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Kurt G Pike, Bernard Barlaam, Elaine Cadogan, Andrew Campbell, Yingxue Chen, Nicola Colclough, Nichola L Davies, Camila de-Almeida, Sebastien L Degorce, Myriam Didelot, Allan Dishington, Richard Ducray, Stephen T Durant, Lorraine A Hassall, Jane Holmes, Gareth D Hughes, Philip A MacFaul, Keith R Mulholland, Thomas M McGuire, Gilles Ouvry, Martin Pass, Graeme Robb, Natalie Stratton, Zhenhua Wang, Joanne Wilson, Baochang Zhai, Kang Zhao, Nidal Al-Huniti
ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution)...
May 10, 2018: Journal of Medicinal Chemistry
Yong-Mei Guan, Wei-Feng Zhu, Xue-Jing Guan, Zheng-Gen Liao, Guo-Wei Zhao, Wei Dong, Xin-Li Liang
The study was aimed to establish a liquid chromatography-tandem mass spectrometric method for the determination of the docetaxel concentration in rat plasma, and study the effect of coumarin constituents (imperatorin, isoimperatorin and oxypeucedanin) in Angelica dahurica on pharmacokinetics of docetaxel.Plasma was precipitated with acetonitrile and determined by LC-MS method with Paclitaxel as an internal standard. The specificity, linearity, range, accuracy, precision and stability of the method were suitable for the determination of docetaxel in plasma...
December 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Manuel Hidalgo, Maria Martinez-Garcia, Christophe Le Tourneau, Christophe Massard, Elena Garralda, Valentina Boni, Alvaro Taus, Joan Albanell, Marie-Paule Sablin, Marie Alt, Ratislav Bahleda, Andrea Varga, Christophe Boetsch, Izolda Franjkovic, Florian Heil, Angelika Lahr, Katharina Lechner, Anthony Morel, Tapan Nayak, Simona Rossomanno, Kevin Smart, Kay Stubenrauch, Oliver Krieter
Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies. Experimental Design: Patients received escalating biweekly (3-30 mg/kg) or weekly (10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control. Results: Forty-two patients were treated...
April 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jing Zhao, Yuan Li, Ming-Xin Shi, Xue Wang, Jing-Qing Zhang
OBJECTIVES: To study the oral phamacokinetics of curcumin ethosomes in rats. METHODS: Pharmacokinetics parameters were detected by DAS 2.1.1 software analysis through data of blood concentrations harvested from HPLC after oral administration of curcumin ethosomes in rats. RESULTS: Analyzed by non-compartmental method, the area under concentration-time curve from 0 to last time [AUC(0-72h)] of curcumin ethosomes was 1.6 times larger than that of free curcumin, the peak concentration (C max) of curcumin ethosomes was 1...
March 2017: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
Helena Rabie, Eric H Decloedt, Anthony J Garcia-Prats, Mark F Cotton, Lisa Frigati, Marc Lallemant, Anneke Hesseling, H Simon Schaaf
In high prevalence settings, tuberculosis and HIV dual infection and co-treatment is frequent. Rifamycins, especially rifampicin, in combination with isoniazid, ethambutol and pyrazinamide are key components of short-course antituberculosis therapy. Areas covered: We reviewed available data, for which articles were identified by a Pubmed search, on rifamycin-antiretroviral interactions in HIV-infected children. Rifamycins have potent inducing effects on phase I and II drug metabolising enzymes and transporters...
April 2017: Expert Opinion on Pharmacotherapy
Allahdad Zarei, Philippa A Hulley, Afsie Sabokbar, M Kassim Javaid, Alireza Morovat
Despite differences in the phamacokinetics of 25-hydroxycholecalciferol (25(OH)D3) and 25-hydroxyergocalciferol (25(OH)D2) in man, the effects of these and their 1α-hydroxylated forms (1,25(OH)2D3 and 1,25(OH)2D2) on cellular activity of vitamin D-responsive cells have hardly been compared. We studied differences in the effects of these metabolites on cell number, gene transcription, protein expression and mineralisation of cultured human bone marrow-derived stromal cells (hBMSC) and rapidly mineralising mouse 2T3 osteoblasts...
2016: PloS One
R K Gherardi, J Aouizerate, J Cadusseau, S Yara, F J Authier
Aluminum oxyhydroxide (Alhydrogel(®)) is a nano-crystalline compound forming aggregates that has been introduced in vaccine for its immunologic adjuvant effect in 1926. It is the most commonly used adjuvant in human and veterinary vaccines but mechanisms by which it stimulates immune responses remain ill-defined. Although generally well tolerated on the short term, it has been suspected to occasionally cause delayed neurologic problems in susceptible individuals. In particular, the long-term persistence of aluminic granuloma also termed macrophagic myofasciitis is associated with chronic arthromyalgias and fatigue and cognitive dysfunction...
