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Background HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease of the central nervous system (CNS). Teriflunomide is an oral agent developed for the treatment of multiple sclerosis (MS) by suppressing the proliferation of autoreactive lymphocytes. This study was conducted to evaluate the efficacy of teriflunomide in HAM/TSP patients in Northeast Iran. Methods This study was a triple-blind, randomized, placebo-controlled trial involving 22 patients with HAM/TSP. The intervention group ( n  = 11) received one tablet of teriflunomide (14 mg daily), while the control group ( n  = 11) received one placebo tablet for 12 months. Muscle strength, spasticity, motor disability, urinary disorders, walking speed, laboratory factors, and drug complications were examined during the study. Results In the intervention group, consumption of teriflunomide decreased the duration of walking according to the T25FW test ( p  = 0.01). The severity of OMDS disability also significantly decreased ( P  < 0.001). Additionally, the total score of UDS in the intervention group decreased. The levels of HTLV-1 proviral load significantly decreased ( p  = 0.003). No adverse effects were observed, and the increase in liver enzyme levels was tolerable and controllable. Conclusions Teriflunomide effectively reduced the proviral load, improved the severity of disability and walking speed, and better controlled urinary and constipation symptoms without any adverse effects. Therefore, teriflunomide can be considered a disease-modifying therapy for patients with HAM/TSP. However, further studies with a large number of patients and longer duration, along with the determination of specific HAM/TSP-associated biomarkers, are needed to validate the results of the present study. Trial registration IRCT20180618040127N3; November 19, 2021.

Objectives To compare the efficacies, frequencies and reasons for treatment interruption of fingolimod (FTY), dimethyl fumarate (DMF) or teriflunomide (TERI) in a nationwide observational cohort. Materials and methods Two cohorts of patients with relapsing–remitting multiple sclerosis (RRMS) having started treatment with FTY, DMF or TERI documented in the Austrian MS Treatment Registry (AMSTR) since 2014 and either staying on therapy for at least 24 months (24 m cohort) or with at least one follow-up visit after start of treatment (total cohort). The 24 m cohort included 629 RRMS patients: 295 in the FTY, 227 in the DMF and 107 in the TERI group. We used multinomial propensity scores for inverse probability weighting in generalized linear and Cox proportional hazards models to correct for the bias of this non-randomised registry study. Results Estimated mean annualized relapse rates (ARR) over 24 months were 0.13 for FTY, 0.09 for DMF and 0.11 for TERI treatment. For TERI in comparison with DMF, we observed higher probability for treatment interruption ( p  = 0.023) and reduced sustained EDSS regression for 12 ( p  = 0.016) and 24 weeks ( p  = 0.031) and, for the comparison of DMF versus FTY, a reduced sustained EDSS progression for 12 weeks ( p  = 0.02). Conclusions Relapse rates with treatment with FTY, DMF and TERI were similar. Patients treated with DMF showed less sustained disability progression for 12 weeks than FTY-treated patients. However, FTY and DMF treatment was associated with more likely EDSS regression for 12 and 24 weeks and a lower probability for treatment interruption as compared to TERI-treated patients.

Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing–remitting multiple sclerosis. This post hoc analysis of the Phase III TOWER study evaluated the effects of teriflunomide treatment on five severe relapse outcomes: relapses with sequelae defined by an increase in Expanded Disability Status Scale (EDSS)/functional system (FS) score (sequelae-EDSS/FS) 30 days post relapse; relapses with sequelae defined by the investigator (sequelae-investigator); relapses leading to hospitalization; relapses treated with intravenous corticosteroids; and intense relapses using the definition of Panitch et al. from the EVIDENCE study based on specified increases in EDSS for severe relapses. Adjusted annualized rates for the five severe relapse outcomes were derived using a Poisson model with robust error variance, with treatment, baseline EDSS strata and region as covariates. Compared with placebo, teriflunomide significantly reduced annualized rates of relapses with sequelae-EDSS/FS [14 mg, 36.6 % ( p  = 0.0021); 7 mg, 31.3 % ( p  = 0.0104)] and sequelae-investigator [14 mg only, 53.5 % ( p  = 0.0004)], relapses leading to hospitalization [14 mg only, 33.6 % ( p  = 0.0155)], relapses requiring intravenous corticosteroids [14 mg, 35.7 % ( p  = 0.0002); 7 mg, 21.5 % ( p  = 0.0337)], and intense relapses [14 mg only, 52.5 % ( p  = 0.0015)]. Patients treated with teriflunomide 14 mg spent significantly fewer nights in hospital for relapse ( p  = 0.009) and had lower annualized rates of all hospitalizations ( p  = 0.030). Taken together, the positive effects of teriflunomide on severe relapses indicate that teriflunomide may reduce relapse-related healthcare costs.

