[Thrombosis during thrombopoietin receptor agonist treatment for immune thrombocytopenia. A French multicentric observational study]. / Thromboses sous agonistes du récepteur de la thrombopoïétine au cours du purpura thrombopénique immunologique. Étude rétrospective multicentrique en France.

INTRODUCTION: Thrombopoietin-receptor agonists (TPO-RA) are marketed for immune thrombocytopenia (ITP). They have been associated to thrombosis occurrence in randomized controlled trials. However, the characteristics of these thromboses in the real-life practice as well as their management are poorly known. The objectives of this study were to determine the risk factors, circumstances and management of thrombosis occurring during exposure to TPO-RA in ITP. METHODS: We carried out a multicentre retrospective study in France. Moreover, all cases reported to the French pharmacovigilance system were also analyzed. RESULTS: Overall, 41 thrombosis (13 arterial) in 36 ITP patients (14 males and 22 females, mean age: 59 years) were recorded between January 2009 and October 2015. Twenty patients were treated with romiplostim, 15 with eltrombopag and 1 was treated by both medications. Thirty-three (92%) of the patients had another risk factor for thrombosis. Ten (28%) had an history of thrombosis and 13 (36%) received immunoglobulin in the month preceding the thrombotic event. Three had antiphospholipid antibodies; congenital low-risk thrombophilia was found in 4 cases; 18 patients (50%) were splenectomized. Median platelet count at the time of thrombosis was 172G/l (1-1049G/l). In 22 patients (56%), a good prognosis was associated with the thrombosis and was not linked with TPO-RA withdrawal. Bleeding events occurred in 14% of the patients treated with antiplatelet or anticoagulant drug, including 5% serious events (1 death of intracranial haemorrhage, 1 death of haemorrhagic shock). CONCLUSIONS: The thrombotic risk may be carefully assessed before starting TPO-RA in ITP patients. The impact of antiphospholipid antibodies and of congenital thrombophilia remains to be defined. Thrombosis evolution seems independent of TPO-RA management. Bleeding manifestations seem rare. Poor prognosis was mainly due to ischemic sequelae.

Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials.

BACKGROUND: Guidelines for type 2 diabetes (T2D) recommend reducing HbA1c through lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 inhibitors [DPP-4Is] among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial. METHODS: A systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials [CENTRAL] and https://clinicaltrials.gov), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia. RESULTS: A total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR=1.03, 95% confidence interval [CI]=0.95-1.12), cardiovascular mortality (RR=1.02, 95% CI=0.92-1.12), myocardial infarction (RR=0.98, 95% CI=0.89-1.08), strokes (RR=1.02, 95% CI=0.88-1.17), renal failure (RR=1.06, 95% CI=0.88-1.27), severe hypoglycaemia (RR=1.14, 95% CI=0.95-1.36) and pancreatic cancer (RR=0.54, 95% CI=0.28-1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR=1.13, 95% CI=1.01-1.26) and of acute pancreatitis (RR=1.57, 95% CI=1.03-2.39). CONCLUSION: There is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future.

Cardiovascular risk profile of patients with peripheral arterial occlusive disease during nilotinib therapy.

