Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 229
Filtrar
1.
Radiat Res ; 191(2): 139-153, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30499383

RESUMO

We quantitated age-related accumulation of senescent cells in irradiated Fanconi anemia (FA) (Fanca-/- mouse cell lines in vitro, and monitored the effect of continuous administration (via drinking water) of the water-soluble radiation mitigator, MMS350, on tissues in vivo over one year after 7.5 Gy total-body irradiation (TBI). Irradiated Fanca-/- mouse bone marrow stromal cell lines showed increased numbers of beta-galactosidase- and p21-positive senescent cells compared to Fanca+/+ cell lines, which was reduced by MMS350. One week after 7.5 Gy TBI, Fanca-/- mice showed increased numbers of senescent cells in spleen compared to Fanca+/+ controls, decreased bone marrow cellularity, failure of explanted bone marrow to proliferate in vitro to form a hematopoietic microenvironment and no detectable single stromal cell cloning capacity. There was no detectable amelioration by MMS350 administration at one week. In contrast, one year post-TBI, Fanca-/- mice demonstrated fewer senescent cells in brain and spleen compared to Fanca+/+ controls. While Fanca-/- mouse bone marrow stromal cells explanted one year post-TBI still failed to proliferate in vitro, continuous oral administration of 400 µ M, MMS350 in drinking water restored explanted stromal cell proliferation. The data indicate that continuous administration of MMS350 modulated several properties of TBI-accelerated aging in Fanca-/- mice as well as control mice, and support further study of MMS350 as a modulator of radiation late effects.


Assuntos
Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Éteres Cíclicos/administração & dosagem , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/patologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos da radiação , Protetores contra Radiação/administração & dosagem , Sulfóxidos/administração & dosagem , Irradiação Corporal Total , Administração Oral , Animais , Éteres Cíclicos/farmacologia , Feminino , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Knockout , Protetores contra Radiação/farmacologia , Sulfóxidos/farmacologia , Microambiente Tumoral
2.
Cancer Res Treat ; 51(3): 1167-1179, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30514066

RESUMO

PURPOSE: The DNA damage response (DDR) is a multi-complex network of signaling pathways involved in DNA damage repair, cell cycle checkpoints, and apoptosis. In the case of biliary tract cancer (BTC), the strategy of DDR targeting has not been evaluated, even though many patients have DNA repair pathway alterations. The purpose of this study was to test the DDR-targeting strategy in BTC using an ataxia-telangiectasia and Rad3-related (ATR) inhibitor. MATERIALS AND METHODS: A total of nine human BTC cell lines were used for evaluating anti-tumor effect of AZD6738 (ATR inhibitor) alone or combination with cytotoxic chemotherapeutic agents through MTT assay, colony-forming assays, cell cycle analyses, and comet assays. We established SNU478-mouse model for in vivo experiments to confirm our findings. RESULTS: Among nine human BTC cell lines, SNU478 and SNU869 were the most sensitive to AZD6738, and showed low expression of both ataxia-telangiectasia mutated (ATM) and p53. AZD6738 blocked p-Chk1 and p-glycoprotein and increased γH2AX, a marker of DNA damage, in sensitive cells. AZD6738 significantly increased apoptosis, G2/M arrest and p21, and decreased CDC2. Combinations of AZD6738 and cytotoxic chemotherapeutic agents exerted synergistic effects in colony-forming assays, cell cycle analyses, and comet assays. In our mouse models, AZD6738 monotherapy decreased tumor growth and the combination with cisplatin showed more potent effects on growth inhibition, decreased Ki-67, and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling than monotherapy with each drug. CONCLUSION: In BTC, DDR targeting strategy using ATR inhibitor demonstrated promising antitumor activity alone or in combination with cytotoxic chemotherapeutic agents. This supports further clinical development of DDR targeting strategy in BTC.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias do Sistema Biliar/tratamento farmacológico , Cisplatino/administração & dosagem , Pirimidinas/administração & dosagem , Sulfóxidos/administração & dosagem , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Neoplasias do Sistema Biliar/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Reparo do DNA , Regulação para Baixo , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Pirimidinas/farmacologia , Sulfóxidos/farmacologia , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Lung Cancer ; 123: 14-21, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30089585

RESUMO

OBJECTIVES: This phase Ib/II study evaluated safety, pharmacokinetics, maximum tolerated dose (MTD), and efficacy of the pan-cyclin-dependent kinase inhibitor roniciclib with cisplatin-etoposide (CIS-ETOP) or carboplatin-etoposide (CARBO-ETOP) in patients with extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: In this open-label, non-randomized study, patients with previously untreated ED-SCLC received roniciclib twice daily (BID) in a 3 days on/4 days off schedule. Cisplatin 75 mg/m2 or carboplatin (AUC5) dose was administered on day 1, and etoposide 100 mg/m2 on days 1-3, of 21-day cycles. Phase Ib used a dose-escalation design to define the MTD for phase II. Pharmacokinetics were assessed. RESULTS: Forty-three patients received treatment (roniciclib 2.5 mg BID [+ CARBO-ETOP, n = 4; + CIS-ETOP, n = 3] and roniciclib 5 mg BID [+ CARBO-ETOP, n = 24; + CIS-ETOP, n = 12]). The MTD of roniciclib was 5 mg BID with CARBO-ETOP or CIS-ETOP. Common adverse events were nausea (90.7%) and vomiting (69.8%). Roniciclib was readily absorbed following oral administration at the MTD (median tmax 0.5-1 h), with a 30-40% reduction in exposure when co-administered with CARBO-ETOP or CIS-ETOP; administration of roniciclib had no effect on etoposide or platinum pharmacokinetics. The response rate was 81.4% (35/43) overall and 86.1% (31/36) in the pooled roniciclib 5 mg BID population (all partial responses). CONCLUSION: Roniciclib co-administered with chemotherapy in patients with ED-SCLC demonstrated tolerability, acceptable pharmacokinetics, and promising efficacy. An observed safety signal in a related phase II study resulted in discontinuation of the present study and termination of further roniciclib development.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Carcinoma de Pequenas Células do Pulmão/mortalidade , Sulfóxidos/administração & dosagem , Sulfóxidos/farmacocinética , Resultado do Tratamento
4.
Br J Cancer ; 116(12): 1505-1512, 2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28463960

RESUMO

BACKGROUND: To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D). METHODS: Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway. RESULTS: Ten patients were evaluable in the 4 weeks on/2 weeks off schedule (terminated following limited tolerability) and 47 in the 3 days on/4 days off schedule dose-escalation cohorts. On the 3 days on/4 days off schedule, RP2D was 5 mg twice daily in solid tumours (n=40); undetermined in lymphoid malignancies (n=7). Common roniciclib-related adverse events included nausea (76.6%), fatigue (65.8%), diarrhoea (63.1%), and vomiting (57.7%). Roniciclib demonstrated rapid absorption and dose-proportional increase in exposure. One partial response (1.0%) was observed. In RP2D expansion cohorts, the disease control rate (DCR) was 40.9% for patients with ovarian cancer (n=25), 17.4% for patients with SCLC (n=33), and 33.3% for patients with CDK-related tumour mutations (n=6). CONCLUSIONS: Roniciclib demonstrated an acceptable safety profile and moderate DCR in 3 days on/4 days off schedule.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Transdução de Sinais/genética , Sulfóxidos/administração & dosagem , Sulfóxidos/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/farmacocinética , Diarreia/induzido quimicamente , Fadiga/induzido quimicamente , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Linfoma/tratamento farmacológico , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/genética , Neoplasias Ovarianas/tratamento farmacológico , Antígeno Nuclear de Célula em Proliferação/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Vômito/induzido quimicamente
5.
Mol Cancer Ther ; 16(4): 566-577, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28138034

RESUMO

Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect. The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer.In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3-dependent apoptosis. In contrast, SNU-484 cells with functional ATM were not sensitive to AZD6738. Inhibition of ATM in SNU-484 cells enhanced AZD6738 sensitivity to a level comparable with that observed in SNU-601 cells, showing that activation of the ATM-Chk2 signaling pathway attenuates AZD6738 sensitivity. In addition, decreased HDAC1 expression was found to be associated with ATM inactivation in SNU-601 cells, demonstrating the interaction between HDAC1 and ATM can affect sensitivity to AZD6738. Furthermore, in an in vivo tumor xenograft mouse model, AZD6738 significantly suppressed tumor growth and increased apoptosis.These findings suggest synthetic lethality between ATR inhibition and ATM deficiency in gastric cancer cells. Further clinical studies on the interaction between AZD 6738 and ATM deficiency are warranted to develop novel treatment strategies for gastric cancer. Mol Cancer Ther; 16(4); 566-77. ©2017 AACR.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pirimidinas/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Sulfóxidos/administração & dosagem , Mutações Sintéticas Letais/efeitos dos fármacos , Animais , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quinase do Ponto de Checagem 2/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilase 1/genética , Humanos , Camundongos , Pirimidinas/farmacologia , Neoplasias Gástricas/genética , Sulfóxidos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Clin Cancer Res ; 23(12): 3097-3108, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27993965

RESUMO

Purpose: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA-mutant (BRCAMUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression.Experimental Design: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776), or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell cycle, genome instability, and apoptosis were evaluated in BRCA1/2MUT HGSOC cells. Tumor growth in vivo was evaluated using a BRCA2MUT patient-derived xenograft (PDX) model.Results: PARPi monotherapy resulted in a decrease in BRCAMUT cell survival, colony formation and suppressed but did not eliminate tumor growth at the maximum tolerated dose (MTD) in a BRCA2MUT PDX. PARPi treatment increased pATR and pCHK1, indicating activation of the ATR-CHK1 fork protection pathway is relied upon for genome stability under PARPi. Indeed, combination of ATRi or CHK1i with PARPi synergistically decreased survival and colony formation compared with single-agent treatments in BRCAMUT cells. Notably, PARPi led to G2 phase accumulation, and the addition of ATRi or CHK1i released cells from G2 causing premature mitotic entry with increased chromosomal aberrations and apoptosis. Moreover, the combinations of PARPi with ATRi or CHK1i were synergistic in causing tumor suppression in a BRCA2MUT PDX with the PARPi-ATRi combination inducing tumor regression and in most cases, complete remission.Conclusions: PARPi causes increased reliance on ATR/CHK1 for genome stability, and combination PARPi with ATR/CHK1i is more effective than PARPi alone in reducing tumor burden in BRCAMUT models. Clin Cancer Res; 23(12); 3097-108. ©2016 AACR.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Neoplasias Ovarianas/tratamento farmacológico , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteína BRCA1/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Instabilidade Genômica/efeitos dos fármacos , Humanos , Camundongos , Terapia de Alvo Molecular , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Sulfóxidos/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Free Radic Biol Med ; 96: 245-54, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27140233

RESUMO

Retinitis Pigmentosa (RP) comprises a group of rare genetic retinal disorders in which one of several different mutations induces photoreceptor death. Oxidative stress and glutathione (GSH) alterations may be related to the pathogenesis of RP. GSH has been shown to be present in high concentrations in the retina. In addition, the retina has the capability to synthesize GSH. In this study, we tested whether the two subunits of glutamate cysteine ligase, the rate-limiting enzyme in GSH synthesis, and the concentrations of retinal GSH, oxidized glutathione (GSSG), cysteine (Cys) and glutamate are altered in the retina of two different RP mice models. Retinas from C3H and rd1 mice at different postnatal days (P7, P11, P15, P19, P21 and P28) and from C57BL/6 and rd10 mice at P21 were obtained. Western blot analysis was performed to determine the protein content of catalytic and modulatory subunits from glutamate cysteine ligase (GCLC and GCLM, respectively). In another set of experiments, control and rd1 mice were administered buthinine sulfoximine, a glutathione synthase inhibitor, or paraquat. GSH, GSSG, glutamate and Cys concentrations were determined, by HPLC. A decrease in retinal GCLC content was observed in C3H and rd1 mice with age, nevertheless, there was an increase in retinal GCLC in rd1 mice compared to control retinas at P19. No modifications in GCLM content with age and no difference between GCLM content in rd1 and control retinas were observed. The GSH concentration decreased in the rd1 retinas compared with control ones at P15, it increased at P19, and was again similar at P21 and P28. No changes in GSSG concentration in control retinas with age were observed; the GSSG levels in rd1 retinas were similar from P7 to P19 and then increased significantly at P21 and P28. Glutamate concentration was increased in the rd1 retinas compared to control mice from P7 to P15 and were comparable at P21 and P28. The Cys concentrations was measured in control and rd1 retinas, but no significant changes were observed between them. BSO administration decreases GSH retinal concentration in control and rd1 mice, while paraquat administration induced an increase in GSH retinal concentration in control mice and a decrease in GSH in rd1 mice retina. Retinal GCLC was significantly increased in rd10 mice at P21 as well as GSSG. Our results suggest alterations in retinal GCLC content and GSH and/or its precursors in these two RP animal models. Regulation of the enzymes related to GSH metabolism and the retinal concentration of glutamate may be a possible target to delay especially cone death in RP.


Assuntos
Glutamato-Cisteína Ligase/genética , Estresse Oxidativo/genética , Retinite Pigmentosa/genética , Animais , Cisteína , Modelos Animais de Doenças , Glutamato-Cisteína Ligase/antagonistas & inibidores , Dissulfeto de Glutationa/biossíntese , Dissulfeto de Glutationa/metabolismo , Humanos , Metionina/administração & dosagem , Metionina/análogos & derivados , Camundongos , Retina/enzimologia , Retina/metabolismo , Retina/patologia , Degeneração Retiniana/enzimologia , Degeneração Retiniana/patologia , Retinite Pigmentosa/enzimologia , Retinite Pigmentosa/patologia , Sulfóxidos/administração & dosagem
8.
Biochem Pharmacol ; 105: 14-22, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26774450

RESUMO

Disturbed redox homeostasis with both elevated reactive oxygen species (ROS) levels and antioxidant defense mechanisms has been reported in acute lymphoblastic leukemia (ALL). We therefore hypothesized that inhibition of pathways responsible for ROS detoxification renders ALL cells more susceptible for cell death. Here, we report that pharmacological inhibitors of key pathways for the elimination of ROS, i.e. Erastin, buthionine sulfoximine (BSO) and Auranofin, sensitize ALL cells for cell death upon treatment with the Smac mimetic LCL161 that antagonizes Inhibitor of Apoptosis (IAP) proteins. Erastin, BSO or Auranofin significantly increase LCL161-induced cell death and also act in concert with LCL161 to profoundly suppress long-term clonogenic survival in several ALL cell lines. Erastin or BSO cooperates with LCL161 to stimulate ROS production and lipid peroxidation prior to cell death. ROS production and lipid peroxidation are required for this cotreatment-induced cell death, since ROS scavengers or pharmacological inhibition of lipid peroxidation provides significant protection against cell death. These results emphasize that inhibition of antioxidant defense mechanisms can serve as a potent approach to prime ALL cells for LCL161-induced cell death.


Assuntos
Antineoplásicos/administração & dosagem , Apoptose/fisiologia , Sistemas de Liberação de Medicamentos/métodos , Homeostase/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Tiazóis/administração & dosagem , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Homeostase/efeitos dos fármacos , Humanos , Células Jurkat , Metionina/administração & dosagem , Metionina/análogos & derivados , Oxirredução/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Sulfóxidos/administração & dosagem
9.
Oncotarget ; 6(42): 44289-305, 2015 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-26517239

RESUMO

ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Sulfóxidos/administração & dosagem , Administração Oral , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Disponibilidade Biológica , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos Nus , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Interferência de RNA , Sulfóxidos/farmacocinética , Transfecção , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Int J Pharm ; 461(1-2): 514-8, 2014 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-24333907

RESUMO

Imidol hydrochloride is a novel agent for the treatment of hepatitis B virus (HBV) infection, which is currently being evaluated in a phase II trial. This study investigated the absorption, excretion and tissue distribution of imidol after an oral dose in rats. The pharmacokinetic parameters were determined for both intravenous and oral dosing. A simple and sensitive UPLC-MS-MS method was employed to determine the imidol levels in rat biological samples. It was applied for the analysis of imidol in plasma, urine, feces, bile and various tissue samples. Imidol was found to have a moderate half-life (∼4 h), a relatively large apparent distribution volume and rapid clearance after an IV dose and oral doses up to 70 mg kg(-1). Dose-dependent linear relationships of AUC0-t and Cmax for imidol was found in the range of 10-70 mg kg(-1) after oral administration to rats. However, the oral bioavailability was low (17.6%). Most of the drug was metabolized and only 20% of the parent drug was excreted. Imidol excreted mainly in feces. The tissue distribution results show that imidol was quickly dispersed to various tissues following an oral dose. Relatively high concentration was found in liver, which is beneficial to the intended indication. Very low levels of imidol were found in brain and testes, indicating that it was difficult for imidol to cross the blood-brain barrier.


Assuntos
Antivirais/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Indóis/farmacocinética , Sulfóxidos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Antivirais/administração & dosagem , Área Sob a Curva , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Relação Dose-Resposta a Droga , Meia-Vida , Hepatite B/tratamento farmacológico , Indóis/administração & dosagem , Injeções Intravenosas , Ratos , Ratos Wistar , Sulfóxidos/administração & dosagem , Distribuição Tecidual
11.
ChemMedChem ; 8(7): 1067-85, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23671017

RESUMO

Lead optimization of a high-throughput screening hit led to the rapid identification of aminopyrimidine ZK 304709, a multitargeted CDK and VEGF-R inhibitor that displayed a promising preclinical profile. Nevertheless, ZK 304709 failed in phase I studies due to dose-limited absorption and high inter-patient variability, which was attributed to limited aqueous solubility and off-target activity against carbonic anhydrases. Further lead optimization efforts to address the off-target activity profile finally resulted in the introduction of a sulfoximine group, which is still a rather unusual approach in medicinal chemistry. However, the sulfoximine series of compounds quickly revealed very interesting properties, culminating in the identification of the nanomolar pan-CDK inhibitor BAY 1000394, which is currently being investigated in phase I clinical trials.


Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Descoberta de Drogas , Neoplasias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfóxidos/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Quinases Ciclina-Dependentes/metabolismo , Relação Dose-Resposta a Droga , Feminino , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Neoplasias Experimentais/enzimologia , Neoplasias Experimentais/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Ratos , Relação Estrutura-Atividade , Sulfóxidos/administração & dosagem , Sulfóxidos/síntese química , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/metabolismo
12.
Mol Cancer Ther ; 11(10): 2265-73, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22821149

RESUMO

Deregulated activity of cyclin-dependent kinases (CDK) results in loss of cell-cycle checkpoint function and increased expression of antiapoptotic proteins, which has been directly linked to the molecular pathology of cancer. BAY 1000394 inhibits the activity of cell-cycle CDKs CDK1, CDK2, CDK3, CDK4, and of transcriptional CDKs CDK7 and CDK9 with IC(50) values in the range between 5 and 25 nmol/L. Cell proliferation was inhibited at low nanomolar concentration in a broad spectrum of human cancer cell lines. In cell-based assays, the inhibition of phosphorylation of the CDK substrates retinoblastoma protein, nucleophosmin, and RNA polymerase II was shown. Cell-cycle profiles were consistent with inhibition of CDK 1, 2, and 4 as shown in cell-cycle block and release experiments. The physicochemical and pharmacokinetic properties of BAY 1000394 facilitate rapid absorption and moderate oral bioavailability. The compound potently inhibits growth of various human tumor xenografts on athymic mice including models of chemotherapy resistance upon oral dosing. Furthermore, BAY 1000394 shows more than additive efficacy when combined with cisplatin and etoposide. These results suggest that BAY 1000394 is a potent pan-CDK inhibitor and a novel oral cytotoxic agent currently in phase I clinical trials.


Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfóxidos/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclo Celular/efeitos dos fármacos , Cisplatino/farmacologia , Quinases Ciclina-Dependentes/metabolismo , Etoposídeo/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Proteína do Retinoblastoma/metabolismo , Sulfóxidos/administração & dosagem , Sulfóxidos/química , Sulfóxidos/farmacocinética , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Dig Dis ; 13(2): 113-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22257480

RESUMO

OBJECTIVE: The aim of this study was to evaluate the effects and safety of different doses of ilaprazole on healthy volunteers without a Helicobacter pylori infection. METHODS: A total of 12 healthy Chinese volunteers were enrolled and divided into four groups randomly, with a 5-day treatment of oral ilaprazole 5mg, 10mg and 20mg or omeprazole 20mg, respectively. After an interval of a 14-day washout phase, each was switched to another dose group and eventually completed all four regimens. The percentage time of intragastric pH>4 was the major index. The polymorphisms of the metabolic enzyme CYP2C19 in these volunteers were also detected. RESULTS: The percentage time of intragastric pH>4 in the ilaprazole 5, 10 and 20mg groups were 80.4%, 88.1% and 91.0%, respectively, during the first 24h, compared to that of the 20mg omeprazole group (76.6%, P>0.05). Ilaprazole 20mg provided a significant higher mean 24-h pH than that of the same dose of omeprazole both on Day 1 (7.78 vs 6.67, P<0.01) and Day 5 (7.95 vs 7.44, P<0.05). No CYP2C19-dependent difference or obvious adverse effect were found in any ilaprazole groups. CONCLUSION: Low dose ilaprazole offers a gastric acid inhibition comparable to a routine dose of omeprazole, and further investigations in patients with acid-associated diseases are needed.


Assuntos
Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Ácido Gástrico/metabolismo , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Inibidores da Bomba de Prótons , Estômago/efeitos dos fármacos , Sulfóxidos/administração & dosagem , Sulfóxidos/efeitos adversos , 2-Piridinilmetilsulfinilbenzimidazóis , Adulto , Hidrocarboneto de Aril Hidroxilases/genética , Estudos Cross-Over , Citocromo P-450 CYP2C19 , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Feminino , Determinação da Acidez Gástrica , Helicobacter pylori , Humanos , Masculino , Omeprazol/administração & dosagem , Polimorfismo Genético , Valores de Referência , Adulto Jovem
14.
J Clin Pharmacol ; 52(7): 976-84, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21593280

RESUMO

It is well known that the CYP2C19 genetic polymorphism influences the pharmacokinetics and pharmacodynamics of proton pump inhibitors (PPIs), but no report has addressed the effects on ilaprazole, a newly developed PPI. To investigate the effects of the CYP2C19 genetic polymorphism on the disposition and pharmacodynamics of ilaprazole, multiple doses of once-daily 10 mg ilaprazole were repeatedly administered for 7 days to 27 healthy Korean participants, comprising 9 homozygous CYP2C19 extensive metabolizers (homo EMs), 10 heterozygous EMs (hetero EMs), and 8 homozygous poor metabolizers (PMs). The plasma concentration and pharmacodynamic response were measured in the last dose interval. Each genotype group was matched for gender and thus was composed of 4 male and 4 female participants when the analysis was conducted. The pharmacokinetic parameters estimated from the plasma concentrations of ilaprazole and its metabolite ilaprazole sulfone, the serum gastrin level, and the 24-hour intragastric pH were compared among the CYP2C19 genotype groups. No statistically significant differences in the maximum plasma concentration at steady state(C(ss,max)) and the area under the concentration-time curve from zero to 24 hours (AUC(τ)) of ilaprazole and ilaprazole sulfone were observed among the homo EM, hetero EM, and PM CYP2C19 genotypes. In addition, the mean 24-hour intragastric pH, the percentage of time at pH >4, and the AUC(τ) of serum gastrin showed no significant differences among the CYP2C19 genotype groups. The data suggests that the pharmacokinetics and pharmacodynamics of ilaprazole are not significantly influenced by the CYP2C19 genetic polymorphism in healthy participants.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Benzimidazóis/farmacocinética , Inibidores da Bomba de Prótons/farmacocinética , Sulfonas/farmacocinética , Sulfóxidos/farmacocinética , 2-Piridinilmetilsulfinilbenzimidazóis , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Citocromo P-450 CYP2C19 , Relação Dose-Resposta a Droga , Feminino , Gastrinas/sangue , Genótipo , Humanos , Concentração de Íons de Hidrogênio , Masculino , Polimorfismo Genético , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/farmacologia , República da Coreia , Sulfóxidos/administração & dosagem , Sulfóxidos/farmacologia , Fatores de Tempo
15.
Int. j. morphol ; 29(3): 816-820, Sept. 2011. ilus
Artigo em Inglês | LILACS | ID: lil-608663

RESUMO

The aim of this work was to evaluate the effect of albendazole sulphoxide (ABZSO) administered to Balb C mice prior to mating on fertilization rate and preimplantational embryo development. Twenty four female mice 5-8 weeks of age were superovulated by intraperitoneal injection of 7.5 UI of equine chorionic gonadotropin (eCG, Novormon®, Laboratorios Syntex S.A., Argentina); 48 h later they received 10 IU of human chorionic gonadotropin (hCG, Profasi®, Laboratorios Serono, Méjico) and were paired with males of proven fertility. Females received 100 mg/kg or 200 mg/kg of ABZSO orally at the time of hCG administration, prior to mating. The control group received carboxymethylcellulose, vehicle used to prepare the drug suspension. Pregnant females were killed by cervical dislocation at day 4 of pregnancy and non fertilized oocyte and embryos were flushed from uteri. The possible effects of ABZSO were evaluated considering the fertilization rate, the total number of collected embryos per female; the percentage of embryos morphologically normal; the differentiation rate (determined by the relation between the number of blastocyst and the total of morphologically normal embryos) and the cleavage rate determined by counting the nuclei. The variables were analyzed on a per litter basis using the Kruskal-Wallis test. The fertilization rate was lower in females administered ABZSO at a dose of 200 mg/kg (P<0.05). However, no statistically significant differences were found in the embryonic parameters after the administration of 100 mg/kg or 200 mg/kg of ABZSO compared to the untreated control group (P>0.05). In conclusion, a single acute exposure to ABZSO prior to mating at around the time of fertilization at a dose higher than the one usually administered in human and veterinary medicine affects the fertilization rate but it has no adverse effects on early embryo development.


El objetivo de este trabajo fue evaluar el efecto de albendazol sulfóxido (ABZSO) administrado a ratonas Balb C previo al apareamiento, sobre la tasa de fertilización y el desarrollo embrionario preimplantacional. Se utilizaron 24 hembras de 5 a 8 semanas de edad las que fueron inducidas a superovular por inyección intraperitoneal de 7,5 UI de gonadotrofina coriónica equina (eCG, Novormon®, Laboratorios Syntex S.A. Argentina) seguidas, 48 h más tarde por 10 UI de gonadotrofina coriónica humana (hCG, Profasi®, Laboratorios Serono, México). Al momento de recibir la dosis de hCG, fueron apareadas con machos de fertilidad probada. Las hembras fueron dosificadas oralmente con ABZSO disuelto en carboximetilcelulosa en dosis de 100 mg/kg (Grupo 100) y 200 mg/kg (Grupo 200) previo al apareamiento. El grupo control recibió carboximetilcelulosa. Las hembras preñadas fueron sacrificadas por dislocación cervical en el día 4 de preñez y se recolectaron ovocitos sin fertilizar y embriones preimplantacionales mediante el lavado de cuernos uterinos. Se determinó la tasa de fertilización, el número promedio de embriones recolectados por hembra, el porcentaje de embriones morfológicamente normales, el porcentaje de diferenciación y la velocidad de clivaje estimada por recuento de núcleos. Las variables fueron analizadas sobre la base de la camada utilizando el test de Kruskal-Wallis. La tasa de fertilización resultó menor para hembras que recibieron albendazol sulfóxido a razón de 200 mg/kg de peso (P<0,05); no obstante, no se observaron diferencias significativas en los parámetros embrionarios luego de la administración de 100 mg/kg ó 200 mg/kg de ABZSO comparado con el grupo control (P>0,05). En conclusión, la exposición aguda de ABZSO realizada previo al apareamiento a una dosis mayor de aquella utilizada en medicina humana y veterinaria afecta la tasa de fertilización pero no muestra efectos adversos sobre el desarrollo embrionario temprano.


Assuntos
Camundongos , Albendazol/administração & dosagem , Albendazol/uso terapêutico , Desenvolvimento Embrionário , Sulfóxidos/administração & dosagem , Camundongos Endogâmicos BALB C/embriologia , Reprodução
16.
J Clin Gastroenterol ; 45(4): 322-9, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20679904

RESUMO

GOALS: To investigate the efficacy and safety of a new proton pump inhibitor (PPI), ilaprazole (IY-81149) in the treatment of duodenal ulcers and provide some characteristics of the dose-response relationship for later studies. BACKGROUND: PPIs have been used therapeutically for many years, and shown great efficacy in accelerating ulcer healing. Currently researches are focused on more potent PPIs. Some preclinical studies have shown that ilaprazole might be such a new substitute. STUDY: 235 patients with at least 1 endoscopically diagnosed active duodenal ulcer were enrolled in a randomized trial. Patients were randomized into 4 groups (5, 10, and 20 mg/d ilaprazole, with 20 mg/d omeprazole as positive control) and treated for up to 4 weeks. Forty patients accepted continuous 24-hour pH measurements after the fifth dose. The primary endpoint was ulcer healing rate at week 4. RESULTS: The efficacy analyses were based on 235 patients. At week 4, 86.4%, 93.1%, 86.4%, and 89.8% patients treated with 5 mg ilaprazole, 10 mg ilaprazole, 20 mg ilaprazole, and 20 mg omeprazole once daily, respectively had ulcers healed (P=0.59). The majority of patients (>70%) became asymptomatic after 4 weeks treatment. Both drugs with stipulated dosages exhibited similar efficacy and safety profiles. Gastric acid suppression increased with increasing dose of ilaprazole in pH study. CONCLUSIONS: Ilaprazole is as tolerable, safe, and efficacious as omeprazole in the treatment of duodenal ulcers, especially at a lower dose (10 mg/d ilaprazole vs. 20 mg/d omeprazole). (ClinicalTrials.gov ID: NCT00953381).


Assuntos
Antiulcerosos/uso terapêutico , Benzimidazóis/uso terapêutico , Úlcera Duodenal/tratamento farmacológico , Omeprazol/uso terapêutico , Inibidores da Bomba de Prótons , Inibidores da Bomba de Prótons/uso terapêutico , Sulfóxidos/uso terapêutico , 2-Piridinilmetilsulfinilbenzimidazóis , Adulto , Antiulcerosos/administração & dosagem , Antiulcerosos/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/administração & dosagem , Omeprazol/efeitos adversos , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Sulfóxidos/administração & dosagem , Sulfóxidos/efeitos adversos , Resultado do Tratamento
17.
Jpn J Ophthalmol ; 54(3): 215-20, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20577855

RESUMO

PURPOSE: To use synthesized onion lachrymatory factor (SOLF) to investigate age-related changes in reflex-tear secretion and ocular-surface sensation. METHODS: We separated 91 healthy volunteers into four groups: groups A, age 20-29 years; B, 30-39; C, 40-49; and D, older than 50 years. We exposed one eye of each subject to SOLF and measured the elapsed time until the subject's limit of irritation tolerance (TLI) was reached and an increase in the tear meniscus radius (DeltaR). After the SOLF stimulus, corneal sensitivity was examined by Cochet-Bonnet esthesiometry (CB), and reflex-tear secretion was examined by the Schirmer I-test (ST). RESULTS: TLI was significantly shorter in group A than in the other groups (P < 0.0001), and the groups B and D also differed significantly from each other (P = 0.0013). The increase in DeltaR was significantly greater in group A than in group C (P = 0.0306) or D (P < 0.0001), and groups B (P = 0.0002) and C (P = 0.0308) also differed significantly from group D. There were no significant intergroup differences in the CB and ST results. CONCLUSIONS: An age-related decrease in reflex-tear secretion and ocular-surface sensation was revealed by the SOLF test but could not be detected by either CB or the ST.


Assuntos
Envelhecimento/fisiologia , Aparelho Lacrimal/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Cebolas , Reflexo/fisiologia , Sulfóxidos/administração & dosagem , Lágrimas/metabolismo , Adulto , Idoso , Feminino , Humanos , Aparelho Lacrimal/inervação , Masculino , Pessoa de Meia-Idade , Sulfóxidos/síntese química , Adulto Jovem
18.
J Gastroenterol ; 44(7): 697-707, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19434360

RESUMO

PURPOSE: Ilaprazole (IY-81149) is a new proton-pump inhibitor (PPI) not previously studied in human patients with ulcer disease. This study evaluated and compared it with a reference PPI, omeprazole, in the treatment of gastric and duodenal ulcers. METHODS: This was a double-blind, parallel, randomized study. Patients aged 18 years and above with at least one endoscopically confirmed active non-malignant gastric/duodenal ulcer were treated with 20 mg/day omeprazole or 5 mg/day or 10 mg/day ilaprazole for four weeks. Healing of ulcer was determined by its resolution from active to scarring stage. Symptoms relief was evaluated using a graded score. Safety and tolerability were evaluated on basis of clinical assessments. Between-group differences were tested using ANOVA or ANCOVA, as appropriate. Statistical significance was assumed at a two-tailed p value of 90%) became asymptomatic after treatment. At the dosages administered, both drugs exhibited similar efficacy and a similar safety profile. CONCLUSIONS: Ilaprazole is as tolerable, safe, and efficacious as omeprazole in the treatment of gastroduodenal ulcers, at a much lower dose (5 vs. 20 mg omeprazole).


