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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 226: 117652, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31654902

RESUMO

Transient absorption spectroscopy in combination with in silico methods has been employed to study the interactions between human serum albumin (HSA) and the anti-psychotic agent chlorpromazine (CPZ) as well as its two demethylated metabolites (MCPZ and DCPZ). Thus, solutions containing CPZ, MCPZ or DCPZ and HSA (molar ligand:protein ratios between 1:0 and 1:3) were submitted to laser flash photolysis and the ΔAmax value at λ = 470 nm, corresponding to the triplet excited state, was monitored. In all cases, the protein-bound ligand exhibited higher ΔAmax values measured after the laser pulse and were also considerably longer-lived than the non-complexed forms. This is in agreement with an enhanced hydrophilicity of the metabolites, due to the replacement of methyl groups with H that led to a lower extent of protein binding. For the three compounds, laser flash photolysis displacement experiments using warfarin or ibuprofen indicated Sudlow site I as the main binding site. Docking and molecular dynamics simulation studies revealed that the binding mode of the two demethylated ligands with HSA would be remarkable different from CPZ, specially for DCPZ, which appears to come from the different ability of their terminal ammonium groups to stablish hydrogen bonding interactions with the negatively charged residues within the protein pocket (Glu153, Glu292) as well as to allocate the methyl groups in an apolar environment. DCPZ would be rotated 180° in relation to CPZ locating the aromatic ring away from the Sudlow site I of HSA.


Assuntos
Clorpromazina/química , Clorpromazina/farmacocinética , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Antipsicóticos/química , Antipsicóticos/farmacocinética , Sítios de Ligação , Carbazóis/química , Carbazóis/farmacocinética , Clorpromazina/análogos & derivados , Clorpromazina/farmacologia , Interações Medicamentosas , Humanos , Ligação de Hidrogênio , Inativação Metabólica , Metilação , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica/efeitos dos fármacos , Albumina Sérica Humana/efeitos dos fármacos , Espectrofotometria Ultravioleta , Estereoisomerismo
2.
Nucleic Acids Res ; 47(22): 11931-11942, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31740959

RESUMO

BMVC is the first fluorescent probe designed to detect G-quadruplexes (G4s) in vivo. The MYC oncogene promoter forms a G4 (MycG4) which acts as a transcription silencer. Here, we report the high-affinity and specific binding of BMVC to MycG4 with unusual slow-exchange rates on the NMR timescale. We also show that BMVC represses MYC in cancer cells. We determined the solution structures of the 1:1 and 2:1 BMVC-MycG4 complexes. BMVC first binds the 5'-end of MycG4 to form a 1:1 complex with a well-defined structure. At higher ratio, BMVC also binds the 3'-end to form a second complex. In both complexes, the crescent-shaped BMVC recruits a flanking DNA residue to form a BMVC-base plane stacking over the external G-tetrad. Remarkably, BMVC adjusts its conformation to a contracted form to match the G-tetrad for an optimal stacking interaction. This is the first structural example showing the importance of ligand conformational adjustment in G4 recognition. BMVC binds the more accessible 5'-end with higher affinity, whereas sequence specificity is present at the weaker-binding 3'-site. Our structures provide insights into specific recognition of MycG4 by BMVC and useful information for design of G4-targeted anticancer drugs and fluorescent probes.


Assuntos
Carbazóis/química , Carbazóis/farmacocinética , Quadruplex G/efeitos dos fármacos , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/genética , Compostos de Piridínio/química , Compostos de Piridínio/farmacocinética , Sítios de Ligação/efeitos dos fármacos , Dicroísmo Circular , DNA/química , DNA/efeitos dos fármacos , DNA/metabolismo , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação de Ácido Nucleico/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/química , Proteínas Proto-Oncogênicas c-myc/efeitos dos fármacos , Especificidade por Substrato
3.
J Exp Med ; 216(11): 2492-2502, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31455602

RESUMO

The pathways of circulation and clearance of cerebrospinal fluid (CSF) in the spine have yet to be elucidated. We have recently shown with dynamic in vivo imaging that routes of outflow of CSF in mice occur along cranial nerves to extracranial lymphatic vessels. Here, we use near-infrared and magnetic resonance imaging to demonstrate the flow of CSF tracers within the spinal column and reveal the major spinal pathways for outflow to lymphatic vessels in mice. We found that after intraventricular injection, a spread of CSF tracers occurs within both the central canal and the spinal subarachnoid space toward the caudal end of the spine. Outflow of CSF tracers from the spinal subarachnoid space occurred predominantly from intravertebral regions of the sacral spine to lymphatic vessels, leading to sacral and iliac LNs. Clearance of CSF from the spine to lymphatic vessels may have significance for many conditions, including multiple sclerosis and spinal cord injury.


