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https://www.readbyqxmd.com/read/29775163/methylprednisolone-inhibits-the-proliferation-of-endogenous-neural-stem-cells-in-nonhuman-primates-with-spinal-cord-injury
#1
Jichao Ye, Yi Qin, Yong Tang, Mengjun Ma, Peng Wang, Lin Huang, Rui Yang, Keng Chen, Chaopeng Chai, Yanfeng Wu, Huiyong Shen
OBJECTIVE The aim of this work was to investigate the effects of methylprednisolone on the proliferation of endogenous neural stem cells (ENSCs) in nonhuman primates with spinal cord injury (SCI). METHODS A total of 14 healthy cynomolgus monkeys ( Macaca fascicularis) (4-5 years of age) were randomly divided into 3 groups: the control group (n = 6), SCI group (n = 6), and methylprednisolone therapy group (n = 2). Only laminectomy was performed in the control animals at T-10. SCI was induced in monkeys using Allen's weight-drop method (50 mm × 50 g) to injure the posterior portion of the spinal cord at T-10...
May 18, 2018: Journal of Neurosurgery. Spine
https://www.readbyqxmd.com/read/29769573/discovery-of-a-novel-il-15-based-protein-with-improved-developability-and-efficacy-for-cancer-immunotherapy
#2
Qiyue Hu, Xin Ye, Xiangdong Qu, Dongbing Cui, Lei Zhang, Zhibin Xu, Hong Wan, Lianshan Zhang, Weikang Tao
Interleukin-15 (IL-15) can promote both innate and adaptive immune reactions by stimulating CD8+ /CD4+ T cells and natural killer cells (NK) while showing no effect in activating T-regulatory (Treg) cells or inducing activation-associated death among effector T cells and NK cells. Thus, IL-15 is considered as one of the most promising molecules for antitumor immune therapy. To improve the drug-like properties of natural IL-15, we create an IL-15-based molecule, named P22339, with the following characteristics: 1) building a complex of IL-15 and the Sushi domain of IL-15 receptor α chain to enhance the agonist activity of IL-15 via transpresentation; 2) through a rational structure-based design, creating a disulfide bond linking the IL-15/Sushi domain complex with an IgG1 Fc to augment its half-life...
May 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29768985/effects-of-monoclonal-antibodies-against-nerve-growth-factor-on-healthy-bone-and-joint-tissues-in-mice-rats-and-monkeys-histopathologic-biomarker-and-microcomputed-tomographic-assessments
#3
Kathryn E Gropp, Cathy S Carlson, Mark G Evans, Cedo M Bagi, William J Reagan, Susan I Hurst, David L Shelton, Mark A Zorbas
Tanezumab, an anti-nerve growth factor (NGF) antibody, is in development for management of chronic pain. During clinical trials of anti-NGF antibodies, some patients reported unexpected adverse events requiring total joint replacements, resulting in a partial clinical hold on all NGF inhibitors. Three nonclinical toxicology studies were conducted to evaluate the effects of tanezumab or the murine precursor muMab911 on selected bone and joint endpoints and biomarkers in cynomolgus monkeys, Sprague-Dawley rats, and C57BL/6 mice...
January 1, 2018: Toxicologic Pathology
https://www.readbyqxmd.com/read/29766827/pain-related-behavior-and-brain-activation-in-a-cynomolgus-macaque-model-of-postoperative-pain
#4
Aldric Hama, Takahiro Natsume, Shin'ya Ogawa, Yūji Awaga, Ikuo Hayashi, Akihisa Matsuda, Hiroyuki Takamatsu
BACKGROUND: Inadequate postoperative pain management could lead to persistent pain and this is, in part, due to incomplete understanding of the mechanism of postoperative pain. Currently available rodent models may have limited translatability to clinical postoperative pain. Thus, a preclinical model of postoperative pain was developed in the cynomolgus macaque, a species that is phylogenetically closer to humans than rodents. METHOD: The presence of pressure hypersensitivity was assessed with non-noxious pressure applied proximally and distally (approximately 10 cm) to an abdominal incision in macaques...
May 15, 2018: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/29757698/prediction-of-non-linear-pharmacokinetics-in-humans-of-an-antibody-drug-conjugate-adc-when-evaluation-of-higher-doses-in-animals-is-limited-by-tolerability-case-study-with-an-anti-cd33-adc
#5
Isabel Figueroa, Doug Leipold, Steve Leong, Bing Zheng, Montserrat Carrasco-Triguero, Aimee Fourie-O'Donohue, Katherine R Kozak, Keyang Xu, Melissa Schutten, Hong Wang, Andrew G Polson, Amrita V Kamath
For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design...
