Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 760
Filtrar
1.
Eur J Pharm Sci ; 139: 105041, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31404621

RESUMO

NEPA is the fixed combination antiemetic composed of the neurokinin-1 receptor antagonist netupitant and the 5-hydroxytryptamine-3 receptor antagonist palonosetron. The intravenous (i.v.) formulation of NEPA (fosnetupitant 235 mg/palonosetron 0.25 mg) was developed to enhance the convenience of NEPA administration. In a phase 3 study, i.v. NEPA showed acceptable safety with low risk for injection-site reactions. This study evaluated the pharmacokinetics and safety of i.v. NEPA in cancer patients. This was a single-center, single-dose phase 1 study in patients receiving highly emetogenic chemotherapy. Patients received a 30-min infusion of i.v. NEPA plus oral dexamethasone (12 mg) prior to chemotherapy, and oral dexamethasone (8 mg/daily) on days 2-4. Twenty-four patients received the complete i.v. NEPA infusion volume. Fosnetupitant maximum plasma concentration (Cmax) was reached at the end of infusion and decreased to <1% of Cmax 30 min later. Netupitant was rapidly released from its prodrug and Cmax of 590 ng/ml was reached at the end of fosnetupitant infusion, with a mean exposure (AUC∞) of 15,588 h∙ng/ml. Palonosetron Cmax was reached at the end of infusion, with a mean AUC∞ of 36.07 h∙ng/ml. The most common adverse events were constipation (29%), nausea (17%), and vasospasm (8%). No i.v. NEPA-related injection site reactions occurred. Fosnetupitant conversion to netupitant occurred rapidly in cancer patients. Netupitant and palonosetron pharmacokinetic profiles in i.v. NEPA were similar to those reported for oral NEPA. i.v. NEPA was well tolerated with a similar safety profile to oral NEPA. i.v. NEPA provides additional administration convenience. Clinical trial registration number: EudraCT 2015-004750-18.


Assuntos
Antieméticos/farmacocinética , Isoquinolinas/farmacocinética , Neoplasias/metabolismo , Piridinas/farmacocinética , Quinuclidinas/farmacocinética , Administração Intravenosa , Adulto , Idoso , Antieméticos/administração & dosagem , Antieméticos/efeitos adversos , Antieméticos/sangue , Combinação de Medicamentos , Feminino , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Isoquinolinas/sangue , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/prevenção & controle , Neoplasias/tratamento farmacológico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/sangue , Quinuclidinas/administração & dosagem , Quinuclidinas/efeitos adversos , Quinuclidinas/sangue , Vômito/induzido quimicamente , Vômito/prevenção & controle
2.
PLoS One ; 14(7): e0219022, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291311

RESUMO

AIMS: Drug-induced liver damage characterized by serum alanine aminotransferase (ALT) elevation often occurs in direct-acting antiviral (DAA) combination therapy for chronic hepatitis C virus (HCV) infection. This study explored single nucleotide polymorphisms (SNPs) at drug metabolism- or transport-related genes that were associated with ALT elevation in asunaprevir plus daclatasvir therapy. METHODS: Subjects were 185 Japanese patients with chronic HCV genotype 1b infection who received asunaprevir plus daclatasvir therapy. Tag SNPs at possible metabolizing enzyme and transporter genes, which were involved in the pharmacokinetics of asunaprevir and daclatasvir, were selected. RESULTS: Among the tag SNPs analyzed, CYP3A4 rs4646437 was significantly associated with ALT elevation (p = 0.013): maximum ALT values in patients with genotype CC were higher than those in patients with genotype non-CC (allele T). The proportion of grades 2-4 in genotype CC patients were significantly greater than those in genotype non-CC patients (p = 0.028). No patients with genotype non-CC showed grade ≥2 ALT elevation. In multivariate analysis, rs4646437 genotype CC and cirrhosis were significant, independent factors associated with grade ≥1 ALT elevation (odds ratio, 2.83 and 1.88; p = 0.040 and 0.045, respectively). In exploratory analyses, although serum concentrations of asunaprevir and daclatasvir were not correlated with maximum ALT values or rs4646437 genotypes, asunaprevir concentrations in patients with grade ≥1 ALT elevation were significantly higher than those in patients with grade <1 ALT elevation (P = 0.023). CONCLUSIONS: CYP3A4 rs4646437 was found to be significantly and independently associated with ALT elevation in Japanese patients receiving ASV plus DCV therapy. Notably, none of the patients with rs4646437 genotype non-CC (allele T) had grade ≥2 ALT elevation. SNP genotyping prior to treatment might be useful for carefully monitoring patients to complete treatment safely.


