RESUMO
Existing methods to measure high-density lipoprotein cholesterol (HDL-C) subclasses (HDL2-C and HDL3-C) are complex and require proficiency, and thus there is a need for a convenient, homogeneous assay to determine HDL-C subclasses in serum. Here, cholesterol reactivities in lipoprotein fractions [HDL2, HDL3, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL)] toward polyethylene glycol (PEG)-modified enzymes were determined in the presence of varying concentrations of dextran sulfate and magnesium nitrate. Particle sizes formed in the lipoprotein fractions were measured by dynamic light scattering. We optimized the concentrations of dextran sulfate and magnesium nitrate before assay with PEG-modified enzymes to provide selectivity for HDL3-C. On addition of dextran sulfate and magnesium nitrate, the sizes of particles of HDL2, LDL, and VLDL increased, but the size of HDL3 fraction particles remained constant, allowing only HDL3-C to participate in coupled reactions with the PEG-modified enzymes. In serum from both healthy volunteers and patients with type 2 diabetes, a good correlation was observed between the proposed assay and ultracentrifugation in the determination of HDL-C subclasses. The assay proposed here enables convenient and accurate determination of HDL-C subclasses in serum on a general automatic analyzer and enables low-cost routine diagnosis without preprocessing.
Assuntos
Bioensaio/métodos , HDL-Colesterol/análise , HDL-Colesterol/sangue , Ensaios Enzimáticos/métodos , Lipoproteínas HDL3/análise , Lipoproteínas HDL3/sangue , Calibragem , Colesterol Oxidase/química , Colesterol Oxidase/metabolismo , HDL-Colesterol/metabolismo , Sulfato de Dextrana/química , Humanos , Lipoproteínas HDL2/análise , Lipoproteínas HDL2/sangue , Lipoproteínas HDL2/metabolismo , Lipoproteínas HDL3/metabolismo , Lipoproteínas LDL/análise , Lipoproteínas LDL/sangue , Lipoproteínas LDL/metabolismo , Lipoproteínas VLDL/análise , Lipoproteínas VLDL/sangue , Lipoproteínas VLDL/metabolismo , Compostos de Magnésio/química , Nitratos/química , Tamanho da Partícula , Polietilenoglicóis/química , Reprodutibilidade dos Testes , Esterol Esterase/química , Esterol Esterase/metabolismo , UltracentrifugaçãoRESUMO
Serum sphingomyelin (SM) has predictive value in the development of atherosclerosis. Furthermore, SM plays important roles in cell membrane structure, signal transduction pathways, and lipid raft formation. A convenient enzymatic method for SM is available for routine laboratory practice, but the enzyme specificity is not sufficient because of nonspecific reactions with lysophosphatidylcholine (LPC). Based on the differential specificity of selected enzymes toward choline-containing phospholipids, a two-step assay for measuring SM was constructed and its performance was evaluated using sera from healthy individuals on a Hitachi 7170 autoanalyzer. Results from this assay were highly correlated with theoretical serum SM concentrations estimated by subtracting phosphatidylcholine (PC) and LPC concentrations from that of total phospholipids determined using previously established methods. There was a good correlation between the results of SM assayed by the proposed method and the existing enzymatic method in sera from healthy individuals. Moreover, the proposed method was superior to the existing method in preventing nonspecific reactions with LPC present in sera. The proposed method does not require any pretreatment, uses 2.5 µl of serum samples, and requires only 10 min on an autoanalyzer. This high-throughput method can measure serum SM with sufficient specificity for clinical purposes and is applicable in routine laboratory practice.
Assuntos
Autoanálise , Ensaios Enzimáticos , Lisofosfatidilcolinas/química , Esfingomielina Fosfodiesterase/metabolismo , Esfingomielinas/sangue , Adulto , Artefatos , Membrana Celular/química , Membrana Celular/metabolismo , Feminino , Humanos , Lisofosfatidilcolinas/metabolismo , Masculino , Pessoa de Meia-Idade , Esfingomielinas/metabolismo , Adulto JovemRESUMO
The purpose of this study was to evaluate the role of CCAAT/enhancer-binding protein homologous protein (CHOP), an important transcription factor that regulates the inflammatory reaction during the endoplasmic reticulum (ER) stress response, in the development of pulmonary fibrosis induced by bleomycin (BLM) in mice. An intratracheal injection of BLM transiently increased the expression of CHOP mRNA and protein in an early phase (days 1 and 3) in mice lungs. BLM-induced pulmonary fibrosis was significantly attenuated in Chop gene deficient (Chop KO) mice, compared with wild-type (WT) mice. Furthermore, the inflammatory reactions evaluated by protein concentration, the total number of leucocytes and neutrophils in the bronchoalveolar lavage fluid (BALF), the mRNA expression of interleukin 1b and caspase 11, and the apoptotic cell death were suppressed in Chop KO mice compared with those in WT mice. In addition, administration of tauroursodeoxycholic acid (TUDCA), a pharmacological agent that can inhibit CHOP expression, inhibited the BLM-induced pulmonary fibrosis and inflammation, and the increase in Chop mRNA expression in WT mice in a dose-dependent manner. These results suggest that the ER stress-induced transcription factor, CHOP, at least in part, plays an important role in the development of BLM-induced pulmonary fibrosis in mice, and that the inhibition of CHOP expression by a pharmacological agent, such as TUDCA, may be a promising strategy for the prevention of pulmonary fibrosis.
Assuntos
Bleomicina/toxicidade , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle , Ácido Tauroquenodesoxicólico/farmacologia , Fator de Transcrição CHOP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Expressão Gênica/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibrose Pulmonar/etiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição CHOP/deficiência , Fator de Transcrição CHOP/genéticaRESUMO
UNLABELLED: This study aimed to determine the population pharmacokinetics of doxapram in low-birth-weight (LBW) infants. A total of 92 serum concentration measurements that were obtained from 34 Japanese neonates were analyzed using nonlinear mixed-effect modeling (NONMEM). Estimates generated by NONMEM indicated that clearance of doxapram (CL; L/kg/h) was affected by postmenstrual age (PMA; weeks), body weight (BW; g), and aspartate aminotransferase (AST; IU/L). In addition, the volume of distribution (Vd; L/kg) was affected by gestational age (GA; weeks). The final pharmacokinetic model was as follows: CL = BW / PMA × 0.0453 × serum AST(-0.373); Vd = 2.54 (if GA >28 weeks) and Vd = 2.54 × 2.11 (if GA ≤28 weeks). The interindividual variabilities in CL and Vd were 39.9 and 83.0 %, respectively, and the residual variability was 20.9 %. To clarify the reasons for large interindividual variations, the enzymes involved in the metabolic pathway of doxapram were also determined. We found that doxapram was metabolized by CYP3A4/5. CONCLUSION: We report the population pharmacokinetics of doxapram in neonates and the involvement of CYP3A4/5 in its metabolism. The final model of population pharmacokinetics may be useful for formulating a safe and effective dosage regimen and for predicting serum doxapram concentrations in neonates.
Assuntos
Apneia/metabolismo , Estimulantes do Sistema Nervoso Central/farmacocinética , Doxapram/farmacocinética , Recém-Nascido de Baixo Peso , Apneia/tratamento farmacológico , Povo Asiático , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450 , Método Duplo-Cego , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Japão , Masculino , Espectrometria de Massas , Modelos BiológicosRESUMO
Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is a widely used analgesic/antipyretic drug with few adverse effects at therapeutic doses; suicidal or unintentional overdose of APAP frequently induces severe hepatotoxicity. To explore a new and effective antidote for APAP hepatotoxicity, this study examined the effects of sodium 4-phenylbutyrate (4-PBA) on liver injury induced by APAP overdose in mice. Liver injury was induced in C57BL/6 male mice by intraperitoneal injection of APAP (400mg/kg). The effects of 4-PBA (100-200mg/kg) treatment at 1h before the APAP injection were evaluated with serum alanine aminotransferase (ALT) and blood ammonia levels, hepatic pathological changes, including histopathology, DNA damage, nitrotyrosine formation, and mRNA or protein expression involved in the development of hepatotoxicity, such as X-box binding protein-1 (XBP1), c-Jun N-terminal kinase (JNK), C/EBP homologous protein (CHOP) and B-cell lymphoma 2 interacting mediator of cell death (Bim). In addition, glutathione depletion and CYP2E1 protein expression, which are measures of the metabolic conversion of APAP to a toxic metabolite, were examined. Furthermore, we examined the effects of post-treatment with 4-PBA against APAP-induced hepatotoxicity in mice. When administered at 1h before APAP injection, 4-PBA significantly prevented the increase in serum ALT and blood ammonia levels, centrilobular necrosis of hepatocytes, DNA fragmentation, and nitrotyrosine formation induced by APAP in mice. 4-PBA also inhibited hepatic Xbp1 mRNA splicing and JNK phosphorylation induced by APAP, but did not suppress CHOP and Bim mRNA and protein expression. In addition, 4-PBA had little effect on hepatic glutathione depletion and CYP2E1 expression, parameters of toxic APAP metabolite production. Post-treatment with 4-PBA administration at 1 or 2h after APAP injection also attenuated the increase in serum ALT and blood ammonia levels and hepatic pathological changes in APAP-induced hepatotoxicity in mice. Although post-treatment with 4-PBA did not show any effects on hepatic Xbp1 mRNA splicing and JNK phosphorylation, it drastically attenuated the DNA fragmentation induced by APAP. The precise molecular mechanisms of the protection afforded by 4-PBA against APAP hepatotoxicity in mice are unclear, but they seem to involve inhibition of hepatocellular DNA fragmentation. We suggest that 4-PBA is a promising candidate as an antidote against APAP-induced liver injury.
Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fenilbutiratos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Alanina Transaminase/sangue , Amônia/sangue , Animais , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocromo P-450 CYP2E1/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Glutationa/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenilbutiratos/administração & dosagem , Fenilbutiratos/farmacologia , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição de Fator Regulador X , Fator de Transcrição CHOP/genética , Fatores de Transcrição/genética , Tirosina/análogos & derivados , Tirosina/metabolismo , Proteína 1 de Ligação a X-BoxRESUMO
Overdoses of acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) cause severe liver injury, yet there is no common or high throughput in vitro human APAP model. This study examined the characteristics and usefulness of HepG2 cells grown in a nano culture plate (NCP) system, a three-dimensional culture method, as an in vitro human model for APAP-induced hepatotoxicity. The NCP-cultured HepG2 cells showed higher expression of mRNA and protein levels of cytochrome P450 2E1, which metabolizes APAP to a toxic metabolite, APAP-cysteine adduct formation, and higher sensitivity against APAP-induced cell injury compared with conventionally cultured cells. We demonstrated that treatment of APAP in NCP-cultured HepG2 cells shows key mechanistic features of APAP-induced hepatotoxicity, such as decreases in intracellular glutathione and mitochondrial membrane potential, activation of JNK, and cellular injury; and pharmacological agents, such as Cyclosporine A (a mitochondrial permeability transition inhibitor) and SP600125 (a JNK inhibitor), prevented cell injury induced by APAP exposure. In addition, the antidote of APAP-induced hepatotoxicity, N-acetylcysteine, could attenuate cellular injury induced by APAP in NCP-cultured HepG2 cells. We suggest that cellular injury induced by APAP treatment using an NCP-HepG2 system is a useful human model to study mechanisms and screen drug candidates of APAP-induced hepatotoxicity.
Assuntos
Acetaminofen/toxicidade , Fígado/efeitos dos fármacos , Nanotecnologia/métodos , Testes de Toxicidade/métodos , Acetaminofen/antagonistas & inibidores , Acetilcisteína/farmacologia , Antracenos/farmacologia , Células Cultivadas , Ciclosporina/farmacologia , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP2E1/fisiologia , Avaliação Pré-Clínica de Medicamentos , Glutationa/metabolismo , Células Hep G2 , Humanos , Fígado/metabolismo , MAP Quinase Quinase 4/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
BACKGROUND: The aims of this study were to evaluate the current awareness of and implementation by pharmacists in Japan of adjustment of drug dosage according to renal function (ADDR) in patients with chronic kidney disease (CKD) and to clarify the factors influencing implementation of ADDR by community pharmacists. METHODS: We conducted a web-based questionnaire of Japanese community and hospital pharmacists. Responders were compared by characteristics, rate of implementation of ADDR, experience with adverse drug events, pharmacist awareness of implementation of ADDR, and obstacles to ADDR implementation experienced by pharmacists. Additionally, the factors influencing the implementation of ADDR by community pharmacists were investigated by logistic regression analysis. RESULTS: Fewer community pharmacists had implemented ADDR than hospital pharmacists. The community pharmacists had less experience with adverse drug events caused by an inappropriate dosage than the hospital pharmacists, while the hospital pharmacists had encountered more severe adverse drug events than the community pharmacists. The community pharmacists had less awareness of ADDR implementation, and believed that problems in implementing ADDR were caused by a lack of information on the renal function of patients. In the logistic regression analysis, the factors influencing implementation of ADDR were "Routinely receiving prescriptions from nephrologists", "Experience with adverse drug events caused by inappropriate dosage for CKD patients", and "Awareness of the need for pharmacists to check the dosage of renally excreted drugs"; they did not include "Lack of information on patient renal function". CONCLUSIONS: This study indicates that fewer Japanese community pharmacists than hospital pharmacists implement ADDR and that implementation of ADDR by community pharmacists is hindered by their limited awareness of the importance of patient renal function. We advocate that many countermeasures be introduced to prevent CKD patients from experiencing adverse drug events caused by inappropriate dosage. Such countermeasures would include a training program to educate pharmacists about the impact of impaired renal function on dosage of drugs that are excreted by the kidneys.
Assuntos
Farmacêuticos , Papel Profissional , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Conscientização , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Japão , Testes de Função Renal , Masculino , Farmácias , Serviço de Farmácia Hospitalar , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Overdosed acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) causes severe liver injury. We examined the effects of ozagrel, a selective thromboxane A2 (TXA2) synthase inhibitor, on liver injury induced by APAP overdose in mice. METHODS: Hepatotoxicity was induced to ICR male mice by an intraperitoneal injection with APAP (330 mg/kg). The effects of ozagrel (200 mg/kg) treatment 30 min after the APAP injection were evaluated with mortality, serum alanine aminotransferase (ALT) levels and hepatic changes, including histopathology, DNA fragmentation, mRNA expression and total glutathione contents. The impact of ozagrel (0.001-1 mg/mL) on cytochrome P450 2E1 (CYP2E1) activity in mouse hepatic microsome was examined. RLC-16 cells, a rat hepatocytes cell line, were exposed to 0.25 mM N-acetyl-p-benzoquinone imine (NAPQI), a hepatotoxic metabolite of APAP. In this model, the cytoprotective effects of ozagrel (1-100 muM) were evaluated by the WST-1 cell viability assay. RESULTS: Ozagel treatment significantly attenuated higher mortality, elevated serum alanine aminotransferase levels, excessive hepatic centrilobular necrosis, hemorrhaging and DNA fragmentation, as well as increase in plasma 2,3-dinor thromboxane B2 levels induced by APAP injection. Ozagrel also inhibited the hepatic expression of cell death-related mRNAs induced by APAP, such as jun oncogene, FBJ osteosarcoma oncogene (fos) and C/EBP homologous protein (chop), but did not suppress B-cell lymphoma 2-like protein11 (bim) expression and hepatic total glutathione depletion. These results show ozagrel can inhibit not all hepatic changes but can reduce the hepatic necrosis. Ozagrel had little impact on CYP2E1 activity involving the NAPQI production. In addition, ozagrel significantly attenuated cell injury induced by NAPQI in RLC-16. CONCLUSIONS: We demonstrate that the TXA2 synthase inhibitor, ozagrel, dramatically alleviates liver injury induced by APAP in mice, and suggest that it is a promising therapeutic candidate for the treatment of APAP-induced liver injury.
Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Metacrilatos/uso terapêutico , Tromboxano-A Sintase/antagonistas & inibidores , Alanina Transaminase/sangue , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Fragmentação do DNA , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Injeções Intraperitoneais , Fígado/metabolismo , Fígado/patologia , Masculino , Metacrilatos/administração & dosagem , Camundongos , Camundongos Endogâmicos ICR , Resultado do TratamentoRESUMO
BACKGROUND: This study was conducted to clarify whether respiratory stimulants used to treat apnea of prematurity (AOP) attenuate or aggravate hypoxia-induced neuronal damage. METHODS: A human neuroblastoma cell line, SH-SY5Y cells, and hippocampal slice cultures from rat pups were exposed to hypoxia to induce cell injury. The effects of respiratory stimulants on cell injury were evaluated. RESULTS: Theophylline and doxapram did not have any effects against cell injury induced by hypoxia in SH-SY5Y cells and hippocampal slice cultures of rat pups, while caffeine protected these cells and the slice cultures from hypoxia. The protective effects of caffeine in SH-SY5Y cells disappeared with co-treatment by the adenosine A2A receptor agonist, CGS21680, and were mimicked by the adenosine A2A R antagonist, SCH58261. Meanwhile, co-treatment with phosphatidylinositol 3-kinase/AKT pathway inhibitors did not affect the protective effects of caffeine. Hydroxy radical scavenging activity of caffeine were not observed at the concentrations that produced cytoprotective activity, and radical scavengers did not have any effects on the cell injury induced by hypoxia in SH-SY5Y cells. CONCLUSIONS: Caffeine significantly attenuated cell injury induced by hypoxia in SH-SY5Y cells and hippocampal slice cultures of rat pups, at least partly through A2A R antagonism. Caffeine can protect neuronal cells from injury induced by hypoxemia, and may be a beneficial treatment for AOP with neuroprotective potential.
Assuntos
Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Medicamentos para o Sistema Respiratório/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Animais Recém-Nascidos , Cafeína/farmacologia , Linhagem Celular , Fármacos Neuroprotetores/farmacologia , RatosRESUMO
This study examined the cytoprotective and anti-oxidative properties of phosphoenolpyruvic acid (PEP), a glycolysis metabolite with a high-energy phosphate group. PEP (0.1-10 mM) significantly attenuated the decrease in cell viability induced by hydrogen peroxide (H(2)O(2)) in HeLa cells in a dose-dependent manner. PEP also inhibited the decrease in calcein-acetomethoxy-stained cells and the increase in propidium iodide-stained cells that were induced by H(2)O(2). The H(2)O(2)-stimulated increase in intracellular reactive oxygen species was significantly reduced by PEP. PEP also demonstrated scavenging potential against hydroxyl radicals, as assessed by the electron paramagnetic resonance method. In addition, PEP demonstrated scavenging potential against the 1,1-diphenyl-2-picrylhydrazyl radical, a representative artificial radical, although the potential is very weak. PEP (10 mM) slightly inhibited the decrease in cellular ATP content induced by H(2)O(2), but did not show any effects at low doses (0.1, 1 mM). PEP (0.1-10 mM) also attenuated the cell injury but not the decrease in intracellular ATP content, induced by 2-deoxy-D-glucose, a glycolysis inhibitor. These results indicate that PEP exerts cytoprotective effects and has anti-oxidative potential, although the precise cytoprotective mechanisms are not fully elucidated. We suggest that PEP is a functional carbohydrate metabolite with cytoprotective and anti-oxidative activity, and is potentially useful as a therapeutic agent against diseases that involve the oxidative stress.
Assuntos
Antioxidantes/farmacologia , Citoproteção/efeitos dos fármacos , Fosfoenolpiruvato/análogos & derivados , Trifosfato de Adenosina/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Desoxiglucose/farmacologia , Glicólise , Células HeLa , Humanos , Peróxido de Hidrogênio/farmacologia , Oxidantes/farmacologia , Fosfoenolpiruvato/farmacologiaRESUMO
BACKGROUND: Vancomycin is frequently used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections; however, determining the optimal dosage for neonates is difficult because of their immature renal function. METHODS: Serum creatinine-based dosing was introduced in Kumamoto City Hospital Neonatal Medical Center. Serum trough concentration and therapeutic efficacy of vancomycin were evaluated before and after the introduction of the creatinine-based dosing. RESULTS: When the therapeutic range of serum trough concentration of vancomycin at steady state was set to 5-15 µg/mL, 20 trough concentrations (48.8%) were within the therapeutic range and 21 trough concentrations were outside the therapeutic range before the introduction of the serum creatinine-based dosing. After the introduction of serum creatinine-based dosing, 18 trough concentrations (81.8%) were within the therapeutic range and 4 trough concentrations were not, and there was an increase in the number of patients with trough concentrations in the therapeutic range (P= 0.01; Fisher's exact test). CONCLUSIONS: The serum creatinine-based dosing of vancomycin is useful in maintaining the appropriate serum level of vancomycin in neonates.