BACKGROUND: Over the past few years, data have suggested that severe peripheral arterial occlusive disease (PAOD) is associated with nilotinib exposure. However, the characteristics of this adverse drug reaction are poorly described since its frequency is low. As far as we know, no study using a spontaneous adverse drug reactions reporting system was performed to describe the characteristics of cases of PAOD related to nilotinib. OBJECTIVE: We performed a study to describe the cardiovascular risk profile of cases of PAOD in patients treated with nilotinib spontaneously reported to the French Pharmacovigilance Database (FPVD). PATIENTS/METHODS: We selected all cases of "vascular disorders," as the System Organ Class in MedDRA®, in which nilotinib was "suspected" and recorded in the French Pharmacovigilance Database between 2007 and 21 October 2014. We then identified cases of PAOD with a Low Level Term and through a detailed summary of the clinical description. RESULTS: We identified 25 cases of POAD. Most of the patients were older than 60 years (84 %) or had another cardiovascular risk factor such as hypercholesterolemia, arterial hypertension, overweight/obesity, smoking, or diabetes mellitus (72 %). Females (13 cases) and males (12 cases) were equally represented, but the presence of cardiovascular risk factors was more frequent in females than in males. The mean time from initiation of nilotinib to PAOD onset was 24 months and was significantly longer in patients aged less than 60 years compared with those aged over 60 years (33.8 ± 24.6 months vs. 22.6 ± 17.5 months, p = 0.002). Pre-existing cardiovascular risk factors, especially diabetes mellitus, also seem to accelerate its occurrence. CONCLUSIONS: The FPVD is a useful tool in describing the cardiovascular risk profile of patients with PAOD during nilotinib exposure. Physicians have to be particularly vigilant in patients older than 60 years of age; in patients younger than 60 years of age, long-term surveillance has to be maintained.

The PREGVAXGRIP study: a cohort study to assess foetal and neonatal consequences of in utero exposure to vaccination against A(H1N1)v2009 influenza.

BACKGROUND: In October 2009, in the context of an A(H1N1)v2009 influenza pandemic, a vaccination campaign was launched in France, in which one of the priority groups was pregnant women, on account of the high risk of developing complications following infection by this virus. OBJECTIVE: The aim of this multicentric, prospective, observational study was to assess safety and pregnancy outcomes in a cohort of pregnant women when receiving the A(H1N1)v2009 influenza pandemic vaccine. METHODS: This was a prospective study that followed up pregnant women recruited mainly in vaccination centres and maternity departments. Following the expected delivery date, follow-up data were collected concerning the delivery, the infant, and, if appropriate, the reasons why the pregnancy did not reach its term. RESULTS: Between 1 November 2009 and 31 March 2010, 2,415 pregnant women were included at the time of vaccination; 97.6 % of women received a vaccine without adjuvant and 2.4 % received an adjuvanted vaccine. Ninety-two (3.9 %) women were vaccinated during the first trimester of pregnancy, 1,090 (46.5 %) during the second trimester, and 1,162 (49.6 %) during the third trimester. One hundred and thirty-three adverse events (5.5 % of women) were reported, of which 12 were unexpected or serious. There were 2,246 (93.0 %) known pregnancy outcomes with 12 spontaneous abortions (0.5 %), 6 stillbirths (0.3 %), and 4 therapeutic abortions (0.2 %). There were 65 neonates with congenital anomalies, among which 31 were major. But only one congenital malformation (1.4 %) was reported for the 92 women vaccinated in their first trimester. Of the women, 93.3 % were delivered full term and 6.7 % preterm. For 96 (4.2 %) neonates, a disorder was reported in the neonatal period and 130 (5.6 %) were transferred to the neonatology department. CONCLUSIONS: This study suggests that exposure to the A(H1N1)v2009 pandemic influenza vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes. However, because of the relatively small number of women exposed during the first trimester, other studies are needed to exclude an increased risk of malformation.

[Treatment of depressed pregnant women by selective serotonin reuptake inhibitors: risk for the foetus and the newborn]. / Traitement par inhibiteurs sélectifs de la recapture de la sérotonine de la dépression chez la femme enceinte: risques pour le foetus et le nouveau-né.

