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https://www.readbyqxmd.com/read/28323965/long-acting-ctp-modified-hgh-mod-4023-results-of-a-safety-and-dose-finding-study-in-ghd-children
#1
Nataliya Zelinska, Violeta Iotova, Julia Skorodok, Oleg Malievsky, Valentina Peterkova, Lubov Samsonova, Ron G Rosenfeld, Zvi Zadik, Michal Jaron-Mendelson, Ronit Koren, Leanne Amitzi, Dmitri Raduk, Oren Hershkovitz, Gili Hart
Context: Daily injections are required for growth hormone replacement therapy, which may cause low compliance as a result of inconvenience and distress in patients. Objective: CTP-modified human growth hormone (MOD-4023) is developed for once-a-week dosing regimen in GH-deficient (GHD) adults and children. The present trial was a safety and dose-finding study for weekly MOD-4023 in GHD children. Design: a multi-center, open-label, randomized, controlled Phase 2 study in children with GHD, evaluating the safety, tolerability, PK/PD and efficacy of 3 different weekly MOD-4023 doses, compared to daily r-hGH...
January 31, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28317872/preclinical-evaluation-of-the-efficacy-pharmacokinetics-and-immunogenicity-of-js-001-a-programmed-cell-death-protein-1-pd-1-monoclonal-antibody
#2
Jie Fu, Fang Wang, Li-Hou Dong, Jing Zhang, Cheng-Lian Deng, Xue-Li Wang, Xin-Yao Xie, Jing Zhang, Ruo-Xian Deng, Li-Bo Zhang, Hai Wu, Hui Feng, Bo Chen, Hai-Feng Song
JS-001 is the first monoclonal antibody (mAb) against programmed cell death protein-1 (PD-1) approved by the China Food and Drug Administration (CFDA) into the clinical trails. To date, however, no pre-clinical pharmacological and pharmacokinetic (PK) data are available. In this study, we investigated the efficacy of JS-001 and conducted a preclinical PK study, including the monitoring of anti-drug antibodies (ADAs). We found that JS-001 specifically bound to PD-1 antigen with an EC50 of 21 nmol/L, and competently blocked the binding of PD-1 antigen to PD-L1 and PD-L2 with IC50 of 3...
March 20, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28301259/novel-treatment-of-melanoma-combined-parasite-derived-peptide-gk-1-and-anti-programmed-death-ligand-1-therapy
#3
Jesus Vera-Aguilera, Armando Perez-Torres, Diego Beltran, Cynthia Villanueva-Ramos, Mitchell Wachtel, Eduardo Moreno-Aguilera, Carlos Vera-Aguilera, Gary Ventolini, Raul Martínez-Zaguilán, Souad R Sennoune
Recent successes in the development of new therapies for metastatic melanoma, such as mitogen-activated protein kinase pathway inhibitors, anticytotoxic T lymphocyte-associated antigen-4, and programmed cell death protein 1/programmed cell death ligand 1 (PD-L1) pathway-blocking antibodies, as well as combination strategies, all yielded promising results, changing the continually evolving landscape of therapeutic options for patients with melanoma. One promising new treatment modality is based on the use of immunomodulatory monoclonal antibodies that enhance the function of components of the antitumor immune response such as T cells or block immunologic checkpoints that restrain effective antitumor immunity...
March 2017: Cancer Biotherapy & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28295451/ccl20-neutralisation-by-a-monoclonal-antibody-in-healthy-subjects-selectively-inhibits-recruitment-of-ccr6-cells-in-an-experimental-suction-blister
#4
Gerben Bouma, Stefano Zamuner, Kirsty Hicks, Andrew Want, João Oliveira, Arpita Choudhury, Sara Brett, Darren Robertson, Leigh Felton, Virginia Norris, Disala Fernando, Michael Herdman, Ruth Tarzi
AIMS: GSK3050002, a humanized IgG1κ antibody with high binding affinity to human CCL20, was administered in a first-in-human study to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). An experimental skin suction blister model was employed to assess target engagement and the ability of the compound to inhibit recruitment of inflammatory CCR6 expressing cells. METHODS: This study was a randomized, double-blind (sponsor open), placebo-controlled, single-centre, single ascending intravenous dose escalation trial in 48 healthy male volunteers...
March 11, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28294526/phase-1-dose-escalating-study-of-the-safety-pharmacokinetics-and-pharmacodynamics-of-activated-factor-x-i-16l
#5
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/28294376/influence-of-the-pharmacokinetic-profile-on-the-plasma-glucose-lowering-effect-of-ppar%C3%AE-agonist-pioglitazone-in-wistar-fatty-rats
#6
Akihiko Goto, Yoshihiko Tagawa, Yoshiaki Kimura, Akifumi Kogame, Yuu Moriya, Nobuyuki Amano
Although the mechanism of action for peroxisome proliferator-activated receptor gamma (PPARγ) agonists has been extensively explored, the impact of the pharmacokinetic (PK) profile on the pharmacodynamic (PD) effects of PPARγ agonists has not been elucidated in detail. We evaluated the importance of the PK profile of PPARγ agonist for its PD effect based on population PK/PD analysis. Pioglitazone hydrochloride, the PPARγ agonist, was administered orally to Wistar fatty rats once a day (qd) or once every other day (q2d) as double the amount for the qd treatment...
March 11, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28287848/immunomodulating-and-immunoresistance-properties-of-cancer-initiating-cells-implications-for-the-clinical-success-of-immunotherapy
#7
Cristina Maccalli, Giorgio Parmiani, Soldano Ferrone
Cancer-initiating cells (CICs) represent a relatively rare subpopulation of cells endowed with self-renewal, stemness properties, tumorigenicity in immunodeficient mice, and resistance to standard therapies as well as to immunotherapy. Here, we review the biological and immunological characteristics of CICs with special focus on the immunomodulating mechanisms they utilize to escape from immunosurveillance. The recently developed immunotherapeutic strategies have yielded remarkable clinical results in many types of tumors, indicating that indeed a patient's immune system can mount an immune response, which is effective in controlling tumor growth...
March 13, 2017: Immunological Investigations
https://www.readbyqxmd.com/read/28276530/overcoming-sorafenib-evasion-in-hepatocellular-carcinoma-using-cxcr4-targeted-nanoparticles-to-co-deliver-mek-inhibitors
#8
Yunching Chen, Ya-Chi Liu, Yun-Chieh Sung, Rakesh R Ramjiawan, Ts-Ting Lin, Chih-Chun Chang, Kuo-Shyang Jeng, Chiung-Fang Chang, Chun-Hung Liu, Dong-Yu Gao, Fu-Fei Hsu, Annique M Duyverman, Shuji Kitahara, Peigen Huang, Simona Dima, Irinel Popescu, Keith T Flaherty, Andrew X Zhu, Nabeel Bardeesy, Rakesh K Jain, Cyril H Benes, Dan G Duda
Sorafenib is a RAF inhibitor approved for several cancers, including hepatocellular carcinoma (HCC). Inhibition of RAF kinases can induce a dose-dependent "paradoxical" upregulation of the downstream mitogen-activated protein kinase (MAPK) pathway in cancer cells. It is unknown whether "paradoxical" ERK activation occurs after sorafenib therapy in HCC, and if so, if it impacts the therapeutic efficacy. Here, we demonstrate that RAF inhibition by sorafenib rapidly leads to RAF dimerization and ERK activation in HCCs, which contributes to treatment evasion...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28275910/mechanisms-of-drug-resistance-in-melanoma
#9
Matthew Winder, Amaya Virós
Metastatic melanoma is associated with poor outcome and is largely refractory to the historic standard of care. In recent years, the development of targeted small-molecule inhibitors and immunotherapy has revolutionised the care and improved the overall survival of these patients. Therapies targeting BRAF and MEK to block the mitogen-activated protein kinase (MAPK) pathway were the first to show unprecedented clinical responses. Following these encouraging results, antibodies targeting immune checkpoint inhibition molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death (PD)-1, and PD-ligand1(PD-L1) demonstrated sustained tumour regression in a significant subset of patients by enabling an anti-tumour immunologic response...
March 9, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28270606/functional-characterization-of-cfi-402257-a-potent-and-selective-mps1-ttk-kinase-inhibitor-for-the-treatment-of-cancer
#10
Jacqueline M Mason, Xin Wei, Graham C Fletcher, Reza Kiarash, Richard Brokx, Richard Hodgson, Irina Beletskaya, Mark R Bray, Tak W Mak
Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28266713/personalised-dosing-of-medicines-for-children
#11
REVIEW
Basma Al-Metwali, Hussain Mulla
OBJECTIVES: Doses for most drugs are determined from population-level information, resulting in a standard ?one-size-fits-all' dose range for all individuals. This review explores how doses can be personalised through the use of the individuals' pharmacokinetic (PK)-pharmacodynamic (PD) profile, its particular application in children, and therapy areas where such approaches have made inroads. KEY FINDINGS: The Bayesian forecasting approach, based on population PK/PD models that account for variability in exposure and response, is a potent method for personalising drug therapy...
March 7, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28264853/pharmacokinetics-and-pharmacodynamics-of-minocycline-against-acinetobacter-baumannii-in-a-neutropenic-murine-pneumonia-model
#12
Jian Zhou, Kimberly R Ledesma, Kai-Tai Chang, Henrietta Abodakpi, Song Gao, Vincent H Tam
Multi-drug resistant (MDR) Acinetobacter baumannii is increasingly more prevalent in nosocomial infections. Although in vitro susceptibility of A. baumannii to minocycline is promising, the in vivo efficacy of minocycline has not been well established. In this study, the in vivo activity of minocycline was evaluated in a neutropenic murine pneumonia model. Specifically, we investigated the relationship between minocycline exposure and bactericidal activity using 5 A. baumannii isolates with a broad range of susceptibility (MIC ranged from 0...
March 6, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28264844/in-vivo-pharmacokinetic-and-pharmacodynamic-profiles-of-antofloxacin-against-klebsiella-pneumoniae-in-a-neutropenic-murine-lung-infection-model
#13
Yu-Feng Zhou, Meng-Ting Tao, Wei Huo, Xiao-Ping Liao, Jian Sun, Ya-Hong Liu
Antofloxacin is a novel broad-spectrum fluoroquinolone under development for the treatment of infections caused by a diverse group of bacterial species. We explored the pharmacodynamic (PD) profile and targets of antofloxacin against seven Klebsiella pneumoniae isolates using a neutropenic murine lung infection model. Plasma and bronchopulmonary pharmacokinetic studies were conducted at single subcutaneous doses of 2.5, 10, 40 and 160 mg/kg. Mice were infected intratracheally with K. pneumoniae and treated using 2-fold increasing total doses of antofloxacin ranging from 2...
March 6, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28263403/alternative-treatment-regimens-with-the-pcsk9-inhibitors-alirocumab-and-evolocumab-a-pharmacokinetic-and-pharmacodynamic-modeling-approach
#14
Nina Scherer, Christiane Dings, Michael Böhm, Ulrich Laufs, Thorsten Lehr
Alirocumab and evolocumab are 2 human monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9). These antibodies can potently lower low-density lipoprotein cholesterol (LDLc) serum concentrations. The aims of this analysis were to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for both antibodies, to simulate and investigate different dosage and application regimens, and finally, to note the effects on LDLc levels. Alirocumab was clinically studied and approved with 2 doses, 75 and 150 mg every 2 weeks (Q2W), whereas evolocumab was tested and approved with 2 dosing intervals, 140 mg Q2W and 420 mg Q4W...
March 6, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28260630/development-and-validation-of-an-elisa-method-for-the-quantification-of-nivolumab-in-plasma-from-non-small-cell-lung-cancer-patients
#15
Alicja Puszkiel, Gaëlle Noé, Pascaline Boudou-Rouquette, Chloé Le- Cossec, Jennifer Arrondeau, Jean-Stephane Giraud, Audrey Thomas-Schoemann, Jérôme Alexandre, Michel Vidal, François Goldwasser, Benoit Blanchet
Nivolumab, an anti PD-1 monoclonal antibody, has been approved for the treatment of previously treated advanced or metastatic non-small-cell lung cancer (NSCLC). The aim of this study was to develop and validate an ELISA method for the quantification of nivolumab in plasma from patients with NSCLC in order to perform future pharmacokinetic/pharmacodynamic (PK/PD) studies. A home-made ELISA was developed and validated according to the general recommendations for the immunoassays. Then, the ELISA method was applied to quantify plasma trough levels (Cmin) of nivolumab (3mg/kg every two weeks) in 27 NSCLC patients at days 14, 28 and 42 after start of treatment...
February 24, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28258068/novel-method-to-predict-in-vivo-liver-to-plasma-kpuu-for-oatp-substrates-using-suspension-hepatocytes
#16
Keith Riccardi, Jian Lin, Zhenhong Li, Mark Niosi, Sangwoo Ryu, Wenyi Hua, Karen Atkinson, Rachel E Kosa, John Litchfield, Li Di
The ability to predict human liver-to-plasma unbound partition coefficient (Kpuu) is of great importance to estimate unbound liver concentration, develop PK/PD relationships, predict efficacy and toxicity in the liver, and model drug-drug interaction (DDI) potential for drugs that are asymmetrically distributed into the liver. A novel in vitro method has been developed to predict in vivo Kpuu with good accuracy using cryopreserved suspension hepatocytes in InVitroGRO HI media with 4% BSA. Validation was performed using six OATP substrates with rat in vivo Kpuu data from IV infusion studies where steady state was achieved...
March 3, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28254373/dosing-antibiotic-prophylaxis-during-cardiopulmonary-bypass-a-higher-level-of-complexity-a-structured-review
#17
REVIEW
Fathima Paruk, Fekade B Sime, Jeffrey Lipman, Jason A Roberts
In highly invasive procedures such as open heart surgery, the risk of post-operative infection is particularly high due to exposure of the surgical field to multiple foreign devices. Adequate antibiotic prophylaxis is an essential intervention to minimise post-operative morbidity and mortality. However, there is a lack of clear understanding on the adequacy of traditional prophylactic dosing regimens, which are rarely supported by data. The aim of this structured review is to describe the relevant pharmacokinetic/pharmacodynamic (PK/PD) considerations for optimal antibiotic prophylaxis for major cardiac surgery including cardiopulmonary bypass (CPB)...
February 27, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28250973/mpp-induces-necrostatin-1-and-ferrostatin-1-sensitive-necrotic-death-of-neuronal-sh-sy5y-cells
#18
Keisuke Ito, Yutaka Eguchi, Yusuke Imagawa, Shuji Akai, Hideki Mochizuki, Yoshihide Tsujimoto
Regulation of cell death is potentially a powerful treatment modality for intractable diseases such as neurodegenerative diseases. Although there have been many reports about the possible involvement of various types of cell death in neurodegenerative diseases, it is still unclear exactly how neurons die in patients with these diseases, thus treatment strategies based on cell death regulation have not been established yet. To obtain some insight into the mechanisms of cell death involved in neurodegenerative diseases, we studied the effect of 1-methyl-4-phenylpyridinium (MPP+) on the human neuroblastoma cell line SH-SY5Y (a widely used model of Parkinson's disease)...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28247754/small-sized-mpeg-plga-nanoparticles-of-schisantherin-a-with-sustained-release-for-enhanced-brain-uptake-and-anti-parkinsonian-activity
#19
Tongkai Chen, Chuwen Li, Ye Li, Xiang Yi, Ruibing Wang, Simon Ming-Yuen Lee, Ying Zheng
Schisantherin A (SA) is a promising anti-Parkinsonism natural product. However, its poor water solubility and rapid serum clearance impose significant barriers to delivery of SA to the brain. This work aimed to develop SA in a nanoparticle formulation that extended SA circulation in the bloodstream and consequently an increased brain uptake and thus to be potentially efficacious for the treatment of Parkinson's disease (PD). Spherical SA nanoparticles with a mean particle size of 70 nm were prepared by encapsulating SA into methoxy poly(ethylene glycol)-block-poly(d,l)-lactic-co-glycolic acid (mPEG-PLGA) nanoparticles (SA-NPs) with an encapsulation efficiency of ∼91% and drug loading of ∼28%...
March 9, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28247332/intranasal-administration-of-gdnf-protects-against-neural-apoptosis-in-a-rat-model-of-parkinson-s-disease-through-pi3k-akt-gsk3%C3%AE-pathway
#20
Peijian Yue, Lin Gao, Xuejing Wang, Xuebing Ding, Junfang Teng
Glial cell line-derived neurotrophic factor (GDNF) plays important roles in protecting the damaged or dying dopamine neurons in the animal models of Parkinson's disease (PD). This study was to determine the effect and mechanisms of GDNF on the apoptosis of neurons in 6-hydroxydopamine (6-OHDA) induced Parkinson's disease model of rats. Healthy male Sprague-Dawley rats (220-240 g) were randomly divided into six groups (n = 10). 6-OHDA was used to establish the PD rat model. Tyrosine hydroxylase (TH) immunohistochemistry was used to assess the neuron loss in 6-OHDA-lesioned rats...
February 28, 2017: Neurochemical Research
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