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1.
Brain Nerve ; 71(11): 1270-1278, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722313

RESUMO

Disease-specific and site-selective deficiency of an RNA editing enzyme, adenosine deaminase acting on RNA 2 (ADAR2), has been demonstrated in sporadic amyotrophic lateral sclerosis (sALS) motor neurons. ADAR2 regulates Ca2+ influx through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors via adenosine-to-inosine conversion at the glutamine/arginine site of GluA2 mRNA, which makes ADAR2 a key factor in acquired Ca2+ resistance in motor neurons. Deficient ADAR2 of sALS motor neurons is supposed to lead to excessive Ca2+ influx through AMPA receptors, resulting in TDP-43 pathology and nuclear pore complex pathology, and eventually motor neuronal death. We considered that AMPA receptor antagonists could strongly prevent excessive Ca2+ influx through AMPA receptors and block motor neuronal degeneration in sALS. Perampanel, a selective non-competitive AMPA receptor antagonist, has been reported to prevent deterioration in a mouse model for sALS, in which ADAR2 is conditionally knocked out in motor neurons. Because of the therapeutic potency of perampanel for sporadic ALS, we have performed a multicenter randomized, double-blinded, placebo-controlled, parallel-group phase 2 clinical trial. The primary outcome measure is the change in ALS functional rating scale-revised after 48 weeks of treatment. The results of this study will be available in early 2020.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Piridonas/uso terapêutico , Humanos , Neurônios Motores/patologia
2.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(9): 700-704, 2019 Sep 12.
Artigo em Chinês | MEDLINE | ID: mdl-31484245

RESUMO

Objective: To explore the effect of pirfenidone in fibrotic interstitial pneumonia with autoimmune features (IPAF) after treatment with corticosteroids and immunosuppressants. Methods: We conducted a retrospective analysis of 2 adult patients with IPAF in the Peking Union Medical College Hospital. As their fibrotic interstitial lung disease failed to improve with further treatment with corticosteroids and immunosuppressants, they were treated with pirfenidone based on corticosteroids and immunosuppressants. Their clinical, chest radiological data and prognosis were collected and relevant literatures were reviewed. Results: One patient was a 43 year old female, the other was a 53 year old male. IPAF was diagnosed with their classic clinical, serological and radiological features. They were partially responded to corticosteroids and immunosuppressants at the initial period. Pirfenidone was suggested for them as their lung fibrosis was not improved further with immunosuppressive therapy. After 4-5 months treatment with pirfenidone, based on corticosteroids and immunosuppressant administration, their clinical and radiological manifestations improved significantly. Conclusions: Pirfenidone might be a good add-on choice for fibrotic IPAF when the disease did not respond well to corticosteroids and immunosuppressants.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças Autoimunes/diagnóstico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Piridonas/uso terapêutico , Corticosteroides/uso terapêutico , Adulto , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
4.
Medicine (Baltimore) ; 98(30): e16325, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348231

RESUMO

INTRODUCTION: The morbidity of idiopathic pulmonary fibrosis (IPF) was found in an increasing trend, progressive worsening of symptoms and deterioration in lung function tend to trigger off a lower quality of life (QoL). Only pirfenidone and nintedanib have been recommended in the guidelines, which can modify the disease process. However, no evidence was verified to significantly alleviate the main clinical manifestations of IPF. At present, Chinese herbal formula (CHF) is widely prescribed as an adjunct to western medicine to treat the disease, and have shown promising benefits on clinical symptoms and QoL. There are mainly 3 Traditional Chinese Medicine (TCM) treatment methods guiding the composition of CHFs, which are devoting to comfort the common symptoms of IPF. Nevertheless, the paucity of direct comparative evidence of them posed a challenge for clinicians to determine the relative merits options. Therefore, we formulate this protocol, which is described for a systematic review to investigate relative advantages among different TCM treatment method and provide more reliable evidence for clinical decision-making. METHODS AND ANALYSIS: A systematic literature search will be employed in 10 electronic databases. Inclusion criteria are randomized control trials of CHFs composed based on the 3 TCM treatment methods, which act as an adjuvant treatment with routine drugs, compared with routine drugs alone. The primary outcomes we focus on include St George's Hospital Respiratory Questionnaire (SGRQ) scores, TCM symptom (dyspnea, cough) scores. The research screening, data extraction, and methodological quality assessment will be conducted by 2 individuals separately, and dispute will be adjudicated by a third senior reviewer. We will employ network meta-analysis (NMA) in a Bayesian framework with vague priors and the surface under the cumulative ranking curve (SUCRA) to obtain the comprehensive rank for the 3 TCM treatment methods. RESULTS: This systematic review will provide an evidence of CHFs composed under the guidance by 3 TCM treatment methods with routine drugs, compared with routine drugs alone for IPF, and will submit to a peer-reviewed journal for publication. CONCLUSION: The conclusion of this systematic review will provide evidence for relative advantages among the 3 TCM treatment methods.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Medicina Tradicional Chinesa/métodos , Projetos de Pesquisa , Acetilcisteína/uso terapêutico , Anti-Inflamatórios não Esteroides/administração & dosagem , Teorema de Bayes , Quimioterapia Combinada , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Indóis/uso terapêutico , Meta-Análise em Rede , Piridonas/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Testes de Função Respiratória , Índice de Gravidade de Doença , Análise de Sobrevida
5.
Expert Opin Pharmacother ; 20(14): 1755-1765, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31264486

RESUMO

Introduction: Antiseizure drugs (ASDs) play a central and crucial role in the treatment of epilepsy patients, as the majority require anticonvulsant treatment for an extended period of time. Since up to 30% of patients are refractory to medical treatment, new therapeutic options are necessary. Perampanel (PER) and brivaracetam (BRV) are the latest approved ASDs that may be considered in a variety of epilepsy syndromes. PER has a distinct and selective mode of action on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and is licensed for use in focal and generalized epilepsies. BRV is a derivative of levetiracetam but exhibits a 20-fold higher affinity and a faster brain entry time as a synaptic vesicle glycoprotein 2A (SV2A) ligand. Areas covered: This article reviews the advances in the epileptic treatment and provides a comparison of PER and BRV. Both drugs have shown comparable results in randomized controlled trials, and both are well tolerated. Expert opinion: PER and BRV have the potential to perform as important, broad-spectrum ASDs with significant market shares. BRV's intravenous formulation and fast penetration into the brain and PER's unique mode of action will result in the more frequent use of both drugs in status epilepticus.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Piridonas/uso terapêutico , Pirrolidinonas/uso terapêutico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Ensaios Clínicos como Assunto , Epilepsia/patologia , Meia-Vida , Humanos , Piridonas/efeitos adversos , Piridonas/farmacocinética , Pirrolidinonas/efeitos adversos , Pirrolidinonas/farmacocinética , Receptores de AMPA/química , Receptores de AMPA/metabolismo , Estado Epiléptico/tratamento farmacológico , Resultado do Tratamento
6.
Nat Med ; 25(7): 1116-1122, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31263281

RESUMO

The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations1. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation2. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patient's lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.


Assuntos
Anormalidades Linfáticas/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Proteínas Proto-Oncogênicas A-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Adulto , Animais , Criança , Feminino , Células HEK293 , Humanos , Anormalidades Linfáticas/tratamento farmacológico , Masculino , Sequenciamento Completo do Exoma , Peixe-Zebra
7.
Expert Opin Ther Pat ; 29(7): 497-507, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31242055

RESUMO

INTRODUCTION: Positive allosteric modulation of mGlu2 has attracted much interest as an alternative approach to classical orthosteric receptor activation. Two mGlu2 PAMS have advanced into the clinic. The results obtained in schizophrenia and MDD phase 2 clinical trials have tempered the high expectations put on selective mGlu2 receptor activation for treating these conditions; nevertheless, the search for novel therapeutic indications and novel chemotypes continues to be an active field of research. AREAS COVERED: 2013-2018 patent literature on mGlu2 receptor PAMs. EXPERT OPINION: After a decade of intensive research, the mGlu2 PAM field has seen a deceleration in the last five years. Negative phase 2 schizophrenia clinical trials with JNJ-40411813 and AZD8529 seem to have tempered the high expectations of the scientific community on the utility of mGlu2 PAMs for the treatment of schizophrenia. Nevertheless, novel therapeutic indications continue to be explored and AZD8529 is currently in a phase 2 study for smoking cessation. The advances in medicinal chemistry and in pharmacology, with novel indications such as epilepsy, have set the stage in the field of mGlu2 receptor PAMs. Ongoing preclinical and clinical studies will contribute to define their optimal therapeutic indication and potential to become novel therapeutic agents.


Assuntos
Indóis/uso terapêutico , Oxidiazóis/uso terapêutico , Piperidinas/uso terapêutico , Piridonas/uso terapêutico , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Humanos , Indóis/farmacologia , Oxidiazóis/farmacologia , Patentes como Assunto , Piperidinas/farmacologia , Piridonas/farmacologia , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia
8.
Lancet Haematol ; 6(7): e359-e365, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31133411

RESUMO

BACKGROUND: Because studies of direct oral anticoagulants in patients with venous thromboembolism and non-valvular atrial fibrillation have had minimal representation of morbidly obese patients (ie, body-mass index [BMI] ≥40 kg/m2), their efficacy and safety in this population are unclear. We investigated whether apixaban and rivaroxaban are as effective and safe as warfarin in morbidly obese patients. METHODS: We did a single-centre, retrospective analysis of chart data for all adult patients aged at least 18 years at Montefiore Medical Center (Bronx, NY, USA) with a BMI of at least 40 kg/m2 who were prescribed apixaban, rivaroxaban, or warfarin for either venous thromboembolism or atrial fibrillation between March 1, 2013, and March 1, 2017. Patients who had both venous thromboembolism and atrial fibrillation were excluded, as were patients with indications other than atrial fibrillation and venous thromboembolism. Outcomes of recurrent venous thromboembolism, stroke, and bleeding were measured from the first prescription date to the earliest of a thrombotic event, medication discontinuation, death, or end of study on June 30, 2017. Analyses were stratified by anticoagulation indication and adjusted for comorbidities, CHA2DS2-VASc score, and age where appropriate. Outcome rates were compared using Pearson's χ2 or Fisher's exact test. Time-to-event analyses accounting for length of follow-up were used to compare risks of outcomes. FINDINGS: We obtained data for 795 patients: 150 prescribed apixaban, 326 rivaroxaban, and 319 warfarin. In 366 patients prescribed an anticoagulant for venous thromboembolism, the incidence of recurrent venous thromboembolism was similar between the apixaban, rivaroxaban, and warfarin cohorts (1/47 [2·1%, 95% CI 0·0-6·3], 3/152 [2·0%, 0·0-4·2], and 2/167 [1·2%, 0·0-2·9], respectively; p=0·74). Incidence of major bleeding in this patient group was also similar between the treatment cohorts (1/47 patients on apixaban [2·1%, 95% CI 0·0-6·3], 2/152 on rivaroxaban [1·3%, 0·0-3·1], and 4/167 on warfarin [2·4%, 0·1-4·7]; p=0·77). In 429 patients prescribed an anticoagulant for atrial fibrillation, incidence of stroke was similar between the treatment cohorts (1/103 patients on apixaban [1·0%, 95% CI 0·0-2·9], 4/174 on rivaroxaban [2·3%, 0·1-4·5], and 2/152 on warfarin [1·3%, 0·0-3·1], p=0·71). In this patient group, major bleeding occurred in 3/103 patients on apixaban (2·9%, 95% CI 0·0-6·2), 5/174 on rivaroxaban (2·9%, 0·4-5·4), and 12/152 on warfarin (7·9%, 3·6-12·2); p=0·063. Time-to-event analyses showed that risk of all outcomes in patients with venous thromboembolism, and stroke and composite bleeding in patients with atrial fibrillation, were similar between the anticoagulant cohorts. INTERPRETATION: Our retrospective study provides further evidence of similar efficacy and safety between the direct oral anticoagulants apixaban and rivaroxaban, and warfarin in morbidly obese patients with atrial fibrillation and venous thromboembolism. These data, if confirmed in prospective studies, might enable patients with a BMI of at least 40 kg/m2 to benefit from more convenient, and possibly safer, anticoagulants. FUNDING: None.


Assuntos
Anticoagulantes/uso terapêutico , Inibidores do Fator Xa/uso terapêutico , Obesidade Mórbida/tratamento farmacológico , Varfarina/uso terapêutico , Adulto , Idoso , Anticoagulantes/efeitos adversos , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Índice de Massa Corporal , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/epidemiologia , Hemorragia/etiologia , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/patologia , Modelos de Riscos Proporcionais , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Piridonas/efeitos adversos , Piridonas/uso terapêutico , Recidiva , Estudos Retrospectivos , Rivaroxabana/efeitos adversos , Rivaroxabana/uso terapêutico , Tromboembolia Venosa/complicações , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/epidemiologia , Varfarina/efeitos adversos
9.
Nat Commun ; 10(1): 2005, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043606

RESUMO

A long-acting injectable formulation of the HIV integrase inhibitor cabotegravir (CAB-LA) is currently in clinical development for PrEP. Although the long plasma half-life of CAB-LA is an important attribute for PrEP, it also raises concerns about drug resistance emergence if someone becomes infected with HIV, or if PrEP is initiated during undiagnosed acute infection. Here we use a macaque model of SHIV infection to model risks of drug resistance to CAB-LA PrEP. Six macaques infected with SHIV received CAB-LA before seroconversion. We show integrase mutations G118R, E92G/Q, or G140R in plasma from 3/6 macaques as early as day 57, and identify G118R and E92Q in viruses from vaginal and rectal fluids. G118R and G140R confer > 800-fold resistance to CAB and cross-resistance to all licensed integrase inhibitors. Our results emphasize the need for appropriate HIV testing strategies before and possibly shortly after initiating CAB LA PrEP to exclude acute infection.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/prevenção & controle , Inibidores de Integrase de HIV/farmacologia , Profilaxia Pré-Exposição/métodos , Piridonas/farmacologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Doença Aguda , Animais , Modelos Animais de Doenças , Farmacorresistência Viral/efeitos dos fármacos , Feminino , Células HEK293 , Infecções por HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , Integrase de HIV/genética , Inibidores de Integrase de HIV/sangue , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , HIV-1/genética , Meia-Vida , Humanos , Macaca , Masculino , Piridonas/sangue , Piridonas/uso terapêutico , Soroconversão , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/imunologia , Fatores de Tempo
10.
Int J Nanomedicine ; 14: 2927-2944, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118614

RESUMO

Background: Liver fibrosis is a chronic liver disease associated with an excessive accumulation of extracellualr matrix (ECM) proteins which ultimately lead to cirrohosis and hepatocellular carcinoma. Purpose: Liver fibrosis therapies that use combination approaches with the ability to affect multiple disease pathways have proven higher efficacies. This study aimed at optimizing and characterizing the co-encapsulation of pirfenidone (PF) and AMD3100 (AMD) into CXCR4-targeted combination liposomes (CTC liposome) for CXCR4 targeting, and the inhibition of major molecular culprits ie α-SMA, CXCR4, TGFß, and P-p38 involved in liver fibrosis in-vitro. Methods: The CTC liposomes were prepared using the thin-film hydration method. The concentration of encapsulated AMD and PF was measured by HPLC and UV spectrophotometry, respectively. Tramsmission electron microscopy (TEM) was used to determine the liposomal morphology. The CXCR4 targeting ability was determined by CXCR4 redistribution assay. Confocal microscopy and flowcytometry were used to determine the CXCR4 mediated cell uptake. The apoptosis inducing and protein downreguating ability of CTC liposomes were determined by apoptosis assay and western blot analysis, respectively. In-vivo biodistribution and Hoechst staining were used to confirm the feasibility of CTC liposome for the in-vivo applications and drug targeted accumulation, respectively. Results: The TEM studies revealed that CTC liposomes were spherical in shape. The cumulative release of AMD and PF from CTC liposome was 67% and 84%, respectively, at 48 h. Compared to the free drug counterparts, encapsulated drugs displayed higher cell viability. The CXCR4 redistribution assay confirmed the CXCR4 targeting and antagonistic ability of CTC liposomes. The CTC liposomes were internalized more effectively via caveolae-mediated endocytic pathways. CTC liposomes displayed aggressive apoptosis (87.3%) in TGFß-induced activated HSC-T6 cells suggesting a propensity to fibrosis regression. Also, CTC liposomes significantly reduced α-SMA (65%), CXCR4 (77%), TGFß (89%), and P-p38 (66%) expressions, better than free drugs. CTC@IR780 liposomes (CTC liposomes incorporating IR780 dye) were more accumulated in fibrotic livers compared to free IR780, as judged by in-vivo imaging, biodistribution analysis, and Hoechst staining. These findings suggest that this simple and stable CTC liposomal system holds a great promise for the treatment and prevention of liver fibrosis.


Assuntos
Sistemas de Liberação de Medicamentos , Células Estreladas do Fígado/patologia , Compostos Heterocíclicos/administração & dosagem , Cirrose Hepática/tratamento farmacológico , Piridonas/administração & dosagem , Receptores CXCR4/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Lipossomos , Camundongos , Piridonas/farmacologia , Piridonas/uso terapêutico , Ratos , Receptores CXCR4/antagonistas & inibidores , Transdução de Sinais , Distribuição Tecidual/efeitos dos fármacos , Fator de Crescimento Transformador beta , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Int J STD AIDS ; 30(7): 718-722, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30975070

RESUMO

The potential for drug-drug interactions (DDIs) between direct oral anticoagulants and antiretroviral therapy (ART) is vast. Ritonavir and cobicistat are used as pharmacokinetic enhancers with either concurrent protease inhibitors or the integrase strand transfer inhibitor, elvitegravir, to optimize therapeutic concentrations by cytochrome P450 (CYP) inhibition. To date, only rivaroxaban and dabigatran have reported cases of use with ritonavir-boosted ART. Apixaban is metabolized similarly to rivaroxaban, but offers a dose reduction in the case of major DDIs. We report the successful use of reduced-dose apixaban to treat and prevent thromboembolic complications in six persons living with human immunodeficiency virus (HIV) on ritonavir- or cobicistat-boosted ART. This case series and available literature support the use of apixaban or dabigatran, depending on the boosted ART regimen.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Cobicistat/uso terapêutico , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Ritonavir/uso terapêutico , Tromboembolia/tratamento farmacológico , Idoso , Interações de Medicamentos , Inibidores do Fator Xa , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Tromboembolia/prevenção & controle , Resultado do Tratamento
12.
BMC Musculoskelet Disord ; 20(1): 135, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30927912

RESUMO

BACKGROUND: Dupuytren's disease (DD) is a progressive, debilitating condition of the hand that can eventually cause contractures of the affected fingers. Transforming growth factor- ß1 (TGF-ß1) has been reported to play a key role in DD pathology. Increased expression of TGF-ß1 has shown to be the main stimulator of myofibroblast activity and in DD contractures. Pirfenidone (PFD), a small active molecule possess the ability to inhibit TGF-ß1-mediated action in various fibrotic disorders. Our recent published findings show that PFD reduced TGF-ß1-mediated cellular functions implicated in DD through SMAD signaling pathways. In the present study, the effect of PFD on TGF-ß1-mediated non-SMAD signaling pathways were investigated in both carpal tunnel (CT) - and DD-derived fibroblasts. METHODS: Fibroblasts harvested from Dupuytren's disease (DD) and carpal tunnel (CT) tissues were cultured in the presence or absence of TGF-ß1 (10 ng/ml) and/or PFD (800 µg/ml). Cell lysates were analyzed using Western blots. Equal amounts of proteins were loaded to determine the phosphorylation levels of phosphatidylinositol-3 kinase (PI3K/AKT), extracellular regulated kinases (ERK1/2), p38 mitogen-activated protein kinase and Rho family related myosin light chain (MLC). RESULTS: We show that the TGF-ß1-induced phosphorylation of AKT was significantly decreased by the addition of PFD (800 µg/mL) in both CT- and DD-derived fibroblasts. Interestingly, there was no significant difference in the phosphorylation levels of both ERK and p38 on TGF-ß1- induced cells in both CT-and DD-derived fibroblasts. But, PFD significantly decreased the TGF- ß1-induced phosphorylation levels of ERK1/2 in both CT- and DD- cells. In contrast, PFD significantly decreased the basal and TGF- ß1-induced phosphorylation levels of p38 in DD-derived fibroblasts. TGF- ß1-induced phosphorylation levels of MLC was decreased by PFD in DD-derived fibroblasts. CONCLUSIONS: These in-vitro results indicate for the first time that PFD has the potential to inhibit TGF-ß1-induced non-SMAD signaling pathways in both CT- and DD-derived fibroblasts but pronounced statistically significant inhibition on all molecules was observed only in DD-derived fibroblasts. Our previous studies show that PFD can inhibit TGF-ß1- induced SMAD signaling pathway proteins, namely p- SMAD2/SMAD3. These broad and complementary actions suggest PFD as a promising candidate to inhibit the TGF-ß1- mediated molecular mechanisms leading to DD fibrosis.


Assuntos
Contratura de Dupuytren/tratamento farmacológico , Fibroblastos/efeitos dos fármacos , Piridonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Síndrome do Túnel Carpal/patologia , Células Cultivadas , Contratura de Dupuytren/patologia , Contratura de Dupuytren/cirurgia , Fáscia/citologia , Fibroblastos/metabolismo , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridonas/uso terapêutico , Fator de Crescimento Transformador beta1/antagonistas & inibidores
13.
Medicine (Baltimore) ; 98(17): e15407, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31027140

RESUMO

BACKGROUND: This study will systematically assess the efficacy and safety of pirfenidone for the treatment of patients with pulmonary fibrosis (PF). METHODS: We will search potential records from following literature sources from their inceptions to the present without language, and publication status limitations: Cochrane Library, EMBASE, PUBMED, the Cumulative Index to Nursing and Allied Health Literature, the Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. In addition, we also search grey literature sources, such as dissertations, conference proceedings, as well as the reference lists of included studies. All randomized controlled trials related to the pirfenidone for treating PF will be included. All the process of study selection, data extraction, and methodological evaluation will be carried out by 2 authors independently. The primary outcome comprises of all-cause-mortality, and lung function status, as measured by forced vital capacity. The secondary outcomes consist of 6-minute walk distance, progression-free survival, dyspnea, acute exacerbation, quality of life, and adverse events. Whenever possible, all results data will be pooled and meta-analysis will be performed. RESULTS: This study will systematically assess the efficacy and safety of pirfenidone for the treatment of patients with PF. CONCLUSION: The findings of the present study will summarize most recent evidence of pirfenidone for PF. ETHICS AND DISSEMINATION: No individual data will be analyzed in this study, thus, no research ethics approval is required in this study. The findings of this study are expected to be disseminated in a peer-reviewed journal or conference presentations. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019126958.


Assuntos
Fibrose Pulmonar/tratamento farmacológico , Piridonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fármacos do Sistema Respiratório/uso terapêutico , Revisão Sistemática como Assunto , Humanos
14.
Drugs Aging ; 36(6): 485-492, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30864023

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating, scarring lung disease with a worse prognosis than some cancers. The incidence of IPF is increasing and while current antifibrotic therapies slow disease progression, they do not offer a cure. The pathobiology of IPF is complex and is driven by aging-associated cellular dysfunction, epithelial injury, and an aberrant wound-healing response characterised by fibroblast activation and extracellular matrix accumulation (ECM) in the interstitium. As understanding of the underlying mechanisms has evolved, new targets for pharmacotherapy have emerged. Novel drugs currently in development for pulmonary fibrosis have diverse molecular properties and mechanisms of action, as well as different routes of administration. A shared primary goal of these agents is reduction of the profibrotic activity of fibroblasts and limitation of ECM deposition, which hinders gas exchange and ultimately leads to respiratory failure. This article provides an overview of some promising new therapeutic options for IPF and considers the challenges for future drug development.


Assuntos
Envelhecimento/patologia , Matriz Extracelular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Piridonas/uso terapêutico , Envelhecimento/metabolismo , Desenvolvimento de Medicamentos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Seizure ; 67: 1-4, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826629

RESUMO

PURPOSE: Using specialized tools, we assessed patients receiving perampanel (PER) to investigate its effects on aggression and depression, as well as the impact of other concomitant antiepileptic drugs (AEDs) on those conditions. METHOD: Seventy-seven patients with epilepsy were initially enrolled, then examined at entry and 12 weeks later (endpoint). At both examinations, assessments were performed with the Buss Perry Aggression Questionnaire (BAQ) and Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). Ultimately, 59 patients completed the study. RESULTS: Total BAQ (p = 0.013) and NDDI-E (p = 0.000) scores at the endpoint were significantly increased in comparison with those at entry. Analysis with 4 subscales showed increases in both verbal and physical aggression, while multivariate analysis revealed that concomitant AED administration did not have a significant impact on the increase of BAQ or NDDI-E score. A dose-dependent effect of PER was confirmed in BAQ, but not NDDI-E results. PER was discontinued due to adverse psychiatric effects in 3.9% of the patients. CONCLUSIONS: The present findings indicate that PER increases assessment scores indicative of aggression as well as depression. No additional aggression-augmenting effect was seen with concomitant AED administration.