Assuntos
Carbazóis/líquido cefalorraquidiano , Vasos Linfáticos/metabolismo , Imagem por Ressonância Magnética/métodos , Sacro/metabolismo , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/líquido cefalorraquidiano , Analgésicos Opioides/farmacocinética , Animais , Buprenorfina/administração & dosagem , Buprenorfina/líquido cefalorraquidiano , Buprenorfina/farmacocinética , Carbazóis/administração & dosagem , Carbazóis/farmacocinética , Líquido Cefalorraquidiano/metabolismo , Meios de Contraste/administração & dosagem , Meios de Contraste/farmacocinética , Região Lombossacral/diagnóstico por imagem , Sistema Linfático/metabolismo , Vasos Linfáticos/diagnóstico por imagem , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Sacro/diagnóstico por imagem , Espaço Subaracnóideo
4.
Cancer Radiother ; 23(5): 432-438, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31331844

RESUMO

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and extend the survival benefit with crizotinib. The role of whole brain irradiation in the treatment of brain metastases diminishes, as this technique is associated with the risk of neurocognitive decline. Stereotactic radiotherapy represents an alternative technique that delivers ablative doses of ionizing radiation to the limited volume of oligometastatic brain disease, offering sparing of the adjacent brain parenchyma and reduced neurotoxicity. The next generation ALK inhibitors were designed to cross the blood-brain barrier more efficiently than crizotinib and achieve higher concentration in the cerebrospinal fluid, offering prominent ability to control central nervous system spread. In the phase III ALEX trial the intracranial control was significantly better with alectinib as compared to crizotinib and it translated into survival benefit. Other next generation ALK inhibitors (i.e. ceritinib, brigatinib, lorlatinib) also demonstrated promising activity in the central nervous system.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Pulmonares , Neoplasias Meníngeas/secundário , Proteínas de Neoplasias/antagonistas & inibidores , Quinase do Linfoma Anaplásico/análise , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/radioterapia , Carbazóis/farmacocinética , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Cisplatino/administração & dosagem , Ensaios Clínicos como Assunto , Terapia Combinada , Irradiação Craniana/efeitos adversos , Irradiação Craniana/métodos , Crizotinibe/farmacocinética , Crizotinibe/uso terapêutico , Gerenciamento Clínico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Meníngeas/enzimologia , Neoplasias Meníngeas/radioterapia , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/análise , Transtornos Neurocognitivos/etiologia , Transtornos Neurocognitivos/prevenção & controle , Estudos Observacionais como Assunto , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Pemetrexede/administração & dosagem , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos
5.
Clin Drug Investig ; 39(6): 553-563, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31037611

RESUMO

BACKGROUND AND OBJECTIVES: Chiglitazar is a novel configuration-restricted non-thiazolidinedione peroxisome proliferator-activated receptor pan-agonist currently in the Phase III clinical development stage for type 2 diabetes mellitus patients. The objective of this Phase I study was to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of chiglitazar tablets taken orally and the effect of food on its pharmacokinetics in healthy Chinese subjects. METHODS: A single-centre, open-label, randomised, two-stage Phase I study was carried out. In the first-stage study, we evaluated a single dose of 8, 16, or 32 mg, and multiple doses of 16 mg, taken once daily for 9 days. The effect of food consumption was also studied in this stage. In the second-stage study, a greater range of single doses (24, 48 or 72 mg) were further evaluated. Pharmacokinetics, safety and tolerability profiles were assessed at each study stage. RESULTS: After a single oral dose of chiglitazar, at doses ranging from 8 to 72 mg, the maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were proportionally increased (165-1599 ng/mL for the mean Cmax and 1356-12,584 ng·h/mL for the mean AUC0-t), with low inter-subject variability. There were no significant changes in the mean terminal phase half-life (t1/2), which ranged from 9.0 to 11.9 h, and the clearance and volume of distribution were similar for all evaluated doses. The results from the examination of multiple dose of 16 mg once daily for nine consecutive days showed that a steady-state condition was achieved by Day 6. There was no apparent accumulation of chiglitazar observed at Day 9, as compared with the first administration. While food increased the AUC0-t of chiglitazar by about 13%, there were no effects on other parameters, including Cmax, Tmax and t1/2. There were no serious or severe adverse events observed in the single- or multiple-dose studies. CONCLUSIONS: Chiglitazar tablets showed a good dose-dependent linear pharmacokinetic profile in the dose range of 8-72 mg. There was no accumulation after multiple daily administration of chiglitazar at a dose of 16 mg.  High-fat/calorie food increased the absorption of the drug, but there were no significant changes in exposure and other pharmacokinetic parameters. Chiglitazar was safe and well tolerated in healthy Chinese subjects at the dose levels and administration regimens evaluated.


Assuntos
Carbazóis/administração & dosagem , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Propionatos/administração & dosagem , Administração Oral , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Carbazóis/efeitos adversos , Carbazóis/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Propionatos/efeitos adversos , Propionatos/farmacocinética , Comprimidos , Adulto Jovem
6.
Drug Metab Dispos ; 47(7): 699-709, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31068367

RESUMO

Alectinib is a tyrosine kinase inhibitor currently used as a first-line treatment of anaplastic lymphoma kinase-positive metastatic nonsmall cell lung cancer (NSCLC). In the present work, we investigated possible interactions of this novel drug with ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 (P450) biotransformation enzymes that play significant roles in the phenomenon of multidrug resistance (MDR) of cancer cells as well as in pharmacokinetic drug-drug interactions. Using accumulation studies in Madin-Darby canine kidney subtype 2 (MDCKII) cells alectinib was identified as an inhibitor of ABCB1 and ABCG2 but not of ABCC1. In subsequent drug combination studies, we demonstrated the ability for alectinib to effectively overcome MDR in ABCB1- and ABCG2-overexpressing MDCKII and A431 cells. To describe the pharmacokinetic interaction profile of alectinib in a complete fashion, its possible inhibitory properties toward clinically relevant P450 enzymes (i.e., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP3A5) were evaluated using human P450-expressing insect microsomes, revealing alectinib as a poor interactor. Advantageously for its use in pharmacotherapy, alectinib further exhibited negligible potential to cause any changes in expression of ABCB1, ABCG2, ABCC1, CYP1A2, CYP3A4, and CYP2B6 in intestine, liver, and NSCLC models. Our in vitro observations might serve as a valuable foundation for future in vivo studies that could support the rationale for our conclusions and possibly enable providing more efficient and safer therapy to many oncological patients.


Assuntos
Transportadores de Cassetes de Ligação de ATP/efeitos dos fármacos , Carbazóis/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Biotransformação , Carbazóis/farmacocinética , Cães , Humanos , Células Madin Darby de Rim Canino , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética
7.
Pharmazie ; 74(2): 79-82, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30782255

RESUMO

IG-105, N-(2, 6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide, a novel carbazole sulfonamide, shows a potent anticancer activity in a variety of human tumor cells in vitro and in vivo. In the present study, a rapid and convenient liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and applied to the pharmacokinetic study of IG-105 in rats. Chromatographic separation was accomplished on a C18 column using an isocratic mobile phase of acetonitrile-water-acetic acid (56:44:0.2, v/v/v). The ion transitions of IG-105 and combretastatin A4 (internal standard) in selected reaction monitoring mode were m/z 398→154 and m/z 317→286, respectively. The assay exhibited good linearity over the range of 2-512 ng/mL. Intra- and inter-day precisions were within 8.2 %, and the accuracies ranged from -6.0 to 3.7 %. The extraction recoveries were higher than 90 %, and the matrix effects were negligible. All quality control samples were stable at different storage conditions. The validated LC-MS/MS method was successfully applied to a preclinical pharmacokinetic study of IG-105 in rats after a single oral dose of 100, 250, or 1000 mg/kg which showed tumor growth inhibition activity. The absorption of IG-105 was proved to be rapid but saturated to a certain extent into the blood circulation, from where it was distributed and eliminated gradually.


Assuntos
Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Carbazóis/sangue , Carbazóis/farmacocinética , Cromatografia Líquida/métodos , Sulfonamidas/sangue , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Moduladores de Tubulina , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Moduladores de Tubulina/sangue , Moduladores de Tubulina/farmacocinética
8.
Clin Pharmacol Drug Dev ; 8(7): 934-941, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30809967

RESUMO

Chiglitazar (CHI) is a potent and selective peroxisome proliferator-activated receptor potentially for the treatment of patients with type 2 diabetes mellitus (T2DM). An open-label, randomized, 3-period crossover and self-controlled study was conducted to investigate drug-drug interaction potential between CHI and metformin hydrochloride (MET). Eligible subjects received a single oral dose of CHI (48 mg), MET (1000 mg), or a combination in each period, followed by serial blood sampling collected for up to 48 hours postdose, and safety was assessed throughout the trial. The area under the plasma concentration-time curves from time 0 to 48 hours (AUC0-48 h ) of CHI was similar following administration alone or with MET (AUC0-48h , 12 540 ng·h/mL [9811-15 269 ng·h/mL] vs 12 130 ng·h/mL [9304-14 956 ng·h/mL]; 90% confidence interval [CI] of its geometric mean ratio [GMR], 89.7%-103.8%), whereas the maximum concentration (Cmax ) of CHI was reduced during coadministration, as its 90%CI of the GMR was slightly outside the acceptance range for bioequivalence (Cmax , 1620 ng/mL [1418-1822 ng/mL] vs 1420 ng/mL [1049-1791 ng/mL], 90%CI GMR, 77.%-94.1%). However, it was not considered clinically meaningful. The MET exposures remained consistent in the absence or presence of CHI (AUC0-48 h , 12 570 ng·h/mL [10681-14 459 ng·h/mL] vs 13 190 [10973-15 407 ng·h/mL); 90%CI of GMR: 99.1%-110.5%; Cmax , 1790 ng/mL [1448-2132 ng/mL] vs 1820 ng/mL [1510-2130 ng/mL]; 90%CI of GMR, 94.2%-110.9%). No moderate to severe adverse events were reported. Our study indicated no clinically significant pharmacokinetic drug-drug interaction between CHI and MET and demonstrated good tolerance in subjects. These results support future application of CHI in combination with MET for treatment of T2DM.


Assuntos
Carbazóis/administração & dosagem , Carbazóis/farmacocinética , Metformina/administração & dosagem , Metformina/farmacocinética , Propionatos/administração & dosagem , Propionatos/farmacocinética , Administração Oral , Área Sob a Curva , China , Estudos Cross-Over , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Masculino , Equivalência Terapêutica
9.
Clin Pharmacokinet ; 58(4): 403-420, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29915924

RESUMO

The identification of anaplastic lymphoma kinase rearrangements in 2-5% of patients with non-small-cell lung cancer led to rapid advances in the clinical development of oral tyrosine kinase inhibitors. Anaplastic lymphoma kinase inhibitors are an effective treatment in preclinical models and patients with anaplastic lymphoma kinase-translocated cancers. Four anaplastic lymphoma kinase inhibitors (crizotinib, ceritinib, alectinib, and brigatinib) have recently been approved. Post-marketing studies provided additional pharmacokinetic information on their pharmacokinetic parameters. The pharmacokinetic properties of approved anaplastic lymphoma kinase inhibitors have been reviewed herein. Findings from additional studies on the effects of drug-metabolizing enzymes, drug transporters, and drug-drug interactions have been incorporated. Crizotinib, ceritinib, and alectinib reach their maximum plasma concentrations after approximately 6 h and brigatinib after 1-4 h. These drugs are primarily metabolized by cytochrome P450 3A with other cytochrome P450 enzymes. They are mainly excreted in the feces, with only a minor fraction being eliminated in urine. Crizotinib, ceritinib, and brigatinib are substrates for the adenosine triphosphate binding-cassette transporter B1, whereas alectinib is not. The different substrate specificities of the transporters play a key role in superior blood-brain barrier penetration by alectinib than by crizotinib and ceritinib. Although the absorption, distribution, and excretion of anaplastic lymphoma kinase inhibitors are regulated by drug transporters, their transporter-mediated pharmacokinetics have not yet been elucidated in detail in patients with non-small-cell lung cancer. Further research to analyze the contribution of drug transporters to the pharmacokinetics of anaplastic lymphoma kinase inhibitors in patients with non-small-cell lung cancer will be helpful for understanding the mechanisms of the inter-individual differences in the pharmacokinetics of anaplastic lymphoma kinase inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carbazóis/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Crizotinibe/farmacocinética , Neoplasias Pulmonares/metabolismo , Compostos Organofosforados/farmacocinética , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Sulfonas/farmacocinética , Animais , Interações Medicamentosas , Humanos , Proteínas de Membrana Transportadoras/metabolismo
10.
J Pharm Sci ; 108(2): 851-859, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30053555

RESUMO

The objective of the present study was to develop polymeric nanoparticles (PNPs) of frovatriptan succinate for brain targeting by nasal route. Double emulsion method was used to increase the entrapment efficiency of hydrophilic drug, and formulation was optimized by central composite design to achieve critical quality attributes namely particle size, zeta potential, and entrapment efficiency. Optimized batch was evaluated for surface morphology, in vitro release, permeation across nasal mucosa, stability, histopathology, and brain tissue uptake study. Prepared PNPs were found to be smooth with particle size of 264.4 ± 0.04 nm, zeta potential -35.17 ± 0.07 mV, and 65.2 ± 0.06% entrapment efficiency. PNPs showed biphasic release pattern, initial burst release followed by sustained release up to 72 h. Ex vivo diffusion study using goat nasal mucosa at pH 6.8 revealed that PNPs permeation across nasal mucosa was about 3 times more than the pure drug solution, and quick delivery of PNPs in brain region was confirmed by fluorescence microscopic evaluation in male Wistar rats after intranasal administration. Histopathology studies further revealed integrity of nasal mucosa after treatment with PNPs. The investigation indicated that hydrophilic drug, frovatriptan succinate can be successfully entrapped in PNPs to target brain via nasal delivery, and thus it could be an effective approach for nose to brain delivery.


Assuntos
Encéfalo/metabolismo , Carbazóis/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanopartículas/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Triptaminas/administração & dosagem , Administração Intranasal , Animais , Carbazóis/farmacocinética , Portadores de Fármacos/metabolismo , Liberação Controlada de Fármacos , Masculino , Polímeros/metabolismo , Ratos Wistar , Agonistas do Receptor de Serotonina/farmacocinética , Triptaminas/farmacocinética
11.
J Neuroinflammation ; 15(1): 307, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400912

RESUMO

BACKGROUND: Causal associations between microglia activation and ß-amyloid (Aß) accumulation during the progression of Alzheimer's disease (AD) remain a matter of controversy. Therefore, we used longitudinal dual tracer in vivo small animal positron emission tomography (µPET) imaging to resolve the progression of the association between Aß deposition and microglial responses during aging of an Aß mouse model. METHODS: APP-SL70 mice (N = 17; baseline age 3.2-8.5 months) and age-matched C57Bl/6 controls (wildtype (wt)) were investigated longitudinally for 6 months using Aß (18F-florbetaben) and 18 kDa translocator protein (TSPO) µPET (18F-GE180). Changes in cortical binding were transformed to Z-scores relative to wt mice, and microglial activation relative to amyloidosis was defined as the Z-score difference (TSPO-Aß). Using 3D immunohistochemistry for activated microglia (Iba-1) and histology for fibrillary Aß (methoxy-X04), we measure microglial brain fraction relative to plaque size and the distance from plaque margins. RESULTS: Aß-PET binding increased exponentially as a function of age in APP-SL70 mice, whereas TSPO binding had an inverse U-shape growth function. Longitudinal Z-score differences declined with aging, suggesting that microglial response declined relative to increasing amyloidosis in aging APP-SL70 mice. Microglial brain volume fraction was inversely related to adjacent plaque size, while the proximity to Aß plaques increased with age. CONCLUSIONS: Microglial activity decreases relative to ongoing amyloidosis with aging in APP-SL70 mice. The plaque-associated microglial brain fraction saturated and correlated negatively with increasing plaque size with aging.


Assuntos
Envelhecimento , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Microglia/metabolismo , Tomografia por Emissão de Pósitrons , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Amiloidose/diagnóstico por imagem , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Carbazóis/farmacocinética , Modelos Animais de Doenças , Fluordesoxiglucose F18/farmacocinética , Estudos Longitudinais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Radioquímica , Receptores de GABA/metabolismo
12.
Transl Psychiatry ; 8(1): 202, 2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30258178

RESUMO

There is a critical need for translating basic science discoveries into new therapeutics for patients suffering from difficult to treat neuropsychiatric and neurodegenerative conditions. Previously, a target-agnostic in vivo screen in mice identified P7C3 aminopropyl carbazole as capable of enhancing the net magnitude of postnatal neurogenesis by protecting young neurons from death. Subsequently, neuroprotective efficacy of P7C3 compounds in a broad spectrum of preclinical rodent models has also been observed. An important next step in translating this work to patients is to determine whether P7C3 compounds exhibit similar efficacy in primates. Adult male rhesus monkeys received daily oral P7C3-A20 or vehicle for 38 weeks. During weeks 2-11, monkeys received weekly injection of 5'-bromo-2-deoxyuridine (BrdU) to label newborn cells, the majority of which would normally die over the following 27 weeks. BrdU+ cells were quantified using unbiased stereology. Separately in mice, the proneurogenic efficacy of P7C3-A20 was compared to that of NSI-189, a proneurogenic drug currently in clinical trials for patients with major depression. Orally-administered P7C3-A20 provided sustained plasma exposure, was well-tolerated, and elevated the survival of hippocampal BrdU+ cells in nonhuman primates without adverse central or peripheral tissue effects. In mice, NSI-189 was shown to be pro-proliferative, and P7C3-A20 elevated the net magnitude of hippocampal neurogenesis to a greater degree than NSI-189 through its distinct mechanism of promoting neuronal survival. This pilot study provides evidence that P7C3-A20 safely protects neurons in nonhuman primates, suggesting that the neuroprotective efficacy of P7C3 compounds is likely to translate to humans as well.


