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1.
Mod Rheumatol ; 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38780239

RESUMEN

OBJECTIVES: To assess the efficacy of golimumab (GLM) in patients with poor prognostic factors (PPFs). METHODS: This is a post-hoc analysis of GO-FORTH phase 2/3 study. Cluster analysis was used to determine a patient population with high-risk patterns based on seven PPFs suggested by EULAR recommendations and limited physical function. Radiographic progression, disease activity, and physical function and associated factors were evaluated over 52 weeks. RESULTS: Overall, 261 RA patients were classified into three clusters characterised by high disease activity, high CRP levels, and limited physical function at baseline. GLM showed suppression of progressive modified total sharp score (mTSS) and decreases in Disease Activity Score 28‒joint counts with erythrocyte sedimentation rate and Health Assessment Questionnaire‒Disease Index, in all the clusters. In cluster C that showed almost all the PPF-characteristics, a higher rate of ΔmTSS≤0 was observed in GLM 100 mg group than in GLM 50 mg group (63.9% vs 46.5%). CRP concentration and physical limitation were associated with radiographic progression of cluster C in GLM treatment. CONCLUSIONS: GLM was effective in RA patients in a subpopulation at high risk of PPF in GO-FORTH study. A dose of 100 mg may be more beneficial in preventing radiographic progression in this population. Short title: Impact of poor prognostic factors on GLM efficacy.

2.
J Gastroenterol Hepatol ; 36(11): 3069-3076, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34180096

RESUMEN

BACKGROUND AND AIM: Ustekinumab, a human anti-interleukin-12/23 monoclonal antibody, has been approved in Japan for the treatment of Crohn's disease. Here, we report the findings from an 8-week interim analysis of post-marketing surveillance to evaluate the safety and effectiveness of ustekinumab in Japanese patients with Crohn's disease. METHODS: Patients initiating ustekinumab treatment were prospectively evaluated from May 2017 to June 2020 at 91 medical centers in Japan. Adverse drug reactions (ADRs) and serious ADRs (SADRs) were monitored. Effectiveness was evaluated by clinical response, clinical remission, and changes in Crohn's Disease Activity Index (CDAI) and C-reactive protein (CRP) from baseline to week 8. Presence of perianal disease was documented at baseline and week 8. RESULTS: In total, 341 patients were enrolled in the study, of which 339 were included in the safety analysis while 334 were included in the effectiveness analysis. The overall incidences of ADRs and SADRs were 5.3% and 2.1%, respectively. Worsening of Crohn's disease was the most common event. The clinical response and clinical remission rate at week 8 were 40.0% and 48.5%, respectively. Significant improvements in CDAI and serum CRP (P < 0.001) were observed at week 8. CDAI decreased significantly (mean difference: -31.4; 95% confidence interval: -61.1, -1.7; P = 0.038) in biologics-naïve patients versus patients who had received two or more biologics. CONCLUSIONS: This 8-week interim analysis of the real-world study confirmed the effectiveness of ustekinumab-based therapy in Japanese patients with Crohn's disease. No new safety concerns were found during 8-week induction period in the Japanese clinical settings.


Asunto(s)
Productos Biológicos , Enfermedad de Crohn , Ustekinumab , Adulto , Productos Biológicos/efectos adversos , Productos Biológicos/uso terapéutico , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/epidemiología , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Vigilancia de Productos Comercializados , Inducción de Remisión , Resultado del Tratamiento , Ustekinumab/efectos adversos , Ustekinumab/uso terapéutico , Adulto Joven
3.
Bioorg Med Chem ; 27(15): 3339-3346, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31204225

RESUMEN

The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(-)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(-)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(-)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(-)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Bencilatos/farmacología , Broncodilatadores/farmacología , Piperidinas/farmacología , Enfisema Pulmonar/tratamiento farmacológico , Receptor Muscarínico M3/antagonistas & inhibidores , Administración por Inhalación , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Bencilatos/administración & dosificación , Bencilatos/química , Broncodilatadores/administración & dosificación , Broncodilatadores/química , Relación Dosis-Respuesta a Droga , Ratones , Estructura Molecular , Elastasa Pancreática/metabolismo , Piperidinas/administración & dosificación , Piperidinas/química , Enfisema Pulmonar/metabolismo , Receptor Muscarínico M3/metabolismo , Relación Estructura-Actividad , Porcinos
4.
Biochem Biophys Res Commun ; 472(1): 125-30, 2016 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-26915803

