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1.
Clin Nucl Med ; 44(6): 507-509, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30985435

RESUMO

An 86-year-old woman with cognitive impairment and left hemiparesis underwent F-THK5351 PET 4 months before her death. In addition to "normal" off-target binding in the basal ganglia, abnormal accumulation was observed along the pyramidal tract and around the right basal ganglia as ring-shaped uptake that overlapped a gadolinium-enhanced lesion. Postmortem pathological examination revealed that she had glioblastoma multiforme with associated gliosis, in which monoamine oxidase B (MAO-B) activity is increased. In vitro autoradiography of the corresponding lesion demonstrated specific binding of F-THK5351, which was blocked by an MAO-B-selective ligand. Thus, F-THK5351 PET may reflect glioblastomas and associated gliosis by binding to MAO-B.


Assuntos
Aminopiridinas/farmacocinética , Neoplasias Encefálicas/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Quinolinas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Idoso de 80 Anos ou mais , Feminino , Humanos , Monoaminoxidase/metabolismo , Ligação Proteica
2.
Expert Rev Anti Infect Ther ; 17(3): 159-168, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30686133

RESUMO

INTRODUCTION: Impetigo is the most common bacterial skin infection in children. Treatment is becoming complicated due to the development of antimicrobial resistance, especially in the main pathogen, Staphylococcus aureus. Ozenoxacin, a novel non-fluorinated topical quinolone antimicrobial, has demonstrated efficacy in impetigo. Areas covered: This article reviews the microbiology, pharmacodynamic and pharmacokinetic properties of ozenoxacin, and its clinical and microbiological efficacy in impetigo. Expert opinion: In an environment of increasing antimicrobial resistance and concurrent slowdown in antimicrobial development, the introduction of a new agent is a major event. Ozenoxacin is characterized by simultaneous affinity for DNA gyrase and topoisomerase IV, appears to be impervious to certain efflux pumps that confer bacterial resistance to other quinolones, shows low selection of resistant mutants, and has a mutant prevention concentration below its concentration in skin. These mechanisms protect ozenoxacin against development of resistance, while the absence of a fluorine atom in its structure confers a better safety profile versus fluoroquinolones. In vitro studies have demonstrated high potency of ozenoxacin against staphylococci and streptococci including resistant strains of S. aureus. Clinical trials of ozenoxacin in patients with impetigo reported high clinical and microbiological success rates. Preserving the activity and availability of ozenoxacin through antimicrobial stewardship is paramount.


Assuntos
Aminopiridinas/uso terapêutico , Antibacterianos/uso terapêutico , Impetigo/tratamento farmacológico , Quinolonas/uso terapêutico , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Criança , Farmacorresistência Bacteriana , Humanos , Impetigo/microbiologia , Quinolonas/farmacocinética , Quinolonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificação , Resultado do Tratamento
3.
Biomed Chromatogr ; 33(6): e4491, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30663096

RESUMO

A simple, sensitive and rapid assay method has been developed and validated as per regulatory guidelines for the estimation of enasidenib on mouse dried blood spots (DBS) using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The method employs liquid extraction of enasidenib from DBS disks of mouse whole blood followed by chromatographic separation using 0.2% formic acid-acetonitrile (25:75, v/v) at a flow rate of 1.0 mL/min on an Atlantis dC18 column with a total run time of 2.0 min. The MS/MS ion transitions monitored were m/z 474.0 → 267.1 for enasidenib and m/z 309.2 → 251.3 for the internal standard (warfarin). The assay was linear in the range of 1.01-3044 ng/mL. The within-run and between-run precisions were in the range of 3.18-9.06 and 4.66-8.69%, respectively. Stability studies showed that enasidenib was stable on DBS cards for 1 month. This novel method has been applied to analyze the DBS samples of enasidenib obtained from a pharmacokinetic study in mice.


