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Smoking during lactation harmfully affects the amount and constituents of breast milk. Infants who consume breast milk containing miR-210-5p may have a higher risk of brain-related diseases. We investigated whether smoking during lactation decreases ß-casein concentrations in milk and whether miR-210-5p expression is involved in smoking-induced ß-casein suppression. During lactation, maternal CD1 mice were exposed to cigarette smoke (1.7 mg of tar and 14 mg of nicotine) in a smoke chamber for 1 h twice/day for five consecutive days. Control mice were placed in an air-filled chamber equivalent in size to the smoke chamber, with maternal separation times identical to those of the smoked mice. Maternal exposure to smoke during lactation significantly decreased ß-casein expression in the mammary epithelia of smoked mice compared to that of the control mice. Signal transducer and activator transcription 5 (STAT5) and phosphorylated STAT5 (pSTAT5) are transcription factors involved in ß-casein expression. In the mammary epithelia of smoked mice, the pSTAT5 and STAT5 levels were significantly lower, and miR-210-5p expression was significantly higher than that of the control mice. The ß-casein, pSTAT5, and STAT5 protein levels of miR-210-5p mimic-transfected human mammary epithelial MCF-12A cells were significantly lower than those of control siRNA-transfected cells. These results indicate that smoke exposure led to an increase in miR-210-5p expression in mammary epithelium and a decrease in pSTAT5 and ß-casein protein levels through the inhibition of STAT5 expression. Moreover, nicotine treatment decreased ß-casein protein levels and increased miR-210-5p expression in non-malignant human mammary epithelial MCF-12A cells in a concentration-dependent manner, demonstrating that nicotine significantly affects the ß-casein and miR-210-5p levels of breast milk. These results highlight the adverse effects of smoking on breast milk, providing essential information for healthcare professionals and general citizens.
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INTRODUCTION: Vancomycin requires a population pharmacokinetic (popPK) model to estimate the area under the concentration-time curve (AUC), and an AUC-guided dosing strategy is necessary. This study aimed to develop a popPK model for vancomycin using a real-world database pooled from a nationwide web application (PAT). METHODS: In this retrospective study, the PAT database between December 14, 2022 and April 6, 2023 was used to develop a popPK model. The model was validated and compared with six existing models based on the predictive performance of datasets from another PAT database and the Kumamoto University Hospital. The developed model determined the dosing strategy for achieving the target AUC. RESULTS: The modeling populations consisted of 7146 (13,372 concentrations from the PAT database), 3805 (7540 concentrations from the PAT database), and 783 (1775 concentrations from Kumamoto University Hospital) individuals. A two-compartment popPK model was developed that incorporated creatinine clearance as a covariate for clearance and body weight for central and peripheral volumes of distribution. The validation demonstrated that the popPK model exhibited the smallest mean absolute prediction error of 5.07, outperforming others (ranging from 5.10 to 5.83). The dosing strategies suggested a first dose of 30 mg/kg and maintenance doses adjusted for kidney function and age. CONCLUSIONS: This study demonstrated the updating of PAT through the validation and development of a popPK model using a vast amount of data collected from anonymous PAT users.
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BACKGROUND: Cancer has been identified as a risk factor for severe illness and mortality in coronavirus disease (COVID-19), underscoring the importance of recommending COVID-19 vaccinations to patients with cancer. However, few reports have focused on the vaccination status and the incidence of adverse events among patients with cancer. In this study, we aimed to evaluate the vaccination status, incidence of adverse events, concerns, and anxiety related to COVID-19 vaccination among patients with cancer. In addition, we explored the utilization of information sources by these patients and the ease of use. METHODS: A survey was conducted among outpatients undergoing chemotherapy who received medication counseling from a pharmacist at Juntendo University Hospital. Responses were gathered from 60 out of the 143 participants. Of the respondents, 96.7% had received two doses of the COVID-19 vaccine. RESULTS: Common adverse events included pain at the injection site, fever, and fatigue, which were experienced by nearly half of the respondents. Approximately 80% expressed some concern regarding vaccination, with predominant concerns about timing in the context of ongoing cancer treatment and surgery. Among the respondents, 41.7% consulted primary care physicians regarding the vaccine, with only one mentioning consultation with hospital pharmacists. Notably, primary care physicians were considered the most approachable and useful healthcare professionals. CONCLUSIONS: These results suggest that patients with cancer can safely receive the vaccine, comparable to patients without cancer. However, they still harbor concerns, even when seeking advice from primary care physicians. Few patients consulted pharmacists about vaccination, highlighting an opportunity for pharmacist intervention. Pharmacists fostering trust with patients with cancer is imperative to explore pharmacist intervention methods to promote the continued administration of COVID-19 vaccines and enhance the quality of life for them.
