Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.640
Filtrar
1.
Int J Nanomedicine ; 14: 7053-7064, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564865

RESUMO

Background: Food allergy (FA) is a significant public health problem. The therapeutic efficacy for FA is unsatisfactory currently. The breakdown of intestinal immune tolerance is associated with the pathogenesis of FA. Therefore, it is of great significance to develop novel therapeutic methods to restore immune tolerance in treating FA. Methods: We proposed an oral administration strategy to treat FA by co-delivering food allergen epitope fragment (peptide: IK) and adjuvant R848 (TLR7 ligand) in the mPEG-PDLLA nanoparticles (PPLA-IK/R848 NPs). The generation of tolerogenic dendritic cells (DCs) and regulatory T cells (Tregs) induced by PPLA-IK/R848 NPs were evaluated in vitro and in vivo. The therapeutic effects of PPLA-IK/R848 NPs were also assessed in an OVA-induced FA model. Results: PPLA-IK/R848 NPs could efficiently deliver IK to DCs to drive DCs into the tolerogenic phenotypes and promote the differentiation of Tregs in vitro and in vivo, significantly inhibited FA responses through the recovery of intestinal immune tolerance. Conclusion: Oral administration of PPLA-IK/R848 NPs could efficiently deliver IK and R848 to intestinal DCs and stimulate DCs into allergen tolerogenic phenotype. These tolerogenic DCs could promote the differentiation of Tregs, which significantly protected mice from food allergic responses. This study provided an efficient formulation to alleviate FA through the recovery of immune tolerance.


Assuntos
Alérgenos/imunologia , Células Dendríticas/imunologia , Sistemas de Liberação de Medicamentos , Epitopos/imunologia , Hipersensibilidade Alimentar/tratamento farmacológico , Hipersensibilidade Alimentar/imunologia , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Tolerância Imunológica , Linfócitos T Reguladores/imunologia , Sequência de Aminoácidos , Animais , Diferenciação Celular , Células Dendríticas/efeitos dos fármacos , Imidazóis/química , Imidazóis/farmacologia , Tolerância Imunológica/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Peptídeos/química , Poliésteres/química , Polietilenoglicóis/química , Linfócitos T Reguladores/efeitos dos fármacos
2.
Chem Commun (Camb) ; 55(90): 13506-13509, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31626260
3.
Nat Med ; 25(9): 1422-1427, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31406350

RESUMO

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition1-8. With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors9-11. Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Receptor trkA/genética , Adolescente , Adulto , Animais , Benzamidas/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Ácidos Nucleicos Livres/efeitos dos fármacos , Ácidos Nucleicos Livres/genética , Criança , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Xenoenxertos , Humanos , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/patologia , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinonas/administração & dosagem , Adulto Jovem
4.
Am J Vet Res ; 80(9): 868-877, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31449445

RESUMO

OBJECTIVE: To determine the effects of 3 α2-adrenergic receptor agonists (α2-ARAs), alone or in combination with butorphanol tartrate, on objective measurements of lameness in horses. ANIMALS: 17 adult polo horses with naturally occurring forelimb or hind limb lameness (or both). PROCEDURES: In a crossover design, each horse received each protocol (saline [0.09% NaCl] solution [2 mL, IV] or xylazine hydrochloride [0.33 mg/kg, IV], detomidine hydrochloride [0.007 mg/kg, IV], or romifidine hydrochloride [0.033 mg/kg, IV] alone or in combination with butorphanol [0.007 mg/kg, IV]) in random order, with a washout period (≥ 7 days) between protocols. Horses were assessed immediately prior to (baseline) and 10, 15, 20, 30, and 40 minutes after administration of each protocol for degree of sedation, mechanical nociceptive threshold (MNT), and objective lameness measurements. RESULTS: Compared with baseline values, sedation scores and MNTs were significantly higher at all evaluated time points following administration of all sedation protocols except xylazine alone; following administration of xylazine alone, sedation scores and MNTs were significantly higher at ≤ 30 minutes and ≤ 20 minutes, respectively. Significant differences in objective forelimb lameness measurements were noted after administration of the 3 α2-ARA-butorphanol combinations. Most significant differences in objective measurements of hind limb lameness were detected after administration of detomidine or romifidine, alone or in combination with butorphanol. CONCLUSIONS AND CLINICAL RELEVANCE: In the study horses, xylazine alone had the least impact on objective lameness measurements. The administration of α2-ARAs, particularly detomidine or romifidine, alone or in combination with butorphanol, resulted in small but significant effects on objective lameness measurements.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Butorfanol/uso terapêutico , Imidazóis/uso terapêutico , Coxeadura Animal/tratamento farmacológico , Xilazina/uso terapêutico , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Animais , Estudos Cross-Over , Quimioterapia Combinada , Feminino , Membro Anterior/efeitos dos fármacos , Marcha/efeitos dos fármacos , Cavalos , Imidazóis/administração & dosagem , Masculino , Distribuição Aleatória
6.
Braz J Med Biol Res ; 52(8): e8519, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389490

