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We created a one-minute video titled "a simple method of eye-drop instillation" (video) for online instillation guidance, to compare the instillation method before and after study participants watch the video and verify the usefulness of watching the video. Moreover, we prepared a document questionnaire to investigate instillation habits and clarify instillation behavior. Study participants were randomly recruited from among students and faculty members via a poster posted at Tokushima Bunri University. The instillation behavior of the study participants was videotaped before and after they watched the video created by the authors. The images were played in a super slow motion, to confirm success or failure in instillation, drop sites, and eye-opening method. Of the 109 participants in the study, the successful instillation rate before and after watching the video was 55.0% and 69.7%, respectively. The use rate of wet wipes for finger disinfection before instillation increased from 0.0% before watching the video to 74.3% after watching the video. After watching the video, the blinking rate after instillation decreased from 95.4 to 45.0%, the rate of pressing the nasolacrimal duct increased from 2.8 to 77.1%, and the rate of wiping the drug solution spilled around the eyes increased from 89.9 to 98.2%. According to the questionnaire, 72.5% of the participants instilled one drop, 22.0% instilled two drops, and 5.5% instilled three drops or more. Watching the video significantly increased the successful instillation rate and improved instillation behavior. Thus, the video created by the authors can be used for online instillation guidance.
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Ojo , Humanos , Soluciones OftálmicasRESUMEN
We report a haemodialysis patient with end-stage renal failure whom a pharmacist aided in the management of acyclovir (ACV) encephalopathy, which may have been related to valacyclovir hydrochloride (VACV) administered without sufficient dose reduction. The patient 78 years was admitted with a tentative diagnosis of varicella zoster viral meningitis. A pharmacist suspected ACV encephalopathy related to excessive VACV administration and raised a query with the attending physician. According to the pharmacist's proposal, ACV administration was discontinued and continuous hemodiafiltration (CHDF) was performed. On day 5 of hospitalisation, the consciousness disorder was improved. In this report, we showed the detailed CHDF conditions of the present case, and the contribution of a pharmacist to treating and avoiding ACV encephalopathy was discussed.
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Encefalopatías , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Aciclovir/efectos adversos , Encefalopatías/inducido químicamente , Encefalopatías/tratamiento farmacológico , Humanos , Farmacéuticos , ValaciclovirRESUMEN
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors such as afatinib are used for non-small cell lung cancer (NSCLC) and show varying efficacy depending on EGFR gene mutation. Few studies have examined the relationship between EGFR gene mutations and the adverse events of afatinib in NSCLC. This retrospective study included 32 Japanese patients with NSCLC with EGFR gene mutation who were treated with afatinib between May 2014 and August 2018 at Kagawa University Hospital. Among the 32 Japanese patients with NSCLC treated with afatinib, 19 patients were positive for exon 19 deletion mutation (Del 19) and 13 patients were negative for Del 19. The incidence of grade ≥â 2 skin rash was slightly higher in patients positive for Del 19 (42.1% vs. 7.7%, Pâ =â 0.050). No significant differences were detected in other adverse events between the two patient groups. Patients positive for Del 19 also showed significantly longer median progression-free survival (288 vs. 84 days, Pâ =â 0.049). Our study indicates a higher incidence of skin rash associated with afatinib treatment in Japanese patients with NSCLC positive for Del 19 compared with patients without Del 19. The Del 19 positive patient group also showed better progression-free survival. J. Med. Invest. 68 : 125-128, February, 2021.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Afatinib/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Estudios RetrospectivosRESUMEN
Bioactive N-acylethanolamines (NAEs) include palmitoylethanolamide, oleoylethanolamide, and anandamide, which exert anti-inflammatory, anorexic, and cannabimimetic actions, respectively. The degradation of NAEs has been attributed to two hydrolases, fatty acid amide hydrolase and NAE acid amidase (NAAA). Acid ceramidase (AC) is a lysosomal enzyme that hydrolyzes ceramide (N-acylsphingosine), which resembles NAAA in structure and function. In the present study, we examined the role of AC in the degradation of NAEs. First, we demonstrated that purified recombinant human AC can hydrolyze various NAEs with lauroylethanolamide (C12:0-NAE) as the most reactive NAE substrate. We then used HEK293 cells metabolically labeled with [14C]ethanolamine, and revealed that overexpressed AC lowered the levels of 14C-labeled NAE. As analyzed with liquid chromatography-tandem mass spectrometry, AC overexpression decreased the amounts of different NAE species. Furthermore, suppression of endogenous AC in LNCaP prostate cells by siRNA increased the levels of various NAEs. Lastly, tissue homogenates from mice genetically lacking saposin D, a presumable activator protein of AC, showed much lower hydrolyzing activity for NAE as well as ceramide than the homogenates from wild-type mice. These results demonstrate the ability of AC to hydrolyze NAEs and suggest its physiological role as a third NAE hydrolase.
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Ceramidasa Ácida/metabolismo , Etanolaminas/metabolismo , Animales , Células HEK293 , Humanos , Hidrólisis , Masculino , RatonesRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Our objective is to report on a case of posterior reversible encephalopathy syndrome associated with pazopanib. CASE DESCRIPTION: A 64-year-old patient with uterine sarcoma developed PRES 3 days after pazopanib was initiated. After the discontinuation of pazopanib, the symptoms of PRES improved. WHAT IS NEW AND CONCLUSION: The first report worldwide to describe a patient with uterine sarcoma experiencing PRES caused by pazopanib. Patients with uterine sarcoma may experience PRES, even in the early phase of pazopanib therapy.
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Inhibidores de la Angiogénesis/uso terapéutico , Indazoles/uso terapéutico , Síndrome de Leucoencefalopatía Posterior/diagnóstico , Pirimidinas/uso terapéutico , Sarcoma/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Neoplasias Uterinas/tratamiento farmacológico , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Diagnóstico Diferencial , Femenino , Humanos , Indazoles/administración & dosificación , Indazoles/efectos adversos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Síndrome de Leucoencefalopatía Posterior/inducido químicamente , Síndrome de Leucoencefalopatía Posterior/diagnóstico por imagen , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversosRESUMEN
We investigated the success rates of eyedrop instillation and the distance between the cornea and the dropper tip in 100 volunteers using high-speed digital video recording. Past eyedrop adherence studies assumed that instillation occurred without failure. The ideal distance between the cornea and dropper tip remained unclear, although the general estimate was approximately 2.54 cm (1 inch). This study was approved by the Institutional Review Boards of all participating medical institutions, and all volunteers provided written, informed consent. Successful instillation was defined as when 1 drop fell accurately into the eye on the first attempt. The instillation of ≥2 drops or drops delivered outside the eye was considered a failure. The distance between the eye and dropper tip was measured using still images from a paused digital video camera and a digital ruler. Forty percent of the volunteers instilled eyedrops without instructions from ophthalmologists, pharmacists, or other healthcare workers. When the images were analyzed, the success rate of the first instillation was 70.1%. When the eye was arbitrarily divided into 9 sections, most of the drop sites were the iris or the center of the eye. The distance between the dropper tip and cornea was 2.62±1.75 (median 2.20) cm. These results indicate that the generally recommended distance is usually followed. The successful instillation rate based on the distance from the dropper tip to the cornea was 77% at 1.6±0.88 cm and 54.9% at 4.8±1.25 cm.
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Soluciones Oftálmicas/administración & dosificación , Grabación en Video/métodos , Córnea , Humanos , Instilación de Medicamentos , Estudios ProspectivosRESUMEN
Several reports have investigated relationships between epidermal growth factor receptor (EGFR) mutations and the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer; however, there have been insufficient analyses of relationships between EGFR mutations and adverse reactions. This study investigated the relationships between EGFR mutations and skin rash. We first compared skin rash grades between different mutations, then tested factors possibly affecting skin rash by multivariate analysis. The main outcome measure was the significant difference in incidence of skin rash between each group with different mutations. Our study suggested that the risk of skin rash is low in patients with exon 19 deletion mutations who are taking EGFR-TKIs, whereas it is high in those with exon 21 point mutations. These results will be useful indicators for instructions regarding daily examinations, skin care, and use of oral antibiotics or topical steroids in patients taking EGFR-TKIs with skin rash.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Exantema/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Factores de Edad , Anciano , Anciano de 80 o más Años , Superficie Corporal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores SexualesRESUMEN
BACKGROUND: The new Clinical Trials Act that recently came into effect in Japan emphasizes the reliability of investigator-initiated clinical trials. Although Japanese clinical research coordinators have been mainly engaged in operational roles in industry-initiated clinical trials for drug approval (registration trials), broadening their contribution to cover more types of clinical research may lead to quality improvement of clinical research. To ultimately establish a clinical research infrastructure that meets the needs of the new era of Clinical Trials Act, here we gathered basic information on how clinical research coordinators might make such contributions. METHODS: We conducted a survey using self-reporting questionnaires in clinical research-related personnel to examine present status and the perspectives toward broader contribution of clinical research coordinators. The study participants were attendee of group discussion of a clinical research-related meeting in Shikoku area of Japan held in August 2017. RESULTS: Among 88 participants, 69 responded (response rate: 78.4%) and 68 respondents (98.6%) were engaged in support and management of clinical research. The main area of involvement was industry-initiated registration trials (48, 69.7%), and main roles of involvement were cooperators who plays roles under the guidance of investigators (41, 59.5%). When divided by occupation into clinical research coordinators (n = 41) and other clinical research-related personnel (n = 28), approximately half of the respondents in each group replied positively to wanting broader involvement of clinical research coordinators as a clinical research professional. CONCLUSION: The present study revealed that about half of the clinical research coordinators and other clinical research-related personnel view a broadening of involvement of clinical research coordinators in research activities positively. Accordingly, a structured practical program aimed at encouraging such involvement may help to expand and strengthen their contribution into the future. Whether greater involvement of clinical research coordinators in clinical research will help to ensure the reliability of investigator-initiated clinical research warrants further study.
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Bevacizumab (BV), an inhibitor of vascular endothelial growth factor, is used in combination with paclitaxel (PTX) to treat advanced breast cancer. Hypertension and proteinuria are characteristic adverse events of BV therapy. We assessed the potential of these adverse events as predictors of BV treatment responses. Our results revealed that groups that developed hypertension and proteinuria early (by day 56) had a stronger antitumor response (Fisher's exact test p<0.05). However, no significant difference was observed in progression-free survival (the Kaplan-Meier method and Log-rank test). As a reference, age, the treatment line, subtypes, liver and renal function, diabetes mellitus and hyperlipidemia history, body mass index, influencing concomitant medicine, average relative dose intensity and hematotoxicity did not significantly differ between groups with or without hypertension and with or without proteinuria. These results indicate the potential of the development of hypertension and proteinuria as predictors of improved outcomes with PTX plus BV therapy in patients with breast cancer. However, since both adverse events may preclude the continuation of treatment, their earlier management may be required.
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Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Hipertensión/inducido químicamente , Proteinuria/inducido químicamente , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Bevacizumab/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Paclitaxel/uso terapéutico , Resultado del TratamientoRESUMEN
The human gut commensal Bacteroides fragilis produces sialidases that remove a terminal sialic acid from host-derived polysaccharides. Sialidase is considered to be involved in B. fragilis infection pathology. A native B. fragilis sialidase has been purified and characterized, and was shown to be post-translationally modified by glycosylation. However, the biochemical properties of recombinant B. fragilis sialidase expressed in a heterologous host remain uncharacterized. In this study, we examined the enzymatic properties of the 60-kDa sialidase NanH1 of B. fragilis YCH46, which was prepared as a recombinant protein (rNanH1) in Escherichia coli. In E. coli rNanH1 was expressed as inclusion bodies, which were separated from soluble proteins to allow solubilization of insoluble rNanH1 in a buffer containing 8â¯M urea and renaturation in refolding buffer containing 100â¯mM CaCl2 and 50â¯mM L-arginine. The specific activity of renatured rNanH1 measured using 4-methylumberiferyl-α-D-N-acetyl neuraminic acid as a substrate was 6.16⯵mol/min/mg. The optimal pH of rNanH1 ranged from 5.0 to 5.5. The specific activity of rNanH1 was enhanced in the presence of calcium ions. rNanH1 preferentially hydrolyzed the sialyl α2,8 linkage and cleaved sialic acids from mucin and serum proteins (e.g., fetuin and transferrin) but not from α1-acid glycoprotein, which is similar to the previously observed biochemical properties for a native sialidase purified from B. fragilis SBT3182. The results and methods described in this study will be useful for preparing and characterizing recombinant proteins for other B. fragilis sialidase isoenzymes.
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Bacteroides fragilis/enzimología , Bacteroides fragilis/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Neuraminidasa/genética , Neuraminidasa/metabolismo , Proteínas Recombinantes , Activación Enzimática , Hidrólisis , Iones , Mucinas/química , Mucinas/metabolismo , Ácido N-Acetilneuramínico/química , Ácido N-Acetilneuramínico/metabolismo , Neuraminidasa/química , Neuraminidasa/aislamiento & purificación , Replegamiento ProteicoRESUMEN
INTRODUCTION: Therapeutic drug monitoring is necessary for lithium, but clinical application of several prediction strategies is still limited because of insufficient predictive accuracy. We herein proposed a suitable model, using creatinine clearance (CLcr)-based lithium clearance (Li-CL). METHODS: Patients receiving lithium provided the following information: serum lithium and creatinine concentrations, time of blood draw, dosing regimen, concomitant medications, and demographics. Li-CL was calculated as a daily dose per trough concentration for each subject, and the mean of Li-CL/CLcr was used to estimate Li-CL for another 30 subjects. Serum lithium concentrations at the time of sampling were estimated by 1-compartment model with Li-CL, fixed distribution volume (0.79 L/kg), and absorption rate (1.5/hour) in the 30 subjects. RESULTS: One hundred thirty-one samples from 82 subjects (44 men; mean±standard deviation age: 51.4±16.0 years; body weight: 64.6±13.8 kg; serum creatinine: 0.78±0.20 mg/dL; dose of lithium: 680.2±289.1 mg/day) were used to develop the pharmacokinetic model. The mean±standard deviation (95% confidence interval) of absolute error was 0.13±0.09 (0.10-0.16) mEq/L. DISCUSSION: Serum concentrations of lithium can be predicted from oral dosage with high precision, using our prediction model.
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Trastorno Bipolar/sangre , Depresión/sangre , Litio/sangre , Modelos Biológicos , Esquizofrenia/sangre , Adulto , Anciano , Anciano de 80 o más Años , Trastorno Bipolar/tratamiento farmacológico , Creatinina/sangre , Depresión/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Humanos , Litio/uso terapéutico , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Esquizofrenia/tratamiento farmacológico , Adulto JovenRESUMEN
Some patients do not inform healthcare professionals of adverse drug reactions (ADRs) because they fear termination of aggressive medication therapies. Preferences for aggressive medication therapies may differ between patients and pharmacists. The goal of this study was to estimate whether pharmacists were able to accurately assess patient preference for aggressive medication therapies with potentially stronger ADRs. A cross-sectional study was conducted of hospitalized patients (35 to 74 years of age) receiving oral medications for a chronic disease or systemic chemotherapy at three hospitals in Japan. We estimated the extent of agreement between patient responses and pharmacist predictions using a scenario-based investigation (1) to examine the choice between an aggressive medication therapy and the standard therapy, and (2) to assess increased life expectancy as a result of aggressive medication therapy. The extent of agreement was estimated using the kappa statistic. Of 113 patients, 43 (38.1%) chose the aggressive medication therapy. Pharmacists correctly predicted the choice of 25 (58.1%) of these patients [kappa 0.32 (95% confidence interval 0.15-0.50)]. Of 111 patients, 42 (37.8%) expected one additional life expectancy year. However, pharmacists predicted that as many as 36 (85.7%) of these patients would require more years of added life expectancy before choosing an aggressive medication therapy [kappa 0.24 (0.08-0.40)]. Agreement between patients and pharmacists on the choice of aggressive medication therapy was generally poor. Pharmacists should make an effort to identify patients who might prefer more aggressive medication therapies with potentially stronger ADRs in order to minimize ADR risk.
