Sophie Gautier

Neutrophils contribute to intracerebral haemorrhages after treatment with recombinant tissue plasminogen activator following cerebral ischaemia

Background and purpose:  Polymorphonuclear neutrophils (PMNs) contribute to the vascular damage caused by transient cerebral ischaemia. Here we have evaluated the role of PMNs in intracerebral haemorrhage (ICH) induced in a model of thrombolysis with recombinant tissue plasminogen activator (t‐PA) during the acute phase of cerebral ischaemia.

Effects of the PPAR-α Agonist Fenofibrate on Acute and Short-Term Consequences of Brain Ischemia

In stroke, there is an imperative need to develop disease-modifying drugs able to (1) induce neuroprotection and vasculoprotection, (2) modulate recovery and brain plasticity, and (3) limit the short-term motor and cognitive consequences. We hypothesized that fenofibrate, a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, could exert a beneficial effect on immediate and short-term poststroke consequences related to its pleiotropic mechanisms. Rats or mice were subjected to focal ischemia to determine the effects of acute treatment by fenofibrate on (i) motor and memory impairment, (2) both cerebral and vascular compartments, (3) inflammation, (4) neurogenesis, and (5) amyloid cascade. We show that fenofibrate administration results in both neuronal and vascular protection and prevents the short-term motor and cognitive poststroke consequences by interaction with several mechanisms. Modulation of PPAR-α generates beneficial effects in the immediate poststroke consequences by mechanisms involving the interactions between polynuclear neutrophils and the vessel wall, and microglial activation. Fenofibrate modulates mechanisms involved in neurorepair and amyloid cascade. Our results suggest that PPAR-α agonists could check the key points of a potential disease-modifying effect in stroke.

Bullous pemphigoid induced by vildagliptin: a report of three cases.

To report three cases of bullous pemphigoid in patients treated with vildagliptin. Case 1: An 86‐year‐old woman presented with bullous pemphigoid after 1 month of treatment with vildagliptin and metformin. After introduction of clobetasol, the symptoms resolved although vildagliptin was continued. However, the skin lesions reappeared 3 months later. Sustained remission was achieved only after definitive withdrawal of vildagliptin. Case 2: A 79‐year‐old man presented with bullous pemphigoid after 37‐month treatment with gliclazide, vildagliptin and metformin. The disease at first responded to clobetasol but 3 months later the lesions reappeared. They finally regressed when the gliptin was discontinued. Case 3: A 77‐year‐old woman, treated with gliclazide and vildagliptin for 26 months, presented with bullous pemphigoid, which responded well to discontinuation of the gliptin and topical clobetasol. Gliptins are new molecules for treatment of type 2 diabetes mellitus, which have been suspected of implication in bullous pemphigoid. Such cases have been described in the literature (seven with vildagliptin and three with sitagliptin). In nine of these cases, the gliptin was associated with metformin, but the latter had never been considered responsible. The mechanism implicated in the development of bullous pemphigoid has not yet been clearly identified, but may involve a modified immune response or alteration of the antigenic properties of the epidermal basement membrane. These reports support the risk of bullous pemphigoid in patients exposed to gliptins.

Pharmacological neutropenia prevents endothelial dysfunction but not smooth muscle functions impairment induced by middle cerebral artery occlusion