Assuntos
Carbazóis/administração & dosagem , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Administração Oral , Animais , Carbazóis/farmacocinética , Hipocampo/fisiologia , Macaca mulatta , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/fisiologia , Neurônios/fisiologia , Projetos Piloto
13.
ACS Nano ; 12(9): 9532-9540, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30134104

RESUMO

The development of fluorogens with deep-red emission is one of the hottest topics of investigation in the field of bio/chemosensors and bioimaging. Herein, the tunable fluorescence of perylene diimide (PDI) derivatives was achieved by the incorporation of varied isolation groups linked on the PDI core. With the enlarged sizes of isolation groups, the conversion from aggregation caused quenching to aggregation-induced emission was obtained in their fluorescence variations from solutions to nanoparticles, as the result of the efficient inhibition of π-π stacking by the larger isolation groups. Accordingly, DCzPDI bearing 1,3-di(9H-carbazol-9-yl)benzene as the biggest isolation group exhibited the bright deep-red emission in the aggregated state with a quantum yield of 12.3%. Combined with the three-photon excited fluorescence microscopy (3PFM) technology, through-skull 3PFM imaging of mouse cerebral vasculature can be realized by DCzPDI nanoparticles with good biocompatibility, and the penetration depth can be as deep as 450 µm.


Assuntos
Derivados de Benzeno/química , Carbazóis/química , Corantes Fluorescentes/química , Imidas/química , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Nanopartículas/química , Imagem Óptica/métodos , Perileno/análogos & derivados , Animais , Derivados de Benzeno/farmacocinética , Derivados de Benzeno/toxicidade , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Carbazóis/farmacocinética , Carbazóis/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Corantes Fluorescentes/farmacocinética , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Imidas/farmacocinética , Imidas/toxicidade , Camundongos , Perileno/química , Perileno/farmacocinética , Perileno/toxicidade , Distribuição Tecidual
14.
J Pharm Biomed Anal ; 161: 136-143, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30149189

RESUMO

Several second and third generation ALK inhibitors have been introduced in recent years. A bioanalytical assay for simultaneous quantification of alectinib, brigatinib, and lorlatinib was developed and validated for human plasma. The method was also partially validated for diluted mouse plasma and tissue homogenates of brain, liver, kidney, and spleen. Samples (40 µl) were pretreated in a 96-well plate by protein precipitation with acetonitrile containing the internal standard [2H8]-alectinib. After chromatographic separation on an ethylene bridged octadecyl silica column by gradient elution at 600 µl/min using 1% (v/v) formic acid (in water) and acetonitrile, compounds were ionized by a turbo electrospray and monitored by selected reaction monitoring on a triple quadrupole mass spectrometer. Validation was performed in a 2-2000 ng/ml concentration range for alectinib and lorlatinib and a 4-4000 ng/ml range for brigatinib. Precisions (within-day and between-day) were in the range 2.2-15.0% and accuracies were in between 87.2 and 110.2% for all matrices and levels. Compounds were sufficiently stable under most investigated conditions. Results of a pilot pharmacokinetic and tissue distribution study for brigatinib in mice are reported. Finally, successful incurred samples reanalysis of tissue homogenate samples containing brigatinib and lorlatinib is presented. Lorlatinib homogenate samples were also successfully reanalyzed using a second independent assay (cross-validation).


Assuntos
Carbazóis/sangue , Carbazóis/farmacocinética , Cromatografia Líquida/métodos , Lactamas Macrocíclicas/sangue , Lactamas Macrocíclicas/farmacocinética , Compostos Organofosforados/sangue , Compostos Organofosforados/farmacocinética , Piperidinas/sangue , Piperidinas/farmacocinética , Pirimidinas/sangue , Pirimidinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Humanos , Masculino , Camundongos , Inibidores de Proteínas Quinases/farmacocinética , Distribuição Tecidual
15.
Drugs ; 78(12): 1247-1257, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30030733

RESUMO

Alectinib (Alecensa®) is a potent and highly selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor. Oral alectinib monotherapy is approved in the EU as first-line treatment for adults with advanced ALK-positive non-small cell lung cancer (NSCLC) and for the treatment of adults with advanced ALK-positive NSCLC previously treated with crizotinib. In the USA, alectinib is indicated for the treatment of adults with ALK-positive metastatic NSCLC. The recommended dosage for alectinib in the EU and USA is 600 mg twice daily. Well-designed phase III studies in patients with ALK-positive NSCLC showed that during up to ≈ 19 months' follow-up, progression-free survival (PFS) was significantly improved with alectinib relative to crizotinib as first-line therapy (ALEX study), and relative to chemotherapy in patients previously treated with crizotinib and platinum-doublet chemotherapy (ALUR study). Central nervous system (CNS)-related outcomes were significantly improved with alectinib in both these settings. Two phase II registrational studies (NP28673 and NP28761) in patients previously treated with crizotinib also demonstrated the efficacy of alectinib, as assessed by objective response rates (ORRs), during up to 21 months' follow-up. Overall, alectinib had a manageable tolerability profile in these settings, with most adverse events (AEs) of mild or moderate severity. Current evidence indicates that alectinib is an important treatment option for patients with advanced ALK-positive NSCLC who are previously untreated or those previously treated with crizotinib. Given its efficacy and tolerability, current guidelines include alectinib as a treatment option in these settings, with the NCCN guidelines recommending it as a preferred option for first-line therapy.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Administração Oral , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Carbazóis/farmacocinética , Carbazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Ensaios Clínicos como Assunto , Aprovação de Drogas , Resistencia a Medicamentos Antineoplásicos , Europa (Continente) , Humanos , Neoplasias Pulmonares/enzimologia , Piperidinas/farmacocinética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento
16.
J Clin Pharmacol ; 58(12): 1618-1628, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30052269

RESUMO

Alectinib is approved and recommended as the preferred first-line treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer. The effect of hepatic impairment on the pharmacokinetics (PK) of alectinib was assessed with physiologically based PK modeling prospectively and in a clinical study. An open-label study (NCT02621047) investigated a single 300-mg dose of alectinib in moderate (n = 8) and severe (n = 8) hepatic impairment (Child-Pugh B/C), and healthy subjects (n = 12) matched for age, sex, and body weight. Physiologically based PK modeling was conducted prospectively to inform the clinical study design and support the use of a lower dose and extended PK sampling in the study. PK parameters were calculated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Unbound concentrations were assessed at 6 and 12 hours postdose. Administration of alectinib to subjects with hepatic impairment increased the area under the plasma concentration-time curve from time 0 to infinity of the combined exposure of alectinib and M4 to 136% (90% confidence interval [CI], 94.7-196) and 176% (90%CI 98.4-315), for moderate and severe hepatic impairment, respectively, relative to matched healthy subjects. Unbound concentrations for alectinib and M4 did not appear substantially different between hepatic-impaired and healthy subjects. Moderate hepatic impairment had only a modest, not clinically significant effect on alectinib exposure, while the higher exposure observed in severe hepatic impairment supports a dose adjustment in this population.


Assuntos
Carbazóis/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Hepatopatias/metabolismo , Fígado/metabolismo , Piperidinas/farmacocinética , Adulto , Área Sob a Curva , Carbazóis/metabolismo , Estudos de Casos e Controles , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética
17.
Int J Pharm ; 547(1-2): 303-314, 2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-29803794

RESUMO

A novel delivery system based on self-assembled liposome from multi-layered fibrous mucoadhesive membrane has been developed to improve the bioavailability of Carvedilol (Car). This system consisted of an electrospun layer (enable self-assembly of liposome once contacting with water), an adhesive layer (prolong the retention period in the mouth) and a backing layer. SEM, DSC and FTIR were applied to characterize the fiber. The TEM and fluorescence study demonstrated the formation of self-assembled liposome when electrospun fiber encountered water. The ratio of PC to Car and the molecular weight of PVP both had a significant impact on the drug encapsulation efficiency. In vitro and in vivo adhesive tests were conducted to evaluate the bioadhesive performance of the adhesive layer. The dialysis dissolution and permeation study through porcine buccal mucosa were carried out. The electrospun fiber showed excellent drug permeation amount compared to pure Car. The drug concentration-time curves, in rabbits, of fibrous mucoadhesive membrane and Car suspension were different, and possible reasons were analyzed. The pharmacokinetic study demonstrated 154% increase in the relative bioavailability compared to Car suspension. This drug delivery system offered a novel platform for potential buccal delivery of drugs with high first-pass effect.


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Carbazóis/administração & dosagem , Sistemas de Liberação de Medicamentos , Mucosa Bucal/metabolismo , Propanolaminas/administração & dosagem , Adesividade , Adesivos/química , Administração Bucal , Antagonistas Adrenérgicos beta/farmacocinética , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Carbazóis/farmacocinética , Carvedilol , Química Farmacêutica/métodos , Lipossomos , Microscopia Eletrônica de Varredura , Propanolaminas/farmacocinética , Coelhos , Espectroscopia de Infravermelho com Transformada de Fourier , Suínos
18.
Biopharm Drug Dispos ; 39(4): 232-242, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29607517

RESUMO

Carvedilol (CAR) belongs to biopharmaceutics classification system class-II drugs, with poor aqueous solubility and pH-dependent solubility. The present study aimed to develop a novel amorphous solid dispersion (ASD) of CAR with acidic counter ions for pH modifications in microenvironment to improve the pharmacokinetic properties under hypochlorhydric conditions. CAR-ASD was prepared by freeze-drying in combination with counter ions and hydroxypropyl cellulose, and their physicochemical properties including dissolution behavior, storage stability, and photostability were characterized. Pharmacokinetic studies were carried out after oral administration of CAR samples in both normal and omeprazole-treated (30 mg/kg, p.o.) rats as a hypochlorhydria model. Among the tested six counter ions, citric acid (CA) was found to be a preferable pH-modifier of CAR with respect to the dissolution profile and photostability (both potency and colorimetric evaluation). In CAR-ASD formulation with 50% loading of CA (CAR-ASD/CA50), amorphization of CAR was observed during the preparation process. After the oral administration of crystalline CAR in rats under hypochlorhydric condition, there was a 34.4% reduction in the systemic exposure of CAR compared with that in normal rats. However, orally-dosed CAR-ASD/CA50 resulted in limited alterations of pharmacokinetic behavior between normal and omeprazole-treated rats. From these findings, addition of CA as pH-modifier in CAR-ASD might provide consistent pharmacokinetic behavior of CAR even under hypochlorhydric conditions.


Assuntos
Acloridria/metabolismo , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacocinética , Carbazóis/administração & dosagem , Carbazóis/farmacocinética , Omeprazol/farmacologia , Propanolaminas/administração & dosagem , Propanolaminas/farmacocinética , Administração Oral , Animais , Anti-Hipertensivos/sangue , Carbazóis/sangue , Carvedilol , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Masculino , Propanolaminas/sangue , Ratos Sprague-Dawley
19.
Eur J Pharm Sci ; 118: 176-182, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29605455

RESUMO

Bioequivalence implementation in developing countries where a high proportion of similar drug products are being marketed has found several obstacles, impeding regulatory agencies to move forward with this policy. Biopharmaceutical quality of these products, several of which are massively prescribed, remains unknown. In this context, an in vitro-in silico-in vivo approach is proposed as a mean to screen product performance and target specific formulations for bioequivalence assessment. By coupling in vitro biorelevant dissolution testing in USP-4 Apparatus (flow-through cell) with physiologically-based pharmacokinetic (PBPK) modeling in PK-Sim® software (Bayer, Germany), the performance of seven similar products of carvedilol tablets containing 25 mg available in the Uruguayan market were compared with the brand-name drug Dilatrend®. In silico simulations for Dilatrend® were compared with published results of bioequivalence studies performed in fasting conditions allowing model development through a learning and confirming process. Single-dose pharmacokinetic profiles were then simulated for the brand-name drug and two similar drug products selected according to in vitro observations, in a virtual Caucasian population of 1000 subjects (50% male, aged between 18 and 50 years with standard body-weights). Population bioequivalence ratios were estimated revealing that in vitro differences in drug release would have a major impact in carvedilol maximum plasma concentration, leading to a non-bioequivalence outcome. Predictions support the need to perform in vivo bioequivalence for these products of extensive use. Application of the in vitro-in silico-in vivo approach stands as an interesting alternative to tackle and reduce drug product variability in biopharmaceutical quality.


Assuntos
Anti-Hipertensivos/farmacocinética , Carbazóis/farmacocinética , Modelos Biológicos , Propanolaminas/farmacocinética , Administração Oral , Adolescente , Adulto , Carvedilol , Simulação por Computador , Liberação Controlada de Fármacos , Jejum/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Comprimidos , Equivalência Terapêutica , Adulto Jovem
20.
J Vet Pharmacol Ther ; 41(4): 605-613, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29691872

RESUMO

The alleviation of pain and prevention of suffering are key aspects of animal welfare. Unfortunately, analgesic drugs are not available for all species. White rhinoceros (Ceratotherium simum), representing one of such species, which survive poaching attempts inflicted with severe facial injuries and gunshot wounds, nonetheless require analgesic support. To improve treatment conditions, this study explored the use of carprofen for the treatment of pain and inflammation in white rhinoceros. The pharmacokinetics of 1 mg/kg intramuscular carprofen was evaluated in six healthy white rhinoceros. The half-life of λz and mean residence time was 105.71 ± 15.67 and 155.01 ± 22.46 hr, respectively. The area under the curve and the maximum carprofen concentration were 904.61 ± 110.78 µg ml-1  hr-1 and 5.77 ± 0.63 µg/ml, respectively. Plasma TXB2 inhibition demonstrated anti-inflammatory properties and indicated that carprofen may be effective for a minimum of 48 hr in most animals. With its long half-life further indicating that a single dose could be effective for several days, we suggest that carprofen may be a useful drug for the treatment of white rhinoceros.


Assuntos
Analgesia/veterinária , Analgésicos/farmacocinética , Carbazóis/farmacocinética , Perissodáctilos/metabolismo , Tromboxanos/antagonistas & inibidores , Analgesia/métodos , Analgésicos/administração & dosagem , Analgésicos/sangue , Analgésicos/farmacologia , Animais , Carbazóis/administração & dosagem , Carbazóis/sangue , Carbazóis/farmacologia , Feminino , Meia-Vida , Injeções Intramusculares/veterinária , Masculino , Perissodáctilos/sangue
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