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Longterm safety and efficacy data generated in Europe from usage of fumaric acid formulations in the latter disease constituted grounds to investigate their effects in MS patients. Dimethyl fumarate (DMF) was found to be the active principle in those formulations and in vitro studies have demonstrated that DMF has immune-modulatory properties exerted through abilities to divert cytokine production toward a Th2 profile, both on lymphocytes and microglial cells. More importantly, DMF was discovered to impact the anti-oxidative stress cell machinery promoting the transcription of genes downstream to the activation of the nuclear factor (erythroid derived 2)-like2 (NRF2). DMF exposure increases the cytosol concentrations of NRF2, which besides immune regulatory effects, has the potential for cytoprotection on glial cells, oligodendrocytes and neurons. Extensive and rigorous clinical trials have assessed the efficacy and safety of DMF at the dose of 240 mg twice and three times a day in relapsingremitting MS patients during one phase IIb and two phase III trials. Robust, positive results were obtained across a number of clinical and paraclinical parameters. In one study (DEFINE), the relative reductions of the adjusted annualized relapse rate of the low and high dose regimens in comparison with placebo were 53% and 48%, respectively (p < 0.001 for both comparisons). In the other trial (CONFIRM), DMF decreased the annualized relapse rate in comparison with placebo by 44% in the lower and by 51% in higher dosage group (also p < 0.001). The number and size of lesions as detected by magnetic resonance imaging were also significantly decreased in comparison with the patients receiving DMF at every dosage. Multiple post hoc and subgroup analyses corroborated the clinical data, rendering DMF an appealing medication whose potential for impacting the degenerative aspects of MS remains to be explored. |

至尊木蟲 (著名寫手)
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長期 歐洲使用延胡索酸配方治療晚期疾病得到的安全和有效性的資料成為研究該類配方對多發(fā)性硬化癥療效的基礎(chǔ)。二甲基延胡索酸(DMF)是該類配方的主要活性成分。體外使用表明,DMF 具有免疫調(diào)節(jié)特性,表現(xiàn)為能歧化淋巴細(xì)胞和小膠質(zhì)細(xì)胞的細(xì)胞因子產(chǎn)生朝Th2方向。更重要的是DMF能動員抗氧化應(yīng)激細(xì)胞機(jī)制提高激活核因子(紅細(xì)胞樣衍化因子2)(NRF2)下游基因轉(zhuǎn)錄活性。膠質(zhì)細(xì)胞、少突細(xì)胞和神經(jīng)元暴露于DMF后,細(xì)胞質(zhì)NRF2濃度升高。這不僅具有免疫調(diào)節(jié)作用,還具有保護(hù)細(xì)胞的潛能。廣泛而嚴(yán)格的臨床試驗已證實了DMF 的療效和安全性。在一個IIb和兩個III期臨床試驗中DMF在240mg,每天2次和3次的劑量可延遲多發(fā)性硬化癥病人的復(fù)發(fā)。在許多臨床和亞臨床參數(shù)中得到穩(wěn)定的陽性結(jié)果。在一項研究(確定)中,低劑量和高劑量組與安慰劑組比較,調(diào)整的年復(fù)發(fā)率相對減少,分別為53%和48% (二者比較均p<0.001).在另一個臨床試驗(確認(rèn))中,DMF組與安慰劑組比較減少年復(fù)發(fā)率在低劑量為44%,高劑量為51%(也是p<0.001)。在每一個劑量下接受DMF的病人經(jīng)核磁共振成像檢測損傷的數(shù)量和大小都顯著降低。多次隨訪和子群分析確證了臨床資料,使DMF成為有希望的治療藥物。它對多發(fā)性硬化癥變性方面的影響有待進(jìn)一步探索。 |
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