Several observational studies have found a link between the long-term use of benzodiazepines and dementia, which remains controversial. Our study was designed to assess (i) whether the long-term use ...of benzodiazepines, at two different doses, has an irreversible effect on cognition, (ii) and whether there is an age-dependent effect. One hundred and five C57Bl/6 male mice were randomly assigned to the 15 mg/kg/day, the 30 mg/kg/day diazepam-supplemented pellets, or the control group. Each group comprised mice aged 6 or 12 months at the beginning of the experiments and treated for 16 weeks. Two sessions of behavioral assessment were conducted: after 8 weeks of treatment and after treatment completion following a 1-week wash-out period. The mid-treatment test battery included the elevated plus maze test, the Y maze spontaneous alternation test, and the open field test. The post-treatment battery was upgraded with three additional tests: the novel object recognition task, the Barnes maze test, and the touchscreen-based paired-associated learning task. At mid-treatment, working memory was impaired in the 15 mg/kg diazepam group compared to the control group (p = 0.005). No age effect was evidenced. The post-treatment assessment of cognitive functions (working memory, visual recognition memory, spatial reference learning and memory, and visuospatial memory) did not significantly differ between groups. Despite a cognitive impact during treatment, the lack of cognitive impairment after long-term treatment discontinuation suggests that benzodiazepines alone do not cause irreversible deleterious effects on cognitive functions and supports the interest of discontinuation in chronically treated patients.
The intravenous form of fosfomycin, a bactericide antibiotic used to treat multiresistant bacterial infections is little prescribed. The most common reported adverse effects are hypokaliemia and ...hypernatremia. We describe a case of agranulocytosis, a rarely described side effect that may be fatal. This is the third paper reporting agranulocytosis induced by fosfomycin, and the first detailed description of a case. Based on chronological and semiological criteria and bibliographic data, the event was qualified as probable with the Naranjo adverse drug probability scale. Literature data is scarce. The summary of product characteristics mentions that only a few cases of transient neutropenia and agranulocytosis have been reported. An analysis of the FDA Adverse Event Reporting System Database highlighted a higher than expected frequency of agranulocytosis in patients treated with fosfomycin. Parenteral fosfomycin is often used in patients receiving other medications, so that it is rarely the only suspect. In our case, the results of the bone marrow aspiration, the sudden drop of the neutrophil count with concomitant eosinophilia and the absence of improvement despite the dose decrease, point towards an immuno-allergic mechanism. However, the overlap between the suspected DRESS induced by meropenem and the agranulocytosis do not allow to conclude with certainty on the causality. Awareness should be raised about this side effect.
Stroke is one of the major causes of mortality and disability in adults in industrialized countries. Despite numerous preclinical studies and clinical trials in the field of cerebral ischemia, no ...pharmacological agent has been validated in the treatment of acute ischemic, except thrombolysis. Cerebral ischemia is not only a neuronal disease but it affects the entire neurovascular unit. The therapeutic strategy in stroke should be more global and combine preventive approaches, acute phase treatment and long-term care to improve recovery and prevent or treat affective and cognitive post-stroke consequences. There is an imperative need to develop disease-modifying drugs, which should be able to induce neuroprotection, to serve as adjuvants for thrombolysis by decreasing the hemorrhagic risk and to limit the long-term post-stroke consequences. This review presents the potential effects of Peroxisome Proliferator-Activated Receptors (PPARs) and of their agonists in stroke. We focus on each PPAR receptor and detail their implication in stroke. PPARs are nuclear receptors, acting as ligand-dependent transcription factors. They are expressed in the neurovascular unit that suggests that PPARs could play a role in stroke. Indeed, it has been shown that they are able to interfere with pathways implicated in the pathophysiology of stroke. They could be an answer to this disease-modifying drug concept, being able to act on the different phases of ischemia.
The benefits of prophylactic antibiotics for hospitalized patients with severe alcohol-related hepatitis are unclear.
To determine the efficacy of amoxicillin-clavulanate, compared with placebo, on ...mortality in patients hospitalized with severe alcohol-related hepatitis and treated with prednisolone.
Multicenter, randomized, double-blind clinical trial among patients with biopsy-proven severe alcohol-related hepatitis (Maddrey function score ≥32 and Model for End-stage Liver Disease MELD score ≥21) from June 13, 2015, to May 24, 2019, in 25 centers in France and Belgium. All patients were followed up for 180 days. Final follow-up occurred on November 19, 2019.
