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1.
Chem Pharm Bull (Tokyo) ; 67(11): 1211-1224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31685749

RESUMO

A novel series of 2,6,7-substituted 3-unsubstituted 1,2,3,4-tetrahydroisoquinoline derivatives were synthesized to find a peroxisome proliferator-activated receptor γ (PPARγ) partial agonist. Among the derivatives, (E)-7-[2-(cyclopent-3-eny)-5-methyloxazol-4-ylmethoxy]-2-[3-(2-furyl)acryloyl]-6-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydroisoquinoline (20g) exhibited potent partial agonist activity (EC50 = 13 nM, maximal response 30%) and very weak protein tyrosine phosphatase 1B (PTP1B) inhibition (IC50 = 1100 nM), indicating a selective PPARγ partial agonist. A computational docking calculation revealed that 20g bound to PPARγ in a similar manner to that of known partial agonists. In male and female KK-Ay mice with insulin resistance and hyperglycemia, 20g at 30 mg/kg for 7 d significantly reduced plasma glucose levels, but not triglyceride levels. The effects of 20g were similar to those of pioglitazone at 10 mg/kg. In conclusion, the 2,6,7-substituted 1,2,3,4-tetrahydroisoquinoline with an acidic group at the 6-position provides a novel scaffold for selective PPARγ partial agonists and 20g exerted anti-diabetic effects via the partial activation of PPARγ.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Tetra-Hidroisoquinolinas/farmacologia , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Cristalografia por Raios X , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Resistência à Insulina , Masculino , Camundongos , Camundongos Transgênicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/química
2.
Biomed Pharmacother ; 115: 108881, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31028997

RESUMO

Higenamine (HG) is a well-known selective activator of beta2-adrenergic receptor (ß2-AR) with a positive inotropic effect. The present study showed that HG combined with [6]-gingerol (HG/[6]-GR) protects H9c2 cells from doxorubicin (DOX)-induced mitochondrial energy metabolism disorder and respiratory dysfunction. H9c2 cells were pretreated with HG/[6]-GR for 2 h before DOX treatment in all procedures. Cell viability was quantified by a cell counting kit­8 assay. Cardiomyocyte morphology, proliferation, and mitochondrial function were detected by a high content screening (HCS) assay. Cell mitochondrial stress was measured by a Seahorse XFp analyzer. To further investigate the protective mechanism of HG/[6]-GR, mRNA and protein expression levels of PPARα/PGC-1α/Sirt3 pathway-related molecules were detected. The present data demonstrated that protective effects of HG/[6]-GR combination were presented in mitochondria, which increased cell viability, ameliorated DOX-induced mitochondrial dysfunction, increased mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Most importantly, the protective effects were abrogated by GW6471 (a PPARα inhibitor) and ameliorated by Wy14643 (a PPARα agonist). Moreover, the combined use of HG and [6]-GR exerted more profound protective effects than either drug as a single agent. In conclusion, the results suggested that HG/[6]-GR ameliorates DOX-induced mitochondrial energy metabolism disorder and respiratory function impairment in H9c2 cells, and it indicated that the protective mechanism may be related to upregulation of the PPARα/PGC-1α/Sirt3 pathway, which promotes mitochondrial energy metabolism and protects against heart failure.


Assuntos
Alcaloides/farmacologia , Catecóis/farmacologia , Doxorrubicina/toxicidade , Álcoois Graxos/farmacologia , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Tetra-Hidroisoquinolinas/farmacologia , Translocador 1 do Nucleotídeo Adenina/genética , Translocador 1 do Nucleotídeo Adenina/metabolismo , Agonistas Adrenérgicos beta/administração & dosagem , Agonistas Adrenérgicos beta/farmacologia , Alcaloides/administração & dosagem , Animais , Antibióticos Antineoplásicos/toxicidade , Catecóis/administração & dosagem , Linhagem Celular , Sobrevivência Celular , Metabolismo Energético/efeitos dos fármacos , Álcoois Graxos/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , PPAR alfa/genética , PPAR alfa/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Sirtuínas/genética , Sirtuínas/metabolismo , Tetra-Hidroisoquinolinas/administração & dosagem , Fatores de Transcrição de p300-CBP/genética , Fatores de Transcrição de p300-CBP/metabolismo
3.
Pharm Dev Technol ; 24(6): 788-793, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30885016

