RESUMO
Oral mucositis is a common and distressing complication in patients receiving high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT). We reported previously in a single-center retrospective analysis that zinc-L-carnosine (polaprezinc [PZ]) reduced the incidence of oral mucositis associated with HSCT. To verify the accuracy of the prophylactic effect of PZ against oral mucositis, we carried out a multi-institutional prospective randomized controlled study. Patients were randomly allocated to either the prevention group, in which PZ lozenge treatment was started before chemotherapy, or the control group, in which administration of PZ lozenges was initiated immediately after the onset of Grade 2 oral mucositis. Oral mucositis was evaluated daily from the start of chemotherapy to 35 days after transplantation. A total of 91 patients were enrolled, and 88 patients (47 in the control group and 41 in the prevention group) were eligible for data analysis. The incidence of Grade ≥2 but not Grade ≥3 oral mucositis was significantly reduced in the prevention group compared to the control group (44.7% in control group vs 22.0% in the prevention group, P = .025). There were no significant differences in the incidence rates of other adverse events or the rate of engraftment (95.6% vs 97.2%, P = .693) between the two groups. These findings suggest that PZ lozenge is effective for prophylaxis against Grade ≥2 oral mucositis associated with chemotherapy in patients undergoing HSCT without any influence on the HSCT outcome.
Assuntos
Antiulcerosos/administração & dosagem , Antineoplásicos/efeitos adversos , Carnosina/análogos & derivados , Compostos Organometálicos/administração & dosagem , Estomatite/induzido quimicamente , Estomatite/tratamento farmacológico , Adolescente , Adulto , Idoso , Carnosina/administração & dosagem , Feminino , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Adulto Jovem , Compostos de Zinco/administração & dosagemRESUMO
BACKGROUND: Antimicrobial stewardship is required to ensure the appropriate use of antimicrobials. However, few reports have shown the impact of antimicrobial stewardship on clinical outcomes. METHODS: To evaluate the clinical outcomes of implementing a prospective audit with intervention and feedback without carbapenem pre-authorisation, we conducted a single-centre, prospective cohort study in patients who received carbapenem injection. Subjects were allocated to groups receiving antimicrobial agents before (non-intervention group) or after (intervention group) the implementation of an antimicrobial stewardship programme in the clinical setting. RESULTS: The intervention facilitated the rate of choice of effective antimicrobials on day 2 from the onset of infection (from 63.2% to 90.2%; P < 0.001). Moreover, the rates of clinical failure-free survival (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.47-0.89; P = 0.008) and re-infection-free survival (HR, 0.35; 95% CI, 0.18-0.68; P = 0.002) were significantly higher in the intervention group than in the non-intervention group. A multivariate Cox proportional hazard analysis indicated that non-implementation of antimicrobial stewardship was a significant risk factor for clinical failure in patients receiving carbapenem injection (HR, 1.56; 95% CI, 1.11-2.19; P = 0.010). CONCLUSIONS: Our prospective audit with intervention and feedback strategy without carbapenem restriction facilitated the choice of optimal antimicrobials at an early stage of infection and improved clinical outcomes in patients who received carbapenem.
Assuntos
Antibacterianos/uso terapêutico , Gestão de Antimicrobianos/métodos , Infecções Bacterianas/tratamento farmacológico , Carbapenêmicos/uso terapêutico , Idoso , Intervalo Livre de Doença , Retroalimentação , Feminino , Humanos , Injeções , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos ProspectivosRESUMO
WHAT IS KNOWN AND OBJECTIVE: Implementation of an antifungal stewardship programme is a recognized need. However, there is insufficient information to confirm the impact of antifungal stewardship interventions. Further, few studies have evaluated the clinical effects of an antifungal stewardship intervention using 1-3, ß-D-glucan (ßDG) testing. The aim of the present study was to evaluate the impact of implementing an antifungal stewardship with monitoring of ßDG values on antifungal use and clinical outcomes. METHODS: A single institutional prospective cohort study was conducted to evaluate the impact of implementing daily reviews of antifungal agents and monitoring patients who measured ßDG values since August 2013. Antifungal consumption and clinical outcomes in patients with Candida bloodstream infection were compared before and after the intervention. RESULTS: After implementation of the programme, parental antifungal use was significantly reduced compared to that before intervention (P = 0.006). In the after-intervention group, the rate of 60-day clinical failure in patients with Candida bloodstream infection was significantly reduced, from 80.0% (28/35) to 36.4% (8/22) (P < 0.001), and the rate of 60-day mortality associated with Candida bloodstream infection tended to be reduced, from 42.9% (15/35) to 18.2% (4/22) (P = 0.081) compared to the before-intervention group. The incidence of adverse events associated with antifungal agents was significantly lower in the after-intervention group than in the before-intervention group (51.4% [18/35] vs 13.6% [3/22], P = 0.004). WHAT IS NEW AND CONCLUSION: Our findings suggest that daily review of the use of antifungal agents and monitoring of measured ßDG values was highly effective in reducing antifungal consumption and improving the clinical outcomes of patients with Candida bloodstream infection.