Assuntos
Aminopiridinas/sangue , Aminopiridinas/farmacocinética , Cromatografia Líquida/métodos , Teste em Amostras de Sangue Seco/métodos , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue , Triazinas/farmacocinética , Aminopiridinas/química , Animais , Limite de Detecção , Modelos Lineares , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Reprodutibilidade dos Testes , Triazinas/química
4.
J Pharm Biomed Anal ; 166: 197-204, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30660034

RESUMO

Ribociclib is a selective, orally bioavailable inhibitor of cyclin-dependent kinase (CDK) 4/6, which has therapeutic potential for a variety of cancer types. This study was to develop and validate a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for determining total and unbound concentrations of ribociclib in human plasma and brain tumor tissue samples. Plasma and tumor homogenate samples were extracted using protein precipitation with acetonitrile. Unbound fraction in plasma or tumor homogenate was determined by equilibrium dialysis method. Chromatographic separation was achieved based on aqueous normal-phase chromatography mechanism on a Waters XBridge™ Amide column under isocratic elution with acetonitrile-ammonium formate (10 mM, pH 3) (75:25, v/v) at a flow rate of 0.8 mL/min. Ribociclib and the internal standard ([13C6]ribociclib) were monitored at the mass transitions m/z, 435.3 > 367.2 and 441.3 > 373.2, respectively, using positive electrospray ionization mode. The lower limit of quantitation (LLOQ) was 0.5 nM of ribociclib in plasma. Linear calibration curve was established at the concentration range of 0.5-1000 nM in plasma. Intra- and inter-day precision and accuracy were within the generally accepted criteria for bioanalytical method. The developed method was successfully applied to determine the plasma pharmacokinetics and central nervous system penetration of ribociclib in patients with malignant primary brain cancer.


Assuntos
Aminopiridinas/sangue , Antineoplásicos/sangue , Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Purinas/sangue , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Encéfalo/enzimologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Calibragem , Cromatografia Líquida , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Ligação Proteica , Purinas/farmacocinética , Purinas/uso terapêutico , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
5.
Expert Opin Drug Metab Toxicol ; 15(2): 85-91, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30577708

RESUMO

INTRODUCTION: The combination of cyclin-dependent kinases 4 and 6 (CDK 4 and 6) inhibitors with endocrine therapy represents a new standard of care for endocrine-receptor positive metastatic breast cancer. Currently, three compounds are approved. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration in view of the results of the MONARCH1 and 2 trials. Area covered: In this article, we review the preclinical and clinical development of abemaciclib in advanced breast cancer, describing current therapeutic indications and open questions. Expert opinion: Results of phase III trials investigating abemaciclib in patients with endocrine-receptor positive metastatic breast cancer have shown a substantial improvement in progression-free-survival, with a safe and manageable toxicity profile. In order to better select patients who will more likely respond to CDK4/6 inhibitors, biomarkers need to be identified. To optimize CDK4/6 targeting, combination therapies are being tested in several ongoing trials.


Assuntos
Aminopiridinas/administração & dosagem , Benzimidazóis/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Intervalo Livre de Doença , Feminino , Humanos , Metástase Neoplásica , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia
6.
Drug Des Devel Ther ; 12: 4047-4057, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30538429

RESUMO

Purpose: To determine the pharmacokinetic properties of the common tablet of roflumilast administered in single and multiple oral doses in Chinese subjects. Subjects and methods: Both the single- and multiple-dose studies included 12 adults (6 males and 6 females). In this single-center, open-label study, single doses of 0.25, 0.375, and 0.5 mg were administered using a randomized, three-way crossover design, and then, the 0.375 mg dose was continued for 11 days once daily. The pharmacokinetic parameters for roflumilast and roflumilast N-oxide were determined and the safety evaluation included adverse events assessed by monitoring, physical examination, vital sign tests, and clinical laboratory tests. Results: After every single dose, the time to the maximum concentration (C max) of roflumilast (T max) was 0.25-2.0 hours; thereafter, the concentration declined, with a mean half-life (t 1/2) of 19.7-20.9 hours over the range of 0.25-0.50 mg. As for roflumilast N-oxide, the mean t 1/2 was 23.2-26.2 hours. The area under curve from the beginning to 24 hours (AUC0-24 h), the AUC until infinity (AUCinf), and the C max of roflumilast and roflumilast N-oxide increased in a dose-proportional manner. After multiple doses, the accumulation index (Rac) on the 11th day of the steady state was ~1.63 for roflumilast and 3.20 for roflumilast N-oxide. No significant sex differences were observed in the pharmacokinetic parameters of roflumilast and roflumilast N-oxide. In addition, there were no serious adverse events across the trial. Conclusion: Roflumilast was safe and well-tolerated in healthy volunteers, and a linear increase in its C max and AUC values was observed at doses ranging from 0.25 to 0.50 mg.