RESUMO

The purpose of this research was to develop a novel revaprazan-loaded surface-modified solid dispersion (SMSD) with improved drug solubility and oral bioavailability. The impact of carriers on aqueous solubility of revaprazan was investigated. HPMC and Cremophor A25 were selected as an appropriate polymer and surfactant, respectively, due to their high drug solubility. Numerous SMSDs were prepared with various concentrations of carriers, using distilled water, and the drug solubility of each was assessed. Moreover, the physicochemical properties, dissolution and pharmacokinetics of selected SMSD in rats were assessed in comparison to revaprazan powder. Of the SMSDs assessed, the SMSD composed of revaprazan/HPMC/Cremophor A25 at the weight ratio of 1:0.28:1.12 had the most enhanced drug solubility (∼6000-fold). It was characterized by particles with a relatively rough surface, suggesting that the carriers were attached onto the surface of the unchanged crystalline revaprazan powder. It had a significantly higher dissolution rate, AUC and Cmax, and a faster Tmax value in comparison to revaprazan powder, with a 5.3-fold improvement in oral bioavailability of revaprazan. Therefore, from an environmental perspective, this SMSD system prepared with water, and without organic solvents, should be recommended as a revaprazan-loaded oral pharmaceutical alternative.


Assuntos
Portadores de Fármacos/química , Derivados da Hipromelose/química , Polietilenoglicóis/química , Inibidores da Bomba de Prótons/química , Pirimidinonas/química , Tensoativos/química , Tetra-Hidroisoquinolinas/química , Administração Oral , Cristalização , Inibidores da Bomba de Prótons/administração & dosagem , ATPases Translocadoras de Prótons/antagonistas & inibidores , Pirimidinonas/administração & dosagem , Solubilidade , Tetra-Hidroisoquinolinas/administração & dosagem
4.
Eur J Pharm Biopharm ; 136: 120-130, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30660696

RESUMO

Lorlatinib, a novel generation oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor with high membrane and blood-brain barrier permeability, recently received accelerated approval for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), and its further clinical development is ongoing. We previously found that the efflux transporter P-glycoprotein (MDR1/ABCB1) restricts lorlatinib brain accumulation and that the drug-metabolizing enzyme cytochrome P450-3A (CYP3A) limits its oral availability. Using genetically modified mouse models, we investigated the impact of targeted pharmacological inhibitors on lorlatinib pharmacokinetics and bioavailability. Upon oral administration of lorlatinib, the plasma AUC0-8h in CYP3A4-humanized mice was ∼1.8-fold lower than in wild-type and Cyp3a-/- mice. Oral coadministration of the CYP3A inhibitor ritonavir caused reversion to the AUC0-8h levels seen in wild-type and Cyp3a-/- mice, without altering the relative tissue distribution of lorlatinib. Moreover, simultaneous pharmacological inhibition of P-glycoprotein and CYP3A4 with oral elacridar and ritonavir in CYP3A4-humanized mice profoundly increased lorlatinib brain concentrations, but not its oral availability or other relative tissue distribution. Oral lorlatinib pharmacokinetics was not significantly affected by absence of the multispecific Oatp1a/1b drug uptake transporters. The absolute oral bioavailability of lorlatinib over 8 h in wild-type, Cyp3a-/-, and CYP3A4-humanized mice was 81.6%, 72.9%, and 58.5%, respectively. Lorlatinib thus has good oral bioavailability, which is markedly restricted by human CYP3A4 but not by mouse Cyp3a. Pharmacological inhibition of CYP3A4 reversed these effects, and simultaneous P-gp inhibition with elacridar boosted absolute brain levels of lorlatinib by 16-fold without obvious toxicity. These insights may help to optimize the clinical application of lorlatinib.


Assuntos
Acridinas/metabolismo , Quinase do Linfoma Anaplásico/metabolismo , Encéfalo/metabolismo , Lactamas Macrocíclicas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Ritonavir/metabolismo , Tetra-Hidroisoquinolinas/metabolismo , Acridinas/administração & dosagem , Administração Intravenosa , Administração Oral , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/metabolismo , Interações de Medicamentos/fisiologia , Sinergismo Farmacológico , Lactamas Macrocíclicas/administração & dosagem , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Ritonavir/administração & dosagem , Tetra-Hidroisoquinolinas/administração & dosagem
5.
Int J Nanomedicine ; 13: 6855-6870, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30498347

RESUMO

Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells. Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo. Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity. Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs.


Assuntos
Acridinas/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Neoplasias Hepáticas/terapia , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Transplante de Células-Tronco , Tetra-Hidroisoquinolinas/administração & dosagem , Vitamina E/química , Acridinas/farmacocinética , Acridinas/farmacologia , Acridinas/uso terapêutico , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Morte Celular/efeitos dos fármacos , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Sinergismo Farmacológico , Endocitose/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Ratos Sprague-Dawley , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Tela Subcutânea/efeitos dos fármacos , Tela Subcutânea/patologia , Tetra-Hidroisoquinolinas/farmacocinética , Tetra-Hidroisoquinolinas/farmacologia , Tetra-Hidroisoquinolinas/uso terapêutico , Distribuição Tecidual , Ensaio Tumoral de Célula-Tronco
6.
Eur J Pharm Biopharm ; 133: 240-249, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30367935

RESUMO

Gastric cancer is the third leading cause of cancer-related mortality worldwide. A dominant hindrance towards curative cancer therapy is multidrug resistance (MDR) mediated by ATP-dependent efflux pumps. We have previously demonstrated the ability of ß-casein (ß-CN) micelles and re-assembled casein micelles to serve as nanovehicles for oral delivery and target-activated release of hydrophobic chemotherapeutics in the stomach, and to overcome P-glycoprotein-dependent MDR in gastric cancer. Herein we investigated the modularity and versatility of this ß-CN-based delivery system using a different synergistic drug duo to treat MDR gastric cancer cells overexpressing the breast cancer resistance protein (BCRP). The chemotherapeutic drug SN-38, a BCRP transport substrate, and the BCRP efflux transport inhibitor, elacridar, exhibited high binding affinity to ß-CN, as demonstrated by spectrophotometry and spectrofluorometry. Furthermore, light microscopy and dynamic light scattering confirmed that ß-CN solubilized these drugs and suppressed drug crystal growth. In vitro cytotoxicity against MDR human gastric carcinoma cells overexpressing BCRP revealed a synergistic activity of this drug combination and a complete MDR reversal. Hence, our findings highlight the great promise of casein-based nanovehicles, harboring hydrophobic synergistic drug combinations, as a modular and versatile oral delivery system for local drug release in the stomach to overcome chemoresistance in gastric cancer.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Acridinas/administração & dosagem , Caseínas/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Irinotecano/administração & dosagem , Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Tetra-Hidroisoquinolinas/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Acridinas/química , Administração Oral , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Humanos , Irinotecano/química , Micelas , Nanopartículas/química , Neoplasias Gástricas/metabolismo , Tetra-Hidroisoquinolinas/química
7.
Neuroscience ; 392: 25-37, 2018 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-30267833

RESUMO

Amyloid plaque is a prominent pathologic hallmark in the brains of patients with Alzheimer's disease (AD), and it has been shown to be associated with endoplasmic reticulum (ER) stress response. However the precise regulation mechanism of amyloid-beta (Aß) toxicity remains unclear. Here, we found that dauricine could activate X-box binding protein 1 (XBP-1; active form XBP-1S) and eukaryotic translation initiation factor eIF2α and thus delay the progression of AD in the Aß1-42-transgenic Caenorhabditis elegans CL2120. The ER stress response factor XBP-1 can be activated and shows neuroprotective activity through acceleration of Aß clearance. Our study reveals that dauricine activates the ire-1/xbp-1 and perk/eIF2α pathways of the unfolded protein response, attenuates translation, and enhances ER-associated degradation, which reduces Aß expression and attenuates Aß-associated toxicity. On the contrary, xbp-1 depletion counteracts the effects of dauricine on Aß-associated toxicity. These results underscore the functional relevance of XBP-1 in Aß toxicity and degradation, and highlight the potentially pharmacodynamic value of dauricine in preventing the progression of AD.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Benzilisoquinolinas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Fragmentos de Peptídeos/metabolismo , Tetra-Hidroisoquinolinas/administração & dosagem , Resposta a Proteínas não Dobradas , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/toxicidade , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Fragmentos de Peptídeos/toxicidade , Proteólise , Transdução de Sinais
8.
BMC Cancer ; 18(1): 840, 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30126369

RESUMO

BACKGROUND: Pleomorphic liposarcoma (PLPS) is a rare, heterogeneous and an aggressive variant of liposarcoma. Therefore, individualized therapy is urgently needed. Our recent reports suggest that trabectedin (TRAB) is effective against several patient-derived orthotopic xenograft (PDOX) mouse models. Here, we compared the efficacy of first-line therapy, doxorubicin (DOX), and TRAB in a platelet-derived growth factor receptor-α (PDGFRA)-amplified PLPS. METHODS: We used a fresh sample of PLPS tumor derived from a 68-year-old male patient diagnosed with a recurrent PLPS. Subcutaneous implantation of tumor tissue was performed in a nude mouse. After three weeks of implantation, tumor tissues were isolated and cut into small pieces. To match the patient a PDGFRA-amplified PLPS PDOX was created in the biceps femoris of nude mice. Mice were randomized into three groups: Group 1 (G1), control (untreated); Group 2 (G2), DOX-treated; Group 3 (G3), TRAB-treated. Measurement was done twice a week for tumor width, length, and mouse body weight. RESULTS: The PLPS PDOX showed resistance towards DOX. However, TRAB could arrest the PLPS (p < 0.05 compared to control; p < 0.05 compared to DOX) without any significant changes in body-weight. CONCLUSIONS: The data presented here suggest that for the individual patient the PLPS PDOX model could specifically distinguish both effective and ineffective drugs. This is especially crucial for PLPS because effective first-line therapy is harder to establish if it is not individualized.


Assuntos
Dioxóis/administração & dosagem , Doxorrubicina/administração & dosagem , Lipossarcoma/tratamento farmacológico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Tetra-Hidroisoquinolinas/administração & dosagem , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doxorrubicina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Lipossarcoma/genética , Lipossarcoma/patologia , Masculino , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Trabectedina , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Pharm Res ; 35(10): 190, 2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30105478

RESUMO

PURPOSE: This study was designed to investigate the effects of P-glycoprotein (P-gp) expressed in the intestine on the nonlinear pharmacokinetics (PK) of T-3256336, an inhibitor of apoptosis protein inhibitor, and food effects on its bioavailability in rats. METHODS: To investigate the factors that contribute to nonlinear PK of T-3256336 in the intestine and liver, rats double-cannulated in the portal vein and femoral artery (PS rats) were used. FaFg (Fa, absorption ratio; Fg, intestinal availability) and hepatic availability (Fh) were simultaneously evaluated based on the difference between the portal and systemic blood area under the concentration-time curve (AUC). Elacridar was used as a P-gp inhibitor to assess the impact of P-gp on the intestinal absorption. RESULTS: After oral administration of T-3256336 to PS rats at 3 and 30 mg/kg, FaFg value increased with dose escalation, whereas Fh value was nearly constant. Moreover, co-administration of elacridar resulted in a 5-fold increase in the FaFg value at 3 mg/kg. The AUC value of T-3256336 under fed conditions was 3-fold lower than that under fasted conditions. This food effect on the oral bioavailability (BA) was reduced by concomitant administration of elacridar. CONCLUSION: P-gp expressed in the intestine would cause nonlinear PK and a food effect on BA of T-3256336 in rats.


Assuntos
Alimentos/efeitos adversos , Glicoproteínas/farmacocinética , Proteínas Inibidoras de Apoptose/metabolismo , Absorção Intestinal/efeitos dos fármacos , Oligopeptídeos/farmacocinética , Pirazinas/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Acridinas/administração & dosagem , Acridinas/farmacocinética , Animais , Humanos , Proteínas Inibidoras de Apoptose/administração & dosagem , Células LLC-PK1 , Masculino , Oligopeptídeos/administração & dosagem , Pirazinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Suínos , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/farmacocinética
10.
J Microencapsul ; 35(5): 421-427, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30136606

RESUMO

To develop a novel revaprazan-loaded gelatine microsphere with enhanced solubility and oral bioavailability, numerous gelatine microspheres were prepared using a spray-drying technique. The impact of gelatine amount on drug solubility in the gelatine microspheres was investigated. The physicochemical properties of the selected gelatine microsphere, such as shape, particle size and crystallinity, were evaluated. Moreover, its dissolution and pharmacokinetics in rats were assessed in comparison with revaprazan powder. Amongst the gelatine microspheres tested, the gelatine microsphere consisting of revaprazan and gelatine (1:2, w/w), which gave about 150-fold increased solubility, had the most enhanced drug solubility. It provided a spherical shape, amorphous drug and reduced particle size. Furthermore, it gave a higher dissolution rate and plasma concentration than did revaprazan powder. Particularly, it gave about 2.3-fold improved oral bioavailability in comparison with revaprazan powder. Therefore, this novel gelatine microsphere system is recommended as an oral pharmaceutical product of poorly water-soluble revaprazan.


Assuntos
Portadores de Fármacos/química , Gelatina/química , Pirimidinonas/administração & dosagem , Tetra-Hidroisoquinolinas/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Composição de Medicamentos , Masculino , Tamanho da Partícula , Pirimidinonas/química , Pirimidinonas/farmacocinética , Ratos Sprague-Dawley , Solubilidade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacocinética
11.
J Cancer Res Clin Oncol ; 144(6): 1185-1195, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29623421

RESUMO

PURPOSE: The OVA-YOND study is the first prospective, non-interventional trial designed to evaluate trabectedin (1.1 mg/m2) plus PLD (30 mg/m2) in patients with platinum-sensitive recurrent ovarian cancer (ROC), given according to the marketing authorization in real-life clinical practice across Germany. METHODS: Eligible patients were adults with platinum-sensitive ROC, pretreated with ≥ 1 platinum-containing regimen/s. The primary endpoint was to assess safety/tolerability of the combination. RESULTS: Seventy-seven patients with platinum-sensitive relapse from 31 sites were evaluated. Patients received a median of 6 cycles (range 1-21) with 39 patients (50.6%) receiving ≥ 6 cycles. Median treatment duration was 4.2 months (range 0.7-18.8), mostly on an outpatient basis (88.3% of patients). Most common grade 3/4 trabectedin-related adverse events (AEs) were leukopenia (18.2%), neutropenia (15.6%), thrombocytopenia (9.1%), alanine (7.8%) and aspartate aminotransferase (6.5%) increase, and nausea/vomiting (5.2% each). Neutropenia (18.2%), leukopenia (15.6%), thrombocytopenia (10.4%), and nausea/vomiting (5.2% each) were the most frequent grade 3/4 PLD-related AEs. No deaths attributed to drug-related AEs or unexpected AEs occurred. Five patients (6.5%) had a complete response and 19 patients (24.7%) achieved a partial response for an objective response rate of 31.2% with median response duration of 6.25 months. Sixteen patients (20.8%) had disease stabilization for a disease control rate of 51.9%. Median progression-free survival was 6.3 months and median overall survival was 16.4 months. CONCLUSION: Trabectedin plus PLD confer clinically meaningful benefit to pre-treated patients with platinum-sensitive ROC, being comparable to those previously observed in selected populations from clinical trials and with a manageable safety profile.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Feminino , Humanos , Pessoa de Meia-Idade , Compostos Organoplatínicos/farmacologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Estudos Prospectivos , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Trabectedina
12.
Psychopharmacology (Berl) ; 235(5): 1581-1591, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29492614

RESUMO

RATIONALE: Studies suggest that the κ-opioidergic system becomes overactivated as ethanol use disorders develop. Nalmefene, a currently approved treatment for ethanol use disorders, may also elicit some of its main effects via the κ-opioidergic system. However, the exact role of κ-opioid receptors on regulating ethanol intake and contribution to the development of ethanol addiction remains to be elucidated. OBJECTIVES: The aim of the present study was to clarify the role of accumbal κ-opioid receptors in controlling ethanol intake in alcohol-preferring Alko Alcohol (AA) rats. METHODS: Microinfusions of the long-acting and selective κ-opioid receptor antagonist JDTic (1-15 µg/site) were administered bilaterally into the nucleus accumbens shell of AA rats voluntarily consuming 10% ethanol solution in the intermittent, time-restricted two-bottle choice access paradigm. JDTic (10 mg/kg) was also administered subcutaneously. Both the acute and long-term effects of the treatment on ethanol intake were examined. As a reference, nor-BNI (3 µg/site) was administered intra-accumbally. RESULTS: Systemically administered JDTic decreased ethanol intake significantly 2 days and showed a similar trend 4 days after administration. Furthermore, intra-accumbally administered JDTic showed a weak decreasing effect on ethanol intake long-term but had no acute effects. Intra-accumbal administration of nor-BNI tended to decrease ethanol intake. CONCLUSIONS: The results provide further evidence that κ-opioid receptors play a role in controlling ethanol intake and that accumbal κ-opioid receptors participate in the modulation of the reinforcing effects of ethanol. Furthermore, the results suggest that κ-opioid receptor antagonists may be a valuable adjunct in the pharmacotherapy of ethanol use disorders.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Etanol/administração & dosagem , Piperidinas/administração & dosagem , Receptores Opioides kappa/antagonistas & inibidores , Tetra-Hidroisoquinolinas/administração & dosagem , Consumo de Bebidas Alcoólicas/psicologia , Animais , Etanol/antagonistas & inibidores , Masculino , Microinjeções , Antagonistas de Entorpecentes/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Ratos , Receptores Opioides kappa/fisiologia
13.
Biomed Pharmacother ; 100: 282-295, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29448205

RESUMO

In this study, we investigated the in vivo antiproliferative activity of 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (M1) in dimethylhydrazine (DMH) induced colorectal carcinoma (CRC) using albino Wistar rats. M1 was administered to DMH induced CRC rats at 10 and 25 mg/kg doses for 15 days. Various physiological, oxidative parameters, histopathology, ELISA, gene and protein expression studies were conducted to evaluate the anti-CRC potential of M1. The histopathology and biochemical tests indicated the protective action of M1 in DMH-induced colon cancer. ELISA confirms that M1 reduced the increased concentration of IL-6 more prominently than those of IL-2 and COX-2. Gene expression analysis revealed that M1 attenuated the increased mRNA over-expression of IL-6, JAK2 and STAT3. The result obtained from quantitative western blot analysis demonstrated that the CRC condition was produced by the IL-6 induced activation/phosphorylation of JAK2 and STAT3 and further down-regulated with M1 treatment. This evidence was supported well with the application of data-based mathematical modeling. Applying the fitted model, we predicted the quantitative behavior of STAT3 populations not accessible to experimental measurement. Later, 1H NMR based serum metabolic profiling was carried out using rat sera to investigate the impact of M1 on CRC-induced metabolic alterations. M1 showed its ability to restore the perturbed metabolites in CRC condition. Altogether, our study provided the first time evidence that M1 exhibits anti-CRC potential through the blockade of IL-6/JAK2/STAT3 oncogenic signaling.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Tetra-Hidroisoquinolinas/uso terapêutico , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Dimetilidrazinas/farmacologia , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Interleucina-6/genética , Masculino , Modelos Teóricos , Mucuna/química , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/isolamento & purificação
14.
Drug Deliv Transl Res ; 8(3): 536-542, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29294257

RESUMO

Elacridar (GF120918) is a highly potent inhibitor of both P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), the main efflux transporters expressed at the blood-brain barrier (BBB). Elacridar shows very low aqueous solubility, which complicates its formulation for i.v. administration. An intravenous infusion protocol would be preferred to achieve high and controlled plasma concentrations of elacridar in large animals, including nonhuman primates. Formulation of elacridar for i.v. infusion was achieved using a co-solvent strategy, resulting in an aqueous dispersion with a final concentration of 5 g L-1 elacridar with tetrahydrofuran (5% w/v) in aqueous D-glucose solution (2.5%, w/v). Particle size (mean = 2.8 ± 0.9 µm) remained stable for 150 min. The preparation was i.v. administered as a continuous infusion (12 mg kg-1 h-1 for 90 min) to three baboons. Arterial and venous plasma pharmacokinetics (PK) of elacridar were monitored using a newly developed and validated HPLC-UV method. Elacridar concentration increased rapidly to reach a plateau at 9.5 µg mL-1 within 20 min after the start of infusion. Elacridar PK in venous plasma did not differ from arterial plasma facing the BBB, indicating the absence of an arteriovenous concentration gradient. Intravenous infusion of elacridar allows for controlled exposure of the BBB and offers a useful tool to assess the impact of ABCB1/ABCG2 on drug disposition to the brain in nonhuman primates, a relevant animal model for the study of transporter function at the BBB.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Acridinas/administração & dosagem , Proteínas de Neoplasias/antagonistas & inibidores , Tetra-Hidroisoquinolinas/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Acridinas/farmacocinética , Animais , Encéfalo/metabolismo , Furanos/administração & dosagem , Furanos/química , Infusões Intravenosas , Masculino , Papio , Solventes/administração & dosagem , Solventes/química , Tetra-Hidroisoquinolinas/sangue , Tetra-Hidroisoquinolinas/farmacocinética
15.
Drug Deliv Transl Res ; 8(2): 375-386, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28462499

RESUMO

Lipid-based drug delivery systems, a well-tolerated class of formulations, have been evaluated extensively to enhance the bioavailability of poorly soluble drugs. However, it has been difficult to predict the in vivo performance of lipid dosage forms based on conventional in vitro techniques such as cell monolayer permeability studies because of the complexity of the gastrointestinal processing of lipid formulations. In the current study, we explored the feasibility of coupling Caco-2 and Madin-Darby canine kidney monolayer permeability studies with lipolysis, a promising in vitro technique to evaluate lipid systems. A self-emulsifying lipid delivery system was formulated using a blend of oil (castor oil), surfactant (Labrasol® or PL497), and co-surfactant (lecithin). Formulations demonstrating high drug solubility and rapid self-emulsification were selected to study the effect of lipolysis on in vitro cell permeability. Lipolysis of the formulations was carried out using pancreatin as the digestive enzyme. All the digested formulations compromised monolayer integrity as indicated by lowered trans-epithelial electrical resistance (TEER) and enhanced Lucifer yellow (LY) permeability. Further, the changes in TEER value and LY permeability were attributable to the digestion products of the formulation rather than the individual lipid excipients, drug, digestion enzyme, or the digestion buffer. The digested formulations were fractionated into pellet, oily phase, and aqueous phase, and the effect of each of these on cell viability was examined. Interestingly, the aqueous phase, which is considered important for in vivo drug absorption, was responsible for cytotoxicity. Because lipid digestion products lead to disruption of cell monolayer, it may not be appropriate to combine lipolysis with cell monolayer permeability studies. Additional in vivo studies are needed to determine any potential side effects of the lipolysis products on the intestinal permeability barrier, which could determine the suitability of lipid-based systems for oral drug delivery.


Assuntos
Sistemas de Liberação de Medicamentos , Acridinas/administração & dosagem , Acridinas/química , Administração Oral , Animais , Células CACO-2 , Óleo de Rícino/administração & dosagem , Óleo de Rícino/química , Sobrevivência Celular/efeitos dos fármacos , Cães , Excipientes/administração & dosagem , Excipientes/química , Humanos , Lecitinas/administração & dosagem , Lecitinas/química , Lipólise , Células Madin Darby de Rim Canino , Permeabilidade , Tensoativos/administração & dosagem , Tensoativos/química , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/química
16.
J Pharmacol Exp Ther ; 364(1): 46-54, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29061656

RESUMO

Although cancer cell genetic instability contributes to characteristics that mediate tumorigenicity, it also contributes to the tumor-selective toxicity of some chemotherapy drugs. This synthetic lethality can be enhanced by inhibitors of DNA repair. To exploit this potential Achilles heel, we tested the ability of a RAD51 inhibitor to potentiate the cytotoxicity of chemotherapy drugs. 2-(Benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline (IBR2) inhibits RAD51-mediated DNA double-strand break repair but also enhances cytotoxicity of the Bcr-Abl inhibitor imatinib. The potential for synergy between IBR2 and more drugs was examined in vitro across a spectrum of cancer cell lines from various tissues. Cells were exposed to IBR2 simultaneously with inhibitors of receptor tyrosine kinases, DNA-damaging agents, or microtubule disruptors. IBR2, at concentrations that inhibited proliferation between 0% and 75%, enhanced toxicity by up to 80% of imatinib and regorafenib (targets RAF and kit); epidermal growth factor receptor inhibitors erlotinib, gefitinib, afatinib, and osimertinib; and vincristine, an inhibitor of microtubule function. However, IBR2 antagonized the action of olaparib, cisplatin, melphalan, and irinotecan. A vincristine-resistant squamous cell line was not cross resistant to imatinib, but IBR2 and another RAD51 inhibitor (B02) enhanced imatinib toxicity in this cell line, its HN-5a parent, and the colon cancer line HT-29 by up to 60% and much better than verapamil, a P-glycoprotein inhibitor (P < 0.05). Given the disparate agents the functions of which are enhanced by IBR2, the mechanisms of enhancement may be multimodal. Whether RAD51 is common to these mechanisms remains to be elucidated, but it provides the potential for selectivity to tumor cells.


Assuntos
Proliferação de Células/efeitos dos fármacos , Indóis/administração & dosagem , Proteínas dos Microtúbulos/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Rad51 Recombinase/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Tetra-Hidroisoquinolinas/administração & dosagem , Células A549 , Antineoplásicos/administração & dosagem , Proliferação de Células/fisiologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Células HEK293 , Células HT29 , Humanos , Células K562 , Células MCF-7 , Proteínas dos Microtúbulos/metabolismo , Rad51 Recombinase/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo
17.
Eur J Cancer ; 88: 87-91, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29202389

RESUMO

In the last decade the limited treatment options for patients with metastatic soft tissue sarcoma have expanded considerably. With the addition of olaratumab to first-line treatment with doxorubicin, the introduction of several new agents in second-line treatment and beyond and other promising agents in the pipeline, perspectives of patients with metastatic soft tissue sarcoma are improving. Due to increasing insight into the biology of the different soft tissue sarcoma subtypes, choice of treatment has become much more histology-driven, although more prognostic and predictive factors are needed to further personalise therapy. This report summarises the current state of the art and discusses the promising developments in the treatment of patients with metastatic soft tissue sarcoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sarcoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Dioxóis/administração & dosagem , Doxorrubicina/administração & dosagem , Tratamento Farmacológico/métodos , Tratamento Farmacológico/tendências , Previsões , Humanos , Metástase Neoplásica , Pirimidinas/administração & dosagem , Sarcoma/patologia , Sulfonamidas/administração & dosagem , Tetra-Hidroisoquinolinas/administração & dosagem , Trabectedina
18.
Bioorg Med Chem ; 26(2): 470-482, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29258712

RESUMO

A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.


Assuntos
Descoberta de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Tetra-Hidroisoquinolinas/farmacologia , Administração Oral , Animais , Cristalografia por Raios X , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Humanos , Injeções Intradérmicas , Interleucina-23/administração & dosagem , Interleucina-23/farmacologia , Células Jurkat , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Modelos Moleculares , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/química
19.
Ann Oncol ; 28(suppl_8): viii51-viii56, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29232464

RESUMO

Despite optimal surgery and appropriate first-line chemotherapy, ∼70%-80% of patients with epithelial ovarian cancer will develop disease relapse. The same modalities as used primarily are available for treatment of recurrent ovarian cancer (ROC). The rationale for repetitive surgery in ROC was based on a stable body of retrospective data; however, prospective data were missing. Now, preliminary data from the prospective AGO-DESKTOP III give evidence that surgery for ROC seems to be of benefit for selected patients with platinum-sensitive relapse undergoing complete resection. With respect to systemic therapy, tumor histology, BRCA status, the platinum-free interval (PFI) and previous treatment with bevacizumab (anti-VEGF monoclonal antibody) are considered the most important features that influence treatment choice in ROC. In patients with resistant or refractory relapse (PFI < 6 months), monotherapy with a non-platinum drug or participation in clinical trials is indicated. The association of non-platinum monotherapy with bevacizumab, followed by maintenance has been approved in this setting in some European countries due to PFS benefit. In patients with partially sensitive relapse (PFI between 6 and 12 months), two options are available: platinum doublets or non-platinum therapy (single agent or combination). The pegylated liposomal doxorubicin/trabectedin combination represents a viable alternative in patients that cannot receive platinum. In platinum-sensitive patients, treatment with platinum-based combinations is associated with PFS advantage compared with single agents or non-platinum combinations. The presence of germline or somatic BRCA mutations allows platinum-responsive patients to optimize chemotherapy efficacy and prolonging PFS by the use of olaparib (PARP inhibitor) given as maintenance therapy until progression. In patients not pretreated with bevacizumab in first line, the carboplatin/gemcitabine/bevacizumab combination, followed by maintenance is a viable alternative in platinum-sensitive patients (PFI> 6 months). The integration of surgery, with a 'personalized' approach by the use of antiangiogenic agent and of PARP inhibitors is affecting survival of patients with recurrent disease and will help epithelial ovarian cancer to become a chronic disease.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/cirurgia , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Bevacizumab/administração & dosagem , Bevacizumab/uso terapêutico , Carcinoma Epitelial do Ovário , Ensaios Clínicos Fase III como Assunto , Dioxóis/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Recidiva Local de Neoplasia/mortalidade , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/mortalidade , Polietilenoglicóis/administração & dosagem , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Tetra-Hidroisoquinolinas/administração & dosagem , Trabectedina
20.
Int J Gynecol Cancer ; 27(9): 1872-1876, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28976446

RESUMO

INTRODUCTION: In ovarian cancer, it is uncertain which chemotherapy regimen is more clinically effective and cost-effective for the treatment of recurrence; therefore, it might be interesting to make a balance between the cost of the drugs administered and the difference in progression-free survival (PFS) and overall survival (OS). METHODS: The present evaluation was restricted to pivotal phase 3 randomized controlled trials. We calculated the pharmacological costs necessary to get the benefit in PFS and OS. The costs of drugs are at the pharmacy of our hospital and are expressed in Euros (&OV0556;). We have subsequently applied the European Society for Medical Oncology Magnitude of Clinical Benefit Scale. RESULTS: Our study evaluated 3 phase 3 randomized controlled trials, including 2004 patients. The most relevant increase of costs was associated with the combination chemotherapy including trabectedin, with the highest costs for month of PFS gained (15,836 &OV0556;) and for month of OS gained (7198 &OV0556;), but it substantially differs considering the data of partially platinum-sensitive populations (platinum-free interval of 6-12 months), with 3959 &OV0556; for month of OS gained. CONCLUSIONS: The addition of trabectedin to pegylated liposomal doxorubicin for the treatment of recurrent ovarian cancer can lead to an increase of pharmacological costs. Differently, considering OS in patients with platinum-free interval of 6 to 12 months, there is a halving of pharmacological costs with the addition of trabectedin to pegylated liposomal doxorubicin. These costs are in line with the spending suggested as sustainable (thresholds of <$61,500 per life-year gained).


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/economia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Carboplatina/administração & dosagem , Carboplatina/economia , Carcinoma Epitelial do Ovário , Ensaios Clínicos Fase III como Assunto/economia , Análise Custo-Benefício , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/economia , Dioxóis/administração & dosagem , Dioxóis/economia , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Doxorrubicina/economia , Custos de Medicamentos , União Europeia , Feminino , Humanos , Recidiva Local de Neoplasia/economia , Neoplasias Epiteliais e Glandulares/economia , Neoplasias Ovarianas/economia , Paclitaxel/administração & dosagem , Paclitaxel/economia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/economia , Ensaios Clínicos Controlados Aleatórios como Assunto/economia , Taxa de Sobrevida , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/economia , Trabectedina
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