Assuntos
Alanina Transaminase/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Citocromo P-450 CYP3A/genética , Hepatite C Crônica/tratamento farmacológico , Imidazóis/administração & dosagem , Isoquinolinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Hepática Induzida por Substâncias e Drogas/sangue , Quimioterapia Combinada/efeitos adversos , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/genética , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacocinética , Japão , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Regulação para Cima
3.
Eur J Med Chem ; 176: 410-418, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31125895

RESUMO

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), has a high diagnostic potential in neurodegenerative disorders and cancer. However, TSPO is considered a challenge for molecular imaging due to the poor availability of suitable radiotracers with adequate pharmacokinetic properties. Here, we describe the development of a radiofluorinated pyridinyl isoquinoline analogue of the established TSPO PET tracer (R)-[11C]PK11195 with improved binding properties in all known human TSPO phenotypes. We conducted a complete preclinical evaluation using in vitro, in vivo and ex vivo methods to assess the performance of this novel radiotracer and observed high specific binding of the radiotracer to TSPO, as well as high metabolic stability. Therefore, we propose this radiolabeled compound for further evaluation in animal models as well as in clinical trials.


Assuntos
Isoquinolinas/metabolismo , Piridinas/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Receptores de GABA/metabolismo , Animais , Feminino , Radioisótopos de Flúor/química , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Isoquinolinas/farmacocinética , Marcação por Isótopo , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
4.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1118-1119: 33-39, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31005772

RESUMO

In Positron Emission Tomography (PET) research, it is important to assess not only pharmacokinetics of a radiotracer in vivo, but also of the drugs used in blocking/displacement PET studies. Typically, pharmacokinetic/pharmacodynamic (PK/PD) analyses of drugs used in rodent PET studies are based on population average pharmacokinetic profiles of the drugs due to limited blood volume withdrawal while simultaneously maintaining physiological homeostasis. This likely results in bias of PET data quantification, including unknown bias of target occupancy (TO) measurements. This study aimed to develop a High Performance Liquid Chromatography (HPLC) method for PK/PD quantification of drugs used in preclinical rodent PET research, specifically the translocator 18 kDa protein (TSPO) selective drug, PK11195, that used sub-millilitre blood volumes. The lowest detection limit for the proposed HPLC method ranged between 7.5 and 10 ng/mL depending on the method used to calculate the limit of detection, and the measured average relative standard deviation for intermediate precision was equal to 17.2%. Most importantly, we were able to demonstrate a significant difference between calculated PK11195 concentrations at 0.5, 1, 2, 3, 5, 15 and 30 min post-administration and individually measured whole blood levels (significance level range from p < 0.05 to p < 0.001; one-way ANOVA, Dunnet's post hoc test, p < 0.05). The HPLC method developed here uses sub-millilitre sample volumes to reproducibly assess PK/PD of PK11195 in rodent blood. This study highlights the importance of individually measured PK/PD drug concentrations when quantifying the TO from blocking/displacement rodent PET experiments.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Isoquinolinas/análise , Isoquinolinas/farmacocinética , Administração Intravenosa , Animais , Isoquinolinas/administração & dosagem , Limite de Detecção , Modelos Lineares , Masculino , Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Distribuição Tecidual
5.
Drugs ; 79(5): 563-572, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30805897

RESUMO

Roxadustat (Ai Rui Zhuo® in China) is an orally administered, small molecule hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that is being developed by FibroGen, in collaboration with Astellas and AstraZeneca, for the treatment of anaemia in patients with dialysis-dependent chronic kidney disease (CKD), non-dialysis-dependent CKD and in patients with myelodysplastic syndromes. The drug reversibly binds to and inhibits HIF-prolyl hydroxylase enzymes that are responsible for the degradation of transcription factors in the HIF family under normal oxygen conditions. Inhibition of these enzymes reduces HIF breakdown and promotes HIF activity, leading to an increase in endogenous erythropoietin production, thereby enhancing erythropoiesis. It also reduces the expression of the peptide hormone hepcidin, improves iron availability and increases haemoglobin levels. HIF regulates the expression of genes in response to reduced oxygen levels, including genes required for erythropoiesis and iron metabolism. Roxadustat is approved in China and is under regulatory review in Japan for the treatment of anaemia in patients with dialysis-dependent CKD. Studies are underway to investigate long-term cardiovascular outcomes with roxadustat versus placebo (for non-dialysis-dependent CKD) or standard of care (for dialysis-dependent CKD). This article summarizes the milestones in the development of roxadustat leading to this first approval.


Assuntos
Anemia/tratamento farmacológico , Glicina/análogos & derivados , Isoquinolinas/farmacocinética , Inibidores de Prolil-Hidrolase/farmacocinética , Anemia/metabolismo , China , Aprovação de Drogas , Eritropoese/efeitos dos fármacos , Eritropoetina/metabolismo , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Glicina/uso terapêutico , Hepcidinas/metabolismo , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Isoquinolinas/uso terapêutico , Inibidores de Prolil-Hidrolase/administração & dosagem , Inibidores de Prolil-Hidrolase/efeitos adversos , Inibidores de Prolil-Hidrolase/uso terapêutico , Diálise Renal
6.
Invest Ophthalmol Vis Sci ; 60(2): 624-633, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30735565