Assuntos
Aminopiridinas/farmacocinética , Benzamidas/farmacocinética , Adolescente , Adulto , Aminopiridinas/administração & dosagem , Aminopiridinas/química , Benzamidas/administração & dosagem , Benzamidas/química , China , Estudos Cross-Over , Ciclopropanos/administração & dosagem , Ciclopropanos/química , Ciclopropanos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Comprimidos , Adulto Jovem
7.
Future Microbiol ; 13: 31-40, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29745239

RESUMO

AIM: Ozenoxacin is a nonfluorinated quinolone antibacterial approved for topical treatment of impetigo. Because quinolones have known chondrotoxic effects in juvenile animals, the potential toxicity of ozenoxacin was assessed in preclinical studies. MATERIALS & METHODS: Ozenoxacin or ofloxacin (300 mg/kg/day for 5 days, for each compound) was orally administered to juvenile rats, and oral ozenoxacin (10-100 mg/kg/day for 14 days) was administered to juvenile dogs. RESULTS: In juvenile rats, ozenoxacin showed no chondrotoxicity, whereas ofloxacin produced typical quinolone-induced lesions in articular cartilage in three of ten rats. Oral ozenoxacin administration to juvenile dogs showed no chondrotoxicity or toxicologically relevant findings in selected target organs. CONCLUSION: Ozenoxacin was generally well-tolerated in juvenile rats and dogs, with no evidence of quinolone-induced arthropathy.


Assuntos
Aminopiridinas/toxicidade , Antibacterianos/toxicidade , Cartilagem Articular/efeitos dos fármacos , Artropatias/induzido quimicamente , Quinolonas/toxicidade , Administração Oral , Aminopiridinas/farmacocinética , Animais , Antibacterianos/farmacocinética , Biomarcadores/sangue , Biomarcadores/urina , Cartilagem Articular/patologia , Cães , Feminino , Humanos , Masculino , Ofloxacino/farmacocinética , Ofloxacino/toxicidade , Quinolonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Estatísticas não Paramétricas
8.
Expert Opin Pharmacother ; 19(5): 517-524, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29522364

RESUMO

INTRODUCTION: There have been numerous clinical trials of CDK4/6 inhibitors performed on various carcinomas including breast cancer. One such inhibitor tested and which has ongoing clinical trials for breast cancer is abemaciclib. Abemaciclib is a molecular-targeted agent that targets basic cell cycle regulatory mechanisms. Areas covered: This review discusses the available clinical data and ongoing clinical trials of abemaciclib in breast cancer. Expert opinion: Abemaciclib has demonstrated a clear anti-tumour effect and manageable toxicity against HR-positive, HER2-negative breast cancer in many clinical trials and is expected to be an important standard therapy. However, currently, besides oestrogen receptor expression, there is a definite lack of predictive biomarkers for response and/or tolerance to abemaciclib, which is important for patient selection. Another problem is that its contribution to overall survival (OS) has not been shown. And while two large the phase 3 study highlighted the anti-tumour effect of abemaciclib, the OS results are awaited. Furthermore, the effect on brain metastases is expected to be unique to abemaciclib as the response of brain metastasis in HR-positive breast cancer patients has been confirmed in a few cases with case collection still ongoing.