Treatment of multiple sclerosis (MS) is challenging: disease-modifying treatments (DMTs) must both limit unwanted immune responses associated with disease initiation and propagation (as T and B lymphocytes are critical cellular mediators in the pathophysiology of relapsing MS), and also have minimal adverse impact on normal protective immune responses. In this review, we summarize key preclinical and clinical data relating to the proposed mechanism of action of the recently approved DMT teriflunomide in MS. Teriflunomide selectively and reversibly inhibits dihydro-orotate dehydrogenase, a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway, leading to a reduction in proliferation of activated T and B lymphocytes without causing cell death. Results from animal experiments modelling the immune activation implicated in MS demonstrate reductions in disease symptoms with teriflunomide treatment, accompanied by reduced central nervous system lymphocyte infiltration, reduced axonal loss, and preserved neurological functioning. In agreement with the results obtained in these model systems, phase 3 clinical trials of teriflunomide in patients with MS have consistently shown that teriflunomide provides a therapeutic benefit, and importantly, does not cause clinical immune suppression. Taken together, these data demonstrate how teriflunomide acts as a selective immune therapy for patients with MS.

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identi ed two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic pro les, which all showed broadspectrum antiviral effects against various RNA viruses, including in uenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC 50 of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the rst to validate that DHODH is an attractive host target through high antiviral ef cacy in vivoand low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Le unomide/Teri unomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes, inflammation and fibrosis play an important role in its progression. Histone lysine crotonylation (Kcr) was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the study of sodium crotonate (NaCr) and histone Kcr in kidney diseases. However, the effects of NaCr and NaCr-induced Kcr on DKD remain unclear. In this study, db/db mice and high glucose-induced human tubular epithelial cells (HK-2) were used respectively, and exogenous NaCr and crotonoyl-coenzyme A (Cr-CoA) as intervention reagents, histone Kcr and DKD-related indicators were detected. The results confirmed that NaCr had an antidiabetic effect and decreased blood glucose and serum lipid levels and alleviated renal function and DKD-related inflammatory and fibrotic damage. NaCr also induced histone Kcr and histone H3K18 crotonylation (H3K18cr). However, NaCr and Cr-CoA-induced histone Kcr and protective effects were reversed by inhibiting the activity of Acyl-CoA synthetase short-chain family member 2 (ACSS2) or histone acyltransferase P300 in vitro. In summary, our data reveal that NaCr may mitigate DKD via an antidiabetic effect as well as through ACSS2 and P300-induced histone Kcr, suggesting that Kcr may be the potential molecular mechanism and prevention target of DKD.

PurposeThe present investigation was aimed at developing Teriflunomide (TEF) and Methotrexate (MTX) loaded hydroxyapatite nanoparticles and increasing tolerability towards combination therapy against rheumatoid arthritis by reducing hepatotoxicity.MethodsDrug-loaded HAp-NPs were synthesized by wet-chemical precipitation method and optimized by Box-Behnken experimental design. The developed NPs were subjected to in vitro and in vivo characterization. In-vivo pharmacodynamics and biochemical studies were performed on adjuvant- induced arthritis model treated with different formulations; MTX-TEF-SOL, TEF-HAp-NP, MTX-HAp-NP, TEF-MTX-HAp-NP, FOLITRAX-10 and AUBAGIO.ResultsThe size of the optimized formulations, TEF-HAp-NP and MTX-HAp-NP, was found to be 224.3 ± 83.80 nm and 268.3 ± 73.86 nm with drug loading 53.11 ± 0.84% and 67.04 ± 1.12% respectively. In vitro release of TEF from TEF-HAp-NP (70.41 ± 1.22%) and MTX from MTX-HAp-NP (82.43 ± 1.31%) up to 24 h revealed sustained release pattern. Results of the arthritic assessment study showed a significant (P < 0.05) reduction in ankle diameter (61.30 ± 7.42) and arthritis score (2.35 ± 0.24) with a marked restoration of ankle joint micro-architecture in TEF-MTX-HAp-NP treated group. During Hepatotoxicity studies, liver histopathology revealed that the formulation MTX-TEF-HAp-NP was least hepatotoxic with less hepatocyte swelling and fibrous connective tissue proliferation while Folitrax-10 was found to be most hepatotoxic. Biochemical studies revealed that Folitrax-10 significantly (P < 0.05) increased the GOT (313.64 ± 16) and GPT level (334.46 ± 13) while insignificant (P > 0.05) change in GOT (263.68 ± 17) and GPT (229.38 ± 10) level was recorded with TEF-MTX-HAp-NP.ConclusionsWe report that the subcutaneous delivery of TEF-MTX-HAp-NP was most effective as it successfully reduced the dosage by half for maximizing therapeutic efficacy and minimizing side effects.

Teriflunomide (Aubagio ® ) is a disease-modifying immunomodulatory drug with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydro-orotate dehydrogenase, with consequent inhibition of de novo pyrimidine synthesis and reduced lymphocyte proliferation. Based on extensive evidence from randomized controlled trials (RCTs) and the real-world setting, oral teriflunomide is an effective and generally well tolerated treatment in patients with relapsing multiple sclerosis (MS), with these benefits maintained during long-term treatment (≥ 10 years) and no new safety signals identified. In pivotal RCTs in this patient population, teriflunomide provided significantly better efficacy than placebo (TEMSO and TOWER) and was as effective as interferon β-1a (TENERE) in terms of improvements in clinical outcomes (such as reduced annualized relapse rates, prevention of disability progression) and/or MRI-assessed disease activity measures. Albeit head-to-head trials would definitively establish the relative efficacy of oral disease-modifying therapies, given its convenient oral regimen and beneficial effects in reducing relapses and disease activity, teriflunomide remains an effective option for the management of relapsing–remitting MS (RRMS).

Background Promotion of myelin repair in the context of demyelinating diseases such as multiple sclerosis (MS) still represents a clinical unmet need, given that this disease is not only characterized by autoimmune activities but also by impaired regeneration processes. Hence, this relates to replacement of lost oligodendrocytes and myelin sheaths—the primary targets of autoimmune attacks. Endogenous remyelination is mainly mediated via activation and differentiation of resident oligodendroglial precursor cells (OPCs), whereas its efficiency remains limited and declines with disease progression and aging. Teriflunomide has been approved as a first-line treatment for relapsing remitting MS. Beyond its role in acting via inhibition of de novo pyrimidine synthesis leading to a cytostatic effect on proliferating lymphocyte subsets, this study aims to uncover its potential to foster myelin repair. Methods Within the cuprizone mediated de-/remyelination model teriflunomide dependent effects on oligodendroglial homeostasis and maturation, related to cellular processes important for myelin repair were analyzed in vivo. Teriflunomide administration was performed either as pulse or continuously and markers specific for oligodendroglial maturation and mitochondrial integrity were examined by means of gene expression and immunohistochemical analyses. In addition, axon myelination was determined using electron microscopy. Results Both pulse and constant teriflunomide treatment efficiently boosted myelin repair activities in this model, leading to accelerated generation of oligodendrocytes and restoration of myelin sheaths. Moreover, teriflunomide restored mitochondrial integrity within oligodendroglial cells. Conclusions The link between de novo pyrimidine synthesis inhibition, oligodendroglial rescue, and maintenance of mitochondrial homeostasis appears as a key for successful myelin repair and hence for protection of axons from degeneration.

Signal abnormalities in human cells usually cause unexpected consequences for individual health. We focus on these kinds of events involved in JAK-STAT signal pathways, especially the ones triggered by aberrant activated STAT3, an oncoprotein which participates in essential processes of cell survival, growth and proliferation in many types of tumors, as well as immune diseases. By establishing a STAT3 signal based high-throughput drug screening system in human lung cancer A549 cells, we have screened a library from natural products which contained purified compounds from medicinal herbs. One compound, named Brevilin A, exhibited both strong STAT3 signal inhibition and STAT3 signal dependent cell growth inhibition. Further investigations revealed that Brevilin A not only inhibits STAT3 signaling but also STAT1 signaling for cytokines induced phosphorylation of STAT3 and STAT1 as well as the expression of their target genes. In addition, we found Brevilin A could attenuate the JAKs activity by blocking the JAKs tyrosine kinase domain JH1. The levels of cytokine induced phosphorylation of STATs and other substrates were dramatically reduced by treatment of Brevilin A. The roles of Brevilin A targeting on JAKs activity indicate that Brevilin A may not only be used as a STAT3 inhibitor but also a compound blocking other JAK-STAT hyperactivation. Thus, these findings provided a strong impetus for the development of selective JAK-STAT inhibitors and therapeutic drugs in order to improve survival of patients with hyperactivated JAKs and STATs.