May 14, 2018: MAbs
https://www.readbyqxmd.com/read/29757653/metabolism-of-an-oxime-linked-antibody-drug-conjugate-ags62p1-and-characterization-of-its-identified-metabolite
#6
Josh T Snyder, Maria-Christina Malinao, Julien Dugal-Tessier, John E Atkinson, Banmeet S Anand, Akihiro Okada, Brian A Mendelsohn
AGS62P1 is an antibody drug conjugate (ADC) composed of a human IgG1κ monoclonal antibody against FLT3 (FMS-like tyrosine kinase 3) with a p-acetyl phenylalanine (pAF) residue inserted at position 124 of each heavy chain linked to the proprietary microtubule disrupting agent AGL-0182-30 via an alkoxyamine linker that forms an oxime upon conjugation to the antibody. AGS62P1 is currently in Phase I human clinical trials for acute myelogenous leukemia (AML). The identified primary metabolite of an oxime-linked ADC is presented for the first time...
May 14, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29755109/regulated-intratumoral-expression-of-il-12-using-a-rheoswitch-therapeutic-system-%C3%A2-rts-%C3%A2-gene-switch-as-gene-therapy-for-the-treatment-of-glioma
#7
John A Barrett, Hongliang Cai, John Miao, Pranay D Khare, Paul Gonzalez, Jessica Dalsing-Hernandez, Geeta Sharma, Tim Chan, Laurence J N Cooper, Francois Lebel
The purpose of this study was to determine if localized delivery of IL-12 encoded by a replication-incompetent adenoviral vector engineered to express IL-12 via a RheoSwitch Therapeutic System® (RTS® ) gene switch (Ad-RTS-IL-12) administered intratumorally which is inducibly controlled by the oral activator veledimex is an effective approach for glioma therapy. Mice bearing 5-10-day-old intracranial GL-261 gliomas were intratumorally administered Ad-RTS-mIL-12 in which IL-12 protein expression is tightly controlled by the activator ligand, veledimex...
May 14, 2018: Cancer Gene Therapy
https://www.readbyqxmd.com/read/29754833/discovery-of-benzimidazole-derivatives-as-orally-active-renin-inhibitors-optimization-of-3-5-disubstituted-piperidine-to-improve-pharmacokinetic-profile
#8
Hidekazu Tokuhara, Yasuhiro Imaeda, Yoshiyuki Fukase, Koichi Iwanaga, Naohiro Taya, Koji Watanabe, Ray Kanagawa, Keisuke Matsuda, Yumiko Kajimoto, Keiji Kusumoto, Mitsuyo Kondo, Gyorgy Snell, Craig A Behnke, Takanobu Kuroita
We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity...
April 27, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29750005/persistence-of-vertebral-growth-plate-cartilage-in-aged-cynomolgus-monkeys
#9
Munetaka Iwata, Wataru Yamamoto, Takasumi Shimomoto, Yuki Okada, Satomi Oosawa, Daishiro Miura, Yasushi Hara
Growth plates at each end of vertebral bodies play a pivotal role in longitudinal spinal growth. Epiphyseal closures are formed in adult humans. Although monkeys are frequently employed in bone and disc research, the age of epiphyseal closure has not been well documented. In this study, histological analyses of lumbar vertebral end plates and the surrounding tissue were performed in 11 normal cynomolgus monkeys aged approximately 9 to 15 years, and unclosed growth plate cartilage was detected in all the end plates...
April 2018: Journal of Toxicologic Pathology
https://www.readbyqxmd.com/read/29750004/testicular-microlithiasis-in-a-clinically-healthy-cynomolgus-monkey-macaca-fascicularis
#10
Norimitsu Shirai, Mark G Evans
The present article describes an occurrence of testicular microlithiasis in a cynomolgus monkey from a routine regulatory toxicology study. The monkey was from a negative control group. Microscopically, the lesion was characterized by multiple extracellular mineralized calculi within seminiferous tubular epithelia of both testes without any tissue reaction or abnormal condition such as cryptorchidism, testicular neoplasm, or hypogonadism. The present case is remarkable in that there is a paucity of reports on spontaneous testicular microlithiasis in nonhuman primates...
