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Dynamic treatment regimens

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https://www.readbyqxmd.com/read/27930382/ym155-induces-apoptosis-in-p53-deficient-t-acute-lymphoblastic-leukemia-cells-independent-of-survivin-inhibition
#1
Leilane Sales, Graziella R de Sousa, Guilherme Á Ferreira-Silva, Angel M Castro-Gamero, Marisa Ionta, Jaqueline C de Oliveira
T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that arises from the malignant transformation of T-cell progenitors. Despite the significant progress in current treatment, challenges remain the lifelong morbidity after current chemotherapy regimens and postrelapse survival. In addition, patients with T-ALL have inferior outcomes compared with those with B-cell precursor; consequently, novel therapeutic approaches are still necessary to improve the outcome in this cohort. YM155 is an imidazolium derivative originally discovered as a suppressant of survivin expression...
December 7, 2016: Anti-cancer Drugs
https://www.readbyqxmd.com/read/27929726/treatment-of-amblyopia-using-personalized-dosing-strategies-statistical-modelling-and-clinical-implementation
#2
Michael P Wallace, Catherine E Stewart, Merrick J Moseley, David A Stephens, Alistair R Fielder
PURPOSE: To generate a statistical model for personalizing a patient's occlusion therapy regimen. METHODS: Statistical modelling was undertaken on a combined data set of the Monitored Occlusion Treatment of Amblyopia Study (MOTAS) and the Randomized Occlusion Treatment of Amblyopia Study (ROTAS). This exercise permits the calculation of future patients' total effective dose (TED)-that predicted to achieve their best attainable visual acuity. Daily patching regimens (hours/day) can be calculated from the TED...
December 2016: Strabismus
https://www.readbyqxmd.com/read/27920397/optimizing-combination-therapy-for-acute-lymphoblastic-leukemia-using-a-phenotypic-personalized-medicine-digital-health-platform-retrospective-optimization-individualizes-patient-regimens-to-maximize-efficacy-and-safety
#3
Dong-Keun Lee, Vivian Y Chang, Theodore Kee, Chih-Ming Ho, Dean Ho
Acute lymphoblastic leukemia (ALL) is a blood cancer that is characterized by the overproduction of lymphoblasts in the bone marrow. Treatment for pediatric ALL typically uses combination chemotherapy in phases, including a prolonged maintenance phase with oral methotrexate and 6-mercaptopurine, which often requires dose adjustment to balance side effects and efficacy. However, a major challenge confronting combination therapy for virtually every disease indication is the inability to pinpoint drug doses that are optimized for each patient, and the ability to adaptively and continuously optimize these doses to address comorbidities and other patient-specific physiological changes...
December 5, 2016: Journal of Laboratory Automation
https://www.readbyqxmd.com/read/27914088/murine-mycobacterium-marinum-infection-as-a-model-for-tuberculosis
#4
Julia Lienard, Fredric Carlsson
Mycobacteria are a major human health problem globally. Regarding tuberculosis the situation is worsened by the poor efficacy of current vaccine regimens and by emergence of drug-resistant strains (Manjelievskaia J et al, Trans R Soc Trop Med Hyg 110: 110, 2016; Pereira et al., Lancet Infect Dis 12:300-306, 2012; http://www.who.int/tb/publications/global_report/en/) undermining both disease-prevention and available treatments. Thus, increased basic understanding of mycobacterial-and particularly Mycobacterium tuberculosis-virulence strategies and pathogenesis is of great importance...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27907963/optimizing-medication-outcomes-in-neurocritical-care-focus-on-clinical-pharmacology
#5
Denise H Rhoney, Kathryn Morbitzer, Jimmi Hatton-Kolpek
Drug dosing in neurocritically ill patients presents enormous challenges for clinicians due to the complex pathophysiological alterations. These alterations are dynamic both between and within patients. Unpredictable exposure from standard dosing regimens, which were extrapolated to intensive care unit patients from healthy volunteer studies, may influence medication outcomes. Knowledge of potential alterations in pharmacokinetics/pharmacodynamics in these patients could be applied to maximize the clinical response and minimize adverse effects...
December 2016: Seminars in Neurology
https://www.readbyqxmd.com/read/27895011/evaluation-of-fluoroquinolone-activity-against-emergence-of-resistant-salmonella-enterica-serovar-typhimurium-using-in-vitro-dynamic-models
#6
Seung-Jin Lee, Elias Gebru Awji, Na-Hye Park, Seung-Chun Park
The objectives of this study were to determine pharmacokinetic/pharmacodynamic (PK/PD) indices of fluoroquinolones that minimize the emergence of resistant Salmonella enterica serovar Typhimurium (S. Typhimurium) using in vitro dynamic models, and to establish mechanisms of resistance. Three fluoroquinolones, difloxacin (DIF), enrofloxacin (ENR) and marbofloxacin (MAR), at five dose levels and 3 days of treatment were simulated. Bacterial killing-regrowth kinetics and emergence of resistant bacteria after antibacterial drug- exposure were quantified...
November 28, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27892497/optimising-antibiotic-usage-to-treat-bacterial-infections
#7
Iona K Paterson, Andy Hoyle, Gabriela Ochoa, Craig Baker-Austin, Nick G H Taylor
The increase in antibiotic resistant bacteria poses a threat to the continued use of antibiotics to treat bacterial infections. The overuse and misuse of antibiotics has been identified as a significant driver in the emergence of resistance. Finding optimal treatment regimens is therefore critical in ensuring the prolonged effectiveness of these antibiotics. This study uses mathematical modelling to analyse the effect traditional treatment regimens have on the dynamics of a bacterial infection. Using a novel approach, a genetic algorithm, the study then identifies improved treatment regimens...
November 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27889646/mirvetuximab-soravtansine-imgn853-a-folate-receptor-alpha-targeting-antibody-drug-conjugate-potentiates-the-activity-of-standard-of-care-therapeutics-in-ovarian-cancer-models
#8
Jose F Ponte, Olga Ab, Leanne Lanieri, Jenny Lee, Jennifer Coccia, Laura M Bartle, Marian Themeles, Yinghui Zhou, Jan Pinkas, Rodrigo Ruiz-Soto
Elevated folate receptor alpha (FRα) expression is characteristic of epithelial ovarian cancer (EOC), thus establishing this receptor as a candidate target for the development of novel therapeutics to treat this disease. Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate (ADC) that targets FRα for tumor-directed delivery of the maytansinoid DM4, a potent agent that induces mitotic arrest by suppressing microtubule dynamics. Here, combinations of IMGN853 with approved therapeutics were evaluated in preclinical models of EOC...
November 24, 2016: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/27872078/polymyxin-b-in-combination-with-rifampin-and-meropenem-against-polymyxin-b-resistant-kpc-producing-klebsiella-pneumoniae
#9
John Diep, David M Jacobs, Rajnikant Sharma, Jenna Covelli, Dana R Bowers, Thomas A Russo, Gauri G Rao
Safe and effective therapies are urgently needed to treat polymyxin-resistant KPC-producing K. pneumoniae and suppress the emergence of resistance. We investigated the pharmacodynamics of polymyxin B, rifampin, and meropenem alone and as polymyxin B-based double and triple combinations against KPC-producing K. pneumoniae The rate and extent of killing with polymyxin B (1-128mg/L), rifampin (2-16mg/L), and meropenem (10-120mg/L) were evaluated against polymyxin B-susceptible (PB(S)) and -resistant (PB(R)) clinical isolates using 48h static time-kills...
November 21, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27869358/disease-systems-analysis-of-bone-mineral-density-and-bone-turnover-markers-in-response-to-alendronate-placebo-and-washout-in-postmenopausal-women
#10
J Berkhout, J A Stone, K M Verhamme, M Danhof, T M Post
A previously established mechanism-based disease systems model for osteoporosis that is based on a mathematically reduced version of a model describing the interactions between osteoclast (bone removing) and osteoblast (bone forming) cells in bone remodeling has been applied to clinical data from women (n = 1,379) receiving different doses and treatment regimens of alendronate, placebo, and washout. The changes in the biomarkers, plasma bone-specific alkaline phosphatase activity (BSAP), urinary N-telopeptide (NTX), lumbar spine bone mineral density (BMD), and total hip BMD, were linked to the underlying mechanistic core of the model...
November 21, 2016: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/27859030/model-informed-development-and-registration-of-a-once-daily-regimen-of-extended-release-tofacitinib
#11
Manisha Lamba, Matthew M Hutmacher, Daniel E Furst, Ara Dikranian, Martin E Dowty, Daniela Conrado, Thomas Stock, Chudy Nduaka, Jack Cook, Sriram Krishnaswami
Extended-release (XR) formulations enable less frequent dosing versus conventional (e.g., immediate release [IR]) formulations. Regulatory registration of such formulations typically requires pharmacokinetic (PK) and clinical efficacy data. Here we illustrate a model-informed, exposure-response (E-R) approach to translate controlled trial data from one formulation to another without a Phase III trial, using a tofacitinib case study. Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA)...
November 17, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27855693/modelling-the-effect-of-short-course-multidrug-resistant-tuberculosis-treatment-in-karakalpakstan-uzbekistan
#12
James M Trauer, Jay Achar, Nargiza Parpieva, Atadjan Khamraev, Justin T Denholm, Dennis Falzon, Ernesto Jaramillo, Anita Mesic, Philipp du Cros, Emma S McBryde
BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is a major threat to global TB control. MDR-TB treatment regimens typically have a high pill burden, last 20 months or more and often lead to unsatisfactory outcomes. A 9-11 month regimen with seven antibiotics has shown high success rates among selected MDR-TB patients in different settings and is conditionally recommended by the World Health Organization. METHODS: We construct a transmission-dynamic model of TB to estimate the likely impact of a shorter MDR-TB regimen when applied in a low HIV prevalence region of Uzbekistan (Karakalpakstan) with high rates of drug resistance, good access to diagnostics and a well-established community-based MDR-TB treatment programme providing treatment to around 400 patients...
November 18, 2016: BMC Medicine
https://www.readbyqxmd.com/read/27829479/metabolic-and-reproductive-characteristics-of-replacement-beef-heifers-subjected-to-an-early-weaning-regimen-involving-high-concentrate-feeding
#13
A L Zezeski, V L McCracken, R K Poole, A Al Naib, J K Smith, M A McCann, M L Rhoads
In an effort to better understand the consequences of early weaning (EW) for replacement beef heifers, a two-phase experiment was conducted investigating the impact on metabolic function and documenting reproductive characteristics. In phase 1, Angus×Simmental heifers (n=35) were stratified by BW and sire, and randomly assigned to either a normal weaning (NW, n=18) or EW (n=17) treatment. EW heifers were weaned at 107±3 days of age and provided access to a concentrate-based ration ad libitum with limit-fed mixed grass hay...
November 10, 2016: Animal: An International Journal of Animal Bioscience
https://www.readbyqxmd.com/read/27825920/a-generic-viral-dynamic-model-to-systematically-characterize-the-interaction-between-oncolytic-virus-kinetics-and-tumor-growth
#14
Melanie I Titze, Julia Frank, Michael Ehrhardt, Sigrun Smola, Norbert Graf, Thorsten Lehr
Oncolytic viruses (OV) represent an encouraging new therapeutic concept for treatment of human cancers. OVs specifically replicate in tumor cells and initiate cell lysis whilst tumor cells act as endogenous bioreactors for virus amplification. This complex bidirectional interaction between tumor and oncolytic virus hampers the establishment of a straight dose-concentration-effect relation. We aimed to develop a generic mathematical pharmacokinetic/pharmacodynamics (PK/PD) model to characterize the relationship between tumor cell growth and kinetics of different OVs...
November 5, 2016: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/27806815/new-direct-acting-antiviral-agents-for-the-treatment-of-hepatitis-c-2016-and-beyond
#15
Muhammad Umar, Tayyab Saeed Akhter
Hepatitis C is one of the commonest public health problems with 130 million people infected worldwide and the burden is increasing. Previously, Interferon along with Ribavirin was the mainstay of treatment but it was associated with toxic side effects. An all-oral regimen with higher rates of sustained viral response (SVR), minimal side effects and no restriction for liver fibrosis staging, was long awaited. Several all-oral interferon-free direct acting antiviral agents (DAAs) have now been approved by FDAfor different genotypes of HCV...
October 2016: Journal of the College of Physicians and Surgeons—Pakistan: JCPSP
https://www.readbyqxmd.com/read/27806064/antiretroviral-drug-activity-in-macaques-infected-during-pre-exposure-prophylaxis-has-a-transient-effect-on-cell-associated-shiv-dna-reservoirs
#16
Mian-Er Cong, Chou-Pong Pau, Walid Heneine, J Gerardo García-Lerma
BACKGROUND: Pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) is a novel HIV prevention strategy. Suboptimal PrEP adherence and HIV infection creates an opportunity for continued antiretroviral drug activity during undiagnosed infection. We previously showed that macaques infected with SHIV during PrEP with FTC/TDF display reduced acute plasma viremias and limited virus diversity. We investigated the effect of PrEP on acute SHIV DNA dynamics and on the size of the persistent virus reservoir in lymphoid tissues...
2016: PloS One
https://www.readbyqxmd.com/read/27801609/persistence-to-anti-cancer-treatments-in-the-stationary-to-proliferating-transition
#17
Sivan Pearl Mizrahi, Orit Gefen, Itamar Simon, Nathalie Q Balaban
The heterogeneous responses of clonal cancer cells to treatment is understood to be caused by several factors, including stochasticity, cell-cycle dynamics, and different micro-environments. In a tumor, cancer cells may encounter fluctuating conditions and transit from a stationary culture to a proliferating state, for example this may occur following treatment. Here, we undertake a quantitative evaluation of the response of single cancerous lymphoblasts (L1210 cells) to various treatments administered during this transition...
November 1, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27795380/pharmacodynamics-of-aerosolized-fosfomycin-and-amikacin-against-resistant-clinical-isolates-of-pseudomonas-aeruginosa-and-klebsiella-pneumoniae-in-a-hollow-fiber-infection-model-experimental-basis-for-combination-therapy
#18
Fekade Bruck Sime, Adam Johnson, Sarah Whalley, Anahi Santoyo-Castelazo, A Bruce Montgomery, Kathie Ann Walters, Jeffrey Lipman, William W Hope, Jason A Roberts
There has been a resurgence of interest in aerosolization of antibiotics for treatment of patients with severe pneumonia, caused by multi-drug resistant pathogens. A combination formulation of amikacin/fosfomycin is currently undergoing clinical testing although the exposure response-relationships of these drugs have not been fully characterized. The aim of this study was to describe the individual and combined antibacterial effects of simulated epithelial lining fluid exposures of aerosolized amikacin and fosfomycin against resistant clinical isolates of Pseudomonas aeruginosa (MICs 16 mg/L; 64 mg/L) and Klebsiella pneumoniae (MICs 2 mg/L; 64 mg/L) using the dynamic hollow-fiber infection model over 7-days...
October 24, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27793849/predictive-modeling-of-the-outcomes-of-chemotherapy-induced-febrile-neutropenia-prophylaxis-with-biosimilar-filgrastim-monitor-gcsf-study
#19
M Aapro, H Ludwig, C Bokemeyer, P Gascón, M Boccadoro, K Denhaerynck, A Krendyukov, M Gorray, K MacDonald, I Abraham
BACKGROUND: Risk models of chemotherapy-induced (CIN) and febrile neutropenia (FN) have to date focused on determinants measured at the start of chemotherapy. We extended this static approach with a dynamic approach of CIN/FN risk modeling at the start of each cycle. DESIGN: We applied predictive modeling using multivariate logistic regression to identify determinants of CIN/FN episodes and related hospitalizations and chemotherapy disturbances (CIN/FN consequences) in analyses at the patient ('ever' during the whole period of chemotherapy) and cycle-level (during a given chemotherapy cycle)...
November 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27789196/local-consolidative-therapy-versus-maintenance-therapy-or-observation-for-patients-with-oligometastatic-non-small-cell-lung-cancer-without-progression-after-first-line-systemic-therapy-a-multicentre-randomised-controlled-phase-2-study
#20
Daniel R Gomez, George R Blumenschein, J Jack Lee, Mike Hernandez, Rong Ye, D Ross Camidge, Robert C Doebele, Ferdinandos Skoulidis, Laurie E Gaspar, Don L Gibbons, Jose A Karam, Brian D Kavanagh, Chad Tang, Ritsuko Komaki, Alexander V Louie, David A Palma, Anne S Tsao, Boris Sepesi, William N William, Jianjun Zhang, Qiuling Shi, Xin Shelley Wang, Stephen G Swisher, John V Heymach
BACKGROUND: Evidence from retrospective studies suggests that disease progression after first-line chemotherapy for metastatic non-small-cell lung cancer (NSCLC) occurs most often at sites of disease known to exist at baseline. However, the potential effect of aggressive local consolidative therapy for patients with oligometastatic NSCLC is unknown. We aimed to assess the effect of local consolidative therapy on progression-free survival. METHODS: In this multicentre, randomised, controlled, phase 2 study, eligible patients from three hospitals had histological confirmation of stage IV NSCLC, three or fewer metastatic disease lesions after first-line systemic therapy, an Eastern Cooperative Oncology Group performance status score of 2 or less, had received standard first-line systemic therapy, and had no disease progression before randomisation...
December 2016: Lancet Oncology
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