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1.
Int J Pharm ; 495(2): 940-7, 2015 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-26456295

RESUMO

Poly(propylene imine) (PPI) dendrimers contained surface maltose modification are proposed as drug carriers for nucleoside analog (NA) 5'-triphosphates. The aim of this study was to investigate the interactions between PPI dendrimers of 3rd (G3) or 4th (G4) generation and cytidine-5'-triphosphate (CTP) by Isothermal Titration Calorimetry method. CTP was used as a model molecule of pyrimidine nucleoside analog-cytarabine (ara-CTP) commonly used in leukemia treatment. Complexes of PPI dendrimers with NAs may help to overcome severe limitations of NAs associated with their low solubility and stability or resistance in cancer cells. In the present work, we evaluated stoichiometry and a mechanism of forming complexes between dendrimers and the nucleotide. Moreover, we examined the efficiency of complex formation in relation to dendrimer generations, a type of dendrimer modification with maltose residues and a type of solvent. It was observed that PPI dendrimers create complexes with CTP with high efficiency that makes them promising candidates for a drug delivery system.


Assuntos
Citidina Trifosfato/administração & dosagem , Dendrímeros/química , Portadores de Fármacos/química , Maltose/química , Polipropilenos/química , Calorimetria/métodos , Solubilidade
2.
Biomaterials ; 34(13): 3447-58, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23380359

RESUMO

Nucleoside analogs are a significant class of anti-cancer agent. As prodrugs, they terminate the DNA synthesis upon transforming to their active triphosphate metabolites. We have encapsulated a biologically activate nucleotide analog (i.e. gemcitabine triphosphate (GTP)), instead of the nucleoside (i.e. gemcitabine) derivative, into a novel Lipid/Calcium/Phosphate nanoparticle (LCP) platform. The therapeutic efficacy of LCP-formulated GTP was evaluated in a panel of human non-small-cell lung cancer (NSCLC) and human pancreatic cancer models after systemic administrations. GTP-loaded LCPs induced cell death and arrested the cell cycle in the S phase. In vivo efficacy studies showed that intravenously injected GTP-loaded LCPs triggered effective apoptosis of tumor cells, significant reduction of tumor cell proliferation and cell cycle progression, leading to dramatic inhibition of tumor growth, with little in vivo toxicity. Broadly speaking, the current study offers preclinical proof-of-principle that many active nucleotide or phosphorylated nucleoside analogs could be encapsulated in the LCP nanoplatform and delivered systemically for a wide variety of therapeutic applications.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Citidina Trifosfato/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cálcio/química , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citidina Trifosfato/administração & dosagem , Citidina Trifosfato/farmacocinética , Citidina Trifosfato/farmacologia , Citidina Trifosfato/uso terapêutico , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Lipídeos/química , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Nanopartículas/ultraestrutura , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Tamanho da Partícula , Fosfatos/química , Poli(ADP-Ribose) Polimerases/metabolismo , Polietilenoglicóis/química , Fase S/efeitos dos fármacos , Eletricidade Estática , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Infection ; 41(2): 379-85, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22875535

RESUMO

PURPOSE: Identifying factors that determine concentrations of antiretroviral drugs in CD4 cells are important for improving therapeutic efficacy. Experimental models indicate that the nucleoside reverse transcriptase inhibitor lamivudine is transported by the organic cation transporters 1 and 2 (OCT1 and OCT2, respectively). Here, we tested whether OCT1 and OCT2 contribute to the uptake of lamivudine into native CD4 cells of human immunodeficiency virus (HIV)-infected individuals. METHODS: CD4 cells obtained by non-activated cell sorting from 35 individuals with HIV-1 infection were incubated with lamivudine (10 µM, 30 min), and intracellular concentrations of lamivudine and its active metabolite lamivudine triphosphate were determined by liquid chromatography tandem mass spectrometry. The expression of OCT1 and OCT2 mRNA was measured by quantitative real-time polymerase chain reaction (PCR). A model of OCT2-transfected CD4 cells was established for mechanistic investigations. RESULTS: Intracellular concentrations of lamivudine and its active metabolite lamivudine triphosphate showed strong linear correlations with each other and with the CD4 mRNA expression of OCT1 and OCT2 (r > 0.80). Coincubation with protease inhibitors (ritonavir, nelfinavir) that inhibit OCT1 and OCT2 yielded decreased intracellular concentrations of lamivudine and lamivudine triphosphate. Incubation of CD4 cells from healthy donors transfected with an OCT2 expression vector yielded increased concentrations of lamivudine and lamivudine triphosphate. CONCLUSION: Our studies indicate a role of OCT1 and OCT2 for the cellular accumulation of lamivudine in HIV-infected individuals.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Citidina Trifosfato/análogos & derivados , Didesoxinucleotídeos/farmacocinética , Infecções por HIV/tratamento farmacológico , Lamivudina/análogos & derivados , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 1 de Cátions Orgânicos/metabolismo , Adulto , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/metabolismo , Citidina Trifosfato/administração & dosagem , Citidina Trifosfato/farmacocinética , Didesoxinucleotídeos/administração & dosagem , Feminino , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/farmacocinética , HIV-1/efeitos dos fármacos , Humanos , Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Masculino , Pessoa de Meia-Idade , Nelfinavir/farmacologia , Proteínas de Transporte de Cátions Orgânicos/genética , Transportador 1 de Cátions Orgânicos/genética , Transportador 2 de Cátion Orgânico , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Ritonavir/farmacologia , Espectrometria de Massas em Tandem , Transfecção , Adulto Jovem
4.
Ann Oncol ; 17 Suppl 5: v142-7, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16807444

RESUMO

BACKGROUND: The study determined pharmacokinetic parameters, toxicity profile and preliminary clinical activity of gemcitabine administered i.v. at different infusion rates in patients with a range of solid tumors. PATIENTS AND METHODS: Twenty patients were enrolled for both pharmacokinetic and clinical studies. Gemcitabine 300 mg/m(2) was administered during 1 h, 2 h or 3 h, and as a conventional dose of 1000 mg/m(2) during 30 min infusion. Administration was on days 1, 8 and 15 every 4 weeks. RESULTS: Patients were randomly assigned to one of the four arms. After 30 min infusion of 1000 mg/m(2) gemcitabine the plasma concentration remained above the saturation level of 10-20 microM, whereas after 1, 2 or 3 h infusion 300 mg/m(2) gemcitabine it remained below the saturation level for most of the time (being in the range 2.5-10 microM). Gemcitabine triphosphate was determined in the four arms in white blood cells; for infusion times from 0.5 to 3 h there was a progressive enhancement of gemcitabine triphosphate levels. In all evaluable patients the toxicity was mild, myelosuppression being the main toxicity. No grade 3 or 4 toxicities occurred. Clinical response was similar in patients receiving 300 mg/m(2) gemcitabine in 2 and 3 h and in the 1000 mg/m(2) arm. CONCLUSIONS: 300 mg/m(2) gemcitabine during 3 h infusion produced the highest accumulation of gemcitabine triphosphate. Thus, to achieve the highest possible gemcitabine triphosphate level, prolonged infusion time would appear to be more important than a high dose administered as a short infusion. However, there was no substantial difference in toxicity or antitumoral activity in the all different patient groups.


Assuntos
Citidina Trifosfato/análogos & derivados , Desoxicitidina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Citidina Trifosfato/administração & dosagem , Citidina Trifosfato/efeitos adversos , Citidina Trifosfato/farmacocinética , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/mortalidade , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Gencitabina
6.
Antivir Ther ; 9(4): 529-36, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15456084

RESUMO

Reverset (2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, RVT) is a potent inhibitor of HIV-1 replication in cell culture, with a 90% effective concentration at or below 1 microM. In vitro, RVT retains its activity against isolates harbouring mutations in the reverse transcriptase (RT) gene that otherwise confer resistance to lamivudine and/or zidovudine. The pharmacokinetics and safety of single oral doses of RVT (10-200 mg) were evaluated in an initial Phase I clinical trial. The viral load changes were determined on 18 HIV-1-infected antiretroviral therapy-naive subjects that were randomized into three cohorts, each cohort consisting of three study periods. The subjects received up to two oral doses of active drug and one placebo dose with a 1-week washout period separating the three study periods. Quantification of viral RNA was performed on the pre-dose, 12, 24 and 48 h post-dose plasma samples. A single oral dose of RVT to antiretroviral-naive subjects significantly reduced plasma viral load by 0.45 +/- 0.10 log10 copies/ml (P=0.0003). A mean drop of 0.37 +/- 0.12 log10 copies/ml (P=0.001) was obtained at the lowest dose of 10 mg. Sequence analysis of the HIV-1 RT gene performed before and after RVT dosing detected no genotypic changes in this short-term study. The viral RT gene of one subject had at predose the following genotype: L41 + N103 + C181 + W210 + D215, indicating prior exposure to zidovudine and non-nucleoside analogues, and anticipating high-level resistance against these agents. A single 10 mg RVT dose resulted in a viral load drop of 0.61 +/- 0.05 log10 providing evidence that a viral strain with the indicated genotype is susceptible to RVT.


Assuntos
Citidina Trifosfato/análogos & derivados , Citidina Trifosfato/uso terapêutico , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/isolamento & purificação , Inibidores da Transcriptase Reversa/uso terapêutico , Administração Oral , Adolescente , Adulto , Estudos de Coortes , Citidina Trifosfato/administração & dosagem , Citidina Trifosfato/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Genótipo , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/genética , Humanos , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/farmacocinética , Análise de Sequência de RNA , Carga Viral , Zalcitabina/análogos & derivados
7.
Zhonghua Er Bi Yan Hou Ke Za Zhi ; 37(4): 277-9, 2002 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-12772414

RESUMO

OBJECTIVE: To investigate the effect of application of cytridini triphosphatis (CTP) combined with dexamethasone on sudden deafness. METHODS: Two-hundred and seven patients (312 ears) with sudden deafness were randomly divided into CTP group (n = 159 ears) and control group (n = 153 ears). Besides intravenous administration of CTP, another treatments in CTP group were the same as that in control group including hyperbaric oxygen, vasodilator, energy preparation such as ATP, CoA and dexamethasone (DXM). RESULTS: The hearing threshold was (75.56 +/- 30.24) dB HL in CTP group and (72.50 +/- 40.50)dB HL in control group (P > 0.05) before treatment. The average value of the hearing threshold after treatment was decreased by (50.08 +/- 21.47) dB HL in CTP group and (19.45 +/- 19.12) dB in control group(P < 0.05), respectively. CONCLUSION: The application of CTP combined with DXM can significantly improve the effect of treatment on sudden deafness and CTP may enhance the recovery rate in the patients with sudden deafness, which was much higher than that treated by the traditional methods. However, the mechanism of the effect of CTP coupled with DXM is still unknown and further study is necessary.


Assuntos
Citidina Trifosfato/administração & dosagem , Dexametasona/administração & dosagem , Perda Auditiva Súbita/terapia , Adolescente , Adulto , Idoso , Audiometria de Tons Puros , Quimioterapia Combinada , Feminino , Perda Auditiva Súbita/tratamento farmacológico , Humanos , Oxigenoterapia Hiperbárica , Masculino , Pessoa de Meia-Idade
8.
Biochemistry ; 33(13): 3913-8, 1994 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-8142394

RESUMO

The allosteric control of Escherichia coli aspartate transcarbamylase (ATCase) involves synergistic feedback inhibition by CTP and UTP. Previously reported results [England, P., & Hervé, G. (1992) Biochemistry 31, 9725-9732] suggest that this phenomenon relies entirely on interactions between the two neighboring allosteric sites, which belong to the same regulatory dimer. Furthermore, it has been demonstrated that UTP alone binds to the enzyme, but that it is only in the presence of CTP that this binding inhibits the catalytic activity. The properties of mutants in which the synergistic inhibition is totally abolished suggested that the terminal gamma-phosphate of the pyrimidine triphosphate nucleotides may play a crucial role in promoting site-site interactions within the regulatory dimer. In the present work, kinetic studies and binding experiments by continuous-flow dialysis were performed, using combinations of diphosphate and triphosphate nucleotides. The results obtained show that the gamma-phosphate lf UTP is indeed essential for synergistic inhibition to occur, as UDP is unable to inhibit ATCase activity, whether alone or in combination with CTP. On the contrary, the gamma-phosphate of CTP can be suppressed without modifying the inhibitory properties of this nucleotide and its synergy of action with UTP. These results indicate that the mutual effects of CTP and UTP on their respective binding are not symmetrical and that the signals emitted upon binding of the two triphosphate pyrimidine nucleotides to the regulatory sites do not follow the same pathway and involve different mechanisms.


Assuntos
Aspartato Carbamoiltransferase/antagonistas & inibidores , Citidina Trifosfato/administração & dosagem , Uridina Trifosfato/administração & dosagem , Sinergismo Farmacológico , Escherichia coli/enzimologia , Cinética , Relação Estrutura-Atividade , Uridina Trifosfato/química
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