RESUMO

Purpose: The purpose of this study was to investigate the IOP-lowering effects of the ITRI-E-212, a new Rho-associated protein kinase (ROCK) inhibitor. ITRI-E-212 improved fluid outflow through the trabecular meshwork and reduced IOP with transient and mild conjunctival hyperemia. ITRI-E-212 can potentially be developed into new antiglaucoma agents. Methods: ITRI-E-212 was selected from more than 200 amino-isoquinoline structures because of its adequate solubility and drug-loading percentage in eye drops. ITRI-E-212 has less than 50% inhibitory concentration (IC50) against ROCK2. The in vitro kinase inhibition was evaluated using the ADP-Glo kinase assay. A comprehensive analysis of the kinase inhibitor selectivity of ITRI-E-212 was performed using the KINOMEscan methodology. The IOP-lowering effect and tolerability of ITRI-E-212 were investigated in normotensive and ocular hypertensive rabbits. The pharmacokinetics study was performed in vivo in the aqueous humor (AH), and hyperemia was assessed. Results: ITRI-E-212 showed high in vitro inhibitory activity against ROCK2 and high specificity against AGC kinases. The mean IOP-lowering effect of ITRI-E-212 in normotensive and ocular hypertensive models was 24.9% and 28.6%, respectively; 1% ITRI-E-212 produced notable reductions in IOP that were sustained for at least 6 hours after each dose once per day. Only transient, mild hyperemia was observed. The compound extracted from the AH reached 78.4% ROCK2 kinase inhibition at 1 hour after dose administration and was sustained for 4 hours. Conclusions: ITRI-E-212 is a novel and highly specific ROCK2 inhibitor with the ability to lower IOP in animal models. It has favorable pharmacokinetic and ocular tolerability profiles with only minimal conjunctival hyperemia.


Assuntos
Anti-Hipertensivos/administração & dosagem , Glaucoma/tratamento farmacológico , Hiperemia/induzido quimicamente , Pressão Intraocular/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Quinases Associadas a rho/antagonistas & inibidores , Administração Oftálmica , Animais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacocinética , Humor Aquoso/metabolismo , Túnica Conjuntiva/irrigação sanguínea , Modelos Animais de Doenças , Pálpebras/irrigação sanguínea , Glaucoma/fisiopatologia , Hiperemia/epidemiologia , Incidência , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacocinética , Masculino , Cadeias Leves de Miosina/metabolismo , Soluções Oftálmicas , Fosforilação , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Coelhos
7.
J Vet Pharmacol Ther ; 42(2): 197-206, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30350369

RESUMO

Sanguinarine (SA) and chelerythrine (CHE) are the main active components of the phytogenic livestock feed additive, Sangrovit®. However, little information is available on the pharmacokinetics of Sangrovit® in poultry. The goal of this work was to study the pharmacokinetics of SA, CHE, and their metabolites, dihydrosanguinarine (DHSA) and dihydrochelerythrine (DHCHE), in 10 healthy female broiler chickens following oral (p.o.) administration of Sangrovit® and intravenous (i.v.) administration of a mixture of SA and CHE. The plasma samples were processed using two different simple protein precipitation methods because the parent drugs and metabolites are stable under different pH conditions. The absorption and metabolism of SA following p.o. administration were fast, with half-life (t1/2 ) values of 1.05 ± 0.18 hr and 0.83 ± 0.10 hr for SA and DHSA, respectively. The maximum concentration (Cmax ) of DHSA (2.49 ± 1.4 µg/L) was higher that of SA (1.89 ± 0.8 µg/L). The area under the concentration vs. time curve (AUC) values for SA and DHSA were 9.92 ± 5.4 and 6.08 ± 3.49 ng/ml hr, respectively. Following i.v. administration, the clearance (CL) of SA was 6.79 ± 0.63 (L·h-1 ·kg-1 ) with a t1/2 of 0.34 ± 0.13 hr. The AUC values for DHSA and DHCHE were 7.48 ± 1.05 and 0.52 ± 0.09 (ng/ml hr), respectively. These data suggested that Sangrovit® had low absorption and bioavailability in broiler chickens. The work reported here provides useful information on the pharmacokinetic behavior of Sangrovit® after p.o. and i.v. administration in broiler chickens, which is important for the evaluation of its use in poultry.


Assuntos
Benzofenantridinas/farmacocinética , Galinhas/metabolismo , Isoquinolinas/farmacocinética , Administração Oral , Animais , Benzofenantridinas/administração & dosagem , Benzofenantridinas/sangue , Galinhas/sangue , Cromatografia Líquida de Alta Pressão/veterinária , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Feminino , Meia-Vida , Injeções Intravenosas/veterinária , Isoquinolinas/administração & dosagem , Isoquinolinas/sangue , Espectrometria de Massas/veterinária
8.
Bioorg Chem ; 82: 100-108, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30278281

RESUMO

Reported herein is the design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists constructed on a N1-(isoquinolin-5-yl)-N2-phenylpyrrolidine-1,2-dicarboxamide platform that evolved from a 5-aminoisoquinoline urea lead. Advancing the SAR of this series led to the eventual identification of 3b, comprising a p-Br substituted phenyl. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 3b displayed potent antagonism activated by capsaicin (IC50 = 0.084 µM) and protons (IC50 = 0.313 µM). In the preliminary analgesic and body temperature tests, 3b exhibited good efficacy in capsaicin-induced and heat-induced pain models and without hyperthermia side-effect. On the basis of its superior profiles, 3b could be considered as the lead candidate for the further development of antinociceptive drugs.


