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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
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
13.
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
14.
Int J Pharm ; 541(1-2): 1-10, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29458210

RESUMO

Hot-melt extrusion (HME) has gained increasing attention in the pharmaceutical industry; however, its potential in the preparation of solid self-emulsifying drug delivery systems (S-SMEDDS) is still unexplored. This study sought to prepare enteric S-SMEDDS by HME and evaluate the effects of the process and formulation variables on S-SMEDDS properties via Box-Behnken design. Liquid SMEDDS were developed, and carvedilol was used as a class II model drug. Mean size, polydispersity index (PdI) and zeta potential of the resulting microemulsions were determined. The extrudates were then obtained by blending the lipid mixture and HPMCAS using a twin-screw hot-melt extruder. SEM, optical microscopy and PXRD were used to characterize the extrudates. In vitro microemulsion reconstitution and drug release were also studied. L-SMEDDS gave rise to microemulsions with low mean size, PdI and zeta potential (140.04 ±â€¯7.22 nm, 0.219 ±â€¯0.011 and -9.77 ±â€¯0.86 mV). S-SMEDDS were successfully prepared by HME, and an HMPCAS matrix was able to avoid microemulsion reconstitution and retain drug release in pH 1.2 (12.97%-25.54%). Conversely, microemulsion reconstitution and drug release were gradual in pH 6.8 and complete for some formulations. Extrudates prepared at the lowest drug concentration and highest temperature and recirculation time promoted a complete and rapid drug release in pH 6.8 giving rise to small and uniform microemulsion droplets.


Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos , Emulsões/química , Carbazóis/administração & dosagem , Carbazóis/farmacocinética , Carvedilol , Química Farmacêutica/instrumentação , Liberação Controlada de Fármacos , Temperatura Alta , Concentração de Íons de Hidrogênio , Lipídeos/química , Metilcelulose/análogos & derivados , Metilcelulose/química , Tamanho da Partícula , Propanolaminas/administração & dosagem , Propanolaminas/farmacocinética , Solubilidade
15.
Mol Cancer Ther ; 17(3): 614-624, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29339551

RESUMO

Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myelogenous leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here, we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations. EC-70124 potently inhibits wild-type and mutant FLT3, and also other important kinases such as PIM kinases. EC-70124 inhibits proliferation of AML cell lines, inducing cell-cycle arrest and apoptosis. EC-70124 is orally bioavailable and displays higher metabolic stability and lower human protein plasma binding compared with midostaurin. Both in vitro and in vivo pharmacodynamic analyses demonstrate inhibition of FLT3-STAT5, Akt-mTOR-S6, and PIM-BAD pathways. Oral administration of EC-70124 in FLT3-ITD xenograft models demonstrates high efficacy, reaching complete tumor regression. Ex vivo, EC-70124 impaired cell viability in leukemic blasts, especially from FLT3-ITD patients. Our results demonstrate the ability of EC-70124 to reduce proliferation and induce cell death in AML cell lines, patient-derived leukemic blast and xenograft animal models, reaching best results in FLT3 mutants that carry other molecular pathways' alterations. Thus, its unique inhibition profile warrants EC-70124 as a promising agent for AML treatment based on its ability to interfere the complex oncogenic events activated in AML at several levels. Mol Cancer Ther; 17(3); 614-24. ©2018 AACR.


Assuntos
Carbazóis/farmacologia , Indóis/farmacologia , Leucemia Mieloide/tratamento farmacológico , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Doença Aguda , Animais , Disponibilidade Biológica , Células CACO-2 , Carbazóis/farmacocinética , Carbazóis/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Indóis/farmacocinética , Indóis/uso terapêutico , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Camundongos SCID , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/genética , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Células THP-1 , Tirosina Quinase 3 Semelhante a fms/metabolismo
16.
Clin Pharmacol Ther ; 104(3): 505-514, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29226313

RESUMO

Alectinib is a selective anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. Alectinib and its major active metabolite M4 exhibited drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8 in vitro. Clinical relevance of the DDI risk was investigated as part of a rapid development program to fulfill the breakthrough therapy designation. Therefore, a strategy with a combination of physiologically based pharmacokinetic (PBPK) modeling and limited clinical trials focused on generating informative data for modeling was made to ensure extrapolation ability of DDI risk. The PBPK modeling has provided mechanistic insight into the low victim DDI risk of alectinib through CYP3A4 by a novel two-dimensional analysis for fmCYP3A4 and FG , and demonstrated negligible CYPs 2C8 and 3A4 enzyme-modulating effects at clinically relevant exposure. This work supports that alectinib can be prescribed without dose adjustment for CYP-mediated DDI liabilities.


Assuntos
Carbazóis/farmacocinética , Simulação por Computador , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Desenvolvimento de Medicamentos/métodos , Modelos Biológicos , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Ativação Metabólica , Carbazóis/efeitos adversos , Inibidores do Citocromo P-450 CYP2C8/efeitos adversos , Inibidores do Citocromo P-450 CYP2C8/farmacocinética , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Aprovação de Drogas , Interações de Medicamentos , Humanos , Segurança do Paciente , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Medição de Risco , Especificidade por Substrato , Estados Unidos , United States Food and Drug Administration
17.
Xenobiotica ; 48(6): 546-554, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28657423

RESUMO

1. The in vitro metabolism of alectinib, a potent and highly selective oral anaplastic lymphoma kinase inhibitor, was investigated. 2. The main metabolite (M4) in primary human hepatocytes was identified, which is produced by deethylation at the morpholine ring. Three minor metabolites (M6, M1a, and M1b) were also identified, and a minor peak of hydroxylated alectinib (M5) was detected as a possible precursor of M4, M1a, and M1b. 3. M4, an important active major metabolite, was produced and further metabolized to M6 by CYP3A, indicating that CYP3A enzymes were the principal contributors to this route. M5 is possibly produced by CYP3A and other isoforms as the primary step in metabolism, followed by oxidation to M4 mainly by CYP3A. Alternatively, M5 could be oxidized to M1a and M1b via an NAD-dependent process. None of the non-CYP3A-mediated metabolism appeared to be major. 4. In conclusion, this study suggests that involvement of multiple enzymes in the metabolism of alectinib reduces its potential for drug-drug interactions.


Assuntos
Carbazóis , Citocromo P-450 CYP3A/metabolismo , Hepatócitos/enzimologia , Piperidinas , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Quinase do Linfoma Anaplásico , Carbazóis/farmacocinética , Carbazóis/farmacologia , Células Cultivadas , Hepatócitos/citologia , Humanos , Piperidinas/farmacocinética , Piperidinas/farmacologia
18.
Eur J Med Chem ; 143: 1436-1447, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29126730

RESUMO

Recently, the development of the fluorinated PET tracer [18F]1a for imaging of CB2 receptors in the central nervous system was reported. [18F]1a showed high CB2 affinity and selectivity over the CB1 subtype, but rapid biotransformation in mice. In addition to the amide hydrolysis, oxidative N-dealkylation and carbazole oxidation were postulated as main metabolic pathways. Based on these results, novel carbazole derivatives with additional 6-substituents (23a, 24a), modified hydrogenation state (26a) and enlarged fluoroalkyl substituent (13a, 13b) were synthesized and pharmacologically evaluated. The key step in the synthesis of substituted carbazoles 23a, 24a and 26a was a Fischer indole synthesis. Nucleophilic substitution of tosylated lactate 5 by carbazole anion provided the fluoroisopropyl derivatives 13a and 13b. Partial hydrogenation of the aromatic carbazole system (26a) was not tolerated by the CB2 receptor. A methylsulfonyl moiety in 6-position (24a) led to considerably reduced CB2 affinity, whereas a 6-methoxy moiety (23a) was well tolerated. An additional methyl moiety in the fluoroethyl side chain of 1a resulted in fluoroisopropyl derivatives 13 with unchanged high CB2 affinity and CB2: CB1 selectivity. Compared with the fluoroethyl derivative 1a, the carbazole N-atom of the fluoroisopropyl derivative 13a (Ki(CB2) = 2.9 nM) is better shielded against the attack of CYP enzymes as formation of N-oxides was not observed and N-dealkylation took place to a less amount.


Assuntos
Carbazóis/química , Carbazóis/farmacocinética , Receptor CB2 de Canabinoide/metabolismo , Animais , Carbazóis/metabolismo , Carbazóis/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Camundongos , Proteólise/efeitos dos fármacos , Relação Estrutura-Atividade
19.
Eur J Pharm Sci ; 111: 13-19, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28942006

RESUMO

Dronedarone is a CYP2D6 inhibitor; therefore, it is prudent to exercise caution when concurrently administering CYP2D6-metabolized ß-blockers because of a lack of published data on potential drug interactions. The aim of this study was to investigate the effect of dronedarone on the pharmacokinetics of orally administered carvedilol in rats. Twenty male Sprague-Dawley rats were randomly divided into two groups and 10mg/kg carvedilol was administered to the rat with or without dronedarone pretreatment in a parallel design. Blood samples were collected before and after 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, and 24h of drug administration. The plasma concentration of carvedilol was determined using LC-MS/MS. The systemic exposure to carvedilol was significantly increased and elimination of carvedilol was significantly decreased in the dronedarone-pretreated rats than in the vehicle-pretreated rats. The one-compartment model with first-order absorption and elimination was sufficient to explain the pharmacokinetic characters after single oral administration of carvedilol to both vehicle-pretreated and dronedarone-pretreated rats. This study suggests that dronedarone inhibits CYP2D6-mediated carvedilol metabolism, and dose adjustment is needed in carvedilol and dronedarone combination therapy. Further studies are needed to clarify the effect of dronedarone on carvedilol and CYP2D6 substrates in clinical use.


Assuntos
Antagonistas Adrenérgicos beta/farmacocinética , Amiodarona/análogos & derivados , Carbazóis/farmacocinética , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Modelos Biológicos , Propanolaminas/farmacocinética , Administração Oral , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/sangue , Amiodarona/administração & dosagem , Amiodarona/farmacologia , Animais , Carbazóis/administração & dosagem , Carbazóis/sangue , Carvedilol , Inibidores do Citocromo P-450 CYP2D6/administração & dosagem , Dronedarona , Interações de Medicamentos , Masculino , Propanolaminas/administração & dosagem , Propanolaminas/sangue , Ratos Sprague-Dawley , Especificidade por Substrato
20.
Chemosphere ; 190: 80-89, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28985539

RESUMO

Veterinary medicines can be extremely damaging to the environment, as seen with the catastrophic declines in Gyps vulture in South Asia due to their secondary exposure to diclofenac in their primary food source. Not surprisingly, concern has been raised over other similar drugs. In this study, we evaluate the toxicity of carprofen to the Gyps vulture clade through plasma pharmacokinetics evaluations in Bos taurus cattle (their food source) and Gyps africanus (a validated model species); tissue residues in cattle; and the effect of carprofen as a secondary toxicant as both tissue-bound residue or pure drug at levels expected in cattle tissues. Carprofen residues were highest in cattle kidney (7.72 ± 2.38 mg/kg) and injection site muscle (289.05 ± 98.96 mg/kg of dimension of 5 × 5 × 5 cm). Vultures exposed to carprofen as residues in the kidney tissue or pure drug equivalents showed no toxic signs. When exposed to average injection site concentrations (64 mg/kg) one of two birds died with evidence of severe renal and liver damage. Toxicokinetic analysis revealed a prolonged drug half-life of 37.75 h in the dead bird as opposed to 13.99 ± 5.61 h from healthy birds dosed intravenously at 5 mg/kg. While carprofen may generally be harmless to Gyps vultures, its high levels at the injection site in treated cattle can result in lethal exposure in foraging vultures, due to relative small area of tissue it is found therein. We thus suggest that carprofen not be used in domesticated ungulates in areas where carcasses are accessible or provided to vultures at supplementary feeding sites.


Assuntos
Carbazóis/toxicidade , Falconiformes , Drogas Veterinárias/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/toxicidade , Ásia , Carbazóis/farmacocinética , Bovinos , Morte , Diclofenaco/farmacocinética , Diclofenaco/toxicidade , Meia-Vida , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Toxicocinética , Drogas Veterinárias/farmacocinética
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