RESUMO
In previous work, we discovered a lead compound and conducted initial SAR studies on a novel series of dioxotriazines to identify the compound as one of the P2X3 receptor antagonists. This compound showed high P2X3 receptor selectivity and a strong analgesic effect. Although not selected for clinical development, the compound was evaluated from various aspects as a tool compound. In the course of the following study, the molecular structures of the dioxotriazines were modified based on pharmacokinetic/pharmacodynamic (PK/PD) analyses. As a result of these SAR studies, Sivopixant (S-600918) was identified as a clinical candidate with potent and selective antagonistic activity (P2X3 IC50, 4.2 nM; P2X2/3 IC50, 1100 nM) and a strong analgesic effect in the rat partial sciatic nerve ligation model (Seltzer model) of allodynia (ED50, 0.4 mg/kg).
Assuntos
Compostos de Anilina/farmacologia , Descoberta de Drogas , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/farmacologia , Receptores Purinérgicos P2X3/metabolismo , Triazinas/farmacologia , Compostos de Anilina/síntese química , Compostos de Anilina/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/químicaRESUMO
BACKGROUND: Transfusion-associated circulatory overload (TACO) is an adverse reaction associated with a high risk of mortality. The actual incidence of TACO and hypertension associated with transfusion in Japan is unknown. METHODS: A multicentre retrospective observational study was conducted across 23 institutions during the 1-year period of 2016. Patients were included if they developed TACO or their blood pressure (either systolic or diastolic) increased by at least 30 mmHg during the transfusion. TACO was confirmed by the primary physicians and transfusion medicine teams and recorded in the data on passive surveillance, and additional data were extracted from electronic medical records. RESULTS: In our patient cohort of 31 384 patients who underwent transfusion, the incidence of TACO and hypertension was 0·03% and 0·2%, respectively. However, 43% of the participating institutions didn't report any cases. When comparing risk factors between the TACO and hypertension groups, there were significant differences in comorbidities, such as abnormal findings on chest x-ray. Significant differences between the two groups were observed post-transfusion pulse rate, body temperature and oxygen saturation (P < 0·01). In the group of patients with hypertension, the level of BNP increased significantly after transfusion in 45% (5/11) of the patients. We identified 4 patients in the hypertension group who met the new ISBT's TACO criteria. CONCLUSION: Our study suggests that more attention should be given to TACO in Japan, particularly in terms of improving surveillance systems. For the early diagnosis of TACO, it is crucial to carefully monitor vital signs including blood pressure.
Assuntos
Hipertensão , Reação Transfusional , Transfusão de Sangue , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/etiologia , Japão/epidemiologia , Estudos RetrospectivosRESUMO
Plasma removal by washing platelet concentrates (PCs) is effective in preventing adverse reactions to PC transfusions. The Japanese Red Cross Society (JRCS) started releasing washed PCs (WPCs) as a commercially approved blood product in September 2016. This retrospective multicenter study investigated the change in the number of transfused WPCs and the impact on the incidence of adverse reactions to PCs before and after the release. The numbers and types of transfused PCs and the adverse reactions to the PCs for a year before the start of the WPC release and for a year after the release were reported by 27 medical institutes in Japan. Transfusion information for approximately 8% of the amount of PCs supplied in Japan was analyzed during the study period. After the start of WPC release by the JRCS, the number of transfused WPCs doubled. The rate of adverse reactions to PCs decreased significantly (p = 0.0223), from 4.30% before the release to 4.05% after the release. The rates of adverse reactions to unwashed and WPCs were 4.13% and 0.84%, respectively. Allergic adverse reactions were significantly decreased after the release (3.60% before versus 3.37% after). No severe allergic reactions to WPCs were reported. The release of WPCs by the JRCS significantly reduced transfusion-related adverse reactions to PCs in Japan.