Assuntos
Antifúngicos/administração & dosagem , Candidíase/tratamento farmacológico , Glucanos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Candida/efeitos dos fármacos , Candidíase/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
The objective of this study was to analyze the relationship between the pharmacokinetic (PK)/pharmacodynamic (PD) parameters of a single 2-g dose of extended-release formulation of azithromycin (AZM-SR) and its microbiological efficacy against gonococcal urethritis. Fifty male patients with gonococcal urethritis were enrolled in this study. In 36 patients, the plasma AZM concentrations were measured using liquid chromatography-tandem mass spectrometry, the AZM MIC values for the Neisseria gonorrhoeae isolates were determined, and the microbiological outcomes were assessed. AZM-SR monotherapy eradicated N. gonorrhoeae in 30 (83%) of the 36 patients. AZM MICs ranged from 0.03 to 2 mg/liter. The mean value of the area under the concentration-time curve (AUC), estimated by population PK analysis using a two-compartment model, was 20.8 mg · h/liter. Logistic regression analysis showed that the PK/PD target value required to predict an N. gonorrhoeae eradication rate of ≥95% was a calculated AUC/MIC of ≥59.5. The AUC/MIC value was significantly higher in patients who achieved microbiological cure than in patients who achieved microbiological failure. Monte Carlo simulation using this MIC distribution revealed that the probability that AZM-SR monotherapy would produce an AUC/MIC exceeding the AUC/MIC target of 59.5 was 47%. Furthermore, the MIC distribution for strains isolated in this study was mostly consistent with that for strains currently circulating in Japan. In conclusion, in Japan, AZM-SR monotherapy may not be effective against gonococcal urethritis. Therefore, use of a single 2-g dose of AZM-SR either with or without other antibiotics could be an option to treat gonococcal urethritis if patients are allergic to ceftriaxone and spectinomycin or are diagnosed to be infected with an AZM-sensitive strain.
Assuntos
Antibacterianos/uso terapêutico , Azitromicina/farmacocinética , Azitromicina/uso terapêutico , Gonorreia/tratamento farmacológico , Neisseria gonorrhoeae/efeitos dos fármacos , Uretrite/tratamento farmacológico , Adulto , Antibacterianos/farmacocinética , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Gonorreia/microbiologia , Humanos , Japão , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Resultado do Tratamento , Uretrite/microbiologia , Adulto JovemRESUMO
BACKGROUND: Because clinical data to confirm the safety and effectiveness of fosphenytoin, a prodrug of phenytoin, are insufficient, the length of administration of fosphenytoin is restricted. Nevertheless, some cases require fosphenytoin administration for more than a few days. The aim of this study was to retrospectively investigate the serum concentration of phenytoin in adult Japanese patients who received intravenous fosphenytoin therapy for more than 3 days. METHODS: Patients injected with intravenous fosphenytoin for more than 3 days at Gifu University Hospital between January 2012 and September 2014 were enrolled. Individual pharmacokinetic parameters were predicted by Bayesian estimation using NONMEM software, and the maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration (10-20 mcg/mL) was calculated from the parameters. RESULTS: Among a total of 8 patients, the serum trough concentration of phenytoin decreased with each day after repeated injection of fosphenytoin. The incidence rate of significant convulsive seizures was increased time dependently (0% on day 1, 12.5% on day 2, 25% on day 3, and 66.7% on day 4 and after). Phenytoin clearance showed a time-dependent increase. The maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration was simulated to be 779.8 ± 316.8 mg/d, a dose that was markedly higher than the actual maintenance dose (414.1 ± 55.7 mg/d). CONCLUSIONS: Prolonged use of fosphenytoin, for such patients as those with autoimmune-mediated encephalopathy accompanied with reflux disease and/or ileus, time dependently decreased the serum concentration of phenytoin and increased the risk of convulsion. Therefore, the maintenance dose should be increased to maintain the therapeutic serum concentration.
Assuntos
Fenitoína/análogos & derivados , Fenitoína/sangue , Convulsões/epidemiologia , Administração Intravenosa , Adolescente , Adulto , Idoso , Anticonvulsivantes/sangue , Teorema de Bayes , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenitoína/administração & dosagem , Fenitoína/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Estudos Retrospectivos , Fatores de Tempo , Adulto JovemRESUMO
PURPOSE: Topical ketoprofen patch has been developed to reduce the risk of systemic adverse effects such as gastrointestinal injury and renal toxicity. MATERIALS AND METHODS: We reported here a case of lower intestinal bleeding associated with chronic excessive use of topical ketoprofen patch in an elderly patient. RESULTS: A 74-year-old female visited to the outpatient clinic of the Gifu University Hospital and admitted thereafter. She had fecal occult blood and anemia. Enteroscopic examination showed several ulcerative lesions and a protruded lesion accompanied with redness in the small intestinal mucosa. She used 8 sheets of 20 mg ketoprofen patch every day for a long period to relieve pain in the shoulder, lower back and lower limb. She had no diseases that are related to the initiation of gastrointestinal bleeding, including infection, inflammatory bowel disease, autoimmune disease and malignant disease. Thus, the present lower intestinal bleeding was concluded to be due to the use of topical ketoprofen patch. The symptoms were recovered after cessation of the patch. CONCLUSIONS: Extensive care should be taken to avoid ulcerative intestinal hemorrhage to elderly patients receiving multiple doses of non-steroidal anti-inflammatory drug patch for multiple days.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Hemorragia Gastrointestinal/induzido quimicamente , Cetoprofeno/efeitos adversos , Úlcera/induzido quimicamente , Administração Tópica , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Overdose de Drogas , Endoscopia Gastrointestinal , Feminino , Humanos , Cetoprofeno/administração & dosagem , Adesivo TransdérmicoRESUMO
While it is well known that L-carnitine [3-hydroxy-4-(trimethylazaniumyl)-butanoate] is an essential molecule for ß-oxidation, it provides anti-oxidative effects as well. Since these effects have been observed in photoreceptor cells, the carnitine's intracellular concentration is considered to play a protective role against oxidative damage to those cells. However, even though its high hydrophilicity makes it likely that carnitine import is accomplished via a dedicated host transport system, the specific uptake process into those cells is currently unknown. Therefore, in this study, we sought to identify and characterize photoreceptor cell carnitine uptake transporter(s) utilizing 661W cells as a photoreceptor cell model. The results of our uptake assays showed that carnitine was transported into 661W cells in a saturable manner (Km=5.5 mM), and that the activity was susceptible to extracellular pH and Na+. While these data suggest the involvement of a transporter in 661W cell carnitine uptake, the observed transport profile did not correspond to any of the currently known carnitine transporters such as organic cation/carnitine transporter 1 (Octn1), Octn2, Octn3, B0,+ and Ct2. In fact, in our experiments, the mRNA expressions for such carnitine transporters in 661W cells were consistently very low and the carnitine transporter substrates did not inhibit the uptake activities. Taken as a whole, our results indicate that carnitine is transported into 661W cells in a carrier-mediated manner. However, since its transport modes cannot be fully explained by known carnitine transporters, it is highly likely that photoreceptor cells utilize a unique molecularly-based carnitine uptake system.
Assuntos
Antioxidantes/farmacocinética , Transporte Biológico Ativo/fisiologia , Carnitina/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Células Fotorreceptoras/fisiologia , Animais , Linhagem Celular , Concentração de Íons de Hidrogênio , Degeneração Macular/tratamento farmacológico , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Sódio/metabolismoRESUMO
Management of constipation in patients receiving cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CHOP-like chemotherapy regimens is important for prevention of paralytic ileus. We reported earlier that the laxative action of magnesium oxide is reversed by the concomitant use of antacids in cancer patients receiving opioid analgesics. Here, we assessed the prevalence of prophylactic laxative medication for the control of constipation in patients receiving CHOP or CHOP-like regimens for non-Hodgkin's lymphoma. Data obtained from 211 eligible patients were retrospectively analyzed. Almost all patients (99%) received anti-ulcer agents such as proton pump inhibitors and H2 receptor antagonists for the prophylaxis of gastric disorders associated with prednisolone. Prophylactic laxatives were prescribed in 86 patients (40.8%), in which magnesium oxide was used most predominantly (88.4%). However, magnesium oxide at doses of â¦2000 mg/d was not effective for prevention of constipation, although the compound totally inhibited the incidence of constipation at doses higher than 2000 mg/d. Therefore, it is important to avoid negative drug interaction between magnesium oxide and antacids in patients receiving CHOP chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/prevenção & controle , Laxantes/uso terapêutico , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiácidos/uso terapêutico , Constipação Intestinal/epidemiologia , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Feminino , Humanos , Incidência , Óxido de Magnésio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Estudos Retrospectivos , Vincristina/efeitos adversos , Adulto JovemRESUMO
Leptomeningeal metastases occur in 1% of patients with non-small-cell lung cancer. There have been several reports on the treatment of leptomeningeal metastases with afatinib. Our patient was a 41-year-old woman who had never smoked and was diagnosed with stage IV adenocarcinoma of the lung with an epidermal growth factor receptor (EGFR) mutation. She was treated with afatinib for the recurrence of leptomeningeal metastases. After the treatment with afatinib was initiated, the neurological symptoms dramatically regressed, and she achieved progression-free survival for 7 months. The concentration of afatinib in the cerebrospinal fluid (CSF) ranged from 0.05 to 0.14 ng/mL, and the penetration rate of afatinib from the plasma to the CSF ranged from 0.28 to 0.40%. This concentration might be sufficient to achieve a clinical effect for leptomeningeal carcinomatosis. Therefore, afatinib administered at the usual doses may be an effective treatment for leptomeningeal carcinomatosis of EGFR-mutated or EGFR-tyrosine kinase inhibitor-sensitive lung adenocarcinoma.
Assuntos
Carcinomatose Meníngea/tratamento farmacológico , Quinazolinas/uso terapêutico , Radiossensibilizantes/uso terapêutico , Adulto , Afatinib , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/secundário , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Gefitinibe , Humanos , Imageamento por Ressonância Magnética , Carcinomatose Meníngea/complicações , Mutação , Recidiva Local de Neoplasia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/administração & dosagem , Quinazolinas/sangue , Quinazolinas/líquido cefalorraquidiano , Resultado do TratamentoRESUMO
We investigated the quantitation of oxidative chemical modifications, such as thiol oxidation and carbonylation, in medical-grade human serum albumin (HSA) preparations, in comparison with those of healthy and diseased subjects. Four kinds of HSA products were obtained from three major suppliers in Japan. Eight male collegiate students and six healthy male volunteers were recruited as the young (21.6 years) and older (57.2 years) groups, respectively. Four male stable patients (64.3 years) treated with regular hemodialysis (HD) also enrolled in this study. Quantitative analyses for thiol oxidation and carbonylation were performed using HPLC and spectroscopic methods, respectively. Structural characterization was further investigated by differential scanning calorimetry (DSC) and circular dichroism (CD) spectropolarimetry. Significantly larger amounts of thiol-oxidized and carbonylated HSA products were observed than HSA obtained from healthy subjects. In the structural characterization, the midpoint temperature of the denaturation curve (Tm) analyzed by DSC was relatively high, and may have been caused by the added albumin-specific stabilizers, and CD-resolved secondary structure showed that HSA products had a helical conformation. Commercial HSA products for clinical use have a more thermally stable state and remain in a helix-rich structure, even though their specific amino acids (mainly Cys and Lys residues) are oxidatively modified.
Assuntos
Albumina Sérica/química , Adulto , Idoso , Varredura Diferencial de Calorimetria , Dicroísmo Circular , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Carbonilação Proteica , Diálise Renal , Compostos de Sulfidrila/química , Adulto JovemRESUMO
Insufficient information is available to confirm the beneficial effects of implementing an antimicrobial stewardship program in reducing mortality of patients with bloodstream infections. A single institutional cohort study was conducted to evaluate clinical outcomes after implementation of a daily review of antimicrobials used to treat patients with bloodstream infections. Subjects were allocated to groups receiving either intervention or nonintervention. After implementation of an antimicrobial stewardship program, the day from the onset of infection required to administer effective intravenous antimicrobial treatment was significantly shortened (p=0.022), and the rate of de-escalation was significantly elevated (p<0.001) compared with the nonintervention group. Further, the rate of 30-d death associated with bloodstream infection was siginificantly reduced from 11.4 to 5.4% (p=0.030) compared with the nonintervention group. The incidence of adverse events was significantly lower in the intervention group than in the nonintervention group (7.7 vs. 28.0%, p<0.001). Our present findings suggest that daily review of the use of antimicrobials was highly effective for optimizing early antimicrobial therapy and improved clinical outcomes of patients with bloodstream infections.
Assuntos
Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Monitoramento de Medicamentos , Idoso , Antibacterianos/efeitos adversos , Bacteriemia/microbiologia , Bactérias/isolamento & purificação , Uso de Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Control of chemotherapy-induced nausea is still incomplete, regardless of adherence to the antiemetic guideline. The present study was designed to assess the control rates of nausea and vomiting in the outpatient chemotherapy clinic and to determine risk factors for nausea. METHODS: A single-center prospective observational study was carried out in 779 patients who received 5511 chemotherapy cycles from January 2013 to December 2014 in the outpatient chemotherapy clinic. A checklist for adverse events was provided to all patients, and nausea and vomiting were monitored on the next visit. Complete protection from nausea and vomiting during acute (within 24 h) and delayed (during 2-7 days) periods was assessed. RESULTS: Under the condition of 76-99 % rates of adherence to the Japanese Society of Clinical Oncology guideline for antiemesis, the rates of complete protection from acute and delayed nausea in the first cycle of chemotherapy were 60 % and 45 %, respectively, for high emetic risk chemotherapy (HEC), and 85 % and 70 % for moderate emetic risk chemotherapy (MEC). The rates were improved in the overall cycles. On the other hand, vomiting was well controlled, in which complete protection ranged from 83 % (HEC) to 99 % (minimum). A multivariate analysis indicated that being female, age less than 60 years, high or moderate risk chemotherapy, and anthracycline/cyclophosphamide (A/C) were significant risks for overall nausea. Indeed, the control of delayed nausea was extremely poor in the first cycle of A/C, although there was no difference in the control of nausea among MEC. CONCLUSION: Antiemetic medication in consideration of the risk factors is required to improve the control of nausea.
Assuntos
Antieméticos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Náusea/tratamento farmacológico , Neoplasias/tratamento farmacológico , Vômito/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Pacientes Ambulatoriais , Prognóstico , Estudos Prospectivos , Fatores de Risco , Vômito/induzido quimicamente , Adulto JovemRESUMO
A simultaneous, selective, sensitive and rapid liquid chromatography/tandem mass spectrometry method was developed and validated for the quantification of gefitinib, erlotinib and afatinib in 250 µL samples of human blood plasma. Diluted plasma samples were extracted using a liquid-phase extraction procedure with tert-butyl methyl ether. The three drugs were separated by high-performance liquid chromatography using a C18 column and an isocratic mobile phase running at a flow rate of 0.2 mL/min for 5 min. The drugs were detected using a tandem mass spectrometer with electrospray ionization using imatinib as an internal standard. Calibration curves were generated over the linear concentration range of 0.05-100 nm in plasma with a lower limit of quantification of 0.01 or 0.05 nm for all compounds. Finally, the validated method was applied to a clinical pharmacokinetic study in patients with nonsmall-cell lung cancer (NSCLC) following the oral administration of afatinib. These results indicate that this method is suitable for assessing the risks and benefits of chemotherapy in patients with NSCLC and is useful for therapeutic drug monitoring for NSCLC treatment. As far as we know, this is the first report on LC-MS/MS method for the simultaneous quantification of NSCLC tyrosine kinase inhibitor plasma concentrations including afatinib. Copyright © 2015 John Wiley & Sons, Ltd.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/sangue , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/sangue , Afatinib , Calibragem , Carcinoma Pulmonar de Células não Pequenas/sangue , Cromatografia Líquida/métodos , Gefitinibe , Humanos , Limite de Detecção , Neoplasias Pulmonares/sangue , Espectrometria de Massas em Tandem/métodosRESUMO
Extracellular-superoxide dismutase (genetic name SOD3) is a secreted anti-oxidative enzyme, and its presence in vascular walls may play an important role in protecting the vascular system against oxidative stress. Oxidative stress has been implicated in the pathogenesis of diabetic retinopathy; therefore, increases in extracellular-superoxide dismutase have been suggested to inhibit the progression of diabetic retinopathy. Incretin-based drugs such as glucagon-like peptide-1 receptor agonists are used in the treatment of type 2 diabetes. Glucagon-like peptide-1 receptor agonists are expected to function as extrapancreatic agents because the glucagon-like peptide-1 receptor is expressed not only in pancreatic tissues, but also in many other tissue types. We herein demonstrated that exendin-4, a glucagon-like peptide-1 receptor agonist, induced the expression of extracellular-superoxide dismutase in human retinal microvascular endothelial cells through epigenetic regulation. The results of the present study demonstrated that exendin-4 induced the expression of extracellular-superoxide dismutase through histone H3 acetylation at the SOD3 proximal promoter region. Moreover, plasma extracellular-superoxide dismutase concentrations in diabetic patients were elevated by incretin-based therapies. Therefore, incretin-based therapies may exert direct extrapancreatic effects in order to protect blood vessels by enhancing anti-oxidative activity.
RESUMO
PURPOSE: Although anti-EGFR monoclonal antibodies, including cetuximab and panitumumab, are highly effective in KRAS wild-type advanced colorectal cancer, these drugs frequently cause several adverse events. These events include hypomagnesemia and acneiform rash, which may lead to the dose reduction or discontinuation of therapy. In the present study, we retrospectively investigated the incidence of hypomagnesemia and acneiform rash in patients with metastatic colorectal cancer (mCRC). We examined the relationship between the incidence of such adverse events and the therapeutic effect. METHODS: Thirty-four mCRC patients receiving anti -EGFR monoclonal antibody as a first-line therapy during April 2012 to March 2015 were the subjects of the present study. The symptoms of hypomagnesemia and acneiform rash were graded in accordance with the Common Terminology Criteria for Adverse Events, v4.0. RESULTS: The incidence rates of hypomagnesemia (all grades) and the acneiform rash (≥grade 2) were 29%and 50%, respectively. Eight patients (24%) exhibited both of these adverse events. The tumor response rate was notable, as it was significantly higher in patients who experienced both of these adverse events compared to those who did not(88% vs 38% for complete response plus partial response, p=0.039). However, the tumor response rate tended to be higher, although not significantly, in patients with either of these adverse events compared to those without it. CONCLUSION: Concurrent onset of hypomagnesemia and acneiform rash may become a reliable factor capable of predicting the therapeutic effect of anti-EGFR monoclonal antibody.
Assuntos
Erupções Acneiformes/epidemiologia , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Exantema/epidemiologia , Deficiência de Magnésio/epidemiologia , Magnésio/sangue , Erupções Acneiformes/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/patologia , Receptores ErbB/imunologia , Exantema/induzido quimicamente , Feminino , Humanos , Incidência , Deficiência de Magnésio/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Panitumumabe , Estudos RetrospectivosRESUMO
Purpose: We aimed to preliminarily compare the glaucoma detection accuracy of a head-mounted binocular visual perimeter "imo" screening program (ISP) with that of frequency doubling technology (FDT). Methods: This multicenter, diagnostic accuracy study based on prospectively collected data included 76 non-glaucoma (including pre-perimetric glaucoma) eyes and 92 glaucomatous eyes from patients visiting two hospitals. Patients underwent ISP and FDT (C-20-1 screening program) on the same day. Diagnostic efficacy was evaluated using receiver operating characteristic curves and areas under the curve (AUCs). In addition, we compared the ISP and FDT testing times. Results: AUC values for ISP versus FDT were as follows: (1) mild-stage glaucoma (mean deviation [MD] > -6 dB), 0.82 (95% confidence interval [CI], 0.75-0.88) versus 0.76 (95% CI, 0.68-0.83); moderate-stage glaucoma (-6 dB ≥ MD ≥ -12 dB), 0.98 (95% CI, 0.95-1.00) versus 0.96 (95% CI, 0.93-1.00); and advanced-stage glaucoma (-12 dB > MD), 1.00 (95% CI, 1.00-1.00) versus 0.99 (95% CI, 0.98-1.00). In addition, mild-stage glaucoma was classified into two stages (MD > -3 D) and (-3 D ≥ MD > -6 D). AUC values were 0.81 (95% CI, 0.73-0.88) versus 0.76 (95% CI, 0.68-0.84) for MD > -3 D and 0.86 (95% CI, 0.77-0.94) versus 0.73 (95% CI, 0.61-0.86) for -3 D ≥ MD > -6 D. The testing time for the ISP was significantly shorter than that of FDT for all glaucoma stages (P < 0.001). Conclusions: The ISP demonstrates non-inferiority in detecting glaucoma and has a shorter testing time compared with FDT. These findings provide evidence for applied further studies on large-scale population-based glaucoma screening. Translational Relevance: Our study provides a non-inferior and quicker glaucoma screening than existing tools.
Assuntos
Glaucoma , Testes de Campo Visual , Humanos , Feminino , Masculino , Testes de Campo Visual/métodos , Testes de Campo Visual/instrumentação , Pessoa de Meia-Idade , Glaucoma/diagnóstico , Idoso , Estudos Prospectivos , Curva ROC , Campos Visuais/fisiologia , Área Sob a Curva , Visão Binocular/fisiologia , Adulto , Pressão Intraocular/fisiologiaRESUMO
Prolonged use of benzodiazepines often leads to dependence and withdrawal syndrome. However, the cellular mechanisms underlying benzodiazepine dependence have not been fully clarified. Several investigators have shown an involvement of metabotropic glutamate receptors (mGluRs) in the pathophysiology of dependence or withdrawal. This study was performed to elucidate the role of mGluRs in benzodiazepine dependence. Withdrawal signs were precipitated in mice by flumazenil injection (25 mg/kg) after continuous subcutaneous infusion of benzodiazepines for 7 days, and the effects of several Gi-coupled receptor ligands on forskolin-stimulated cyclic AMP accumulation were examined in the cerebral cortex of mice. The mRNA expression for mGluRs was determined by RT-PCR. A single injection of flumazenil precipitated typical withdrawal signs such as tail elevation and tremor in mice treated with diazepam or alprazolam, but not quazepam. The inhibitory effect of nonselective mGluR ligands on adenylate cyclase activity was diminished in mice that showed signs of benzodiazepine withdrawal. The mRNA expression levels of mGluR2 and mGluR3 were lowered in the cerebral cortex of mice pretreated with diazepam or alprazolam. Our findings suggest that the reduction in the expression of group II mGluRs subunits may be involved in the development of benzodiazepine dependence.
Assuntos
Benzodiazepinas/farmacologia , Receptores de Glutamato Metabotrópico/genética , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Córtex Cerebral/metabolismo , Dopamina/metabolismo , Flumazenil/farmacologia , Moduladores GABAérgicos/farmacologia , Ácido Homovanílico/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Camundongos , Serotonina/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Tremor/induzido quimicamenteRESUMO
In the outpatient cancer chemotherapy clinic of Gifu University Hospital, pharmacists contributed to the provision of safe and efficacious cancer chemotherapy as full-time staff, together with doctors, nurses and other medical staff. Since April 2010, three pharmacists have been in charge of the provision of pharmaceutical care services(PCS)to all patients. Furthermore, pharmaceutical intervention before medical examination(pre-PCS)was initiated in May 2011. As a consequence, the time spent for patient education and monitoring significantly(p<0. 001)increased from 39. 7±3. 2min/patient in 2010 to 48. 0±2. 6min/patient in 2011. The number of proposals on prescriptions also significantly increased, 2. 5 times, compared to 2010. The percentage of the acceptance of proposals was 94% in fiscal year 2011. Importantly, pre-PCS improved the control of chemotherapy-induced nausea and vomiting, peripheral neuropathy and skin rash. These results suggest that pre-PCS by pharmacists would be beneficial to progress the quality of outpatient cancer chemotherapy.
Assuntos
Instituições de Assistência Ambulatorial , Institutos de Câncer , Neoplasias , Assistência Farmacêutica , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Neoplasias/tratamento farmacológico , Educação de Pacientes como Assunto , Fatores de TempoRESUMO
PRCIS: A novel visual field screening program with a head-mounted perimeter 'imo' could detect glaucoma at all stages in a short time with high accuracy. PURPOSE: The present study aimed to examine the accuracy and availability of a novel glaucoma visual field screening program using a head-mounted visual perimeter 'imo.' PARTICIPANTS AND METHODS: Eyes of 76 non-glaucoma participants and 92 glaucoma patients were examined. All patients underwent visual field tests using the Humphrey Visual Field Analyzer (30-2 or 24-2 Swedish Interactive Thresholding Algorithm standard program) and imo (the visual field screening program). We evaluated five visual field screening program indicators: sensitivity, specificity, positive predictive value, negative predictive value, and testing time. We also evaluated the ability of this visual field screening program to differentiate between glaucoma patients and normal controls using the receiver operating characteristic curves and areas under the receiver operating characteristic curves. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of the visual field screening program were 76%-100%, 91%-100%, 86%-89%, and 79%-100%, respectively. The visual field screening program test time was 46±13 seconds for normal controls and 61±18, 82±21, and 105±16 econds, respectively for mild, moderate, and advanced-stage patients. The areas under the receiver operating characteristic curves were 0.77, 0.97, and 1.0 in the mild, moderate, and advanced stages, respectively. CONCLUSIONS: Visual field screening using a head-mounted perimeter 'imo' detected glaucoma at all stages in a short time with high accuracy.
Assuntos
Glaucoma , Campos Visuais , Humanos , Pressão Intraocular , Glaucoma/complicações , Glaucoma/diagnóstico , Testes de Campo Visual , Olho , Sensibilidade e EspecificidadeRESUMO
Purpose: Over 50% of patients with early-stage glaucoma discontinue topical therapy within the first 6 months of treatment initiation. This risk of discontinuation could be reduced by how the ophthalmologist explains the treatment plan. Ophthalmologists can explain the treatment plan to patients in either positive or negative contexts. Although explanations in a negative context can be selected depending on the medical situation, identification of patients who will choose the treatment with explicit statistical prediction after an explanation in a negative context is important; personality traits are related to these emotional decisions. Therefore, in the present study, we examined the personality traits associated with choice of treatment with explicit statistical prediction after an explanation in a negative context. Patients and Methods: A total of 147 patients with glaucoma were recruited for this study. The questionnaire booklets used contained positively framed or negatively framed versions of an "Asian disease problem" to enable examination of the influence of the way in which a problem is framed (framing effect) on the participants' decision-making. The Japanese version of the Ten-Item Personality Inventory was used to estimate the personality traits of the participants. Results: Low conscientiousness was identified as the only variable that was strongly predictive of the choice of treatment with explicit statistical prediction (ß = -0.44, z = 2.19, p = 0.03). In addition, while the association was not statistically significant, low neuroticism was found to be weakly predictive of the choice of uncertain treatment (ß = -0.37, z = 1.73, p = 0.08). Conclusion: In conclusion, we showed that low levels of conscientiousness predict the choice of treatment with explicit statistical prediction (ie, topical treatment) for glaucoma after an explanation in a negative context.