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First-in-human phase 1 study

Sihem Ait-Oudhia, Donald E Mager
Cancer is a complex disease that is characterized by an uncontrolled growth and spread of abnormal cells. Drug development in oncology is particularly challenging and is associated with one of the highest attrition rates of compounds despite substantial investments in resources. Pharmacokinetic and pharmacodynamic (PK/PD) modeling seeks to couple experimental data with mathematical models to provide key insights into factors controlling cytotoxic effects of chemotherapeutics and cancer progression. PK/PD modeling of anti-cancer compounds is equally challenging, partly based on the complexity of biological and pharmacological systems...
October 22, 2016: Journal of Pharmacokinetics and Pharmacodynamics
S Kanda, K Goto, H Shiraishi, E Kubo, A Tanaka, H Utsumi, K Sunami, S Kitazono, H Mizugaki, H Horinouchi, Y Fujiwara, H Nokihara, N Yamamoto, H Hozumi, T Tamura
BACKGROUND: The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible...
October 20, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Alistair K Brown, Charles S Wong
Recent data suggests there are non-trivial amounts of human pharmaceutical conjugates potentially entering environmental surface waters. These compounds could contribute to eliciting toxic effects on aquatic biota either directly or indirectly, via de-conjugation. The need for developing a single method for quantifying both parents and conjugates is necessary. Propranolol (PRO), sulfamethoxazole (SMX), and their respective major conjugates 4-OH-propranolol sulfate (PRO-Sul) and sulfamethoxazole-β-glucuronide (SMX-Glc) were successfully simultaneously extracted through weak anion exchange solid phase extraction cartridges from primary and secondary clarification wastewaters from the North End Winnipeg Water Pollution Treatment Plant in Winnipeg, Canada...
October 11, 2016: Journal of Chromatography. A
Henry Zakumumpa, Modupe Oladunni Taiwo, Alex Muganzi, Freddie Ssengooba
BACKGROUND: Human resources for health (HRH) constraints are a major barrier to the sustainability of antiretroviral therapy (ART) scale-up programs in Sub-Saharan Africa. Many prior approaches to HRH constraints have taken a top-down trend of generalized global strategies and policy guidelines. The objective of the study was to examine the human resources for health strategies adopted by front-line providers in Uganda to sustain ART delivery beyond the initial ART scale-up phase between 2004 and 2009...
October 19, 2016: Human Resources for Health
Roland Schmieder, Christian Ott, Peter Linz, Agnes Jumar, Stefanie Friedrich, Jens Titze, Matthias Hammon, Michael Uder, Iris Kistner
OBJECTIVE: Sodium tissue content by Na magnetic resonance imaging (Na-MRI) has been validated in experimental and human studies. SGLT-2 inhibition blocks the reabsorption of glucose and, in parallel, of sodium in the proximal tubular cells in a 1:1 fashion. We hypothesized that SGLT-2 inhibition in patients with type 2 diabetes leads to decreased tissue sodium content due to its pharmacological action. DESIGN AND METHOD: In a prospective, double blind, placebo controlled, cross-over trial 59 patients (61 ± 7...
September 2016: Journal of Hypertension
Alexander Reinthaller
Angiogenesis plays a pivotal role in normal ovarian physiology as well as in the formation and progression of ovarian cancer. Several well-designed phase II and III trials studied the efficacy of antiangiogenic agents in advanced ovarian cancer. The results of these trials demonstrated significantly prolonged progression-free survival when antiangiogenic agents were used as a maintenance therapy. To date, no effect on overall survival could be ascertained. The most widely studied antiangiogenic agent, bevacizumab - a monoclonal humanized antibody against vascular endothelial growth factor - was effective in all phases of the disease (first-line therapy, platinum-sensitive and platinum-resistant recurrence)...
2016: Memo
Yves Claude Guillaume, Lydie Lethier, Claire André
TRAIL is a member of the TNF family of cytokines which induces apoptosis of cancer cells via its binding to its cognate receptors, DR5 a high affinity site and DR4 a site of low affinity. Our working group has recently demonstrated that nanovectorization of TRAIL with single wall carbon nanotubes (abbreviated NPT) enhanced TRAIL affinity to the high affinity site DR5 and increased pro apoptotic potential in different human tumor cell lines. In this paper, the DR4 low affinity site was immobilized on a chromatographic support and the effect of temperature on a wide temperature range 1°C-50°C was studied to calculate the thermodynamic parameters of the binding of TRAIL and NPT to DR4 and DR5 receptors...
October 12, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Alina Gavrila, Per-Olof Hasselgren, Allison Glasgow, Ashley N Doyle, Alice Lee, Peter Fox, Gautam Shiva, James V Hennessey, Gerald M Kolodny, Aaron M Cypess
BACKGROUND: In addition to its role in adaptive thermogenesis, brown adipose tissue (BAT) may protect from weight gain, insulin resistance/diabetes and metabolic syndrome. Prior studies have shown contradictory results regarding the influence of thyroid hormone (TH) levels on BAT volume and activity. The aim of this pilot study was to gain further insight regarding the effect of TH treatment on BAT function in adult humans by evaluating the BAT mass and activity prospectively in six patients, first in the hypothyroid and then in the thyrotoxic phase...
October 17, 2016: Thyroid: Official Journal of the American Thyroid Association
Aaron F Cipriano, Amy Sallee, Myla Tayoba, Mayra C Cortez, Alan Lin, Ren-Guo Guan, Zhan-Yong Zhao, Huinan Liu
: Crystalline Mg-Zinc (Zn)-Strontium (Sr) ternary alloys consist of elements naturally present in the human body and provide attractive mechanical and biodegradable properties for a variety of biomedical applications. The first objective of this study was to investigate the degradation and cytocompatibility of four Mg-4Zn-xSr alloys (x = 0.15, 0.5, 1.0, 1.5 wt.%; designated as ZSr41A, B, C, and D respectively) in the direct culture with human umbilical vein endothelial cells (HUVEC) in vitro...
October 13, 2016: Acta Biomaterialia
Maria J S Guerreiro, Lisa Putzar, Brigitte Röder
Recent neuroimaging studies have demonstrated that a brief period of congenital blindness induces long-lasting reorganization within the visual cortex of sight-recovery humans [1, 2]. However, the behavioral consequences of this cross-modal reorganization are not yet known. Here we investigated this question by examining the transfer of motion aftereffects across the visual and auditory modalities within six individuals who had been born blind due to dense bilateral cataracts and regained sight when they were treated at 5-24 months of age...
October 1, 2016: Current Biology: CB
Feng-Hua Wang, Yun Wang, Zhen-Dong Chen, Jian-Hua Chen, Feng-Zhan Qin, Wen-Qi Jiang, Yu-Hong Li
Recombinant human lymphotoxin-α derivative (rhLTα-Da) is a lymphotoxin-α derivative missing 27 N-terminal amino acid residues. This multicenter phase IIa trial was conducted to evaluate the safety, efficacy and pharmacokinetics of rhLTα-Da with cisplatin (DDP) and 5-fluorouracil (5-Fu) for metastatic esophageal squamous cell cancer (ESCC) and gastric adenocarcinoma (GC). Two different rhLTα-Da doses (10 µg/m(2)/d and 20 µg/m(2)/d) in combination with DDP and 5-Fu were evaluated in this study. The first 6 ESCC and 6 GC patients were given 10 µg/m(2)/d rhLTα-Da followed by DDP (15 mg/m(2)/d) and 5-Fu (750 mg/m(2)/d) on days 1-5...
November 2016: Medical Oncology
Ronan T Swords, Peter L Greenberg, Andrew H Wei, Simon Durrant, Anjali S Advani, Mark S Hertzberg, Ian D Lewis, Gabriel Rivera, Dita Gratzinger, Alice C Fan, Dean W Felsher, Jorge E Cortes, Justin M Watts, Geoff T Yarranton, Jackie M Walling, Jeffrey E Lancet
EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP)...
September 28, 2016: Leukemia Research
M Moore, S Gill, T Asmis, S Berry, R Burkes, K Zbuk, T Alcindor, A Jeyakumar, T Chan, S Rao, J Spratlin, P A Tang, J Rothenstein, E Chan, J Bendell, F Kudrik, J Kauh, S Tang, L Gao, S R P Kambhampati, F Nasroulah, L Yang, N Ramdas, P Binder, E Strevel
BACKGROUND: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind VEGF receptors 1 and 2 (VEGFR-1 and -2), respectively. This randomized phase II study evaluated the antitumor activity and safety of icrucumab and ramucirumab each in combination with mFOLFOX-6 in patients with metastatic colorectal cancer after disease progression on first-line therapy with a fluoropyrimidine and irinotecan. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive mFOLFOX-6 alone (mFOLFOX-6) or in combination with ramucirumab 8 mg/kg IV (RAM+mFOLFOX-6) or icrucumab 15 mg/kg IV (ICR+mFOLFOX-6) every 2 weeks...
October 11, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Erika E Doxtader, Jennifer A Brainard, Dawn Underwood, Deborah J Chute
BACKGROUND: Because of cervical cancer screening recommendations and forthcoming first-line human papillomavirus (HPV) screening, many Papanicolaou (Pap) tests will be performed in patients with known concurrent HPV results. This study was designed to evaluate whether knowledge of the HPV status affects cytotechnologists' interpretation of Pap tests. METHODS: A retrospective search of cervical screening Pap tests with known concurrent HPV results provided 250 ThinPrep Pap tests, which were chosen to reflect an atypical rate similar to the rate of the Cleveland Clinic's normal practice...
October 12, 2016: Cancer
Mohamed Salah I Abaza, Mohammad Afzal, Raja'a J Al-Attiyah, Radhika Guleri
BACKGROUND: Natural products are valuable sources for anticancer agents. In the present study, methylferulate (MF) was identified for the first time from Tamarix aucheriana. Spectral data were used for identification of MF. The potential of MF to control cell growth, cell cycle, apoptosis, generation of reactive oxygen species (ROS), cancer cell invasion, nuclear factor kappa B (NFkB) DNA-binding activity and proteasomal activities, as well as the enhancement of chemosensitivity in human colorectal cancer cells, were evaluated...
October 1, 2016: BMC Complementary and Alternative Medicine
Evaggelos Kiriazopoulos, Sabina Zaharaki, Ariadni Vonaparti, Panagiota Vourna, Eirini Panteri-Petratou, Dimitra Gennimata, Kara Lombardo, Irene Panderi
The use of cephalosporins during breast feeding raises several issues, including the risk of drug exposure through breast milk for the infant. In this article a hydrophilic interaction liquid chromatography/ positive ion electrospray mass spectrometric assay (HILIC/ESI-MS) was developed for the quantitation of cefuroxime, cefoxitin and cefazolin in breast milk and human plasma. The assay was based on the use of small sample size, 25 μL of biological samples, following acetonitrile precipitation of proteins and filtration that enabled injection into the HILIC/ESI-MS system...
October 7, 2016: Drug Testing and Analysis
Dennis C Liotta, George R Painter
The HIV/AIDS epidemic, which was first reported on in 1981, progressed in just 10 years to a disease afflicting 10 million people worldwide including 1 million in the US. In 1987, AZT was approved for treating HIV/AIDS. Unfortunately, its clinical usefullness was severly limited by associated toxicities and the emergence of resistance. Three other drugs that were approved in the early 1990s suffered from similar liabilities. In 1990, the Liotta group at Emory University developed a highly diastereoselective synthesis of racemic 3'-thia-2',3'-dideoxycytidine and 3'-thia-2',3'-5-fluorodideoxycytidine and demonstrated that these compounds exhibited excellent anti-HIV activity with no apparent cytotoxicity...
October 5, 2016: Accounts of Chemical Research
Joanne M Langley, Naresh Aggarwal, Azhar Toma, Scott A Halperin, Shelly A McNeil, Laurence Fissette, Walthere Dewé, Maarten Leyssen, Jean-François Toussaint, Ilse Dieussaert
BACKGROUND:  RSV is a leading cause of childhood bronchiolitis and pneumonia, particularly in early infancy. Immunization of pregnant women could boost pre-existing immune responses, providing passive protection to the newborn through placental transfer of anti-RSV antibody. METHODS:  In this first-in-humans clinical trial of a purified recombinant RSV protein F vaccine engineered to preferentially maintain pre-fusion conformation (RSV-PreF), 128 healthy men 18-44 years old were randomized to one dose of a RSV-PreF vaccine containing 10, 30 or 60 µg of RSV-PreF antigen with or without alum adjuvant, or control, and followed for one year for safety and immunogenicity outcomes...
September 29, 2016: Journal of Infectious Diseases
Zhenlei Wang, Qian Zhao, Lili Li, Pei Hu, Kai Dong, Shuai Chen, Ji Jiang
A rapid, accurate and robust method was firstly developed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay to quantify kukoamine B, which is a novel drug under clinical development for the treatment of sepsis, in human plasma. Solid-phase extraction (SPE) was used to extract kukoamine B from human plasma. The extracts were separated on a Waters Acquity HSS T3 column (2.1×50mm i.d., 1.8μm) with a gradient elution method, using mobile phases of A (formic acid-water (1:1000, v/v)) and B(formic acid-methanol (1:1000, v/v))...
September 26, 2016: Journal of Pharmaceutical and Biomedical Analysis
Yuqiang Sun, Xiaofeng Wang, Zeyang Wang, Yuanyang Zhang, Ningwei Che, Xiadong Luo, Zeshi Tan, Xu Sun, Xinyu Li, Kang Yang, Guanyu Wang, Lan Luan, Yaoling Liu, Xiao Zheng, Minghai Wei, Huakun Cheng, Jian Yin
OBJECTIVE: Numerous microRNAs (miRNAs) are differentially expressed in specific diseases, suggesting possible use as diagnostic or prognostic biomarkers. The purpose of this study is to investigate the expression levels of miR-129-2-3p and miR-935 in cortical brain tissue and plasma samples from controls and refractory temporal lobe epilepsy (TLE) patients to evaluate the utility of these measures as diagnostic biomarkers. METHODS: The study was divided into three phases...
September 23, 2016: Epilepsy Research
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