Disease modification in multiple sclerosis by flupirtine-results of a randomized placebo controlled phase II trial

Central nervous system inflammation and neurodegeneration are the pathophysiological hallmarks of multiple sclerosis (MS). While inflammation can readily be targeted by current disease modifying drugs, neurodegeneration is by far less accessible to treatment. Based on suggested additional neuroprotective capacities of the orally available non-opioid and centrally acting analgesic drug flupirtine maleate we hypothesized that treatment with flupirtine maleate might be beneficial in MS patients. The flupirtine as oral treatment in multiple sclerosis (FLORIMS) study was a multi-center, randomized and stratified, placebo-controlled double-blind phase II trial to investigate safety and efficacy in terms of clinical and radiographical activity of flupirtine maleate (300 mg per day) given orally for 12 months, add-on to interferon beta 1b subcutaneously in patients with relapsing remitting MS. Due to a substantial delay in recruitment, enrolment of patients was prematurely terminated after randomization of only 30 of the originally planned 80 patients. Of these, 24 regularly terminated study after 12 months of treatment. Data were analyzed as originally planned. Treatment with flupirtine maleate was overall well tolerated. We observed moderate and asymptomatic elevations of liver enzymes in several cases but no overt hepatotoxicity. Neither the intention to treat nor the per protocol analysis revealed any significant treatment effects of flupirtine maleate with respect to occurrence of MS relapses, disability progression, or development of new lesions on cranial MRI. However, substantial methodological limitations need to be considered when interpreting these results. In conclusion, the results of the FLORIMS study neither add further evidence to nor argue against the hypothesized neuroprotective or disease modifying effects of flupirtine maleate in MS

第985回千葉医学会例会・第二内科例会

Magnetic resonance spectroscopy (MRS) provides the unique ability to monitor several disease-related pathological processes via their characteristic metabolic markers in vivo. In the present study metabolic compositions were assessed every six months over the period of two years in 36 patients with Multiple Sclerosis (MS) including 21 relapsing-remitting (RR), 15 secondary progressive (SP) patients and 12 normal subjects. The concentrations of the main MRS-detectable metabolites N-acetylaspartate and N-acetylaspartylglutamate (tNAA), creatine and phosphocreatine (tCr), choline containing compounds (Cho), myo-Inositol (Ins), glutamine and glutamate (Glx) and their ratios were calculated in the normal appearing white matter (NAWM) and in selected non-enhancing white matter (WM) lesions. Association between metabolic concentrations in the NAWM and disability were investigated. Concentration of tNAA, a marker for neuroaxonal integrity, did not show any difference between the investigated groups. However, the patients with SPMS showed significant reduction of tNAA in the NAWM over the investigation period of two years indicating diffuse neuroaxonal loss during the disease course. Furthermore, we found a significant increase of Ins, Ins/tCr and Ins/tNAA in WM lesions independently from the course of the disease suggesting ongoing astrogliosis in silent-appearing WM lesions. Analyzing correlations between MRS metabolites in the NAWM and patients clinical status we found the positive correlation of Ins/tNAA with disability in patients with RRMS. In SPMS positive correlation of Cho with disability was found

Erythropoietin: a multimodal neuroprotective agent

The tissue protective functions of the hematopoietic growth factor erythropoietin (EPO) are independent of its action on erythropoiesis. EPO and its receptors (EPOR) are expressed in multiple brain cells during brain development and upregulated in the adult brain after injury. Peripherally administered EPO crosses the blood-brain barrier and activates in the brain anti-apoptotic, anti-oxidant and anti-inflammatory signaling in neurons, glial and cerebrovascular endothelial cells and stimulates angiogenesis and neurogenesis. These mechanisms underlie its potent tissue protective effects in experimental models of stroke, cerebral hemorrhage, traumatic brain injury, neuroinflammatory and neurodegenerative disease. The preclinical data in support of the use of EPO in brain disease have already been translated to first clinical pilot studies with encouraging results with the use of EPO as a neuroprotective agent

Seruma neirofilamenti multiplās sklerozes pacientiem

MedicīnaVeselības aprūpeMedicineHealth CareMultiplā skleroze (MS) ir visizplatītākā imūnmediētā centrālās nervu sistēmas (CNS) demielinizējošā slimība gados jauniem cilvēkiem. Pašreizējie klīniskie kritēriji bieži vien ir nepietiekami, lai noteiktu agrīnu diagnozi, prognozētu slimības paasinājumus un noteiktu ārstēšanas iznākumu MS pacientiem. Lai novērstu šos trūkumus, literatūrā ir ierosināti daudzi laboratoriskie, attēlu vai imūnģenētiskie parametri. No visiem pašlaik atklātajiem potenciālajiem biomarķieriem par visdaudzsološāko tika atzīta neirofilamentu vieglās ķēdes (NfL).Multiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system (CNS) in young adults. Current clinical criteria are often inadequate in establishing early diagnosis, predicting relapses, and determining treatment outcome in MS patients. To address these shortcomings, numerous laboratory, imaging, or immunogenetic parameters have been proposed in the literature. Of all potential biomarkers discovered at present, neurofilament light chain (NfL) was found to be the most promising

Using REACH registration data to rank the environmental emission potential of persistent and mobile organic chemicals

Organic chemicals that are persistent and mobile in the aquatic environment exhibit a hazard to contaminate drinking water resources. In this study an emission score model was developed to rank the potential of substances registered under the REACH legislation to be emitted into the environment. It was applied to a list of 2167 REACH registered substances thatwere previously identified to be persistent andmobile organic chemicals (PMOCs) in groundwater or to be hydrolyzed to form transformation products fulfilling the PMOC criteria. The emission score model is based on the tonnage placed on the European market and on seven emission-related use characteristics (high release to environment, wide dispersive use, intermediate use, closed system use, professional use, consumer use, and substance in article), reported in the companies' registrations under REACH. Applying the model resulted in a list of 1110 substances (936 PMOCs and 174 precursors to PMOCs) that were estimated to be released into the environment,while 1054 substances had indicators of negligible environmental emissions and 3 substances could not be evaluated due to severe data gaps. The 936 PMOCs and the 174 precursors were ranked in two lists with regard to their emission potential. The model was shown to be fit for purpose in terms of suggesting and prioritizing substances for scientific investigations with a focus on environmental water quality. Though targeted for PMOCs, the presented scoring systemis illustrative of how REACH registration data can be used to assess the emission potential of various substances.acceptedVersio

A numerical analysis of the in-bore motion of small caliber projectiles

Finite Element simulations have become a popular tool to investigate the mechanisms of launch dynamics. However, the common techniques for evaluating the simulation results in terms of target impact accuracy are far from ideal. This paper presents a method for the postprocessing of such simulations. The approach is based on a decomposition of the bullet’s transverse motion during launch into a regular rotation caused by the rifling, irregular oscillations (balloting) and muzzle motion. Target impact dispersion is evaluated separately for each of these motion components, which provides a deeper understanding of the dynamic processes determining the weapon’s hit performance. In contrast to traditional methods, where the assessment of dispersion requires large numbers of simulations with varying launch conditions, the evaluation of accuracy is based on a single simulation