Assuntos
Antiulcerosos/administração & dosagem , Benzimidazóis/administração & dosagem , Omeprazol/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Sulfóxidos/administração & dosagem , 2-Piridinilmetilsulfinilbenzimidazóis , Benzimidazóis/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Úlcera Duodenal/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/efeitos adversos , Úlcera Gástrica/tratamento farmacológico , Sulfóxidos/efeitos adversos
19.
Behav Brain Res ; 193(2): 183-91, 2008 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-18573547

RESUMO

Interleukin-6 (IL-6), a proinflammatory cytokine, is well known as a mediator in early stage inflammatory immune reactions. In recent years, accumulating evidence has shown that IL-6 is concomitant with the occurrence of major depression. However, the identification of the role of IL-6, as either an illness causation or immunotherapy in depression, remains to be further established. In the present study, 5-week old male Sprague-Dawley (SD) rats were used along with the forced swim test (FST) and pharmacological techniques. The data show that rats subjected to 3-day intra-amygdala or intra-hippocampus, but not intra-frontal cortex, IL-6 treatments manifested a significant increase in the immobility time (IMT) in the FST. In addition, there was no obvious difference in body temperature between normal and 3-day IL-6 treated rats. Conversely, the rats receiving 3-day intra-amygdala or intra-hippocampus IL-6 inhibitor treatment expressed a significant reduction in IMT in the FST. Moreover, the 3-day IL-6 treated rats treated with SL 327, a blood-brain barrier penetrating MEK inhibitor, prior to the FST showed a significant decrease in the IL-6 elevated IMT. In addition, the results in the Western blot analysis were in parallel with those in the behavioral tests. Taken together, the results show that the immobile behavior of rats in the FST could be modulated by IL-6 via the amygdala or the hippocampus. Furthermore, the Erk1/2 activation in the amygdala or hippocampus seemed to play a role in the IL-6 mediated immobile behavioural alterations of rats in the FST.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Interleucina-6/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Aminoacetonitrila/administração & dosagem , Aminoacetonitrila/análogos & derivados , Aminoacetonitrila/farmacologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiologia , Animais , Comportamento Animal/fisiologia , Western Blotting , Temperatura Corporal/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiologia , Resposta de Imobilidade Tônica/efeitos dos fármacos , Resposta de Imobilidade Tônica/fisiologia , Interleucina-6/administração & dosagem , Interleucina-6/metabolismo , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Sulfóxidos/administração & dosagem , Sulfóxidos/farmacologia , Natação/fisiologia , Tetrazóis/administração & dosagem , Tetrazóis/farmacologia
20.
J Pharmacol Exp Ther ; 322(3): 1286-93, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17575073

RESUMO

We compared the neurokinin 1 receptor (NK(1)R) antagonists aprepitant, CP-99994 [(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], and ZD6021 [3-cyano-N-((2S)-2-(3,4-dichlorophenyl)-4-[4-[2-(methyl-(S)-sulfinyl)phenyl]piperidino]butyl)-N-methyl]napthamide]] with respect to receptor interactions and duration of efficacy in vivo. In Ca(2+) mobilization assays (fluorometric imaging plate reader), antagonists were applied to human U373MG cells simultaneously with or 2.5 min before substance P (SP). In reversibility studies, antagonists were present for 30 min before washing, and responses to SP were repeatedly measured afterward. The compounds were administered i.p. to gerbils, and the gerbil foot tap (GFT) response was monitored at various time points. The NK(1)R receptor occupancy for aprepitant was determined in striatal regions. Levels of compound in brain and plasma were measured. Antagonists were equipotent at human NK(1)R and acted competitively with SP. After preincubation, aprepitant and ZD6021 attenuated the maximal responses, whereas CP-99994 only shifted the SP concentration-response curve to the right. The inhibitory effect of CP-99994 was over within 30 min, whereas for ZD6021, 50% inhibition still persisted after 60 min. Aprepitant produced maximal inhibition lasting at least 60 min. CP-99994 (3 micromol/kg) inhibited GFT by 100% 15 min after administration, but the effect declined rapidly together with brain levels thereafter. The efficacy of ZD6021 (10 micromol/kg) lasted 4 h and correlated well with brain levels. Aprepitant (3 micromol/kg) inhibited GFT and occupied striatal NK(1)R by 100% for >48 h despite that brain levels of compound were below the limit of detection after 24 h. Slow functional reversibility is associated with long-lasting in vivo efficacy of NK(1)R antagonists, whereas the efficacy of compounds with rapid reversibility is reflected by their pharmacokinetics.


Assuntos
Antagonistas do Receptor de Neuroquinina-1 , Piperidinas/farmacocinética , Sulfóxidos/farmacocinética , Animais , Comportamento Animal/efeitos dos fármacos , Sinalização do Cálcio , Linhagem Celular , Gerbillinae , Humanos , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Sulfóxidos/administração & dosagem , Sulfóxidos/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA