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https://www.readbyqxmd.com/read/28331050/first-in-human-clinical-trial-of-oral-onc201-in-patients-with-refractory-solid-tumors
#1
Mark N Stein, Joseph R Bertino, Howard L Kaufman, Tina Mayer, Rebecca Moss, Ann Silk, Nancy Chan, Jyoti Malhotra, Lorna Rodriguez-Rodriguez, Joseph Aisner, Robert D Aiken, Bruce G Haffty, Robert S DiPaola, Tracie Saunders, Andrew Zloza, Sherri Damare, Yasmeen Beckett, Bangning Yu, Saltanat Najmi, Christian Gabel, Siobhan Dickerson, Ling Zheng, Wafik S El-Deiry, Joshua Allen, Martin Stogniew, Wolfgang Oster, Janice M Mehnert
Purpose ONC201 is a small molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design This open-label study treated 10 patients during dose escalation with histologically-confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design...
March 22, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28329053/sofosbuvir-plus-ribavirin-without-interferon-for-treatment-of-acute-hepatitis-c-virus-infection-in-hiv-1-infected-individuals-swift-c
#2
Susanna Naggie, Kristen M Marks, Michael Hughes, Daniel S Fierer, Christine Macbrayne, Arthur Kim, Kimberly Hollabaugh, Jhoanna Roa, Bill Symonds, Diana M Brainard, John G McHutchison, Marion G Peters, Jennifer J Kiser, Raymond Chung
Background.: Historically, acute hepatitis C virus (HCV) infection was treated with shorter durations of interferon-containing therapies. In the era of direct-acting antivirals (DAAs), it is unclear whether the efficacy of treatment achieved in chronic infection can be maintained with abbreviated courses of therapy during the acute phase. Methods.: The sofosbuvir-containing regimens without interferon for treatment of acute HCV in HIV-1 infected individuals (SWIFT-C) is an open-label, 2-cohort clinical trial in which the first cohort assessed for the safety and efficacy of 12 weeks of sofosbuvir plus ribavirin for the treatment of acute HCV infection in participants with chronic human immunodeficiency virus type 1 (HIV-1) infection...
February 27, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/28328020/detection-of-glutathione-conjugates-of-amiodarone-and-its-reactive-diquinone-metabolites-in-rat-bile-using-mass-spectrometry-tools
#3
Keyur R Parmar, Shalu Jhajra, Saranjit Singh
RATIONALE: Amiodarone is reported to cause hepato and pulmonary toxicity in humans, which has been envisaged to be due to formation of its reactive metabolites, essentially based on its structural similarity to benzbromarone, a drug withdrawn from the market due to reasons of similar hepatotoxicity. Therefore, the purpose of this study was to detect glutathione conjugates of amiodarone and its reactive diquinone metabolites in rat bile using mass spectrometry tools. METHODS: Wistar rats were dosed orally with an amiodarone suspension and bile was collected via bile duct cannulation followed by solid-phase extraction, protein precipitation and centrifugation...
May 30, 2016: Rapid Communications in Mass Spectrometry: RCM
https://www.readbyqxmd.com/read/28327200/a-first-in-human-phase-1-study-of-a-hepcidin-monoclonal-antibody-ly2787106-in-cancer-associated-anemia
#4
Saroj Vadhan-Raj, Rafat Abonour, Jonathan W Goldman, David A Smith, Christopher A Slapak, Robert L Ilaria, Ramon V Tiu, Xuejing Wang, Sophie Callies, Joanne Cox, Jay L Tuttle, Yiu-Keung Lau, Eric J Roeland
BACKGROUND: Hepcidin plays a central role in iron homeostasis and erythropoiesis. Neutralizing hepcidin with a monoclonal antibody (mAb) may prevent ferroportin internalization, restore iron efflux from cells, and allow transferrin-mediated iron transport to the bone marrow. This multicenter, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of a fully humanized mAb (LY2787106) with high affinity for hepcidin in cancer patients with anemia...
March 21, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28327055/the-evaluation-of-the-anti-cancer-activity-of-ixazomib-on-caco2-colon-solid-tumor-cells-comparison-with-bortezomib
#5
Selin Engür, Miriş Dikmen
Proteasome inhibition has recently emerged as a clinically effective anticancer therapeutic approach. The first proteasome inhibitor, bortezomib (Velcade, PS-341), and new proteasome inhibitors including ixazomib have become more important in the development of targeted cancer therapies. Under physiological conditions, MLN9708 (ixazomib citrate), the stable citrate ester drug substance, hydrolyzes rapidly to MLN2238 (ixazomib), the biologically active boronic acid. It is a second-generation proteasome inhibitor, similar to the well-known proteasome inhibitor bortezomib, which is currently being investigated in phase 3 trials as a treatment for multiple Myeloma...
March 22, 2017: Acta Clinica Belgica
https://www.readbyqxmd.com/read/28326563/early-structural-and-functional-signature-of-3-day-human-skeletal-muscle-disuse-using-the-dry-immersion-model
#6
Rémi Demangel, Loïc Treffel, Guillaume Py, Thomas Brioche, Allan F Pagano, Marie-Pierre Bareille, Arnaud Beck, Laurence Pessemesse, Robin Candau, Claude Gharib, Angèle Chopard, Catherine Millet
Microgravity and hypoactivity are associated with skeletal muscle deconditioning. The decrease of muscle mass is an exponential decay with major changes in the first days. The purpose of the study was to dissect out the effects of a short-term 3-day dry immersion (DI) on human quadriceps muscle function and structure. The DI model, by suppressing all support zones, accurately reproduces the effects of microgravity. Twelve healthy volunteers (32 ± 5 yrs) completed 3 days of DI. Muscle function was investigated through maximal voluntary contraction (MVC) tests and muscle viscoelasticity...
March 22, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28326038/ganoderic-acid-a-metabolites-and-their-metabolic-kinetics
#7
Fang-Rui Cao, Li Feng, Lin-Hu Ye, Li-Sha Wang, Bing-Xin Xiao, Xue Tao, Qi Chang
Ganoderic acid A (GAA), a representative active triterpenoid from Ganoderma lucidum, has been reported to exhibit antinociceptive, antioxidative, cytotoxic, hepatoprotective and anticancer activities. The present study aims (1) to identify GAA metabolites, in vivo by analyzing the bile, plasma and urine after intravenous administration to rats (20 mg/kg), and in vitro by incubating with rat liver microsomes (RLMs) and human liver microsomes (HLMs); (2) to investigate the metabolic kinetics of main GAA metabolites...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28320610/carbon-monoxide-releasing-molecule-401-suppresses-polymorphonuclear-leukocyte-migratory-potential-by-modulating-f-actin-dynamics
#8
Ken Inoue, Eric K Patterson, Alfredo Capretta, Abdel R Lawendy, Douglas D Fraser, Gediminas Cepinskas
Carbon monoxide-releasing molecules (CORMs) suppress inflammation by reducing polymorphonuclear leukocyte (PMN) recruitment to the affected organs. We investigated modulation of PMN-endothelial cell adhesive interactions by water-soluble CORM-401 using an experimental model of endotoxemia in vitro. Human umbilical vein endothelial cells grown on laminar-flow perfusion channels were stimulated with 1 μg/mL lipopolysaccharide for 6 hours and perfused with 100 μmol/L CORM-401 (or inactive compound iCORM-401)-pretreated PMN for 5 minutes in the presence of 1...
March 17, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28319448/rationale-and-design-of-a-phase-1-clinical-trial-to-evaluate-hsv-g207-alone-or-with-a-single-radiation-dose-in-children-with-progressive-or-recurrent-malignant-supratentorial-brain-tumors
#9
Alicia M Waters, James M Johnston, Alyssa T Reddy, John Fiveash, Avi Madan-Swain, Kara Kachurak, Asim K Bag, G Yancey Gillespie, James M Markert, Gregory K Friedman
Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors...
March 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/28317135/free-mycophenolic-acid-determination-in-human-plasma-ultrafiltrate-by-a-validated-liquid-chromatography-tandem-mass-spectrometry-method
#10
Paulina Łuszczyńska, Tomasz Pawiński, Paweł K Kunicki, Katarzyna Sikorska, Ryszard Marszałek
OBJECTIVES: The aim of this study was to develop and fully validate LC-MS/MS method for free mycophenolic acid (MPA) concentration measurements in plasma ultrafiltrate that will be reliable and simple in preparation with deuterated MPA (MPA-d3) chosen as an internal standard. METHODS: The chromatographic separation was made with Zorbax Eclipse XDB-C18 column (4.6x150 mm) using a gradient of two solutions as a mobile phase: A) water and B) methanol, each containing 0...
March 20, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28314990/an-apparent-clinical-pharmacokinetic-drug-drug-interaction-between-bevacizumab-and-the-anti-placental-growth-factor-monoclonal-antibody-ro5323441-via-a-target-trapping-mechanism
#11
Ka Wang, Franziska Schaedeli Stark, Tilman Schlothauer, Angelika Lahr, Valerie Cosson, Jianguo Zhi, Kai Habben, Jean Tessier, Eginhard Schick, Roland F Staack, Oliver Krieter
PURPOSE: RO5323441 is a humanized anti-placental growth factor (PlGF) monoclonal antibody that has shown preclinical activity in several cancer models. The objective of this analysis is to examine the pharmacokinetic (PK) results from four Phase I studies that have been conducted with RO5323441 (n = 61) and to report an apparent drug-drug interaction observed when RO5323441 was administered in combination with bevacizumab. METHODS: The four Phase I studies were a multiple-ascending dose study in 23 patients with solid tumors (Study 1), an open-label study in seven patients with colorectal/ovarian cancer (Study 2), a sorafenib combination study in nine patients with hepatocellular carcinoma (Study 3), and a bevacizumab combination study in 22 patients with recurrent glioblastoma (Study 4)...
April 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28301273/a-cross-sectional-study-of-changes-in-markers-of-immunological-effects-and-lung-health-due-to-exposure-to-multi-walled-carbon-nanotubes
#12
Jelle Vlaanderen, Anjoeka Pronk, Nathaniel Rothman, Allan Hildesheim, Debra Silverman, H Dean Hosgood, Suzanne Spaan, Eelco Kuijpers, Lode Godderis, Peter Hoet, Qing Lan, Roel Vermeulen
Background Multi Wall Carbon nanotubes (MWCNTs) are manufactured nanomaterials to which workers and the general population will be increasingly exposed in coming years. Little is known about potential human health effects of exposure to MWCNTs, but effects on the lung and the immune system have been reported in animal and mechanistic studies. Objectives We conducted a cross-sectional study to assess the association between occupational exposure to MWCNTs and effects on lung health and the immune system. Methods We assessed fifty-one immune markers and three pneumoproteins in serum, complete blood cell counts (CBC), fractional exhaled nitric oxide (FENO), and lung function among twenty-two workers of a MWCNT producing facility and thirty-nine age- and gender-matched, unexposed controls...
March 16, 2017: Nanotoxicology
https://www.readbyqxmd.com/read/28295190/phase-i-study-of-cord-blood-derived-natural-killer-cells-combined-with-autologous-stem-cell-transplantation-in-multiple-myeloma
#13
Nina Shah, Li Li, Jessica McCarty, Indreshpal Kaur, Eric Yvon, Hila Shaim, Muharrem Muftuoglu, Enli Liu, Robert Z Orlowski, Laurence Cooper, Dean Lee, Simrit Parmar, Kai Cao, Catherine Sobieiski, Rima Saliba, Chitra Hosing, Sairah Ahmed, Yago Nieto, Qaiser Bashir, Krina Patel, Catherine Bollard, Muzaffar Qazilbash, Richard Champlin, Katy Rezvani, Elizabeth J Shpall
Multiple myeloma (MM) is a disease with known immune dysregulation. Natural killer (NK) cells have shown preclinical activity in MM. We conducted a first-in-human study of umbilical cord blood-derived (CB) NK cells for MM patients undergoing high dose chemotherapy and autologous haematopoietic stem cell transplantation (auto-HCT). Patients received lenalidomide (10 mg) on days -8 to -2, melphalan 200 mg/m(2) on day -7, CB-NK cells on day -5 and auto-HCT on day 0. Twelve patients were enrolled, three on each of four CB-NK cell dose levels: 5 × 10(6) , 1 × 10(7) , 5 × 10(7) and 1 × 10(8) CB-NK cells/kg...
March 14, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28294526/phase-1-dose-escalating-study-of-the-safety-pharmacokinetics-and-pharmacodynamics-of-activated-factor-x-i-16l
#14
Dana Parsons-Rich, Fei Hua, Gang Li, Constantino Kantaridis, Debra D Pittman, Steven Arkin
BACKGROUND: FXa(I16L) (PF-05230907) is a zymogen-like variant of activated coagulation factor X (FXa). It exhibits enhanced resistance to inactivation by endogenous inhibitors compared with wild-type FXa and restores hemostatic activity in nonclinical models of various bleeding conditions. OBJECTIVES: To evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of FXa(I16L) , a phase 1, first-in-human, dose escalation clinical trial in healthy adult volunteers was conducted METHODS: Participants were assigned to 1 of 6 ascending single-dose cohorts (0...
March 14, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28291776/first-in-human-phase-1-of-ys110-a-monoclonal-antibody-directed-against-cd26-in-advanced-cd26-expressing-cancers
#15
Eric Angevin, Nicolas Isambert, Véronique Trillet-Lenoir, Benoit You, Jérôme Alexandre, Gérard Zalcman, Philippe Vielh, Françoise Farace, Fanny Valleix, Thomas Podoll, Yu Kuramochi, Itaru Miyashita, Osamu Hosono, Nam H Dang, Kei Ohnuma, Taketo Yamada, Yutaro Kaneko, Chikao Morimoto
BACKGROUND: YS110 is a humanised IgG1 monoclonal antibody with high affinity to the CD26 antigen. YS110 demonstrated preclinical anti-tumour effects without significant side effects. METHODS: This FIH study was designed to determine the maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D) to assess the tolerance, pharmacokinetics (PK) and pharmacodynamics profiles of YS110 and preliminary efficacy. YS110 were initially administered intravenously once every 2 weeks (Q2W) for three doses and then, based on PK data, once every week (Q1W) for five doses in patients with CD26-expressing solid tumours...
March 14, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28284082/simultaneous-determination-of-glipizide-and-its-four-hydroxylated-metabolites-in-human-urine-using-lc-ms-ms-and-its-application-in-urinary-phenotype-study
#16
Bo Tan, Aidong Yang, Weian Yuan, Yue Li, Lei Jiang, Jian Jiang, Furong Qiu
Cytochrome P450 (CYP) 2C9 and CYP2C19 genetic mutant could influence the plasma concentration of glipizide in human subjects, which refers to glipizide safety and adverse effects in clinic practice. A further study to investigate the relationship of the concentrations between glipizide and its metabolites in human with different CYP mutants was valuable. We firstly develop a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of glipizide and its hydroxylated metabolites in human urine...
March 6, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28283687/impact-of-gain-of-function-mutations-in-the-low-density-lipoprotein-receptor-related-protein-5-lrp5-on-glucose-and-lipid-homeostasis
#17
D Foer, M Zhu, R L Cardone, C Simpson, R Sullivan, S Nemiroff, G Lee, R G Kibbey, K F Petersen, K L Insogna
LRP5 loss-of-function mutations have been shown to cause profound osteoporosis and have been associated with impaired insulin sensitivity and dysregulated lipid metabolism. We hypothesized that gain-of-function mutations in LRP5 would also affect these parameters. We therefore studied individuals with LRP5 gain-of-function mutations exhibiting high bone mass (HBM) phenotypes and found that while there was no detected change in insulin sensitivity, there was a significant reduction in serum LDL. INTRODUCTION: Wnt signaling through LRP5 represents a newly appreciated metabolic pathway, which potentially represents a target for drug discovery in type 2 diabetes and hyperlipidemia...
March 10, 2017: Osteoporosis International
https://www.readbyqxmd.com/read/28282611/phase-ib-dose-finding-study-of-abiraterone-acetate-plus-buparlisib-bkm120-or-dactolisib-bez235-in-patients-with-castration-resistant-prostate-cancer
#18
Christophe Massard, Kim Nguyen Chi, Daniel Castellano, Johann de Bono, Gwenaelle Gravis, Luc Dirix, Jean-Pascal Machiels, Alain Mita, Begona Mellado Gonzalez, Sabine Turri, Joan Maier, Denes Csonka, Arunava Chakravartty, Karim Fizazi
BACKGROUND: The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signalling axis and androgen receptor (AR) pathways exhibit reciprocal feedback regulation in phosphatase and tensin homologue (PTEN)-deficient metastatic castration-resistant prostate cancer (CRPC) in preclinical models. This phase Ib study evaluated the pan-PI3K inhibitor buparlisib (BKM120) and the dual pan-PI3K/ mammalian target of rapamycin (mTOR) inhibitor dactolisib (BEZ235) in combination with abiraterone acetate (AA) in patients with CRPC...
March 3, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28279931/quantitative-chiral-and-achiral-determination-of-ketamine-and-its-metabolites-by-lc-ms-ms-in-human-serum-urine-and-fecal-samples
#19
Mahmoud Hasan, Robert Hofstetter, Georg M Fassauer, Andreas Link, Werner Siegmund, Stefan Oswald
Ketamine (KET) is a widely used anesthetic drug which is metabolized by CYP450 enzymes to norketamine (n-KET), dehydronorketamine (DHNK), hydroxynorketamine (HNK) and hydroxyketamine (HK). Ketamine is a chiral compound and S-ketamine is known to be the more potent enantiomer. Here, we present the development and validation of three LC-MS/MS assays; the first for the quantification of racemic KET, n-KET and DHNK in human serum, urine and feces; the second for the separation and quantification of the S- and R-enantiomers of KET, n-KET and DHNK, and the third for separation and quantification of 2S,6S-hydroxynorketamine (2S,6S-HNK) and 2R,6R-hydroxynorketamine (2R,6R-HNK) in serum and urine with the ability to separate and detect 10 additional hydroxylated norketamine metabolites of racemic ketamine...
February 27, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28276938/relationship-power-among-same-sex-male-couples-in-new-york-and-san-francisco-laying-the-groundwork-for-sexual-risk-reduction-interventions-focused-on-interpersonal-power
#20
Shari L Dworkin, Jennifer M Zakaras, Chadwick Campbell, Patrick Wilson, Kirk Grisham, Deepalika Chakravarty, Torsten B Neilands, Colleen Hoff
Research is clear that power differentials between women and men shape women's human immunodeficiency virus (HIV) risks; however, little research has attempted to examine power differentials within same-sex male (SSM) couples and whether these influence sexual risk outcomes. To produce the first quantitative scale that measures power in SSM relationships, the current work was a Phase 1 qualitative study that sought to understand domains of relationship power and how power operated in the relationship among 48 Black, White, and interracial (Black-White) SSM couples recruited from San Francisco and New York...
February 16, 2017: Journal of Sex Research
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