Assuntos
Analgésicos/farmacologia , Isoquinolinas/farmacologia , Pirrolidinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/síntese química , Analgésicos/farmacocinética , Animais , Temperatura Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Drogas , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Masculino , Camundongos , Estrutura Molecular , Dor/tratamento farmacológico , Pirrolidinas/administração & dosagem , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Relação Estrutura-Atividade
9.
J Clin Pharmacol ; 58(11): 1468-1478, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30063254

RESUMO

Daclatasvir is a nonstructural protein 5A replication complex inhibitor, and asunaprevir is a nonstructural protein 3 protease inhibitor for hepatitis C virus (HCV). In 2014, the combination therapy of daclatasvir and asunaprevir received the first global approval in Japan as the first nonribavirin, all-oral therapy for HCV treatment. The population pharmacokinetics (popPK) of daclatasvir and asunaprevir were characterized by nonlinear mixed-effects modeling using 3801 and 2626 concentration data from 336 and 265 Japanese HCV subjects, respectively. The plasma pharmacokinetic profiles of daclatasvir and asunaprevir were described by a 1-compartment model. Parameter estimates (interindividual variability) of daclatasvir apparent clearance (CL/F) and apparent volume of the central compartment (V/F) were 5.29 L/h (39.4%) and 64.2 L (38.1%). The effects of all statistically significant covariates on daclatasvir PK parameters were within or overlapped the 80% to 125% boundaries, suggesting a lack of clinical relevance. Parameter estimates (interindividual variability) of asunaprevir CL/F and V/F were 52.1 L/h (41.5%) and 75.1 L (93.4%), respectively. Baseline and time-varying aspartate aminotransferase (AST) and cirrhosis on CL/F and formulation (soft-gel capsule or tablet) on F were included as significant covariates in the asunaprevir popPK model. The effects of all covariates exceeded the 80% to 125% boundaries, indicating that the asunaprevir soft-gel capsule had higher bioavailability than the tablet and that asunaprevir exposure increased with cirrhosis and increasing baseline and time-varying AST values. The popPK models adequately described the PK profiles of daclatasvir and asunaprevir in Japanese HCV subjects.


Assuntos
Antivirais/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Imidazóis/farmacocinética , Isoquinolinas/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Idoso , Antivirais/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Imidazóis/uso terapêutico , Isoquinolinas/uso terapêutico , Japão , Cirrose Hepática/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Sulfonamidas/uso terapêutico
10.
Am J Hematol ; 93(11): 1318-1326, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30094870

RESUMO

Duvelisib (IPI-145), an oral, dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ, was evaluated in a Phase 1 study in advanced hematologic malignancies, which included expansion cohorts in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and treatment-naïve (TN) CLL. Per protocol, TN patients were at least 65 years old or had a del(17p)/TP53 mutation. Duvelisib was administered twice daily (BID) in 28-day cycles at doses of 8-75 mg in RR patients (n = 55) and 25 mg in TN patients (n = 18.) Diarrhea was the most common nonhematologic AE (TN 78%, RR 47%); transaminase elevations the most frequent lab-abnormality AE (TN 33.3%, RR 30.9%); and neutropenia the most common ≥grade 3 AE (RR 44%, TN 33%). The overall response rates were 56.4% for RR patients (1.8% CR, 54.5% PR) and 83.3% for TN patients (all PRs); median response duration was 21.0 months in RR patients but was not reached for TN patients. Based upon phase 1 efficacy, pharmacodynamics, and safety, duvelisib 25 mg BID was selected for further investigation in a phase 3 study in RR CLL/SLL.


Assuntos
Isoquinolinas/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Purinas/administração & dosagem , Adulto , Idoso , Feminino , Humanos , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacocinética , Leucemia Linfocítica Crônica de Células B/complicações , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Purinas/efeitos adversos , Purinas/farmacocinética , Indução de Remissão/métodos , Transaminases/efeitos dos fármacos , Resultado do Tratamento
11.
Alzheimers Res Ther ; 10(1): 74, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-30064520