Assuntos
Transfusão de Sangue/métodos , Reação Transfusional/complicações , Plaquetas , Feminino , Humanos , Japão , Estudos RetrospectivosRESUMO
Benzo-18-crown-6 ether resin embedded in porous silica beads was synthesized and used as the packing material for chromatographic separation of (48)Ca isotope. The aim of the present work is to develop efficient isotope enrichment process for double ß decay nuclide (48)Ca. To this end, ethanol/HCl mixed solvent was selected as the medium for the chromatographic separation. Adsorption of calcium on the resin was studied at different HCl concentrations and different ethanol mixing ratios in batch-wise experiments. A very interesting phenomenon was observed; Ca adsorption is controlled not by the overall HCl concentration of the mixed solvent, but by the initial concentration of added HCl solution. Calcium break-through chromatography experiments were conducted by using 75v/v% ethanol/25v/v% 8M HCl mixed solvent at different flow rates. The isotope separation coefficient between (48)Ca and (40)Ca was determined as 3.8×10(-3), which is larger than that of pure HCl solution system. Discussion is extended to the chromatographic HETP, height equivalent to a theoretical plate.
Assuntos
Isótopos de Cálcio/isolamento & purificação , Éteres de Coroa/química , Etanol , Ácido Clorídrico , Dióxido de Silício/química , Adsorção , Cromatografia Líquida , SolventesRESUMO
Transplantation of peripheral blood mononuclear cells (PBMNCs) is a promising therapeutic approach for the treatment of hindlimb ischemia. However, insufficient angiogenesis in ischemic hindlimb after cell transplantation reduces the importance and practicality of this approach. Previously, we demonstrated using mouse models that hypoxic preconditioning augmented the cellular functions of rodent PBMNCs, such as increased cell adhesion capacity and accelerated neovascularization in ischemic hindlimb. To test the clinical application of this therapeutic strategy in this study, we investigated whether the protocol of hypoxic preconditioning, which was established in a condition of 2% O2 for 24 h, can be made available for human PBMNCs (hPBMNCs). In addition, we grafted preconditioned hPBMNCs in a hindlimb ischemia mouse model. Hypoxic preconditioning enhanced cell adhesion capacity and oxidative stress resistance in hPBMNCs. We also observed an up-regulation of platelet endothelial cell adhesion molecule-1 (PECAM-1) in hPBMNCs by hypoxic preconditioning. Furthermore, preconditioned hPBMNCs significantly recovered limb blood flow in ischemic mice after transplantation. These results indicate that our established preconditioning protocol is available for hPBMNCs to effectively reinforce multiple cellular functions. Taken together with our series of study, we believe that this simple but powerful therapeutic strategy will be helpful in curing patients with severe hindlimb ischemia.
RESUMO
Peripheral blood mononuclear cell (PBMNC) is one of powerful tools for therapeutic angiogenesis in hindlimb ischemia. However, traditional approaches with transplanted PBMNCs show poor therapeutic effects in severe ischemia patients. In this study, we used autograft models to determine whether hypoxic pretreatment effectively enhances the cellular functions of PBMNCs and improves hindlimb ischemia. Rabbit PBMNCs were cultured in the hypoxic condition. After pretreatment, cell adhesion, stress resistance, and expression of angiogenic factor were evaluated in vitro. To examine in vivo effects, we autografted preconditioned PBMNCs into a rabbit hindlimb ischemia model on postoperative day (POD) 7. Preconditioned PBMNCs displayed significantly enhanced functional capacities in resistance to oxidative stress, cell viability, and production of vascular endothelial growth factor. In addition, autologous transplantation of preconditioned PBMNCs significantly induced new vessels and improved limb blood flow. Importantly, preconditioned PBMNCs can accelerate vessel formation despite transplantation on POD 7, whereas untreated PBMNCs showed poor vascularization. Our study demonstrated that hypoxic preconditioning of PBMNCs is a feasible approach for increasing the retention of transplanted cells and enhancing therapeutic angiogenesis in ischemic tissue.