June 2016: Morphologie: Bulletin de L'Association des Anatomistes
Omar M Rashid, Kazuaki Takabe
INTRODUCTION: Despite massive expenditures in research and development to cure breast cancer, few agents that pass preclinical trials demonstrate efficacy in humans. Although this endeavor relies on murine models to screen for efficacy before progressing to clinical trials, historically there has been little focus on the validation of these models, even in the era of targeted therapy where understanding the genetic signatures of tumors under study is critical. AREAS COVERED: This review includes the transgenic, xenograft, and syngeneic murine breast cancer models, the ectopic, orthotopic and intravenous methods of cell implantation, and the ethics of animal experimentation...
February 2015: Expert Opinion on Drug Metabolism & Toxicology
Ana P Castano, Tatiana N Demidova, Michael R Hamblin
Photodynamic therapy (PDT) has been known for over a hundred years, but is only now becoming widely used. Originally developed as cancer therapy, some of its most successful applications are for non-malignant disease. The majority of mechanistic research into PDT, however, is still directed towards anti-cancer applications. In the final part of series of three reviews, we will cover the possible reasons for the well-known tumor localizing properties of photosensitizers (PS). When PS are injected into the bloodstream they bind to various serum proteins and this can affect their phamacokinetics and biodistribution...
June 2005: Photodiagnosis and Photodynamic Therapy
Yang Yang, Chun-Mei Fan, Xuan He, Ke Ren, Jin-Kun Zhang, Ying-Ju He, Luo-Ting Yu, Ying-Lan Zhao, Chang-Yang Gong, Yu Zheng, Xiang-Rong Song, Jun Zeng
Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl) benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE) were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR) of NCE were estimated in different phosphate buffers. Effective intestinal permeability (P(eff)) of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations...
2014: International Journal of Molecular Sciences
J Beyer-Westendorf, S Gehrisch
BACKGROUND: The direct factor Xa inhibitor rivaroxaban is approved for venous thromboembolism (VTE) treatment in adults. However, in all phase-III trials children or adolescents have not been included. For under-aged VTE patients, current standard treatment consists of low molecular weight heparin or Vitamin K antagonists. Rivaroxaban could be an attractive alternative, however, no data on the pharmacokinetics (PK) of rivaroxaban in adolescents are currently available. PATIENT, METHODS: We report PK data for rivaroxaban derived from a girl (age:15 years), who presented three month after acute deep vein thrombosis, already receiving rivaroxaban therapy...
2014: Hämostaseologie
Erica K M Reeves, Eric P Hoffman, Kanneboyina Nagaraju, Jesse M Damsker, John M McCall
Δ9,11 modifications of glucocorticoids (21-aminosteroids) have been developed as drugs for protection against cell damage (lipid peroxidation; lazaroids) and inhibition of neovascularization (anecortave). Part of the rationale for developing these compounds has been the loss of glucocorticoid receptor binding due to the Δ9,11 modification, thus avoiding many immunosuppressive activities and deleterious side effect profiles associated with binding to glucocorticoid and mineralocorticoid receptors. We recently demonstrated that anecortave acetate and its 21-hydroxy analog (VBP1) do, in fact, show glucocorticoid and mineralocorticoid receptor binding activities, with potent translocation of the glucocorticoid receptor to the cell nucleus...
April 15, 2013: Bioorganic & Medicinal Chemistry
C Devesa García, C Matoses Chirivella, L Peral Ballester, G Sanz Tamargo, A C Murcia López, A Navarro Ruiz
BACKGROUND AND OBJECTIVE: To asses the outcomes of posological adjust program in renal impairment inpatients, describe the drugs more usually involved, and determine the degree of acceptance of the pharmaceutical intervention made. MATERIAL AND METHOD: A fifteen months-prospective study, in renal insufficiency inpatients (serum creatinine > 1,4 mg/dL) treated with drugs that needs posological adjustment. The primary outcome was the ratio of adequate dosage of the treatment, according with the glomerular filtration rate...
November 2012: Farmacia Hospitalaria
Anna Park, Denise M Honey, Lihui Hou, Julie J Bird, Christine Zarazinski, Michelle Searles, Christian Braithwaite, Jonathan S Kingsbury, Josephine Kyazike, Kerry Culm-Merdek, Ben Greene, James E Stefano, Huawei Qiu, John M McPherson, Clark Q Pan
Thyrogen (thyrotropin alfa for injection), recombinant human TSH (rhTSH), has been successfully used to enhance diagnostic radioiodine scanning and thyroglobulin testing in the follow-up of patients with thyroid cancer and as an adjunctive treatment for radioiodine thyroid remnant ablation. However, the short half-life of rhTSH in the circulation requires a multidose regimen. We developed novel sialic acid-mediated and galactose-mediated conjugation chemistries for targeting polyethylene glycol (PEG) to the three N-linked glycosylation sites on the protein, to prolong plasma half-life by eliminating kidney filtration and potential carbohydrate-mediated clearance...