Assuntos
Infecções Bacterianas/sangue , Creatinina/sangue , Unidades de Terapia Intensiva Neonatal , Vancomicina/administração & dosagem , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Infecções Bacterianas/tratamento farmacológico , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Reprodutibilidade dos Testes , Estudos Retrospectivos , Vancomicina/farmacocinéticaRESUMO
The effects of Sho-seiryu-to (TJ-19), an ethical Kampo formulation, on bleomycin (BLM)-induced pulmonary fibrosis in rats was examined. Pulmonary fibrosis was induced by intratracheal instillation of a single dose of BLM (5 mg/kg). The TJ-19 used consisted of at least 21 constituents, as determined by three-dimensional HPLC analysis, and was administered orally twice a day at a dose of 1.5 g/kg until the end of the study period. Changes in general appearance and body weight were monitored. Twenty-eight days after BLM instillation, the animals were sacrificed and the study parameters were measured. TJ-19 attenuated the loss in body weight, increase in lung/body weight ratio and concentration of hydroxyproline and malondialdehyde in the lung tissues induced by BLM administration. TJ-19 also prevented BLM-induced fibrotic changes in the lung histology. These protective effects of TJ-19 were observed when administration was started 1 week before and simultaneously with the instillation of BLM. These results suggest that TJ-19 has prophylactic potential against BLM-induced pulmonary fibrosis, and may therefore be a promising drug candidate and medicinal resource for preventing BLM-induced and idiopathic pulmonary fibrosis.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Fibrose Pulmonar Idiopática/prevenção & controle , Pulmão/efeitos dos fármacos , Medicina Kampo , Animais , Bleomicina , Cromatografia Líquida de Alta Pressão , Colágeno/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peróxidos Lipídicos/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: To compare the effect of low-dose prednisolone (PSL) (≤5 mg/day) and high-dose PSL (>5 mg/day) therapy on the QOL and activity of daily living (ADL) in patients with MG. METHODS: A total of 679 patients with MG underwent a survey using Japanese versions of the MG-QOL 15-J and MG-ADL scales. Higher scores of these scales suggest deterioration of the QOL and ADL, respectively. RESULTS: The total MG-QOL 15-J scores of the high-dose group (27.0±13.8) were significantly higher than those of the low-dose group (20.9±14.6). Similarly, the total MG-ADL scores of the high-dose group (6.3±4.1) were significantly higher than those of the low-dose group (5.3±4.1). CONCLUSION: These results showed that the QOL of patients in the low-dose group appeared better than that in the high-dose group. Low-dose PSL therapy may help achieve minimal manifestations level in Japanese patients with MG.
Assuntos
Miastenia Gravis , Qualidade de Vida , Atividades Cotidianas , Humanos , Miastenia Gravis/tratamento farmacológico , Prednisolona , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Improvement in quality of life (QoL) of patients is one of the most important goals of palliative care, but evaluation of QoL of patients is difficult. AIM: To evaluate QoL of patients who died at home or in a hospital. METHODS: We administered the Good Death Inventory (10 core and 8 optional domains) to the bereaved families of patients who died at home or in a hospital. A total of 107 bereaved families undertook a survey. FINDINGS: If a bereaved family chose 'somewhat agree', 'agree' or 'absolutely agree', the answer was regarded as a 'satisfactory answer'. Regarding the 10 core domains, of patients who died in a hospital, <50% respondents gave a 'satisfactory answer' to three questions, whereas of patients who died at home, >60% of respondents gave a 'satisfactory answer' to seven questions. Regarding the eight optional domains, of patients who died in a hospital, <50% respondents gave a 'satisfactory answer' to five questions, whereas of patients who died at home, >60% of respondents gave a 'satisfactory answer' to four questions. CONCLUSIONS: QoL of patients who died at home appeared higher than that of those who died in a hospital. Patients prefer to remain at home rather than in a hospital, probably because at home they are surrounded by familiar things and can live according to their usual habits.
Assuntos
Família , Hospitais , Neoplasias , Cuidados Paliativos , Preferência do Paciente , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Luto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto JovemRESUMO
This study examined the effect of ozagrel, a thromboxane A(2) synthase inhibitor, on the accumulation of leucocytes and chemokine mRNA expression in lungs experimentally injured using oleic acid (OA). OA injection into guinea pigs rapidly increased thromboxane A(2) generation and subsequently increased total protein concentration and the numbers of macrophages and neutrophils in bronchoalveolar lavage fluid and increased monocyte chemoattractant protein-1 and interleukin-8 mRNA expression in the whole lung. Administration of ozagrel prevented these changes associated with OA injection. Ozagrel is a promising drug candidate for preventing acute lung injury.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Quimiocina CCL2/metabolismo , Interleucina-8/metabolismo , Ácido Oleico/metabolismo , Tromboxano A2/antagonistas & inibidores , Lesão Pulmonar Aguda/prevenção & controle , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Amarelo de Eosina-(YS)/metabolismo , Cobaias , Contagem de Leucócitos , Macrófagos/metabolismo , Masculino , Metacrilatos , Azul de Metileno/metabolismo , Neutrófilos/metabolismo , Proteínas/análise , RNA Mensageiro/metabolismo , Coloração e Rotulagem/métodos , Fatores de TempoRESUMO
OBJECTIVES: The effect of a herbal medicine, Sho-seiryu-to (TJ-19), on oleic acid-induced lung injury, an animal model of acute respiratory distress syndrome or acute lung injury (ARDS/ALI), was examined. METHODS: Acute lung injury was induced by an intravenous injection of 15 microl/kg oleic acid to guinea-pigs. TJ-19 was administered by a single oral dose (3 g/kg) or by multiple oral doses (0.75 g/kg). KEY FINDINGS: The decrease in partial oxygen pressure of arterial blood (Pao(2)) and the increase in airway vascular permeability induced by the oleic acid injection were attenuated by a single dose of TJ-19. When TJ-19 was administered orally twice a day for two weeks and then oleic acid was injected, a potent prophylactic effect of the drug was observed. TJ-19 also prevented airway vascular hyperpermeability, lung cell injury, oxidative stress and thromboxane A(2) generation, associated with the oleic acid injection. CONCLUSIONS: TJ-19 significantly attenuated the oleic acid-induced lung injury probably through the antioxidative effect and inhibitory effect of thromboxane A(2) generation, although the precise inhibitory mechanisms were not fully elucidated due to the diversity in constituents of the herbal medicine. We suggest that TJ-19 is a promising drug candidate and a medicinal resource for preventing ARDS/ALI.
Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Medicamentos de Ervas Chinesas/uso terapêutico , Fitoterapia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Cobaias , Medicina Herbária , Masculino , Ácido Oleico , Estresse Oxidativo/efeitos dos fármacos , Plantas Medicinais , Tromboxano A2/antagonistas & inibidores , Tromboxano A2/biossínteseRESUMO
BACKGROUND: Many types of inhaled medications are used for the treatment of asthma; however, inadequate inhalation techniques and poor adherence cause exacerbations of asthma symptoms. It is necessary to therefore provide adequate instruction to acquire correct inhalation techniques. This study aimed to evaluate the usefulness of individualized inhalation instruction in asthmatic outpatients by a community pharmacist for an improvement of the inhalation techniques and asthma control. METHODS: Twenty-eight asthmatic outpatients who have developed asthma over a long period and received prescriptions from Kumamoto Chuo Hospital from April to August 2008 were instructed by a pharmacist on inhalation techniques at Shimokawa Hamasen Pharmacy. Individual instruction by the pharmacist consisted of a skill-check with inhalers, followed by the use of a checklist of inhalation technique, a self-evaluation checklist, and visual information for the patients. Outcomes were evaluated based on changes in inhalation technique mastery between their first visit and the subsequent visit. Nineteen of the 28 patients who completed the Asthma Control Test (ACT) were also evaluated for asthma control according to changes in their ACT scores. RESULTS: Twenty patients showed inadequate inhalation techniques. The individualized instruction resulted in significant improvement in the inhalation techniques. Moreover, there were significant improvement in the ACT scores (from 19.1 to 21.4) of 19 patients who received the individualized instruction. CONCLUSION: The individualized instruction to the asthmatic outpatients enables them to improve the inhalation techniques to mend their asthmatic symptoms. We suggest that coordination with hospital and community pharmacy improves therapeutic outcomes in inhaled medication for the asthmatic outpatients.
Assuntos
Asma/tratamento farmacológico , Educação de Pacientes como Assunto/métodos , Farmácias/estatística & dados numéricos , Administração por Inalação , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esteroides/administração & dosagemRESUMO
Acetaminophen, a common analgesic/antipyretic, is a frequent cause of acute liver failure in Western countries. The development of an effective cure against acetaminophen hepatotoxicity is crucial. Ethyl pyruvate, an ethyl ester derivative of pyruvic acid, has been identified as a possible candidate against acetaminophen hepatotoxicity in animal experiments. However, the mode of the hepatoprotective action of ethyl pyruvate remains unclear. We examined the hepatoprotective effect of ethyl pyruvate against hepatocyte injury and oxidative stress in a mouse model of acetaminophen hepatotoxicity. In addition, to examine whether ethyl pyruvate has direct hepatocellular protection against acetaminophen hepatotoxicity to counteract the influence of inflammatory cells, such as macrophages, we examined the effects of ethyl pyruvate on cellular injury induced by N-acetyl-p-benzoquinone imine, a toxic metabolite of acetaminophen, in a human hepatocyte cell line, HepG2 cells. Treatment with ethyl pyruvate significantly prevented increases in serum transaminase levels and hepatic centrilobular necrosis induced with an acetaminophen overdose in mice in a dose-dependent manner. Although hepatic DNA fragmentation induced by acetaminophen was also attenuated with ethyl pyruvate, nitrotyrosine formation was not inhibited. Ehyl pyruvate significantly attenuated mitochondria dehydrogenase inactivity induced by N-acetyl-p-benzoquinone imine in HepG2 cells. The attenuating effect was also observed in a rat hepatocyte cell line. Increases in annexin V and propidium iodide-stained cells induced by N-acetyl-p-benzoquinone imine were prevented with ethyl pyruvate in HepG2 cells. Pyruvic acid, a parent compound of ethyl pyruvate, tended to attenuate these changes. The results indicate that ethyl pyruvate has direct hepatocellular protection against N-acetyl-p-benzoquinone imine induced injury observed in acetaminophen overdose. The in vivo and in vitro results suggest that ethyl pyruvate attenuates acetaminophen-induced liver injury via, at least in part, its cellular protective potential.
RESUMO
BACKGROUND: We used a cyclodextrin-based drug delivery system, consisting of levobupivacaine complexed with maltosyl-beta-cyclodextrin (G2-beta-CD), in spinal and sciatic nerve blocks in rats to investigate prolongation of the local anesthetic effect. METHODS: Rats were assigned to four groups (n = 6 in each) and received intrathecally 30 microL of 1% levobupivacaine complexed with 0 (control), 50, 100, or 200 mM of G2-beta-CD. Muscle tone and tail flick latency were studied after intrathecal administration. Four more groups (n = 6) of rats received a sciatic nerve block with 0.5% or 1% levobupivacaine complexed with either 0 or 100 mM of G2-beta-CD. The time course of changes in proprioception, motor function, and nociception after circumferential subcutaneous administration to the sciatic nerve was examined. RESULTS: With the intrathecal block, all rats stopped tail movement immediately after injection of the local anesthetic. The mean time to recovery of muscle tone with 1% levobupivacaine complexed with 100 mM (80.0 +/- 8.9 min) and 200 mM (91.7 +/- 7.0 min) of G2-beta-CD was significantly longer than that of the control group (38.3 +/- 3.1 min), but tail flick latency was not prolonged. With the sciatic nerve block, all rats were temporarily immobilized after levobupivacaine injection. The anesthetic effects of 0.5% levobupivacaine with 100 mM of G2-beta-CD were twice as long as those for 0.5% levobupivacaine alone, and those of 1% levobupivacaine with 100 mM of G2-beta-CD were 1.4 times longer than those for 1% levobupivacaine alone. CONCLUSIONS: The complex of levobupivacaine with G2-beta-CD prolonged the anesthetic effect of levobupivacaine in both intrathecal and sciatic nerve blocks in rats.