxygenase pathway. However, other metabolites from DHA can be produced through this pathway, and other polyunsaturated fatty acids (PUFAs) of nutritional value may be oxygenated as well. Their biological activities remain unknown. Isomers of protectin D1 were synthesized using soybean lipoxygenase and tested for their ability to inhibit human blood platelet aggregation. A geometric isomer called PDX, previously described with the 11E,13Z,15E geometry, instead of 11E,13E,15Z in PD1, inhibited platelet aggregation at submicromolar concentrations when induced by either collagen, arachidonic acid, or thromboxane. The inhibition occurred at the level of both the cyclooxygenase activity and thromboxane receptor site. Interestingly, all the metabolites tested exhibiting the E,Z,E-conjugated triene were active, whereas E,E,Z trienes (as in PD1) or all-trans (E,E,E) trienes were inactive. We conclude that PDX and other oxygenated products from PUFAs of nutritional interest, having the E,Z,E-conjugated triene motif and collectively named poxytrins (PUFA oxygenated trienes), might have antithrombotic potential.

International audience

International audience; Leberagin-C, a new member of the disintegrin-like/cysteine-rich (D/C) family, was purified to homogeneity from the venom of Tunisian snake Macrovipera lebetina transmediterranea. It is a monomeric protein with a molecular mass of 25,787 Da. Its complete sequence of 205 amino acid residues was established by cDNA cloning. The leberagin-C shows many conserved sequences with other known D/C proteins, like the SECD binding sites and a pattern of 28 cysteines. It is the first purified protein from M. lebetina transmediterranea with only two disintegrin-like/cysteine-rich domains. Leberagin-C is able to inhibit platelet aggregation induced by thrombin and arachidonic acid with IC(50) of 40 and 50 nM respectively. It was also able to inhibit the adhesion of melanoma tumour cells on fibrinogen and fibronectin, by interfering with the function of alphavbeta3 and, to a lesser extent, with alphavbeta6 and alpha5beta1 integrins. To our knowledge, leberagin-C is the sole described D/C protein that does not specifically interact with the alpha2beta1 integrin. Structure-activity relationship study of leberagin-C suggested that there are some important amino acid differences with jararhagin, the most studied PIII metalloprotease from Bothrops jararaca, notably around the SECD motif in its disintegrin-like domain. Other regions implicated in leberagin-C specificities could not be excluded.

International audience; BACKGROUND: Acute coronary syndromes, including myocardial infarction and unstable angina, are important causes of premature mortality, morbidity and hospital admissions. Acute coronary syndromes consume large amounts of health care resources, and have a major negative economic and social impact through days lost at work, support for disability, and coping with the psychological consequences of illness. Several registries have shown that evidence based treatments are under-utilised in this patient population, particularly in high-risk patients. There is evidence that systematic educational programmes can lead to improvement in the management of these patients. Since application of the results of important clinical trials and expert clinical guidelines into clinical practice leads to improved patient care and outcomes, we propose to test a quality improvement programme in a general group of hospitals in Europe. METHODS/DESIGN: This will be a multi-centre cluster-randomised study in 5 European countries: France, Spain, Poland, Italy and the UK. Thirty eight hospitals will be randomised to receive a quality improvement programme or no quality improvement programme. Centres will enter data for all eligible non-ST segment elevation acute coronary syndrome patients admitted to their hospital for a period of approximately 10 months onto the study database and the sample size is estimated at 2,000-4,000 patients. The primary outcome is a composite of eight measures to assess aggregate potential for improvement in the management and treatment of this patient population (risk stratification, early coronary angiography, anticoagulation, beta-blockers, statins, ACE-inhibitors, clopidogrel as a loading dose and at discharge). After the quality improvement programme, each of the eight measures will be compared between the two groups, correcting for cluster effect. DISCUSSION: If we can demonstrate important improvements in the quality of patient care as a result of a quality improvement programme, this could lead to a greater acceptance that such programmes should be incorporated into routine health training for health professionals and hospital managers. TRIAL REGISTRATION: Clinicaltrials.gov NCT00716430.

