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ABSTRACT Inflammatory environments induce the generation of dysfunctional IFNγ+T‐bet+FOXP3+ Th1‐like Tregs, which show defective function and are found in autoimmune conditions including multiple sclerosis (MS). The pathways that control the generation of Th1‐like Tregs are not well understood. Sphingosine‐1‐phosphate (S1P) signalling molecules are upregulated in Th1‐like Tregs, and in vivo S1P inhibition with Fingolimod (FTY720) inhibits the expression of genes responsible for Treg plasticity in MS patients. However, the underlying mechanisms are unknown. Here we show that S1P signalling inhibition by FTY720 inhibits the generation of Th1‐like Tregs and rescues their suppressive function. These effects are mediated by a decrease in mTORC1 signalling and reversal of the mitochondrial uncoupling that Tregs undergo during their reprogramming into Th1‐like Tregs in vitro. Finally, these results are validated in in vivo‐generated Th1‐like Tregs, as Tregs from MS patients treated with FTY720 display decreased Th1‐like Treg frequency, increased suppressive function and mitochondrial metabolism rebalance. These results highlight the involvement of mitochondrial uncoupling in Treg reprogramming and identify S1P signalling inhibition as a target to suppress the generation of dysfunctional Th1‐like Tregs. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion Fingolimod is the first oral sphingosine‐1‐phosphate receptor modulator approved in Japan for multiple sclerosis (MS). A large Japanese observational study of fingolimod in patients with MS was carried out to support its safety and effectiveness in a real‐world setting.This 2‐year, prospective, multicenter, single‐cohort, observational study included all Japanese patients with MS who initiated fingolimod (0.5 mg/day). Safety endpoints included adverse events and adverse drug reactions. Effectiveness endpoints included the annualized relapse rate, Kurtzke's Expanded Disability Status Scale score and physician clinical global impression. All endpoints were analyzed in fingolimod‐naïve patients.Of the 1792 patients who started fingolimod between 28 November 2011 and 31 May 2013, 1624 and 1623 fingolimod‐naïve patients were included in the safety and effectiveness analysis sets, respectively. The most common MS type was relapsing–remitting MS (89.47%). Adverse events, adverse events leading to discontinuation of fingolimod, adverse drug reactions and serious adverse drug reaction incidences were 64.10%, 15.33%, 57.88% and 23.46%, respectively. No new/unexpected safety signals were identified. The annualized relapse rate was 0.97 during the 1 year before baseline, and decreased to 0.22 after treatment. The mean Expanded Disability Status Scale score remained stable throughout treatment, irrespective of the baseline Expanded Disability Status Scale score (≥3 or <3). Physician clinical global impression was classified as ‘effective’ in the majority of patients (70.3%–90.1%) throughout the treatment period.Fingolimod was well tolerated and no new safety concerns were identified in this Japanese 2‐year post‐marketing study. Additionally, fingolimod was effective in preventing MS relapse and physical disability progression in this real‐world population comprising mainly relapsing–remitting MS patients. [ABSTRACT FROM AUTHOR]

Fingolimod is an oral drug for the escalation of treatment of relapsing–remitting multiple sclerosis in patients with persistent disease activity on first‐line drugs or in patients with rapidly progressive severe relapsing–remitting multiple sclerosis. An ultra‐high‐performance liquid chromatography–tandem mass spectrometry method for determining the concentrations of fingolimod and its active metabolite fingolimod phosphate in whole blood has been developed and validated. The advantages of this method are the easy, fast and cheap sample preparation using protein precipitation from blood with a mixture of acetonitrile–methanol (40:60, v/v). Chromatographic separation was performed on a ultra‐high performance liquid chromatography BEH C18 1.7 μm (100 × 2.1 mm) column. Two modes of ionization, electrospray ionization and atmospheric pressure chemical ionization, were tested and compared. For validation, the electrospray ionization mode was chosen. As internal standard, isotopically labeled fingolimod‐D4 was used to quantify the analytes. The method was validated according to the rules of the European Medicines Agency. The coefficients of variation for fingolimod were in the range of 1.13–11.88%, and the recovery was 98.80–106.00%. The coefficients of variation for fingolimod phosphate were in the range of 2.73–9.31%, and the recovery was 90.08–107.00%. The method is quite easy and fast and can be used for routine analysis. [ABSTRACT FROM AUTHOR]

Key Clinical Message: A report of Balo's concentric sclerosis developed alongside with fingolimod use in a patient with previously diagnosed multiple sclerosis. [ABSTRACT FROM AUTHOR]

The small‐molecule drug, FTY720 (fingolimod), is a synthetic sphingosine 1‐phosphate (S1P) analogue currently used to treat relapsing–remitting multiple sclerosis in both adults and children. FTY720 can cross the blood–brain barrier (BBB) and, over time, accumulate in lipid‐rich areas of the central nervous system (CNS) by incorporating into phospholipid membranes. FTY720 has been shown to enhance cell membrane fluidity, which can modulate the functions of glial cells and neuronal populations involved in regulating behaviour. Moreover, direct modulation of S1P receptor‐mediated lipid signalling by FTY720 can impact homeostatic CNS physiology, including neurotransmitter release probability, the biophysical properties of synaptic membranes, ion channel and transmembrane receptor kinetics, and synaptic plasticity mechanisms. The aim of this study was to investigate how chronic FTY720 treatment alters the lipid composition of CNS tissue in adolescent mice at a key stage of brain maturation. We focused on the hippocampus, a brain region known to be important for learning, memory, and the processing of sensory and emotional stimuli. Using mass spectrometry‐based lipidomics, we discovered that FTY720 increases the fatty acid chain length of hydroxy‐phosphatidylcholine (PCOH) lipids in the mouse hippocampus. It also decreases PCOH monounsaturated fatty acids (MUFAs) and increases PCOH polyunsaturated fatty acids (PUFAs). A total of 99 lipid species were up‐regulated in the mouse hippocampus following 3 weeks of oral FTY720 exposure, whereas only 3 lipid species were down‐regulated. FTY720 also modulated anxiety‐like behaviours in young mice but did not affect spatial learning or memory formation. Our study presents a comprehensive overview of the lipid classes and lipid species that are altered in the hippocampus following chronic FTY720 exposure and provides novel insight into cellular and molecular mechanisms that may underlie the therapeutic or adverse effects of FTY720 in the central nervous system. [ABSTRACT FROM AUTHOR]

Extensive vascular leakage and shock is a major cause of dengue‐associated mortality. At present, there are no specific treatments available. Sphingolipid pathway is a key player in the endothelial barrier integrity; and is mediated through the five sphingosine‐1‐phosphate receptors (S1PR1‐S1PR5). Signaling through S1PR2 promotes barrier disruption; and in Dengue virus (DENV)‐infection, there is overexpression of this receptor. Fingolimod (FTY720) is a specific agonist that targets the remaining barrier‐protective S1P receptors, without targeting S1PR2. In the present study, we explored whether FTY720 treatment can alleviate DENV‐induced endothelial hyperpermeability. In functional assays, in both in vitro systems and in AG129 animal models, FTY720 treatment was found effective. Upon treatment, there was complete restoration of the monolayer integrity in DENV serotype 2‐infected human microvascular endothelial cells (HMEC‐1). At the molecular level, the treatment reversed activation of the S1P pathway. It significantly reduced the phosphorylation of the key molecules such as PTEN, RhoA, and VE‐Cadherin; and also, the expression levels of S1PR2. In DENV2‐infected AG129 mice treated with FTY720, there was significant improvement in weight gain, in overall clinical symptoms, and in survival. Whereas 100% of the DENV2‐infected, untreated animals died by day‐10 post‐infection, 70% of the FTY720‐treated animals were alive; and at the end of the 15‐day post‐infection observation period, 30% of them were still surviving. There was a significant reduction in the Evan's‐blue dye permeability in the organs of FTY720‐treated, DENV‐2 infected animals; and also improvement in the hemogram, with complete restoration of thrombocytopenia and hepatic function. Our results show that the FDA‐approved molecule Fingolimod (FTY720) is a promising therapeutic intervention in severe dengue. [ABSTRACT FROM AUTHOR]

