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1.
Blood ; 133(15): 1619-1629, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30718230

RESUMO

Myelofibrosis in myeloproliferative neoplasms (MPNs) with mutations such as JAK2V617F is an unfavorable sign for uncontrollable disease progression in the clinic and is complicated with osteosclerosis whose pathogenesis is largely unknown. Because several studies have revealed that macrophages are an indispensable supporter for bone-forming osteoblasts, we speculated that macrophages might play a significant role in the proliferation of collagen-producing myofibroblasts in marrow fibrotic tissues. Here, we show that myelofibrosis critically depends on macrophages whose differentiation is skewed by vitamin D receptor (VDR) signaling. In our novel myelofibrosis model established by transplantation of VDR+/+ hematopoietic stem/progenitor cells into VDR-/- mice, donor-derived F4/80+ macrophages proliferated together with recipient-derived α-smooth muscle actin-positive myofibroblasts, both of which comprised fibrotic tissues with an indistinguishable spindle-shaped morphology. Interfering VDR signals, such as low vitamin D diet and VDR deficiency in donor cells as well as macrophage depletion prevented myelofibrosis in this model. These interventions also ameliorated myelofibrosis in JAK2V617F-driven murine MPNs likely in a transforming growth factor-ß1- or megakaryocyte-independent manner. These results suggest that VDR and macrophages may be novel therapeutic targets for MPNs with myelofibrosis.


Assuntos
Diferenciação Celular , Macrófagos/patologia , Osteosclerose/etiologia , Mielofibrose Primária/etiologia , Receptores de Calcitriol , Animais , Proliferação de Células , Modelos Animais de Doenças , Transplante de Células-Tronco Hematopoéticas , Xenoenxertos , Humanos , Camundongos , Camundongos Knockout , Miofibroblastos/patologia , Mielofibrose Primária/complicações , Mielofibrose Primária/patologia , Mielofibrose Primária/prevenção & controle , Receptores de Calcitriol/metabolismo , Transdução de Sinais , Deficiência de Vitamina D
2.
J Gastroenterol ; 53(1): 140-151, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28669071

RESUMO

BACKGROUND: We aimed to investigate the efficacy of canagliflozin (based on its effect on liver function and blood glucose levels) and its safety in high alanine aminotransferase (ALT) patients (ALT >30 U/L). METHODS: This post hoc analysis of canagliflozin in type 2 diabetes mellitus (T2DM) patients was divided into Study 1 (pooled analysis of 12- and 24-week placebo-controlled, monotherapy studies) and Study 2 (52-week monotherapy/combination therapy study). The canagliflozin 100 mg group data were compared with placebo or baseline ALT subgroup (baseline ALT >30 or ≤30 U/L) data. The primary endpoint was change in ALT level from baseline. Secondary endpoints were changes in efficacy-related parameters. Adverse events (AEs) were evaluated. RESULTS: The mean ALT change at 12 weeks was -10.3 ± 11.7 and -3.2 ± 17.6 U/L in the canagliflozin vs. placebo group in the high ALT subgroup (P = 0.0206); no significant difference was shown in the low ALT subgroup (Study 1). In both ALT subgroups, glycosylated hemoglobin (HbA1c) and body weight were significantly reduced in the canagliflozin vs. placebo group (all P < 0.0001). The mean change in ALT at 52 weeks was -16.0 ± 18.8 U/L in the high ALT subgroup (P < 0.0001, Study 2). The incidence of AEs or serious AEs in the high ALT subgroup in the canagliflozin group was similar to that in the placebo group (Study 1) or low ALT subgroup (Studies 1 and 2). CONCLUSIONS: In T2DM patients with impaired liver function, canagliflozin may improve liver function, reduce HbA1c and body weight, and be well tolerated.


Assuntos
Canagliflozina/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Adulto , Idoso , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Canagliflozina/efeitos adversos , Canagliflozina/farmacologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Hepatopatias/tratamento farmacológico , Hepatopatias/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
3.
Blood ; 129(5): 587-597, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-27827823