Assuntos
Modelos Animais de Doenças , Membro Posterior/irrigação sanguínea , Hipóxia/fisiopatologia , Isquemia/sangue , Animais , Masculino , CoelhosRESUMO
In 2003, we started autologous bone marrow cell infusion (ABMi) therapy for treating liver cirrhosis. ABMi therapy uses 400 mL of autologous bone marrow obtained under general anesthesia and infused mononuclear cells from the peripheral vein. The clinical study expanded and we treated liver cirrhosis induced by HCV and HBV infection and alcohol consumption. We found that the ABMi therapy was effective for cirrhosis patients and now we are treating patients with combined HIV and HCV infection and with metabolic syndrome-induced liver cirrhosis. Currently, to substantiate our findings that liver cirrhosis can be successfully treated by the ABMi therapy, we are conducting randomized multicenter clinical studies designated "Advanced medical technology B" for HCV-related liver cirrhosis in Japan. On the basis of our clinical study, we developed a proof-of-concept showing that infusion of bone marrow cells (BMCs) improved liver fibrosis and sequentially activated proliferation of hepatic progenitor cells and hepatocytes, further promoting restoration of liver functions. To treat patients with severe forms of liver cirrhosis, we continued translational research to develop less invasive therapies by using mesenchymal stem cells derived from bone marrow. We obtained a small quantity of BMCs under local anesthesia and expanded them into mesenchymal stem cells that will then be used for treating cirrhosis. In this review, we present our strategy to apply the results of our laboratory research to clinical studies.
Assuntos
Células da Medula Óssea/patologia , Transplante de Medula Óssea/tendências , Cirrose Hepática/patologia , Cirrose Hepática/terapia , Regeneração Hepática/fisiologia , Transplante de Células-Tronco Mesenquimais/tendências , Células-Tronco Mesenquimais/patologia , Animais , Diferenciação Celular , Previsões , Humanos , Engenharia Tecidual/tendênciasRESUMO
The isotope effects of neodymium in Nd-glycolate ligand exchange system were studied by using ion exchange chromatography. The separation coefficients of neodymium isotopes, ε's, were calculated from the observed isotopic ratios at the front and rear boundaries of the neodymium adsorption band. The values of separation coefficients of neodymium isotopes, ε's, for the Nd-glycolate ligand exchange system were compared with those of Nd-malate and Nd-citrate, which indicated that the isotope effects of neodymium as studied by the three ligands takes the following direction Malate > Citrate > Glycolate. This order agrees with the number of available sites for complexation of each ligand. The values of the plate height, HETP of Nd in Nd-ligand exchange systems were also calculated.
RESUMO
BACKGROUND: A surveillance system for transfusion-related adverse reactions and infectious diseases in Japan was started at a national level in 1993, but current reporting of events in recipients is performed on a voluntary basis. A reporting system which can collect information on all transfusion-related events in recipients is required in Japan. METHODS: We have developed an online reporting system for transfusion-related events and performed a pilot study in 12 hospitals from 2007 to 2010. RESULTS: The overall incidence of adverse events per transfusion bag was 1.47%. Platelet concentrates gave rise to statistically more adverse events (4.16%) than red blood cells (0.66%) and fresh-frozen plasma (0.93%). In addition, we found that the incidence of adverse events varied between hospitals according to their size and patient characteristics. CONCLUSION: This online reporting system is useful for collection and analysis of actual adverse events in recipients of blood transfusions and may contribute to enhancement of the existing surveillance system for recipients in Japan.
Assuntos
Segurança do Sangue/métodos , Sistemas On-Line , Reação Transfusional , Segurança do Sangue/instrumentação , Coleta de Dados , Humanos , Incidência , Japão , Projetos PilotoRESUMO
The optimization of a series of 3-carbamoyl 2-pyridone derivatives as CB agonists is reported. These efforts resulted in the discovery of 3-(2-(1-(cyclohexylmethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocycloocta[b]pyridine-3-carboxamido)thiazol-4-yl)propanoic acid (21), a potent dual CB1/CB2 agonist without CNS side effects induced by CB1 receptor activation. It exhibited strong inhibition of scratching as a 1.0% acetone solution in the pruritic model.