Patients were randomly assigned (1:1 allocation) to receive prednisolone combined with amoxicillin-clavulanate (n = 145) or prednisolone combined with placebo (n = 147).
The primary outcome was all-cause mortality at 60 days. Secondary outcomes were all-cause mortality at 90 and 180 days; incidence of infection, incidence of hepatorenal syndrome, and proportion of participants with a MELD score less than 17 at 60 days; and proportion of patients with a Lille score less than 0.45 at 7 days.
Among 292 randomized patients (mean age, 52.8 SD, 9.2 years; 80 27.4% women) 284 (97%) were analyzed. There was no significant difference in 60-day mortality between participants randomized to amoxicillin-clavulanate and those randomized to placebo (17.3% in the amoxicillin-clavulanate group and 21.3% in the placebo group P = .33; between-group difference, -4.7% 95% CI, -14.0% to 4.7%; hazard ratio, 0.77 95% CI, 0.45-1.31). Infection rates at 60 days were significantly lower in the amoxicillin-clavulanate group (29.7% vs 41.5%; mean difference, -11.8% 95% CI, -23.0% to -0.7%; subhazard ratio, 0.62; 95% CI, 0.41-0.91; P = .02). There were no significant differences in any of the remaining 3 secondary outcomes. The most common serious adverse events were related to liver failure (25 in the amoxicillin-clavulanate group and 20 in the placebo group), infections (23 in the amoxicillin-clavulanate group and 46 in the placebo group), and gastrointestinal disorders (15 in the amoxicillin-clavulanate group and 21 in the placebo group).
In patients hospitalized with severe alcohol-related hepatitis, amoxicillin-clavulanate combined with prednisolone did not improve 2-month survival compared with prednisolone alone. These results do not support prophylactic antibiotics to improve survival in patients hospitalized with severe alcohol-related hepatitis.
ClinicalTrials.gov Identifier: NCT02281929.
Background and purpose
Although several case series have described nitrous‐oxide‐associated neurological disorders, a comprehensive assessment of exposure characteristics (e.g., time to onset, level ...of exposure) in substance abusers has not been performed. The aim of this study was to describe the onset patterns of recreational use of nitrous‐oxide‐induced neurological disorders.
Methods
All cases of neurological disorders related to nitrous oxide recreational use reported to the Hauts‐de‐France addictovigilance center between January 2019 and August 2020 were selected. Only cases requiring hospitalization with informative data to perform the nitrous oxide causality assessment were included.
Results
A total of 20 cases from five hospitals were included. The male‐to‐female ratio was 6:1 and the median age was 19 years (range 16–34). The neurological presentation (myeloneuropathy 64%, 7/11; sensorimotor neuropathy 36%, 4/11) included for all patients gait disorders due to proprioceptive ataxia and limb hypoesthesia. The median dose used per occasion was 100 cartridges (range 5–960; n = 19). The median time from the start of nitrous oxide use to the onset of neurological symptoms was 6 months (range 0.7–54; n = 16). The cumulative dose was significantly higher in patients with damage to all four limbs than in patients with lower limb symptoms only (p = 0.042).
Conclusions
A low intermittent exposure may be sufficient to cause neurological damage in some subjects, suggesting that, at the population level, there is no safe exposure to nitrous oxide in recreational settings. The severity of neurological impairment could increase once used at high doses and for prolonged durations of nitrous oxide.
Although several case series have described nitrous‐oxide‐associated neurological disorders, a comprehensive assessment of exposure characteristics (e.g., time to onset, level of exposure) in substance abusers has not been performed.
The risk of intracerebral hemorrhage still greatly limits the use of tPA in stroke patients. Research is ongoing in order to identify the pathophysiological mechanisms at play, detect predictive ...biomarkers and discover new pharmacological targets to develop preventive or curative treatments. Going through experimental and clinical studies, this review focuses on the role of neutrophils as key predictive biomarkers for thrombolysis-induced hemorrhages and as pharmacological targets to limit their occurrence. To date, there are no established pharmacological modulators of neutrophils for ischemic stroke and its hemorrhagic complications. Several strategies are under evaluation, including lipid-lowering drugs, free radical scavengers, or minocycline, as well as non-pharmacological interventions such as physical exercise.
Cerebral microbleeds (CMBs) could contribute to cognitive impairment in the general population and in patients with dementia. We designed a study to (i) develop a murine model of CMBs, (ii) assess ...whether CMBs affect cognition in this model and (iii) assess whether this model is sensitive to pharmacological modulation. Male C57Bl6/J mice were stereotactically administered collagenase to induce cortical lesion analysed by MRI at 24 h. CMB-mice were assessed at six weeks post-lesion for cognitive performances (Barnes maze and Touchscreen automated paired-associated learning (PAL) task) and for cerebral metabolism (in vivo PET/CT with fluorodeoxyglucose (FDG)). CMB-model sensitivity to pharmacological modulation was assessed by administering atorvastatin (5 mg/kg/day) over the follow-up period. CMB mice were compared to naïve littermates. Collagenase at 0.8 µU/µl appeared suitable to induce reproducible and reliable CMBs. At six weeks, a decline in learning, spatial and visuospatial memory was significantly observed in CMB-mice. Brain metabolism was impaired in all cortex, striatum and the ipsilateral dentate gyrus. A significant improvement in cognition performances was depicted under atorvastatin. In this novel murine model of CMBs, we validated that CMBs lowered cognitive performances and affected regional metabolism. We also proved that this CMB-model is sensitive to pharmacological modulation.
Alcohol and benzodiazepines are psychoactive substances frequently associated in voluntary drug intoxications that share common mechanisms of action, including facilitation of GABAergic transmission. ...This study aimed to assess the separate and combined effects of ethanol and diazepam acute exposure on hippocampal metabolite levels, as well as on delayed cognitive performance, in rats anesthetized with isoflurane. Adult male Wistar rats received one intraperitoneal injection containing either saline solution (“CTL” group, N = 15), a 5‐mg/kg dose of diazepam (“DIA” group, N = 16), a 2‐g/kg dose of ethanol (“EtOH” group, N = 18), or a 5‐mg/kg dose of diazepam + a 2‐g/kg dose of ethanol (“DIA + EtOH” group, N = 24). The levels of brain metabolites in the hippocampal region were assessed using in vivo magnetic resonance spectroscopy (MRS) before and after injection. Behavioral testing, including working memory and visual recognition memory assessment, was performed at week 3, while a new MRS acquisition was conducted 4 weeks after the injection. In the hour following acute exposure, a decrease in glutamate levels was found in the DIA + EtOH group only. Four weeks after injection, a decrease in GABA and glutamate levels and an increase in NAA levels were found in the EtOH group only. No significant between‐group differences were found in the behavioral assessment. While the initial decrease in glutamate levels in the DIA + EtOH group suggests an early potentiation effect between ethanol and diazepam, the long‐term modifications found only in the EtOH group suggest a possible downregulation of ethanol's effect by diazepam at 4 weeks.
Background and Purposes
Cerebral microhaemorrhages (CMHs) are associated with cognitive decline in humans. In rodents, CMHs induces cognitive impairment in male mice along with sex‐specific cortical ...and hippocampal changes affecting neural, glial and vascular functions. Statins, have been proposed to prevent cognitive decline. We tested here the action of atorvastatin on CMH‐induced cognitive impairment in a murine model of CMH.
Experimental Approach
Using a multimodal approach combining behavioural tests, in vivo imaging, biochemistry and molecular biology, the effects of oral administration of atorvastatin on the sex‐specific changes induced by a cortical CMH were studied in male and female mice (C57BL/6J) at 6‐week post‐induction using a collagenase‐induced model.
Key Results
Atorvastatin caused specific effects according to the sex‐specific CMH‐induced changes. In males, atorvastatin improved the visuospatial memory, induced a local modulation of microglial response and enhanced brain‐derived neurotrophic factor (BDNF)‐tropomyosin receptor kinase B (trkB) and vascular endothelial growth factor (VEGF) expression in the cortex. In the hippocampus, atorvastatin increased glucose metabolism and modulated astrocytes morphology. In females, atorvastatin did not modulate visuospatial memory despite the increased expression of cortical BDNF and the decrease in the number of hippocampal astrocytes. Atorvastatin also induced a decrease in the expression of cortical oestrogen receptors but did not modify body weight nor serum cholesterol levels in both sexes.
Conclusion and Implications
Atorvastatin modulated the sex‐specific cognitive impairment induced by the CMH with a pathophysiological impact mainly within the cortical area. It could represent a promising candidate for future sex‐stratified clinical trials in patients with CMH.
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