1 The polymorphonuclear neutrophils (PMN) activation and mobilization observed in acute cerebral infarction contribute to the brain tissue damage, but PMN could also be involved in postischemic functional injury of ischemied blood vessel. 2 This study was undertaken to investigate whether pharmacological neutropenia could modify the postischemic endothelial dysfunction in comparison to smooth muscle whose impairment is likely more related to reperfusion and oxidative stress. 3 A cerebral ischemia–reperfusion by endoluminal occlusion of right middle cerebral artery (MCA) was performed 4 days after intravenous administration of vinblastine or 12 h after RP‐3 anti‐rat neutrophils monoclonal antibody (mAb RP‐3) injection into the peritoneal cavity, on male Wistar rats with 1‐h ischemia then followed by 24‐h reperfusion period. Brain infarct volume was measured by histomorphometric analysis and vascular endothelial and smooth muscle reactivity of MCA was analysed using Halpern myograph. 4 Neutropenia induced a neuroprotective effect as demonstrated by a significant decrease of brain infarct size. In parallel to neuroprotection, neutropenia prevented postischemic impairment of endothelium‐dependent relaxing response to acetylcholine. In contrast, smooth muscle functional alterations were not prevented by neutropenia. Ischemia–reperfusion‐induced myogenic tone impairment remained unchanged in vinblastine and mAb RP‐3‐treated rats. Postischemic Kir2.x‐dependent relaxation impairment was not prevented in neutropenic conditions. The fully relaxation of smooth muscle response to sodium nitroprusside was similar in all groups. 5 Our results evidenced the dissociate prevention of pharmacologically induced neutropenia on postischemic vascular endothelial and smooth muscle impairment. The selective endothelial protection by neutropenia is parallel to a neuroprotective effect suggesting a possible relationship between the two phenomena.

Eosinophilic esophagitis after desensitization to dust mites with sublingual immunotherapy

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by esophageal dysfunction and eosinophilic infiltration of the esophageal mucosa. The disease affects both children and adults, with a prevalence of 5 per 10,000 inhabitants in Europe and the United States.1 Childhood cases are generally diagnosed between 5 and 10 years of age and adult cases between 30 and 40 years of age. The male-female sex ratio is 3:1 in a published series.2 The symptoms vary according to the age of the individual and consist of difficulties in feeding and in gaining weight in small children, abdominal pain and vomiting in older children, and solid food dysphagia and symptoms that suggest gastroesophageal reflux in adults.3 Histopathologic examination revealing more than 15 polynuclear eosinophils (PNEs) per 40 field is indispensable to establish the diagnosis of EoE. An atopic or allergic history and genetic susceptibility are risk factors for the development of EoE.4 In predisposed individuals, exposure to certain food allergens and aeroallergens can trigger the disorder.Wedescribe thefirst reportedcase, toourknowledge, ofEoE ina child after sublingual immunotherapy (SLIT) for dustmite allergy. A 10-year-old girl, one of twins, with a history of asthma, allergic rhinitis, and dust mite allergy started daily SLIT (where drops are placed under the tongue for 2 minutes and then swallowed) for dust mite desensitization at the end of January 2013. SLIT wasmade of a Staloral (Stallergenes S.A., Antony, France) standardized Dermatophagoides pteronyssinus and Dermatophagoides farinae 50/50 extract at 300 IR concentration. In March 2013, six weeks after the start of SLIT, the patient attended the emergency department for reflux and vomiting of 1-month duration accompanied by pain, retrosternal chest discomfort, and weight loss. There was no trigger factor and no time pattern. She had no fever or abdominal injury. Local antacids and domperidone were not effective. During a previous emergency consultation, she had been prescribed proton pump inhibitors (PPIs), omeprazole (20 mg/d), and sodium alginate, which temporarily relieved the symptoms for 48 hours. The complete blood cell count, erythrocyte sedimentation rate, and liver function test results were normal. The C-reactive protein level was 14 mg/L. Upper endoscopy, performed 12 days after starting PPI treatment, revealed a slightly congested appearance of the lower third of the esophagus, without ulceration. The gastric mucosa revealed focal congestion, with no ulcer, ulceration, or nodular appearance. Eight esophageal biopsy specimens (3 from the distal third, 3 from the middle third, and 2 from the upper third), 5 stomach specimens (3 from the antrum and 2 from the fundus), and 2 duodenal specimens (1 from the bulb) were obtained. Histopathologic examination of these specimens

Acute kidney injury after high dose etoposide phosphate: A retrospective study in children receiving an allogeneic hematopoetic stem cell transplantation

Etoposide phosphate (EP; single injection, 60 mg/kg) followed by total body irradiation (TBI) at 12 Gy has been used as an allogeneic stem cell transplantation (allo‐SCT) conditioning regimen for children since 2010. In our institution, EP has been suspected of leading to acute nephrotoxicity. The aim of this study was to assess the potential renal toxicity of EP in this context.