RESUMO

BACKGROUND: Imaging agents capable of quantifying the brain's tau aggregates will allow a more precise staging of Alzheimer's disease (AD). The aim of the present study was to examine the in vitro properties as well as the in vivo kinetics, using gold standard methods, of the novel positron emission tomography (PET) tau imaging agent [18F]MK-6240. METHODS: In vitro properties of [18F]MK-6240 were estimated with autoradiography in postmortem brain tissues of 14 subjects (seven AD patients and seven age-matched controls). In vivo quantification of [18F]MK-6240 binding was performed in 16 subjects (four AD patients, three mild cognitive impairment patients, six healthy elderly individuals, and three healthy young individuals) who underwent 180-min dynamic scans; six subjects had arterial sampling for metabolite correction. Simplified approaches for [18F]MK-6240 quantification were validated using full kinetic modeling with metabolite-corrected arterial input function. All participants also underwent amyloid-PET and structural magnetic resonance imaging. RESULTS: In vitro [18F]MK-6240 uptake was higher in AD patients than in age-matched controls in brain regions expected to contain tangles such as the hippocampus, whereas no difference was found in the cerebellar gray matter. In vivo, [18F]MK-6240 displayed favorable kinetics with rapid brain delivery and washout. The cerebellar gray matter had low binding across individuals, showing potential for use as a reference region. A reversible two-tissue compartment model well described the time-activity curves across individuals and brain regions. Distribution volume ratios using the plasma input and standardized uptake value ratios (SUVRs) calculated after the binding approached equilibrium (90 min) were correlated and higher in mild cognitive impairment or AD dementia patients than in controls. Reliability analysis revealed robust SUVRs calculated from 90 to 110 min, while earlier time points provided inaccurate estimates. CONCLUSIONS: This evaluation shows an [18F]MK-6240 distribution in concordance with postmortem studies and that simplified quantitative approaches such as the SUVR offer valid estimates of neurofibrillary tangle load 90 min post injection. [18F]MK-6240 is a promising tau tracer with the potential to be applied in the disease diagnosis and assessment of therapeutic interventions.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Isoquinolinas/farmacocinética , Emaranhados Neurofibrilares/patologia , Adulto , Fatores Etários , Idoso , Doença de Alzheimer/diagnóstico por imagem , Autopsia , Autorradiografia , Encéfalo/patologia , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Imagem Tridimensional , Técnicas In Vitro , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/metabolismo , Tomografia por Emissão de Pósitrons , Adulto Jovem
12.
Eur J Med Chem ; 156: 344-367, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30015072

RESUMO

Selective targeting of cancer cells over normal cells is a key objective of targeted therapy. However few approaches achieve true mechanistic selectivity resulting in debilitating side effects and dose limitation. In this work we describe the discovery of A131 (4a), a new agent with an unprecedented dual mechanism of action targeting both mitosis and autophagy. Compound 4a was first identified in a phenotypic screen in which HeLa cells treated with 4a manifested mitotic arrest along with formation of multiple vesicles. Further investigations showed that 4a causes an increase in mitotic marker pH3 and autophagy marker LC3. Importantly 4a induces cell death in cancer cells while sparing normal cells which regrow after 4a is removed. Dual activities against pH3 and LC3 markers are required for cancer cell selectivity. An extensive SAR investigation confirmed 4a as the optimal dual inhibitor with potency against a panel of 30 cancer cell lines (average antiproliferative GI50 1.5 µM). In a mouse model of paclitaxel-resistant colon cancer, 4a showed 74% tumor growth inhibition when administered at a dose of 20 mg/kg IP twice a day.


Assuntos
Acrilonitrila/análogos & derivados , Acrilonitrila/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Neoplasias/tratamento farmacológico , Acrilonitrila/farmacocinética , Acrilonitrila/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoquinolinas/farmacocinética , Isoquinolinas/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitose/efeitos dos fármacos , Neoplasias/metabolismo , Neoplasias/patologia , Ratos
13.
J Clin Pharm Ther ; 43(5): 633-639, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29981285

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor currently being investigated for the treatment of anemia in chronic kidney disease. Lanthanum carbonate is a phosphate binder that is commonly used to treat hyperphosphatemia in patients with chronic kidney disease. This study investigated the effect of lanthanum carbonate on the pharmacokinetics, safety and tolerability of a single oral dose of roxadustat in healthy non-elderly adult male subjects. METHODS: This was an open-label, randomized, two-period, two-sequence crossover study in non-elderly healthy adult males. Subjects randomized to Group 1 received roxadustat alone during Period 1 and roxadustat concomitantly with lanthanum carbonate during Period 2; subjects randomized to Group 2 received roxadustat concomitantly with lanthanum carbonate during Period 1 and roxadustat alone during Period 2. All subjects received a single oral dose of 100 mg roxadustat on Day 1 in both periods. Subjects receiving concomitant lanthanum carbonate received 750 mg lanthanum carbonate three times daily on Days 1 and 2. Pharmacokinetic assessments were conducted on Days 1-4 in both periods. The primary study outcomes were the area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf ), and maximum concentration (Cmax ); the geometric least squares mean ratio (GMR; roxadustat + lanthanum carbonate/roxadustat alone) and corresponding 90% confidence interval (CI) was calculated for AUCinf and Cmax . Safety was assessed by the occurrence of treatment-emergent adverse events (TEAEs), laboratory test results, vital signs and standard 12-lead electrocardiogram. RESULTS AND DISCUSSION: A total of 18 subjects were enrolled (Group 1, n = 9; Group 2, n = 9); no subjects discontinued from the study. Roxadustat was rapidly absorbed, reaching maximum plasma concentration between 1 and 4 hours. The GMRs for AUCinf and Cmax were 88.00% (90% CI: 84.01, 92.17) and 98.58% (90% CI: 92.92, 104.58), respectively. The 90% CIs for both parameters were within the no-effect boundaries of 80% and 125%, indicating a lack of effect of lanthanum carbonate on roxadustat absorption. No deaths or serious TEAEs occurred. WHAT IS NEW AND CONCLUSIONS: Concomitant administration of a single oral dose of 100 mg roxadustat and 750 mg lanthanum carbonate three times daily did not impact the AUCinf or Cmax of roxadustat and was considered safe and well tolerated in non-elderly healthy adult male Japanese subjects.