Assuntos
Antipruriginosos/química , Descoberta de Drogas , Piridonas/agonistas , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Tiazóis/agonistas , Animais , Antipruriginosos/farmacologia , Células CHO , Cricetinae , Humanos , Camundongos , Ligação Proteica/efeitos dos fármacos , Piridonas/química , Piridonas/farmacologia , Tiazóis/química , Tiazóis/farmacologiaRESUMO
Our lead compound 1 showed high affinity for both CB1 and CB2 receptors, suggesting the possibility of inducing psychoactive side effects through the CB1 receptor in the brain. To solve this issue, polar functional groups were introduced at the 3-position of the pyridone core of compound 1 to find CB1/2 dual agonists such as 17 and 20 which did not show any CNS side effects.
Assuntos
Antipruriginosos , Sistema Nervoso Central/efeitos dos fármacos , Piridonas/química , Piridonas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Animais , Antipruriginosos/química , Antipruriginosos/farmacologia , Comportamento Animal , Carbamatos/efeitos adversos , Carbamatos/química , Carbamatos/farmacologia , Modelos Animais de Doenças , Humanos , Camundongos , Estrutura Molecular , Piridonas/efeitos adversosRESUMO
The discovery of novel CB2 ligands based on the 3-carbamoyl-2-pyridone derivatives by adjusting the size of side chain at 1-, 5- and 6-position is reported. The structure-activity relationship around this template lead to the identification of S-777469 as a selective CB2 receptor agonist, which exhibited the significant inhibition of scratching induced by Compound 48/80 at 1.0 mg/kg po and 10 mg/kg po (55% and 61%, respectively).
Assuntos
Antipruriginosos/química , Antipruriginosos/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Administração Oral , Animais , Antipruriginosos/administração & dosagem , Células CHO , Cricetinae , Modelos Animais de Doenças , Concentração Inibidora 50 , Ligantes , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Piridonas/químicaRESUMO
BACKGROUND: In 2003, we initiated a clinical trial to examine autologous bone marrow cell infusion (ABMi) therapy for cirrhotic patients and reported the clinical effect of the therapy. To analyze how splenectomy may potentiate the effects of bone marrow cell infusion on cirrhosis, we performed a mouse study and a clinical trial on patients with cirrhosis. METHODS: In mice, we analyzed the effect of splenectomy on bone marrow cell infusion in four experimental groups (group A, splenectomy + bone marrow cell infusion + CCl(4); group B, sham operation + bone marrow cell infusion + CCl(4); group C, splenectomy + CCl(4); group D, sham operation + CCl(4)). In clinical, we compared the effect of splenectomy on ABMi therapy. RESULTS: We observed significantly increased average serum albumin levels and higher expression of green fluorescent protein (GFP), matrix metalloproteinase 9 (MMP9), and proliferating cell nuclear antigen in the livers of group A. We observed MMP9/GFP double-positive cells in the cirrhotic livers. A significant decrease in the liver fibrosis areas was observed in group A. Splenectomy enhanced the repopulation of bone marrow cells into the cirrhotic liver and improved the liver microenvironment via expression of MMP9 secreted from repopulating GFP-positive cells. Next, we performed a clinical trial to compare the effect of splenectomy on the efficacy of ABMi therapy. Cirrhotic patients who underwent splenectomy before ABMi therapy tended to have a greater improvement in liver function. CONCLUSION: ABMi therapy with splenectomy may be an effective therapeutic modality for cirrhosis.
