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Jiang-Tao Tang, Brenda C de Winter, Dennis A Hesselink, Ferdi Sombogaard, Lan-Lan Wang, Teun van Gelder
AIM: Elderly transplant recipients have a lower incidence of acute rejection, and a higher risk to die from infectious complications. Potentially this may be caused by differences in the pharmacokinetics (PK) or pharmacodynamics (PD) of the immunosuppressive drugs they are taking. This study was designed to comprehensively evaluate the influence of age on the PK and PD of mycophenolic acid (MPA). METHODS: In this study the PK and PD of MPA was studied in 26 elderly and 54 younger renal transplant recipients treated with mycophenolate mofetil and tacrolimus...
October 18, 2016: British Journal of Clinical Pharmacology
Haiying Shen, Kiyoon Kim, Yoojung Oh, Kyung Sik Yoon, Hyung Hwan Baik, Sung Soo Kim, Joohun Ha, Insug Kang, Wonchae Choe
β-N-methylamino-L-alanine (BMAA) is a neurotoxin that is closely associated with the incidence of amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. In cultured neuronal cells, BMAA notably induces the upregulation of endoplasmic reticulum (ER) chaperons and activates the unfolded protein response (UPR) receptor pathways of protein kinase RNA‑like endoplasmic reticulum kinase, inositol‑requiring kinase 1 and transcription factor 6. The ER stress‑specific protein CCAAT/‑enhancer‑binding protein homologous protein (CHOP) affords pro‑apoptotic responses that cause mitochondrial damage and caspase activation...
October 5, 2016: Molecular Medicine Reports
Kyoji Tsuchikama, Zhiqiang An
The antibody-drug conjugate (ADC), a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules (payloads) through chemical linkers, is a novel therapeutic format and has great potential to make a paradigm shift in cancer chemotherapy. This new antibody-based molecular platform enables selective delivery of a potent cytotoxic payload to target cancer cells, resulting in improved efficacy, reduced systemic toxicity, and preferable pharmacokinetics (PK)/pharmacodynamics (PD) and biodistribution compared to traditional chemotherapy...
October 14, 2016: Protein & Cell
Tongkai Chen, Chuwen Li, Ye Li, Yi Xiang, Simon Ming Yuen Lee, Ying Zheng
Schisantherin A (SA) is a promising anti-Parkinsonism Chinese herbal medicine but with poor water solubility and challenges to be delivered to the brain. We formulated SA as nanocrystals (SA-NC), aiming to improve its solubility, pharmacokinetic profile and thus provide a potential therapeutic agent for the treatment of Parkinson's disease (PD). The rod-shaped SA-NC had a particle size of ~160 nm with 33.3% drug loading, and the nanocrystals exhibited a fast dissolution rate in vitro. The intact drug nanocrystals could be internalized into Madin-Darby canine kidney (MDCK) cells, which were followed by rapid intracellular release, and most of the drug was transported to the basolateral side in its soluble form...
October 14, 2016: Molecular Pharmaceutics
Emilio Fernández-Varón, Carlos Cárceles-García, Juan Manuel Serrano-Rodríguez, Carlos M Cárceles-Rodríguez
BACKGROUND: Bacterial pneumonia in goats is usually caused by Mannheimia haemolytica and Pasteurella multocida. Another important infection disease in lactating goats is intramammary infection producing mastitis, usually associated with coagulase-negative Staphylococcus spp. However, treatment of bacterial pneumonia in goats not affected by mastitis problems should be restricted to antimicrobials with scant penetration to milk in order to avoid long withdrawal times. Ceftiofur is a third-generation cephalosporin antimicrobial with activity against various gram-positive and gram-negative, aerobic and anaerobic bacteria encountered by domestic animals...
October 13, 2016: BMC Veterinary Research
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
J C Soria, H K Gan, S P Blagden, R Plummer, H T Arkenau, M Ranson, T R J Evans, G Zalcman, R Bahleda, A Hollebecque, C Lemech, E Dean, J Brown, D Gibson, V Peddareddigari, S Murray, N Nebot, J Mazumdar, L Swartz, K R Auger, R A Fleming, R Singh, M Millward
BACKGROUND: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. PATIENTS AND METHODS: The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined...
October 11, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Michael Osthoff, Martin Siegemund, Gianmarco Balestra, Mohd Hafiz Abdul-Aziz, Jason A Roberts
Prolonged infusion of β-lactam antibiotics as either extended (over at least 2 hours) or continuous infusion is increasingly applied in intensive care units around the world in an attempt to optimise treatment with this most commonly used class of antibiotics, whose effectiveness is challenged by increasing resistance rates. The pharmacokinetics of β-lactam antibiotics in critically ill patients is profoundly altered secondary to an increased volume of distribution and the presence of altered renal function, including augmented renal clearance...