A study has found that clusterin deficiency may be a biomarker for a lack of response to teriflunomide, an oral therapy for multiple sclerosis (MS). The study used RNA sequencing to identify genes that showed differential expression in responders and non-responders to teriflunomide treatment, and clusterin was the only gene that was validated and found to be downregulated in non-responders. Further analysis revealed that clusterin expression was primarily reduced in certain T cells from non-responders. Another study investigated the effects of teriflunomide treatment on T-cell metabolism, apoptosis, and proliferation in MS patients. It found that teriflunomide treatment reduced the respiratory and glycolytic capacities of T-cells, but there were no significant differences in the metabolic profile between responders and non-responders. Non-responders had a higher resistance to apoptosis and a reduced proliferative response in memory T-cell populations compared to responders. These findings suggest that teriflunomide non-responders may have abnormal persistence of pathogenic T-cells in the blood. Further research is needed to validate these findings and their implications for identifying non-responders to teriflunomide treatment. [Extracted from the article]

Background: Diffuse brain injury (DBI) models are characterized by intense global brain inflammation and edema, which characterize the most severe form of TBI. In a previous experiment, we found that fingolimod promoted recovery after controlled cortical impact injury (CCI) by modulating inflammation around brain lesions. However, it remains unclear whether fingolimod can also attenuate DBI because of its different injury mechanisms. Furthermore, whether fingolimod has additional underlying effects on repairing DBI is unknown. Methods: The impact acceleration model of DBI was established in adult Sprague–Dawley rats. Fingolimod (0.5 mg/kg) was administered 0.5, 24, and 48 h after injury for 3 consecutive days. Immunohistochemistry, immunofluorescence analysis, cytokine array, and western blotting were used to evaluate inflammatory cells, inflammatory factors, AQP4 polarization, apoptosis in brain cells, and the accumulation of APP after DBI in rats. To evaluate the function of the glymphatic system (GS), a fluorescent tracer was injected into the cistern. The neural function of rats with DBI was evaluated using various tests, including the modified neurological severity score (mNSS), horizontal ladder‐crossing test, beam walking test, and tape sensing and removal test. Brain water content was also measured. Results: Fingolimod administration for 3 consecutive days could reduce the levels of inflammatory cytokines, neutrophil recruitment, microglia, and astrocyte activation in the brain following DBI. Moreover, fingolimod reduced apoptotic protein expression, brain cell apoptosis, brain edema, and APP accumulation. Additionally, fingolimod inhibited the loss of AQP4 polarization, improved lymphatic system function, and reduced damage to nervous system function. Notably, inhibiting the GS weakened the therapeutic effect of fingolimod on the neurological function of rats with DBI and increased the accumulation of APP in the brain. Conclusions: In brief, these findings suggest that fingolimod alleviates whole‐brain inflammation and GS system damage after DBI and that inhibiting the GS could weaken the positive effect of fingolimod on nerve function in rats with DBI. Thus, inhibiting inflammation and regulating the GS may be critical for the therapeutic effect of fingolimod on DBI. [ABSTRACT FROM AUTHOR]

Long‐term exposure to non‐physiologically compatible dialysate inevitably leads to peritoneal fibrosis (PF) in patients undergoing peritoneal dialysis (PD), and there is no effective prevention or treatment for PF. Sphingosine‐1‐phosphate (S1P) is a bioactive sphingolipid produced after catalysis by sphingosine kinase (SPHK) 1/2 and activates signals through the S1P receptor (S1PR) via autocrine or paracrine. However, the role of SPHK1/S1P/S1PR signaling has never been elucidated in PF. In our research, we investigated S1P levels in peritoneal effluents and demonstrated the role of SPHK1/S1P/S1PR pathway in peritoneal fibrosis. It was found that S1P levels in peritoneal effluents were positively correlated with D/P Cr (r = 0.724, p <.001) and negatively correlated with 4 h ultrafiltration volume (r = −0.457, p <.001). S1PR1 and S1PR3 on peritoneal cells were increased after high glucose exposure in vivo and in vitro. Fingolimod was applied to suppress S1P/S1PR pathway. Fingolimod restored mouse peritoneal function by reducing interstitial hyperplasia, maintaining ultrafiltration volume, reducing peritoneal transport solute rate, and mitigating the protein expression changes of fibronectin, vimentin, α‐SMA, and E‐cadherin induced by PD and S1P. Fingolimod preserved the morphology of the human peritoneal mesothelial cells, MeT‐5A, and moderated the mesothelial‐mesenchymal transition (MMT) process. We further delineated that SPHK1 was elevated in peritoneal cells after high glucose exposure and suppression of SPHK1 in MeT‐5A cells reduced S1P release. Overexpression of SPHK1 in MeT‐5A cells increased S1P levels in the supernatant and fostered the MMT process. PF‐543 treatment, targeting SPHK1, alleviated deterioration of mouse peritoneal function. In conclusion, S1P levels in peritoneal effluent were correlated with the deterioration of peritoneal function. SPHK1/S1P/S1PR pathway played an important role in PF. [ABSTRACT FROM AUTHOR]

Background and purpose: Newly appearing lesions in multiple sclerosis (MS) may evolve into chronically active, slowly expanding lesions (SELs), leading to sustained disability progression. The aim of this study was to evaluate the incidence of newly appearing lesions developing into SELs, and their correlation to clinical evolution and treatment. Methods: A retrospective analysis of a fingolimod trial in primary progressive MS (PPMS; INFORMS, NCT 00731692) was undertaken. Data were available from 324 patients with magnetic resonance imaging scans up to 3 years after screening. New lesions at year 1 were identified with convolutional neural networks, and SELs obtained through a deformation‐based method. Clinical disability was assessed annually by Expanded Disability Status Scale (EDSS), Nine‐Hole Peg Test, Timed 25‐Foot Walk, and Paced Auditory Serial Addition Test. Linear, logistic, and mixed‐effect models were used to assess the relationship between the Jacobian expansion in new lesions and SELs, disability scores, and treatment status. Results: One hundred seventy patients had ≥1 new lesions at year 1 and had a higher lesion count at screening compared to patients with no new lesions (median = 27 vs. 22, p = 0.007). Among the new lesions (median = 2 per patient), 37% evolved into definite or possible SELs. Higher SEL volume and count were associated with EDSS worsening and confirmed disability progression. Treated patients had lower volume and count of definite SELs (β = −0.04, 95% confidence interval [CI] = −0.07 to −0.01, p = 0.015; β = −0.36, 95% CI = −0.67 to −0.06, p = 0.019, respectively). Conclusions: Incident chronic active lesions are common in PPMS, and fingolimod treatment can reduce their number. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma has high recurrence and cisplatin resistance. As cancer stem cells, autophagy, and sphingolipids have been appointed as associated with chemotherapy resistance, we tested combined treatments targeting autophagy and/or sphingolipid metabolism with paclitaxel using cisplatin‐resistant oral squamous cell carcinoma cells. Methods: Cisplatin‐resistant oral squamous cell carcinoma cells were maintained under exposition to FTY720 and chloroquine combined with paclitaxel and submitted to viability, clonogenicity, and spheres formation assays. The xenograft tumor model using cisplatin‐resistant CAL27 cells was adopted to examine the drug combinations' potential antitumoral efficacy. Using an animal model, sphingolipids profiles from plasma and tissue samples were obtained by liquid chromatography coupled to mass spectrometry to identify potential lipids associated with drug response. Results and Discussion: Our results showed higher autophagic flux in cisplatin‐resistant Ooral squamous cell carcinoma (CAL27 and SCC9) cells than in parental cells. The combinations of an autophagy inhibitor (chloroquine) or an autophagy inducer/sphingosine kinase 1 antagonist (FTY720) with paclitaxel (PTX) had a synergistic antitumor effect. Treated CisR cells lost clonogenicity and tumor sphere abilities and reduced proteins associated with proliferation, survival, and cancer stem cells. FTY720 plus PTX had higher antitumor efficacy than PTX against CAL27 CisR xenograft tumor formation. Additionally, increases in glucosylceramide, dehydroglucosylceramide, and sphingomyelin were presented in responsive tumors. Conclusion: FTY720 sensitizes cisplatin‐resistant oral squamous cell carcinoma cells for paclitaxel. [ABSTRACT FROM AUTHOR]

