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https://www.readbyqxmd.com/read/28922811/a-programme-to-create-short-course-chemotherapy-for-pulmonary-mycobacterium-avium-disease-based-on-pharmacokinetics-pharmacodynamics-and-mathematical-forecasting
#1
Devyani Deshpande, Shashikant Srivastava, Tawanda Gumbo
Objectives: Pulmonary Mycobacterium avium complex (MAC) prevalence is on the rise worldwide. The average therapy duration is 1.5 years, which is associated with poor cure rates. Our objective was to develop a programme to design a combination therapy regimen for pulmonary MAC to be administered for 6 months or less with efficacy in > 90% of patients. Methods: We performed a literature search for the following MeSH headings 'Mycobacterium avium' AND 'pharmacokinetics/pharmacodynamics' in PubMed up to 2016...
September 1, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28922807/tedizolid-is-highly-bactericidal-in-the-treatment-of-pulmonary-mycobacterium-avium-complex-disease
#2
Devyani Deshpande, Shashikant Srivastava, Jotam G Pasipanodya, Pooi S Lee, Tawanda Gumbo
Objectives: To determine if tedizolid is effective for pulmonary Mycobacterium avium complex (MAC) disease, and to use pharmacokinetics/pharmacodynamics to design optimal doses. Methods: We performed an exposure-response experiment in the hollow-fibre system model of intracellular MAC (HFS-MAC). We mimicked the tedizolid concentration-time profiles achieved in the lungs of patients treated once daily for 28 days. The HFS-MAC was sampled at intervals to determine the tedizolid pharmacokinetics and MAC intracellular burden...
September 1, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28922806/linezolid-as-treatment-for-pulmonary-mycobacterium-avium-disease
#3
Devyani Deshpande, Shashikant Srivastava, Jotam G Pasipanodya, Tawanda Gumbo
Objectives: To identify the pharmacokinetic/pharmacodynamic parameters and exposures of linezolid in the treatment of pulmonary Mycobacterium avium complex (MAC) disease. Methods: Human-derived monocytes infected with MAC were inoculated into hollow-fibre systems for dose-effect and dose-scheduling studies. We mimicked linezolid concentration-time profiles achieved in adult human lungs treated for 28 days. Sampling to confirm that the intended linezolid pharmacokinetics had been achieved, and for enumeration of MAC colony-forming units, was performed based on repetitive sampling from each system over the 28 days...
September 1, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28922466/blinatumomab-pharmacodynamics-and-exposure-response-relationships-in-relapsed-refractory-acute-lymphoblastic-leukemia
#4
Min Zhu, Andrea Kratzer, Jessica Johnson, Chris Holland, Christian Brandl, Indrajeet Singh, Andreas Wolf, Sameer Doshi
We evaluated blinatumomab pharmacokinetics, pharmacodynamics (CD3+ T-cell, CD19+ B-cell, and cytokine levels), and their associations with efficacy or safety in relapsed/refractory acute lymphoblastic leukemia. Blinatumomab pharmacokinetics (continuous intravenous infusion) from a phase 2 study (n = 189; NCT01466179) were assessed noncompartmentally. Associations between steady-state concentration (Css ) and efficacy (complete remission [CR] or CR with partial hematologic recovery [CRh]) or safety (cytokine release syndrome [CRS] and neurologic events [NEs]) were evaluated with statistical models...
September 18, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28921890/phase-ii-study-of-dabigatran-in-children-with-venous-thrombosis-pharmacokinetics-safety-and-tolerabilty
#5
J M L Halton, M Albisetti, B Biss, L Bomgaars, M Brueckmann, S Gropper, R Harper, F Huang, M Luciani, H Maas, I Tartakovsky, L G Mitchell
BACKGROUND: The current standard-of-care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option. OBJECTIVES: To assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of DE oral liquid formulation (OLF) in pediatric patients with VTE. PATIENTS/METHODS: Patients who had completed planned treatment with low-molecular-weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2-<12 and 1-<2 years) and received DE OLF based on an age- and weight-adjusted nomogram...