Assuntos
Aminopiridinas/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Aminopiridinas/farmacocinética , Benzimidazóis/farmacocinética , Biomarcadores/análise , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Quimioterapia Combinada , Estradiol/análogos & derivados , Estradiol/uso terapêutico , Feminino , Fulvestranto , Humanos , Estadiamento de Neoplasias , Prognóstico
9.
Artigo em Inglês | MEDLINE | ID: mdl-29563781

RESUMO

Background: The oral selective phosphodiesterase-4 inhibitor roflumilast (ROF) reduces exacerbations in patients with severe COPD. Adverse events (AEs) can cause early ROF discontinuation. Alternative dosing strategies may help patients continue their therapy. Methods: In this multicenter, double-blind trial, 1,321 patients with severe COPD were randomized 1:1:1 to 4 weeks' treatment with ROF 250 µg once daily (OD), 500 µg every other day (EOD), or 500 µg OD, each followed by ROF 500 µg OD for 8 weeks, plus standard therapy. The primary end point was the percentage of patients prematurely discontinuing study treatment. Results: Patients in the 250 µg OD/500 µg OD group had significantly fewer treatment discontinuations (odds ratio [OR] 0.66 [95% CI 0.47-0.93], p=0.017) and lower rates of AEs of interest such as diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain (OR 0.63 [95% CI 0.47-0.83], p=0.001) compared with those in the 500 µg OD group. Although rates of discontinuation and AEs of interest were numerically lower with ROF 500 µg EOD/500 µg OD, the difference was not significant (OR 0.76, p=0.114, and OR 0.78, p=0.091, respectively) compared with ROF 500 µg OD. Conclusion: A dose of ROF 250 µg OD for 4 weeks before escalation to the approved maintenance dose of 500 µg OD resulted in reduced treatment discontinuation and improved tolerability.


Assuntos
Aminopiridinas/administração & dosagem , Benzamidas/administração & dosagem , Pulmão/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Idoso , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Ciclopropanos/farmacocinética , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Modelos Logísticos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Inibidores da Fosfodiesterase 4/efeitos adversos , Inibidores da Fosfodiesterase 4/farmacocinética , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
10.
Anal Bioanal Chem ; 410(11): 2815-2828, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29546543

RESUMO

Generation of skin distribution profiles and reliable determination of drug molecule concentration in the target region are crucial during the development process of topical products for treatment of skin diseases like psoriasis and atopic dermatitis. Imaging techniques like mass spectrometric imaging (MSI) offer sufficient spatial resolution to generate meaningful distribution profiles of a drug molecule across a skin section. In this study, we use matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to generate quantitative skin distribution profiles based on tissue extinction coefficient (TEC) determinations of four different molecules in cross sections of human skin explants after topical administration. The four drug molecules: roflumilast, tofacitinib, ruxolitinib, and LEO 29102 have different physicochemical properties. In addition, tofacitinib was administrated in two different formulations. The study reveals that with MALDI-MSI, we were able to observe differences in penetration profiles for both the four drug molecules and the two formulations and thereby demonstrate its applicability as a screening tool when developing a topical drug product. Furthermore, the study reveals that the sensitivity of the MALDI-MSI techniques appears to be inversely correlated to the drug molecules' ability to bind to the surrounding tissues, which can be estimated by their Log D values. Graphical abstract.


Assuntos
Descoberta de Drogas/métodos , Absorção Cutânea , Pele/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Acetamidas/administração & dosagem , Acetamidas/farmacocinética , Administração Tópica , Aminopiridinas/administração & dosagem , Aminopiridinas/farmacocinética , Benzamidas/administração & dosagem , Benzamidas/farmacocinética , Ciclopropanos/administração & dosagem , Ciclopropanos/farmacocinética , Humanos , Inibidores da Fosfodiesterase 4/administração & dosagem , Inibidores da Fosfodiesterase 4/farmacocinética , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirróis/administração & dosagem , Pirróis/farmacocinética
11.
Regul Toxicol Pharmacol ; 94: 124-143, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29407202