International audience; AIMS: The effect of a cardiovascular rehabilitation program on arterial compliance in type 2 diabetes mellitus with coronary disease was studied. METHODS: Hemodynamic data and arterial compliance were measured with a tonometer (HDI/Pulse wave CR-2000) in coronary artery disease patients with (n=32) and without (n=24) type 2 diabetes before and after a 6-week multidisciplinary cardiac rehabilitation program. RESULTS: A decrease in heart rate and an increase in stroke volume without significant change in resting cardiac output were obtained in diabetic patients. Arterial compliance of both small and large arteries was significantly increased. In 10 diabetic patients, this increase could be related to an increase in the anti-hypertensive treatment and to the decreased blood pressure. In the 22 remainders, the small artery compliance was significantly increased independently of blood pressure change. CONCLUSIONS: Exercise training as well as optimization of diabetes and dyslipidemia treatment could explain the improvement of arterial compliance. If these changes are long-lasting and if they improve prognosis remains to be evaluated.

Udgivelsesdato: 2009-May-14 BACKGROUND: Vitamin K antagonists reduce the risk of stroke in patients with atrial fibrillation but are considered unsuitable in many patients, who usually receive aspirin instead. We investigated the hypothesis that the addition of clopidogrel to aspirin would reduce the risk of vascular events in patients with atrial fibrillation. METHODS: A total of 7554 patients with atrial fibrillation who had an increased risk of stroke and for whom vitamin K-antagonist therapy was unsuitable were randomly assigned to receive clopidogrel (75 mg) or placebo, once daily, in addition to aspirin. The primary outcome was the composite of stroke, myocardial infarction, non-central nervous system systemic embolism, or death from vascular causes. RESULTS: At a median of 3.6 years of follow-up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8% per year) and in 924 patients receiving placebo (7.6% per year) (relative risk with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.01). The difference was primarily due to a reduction in the rate of stroke with clopidogrel. Stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; 95% CI, 0.62 to 0.83; P

We report that administration of the low-molecular-weight thiol pantethine prevented the cerebral syndrome in Plasmodium berghei ANKA-infected mice. The protection was associated with an impairment of the host response to the infection, with in particular a decrease of circulating microparticles and preservation of the blood–brain barrier integrity. Parasite development was unaffected. Pantethine modulated one of the early steps of the inflammation–coagulation cascade, i.e., the transbilayer translocation of phosphatidylserine at the cell surface that we demonstrated on red blood cells and platelets. In this, pantethine mimicked the inactivation of the ATP-binding-cassette transporter A1 (ABCA1), which also prevents the cerebral syndrome in this malaria model. However, pantethine acts through a different pathway, because ABCA1 activity was unaffected by the treatment. The mechanisms of pantethine action were investigated, using the intact molecule and its constituents. The disulfide group (oxidized form) is necessary to lower the platelet response to activation by thrombin and collagen. Thio-sensitive mechanisms are also involved in the impairment of microparticle release by TNF-activated endothelial cells. In isolated cells, the effects were obtained by cystamine that lacks the pantothenic moiety of the molecule; however, the complete molecule is necessary to protect against cerebral malaria. Pantethine is well tolerated, and it has already been administered in other contexts to man with limited side effects. Therefore, trials of pantethine treatment in adjunctive therapy for severe malaria are warranted.

ERMA; International audience; BACKGROUND: Several studies highlight the underestimation of peripheral arterial disease (PAD) rates in general population, leading to a lack of opportunity to detect subjects at a high risk for cardiovascular events. We sought to investigate (i) the prevalence of unrecognised PAD in patients hospitalised for non-vascular diseases and (ii) the intensity of preventive drug therapies in this population. DESIGN AND METHODS: This study was of the cross-sectional design in a tertiary care hospital, which included 291 randomly selected patients of >or=40 years of age. Patients were assessed for medical history, pulse palpation and ankle-brachial index (ABI). The Edinburgh Claudication Questionnaire (ECQ) was administered. PAD was defined either by an ABIor=1.4 or in case of limb revascularisation history. RESULTS: Overall PAD prevalence was 29%; 21 patients (7.2%) with a history of PAD, while 65 (22.3%) had an unknown PAD. Among patients with unknown PAD, a typical intermittent claudication was unusual (3%). In patients without cardiovascular disease (CVD), four factors were associated with unrecognised PAD: absence of posterior tibial pulse (OR 4.49, 95% CI 1.89-10.51; p70 years (OR 2.44, 95% CI 1.07-5.58; p=0.04), CVD risk factors>or=2 (OR 2.63, 95% CI 1.20-5.76; p=0.02). Antiplatelet therapy and statins were each prescribed in 35.5% of the unrecognised PAD patients with ABIor=1.4. CONCLUSIONS: In a tertiary care hospital, the prevalence of unrecognised PAD among patients hospitalised for non-PAD-related causes is high and the preventive CVD therapy rates are low. Hospitalisation is a good opportunity to detect PAD.

International audience; Recent studies highlight the contribution of antiplatelet therapy to clinical severity and increased mortality of intracerebral hemorrhage (ICH) but results are discrepant. The aim of this report was to evaluate the association between antiplatelet drug use preceding the onset of ICH and the mortality, assessed at regular intervals, among patients with acute ICH. We analyzed data from a randomized study which enrolled consecutive patients with a documented acute ICH to evaluate the efficacy of intermittent pneumatic compression of the legs in venous thrombosis prevention. Clinical characteristics and treatment used before the onset of ICH were checked at the time of inclusion. Mortality was assessed at regular intervals until 3 months after ICH diagnosis. Among 138 patients included in this report, 30 were current users of antiplatelet therapy at the time of ICH; they were significantly older and less frequently heavy drinkers than non-users of antiplatelet drugs. Mortality rates were 20% at 8 days, 40% at 1 month, and 47% at 3 months among antiplatelet drug users compared with 6.5%, 13% and 19% among non-users. The corresponding estimated risks for mortality related to antiplatelet drug use were 3.6 (95% CI 1.1-12), 4.5 (95% CI 1.8-11), and 3.6 (95% CI 1.5-8.6). Adjusted for age, hypertension and alcohol over use, antiplatelet therapy remained significantly associated with an increased mortality rate of acute ICH. Current antiplatelet drug use preceding the onset of ICH is associated with increased short-term ICH mortality, independently of age.

heparin (Fragmin) in patients with venous thromboembolism andcontraindications to coumarin. Thromb Haemost 1994; 71: 7–11.13 Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, Kelton JG.Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. NEnglJMed1995; 332: 1330–5.14 Pini M, Aiello S, Manotti C, Pattacini C, Quintavalla R, Poli T,Tagliaferri A, Dettori AG. Low-molecular-weight heparin versuswarfarin in the prevention of recurrences after deep vein thrombosis.Thromb Haemost 1994; 72: 191–7.15 Lopaciuk S, Bielska-Falda H, Noszczyk W, Bielawiec M, WitkiewiczW, Filipecki S, Michalak J, Ciesielski L, Mackiewicz Z, Czes-tochowska E, Zawilska K, Cencora A. Low molecular weight heparinversus acenocoumarol in the secondary prophylaxis of deep veinthrombosis. Thromb Haemost 1999; 81: 26–31.16 Santamaria A, Juarez S, Reche A, Gomez-Outes A, Martinez-Gonzalez J, Fontcuberta J, ESFERA Investigators, Low-molecular-weight heparin, bemiparin, in the outpatient treatment and secondaryprophylaxis of venous thromboembolism in standard clinical practice:the ESFERA Study. Int J Clin Pract 2006; 60: 518–25.17 Gomez-Outes A, Rocha E, Martinez Gonzalez J, Kakkar VV. Costeffectiveness of bemiparin versus unfractionated heparin and oralanticoagulants in the acute and long-term treatment of deep veinthrombosis. Pharmacoeconomics 2006; 24: 81–92.

BACKGROUND: Incidence of perioperative in-stent thrombosis associated with myocardial infarction in patients undergoing major lung resection within 3 months of coronary stenting. METHODS: Retrospective multi-institutional trial including all patients undergoing major lung resection (lobectomy or pneumonectomy) within 3 months of coronary stenting with non-drug-eluting stents between 1999 and 2004. RESULTS: There were 32 patients (29 men and 3 women), with age ranging from 46 to 82 years. One, two or four coronary stents were deployed in 72%, 22% and 6% of the patients, respectively. The time intervals between stenting and lung surgery were

International audience; The objective of this study was to evaluate the effects of ticlopidine on the generation of eicosanoids and nitric oxide in heart-transplant recipients. In a randomized double-blind study, we studied the urinary excretion of the stable metabolites of thromboxane, prostacyclin, and nitric oxide before and after ticlopidine (250 mg/day). Platelet aggregation was significantly reduced in ticlopidine-treated patients [from 40.2 +/- 24.2% of maximal aggregation to 14.7 +/- 8.2% in response to adenosine diphosphate (ADP); p < 0.001] but not in the placebo group, confirming the efficacy of the drug with that dosage in these specific patients. The 24-h urinary excretion of prostacyclin metabolites was not modified by ticlopidine (1,865 +/- 833 ng/24 h at day 14 and 1,664 +/- 425 ng/24 h at day 0), whereas the excretion of thromboxane B2 tended to increase in the ticlopidine group (from 3,854 +/- 1,163 ng/24 h at day 0 to 5,014 +/- 2,914 ng/24 h at day 14), although not significantly. The excretion of nitric oxide metabolites (although not different from that of healthy nonimmunosuppressed subjects) was significantly (p < 0.005) increased in the ticlopidine group (from 3,082 +/- 1,683 micromol/24 h at day 0 to 4,133 +/- 2,262 micromol/24 h at day 14), but not in controls. Thus ticlopidine does not reduce prostacyclin but increases the systemic generation of nitric oxide, both substances having major antiplatelet and vasodilator properties. Further studies are warranted to examine whether ticlopidine could reduce the incidence of thromboembolic complications in these patients and whether this possible novel property of ticlopidine is restricted to immunosuppressed heart-transplant recipients.

Objectives: Previous uncontrolled studies have suggested an interaction between ticlopidine, a major antiplatelet agent, and cyclosporin in heart- and kidney-transplant recipients. The aims of this study were to examine in a randomised, double-blind fashion, the possible interaction between cyclosporin A and ticlopidine (250 mg per day) and the tolerability of this combination in heart-transplant recipients. Methods: Twenty heart-transplant recipients were randomised into either a treated or a placebo group. Blood samples were drawn for time-course evaluation of cyclosporin blood levels over a period of 12 h, following the morning intake of cyclosporin and, for platelet aggregation studies, before and after 14 days of ticlopidine administration. Twenty four-hour urine samples were collected for 6-β-hydroxycortisol measurements, before and after 14 days of ticlopidine. Results: Although given at half the recommended daily dosage, ticlopidine significantly reduced platelet aggregation. Pharmacokinetic parameters indicate that the bioavailability of cyclosporin A was not significantly modified by ticlopidine. However, one patient in the ticlopidine group was withdrawn because of a major fall in cyclosporin blood level within 3 days of treatment. Urinary excretion of 6-β-hydroxycortisol was augmented after treatment in the ticlopidine group compared with the placebo group, suggesting that induction of drug metabolism might have occurred. Data also show quite a large intra-individual variability in cyclosporin bioavailability in the placebo group, suggesting that poor absorption of the drug formulation and/or poor compliance might have contributed to the decreased cyclosporin blood levels in the patient withdrawn from this study and in previous uncontrolled studies. Conclusion: Cyclosporin bioavailability was not clearly modified by a half dosage of ticlopidine in this study. We, however, recommend closely monitoring cyclosporin blood levels when prescribing ticlopidine. Further studies will be needed with new formulations of cyclosporin or when using the full dosage of ticlopidine.

International audience; A fluorescent lactotransferrin probe was prepared by coupling 5-(([2-(carbhydrazino)methyl]-thio)acetyl)amino fluorescein to aldehyde groups that were produced by a mild periodic-acid oxidation of the glycan moieties of lactotransferrin. In this manner, the receptor-binding site of the lactotransferrin remains active in contrast to the binding site of the lactotransferrin derivatized with fluorescein isothiocyanate. The fluorescent probe allowed us to characterize, by flow cytometry, the binding of lactotransferrin to non-activated human platelets. The putative lactotransferrin platelet receptor was purified and its immunological and physico-chemical properties were found to be very similar to those of the receptor previously isolated from activated human lymphocytes. Lactotransferrin inhibits ADP-induced platelet aggregation at concentrations down to 5 nM, which can be reached in the plasma after leukocyte degranulation. Inhibition of platelet aggregation was also observed with the N-terminal fragment of lactotransferrin (residues 3-281; 50% inhibition = 2 microM) and with CFQWQRNMRKVRGPPVSC synthetic octodecapeptide (residues 20-37; 50% inhibition = 20 microM) corresponding to one of the two external loops (residues 28-34 and 39-42) where we recently located the receptor-binding site. The activity (50% inhibition = 500 microM) of the tetrapeptide KRDS (residues 39-42), which has already been described, was at least 25-times and 16000-times lower than the activity of the octodecapeptide and of the lactotransferrin molecules, respectively. Finally, the inhibition was demonstrated to be mediated by a mechanism which requires the binding of lactotransferrin to its putative receptor and not to platelet glycoprotein IIb-IIIa.