RESUMEN

Functional dyspepsia (FD), a functional gastrointestinal disorder, is characterized by persistent or recurrent postprandial upper abdominal discomfort and epigastric pain. The high prevalence of FD and associated healthcare costs suggests that treatment of this condition by methods other than prescribed medicines, such as natural products, could be beneficial. Delayed gastric emptying and impaired gastric accommodation play important roles in the development of FD. Anethole (1-methoxy-4-((E)-propenyl)-benzene), a major component of essential fennel oil, has been used as a flavoring, in alcoholic beverage production and in pharmaceutical formulations for many years. In this study, we examined the effects of anethole on delayed gastric emptying and impaired gastric accommodation in rodents. Oral administration of anethole improved clonidine-induced delayed gastric emptying but did not affect normal gastric emptying in mice. Fennel oil and Anchu-san (a Japanese herbal medicine containing anethole) also restored delayed gastric emptying. Furthermore, oral administration of anethole stimulated gastric accommodation in rats. These results suggest that anethole could be beneficial for the treatment of FD.


Asunto(s)
Anisoles/farmacología , Dispepsia/tratamiento farmacológico , Vaciamiento Gástrico/efectos de los fármacos , Gastroparesia/tratamiento farmacológico , Acetilcolinesterasa/metabolismo , Administración Oral , Derivados de Alilbenceno , Animales , Anisoles/administración & dosificación , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/farmacología , Modelos Animales de Enfermedad , Dispepsia/fisiopatología , Vaciamiento Gástrico/fisiología , Gastroparesia/fisiopatología , Masculino , Ratones , Ratones Endogámicos ICR , Ratas , Ratas Sprague-Dawley
5.
Biochem Biophys Res Commun ; 469(4): 873-7, 2016 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-26721432

RESUMEN

In the stress response, activation of the hypothalamic-pituitary-adrenal axis, and particularly the release of glucocorticoids, plays a critical role. However, dysregulation of this system and sustained high plasma levels of glucocorticoids can result in depression. Recent studies have suggested the involvement of reactive oxygen species (ROS), such as superoxide anion, in depression. However, direct evidence for a role of ROS in the pathogenesis of this disorder is lacking. In this study, using transgenic mice expressing human Cu/Zn-superoxide dismutase (SOD1), an enzyme that catalyzes the dismutation of superoxide anions, we examined the effect of SOD1 overexpression on depressive-like behavioral phenotypes in mice. Depressive-like behaviors were induced by daily subcutaneous administration of the glucocorticoid corticosterone for 4 weeks, and was monitored with the social interaction test, the sucrose preference test and the forced swim test. These tests revealed that transgenic mice overexpressing SOD1 are more resistant to glucocorticoid-induced depressive-like behavioral disorders than wild-type animals. Furthermore, compared with wild-type mice, transgenic mice showed a reduction in the number of 8-hydroxy-2'-deoxyguanosine (a marker of oxidative stress)-positive cells in the hippocampal CA3 region following corticosterone administration. These results suggest that overexpression of SOD1 protects mice against glucocorticoid-induced depressive-like behaviors by decreasing cellular ROS levels.


Asunto(s)
Trastorno Depresivo/metabolismo , Trastorno Depresivo/prevención & control , Trastornos Mentales/metabolismo , Trastornos Mentales/prevención & control , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Animales , Conducta Animal , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Trastorno Depresivo/inducido químicamente , Glucocorticoides , Masculino , Trastornos Mentales/inducido químicamente , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Estrés Oxidativo/efectos de los fármacos , Fenotipo , Regulación hacia Arriba
6.
J Pharmacol Exp Ther ; 350(1): 79-88, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24769542

RESUMEN

Idiopathic pulmonary fibrosis is thought to involve lung injury caused by reactive oxygen species (ROS), which in turn is followed by abnormal fibrosis. A transforming growth factor (TGF)-ß1-induced increase in myofibroblast number plays an important role in this abnormal fibrosis. We recently found that mepenzolate bromide (mepenzolate), which has been used clinically to treat gastrointestinal disorders, has ROS-reducing properties. In the present study, we examined the effect of mepenzolate on bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. The severity of pulmonary fibrosis was assessed by histopathologic evaluation and determination of hydroxyproline levels. Lung mechanics (elastance) and respiratory function [forced vital capacity (FVC)] were assessed using a computer-controlled ventilator. Respiratory function was also evaluated by monitoring percutaneous arterial oxygen saturation (SpO2). Intratracheal administration of mepenzolate prior to bleomycin treatment reduced the extent of pulmonary fibrosis and changes in lung mechanics and led to a significant recovery of both FVC and SpO2 compared with control. Furthermore, mepenzolate produced a therapeutic effect even when it was administered after the development of fibrosis. Administration of mepenzolate also prevented bleomycin-induced pulmonary cell death and inflammatory responses and increased myofibroblast number. Mepenzolate also decreased NADPH oxidase activity and active TGF-ß1 level or increased glutathione S-transferase (GST) activity in the presence of bleomycin treatment. These results show that the intratracheal administration of mepenzolate reduced bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. These effects may be due to this drug's inhibitory effect on NADPH oxidase and TGF-ß1 activities and its stimulatory effect on GST.


Asunto(s)
Bencilatos/uso terapéutico , Piperidinas/uso terapéutico , Fibrosis Pulmonar/tratamiento farmacológico , Animales , Bencilatos/farmacología , Bleomicina , Líquido del Lavado Bronquioalveolar/citología , Recuento de Células , Muerte Celular/efectos de los fármacos , Glutatión Transferasa/metabolismo , Hidroxiprolina/metabolismo , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Rendimiento Pulmonar/efectos de los fármacos , Masculino , Ratones , Miofibroblastos/efectos de los fármacos , NADPH Oxidasas/metabolismo , Oxígeno/sangre , Piperidinas/farmacología , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/complicaciones , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Factor de Crecimiento Transformador beta1/metabolismo , Capacidad Vital/efectos de los fármacos
7.
Bioorg Med Chem ; 22(13): 3488-97, 2014 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-24844758

RESUMEN

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist mepenzolate bromide (mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-mepenzolate) and to examine their biochemical and pharmacological activities. (R)- or (S)-mepenzolate was synthesized by condensation of benzilic acid with (R)- or (S)-alcohol, respectively, followed by quaternization of the tertiary amine. As predicted by computational simulation, a filter-binding assay in vitro revealed that (R)-mepenzolate showed a higher affinity for the muscarinic M3 receptor than (S)-mepenzolate. In vivo, the bronchodilatory activity of (R)-mepenzolate was superior to that of (S)-mepenzolate, whereas anti-inflammatory activity was indistinguishable between the two enantiomers. We confirmed that each mepenzolate maintained its original stereochemistry in the lung when administered intratracheally. These results suggest that (R)-mepenzolate may have superior properties to (S)-mepenzolate as a drug to treat COPD patients given that the former has more potent bronchodilatory activity than the latter.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Bencilatos/farmacología , Broncodilatadores/farmacología , Piperidinas/farmacología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptor Muscarínico M3/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Bencilatos/administración & dosificación , Bencilatos/química , Broncodilatadores/administración & dosificación , Broncodilatadores/química , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Modelos Moleculares , Simulación de Dinámica Molecular , Estructura Molecular , Piperidinas/administración & dosificación , Piperidinas/química , Estereoisomerismo , Relación Estructura-Actividad
8.
Crohns Colitis 360 ; 6(2): otae035, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38827168