Objectives: Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to myelin sheaths. While all current disease‐modifying treatments (DMTs) are very effective at reducing relapses, they do not slow the progression of the disease, and there is little evidence that these treatments are able to repair or remyelinate damaged axons. Recent evidence suggests that activating kappa opioid receptors (KORs) has a beneficial effect on the progression of MS, and this study investigates the effects of KOR agonists treatment in combination with two current DMTs. Methods: Using the well‐established murine model for immune‐driven demyelination of MS, experimental autoimmune encephalomyelitis, the effect of KOR agonists in combination with DMTs fingolimod or dimethyl fumarate on disease progression, immune cell infiltration and activation as well as myelination were analysed. Results: Fingolimod in combination with the KOR agonist, nalfurafine, significantly increased each individual beneficial effect as measured by increased recovery of mice and reduced relapses. These beneficial effects correlated with a reduction in immune cell infiltration into the CNS as well as peripheral immune cell alterations including a reduction in autoreactive CD4+ T‐cell cytokine production as well as increased myelination in the spinal cords of co‐treated animals. In contrast, while the use of dimethyl fumarate in combination with nalfurafine did not adversely affect the benefits of nalfurafine, the combination did not significantly enhance those benefits. Conclusion: This study indicates that KOR agonists can be used in combination with fingolimod and dimethyl fumarate with the nalfurafine–fingolimod combination providing enhanced benefits. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF)‐β1, a member of the TGF‐β superfamily, is produced by many immune and nonimmune cells and has pleiotropic effects on both innate and adaptive immunity, especially in the control of T‐cell differentiation and function. Consistently, loss of TGF‐β1 function is associated with exacerbated T‐cell‐dependent inflammatory responses that culminate in pathological processes in allergic and immune‐mediated diseases. In this review, we highlight the roles of TGF‐β1 in immunity, focusing mainly on its ability to promote differentiation of regulatory T cells, T helper (Th)‐17, and Th9 cells, thus contributing to amplifying or restricting T‐cell responses in health and human diseases (e.g., inflammatory bowel diseases, type 1 diabetes, asthma, and MS). In addition, we discuss the involvement of Smad7, an inhibitor of TGF‐β1 signaling, in immune‐mediated disorders (e.g., psoriasis, rheumatoid arthritis, MS, and inflammatory bowel diseases), as well as the discordant results of clinical trials with mongersen, an oral pharmaceutical compound containing a Smad7 antisense oligonucleotide, in patients with Crohn's disease. Further work is needed to ascertain the reasons for such a discrepancy as well as to identify better candidates for treatment with Smad7 inhibitors. [ABSTRACT FROM AUTHOR]

Background: Patients with multiple sclerosis (MS) who discontinue fingolimod might present with rebound activity. The reasons for the development of rebound have been identified, but there are limited data on the long‐term clinical outcomes of these patients. This study aimed to compare the long‐term outcomes of patients with MS with and without rebound activity after fingolimod discontinuation. Methods: A total of 31 patients who discontinued fingolimod for various reasons with a minimum follow‐up of 5 years were included in the study. Of these, 10 were assigned to the rebound group and 21 to the non‐rebound group. Clinical and demographic data and 5‐year clinical outcomes of both groups were prospectively examined. Results: At fingolimod initiation, there were no significant differences in age, disease duration, and Expanded Disability Status Scale (EDSS) score. The annualized relapse rate (ARR) was significantly higher in the rebound group than in the non‐rebound group before the fingolimod treatment (p = 0.005). In the rebound group, EDSS scores 2 months after rebound treatment and at the 5‐year follow‐up were not significantly different than before fingolimod initiation (p = 0.14 and p = 0.46, respectively). The last recorded EDSS was significantly higher in the non‐rebound group than in the rebound group (3.6 ± 2.3 vs. 2.15 ± 1.4, p = 0.045). At the last follow‐up, one patient was diagnosed with secondary progressive multiple sclerosis in the rebound group (10%), and 11 patients were in the non‐rebound group (52.4%, p = 0.05). Conclusion: When rebound activity is well‐monitored and treated after fingolimod discontinuation, no overall EDSS change is expected in the long‐term follow‐up. [ABSTRACT FROM AUTHOR]

Fingolimod has generally shown neuroprotective effects in stroke models. Here, we tested the hypothesis that fingolimod modulates T‐cell cytokine production towards a regulatory phenotype. Second, we investigated how fingolimod altered the Treg suppressive function and the sensitivity of effector T cells to regulation. Mice that had underwent the permanent electrocoagulation of the left middle cerebral artery received saline or fingolimod (0.5 mg/kg) daily for 10‐days post‐ischaemia. Fingolimod improved neurobehavioural recovery compared to saline control and increased Treg frequency in the periphery and brain. Tregs from fingolimod‐treated animals had a higher expression of CCR8. Fingolimod increased the frequencies of CD4+IL‐10+, CD4+ IFN‐γ+ and CD4+IL‐10+IFN‐γ+ cells in spleen and blood, and CD4+ IL‐17+ cells in the spleen, with only minor effects on CD8+ T‐cell cytokine production. Treg from post–ischaemic mice had reduced suppressive function compared to Treg from non‐ischaemic mice. Fingolimod treatment rescued this function against saline‐treated but not fingolimod‐treated CD4+ effector T cells. In conclusion, fingolimod seems to improve the suppressive function of Treg post‐stroke while also increasing the resistance of CD4+ effector cells to this suppression. Fingolimod's capacity to increase both effector and regulatory functions may explain the lack of consistent improvement in functional recovery in experimental brain ischaemia. [ABSTRACT FROM AUTHOR]

Background and purpose: Although two doses of COVID‐19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease‐modifying therapies (DMTs) showed less efficient responses. Methods: This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS. Results: Four hundred seventy‐three pwMS were analyzed. Compared to untreated patients, there was a 50‐fold decrease (95% confidence interval [CI] = 14.3–100.0, p < 0.001) in serum SARS‐CoV‐2 antibody levels in those on rituximab, a 20‐fold decrease (95% CI = 8.3–50.0, p < 0.001) in those on ocrelizumab, and a 2.3‐fold decrease (95% CI = 1.2–4.6, p = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti‐CD20 drugs rituximab and ocrelizumab showed a 2.3‐fold lower gain (95% CI = 1.4–3.8, p = 0.001), whereas those on fingolimod showed a 1.7‐fold higher gain (95% CI = 1.1–2.7, p = 0.012), compared to patients treated with other DMTs. Conclusions: All pwMS increased their serum SARS‐CoV‐2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (>659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Malignancies were reported in some studies following taking Fingolimod. We reported a case of bladder lymphoma after taking Fingolimod. Physicians should consider the carcinogenic effects of Fingolimod in long‐term use and replace it with safer medicines. Fingolimod is a medication with a potential cure to control multiple sclerosis (MS) relapses. Here we describe a 32‐year‐old woman with relapsing–remitting multiple sclerosis who developed bladder lymphoma induced by long‐term use of Fingolimod. Physicians should consider the carcinogenic effects of Fingolimod in long‐term use and replace it with safer medicines. [ABSTRACT FROM AUTHOR]