Assuntos
Glicina/análogos & derivados , Isoquinolinas/farmacocinética , Lantânio/efeitos adversos , Administração Oral , Adulto , Anemia/tratamento farmacológico , Anemia/etiologia , Área Sob a Curva , Estudos Cross-Over , Glicina/farmacocinética , Glicina/uso terapêutico , Humanos , Isoquinolinas/uso terapêutico , Masculino , Insuficiência Renal Crônica/complicações , Adulto Jovem
14.
Expert Opin Drug Metab Toxicol ; 14(6): 649-657, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29855221

RESUMO

INTRODUCTION: Many reports have evaluated the clinical efficacy and safety of the fixed-dose all-oral combination of daclatasvir, asunaprevir, and beclabuvir (DCV-TRIO), which was approved in Japan in December 2016 for the treatment of hepatitis C genotype (GT)-1 infection. Areas covered: This article reviews the pharmacodynamic and pharmacokinetic properties of the DCV-TRIO combination. The topics covered include data regarding the drug's absorption, distribution, metabolism, excretion, and antiviral activity strategies. Its therapeutic efficacy and safety in GT-1 infection from phase 2/3 clinical trials are also discussed. Expert opinion: The ideal regimen for the treatment of Hepatitis C virus infection should be potent, pangenotypic, Ribavirin-free, safe, co-formulated, and affordable. Considering these characteristics, DCV-TRIO is neither pangenotypic nor potent enough against GT-1a, regardless of the presence or absence of cirrhosis. Other potential limitations of this regimen are its dosification (twice-daily), and the fact that since it includes a protease inhibitor, it is contraindicated in decompensated cirrhosis. For these reasons, it has only been approved in Japan, where more than 70% of the patients are infected with GT-1b. However, this co-formulation might still have a place in the treatment of non-cirrhotic patients infected with GT-1b provided that massive access to treatment is facilitated.


Assuntos
Antivirais/administração & dosagem , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Administração Oral , Antivirais/farmacocinética , Antivirais/farmacologia , Benzazepinas/administração & dosagem , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Combinação de Medicamentos , Genótipo , Hepacivirus/isolamento & purificação , Hepatite C/virologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Imidazóis/farmacologia , Indóis/administração & dosagem , Indóis/farmacocinética , Indóis/farmacologia , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Japão , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia
15.
Int J Pharm ; 547(1-2): 315-329, 2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-29886095

RESUMO

Based on the knowledge that poly(sialic acid) is a critical element for tumour development and that the receptors for its monomer are expressed on neutrophils, which play important roles in the progression and invasion of tumours, a poly(sialic acid)-p-octadecylamine conjugate (PSA-p-ODA) was synthesised and used to modify the surface of liposomal pixantrone (Pix-PSL) to improve the delivery of Pix to peripheral blood neutrophils (PBNs). The liposomes were fabricated using a remote loading technology via a pH gradient, and were then assessed for particle size, encapsulation efficiency, in vitro release, in vitro cytotoxicity, and pharmacokinetics. Simultaneously, in vitro and in vivo cellular uptake studies demonstrated that Pix-PSL provided an enhanced accumulation of Pix in PBNs. An in vivo study showed that the anti-tumour activity of Pix-PSL was superior to that of other formulations, probably owing to the efficient targeting of PBNs by Pix-PSL, after which PBNs containing Pix-PSL (Pix-PSL/PBNs) in the circulatory system are recruited by the tumour microenvironment. These findings suggest that PSA-p-ODA-decorated liposomal Pix may provide a neutrophil-mediated drug delivery system (DDS) for the eradication of tumours, and thus represents a promising approach for the tumour targeting of chemotherapeutic treatments.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Isoquinolinas/administração & dosagem , Aminas/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Lipossomos , Masculino , Camundongos , Ácido N-Acetilneuramínico/química , Neutrófilos/metabolismo , Tamanho da Partícula , Ratos , Ratos Wistar , Sarcoma 180/tratamento farmacológico , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Eur J Drug Metab Pharmacokinet ; 43(6): 685-692, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29752643

