Injectable Hydrogel Loaded with CDs and FTY720 Combined with Neural Stem Cells for the Treatment of Spinal Cord Injury.

Purpose: Spinal cord injury (SCI) is an incurable and disabling event that is accompanied by complex inflammation-related pathological processes, such as the production of excessive reactive oxygen species (ROS) by infiltrating inflammatory immune cells and their release into the extracellular microenvironment, resulting in extensive apoptosis of endogenous neural stem cells. In this study, we noticed the neuroregeneration-promoting effect as well as the ability of the innovative treatment method of FTY720-CDs@GelMA paired with NSCs to increase motor function recovery in a rat spinal cord injury model. Methods: Carbon dots (CDs) and fingolimod (FTY720) were added to a hydrogel created by chemical cross-linking GelMA (FTY720-CDs@GelMA). The basic properties of FTY720-CDs@GelMA hydrogels were investigated using TEM, SEM, XPS, and FTIR. The swelling and degradation rates of FTY720-CDs@GelMA hydrogels were measured, and each group's ability to scavenge reactive oxygen species was investigated. The in vitro biocompatibility of FTY720-CDs@GelMA hydrogels was assessed using neural stem cells. The regeneration of the spinal cord and recovery of motor function in rats were studied following co-treatment of spinal cord injury using FTY720-CDs@GelMA hydrogel in combination with NSCs, utilising rats with spinal cord injuries as a model. Histological and immunofluorescence labelling were used to determine the regeneration of axons and neurons. The recovery of motor function in rats was assessed using the BBB score. Results: The hydrogel boosted neurogenesis and axonal regeneration by eliminating excess ROS and restoring the regenerative environment. The hydrogel efficiently contained brain stem cells and demonstrated strong neuroprotective effects in vivo by lowering endogenous ROS generation and mitigating ROS-mediated oxidative stress. In a follow-up investigation, we discovered that FTY720-CDs@GelMA hydrogel could dramatically boost NSC proliferation while also promoting neuronal regeneration and synaptic formation, hence lowering cavity area. Conclusion: Our findings suggest that the innovative treatment of FTY720-CDs@GelMA paired with NSCs can effectively improve functional recovery in SCI patients, making it a promising therapeutic alternative for SCI.

Association of oral disease-modifying agents and their adherence trajectories with annual relapses in multiple sclerosis.

BACKGROUND: Real-world effectiveness can vary across oral disease-modifying agents (DMAs) and their adherence trajectories in patients with multiple sclerosis (MS). However, previous studies have not considered longitudinal adherence patterns while evaluating oral DMAs. OBJECTIVES: This study aimed to evaluate the association of oral DMAs and their adherence trajectories with annualized relapse rate (ARR) in patients with MS. METHODS: This retrospective observational cohort study based on the 2015-2019 MarketScan Commercial Claims and Encounters Database involved continuous enrolled adults (18-64 years) with ≥1 MS diagnosis (ICD-9/10-CM:340/G35) and ≥ 1 oral DMA prescription. Patients were grouped into incident fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users based on the index DMA with a one-year washout period. Annual DMA adherence trajectories based on the monthly Proportion of Days Covered (PDC) one year after treatment initiation were identified using Group-Based Trajectory Modeling (GBTM). The validated claims-based ARR was evaluated during the one-year follow-up period using generalized boosted model-based inverse probability treatment weights with negative binomial regression model. RESULTS: The study cohort consisted of 994 MS patients who initiated with FIN (23.0%), TER (22.3%), and DMF (54.7%) during the study period. GBTM grouped eligible patients into three adherence trajectories: complete adherers (59.2%), slow decliners (23.8%), and rapid decliners (17.0%). The proportion of complete adherers varied across the oral DMAs (FIN: 67.1%, TER: 55.4%, and DMF: 57.4%). The negative binomial regression modeling revealed that, while there was no difference in ARR across the three DMAs, rapid decliners (adjusted incidence rate ratio[aIRR]: 1.6, 95% CI: 1.1-2.4) had a higher rate of relapses compared to completely adherent patients. The type of oral DMAs did not moderate the relationship between ARR and the adherence trajectory groups. CONCLUSIONS: Adherence trajectories classified as rapid decliners were associated with a higher ARR than complete adherers after adjusting for their type of oral DMAs. Longitudinal medication adherence patterns are critical in reducing relapse rates in MS.

