RÉSUMÉ
We present the case of a patient with a history of multiple sclerosis under chronic fingolimod treatment who presents abdominal pain associated with jaundice associated with transaminitis that by biopsy is associated with late hepatotoxicity due to fingolimod. (AU)
Se presenta el caso de una paciente con antecedente de esclerosis múltiple en manejo con fingolimod de manera crónica quien presenta dolor abdominal asociado a ictericia asociado a transaminitis que por biopsia se asocia a hepatotoxicidad tardía debido a fingolimod. (AU)
Sujet(s)
Humains , Femelle , Adulte d'âge moyen , Lésions hépatiques dues aux substances/diagnostic , Lésions hépatiques dues aux substances/thérapie , Chlorhydrate de fingolimod/toxicitéRÉSUMÉ
Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibody-related disease (MOG disease) are inflammatory demyelinating diseases of the central nervous system (CNS). The disruption of the blood-brain barrier (BBB) is considered a key step in the pathogenesis of NMO and MOG disease. Although a previous report indicated that circulating immunoglobulin G (IgG) from NMO patients disrupts the BBB, the effect of IgG from patients with MOG disease has not been elucidated. In addition, it has been reported that some disease-modifying drugs for multiple sclerosis are harmful to NMO by an unknown mechanism. This study aimed to examine the effects of IgG from patients with NMO or MOG disease on BBB integrity. We also examined the effects of disease-modifying drugs (fingolimod [FTY720] and dimethyl fumarate [DMF]) on IgG-treated brain capillary endothelial cells. We used in vitro BBB models constructed with rat brain capillary endothelial cells (RBECs) to examine the effects on BBB function. The integrity of the RBECs was assessed by measuring transendothelial resistance (TEER) and cell viability. NMO or MOG-IgG treatment decreased TEER and cell viability in the endothelial monolayer model. Although FTY720 and DMF did not affect barrier function or cell viability under normal conditions, disease IgG-induced barrier dysfunctions were worsened by the presence of FTY720. These data indicate that circulating IgG in patients with NMO or MOG disease worsens BBB function. Furthermore, in patients with NMO or MOG disease treated with FTY720, changes in the integrity of the BBB were found to exacerbate the disease.
Sujet(s)
Barrière hémato-encéphalique/effets des médicaments et des substances chimiques , Chlorhydrate de fingolimod/toxicité , Immunoglobuline G/toxicité , Glycoprotéine MOG/toxicité , Neuromyélite optique , Modulateurs des récepteurs de la sphingosine 1 phosphate/toxicité , Animaux , Barrière hémato-encéphalique/immunologie , Barrière hémato-encéphalique/métabolisme , Cellules cultivées , Relation dose-effet des médicaments , Humains , Mâle , Neuromyélite optique/immunologie , Neuromyélite optique/métabolisme , Rats , Rat WistarRÉSUMÉ
Hypoxia-induced neonatal seizure mainly leads to deleterious effects on brain function, especially cognitive impairments and increased susceptibility to epilepsy later in life. Early inflammation plays an important role in the pathology of these consequences. Therefore, we explored the long-term outcomes of Fingolimod treatment as an anti-inflammatory and neuroprotective agent in a rat model of HINS. Seizures were induced in rats (postnatal day 10) by 5% O2 exposure for 15 min. Sixty minutes after the onset of hypoxia, pups received FTY720 (0.3 mg.kg-1) or normal saline for 12 consecutive days (lactation period), and they were used at P60-P63 for behavioral tests, ELISA and Pentylenetetrazole kindling model. The results of open field, novel object recognition and elevated plus maze tasks showed that Fingolimod prevents hippocampal memory dysfunction and anxiety-like behavior in both male and female hypoxic groups, which was accompanied with decreased TNF-α level in hippocampus. In addition, FTY720 postponed epileptogenesis just in female hypoxic + FTY group and decreased severity of seizures in both genders. Our results suggest that, FTY720 treatment in immature rats, which were previously subjected to HINS, prevented the long-lasting deficits, like cognitive impairments, decreased the severity of seizures and related inflammation. In addition, FTY720 did not show significant interaction with gender in most of the experiments, except the average day to reach fully kindled state. Taken together, FTY720 has therapeutic potential for long lasting effects of HINS in both male and female animals at puberty.