April 2018: Journal of Toxicologic Pathology
https://www.readbyqxmd.com/read/29743440/hepatic-histopathological-changes-and-dysfunction-in-primates-following-exposure-to-organic-arsenic-diphenylarsinic-acid
#11
Tomoyuki Masuda, Kazuhiro Ishii, Yukio Morishita, Nobuaki Iwasaki, Yasuyuki Shibata, Akira Tamaoka
Organic arsenic diphenylarsinic acid (DPAA[V]) accumulates at high concentrations in the liver of primates after its subchronic administration. However, no studies on the hepatic effects of organic arsenic compounds, including DPAA(V), on primates have been reported to date. To clarify the toxicokinetics of DPAA(V) in the liver of primates, hepatic tissue specimens were collected from cynomolgus monkeys (n = 32) at 5, 29, 170, and 339 days after repeated administration of DPAA(V) for 28 days. Four histopathological changes in the specimens were observed and pathologically evaluated...
2018: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/29743078/nonclinical-and-clinical-pharmacological-characterization-of-the-potent-and-selective-cathepsin-k-inhibitor-miv-711
#12
Erik Lindström, Biljana Rizoska, Ian Henderson, Ylva Terelius, Markus Jerling, Charlotte Edenius, Urszula Grabowska
BACKGROUND: Cathepsin K is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (OA). The current paper characterized the pharmacological profile of the potent and selective cathepsin K inhibitor, MIV-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man. METHODS: The potency and selectivity of MIV-711 were assessed in vitro using recombinant enzyme assays and differentiated human osteoclasts...
May 9, 2018: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29742964/efficient-generation-of-cynomolgus-monkey-induced-pluripotent-stem-cell-derived-intestinal-organoids-with-pharmacokinetic-functions
#13
Daichi Onozato, Misaki Yamashita, Ryosuke Fukuyama, Takumi Akagawa, Yuriko Kida, Akiko Koeda, Tadahiro Hashita, Takahiro Iwao, Tamihide Matsunaga
In preclinical studies, the cynomolgus monkey (CM) model is frequently used to predict the pharmacokinetics of drugs in the human small intestine, because of its evolutionary closeness to humans. Intestinal organoids that mimic the intestinal tissue have attracted attention in regenerative medicine and drug development. In this study, we generated intestinal organoids from CM induced pluripotent stem (CMiPS) cells and analysed their pharmacokinetic functions. CMiPS cells were induced into the hindgut; then, the cells were seeded on microfabricated culture vessel plates to form spheroids...
May 10, 2018: Stem Cells and Development
https://www.readbyqxmd.com/read/29737459/safety-of-intra-articular-transplantation-of-lentivirally-transduced-mesenchymal-stromal-cells-for-haemophilic-arthropathy-in-a-non-human-primate
#14
Tsukasa Ohmori, Hiroaki Mizukami, Yuko Katakai, Sho Kawai, Hitoyasu Nakamura, Makoto Inoue, Tsugumine Shu, Hideharu Sugimoto, Yoichi Sakata
Joint bleeding and resultant arthropathy are major determinants of quality of life in haemophilia patients. We previously developed a mesenchymal stromal cell (MSC)-based treatment approach for haemophilic arthropathy in a mouse model of haemophilia A. Here, we evaluated the long-term safety of intra-articular injection of lentivirally transduced autologous MSCs in non-human primates. Autologous bone-marrow-derived MSCs transduced with a lentiviral vector expressing coagulation factor VIII (FVIII) were injected into the left knee joint of cynomolgus monkeys...
May 8, 2018: International Journal of Hematology
https://www.readbyqxmd.com/read/29731087/seven-years-of-experiences-of-preclinical-experiments-of-xeno-heart-transplantation-of-pig-to-non-human-primate-cynomolgus-monkey
#15
S J Lee, J S Kim, H K Chee, I J Yun, K S Park, H S Yang, J H Park
BACKGROUND: The absolute shortage of donors compared with patients requiring transplantation is currently an unsolved problem, and the only possible solution may be xenotransplantation. To establish a successful clinical trial, a preclinical study using nonhuman primates is essential. Starting in November 2011, our team initiated heterotopic abdominal heart xenotransplantation, the first in the Republic of Korea. We present here the initial 7-year results. METHODS: A total of 22 xenotransplantation procedures have been performed since 2011...
May 2018: Transplantation Proceedings
https://www.readbyqxmd.com/read/29730448/a-big-data-approach-to-the-concordance-of-the-toxicity-of-pharmaceuticals-in-animals-and-humans
#16
Matthew Clark
Although lack of efficacy is an important cause of late stage attrition in drug development the shortcomings in the translation of toxicities observed during the preclinical development to observations in clinical trials or post-approval is an ongoing topic of research. The concordance between preclinical and clinical safety observations has been analyzed only on relatively small data sets, mostly over short time periods of drug approvals. We therefore explored the feasibility of a big-data analysis on a set of 3290 approved drugs and formulations for which 1,637,449 adverse events were reported for both humans animal species in regulatory submissions over a period of more than 70 years...
May 3, 2018: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29728897/translational-pk-pd-modeling-analysis-of-mcla-128-a-her2-her3-bispecific-monoclonal-antibody-to-predict-clinical-efficacious-exposure-and-dose
#17
Aurelia H M de Vries Schultink, Robert P Doornbos, Alexander B H Bakker, Kees Bol, Mark Throsby, Cecile Geuijen, David Maussang, Jan H M Schellens, Jos H Beijnen, Alwin D R Huitema
Introduction MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors. Pharmacokinetics (PK) and pharmacodynamics (PD) of MCLA-128 have been evaluated in preclinical studies in cynomolgus monkeys and mice. The aim of this study was to characterize the PK and PD of MCLA-128 and to predict a safe starting dose and efficacious clinical dose for the First-In-Human study. Methods A PK-PD model was developed based on PK data from cynomolgus monkeys and tumor growth data from a mouse JIMT-1 xenograft model...
May 5, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29724685/species-specific-involvement-of-integrin-%C3%AE-iib%C3%AE-3-in-a-monoclonal-antibody-ch12-triggers-off-target-thrombocytopenia-in-cynomolgus-monkeys
#18
Yiting Zhang, Jianhua Sun, Minjia Tan, Yongzhen Liu, Qian Li, Hua Jiang, Huamao Wang, Zonghai Li, Wei Wan, Hualiang Jiang, Henglei Lu, Bingshun Wang, Jin Ren, Likun Gong
CH12 is a novel humanized monoclonal antibody against epidermal growth factor receptor variant III (EGFRvIII) for cancer treatment. Unfortunately, in pre-clinical safety evaluation studies, acute thrombocytopenia was observed after administration of CH12 in cynomolgus monkeys, but not rats. More importantly, in vitro experiments found that CH12 can bind and activate platelets in cynomolgus monkey, but not human peripheral blood samples. Cynomolgus monkey-specific thrombocytopenia has been reported previously; however, the underlying mechanism remains unclear...
April 7, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29723247/fc-engineering-of-anti-nectin-2-antibody-improved-thrombocytopenic-adverse-event-in-monkey
#19
Tsutomu Oshima, Hideaki Miyashita, Yoshimasa Ishimura, Yuki Ito, Yoko Tanaka, Akira Hori, Toshio Kokubo, Tomofumi Kurokawa
Nectin-2 is a transmembrane glycoprotein which is involved in the process of Ca2+-independent cell-cell adhesion. In our previous study, we have demonstrated that Nectin-2 is over-expressed in breast and ovarian cancer tissues by using gene expression analysis and immunohistochemistry. Furthermore, we discovered multiple anti-Nectin-2 fully human monoclonal antibodies which inhibited tumor growth in in vivo subcutaneous xenograft models with antibody-dependent cellular cytotoxicity (ADCC) as the principal mechanism of action...
2018: PloS One
https://www.readbyqxmd.com/read/29720516/seminal-siv-in-chronically-infected-cynomolgus-macaques-is-dominated-by-virus-originating-from-multiple-genital-organs
#20
Laurent Houzet, Marcos Pérez-Losada, Giulia Matusali, Claire Deleage, Nathalie Dereuddre-Bosquet, Anne-Pascale Satie, Florence Aubry, Emmanuelle Becker, Bernard Jégou, Roger Le Grand, Brandon F Keele, Keith A Crandall, Nathalie Dejucq-Rainsford
The sexual transmission of viruses is responsible for the spread of multiple infectious diseases. Although the HIV/AIDS pandemic remains fueled by sexual contacts with infected semen, the origin of virus in semen is still unknown. In a substantial number of HIV- infected men, viral strains present in semen differ from the ones in blood, suggesting that HIV is locally produced within the genital tract. Such local production may be responsible for the persistence of HIV in semen despite effective antiretroviral therapy...
May 2, 2018: Journal of Virology
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