RESUMO
BACKGROUND: Ibudilast has shown beneficial effects on several imaging outcomes in progressive multiple sclerosis (MS). Slowly enlarging lesions are a proposed imaging biomarker of compartmentalized inflammation within chronic active lesions. OBJECTIVE: To assess the treatment effect of ibudilast on slowly enlarging lesion volumes over 96 weeks from a phase II clinical trial of ibudilast (Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). METHODS: In total, 255 participants with progressive MS from 28 sites were randomized to oral ibudilast or placebo. Participants with at least four analyzable magnetic resonance imaging (MRI) were included. Slowly enlarging lesions were quantified using Jacobian determinant maps. A linear model was used to assess the effect of ibudilast. Magnetization transfer ratio within slowly enlarging lesions was assessed to determine the effect of ibudilast on tissue integrity. RESULTS: In total, 195 participants were included in this analysis. Ibudilast significantly decreased slowly enlarging lesion volume (23%, p = 0.003). Ibudilast also reduced magnetization transfer ratio change in slowly enlarging lesions: 0.22%/year, p = 0.04. CONCLUSION: Ibudilast showed a significant effect on baseline volume of lesions that were slowly enlarging and magnetization transfer ratio in slowly enlarging lesions. The results support the use of slowly enlarging lesions for assessment of compartmentalized inflammation represented by chronic active lesions and provide further support for the neuroprotective effects of ibudilast in progressive MS.
Assuntos
Indolizinas , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Pirazóis , Humanos , Encéfalo/patologia , Inflamação/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Piridinas/uso terapêuticoRESUMO
BACKGROUND: Thalamic volume loss is known to be associated with clinical and cognitive disability in progressive multiple sclerosis (PMS). OBJECTIVE: To investigate the treatment effect of ibudilast on thalamic atrophy more than 96 weeks in the phase 2 trial in progressive(MS Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). METHODS: A total of 231 participants were randomized to either ibudilast (n = 114) or placebo (n = 117). Thalamic volume change was computed using Bayesian Sequence Adaptive Multimodal Segmentation tool (SAMseg) incorporating T1, fluid-attenuated inversion recovery (FLAIR), and fractional anisotropy maps and analyzed with a mixed-effects repeated-measures model. RESULTS: There was no significant difference in thalamic volumes between treatment groups. On exploratory analysis, participants with primary progressive multiple sclerosis (PPMS) on placebo had a 0.004% greater rate of thalamic atrophy than PPMS participants on ibudilast (p = 0.058, 95% confidence interval (CI) = -0.008 to <0.001). Greater reductions in thalamic volumes at more than 96 weeks were associated with worsening multiple sclerosis functional composite (MSFC-4) scores (p = 0.002) and worsening performance on the symbol digit modality test (SDMT) (p < 0.001). CONCLUSION: In a phase 2 trial evaluating ibudilast in PMS, no treatment effect was demonstrated in preventing thalamic atrophy. Participants with PPMS exhibited a treatment effect that trended toward significance. Longitudinal changes in thalamic volume were related to worsening of physical and cognitive disability, highlighting this outcome's clinical importance.
Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Teorema de Bayes , Atrofia/tratamento farmacológicoRESUMO
BACKGROUND: Thalamic volume (TV) is a sensitive biomarker of disease burden of injury in multiple sclerosis (MS) and appears to reflect overall lesion loads. Ibudilast showed significant treatment effect on brain atrophy and magnetization transfer ratio (MTR) of normal-appearing brain tissue but not in new/enlarging T2 lesion in the SPRINT-MS randomized clinical trial. OBJECTIVE: To evaluate the effect of ibudilast on thalamic tissue integrity and volume in the SPRINT-MS. METHODS: A total of 255 participants with progressive MS were randomized to oral ibudilast or placebo, and thalamic MTR and normalized TV over 96 weeks were quantified. Mixed-effect modeling assessed treatment effects on the thalamic MTR and TV, separately. Similarly, the measures were compared between the participants with confirmed disability progression (CDP). RESULTS: Ibudilast's treatment effect was observed compared to placebo for thalamic MTR (p = 0.03) but not for TV (p = 0.68) while TV correlated with T2 lesion volume (p < 0.001). CDP associated with thalamic MTR (p = 0.04) but not with TV (p = 0.7). CONCLUSION: Ibudilast showed an effect on thalamic MTR, which was associated with CDP, suggesting a clinically relevant effect on thalamic tissue integrity. However, the treatment effect was not observed in TV, suggesting that thalamic atrophy is more closely associated with global inflammatory activity than local tissue integrity. CLINICALTRIALS.GOV: NCT01982942.
Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Piridinas/uso terapêutico , Atrofia/tratamento farmacológico , Atrofia/patologiaRESUMO
Wolfram syndrome is a rare multisystem disease characterized by childhood-onset diabetes mellitus and progressive neurodegeneration. Most cases are attributed to pathogenic variants in a single gene, Wolfram syndrome 1 (WFS1). There currently is no disease-modifying treatment for Wolfram syndrome, as the molecular consequences of the loss of WFS1 remain elusive. Because diabetes mellitus is the first diagnosed symptom of Wolfram syndrome, we aimed to further examine the functions of WFS1 in pancreatic ß cells in the context of hyperglycemia. Knockout (KO) of WFS1 in rat insulinoma (INS1) cells impaired calcium homeostasis and protein kinase B/Akt signaling and, subsequently, decreased cell viability and glucose-stimulated insulin secretion. Targeting calcium homeostasis with reexpression of WFS1, overexpression of WFS1's interacting partner neuronal calcium sensor-1 (NCS1), or treatment with calpain inhibitor and ibudilast reversed deficits observed in WFS1-KO cells. Collectively, our findings provide insight into the disease mechanism of Wolfram syndrome and highlight new targets and drug candidates to facilitate the development of a treatment for this disorder and similar diseases.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação a Calmodulina/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Piridinas/farmacologia , Síndrome de Wolfram/tratamento farmacológico , Animais , Cálcio/metabolismo , Proteínas de Ligação a Calmodulina/genética , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Glicoproteínas , Homeostase , Hiperglicemia , Secreção de Insulina , Proteínas de Membrana/genética , Receptor de Insulina , Transcriptoma , Síndrome de Wolfram/genéticaRESUMO
Background: Inflammation is implicated in alcohol use disorder (AUD). Ibudilast, a neuroimmune modulator, shows promise for the treatment of AUD. Elevated inflammation, indicated by high levels of C-reactive protein (CRP), represents a possible subtype of AUD, which may be associated with treatment response to ibudilast.Objectives: The current study evaluated CRP as a predictor of treatment response to ibudilast; hypothesizing that ibudilast would be more effective at reducing drinking and alcohol cue-reactivity in individuals with higher CRP levels.Methods: This is a secondary analysis of a clinical trial of ibudilast for AUD, which found that ibudilast reduced heavy drinking in individuals with AUD. Fifty-one individuals were randomized to receive ibudilast (n = 24 [16 M/8F]) or placebo (n = 27 [18 M/9F]) for two weeks. Participants provided blood samples at baseline to assess CRP levels, completed daily assessments of alcohol use, and an fMRI alcohol cue-reactivity task at study mid-point. Models tested the effects of medication, CRP levels, and their interaction on drinks per drinking day and alcohol cue-reactivity.Results: There was a significant interaction between medication and CRP (F = 3.80, p = .03), such that the ibudilast high CRP group had fewer drinks per drinking day compared to the ibudilast low CRP group. CRP moderated the effect of medication on brain activation in a cluster extending from the left inferior frontal gyrus to the right-dorsal striatum (Z = 4.55, p < .001). This interaction was driven by attenuated cue-reactivity in the ibudilast high CRP group relative to the ibudilast low CRP and placebo high CRP groups.Conclusions: This study serves as an initial investigation into predictors of clinical response to ibudilast treatment and suggests that a baseline proinflammatory profile may enhance clinical efficacy.
Assuntos
Alcoolismo , Proteína C-Reativa , Humanos , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Proteína C-Reativa/metabolismo , Etanol , InflamaçãoRESUMO
To develop the macrophage migration inhibitory factor (MIF) directed therapeutic approach for the treatment of leptospirosis, we identified potential MIF inhibitors by screening 10 essential tautomerase inhibition classes of chemical compounds and 7 existing anti-inflammatory and anti-microbial drugs. Dopachrome tautomerase assay was performed to measure the anti-MIF activity of selected compounds. Among 17 chemical compounds, ibudilast, an anti-inflammatory agent showed the MIF tautomerase IC50 value at a very lower concentration (9.5 ± 5.6 µM) which is considered similar to the IC50 of standard MIF antagonist, ISO-1 (6.2 ± 3.8 µM) with non-significant cytotoxicity. The in vitro analysis of the therapeutic potential of MIF inhibitor revealed that ibudilast significantly reduced the leptospiral lipopolysaccharide (LPS) mediated expression of inflammatory mediators such as intercellular adhesion molecule (ICAM), p38 and p44/42 mitogen-activated protein kinase (MAPK), inflammatory cytokines, and decreased the reactive oxygen species (ROS) production, mitochondrial membrane potential (ΔΨm) loss and cell death of LPS treated THP-1 cells. In vivo analysis demonstrated that the administration of anti-MIF Ibudilast significantly reduced the histopathological changes, downregulates the pro-inflammatory cytokines, and protects the leptospiral BALB/c model from lethality by increasing the survival rate from 25% to 66%. Finally, the biocompatibility of the evaluated anti-MIF compound was explored by cytotoxicity, hemocompatibility, and cell death assay. Ibudilast showed no significant cytotoxicity and hemolytic activity was noticed even at the higher concentration of ≤50 µM and ≥250 µM, when compared with the positive control, 0.1% Triton X-100; no significant cell death was observed at ≤50 µM concentration of Ibudilast in THP-1 cells. From these lines of evidence, we propose that Ibudilast may be a great MIF targeting repurposing drug for reliable supportive treatment of severe leptospirosis.
Assuntos
Leptospirose , Fatores Inibidores da Migração de Macrófagos , Humanos , Anti-Inflamatórios/farmacologia , Reposicionamento de Medicamentos , Oxirredutases Intramoleculares , Leptospirose/tratamento farmacológico , Lipopolissacarídeos , Fatores Inibidores da Migração de Macrófagos/química , Fatores Inibidores da Migração de Macrófagos/metabolismo , Camundongos Endogâmicos BALB C , Células THP-1RESUMO
Neurotoxicity is one of the major side effects caused by calcineurin inhibitors such as tacrolimus in clinical practice. The underlying mechanisms remain unclear, and no potential protective agents have been identified yet. Here, we aimed to investigate tacrolimus-induced neurotoxicity and assess the protective effects of ibudilast, a nonselective phosphodiesterase inhibitor with neuroprotective effects, against tacrolimus-induced neurotoxicity. An in vitro assay of human neuroblastoma SH-SY5Y cells showed that ibudilast reduced tacrolimus-induced cell death. Subsequently, using in vivo studies, we assessed the pathological mechanism of neurotoxicity and evaluated the protective effect of ibudilast. Wistar rats were subcutaneously administered tacrolimus (2.5 or 5.0 mg/kg/day) for 14 d, and ibudilast (7.5 mg/kg/day) was intraperitoneally administered once a day beginning 2 d prior to tacrolimus (5 mg/kg/day) administration. We observed that ibudilast significantly reduced the tacrolimus-induced neurotoxic events. From the assessment of excised brains, we found that tacrolimus was penetrated to brain and the brain concentration was correlated with the neurotoxicity-score, although ibudilast had no effect on this pharmacokinetics. Tacrolimus-induced neuronal damage was histopathologically evaluated using Nissl and TUNEL staining, where only the cerebral cortex and CA1 region in hippocampus exhibited neuronal death, but not the CA3 region, dendrite gyrus, and cerebellum. Co-administration of ibudilast significantly attenuated these histopathological changes. In conclusion, these results suggest that tacrolimus translocation into the brain and neuronal damage in the cerebral cortex and CA1 are the underlying mechanisms of tacrolimus-induced neurotoxicity and that ibudilast could be a protective agent against this adverse event.
Assuntos
Neuroblastoma , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Animais , Humanos , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Piridinas , Ratos , Ratos Wistar , Tacrolimo/toxicidadeRESUMO
In Japan, ibudilast (IBD) is a therapeutic agent used to treat asthma, allergic conjunctivitis, and dizziness caused by cerebrovascular disease. Previously, we have reported that IBD could reduce the secretion of proinflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor (TNF)-α, in lipopolysaccharide (LPS)-treated RAW264.7 monocyte-linage cells in vitro. In the present study, we examined the anti-inflammatory effects of IBD in vivo. As IL-6 is a biomarker for sepsis and has been suggested to exacerbate symptoms, we determined whether IBD reduces IL-6 levels in vivo and improves sepsis symptoms in animal models. We observed that IBD treatment reduced IL-6 levels in the lungs of LPS-treated mice and improved LPS-induced hypothermia, one of the symptoms of sepsis. In addition, IBD reduced IL-6 and attenuated plasminogen activator inhibitor-1 (PAI-1) and alanine aminotransferase (ALT) levels in the serum of LPS-treated mice. Elevated PAI-1 levels exacerbate sepsis-induced disseminated intravascular coagulation (DIC), and ALT is a biomarker for liver dysfunction. IBD improved the survival of mice administered a lethal dose of LPS. IBD administration ameliorated kidney pathology of model mice. Overall, these results suggest that IBD exerts anti-inflammatory functions in vivo and could be a drug candidate for treating endotoxemia, including sepsis.
Assuntos
Interleucina-6 , Piridinas/uso terapêutico , Sepse , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Sepse/induzido quimicamente , Sepse/tratamento farmacológico , Sepse/metabolismo , Fator de Necrose Tumoral alfaRESUMO
Ibudilast, a neuroimmune modulator, shows promise as a pharmacotherapy for alcohol use disorder (AUD). In vivo administration of ibudilast reduces the expression of pro-inflammatory cytokines in animal models, but its effects on markers of inflammation in humans are unknown. This preliminary study examined the effect of ibudilast on peripheral and potential central markers of inflammation in individuals with AUD. This study also explored the predictive relationship of neurometabolite markers with subsequent drinking in the trial. Non-treatment-seeking individuals with an AUD (n = 52) were randomized to receive oral ibudilast (n = 24) or placebo (n = 28) for 2 weeks. Plasma levels of peripheral inflammatory markers were measured at baseline and after 1 and 2 weeks of medication. At study mid-point, proton magnetic resonance spectroscopy was performed to measure potential neurometabolite markers of inflammation: choline-compounds (Cho), myo-inositol (MI) and creatine + phosphocreatine (Cr) in frontal and cingulate cortices from 43 participants (ibudilast: n = 20; placebo: n = 23). The treatment groups were compared on peripheral and central markers. Ibudilast-treated participants had lower Cho in superior frontal white matter and nominally lower MI in pregenual anterior cingulate cortex. Ibudilast-treated participants had nominally lower C-reactive protein levels at visit 2 and nominally lower TNF-α/IL-10 ratios, relative to placebo. C-reactive protein and Cho levels were correlated, controlling for medication. Superior frontal white matter Cho predicted drinking in the following week. Micro-longitudinal ibudilast treatment may induce peripheral and putative central anti-inflammatory responses in patients with AUD. The neurometabolite responses may be associated with reduction in drinking, suggesting an anti-inflammatory component to the therapeutic action of ibudilast.
Assuntos
Alcoolismo , Consumo de Bebidas Alcoólicas/metabolismo , Alcoolismo/tratamento farmacológico , Alcoolismo/metabolismo , Animais , Ácido Aspártico , Proteína C-Reativa , Colina/metabolismo , Creatina/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inositol/metabolismo , PiridinasRESUMO
Neurodegenerative diseases constitute a broad range of central nervous system disorders, characterized by neuronal degeneration. Alzheimer's disease, Parkinson's disease, amyolotrophic lateral sclerosis (ALS), and progressive forms of multiple sclerosis (MS) are some of the most frequent neurodegenerative diseases. Despite their diversity, these diseases share some common pathophysiological mechanisms: the abnormal aggregation of disease-related misfolded proteins, autophagosome-lysosome pathway dysregulation, impaired ubiquitin-proteasome system, oxidative damage, mitochondrial dysfunction and excessive neuroinflammation. There is still no effective drug that could halt the progression of neurodegenerative diseases, and the current treatments are mainly symptomatic. In this regard, the development of novel multi-target pharmaceutical approaches presents an attractive therapeutic strategy. Ibudilast, an anti-inflammatory drug firstly developed as an asthma treatment, is a cyclic nucleotide phosphodiesterases (PDEs) inhibitor, which mainly acts by increasing the amount of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), while downregulating the pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α), macrophage migration inhibitory factor (MIF) and Toll-like receptor 4 (TLR-4). The preclinical evidence shows that ibudilast may act neuroprotectively in neurodegenerative diseases, by suppressing neuroinflammation, inhibiting apoptosis, regulating the mitochondrial function and by affecting the ubiquitin-proteasome and autophagosome-lysosome pathways, as well as by attenuating oxidative stress. The clinical trials in ALS and progressive MS also show some promising results. Herein, we aim to provide an update on the emerging preclinical and clinical evidence on the therapeutic potential of ibudilast in these disorders, discuss the potential challenges and suggest the future directions.
Assuntos
Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Diester Fosfórico Hidrolases , Complexo de Endopeptidases do Proteassoma , Piridinas/farmacologia , UbiquitinaRESUMO
BACKGROUND: The SPRINT-MS trial demonstrated benefit of ibudilast on brain atrophy over 96 weeks in progressive multiple sclerosis (MS). Optical coherence tomography (OCT) was performed in all trial participants. OBJECTIVE: Report the OCT results of the SPRINT-MS trial. METHODS: OCT was obtained at baseline and every 6 months using spectral domain OCT and analyzed by an OCT reading center. Change in each OCT outcome measure by treatment group was estimated using linear mixed models. RESULTS: Change in pRNFL thickness was +0.0424 uM/year (95% confidence interval (CI): -0.3091 to 0.3939) for ibudilast versus -0.2630 uM (95% CI: -0.5973 to 0.0714) for placebo (n = 244, p = 0.22). Macular volume change was -0.00503 mm3/year (-0.02693 to 0.01688) with ibudilast versus -0.03659 mm3/year (-0.05824 to -0.01494) for placebo in the Spectralis cohort (n = 61, p = 0.044). For the Cirrus cohort, macular volume change was -0.00040 mm3/year (-0.02167, 0.020866) with ibudilast compared to -0.02083 mm3/year (-0.04134 to -0.00033) for placebo (n = 183, p = 0.1734). Ganglion cell-inner plexiform layer thickness change, available from Cirrus, was -0.4893 uM/year (-0.9132, -0.0654) with ibudilast versus -0.9587 uM/year (-1.3677, -0.5498) with placebo (n = 183, p = 0.12). CONCLUSION: Retinal thinning in MS may be attenuated by ibudilast. Sample size estimates suggest OCT can be a viable outcome measure in progressive MS trials if a therapy has a large treatment effect. TRIAL REGISTRATION: NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.
Assuntos
Esclerose Múltipla Crônica Progressiva , Piridinas/uso terapêutico , Humanos , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Tomografia de Coerência ÓpticaRESUMO
BACKGROUND: Ibudilast, a novel neuroimmune modulator being studied to treat alcohol use disorder (AUD), was shown in a randomized controlled trial (NCT03489850) to reduce ventral striatum (VS) activation in response to visual alcohol cues. The present study extended this finding by probing the effects of ibudilast on alcohol cue-elicited functional connectivity (i.e., temporally correlated activation) with the VS seed. The study also tests the association between functional connectivity and alcohol use during the trial. METHODS: Non-treatment-seeking participants (n = 45) with current alcohol use disorder were randomized to receive twice-daily dosing with either ibudilast (50 mg; n = 20) or placebo (n = 25). Upon reaching the target dosagee of the medication or placebo, participants completed a functional neuroimaging alcohol cue reactivity paradigm. Drinks per drinking day were assessed at baseline and daily during the 2-week trial. RESULTS: Ibudilast reduced alcohol cue-elicited functional connectivity between the VS seed and reward-processing regions including the orbitofrontal and anterior cingulate cortices compared with placebo (p < 0.05). Cue-elicited functional connectivity was correlated with drinks per drinking day (R2 = 0.5351, p < 0.001), and ibudilast reduced this association in similar reward-processing regions compared with placebo. CONCLUSIONS: Ibudilast's effects on drinking outcomes may be related to the attenuation of functional connectivity in frontostriatal circuits related to reward processing. These results provide an important proof of concept for this novel pharmacotherapy and support the clinical utility of incorporating neuroimaging-and especially functional connectivity-analyses into medication development.
Assuntos
Alcoolismo/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Inibidores de Fosfodiesterase/uso terapêutico , Piridinas/uso terapêutico , Adulto , Encéfalo/diagnóstico por imagem , Conectoma , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Inibidores de Fosfodiesterase/farmacologia , Piridinas/farmacologia , Adulto JovemRESUMO
Oxaliplatin is a key drug used in the management of solid tumors, such as colorectal cancer; however, it causes peripheral neuropathy. In this study, we investigated the effect of ibudilast, a phosphodiesterase inhibitor, on oxaliplatin-induced mechanical allodynia and histological changes in rats. Ibudilast (7.5 mg/kg, i.p., 5 times per week) reduced mechanical allodynia and histological changes induced by oxaliplatin (4 mg/kg, i.p., twice a week). In contrast, ibudilast (0.01-10 µM) had no effect on oxaliplatin-induced tumor cytotoxicity in murine colon adenocarcinoma 26 cells. These findings suggest that ibudilast could be useful for preventing oxaliplatin-induced peripheral neuropathy in clinical settings.
Assuntos
Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Hiperalgesia/patologia , Masculino , Camundongos , Oxaliplatina/uso terapêutico , Doenças do Sistema Nervoso Periférico/patologia , Ratos Sprague-Dawley , Células Tumorais CultivadasRESUMO
Mucus hypersecretion is a hallmark of respiratory diseases, and excess airway mucus can worsen these conditions. Therefore, it is important to control the production of airway mucus in the treatment of respiratory diseases. The phosphodiesterase inhibitor ibudilast has been reported to be effective in treating sputum and postnasal drip in patients with chronic airway inflammation. On the basis of the hypothesis that ibudilast could inhibit mucus production in the airway, in the present study, we examined the effects of ibudilast on the production of MUC5AC, a major protein component of mucus. In in vitro studies using NCI-H292 cells, ibudilast suppressed MUC5AC production induced by various stimuli. In addition, ibudilast inhibited extracellular signal-regulated kinase (ERK)1/2 phosphorylation and MUC5AC gene transcription. Furthermore, it attenuated MUC5AC production and Muc5ac mRNA expression in lipopolysaccharide-treated mice in vivo. Collectively, these findings demonstrate that ibudilast has an inhibitory effect on mucus production, which could at least partly be attributed to the inhibition of ERK1/2 phosphorylation and the repression of MUC5AC gene transcription.
Assuntos
Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Mucina-5AC/antagonistas & inibidores , Muco/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Piridinas/farmacologia , Animais , Linhagem Celular , Humanos , Peróxido de Hidrogênio/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos ICR , Mucina-5AC/genética , Mucina-5AC/metabolismo , Fosforilação/efeitos dos fármacos , Fumaça , NicotianaRESUMO
Bacterial infection in orthopedic surgery is challenging because cell wall components released after bactericidal treatment can alter osteoblast and osteoclast activity and impair fracture stability. However, the precise effects and mechanisms whereby cell wall components impair bone healing are unclear. In this study, we characterized the effects of lipopolysaccharide (LPS) on bone healing and osteoclast and osteoblast activity in vitro and in vivo and evaluated the effects of ibudilast, an antagonist of toll-like receptor 4 (TLR4), on LPS-induced changes. In particular, micro-computed tomography was used to reconstruct femoral morphology and analyze callus bone content in a femoral defect mouse model. In the sham-treated group, significant bone bridge and cancellous bone formation were observed after surgery, however, LPS treatment delayed bone bridge and cancellous bone formation. LPS inhibited osteogenic factor-induced MC3T3-E1 cell differentiation, alkaline phosphatase (ALP) levels, calcium deposition, and osteopontin secretion and increased the activity of osteoclast-associated molecules, including cathepsin K and tartrate-resistant acid phosphatase in vitro. Finally, ibudilast blocked the LPS-induced inhibition of osteoblast activation and activation of osteoclast in vitro and attenuated LPS-induced delayed callus bone formation in vivo. Our results provide a basis for the development of a novel strategy for the treatment of bone infection.
Assuntos
Lipopolissacarídeos/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Piridinas/farmacologia , Animais , Biomarcadores , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Linhagem Celular , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Camundongos , Osteogênese/efeitos dos fármacos , Cicatrização , Microtomografia por Raio-XRESUMO
A key feature of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders including Alzheimer disease (AD), Parkinson disease (PD) and Huntington's disease (HD) is abnormal aggregation and deposition of misfolded proteins. Previous studies have shown that autophagy plays an important role in the clearance of disease-linked protein aggregates. In the current study, we report that ibudilast, which is a non-selective inhibitor of phosphodiesterases (PDEs) and an anti-inflammation drug, can induce autophagy and lysosomal biogenesis through mammalian target of rapamycin complex 1 - transcription factor EB (mTORC1-TFEB) signaling. We have found that ibudilast significantly enhances the clearance of disease-linked TAR DNA binding protein (TDP-43) and superoxide dismutase 1 (SOD1) protein aggregates in transfected cellular models carrying corresponding gene mutations. The mechanistic study revealed that ibudilast could markedly enhance TFEB nuclear translocation and increase the autolysosomes by inhibiting mTORC1 activity. We have also demonstrated that ibudilast could protect TDP-43-induced cytotoxicity in motor neuron-like NSC-34 cells. Collectively, our study identifies ibudilast as an autophagy enhancer and provides insights into the molecular basis of ibudilast for the potential treatment of several neurodegenerative disorders.
Assuntos
Autofagia , Proteínas de Ligação a DNA/metabolismo , Lisossomos/metabolismo , Fármacos Neuroprotetores/farmacologia , Agregados Proteicos , Piridinas/farmacologia , Superóxido Dismutase-1/metabolismo , Esclerose Lateral Amiotrófica/patologia , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Morte Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Células HEK293 , Humanos , Lisossomos/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fusão de Membrana/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacosRESUMO
Ibudilast (AV-411) is a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It is currently marketed for human use in Asian countries for the treatment of asthma, cerebrovascular disorders and ocular allergies. Ibudilast has also been found to have an analgesic action for neuropathic pain at doses 5-10 times higher than those used in asthma therapy. Six healthy Labrador dogs were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, cross-over design (2x2 Latin-square). Dogs in group 1 (n=3) were fasted for at least 10 hours overnight before the beginning of the experiment and 4 h following dosing while dogs in group 2 (n=3) received food ad libitum. During the first phase, each dog in group 1 and 2 received a single dose of 5 mg/kg ibudilast administered orally. After 1-week washout period the groups were rotated and the experiment was repeated. The analytical method, validated for dog plasma, was shown to be linear in the range 0.10-20 µg/mL. The limit of detection (LOD) and quantification (LOQ) were 0.03 and 0.1 µg/mL, respectively. No behavioural or health alterations were observed in the animals during or after the study. Ibudilast was detectable in plasma for up to 24 h showing a wide variability between animals. Although no statistically significant differences were observed in the present study between the fed and fasted states, examination of the raw data suggests that an effect may be present. The wide degree of variation observed in area under the curve (AUC) suggests that the investigation of population pharmacokinetic modelling is warranted.
Assuntos
Interações Alimento-Droga , Inibidores de Fosfodiesterase , Piridinas , Administração Oral , Animais , Área Sob a Curva , Estudos Cross-Over , Cães , Jejum , Inibidores de Fosfodiesterase/farmacocinética , Piridinas/farmacocinéticaRESUMO
BACKGROUND: Medication overuse headache (MOH) is a condition bordering between a chronic pain condition and a substance dependence disorder. Activation of immunocompetent glial cells in the central nervous system has been linked to both pathological pain and drug addiction/reward. Preclinically, ibudilast attenuates glial activation and is able to reduce neuropathic pain and markers of substance dependence. We therefore hypothesized ibudilast would reduce headache burden and opioid analgesic requirements in patients with opioid overuse headache. OBJECTIVE: To determine if treatment with ibudilast provides a greater reduction in headache index than placebo in MOH patients consuming opioids. METHODS: Participants with MOH who were using opioids were randomized via computer-generated code to ibudilast 40 mg or placebo twice daily for 8 weeks in a double-blind, parallel groups study. Before randomization participants completed a 4-week baseline headache diary. During treatment, headache diary data collection continued and participants attended 4 study visits during which quantitative sensory testing was performed. Blood samples for immune biomarker analyses were collected before and after treatment in a subgroup of participants. RESULTS: Thirty-four participants were randomized, 13 of 15 randomized to ibudilast and 17 of 19 randomized to placebo completed treatment. Ibudilast was generally well-tolerated with mild, transient nausea reported as the most common adverse event (66.7% vs 10.5% in placebo group). Results are shown as mean (SD). At the end of treatment no differences in the primary outcome average daily headache index (placebo 62 [44] vs ibudilast 77 [72] groups, difference -15, CI -65 to 35 h × numerical rating scale), or secondary outcomes headache frequency (placebo 23 [8.1] vs ibudilast 24.5 [6.2], difference -1.5, CI -7.7 to 4.8 days/month) and opioid intake (placebo 20.6 [43] vs ibudilast 19 [24.3], difference 1.6, CI -31.5 to 34.8 mg morphine equivalent) were observed between placebo and ibudilast groups. CONCLUSIONS: Using the current dosing regimen, ibudilast does not improve headache or reduce opioid use in patients with MOH without mandated opioid withdrawal. However, it would be of interest to determine in future trials if ibudilast is able to improve ease of withdrawal during a forced opioid down-titration when incorporated into an MOH detoxification program.
Assuntos
Transtornos da Cefaleia Secundários/tratamento farmacológico , Piridinas/uso terapêutico , Vasodilatadores/uso terapêutico , Adulto , Área Sob a Curva , Método Duplo-Cego , Feminino , Humanos , Hiperalgesia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neuroglia/efeitos dos fármacos , Projetos Piloto , Curva ROCRESUMO
Neuroinflammatory signaling pathways in the central nervous system are of current interest as potential pharmacotherapy targets for alcohol dependence. In this study, we examined the ability of ibudilast, a non-selective phosphodiesterase inhibitor, to reduce alcohol drinking and relapse in alcohol-preferring P rats, high-alcohol drinking HAD1 rats, and in mice made dependent on alcohol through cycles of alcohol vapor exposure. When administered twice daily, ibudilast reduced alcohol drinking in rats by approximately 50% and reduced drinking by alcohol-dependent mice at doses which had no effect in non-dependent mice. These findings support the viability of ibudilast as a possible treatment for alcohol dependence.
Assuntos
Consumo de Bebidas Alcoólicas , Alcoolismo , Comportamento Animal/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Piridinas/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , RatosRESUMO
BACKGROUND: Many patients with chronic cerebrovascular diseases suffer dizziness. Our earlier findings suggested that prolonged terms of dizziness episodes may decrease the regional cerebral blood flow (CBF) in the occipital visual cortex via a remote effect from the vestibular cortex. METHODS: We studied 9 patients who suffered episodes of dizziness since the onset of chronic cerebral ischemia. Their at-rest CBF was measured at entry into the study and approximately 3 months after the start of ibudilast therapy when all patients reported the resolution of dizziness. RESULTS: After 3 months of ibudilast their at-rest CBF was significantly increased in the left occipital lobe (P = .02). CBF after acetazolamide (ACZ) loading was significantly increased in the bilateral occipital lobes (right, P = .049; left, P = .02) and in the bilateral parieto-insular vestibular cortex (PIVC; right and left, P = .02). There were no significant CBF changes in any other areas. CONCLUSIONS: Our findings indicate that the occipital cortex and PIVC were implicated in their dizziness after cerebral ischemia. We discuss the underlying mechanism(s) and the relationship between dizziness and reciprocal inhibitory visual-vestibular interactions.