Assuntos
Agressão/efeitos dos fármacos , Anticonvulsivantes/efeitos adversos , Depressão/induzido quimicamente , Epilepsia/tratamento farmacológico , Piridonas/efeitos adversos , Adolescente , Adulto , Idoso , Anticonvulsivantes/uso terapêutico , Relação Dose-Resposta a Droga , Epilepsia/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Piridonas/uso terapêutico , Resultado do Tratamento , Adulto Jovem
16.
Cochrane Database Syst Rev ; 3: CD010019, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30839095

RESUMO

BACKGROUND: Pulmonary embolism (PE) is a common life-threatening cardiovascular condition, with an incidence of 23 to 69 new cases per 100,000 people each year. For selected low-risk patients with acute PE, outpatient treatment might provide several advantages over traditional inpatient treatment, such as reduction of hospitalisations, substantial cost savings, and improvements in health-related quality of life. This is an update of the review first published in 2014. OBJECTIVES: To compare the efficacy and safety of outpatient versus inpatient treatment in low-risk patients with acute PE for the outcomes of all-cause and PE-related mortality; bleeding; adverse events such as haemodynamic instability; recurrence of PE; and patients' satisfaction. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers, to 26 March 2018. We also undertook reference checking to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials of outpatient versus inpatient treatment of adults (aged 18 years and over) diagnosed with low-risk acute PE. DATA COLLECTION AND ANALYSIS: Two review authors selected relevant trials, assessed methodological quality, and extracted and analysed data. We calculated effect estimates using risk ratio (RR) with 95% confidence intervals (CIs), or mean differences (MDs) with 95% CIs. We used standardised mean differences (SMDs) to combine trials that measured the same outcome but used different methods. We assessed the quality of the evidence using GRADE criteria. MAIN RESULTS: One new study was identified for this 2018 update, bringing the total number of included studies to two and the total number of participants to 451. Both trials discharged patients randomised to the outpatient group within 36 hours of initial triage and both followed participants for 90 days. One study compared the same treatment regimens in both outpatient and inpatient groups, and the other study used different treatment regimes. There was no clear difference in treatment effect for the outcomes of short-term mortality (30 days) (RR 0.33, 95% CI 0.01 to 7.98, P = 0.49; low-quality evidence), long-term mortality (90 days) (RR 0.98, 95% CI 0.06 to 15.58, P = 0.99, low-quality evidence), major bleeding at 14 days (RR 4.91, 95% CI 0.24 to 101.57, P = 0.30; low-quality evidence) and at 90 days (RR 6.88, 95% CI 0.36 to 132.14, P = 0.20; low-quality evidence), minor bleeding (RR 1.08, 95% CI 0.07 to 16.79; P = 0.96, low-quality evidence), recurrent PE within 90 days (RR 2.95, 95% CI 0.12 to 71.85, P = 0.51, low-quality evidence), and participant satisfaction (RR 0.97, 95% CI 0.90 to 1.04, P = 0.39; moderate-quality evidence). We downgraded the quality of the evidence because the CIs were wide and included treatment effects in both directions, the sample sizes and numbers of events were small, and because the effect of missing data and the absence of publication bias could not be verified. PE-related mortality, and adverse effects such as haemodynamic instability and compliance, were not assessed by the included studies. AUTHORS' CONCLUSIONS: Currently, only low-quality evidence is available from two published randomised controlled trials on outpatient versus inpatient treatment in low-risk patients with acute PE. The studies did not provide evidence of any clear difference between the interventions in overall mortality, bleeding and recurrence of PE.


Assuntos
Assistência Ambulatorial , Enoxaparina/uso terapêutico , Hospitalização , Embolia Pulmonar/terapia , Doença Aguda , Adulto , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Intervalos de Confiança , Enoxaparina/efeitos adversos , Hemorragia/epidemiologia , Humanos , Embolia Pulmonar/mortalidade , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Rivaroxabana/efeitos adversos , Rivaroxabana/uso terapêutico
17.
Medicina (Kaunas) ; 55(3)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875765

RESUMO

A 39 years old African man presented with fatigue, loss of weight and night sweats; radiology showed a possible usual interstitial pneumonia pattern. The patient missed follow-up visits, and presented again after 3 years with productive cough and general illness. Pulmonary function tests showed a decline of FVC compared to a previous investigation. The CT scans showed progression of the interstitial lung disease, and a multidisciplinary conference recommended to proceed with a surgical lung biopsy. Histopathology showed an atypical pattern, with bronchiolar metaplasia. A new multidisciplinary conference made a diagnosis of IPF, and the patient was treated with antifibrotic drugs with a good effect, reaching stability of lung function. This case report highlights the need to improve knowledge and to better characterize rare pulmonary diseases, and especially IPF, among African patients.


Assuntos
Fibrose Pulmonar Idiopática/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Raras/diagnóstico por imagem , Doenças Raras/diagnóstico , Adulto , Grupo com Ancestrais do Continente Africano/psicologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Biópsia , Broncoscopia , Diagnóstico Diferencial , Seguimentos , Conhecimentos, Atitudes e Prática em Saúde/etnologia , Hospitais Universitários , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Masculino , Piridonas/uso terapêutico , Doenças Raras/tratamento farmacológico , Doenças Raras/etnologia , Testes de Função Respiratória , Fumantes , Suécia/etnologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
18.
Eur Respir Rev ; 28(151)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30814139

RESUMO

Patients with certain types of fibrosing interstitial lung disease (ILD) are at risk of developing a progressive phenotype characterised by self-sustaining fibrosis, decline in lung function, worsening quality of life, and early mortality. It has been proposed that such progressive fibrosing ILDs, which show commonalities in clinical behaviour and in the pathogenetic mechanisms that drive progressive fibrosis, may be "lumped" together for the purposes of clinical research and, potentially, for treatment. At present, no drugs are approved for the treatment of ILDs other than nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis. For other progressive fibrosing ILDs, the mainstay of drug therapy is immunosuppression. However, it is postulated that, once the response to lung injury in fibrosing ILDs has reached the stage at which fibrosis has become progressive and self-sustaining, targeted antifibrotic therapy would be required to slow disease progression. Nintedanib, an intracellular inhibitor of tyrosine kinases, has shown antifibrotic, anti-inflammatory and vascular remodelling effects in several non-clinical models of fibrosis, irrespective of the trigger for the injury. Ongoing clinical trials will provide insight into the role of antifibrotic treatment with nintedanib or pirfenidone in the management of fibrosing ILDs with a progressive phenotype.


Assuntos
Doenças Pulmonares Intersticiais , Pulmão , Fibrose Pulmonar , Progressão da Doença , Nível de Saúde , Humanos , Indóis/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/fisiopatologia , Fenótipo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/mortalidade , Fibrose Pulmonar/patologia , Fibrose Pulmonar/fisiopatologia , Piridonas/uso terapêutico , Qualidade de Vida , Fármacos do Sistema Respiratório/uso terapêutico , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
19.
Drugs ; 79(6): 621-631, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30905033

RESUMO

Cancer accounts for 20% of all venous thromboembolism (VTE) worldwide and cancer patients are at four- to sevenfold increased risk of thrombosis compared to non-cancer patients. VTE is also a morbid complication of cancer and its incidence is rising. Thrombosis is also a second leading cause of death in cancer patients. The standard of care management for the prevention and treatment of cancer-associated thrombosis (CAT) remains the administration of low-molecular-weight heparins (LMWHs). In the last decade, five direct oral anticoagulants (DOACs), dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban, have been approved for the treatment and prevention of VTE in the general patient population. In this review, we discuss the results of the already published clinical trials with DOACs in the treatment of CAT and the ongoing clinical trials with DOACs in the prevention and treatment of CAT.


Assuntos
Anticoagulantes/uso terapêutico , Neoplasias/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/prevenção & controle , Administração Oral , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacologia , Benzamidas/uso terapêutico , Dabigatrana/uso terapêutico , Heparina de Baixo Peso Molecular , Humanos , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Piridonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Rivaroxabana/uso terapêutico , Tiazóis/uso terapêutico
20.
N Engl J Med ; 380(16): 1509-1524, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30883055

RESUMO

BACKGROUND: Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear. METHODS: In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y12 inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events. RESULTS: Enrollment included 4614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P = 0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group. CONCLUSIONS: In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both. (Funded by Bristol-Myers Squibb and Pfizer; AUGUSTUS ClinicalTrials.gov number, NCT02415400.).


Assuntos
Síndrome Coronariana Aguda/complicações , Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Intervenção Coronária Percutânea , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Vitamina K/antagonistas & inibidores , Síndrome Coronariana Aguda/terapia , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Aspirina/efeitos adversos , Fibrilação Atrial/complicações , Método Duplo-Cego , Quimioterapia Combinada , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/uso terapêutico , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Pirazóis/efeitos adversos , Piridonas/efeitos adversos
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