Platelet Membrane Nanocarriers Cascade Targeting Delivery System to Improve Myocardial Remodeling Post Myocardial Ischemia-Reperfusion Injury.

Although treatments for myocardial infarction have advanced significantly, the global mortality due to ischemia and subsequent reperfusion injury remains high. Here, a platelet (PLT) membrane nanocarrier (PL720) that encapsulates L-arginine and FTY720 to facilitate the cascade-targeted delivery of these substances to the myocardial injury site and enable the controlled release of L-arginine and FTY720 is developed. Such an innovative approach shows enhanced cardioprotection through multiple target strategies involved in ischemia-reperfusion injury and late reperfusion inflammation. During the ischemia-reperfusion phase, PL720 targets and accumulates in damaged coronary arteries. PL720 rapidly releases L-arginine, stimulating endothelial cells to produce NO, thereby dilating blood vessels and promoting blood flow recovery, while FTY720's sustained release exerts anti-apoptotic effects. During the late reperfusion inflammatory phase, PL720 is captured by circulating inflammatory monocytes and transported into a deeper ischemic myocardial lesion. PL720 promotes macrophage polarization and accelerates the inflammatory repair. Furthermore, the issue of bradycardia associated with the clinical use of FTY720 is innovatively relieved. Therefore, PL720 is a vascular injury and inflammation dual targeting strategy, exhibiting significant potential for multi-targeted therapy and clinical translation for cardiac injury.

Eficacia en la vida real del fingolimod en pacientes con esclerosis múltiple en Bulgaria / Real-world effectiveness of fingolimod in patients with multiple sclerosis in Bulgaria

Introducción El fingolimod es un agonista del receptor de esfingosina-1-fosfato utilizado para el tratamiento de la esclerosis múltiple (EM). Nuestro objetivo era evaluar los resultados del fingolimod en la calidad de vida de los pacientes con EM recurrente-remitente tras dos años de tratamiento en este estudio de la vida real. Pacientes y métodos Se trata de un estudio observacional prospectivo de dos años de duración realizado en Bulgaria en pacientes con EM recurrente-remitente tratados con fingolimod. Se evaluó la calidad de vida mediante la versión en búlgaro de la escala Multiple Sclerosis Quality of Life-54 (MSQoL-54). El criterio de valoración principal fue el cambio respecto al valor inicial en la puntuación en la MSQoL-54 tras dos años de tratamiento. Los criterios de valoración secundarios fueron el cambio respecto al valor inicial en la puntuación en la MSQoL-54 tras un año de tratamiento, además de la evaluación del nivel de depresión mediante la puntuación de la escala de puntuación de la depresión de Hamilton (HAM-D17). Resultados En el estudio se incluyó a 87 pacientes elegibles con una edad media de 38,7 ± 8,45 años. La mediana de la puntuación en la Expanded Disability Status Scale (EDSS) fue de 3,5 puntos. Se halló una mejora estadísticamente significativa en 10 subescalas en el mes 12 y en siete subescalas en el mes 24. La puntuación combinada de salud mental aumentó de 64 ± 16,69 puntos a 67,5 ± 15,94 puntos en el mes 24 (p = 0,012). La puntuación combinada de salud física aumentó de 61,7 ± 17,61 a 66,3 ± 16,7 (p = 0,001). El nivel de depresión medido por la HAM-D17 disminuyó considerablemente en el mes 12 y en el mes 24. La puntuación de la EDSS disminuyó o se mantuvo estable en más de la mitad de los pacientes (61,6%). Detectamos una mejor calidad de vida en los pacientes con una puntuación más baja en la EDSS. Conclusiones Las puntuaciones de calidad de vida y el nivel de depresión mejoraron ... (AU)