Sujet(s)
Dysfonctionnement cognitif/étiologie , Chlorhydrate de fingolimod/toxicité , Hypoxie/induit chimiquement , Inflammation/traitement médicamenteux , Crises épileptiques/traitement médicamenteux , Vieillissement , Animaux , Animaux nouveau-nés , Dysfonctionnement cognitif/traitement médicamenteux , Dysfonctionnement cognitif/physiopathologie , Épilepsie/traitement médicamenteux , Épilepsie/physiopathologie , Femelle , Hippocampe/effets des médicaments et des substances chimiques , Mâle , Neuroprotecteurs/pharmacologie , Pentétrazol/pharmacologie , Rats , Crises épileptiques/étiologie , Crises épileptiques/physiopathologie , Indice de gravité de la maladieRÉSUMÉ
Acute myeloid leukemia (AML) is an aggressive disease associated with very poor prognosis. Most patients are older than 60 years, and in this group only 5-15% of cases survive over 5 years. Therefore, it is urgent to develop more effective targeted therapies. Inactivation of protein phosphatase 2â¯A (PP2A) is a recurrent event in AML, and overexpression of its endogenous inhibitor SET is detected in ~30% of patients. The PP2A activating drug FTY720 has potent anti-leukemic effects; nevertheless, FTY720 induces cardiotoxicity at the anti-neoplastic dose. Here, we have developed a series of non-phosphorylable FTY720 analogues as a new therapeutic strategy for AML. Our results show that the lead compound CM-1231 re-activates PP2A by targeting SET-PP2A interaction, inhibiting cell proliferation and promoting apoptosis in AML cell lines and primary patient samples. Notably, CM-1231 did not induce cardiac toxicity, unlike FTY720, in zebrafish models, and reduced the invasion and aggressiveness of AML cells more than FTY720 in zebrafish xenograft models. In conclusion, CM-1231 is safer and more effective than FTY720; therefore, this compound could represent a novel and promising approach for treating AML patients with SET overexpression.
Sujet(s)
Cardiotoxicité/prévention et contrôle , Protéines de liaison à l'ADN/métabolisme , Chlorhydrate de fingolimod/administration et posologie , Chaperons d'histones/métabolisme , Leucémie aigüe myéloïde/traitement médicamenteux , Protein Phosphatase 2/métabolisme , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Animaux , Apoptose/effets des médicaments et des substances chimiques , Cardiotoxicité/étiologie , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Femelle , Chlorhydrate de fingolimod/analogues et dérivés , Chlorhydrate de fingolimod/toxicité , Rythme cardiaque/effets des médicaments et des substances chimiques , Humains , Leucémie aigüe myéloïde/anatomopathologie , Mâle , Adulte d'âge moyen , Liaison aux protéines/effets des médicaments et des substances chimiques , Tests de toxicité aigüe , Tests d'activité antitumorale sur modèle de xénogreffe , Danio zébréRÉSUMÉ
FTY-720 (Fingolimod) was one of the first compounds authorized for the treatment of multiple sclerosis. Among its other activities, this sphingosine analogue enhances exocytosis in neuroendocrine chromaffin cells, altering the quantal release of catecholamines. Surprisingly, the size of chromaffin granules is reduced within few minutes of treatment, a process that is paralleled by the homotypic fusion of granules and their heterotypic fusion with mitochondria, as witnessed by dynamic confocal and TIRF microscopy. Electron microscopy studies support these observations, revealing the fusion of several vesicles with individual mitochondria to form large, round mixed organelles. This cross-fusion is SNARE-dependent, being partially prevented by the expression of an inactive form of SNAP-25. Fused mitochondria exhibit an altered redox potential, which dramatically enhances cell death. Therefore, the cross-fusion of intracellular organelles appears to be a new mechanism to be borne in mind when considering the effect of FTY-720 on the survival of neuroendocrine cells.
Sujet(s)
Granules chromaffines/effets des médicaments et des substances chimiques , Chlorhydrate de fingolimod/toxicité , Sclérose en plaques/traitement médicamenteux , Cellules neuroendocrines/effets des médicaments et des substances chimiques , Animaux , Bovins , Cellules cultivées , Granules chromaffines/métabolisme , Granules chromaffines/anatomopathologie , Humains , Microscopie électronique à transmission , Mitochondries/effets des médicaments et des substances chimiques , Mitochondries/anatomopathologie , Dynamique mitochondriale/effets des médicaments et des substances chimiques , Cellules neuroendocrines/cytologie , Cellules neuroendocrines/métabolisme , Culture de cellules primaires , Protéine SNAP-25/métabolisme , Tests de toxicitéRÉSUMÉ
We examined whether fingolimod (FTY720), an S1PR (sphingosine-1-phosphate receptor) modulator, has beneficial or harmful effects on mineralocorticoid/salt-induced renal injury. Uninephrectomized rats on 0.9% NaCl/0.3% KCl drinking solution were randomly divided into control, control+FTY720, deoxycorticosterone acetate (DOCA), and DOCA+FTY720 groups and administered vehicle, vehicle+FTY720, DOCA+vehicle, and DOCA+FTY720 for 4 weeks, respectively. Only the DOCA+FTY720 group had reduced survival rates and showed hemolysis because of intravascular mechanical fragmentation of erythrocytes and thrombocytopenia. Both the DOCA+FTY720 and DOCA groups developed malignant hypertension, which was more severe in the DOCA+FTY720 group. In the DOCA+FTY720 group only, thrombotic microangiopathy involving severe renal arteriole endothelial cell injury was observed and was characterized by fibrinoid necrosis and onion-skin lesions in arterioles. There were fewer circulating endothelial progenitor cells in the DOCA+FTY720 group but more in the DOCA group compared with the control group. Expression levels of VEGF (vascular endothelial growth factor), S1PR1, and S1PR3 in renal arteriole endothelial cells were significantly greater in the DOCA+FTY720 and DOCA groups compared with the control group, with levels being similar between the 2 groups. Expression levels of endothelial nitric oxide synthase in renal arteriole endothelial cells were significantly lower in the DOCA+FTY720 group only. The control+FTY720 group showed reduced circulating endothelial progenitor cells but no significant functional or pathological changes in kidneys or changes in blood pressure. Exposure of uninephrectomized rats to DOCA/salt+FTY720 for 4 weeks induced renal arteriolar endothelial cell injury, resulting in the development of thrombotic microangiopathy. Consideration of this possibility is recommended when prescribing FTY720.
Sujet(s)
Chlorhydrate de fingolimod/usage thérapeutique , Hypertension artérielle/physiopathologie , Sclérose en plaques récurrente-rémittente/traitement médicamenteux , Microangiopathies thrombotiques/physiopathologie , Animaux , Artérioles/métabolisme , Artérioles/physiopathologie , Pression sanguine/effets des médicaments et des substances chimiques , Pression sanguine/physiologie , Acétate de désoxycorticostérone , Endothélium vasculaire/effets des médicaments et des substances chimiques , Endothélium vasculaire/anatomopathologie , Endothélium vasculaire/physiopathologie , Chlorhydrate de fingolimod/toxicité , Humains , Hypertension artérielle/induit chimiquement , Rein/vascularisation , Mâle , Néphrectomie , Nitric oxide synthase type III/métabolisme , Rat Sprague-Dawley , Chlorure de sodium , Microangiopathies thrombotiques/induit chimiquementRÉSUMÉ
Cardiac arrhythmias and ECG abnormalities including bradycardia, prolongation of the QT interval, and atrioventricular (AV) conduction blocks have been extensively observed with fingolimod, the first marketed oral drug for treating the relapsing-remitting form of multiple sclerosis. This study was aiming to further elucidate the effects of fingolimod on cardiac electrophysiology at three different levels: (i) in vitro, (ii) ex vivo, and (iii) in vivo. (i) Patch-clamp experiments in whole cell configuration were performed on Cav 1.2-transfected tsA201 cells exposed to fingolimod-phosphate 100 or 500 nmol/L (n = 27 cells, total) to measure drug effect on L-type calcium current (ICaL ). (ii) Langendorff perfusion experiments were undertaken on male Hartley guinea-pigs isolated hearts (n = 4) exposed to fingolimod 10 and 100 nmol/L to evaluate drug-induced effects on monophasic action potential duration measured at 90% repolarization (MAPD90 ). (iii) Implanted cardiac telemeters were used to record ECGs in guinea-pigs (n = 7) treated with a single dose of fingolimod 0.0625 mg/kg suspension, administered as an oral gavage. (i) In vitro cellular experiments showed that fingolimod-phosphate causes a concentration-dependent reduction in ICaL . (ii) Ex vivo Langendorff experiments revealed that fingolimod had no significant effect on MAPD90 . (iii) Fingolimod caused significant prolongations of the RR, PR, QT, and QTcF intervals in vivo. Reversible AV blocks were also observed in 7/7 animals. Fingolimod possesses ICaL -blocking properties, further contributing to its AV conduction-slowing effects. These properties are also consistent with its mitigated effect on the QT interval in humans, despite previously shown HERG-blocking effect.
Sujet(s)
Bloc atrioventriculaire/physiopathologie , Bradycardie/physiopathologie , Canaux calciques de type L/physiologie , Chlorhydrate de fingolimod/pharmacologie , Rythme cardiaque/physiologie , Sclérose en plaques/physiopathologie , Animaux , Bloc atrioventriculaire/induit chimiquement , Bradycardie/induit chimiquement , Inhibiteurs des canaux calciques/pharmacologie , Inhibiteurs des canaux calciques/usage thérapeutique , Inhibiteurs des canaux calciques/toxicité , Chlorhydrate de fingolimod/usage thérapeutique , Chlorhydrate de fingolimod/toxicité , Cochons d'Inde , Coeur/effets des médicaments et des substances chimiques , Coeur/physiologie , Système de conduction du coeur/effets des médicaments et des substances chimiques , Système de conduction du coeur/physiologie , Rythme cardiaque/effets des médicaments et des substances chimiques , Immunosuppresseurs/pharmacologie , Immunosuppresseurs/usage thérapeutique , Immunosuppresseurs/toxicité , Mâle , Sclérose en plaques/traitement médicamenteuxRÉSUMÉ
BACKGROUND: Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet. METHODS: Cell viability and anchorage-independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy. The mechanism of action of FTY720 in MM was assessed by measuring the activity of phosphatase protein 2A (PP2A)-a major target of FTY720. The binding of the endogenous inhibitor SET to PP2A in presence of FTY720 was evaluated by immunoblotting and immunoprecipitation. Signaling and activation of programmed cell death were evaluated by immunoblotting and flow cytometry. A syngeneic mouse model was used to evaluate anti-tumor efficacy and toxicity profile of FTY720 in vivo. RESULTS: We show that FTY720 significantly suppressed MM cell viability and anchorage-independent growth without affecting normal HM cells. FTY720 inhibited the phosphatase activity of PP2A by displacement of SET protein, which appeared overexpressed in MM, as compared to HM cells. FTY720 promoted AKT dephosphorylation and Bcl-2 degradation, leading to induction of programmed cell death, as demonstrated by caspase-3 and PARP activation, as well as by cytochrome c and AIF intracellular translocation. Moreover, FTY720 administration in vivo effectively reduced tumor burden in mice without apparent toxicity. CONCLUSIONS: Our preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment.
Sujet(s)
Chlorhydrate de fingolimod/usage thérapeutique , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/anatomopathologie , Mésothéliome/traitement médicamenteux , Mésothéliome/anatomopathologie , Animaux , Apoptose/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Chlorhydrate de fingolimod/pharmacologie , Chlorhydrate de fingolimod/toxicité , Mésothéliome malin , Souris , Protein Phosphatase 2/métabolisme , Protéines suppresseurs de tumeurs/métabolismeRÉSUMÉ
BACKGROUND: FTY720 is an immunosuppressive molecule licensed for the treatment of chronic relapsing multiple sclerosis (MS). It attenuates the adaptive immune response by sequestering T cells within secondary lymphoid organs via its action as functional antagonist of sphingosine-1-phasphate. To date, it is unknown whether FTY-induced lymphopenia puts MS patients at increased risk for severe forms of postoperative infectious complications such as abdominal sepsis. OBJECTIVES: To determine the effect of FTY720-induced lymphopenia on survival to sepsis secondary to postoperative intraabdominal infections in a murine model of polymicrobial sepsis. METHODS: Detailed analysis of cellular dynamics in secondary lymphoid organs and of cytokine profiles was performed in FTY720-treated or placebo-treated C57BL/6 mice after induction of colon ascendens stent peritonitis (CASP). Furthermore, survival analysis was performed in FTY720-treated and placebo-treated animals in severe CASP. Fifty percent of each group were treated with broad spectrum antibiotics. RESULTS: FTY720 treatment resulted in remodeling of cell populations present in the peripheral blood, the peritoneal cavity, and the spleen after CASP induction. Both lymphoid and myeloid cell lines were affected. However, survival in lymphopenic FTY720-treated animals was similar to placebo-treated mice following CASP. Antibiotic treatment increases survival in untreated as well as FTY720-treated animals to a similar extent. DISCUSSION: Our data demonstrate that inhibition of T-cell migration and induction of peripheral lymphopenia did not affect survival in a model of severe murine sepsis. The presence of reduced T- and B-cell numbers in the peripheral blood during a septic challenge did not negatively affect sepsis mortality in our model of severe abdominal sepsis. The absence of increased mortality under FTY720 treatment in the CASP model suggests that FTY720 treatment will probably not result in increased mortality in MS patients suffering from sepsis.
Sujet(s)
Chlorhydrate de fingolimod/toxicité , Lymphopénie/induit chimiquement , Sepsie/traitement médicamenteux , Sepsie/anatomopathologie , Animaux , Modèles animaux de maladie humaine , Femelle , Cytométrie en flux , Lymphopénie/métabolisme , Souris , Souris de lignée C57BL , Péritonite/métabolisme , Sepsie/métabolismeRÉSUMÉ
AIM: The aim of this study was to evaluate the effects of the sphingosine analogue, FTY720 (Fingolimod), on the outcomes of myocardial ischaemia/reperfusion (I/R) injury. METHODS: Two concentrations of FTY720 (1 or 2.5 µM were administered either prior to (PreFTY), or following (PostFTY) 20 minutes' global (GI) or 35 minutes' regional ischaemia (RI) in the isolated, perfused, working rat heart. Functional recovery during reperfusion was assessed following both models of ischaemia, while infarct size (IFS) was determined following RI. RESULTS: FTY720 at 1 µM exerted no effect on functional recovery, while 2.5 µM significantly impaired aortic output (AO) recovery when administered prior to GI (% recovery: control: 33.88 ± 6.12% vs PreFTY: 0%, n = 6-10; p < 0.001), as well as before and after RI ( % recovery: control: 27.86 ± 13.22% vs PreFTY: 0.62% ; p < 0.05; and PostFTY: 2.08%; p = 0.0585, n = 6). FTY720 at 1 µM administered during reperfusion reduced IFS (% of area at risk (AAR): control: 39.89 ± 3.93% vs PostFTY: 26.56 ± 4.32%, n = 6-8; p < 0.05), while 2.5 µM FTY720 reduced IFS irrespective of the time of administration ( % of AAR: control: 39.89 ± 3.93% vs PreFTY: 29.97 ± 1.03% ; and PostFTY: 30.45 ± 2.16%, n = 6; p < 0.05). CONCLUSION: FTY720 exerted divergent outcomes on function and tissue survival depending on the concentration administered, as well as the timing of administration.
Sujet(s)
Chlorhydrate de fingolimod/administration et posologie , Hémodynamique/effets des médicaments et des substances chimiques , Contraction myocardique/effets des médicaments et des substances chimiques , Infarctus du myocarde/prévention et contrôle , Lésion de reperfusion myocardique/prévention et contrôle , Myocarde/anatomopathologie , Animaux , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Calendrier d'administration des médicaments , Chlorhydrate de fingolimod/toxicité , Préparation de coeur isolé , Mâle , Infarctus du myocarde/anatomopathologie , Infarctus du myocarde/physiopathologie , Lésion de reperfusion myocardique/anatomopathologie , Lésion de reperfusion myocardique/physiopathologie , Rat Wistar , Facteurs temps , Survie tissulaire/effets des médicaments et des substances chimiquesRÉSUMÉ
Fingolimod, a sphingosine 1-phosphate (S1P) receptor subtype 1, 3, 4 and 5 modulator, has been used for the treatment of patients with relapsing forms of multiple sclerosis, but atrioventricular conduction block and/or QT-interval prolongation have been reported in some patients after the first dose. In this study, we directly compared the electropharmacological profiles of fingolimod with those of siponimod, a modulator of sphingosine 1-phosphate receptor subtype 1 and 5, using in vivo guinea-pig model and in vitro human ether-a-go-go-related gene (hERG) assay to better understand the onset mechanisms of the clinically observed adverse events. Fingolimod (0.01 and 0.1mg/kg) or siponimod (0.001 and 0.01mg/kg) was intravenously infused over 10min to the halothane-anaesthetized guinea pigs (n=4), whereas the effects of fingolimod (1µmol/L) and siponimod (1µmol/L) on hERG current were examined (n=3). The high doses of fingolimod and siponimod induced atrioventricular conduction block, whereas the low dose of siponimod prolonged PR interval, which was not observed by that of fingolimod. The high dose of fingolimod prolonged QT interval, which was not observed by either dose of siponimod. Meanwhile, fingolimod significantly inhibited hERG current, which was not observed by siponimod. These results suggest that S1P receptor subtype 1 in the heart could be one of the candidates for fingolimod- and siponimod-induced atrioventricular conduction block since S1P receptor subtype 5 is localized at the brain, and that direct IKr inhibition may play a key role in fingolimod-induced QT-interval prolongation.