To cite this version:Katrin Schuh, Andreas Pahl. Inhibition of the MAP kinase ERK protects from lipopolysaccharideinduced lung injury.Biochemical Pharmacology, Elsevier, 2009, 77 (12) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Background:As patients with multiple sclerosis (MS) require lifelong treatment, optimization of therapy with respect to efficacy and safety is needed to limit long-term disease progression. Patients with MS also need a range of health-related services. Satisfaction with these as well as treatment is clinically relevant because satisfied patients are more likely to adhere to therapy. The aim of this study was to determine the status of patient satisfaction and of healthcare services in 70 specialized MS centres in Germany.Methods:In 2011, patients with MS responded to a questionnaire, which solicited clinical and demographic information, as well as patients’ perceptions of their overall situation and their satisfaction with treatment.Results:Of 2791 patients surveyed, 81.9% had relapsing-remitting MS with mild disability [mean (standard deviation) Expanded Disability Status Scale score: 2.6 (1.8)]. Disease activity data were collected from 2205 patients, of whom 57.6% had remained relapse-free during the preceding 12 months. However, 38.9% had experienced one or more relapses, most of whom (67.3%) while receiving immunomodulatory treatment. About one-third of the patients indicated that they were more dissatisfied with their overall situation compared with the time before diagnosis. However, many patients (58.3%) were satisfied with their existing medication. Overall, 72.8% of patients would prefer oral to injectable treatments, assuming there was no difference in their efficacy.Conclusions:A substantial proportion of patients experienced breakthrough disease on treatment and may potentially benefit from a change of therapy. Although largely satisfied with treatment, most patients with MS would choose oral over injectable treatments.
BackgroundFatigue is a major symptom of multiple sclerosis (MS) in patients, and it has been shown to improve with physical exercise. Although fingolimod might lessen fatigue, it is unclear how patients treated with fingolimod react to physical activity regarding fatigue.ObjectiveThis study evaluated the effect of an exercise intervention on fatigue in relapsing–remitting MS patients receiving fingolimod.MethodsPeople with MS (PwMS) were randomized to either a structured internet-based exercise program (e-training) or no e-training intervention. The primary endpoint was the change in the Modified Fatigue Impact Scale (mFIS) after six months.ResultsThe primary analysis showed no statistically significant difference between groups in the mFIS change. Subgroup analyses revealed a beneficial effect of physical exercise for PwMS with low aerobic capacity and with low aerobic capacity plus more severe fatigue. The incidence of adverse events was similar in both groups. No cardiovascular events were reported. The majority of PwMS were relapse free.ConclusionPhysical exercise benefits on fatigue may depend on the physical capacity of the patient and requires individualized training. Consistent with previous studies, these results suggest that physical exercise generally does not impose a risk and that this holds true also for patients receiving fingolimod.Trial registration: ClinicalTrials.gov, NCT01490840.
BackgroundFirst dose observation for cardiac effects is required for fingolimod, but recommendations on the extent vary. This study aims to assess cardiac safety of fingolimod first dose. Individual bradyarrhythmic episodes were evaluated to assess the relevance of continuous electrocardiogram (ECG) monitoring.MethodsSTART is an ongoing open-label, multi-center study. At the time of analysis 3951 patients were enrolled. The primary endpoints are the incidence of bradycardia (heart rate < 45 bpm) and second-/third-degree AV blocks during treatment initiation. The relevance of Holter was assessed by matching ECG findings with the occurrence of clinical symptoms as well as by rigorous analysis of AV blocks with regard to the duration of pauses and the minimal heart rate recorded during AV block.ResultsThirty-one patients (0.8%) developed bradycardia (<45 bpm), 62 patients (1.6%) had second-degree Mobitz I and/or 2:1 AV blocks with a lowest reading (i.e. mean of ten consecutive beats) of 35 bpm and the longest pause lasting for 2.6 s. No Mobitz II or third-degree AV blocks were observed. Only one patient complained about mild chest discomfort and fatigue. After 1 week, there was no second-/third-degree AV block.ConclusionsContinuous Holter ECG monitoring in this large real-life cohort revealed that bradycardia and AV conduction abnormalities were rare, transient and benign. No further unexpected abnormalities were detected. The data presented here give an indication that continuous Holter ECG monitoring does not add clinically relevant value to patients’ safety.Trial registration NCT01585298; registered April 23, 2012.
Objectives: Approximately one in two patients with multiple sclerosis (MS) suffer from comorbid depression. The primary objective of this study was to evaluate the safety and tolerability of fingolimod and antidepressant combination in relapsing-remitting MS patients with mild-to-moderate depression. Efficacy outcome variables were quality of life (QoL), fatigue, disability and depression. Methods:Patients received open-label fingolimod 0.5 mg over 2 weeks, followed by fingolimod plus citalopram (40 mg), fluoxetine (40 mg) or venlafaxine (150 mg) over 16 weeks. The antidepressant was selected at the physician's discretion. Results: In total, 54 patients were recruited at 25 centres across Germany. No new safety signals (including cardiac) emerged compared with previous clinical studies. Adverse events (mostly mild-to-moderate) were reported in 43 patients. A total of three patients had serious adverse events and 10 discontinued the study. QoL (mean [95% confidence interval]) improved by 2.2 (−3.3, −1.2; Patient Reported Indices for MS questionnaire), fatigue by 8.2 (−13.1, −3.3; modified Fatigue Impact Scale) and depression by 6.3 (−8.4, −4.2; Hamilton Depression Scale) points. However, the results must be interpreted cautiously owing to limited patient numbers. Conclusions: Combination of fingolimod with antidepressant medication showed no unexpected safety signals. Patient-reported outcomes (QoL, disability, fatigue and depression) remained stable or improved.
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