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Efficacy and safety of fingolimod in stroke:A systemic review and meta-analysis

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World Journal of Meta-Analysis 2021年第6期9卷 585-597页

作者： Kai Zhao Yu Guo Ming-Fei Yang Qiang Zhang Graduate School Qinghai UniversityXining 810016Qinghai ProvinceChina Department of Neurosurgery Qinghai Provincial People's HospitalXining 810007Qinghai ProvinceChina

BACKGROUND Brain tissue injury in stroke patients involves inflammation around the infarction lesion or hematoma,which is an important reason for disease deterioration and can result in a poor *** meta-analysis of animal experiments has concluded that fingolimod could treat stroke in animal models by effectively reducing lymphocyte ***,no evidence-based efficacy and safety evaluation of fingolimod in stroke patients is currently *** To determine whether fingolimod could promote reduction of infarction lesion or hematoma and improve neurological prognosis in stroke *** Data extracted for treatment effect included count of T-lymphocytes with cluster of differentiation 8 expression(CD8^(+)T cells,×106/mL),lesion volume(infarction or hematoma,mL),and modified Barthel *** extracted for safety was risk ratio(RR).Overall standard mean difference(SMD)with its 95%confidence interval(95%CI)and pooled effect with its 95%CI were calculated with a fixedeffects model.I-square(I^(2))was used to test the *** plot symmetry and Egger's regression were used to evaluate publication *** Four high-quality randomized controlled trials were *** was a significant difference in CD8^(+)T cell count(I^(2)=0,overall SMD=-3.59,95%CI:-4.37-2.80,P=0.737)and modified Barthel index(I^(2)=0,overall SMD=2.42,95%CI:1.63-3.21,P=0.290)between the fingolimod and control ***,there was no significant difference in lesion volume(I^(2)=10.6%,overall SMD=-0.17,95%CI:-0.75-0.42,P=0.917),fever(pooled RR=0.93,95%CI:0.97-2.32,P=0.864),suspected lung infection(pooled RR=0.90,95%CI:0.33-2.43,P=0.876),or any adverse events occurring at least once(pooled RR=0.82,95%CI:0.36-1.87,P=0.995)between the fingolimod and control *** was no publication *** of the results were stable as revealed by sensitivity *** fingolimod improves neurological function in stroke patients without promotion of

关键词： Acute ischemic stroke Intracerebral hemorrhage fingolimod Meta-analysis Treatment

Combinatory use of fingolimod and low-dose adjuvant vaccine mimics regular T-cell priming through accumulation of cDC1

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Combinatory use of fingolimod and low-dose adjuvant vaccine ...

免疫调节剂fingolimod治疗多发性硬化症的机制和研究进展

第十三届全国免疫学学术大会

作者： Changxing Gao Mingyan Li Qing Zhu Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College State Key Laboratory of Bioactive Substance and Function of Natural Medicines Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study

Background: fingolimod blocks T cells egress from lymph nodes by acting as sphingosine-1-phosphate(S1 P) analog. S1 P causes desensitization of S1 P receptor 1 on na?ve T cells to prolong intranodal retention in lymph nodes, allowing adequate immunosurveillance or priming. fingolimod promotes na?ve T-cell accumulation in lymph nodes but does not impede function of effector cells. Due to the regulation role of fingolimod in T-cell migration, we have developed a strategic approach to the T-cell priming with protein vaccine containing low-dose adjuvants to induce antigen-specific CD8 T cell responses as efficiently as using regular-dose adjuvants ***: To investigate the mechanism by which fingolimod facilitates primary T-cell ***: Mice were given locally one low dose of fingolimod following vaccination by footpad injection. Cells from popliteal lymph nodes were isolated, stained and analyzed by flow cytometry. Proliferation of transferred antigen-specific cells and local inflammation of vaccination site were ***: Combined with time-specific local administration of fingolimod following vaccination, low-dose adjuvant vaccine induced sustained levels of total lymphocytes and antigen-specific CD8 T cells throughout the duration from d3 to d9 before returning to baseline at d11, displaying a similar cell expansion kinetics as regular-dose adjuvant vaccine. Moreover, transferred OT-I cells recovered from fingolimod-treated mice proliferated as efficiently as vaccinated with regular-dose adjuvant. In contrast to vaccine alone, the cDC1 number and DC-to-T cell ratio of the fingolimod group increased more appreciably over time from d3 to d7. Additionally, no obvious cutaneous edema or epidermal thickening in hind-paw was observed in fingolimod-treated mice, consistent with lower inflammatory cytokine ***: Strategic fingolimod administration closely resembles T-cell priming with reduced need of adjuvants and minimized adverse

关键词： fingolimod T-cell immunity CD8+ T cell priming vaccine development

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医学综述 2013年第7期19卷 1193-1195页

作者：林施施杨欣黄锦海温州医学院附属眼视光医院温州医学院眼视光学院浙江温州325027 西安市第四医院眼科西安710000

T淋巴细胞通过血脑屏障作用于髓鞘,引起髓鞘脱失是多发性硬化症(MS)发病机制的主要原因,而1-磷酸鞘氨醇(S1P)是影响淋巴细胞迁移的重要因素。fingolimod作为第一种美国食品药品管理局批准的用于治疗复发缓解型MS的口服药物,其磷酸化后与... 详细信息

T淋巴细胞通过血脑屏障作用于髓鞘,引起髓鞘脱失是多发性硬化症(MS)发病机制的主要原因,而1-磷酸鞘氨醇(S1P)是影响淋巴细胞迁移的重要因素。fingolimod作为第一种美国食品药品管理局批准的用于治疗复发缓解型MS的口服药物,其磷酸化后与S1P结构相似,相当于S1P的功能拮抗剂,可使淋巴细胞停留在淋巴结中,从而抑制免疫反应对髓鞘的破坏。

关键词： fingolimod 免疫调节剂 1-磷酸鞘氨醇多发性硬化症

Treatment strategies for multiple sclerosis:When to start,when to change,when to stop?

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World Journal of Clinical Cases 2015年第7期3卷 545-555页

作者： Alberto Gajofatto Maria Donata Benedetti Department of Neurological and Movement Sciences University of Verona Regional Center for Multiple Sclerosis Unit of NeurologyPoliclinico Borgo RomaAzienda Ospedaliera Universitaria Integrata Verona

Multiple sclerosis(MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies.

关键词： Multiple sclerosis Disease-modifying therapy Treatment start Treatment switch Treatment stop Interferon beta Glatiramer acetate Azathioprine Natalizumab fingolimod

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多发性硬化症治疗药芬戈莫德

药学进展 2010年第12期34卷 574-575页

作者：赵玉娜邢爱敏

诺华(Novartis)公司开发的鞘氨醇-1-磷酸受体(S1P)调节剂芬戈莫德(fingolimod,FTY-720)为美国批准上市的首个治疗多发性硬化症(MS)的口服药物,其可降低该病的复发率及减缓致残进程.

关键词：多发性硬化症 fingolimod 免疫抑制剂

溶血磷脂受体调节因子芬戈莫德:从传统中药到FDA批准药物(英文)

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中国药理学与毒理学杂志 2015年第S1期29卷 1-1页

作者： Jerold CHUN Dorris Neuroscience Center The Scripps Research Institute La Jolla CA USA

Lysophospholipids are small,membrane-derived lipids that act through a growing family of G protein-coupled receptors(GPCRs)that account for around 40% of the known lipid *** comprise a range of distinct chemical structures and include glycerophospholipids like lysophosphatidic acid(LPA)and sphingoid lipids like sphingosine 1-phosphate(S1P).S1 Phas five cognate GPCRs,four of which mediate the actions of a current medicine used in the treatment of multiple sclerosis(MS):fingolimod(also known as FTY720 or Gilenya),which was approved by the FDA in *** has its origins in Chinese medicine as a derivative of fungal natural ***′s mechanism of action in MS is partly known,through effects on lymphocyte trafficking,however current research has identified direct CNS actions that may represent a particular opportunity area for natural products and their derivatives that can target lysophospholipid *** history of lysophospholipid receptors and fingolimod will be discussed,along with mechanistic aspects of receptor-ligand interactions,particularly those with disease relevance.

关键词： fingolimod lysophospholipid receptor modulator tra

Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —II

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Pharmacology & Pharmacy 2013年第8期4卷 638-646页

作者： Noriyasu Seki Hirotoshi Kataoka Kunio Sugahara Atsushi Fukunari Kenji Chiba Advanced Medical Research Laboratories Research Division Mitsubishi Tanabe Pharma Corporation Yokohama Japan. Pharmacology Research Laboratories I Research Division Mitsubishi Tanabe Pharma Corporation Yokohama Japan Pharmacology Research Laboratories I Research Division Mitsubishi Tanabe Pharma Corporation Yokohama Japan Pharmacology Research Laboratories I Research Division Mitsubishi Tanabe Pharma Corporation Yokohama Japan Advanced Medical Research Laboratories Research Division Mitsubishi Tanabe Pharma Corporation Yokohama Japan.

Therapeutic administration of fingolimod hydrochloride (FTY720), the functional antagonist at sphingosine 1-phosphate (S1P) receptor 1 (S1P1) shows a marked improving effect on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. However, this treatment showed an only partial inhibition of Th1/Th17 cell infiltration into the central nervous system (CNS), suggesting that down-regulation of lymphocytic S1P1 is insufficient to explain the therapeutic effect of FTY720 on EAE. On the other hand, the therapeutic administration of FTY720 reduced the mRNA expressions of IL-6, CCL2, and glial fibrillary acidic protein, an activation marker of astrocytes, in the CNS of EAE mice. In human astrocytic glyoma, U373MG cells, mRNA expression of S1P1 was higher as compared with those of the other S1P receptor subtypes and phosphorylation of Akt was induced by S1P, FTY720-phosphate (FTY720-P), or an S1P1-selective agonist, SEW2871. FTY720-P appeared to induce down-regulation of S1P1 in U373MG cells, implying a functional antagonism at S1P1 on astrocytes. S1P but not FTY720-P induced production of IL-6, IL-8, and CCL2 significantly and treatment with FTY720-P or SEW2871 inhibited production of these pro-inflammatory cytokines from U373MG cells stimulated with S1P. These results suggest that S1P-S1P1 axis induces production of pro-inflammatory cytokines by astrocytes. Consequently, it is highly probable that the therapeutic effects of FTY720 on EAE are caused by inhibiting not only egress of myelin-specific Th cells from the draining lymph nodes but also activation of astrocytes in the CNS.

关键词： Sphingosine 1-Phosphosphate Receptor 1 fingolimod Hydrochloride (FTY720) Experimental Autoimmune Encephalomyelitis Astrocytes Pro-Inflammatory Cytokines

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芬戈莫德的合成工艺进展

化工管理 2016年第21期 115-页

作者：刘魏华北制药集团新药研究开发有限责任公司微生物药物国家工程研究中心河北省工业微生物代谢工程技术研究中心抗体药物研制国家重点实验室河北石家庄050015

芬戈莫德为鞘氨醇-1-磷酸受体调节剂,成为首个被FDA批准可经口给药的用于治疗复发-缓解型多发性硬化症,本文就其合成方法进行综述,为医药开发提供参考。

关键词：芬戈莫德合成氨基丙二醇 fingolimod