September 16, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28921650/antibody-drug-conjugates-as-cancer-therapeutics-past-present-and-future
#6
Heather E Vezina, Monette Cotreau, Tae H Han, Manish Gupta
Antibody-drug conjugates (ADCs) represent an innovative therapeutic approach that provides novel treatment options and hope for patients with cancer. By coupling monoclonal antibodies (mAbs) to cytotoxic small-molecule payloads with a plasma-stable linker, ADCs offer the potential for increased drug specificity and fewer off-target effects than systemic chemotherapy. As evidence for the potential of these therapies, many new ADCs are in various stages of clinical development. Because their structure poses unique challenges to pharmacokinetic and pharmacodynamic characterization, it is critical to recognize the differences between ADCs and conventional chemotherapy in the design of ADC clinical development strategies...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28921642/clinical-pharmacology-tools-and-evaluations-to-facilitate-comprehensive-dose-finding-in-oncology-a-continuous-risk-benefit-approach
#7
Julie M Bullock, Tiffany Lin, Sanela Bilic
Targeted therapies are now considered an integral component in the treatment armamentarium for many malignancies, and the approach to developing these drugs needs to be refined from the previous cytotoxic paradigm of toxicity-guided dose finding and identification of maximum tolerated dose to a paradigm driven by target activity. Moving away from the toxicity-driven dose finding and justification model requires an integrated approach in order to adequately characterize the risk-benefit of a drug. This approach starts with understanding the importance of collecting samples for pharmacokinetic and pharmacodynamic assessments in all phases of clinical development to fully characterize the pharmacokinetics and identify covariates and then correlating exposure to key markers of safety and efficacy in pharmacometric analyses to perform a robust risk-benefit assessment and establish the right dose...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28921641/pharmacokinetic-guided-dosing-of-new-oral-cancer-agents
#8
Catherine J Lucas, Jennifer H Martin
Generally, licensed drug-dosing recommendations for chemotherapy are based on results from clinical trials in which subjects are usually of relatively normal body size, middle-aged, and are relatively racially homogeneous, with minimal comorbidity and specific tumor characteristics. Very few nontrial patients meet these characteristics, resulting in clinical practice having to extrapolate dosing recommendations to the specific patient. There is insufficient research on the impact of obesity-associated physiological changes prevalent in patients with common cancers on standard pharmacokinetic and pharmacodynamic parameters...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28921624/pharmacodynamics-and-pharmacokinetics-of-ticagrelor-versus-clopidogrel-in-patients-with-acute-coronary-syndromes-and-chronic-kidney-disease
#9
Heyang Wang, Jing Qi, Yi Li, Yunbiao Tang, Chao Li, Jing Li, Yaling Han
BACKGROUND: Pivotal clinical trials found ticagrelor reduced ischemic complications to a greater extent than clopidogrel and what is more, the benefit gradually increased with the reduction on creatinine clearance. However, the underlying mechanisms remains poorly explored. METHODS: This is a single-center, prospective, randomized clinical trial involving 60 hospitalized P2Y12 inhibitor naïve patients with CKD (eGFR<60ml/min/1.73m(2) ) and NSTE-ACS. Eligible patients were randomly assigned in a 1:1 ratio to receive ticagrelor(180 mg loading dose, then 90 mg twice daily followed) or clopidogrel(600 mg loading dose, then 75 mg qd followed)...
September 15, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28921565/the-impact-of-p-glycoprotein-and-breast-cancer-resistance-protein-on-the-brain-pharmacokinetics-and-pharmacodynamics-of-a-panel-of-mek-inhibitors
#10
Mark C de Gooijer, Ping Zhang, Ruud Weijer, Levi C M Buil, Jos H Beijnen, Olaf van Tellingen
Mitogen/extracellular signal-regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood-brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP-dependent efflux transport proteins, of which P-gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain...
September 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28921436/strategies-to-develop-therapeutic-n-and-o-hyperglycosylated-proteins
#11
Agustina Gugliotta, Natalia Ceaglio, Marina Etcheverrigaray, Ricardo Kratje, Marcos Oggero
Glycoengineering by N- and/or O-hyperglycosylation represents a procedure to introduce potential sites for adding N- and/or O-glycosyl structures to proteins with the aim of producing biotherapeutics with improved pharmacodynamic and pharmacokinetic properties. In this chapter, a detailed description of the steps routinely performed to generate new proteins having high content of N- and/or O-glycosyl moieties is carried out. The rational strategy involves the initial stage of designing N- and/or O-hyperglycosylated muteins to be expressed by mammalian cells and includes the upstream and downstream processing stages necessary to develop hyperglycosylated versions of the proteins of interest with the purpose of beginning the long road toward producing biobetters...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28921160/gp2013-a-rituximab-biosimilar
#12
Hannah A Blair
GP2013 is the second biosimilar of the reference monoclonal anti-CD20 antibody rituximab to be approved in the EU. It is approved for use in all indications for which reference rituximab is approved, including follicular lymphoma (FL), diffuse large B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, rheumatoid arthritis (RA), granulomatosis with polyangiitis and microscopic polyangiitis. GP2013 has similar physicochemical and pharmacodynamic properties to those of reference rituximab, and the pharmacokinetic biosimilarity of the agents has been shown in patients with RA...
September 18, 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/28920452/challenges-and-opportunities-in-bioanalytical-support-for-gene-therapy-medicinal-product-development
#13
Mark Ma, Nanda Balasubramanian, Robert Dodge, Yan Zhang
Gene and nucleic acid therapies have demonstrated patient benefits to address unmet medical needs. Beside considerations regarding the biological nature of the gene therapy, the quality of bioanalytical methods plays an important role in ensuring the success of these novel therapies. Inconsistent approaches among bioanalytical labs during preclinical and clinical phases have been observed. There are many underlying reasons for this inconsistency. Various platforms and reagents used in quantitative methods, lacking of detailed regulatory guidance on method validation and uncertainty of immunogenicity strategy in supporting gene therapy may all be influential...
September 18, 2017: Bioanalysis
https://www.readbyqxmd.com/read/28919776/safety-pharmacokinetics-and-pharmacodynamics-of-oral-omaveloxolone-rta-408-a-synthetic-triterpenoid-in-a-first-in-human-trial-of-patients-with-advanced-solid-tumors
#14
Ben C Creelan, Dmitry I Gabrilovich, Jhanelle E Gray, Charles C Williams, Tawee Tanvetyanon, Eric B Haura, Jeffrey S Weber, Geoffrey T Gibney, Joseph Markowitz, Joel W Proksch, Scott A Reisman, Mark D McKee, Melanie P Chin, Colin J Meyer, Scott J Antonia
BACKGROUND: Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity. METHODS: Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28918665/considerations-in-establishing-bioequivalence-of-inhaled-compounds
#15
Irvin Mayers, Mohit Bhutani
Generic inhalers are often perceived as inferior to their branded counterparts; however, they are safe and effective if they can meet the regulatory requirements. The approach to assess bioequivalence (BE) in oral dosage form products is not sufficient to address the complexities of inhalational products (e.g., patient-device interface); hence, more considerations are needed and caution should be applied in determining BE of inhaled compounds. Areas covered: This review outlines the evaluation process for generic inhalers, explores the regulatory approaches in BE assessment, and highlights the considerations and challenges in the current in vitro and in vivo approaches (lung deposition, pharmacokinetic, pharmacodynamic/clinical studies, and patient-device interface) for establishing BE of inhaled compounds...
September 18, 2017: Expert Opinion on Drug Delivery
https://www.readbyqxmd.com/read/28918591/platform-model-describing-pharmacokinetic-properties-of-vc-mmae-antibody-drug-conjugates
#16
Matts Kågedal, Leonid Gibiansky, Jian Xu, Xin Wang, Divya Samineni, Shang-Chiung Chen, Dan Lu, Priya Agarwal, Bei Wang, Ola Saad, Neelima Koppada, Bernard M Fine, Jin Y Jin, Sandhya Girish, Chunze Li
Antibody-drug conjugates (ADCs) developed using the valine-citrulline-MMAE (vc-MMAE) platform, consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile vc linker. Recently, clinical data for a variety of vc-MMAE ADCs has become available. The goal of this analysis was to develop a platform model that simultaneously described antibody-conjugated MMAE (acMMAE) pharmacokinetic (PK) data from eight vc-MMAE ADCs, against different targets and tumor indications; and to assess differences and similarities of model parameters and model predictions, between different compounds...
September 16, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28918570/mathematical-description-of-drug-target-interactions-application-to-biologics-that-bind-to-targets-with-two-binding-sites
#17
Leonid Gibiansky, Ekaterina Gibiansky
The emerging discipline of mathematical pharmacology occupies the space between advanced pharmacometrics and systems biology. A characteristic feature of the approach is application of advance mathematical methods to study the behavior of biological systems as described by mathematical (most often differential) equations. One of the early application of mathematical pharmacology (that was not called this name at the time) was formulation and investigation of the target-mediated drug disposition (TMDD) model and its approximations...
September 16, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28918342/the-potential-effect-of-ultra-long-insulin-degludec-on-glycemic-variability
#18
REVIEW
M Rodacki, R M Carvalho, L Zajdenverg
Despite the therapeutic advances in the treatment of diabetes, metabolic control instability due to glycemic variability (GV) is frequently observed in patients with diabetes on intensive insulin therapy and is associated with hyperglycemic peaks and hypoglycemic episodes. Hyperglycemia associated with GV has been implicated in the development of chronic complications due to its pro-oxidative consequences. On the other hand, hypoglycemia can be associated with increased cardiovascular risk secondarily to adrenergic activation...
June 30, 2017: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/28918016/therapeutic-mirna-and-sirna-moving-from-bench-to-clinic-as-next-generation-medicine
#19
REVIEW
Chiranjib Chakraborty, Ashish Ranjan Sharma, Garima Sharma, C George Priya Doss, Sang-Soo Lee
In the past few years, therapeutic microRNA (miRNA) and small interfering RNA (siRNA) are some of the most important biopharmaceuticals that are in commercial space as future medicines. This review summarizes the patents of miRNA- and siRNA-based new drugs, and also provides a snapshot about significant biopharmaceutical companies that are investing for the therapeutic development of miRNA and siRNA molecules. An insightful view about individual siRNA and miRNA drugs has been depicted with their present status, which is gaining attention in the therapeutic landscape...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28917201/in-silico-investigation-of-propofol-binding-sites-in-human-serum-albumin-using-explicit-and-implicit-solvation-models
#20
Sergey Shityakov, Norbert Roewer, Carola Förster, Jens-Albert Broscheit
All-atom molecular dynamics (MD) simulations are presented on general anesthetic propofol bound to human serum albumin (HSA) due to the drug pharmacokinetics and pharmacodynamics in the circulatory system. We implemented the explicit and implicit solvation models to compare the binding affinity of propofol at the different binding sites (PR1 and PR2) in the HSA protein. Only the implicit solvation models provided the evidence in accordance with the experimental data indicating that the HSA-ligand interactions are dominanted by hydrophobic forces due to the higher drug affinity at the PR1 position with a ΔGMM-PB/SA value of -23...
July 4, 2017: Computational Biology and Chemistry
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