1,720,980 research outputs found
A minimal physiologically based pharmacokinetic model for high-dose methotrexate
Full text linkPurpose: High-dose methotrexate (HDMTX) is administered for the treatment of a variety of malignant tumors. Wide intra- and inter-individual variabilities characterize the pharmacokinetics of MTX, which is mostly excreted renally. HDMTX dosages are prescribed as a function of body surface area whereas dose adjustments depending on renal function are not well defined. We develop a population pharmacokinetic model with a physiological description of renal excretion as the basis for clinical tools able to suggest model-informed dosages and support therapeutic monitoring. Methods: This article presents a minimal physiologically based pharmacokinetic (PBPK) model for HDMTX, which specifically accounts for individual characteristics such as body weight, height, gender, age, hematocrit, and serum creatinine to provide individualized predictions. The model supplies a detailed and mechanistic description of capillary and cellular exchanges between plasma, interstitial fluid, and intracellular fluid compartments, and focuses on an individualized description of renal excretion. Results: The minimal PBPK model is identified and validated with a literature dataset based on Chinese patients suffering from primary central nervous system lymphoma. A comparison with a pharmacokinetic model from the literature suggests that the proposed model provides improved predictions. Remarkably, the model does not present any significant bias in a wide range of degrees of renal function. Conclusion: Results show that model predictions can capture the wide intra- and inter-individual variability of HDMTX, and highlight the role played by the individual degree of renal function. The proposed model can be the basis for the development of clinical decision-support systems for individualized dosages and therapeutic monitoring
Optimal dose and uncertainty estimation for individualized drug administration using pharmacokinetic models
No full textWe propose and implement a pharmacokinetic model to estimate optimal dosages of methotrexate as a function of the patient's characteristics. This approach tries to improve the standard protocol that is based on either fixed doses or a function of single covariates, which are generally sub-optimal for most patients. Specifically, we focus on high-dose methotrexate administration and apply two pharmacokinetic models from the literature to assess the dose-response as a function of the individual degree of renal function, due to its importance in methotrexate elimination. We estimate model-informed optimal doses according to different targets, and the risk of methotrexate toxicity. We perform a Monte Carlo analysis to estimate the uncertainty associated with both suggested doses and the toxicity threshold. Results show how pharmacokinetic models can support clinical drug administration by identifying room for improvement in current drug dosing and guiding the design of improved personalized clinical treatments
A minimal physiologically based pharmacokinetic model for high-dose methotrexate
No full textPurpose: High-dose methotrexate (HDMTX) is administered for the treatment of a variety of malignant tumors. Wide intra- and inter-individual variabilities characterize the pharmacokinetics of MTX, which is mostly excreted renally. HDMTX dosages are prescribed as a function of body surface area whereas dose adjustments depending on renal function are not well defined. We develop a population pharmacokinetic model with a physiological description of renal excretion as the basis for clinical tools able to suggest model-informed dosages and support therapeutic monitoring. Methods: This article presents a minimal physiologically based pharmacokinetic (PBPK) model for HDMTX, which specifically accounts for individual characteristics such as body weight, height, gender, age, hematocrit, and serum creatinine to provide individualized predictions. The model supplies a detailed and mechanistic description of capillary and cellular exchanges between plasma, interstitial fluid, and intracellular fluid compartments, and focuses on an individualized description of renal excretion. Results: The minimal PBPK model is identified and validated with a literature dataset based on Chinese patients suffering from primary central nervous system lymphoma. A comparison with a pharmacokinetic model from the literature suggests that the proposed model provides improved predictions. Remarkably, the model does not present any significant bias in a wide range of degrees of renal function. Conclusion: Results show that model predictions can capture the wide intra- and inter-individual variability of HDMTX, and highlight the role played by the individual degree of renal function. The proposed model can be the basis for the development of clinical decision-support systems for individualized dosages and therapeutic monitoring
Development of a whole-body physiologically-based pharmacokinetic model for high-dose methotrexate
No full textPrimary central nervous system lymphomas: Salvage treatment after failure to high-dose methotrexate
No full textThis review analyzes the major methodological caveats related to the design and conduction of trials addressing new active drugs in patients with failed primary CNS lymphoma (PCNSL) and provides some recommendations for their therapeutic management. The enrolment of patients in well-designed prospective trials is the best option at failure. In the clinical practice, radiotherapy is an option for unirradiated patients and re-treatment with high-dose methotrexate (HD-MTX) can be suggested to relapsing patients who experienced a prolonged lymphoma remission after first-line chemotherapy containing HD-MTX. Salvage monochemotherapy with temozolomide or topotecan in patients previously managed with a radiotherapy-containing approach is supported by prospective trials, while the combination chemotherapy remains investigational. High-dose chemotherapy supported by stem cell amotransplant and intrathecal chemotherapy in meningeal failure have to be further investigated in prospective trials. (c) 2007 Elsevier Ireland Ltd. All rights reserved
The impact of histopathologic diagnosis on the proper management of testis neoplasms.
No full textBACKGROUND: A 45-year-old man underwent a right orchiectomy for a rapidly growing testicular mass. After histologic and imaging examinations the patient was diagnosed with stage I (T1N0M0) seminoma. Approximately 2 months after surgery the patient began to complain of abdominal pain and a CT scan revealed a bulky retroperitoneal mass. The patient did not receive the planned prophylactic radiotherapy and was treated with combined cisplatin, etoposide and bleomycin chemotherapy; after the completion of this treatment he achieved complete remission. Three years later, and while still undergoing follow-up, the patient developed multiple neurological motor deficits.INVESTIGATIONS: Brain MRI and CT-guided biopsy.DIAGNOSIS: Diffuse large B-cell lymphoma of the testis, relapsing in the central nervous system.MANAGEMENT: High-dose methotrexate alone or in combination with high-dose cytarabine
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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