RESUMO

Granulocyte colony-stimulating factor (G-CSF) is widely used for peripheral blood stem/progenitor mobilization. G-CSF causes low-grade fever that is ameliorated by nonsteroidal anti-inflammatory drugs (NSAIDs), suggesting the activation of arachidonic acid (AA) cascade. How G-CSF regulated this reaction was assessed. G-CSF treatment in mice resulted in fever, which was canceled in prostaglandin E synthase (mPGES-1)-deficient mice. Mobilization efficiency was twice as high in chimeric mice lacking mPGES-1, specifically in hematopoietic cells, suggesting that prostaglandin E2 (PGE2) from hematopoietic cells modulated the bone marrow (BM) microenvironment. Neutrophils from steady-state BM constitutively expressed mPGES-1 and significantly enhanced PGE2 production in vitro by ß-adrenergic stimulation, but not by G-CSF, which was inhibited by an NSAID. Although neutrophils expressed all ß-adrenergic receptors, only ß3-agonist induced this phenomenon. Liquid chromatography-tandem mass spectrometry traced ß-agonist-induced PGE2 synthesis from exogenous deuterium-labeled AA. Spontaneous PGE2 production was highly efficient in Gr-1high neutrophils among BM cells from G-CSF-treated mice. In addition to these in vitro data, the in vivo depletion of Gr-1high neutrophils disrupted G-CSF-induced fever. Furthermore, sympathetic denervation eliminated both neutrophil priming for PGE2 production and fever during G-CSF treatment. Thus, sympathetic tone-primed BM neutrophils were identified as one of the major PGE2 producers. PGE2 upregulated osteopontin, specifically in preosteoblasts, to retain progenitors in the BM via EP4 receptor. Thus, the sympathetic nervous system regulated neutrophils as an indispensable PGE2 source to modulate BM microenvironment and body temperature. This study provided a novel mechanistic insight into the communication of the nervous system, BM niche components, and hematopoietic cells.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Dinoprostona/metabolismo , Febre/induzido quimicamente , Fator Estimulador de Colônias de Granulócitos/farmacologia , Neutrófilos/efeitos dos fármacos , Agonistas Adrenérgicos beta/farmacologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Linhagem Celular , Febre/genética , Deleção de Genes , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Neutrófilos/metabolismo , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/metabolismo , Receptores Adrenérgicos beta/metabolismo
4.
Int J Hematol ; 105(5): 646-657, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28013483

RESUMO

We report a pilot series of five patients who received stem cell transplantation (SCT) from a spouse for post-transplant relapse or rejection. The inclusion criterion regarding HLA disparities was three or fewer antigen mismatches in the graft-versus-host direction at the HLA-A, B, and DR loci. Four patients received spousal SCT as a third transplant attempt after post-transplant relapse and one as rescue for graft rejection. The reduced intensity conditioning (RIC) regimen consisted of fludarabine, melphalan, and anti-thymocyte globulin (ATG) with 3 Gy of total body irradiation (TBI) for relapse cases and ATG plus 4 Gy of TBI for the rejection case. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, methylprednisolone, and mycophenolate mofetil. Peripheral blood stem cells were transplanted. Granulocyte engraftment was achieved in all cases between days 9 and 11 (median, 10) with complete spousal chimerism. In three of the five patients, no acute GVHD was observed, while one case developed grade III GVHD and one case grade IV. All four patients evaluable for the anti-leukemic effect achieved complete remission; however, all relapsed between 106 and 334 day post-transplant, and died between days 152 and 548. We suggest that spousal SCT can be performed as a repetitive SCT using a RIC regimen with low-dose ATG and steroid-containing GVHD prophylaxis.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Cônjuges , Adulto , Aloenxertos , Soro Antilinfocitário/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Evolução Fatal , Feminino , Antígenos HLA , Histocompatibilidade , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Recidiva , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
5.
Ann Hematol ; 94(10): 1707-15, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26193851

RESUMO

Human leukocyte antigen (HLA)-haploidentical stem cell transplantation (haplo-SCT) is associated with a high incidence of cytomegalovirus (CMV) infection, probably originating from the delayed reconstitution of CMV-specific T cell immunity. There have been few reports on the presence of CMV-specific cytotoxic T lymphocytes (CMV-CTLs) after haplo-SCT. We have studied CMV-specific immune reconstitution by measuring the absolute number of CMV-CTLs using a flow cytometry method with HLA-A2-restricted NLVPMVATV peptide dextramers. We examined the association between reconstitution patterns of CMV-CTLs and the duration of CMV antigenemia in 15 patients who underwent first allogeneic SCT from HLA-haploidentical-related donors with HLA-A2. In seven and eight patients, CMV antigenemia consecutively resolved for more than 4 weeks (the CMV antigenemia 'resolved' group) and intermittently persisted (the CMV antigenemia 'persistent' group) during a 100-day observation period, respectively. The group of the seven patients, in whom levels of CMV antigenemia were reduced to zero, had a significantly lower maximum level of CMV antigenemia than the CMV antigenemia persistent group. In contrast, the CMV antigenemia persistent group had a significantly higher maximum level of CMV-CTLs, but the levels took longer to peak. Despite no difference in general lymphocyte recovery between the two groups, the CMV antigenemia resolved group had significantly higher median CMV-CTL counts than the CMV antigenemia persistent group at 6 weeks after onset of CMV infection. Flow cytometry analysis of CMV-CTLs is a convenient method of monitoring reconstitution of CMV-specific lymphocyte immunity following haplo-SCT.


Assuntos
Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfócitos T Citotóxicos/imunologia , Adulto , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/mortalidade , Feminino , Seguimentos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida/tendências , Linfócitos T Citotóxicos/virologia , Transplante Homólogo
6.
Biol Blood Marrow Transplant ; 21(8): 1495-505, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25921715

RESUMO

This prospective, multicenter phase I/II study of unmanipulated HLA-haploidentical reduced-intensity stem cell transplantation using a low dose of anti-T lymphocyte globulin (ATG) and steroid was conducted in 5 institutions in Japan. Thirty-four patients with hematologic malignancies who were in an advanced stage or at a high risk of relapse at the time of transplantation were enrolled. Among them, 7 patients underwent transplantation as a second transplantation because of relapse after the previous allogeneic stem cell transplantation. The conditioning regimen consisted of fludarabine, busulfan, and ATG (Fresenius, 8 mg/kg), and graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). All patients except 1 (97.1%) achieved donor-type engraftment. Rapid hematopoietic engraftment was achieved, with neutrophils > .5 × 10(9)/L on day 11 and platelets > 20 × 10(9)/L on day 17.5. Treatment was started for ≥grade I GVHD, and the cumulative incidences of acute grade I and grade II to IV GVHD were 27.5% and 30.7%, respectively. The incidence of chronic GVHD (extensive type) was 20%. Fourteen patients (41.2%) had a relapse. The cumulative incidence of transplantation-related mortality at 1 year after transplantation was 26.5%. The survival rate at day 100 was 88.2%. The survival rates at 1 year for patients with complete remission (CR)/chronic phase (n = 8) and non-CR (n = 26) status before transplantation were 62.5% and 42.3%, respectively. In the multivariate analysis, non-CR status before transplantation was the only factor significant prognostic factor of increased relapse (P = .0424), which tended to be associated with a lower survival rate (P = .0524). This transplantation protocol is safe and feasible, if a suitable donor is not available in a timely manner. As the main cause of death was relapse and not GVHD, more intensified conditioning or attenuation of GVHD prophylaxis and/or donor lymphocyte infusion may be desirable for patients with non-CR status.


Assuntos
Soro Antilinfocitário/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Esteroides/uso terapêutico , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Adulto , Soro Antilinfocitário/administração & dosagem , Soro Antilinfocitário/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bussulfano/efeitos adversos , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Esteroides/efeitos adversos , Vidarabina/efeitos adversos , Vidarabina/uso terapêutico
7.
Rinsho Ketsueki ; 55(6): 697-702, 2014 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-24975340

RESUMO

We report two patients (70- and 49-year-old Japanese men) with acute exacerbation of chronic idiopathic thrombocytopenic purpura (ITP) and deep venous thrombosis of the lower extremities. Both were successfully managed with thrombopoietin receptor agonist (TPO-RA) administration. Both had ITP refractory to steroid treatment. Their immature platelet fraction (absolute-IPF) counts were increased and paralleled the platelet recoveries after TPO-RA (eltrombopag and romiplostim, respectively) without progression of thrombosis. Although ITP has recently been evaluated as a thrombophilic disorder, reports on acute exacerbation of ITP with newly diagnosed thrombosis are limited, and the pathophysiology and association between ITP and thrombosis remain to be elucidated. Moreover, the influences of TPO-RA on thrombosis are still controversial. To our knowledge, this is the first case report describing patients with exacerbation of ITP who developed thrombosis and were treated with TPO-RA. The outcomes of our cases underscore the importance of monitoring thrombosis and not delaying the initiation of anticoagulation treatment during the use of TPO-RA.


Assuntos
Extremidade Inferior , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores de Trombopoetina/agonistas , Trombose Venosa/tratamento farmacológico , Varfarina/uso terapêutico , Idoso , Anticoagulantes , Humanos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/complicações , Trombose Venosa/complicações
8.
Int J Hematol ; 99(4): 463-70, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24599414

RESUMO

In the present study, we analyzed the kinetics of serum soluble interleukin-2 receptor (sIL-2R) using data from 77 patients undergoing HLA-haploidentical transplantation using reduced-intensity conditioning (RIC), who were at an advanced stage or at high risk for relapse, to clarify the usefulness of sIL-2R as a biomarker of acute graft-versus-host disease (GVHD). Anti-T-lymphocyte globulin and methylprednisolone were used as GVHD prophylaxis. While the median sIL-2R in 38 patients not developing GVHD was suppressed at levels <740 U/ml, sIL-2R in 25 patients developing severe GVHD peaked on day 11 (1,663 U/ml), and thereafter decreased to <1,000 U/ml after day 30. The occurrence of GVHD was not limited to times of high sIL-2R level, but occurred at any time point on the sIL-2R curve. Most patients developing GVHD, however, experienced a higher sIL-2R level early in their transplant course. The combination of RIC and glucocorticoids sufficiently suppressed sIL-2R levels after HLA-haploidentical transplantation. In a multivariate analysis to identify factors associated with GVHD, day 7 sIL-2R >810 U/ml was the only factor significantly associated with the occurrence of severe GVHD (p = 0.0101).


Assuntos
Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Haplótipos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Receptores de Interleucina-2/sangue , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Adulto Jovem
11.
Eur J Pharmacol ; 723: 207-15, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24309217

RESUMO

Dipeptidyl peptidase-4 (DPP-4)-deficient mice exhibit prevention of obesity with increased energy expenditure, whereas currently available DPP-4 inhibitors do not induce similar changes. We investigated the impact of the novel DPP-4 inhibitor teneligliptin on body weight, energy expenditure, and obesity-related manifestations in diet-induced obese mice. Six-weeks-old C57BL/6N mice were fed a high-fat diet (60%kcal fat) ad libitum and administered teneligliptin (30 or 60mg/kg) via drinking water for 10 weeks. Mice fed a high-fat diet showed accelerated body weight gain. In contrast, compared with the vehicle group, the administration of teneligliptin reduced body weight to 88% and 71% at dose of 30mg/kg/day and 60mg/kg/day, respectively. Although there was no change in locomotor activity, indirect calorimetry studies showed that teneligliptin (60mg/kg) increased oxygen consumption by 22%. Adipocyte hypertrophy and hepatic steatosis induced by a high-fat diet were suppressed by teneligliptin. The mean adipocyte size in the 60-mg/kg treatment group was 44% and hepatic triglyceride levels were 34% of the levels in the vehicle group. Furthermore, treatment with teneligliptin (60mg/kg) reduced plasma levels of insulin to 40% and increased the glucose infusion rate to 39%, as measured in the euglycemic clamp study, indicating its beneficial effect on insulin resistance. We showed for the first time that the DPP-4 inhibitor prevents obesity and obesity-related manifestations with increased energy expenditure. Our findings suggest the potential utility of teneligliptin for the treatment of a broad spectrum of metabolic disorders related to obesity beyond glycemic control.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Obesidade/tratamento farmacológico , Pirazóis/uso terapêutico , Tiazolidinas/uso terapêutico , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/patologia , Animais , Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica , Inibidores da Dipeptidil Peptidase IV/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Pirazóis/farmacologia , Tiazolidinas/farmacologia , Ganho de Peso/efeitos dos fármacos
13.
Am J Hematol ; 88(10): 853-7, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23757212

RESUMO

Severe peripheral neuropathy and myelopathy are rare complications after stem cell transplantation (SCT). In our institution, seven patients of precursor T lymphoblastic leukemia/lymphoma without the central nervous involvement who had been treated by nelarabine to control their diseases received SCT from HLA-haploidentical familial donor (HLA-haploidentical SCT) with the conditioning regimen including high-dose cytarabine (HDAC). Three of evaluable six patients developed irreversible paresthesia and muscle weakness in both lower extremities after neutrophil engraftment. The results of nerve conduction studies and short latency somatosensory evoked potentials suggested axonal neuropathy of both lower extremities in all three patients and myelopathy in two patients. Negative findings of PET-CT, and analyses of repeated cerebrospinal fluid samples and the bone marrow also indicated that tumor involvement was improbable. In all three patients, the symptoms worsened or persisted despite administration of corticosteroid and intravenous immunoglobulin. The high frequency of the neurological symptoms in our patients previously treated by nelarabine strongly suggested the association of the nelarabine use. Furthermore, the HLA-haploidentical SCT setting and the use of a potentially neurotoxic agent, HDAC might augment the neurotoxicity of nelarabine. It may be desirable that HLA-haploidentical SCT candidates avoid receiving nelarabine.


Assuntos
Arabinonucleosídeos/efeitos adversos , Extremidade Inferior , Debilidade Muscular , Parestesia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Doadores de Tecidos , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Adulto , Arabinonucleosídeos/administração & dosagem , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Feminino , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/efeitos adversos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Extremidade Inferior/patologia , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/induzido quimicamente , Debilidade Muscular/patologia , Debilidade Muscular/fisiopatologia , Parestesia/induzido quimicamente , Parestesia/patologia , Parestesia/fisiopatologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Transplante Homólogo
14.
Support Care Cancer ; 21(8): 2161-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23475197

RESUMO

PURPOSE: The aim of this study was to investigate the relationship between corticosteroid dose and degree of physical function decrease in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients during the early stage of recovery. We further investigated the confounding factors affecting loss of physical function. METHODS: The study included 113 patients who underwent allo-HSCT between July 2007 and April 2012 at Hyogo College of Medicine Hospital in Japan. Physical function was assessed using tests for hand-grip strength, knee-extensor strength, and the 6-min walk test (6MWT). Fatigue was measured using the Piper Fatigue Scale. Total corticosteroid dose, frequency of physical therapy, body weight, and nutritional status were also collected from medical records. RESULTS: Total corticosteroid dose was correlated with decrease of hand-grip and knee-extensors strength (P < 0.01) but was not correlated with 6MWT performance. Results of multivariate analysis confirmed that low physical function was associated not only with high corticosteroid dose but also with low frequency of physical therapy, increase in fatigue, and body weight loss (P < 0.05). Also, hemoglobin levels were associated with 6MWT (P < 0.05). CONCLUSIONS: This study showed the relationship between corticosteroid dose and declines in physical function and also showed other clinical factors affecting loss of physical function among allo-HSCT patients. Our results indicate that the effectiveness of rehabilitation may be influenced by corticosteroid treatment.


Assuntos
Corticosteroides/administração & dosagem , Doenças Hematológicas/cirurgia , Transplante de Células-Tronco Hematopoéticas , Qualidade de Vida , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Peso Corporal , Relação Dose-Resposta a Droga , Fadiga/diagnóstico , Fadiga/fisiopatologia , Feminino , Força da Mão/fisiologia , Doenças Hematológicas/fisiopatologia , Doenças Hematológicas/reabilitação , Humanos , Japão , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Modalidades de Fisioterapia , Estudos Prospectivos , Transplante Homólogo , Caminhada/fisiologia , Adulto Jovem
15.
Biochem Biophys Res Commun ; 434(2): 191-6, 2013 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-23501107

RESUMO

In recent years, various dipeptidyl peptidase IV (DPP-4) inhibitors have been released as therapeutic drugs for type 2 diabetes in many countries. In spite of their diverse chemical structures, no comparative studies of their binding modes in the active site of DPP-4 have been disclosed. We determined the co-crystal structure of vildagliptin with DPP-4 by X-ray crystallography and compared the binding modes of six launched inhibitors in DPP-4. The inhibitors were categorized into three classes on the basis of their binding subsites: (i) vildagliptin and saxagliptin (Class 1) form interactions with the core S1 and S2 subsites and a covalent bond with Ser630 in the catalytic triad; (ii) alogliptin and linagliptin (Class 2) form interactions with the S1' and/or S2' subsites in addition to the S1 and S2 subsites; and (iii) sitagliptin and teneligliptin (Class 3) form interactions with the S1, S2 and S2 extensive subsites. The present study revealed that the additional interactions with the S1', S2' or S2 extensive subsite may increase DPP-4 inhibition beyond the level afforded by the fundamental interactions with the S1 and S2 subsites and are more effective than forming a covalent bond with Ser630.


Assuntos
Adamantano/análogos & derivados , Domínio Catalítico , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Nitrilos/química , Pirrolidinas/química , Adamantano/química , Cristalografia por Raios X , Dipeptídeos/química , Humanos , Complexos Multiproteicos/análise , Complexos Multiproteicos/química , Oligopeptídeos/química , Piperidinas/química , Ligação Proteica , Mapeamento de Interação de Proteínas , Pirazinas/química , Pirazóis/química , Serina/química , Fosfato de Sitagliptina , Relação Estrutura-Atividade , Tiazolidinas/química , Triazóis/química , Uracila/análogos & derivados , Uracila/química , Vildagliptina , Difração de Raios X
16.
Psychooncology ; 22(5): 1159-66, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22736382

RESUMO

OBJECTIVE: The aim of this study was to examine gender differences in quality of life (QOL), physical function and psychological status before and in the early phase after allogeneic haematopoietic stem cell transplantation (allo-HSCT). METHODS: One hundred patients (66 men, 34 women) who underwent allo-HSCT between July 2007 and June 2011 at Hyogo College of Medicine Hospital were included in this study. Patients were evaluated for health-related QOL using the Medical Outcome Study 36-item Short Form Health Survey; exercise capacity was measured with the 6-min walk test, hand grip strength and knee extensor strength. Fatigue and psychological status were measured by the Piper Fatigue Scale and Hospital Anxiety and Depression Scale, respectively. RESULTS: Women had significantly lower scores for physical function and general health on health-related QOL tests compared with men (p < 0.01). No difference between genders was found in decline of physical function. In women, exercise capacity was strongly associated with QOL (p < 0.01). In men, depression and anxiety were closely related to QOL (p < 0.01). CONCLUSIONS: Gender-appropriate rehabilitation in allo-HSCT patients is important. Women may need more endurance exercises and training for activities of daily life. Men may need rehabilitation including a psychological approach.


Assuntos
Transplante de Células-Tronco Hematopoéticas/psicologia , Qualidade de Vida/psicologia , Adaptação Psicológica , Adulto , Ansiedade/etiologia , Depressão/etiologia , Fadiga/etiologia , Feminino , Força da Mão , Nível de Saúde , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular , Resistência Física , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Fatores Sexuais , Transplante Homólogo
17.
Int J Hematol ; 97(2): 287-90, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23271411

RESUMO

Cytomegalovirus (CMV) meningoencephalitis is a rather rare complication after allogeneic stem cell transplantation. We describe here the case of a 59-year-old man with acute myeloid leukemia who developed CMV meningoencephalitis after cord blood transplantation. The patient presented with a sudden onset of neurological symptoms, such as convulsion, on day 37. The analysis of cerebrospinal fluid (CSF) sample revealed an increase in the number of cells, which were of donor (cord blood) origin, consisting mainly of T cells. No bacteria were detected in the CSF sample. Real-time PCR analysis revealed that the CSF sample was positive for CMV, but was negative for HHV-6, adenovirus, or BK virus. The patient was diagnosed with CMV meningoencephalitis and received cidofovir. His neurological symptoms were gradually improved and completely disappeared by day 60. CMV-specific dextramer-positive CD8(+) T cells were detected in the peripheral blood and CSF samples, with the frequency being much higher in the CSF. To our knowledge, this is the first report on the appearance of CMV-specific T cells in CSF samples from a patient with CMV meningoencephalitis. Cord blood-derived CMV-specific T cells may develop early after transplantation, enter the intrathecal compartment, and likely contribute to the regulation of CMV-meningoencephalitis.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/transmissão , Citomegalovirus/imunologia , Meningoencefalite/etiologia , Meningoencefalite/transmissão , Subpopulações de Linfócitos T/imunologia , Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/imunologia , Citomegalovirus/genética , Infecções por Citomegalovirus/diagnóstico , Humanos , Masculino , Meningoencefalite/diagnóstico , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/metabolismo , Doadores de Tecidos
18.
Eur J Pharmacol ; 696(1-3): 194-202, 2012 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-23022337

RESUMO

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been demonstrated to improve glycemic control, in particular postprandial hyperglycemic control, in patients with type 2 diabetes. Teneligliptin is a novel chemotype prolylthiazolidine-based DPP-4 inhibitor. The present study aimed to characterize the pharmacological profiles of teneligliptin in vitro and in vivo. Teneligliptin competitively inhibited human plasma, rat plasma, and human recombinant DPP-4 in vitro, with IC(50) values of approximately 1 nmol/l. Oral administration of teneligliptin in Wistar rats resulted in the inhibition of plasma DPP-4 with an ED(50) of 0.41 mg/kg. Plasma DPP-4 inhibition was sustained even at 24h after administration of teneligliptin. An oral carbohydrate-loading test in Zucker fatty rats showed that teneligliptin at ≥ 0.1mg/kg increased the maximum increase in plasma glucagon-like peptide-1 and insulin levels, and reduced glucose excursions. This effect was observed over 12h after a dose of 1mg/kg. An oral fat-loading test in Zucker fatty rats also showed that teneligliptin at 1mg/kg reduced triglyceride and free fatty acid excursions. In Zucker fatty rats, repeated administration of teneligliptin for two weeks reduced glucose excursions in the oral carbohydrate-loading test and decreased the plasma levels of triglycerides and free fatty acids under non-fasting conditions. The present studies indicate that teneligliptin is a potent, competitive, and long-lasting DPP-4 inhibitor that improves postprandial hyperglycemia and dyslipidemia by both single and repeated administrations.


Assuntos
Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hiperglicemia/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/uso terapêutico , Pirazóis/uso terapêutico , Tiazolidinas/uso terapêutico , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/sangue , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeo 1 Semelhante ao Glucagon/sangue , Hiperglicemia/sangue , Hipertrigliceridemia/sangue , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Insulina/sangue , Masculino , Nitrilos/farmacologia , Pirazinas/farmacologia , Pirazóis/farmacologia , Pirrolidinas/farmacologia , Ratos , Ratos Wistar , Ratos Zucker , Fosfato de Sitagliptina , Tiazolidinas/farmacologia , Triazóis/farmacologia , Vildagliptina
19.
Transpl Immunol ; 27(4): 162-5, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23000337

RESUMO

Hematopoietic stem cell transplantation (HSCT) from an HLA haploidentical family donor is an option for patients who do not have a full HLA matched donor and lack the time to find an unrelated one [1,2]. Furthermore, it may facilitate a powerful graft versus leukemia/lymphoma (GVL) effect to help combat hematological malignancies by directly targeting the mismatched HLA expressed on leukemia/lymphoma cells [3]. On the contrary, leukemia/lymphoma cells escape from the surveillance of the donor-derived GVL effect by losing the target HLA (mismatched HLA in GVH direction). This mechanism has been called loss of heterozygosity (LOH) in the HLA gene region on chromosome 6 [4,5]. Taking the above into account, in this case report, we present a case of lymphoma with monosomy 6, which means natural LOH of HLA, and suggest that selection of a haploidentical family donor matched with the missing HLA haplotype seems to be very effective.


Assuntos
Cromossomos Humanos Par 6/genética , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/terapia , Monossomia , Feminino , Efeito Enxerto vs Tumor/genética , Efeito Enxerto vs Tumor/imunologia , Haplótipos , Teste de Histocompatibilidade , Humanos , Perda de Heterozigosidade , Linfoma Difuso de Grandes Células B/genética , Masculino , Linhagem , Indução de Remissão , Doadores de Tecidos
20.
Bioorg Med Chem ; 20(19): 5705-19, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22959556

RESUMO

Dipeptidyl peptidase IV (DPP-4) inhibition is suitable mechanism for once daily oral dosing regimen because of its low risk of hypoglycemia. We explored linked bicyclic heteroarylpiperazines substituted at the γ-position of the proline structure in the course of the investigation of l-prolylthiazolidines. The efforts led to the discovery of a highly potent, selective, long-lasting and orally active DPP-4 inhibitor, 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine (8 g), which has a unique structure characterized by five consecutive rings. An X-ray co-crystal structure of 8 g in DPP-4 demonstrated that the key interaction between the phenyl ring on the pyrazole and the S(2) extensive subsite of DPP-4 not only boosted potency, but also increased selectivity. Compound 8 g, at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats. Compound 8 g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Pirazóis/química , Pirazóis/uso terapêutico , Tiazolidinas/química , Tiazolidinas/uso terapêutico , Animais , Glicemia/metabolismo , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/enzimologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacologia , Teste de Tolerância a Glucose , Haplorrinos , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Masculino , Simulação de Acoplamento Molecular , Pirazóis/farmacocinética , Pirazóis/farmacologia , Ratos , Ratos Wistar , Ratos Zucker , Tiazolidinas/farmacocinética , Tiazolidinas/farmacologia
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