March 2013: Endocrinology
Om Prakash, Feroz Khan, Rajender Singh Sangwan, Laxminarain Misra
The present study deals with the development of an artificial neural network based quantitative structure activity relationship (QSAR) model for virtual screening of active compounds which contain androstenedione carbonskeleton or their similar skeleton at the core. An empirical data modeling (with fitted data mapping) has been performed on the basis of bioassay record for human breast cancer cell line MCF7. The whole experimental data set was considered as test set. Standard feed-forward back-propagation neural network technique was applied to build the model...
January 2013: Combinatorial Chemistry & High Throughput Screening
Juan Jose Marugan, Wenwei Huang, Omid Motabar, Wei Zheng, Jingbo Xiao, Samarjit Patnaik, Noel Southall, Wendy Westbroek, Wendy A Lea, Anton Simeonov, Ehud Goldin, Maria A Debernardi, Ellen Sidransky
Small molecule chaperones are a promising therapeutic approach for the Lysosomal Storage Disorders (LSDs). Here, we report the discovery of a new series of non-iminosugar glucocerebrosidase inhibitors with chaperone capacity, and describe their structure activity relationship (SAR), selectivity, cell activity phamacokinetics.
January 2012: MedChemComm
Yufeng Ma, Wen Li, Fangdi Hu, Yikai Shi, Yingyan Bi, Shilan Feng
OBJECTIVE: To determine bergapten's concentration in plasma and observe its pharmacokinetics in rats using a combined LC-MS/MS analytical method. METHOD: Blood samples were separated on a Hypersil ODS column (4.6 mm x 250 mm, 5 mm) at a temperature of 30 degrees C, and mobile phase consisted of water and methanol (22.5: 77.5) at a flow rate of 0.8 mL x min(-1). RESULT: The methodological study showed a good linear relationship of 8.12-162...
February 2012: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Yoshiyuki Suzuki, Satoshi Ichinomiya, Mieko Kurosawa, Junichiro Matsuda, Seiichiro Ogawa, Masami Iida, Takatoshi Kubo, Miho Tabe, Masayuki Itoh, Katsumi Higaki, Eiji Nanba, Kousaku Ohno
Therapeutic chaperone effect of a valienamine derivative N-octyl 4-epi-β-valienamine (NOEV) was studied in G(M1)-gangliosidosis model mice. Phamacokinetic analysis revealed rapid intestinal absorption and renal excretion after oral administration. Intracellular accumulation was not observed after continuous treatment. NOEV was delivered to the central nervous system through the blood-brain barrier to induce high expression of the apparently deficient β-galactosidase activity. NOEV treatment starting at the early stage of disease resulted in remarkable arrest of neurological progression within a few months...
May 2012: Molecular Genetics and Metabolism
Eugen Lounkine, Florian Nigsch, Jeremy L Jenkins, Meir Glick
From a medicinal chemistry point of view, one of the primary goals of high throughput screening (HTS) hit list assessment is the identification of chemotypes with an informative structure-activity relationship (SAR). Such chemotypes may enable optimization of the primary potency, as well as selectivity and phamacokinetic properties. A common way to prioritize them is molecular clustering of the hits. Typical clustering techniques, however, rely on a general notion of chemical similarity or standard rules of scaffold decomposition and are thus insensitive to molecular features that are enriched in biologically active compounds...
December 27, 2011: Journal of Chemical Information and Modeling
Qiang Tan, Aimie M Ogawa, Susan L Raghoobar, Douglas Wisniewski, Lawrence Colwell, Young-Whan Park, Katherine Young, Jeffrey D Hermes, Frank P Dininno, Milton L Hammond
The preparation and characterization of a series of thiophenyl oxime phosphonate beta-lactamase inhibitors is described. A number of these analogs were potent and selective inhibitors of class C beta-lactamases from Pseudomonas aeruginosa and Enterobacter cloacae. Compounds 3b and 7 reduced the MIC of imipenem against an AmpC expressing strain of imipenem-resistant P. aeruginosa. A number of the title compounds retained micromolar potency against the class D OXA-40 beta-lactamase from Acinetobacter baumannii and at high concentrations compound 3b was shown to reduce the MIC of imipenem against a highly imipenem-resistant strain of A...
July 15, 2011: Bioorganic & Medicinal Chemistry Letters
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