Objective: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune‐mediated disease that targets the myelin sheaths of the peripheral nerves. Fingolimod is a sphingosine 1 phosphate (S1P) receptor antagonist with a high affinity for S1P receptors through the Akt–mTOR pathway, and prior research has suggested that it might be helpful in autoimmune illnesses. Methods: Chronic experimental autoimmune neuritis (c‐EAN) was induced by immunizing Lewis rats with the S‐palm P0(180–199) peptide, and then the treatment group was intraperitoneally injected with fingolimod (1 mg/kg) daily. Hematoxylin and eosin staining was used to assess the severity of nerve injury. Immunohistochemistry staining showed that fingolimod's anti‐inflammatory effects on c‐EAN rats might be realized through the NF‐κB signaling pathway. Tumor necrosis factor‐α (TNF‐α), interferon‐γ (INF‐γ), interleukin‐1beta (IL‐1β), interleukin 6 (IL‐6), inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule‐1 (ICAM‐1) were measured to evaluate the inflammation levels, and pAkt, p‐S6, and p‐p65 were used to measure the abundance of downstream activation markers to determine whether the Akt/mTOR/NF‐κB signaling pathway was activated in the c‐EAN model. Results: Fingolimod treatment reduced the inflammatory reaction and the expression of NF‐κB in sciatic nerves. It also decreased the mRNA levels of the proinflammatory cytokines TNF‐α, IFN‐γ, IL‐1β, IL‐6, iNOS, and ICAM‐1 and pAkt, p‐S6, and p‐p65, representing the Akt/mTOR/NF‐κB signaling pathway. Conclusion: Our data showed that fingolimod could improve the disease course, alleviate the decrease in inflammation, and reduce proinflammatory cytokines through the Akt/mTOR/NF‐κB axis in c‐EAN rats, which could be beneficial for the development of CIDP‐related research. [ABSTRACT FROM AUTHOR]

The current study was designed to investigate the potential anti‐inflammatory and antioxidant effects of fingolimod against Ovalbumin (Ova)‐induced allergic airway inflammation compared to dexamethasone. Fingolimod was given (0.5 mg/kg/day, p.o.) for sensitized mice 1 h before Ova challenge from Days 19 to 24. Fingolimod significantly inhibited Ova‐induced elevation of inflammatory cells and eosinophils numbers in bronchoalveolar lavage fluid (BALF) and reduced concentrations of immunoglobulin E in serum and of sphingosine‐1‐phosphate, interleukin (IL)‐4, and IL‐13 in BALF. Fingolimod inhibited microvascular leakage and edema as reflected by the decreased lung/body weight index. These findings were supported by histopathological examination results showing that fingolimod substantially decreased perivascular edema and inflammatory cell infiltration. Fingolimod also attenuated Ova‐induced oxidative stress as evidenced by decreased malondialdehyde concentration along with increasing concentrations of reduced glutathione and superoxide dismutase in lung tissues. Fingolimod also significantly decreased monocyte chemoattractant protein‐1 (MCP‐1), p‐ERK, and p‐P38 in lung tissues of Ova‐challenged mice. In conclusion, the current study demonstrated the anti‐inflammatory and antioxidant effects of fingolimod in allergic airway inflammation that might be associated with the downregulation of mitogen activated kinases signaling to decrease T helper 2 cytokine secretion (IL‐4 and IL‐13) and MCP‐1 expression, along with the inhibition of oxidative stress. [ABSTRACT FROM AUTHOR]

This article discusses a case of disseminated molluscum contagiosum (MC) in a child undergoing fingolimod treatment for relapsing-remitting multiple sclerosis (RRMS). Fingolimod is an oral drug approved by the FDA for treating RRMS, and it functions by modulating sphingosine-1-phosphate. Previous case series have suggested an increased susceptibility to infections during fingolimod treatment, including MC. The child in this case developed extensive MC lesions that did not respond well to topical treatment. The article emphasizes the importance of early recognition and intervention to prevent disfigurement and frequent hospital visits. [Extracted from the article]

Hyper-inflammation, cytokine storm, and recruitment of immune cells lead to uncontrollable endothelial cell damage in patients with coronavirus disease 2019 (COVID-19). Sphingosine 1-phosphate (S1P) signaling is needed for endothelial integrity and its de-creased serum level is a predictor of clinical severity in COVID-19. In this clinical trial, the effect of Fingolimod, an agonist of S1P, was evaluated on patients with COVID-19. Forty patients with moderate to severe COVID-19 were enrolled and divided into two groups including (1) the control group (n =21) receiving the national standard regimen for COVID-19 patients and (2) the intervention group (n =19) that prescribed daily Fingolimod (0.5 mg) for 3days besides receiving the standard national regimen for COVID-19. The hospitalization period, re-admission rate, intensive care unit (ICU) administration, need for mechanical ventilation, and mortality rate were assessed as primary outcomes in both groups. The results showed that re-admission was significantly decreased in COVID-19 patients who received Fingolimod compared to the controls (p = .04). In addition, the hemoglobin levels of the COVID-19 patients in the intervention group were increased compared to the controls (p = .018). However, no significant differences were found regarding the intubation or mortality rate between the groups (p > .05). Fingolimod could significantly reduce the re-admission rate after hospitalization with COVID-19. Fingolimod may not enhance patients' outcomes with moderate COVID-19. It is necessary to examine these findings in a larger cohort of patients with severe to critical COVID-19. [ABSTRACT FROM AUTHOR]

Background and Purpose: Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti‐inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)‐induced schizophrenia. Experimental Approach: Male Sprague–Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated using immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain‐derived neurotrophic factor expression and phosphorylation of extracellular signal‐regulated kinase were determined using western blot analysis. Key Results: Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose‐dependent manner in PCP‐treated rats. Fingolimod treatment exerted anti‐inflammatory effects by inhibiting microglial activation and IL‐6 and IL‐1β pro‐inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain‐derived neurotrophic factor protein expression and activation of the ERK signalling pathway. Conclusion and Implications: This is the first preclinical assessment of the effects of fingolimod on cognitive function in a model for schizophrenia. Our results suggest the immune system plays an crucial role in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia. [ABSTRACT FROM AUTHOR]

The pharmacometric analysis of the double‐blind, randomized, phase II study (NCT02975349) investigating the safety and efficacy of evobrutinib, explored exposure–response relationships and suitable dosing regimens of evobrutinib for relapsing multiple sclerosis. Population pharmacokinetic (PK)/pharmacodynamic modeling was applied to data collected in fasted patients treated with placebo or evobrutinib (25 mg once‐daily [q.d.], 75 mg q.d., or 75 mg twice‐daily [b.i.d.]) for 24 weeks, followed by a 24‐week blinded extension (placebo patients switched to 25 mg q.d.). Model‐based exposures for PK and Bruton's tyrosine kinase occupancy (BTKO) were used for exposure–response analyses (maximum 207 patients). PK, BTKO profiles, and annualized relapse rate (ARR) after 48 weeks of treatment under alternative dosing regimens were simulated. Exposure–response modeling identified a relationship between evobrutinib exposure and clinical response for total number of T1 Gd+ and new/enlarging T2 lesions at weeks 12–24, and ARR at week 48. Area under the concentration–time curve over 24 h at steady‐state (AUC0–24,SS) of 468 and ≥400 ng/ml h was associated with T1 Gd+/T2 lesion reduction and ARR improvement, respectively. These exposures were associated with steady‐state (SS) predose BTKO ≥95%. Based on PK and BTKO profile simulations, evobrutinib 75 mg b.i.d. while fasted is predicted to maintain SS predose BTKO >95% in 92% of patients. Evobrutinib 45 mg b.i.d. with food is predicted to achieve similar exposure as 75 mg b.i.d. while fasted (predose BTKO >95% in 93% of patients). Evobrutinib 45 mg b.i.d. with food is predicted to have comparable exposure and BTKO to 75 mg b.i.d. without food (phase II) and will be pharmacologically effective and appropriate for clinical use in phase III multiple sclerosis studies. [ABSTRACT FROM AUTHOR]

Molluscum contagiosum (MC) is a skin infection caused by a virus of the DNA poxvirus family that has already been reported by Fingolimod. We report two cases. MC can resist standard therapy and discontinuation of the fingolimod may be the only way to treat it. [ABSTRACT FROM AUTHOR]