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Quimioterapia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Pacientes Internos , Prioridad del Paciente , Farmacéuticos , Adulto , Anciano , Comunicación , Estudios Transversales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Relaciones Profesional-PacienteRESUMEN
The survival of patients with metastatic breast cancer (MBC) has not improved, despite recent advances in therapeutic strategies. This is mainly due to the fact that cytotoxic agents cannot be administered over a long period, even if they exhibit favorable activity, due to treatment-related side effects or acquisition of tumor resistance to the administered agents. Thus, the development of therapeutic strategies that may be used over a long time period is required to improve survival. We assessed the availability and clinical outcomes of metronomic chemotherapy, which is defined as continuous or frequent treatment with low doses of cytotoxic drugs. A total of 80 patients with MBC received chemotherapy in the metastatic setting, and the clinicopathological factors and clinical outcomes were retrospectively compared between 52 patients who received metronomic regimens and 28 patients who received other cytotoxic regimens. As regards clinical outcomes, the median time-to-treatment failure (TTF) and overall survival (OS) were significantly longer in the metronomic group compared with those in the non-metronomic group (TTF, 15 vs. 4 months, P=0.0001; and OS, 53 vs. 28 months P=0.0012, respectively). In the metronomic group, none of the 18 patients who responded to the regimen had triple-negative (TN) cancer (17 had luminal-type tumors and 1 had a human epidermal factor receptor 2-type tumor). Furthermore, TTF and OS were significantly longer in patients with non-TN cancer compared with those in patients with TN cancer in the metronomic group (TTF, 16 vs. 7 months, P=0.0014; and OS, 108 vs. 20 months, P=0.000007, respectively). The proportion of patients who experienced treatment-related adverse events was significantly lower in the metronomic group compared with that in the non-metronomic group (36.5 vs. 61.5%, respectively; P=0.038). In conclusion, metronomic chemotherapy is a viable option for luminal-type MBC in terms of effectiveness and minimal toxicity, regardless of metastatic sites or prior treatment. However, an alternative treatment is required for TN cancer.
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PURPOSE: Cancer patients receiving chemotherapy will sometimes conceal their discomfort, but an excessive endurance for adverse drug reactions (ADRs) can lead to a poorer prognosis. The aim of this study was to clarify the association between ADR endurance and a preference of cancer patients for aggressive treatments. METHODS: A cross-sectional study was undertaken of inpatients under 75 years of age receiving injectable systemic chemotherapy or oral chronic medications at hospitals in Japan. Subjects were asked to respond to a validated questionnaire to assess the extent of their ADR endurance and whether they would choose a novel, more aggressive therapy if their life expectancy was estimated at 2 years. RESULTS: Study participants were separated into the chemotherapy group (n = 36) and the non-chemotherapy group (n = 78). In the chemotherapy group, patients who had moderate ADR endurance scores were more likely to choose the new therapy (0-33, 34-67, and 68-100 points: 0.0, 54.5, and 27.3 %; χ (2) test, p = 0.15). Additionally, every patient on long-term chemotherapy (≥3 years) had high ADR endurance scores but did not choose the new, riskier treatment. In the non-chemotherapy group, the proportion of those choosing the new therapy was linearly associated with higher ADR endurance scores (25.9, 38.2, and 64.7 %; p = 0.04). CONCLUSION: Cancer patients may prefer aggressive therapies, even when self-estimations of ADR endurance are not very high, especially if they have been receiving chemotherapy for a short period of time. These patients should be observed with great caution.
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Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/psicología , Prioridad del Paciente , Sobrevivientes/psicología , Adaptación Psicológica , Adulto , Anciano , Antineoplásicos/administración & dosificación , Estudios Transversales , Toma de Decisiones , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Although survival of patients with metastatic breast cancer (MBC) has been significantly prolonged over the past decade due to improvement of anti-cancer therapeutics, only a few patients survive for more than 10 years. It has not been determined which patients can have long-term survival with treatment. METHODS: To determine prognostic factors responsible for long-term survival, we retrospectively compared clinicopathologic factors of patients with MBC who survived for 50 months or more after diagnosis with patients who did not. Of 70 patients with MBC who received chemotherapy between November 2005 and September 2011, 23 patients who survived for 50 months or more after diagnosis and 28 patients who died within 50 months after diagnosis were assessed for their clinicopathologic factors and outcomes. RESULTS: The proportion of patients with hormone receptor-positive (HR+) tumors was significantly higher and the proportion of patients with triple negative tumors (TN) was lower in long-term survivors than in non-long-term survivors (HR+: 87% versus 28.6%, P=0.000037; TN: 13.1% versus 53.6%, P=0.0028). Metastatic site, number of disease sites, prior chemotherapeutic regimens and human epidermal growth factor receptor-2 (HER2) status did not differ between the two groups. The proportion of patients who received metronomic regimens was significantly higher in long-term survivors than in non-long-term survivors (65.2% versus 35.7%, P=0.034) when the most effective regimen among regimens that were received in metastatic settings was compared between the two groups. Overall response rate was significantly higher (82.6% versus 17.9%, P<0.00001) and time to treatment failure after receiving the most effective regimen was longer in long-term survivors than in non-long-term survivors (26 versus 5 months, P=0.0001). The number of chemotherapeutic regimens for breast cancer and that for MBC did not differ between the two groups. CONCLUSIONS: Patients with luminal-type MBC who benefit at least once from chemotherapy including metronomic regimens, or patients who continued to receive the most effective regimen for more than two years can be expected to have long-term survival after diagnosis of MBC, regardless of the number of chemotherapeutic regimens they had received.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Factores de TiempoRESUMEN
Bayesian estimation enables the individual pharmacokinetic parameters of the medication administrated to be estimated using only a few blood concentrations. Due to wide inter-individual variability in the pharmacokinetics of methotrexate (MTX), the concentration of MTX needs to be frequently determined during high-dose MTX therapy in order to prevent toxic adverse events. To apply the benefits of Bayesian estimation to cases treated with this therapy, we attempted to develop an estimation method using the Bayesian least-squares method, which is commonly used for therapeutic monitoring in a clinical setting. Because this method hypothesizes independency among population pharmacokinetic parameters, we focused on correlations among population pharmacokinetic parameters used to estimate individual parameters. A two-compartment model adequately described the observed concentration of MTX. The individual pharmacokinetic parameters of MTX were estimated in 57 cases using the maximum likelihood method. Among the available parameters accounting for a 2-compartment model, V1, k10, k12, and k21 were found to be the combination showing the weakest correlations, which indicated that this combination was best suited to the Bayesian least-squares method. Using this combination of population pharmacokinetic parameters, Bayesian estimation provided an accurate estimation of individual parameters. In addition, we demonstrated that the degree of correlation among population pharmacokinetic parameters used in the estimation affected the precision of the estimates. This result highlights the necessity of assessing correlations among the population pharmacokinetic parameters used in the Bayesian least-squares method.
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Teorema de Bayes , Metotrexato/administración & dosificación , Metotrexato/farmacocinética , Modelos Estadísticos , Modelación Específica para el Paciente , Adolescente , Adulto , Anciano , Neoplasias Óseas/tratamiento farmacológico , Niño , Relación Dosis-Respuesta a Droga , Humanos , Análisis de los Mínimos Cuadrados , Linfoma/tratamiento farmacológico , Persona de Mediana Edad , Osteosarcoma/tratamiento farmacológico , Estudios Retrospectivos , Adulto JovenRESUMEN
Mycophenolate mofetil (MMF) is used for oral administration to prevent rejection in renal transplant recipients, and is rapidly converted into mycophenolic acid (MPA), the active metabolite, by hydrolysis in vivo. The area under the concentration-time curve (AUC(0-12 h)) of MPA is considered to be an effective pharmacokinetics parameter for predicting acute rejection. However, frequent blood sampling is required to calculate AUC(0-12 h), which imposes a burden on patients and providers. Therefore, we examined a limited sampling strategy (LSS) for estimation of MPA-AUC(0-12 h) using only a trough level (C0) and two points including C0 in Japanese living-related renal transplant recipients with concomitant extended-release tacrolimus (ER-TAC). The present study suggests that better estimation of MPA-AUC(0-12 h) can be obtained by using two points including C0 as compared with only C0 regardless of transplant progress. Furthermore, blood collection points showing the highest estimation of MPA-AUC(0-12 h) by adding to C0 were C4 at pre-transplantation (Tx) and 1 month post-Tx, and C6 at 3 months post-Tx. We conjecture that changes in renal function and serum albumin (Alb) accompanying transplant progress are aggravating factors in terms of estimation, because there was also a significant difference in the reciprocal of serum creatinine (1/Scr) and Alb between pre-Tx and post-Tx in this study. In conclusion, the present study provides useful information for effective and efficient monitoring of MPA levels in Japanese living-related renal transplant recipients.
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Preparaciones de Acción Retardada/administración & dosificación , Inmunosupresores/administración & dosificación , Trasplante de Riñón , Ácido Micofenólico/farmacocinética , Tacrolimus/administración & dosificación , Adulto , Anciano , Área Bajo la Curva , Pueblo Asiatico , Recolección de Muestras de Sangre/métodos , Monitoreo de Drogas/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/sangre , Adulto JovenRESUMEN
We examined the effects of angiotensin II AT1-receptor blockade with olmesartan on high fat (HF) diet-induced vascular oxidative stress and endothelial dysfunction in normal salt (NS) diet-fed Dahl salt-sensitive (DSS) rats. Treatment with NS + HF diet (32% crude fat, 0.3% NaCl) for 20 weeks significantly increased blood pressure in DSS rats. NS + HF diet-fed DSS rats also showed higher plasma levels of thiobarbituric acid-reactive substances, aortic superoxide production, and mRNA levels of p22(phox) and gp91(phox) in aortic tissues than NS diet-fed DSS rats. Furthermore, acetylcholine-induced vasorelaxation of aorta from NS + HF diet-fed DSS rats was significantly reduced. In NS + HF diet-fed DSS rats, treatment with olmesartan medoxomil (10 mg/kg per day, p.o.) and hydralazine (25 mg/kg per day, p.o.) similarly decreased blood pressure. However, in these animals, only olmesartan normalized plasma levels of thiobarbituric acid-reactive substances, vascular superoxide in aortic tissues, and acetylcholine-induced vasorelaxation. These data indicate that HF diet-induced hypertension is associated with vascular oxidative stress and endothelial dysfunction in NS diet-treated DSS rats. Inhibition of angiotensin II AT1 receptors may elicit beneficial effects on HF-induced hypertension and vascular injury in subjects that have genetically enhanced sodium-sensitive blood pressure.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Dieta Alta en Grasa/efectos adversos , Endotelio Vascular/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Receptor de Angiotensina Tipo 1/metabolismo , Animales , Antihipertensivos/farmacología , Aorta/efectos de los fármacos , Aorta/metabolismo , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Endotelio Vascular/metabolismo , Hidralazina/farmacología , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Hipertensión/fisiopatología , Imidazoles/farmacología , Masculino , Glicoproteínas de Membrana/metabolismo , NADPH Oxidasa 2 , NADPH Oxidasas/biosíntesis , NADPH Oxidasas/metabolismo , Olmesartán Medoxomilo , Ratas , Ratas Endogámicas Dahl , Superóxidos/metabolismo , Tetrazoles/farmacología , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Vasodilatación/efectos de los fármacosRESUMEN
We assessed the clinical usefulness of human epidermal growth factor receptor-2 extracellular domain (HER2ECD) as a biomarker for detecting cancer and monitoring disease status and for predicting the efficacy of anticancer treatment in breast cancer. Five-hundred and eighty serum samples from 252 patients with breast cancer were examined for the concentration of HER2ECD to compare with conventional tumor markers (CEA, CA15-3, NCC-ST439 and BCA225). Also, in 19 patients with HER2-overexpressed advanced or recurrent breast cancer who were treated with trastuzumab, clinical outcomes were evaluated retrospectively to determine whether their serum HER2ECD levels predict clinical responses. The proportion of patients with elevated HER2ECD levels was 15.1%, which was compatible with those with elevated conventional marker levels. In patients with HER2-overexpressed breast cancer, the positive rate of HER2ECD was significantly higher (24.1%) than those of conventional markers (7.4-12.9%), suggesting the usefulness of HER2ECD for detecting cancer in this population. HER2-overexpressed patients responding to trastuzumab (12 of 19 patients) showed significantly higher serum HER2ECD level (p = 0.033) and longer time to progression (TTP) (p = 0.039) and overall survival (OS) (p = 0.031) than did patients not responding (seven patients). Furthermore, higher response rates were observed in patients with elevated HER2ECD levels than in patients without elevated HER2ECD levels (91.3% vs. 14.3%, p = 0.032), whereas there was no difference in survival between the two groups. The results suggest that HER2ECD is a useful biomarker not only for detecting breast cancer recurrence but also for predicting tumor responses to trastuzumab.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/sangre , Carcinoma Ductal de Mama/sangre , Recurrencia Local de Neoplasia/sangre , Receptor ErbB-2/sangre , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Capecitabina , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/secundario , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Docetaxel , Resistencia a Antineoplásicos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Paclitaxel/administración & dosificación , Estructura Terciaria de Proteína , Receptor ErbB-2/química , Taxoides/administración & dosificación , Trastuzumab , Resultado del TratamientoRESUMEN
The objective of treatment for metastatic breast cancer (MBC) is to control the disease or disease-related symptoms. Prolonged survival has also often been achieved by chemotherapeutic regimens in this setting. Long-term administration of one therapeutic regimen is essential for prolonging survival as well as for maintaining quality of life in these patients. In this study, we focused on time to treatment failure (TTF) as a parameter that predicts patient survival and we retrospectively compared clinical outcomes of patients with MBC who showed TTF of ≥12 months (26 patients) and <12 months (29 patients). The proportion of hormone receptor-positive tumors and the number of prior chemotherapy regimens for MBC were significantly higher and tumor grade was lower in patients with TTF ≥12 months compared to those with TTF <12 months. With regard to clinical outcomes, the objective response rate (ORR) in patients with TTF ≥12 months was significantly higher and median time to progression (TTP) and overall survival (OS) were longer compared to those with TTF <12 months. Of note, the proportion of patients who received metronomic regimens was significantly higher in patients with TTF ≥12 months compared to those with TTF <12 months (80.8 vs. 24.1%, P=0.00003). To assess the clinical benefit of metronomic regimens, the efficacy in patients receiving metronomic and those receiving non-metronomic regimens was compared. Although there was no difference in ORR between the two groups, median TTP and OS were significantly longer in the metronomic compared to the non-metronomic group (TTP: 30 vs. 4 months, P=0.0017; OS: 68 vs. 28 months, P=0.0005). The results suggested that metronomic chemotherapy is useful for palliative care and also improved clinical outcomes as a regimen for which long-term administration may be expected.