RESUMO

Ecological risk assessments are often limited in their ability to consider metabolic transformations for fish species due to a lack of data. When these types of evaluations are attempted they are often based on parent chemical only, or by assuming similarity to available mammalian metabolic pathways. The metabolism maps for five pesticides (fluazinam, halauxifen-methyl, kresoxim-methyl, mandestrobin, and tolclofos-methyl) were compared across three species. A rapid and transparent process, utilizing a database of systematically collected information for rat, goat, and fish (bluegill or rainbow trout), and using data evaluation tools in the previously described metabolism pathway software system MetaPath, is presented. The approach demonstrates how comparisons of metabolic maps across species are aided by considering the sample matrix in which metabolites were quantified for each species, differences in analytical methods used to identify metabolites in each study, and the relative amounts of metabolites quantified. By incorporating these considerations, more extensive rat and goat metabolism maps were found to be useful predictors of the more limited metabolism of the five pesticides in fish.


Assuntos
Cabras/metabolismo , Oncorhynchus mykiss/metabolismo , Perciformes/metabolismo , Praguicidas/farmacocinética , Aminopiridinas/farmacocinética , Animais , Feminino , Masculino , Redes e Vias Metabólicas , Compostos Organotiofosforados/farmacocinética , Ratos , Especificidade da Espécie , Estrobilurinas/farmacocinética
12.
Eur J Drug Metab Pharmacokinet ; 43(4): 453-460, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29470718

RESUMO

BACKGROUND AND OBJECTIVES: Ulixertinib (BVD-523) is a novel and selective reversible inhibitor of ERK1/ERK2. The primary objectives of the study were to evaluate the pharmacokinetics of ulixertinib in mice, rats, and dogs followed by prediction of human pharmacokinetic profile by allometric equations with/without correction factors. METHODS: Oral and intravenous pharmacokinetic profiles of ulixertinib were generated in mice, rats, and dogs. The human intravenous pharmacokinetics profiles [volume of distribution (Vss) and clearance (CL)] were predicted employing simple allometry and using correction factors [maximum life span potential (MLP) and brain weight (BW)]. Pharmacokinetic data obtained from dogs were used to simulate human oral profile [area under the curve (AUC) and maximum plasma concentrations (Cmax)]. RESULTS: Post-intravenous administration the CL was moderate in dogs (15.5 mL/min/kg) and low in mice (6.24 mL/min/kg) and rats (1.67 mL/min/kg). Vss was 0.56, 0.36, and 1.61 L/kg in mice, rats, and dogs, respectively. The half-life (t½) of ulixertinib ranged between 1.0 and 2.5 h across the animal species. Following oral administration ulixertinib attained maximum concentration in plasma (Tmax) within 0.50-0.75 h in mice and rats, indicating that absorption was rapid; however, in dogs, Tmax attained at 2 h. Absolute oral bioavailability in mice and rats was > 92%; however, in dogs, it was 34%. By different allometric approaches, simple method and brain weight correction factor shown clear improvement in the prediction efficiency of allometric scaling for Vss (1.34-1.70 L/kg) and CL (4.18-6.09 mL/min/kg), respectively, comparing with the MLP method and simple method for CL. Similarly, simulation of oral human profile was attained from scaled values and dog data to predict reported human profile (AUC and Cmax). CONCLUSIONS: The derived pharmacokinetic parameters (AUC and Cmax at 600 mg dose) and simulated plasma concentration-time profiles of ulixertinib in humans were predicted with good confidence by allometric approach.