INTRODUCTION Fingolimod, a sphingosine-1-phosphate receptor agonist used for the treatment of multiple sclerosis (MS). Our goal was to assess the impact of fingolimod on quality of life in patients with relapsing-remitting multiple sclerosis (RRMS) after 2 years of treatment in this real-world study. PATIENTS AND METHODS This was a 2-year, prospective, observational study conducted in Bulgaria in RRMS patients treated with fingolimod. Quality of life was assessed using the Bulgarian-language version of the MSQoL-54 scale. The primary endpoint was the change from baseline in the MSQoL-54 score after 2 years of treatment. Secondary endpoints included the change from baseline in the MSQoL-54 score after one year of treatment, furthermore the assessment of depression level using the Hamilton D-17 score. RESULTS A total of 87 eligible patients were included in the study with a mean age of 38.7 ± 8.45 years. The median Expanded Disability Status Scale (EDSS) score was 3.5 points. We found statistically significant improvement in 10 subscales at month 12 and in seven subscales at month 24. The mental health composite score increased from 64.0 ± 16.69 points to 67.5 ± 15.94 points at month 24 (p = 0.012). The physical health composite score increased from 61.7 ± 17.61 to 66.3 ± 16.70 (p = 0.001). Depression level measured by the HAM-D17 decreased significantly by month 12 and month 24. The EDSS score decreased or remained stable in more than half of the patients (61.6%). We detected better quality of life in patients with a lower EDSS score. CONCLUSIONS Quality of life scores and the depression level are improved in RRMS patients treated with fingolimod over 2 years in real-life setting. (AU)

CD19+ B cell values predict the increase of anti-SARS CoV2 antibodies in fingolimod-treated and COVID-19-vaccinated patients with multiple sclerosis.

BACKGROUND: Treatment with fingolimod for multiple sclerosis (MS) reduces the efficacy of COVID-19 vaccination. The aim of this exploratory study was to evaluate whether main lymphocyte subsets and demographic features correlated to the subsequent increase in anti-SARS-CoV2 antibodies following the third dose of COVID-19 vaccination in fingolimod-treated MS patients. METHODS: This was a prospective single-center observational exploratory study including a subgroup of adult patients with MS (pwMS) in treatment with fingolimod who underwent COVID-19 vaccination. The association of anti-SARS-CoV2 antibody levels (reported as the Log10 of the difference between the post and pre third dose levels) with the total number and percentage of CD3+ T and CD19+ B was assessed by a linear regression model adjusted for age and sex. RESULTS: We found that peripheral blood CD19+ B lymphocytes before the third dose of vaccination in pwMS treated with fingolimod predict the subsequent increase of anti-SARS-CoV2 antibodies. CONCLUSION: This work suggests that evaluating the percentage of CD19+ B cells may be important to identify patients at risk of not producing SARS-CoV-2 antibodies, with possible reduced protection from COVID-19.

FTY720 in resistant human epidermal growth factor receptor 2-positive breast cancer.

The prognosis of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer has considerably improved. However, no reliable treatment besides anti-HER2 strategies has been available. FTY720, a small-molecule compound used for treating refractory multiple sclerosis, has been reported to have beneficial effects against cancers. We therefore evaluated the efficacy of FTY720 in trastuzumab-resistant breast cancer cells and investigated the possible mechanism involved. This study evaluated morphological changes after FTY720 treatment. Antiproliferative WST-1 assays and LDH Cytotoxicity Assay Kits were used to determine the treatment effects of drugs, whereas Western blot analysis was used to evaluate protein expression. Apoptotic events were investigated through annexin V staining and TUNEL assays using flow cytometry. FTY720 was effective in trastuzumab-resistant breast cancer cell lines despite the presence of PIK3CA mutation. Studied on a xenograft mouse model, FTY720-treated groups had statistically significantly poorer HCC1954 xenograft growth in vivo compared with the control group. Our findings suggest that FTY720 can overcome resistance to trastuzumab therapy in patients with HER2-positive breast cancer, with FTY720 plus trastuzumab might offer even better efficacy in vitro and in vivo.

COVID-19 Infection in Fingolimod- or Siponimod-Treated Patients: Case Series.

BACKGROUND AND OBJECTIVES: A descriptive analysis of COVID-19 infection in patients with multiple sclerosis (MS) receiving fingolimod or siponimod. METHODS: We reviewed the cases of COVID-19 from postmarketing or ongoing clinical trials reported to Novartis through December 27, 2020. RESULTS: As of December 27, 2020, 283 cases had been reported in fingolimod-treated patients. The mean age was 44 years (from n = 224; range 11-69 years), and 190 were women. Of 161 cases with available information, 138 were asymptomatic (6), mild (100), or moderate (32); 50 cases required hospitalization. At the last follow-up, 140 patients were reported as recovered/recovering, condition was unchanged in 22, and deteriorated in 3 patients; 4 patients had a fatal outcome. Information was not available for 114 patients. Of the 54 cases of COVID-19 reported in siponimod-treated patients, 45 were from the postmarketing setting and 9 from an ongoing open-label clinical trial. The mean age was 54 years (from n = 45; range 31-70), and 30 were women. Of 28 cases with available information, 24 were asymptomatic (2), mild (17), or moderate (5); 9 cases required hospitalization. At the last follow-up, 27 patients were reported as recovered/recovering, condition remained unchanged for 1, and 3 patients had a fatal outcome. Information was not available for 23 patients. DISCUSSION: Based on a review of available information, the risk of more severe COVID-19 in patients receiving fingolimod or siponimod seems to be similar to that reported in the general population and the MS population with COVID-19. However, limitations of spontaneous reporting, especially missing data, should be considered in the interpretation of these observations.

