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1.
Arthritis Res Ther ; 24(1): 130, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35650639

RESUMO

BACKGROUND: We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc). METHODS: This trial included three sub-studies: ZEBRA 1-a randomised placebo-controlled, double-blind trial of zibotentan in SSc patients with CKD2 or CKD3 (and glomerular filtration rate (GFR) >45 ml/min) over 26 weeks; ZEBRA 2A-a 26-week placebo-controlled, single-blind trial of zibotentan in scleroderma renal crisis patients not requiring dialysis; and ZEBRA 2B-an open label pharmacokinetic study of zibotentan in patients on haemodialysis. RESULTS: Sixteen patients were screened for ZEBRA 1. Of these, 6 patients were randomised to zibotentan and 7 to placebo. In ZEBRA 1, there were 47 non-serious adverse events (AE) during the trial. Twenty-seven occurred in the placebo group and 20 in the zibotentan group. One serious adverse event (SAE) occurred during ZEBRA1, in the placebo arm. Descriptive statistics did not suggest an effect of study drug on serum sVCAM1. Estimated GFR numerically declined in patients treated with placebo at 26 weeks and 52 weeks. In contrast, average eGFR increased in zibotentan-treated cases. The 4 patients in ZEBRA 2A experienced 8 non-serious AEs, distributed equally between placebo and zibotentan. There was one SAE each in placebo and zibotentan groups, both unrelated to study medication. ZEBRA 2B recruited 8 patients, 6 completed first dosing, and 2 completed a second dosing visit. Pharmacokinetic analysis confirmed zibotentan levels within the therapeutic range. Three patients experienced 3 non-serious AEs. One SAE occurred and was unrelated to study drug. CONCLUSIONS: Zibotentan was generally well-tolerated. ZEBRA 1 did not show any effect of zibotentan on serum sVCAM-1 but was associated with numerical improvement in eGFR at 26 weeks that was more marked at 52 weeks. ZEBRA 2B suggested a feasible dose regimen for haemodialysis patients. TRIAL REGISTRATION: EudraCT no: 2013-003200-39 (first posted January 28, 2014) ClinicalTrials.gov Identifier: NCT02047708 Sponsor protocol number: 13/0077.


Assuntos
Insuficiência Renal Crônica , Escleroderma Sistêmico , Humanos , Pirrolidinas , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/complicações , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Método Simples-Cego
2.
ERJ Open Res ; 8(1)2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35295236

RESUMO

Objective: Baclofen is a centrally acting γ-aminobutyric acid type B (GABAB) receptor agonist which reduces gastro-oesophageal reflux and suppresses the cough reflex; however, central nervous system side-effects limit its use. Lesogaberan is a novel peripherally acting GABAB agonist, but its effects on refractory chronic cough are unknown. Design: We performed a single-centre, placebo-controlled, double-blind randomised crossover study in patients with chronic cough, refractory to the treatment of underlying conditions. Patients were randomised to treatment with lesogaberan 120 mg modified release twice daily or matched placebo for 2 weeks and then crossed over to the alternative therapy after a 2-week washout. The primary end-point was 24-h cough frequency measured with an acoustic monitoring system. In addition, cough responses to capsaicin were measured, and gastro-oesophageal reflux assessed by 24-h pH/impedance at screening. Results: 22 patients were randomised to receive lesogaberan/placebo or placebo/lesogaberan (female (73%); mean±sd age 63.7±7.2 years; median (interquartile range) cough duration 10.5 (5.8-17.0) years; mean (95% CI) 45 (29-67) reflux events in 24 h; two patients had abnormal oesophageal acid exposure times). Although lesogaberan reduced cough counts by 26% over placebo, this did not reach statistical significance (p=0.12). However, lesogaberan did significantly improve cough responses to capsaicin (p=0.04) and the number of cough bouts (p=0.04) compared with placebo. Lesogaberan was well tolerated in this study. Conclusions: Lesogaberan improved cough hypersensitivity and the number of bouts of coughing, but not coughs per hour. This implies a possible role for peripheral GABAB receptors in refractory chronic cough.

3.
Nat Rev Drug Discov ; 18(1): 41-58, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30310233

RESUMO

Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing (also known as drug repositioning), discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing.


Assuntos
Descoberta de Drogas , Indústria Farmacêutica , Reposicionamento de Medicamentos/normas , Humanos
4.
J Cell Physiol ; 233(3): 2398-2408, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28731198

RESUMO

Currently, there are no medications available to treat aseptic loosening of orthopedic implants. Using osteoprotegerin fusion protein (OPG-Fc), we previously blocked instability-induced osteoclast differentiation and peri-prosthetic osteolysis. Wnt/ß-catenin signaling, which regulates OPG secretion from osteoblasts, also modulates the bone tissue response to mechanical loading. We hypothesized that activating Wnt/ß-catenin signaling by inhibiting glycogen synthase kinase-3ß (GSK-3ß) would reduce instability-induced bone loss through regulation of both osteoblast and osteoclast differentiation. We examined effects of GSK-3ß inhibition on regulation of RANKL and OPG in a rat model of mechanical instability-induced peri-implant osteolysis. The rats were treated daily with a GSK-3ß inhibitor, AR28 (20 mg/kg bw), for up to 5 days. Bone tissue and blood serum were assessed by qRT-PCR, immunohistochemistry, and ELISA on days 3 and 5, and by micro-CT on day 5. After 3 days of treatment with AR28, mRNA levels of ß-catenin, Runx2, Osterix, Col1α1, and ALP were increased leading to higher osteoblast numbers compared to vehicle-treated animals. BMP-2 and Wnt16 mRNA levels were downregulated by mechanical instability and this was rescued by GSK-3ß inhibition. Osteoclast numbers were decreased significantly after 3 days of GSK-3ß inhibition, which correlated with enhanced OPG mRNA expression. This was accompanied by decreased serum levels of TRAP5b on days 3 and 5. Treatment with AR28 upregulated osteoblast differentiation, while osteoclastogenesis was blunted, leading to increased bone mass by day 5. These data suggest that GSK-3ß inactivation suppresses osteolysis through regulating both osteoblast and osteoclast differentiation in a rat model of instability-induced osteolysis.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteólise/prevenção & controle , Falha de Prótese , Inibidores de Proteínas Quinases/farmacologia , Tíbia/efeitos dos fármacos , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Placas Ósseas , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Masculino , Osteoblastos/enzimologia , Osteoblastos/patologia , Osteoclastos/enzimologia , Osteoclastos/patologia , Osteólise/enzimologia , Osteólise/genética , Osteólise/patologia , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Implantação de Prótese/instrumentação , Ligante RANK/genética , Ligante RANK/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Fosfatase Ácida Resistente a Tartarato/sangue , Tíbia/enzimologia , Tíbia/patologia , Tíbia/cirurgia , Fatores de Tempo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética , beta Catenina/metabolismo
5.
Mol Pain ; 122016.
Artigo em Inglês | MEDLINE | ID: mdl-27094550

RESUMO

BACKGROUND: Bone metastases occur frequently in advanced breast, lung, and prostate cancer, with approximately 70% of patients affected. Pain is a major symptom of bone metastases, and current treatments may be inadequate or have unacceptable side effects. The mechanisms that drive cancer-induced bone pain are not fully understood; however, it is known that there is sensitization of both peripheral bone afferents and central spinal circuits. It is well established that the N-methyl-D-aspartate receptor plays a major role in the pathophysiology of pain hypersensitivity. Inhibition of the non-receptor tyrosine kinase Src controls N-methyl-D-aspartate receptor activity and inhibiting Src reduces the hypersensitivity associated with neuropathic and inflammatory pains. As Src is also implicated in osteoclastic bone resorption, we have investigated if inhibiting Src ameliorates cancer-induced bone pain. We have tested this hypothesis using an orally bioavailable Src inhibitor (saracatinib) in a rat model of cancer-induced bone pain. RESULTS: Intra-tibial injection of rat mammary cancer cells (Mammary rat metastasis tumor cells -1), but not vehicle, in rats produced hindpaw hypersensitivity to thermal and mechanical stimuli that was maximal after six days and persisted for at least 13 days postinjection. Daily oral gavage with saracatinib (20 mg/kg) beginning seven days after intra-tibial injection reversed the thermal hyperalgesia but not the mechanical allodynia. The analgesic mechanisms of saracatinib appear to be due to an effect on the nervous system as immunoblotting of L2-5 spinal segments showed that mammary rat metastasis tumor cells-1 injection induced phosphorylation of the GluN1 subunit of the N-methyl-D-aspartate receptor, indicative of receptor activation, and this was reduced by saracatinib. Additionally, histology showed no anti-tumor effect of saracatinib at any dose and no significant effect on bone preservation. CONCLUSIONS: This is the first demonstration that Src plays a role in the development of cancer-induced bone pain and that Src inhibition represents a possible new analgesic strategy for patients with bone metastases.


Assuntos
Neoplasias Ósseas/complicações , Neoplasias Ósseas/tratamento farmacológico , Dor do Câncer/complicações , Dor do Câncer/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinases da Família src/antagonistas & inibidores , Animais , Comportamento Animal , Benzodioxóis/farmacocinética , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Neoplasias Ósseas/fisiopatologia , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/complicações , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/fisiopatologia , Dor do Câncer/fisiopatologia , Modelos Animais de Doenças , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/patologia , Quinases da Família src/metabolismo
6.
Nat Rev Drug Discov ; 14(12): 833-41, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26585533

RESUMO

A new model for translational research and drug repositioning has recently been established based on three-way partnerships between public funders, the pharmaceutical industry and academic investigators. Through two pioneering initiatives - one involving the Medical Research Council in the United Kingdom and one involving the National Center for Advancing Translational Sciences of the National Institutes of Health in the United States - new investigations of highly characterized investigational compounds have been funded and are leading to the exploration of known mechanisms in new disease areas. This model has been extended beyond these first two initiatives. Here, we discuss the progress to date and the unique requirements and challenges for this model.


Assuntos
Pesquisa Biomédica , Indústria Farmacêutica , Reposicionamento de Medicamentos , Regulamentação Governamental , Comunicação Interdisciplinar , Pesquisa Translacional Biomédica , Comportamento Cooperativo , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/tendências , Programas Governamentais/métodos , Programas Governamentais/organização & administração , Humanos , Modelos Organizacionais , Pesquisa Translacional Biomédica/métodos , Pesquisa Translacional Biomédica/tendências
7.
Toxicol Appl Pharmacol ; 272(2): 399-407, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23872097

RESUMO

Wnt activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism in rodents making GSK-3 a potential therapeutic target for osteoporotic and osteolytic metastatic bone disease. To understand the wnt pathway related to human disease translation, the ability of 3 potent inhibitors of GSK-3 (AZD2858, AR79, AZ13282107) to 1) drive osteoblast differentiation and mineralisation using human adipose-derived stem cells (hADSC) in vitro; and 2) stimulate rat bone formation in vivo was investigated. Bone anabolism/resorption was determined using clinically relevant serum biomarkers as indicators of bone turnover and bone formation assessed in femurs by histopathology and pQCT/µCT imaging. GSK-3 inhibitors caused ß-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. AZD2858 produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28 days exposure in rats. After 7 days, AZD2858, AR79 or AZ13282107 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. This biomarker profile was differentiated from anabolic agent PTH1-34 or the anti-resorptive Alendronate-induced changes. Increased bone formation in cortical and cancellous bone as assessed by femur histopathology supported biomarker changes. 14 day AR79 treatment increased bone mineral density and trabecular thickness, and decreased trabecular number and connectivity assessed by pQCT/µCT. GSK-3 inhibition caused hADSC osteoblastogenesis and mineralisation in vitro. Increased femur bone mass associated with changes in bone turnover biomarkers confirmed in vivo bone formation and indicated uncoupling of bone formation and resorption.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Animais , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Feminino , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Fêmur/patologia , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/enzimologia , Estrutura Molecular , Osteoblastos/citologia , Osteoblastos/enzimologia , Ratos , Ratos Sprague-Dawley
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