RESUMEN

Background: Crohn's disease (CD) is an immune-mediated inflammatory disorder of the gastrointestinal tract with perianal disease being one of the challenging possible manifestations. Here, we report, an ad hoc analysis of the safety and effectiveness of 1-year use of ustekinumab (UST) for CD in patients with perianal manifestations using post-marketing surveillance (PMS) data in Japan. Methods: Among 341 patients enrolled in the PMS, 229 and 224 patients who had baseline Crohn's Disease Activity Index (CDAI) data used for evaluating perianal manifestations were included in the safety and efficacy analysis sets, respectively. Incidence of adverse drug reactions, clinical remission, the mean or its change in CDAI scores, and CDAI items were evaluated through week 52 in the presence or absence of perianal manifestations at baseline. The prevalence of perianal manifestations was also described. Results: Comparing patients with and without baseline perianal manifestations at week 52, there was no difference in ADR incidence (9.1% [n = 66] vs. 15.3% [n = 163]), no difference in clinical remission (68.3% vs. 59.9%; P = 0.269), and decreased mean change of CDAI score (-82.9 [n = 60] vs. -68.8 [n = 137]). The proportion of patients with perianal manifestations decreased after UST treatment in both biologics-naïve patients (23.5% [n = 4/17]) and patients who had received biologics (35.0% [n = 14/40]) at week 52. Conclusions: In Japanese clinical practice, UST is safe and effective in CD patients with and without perianal manifestations. The therapy might be also beneficial in those with manifestations regardless of prior use of other biologics.

9.
Drugs Real World Outcomes ; 11(2): 285-297, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38598110

RESUMEN

BACKGROUND: Reports on treatment patterns of biologic disease-modifying antirheumatic drugs (bDMARDs)/Janus kinase inhibitors (JAKi) for rheumatoid arthritis (RA) in clinical practice are still sparse in Japan, especially in combination with conventional synthetic DMARDs (csDMARDs). OBJECTIVES: The aim of this study was to investigate treatment patterns of bDMARD/JAKi in the treatment of RA in real-world clinical practice in Japan. METHOD: A retrospective cohort study was conducted using the Japanese Medical Data Vision health claims database. The inclusion criteria required a recorded diagnosis of RA, defined by ICD-10 codes, in patients aged 18 years and older on the index date. We analyzed 39,903 RA patients treated with DMARDs from 2008 to 2020. RESULTS: Among analyzed subjects, 10,196 patients (25.6%) were prescribed bDMARDs/JAKi in combination with csDMARDs, and 3067 patients (7.7%) were prescribed these drugs without csDMARDs. Among the bDMARDs/JAKi, tumor necrosis factor inhibitors (TNFi) were the most commonly prescribed DMARD overall, and also the most common first-line therapy, accounting for 60.0% or 45.5% of patients prescribed these drugs in combination with or without csDMARDs, respectively. Switching, temporary discontinuation (restarting with the same agents), and discontinuation of bDMARDs/JAKi were observed in 3150 (30.9%), 1379 (13.5%), and 2025 (19.9%) patients with csDMARDs, and in 849 (27.7%), 513 (16.7%), and 833 (27.2%) patients without csDMARDs, respectively. CONCLUSIONS: Real-world treatment trajectories of bDMARDs/JAKi with and without csDMARDs was analyzed in RA patients in Japan between 2008 and 2020. TNFi were the predominant first-line therapy, and likely to be switched to different classes. Understanding the current treatment patterns, including discontinuation, is important to find an optimal treatment strategy for RA patients.

10.
Inflamm Intest Dis ; 7(3-4): 128-138, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37064538

RESUMEN

Introduction: Real-world evidence for the effectiveness and safety of golimumab (GLM) in patients with ulcerative colitis (UC) is limited. The aim of this study was to investigate the 52-week effectiveness and safety of GLM treatment for UC. Methods: This prospective, multicentre, post-marketing surveillance study is conducted in 393 patients with UC in Japan (UMIN000027542). Clinical remission (partial Mayo score ≤2), adverse drug reactions (ADRs) and their predictors, and treatment persistence were analysed. Results: The safety analysis sets comprised 391 patients. Patients in clinical remission at baseline were excluded, and 336 were used for effectiveness analysis. Clinical remission was 47.9%, 48.5%, 44.6%, and 39.6% at weeks 6, 22, 36, and 52, respectively, in the intent-to-treat analysis. In biologic-naive patients, clinical remission was slightly higher than that in biologic-experienced patients. At week 52, patients who concomitantly used corticosteroids at baseline showed numerically lower clinical remission rates than non-users of corticosteroids (34.9% vs. 44.5%). Multivariate analysis showed that smoking history (p = 0.040, odds ratio [OR] = 1.911, 95% confidence interval [CI] 1.030-3.546) was an independent factor associated with clinical remission at week 52. ADRs occurred in 71 patients (18.2%) and included 9 cases of rash. Serious ADRs occurred in 40 patients (10.2%), including 8 cases of UC exacerbation. Additionally, the presence of comorbidities was associated with ADR incidence (p = 0.010, OR = 2.000, 95% CI: 1.183-3.380). Conclusion: The real-world effectiveness of GLM treatment was confirmed in biologic-naive and experienced populations. The safety profile of GLM treatment was consistent with previous findings.

11.
Crohns Colitis 360 ; 5(1): otad001, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36777365

RESUMEN

Background: To present the real-world evidence on the safety and effectiveness of ustekinumab (UST) through 52-week treatment for Crohn's disease (CD) under an analysis of post-market surveillance data in Japan. Methods: This prospective, post-marketing surveillance study was conducted in 341 patients from 91 medical facilities in Japan. Patients received UST 90 mg injected subcutaneously once every 12 weeks (or every 8 weeks if patients show weak effectiveness) after an induction dose given intravenously. Clinical response (100-point decrease in Crohn's Disease Activity Index [CDAI] score), clinical remission (CDAI score of <150), steroid-free clinical remission, C-reactive protein, endoscopy, physician global assessment, and adverse drug reactions (ADRs) were evaluated through 52 weeks. Results: The overall rate of clinical remission was 49.2% at week 8 and 56.0% at week 52. The rate of clinical remission in biologic-naive patients was 75.9% and 66.7% at weeks 8 and 52, respectively, whereas the rate in biologic-experienced patients was 41.4% and 52.6% at weeks 8 and 52, respectively. For 52 weeks, the overall incidence of ADRs and serious adverse drug reactions (SADRs) was 11.7% and 6.7%, respectively. The most frequently reported SADRs was worsening of CD (1.8%). In multivariate analysis, ADRs incidence was significantly lower in patients with ileal involvement of CD (odds ratio = 0.25, 95% CI 0.07-0.85, P = .026), although disease location has no association with effectiveness of UST. Conclusions: The present study identified no new safety concerns and effectiveness for CD in Japanese patients treated with UST.

12.
Biochem Biophys Res Commun ; 420(2): 444-9, 2012 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-22430139

RESUMEN

Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain associated with altered bowel habits. Since the prevalence of IBS is very high and thus, involves elevated health-care costs, treatment of this condition by methods other than prescribed medicines could be beneficial. ß-(1,3)-D-glucan with ß-(1,6) branches (ß-glucan) has been used as a nutritional supplement for many years. In this study, we examined the effect of ß-glucan on fecal pellet output and visceral pain response in animal models of IBS. Oral administration of ß-glucan suppressed the restraint stress- or drug-induced fecal pellet output. ß-Glucan also suppressed the visceral pain response to colorectal distension. These results suggest that ß-glucan could be beneficial for the treatment and prevention of IBS.


Asunto(s)
Colon/efectos de los fármacos , Colon/fisiopatología , Glucanos/administración & dosificación , Síndrome del Colon Irritable/tratamiento farmacológico , Síndrome del Colon Irritable/fisiopatología , Administración Oral , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL
13.
Intest Res ; 20(3): 329-341, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34333910

RESUMEN

BACKGROUND/AIMS: Golimumab (GLM) is an anti-tumor necrosis factor-α drug approved for treating moderate-to-severe active ulcerative colitis (UC). A 52-week post-marketing surveillance (PMS) was initiated to evaluate its safety and effectiveness in patients with UC in Japan. We present an interim report of the ongoing PMS. METHODS: Patients received 200 mg of subcutaneous GLM at week 0, 100 mg at week 2, and 100 mg 4 weekly thereafter. The safety analysis set included 392 patients with UC, and the effectiveness analysis set 387 patients. Safety and effectiveness were assessed at week 6. RESULTS: Adverse drug reactions (ADRs) were reported in 8.2% (32/392) and serious ADRs in 4.6% (18/392). The most frequent ADRs were infection and infestation (3.3%), with herpes zoster being the most common. ADRs were significantly higher in patients with concomitant corticosteroid use (odds ratio [OR], 3.45; 95% confidence interval [CI], 1.40-9.68). No significant difference in ADR incidence was observed between patients aged ≥65 and <65 years (OR, 1.23; 95% CI, 0.35-3.47). Six-week effectiveness of GLM was confirmed by a decrease in the partial Mayo score (-2.3; 95% CI, -2.6 to -2.1) and C-reactive protein levels (-0.64; 95% CI, -0.92 to -0.36), including in the biologics-experienced population. CONCLUSIONS: The safety and effectiveness of GLM at week 6 in a real-world setting were demonstrated in patients with UC in Japan. ADR patterns were consistent with previous reports with no new safety signals. Concomitant corticosteroid use may be associated with increased ADR incidence. The final results of the ongoing PMS are necessary for further evaluation.

14.
Sci Rep ; 10(1): 3555, 2020 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-32103051

RESUMEN

The adenosine A2B receptor is a critical protein in intestinal water secretion. In the present study, we screened compound libraries to identify inhibitors of the A2B receptor and evaluated their effect on adenosine-induced intestinal fluid secretion. The screening identified the dihydropyridine calcium antagonists nifedipine and nisoldipine. Their respective affinities for the A2B receptor (Ki value) were 886 and 1,399 nM. Nifedipine and nisoldipine, but not amlodipine or nitrendipine, inhibited both calcium mobilization and adenosine-induced cAMP accumulation in cell lines. Moreover, adenosine injection into the lumen significantly increased fluid volume in the colonic loop of wild-type mice but not A2B receptor-deficient mice. PSB-1115, a selective A2B receptor antagonist, and nifedipine prevented elevated adenosine-stimulated fluid secretion in mice. Our results may provide useful insights into the structure-activity relationship of dihydropyridines for A2B receptor. As colonic fluid secretion by adenosine seems to rely predominantly on the A2B receptor, nifedipine could be a therapeutic candidate for diarrhoea-related diseases.


Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Colon/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Nifedipino/farmacología , Receptor de Adenosina A2B/metabolismo , Adenosina/metabolismo , Antagonistas del Receptor de Adenosina A2/química , Animales , Bloqueadores de los Canales de Calcio/química , AMP Cíclico/metabolismo , Ratones , Estructura Molecular , Nifedipino/química
15.
J Pharmacol Exp Ther ; 330(2): 458-67, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19458285

RESUMEN

In line with improvements in diagnostic procedures to detect intestinal lesions, it has become clear that nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin induce lesions not only in the stomach but also in the small intestine. However, clinical protocols for the treatment of NSAID-induced lesions of the small intestine have not been established. It is known that heat shock proteins (HSPs), particularly HSP70, confer protection against various stressors, and more recently, the anti-inflammatory activity of HSP70 was revealed. In this study, we examined the effect of expression of HSP70 on indomethacin-induced lesions of the small intestine. The extent of indomethacin-induced lesions to the small intestine was reduced in transgenic mice expressing HSP70 compared with controls. Oral administration of indomethacin increased the expression of HSP70 in the small intestine. Administration of indomethacin also induced mucosal cell apoptosis and expression of proinflammatory cytokines in the small intestines of control mice, with both of these responses suppressed in the transgenic mice. Geranylgeranylacetone (GGA), a clinically used antiulcer drug, increased expression of HSP70 in the small intestine and suppressed indomethacin-induced lesions of the small intestines in wild-type mice. These results suggest that indomethacin-induced increase in HSP70 expression reduces the extent of lesions to the small intestine by suppressing mucosal cell apoptosis and inflammatory responses. The HSP-inducing activity of GGA seems to contribute to the protective effect of drug against the lesions. Based on these results, we propose that nontoxic HSP70-inducers, such as GGA, would be therapeutically beneficial for treating NSAID-induced lesions of the small intestine.


Asunto(s)
Proteínas HSP70 de Choque Térmico/fisiología , Indometacina/toxicidad , Úlcera Péptica/metabolismo , Úlcera Péptica/prevención & control , Animales , Proteínas HSP70 de Choque Térmico/biosíntesis , Proteínas HSP70 de Choque Térmico/genética , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Úlcera Péptica/patología
16.
Biochem J ; 413(3): 535-43, 2008 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-18393942

RESUMEN

In eukaryotes, ORC (origin recognition complex), a six-protein complex, is the most likely initiator of chromosomal DNA replication. ORC belongs to the AAA(+) (ATPases associated with a variety of cellular activities) family of proteins and has intrinsic ATPase activity derived from Orc1p, one of its subunits. To reveal the role of this ATPase activity in Saccharomyces cerevisiae (baker's yeast) ORC, we mutated the Orc1p sensor 1 and sensor 2 regions, which are important for ATPase activity in AAA(+) proteins. Plasmid-shuffling analysis revealed that Asn(600), Arg(694) and Arg(704) are essential for the function of Orc1p. In yeast cells, overexpression of Orc1R694Ep inhibited growth, caused inefficient loading of MCM (mini-chromosome maintenance complex of proteins) and slowed the progression of S phase. In vitro, purified ORC-1R [ORC with Orc1R694Ep (Orc1p Arg(694)-->Glu mutant)] has decreased ATPase activity in the presence or absence of origin DNA. However, other activities (ATP binding and origin DNA binding) were indistinguishable from those of wild-type ORC. The present study showed that Arg(694) of the Orc1p subunit is important for the ATPase activity of ORC and suggests that this ATPase activity is required for efficient MCM loading on to origin DNA and for progression of S phase.


Asunto(s)
Adenosina Trifosfatasas/metabolismo , Mutación , Complejo de Reconocimiento del Origen/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Arginina/genética , Arginina/metabolismo , Asparagina/genética , Asparagina/metabolismo , Ciclo Celular/genética , Inmunoprecipitación de Cromatina , Replicación del ADN/genética , ADN de Hongos/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Citometría de Flujo , Immunoblotting , Complejo de Reconocimiento del Origen/genética , Unión Proteica , Proteínas de Saccharomyces cerevisiae/genética
17.
Eur J Pharmacol ; 844: 253-258, 2019 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-30529473

RESUMEN

The use of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammatory pain is limited by gastrointestinal complications. The rapid action of NSAIDs is associated with better pain relief. Previously, we demonstrated that fluoro-loxoprofen, a novel NSAID, has less ulcerogenic potential than other NSAIDs, attributable to its gastroprotective properties. The aim of this study was to investigate and compare the effects of fluoro-loxoprofen on inflammatory pain in rats with those of other NSAIDs. Oral administration of fluoro-loxoprofen, loxoprofen, and celecoxib resulted in equivalent analgesic action against yeast-induced inflammatory pain. The antinociceptive effect of fluoro-loxoprofen was maximized within 1 h after administration, which is less time than that observed for loxoprofen (2 h) and celecoxib (3 h). We confirmed that both fluoro-loxoprofen and loxoprofen suppressed the increases in prostaglandin E2 in inflamed paws. In addition to yeast-induced pain, fluoro-loxoprofen produced a similar effect against adjuvant-induced inflammatory pain, with faster peak analgesic effects than those observed for loxoprofen and celecoxib. Taken together, these results suggest that the analgesic effect of fluoro-loxoprofen is equivalent to that of loxoprofen and celecoxib. Moreover, the analgesic effect of fluoro-loxoprofen against inflammatory pain was more rapid than that of other NSAIDs, and this may be associated with its rapid absorption property.


Asunto(s)
Dolor Agudo/tratamiento farmacológico , Analgésicos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Fenilpropionatos/uso terapéutico , Dolor Agudo/metabolismo , Animales , Dolor Crónico/metabolismo , Dinoprostona/metabolismo , Femenino , Pie , Masculino , Ratas Endogámicas Lew , Ratas Wistar
18.
Cell Death Discov ; 5: 146, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31754474

RESUMEN

Alveolar epithelial injury induced by reactive oxygen species (ROS) and abnormal collagen production by activated fibroblasts (myofibroblasts) is involved in the onset and exacerbation of idiopathic pulmonary fibrosis (IPF). Compared with alveolar epithelial cells, lung fibroblasts, especially myofibroblasts, exhibit an apoptosis-resistance phenotype (apoptosis paradox) that appears to be involved in IPF pathogenesis. Thus, we screened for chemicals eliciting preferential cytotoxicity of LL29 cells (lung fibroblasts from an IPF patient) compared with A549 cells (human lung alveolar epithelial cell line) from medicines already in clinical use. We identified idebenone, a synthetic analogue of coenzyme Q10 (CoQ10, an antioxidant) that has been used clinically as a brain metabolic stimulant. Idebenone induced cell growth inhibition and cell death in LL29 cells at a lower concentration than in A549 cells, a feature that was not observed for other antioxidant molecules (such as CoQ10) and two IPF drugs (pirfenidone and nintedanib). Administration of idebenone prevented bleomycin-induced pulmonary fibrosis and increased pulmonary ROS levels. Importantly, idebenone also improved pulmonary fibrosis and lung function when administered after the development of fibrosis, whereas administration of CoQ10 similarly prevented bleomycin-induced pulmonary fibrosis, but had no effect after its development. Administration of idebenone, but not CoQ10, suppressed bleomycin-induced increases in lung myofibroblasts. In vitro, treatment of LL29 cells with idebenone, but not CoQ10, suppressed TGF-ß-induced collagen production. These results suggest that in addition to antioxidant activity, idebenone exerts inhibitory activity on the function of lung fibroblasts, with the former activity being preventative and the latter therapeutic for bleomycin-induced fibrosis. Thus, we propose that idebenone may be more therapeutically beneficial for IPF patients than current treatments.

19.
J Biochem ; 143(4): 455-65, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18211918

RESUMEN

Origin recognition complex (ORC), a six-protein complex (Orc1p-Orc6p), may deeply involve in initiation of chromosomal DNA replication. However, since most temperature-sensitive orc mutants of Saccharomyces cerevisiae show the accumulation of cells with nearly 2C DNA content, the exact stage at which ORC acts is not fully understood. In this study, we constructed a heat-inducible degron mutant for each ORC subunit. As well as each targeted subunit, other subunits of ORC were also rapidly degraded under non-permissive conditions. In the orc5 degron mutant, incubation under the non-permissive conditions caused accumulation of cells with nearly 2C DNA content, and phosphorylation of Rad53p. When Orc5p (ORC) is depleted, this inhibits G1/S transition and formation of a pre-replicative complex (pre-RC). For pre-RC to form, and G1/S transition to proceed, Orc5p (ORC) must be present in late G1, rather than early G1, or G2/M. Block and release experiments revealed that Orc5p (ORC) is not necessary for S and G2/M phase progression. We therefore propose that ORC is necessary for the G1/S transition and pre-RC formation, and accumulation of cells with nearly 2C DNA content seen in various orc mutants is due to inefficient pre-RC formation, and/or induction of checkpoint systems.


Asunto(s)
Secuencias de Aminoácidos , Mutación , Complejo de Reconocimiento del Origen/metabolismo , Saccharomyces cerevisiae/metabolismo , Replicación del ADN , ADN de Hongos/biosíntesis , Complejo de Reconocimiento del Origen/fisiología , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/fisiología
20.
Front Pharmacol ; 9: 344, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29692733

RESUMEN

The standard treatment for chronic obstructive pulmonary disease is a combination of anti-inflammatory drugs and bronchodilators. We recently found that mepenzolate bromide (MP), an antagonist for human muscarinic M3 receptor (hM3R), has both anti-inflammatory and short-acting bronchodilatory activities. To obtain MP derivatives with longer-lasting bronchodilatory activity, we synthesized hybrid compounds based on MP and two other muscarinic antagonists with long-acting bronchodilatory activity glycopyrronium bromide (GC) and aclidinium bromide (AD). Of these three synthesized hybrid compounds (MP-GC, GC-MP, MP-AD) and MP, MP-AD showed the highest affinity for hM3R and had the longest lasting bronchodilatory activity, which was equivalent to that of GC and AD. Both MP-GC and MP-AD exhibited an anti-inflammatory effect equivalent to that of MP, whereas, in line with GC and AD, GC-MP did not show this effect. We also confirmed that administration of MP-AD suppressed elastase-induced pulmonary emphysema in a mouse model. These findings provide important information about the structure-activity relationship of MP for both bronchodilatory and anti-inflammatory activities.

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