Secondary Immunodeficiency and Risk of Infection Following Immune Therapies in Neurology.

Secondary immunodeficiencies (SIDs) are acquired conditions that may occur as sequelae of immune therapy. In recent years a number of disease-modifying therapies (DMTs) has been approved for multiple sclerosis and related disorders such as neuromyelitis optica spectrum disorders, some of which are frequently also used in- or off-label to treat conditions such as chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis, myositis, and encephalitis. In this review, we focus on currently available immune therapeutics in neurology to explore their specific modes of action that might contribute to SID, with particular emphasis on their potential to induce secondary antibody deficiency. Considering evidence from clinical trials as well as long-term observational studies related to the patients' immune status and risks of severe infections, we delineate long-term anti-CD20 therapy, with the greatest data availability for rituximab, as a major risk factor for the development of SID, particularly through secondary antibody deficiency. Alemtuzumab and cladribine have relevant effects on circulating B-cell counts; however, evidence for SID mediated by antibody deficiency appears limited and urgently warrants further systematic evaluation. To date, there has been no evidence suggesting that treatment with fingolimod, dimethyl fumarate, or natalizumab leads to antibody deficiency. Risk factors predisposing to development of SID include duration of therapy, increasing age, and pre-existing low immunoglobulin (Ig) levels. Prevention strategies of SID comprise awareness of risk factors, individualized treatment protocols, and vaccination concepts. Immune supplementation employing Ig replacement therapy might reduce morbidity and mortality associated with SIDs in neurological conditions. In light of the broad range of existing and emerging therapies, the potential for SID warrants urgent consideration among neurologists and other healthcare professionals.

Exosomes Derived from Nerve Stem Cells Loaded with FTY720 Promote the Recovery after Spinal Cord Injury in Rats by PTEN/AKT Signal Pathway.

BACKGROUND: Spinal cord injury (SCI) remains a challenge owing to limited therapies. The exosome of neural stem cells (NSCs-Exos) and FTY720 transplantation could improve SCI effectively. However, the effect and mechanism of NSCs-Exos combined with FTY720 (FTY720-NSCs-Exos) transplantation in the treatment of SCI are not fully understood. METHODS: Sprague Dawley rats (8-week-old) were used to establish the SCI model, followed by the treatment of NSCs-Exos, FTY720, and FTY720-NSCs-Exos. The effect of FTY720, NSCs-Exos, and FTY720-NSCs-Exos combination treatment on hindlimb function, pathological changes, apoptosis activity, and the expression of spinal edema-related proteins and apoptosis-related proteins in SCI models were investigated by BBB scoring, HE staining, TUNEL staining and immunohistochemistry, and Western blotting. Meanwhile, the effect of these treatments on spinal cord microvascular endothelial cells (SCMECs) was detected under hypoxic circumstance. RESULTS: Our results found that FTY720-NSCs-Exos could alleviate pathological alterations and ameliorate the hindlimb function and oxygen insufficiency in model mice after SCI. In addition, exosomes could ameliorate the morphology of neurons, reduce inflammatory infiltration and edema, decrease the expression of Bax and AQP-4, upregulate the expression of claudin-5 and Bcl-2, and inhibit cell apoptosis. At the same time, in vitro experiments showed that FTY720-NSCs-Exos could protect the barrier of SCMECs under hypoxic circumstance, and the mechanism is related to PTEN/AKT pathway. CONCLUSION: FTY720-NSCs-Exos therapy displayed a positive therapeutic effect on SCI by regulating PTEN/AKT pathway and offered a new therapy for SCI.

The effect of FTY720 at different doses and time-points on LPS-induced acute lung injury in rats.