INTRODUCTION: This article is a review of literature data concerning the use of selective serotonin reuptake inhibitors (SSRIs) by depressed pregnant women. LITERATURE FINDINGS: The adverse effects for the foetus, the newborn and the child were evaluated. The prevalence of depression during pregnancy is of around 10 to 20% of the population of childbearing women. Depression is often misdiagnosed and underestimated in pregnant women. Starting a pharmacological treatment for depression in these women is not easy because data concerning the safety of antidepressants during pregnancy are still unclear. The non-treated pathology is associated with higher risk of maternal morbidity, including arterial hypertension, which could lead to preeclampsia or eclampsia, ideation and suicide attempts, and postpartum depression. Foetal development is also affected and adverse outcomes such as prematurity, low birth weight, irritability, and sleep disorders are frequent. Pharmacological therapy is necessary when non-pharmacological treatment is insufficient. Suicide attempts and relapse of depression have been described when depressive women stopped their pharmacological treatment during pregnancy. Pregnant women diagnosed with depression must be treated. Selective SSRIs are now largely used in this pathology and have replaced tricyclic antidepressants because of fewer side effects. In general, drugs have a low teratogenic potential, only 4 to 5% of malformations are iatrogenic. Teratogenic risk is high between conception until the end of the second month of gestation. Safety of SSRIs treatment during pregnancy and potential risk for the foetus and newborn were unquestioned before publication, in the late 2005, of some alarming data concerning a possible teratogenic effect. Studies showed an increased risk for all congenital malformations with SSRIs and particularly with paroxetin. A few studies after 2005 have also found an association between prenatal exposure to SSRIs (especially paroxetin) and congenital malformations. However, other studies failed to demonstrate this association and the risk for cardiovascular malformations also does not seem to be significantly increased. Numerous studies in pregnant women have shown that SSRI treatments are associated with a significant increase of spontaneous abortion, preterm birth, and low birth weight. Exposure to SSRIs in late pregnancy has been associated with a three-fold increased risk of neonatal behavioural syndrome, including signs of withdrawal or serotonin impregnation. Restlessness, poor tone, respiratory distress, hypoglycaemia were the most frequent signs. These symptoms occur during the first days of life and are usually brief and not serious. Recent studies have also documented an increased risk of persistent pulmonary hypertension and cases of cerebral haemorrhage have been described. Data concerning a possible effect on motor and cognitive development at school age in children prenatally exposed to SSRIs are limited. DISCUSSION: Although a number of studies revealed that SSRIs are not teratogenic, some of them showed congenital malformations associated with use of these antidepressants; in particular an increased risk of cardiac defects with paroxetin. In practice, the potential risk implies that the decision to treat a pregnant woman with SSRIs (notably paroxetin) should be taken carefully; this means double-checking the diagnosis, the potential benefits, adverse effects and possible alternatives. Neonatal toxicity seems to be relatively frequent when SSRIs are prescribed during late pregnancy. For all depressed pregnant women, the severity of the depression must be taken into consideration before introducing a pharmacological treatment. When depressive women are already treated, studies have shown that antidepressants must be maintained during pregnancy to prevent relapse and suicide attempts.

Imipramine, in part through tumor necrosis factor alpha inhibition, prevents cognitive decline and beta-amyloid accumulation in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD), the most common form of dementia in the older people, is a multifactoral pathology, characterized by cognitive deficits, increase in cerebral deposition of the beta-amyloid (Abeta) peptide, neurofibrillary tangles, and neurodegeneration. Studies currently support a central role of neuroinflammation, through production of proinflammatory cytokines including excess tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of AD, especially in Abeta-induced cognitive deficits. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and neuroprotective effects. This study investigates the effect of imipramine on alterations of long-term and short-term memories, TNF-alpha expression, and amyloid precursor protein (APP) processing induced by intracerebroventricular injection of Abeta25-35 in mice. Mice were treated with imipramine (10 mg/kg i.p. once a day for 13 days) from the day after the Abeta25-35 injection. Memory function was evaluated in the water-maze (days 10-14) and Y-maze (day 9) tests. TNF-alpha levels and APP processing were examined in the frontal cortex and the hippocampus (day 14). Imipramine significantly prevented memory deficits caused by Abeta25-35 in the water-maze and Y-maze tests, and inhibited the TNF-alpha increase in the frontal cortex. Moreover, imipramine decreased the elevated levels of Abeta both in frontal cortex and hippocampus with different modulations of APP and C-terminal fragments of APP. So, imipramine prevents memory impairment through its intrinsic property to inhibit TNF-alpha and Abeta accumulation and may represent a potential candidate for AD treatment.

Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer's disease.

Neuronal death is a pathological hallmark of Alzheimer's disease. We have shown previously that phosphorylated double-stranded RNA-dependent protein kinase is present in degenerating hippocampal neurons and in senile plaques of Alzheimer's disease brains and that genetically down-regulating double-stranded RNA-dependent protein kinase activity protects against in vitro beta-amyloid peptide neurotoxicity. In this report, we showed that two double-stranded RNA-dependent protein kinase blockers attenuate, in human neuroblastoma cells, beta-amyloid peptide toxicity evaluated by caspase 3 assessment. In addition, we have used the newly engineered APP(SL)/presenilin 1 knock-in transgenic mice, which display a severe neuronal loss in hippocampal regions, to analyze the activation of double-stranded RNA-dependent protein kinase. Western blots revealed the increased levels of activated double-stranded RNA-dependent protein kinase and the inhibition of eukaryotic initiation factor 2 alpha activity in the brains of these double transgenic mice. Phosphorylated RNA-dependent protein kinase-like endoplasmic reticulum-resident kinase was also increased in the brains of these mice. The levels of activated double-stranded RNA-dependent protein kinase were also increased in the brains of patients with Alzheimer's disease. At 3, 6 and 12 months, hippocampal neurons display double stranded RNA-dependent protein kinase labelings in both the nucleus and the cytoplasm. Confocal microscopy showed that almost constantly activated double-stranded RNA-dependent protein kinase co-localized with DNA strand breaks in apoptotic nuclei of CA1 hippocampal neurons. Taken together these results demonstrate that double-stranded RNA-dependent protein kinase is associated with neurodegeneration in APP(SL)/presenilin 1 knock-in mice and could represent a new therapeutic target for neuroprotection.

Urinary and blood concentrations of beta2-agonists in trained subjects: comparison between routes of use.

We aimed to assess the plasma and urine concentrations of beta2-agonists and evaluate the difference between three routes of administration in trained adults in order to distinguish doping from prevention of exercise-induced asthma. Ten young healthy Caucasian male subjects received during a four treatment period study: 1) inhaled salbutamol (S(I)) 2 x 100 microg t.i.d. for 3 days, 2) inhaled formoterol (F(I)) 2 x 12 microg b.i.d. for 3 days, 3) a single subcutaneous injection of salbutamol (S(S)) 0.5 mg, and 4) salbutamol 2 x 2 mg t.i.d. orally for 3 days (S(O)). Blood samples were taken during the first and the third day of experimentation at baseline, 30 min, 1 h, 2 h, 4 h and 6 h after administration; additional blood samples were drawn at 15 min for S(I), S(S) and F(I) and at 12 h for F(I). Urinary samples were collected at baseline, 2 h, 4 h, 6 h and 12 h after administration. Urinary concentrations were 20 to almost 50 times higher after S(O) than after S(I). Mean urinary concentration after S(O) increased to above 800 ng.mL(-1) within the two hours and above 1000 ng.mL(-1) at 6 to 12 hours post-drug administration. Urinary concentrations after S(S) were maximal during the first 2 hours (mean: 340 +/- 172 ng.mL(-1)). Plasma concentrations were very low, whatever the routes of administration. Results showed that we could eliminate the use of S(I) (authorized) and S(S) administration when individual urinary concentrations are higher than 230 ng.mL(-1) and 615 ng.mL(-1), respectively. Therefore, at rest, the cut-off value used to discriminate therapeutic from doping salbutamol intake could be fixed at 250 ng.mL(-1) instead of the 1000 ng.mL(-1) still authorized by international committees.

Using a WWW-based module for problem-based learning in a cardiovascular pharmacology course.

The authors have constructed a problem-based learning (PBL) computer program that makes full use of Internet facilities, and is aimed at providing a stimulating supplement to standard teaching practices. The authors report on students' reactions to this new method of teaching.