Assuntos
Aminopiridinas/farmacocinética , Pirróis/farmacocinética , Administração Intravenosa , Administração Oral , Aminopiridinas/administração & dosagem , Aminopiridinas/sangue , Animais , Disponibilidade Biológica , Simulação por Computador , Cães , Humanos , Masculino , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Pirróis/administração & dosagem , Pirróis/sangue , Ratos , Especificidade da Espécie
13.
Eur J Med Chem ; 148: 477-486, 2018 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29477888

RESUMO

In the present work, we designed and synthesized new roflumilast analogues with preferential-selective PDE-4B inhibition activity and improved pharmacokinetic properties. The unsubstituted benzo[d]thiazol-2-yl and -6-yl benzamide derivatives (4a and 6a) showed both good potency and preferential selectivity for PDE-4B. More remarkably, 6c revealed 6 times preferential PDE-4B/4D selectivity with a significant increase of in vitro cAMP and good % inhibition of TNF-α concentration. In addition, the in vitro pharmacokinetics of 6c showed good metabolic stability with in vitro CLint (5.67 mL/min/kg) and moderate % plasma protein binding (53.71%). This was reflected onto increased in vivo exposure with a half-life greater than roflumilast by 3 folds (21 h) and a Cmax value of 113.958 ng/mL. Molecular docking attributed its good activity to its key binding interactions in PDE-4B active site with additional hydrogen bonding with amino acids lining the metal pocket. Summing up, 6c can be considered as suitable candidate for further investigation for the treatment of COPD.


Assuntos
Aminopiridinas/síntese química , Aminopiridinas/farmacocinética , Benzamidas/síntese química , Benzamidas/farmacocinética , Simulação de Acoplamento Molecular , Inibidores da Fosfodiesterase 4/síntese química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Aminopiridinas/química , Aminopiridinas/metabolismo , Benzamidas/química , Benzamidas/metabolismo , Domínio Catalítico , AMP Cíclico/metabolismo , Ciclopropanos/síntese química , Ciclopropanos/química , Ciclopropanos/metabolismo , Ciclopropanos/farmacocinética , Ligações de Hidrogênio , Fator de Necrose Tumoral alfa/antagonistas & inibidores
14.
Expert Opin Pharmacother ; 19(3): 299-305, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29355400

RESUMO

INTRODUCTION: Breast cancer (BC) remains the most frequently diagnosed cancer and the most common cause of cancer death among women of all races worldwide. Over 80% of BC cases are hormone receptor (HR)-positive, comprised of luminal A and luminal B per molecular subtypes, imposing an urgent need to fully understand the mechanisms behind progression. Ribociclib is a selective cycline-dependent kinase 4 and 6 inhibitor. A phase 1 and a phase 3 trial have established a definitive role of ribociclib as frontline in the treatment of endocrine-sensitive advanced BC. Areas covered: Herein, the authors provide an overview of the data on ribociclib covering all aspects of the drug from its pharmacokinetics to efficacy and safety. The authors also provide their perspectives for the future. Expert opinion: Ribociclib is offering an opportunity to explore a new compound at the crossroads of different molecular activity and cell targets, which focus on endocrine-resistance reversal in multiple settings including early BC. Moreover, its activity against different subtypes of BC is being studied as is its immune-modulating effect. One cautionary note is that, in a market of concomitant similar competitors, a financial discussion will be mandatory.


Assuntos
Aminopiridinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Purinas/uso terapêutico , Aminopiridinas/metabolismo , Aminopiridinas/farmacocinética , Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Meia-Vida , Humanos , Estadiamento de Neoplasias , Purinas/metabolismo , Purinas/farmacocinética , Receptor ErbB-2/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
15.
Future Oncol ; 14(1): 23-40, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29243965

RESUMO

Mutations in IDH2 genes (mIDH2) occur in approximately 12% of patients with acute myeloid leukemia. Enasidenib is an oral, small-molecule inhibitor of mIDH2 proteins. Enasidenib is shown to suppress the oncometabolite, 2-hydroxyglutarate, and promote differentiation of leukemic bone marrow blasts. In a Phase I dose-escalation and expansion study, 40.3% of patients with relapsed/refractory acute myeloid leukemia responded to enasidenib monotherapy, including 19.3% who achieved complete remission and 11% who proceeded to transplant. Median overall survival was 9.3 months. 2-hydroxyglutarate suppression did not predict response and mIDH2 clearance was possible, but not required for response. Patients with ≥6 co-mutations or NRAS co-mutations were less likely to attain a response. Enasidenib was safe and well tolerated with low rates of treatment-related adverse events. [Formula: see text].


Assuntos
Aminopiridinas/administração & dosagem , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Mutantes/genética , Triazinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Células da Medula Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Intervalo Livre de Doença , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas Mutantes/antagonistas & inibidores , Mutação , Recidiva , Triazinas/efeitos adversos , Triazinas/farmacocinética
16.
Drug Des Devel Ther ; 11: 3441-3448, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29238169

RESUMO

Aim: This study developed a high-performance liquid chromatography-tandem mass spectrometry method to simultaneously determine the concentrations of flupirtine and its major active metabolite D-13223 in human plasma in order to assess the bioequivalence (BE) of two flupirtine maleate capsules among healthy male Chinese volunteers under fasting and fed conditions. Materials and methods: There were two single-center, randomized, single-dose, open-label, laboratory-blinded, two-period, cross-over studies which included 24 healthy male Chinese volunteers under fasting and fed conditions, respectively. Plasma samples were collected prior to and up to 48 h after dosing. The concentrations of flupirtine and its major active metabolite D-13223 in plasma samples were determined by a validated method, that is, high-performance liquid chromatography coupled with a tandem mass spectrometry detector. Pharmacokinetic metrics of area from time zero to the last measurable concentration (AUC0-t), area under the plasma concentration-time curve from administration to infinite time (AUC0-∞), and Cmax were used for BE assessment. Results: Forty-eight healthy volunteers who met the criteria were enrolled and completed the study. According to the observation of vital signs and laboratory measurement, no volunteers had any adverse reactions. Under fasting condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 103.0% (98.1%-108.2%) for AUC0-t, 102.9% (98.2%-107.9%) for AUC0-∞, and 97.0% (85.9%-109.5%) for Cmax. Under fed condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 101.7% (98.4%-105.1%) for AUC0-t, 101.6% (98.5%-104.8%) for AUC0-∞, and 103.5% (94.7%-113.0%) for Cmax. The difference between test and reference formulations, Tmax, was not statistically significant. The 90% CIs of the test/reference AUC ratio and Cmax ratio of D-13223 were also within the acceptance range for BE both under fasting and fed conditions. Conclusion: The two formulations of flupirtine maleate capsule were bioequivalent (the test and the reference products) under fasting and fed conditions, and thus both can be used interchangeably in the clinical setting.


Assuntos
Aminopiridinas/farmacocinética , Jejum , Maleatos/farmacocinética , Adolescente , Adulto , Aminopiridinas/administração & dosagem , Aminopiridinas/química , Cápsulas , China , Estudos Cross-Over , Voluntários Saudáveis , Humanos , Masculino , Maleatos/administração & dosagem , Maleatos/química , Estrutura Molecular , Equivalência Terapêutica , Adulto Jovem
17.
Expert Opin Pharmacother ; 18(18): 2007-2016, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29169282

RESUMO

INTRODUCTION: Breast cancer is the most frequent cancer in women. Despite a decline in breast cancer mortality, prognosis of advanced breast cancer remains poor. In a desperate need to improve breast cancer outcomes, newer agents that target molecular pathways are being tested. Deregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) is frequently found in breast cancer. This can lead to resistance of endocrine therapy and anti-HER2 therapies. Targeting this pathway may restore sensitivity to these compounds. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different tumor types. Areas covered: Buparlisib is one of the most investigated PI3K inhibitors. Preclinical and clinical studies of buparlisib in breast cancer are analyzed and discussed. This article reviews the status of buparlisib, completed and ongoing trials, and its safety. Expert opinion: PI3K inhibitors show promising results in breast cancer. However, we raise a number of issues including the identification of biomarkers to predict treatment response and strategies to counteract resistance. Moreover, its toxicity profile could limit its extensive use.


Assuntos
Aminopiridinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Morfolinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Aminopiridinas/química , Aminopiridinas/farmacocinética , Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Feminino , Meia-Vida , Humanos , Morfolinas/química , Morfolinas/farmacocinética , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
18.
J Med Chem ; 60(23): 9790-9806, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29125744

RESUMO

N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trypanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stages 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (1) as a starting point for the design of a class of potent, brain penetrant inhibitors of T. brucei NMT.


Assuntos
Aciltransferases/antagonistas & inibidores , Aminopiridinas/química , Aminopiridinas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/enzimologia , Tripanossomíase Africana/tratamento farmacológico , Aciltransferases/metabolismo , Aminopiridinas/síntese química , Aminopiridinas/farmacocinética , Animais , Encéfalo/metabolismo , Cristalografia por Raios X , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Tripanossomicidas/síntese química , Tripanossomicidas/farmacocinética , Tripanossomíase Africana/metabolismo
19.
Drug Metab Dispos ; 45(12): 1245-1259, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28939686

RESUMO

Aldehyde oxidase (AO) and xanthine oxidase (XO) are molybdo-flavoenzymes that catalyze oxidation of aromatic azaheterocycles. Differences in AO activity have been reported among various species, including rats, humans, and monkeys. Herein we report a species difference in the enzymes responsible for the metabolism of the negative allosteric modulator of metabotropic glutamate receptor subtype 5 (mGlu5 NAM) VU0424238 (VU238, auglurant). Hepatic S9 incubations with AO and XO specific inhibitors hydralazine and allopurinol indicated that rats and cynomolgus monkeys both oxidized VU238 to the 6-oxopyrimidine metabolite M1 via an AO-mediated pathway, whereas secondary oxidation to the 2,6-dioxopyrimidine metabolite M2 was mediated predominantly by AO in monkeys and XO in rats. Despite differences in enzymatic pathways, intrinsic clearance (CLint) of M1 was similar between species (cynomolgus and rat CLint = 2.00 ± 0.040 and 2.19 ± 0.201 µl/min per milligram of protein, respectively). Inhibitor studies in the S9 of multiple species indicated that oxidation of VU238 to M1 was mediated predominantly by AO in humans, cynomolgus and rhesus monkeys, rats, mice, guinea pigs, and minipigs. Oxidation of M1 to M2 was mediated predominantly by XO in rats and mice and by AO in monkeys and guinea pigs, whereas low turnover prevented enzyme phenotyping in humans and minipigs. Additionally, inhibitor experiments indicated that oxidation at the 2-position of the pyrimidine ring of the known AO substrate, BIBX1382, was mediated by AO in all species, although production of this metabolite was comparatively low in rats and mice. These data may suggest low reactivity of rat AO toward 2-oxidation of pyrimidine-containing compounds and highlight the importance of thoroughly characterizing AO-metabolized drug candidates in multiple preclinical species.


Assuntos
Aldeído Oxidase/metabolismo , Aminopiridinas/metabolismo , Ácidos Picolínicos/metabolismo , Receptor de Glutamato Metabotrópico 5/efeitos dos fármacos , Xantina Oxidase/metabolismo , Aldeído Oxidase/antagonistas & inibidores , Aminopiridinas/farmacocinética , Animais , Inibidores Enzimáticos/farmacologia , Cobaias , Fígado/enzimologia , Macaca fascicularis , Macaca mulatta , Camundongos , Oxirredução , Ácidos Picolínicos/farmacocinética , Ratos , Especificidade da Espécie , Frações Subcelulares/enzimologia , Suínos , Porco Miniatura , Xantina Oxidase/antagonistas & inibidores
20.
Eur J Cancer ; 86: 28-36, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28950146

RESUMO

BACKGROUND: Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms. PATIENTS AND METHODS: PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments. RESULTS: A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12-51%]). CONCLUSION: Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population. TRIAL REGISTRATION ID: NCT01589861.


Assuntos
Aminopiridinas/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Morfolinas/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/administração & dosagem , Administração Oral , Adulto , Idoso , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Resistencia a Medicamentos Antineoplásicos , Feminino , França , Humanos , Lapatinib , Dose Máxima Tolerável , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Receptor ErbB-2/metabolismo , Trastuzumab/efeitos adversos , Resultado do Tratamento
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