RESUMO

Recurrent hepatitis C (HCV) after liver transplantation (LT) is an important cause of morbidity and mortality. Antiviral treatment is recommended to avoid unfavorable outcomes. Direct-acting antivirals (DAA) have transformed HCV treatment, with higher efficacy and fewer side-effects than interferon-based therapies traditionally used. To evaluate DAA treatment outcomes at a Brazilian transplant unit, data of patients who finished HCV treatment at the Liver Transplant Unit of the University of Campinas were analyzed. Treatment consisted of sofosbuvir, daclatasvir, and ribavirin, for 12 or 24 weeks, according to the national guidelines. Fifty-five patients completed antiviral treatment and 54 had HCV-viral load results available. The majority of patients were male (78%), 58 years old on average, 65% had hepatocellular carcinoma (HCC) before LT, and 67% were interferon treatment-experienced. Most patients had HCV genotype 1 (65%), 35% had genotype 3, and started treatment on an average of 38 months after LT (range: 2-228). Fifty-eight percent were treated for 12 weeks and 42% for 24 weeks, using a mean dose of ribavirin of 10.1 mg/kg (4.2-16.1). There were no treatment interruptions due to serious side effects. The sustained virological response rate was 98%. Only one patient relapsed, a genotype 3 cirrhotic treated for 12 weeks. The average follow-up after starting antivirals was 20 months. There were no recurrences of HCC, but there was one rejection episode and one cirrhosis decompensation episode, both 12 weeks after treatment. DAA treatment is safe and effective in the post-LT setting and was not associated to HCC recurrence in the cohort studied.


Assuntos
Antivirais/administração & dosagem , Hepatite C/tratamento farmacológico , Imidazóis/administração & dosagem , Transplante de Fígado/efeitos adversos , Ribavirina/administração & dosagem , Sofosbuvir/administração & dosagem , Adulto , Idoso , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Resposta Viral Sustentada , Resultado do Tratamento , Carga Viral
7.
BMC Ophthalmol ; 19(1): 158, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340775

RESUMO

BACKGROUND: To report the first case of allergic contact dermatitis (ACD) associated with alcaftadine 0.25% ophthalmic solution. CASE PRESENTATION: The patient was a 51-year-old woman with no previous history of side effects to ophthalmic antihistamine agents. She had been prescribed alcaftadine 0.25% for allergic conjunctivitis. On first application of the medication, she did not experience any cutaneous reaction. One day later, after the second alcaftadine 0.25% application, both eyelids became swollen, and erythematous changes were evident. On slit-lamp examination, conjunctival injection was noted in the absence of conjunctival swelling or any other findings. Fundus examination was unremarkable. To evaluate the cause of ACD, a patch test was performed and 48 h later was noted to be positive for alcaftadine 0.25%. Based on the positive patch test, the patient was diagnosed with ACD caused by alcaftadine 0.25%. After 9 days of treatment, the swelling and erythema completely resolved. CONCLUSIONS: Although there have been no previous reports of alcaftadine 0.25%-associated ACD, it should be suspected in patients with swelling and erythematous change of both eyes after using alcaftadine 0.25%.


Assuntos
Benzazepinas/efeitos adversos , Dermatite Alérgica de Contato/etiologia , Imidazóis/efeitos adversos , Administração Oral , Benzazepinas/administração & dosagem , Conjuntivite Alérgica/tratamento farmacológico , Dermatite Alérgica de Contato/diagnóstico , Dermatite Alérgica de Contato/tratamento farmacológico , Feminino , Glucocorticoides/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Humanos , Imidazóis/administração & dosagem , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Soluções Oftálmicas , Órbita/diagnóstico por imagem , Tomografia Computadorizada por Raios X
8.
Eur J Med Chem ; 178: 715-725, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229874

RESUMO

A series of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides (IPAs), based on the structure of WZY02 discovered in our lab, were designed and synthesized as new anti-TB agents. Results reveal that many of them exhibit excellent in vitro inhibitory activity with low nanomolar MIC values against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates. Compounds 15b and 15d display good safety and pharmacokinetic profiles, suggesting their promising potential to be lead compounds for future antitubercular drug discovery.


Assuntos
Antituberculosos/farmacologia , Desenho de Drogas , Imidazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piridinas/farmacologia , Animais , Antituberculosos/administração & dosagem , Antituberculosos/química , Relação Dose-Resposta a Droga , Feminino , Imidazóis/administração & dosagem , Imidazóis/química , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/administração & dosagem , Piridinas/química , Relação Estrutura-Atividade
9.
Vet J ; 249: 53-57, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31239165

RESUMO

The aim of this study was to evaluate changes in epileptic seizures (ES) frequency and semiology in antiepileptic-medication (AEM)-naïve dogs with idiopathic epilepsy (DIE) after initiation of imepitoin (IMP) or phenobarbital (PB) monotherapy. In this observational prospective cohort study, inclusion criteria were as follows: diagnosis of idiopathic epilepsy (based on clinical, laboratory and magnetic resonance imaging investigations) in AEM-naïve dogs and presence of a detailed ES-diary. Exclusion criteria were: occurrence of cluster seizures (CS) or status epilepticus (SE) prior to treatment initiation and concurrent disease and/or treatments. Thirty-one DIE commenced IMP at 10-20mg/kg/12h and 30 dogs commenced PB at 2.50-3.30mg/kg/12h. AEM dosage was increased over time (up to IMP 30mg/kg/12h and PB 5.20mg/kg/12h). All dogs experienced generalised-tonic-clonic ES. In the IMP-group, pre-treatment median ES-frequency was 1.50ES/month (range, 1-4ES/month); post-treatment median ES-frequency was 0.95ES/m (range, 1ES/6m-3ES/m); n=21/31 (67.70%) dogs developed CS 1-18 months after initiation of treatment; n=7/31 (22.60%) dogs experienced unacceptable adverse events in the first month of treatment which required switching to an alternative AEM; and n=3/31(9.70%) dogs did not develop CS with a 3year follow-up. In the PB-group, pre-treatment median ES-frequency was 2.46ES/month (range, 1-7ES/month); post-treatment median ES-frequency was 0.36ES/month (range, 0ES/3years-1ES/month); n=11/30 (36.70%) dogs developed CS between 12-25 months after initiation of treatment. Nineteen of 30 (63.30%) dogs did not develop CS with a 3-year follow-up; three of these 19 dogs were ES free. In this study, AEM-naïve DIE receiving imepitoin-monotherapy developed CS significantly more frequently and earlier in the course of the disease, and developed aggression and required earlier discontinuation of monotherapy than AEM-naïve DIE receiving phenobarbital-monotherapy.


Assuntos
Anticonvulsivantes/uso terapêutico , Doenças do Cão/tratamento farmacológico , Epilepsia/veterinária , Imidazóis/uso terapêutico , Fenobarbital/uso terapêutico , Animais , Estudos de Coortes , Cães , Epilepsia/tratamento farmacológico , Imidazóis/administração & dosagem , Fenobarbital/administração & dosagem , Estudos Prospectivos , Convulsões/veterinária , Resultado do Tratamento
10.
Vet Anaesth Analg ; 46(4): 458-465, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31196750

RESUMO

OBJECTIVE: To determine time to first passage of feces, total fecal piles and incidence of colic in the first 24 hours postprocedure in horses undergoing standing sedation with detomidine, or general anesthesia with or without detomidine. STUDY DESIGN: Retrospective cohort study. ANIMALS: A total of 246 horses. METHODS: Records of all horses that underwent standing sedation or general anesthesia between December 2012 and March 2016 were reviewed. Horses aged <6 months, admitted for colic or cesarean section, with inadequate data, and those not administered xylazine and/or detomidine were excluded. Records included patient signalment, fasting duration, procedure performed, drugs administered, time to first feces, number of fecal piles during 24 hours postprocedure and mention of colic. Chi-square, Fisher's exact and Tukey's post hoc comparison tests were used. Parametric data were reported as mean ± standard deviation with significance defined as p <0.05. RESULTS: In total, 116 and 57 horses underwent general anesthesia without detomidine (group GA) and with detomidine (group GA-D), respectively, and remaining 73 horses underwent standing sedation with detomidine (group S-D). Detomidine dose was significantly higher in group S-D than in group GA-D. Time to first feces was longer (7.1 ± 4.2 hours), and group S-D horses passed one fewer fecal pile (6.3 ± 2.4) than group GA horses. There was no interaction between detomidine treatment and preprocedure food withholding and the time to first feces or the number of fecal piles in the first 24 hours postprocedure. Overall, seven horses (2.8%) showed signs of colic (five, one and one in GA, GA-D and S-D, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Detomidine administration, as part of an anesthetic protocol or for standing sedation procedures, should not be expected to contribute to postprocedural colic.


Assuntos
Cólica/veterinária , Sedação Consciente/veterinária , Fezes , Motilidade Gastrointestinal/fisiologia , Doenças dos Cavalos/cirurgia , Imidazóis/farmacologia , Anestesia/veterinária , Anestésicos/administração & dosagem , Anestésicos/efeitos adversos , Anestésicos/farmacologia , Animais , Cólica/etiologia , Sedação Consciente/efeitos adversos , Feminino , Cavalos , Imidazóis/administração & dosagem , Masculino , Complicações Pós-Operatórias/veterinária , Estudos Retrospectivos
11.
Nat Med ; 25(6): 941-946, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171878

RESUMO

Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK1. Here we performed a randomized phase 2 trial ( NCT02130466 ), in which patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib together with the PD-1-blocking antibody pembrolizumab (triplet; n = 60) or placebo (doublet; n = 60). The primary end point of progression-free survival was numerically improved in the triplet group-16.0 months-compared with 10.3 months in the doublet group (hazard ratio, 0.66; P = 0.043); however, the trial did not reach the planned benefit for a statistically significant improvement. Median duration of response was 18.7 months (95% confidence interval, 10.1-22.1) and 12.5 months (95% confidence interval, 6.0-14.1); 59.8 and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatment, respectively. Grade 3-5 treatment-related adverse events occurred in 58.3 and 26.7% of patients treated with triplet and doublet therapies, respectively, which were most commonly fever, increased transaminase levels and rash. One patient who received triplet therapy died of pneumonitis. In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Imidazóis/administração & dosagem , Estimativa de Kaplan-Meier , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Oximas/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/patologia , Adulto Jovem
12.
Nat Med ; 25(6): 936-940, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171879

RESUMO

Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year1-3. Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity4-6, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab ( NCT02130466 ). Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination. Eleven patients (73%; 95% confidence interval = 45-92%) had an objective response, and six (40%; 95% confidence interval = 16-68%) continued with a response at a median follow-up of 27 months (range = 10.3-38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.


Assuntos
MAP Quinase Quinase Quinases/antagonistas & inibidores , Melanoma/tratamento farmacológico , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Imidazóis/administração & dosagem , Imunoterapia , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Mutação , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/terapia , Adulto Jovem
13.
N Engl J Med ; 381(7): 626-636, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31166680

RESUMO

BACKGROUND: Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors. METHODS: We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively. RESULTS: A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years. CONCLUSIONS: First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline and Novartis; COMBI-d ClinicalTrials.gov number, NCT01584648; COMBI-v ClinicalTrials.gov number, NCT01597908.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imidazóis/administração & dosagem , Melanoma/tratamento farmacológico , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Seguimentos , Humanos , Imidazóis/efeitos adversos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Melanoma/genética , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Mutação , Oximas/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Adulto Jovem
14.
Pharm Dev Technol ; 24(7): 891-901, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31062987

RESUMO

This study was conducted to develop an in situ thermosensitive gel containing sertaconazole-loaded nanostructured lipid carriers (NLCs) for prolonged ocular drug delivery. To this end, sertaconazole-loaded NLCs (sertaconazole-NLCs) were prepared by emulsification solvent-diffusion method and the effects of different formulation variables were assessed using the fractional factorial design. Then, optimized sertaconazole-NLCs were incorporated into the pluronic F127 (PF127)/hydroxy propylmethylcellulose (HPMC) K4M hydrogel. The formulations were examined for pH, gelation temperature, rheological properties, in vitro permeation studies, and anti-fungal activity. The optimized sertaconazole-NLCs showed a mean particle size of 272.40 nm, encapsulation efficiency of 89.97%, zeta potential of 12.9 mV, and polydispersity index of 0.31. All the in situ formulations had acceptable pH, ranging from 5.89 to 6.28. The gelation temperature of the optimized formulation was 35.1 °C after dilution with simulated tear fluid (STF). Sertaconazole-NLCs showed a higher antifungal activity and permeation through the bovine cornea compared to the free drug and the in situ gel formulation. The cornea penetration of sertaconazole for the in situ gel of NLCs was also comparable to that for free drug. The obtained results indicated that the prepared nanocomposite system may have potential for treatment of fungal keratitis.


Assuntos
Antifúngicos/administração & dosagem , Portadores de Fármacos/química , Imidazóis/administração & dosagem , Lipídeos/química , Nanopartículas/química , Tiofenos/administração & dosagem , Animais , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Bovinos , Córnea/metabolismo , Liberação Controlada de Fármacos , Hidrogéis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Ceratite/tratamento farmacológico , Nanopartículas/ultraestrutura , Poloxâmero/química , Temperatura Ambiente , Tiofenos/farmacocinética , Tiofenos/farmacologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-31100047

RESUMO

The aim of the study was to assess the dietary intake of caramel colours and their by-products 4-methylimidazole (4-MEI) and 2-acetyl-4-tetrahydroxybutylimidazole (THI) for the Chinese population. Based on the typical and maximum reported use levels of caramel colours in 15 food categories, the dietary intakes of combined and single-class caramel colours of Classes I, III and IV were estimated with the food consumption data from the China National Nutrient and Health Survey. Using the mean values of 4-MEI and THI contents in Class III and Class IV Caramel colour samples, the exposures to 4-MEI and THI from dietary caramel colours were derived. The results showed that the combined and individual average dietary caramel colour intakes for the Chinese population of different age groups were estimated to be 232-60.3 mg kg-1 bw day-1 for combined caramels, 5.9-29.2 mg kg-1 bw day-1 for Class I, 7.7-29.6 mg kg-1 bw day-1 for Class III, 21.2-54.3 mg kg-1 bw day-1 for Class IV, which were far below the group acceptable daily intake (ADI) and respective ADIs. The combined intake of 4-MEI from Class III and IV caramel colours was estimated to be 3.8-5.2 µg kg-1 bw day-1 on average, and 12.9-27.1 µg kg-1 bw day-1 at 95th-97.5th percentile for the general population. The anticipated exposure to THI from Class III caramel colours was estimated to be 0.1-0.3 µg kg-1 bw day-1 on average and 0.5-1.7 µg kg-1 bw day-1 at 95th-97.5th percentile for the general population. The dietary caramel colours intakes and the exposures to 4-MEI and THI from dietary caramel colour for the Chinese population were considered to be of low health concern based on the present toxicological data. Soy sauce, vinegar and compound seasonings were found to be the main contributors to the dietary intake of caramel colours.


Assuntos
Carboidratos/análise , Exposição Dietética/análise , Corantes de Alimentos/análise , Imidazóis/análise , Adolescente , Adulto , Animais , Carboidratos/administração & dosagem , Criança , Pré-Escolar , Feminino , Análise de Alimentos , Corantes de Alimentos/administração & dosagem , Humanos , Imidazóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Ratos , Adulto Jovem
16.
Vet Anaesth Analg ; 46(3): 325-334, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30935776

RESUMO

OBJECTIVE: To determine the required rate of a detomidine infusion (loading dose 5 µg kg-1; initial rate 12.5 µg kg-1 hour-1) added to a constant infusion of methadone (0.2 mg kg-1; 0.05 mg kg-1 hour-1) for sedation in standing horses and ponies undergoing elective surgeries with appropriate local anaesthetic techniques. STUDY DESIGN: Prospective, clinical study. ANIMALS: Adult, healthy, client-owned, non-food-producing horses or ponies sedated for elective standing surgeries longer than 45 minutes. METHODS: At baseline (in the stables before administration of sedative agents), at 10 minutes after sedation and every 5 minutes thereafter, ataxia, sedation and surgical condition were evaluated; each scored 0-3. These scores were used to adjust the detomidine administration rate using the Ghent Sedation Algorithm. A 10 cm visual analogue scale (VAS) was used by the main surgeon at the end of the procedure to evaluate the surgical conditions. Heart rate, systolic arterial pressure and respiratory frequency were also recorded at each time point. For statistical analysis, anova for normal, Kruskal-Wallis H-test for non-normal variables, and Mann-Whitney U test for VAS were used. RESULTS: From the 42 horses/ponies included in this study, 28 underwent dental procedures and 14 other types of procedures. Overall, dental procedures required higher mean detomidine rates compared with other types of surgeries (16.9 ± 4.5 versus 9.0 ± 1.9 µg kg-1 hour-1) (p < 0.001). Dental procedures were assigned similar VAS scores, median (range), of 7.8 (5.8-10) with other procedures, 8.7 (2.8-10). Cardiovascular changes were not clinically significant. No signs or behavioural changes of abdominal pain were observed postoperatively. CONCLUSIONS AND CLINICAL RELEVANCE: Satisfactory surgical conditions were achieved using a combination of detomidine and methadone infusions with locoregional anaesthesia, with no adverse effects. Dental procedures required higher detomidine dose rates compared with other surgeries.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Anestesia/veterinária , Anestésicos Combinados/administração & dosagem , Cavalos/cirurgia , Hipnóticos e Sedativos/administração & dosagem , Imidazóis/administração & dosagem , Metadona/administração & dosagem , Anestesia Dentária/veterinária , Animais , Infusões Intravenosas/veterinária , Estudos Prospectivos
17.
Mol Biotechnol ; 61(7): 489-497, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31028604

RESUMO

Escape from apoptosis, one of the characteristic features of cancer cells, is a case that reduces the therapeutic efficacy of apoptosis-inducing molecules used in the cancer treatment. Stabilization of the P53 protein, which is responsible for the regulation of apoptosis mechanism in the cell, is therefore an important therapeutic goal. Nutlin3a inhibits the degradation of the P53 protein, triggers P53-mediated apoptosis in cancer cells and enhances the effectiveness of chemotherapeutics. However, its low aqueous solubility is the major disadvantage when it comes to in vivo administration. In order to facilitate an aqueous formulation of Nutlin3a and to enhance its apoptotic activity on cancer cells, Nutlin3a was encapsulated in solid lipid nanoparticles (SLNs) prepared by Ouzo method. Physicochemical characterization was performed and activity of apoptosis induction on wild-type P53 expressing LNCaP prostate cancer cell line was evaluated. Nutlin3a-loaded cationic solid lipid nanoparticles were found to stabilize functional P53 at protein level. In addition, induction rate of apoptosis by nanoparticles was higher than Nutlin3a solution in DMSO, proving this nanoparticle formulation is a promising candidate for increasing the efficiency of Nutlin3a for P53(+) cancer cases. Thus, it is anticipated that the results will contribute to evaluate the use of lipid-based nanocarriers to enhance the therapeutic potential of small molecules that are important in cancer cure.


Assuntos
Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Imidazóis/administração & dosagem , Nanopartículas , Piperazinas/administração & dosagem , Linhagem Celular Tumoral , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Proteína Supressora de Tumor p53/metabolismo
18.
Eur J Pharm Biopharm ; 139: 253-261, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981947

RESUMO

Resiquimod (R848), a member of the imidazoquinoline family, is a Toll-like receptor 7/8 agonist with high potency for cancer immunotherapy. However, tolerance induction and adverse effects limit its development as a drug. Encapsulation in a polymer matrix can circumvent these limitations, as shown in our formerly published approach where R848 was loaded into polylactic acid (PLA)-based nanoparticles (NP). Although the results were encouraging, low rates of encapsulation and rapid release of the drug were observed. In this study, we present a new strategy using mixed NP from modified linear PLA in order to improve the encapsulation and modulate the release profile of R848. Modified PLA polymers were designed and synthesized by microwave-assisted ring opening polymerization of d,l-lactide, using polyethylene glycol as initiator to increase the hydrophilic properties of the polymer or linear saturated aliphatic chains (C8 or C20) to increase the affinity with hydrophobic R848. NP were prepared by solvent evaporation method, leading to particles of 205-288 nm loaded with either R848 or DiO as a tracking agent. The release profile showed longer retention of R848 at both neutral and acidic pH for NP from grafted polymers. Upon exposure to phagocytic immune cells, NP were actively taken up by the cells and no impact on cell viability was observed, independently of the constitutive polymer. All R848-loaded NP activated macrophages to secrete interleukin-6, demonstrating that the drug cargo was immunologically active. Importantly, macrophage activation by NP-delivered R848 was slower than with free R848, in accordance with the in vitro release profiles. Thus, NP prepared from modified PLA polymers showed no signs of toxicity to immune cells and efficiently delivered their immunoactive cargo in a delayed manner. This delivery strategy may enhance the efficacy and safety of small-molecule immunostimulants.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Portadores de Fármacos/química , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Poliésteres/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos/métodos , Imunoterapia/métodos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neoplasias/imunologia , Tamanho da Partícula , Cultura Primária de Células
19.
Ecotoxicol Environ Saf ; 175: 155-163, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30897414

RESUMO

A well-known strategy for managing pest resistance is application of mixture of pesticides. Conventionally formulated pesticides have several environmental incompatibilities. The use of biocompatible and biodegradable nanocarriers in formulating pesticides could improve environmental protection. In this study, a mixture of imidacloprid and lambda-cyhalothrin was co-encapsulated for the first time using liposomes as nanocarrier to simultaneously deliver these insecticides. Ethanol injection was used to produce self-assembled liposomes. The formed nanoliposomes were coated with different concentrations of chitosan. Nanoparticles were characterized by dynamic light scattering (DLS), scanning electron microscope (SEM) and FT-IR spectroscopy. The encapsulation efficiencies of lambda-cyhalothrin and imidacloprid were about 93% and 51%, respectively. The insecticide carrying liposomes had a size and surface charge of 57 nm and +0.6 mV, respectively. The size and surface charge of the particles produced were increased to 69 nm and +31 mV after being coated with chitosan (0.1%, W/V). In this study, residual activity of technical grade imidacloprid, lambda-cyhalothrin and their mixture and the effect of adjuvants used in commercial and nano formulations of these insecticides on Myzus persicae Sulzer was investigated. The insecticidal effects and duration of residual activity of nano-formulations was correlated with concentration of chitosan in final formulation. In accordance with the life cycle of M. persicae, using the mixture of imidacloprid and lambda-cyhalothrin improves the residual effect over their use alone. The use of lipid nanocarriers makes the improvement even further and can be a better alternative to conventional combination of these insecticides due to their more environmental friendliness.


Assuntos
Afídeos/efeitos dos fármacos , Nanopartículas , Neonicotinoides/administração & dosagem , Nitrilos/administração & dosagem , Nitrocompostos/administração & dosagem , Piretrinas/administração & dosagem , Animais , Cápsulas , Imidazóis/administração & dosagem , Inseticidas/administração & dosagem , Lipossomos , Neonicotinoides/farmacologia , Nitrilos/farmacologia , Nitrocompostos/farmacologia , Praguicidas , Piretrinas/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
20.
Eur J Med Chem ; 170: 261-275, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30904783

RESUMO

The 5-HT7 receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT7 receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, Ki 5-HT7R = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain Cmax = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT7 receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain.


Assuntos
Imidazóis/química , Imidazóis/farmacocinética , Indóis/química , Indóis/farmacocinética , Neuralgia/tratamento farmacológico , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacocinética , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Células HEK293 , Halogenação , Humanos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Indóis/administração & dosagem , Indóis/uso terapêutico , Masculino , Camundongos , Modelos Moleculares , Neuralgia/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA