RESUMEN
Xanthine oxidoreductase (XOR) is a clinically validated target for the treatment of hyperuricemia and gout. A series of novel 1,2,4-triazoles were identified as potent XO inhibitors via a fused-pharmacophore strategy based on the interaction modes of febuxostat and topiroxostat. Among them, compound 7i showed an IC50 value of 0.20 nM against XOR, which was superior to febuxostat and topiroxostat. Furthermore, 7i exhibited significant hypouricemic and serum XOR inhibitory effects in potassium oxonate induced hyperuricemia mouse models. A single-dose toxicity assessment of 7i showed no noticeable toxicity at the dose of 50 mg/kg. These results demonstrated that 7i could be a promising lead compound for the treatment of hyperuricemia and gout.
Asunto(s)
Gota , Hiperuricemia , Ratones , Animales , Febuxostat/farmacología , Xantina Deshidrogenasa/uso terapéutico , Hiperuricemia/inducido químicamente , Hiperuricemia/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Triazoles/farmacología , Triazoles/uso terapéutico , Gota/tratamiento farmacológico , Xantina OxidasaRESUMEN
Xanthine oxidase (XO) is an important target for the treatment of hyperuricemia and gout. Based on the two known non-purine xanthine oxidase inhibitors, febuxostat and topiroxostat, 14 oxadiazole derivatives have been designed and synthesized. These compounds have been evaluated against XO and five of them exhibited significant inhibitory activities at the concentrations below 10 µmol·L(-1).
Asunto(s)
Inhibidores Enzimáticos/farmacología , Supresores de la Gota/farmacología , Oxadiazoles/farmacología , Xantina Oxidasa/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Febuxostat , Gota , Supresores de la Gota/síntesis química , Humanos , HiperuricemiaRESUMEN
A series of linear peptides (6a-6o) were designed based on the known non-covalent 20S proteasome inhibitors TMC-95A and compound 5 via a fragment-based approach. These compounds were synthesized and evaluated against the chymotrypsin-like activity of the human 20S proteasome. Three of them (6d, 6e and 6k) were potent inhibitors with IC50 values at the submicromolar level. These three compounds were selective to the ß5-subunit and showed no obvious inhibition against trypsin-like and caspase-like activities of the human 20S proteasome. Docking study of the most potent compound 6e revealed its key interactions with the ß5-subunit of the 20S proteasome. These findings have provided a new chemical template for non-covalent proteasome inhibitors, which is ready for further structural optimization to improve both potency and subunit selectivity.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteasas/farmacología , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Sitios de Unión , Modelos Moleculares , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
OBJECTIVE: To study the long-term in vitro culture of human bone marrow mesenchymal stem cells (hMSC) and their phenotypical and functional properties. METHODS: Adherent hMSC colonies were digested by 0.25% trypsin-EDTA with a clone cycle for in vitro subculture. Flow cytometry was employed to examine the phenotypes of the cells. Their committed differentiation potential to neurons, clone-forming ability and growth curves were all investigated. RESULTS: hMSCs could be subcultured under this culture condition for 20 passages, expressing CD13, CD29 and CD59 but not CD11, CD14, CD31, CD34, CD45, CD80, CD86, CD117 and HLA-DR. The cells could be induced to differentiate into neurons when subcultured for 17 passages. CONCLUSION: hMSCs can be efficiently expanded under this culture condition, and the colony-derived hMSCs can maintain the differentiation potentials and retain their biological characteristics.
Asunto(s)
Células de la Médula Ósea/citología , Diferenciación Celular/fisiología , Neuronas/citología , Células Cultivadas , Humanos , Células Madre/citologíaRESUMEN
OBJECTIVE: To observe the influence of decreasing conditioning regimen intensity on the engraftment of HLA haplotype peripheral blood stem cell transplantation. METHOD: Twelve patients with leukemia, including 4 in complete remission, whose HLAs were full matched with donors, and 8 with refractory leukemia, whose HLAs were mismatched, were transplanted with G-CSF mobilized allogeneic peripheral blood stem cells after conditioned with a regimen consisting of fludarabine (30 mg/m(2) x 6 days), busulfan (4 mg/kg x 2 days) and cyclophosphamide (30 approximately 60 mg/kg x 2 days) (FBC). Donor lymphocytes were infused at day + 30, + 60 and + 90 after transplantation, respectively. Hematopoietic reconstitution was observed. Engraftment was documented by the analysis of short tandem repeats with polymerase chain reaction (STR-PCR). RESULT: Patients in HLA haplotype group received a mean number of 4.87 x 10(8)/kg donor mononuclear cells (MNC), with CD(34)(+) cells of 4.58 x 10(6)/kg and patients in HLA identical group a mean number of 4.85 x 10(8)/kg MNC with CD(34)(+) cells of 4.47 x 10(6)/kg. The mean time of white blood cell count more than 1.0 x 10(9)/L was 14 (10 approximately 18) days in HLA matched patients and 29 (11 approximately 90) days in HLA haplotype group. One three locus mismatched patient failed to engraft, but auto-hematopoiesis was recovered on day + 50. Full donor chimerism was observed in all patients except one with mixed chimera. The mixed chimera was converted into full donor chimera after three times donor lymphocyte infusion. One each died from severe acute GVHD, severe VOD and severe chronic GVHD in HLA haplotype group, and one from chronic GVHD in HLA identical group. CONCLUSION: Patients survived engraftment was not influenced by decreasing conditioning intensity as in this regimen. Haplotype stem cells could be engrafted durable in recipients by this regimen combined with donor lymphocyte infusion.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/uso terapéutico , Leucemia/terapia , Acondicionamiento Pretrasplante , Adolescente , Adulto , Busulfano/uso terapéutico , Ciclofosfamida/uso terapéutico , Femenino , Supervivencia de Injerto/efectos de los fármacos , Enfermedad Injerto contra Huésped/prevención & control , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Tolerancia al Trasplante/efectos de los fármacos , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoRESUMEN
OBJECTIVE: To observe the influence of adding anti-human thymocyte globulin (ATG) into conditioning regimen on graft-versus-host disease (GVHD) and life quality of the patients of allo-peripheral blood stem cell transplantation (PBSCT). METHODS: Patients were distributed into study (19 cases) and control (24 cases) groups at random. Median dose of rabbit ATG was added to the conditioning regimen based on the fludara, busufan and cyclophosphamide (FBC) in study group, and no ATG in the control group. Acute and chronic GVHD disease and Karnofsky scores were compared between two groups after allo-PBSCT. RESULTS: The patients in the study group received a mean of 6.0 (3 - 9) x 10(8)/kg mononucleated cells and 5.5 (4.5 - 7.5) x 10(6)/kg in the control group. The mean CD(34)(+) cells number was 5.5 (3.0 - 6.5) x 10(5)/kg in the study and 5.0 (3.0 - 7.0) x 10(6)/kg in the control group respectively. Eighteen patients in the study group and in the control group were successfully engrafted. The mean time of absolute neutrophil count recovered more than 500/ micro l was 13 days and 12 days respectively. Acute GVHD occurred in 6 patients of the study group, and 15 of the control group. Seven patients suffered from chronic GVHD and 14 got 90 Kanrofsky scores in a mean of 250 days follow-up in the study group, and 19 patients GVHD and 4 patients respectively in a mean of 440 days follow-up in the control group. There was a significant difference for acute and chronic GVHD and life quality between the two groups. CONCLUSIONS: Addition of anti-thymocyte globulin to the FBC conditioning regimen had no effect on stem cells engraftment but could decrease acute and chronic GVHD and improve patients life quality.
Asunto(s)
Suero Antilinfocítico/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre de Sangre Periférica , Linfocitos T/inmunología , Acondicionamiento Pretrasplante , Adolescente , Adulto , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped/etiología , Humanos , Leucemia/psicología , Leucemia/terapia , Masculino , Calidad de Vida , Trasplante HomólogoRESUMEN
In order to observe the curative and side effects in malignant hematologic diseases treated with autologous peripheral blood stem cell transplantation (auto-PBSCT) combined with halotype lymphocyte infusion, auto-PBSCs were mobilized, harvested and stored at -196 degrees C from patients in first CR or PR with intensive chemotherapy (Ara-C 1.0 g/m(2) x 5 days or cyclophosphamide 60 mg/kg x 2 days) and G-CSF. Unpurged auto-PBSCs were infused when patients received the conditioning regimen with busulfan, total irradiation or cyclophosphamide. Halotype lymphocytes [mean 5.0 x 10(7)/kg, (4.5 - 6.5) x 10(7)/kg] irradiated with 7.5 Gy were infused to patients when WBCs were more than 1 x 10(9)/L. Hematopoietic recovery and survival of patients were observed. The results showed that in 12 cases accepted this protocol, five patients with acute non-lymphocytic leukemia got to durable remission, of which 2 had durable remission of more than 50 months. One of three patients with non-Hodgkin's lymphoma IVb reached durable remission, and two relapsed and died on 4 and 6 months after treatment, respectively. Two CML patients were also achieved durable remission. One patient with multiple myeloma relapsed on 36 months later, but he still survived disease-free with treatment of thalidomide. In a follow-up survey of 25 months, the disease-free survival was 83%. No severe side effects were observed except platelet delayed recovery after halotype lymphocyte infusion. STR-PCR analysis showed that infused donor lymphocytes disappeared in 3 recipients at 72 hours after infusion. It is concluded that auto-PBSCT combined with halotype lymphocyte infusion could decrease the relapse of malignant hematologic diseases and improve the effect of auto-PBSCT. Recovery of platelet, however, could be delayed by halotype lymphocyte infusion.
Asunto(s)
Neoplasias Hematológicas/terapia , Transfusión de Linfocitos , Trasplante de Células Madre de Sangre Periférica , Adulto , Busulfano/uso terapéutico , Niño , Terapia Combinada , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/radioterapia , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Inducción de Remisión , Acondicionamiento Pretrasplante , Trasplante Autólogo , Resultado del TratamientoRESUMEN
BACKGROUND & OBJECTIVE: The complete remission of refractory leukemia treated with conventional chemotherapy is below 50 percent. The high dose chemotherapy can cause more mortality of patients with refractory leukemia. Cytolysis of leukemia cells induced by halpotype lymphocytes was observed in vitro in our previous experiment. In order to improve the complete remission of refractory leukemia and decrease the complication of chemotherapy,the authors treated the patients with refractory leukemia by combined chemotherapy and halpotype lymphocytes infusion and to assess the therapeutic effects and the side effects of this modality. METHODS: Sixteen patients with refractory leukemia were treated by combined chemotherapy. Halpotype lymphocytes irradiated by 7.5 Gygamma radial were infused when patient's white cells count was at the lowest after the chemotherapy. A mean number of 1x10(8)/kg (range:0.8-1.2x10(8)/kg) of halpotype lymphocytes irradiated by 7.5 Gygamma radial was infused. The side effects of infusion of halpotype lymphocyte and completed remission rate were observed. RESULTS: Out of thirteen patients with refractory acute non-lymphocyte leukemia, eleven cases got complete remission and two partial remissions. Out of three patients with refractory acute lymphocyte leukemia, two got complete remission and one no reaction. The total remission rate was 81.2%. No severe side effects and no transfusion related graft versus host disease was observed. CONCLUSION: The results show that chemotherapy combined with 7.5 Gy irradiated halpotype lymphocyte infusion could improve the complete remission of refractory leukemia and decrease the complications caused by chemotherapy.