Assuntos
Cirrose Hepática Experimental/terapia , Cirrose Hepática/terapia , Esplenectomia/métodos , Idoso , Animais , Transplante de Medula Óssea , Terapia Combinada , Feminino , Humanos , Testes de Função Hepática , Masculino , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Albumina Sérica/metabolismoRESUMO
Mobilized stem cells in the peripheral blood (PB) must be efficiently harvested at the appropriate time before autologous PB stem cell (PBSC) transplantation. Enumeration of CD34+ cells in the PB before apheresis predicts the number of PBSCs that can be collected, but the cytometric techniques used are complex and expensive. Therefore, it is necessary to identify an alternative to the CD34+ cell count in PBSC harvest-time monitoring. Fully automated flow cytometry using blood cell counters now allows reliable quantification of immature myeloid cells in the PB, referred to as hematopoietic progenitor cells (HPC), and reticulated platelets, expressed as the immature platelet fraction (IPF). Immature or reticulated platelets are thought to correlate with thrombopoietic activity of the marrow. Following a chemotherapy nadir, the recovery of white blood cell and platelet counts has been used to determine the right time for apheresis. Therefore, we examined whether the HPC count and IPF value could be used to predict PBSC mobilization in 20 patients with hematological malignancies. The HPC count was found to be correlated with the CD34+ cell count (r = 0.84, P < 0.01), whereas the IPF value was not (r = 0.37, P = 0.44). Therefore, the HPC count, but not the IPF value, is a possible predictor of the timing of autologous stem cell transplantation.
Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Leucaférese/normas , Valor Preditivo dos Testes , Adulto , Antígenos CD34/análise , Antineoplásicos , Contagem de Células Sanguíneas , Separação Celular , Feminino , Neoplasias Hematológicas/terapia , Mobilização de Células-Tronco Hematopoéticas/normas , Humanos , Leucaférese/métodos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/métodos , Contagem de Plaquetas , Fatores de Tempo , Transplante AutólogoRESUMO
"Identification error between patient and blood product" is the main cause of ABO-incompatible blood transfusion, but "Phlebotomy error" also has serious consequences. In order to prevent ABO-incompatible transfusion, it is important to establish a management system of blood transfusion in the hospital, including a hospital transfusion committee and a responsible medical doctor. In addition, in large hospitals routinely carrying out a considerable number of blood transfusions, it is important to employ specialists in blood banking. More than 50 ml of ABO-incompatible blood transfusion (major ABO mismatch) causes a severe acute hemolytic reaction. Because there is little residual plasma in leukocyte-reduced red cell concentrate (RCC-LR), acute hemolysis is not detected on minor ABO mismatch blood transfusion. In the case of emergent blood transfusion, concerning the risk of acute hemolytic reaction, type-O RCC-LR blood transfusion is safer than ABO-identical RCC-LR when the blood of the patient is tested only once. When red cell antibody screening is not performed, there is a risk of hemolysis due to incompatible blood transfusion irrespective of the ABO blood group system, including a delayed hemolytic transfusion reaction.
Assuntos
Sistema ABO de Grupos Sanguíneos , Incompatibilidade de Grupos Sanguíneos/prevenção & controle , Tipagem e Reações Cruzadas Sanguíneas , Transfusão de Sangue , Transfusão de Sangue/métodos , Hemólise , Humanos , Erros Médicos/prevenção & controle , Risco , Reação TransfusionalRESUMO
We have calculated the nuclear volume term (ln K(nv)) of the isotope fractionation coefficient (epsilon) between (235)U-(238)U isotope pairs by considering the effect of ligand coordination in a U(IV)-U(VI) reaction system. The reactants were modeled as [UO(2)Cl(3)](-) and [UO(2)Cl(4)](2-) for U(VI), and UCl(4) for U(IV). We adopted the Dirac-Coulomb Hartree-Fock method with the Gaussian-type finite nucleus model. The result obtained was ln K(nv)=0.001 90 at 308 K, while the experimentally estimated value of ln K(nv) is 0.002 24. We also discuss how the ligand affects the value of ln K(nv), especially for the various structures of different compounds, and different ligands within the halogen ion series (F, Cl, and Br).
RESUMO
Benzo 18-crown-6-ether resin was synthesised by the phenol condensation polymerisation process in porous silica beads, of which particle diameter was ca 60micro Calcium adsorption chromatography was performed with the synthesised resin packed in a glass column. The effluent was sampled in fractions, and the isotopic abundance ratios of (42)Ca, (43)Ca, (44)Ca, and (48)Ca against (40)Ca were measured by a thermo-ionisation mass spectrometer. The enrichment of heavier calcium isotopes was observed at the front boundary of calcium adsorption chromatogram. The mass dependence of mutual separation of calcium isotopes was analysed by using the three-isotope-plots method. The slopes of three-isotope-plots indicate the relative values of mutual separation coefficients for concerned isotopic pairs. The results have shown the normal mass dependence; isotope fractionation is proportional to the reduced mass difference, (M - M')/MM', where M and M' are masses of heavy and light isotope, respectively. The mass dependence clarifies that the isotope fractionations are originated from molecular vibration. The observed separation coefficient epsilon is 3.1x10(-3) for the pair of (40)Ca and (48)Ca. Productivity of enriched (48)Ca by crown-ether-resin was discussed as the function of the separation coefficient and the height equivalent to the theoretical plate.
Assuntos
Isótopos de Cálcio/isolamento & purificação , Fracionamento Químico , Cromatografia Líquida , Éteres de Coroa/química , Resinas Sintéticas/química , Adsorção , Isótopos de Cálcio/química , Espectrometria de Massas , Peso MolecularRESUMO
Zinc isotope separations were studied by displacement chromatography using the chelating properties of malate, citrate and lactate exchange resin and EDTA as ligands. After each chromatographic operation, the heavier zinc isotopes were found to preferentially fractionated into the carboxylate complex solution phase. The separation coefficients (epsilon) for zinc isotope separation had the largest value and were obtained for the isotopic pairs (68)Zn/(64)Zn (7.16 x 10(-4)) and (66)Zn/(64)Zn (3.08 x 10(-4)), respectively, at 298 +/- 1 K. The separation coefficient per unit mass differences (epsilon/DeltaM) for the isotopic pair of (68)Zn/(64)Zn was found to range around 1.55 x 10(-4).
RESUMO
This paper discusses the nuclear volume dependence of uranium isotope fractionations in the U(3+)-U(4+) and U(4+)-UO(2) (2+) systems by reference to a series of ab initio molecular orbital calculations. Nuclear volume-dependent terms ( identical withln K(nv)) in isotope fractionation coefficients ( identical withepsilon) are calculated from the energetic balance of the isotopomers involved in the systems. We used the Dirac-Coulomb Hartree-Fock (DCHF) method with the Gaussian-type finite-nucleus model. We employed three types of generally contracted Gaussian basis sets to check the basis set dependences. In the U(3+)-U(4+) system, the present values of ln K(nv) for uranium, other than those with the smallest double-zeta basis set, are in good agreement with previous values of ln K(nv) obtained from a numerical atomic multiconfigurational DCHF method with the Fermi-type finite-nucleus model. The present calculations reasonably reproduce the experimental value of epsilon in the U(3+)-U(4+) system, and the value of ln K(nv) in the U(4+)-UO(2) (2+) system, obtained empirically by temperature-dependent fitting of the experimental epsilon values. For instance, in the U(4+)-UO(2) (2+) system, the present ab initio ln K(nv) value for a (235)U-(238)U isotope pair is 0.002 09 using the largest basis set, while the experimental value is 0.002 24. This paper also shows that nuclear volume effects are negligibly small on the U-O bond length and two force constants of UO(2) (2+). Hence, the molecular vibrational terms of the isotope fractionation coefficients mainly depend on the nuclear mass rather than the nuclear volume.