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PURPOSE: High-dose methotrexate therapy (HD-MTX) is a standard treatment for various malignant tumors, but approximately 1-10% of patients experience delayed MTX elimination (DME) that can induce organ damage. Glucarpidase can hydrolyze MTX and thereby lower the level of active MTX in the blood. A multicenter, open-label, phase II investigator-initiated trial (CPG2-PII study) was conducted to evaluate glucarpidase rescue therapy in Japanese patients who showed DME after HD-MTX treatment. To confirm the robustness of this therapy, further corporate-sponsored clinical trial (OP-07-001 study) was conducted. METHODS: The primary endpoint in the CPG2-PII study was to evaluate the proportion of patients of the percentage clinical important reduction (CIR) as an indicator of MTX concentration, which can be managed with leucovorin and supportive care. The primary endpoint of the OP-07-001 study was to evaluate the decreasing rate of plasma MTX concentration at 20 min after glucarpidase administration from the baseline for four patients. Glucarpidase was administered at a dose of 50 U/kg for 15 and 4 patients, respectively in the two studies, and safety was analyzed for each of them. RESULTS: The rate of CIR was 76.9% (95% confidence interval, 46.2-95.0%) in the CPG2-PII study. The median reduction rate of plasma MTX was 98.83% in the OP-07-001 study. Hypersensitivity, blood bilirubin increased, and headache for each patient were the only study drug-related events. CONCLUSION: Glucarpidase showed an effect of reducing plasma MTX concentration in Japanese patients with DME as that observed in a previous US study, confirming its favorable safety and tolerability.
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Antimetabólitos Antineoplásicos , Metotrexato , gama-Glutamil Hidrolase , Humanos , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/efeitos adversos , Adulto , Neoplasias/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Relação Dose-Resposta a DrogaRESUMO
In this study, we aimed to evaluate limited sampling strategies for achieving the therapeutic ranges of the area under the concentration-time curve (AUC) of vancomycin on the first and second day (AUC0-24 , AUC24-48 , respectively) of therapy. A virtual population of 1000 individuals was created using a population pharmacokinetic (PopPK) model, which was validated and incorporated into our model-informed precision dosing tool. The results were evaluated using six additional PopPK models selected based on a study design of prospective or retrospective data collection with sufficient concentrations. Bayesian forecasting was performed to evaluate the probability of achieving the therapeutic range of AUC, defined as a ratio of estimated/reference AUC within 0.8-1.2. The Bayesian posterior probability of achieving the AUC24-48 range increased from 51.3% (a priori probability) to 77.5% after using two-point sampling at the trough and peak on the first day. Sampling on the first day also yielded a higher Bayesian posterior probability (86.1%) of achieving the AUC0-24 range compared to the a priori probability of 60.1%. The Bayesian posterior probability of achieving the AUC at steady-state (AUCSS ) range by sampling on the first or second day decreased with decreased kidney function. We demonstrated that second-day trough and peak sampling provided accurate AUC24-48 , and first-day sampling may assist in rapidly achieving therapeutic AUC24-48 , although the AUCSS should be re-estimated in patients with reduced kidney function owing to its unreliable predictive performance.
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Antibacterianos , Vancomicina , Humanos , Teorema de Bayes , Estudos Retrospectivos , Estudos Prospectivos , Monitoramento de Medicamentos/métodos , Área Sob a CurvaRESUMO
INTRODUCTION: The latest therapeutic drug monitoring guidelines for vancomycin (VCM) recommend that area under the concentration-time curve is estimated based on model-informed precision dosing and used to evaluate efficacy and safety. Therefore, we predicted VCM concentrations in individual methicillin-resistant Staphylococcus aureus-infected patients using existing a physiologically based pharmacokinetic (PBPK) model and 1- and 2-compartment population pharmacokinetic (PPK) models and confirmed and verified the accuracy of the PBPK model in estimating VCM concentrations with the PPK model. METHODS: The subjects of the study are 20 patients, and the predicted concentrations were evaluated by comparing the observed and predicted trough and peak values of VCM concentrations for individual patients. RESULTS: The results showed good correlation between the observed and predicted trough and peak concentrations of VCM was observed generally in the PBPK model, R2 values of 0.72, 0.62, and 0.40 with trough values of 0.49, 0.40, and 0.34 with peak values for PBPK model, 1-compartment, and 2-compartment model, respectively. CONCLUSIONS: Although the performance of the PBPK model is not as predictive as the PPK model, generally similar predictive trends were obtained, suggesting that it may be a valuable tool for rapid and accurate prediction of AUC for VCM.
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Purpose: Whether the coronavirus disease 2019 (COVID-19) pandemic had any effect on the time between blood culture collection and administration of antibiotics in the outpatient Department of Emergency Medicine in a single university hospital in Japan was investigated, and the intervention carried out by the antimicrobial stewardship team (AST) to promote the appropriate use of antibiotics was examined. Patients and Methods: The monthly percentage of patients who visited the outpatient Department of Emergency Medicine between January 2019 and December 2021 and received an intravenous antibiotic within 3 hours of blood culture collection was calculated. The AST calculated a quality indicator (QI) based on the results of the investigation and started QI monitoring and hospital feedback. Results: From January 2020 to March 2021 (the third COVID-19 wave), the implementation rate of antibiotic administration within 3 hours after blood culture collection decreased as the COVID-19 pandemic spread, and the implementation rate tended to increase as the number of COVID-19-positive patients decreased. However, when the AST started monitoring and feedback from April 2021, although there was a temporary decline in the early stages of the fifth wave when the scale of infection was large, the implementation rate rose and was maintained by AST intervention. (the fourth and the fifth COVID-19 waves) (P<0.01). Also, the implementation rate was significantly lower during the COVID-19 pandemic than during the non- pandemic (P<0.05). Conclusion: The early COVID-19 pandemic may have affected the delay in time from blood culture collection to antibiotic administration. Later, in recurring COVID-19 pandemics, AST intervention eliminated this problem. When a bacterial infection such as sepsis is suspected, delayed treatment can be prevented by promptly collecting a blood culture, irrespective of concerns about COVID-19 infection. Calculating the QI may promote AST activities and the appropriate use of antibiotics.
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BACKGROUND: The optimal timing for therapeutic drug monitoring (TDM) of voriconazole in Asians, who have higher rates of poor metabolisers than non-Asians, is unclear. This can cause unexpectedly high concentrations and delays in reaching steady-state levels. OBJECTIVES: To determine the appropriate timing of TDM in Japanese patients receiving voriconazole. PATIENTS/METHODS: Trough levels (Cmin ) were measured on days 3-5 (recommended timing, RT) and days 6-14 (delayed timing, DT) after starting voriconazole in patients receiving an appropriate dosage. Considering bioavailability, Cmin was only compared in patients receiving oral voriconazole. RESULTS: A total of 289 and 186 patients were included in the safety and pharmacokinetic analyses, respectively. There was a significant difference in Cmin measured no later than and after day 5 (3.59 ± 2.12 [RT] vs. 4.77 ± 3.88 µg/mL [DT], p = .023), whereas no significant difference was observed on cutoff day 6 (3.91 ± 2.60 vs. 4.40 ± 3.94 µg/mL, p = .465), suggesting that Cmin close to the steady-state was achieved after day 5. DT causes a delay in achieving the therapeutic range. The hepatotoxicity rates were 21.5% and 36.8% in the RT and DT groups, respectively (p = .004); DT was an independent risk factor for hepatotoxicity. CONCLUSION: Although steady-state concentrations may not be achieved by day 5, early dose optimisation using RT can prevent hepatotoxicity in Japanese patients. TDM should be performed on days 3-5 to ensure safety. However, subsequent TDM may be necessary due to a possible further increase in Cmin .
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Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Voriconazol/efeitos adversos , Antifúngicos/efeitos adversos , Monitoramento de Medicamentos , População do Leste AsiáticoRESUMO
An 80-year-old woman underwent pancreatoduodenectomy. Post-operation, she experienced a fever, and a culture of blood revealed metallo-beta-lactamase-producing Raoultella ornithinolytica. For treatments with aminoglycoside antimicrobial agents, a therapeutic drug monitoring-based dosing design can lower the risk of adverse events and enable appropriate treatment. Key Clinical Message. When aminoglycoside antimicrobial agents are administered for MBL-producing bacteremia, prescription suggestions based on TDM by antimicrobial stewardship team can reduce the occurrence of adverse events and enable appropriate treatment.
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BACKGROUND: Model-informed approaches are important in drug development, including for dose optimization and the collection of evidence in support of efficacy. MATERIALS AND METHODS: We developed a modified Michaelis-Menten pharmacokinetics/pharmacodynamics model and used it to conduct simulations of glucarpidase at doses between 10 and 80 U/kg rescue treatment after high-dose methotrexate therapy. We carried out a dose-finding modeling and simulation study before a phase II study of glucarpidase. Monte-Carlo simulations were conducted using the deSolve package of R software (version 4.1.2). The proportion of samples in which the plasma methotrexate concentration was less than 0.1 and 1.0 µmol/l at 70 and 120 h after methotrexate treatment was evaluated for each dosage of glucarpidase. RESULTS: The proportion of samples in which the plasma methotrexate concentration was less than 0.1 µmol/l at 70 h after methotrexate treatment was 71.8% and 89.6% at 20 and 50 U/kg of glucarpidase, respectively. The proportion of samples in which the plasma methotrexate concentration was less than 0.1 µmol/l at 120 h after methotrexate treatment was 46.4% and 59.0% at 20 and 50 U/kg of glucarpidase, respectively. CONCLUSION: We determined a recommended glucarpidase dose of 50 U/kg to be ethically acceptable. A rebound in the serum concentration of methotrexate may be observed in many patients after the administration of glucarpidase, and long-term monitoring (over 144 h) of the serum methotrexate concentration may be needed after the administration of glucarpidase. Its validity was confirmed in the phase II study and glucarpidase was approved for manufacturing in Japan.
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Antimetabólitos Antineoplásicos , Metotrexato , Humanos , gama-Glutamil Hidrolase/uso terapêutico , Desenvolvimento de MedicamentosRESUMO
Introduction: Glucarpidase (CPG2) reduces the lethal toxicity of methotrexate (MTX) by rapid degradation. Methods: In this study, a CPG2 population pharmacokinetics (popPK) analysis in healthy volunteers (phase 1 study) and a popPK-pharmacodynamics (popPK-PD) analysis in patients (phase 2 study, n = 15) who received 50 U/kg of CPG2 rescue for delayed MTX excretion were conducted. In the phase 2 study, the first CPG2 treatment at a dose of 50 U/kg was intravenously administered for 5 min within 12 h after the first confirmation of delayed MTX excretion. The second dose of CPG2, with a plasma MTX concentration >1 µmol/L, was administered to the patient more than 46 h after the start of CPG2 administration. Results: The population mean PK parameters (95% CI) of MTX, obtained from the final model post hoc, were estimated as follows: CLrMTX = 2.424 L/h (95% CI: 1.755-3.093), VcMTX = 12.6 L (95% CI: 10.8-14.3), VpMTX = 2.15 L (95% CI: 1.60-2.70), and α = 8.131 x 105 (4.864 x 105-11.398 x 105). The final model, including covariates, was CLrMTX (L/h): 3.248 x Body Weight/Serum creatinine/60 (CV 33.5%), VcMTX (L): 0.386 x Body Weight/body surface area (CV 29.1%), VpMTX (L):3.052 x Body Weight/60 (CV 90.6%), and α (L/h): 6.545 x 105 (CV 79.8%). Discussion: These results suggest that the pre-CPG2 dose and 24 h after CPG2 dosing were the most important sampling points in the Bayesian estimation of plasma MTX concentration prediction at 48 h. These CPG2-MTX popPK analysis and Bayesian estimation of rebound in plasma MTX concentrations are clinically important to estimate >1.0 µmol/L 48 h after the first CPG2 dosing. Clinical trial registration: https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=2363, identifier JMA-IIA00078 and https://dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=2782, identifier JMA-IIA00097.
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Teicoplanin, a glycopeptide antimicrobial, is recommended for therapeutic drug monitoring, but it remains unclear how to target the area under the concentration-time curve (AUC). This simulation study purposed to demonstrate the potential of the Bayesian forecasting approach for the rapid achievement of the target AUC for teicoplanin. We generated concordant and discordant virtual populations against a Japanese population pharmacokinetic model. The predictive performance of the Bayesian posterior AUC in limited sampling on the first day against the reference AUC was evaluated as an acceptable target AUC ratio within the range of 0.8-1.2. In the concordant population, the probability for the maximum a priori or Bayesian posterior AUC on the first day (AUC0-24 ) was 61.3% or more than 77.0%, respectively. The Bayesian posterior AUC on the second day (AUC24-48 ) was more than 75.1%. In the discordant population, the probability for the maximum a priori or Bayesian posterior AUC0-24 was 15.5% or 11.7-80.7%, respectively. The probability for the maximum a priori or Bayesian posterior AUC24-48 was 23.4%, 30.2-82.1%. The AUC at steady-state (AUCSS ) was correlated with trough concentration at steady-state, with a coefficient of determination of 0.930; the coefficients on days 7 and 4 were 0.442 and 0.125, respectively. In conclusion, this study demonstrated that early sampling could improve the probability of AUC0-24 and AUC24-48 but did not adequately predict AUCSS . Further studies are necessary to apply early sampling-based model-informed precision dosing in the clinical settings.
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Antibacterianos , Teicoplanina , Humanos , Teorema de Bayes , Previsões , ProbabilidadeRESUMO
Similar to antimicrobial stewardship, the concept of antifungal stewardship (AFS) has also received attention. AFS outcomes include reduced healthcare costs, avoidance of adverse events, and increased implementation of therapeutic drug monitoring (TDM). Several processes and outcome measures have recently been reported for implementing AFS and evaluating its effectiveness in healthcare institutions. This review focuses on our AFS efforts to standardize treatment using a template for pharmacist-led patient intervention for candidemia and to evaluate TDM dosage adequacy rates for voriconazole. The importance of "task shifting", in which the physician's work is transferred or shared with pharmacists and other co-medical staff to alleviate concentration of physician workload, has also been advocated. This review focuses on how pharmacists are involved in AFS.
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Antifúngicos , Candidemia , Humanos , Farmacêuticos , VoriconazolRESUMO
PURPOSE: Voriconazole, an antifungal drug, is metabolized by a cytochrome P450 isozyme. Increased adverse effects are observed in Asians because of the high rate of poor metabolizers. In this therapeutic drug monitoring (TDM) guideline, recommendations were made according to ethnic group. METHODS: Five clinical questions were used. For the preparation of the guideline, the performance of TDM in multicenter studies was surveyed (study 1). We also conducted a systematic review and meta-analysis (study 2) to establish recommendations for non-Asians and Asians. FINDINGS: In study 1, 401 patients were surveyed. A risk of supratherapeutic concentrations was found in Japanese patients who adhered to the recommended dose. Target trough levels were achieved in 87% of patients with dose reductions. Although the trough level measured at the onset of adverse effects (AEs) was significantly associated with hepatotoxicity, no significant correlation was found between the initial trough level and hepatotoxicity, which indicated that hepatotoxicity was successfully prevented by the trough-guided dosing. In study 2, 22 studies (11 Asian locations and 11 non-Asian locations) were included in meta-analysis for the relationship between trough cutoff level (3, 4, 5, 5.5, and 6 µg/mL) and AEs. Significant differences were found for all cutoff levels, with the highest odds ratio for 4.0 µg/mL in Asian locations. In contrast, in non-Asian locations, no more than 1 study was available for any trough cutoff level, except for 5.5 µg/mL, at which level a significant increase in AEs was found. These findings indicate that TDM is strongly recommended to prevent AEs in Asians, and TDM is generally recommended for non-Asians to address subtherapeutic concentrations. TDM on day 3 is recommended to assess pharmacokinetic properties, including loading and maintenance doses. If the patient condition permits, delaying until day 5 is suggested for Asians because of the prolonged t½ in poor metabolizers. A trough level ≥1.0 µg/mL is strongly recommended to improve efficacy. Trough levels ≥2.0 µg/mL are suggested for invasive aspergillosis. To decrease adverse effects, trough levels <4.0 µg/mL are strongly recommended in Asians, whereas trough levels <5.5 µg/mL are generally recommended in non-Asians. Maintenance doses of 4 and 3 mg/kg twice daily are recommended in non-Asians and Asians, respectively. IMPLICATIONS: Different indications, timings, and target trough levels for TDM and different regimens are suggested for Asians and non-Asians.
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Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Adulto , Voriconazol/efeitos adversos , Monitoramento de Medicamentos , Consenso , População do Leste Asiático , Antifúngicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológicoRESUMO
PURPOSE: Several landmark trials have reported that direct oral anticoagulants (DOACs) are more effective in preventing stroke and systemic embolism than vitamin K antagonists. However, nonadherence to DOACs worsens prognosis in patients with nonvalvular atrial fibrillation (NVAF) despite the effectiveness of the drugs. The purpose of this study was to evaluate the effects of a pharmacist-led educational interventional program involving motivational interviewing on medication adherence, as assessed by electronic monitoring, in patients receiving DOACs for the treatment of NVAF. METHODS: This prospective, randomized, interventional study was conducted at outpatient cardiology clinics at general hospitals and pharmacies in Japan. Patients with NVAF who were treated with a once-daily DOAC (edoxaban) or a twice-daily DOAC (apixaban) were randomized to receive either: (1) an educational interventional program involving motivational interviewing regarding adherence to anticoagulants; or (2) standard medication counseling. The primary end point was the change in the medication adherence rate, calculated as the number of days that patients appropriately took the drug, as assessed by an electronic monitoring device, divided by the total number of days that the drug was prescribed, from a 12-week observation period to a 12-week intervention period. The secondary end points were tolerability outcomes. The effect of the educational interventional program on the primary end point was analyzed in subgroups stratified by gender and type of DOAC received. FINDINGS: A total of 268 patients completed the observation period and were randomly assigned to one of the two study groups. The difference in the primary end point between the educational interventional program group and the standard medication counseling group was not significant (mean [SD], 2.9% [7.5%] vs 3.4% [8.3%]). On multiple linear regression analysis, the difference in DOAC adherence between the two groups was not significant, but that adherence to apixaban was significantly improved among men in the educational interventional program (ß = 0.219; P = 0.012). Two patients died of causes considered unrelated to treatment; no stroke/systemic embolism or major bleeding events were observed. IMPLICATIONS: In this randomized, controlled study of the effects of a pharmacist-led educational interventional program using motivational interviewing on adherence to DOACs among patients with NVAF, adherence to DOACs, as assessed using an electronic monitoring device, was not improved with the educational interventional program compared to standard medication counseling . However, adherence to twice-daily apixaban was improved among men, but not among women, in the educational interventional program group. In this study, the selection of DOACs was not randomized, and the lack of assessment of the association between adherence to DOACs and clinical outcomes was a limitation. Japan Registry of Clinical Trials (jRCT) indentifier: jRCTs031180142.
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Fibrilação Atrial , Embolia , Acidente Vascular Cerebral , Masculino , Humanos , Feminino , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Farmacêuticos , Estudos Prospectivos , Administração Oral , Anticoagulantes/efeitos adversos , Acidente Vascular Cerebral/prevenção & controle , EletrônicaRESUMO
BACKGROUND: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. LAY SUMMARY: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.
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Antineoplásicos , Neuroblastoma , Adulto , Antineoplásicos/efeitos adversos , Criança , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Ftalazinas/efeitos adversos , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Poli(ADP-Ribose) PolimerasesRESUMO
BACKGROUND: No factors influencing the blood everolimus (EVL) concentrations has been identified until date. Our aim was to identify factors that can affect the ratio of the trough blood concentration to dose level (C0/D ratio) of EVL in kidney transplant recipients. METHODS: We retrospectively analyzed 448 patients who had undergone kidney transplantation and were subsequently being managed as our hospital between 2011 and 2015. Multivariate analysis were performed in an attempt to identify factors affecting the EVL C0/D ratio. RESULTS: The numbers of patients receiving calcineurin inhibitor (CNI)-free regimen and regimen containing cyclosporine (CsA) or tacrolimus (TAC) were 47, 137 and 264 respectively. The EVL C0/D ratio did not differ significantly between the TAC(+) group and the CNI-free group, while it was significantly higher in the CsA(+) group than the TAC(+) group (p < 0.0001) and CNI-free group (p = 0.0003). In the multivariate analysis, age, gender, diabetes mellitus as a cause of the end-stage renal disease (ESRD), CsA, serum creatinine, and hemoglobin were selected as factors affecting the EVL C0/D ratio (R2 = 0.269, p < 0.0001). Using the stepwise method, although mycophenolate mofetil treatment was selected, did not differ significantly according to multiple linear regression analysis. Furthermore, concomitant use of CsA was identified as the most impactful factor, based on the standardized partial regression coefficients (ß = 0.341). CONCLUSIONS: We obtained an indication of patient characteristics that influences the EVL C0/D ratio. But the accuracy of the regression equation obtained from multiple regression analysis was poor (R2 = 0.269), and it was not accurate enough to predict the EVL C0/D ratio and use it for therapeutic drug monitoring.
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Everolimo , Transplante de Rim , Inibidores de Calcineurina/uso terapêutico , Ciclosporina/uso terapêutico , Quimioterapia Combinada , Everolimo/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Japão , Estudos Retrospectivos , Tacrolimo/uso terapêutico , TransplantadosRESUMO
BACKGROUND: To promote model-informed precision dosing (MIPD) for vancomycin (VCM), we developed statements for therapeutic drug monitoring (TDM). METHODS: Ten clinical questions were selected. The committee conducted a systematic review and meta-analysis as well as clinical studies to establish recommendations for area under the concentration-time curve (AUC)-guided dosing. RESULTS: AUC-guided dosing tended to more strongly decrease the risk of acute kidney injury (AKI) than trough-guided dosing, and a lower risk of treatment failure was demonstrated for higher AUC/minimum inhibitory concentration (MIC) ratios (cut-off of 400). Higher AUCs (cut-off of 600 µg·h/mL) significantly increased the risk of AKI. Although Bayesian estimation with two-point measurement was recommended, the trough concentration alone may be used in patients with mild infections in whom VCM was administered with q12h. To increase the concentration on days 1-2, the routine use of a loading dose is required. TDM on day 2 before steady state is reached should be considered to optimize the dose in patients with serious infections and a high risk of AKI. CONCLUSIONS: These VCM TDM guidelines provide recommendations based on MIPD to increase treatment response while preventing adverse effects.
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Under the Japanese health insurance system, medicines undergoing therapeutic drug monitoring (TDM) can be billed for medical fees if they meet the specified requirements. In Japan, TDM of vancomycin, teicoplanin, aminoglycosides, and voriconazole, which are used for the treatment of infectious diseases, is common practice. This means the levels of antibiotics are measured in-house using chromatography or other methods. In some facilities, the blood and/or tissue concentrations of other non-TDM drugs are measured by HPLC and are applied to treatment, which is necessary for personalized medicine. This review describes personalized medicine based on the use of chromatography as a result of the current situation in Japan.
Assuntos
Antibacterianos , Seguro , Antibacterianos/uso terapêutico , Monitoramento de Medicamentos/métodos , Japão , Vancomicina/uso terapêuticoRESUMO
Area under the concentration-time curve (AUC)-guided vancomycin treatment is associated with decreased nephrotoxicity. It is preferable to obtain two samples to estimate the AUC. This study examined the usefulness of AUC estimation via trough concentration (Cmin)-only sampling of 260 adults infected with methicillin-resistant Staphylococcus aureus (MRSA) who received vancomycin. The exact Cmin sampling time was used for Bayesian estimation. A significantly higher early treatment response was observed in patients with a day 2 AUC ≥ 400 µg·h/mL than those with <400 µg·h/mL, and a significantly higher early nephrotoxicity rate was observed in patients with a day 2 AUC ≥ 600 µg·h/mL than those with <600 µg·h/mL. These AUC cutoff values constituted independent factors for each outcome. In sub-analysis, the discrimination ability for early clinical outcomes using these AUC cutoffs was confirmed only in patients with q12 vancomycin administration. A significant difference in early treatment response using the 400 µg·h/mL cutoff was obtained only in patients with low-risk infections. The usefulness of the vancomycin AUC target to decrease nephrotoxicity while assuring clinical efficacy was even confirmed with a single Cmin measurement. However, assessment with two samples might be required in patients with q24 administration or high/moderate-risk MRSA infections.