We sought to assess the protective effect of different doses of Fingolimod (FTY720) in a rat model of acute lung injury (ALI) induced by intratracheal instillation of lipopolysaccharide (LPS) and explored the underlying mechanisms. The ALI model was established in rats and different doses of FTY720 (0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, or 2 mg/kg) were injected intraperitoneally. Lung computed tomography and blood gas analyses were performed at 6 h, 24 h, and 48 h after intraperitoneal injection, and the lung tissues were extracted to prepare paraffin sections for histopathological examination. The levels of inflammatory cytokines (TNF-α, IL-6, and IL-1ß) were detected by ELISA, and the expressions of inflammatory pathway proteins in each group were measured by Western blot analysis. A single intraperitoneal injection of FTY720 inhibited LPS-induced NF-κB activation, reduced the level of inflammatory cytokines, and decreased the infiltration of inflammatory cells. Moreover, it alleviated lung tissue injury, as shown by marked attenuation of pulmonary oedema and improved arterial partial pressure of oxygen (PaO2) and the general condition of ALI rats. In conclusion, our results demonstrate the protective effect of FTY720 against LPS-induced ALI. The underlying mechanism of the protective effect may involve inhibition of LPS-induced activation of NF-κB and regulation of the inflammatory pathway to alleviate barrier dysfunction of alveolar capillaries.

Antioxidative effects of silymarin on the reduction of liver complications of fingolimod in patients with relapsing-remitting multiple sclerosis: A clinical trial study.

Multiple sclerosis (MS) is a chronic disease that affects the central nervous system and is characterized by inflammation, demyelination, and degenerative changes. Relapsing-remitting MS (RRMS) is the most common form of MS. Fingolimod (FTY720) is a once-daily disease-modifying agent approved to treat RRMS, and it binds to sphingosine 1-phosphate receptors. Milk thistle (silybum marianum; SM) is an herb generally used to protect the liver with antioxidant and antifibrotic effects. The purpose of this study was to evaluate the effects of silymarin on reducing liver complications of FTY720 in patients with RRMS and decrease the oxidative stress that plays an important role in the pathogenesis of this disease. Forty-eight patients with RRMS were divided into two groups using random assignment: the placebo and drug-treated groups. Participants of intervention and control groups took FTY720 with silymarin and placebo without silymarin per day for six months. Findings showed a significant reduction in the level of ALT and AST, reduction of main pathogenic factors in MS containing malondialdehyde, and also a significant rise in total antioxidant capacity, and total thiol groups in the serum of patients treated with silymarin as compared with the placebo group. Our outcomes propose the practical effects of silymarin in multiple sclerosis and reduction of hepatic side effects of fingolimod.

FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4+ T Lymphocytes.

BACKGROUND: Fingolimod (FTY720), a novel immunomodulator, was found to suppress the severity of collagen-induced arthritis (CIA) in mice. However, the potential molecular mechanisms are still unknown, and the effect of FTY720 on the recruitment of immune cells in the affected joints in the CIA model is not clear. MATERIALS AND METHODS: Following the oral administration of FTY720 (2 mg/kg) was treated into CIA mice per day for 35 days, intravital microscopy and immunofluorescence assays were performed to examine immune cell recruitment in the affected joints. Human MH7A synoviocytes were stimulated with tumour necrosis factor (TNF)-α and incubated with FTY720. Interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and interleukin-8 (IL-8) mRNA and protein expression were evaluated using RT-PCR and enzyme-linked immunosorbent assay, respectively. Signal transduction pathway protein expression was measured by Western blotting. Nuclear translocation of nuclear factor (NF)-κB was also analyzed by fluorescence microscopy. RESULTS: In vivo experiments showed that FTY720 inhibited the recruitment of CD4+ lymphocytes in the affected joints of CIA mice. FTY720 reduced the secretion of IL-1ß, IL-6, and IL-8 from TNF-α-stimulated MH7A cells in a dose-dependent manner. FTY720 also inhibited TNF-α-induced phosphorylation of NF-κBp65 and IκBα, as well as NF-κBp65 nuclear translocation, in a dose- and time-dependent manner. Interestingly, FTY720 blocked PI3K/Akt, the upstream targets of the NF-κB pathway. CONCLUSION: Our findings demonstrated that oral administration of FTY720 exerted beneficial effects in CIA mice by inhibiting CD4+ T lymphocyte recruitment to the affected joints. Our data also indicated that FTY720 inhibited TNF-α-induced inflammation by suppressing the AKT/PI3K/NF-κB pathway in MH7A cells.

Incidence and Risk of Infection Associated With Fingolimod in Patients With Multiple Sclerosis: A Systematic Review and Meta-Analysis of 8,448 Patients From 12 Randomized Controlled Trials.

Background and Aims: There is a controversy regarding whether fingolimod is associated with an increased risk of infection in patients with multiple sclerosis (MS). We performed a systematic review and meta-analysis of data from randomized controlled trials (RCTs) to determine the risk of infection in these patients. Methods: We systematically searched PubMed, EMBASE, the Cochrane Library, and clinicaltrials.gov from inception to April 8, 2020, to identify RCTs that reported the occurrence of infection in patients with MS treated with fingolimod. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated using the random-effects model. Results: Twelve RCTs including 8,448 patients were eligible. Compared with the control (placebo and other active treatments), fingolimod significantly increased the risk of infection (RR, 1.16; 95% CI, 1.07-1.27; I2, 81%), regardless of whether the infection was a general infection (RR, 1.14; 95% CI, 1.05-1.25; I2, 78%), or a serious infection (RR, 1.49; 95% CI, 1.06-2.10; I2, 0%). Analyses of subgroups found that fingolimod significantly increased the risk of lower respiratory infection (RR, 1.48; 95% CI, 1.19-1.85; I2, 0%) and herpes virus infection (RR, 1.34; 95% CI, 1.01-1.78; I2, 9%). There appears to be no dose-dependent increase in the risk of infection associated with fingolimod (0.5 mg: RR, 1.15; 95% CI, 1.07-1.25; I2, 91%; 1.25 mg: RR, 1.11; 95% CI, 0.97-1.28; I2, 81%; Pinteraction = 0.66). Conclusions: Compared with a placebo and other active treatments, fingolimod was associated with a 16% increase in the risk of infection, especially lower respiratory infection and herpes virus infection. The risk of infection associated with fingolimod might not be dose related.

Comparative treatment effectiveness of oral fingolimod and conventional injectable disease-modifying agents in multiple sclerosis.

STUDY OBJECTIVE: To compare the effectiveness of oral fingolimod and conventional injectable disease-modifying agents (DMAs) using the composite endpoint of relapse or DMA treatment switch in patients with multiple sclerosis (MS). DESIGN: A retrospective longitudinal cohort study. DATA SOURCE: IBM MarketScan Commercial Claims and Encounters Database from 2010-2012. PATIENTS: Adults (≥18 years) with MS diagnosis (ICD-9-CM:340) who newly initiated DMAs. INTERVENTION: Oral fingolimod and conventional injectable DMAs (interferon beta and glatiramer acetate). MEASUREMENTS: Composite endpoint of time to relapse or DMA treatment switch. MAIN RESULTS: The incident study cohort consisted of 1997 MS patients who initiated oral fingolimod (15.6%) or injectable (84.4%) DMAs. The proportion of patients who had a composite endpoint (relapse/DMA treatment switch) in oral fingolimod and injectable DMA users was found to be 16.72% and 27.16%, respectively. The Cox PH regression model with stabilized IPTW revealed that fingolimod is equally effective as conventional injectable DMAs in reducing the risk of experiencing the composite endpoint of relapse or DMA switch (adjusted hazard ratio [aHR]: 0.67, 95% CI: 0.43-1.03). Additional analysis among patients who were adherent also found no significant difference in the composite endpoint (aHR: 0.70, 95% CI 0.49-1.15) between oral fingolimod and injectable DMA users. CONCLUSIONS: Oral fingolimod has similar effectiveness as conventional injectable DMAs in reducing the risk of experiencing the composite endpoint (relapse or DMA treatment switch). In addition, when assessed independently, oral fingolimod showed no difference in reducing the time to relapse or DMA treatment switch compared to injectable DMAs.

Impairment of Spike-Timing-Dependent Plasticity at Schaffer Collateral-CA1 Synapses in Adult APP/PS1 Mice Depends on Proximity of Aß Plaques.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive and irreversible cognitive decline, with no disease-modifying therapy until today. Spike timing-dependent plasticity (STDP) is a Hebbian form of synaptic plasticity, and a strong candidate to underlie learning and memory at the single neuron level. Although several studies reported impaired long-term potentiation (LTP) in the hippocampus in AD mouse models, the impact of amyloid-ß (Aß) pathology on STDP in the hippocampus is not known. Using whole cell patch clamp recordings in CA1 pyramidal neurons of acute transversal hippocampal slices, we investigated timing-dependent (t-) LTP induced by STDP paradigms at Schaffer collateral (SC)-CA1 synapses in slices of 6-month-old adult APP/PS1 AD model mice. Our results show that t-LTP can be induced even in fully developed adult mice with different and even low repeat STDP paradigms. Further, adult APP/PS1 mice displayed intact t-LTP induced by 1 presynaptic EPSP paired with 4 postsynaptic APs (6× 1:4) or 1 presynaptic EPSP paired with 1 postsynaptic AP (100× 1:1) STDP paradigms when the position of Aß plaques relative to recorded CA1 neurons in the slice were not considered. However, when Aß plaques were live stained with the fluorescent dye methoxy-X04, we observed that in CA1 neurons with their somata <200 µm away from the border of the nearest Aß plaque, t-LTP induced by 6× 1:4 stimulation was significantly impaired, while t-LTP was unaltered in CA1 neurons >200 µm away from plaques. Treatment of APP/PS1 mice with the anti-inflammatory drug fingolimod that we previously showed to alleviate synaptic deficits in this AD mouse model did not rescue the impaired t-LTP. Our data reveal that overexpression of APP and PS1 mutations in AD model mice disrupts t-LTP in an Aß plaque distance-dependent manner, but cannot be improved by fingolimod (FTY720) that has been shown to rescue conventional LTP in CA1 of APP/PS1 mice.

FTY720 Reduces Endothelial Cell Apoptosis and Remodels Neurovascular Unit after Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. A sequence of pathological processes occurred when there is TBI. Previous studies showed that sphingosine-1-phosphate receptor 1 (S1PR1) played a critical role in inflammatory response in the brain after TBI. Thus, the present study was designed to evaluate the effects of the S1PR1 modulator FTY720 on neurovascular unit (NVU) after experimental TBI in mice. The weight-drop TBI method was used to induce TBI. Western blot (WB) was performed to determine the levels of SIPR1, claudin-5 and occludin at different time points. FTY720 was intraperitoneally administered to mice after TBI was induced. The terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL) assay was used to assess endothelial cell apoptosis. Immunofluorescence and WB were performed to measure the expression of tight junction proteins: claudin-5 and occludin. Evans blue (EB) permeability assay and brain water content were applied to evaluate the blood-brain barrier (BBB) permeability and brain edema. Immunohistochemistry was performed to assess the activation of astrocytes and microglia. The results showed that FTY720 administration reduced endothelial cell apoptosis and improved BBB permeability. FTY720 also attenuated astrocytes and microglia activation. Furthermore, treatment with FTY720 not only improved neurological function, but also increased the survival rate of mice significantly. These findings suggest that FTY720 administration restored the structure of the NVU after experimental TBI by decreasing endothelial cell apoptosis and attenuating the activation of astrocytes. Moreover, FTY720 might reduce inflammation in the brain by reducing the activation of microglia in TBI mice.

Novel compounds with dual S1P receptor agonist and histamine H3 receptor antagonist activities act protective in a mouse model of multiple sclerosis.

The sphingosine 1-phosphate (S1P) receptor 1 (S1P1) has emerged as a therapeutic target for the treatment of multiple sclerosis (MS). Fingolimod (FTY720) is the first functional antagonist of S1P1 that has been approved for oral treatment of MS. Previously, we have developed novel butterfly derivatives of FTY720 that acted similar to FTY720 in reducing disease symptoms in a mouse model of experimental autoimmune encephalomyelitis (EAE). In this study, we have synthesized a piperidine derivative of the oxazolo-oxazole compounds, denoted ST-1505, and its ring-opened analogue ST-1478, and characterised their in-vitro and in-vivo functions. Notably, the 3-piperidinopropyloxy moiety resembles a structural motif of pitolisant, a drug with histamine H3R antagonistic/inverse agonist activity approved for the treatment of narcolepsy. Both novel compounds exerted H3R affinities, and in addition, ST-1505 was characterised as a dual S1P1+3 agonist, whereas ST-1478 was a dual S1P1+5 agonist. Both multitargeting compounds were also active in mice and reduced the lymphocyte numbers as well as diminished disease symptoms in the mouse model of MS. The effect of ST-1478 was dependent on SK-2 activity suggesting that it is a prodrug like FTY720, but with a more selective S1P receptor activation profile, whereas ST-1505 is a fully active drug even in the absence of SK-2. In summary, these data suggest that the well soluble piperidine derivatives ST-1505 and ST-1478 hold promise as novel drugs for the treatment of MS and other autoimmune or inflammatory diseases, and by their H3R antagonist potency, they might additionally improve cognitive impairment during disease.

Clinical exacerbation of SARS-CoV2 infection after fingolimod withdrawal.

The role of disease-modifying therapies in patients with autoimmune disorders during severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection is controversial. Immunocompromised patients could have a more severe coronavirus disease-2019 (COVID-19) due to the absence of an adequate immune response against the SARS-CoV-2. However, therapies that act on immune response could play a protective role by dampening the cytokine-release syndrome. Fingolimod is a drug used for immune therapy in patients with multiple sclerosis (MS) through the sequestration of activated lymphocytes in the lymph nodes. We report the case of a 57-year-old man with relapsing-remitting MS treated with fingolimod that showed a reactivation of COVID-19 with signs of hyperinflammation syndrome after fingolimod withdrawal. Our case suggests that discontinuation of fingolimod during COVID-19 could imply a worsening of SARS-CoV2 infection.

Short-term laboratory and related safety outcomes for the multiple sclerosis oral disease-modifying therapies: an observational study.

BACKGROUND: Real-world safety data for the oral multiple sclerosis (MS) disease-modifying therapies (DMTs), dimethyl fumarate (DMF), fingolimod, and teriflunomide are important. We examined laboratory test abnormalities and adverse health conditions in new users. METHODS: Linked laboratory and administrative health data were accessed for all persons with MS (PwMS) filling their first oral DMT prescription in two Canadian provinces. PwMS were followed from first prescription fill until discontinuation, death, emigration or study end. Proportions of PwMS, and incidence rates (IR)/100 person-years, were calculated for ≥1 event of elevated alanine aminotransferase (ALT) (>the upper limit of normal [ULN]; all DMTs), liver toxicity (ALT>3xULN; fingolimod); lymphopenia and proteinuria (DMF), and cardiac arrhythmia, hypertension and pneumonia (all DMTs). RESULTS: Overall, 1,140 PwMS were followed for up to 2 years. De novo elevated alanine aminotransferase affected 13.2% (DMF), 12.4% (teriflunomide), and 30.0% (fingolimod) of users. Liver toxicity affected 2.8% of fingolimod, lymphopenia 3.1% of DMF, and proteinuria 2.9% of DMF users. The incidences of cardiac arrhythmia, pneumonia and hypertension ranged from <1 to 1.86/100 person-years depending on the DMT. CONCLUSIONS: The short-term, real-world incidences of abnormal laboratory results or adverse events were consistent with the pivotal clinical trial findings. Longer-term safety data are still needed.

[A patient with relapsing-remitting multiple sclerosis who relapsed frequently and developed primary biliary cholangitis after pregnancy and discontinuation of fingolimod].

We present the case of a 37-year-old woman who was diagnosed as having relapsing-remitting multiple sclerosis (MS) when she was 25 years old. She remained relapse-free after she was started on treatment with oral fingolimod. However, at the age of 35, when she became pregnant, fingolimod was discontinued, and she began to suffer from frequent relapses. Following her delivery, she was started on treatment with dimethyl fumarate. Subsequently, with elevation of the serum levels of hepatobiliary enzymes and peripheral blood eosinophil count, possibly caused by dimethyl fumarate, her treatment was switched back to fingolimod. However, the elevation of the serum hepatobiliary enzyme levels and peripheral blood eosinophil count persisted. A serological test for autoantibodies revealed the diagnosis of primary biliary cholangitis (PBC). Pregnancy or discontinuation of fingolimod could have influenced the immune status of the patient and worsened the state of MS. There are some reports of autoimmune hepatic diseases, including PBC, being caused by disease modifying drug (DMD), like interferon-ß or even steroid pulse therapy, although the underlying mechanisms remain unknown. This risk should be borne in mind when treating patients with MS, especially younger women, with DMD.