RESUMO

BACKGROUND AND OBJECTIVES: Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease. This study investigated the effect of multiple daily oral doses of omeprazole on the pharmacokinetics, safety, and tolerability of a single oral dose of roxadustat. METHODS: This phase 1, open-label, two-period, one-sequence, crossover study enrolled healthy subjects. During Period 1, subjects received a single oral dose of 100 mg roxadustat. After a ≥ 7-day washout, subjects started Period 2 and received daily oral doses of 40 mg omeprazole on Days 1-9, and a single oral dose of 100 mg roxadustat on Day 7. Roxadustat pharmacokinetics were assessed on Days 1-4 in Period 1 and on Days 7-10 in Period 2. Primary endpoints were area under the concentration-time profile from the time of dosing extrapolated to infinity (AUCinf) and maximum concentration (Cmax). Safety was assessed by vital signs, laboratory tests, electrocardiograms, and nature, frequency, and severity of treatment-emergent adverse events (TEAEs). RESULTS: Eighteen subjects were enrolled. The geometric least squares mean ratio for both AUCinf and Cmax of roxadustat (with omeprazole/alone) was 104.5%; 90% confidence intervals were within the no-effect boundaries of 80.0 and 125.0%, indicating no significant effect of omeprazole on the pharmacokinetics of roxadustat. No serious TEAEs were reported. CONCLUSION: Multiple daily oral doses of 40 mg omeprazole had no significant effect on the pharmacokinetics of a single oral dose of 100 mg roxadustat. Roxadustat was considered safe and well tolerated when administered alone or in combination with multiple daily oral doses of 40 mg omeprazole in healthy subjects.


Assuntos
Glicina/análogos & derivados , Isoquinolinas/administração & dosagem , Omeprazol/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Administração Oral , Adulto , Área Sob a Curva , Estudos Cross-Over , Interações de Medicamentos , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacocinética , Masculino , Pessoa de Meia-Idade , Omeprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia
17.
J Pharm Biomed Anal ; 154: 166-173, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29549855

RESUMO

In recent years, the whole field of ion-selective electrodes(ISEs) in pharmaceutical sciences has expanded far beyond its original roots. The diverse range of opportunities offered by ISEs was broadly used in a number of pharmaceutical applications, with topics presented ranging from bioanalysis of drugs and metabolites, to protein binding studies, green analytical chemistry, impurity profiling, and drug dissolution in biorelevant media. Inspired from these advances and with the aim of extending the functional capabilities of ISEs, the primary focus of the present paper is the utilization of ISE as a tool in personalized medicine. Given the opportunity to explore biological events in real-time (such as drug metabolism) could be central to personalized medicine. (ATR) is a chemo-degradable and bio-degradable pharmaceutically active drug. Laudanosine (LDS) is the major degradation product and metabolite of ATR and is potentially toxic and reported to possess epileptogenic activity which increases the risk of convulsive effects. In this work, ATR have been subjected to both chemical and biological hydrolysis, and the course of the reactions is monitored by means of a ISE. In this study, we have designed an efficient real-time tracking strategy which substantially resolve the challenges of the ATR chemical and biological degradation kinetics. By utilizing a potentiometric sensor, tracking of ATR chemical and biological degradation kinetics can be performed in a very short time with excellent accuracy. The LOD was calculated to be 0.23 µmol L-1, the potential drift was investigated over a period of 60 min and the value was 0.25 mV h-1. Real serum samples for measurement the rate of in vitro metabolism of ATR was performed. Furthermore, a full description of the fabricated screen-printed sensor was presented.


Assuntos
Atracúrio/farmacocinética , Técnicas Biossensoriais/instrumentação , Química Farmacêutica/instrumentação , Eletrodos Íon-Seletivos , Atracúrio/química , Técnicas Biossensoriais/economia , Técnicas Biossensoriais/métodos , Química Farmacêutica/economia , Química Farmacêutica/métodos , Hidrólise , Isoquinolinas/química , Isoquinolinas/farmacocinética , Potenciometria/instrumentação , Potenciometria/métodos
18.
Anesthesiology ; 128(6): 1107-1116, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29494403

RESUMO

BACKGROUND: CW002 is an investigational nondepolarizing, neuromuscular blocking agent with a rapid onset and intermediate duration of action in animals. This is a single ascending dose, healthy subject study exploring tolerability, pharmacokinetics, and potency. METHODS: Population pharmacokinetic and pharmacokinetic/pharmacodynamic models were developed using plasma drug concentration data from a previously published dose-response study in 28 healthy subjects receiving single doses of CW002 during sevoflurane anesthesia. Subjects included in the models were from five different dose cohorts (cohorts 3, 4, 5, 6, and 8 receiving 0.04, 0.06, 0.08, 0.10, and 0.14 mg/kg, respectively). Serial arterial plasma concentrations and muscle twitch heights were monitored. RESULTS: A four-compartment model was fit to the concentration-time data, whereas a transit compartment with a sigmoid Emax model was fit to the pharmacokinetic/pharmacodynamic data. The population pharmacokinetics of CW002 was linear with very low interindividual variability in clearance (10.8%). Simulations were conducted to predict the onset and offset of effect at 2×, 3×, and 4× ED95. The time to 80% block was predicted to be 1.5, 0.8, and 0.7 min for 2×, 3×, and 4× ED95 doses, respectively. The simulated 25 to 75% recovery index was independent of dose. CONCLUSIONS: CW002 has predictable pharmacokinetics and is likely to have a rapid onset with an intermediate duration of action at 3× ED95. This model provides information to inform critical decisions (e.g., dose, study design) for continued development of CW002.


Assuntos
Isoquinolinas/administração & dosagem , Isoquinolinas/farmacocinética , Modelos Biológicos , Bloqueadores Neuromusculares/administração & dosagem , Bloqueadores Neuromusculares/farmacocinética , Adolescente , Adulto , Estudos de Coortes , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Bioconjug Chem ; 29(4): 1141-1154, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29433312

RESUMO

Small molecules that stabilize G-quadruplex structures in telomeres can prevent telomerase enzyme mediated telomere lengthening and subsequently lead to cell death. We herein report two fluoro-isoquinoline derivatives IQ1 and IQ2 as selective ligands for human telomeric G-quadruplex DNA. IQ1 and IQ2 containing different triazolyl side chains have been synthesized by Cu (I) catalyzed azide-alkyne cycloaddition. Fluorescence Resonance Energy Transfer (FRET) melting assay and fluorescence binding titrations indicate that both these ligands exhibit binding preference for telomeric G-quadruplex DNA ( h-TELO) over other promoter DNA quadruplexes and duplex DNA. However, ligand IQ1, containing pyrrolidine side chains, is capable of discriminating among quadruplexes by showing higher affinity toward h-TELO quadruplex DNA. On the contrary, IQ2, containing benzamide side chains, interacts with all the investigated quadruplexes. NMR analysis suggests that IQ1 interacts strongly with the external G-quartets of h-TELO. Biological studies reveal that IQ1 is more potent than IQ2 in inhibiting telomerase activity by selectively interacting with telomeric DNA G-quadruplex. Moreover, a dual luciferase reporter assay indicates that IQ1 is unable to reduce the cellular expression of c-MYC and BCL2 at transcriptional level. Significantly, IQ1 mostly stains the nucleus, induces cell cycle arrest in G0/G1 phase, triggers apoptotic response in cancer cells, and activates caspases 3/7.


Assuntos
Apoptose/efeitos dos fármacos , Flúor/química , Quadruplex G/efeitos dos fármacos , Isoquinolinas/farmacologia , Telômero , Disponibilidade Biológica , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Transferência Ressonante de Energia de Fluorescência , Genes Reporter , Genes myc , Humanos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Luciferases/genética , Ressonância Magnética Nuclear Biomolecular , Proteínas Proto-Oncogênicas c-bcl-2/genética , Telomerase/antagonistas & inibidores
20.
Br J Clin Pharmacol ; 84(5): 876-887, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29346838

RESUMO

AIMS: The aims of the present study were to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class factor XIa inhibitor, in Japanese and non-Japanese healthy subjects. METHODS: This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study of 2-h (part A) and 5-day (part B) intravenous (IV) infusions of BMS-962212. Part A used four doses (1.5, 4, 10 and 25 mg h-1 ) of BMS-962212 or placebo in a 6:2 ratio per dose. Part B used four doses (1, 3, 9 and 20 mg h-1 ) enrolling Japanese (n = 4 active, n = 1 placebo) and non-Japanese (n = 4 active, n = 1 placebo) subjects per dose. The PK, PD, safety and tolerability were assessed throughout the study. RESULTS: BMS-962212 was well tolerated; there were no signs of bleeding, and adverse events were mild. In parts A and B, BMS-962212 demonstrated dose proportionality. The mean half-life in parts A and B ranged from 2.04 to 4.94 h and 6.22 to 8.65 h, respectively. Exposure-dependent changes were observed in the PD parameters, activated partial thromboplastin time (aPTT) and factor XI clotting activity (FXI:C). The maximum mean aPTT and FXI:C change from baseline at 20 mg h-1 in part B was 92% and 90%, respectively. No difference was observed in weight-corrected steady-state concentrations, aPTT or FXI:C between Japanese and non-Japanese subjects (P > 0.05). CONCLUSION: BMS-962212 has tolerability, PK and PD properties suitable for investigational use as an acute antithrombotic agent in Japanese or non-Japanese subjects.


Assuntos
Isoquinolinas/efeitos adversos , Isoquinolinas/farmacologia , Isoquinolinas/farmacocinética , para-Aminobenzoatos/efeitos adversos , para-Aminobenzoatos/farmacologia , para-Aminobenzoatos/farmacocinética , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Fibrinolíticos/farmacologia , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Isoquinolinas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial/estatística & dados numéricos , Adulto Jovem , para-Aminobenzoatos/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA