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1.
Respir Res ; 21(1): 75, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32216814

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvß6) integrin inhibitor, in participants with IPF. METHODS: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvß6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. RESULTS: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. CONCLUSIONS: This study demonstrated engagement of the αvß6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. TRIAL REGISTRATION: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.


Assuntos
Butiratos/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/uso terapêutico , Pirazóis/uso terapêutico , Pirrolidinas/uso terapêutico , Volume de Ventilação Pulmonar/efeitos dos fármacos , Administração por Inalação , Idoso , Antígenos de Neoplasias , Teorema de Bayes , Butiratos/administração & dosagem , Butiratos/farmacocinética , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Masculino , Naftiridinas/administração & dosagem , Naftiridinas/farmacocinética , Nebulizadores e Vaporizadores , Tomografia por Emissão de Pósitrons , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Resultado do Tratamento
2.
PLoS Negl Trop Dis ; 13(11): e0007890, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31751347

RESUMO

Recent outbreaks of the Ebola virus (EBOV) have focused attention on the dire need for antivirals to treat these patients. We identified pyronaridine tetraphosphate as a potential candidate as it is an approved drug in the European Union which is currently used in combination with artesunate as a treatment for malaria (EC50 between 420 nM-1.14 µM against EBOV in HeLa cells). Range-finding studies in mice directed us to a single 75 mg/kg i.p. dose 1 hr after infection which resulted in 100% survival and statistically significantly reduced viremia at study day 3 from a lethal challenge with mouse-adapted EBOV (maEBOV). Further, an EBOV window study suggested we could dose pyronaridine 2 or 24 hrs post-exposure to result in similar efficacy. Analysis of cytokine and chemokine panels suggests that pyronaridine may act as an immunomodulator during an EBOV infection. Our studies with pyronaridine clearly demonstrate potential utility for its repurposing as an antiviral against EBOV and merits further study in larger animal models with the added benefit of already being used as a treatment against malaria.


Assuntos
Antimaláricos/administração & dosagem , Antivirais/administração & dosagem , Doença pelo Vírus Ebola/prevenção & controle , Naftiridinas/administração & dosagem , Animais , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Antivirais/efeitos adversos , Antivirais/farmacocinética , Citocinas/imunologia , Reposicionamento de Medicamentos , Ebolavirus/efeitos dos fármacos , Ebolavirus/genética , Ebolavirus/fisiologia , Feminino , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/virologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Naftiridinas/efeitos adversos , Naftiridinas/farmacocinética
3.
Pharmacol Biochem Behav ; 185: 172761, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31425712

RESUMO

Alcohol use is frequently associated with mood disorders. Similarly, individuals suffering from these disorders have a higher risk of developing alcoholism. Several reports have implicated orexin signaling in different behaviors related to alcohol consumption, whereas antagonists block these actions. However, the involvement of orexin-1-receptor (Orx1R) in ethanol-induced anxiolysis remains relatively unexplored. The purpose of this study was to investigate whether intra-accumbal inhibition of Orx1R blocks the anxiolytic-like effect of ethanol and to determine if ethanol administration modifies orexin-A content and Orx1R expression in the nucleus accumbens (NAc). The elevated-plus-maze test (EPM-test) was used to measure anxiety; orexin-A content and Orx1R expression were determined by enzyme-immunoassay and western blot, respectively. The results showed that the pretreatment with a selective antagonist of Orx1R, SB-334867 (SB, 3 µg/side), prevents the anxiolytic-like behavior induced by acute ethanol (2.5 g/kg). SB-334867 per se had no effect on anxiety levels. Pretreatment with SB-334867 followed by ethanol (SB + Et) increased orexin-A content and Orx1R levels in the NAc in comparison to the groups that only received ethanol (V + Et) or SB-334867 (SB + S). Ethanol treatment significantly augmented Orx1R expression but not the peptide content. The increase in orexin-A observed in SB + Et animals could be due in part to the inhibition of Orx1R, since SB-334867 prevents the binding of orexin-A to the receptor. This increase in orexin-A may, in turn, induce an up-regulation of receptor. Other possible explanations were discussed. In general, these findings suggest that orexin-A contributes largely to expression of ethanol-induced anxiolytic-like effect through the signaling of Orx1R in the NAc.


Assuntos
Ansiolíticos/farmacologia , Benzoxazóis/farmacologia , Etanol/farmacologia , Naftiridinas/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Ureia/análogos & derivados , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Animais , Ansiolíticos/administração & dosagem , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Benzoxazóis/administração & dosagem , Etanol/administração & dosagem , Modelos Lineares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Naftiridinas/administração & dosagem , Núcleo Accumbens/metabolismo , Antagonistas dos Receptores de Orexina/administração & dosagem , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacos , Ureia/administração & dosagem , Ureia/farmacologia
4.
Gastric Cancer ; 22(6): 1153-1163, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31098863

RESUMO

PURPOSE: Casein kinase (CK) 2 activation has been implicated in the proliferation of various tumor types and resistance to chemotherapy. We investigated the mechanistic basis for the association between CK2 activation and paclitaxel resistance in a gastric cancer (GC). EXPERIMENTAL DESIGN: CK2 expression was evaluated in 59 advanced GC patients treated with paclitaxel as the second-line therapy. The efficacy of a CK2 inhibitor, CX-4945, and paclitaxel was evaluated in GC cell lines and a xenograft model. RESULTS: Patients with high CK2 expression (29/59, 39%) showed lower disease control rates (47.7% vs. 72.3%, p = 0.017) and shorter progression-free survival (2.8 vs. 4.8 months, p = 0.009) than patients with low CK2 expression. CK2 protein expression was associated with sensitivity to paclitaxel in 49 GC cell lines. Combination therapy with CX-4945 and paclitaxel exerted synergistic antiproliferative effects and inhibited the downregulation of phosphatidylinositol 3-kinase/AKT signaling in SNU-1 cells. In the SNU-1 xenograft model, the combination treatment was significantly superior to either single agent, suppressing tumor growth without notable toxicities. CONCLUSIONS: These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC.


Assuntos
Caseína Quinase II/antagonistas & inibidores , Naftiridinas/farmacologia , Paclitaxel/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Naftiridinas/administração & dosagem , Paclitaxel/administração & dosagem , Intervalo Livre de Progressão , Neoplasias Gástricas/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Intern Med ; 58(2): 263-266, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30643085

RESUMO

Tosufloxacin, which is not used to treat Mycobacterium tuberculosis, is a fluoroquinolone recommended for pneumonia when the possibility of tuberculosis infection cannot be excluded. In the present case, symptoms and chest infiltrative shadow initially improved by tosufloxacin. Therefore, we regarded this patient as having general pneumonia and did not perform follow-up chest X-ray until the infiltrates had completely disappeared. However, a few weeks later, the symptoms and the infiltrates had worsened, so M. tuberculosis was isolated from the patient's sputum. This case suggests that patients suspected of having pulmonary tuberculosis should be monitored carefully, even if antibiotics without antituberculous activity are initially effective.


Assuntos
Fluoroquinolonas/uso terapêutico , Mycobacterium tuberculosis/isolamento & purificação , Naftiridinas/uso terapêutico , Pneumonia Bacteriana/diagnóstico , Tuberculose Pulmonar/diagnóstico , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/efeitos adversos , Humanos , Masculino , Naftiridinas/administração & dosagem , Naftiridinas/efeitos adversos , Pneumonia Bacteriana/complicações , Pneumonia Bacteriana/diagnóstico por imagem , Pneumonia Bacteriana/tratamento farmacológico , Escarro/microbiologia , Tomografia Computadorizada por Raios X , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/diagnóstico por imagem , Tuberculose Pulmonar/tratamento farmacológico
7.
Anticancer Res ; 38(11): 6147-6156, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30396931

RESUMO

BACKGROUND/AIM: MEK inhibitors are new promising anticancer drugs. The aim of this study was to investigate the effect of the combination treatment of voreloxin with the MEK inhibitor TAK-733 on HL60 myeloid leukemia cells. MATERIALS AND METHODS: MAPK activity, cell viability, apoptosis, oxidative stress induction and AIF (apoptosis-inducing factor) distribution were assessed in HL60 cells cultured with each drug alone or with both drugs. RESULTS: TAK-733 alone at 5 µM significantly reduced MAPK activity and did not influence viability and apoptosis in HL60 cells. Voreloxin at concentration of 0.03-0.48 µM reduced cell viability and increased apoptosis rate. Incubation with both drugs caused further inhibition of cell viability and increased apoptosis associated with generation of reactive oxygen species (ROS) and nuclear translocation of AIF. CONCLUSION: Combination of TAK-733 and voreloxin can exert a synergistic anticancer effect in myeloid leukemia cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinonas/farmacologia , Tiazóis/farmacologia , Apoptose/efeitos dos fármacos , Fator de Indução de Apoptose/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Células HL-60 , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/metabolismo , Microscopia Confocal , Naftiridinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Tiazóis/administração & dosagem
8.
Cochrane Database Syst Rev ; 9: CD009070, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30188565

RESUMO

BACKGROUND: Community-acquired pneumonia (CAP) is a lung infection that can be acquired during day-to-day activities in the community (not while receiving care in a hospital). Community-acquired pneumonia poses a significant public health burden in terms of mortality, morbidity, and costs. Shorter antibiotic courses for CAP may limit treatment costs and adverse effects, but the optimal duration of antibiotic treatment is uncertain. OBJECTIVES: To evaluate the efficacy and safety of short-course versus longer-course treatment with the same antibiotic at the same daily dosage for CAP in non-hospitalised adolescents and adults (outpatients). We planned to investigate non-inferiority of short-course versus longer-term course treatment for efficacy outcomes, and superiority of short-course treatment for safety outcomes. SEARCH METHODS: We searched CENTRAL, which contains the Cochrane Acute Respiratory Infections Group Specialised Register, MEDLINE, Embase, five other databases, and three trials registers on 28 September 2017 together with conference proceedings, reference checking, and contact with experts and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing short- and long-courses of the same antibiotic for CAP in adolescent and adult outpatients. DATA COLLECTION AND ANALYSIS: We planned to use standard Cochrane methods. MAIN RESULTS: Our searches identified 5260 records. We did not identify any RCTs that compared short- and longer-courses of the same antibiotic for the treatment of adolescents and adult outpatients with CAP.We excluded two RCTs that compared short courses (five compared to seven days) of the same antibiotic at the same daily dose because they evaluated antibiotics (gemifloxacin and telithromycin) not commonly used in practice for the treatment of CAP. In particular, gemifloxacin is no longer approved for the treatment of mild-to-moderate CAP due to its questionable risk-benefit balance, and reported adverse effects. Moreover, the safety profile of telithromycin is also cause for concern.We found one ongoing study that we will assess for inclusion in future updates of the review. AUTHORS' CONCLUSIONS: We found no eligible RCTs that studied a short-course of antibiotic compared to a longer-course (with the same antibiotic at the same daily dosage) for CAP in adolescent and adult outpatients. The effects of antibiotic therapy duration for CAP in adolescent and adult outpatients remains unclear.


Assuntos
Antibacterianos/administração & dosagem , Pneumonia/tratamento farmacológico , Adolescente , Adulto , Infecções Comunitárias Adquiridas/tratamento farmacológico , Esquema de Medicação , Fluoroquinolonas/administração & dosagem , Gemifloxacina , Humanos , Cetolídeos/administração & dosagem , Naftiridinas/administração & dosagem , Pacientes Ambulatoriais
9.
J Control Release ; 286: 1-9, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30016731

RESUMO

CX-5461 is currently in Phase I/II clinical trials for advanced hematologic malignancies and triple negative or BRCA-deficient breast cancer. The compound is currently administered to patients intravenously (i.v.) at low pH (3.5) due to solubility challenges. Reliance of low pH to enhance solubility of CX-5461 can adversely impact pharmacokinetics, biodistribution and therapeutic potential. We have addressed this solubility issue through a formulation method that relies on the interactions between CX-5461 and copper. Copper binds CX-5461 through the nitrogens of the pyrazine ring. Here, we describe synthesizing this copper-complexed CX-5461 (Cu(CX-5461)) within liposomes. CX-5461 was added to copper-containing liposomes and incubated at 60 °C for 30 min. The pharmacokinetics of CX-5461 was assessed in mice following a single i.v. injection at 30 mg/kg. Efficacy studies were completed in multiple subcutaneous mouse xenografts as well as in a bone marrow engraftment model of acute myeloid leukemia (AML). The novel Cu(CX-5461) formulation was stable at pH 7.4 and exhibited increased plasma circulation longevity, increasing the total exposure to CX5461 by an order of magnitude. Cu(CX-5461) was more active than CX-5461 in AML models in vivo. In HCT116-B46 and Capan-1 solid tumour models that are BRCA-deficient, the Cu(CX-5461) formulation engendered activity that was comparable to that of the low pH CX-5461 formulation. We have generated the first Cu(CX-5461) formulation suitable for i.v. administration that is more efficacious than the existing low-pH formulation in pre-clinical models of AML. The Cu(CX-5461) formulation may serve as an alternative formulation for CX-5461 in BRCA-deficient cancers.


Assuntos
Antineoplásicos/administração & dosagem , Benzotiazóis/administração & dosagem , Cobre/administração & dosagem , Naftiridinas/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzotiazóis/química , Benzotiazóis/farmacocinética , Benzotiazóis/uso terapêutico , Linhagem Celular Tumoral , Complexos de Coordenação/administração & dosagem , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/uso terapêutico , Cobre/química , Cobre/farmacocinética , Cobre/uso terapêutico , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Lipossomos/química , Camundongos , Naftiridinas/química , Naftiridinas/farmacocinética , Naftiridinas/uso terapêutico , RNA Ribossômico/antagonistas & inibidores , RNA Ribossômico/metabolismo , Distribuição Tecidual
10.
J Mol Cell Cardiol ; 121: 124-133, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29981797

RESUMO

Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore represent an alternative to these molecules in patients with damaged kidney function. The aim of this study is to characterize the effects of Finerenone on the cardiac complications of renal failure in a mouse model of chronic kidney disease (CKD). CKD was induced by subtotal nephrectomy (Nx), and finerenone was administered at a low dose (2.5 mg/kg/d) from week 4 to week 10 post-Nx. Cardiac function was assessed by echocardiography and invasive hemodynamics while cardiac fibrosis was measured by Sirius Red staining. Renal failure induced cardiac systolic and diastolic dysfunctions in the untreated CKD mice, as well as minor changes on cardiac structure. We also observed alterations in the phosphorylation of proteins playing key roles in the calcium handling (Phospholamban, Calmodulin kinase II) in these mice. Finerenone prevented most of these lesions with no effects on neither the renal dysfunction nor kaliemia. The benefits of finerenone suggest that activation of MR is involved in the cardiac complication of renal failure and strengthen previous studies showing beneficial effects of MRA in patients with CKD.


Assuntos
Insuficiência Cardíaca Diastólica/tratamento farmacológico , Naftiridinas/administração & dosagem , Receptores de Mineralocorticoides/genética , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Eplerenona/administração & dosagem , Insuficiência Cardíaca Diastólica/etiologia , Insuficiência Cardíaca Diastólica/genética , Insuficiência Cardíaca Diastólica/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Camundongos , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia
11.
Diabetes Obes Metab ; 20(10): 2399-2407, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29862614

RESUMO

AIM: To determine whether non-steroidal mineralocorticoid receptor (MR) antagonists oppose metabolic syndrome-related end-organ, i.e. cardiac, damage. MATERIALS AND METHODS: In Zucker fa/fa rats, a rat model of metabolic syndrome, we assessed the effects of the non-steroidal MR antagonist finerenone (oral 2 mg/kg/day) on left ventricular (LV) function, haemodynamics and remodelling (using echocardiography, magnetic resonance imaging and biochemical methods). RESULTS: Long-term (90 days) finerenone modified neither systolic blood pressure nor heart rate, but reduced LV end-diastolic pressure and LV end-diastolic pressure-volume relationship, without modifying LV end-systolic pressure and LV end-systolic pressure-volume relationship. Simultaneously, long-term finerenone reduced both LV systolic and diastolic diameters, associated with reductions in LV weight and LV collagen density, while proteinuria and renal nGAL expression were reduced. Short-term (7 days) finerenone improved LV haemodynamics and reduced LV systolic diameter, without modifying LV diastolic diameter. Moreover, short-term finerenone increased myocardial tissue perfusion and reduced myocardial reactive oxygen species, while plasma nitrite levels, an indicator of nitric oxide (NO) bio-availability, were increased. CONCLUSIONS: In rats with metabolic syndrome, the non-steroidal MR antagonist finerenone opposed metabolic syndrome-related diastolic cardiac dysfunction and nephropathy. This involved acute effects, such as improved myocardial perfusion, reduced oxidative stress/increased NO bioavailability, as well as long-term effects, such as modifications in the myocardial structure.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Nefropatias/prevenção & controle , Síndrome Metabólica/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Naftiridinas/administração & dosagem , Animais , Doenças Cardiovasculares/complicações , Esquema de Medicação , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Nefropatias/complicações , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/patologia , Síndrome Metabólica/fisiopatologia , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Naftiridinas/efeitos adversos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Zucker , Fatores de Tempo , Função Ventricular Esquerda/efeitos dos fármacos
13.
J Med Chem ; 61(6): 2472-2489, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29502405

RESUMO

Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.


Assuntos
Naftiridinas/síntese química , Naftiridinas/farmacologia , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/farmacologia , Administração por Inalação , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inaladores de Pó Seco , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Masculino , Naftiridinas/administração & dosagem , Neutrófilos/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/administração & dosagem , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/sangue
14.
J Pharm Sci ; 107(6): 1577-1585, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29421216

RESUMO

Adjuvants are necessary to enable vaccine development against a significant number of challenging pathogens for which effective vaccines are not available. We engineered a novel small-molecule immune potentiator, a benzonaphthyridine agonist targeting toll-like receptor 7 (TLR7), as a vaccine adjuvant. TLR7 agonist (TLR7a) was engineered to be adsorbed onto aluminum hydroxide (AlOH), and the resulting AlOH/TLR7a was evaluated as a vaccine adjuvant. AlOH/TLR7a exploits the flexibility of AlOH formulations, has an application in many vaccine candidates, and induced good efficacy and safety profiles against all tested antigens (bacterial- and viral-derived protein antigens, toxoids, glycoconjugates, and so forth) in many animal models, including nonhuman primates. In this article, we describe the outcome of the physicochemical characterization of AlOH/TLR7a. Reverse-phase ultra performance liquid chromatography, confocal microscopy, flow cytometry, zeta potential, and phosphophilicity assays were used as tools to demonstrate the association of TLR7a to AlOH and to characterize this novel formulation. Raman spectroscopy, nuclear magnetic resonance, and mass spectroscopy were also used to investigate the interaction between TLR7a and AlOH (data not shown). This pivotal work paved the way for AlOH/TLR7a to progress into the clinic for evaluation as an adjuvant platform for vaccines against challenging preventable diseases.


Assuntos
Adjuvantes Imunológicos/química , Hidróxido de Alumínio/química , Naftiridinas/química , Receptor 7 Toll-Like/agonistas , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Adsorção , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/farmacologia , Animais , Humanos , Naftiridinas/administração & dosagem , Naftiridinas/farmacologia
15.
Mol Neurobiol ; 55(9): 7153-7163, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29383691

RESUMO

In patients with stroke and neurodegenerative diseases, overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) causes harmful effects by inducing apoptosis, necrosis, neuroinflammation, and immune dysregulation. The current study investigated the neuroprotective effect of a novel PARP-1 inhibitor, JPI-289, in an animal model of ischemic stroke. A transient middle cerebral artery occlusion (tMCAO, 2 h) model was used to determine the therapeutic effect and the most effective dose and time window of administration of JPI-289. We also investigated the long-term outcomes of treatment with JPI-289 by diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI and by measuring neurological function at 24 h, 7 days, and 28 days after MCAO. The most effective dose and time window of administration of JPI-289 was 10 mg/kg administered 2 h after MCAO with reperfusion. Twenty-four hours after MCAO, infarct volume was reduced by 53% and the number of apoptotic cells was reduced by 56% compared with control. JPI-289 also reduced infarct volume by 16% in the permanent MCAO model. In an MRI-based study, initial infarct volume, as measured using DWI, was similar in the control and JPI-289-treated groups. However, infarct volume and brain swelling were significantly reduced in the group treated with JPI-289 (2 h) at 24 h and 7 days after MCAO. Neurological functions also improved in the group treated with JPI-289 (2 h) until 28 days after MCAO. Inhibition of PARP-1 has neuroprotective effects (reduction of infarct volume and brain swelling) in both tMCAO and pMCAO models of ischemic stroke.


Assuntos
Comportamento Animal , Infarto Encefálico/tratamento farmacológico , Naftiridinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Infarto Encefálico/complicações , Infarto Encefálico/patologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/patologia , Imagem de Difusão por Ressonância Magnética , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Masculino , Naftiridinas/administração & dosagem , Naftiridinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ratos Sprague-Dawley , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologia , Fatores de Tempo
16.
Mar Drugs ; 16(1)2018 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-29315210

RESUMO

Aaptos is a genus of marine sponge which belongs to Suberitidae and is distributed in tropical and subtropical oceans. Bioactivity-guided fractionation of Aaptos sp. methanolic extract resulted in the isolation of aaptamine, demethyloxyaaptamine, and isoaaptamine. The cytotoxic activity of the isolated compounds was evaluated revealing that isoaaptamine exhibited potent cytotoxic activity against breast cancer T-47D cells. In a concentration-dependent manner, isoaaptamine inhibited the growth of T-47D cells as indicated by short-(MTT) and long-term (colony formation) anti-proliferative assays. The cytotoxic effect of isoaaptamine was mediated through apoptosis as indicated by DNA ladder formation, caspase-7 activation, XIAP inhibition and PARP cleavage. Transmission electron microscopy and flow cytometric analysis using acridine orange dye indicated that isoaaptamine treatment could induce T-47D cells autophagy. Immunoblot assays demonstrated that isoaaptamine treatment significantly activated autophagy marker proteins such as type II LC-3. In addition, isoaaptamine treatment enhanced the activation of DNA damage (γH2AX) and ER stress-related proteins (IRE1 α and BiP). Moreover, the use of isoaaptamine resulted in a significant increase in the generation of reactive oxygen species (ROS) as well as in the disruption of mitochondrial membrane potential (MMP). The pretreatment of T-47D cells with an ROS scavenger, N-acetyl-l-cysteine (NAC), attenuated the apoptosis and MMP disruption induced by isoaaptamine up to 90%, and these effects were mediated by the disruption of nuclear factor erythroid 2-related factor 2 (Nrf 2)/p62 pathway. Taken together, these findings suggested that the cytotoxic effect of isoaaptamine is associated with the induction of apoptosis and autophagy through oxidative stress. Our data indicated that isoaaptamine represents an interesting drug lead in the war against breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Naftiridinas/farmacologia , Poríferos/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/patologia , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Naftiridinas/administração & dosagem , Naftiridinas/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
17.
PLoS One ; 13(1): e0190105, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29329306

RESUMO

Autophagy is a highly conserved mechanism for cellular repair that becomes progressively down-regulated during normal ageing. Hence, manipulations that activate autophagy could increase lifespan. Previous reports show that manipulations to the autophagy pathway can result in longevity extension in yeast, flies, worms and mammals. Under standard nutrition, autophagy is inhibited by the nutrient sensing kinase Target of Rapamycin (TOR). Therefore, manipulations of TOR that increase autophagy may offer a mechanism for extending lifespan. Ideally, such manipulations should be specific and minimise off-target effects, and it is important to discover additional methods for 'clean' lifespan manipulation. Here we report an initial study into the effect of up-regulating autophagy on lifespan and fertility in Drosophila melanogaster by dietary addition of Torin1. Activation of autophagy using this selective TOR inhibitor was associated with significantly increased lifespan in both sexes. Torin1 induced a dose-dependent increase in lifespan in once-mated females. There was no evidence of a trade-off between longevity and fecundity or fertility. Torin1-fed females exhibited significantly elevated fecundity, but also elevated egg infertility, resulting in no net change in overall fertility. This supports the idea that lifespan can be extended without trade-offs in fertility and suggest that Torin1 may be a useful tool with which to pursue anti-ageing research.


Assuntos
Autofagia , Drosophila melanogaster/fisiologia , Fertilidade , Naftiridinas/administração & dosagem , Animais , Feminino , Masculino
18.
Artigo em Inglês | MEDLINE | ID: mdl-28971604

RESUMO

Multiple integrins have been implicated in modulating renal function. Modulation of integrin function can lead to pathophysiological processes associated with diabetic nephropathy such as alterations in the glomerular filtration barrier and kidney fibrosis. The complexity of these pathophysiological changes implies that multiple integrin subtypes might need to be targeted to ameliorate the progression of renal disease. To address this hypothesis, we investigated the effects of MK-0429, a compound that was originally developed as an αvß3 inhibitor for the treatment of osteoporosis, on renal function and fibrosis. We demonstrated that MK-0429 is an equipotent pan-inhibitor of multiple av integrins. MK-0429 dose-dependently inhibited podocyte motility and also suppressed TGF-ß-induced fibrosis marker gene expression in kidney fibroblasts. Moreover, in the obese ZSF1 rat model of diabetic nephropathy, chronic treatment with MK-0429 resulted in significant reduction in proteinuria, kidney fibrosis, and collagen accumulation. In summary, our results suggest that inhibition of multiple integrin subtypes might lead to meaningful impact on proteinuria and renal fibrosis in diabetic nephropathy.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Marcadores Genéticos/efeitos dos fármacos , Integrina alfaV/metabolismo , Rim/fisiopatologia , Naftiridinas/administração & dosagem , Propionatos/administração & dosagem , Animais , Linhagem Celular , Colágeno/metabolismo , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Testes de Função Renal , Masculino , Naftiridinas/farmacologia , Propionatos/farmacologia , Ratos
19.
Clin Cancer Res ; 23(21): 6529-6540, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28778862

RESUMO

Purpose: A hallmark of neoplasia is increased ribosome biogenesis, and targeting this process with RNA polymerase I (Pol I) inhibitors has shown some efficacy. We examined the contribution and potential targeting of ribosomal machinery in chemotherapy-resistant and -sensitive models of ovarian cancer.Experimental Design: Pol I machinery expression was examined, and subsequently targeted with the Pol I inhibitor CX-5461, in ovarian cancer cell lines, an immortalized surface epithelial line, and patient-derived xenograft (PDX) models with and without chemotherapy. Effects on viability, Pol I occupancy of rDNA, ribosomal content, and chemosensitivity were examined.Results: In PDX models, ribosomal machinery components were increased in chemotherapy-treated tumors compared with controls. Thirteen cell lines were sensitive to CX-5461, with IC50s 25 nmol/L-2 µmol/L. Interestingly, two chemoresistant lines were 10.5- and 5.5-fold more sensitive than parental lines. CX-5461 induced DNA damage checkpoint activation and G2-M arrest with increased γH2AX staining. Chemoresistant cells had 2- to 4-fold increased rDNA Pol I occupancy and increased rRNA synthesis, despite having slower proliferation rates, whereas ribosome abundance and translational efficiency were not impaired. In five PDX models treated with CX-5461, one showed a complete response, one a 55% reduction in tumor volume, and one maintained stable disease for 45 days.Conclusions: Pol I inhibition with CX-5461 shows high activity in ovarian cancer cell lines and PDX models, with an enhanced effect on chemoresistant cells. Effects occur independent of proliferation rates or dormancy. This represents a novel therapeutic approach that may have preferential activity in chemoresistant populations. Clin Cancer Res; 23(21); 6529-40. ©2017 AACR.


Assuntos
Benzotiazóis/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Naftiridinas/administração & dosagem , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Benzotiazóis/efeitos adversos , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Naftiridinas/efeitos adversos , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Polimerase I/antagonistas & inibidores , RNA Polimerase I/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Haematologica ; 102(10): 1709-1717, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28729302

RESUMO

Vosaroxin is an anti-cancer quinolone-derived DNA topoisomerase II inhibitor. We investigated vosaroxin with decitabine in patients ≥60 years of age with newly diagnosed acute myeloid leukemia (n=58) or myelodysplastic syndrome (≥10% blasts) (n=7) in a phase II non-randomized trial. The initial 22 patients received vosaroxin 90 mg/m2 on days 1 and 4 with decitabine 20 mg/m2 on days 1-5 every 4-6 weeks for up to seven cycles. Due to a high incidence of mucositis the subsequent 43 patients were given vosaroxin 70 mg/m2 on days 1 and 4. These 65 patients, with a median age of 69 years (range, 60-78), some of whom with secondary leukemia (22%), adverse karyotype (35%), or TP53 mutation (20%), are evaluable. The overall response rate was 74% including complete remission in 31 (48%), complete remission with incomplete platelet recovery in 11 (17%), and complete remission with incomplete count recovery in six (9%). The median number of cycles to response was one (range, 1-4). Grade 3/4 mucositis was noted in 17% of all patients. The 70 mg/m2 induction dose of vosaroxin was associated with similar rates of overall response (74% versus 73%) and complete remission (51% versus 41%, P=0.44), reduced incidence of mucositis (30% versus 59%, P=0.02), reduced 8-week mortality (9% versus 23%; P=0.14), and improved median overall survival (14.6 months versus 5.5 months, P=0.007). Minimal residual disease-negative status by multiparametric flow-cytometry at response (± 3 months) was achieved in 21 of 39 (54%) evaluable responders and was associated with better median overall survival (34.0 months versus 8.3 months, P=0.023). In conclusion, the combination of vosaroxin with decitabine is effective and well tolerated at a dose of 70 mg/m2 and warrants randomized prospective evaluation. ClinicalTrials.gov: NCT01893320.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/análogos & derivados , Biomarcadores , Decitabina , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Naftiridinas/administração & dosagem , Neoplasia Residual , Indução de Remissão , Análise de Sobrevida , Tiazóis/administração & dosagem , Resultado do Tratamento
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