Background: CC‐90011 is an oral, potent, selective, reversible inhibitor of lysine‐specific demethylase 1 (LSD1) that was well tolerated, with encouraging activity in patients who had advanced solid tumors or relapsed/refractory marginal zone lymphoma. The authors present long‐term safety and efficacy and novel pharmacodynamic and pharmacokinetic data from the first‐in‐human study of CC‐90011. Methods: CC‐90011‐ST‐001 (ClincalTrials.gov identifier NCT02875223; Eudract number 2015–005243‐13) is a phase 1, multicenter study in which patients received CC‐90011 once per week in 28‐day cycles. The objectives were to determine the safety, maximum tolerated dose, and/or recommended phase 2 dose (primary) and to evaluate preliminary efficacy and pharmacokinetics (secondary). Results: Sixty‐nine patients were enrolled, including 50 in the dose‐escalation arm and 19 in the dose‐expansion arm. Thrombocytopenia was the most common treatment‐related adverse event and was successfully managed with dose modifications. Clinical activity with prolonged, durable responses were observed, particularly in patients who had neuroendocrine neoplasms. In the dose‐escalation arm, one patient with relapsed/refractory marginal zone lymphoma achieved a complete response (ongoing in cycle 58). In the dose‐expansion arm, three patients with neuroendocrine neoplasms had stable disease after nine or more cycles, including one patient who was in cycle 46 of ongoing treatment. CC‐90011 decreased levels of secreted neuroendocrine peptides chromogranin A, progastrin‐releasing peptide, and RNA expression of the blood pharmacodynamic marker monocyte‐to‐macrophage differentiation–associated. Conclusions: The safety profile of CC‐90011 suggested that its reversible mechanism of action may provide an advantage over other irreversible LSD1 inhibitors. The favorable tolerability profile, clinical activity, durable responses, and once‐per‐week dosing support further exploration of CC‐90011 as monotherapy and in combination with other treatments for patients with advanced solid tumors and other malignancies. This first‐in‐human study evaluated CC‐90011, a highly potent, selective, and reversible oral lysine‐specific demethylase 1 inhibitor, in patients with advanced solid tumors and relapsed/refractory lymphoma. The tolerability, clinical activity, and once‐weekly dosing support further exploration of CC‐90011 in patients with advanced malignancies. [ABSTRACT FROM AUTHOR]

Sphingosine‐1‐phosphate (S1P) is a bioactive lysophospholipid that can influence a broad range of biological processes through its binding to five distinct G‐protein‐coupled receptors. S1P receptor modulators are a new group of immunosuppressive agents currently used in the immunotherapy of multiple sclerosis. Inflammation following stroke can exacerbate neuronal injury. Given that S1P signaling is linked to multiple immune processes, therapies targeting the S1P axis may be suitable for treating stroke. In this review, we outline S1P metabolism and S1P receptors, discuss the mechanisms of action of S1P receptor modulators in lymphocyte migration and their direct action on cells of the central nervous system, and provide a concise summary of the efficacy of S1P receptor modulators in animal studies and clinical trials on treatments for stroke. [ABSTRACT FROM AUTHOR]

Fat transplantation is widely used for soft‐tissue filling and wound repair. Owing to the biological changes in adipocytes in some metabolic diseases, allograft fat can provide a better source of donor fat than autologous fat. Fingolimod (FTY720) possesses a powerful immunomodulatory function. This study aimed to investigate the protective effect of FTY720 in allogeneic fat transplantation. C57BL/6J mice that received allografts were randomly divided into two groups and treated with saline and FTY720, respectively. Fat graft samples were obtained at 1, 6, and 20 weeks posttransplantation. Graft volumes, graft structure, and immune cells were estimated using histological examination, immunohistochemistry, staining immunofluorescence (IF), and quantitative real‐time polymerase chain reaction (qRT‐PCR). Inflammatory cytokine mRNA expression in grafts was detected by qRT‐PCR. FTY720 treatment significantly enhanced allograft retention, structural integrity, and neovascularization, thereby demonstrating the potential of FTY720 in improving graft survival. Further IF staining showed that FTY720 increased regulatory T cell infiltration and reduced macrophage infiltration to some extent. FTY720 treatment also enhanced the expression of the anti‐inflammatory cytokines interleukin (IL)‐4 and IL‐10 and weakened the expression of the pro‐inflammatory cytokines TNF‐α and IL‐6. Furthermore, FTY720 treatment upregulated the expression of CD31 positive cells. This study demonstrated the potential efficacy of FTY720 in improving the graft survival rate of syngeneic fat allograft models, possibly by suppressing immune rejection and promoting angiogenesis. Therefore, this study offers key insights into the potential application of a drug‐assisted strategy to prolong allograft fat survival. [ABSTRACT FROM AUTHOR]

Inadequate β‐cell mass is essential for the pathogenesis of type 2 diabetes (T2D). Previous report showed that an immunomodulator FTY720, a sphingosine 1‐phosphate (S1P) receptor modulator, sustainably normalized hyperglycemia by stimulating β‐cell in vivo regeneration in db/db mice. We further examined the effects of FTY720 on glucose homeostasis and diabetic complications in a translational nonhuman primate (NHP) model of spontaneously developed diabetes. The male diabetic cynomolgus macaques of 18–19 year old were randomly divided into Vehicle (Purified water, n = 5) and FTY720 (5 mg/kg, n = 7) groups with oral gavage once daily for 10 weeks followed by 10 weeks drug free period. Compared with the Vehicle group, FTY720 effectively lowered HbA1c, blood concentrations of fasting glucose (FBG) and insulin, hence, decreased homeostatic model assessment of insulin resistance (HOMA‐IR); ameliorated glucose intolerance and restored glucose‐stimulated insulin release, indicating rejuvenation of β‐cell function in diabetic NHPs. Importantly, after withdrawal of FTY720, FBG, and HbA1c remained at low level in the drug free period. Echocardiography revealed that FTY720 significantly reduced proteinuria and improved cardiac left ventricular systolic function measured by increased ejection fraction and fractional shortening in the diabetic NHPs. Finally, flow cytometry analysis (FACS) detected that FTY720 significantly reduced CD4 + and CD8 + T lymphocytes as well as increased DC cells in the circulation. Immunomodulator FTY720 improves glucose homeostasis via rejuvenation of β‐cell function, which can be mediated by suppression of cytotoxic CD8 + T lymphocytes to β‐cells, thus, may be a novel immunotherapy to reverse T2D progression and ameliorate the diabetic complications. [ABSTRACT FROM AUTHOR]

Fingolimod as a useful drug in nerve regeneration is a promising candidate for promoting axonal regeneration by positively affecting neonatal and adult Schwann cells. Nerve tissue engineering show a novel practical approach by recruiting the scientific methods for creating neural extracellular matrix. In this study, fingolimod was incorporated in polylactic‐co‐glycolic acid and then, an electrospun scaffold composed of polyurethane (PU), polycaprolactone (PCL) and gelatin polymers containing different amount of encapsulated fingolimod (0.01%, 0.02%, and 0.03%) were fabricated. The morphology and microstructure of each scaffold were assessed by scanning electron microscopy (SEM). The physicochemical properties of scaffolds including Fourier transform infrared spectroscopy, mechanical properties, water contact angle, and degradation test were evaluated. MTT assay and also SEM were utilized for the investigation of cell viability and adhesion. The results showed that the mean fiber diameter of scaffold was increased from 151 ± 31 to 243 ± 68 nm followed by increase of fingolimod. Young's modulus was showed all scaffold had in the expected range for nerve tissues. Cell viability assessment proved that PU/PCL/Gel/0.01% fingolimod had a higher cell survival among other groups. The results suggest that PU/PCL/gelatin scaffolds loading from 0.01 fingolimod can be a suitable candidate for peripheral nerve regeneration. [ABSTRACT FROM AUTHOR]

Wir beschreiben eine laterale Natriierung von Alkali(hetero)arenen mittels bedarfsgerecht generiertem, in Hexan löslichem (2‐Ethylhexyl)natrium (1) in Gegenwart von TMEDA. (2‐Ethylhexyl)natrium (1) wird mittels eines Natrium‐Festbettreaktors hergestellt und für Metallierungen bei Umgebungstemperatur sowohl im Kolben als auch im kontinuierlichem Durchfluss genutzt. Die entstehenden benzylischen Natriumspezies werden nachfolgend mit verschiedenen Elektrophilen, unter anderem Carbonylverbindungen, Epoxiden, Oxetan, Allyl/Benzylchloriden, Alkylhalogenen und ‐tosylaten abgefangen. Wurtz‐Typ‐Kopplungen mit sekundären Alkylhalogenen und Tosylaten laufen unter kompletter Inversion der Stereochemie ab. Des Weiteren wird die Nützlichkeit dieser lateralen Natriierung durch die Synthese pharmazeutisch relevanter Verbindungen demonstriert. So wird Fingolimod durch die zweifache Anwendung der lateralen Natriierung ausgehend von p‐Xylol hergestellt. Zusätzlich ist 7‐fach Isotopen angereichertes Salmeterol‐d7 und Fenpiprane, sowie Ausgangsmaterialien zu super linearen Alkylbenzyl (SLAB) Tensiden hergestellt worden. [ABSTRACT FROM AUTHOR]

Acute ischemic stroke (AIS) is the most common type of stroke. Fingolimod is a sphingosine analog that acts on sphingosine-1-phosphate receptors (S1PR). Recently, the safety and efficacy of fingolimod in both patients with intracerebral hemorrhage and patients with AIS have been investigated in proof-of-concept trials. In this review, we performed a meta-analysis to evaluate the efficacy and safety of fingolimod for AIS. This study was conducted according to the PRISMA (Preferred Reporting Items for Systemic review and Meta-Analysis) statement. We searched for publications on the PubMed, Embase, Cochrane Central Register of Controlled Trials, Clinical trials, CNKI, Wanfang Data, VIP, CBM up to August 2021. We compiled five studies; a main metaanalysis forest plots were conducted for the values of the proportion of patients whose modified Rankin scale (MRS) score was 0–1 at day 90. There were heterogeneities in each study; the method of sensitivity analysis was performed. A sensitivity analysis was performed with a mean difference (MD) of the efficacy of fingolimod plus standardized treatment versus standardized treatment alone. Random effect model is used for meta-analysis regardless of the I 2 index. The analysis was carried out for categorical variables using the risk ratio (RR), LogRR, and its 95% CI. The methodological quality of each randomized controlled trial (RCTs) was assessed according to the Cochrane Collaboration tool to assess the risk of bias (ROB). A meta-analysis of five studies with 228 participants was conducted. The risk ratio of patients whose MRS score was 0–1 at day 90 between fingolimod plus standardized treatment and standardized treatment alone was 2.59 (95%CI, 1.48–4.56). The Fingolimod plus standard treatment group decreased infarct growth and improved clinical function than the standard treatment. [ABSTRACT FROM AUTHOR]

Background: Because of the approved immunomodulatory activities of fingolimod, the current study aimed at studying the curative potential of fingolimod against experimentally induced ulcerative colitis (UC) via modulating pro/anti‐inflammatory cytokines release and AKT/mTOR signalling. Methods: UC was induced in rats by intracolonic instillation of acetic acid. Fingo (0.5 mg/kg/day, p.o.) was given for 8 consecutive days that started 48 h after UC induction. Results: Fingolimod increased body weight growth rate and colon body/weight and colon weight/length indices compared to the UC group. Fingolimod significantly decreased clinical evaluation score and macroscopic score compared to the UC group. The curative potential of fingolimod was further confirmed by histopathological examination revealing marked attenuation of mucosal injury and inflammatory cells infiltration. Fingolimod significantly decreased colon malondialdehyde content and increased colon glutathione contents compared to the UC group. Fingolimod also significantly decreased the expressions of pro‐inflammatory cytokines interleukin‐9 and T‐helper 17 along with increasing the expression of anti‐inflammatory interleukin‐10 and transforming growth factor‐β compared to the UC group. In addition, fingolimod decreased the expressions of AKT and mTOR compared to the UC group. Conclusion: Fingolimod attenuated acetic acid‐induced UC through its immunomodulatory effect by shifting the balance to favour anti‐inflammatory cytokine production rather than pro‐inflammatory cytokines and modulating the AKT/mTOR signalling. [ABSTRACT FROM AUTHOR]

Background: Previous research has shown that cerebral T1 hypointense lesions are positively correlated with the disability of multiple sclerosis (MS) patients. Hence, they could be used as an objective marker for evaluating the progression of the disease. Up to this date, there has not been a systematic evaluation of the effects of disease‐modifying therapies (DMTs) on this prognostic marker. Objectives: To evaluate the effects of FDA‐approved DMTs on the numbers and volume of T1 hypointense lesions in adult patients with MS. Methods: We included studies with the mentioned desired outcomes. In March 2021, we searched MEDLINE (Ovid), Embase, and CENTRAL to find relevant studies. All included studies were assessed for the risk of bias using the RoB‐2 tool. Extracted data were analyzed using a random‐effects model. Certainty of evidence was assessed using GRADE. Results: Thirteen studies with 7484 participants were included. Meta‐analysis revealed the mean difference between the intervention and comparator groups for the number of lesions was −1.3 (95% CI: −2.1, −0.5) and for the mean volume of lesions was −363.1 (95% CI: −611.6, −114.6). Certainty of evidence was judged to be moderate. Heterogeneity was considerable. Discussion: DMTs reduce the number and volume of T1 hypointense lesions. Although, these findings must be interpreted cautiously due to the high values of heterogeneity. [ABSTRACT FROM AUTHOR]

Background: Noninvasive evaluation of the status of cerebral arteriole perfusion remains a practical challenge in murine stroke models, because conventional magnetic resonance imaging (MRI) is no longer capable of capturing these very small vessels. Purpose To investigate the feasibility of ultrasmall superparamagnetic iron oxide particles (USPIO)‐based susceptibility weighted imaging (SWI)‐MRI (USPIO‐SWI) and T2* map‐MRI (USPIO‐T2* map) for monitoring angiographic perfusion in stroke rats. Study Type: A preclinical randomized controlled trial. Animal Model: Normal rats (N = 9), embolic middle cerebral artery occlusion (eMCAO) rats (N = 66). Field Strength/Sequence: 7 T; T2* map (multigradient echo), SWI (3D gradient echo). Assessment Experiment 1: To develop a method for angiographic reperfusion evaluation with USPIO‐SWI. Normal rats were used to optimize the USPIO dosage (5.6, 16.8, and 56 mg/kg ferumoxytol) as well as scan time points for cerebral arterioles. Contrast‐to‐noise ratio (CNR) was measured. Stroke rats were further used and the number of visual cortical vessels were counted. Experiment 2: To examine whether fingolimod (lymphocytes inhibitor) enhances the action of tissue plasminogen activator (tPA) in eMCAO rats on cerebral angiographic reperfusion. Statistical Tests: Mann–Whitney test and two way‐ANOVA were used. P < 0.05 was considered statistically significant. Results: CNR values of cerebral cortical penetrating arteries in normal rats were significantly increased to 4.4 ± 0.5 (5.6 mg/kg), 6.1 ± 0.5 (16.8 mg/kg), and 3.4 ± 0.9 (56 mg/kg) after USPIO injection. The number of visual cortical vessels on USPIO‐SWI images in ischemic regions was significantly less than in control regions (5 ± 2 vs. 56 ± 20) of eMCAO rats. Compared with eMCAO rats who received tPA only, eMCAO rats who received the combination of fingolimod and tPA exhibited significantly higher proportion of complete angiographic reperfusion (69% vs. 17%). Data Conclusion: This study supports the feasibility of angiographic perfusion evaluation with USPIO‐SWI in stroke rats. Level of Evidence: 2 Technical Efficacy Stage: 1 [ABSTRACT FROM AUTHOR]

An HPLC method has been described in the European Pharmacopoeia and United States Pharmacopeia for the determination of nine organic impurities (imp A–I) in fingolimod hydrochloride, a synthetic sphingosine‐1‐phosphate receptor modulator. The manufacturing process of fingolimod hydrochloride consists of multistep chemical synthesis wherein controls of precursors, intermediates and process steps should be performed to assure the final quality of the drug substance. We synthesized and isolated eight process‐related impurities (FINI imp A–H) of fingolimod, which were different from the pharmacopoeial impurities. One unknown process‐related impurity was found as a key intermediate (FINI) and was identified by LC–MS. Characterization of all of the impurities were done using spectroscopic techniques (1H and 13C NMR, FTIR, MS), and the mechanistic pathways to the formation of these impurities were also discussed. Two of these impurities were evaluated as potential genotoxic impurities owing to their alerting structures and alkylating properties (alkyl sulfonates and alkyl halides, class 3, ICH M7). We also developed and validated an RP‐UPLC method in line with ICH Q2 guidelines for control these impurities (FINI imp A–H) and to assure the pharmacopoeial quality drug substance. [ABSTRACT FROM AUTHOR]

Purpose Multiple sclerosis (MS) is a chronic disease of the central nervous system that disproportionately affects women, with typical onset during reproductive age. Several disease‐modifying therapies (DMTs) are FDA‐approved to slow disease progression, but are not indicated for use during pregnancy. Our objective was to describe trends over time (2010–2019) in monthly point prevalence of DMT use among reproductive‐age women, overall and by generic name. Methods: This study used administrative claims data from the US during 2009–2019 to identify women age 15–44 with MS and continuous insurance coverage for ≥12 months. DMTs were identified using prescription fills and procedural claims for alemtuzumab, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta, mitoxantrone, natalizumab, ocrelizumab, and teriflunomide. Monthly prevalent use was defined as ≥1 days' supply of a DMT in the month. Age‐ and region‐standardized monthly prevalence was estimated nonparametrically. Results: Among 42 281 reproductive‐aged women over 818 179 person‐months, DMT use increased from a minimum monthly prevalence of 49.3% (February, 2011) to a maximum of 58.7% (April, 2019). In 2010, prevalence of injectable DMTs was 43.1% compared to 2.5% for oral DMTs; by 2014, however, oral DMTs (26.5%) surpassed injectable DMTs (23.7%) as the most common route of administration. In the most recent data available (December, 2019), the most common DMTs were dimethyl fumarate, glatiramer acetate, and fingolimod. Conclusions: DMT use among reproductive‐aged women has rapidly evolved during the past decade. Collaborative treatment decision making between women with MS and clinicians may help optimize MS care and improve DMT uptake during reproductive years. [ABSTRACT FROM AUTHOR]

Oral fluid is an alternative matrix that has proven to be useful for the detection of drugs. Oral fluid is easy to collect, noninvasive, and may indicate recent drug use. There are limited methods available that analyze cognitive stimulants in oral fluid. Cognitive stimulants are used to treat attention‐deficit/hyperactivity disorder (ADHD), a neurological disorder that emerges from lack of dopamine in the brain. To combat this disorder, medications inhibit dopamine and norepinephrine reuptake by blocking transporters in the brain. Though commonly diagnosed in children, ADHD may extend beyond adolescence and abuse of medications in college students is not uncommon. The goal of this study was to develop and validate a quantitative method for methylphenidate, ethylphenidate, lisdexamfetamine, and amphetamine in oral fluid using liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Analytes were isolated by solid‐phase extraction and analyzed on an Agilent 1290 Infinity II Liquid Chromatograph coupled to an Agilent 6470 Triple Quadrupole Mass Spectrometer. The linear range was 0.5–100 ng/ml (except lisdexamfetamine at 5–500 ng/ml). Bias and between‐run precision were acceptable (±11.0% bias and ±12.2%CV). No interferences or carryover were observed and dilution integrity was sustained. This validated method was applied to four authentic oral fluid samples collected with Quantisal® devices from college students. Lisdexamfetamine was quantified in one sample at 5.8 ng/ml while amphetamine was quantified in all four samples at 6.0–78.8 ng/ml. This is the first known quantitative method in oral fluid that includes these analytes using LC‐MS/MS and may give rise to interpretive value in a forensic toxicology setting. [ABSTRACT FROM AUTHOR]

Optimal immunogenicity from nucleic acid vaccines requires a balance of antigen expression that effectively engages the host immune system without generating a cellular response that rapidly destroys cells producing the antigen and thereby limiting vaccine antigen expression. We investigated the role of the cellular response on the expression and antigenicity of DNA vaccines using a plasmid DNA construct expressing luciferase. Repeated intramuscular administration led to diminished luciferase expression, suggesting a role for immune‐mediated clearance of expression. To investigate the role of cell trafficking, we used the sphingosine 1‐phosphate receptor (S1PR) modulator, FTY720 (Fingolimod), which traps lymphocytes within the lymphoid tissues. When lymphocyte trafficking was blocked with FTY720, DNA transgene expression was maintained at a constant level for a significantly extended time period. Both continuous and staggered administration of FTY720 prolonged transgene expression. However, blocking lymphocyte egress during primary transgene administration did not result in an increase of transgene expression during secondary administration. Interestingly, there was a disconnect between transgene expression and immunogenicity, as increasing expression by this approach did not enhance the overall immune response. Furthermore, when FTY720 was administered alongside a DNA vaccine expressing the HIV gp140 envelope antigen, there was a significant reduction in both antigen‐specific antibody and T‐cell responses. This indicates that the developing antigen‐specific cellular response clears DNA vaccine expression but requires access to the site of expression in order to develop an effective immune response. DNA vaccine transgene expression in tissue can be extended through the co‐administration of the sphingosine 1‐phosphate receptor (S1PR) modulator, FTY720. Despite extending vaccine transgene expression, the administration of FTY720 can reduce vaccine elicited antibody and T‐cell responses. [ABSTRACT FROM AUTHOR]

Recent epidemiological studies highlighted a possible link between PsO and demyelinating disorders such as MS.[2] Herein, we reported the case of a 40-year-old female who suffered from PsO and MS successfully treated with a combination therapy of secukinumab and fingolimod. Keywords: fingolimod; multiple sclerosis; psoriasis; real-life experience; secukinumab EN fingolimod multiple sclerosis psoriasis real-life experience secukinumab e100 e102 3 02/17/23 20230201 NES 230201 Dear Editor, Psoriasis (PsO) is a chronic inflammatory disease characterized by erythemato-desquamative plaques with systemic involvement (psoriatic arthritis, metabolic syndrome, cardiovascular disorders, Crohn's disease, and depression).[1] Multiple sclerosis (MS) is an auto-immune neurological disease characterized by inflammation, demyelination, gliosis, and neuronal loss. [Extracted from the article]

Introduction: Current treatments for psychosis in Alzheimer's disease (AD), a syndrome characterized by more rapid deterioration and reduced synaptic protein abundance relative to non-psychotic AD, are inadequate. Fingolimod, a currently US Food and Drug Administration (FDA)-approved pharmacotherapy for multiple sclerosis, alters synaptic protein expression and warrants preclinical appraisal as a candidate pharmacotherapy for psychosis in AD. Methods: Presenilin and amyloid precursor protein transgenic mice (APPswe/PSEN1dE9) and wild-type mice were randomized to fingolimod or saline for 7 days. Psychosis-associated behaviors were quantified by open field testing, pre-pulse inhibition of the acoustic startle response testing, and habituation of the acoustic startle response testing. Synaptic proteinswere quantified by liquid chromatography/mass spectrometry in homogenate and postsynaptic density fractions. Results: Fingolimod treatment increased the synaptic protein abundance in cortical homogenates and normalized psychosis-associated behaviors in APPswe/PSEN1dE9 mice relative to saline. Mitochondrial-related proteins were preferentially altered by fingolimod treatment and correlated with improvements in psychosis-associated behaviors. Discussion: Preclinical studies employing complementary psychosis-associated behavioral assessments and proteomic evaluations across multiple AD-related models are warranted to replicate the current study and further investigate fingolimod as a candidate treatment for psychosis in AD. [ABSTRACT FROM AUTHOR]

A few anti-amyloid trials offer a slight possibility of preventing progression of cognitive loss, but none has reversed the process. A possible reason is that amyloid may be necessary but insufficient in the pathogenesis of AD, and other causal factors may need addressing in addition to amyloid. It is argued here that drugs addressing myelination and synaptogenesis are the optimum partners for anti-amyloid drugs, since there is much evidence that early in the process that leads to AD, both neural circuits and synaptic activity are dysfunctional. Evidence to support this argument is presented. Evidence is also presented that clemastine, fingolimod, and rolipram, benefit both myelination and synaptogenesis. It is suggested that a regimen that includes one of them plus an anti-amyloid drug, could reverse AD. [ABSTRACT FROM AUTHOR]

Background and purpose: Studies reporting the baseline determinants of cognitive performance and treatment effect on cognition in patients with multiple sclerosis (MS) are limited. We investigated the baseline correlates of cognition and the long‐term treatment effects of fingolimod 0.5 mg once daily on cognitive processing speed and attention in patients with relapsing‐remitting MS. Methods: This post hoc analysis pooled data from the phase 3 FREEDOMS and FREEDOMS II trials (N = 1556). We assessed the correlation between baseline patient demographic and disease characteristics and baseline 3‐second Paced Auditory Serial Addition Test (PASAT‐3) scores (Spearman's rank test) and the changes from baseline in PASAT‐3 (mixed model repeated measures model) in the fingolimod and placebo (up to 24 months) or placebo‐fingolimod switched (from Month 24 up to 120 months) groups. Additionally, the predictive value of PASAT‐3 score for future disease outcomes was assessed (Cox or logistic regression models). Results: Among the variables assessed, lower PASAT‐3 score at baseline correlated with higher disease burden (total brain volume, T2 lesion volume, and Expanded Disability Status Scale score), longer disease duration and older age (p < 0.0001 for all). Fingolimod significantly improved PASAT‐3 scores from baseline versus placebo at 6 (1.3; p = 0.0007), 12 (1.1; p = 0.0044) and 24 months (1.1; p = 0.0028), with a sustained effect (overall treatment effect p = 0.0012) up to 120 months. Improvements were seen regardless of baseline cognitive status (PASAT quartile). Baseline PASAT‐3 score was predictive of both clinical and magnetic resonance imaging measures of disease activity at Month 24 (p < 0.001 for all). Conclusion: Early fingolimod treatment may offer long‐term cognitive benefit in patients with relapsing‐remitting MS. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a devastating clinical problem that can lead to permanent motor dysfunction. Fingolimod (FTY720) is a sphingosine structural analogue, and recently, its therapeutic benefits in SCI have been reported. The present study aimed to evaluate the therapeutic efficacy of fingolimod‐incorporated poly lactic‐co‐glycolic acid (PLGA) nanoparticles (nanofingolimod) delivered locally together with neural stem/progenitor cells (NS/PCs) transplantation in a mouse model of contusive acute SCI. Fingolimod was encapsulated in PLGA nanoparticles by the emulsion–evaporation method. Mouse NS/PCs were harvested and cultured from embryonic Day 14 (E14) ganglionic eminences. Induction of SCI was followed by the intrathecal delivery of nanofingolimod with and without intralesional transplantation of PuraMatrix‐encapsulated NS/PCs. Functional recovery, injury size and the fate of the transplanted cells were evaluated after 28 days. The nanofingolimod particles represented spherical morphology. The entrapment efficiency determined by UV–visible spectroscopy was approximately 90%, and the drug content of fingolimod loaded nanoparticles was 13%. About 68% of encapsulated fingolimod was slowly released within 10 days. Local delivery of nanofingolimod in combination with NS/PCs transplantation led to a stronger improvement in neurological functions and minimized tissue damage. Furthermore, co‐administration of nanofingolimod and NS/PCs not only increased the survival of transplanted cells but also promoted their fate towards more oligodendrocytic phenotype. Our data suggest that local release of nanofingolimod in combination with three‐dimensional (3D) transplantation of NS/PCs in the acute phase of SCI could be a promising approach to restore the damaged tissues and improve neurological functions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Finding novel and effective drugs for the treatment of ischemic stroke is warranted because there is not a definitive treatment for this prevalent disease. Due to the relevance between the sphingosine 1‐phosphate (S1P) receptor and several neurological diseases including ischemic stroke, it seems that fingolimod (FTY720), as an agonist of S1P receptor, can be a useful therapeutic strategy in these patients. FTY720 is the first oral drug approved by the US food and drug administration for the treatment of multiple sclerosis. Three important mechanisms for neuroprotective effects of FTY720 have been described. First, the functional antagonistic mechanism that is associated with lymphopenia and reduced lymphocytic inflammation. This effect results from the down‐regulation and degradation of lymphocytes' S1P receptors, which inhibits lymph node lymphocytes from entering the bloodstream. Second, a functional agonistic activity that is mediated through direct effects via targeting S1P receptors on the membrane of various cells including neurons, microglia, oligodendrocytes, astrocytes, and endothelial cells of blood vessels in the central nervous system (CNS), and the third, receptor‐independent mechanisms that are displayed by binding to specific cellular proteins that modulate intracellular signaling pathways or affect epigenetic transcriptions. Therefore, we review these mechanisms in more detail and describe the animal model and in clinical trial studies that support these three mechanisms for the neuroprotective action of FTY720 in ischemic stroke. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE: Fingolimod has a favorable effect on conventional MRI measures; however, its neuroprotective effect is not clear. We aim to investigate changes of conventional and advanced MRI measures in lesions and normal‐appearing white matter (NAWM) over 2 years in fingolimod‐treated patients. METHODS: Fifty relapsing‐remitting multiple sclerosis patients and 27 healthy controls were enrolled in the study and underwent baseline, 1‐year, and 2‐year 3T MRI scans. T2 lesion volume, whole brain volume, cortical gray matter volume, white matter volume, corpus callosum area, percentage brain volume change (PBVC), Expanded Disability Status Scale, gadolinium‐enhancing lesions, PBVC, magnetization transfer ratio (MTR), and diffusion tensor imaging metrics (fractional anisotropy [FA] and median diffusivity [MD]) in lesions and NAWM were calculated. Longitudinal changes were examined using one‐way repeated measures ANOVA. Bonferroni correction for multiple testing was used when appropriate. RESULTS: Conventional MRI measures were unchanged in both groups. Lesion MTR increased significantly (P <.001), but NAWM‐MTR remained unchanged. Lesion FA improved significantly in year 1 (P =.003) and over the study duration (P =.05). Lesion MD changed significantly from baseline to year 1 (P <.001) and remained stable over 2 years. NAWM‐FA was significant from baseline to year 1 (P =.002) and from baseline to year 2 (P <.001). NAWM‐MD was significant only from baseline to year 1 (P =.001). CONCLUSIONS: These findings suggest a possible neuroreparative effect of fingolimod on the MS lesions and NAWM. Larger and longer randomized studies are required to confirm these results. [ABSTRACT FROM AUTHOR]

Background: The use of concurrent medications is necessary in trials of treatment of canine atopic dermatitis. Our aim was to use the best available evidence to construct and then to validate a medication score (MS) formula that will estimate the impact of concurrent medications on trial outcomes. Methods: Trials of 15 interventions were scrutinized to find those that were consistent in terms of specific medication, administration route and dosage regimen. A MS was constructed in five steps, starting from assigning a score of 1 for each day on oral prednisone, prednisolone or methylprednisolone at 0.5–1.0 mg/kg. The MS score was validated using the clinical records of 35 dogs with atopic dermatitis that had been treated for a period of 12 ± 2 weeks with six of these medications and compared with a previously published non‐validated MS. Results: A MS could be assigned to eight treatments, six of which had been administered to the 35 dogs. A positive correlation was seen with the previously published MS and a negative correlation with changes in lesional and pruritus scores. Conclusion: This MS may be a useful tool in new studies evaluating the efficacy of treatments in canine atopic dermatitis [ABSTRACT FROM AUTHOR]

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. Highlights: We report a patient with Multiple Sclerosis presenting COVID‐19 when treated with fingolimod.Hyperinflammation syndrome was observed after fingolimod withdrawal.Discontinuation of fingolimod during COVID‐19 could imply a worsening of SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]