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1.
Biol Pharm Bull ; 44(5): 669-677, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33612567

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive condition that frequently results in right ventricular (RV) remodeling. The objectives of this study are to investigate effects of rivaroxaban on RV remodeling in a rat model of PAH, created with Sugen5416 and chronic hypoxia, and the in vitro effects of rivaroxaban on human cardiac microvascular endothelial cells (HCMECs). To create the PAH model, male Sprague-Dawley rats were subcutaneously injected with Sugen5416 (20 mg/kg) and exposed to 2 weeks of hypoxia (10% O2), followed by 2 weeks of exposure to normoxia. The animals were then divided into 2 groups with or without administration of rivaroxaban (12 mg/kg/d) for a further 4 weeks. HCMECs were cultured under hypoxic conditions (37 °C, 1% O2, 5% CO2) with Sugen5416 and with or without rivaroxaban. In the model rats, RV systolic pressure and Fulton index increased by hypoxia with Sugen5416 were significantly decreased when treated with rivaroxaban. In HCMECs, hypoxia with Sugen5416 increased the expression of protease-activated receptor-2 (PAR-2) and the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB), while treatment with rivaroxaban significantly suppressed the expression of these proteins. Rivaroxaban attenuated RV remodeling in a rat model of PAH by reducing ERK, JNK and NF-κB activation. Rivaroxaban has the possibility of providing additive effects on RV remodeling in patients with PAH.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Inibidores do Fator Xa/uso terapêutico , Ventrículos do Coração/efeitos dos fármacos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Rivaroxabana/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Técnicas de Cultura de Células , Modelos Animais de Doenças , Células Endoteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inibidores do Fator Xa/farmacologia , Humanos , Hipóxia , Indóis , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , NF-kappa B/metabolismo , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Pirróis , Ratos Sprague-Dawley , Rivaroxabana/farmacologia
2.
Toxicol In Vitro ; 71: 105063, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33271325

RESUMO

Vascular endothelial growth factor (VEGF) promotes tumor angiogenesis through stimulating the proliferation and survival of endothelial cells. The severe adverse events caused by VEGF inhibitors might include immune-related ones; however, details of the mechanism have not been elucidated. We tested whether axitinib, pazopanib, sorafenib, and sunitinib, which are tyrosine kinase inhibitors (TKIs) of VEGF receptor used for the therapy of renal cell carcinoma can activate inflammasomes in differentiated THP-1 cells, a human macrophage cell line. We also performed similar studies with semaxanib. In this study, semaxanib and sorafenib activated the inflammasome of differentiated THP-1 cells. Although pazopanib increased the production of IL-1ß, inflammasomes were not activated because caspase-1 was not activated in differentiated THP-1 cells. Our results support the hypothesis that activation of inflammasomes contributes to the idiosyncratic reactions associated with semaxanib and sorafenib. Although pazopanib did not activate inflammasomes, it did cause increased IL-1ß production, which may facilitate the induction of idiosyncratic reactions.


Assuntos
Antineoplásicos/farmacologia , Inflamassomos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/efeitos adversos , Axitinibe/efeitos adversos , Axitinibe/farmacologia , Caspases/metabolismo , Proteína HMGB1/metabolismo , Humanos , Indazóis/efeitos adversos , Indazóis/farmacologia , Indóis/efeitos adversos , Indóis/farmacologia , Interleucina-1beta/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirróis/efeitos adversos , Pirróis/farmacologia , Sorafenibe/efeitos adversos , Sorafenibe/farmacologia , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Sunitinibe/efeitos adversos , Sunitinibe/farmacologia , Células THP-1
3.
J Pharm Pharmacol ; 72(1): 17-28, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31713883

RESUMO

OBJECTIVES: For dry powder inhalers, the airflow properties in the airways could affect the deposition of inhaled particles; the flow patterns vary inherently between patients. This paper provides an evaluation of the effects of six airflow patterns on the behaviour of inhaled particles, as determined by using numerical simulations. METHODS: Constant-velocity and unsteady inhalation flows were employed. The unsteady inhalation flow was set as an inhalation curve with a peak inspiratory flow rate. Under a constant flow of 28.3 l/min, the total flow rates were calculated to confirm the validity of the numerical simulation. The effects of different inhalation patterns on the particle behaviour in a realistic human airway model were revealed via numerical simulation. KEY FINDINGS: Different flow rates affected the behaviour and deposition of the inhaled particles. Under an inhalation flow pattern, different airflow tendencies were observed between the right and left bronchi. Particle deposition in the airways was promoted by a vortex following terminal-velocity-like breath-holding. The inhalation flow pattern affected the behaviour and deposition of inhaled particles in the airway. CONCLUSIONS: Our results indicated that particle deposition in a realistic human airway model was promoted by a vortex formation following the terminal-velocity-like breath-holding. Moreover, the inhalation flow pattern significantly influenced the behaviour and deposition of inhaled particles in the airways. Additionally, the effect of flow patterns on the particle deposition in each airway position was quantitatively evaluated by numerical simulations for a realistic human airway model.


Assuntos
Simulação por Computador , Inalação , Modelos Teóricos , Preparações Farmacêuticas/administração & dosagem , Sistema Respiratório/anatomia & histologia , Administração por Inalação , Inaladores de Pó Seco , Humanos , Hidrodinâmica , Movimento (Física) , Tamanho da Partícula , Preparações Farmacêuticas/química , Sistema Respiratório/diagnóstico por imagem , Fatores de Tempo , Tomografia Computadorizada por Raios X
4.
Biopharm Drug Dispos ; 40(7): 242-249, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31219617

RESUMO

The protein binding rates (PBR) of platinum-containing agents cisplatin (CDDP), carboplatin (CBDCA) and oxaliplatin (L-OHP) have been reported as 98%, 25-50% and 98%, respectively. To investigate the protein-binding properties of albumin with cisplatin, carboplatin and oxaliplatin, inductively coupled plasma mass spectrometry (ICP-MS) was used to measure their plasma concentration in rats over time. The study also examined the effects of cisplatin, carboplatin and oxaliplatin-binding on albumin in vitro, using CD spectrometry and native-polyacrylamide gel electrophoresis (native PAGE). The ratios of PBR to irreversible PBR, of cisplatin and oxaliplatin were 98%:98% and 90%:87%, respectively, indicating a higher affinity for irreversible binding with albumin. That of carboplatin was 25%:10%, indicating 60-70% reversible binding with albumin. The plasma protein binding rate concentrations of cisplatin, carboplatin and oxaliplatin after in vivo administration were 96%, 15% and 80%, respectively. The CD spectrometry of albumin was unaffected by cisplatin, carboplatin and oxaliplatin binding. Though similar protein binding rates were observed with oxaliplatin and cisplatin, oxaliplatin had a higher mobility rate during PAGE. It was confirmed that the binding of cisplatin and oxaliplatin with albumin affected its electric charge but not the structure. In conclusion, cisplatin and oxaliplatin bind irreversibly with albumin in plasma and may irreversibly interact with tissue protein and/or DNA. The difficulties involved with predicting the tissue concentrations of cisplatin and oxaliplatin from their plasma concentration inhibits their therapeutic drug monitoring. On the contrary, carboplatin, like some generic drugs, reversibly binds to plasma proteins. It is, therefore, possible to conduct therapeutic drug monitoring for carboplatin.


Assuntos
Antineoplásicos/farmacologia , Carboplatina/farmacologia , Cisplatino/farmacologia , Oxaliplatina/farmacologia , Animais , Antineoplásicos/farmacocinética , Proteínas Sanguíneas/metabolismo , Carboplatina/farmacocinética , Cisplatino/farmacocinética , Interações Medicamentosas , Masculino , Espectrometria de Massas , Oxaliplatina/farmacocinética , Ligação Proteica , Ratos Wistar
5.
J Pharmacol Sci ; 137(3): 274-282, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30055890

RESUMO

Patients with obstructive sleep apnea (OSA) have a high prevalence of atrial fibrillation (AF). Rivaroxaban, a coagulation factor Xa inhibitor, has recently been reported to show pleiotropic effects. This study investigated the influence of rivaroxaban on cardiac remodeling caused by intermittent hypoxia (IH). Male C57BL/6J mice were exposed to IH (repeated cycles of 5% oxygen for 1.5 min followed by 21% oxygen for 5 min) for 28 days with/without rivaroxaban (12 mg/kg/day) or FSLLRY, a protease-activated receptor (PAR)-2 antagonist (10 µg/kg/day). IH caused endothelial cell degeneration in the small arteries of the right atrial myocardium and increased the level of %fibrosis and 4-hydroxy-2-nonenal protein adducts in the left ventricular myocardium. IH also increased the expression of PAR-2 as well as the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and nuclear factor-kappa B (NF-κB) were increased in human cardiac microvascular endothelial cells. However, rivaroxaban and FSLLRY significantly suppressed these changes. These findings demonstrate that rivaroxaban attenuates both atrial and ventricular remodeling induced by IH through the prevention of oxidative stress and fibrosis by suppressing the activation of ERK and NF-κB pathways via PAR-2. Treatment with rivaroxaban could potentially become a novel therapeutic strategy for cardiac remodeling in patients with OSA and AF.


Assuntos
Inibidores do Fator Xa/farmacologia , Hipóxia/complicações , Rivaroxabana/farmacologia , Rivaroxabana/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Fibrilação Atrial/etiologia , Fibrilação Atrial/patologia , Células Cultivadas , Células Endoteliais/patologia , Fibrose/prevenção & controle , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Miocárdio/patologia , NF-kappa B/metabolismo , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Receptor PAR-2/antagonistas & inibidores , Receptor PAR-2/metabolismo , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/patologia
6.
Xenobiotica ; 48(1): 60-72, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28081667

RESUMO

1. Drug-induced liver injury is difficult to predict at the pre-clinical stage. This study aimed to clarify the roles of caspase-8 and -9 in CYP2E1 metabolite-induced liver injury in both rats and cell cultures in vitro treated with carbon tetrachloride (CCl4), halothane or sevoflurane. The human hepatocarcinoma functional liver cell line was maintained in 3-dimensional culture alone or in co-culture with human acute monocytic leukemia cells. 2. In vivo, laboratory indices of liver dysfunction and histology were normal after administration of sevoflurane. CCl4 treatment increased blood AST/ALT levels, liver caspase-3 and -9 activities and liver malondialdehyde, accompanied by centrilobular hepatocyte necrosis. Halothane increased AST/ALT levels, caspase-3 and -8 activities (but not malondialdehyde) concomitant with widespread hepatotoxicity. In vitro, CCl4 treatment increased caspase-9 activity and decreased both mitochondrial membrane potential (MMP) and cell viability. In co-culture, halothane increased caspase-8 activity and decreased MMP and cellular viability. There were no toxic responses in CYP2E1 knockdown in monoculture and co-culture. 3. CYP2E1-inducing compounds play a pivotal role in halogenated hydrocarbon toxicity. 4. Changes in hepatocyte caspase-8 and -9 activities could be novel biomarkers of metabolites causing DILI, and in pre-clinical development of new pharmaceuticals can predict nascent DILI in the clinical stage.


Assuntos
Caspase 8/metabolismo , Caspase 9/metabolismo , Substâncias Perigosas/toxicidade , Hidrocarbonetos Halogenados/toxicidade , Animais , Linhagem Celular , Técnicas de Cocultura , Citocromo P-450 CYP2E1/metabolismo , Substâncias Perigosas/metabolismo , Humanos , Hidrocarbonetos Halogenados/metabolismo , Ratos
7.
Curr Vasc Pharmacol ; 15(6): 589-598, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28460626

RESUMO

BACKGROUND: Sugen5416 (semaxinib) is an inhibitor of the vascular endothelial growth factor (VEGF) receptor. A rat model of Pulmonary Arterial Hypertension (PAH), created with Sugen5416 and chronic hypoxia, is known to have similar histological findings to those of PAH patients. OBJECTIVE: To evaluate the pathophysiological mechanisms of cardiac remodeling due to hypoxic stress with Sugen5416 in vivo. METHODS: Male Sprague-Dawley rats were exposed to hypoxia (10 ± 1% O2) for 2 weeks after a single injection of Sugen5416 (SU-hypoxia group) or the vehicle (V-hypoxia group). RESULTS: Hypoxia elevated right ventricular (RV) systolic pressure and caused RV remodeling on Day 14. By electron microscopy, metamorphosis of capillaries with endothelial cell occlusive degeneration was observed in the RV myocardium of the SU-hypoxia group from Day 3. After reoxygenation, progressive RV remodeling with extensive degeneration of cardiomyocytes was observed in the SUhypoxia group, associated with a significant increase of oxidative stress and TUNEL-positive cells in both RV and left ventricular myocardium on Day 84. The expression of VEGF mRNA in the RV myocardium was significantly suppressed in the SU-hypoxia group on Day 3, whereas delayed activation of VEGF/extracellular signal-regulated kinase (ERK) signaling pathway on Day 14 were observed. CONCLUSION: Capillary degeneration and activation of VEGF/ERK signaling pathway might be crucial to accelerate the cardiac remodeling due to hypoxic stress with Sugen5416.


Assuntos
Capilares/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Hipóxia/patologia , Indóis/farmacologia , Pirróis/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Capilares/patologia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Ventrículos do Coração/metabolismo , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipóxia/metabolismo , Marcação In Situ das Extremidades Cortadas/métodos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
Biol Pharm Bull ; 40(3): 290-296, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27980242

RESUMO

Cisplatin is the most widely used anticancer drug in the world. Mono-chloro and none-chloro complexes of cisplatin may be believed to be the activated compounds. The separation of these compounds using octa decyl silyl column or aminopropylsilyl silica gel column is difficult because of high-reactivity and structural similarity. In this study, cisplatin, hydroxo complexes, and OH-dimer were determined by HPLC using a naphthylethyl group bonded with silica gel (πNAP) column. The analytical conditions of HPLC were as follows: analytical column, πNAP column; wave length, 225 nm; column temperature, 40°C; mobile phase, 0.1 M sodium perchlorate, acetonitrile, and perchloric acid (290 : 10 : 3), flow rate, 1.0 mL/min. Sample (20 µL) was injected onto the HPLC system. Retention time of cisplatin, mono-chloride, OH-dimer, and none-chloride was 3.2, 3.4, 3.6, and, 4.3-6.6 min, respectively. Measurable ranges with this method were 1×10-5 to 4×10-3 M for cisplatin. Correlation coefficient of the calibration curves of cisplatin was 0.999 (p<0.01). The within- and between-day variations of coefficient of variation (CV) were 5% or lower. In this study, injectable formulations in physiological saline solution, water for injection, 5% glucose solution, and 7% sodium bicarbonate precisely were measured the stability and compositional changes upon mixing by πNAP column rather than C18 column. We successfully determined cisplatin, hydroxo complexes, and OH-dimer by HPLC using a πNAP column. Thus the measurement of cisplatin (cis-diamminedichloro-platinum(II), cis-[PtCl2(NH3)2]) (CDDP) should be done using a πNAP column rather than a C18 column or aminopropylsilyl silica gel column.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cisplatino/análise , Antineoplásicos/análise , Cisplatino/análogos & derivados , Cisplatino/química , Indicadores e Reagentes , Estrutura Molecular , Sílica Gel , Tecnologia Farmacêutica/métodos
9.
J Clin Pharmacol ; 42(7): 806-11, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12092748

RESUMO

The effect of calcium polycarbophil on the absorption of ciprofloxacin, a broad-spectrum antibacterial agent, was evaluated in an in vitro and in vivo study. In the in vitro study, the release of ciprofloxacin from the cellulose membrane in the presence or absence of metal cations was measured using the dissolution test procedure. In the in vivo study, male ST Wistar rats and male volunteers were employed. First, 20 mg/kg of ciprofloxacin alone (Rat Study 1) or 20 mg/kg of ciprofloxacin in combination with 64 mg/kg of calcium chloride (Rat Study 2) was administered orally to 3 rats. Second, a volunteer study was employed and a randomized crossover design with twophases was used. In onephase, volunteers received 400 mg of ciprofloxacin alone (Study 1); in the other phase, they received 400 mg of ciprofloxacin and 1200 mg of fine calcium polycarbophil granules concomitantly (Study 2). The plasma and serum concentrations of ciprofloxacin were measured by high-performance liquid chromatography. The release of ciprofloxacin from the cellulose membrane in the presence of aluminum, calcium, or iron ions was slower than that in the absence of these metal ions. The AUC0-4 and Cmax in Rat Study 2 were lower than those respective values in Rat Study 1. AUC0-4 was approximately 60% lower in Rat Study 2 than Rat Study 1. In the volunteer study, the AUC0-12 and Cmax in Study 2 were lower than those respective values in Study 1. In particular, AUC0-12 was approximately 50% lowerin Study 2 than in Study 1. These findings suggest that when ciprofloxacin and calcium polycarbophil were coadministered concomitantly, a decrease of ciprofloxacin absorption was observed, and this action was caused by the formation of chelate complexes. Therefore, it seems clear that we should avoid the concomitant administration of ciprofloxacin and calcium polycarbophil.


Assuntos
Resinas Acrílicas/química , Anti-Infecciosos/farmacocinética , Catárticos/química , Ciprofloxacina/farmacocinética , Absorção , Adulto , Compostos de Alúmen/química , Animais , Anti-Infecciosos/sangue , Anti-Infecciosos/química , Área Sob a Curva , Disponibilidade Biológica , Cálcio/química , Cloreto de Cálcio/química , Cátions , Celulose/química , Quelantes/química , Ciprofloxacina/sangue , Ciprofloxacina/química , Estudos Cross-Over , Interações Medicamentosas , Compostos Ferrosos/química , Humanos , Técnicas In Vitro , Masculino , Membranas Artificiais , Pessoa de Meia-Idade , Ratos , Ratos Wistar
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