On‐the‐ground application of the “temporary recommendation for use” regulatory measure on off‐label use of baclofen for alcohol dependence in France: a regional survey of community pharmacies

The ‘temporary recommendation for use’ (TRU) is a French novel regulatory measure for off‐label drug. The first TRU to be issued by the French drug agency (in March 2014) pertained to the off‐label use of baclofen for alcohol dependence (AD). We performed a questionnaire‐based survey of the on‐the‐ground application of the baclofen TRU among community pharmacies in northern France. A pharmacist from 70 of the 219 pharmacies contacted (response rate: 32.0%) completed the questionnaire. The mean ± standard deviation number of off‐label baclofen prescriptions for AD was 2.3 ± 2.2 per pharmacy per month. 65.2% of these prescriptions were issued by primary care physicians. 65.7% of the pharmacists had never seen ‘TRU’ written on the prescription, and 80.3% delivered a prescription without checking whether the patient had been included by the prescriber in the TRU. The main criterion used to identify off‐label prescribing was the patients medical history (according to 74.6% of pharmacists) and the prescription of an above‐threshold dose (73.1%). 87.1% of the pharmacists were aware of the baclofen TRU, and 42.9% had actually read the document. 17.9% of the pharmacists estimated that the TRU had changed their attitude to off‐label baclofen prescription, and 29.9% (20 out of 67) of them wanted to be more involved in the TRU process. Community pharmacists were well informed about the off‐label use of baclofen for AD and the TRU. However, a majority of baclofen prescribers did not fulfill the TRU requirements while a majority of pharmacists did not exert any control over these off‐label prescriptions. In practice, in 2015 the TRU measure had thus a limited impact on both the baclofen prescribing and delivery practices.

Nicorandil and cutaneous ulcerations, their misdiagnosis and consequences: Illustration by five cases reports and a review of the French pharmacovigilance database

While physicians increasingly recognize nicorandil-related mucocutaneous ulcerations, there are still misdiagnoses, particularly in the case of unusual location and late onset ulceration after nicorandil introduction. The goal of our study was to remind clinicians about the link between nicorandil use and the development of cutaneous ulcerations and to highlight the risk of misdiagnosis. We describe five reports diagnosed by the same dermatologist, complemented by an analysis of the French pharmacovigilance database (FPVD) from 1 January 1994 to 5 January 2017. During this period, 28 reports of strict cutaneous ulcerations due to nicorandil, in addition to our five reports, were registered in the FPVD. For those 28 reports, the time to onset between nicorandil introduction and cutaneous ulcerations was quite long and exceeded one year in 16 reports (information specified in 25 reports). The delay between ulcerations observation and nicorandil discontinuation was variable, with immediate diagnosis in seven reports, but ranged from fifteen days to twelve years in 21 reports. The main locations were lower limbs, thorax and face. Ulcerations could be localized on surgery or trauma scars. Regression after nicorandil discontinuation was observed in all but two reports and ranged from three days to three months. Characteristics were comparable in our five patients series. All patients exposed to nicorandil and healthcare practitioners prescribing nicorandil should be aware of the risk of cutaneous ulcerations to enable early diagnosis and drug withdrawal. The risk of misdiagnosis of this serious adverse drug reaction, along with the risk of sequelae, the costs of unnecessary additional investigations and the recent update on nicorandil as second-line treatment for stable angina, with existing alternative drugs, question about the benefit/risk balance of nicorandil.