2016: Swiss Medical Weekly
Soo Min Han, Joonhee Park, Ji Hyun Lee, Sang Seop Lee, Hyoki Kim, Hyojun Han, Yuhnam Kim, Sojeong Yi, Joo-Youn Cho, In-Jin Jang, Min Goo Lee
Phenotypic differences in drug responses have been associated with known pharmacogenomic loci, but many remain to be characterized. We therefore developed next-generation sequencing (NGS) panels to enable broad and unbiased inspection of genes that are involved in pharmacokinetics (PK) and pharmacodynamics (PD). These panels feature repetitively optimized probes to capture up to 114 PK/PD-related genes with high coverage (99.6%) and accuracy (99.9%). Sequencing of a Korean cohort (n = 376) with the panels enabled profiling of actionable variants as well as rare variants of unknown functional consequences...
October 11, 2016: Clinical Pharmacology and Therapeutics
Hannah C Slater, Lucy C Okell, Azra C Ghani
Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used at the population level, to clear infections, provide chemoprevention, and to reduce onward transmission of infection. However, there is less clarity on the extent to which different drug properties are important for these different uses. In addition, the emergence of drug resistance poses new threats to longer-term use and highlights the need for rational drug development...
October 7, 2016: Trends in Parasitology
Hai-Yun Xiao, Scott H Watterson, Charles M Langevine, Anurag S Srivastava, Soo S Ko, Yanlei Zhang, Robert Joseph Cherney, Weiwei Guo, John L Gilmore, James E Sheppeck, Dauh-Rurng Wu, Peng Li, Duraisamy Ramasamy, Pirama Nayagam Arunachalam, Arvind Mathur, Tracy L Taylor, David J Shuster, Kim W McIntyre, Ding Ren Shen, Melissa Yarde, Mary Ellen Cvijic, Anthony M Marino, Praveen V Balimane, Zheng Yang, Dana M Banas, Georgia Cornelius, Celia J D Arienzo, Bethanne M Warrack, Lois D Lehman-McKeeman, Luisa M Salter-Cid, Jenny H Xie, Joel C Barrish, Percy H Carter, Alaric J Dyckman, T G Murali Dhar
Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a non-selective S1P receptor agonist, agonism specifically of S1P1 is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P1 while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P1 with selectivity over S1P3 and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes...
October 11, 2016: Journal of Medicinal Chemistry
Kai Wu, Jianfeng Xu, Regan Fong, Xiaozhou Yao, Yanmei Xu, William Guiney, Frank Gray, Andrew Lockhart
OBJECTIVE: To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor). METHODS: Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 - 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544...
October 10, 2016: International Journal of Clinical Pharmacology and Therapeutics
Emine Alp
Septic shock is still a lethal disease in intensive care units (ICU). The mortality can exceed 40% even with therapeutic management. The high mortality is clearly associated with the delay of appropriate antimicrobial therapy. Early diagnosis and identification of infectious source is the mainstay of optimal therapeutic management. On the other hand, source control and optimize antibiotic dosing according to pharmacokinetics (PK)/pharmacodynamics (PD) properties of antibiotics and organ dysfunction of patients are required to get the best clinical outcome...
September 2016: Annals of Translational Medicine
Luca Loprete, Chiara Leuratti, Carlo Cattaneo, Mita M Thapar, Colm Farrell, Marco Sardina
Safinamide is an orally administered α-aminoamide derivative with both dopaminergic and non-dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PKPD) analyses were developed using records from, respectively, 623 and 668 patients belonging to two Phase 3, randomized, placebo-controlled, double-blind efficacy studies. The aim was to estimate safinamide population PK parameters in patients with Parkinson's disease (PD) on stable levodopa therapy, and to develop a model of safinamide effect on the PD phase of normal functioning (ON-time)...
October 2016: Pharmacology Research & Perspectives
Markus V Heppt, Cecilia Dietrich, Saskia A Graf, Thomas Ruzicka, Julia K Tietze, Carola Berking
Melanoma is a common type of skin cancer with a high propensity to metastasize. Tyrosine kinase inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway and immune checkpoint blockade have recently revolutionized the management of unresectable and metastatic disease. However, acquired resistance and primary non-response to therapy require novel treatment strategies and combinations. The purpose of this review is to provide a brief and up-to-date overview on the clinical management and current trial landscape in melanoma...
2016: Oncology Research and Treatment
Richard Burdick, Todd Coffey, Hiten Gutka, Gyöngyi Gratzl, Hugh D Conlon, Chi-Ting Huang, Michael Boyne, Henriette Kuehne
Protein therapeutics have unique critical quality attributes (CQAs) that define their purity, potency, and safety. The analytical methods used to assess CQAs must be able to distinguish clinically meaningful differences in comparator products, and the most important CQAs should be evaluated with the most statistical rigor. High-risk CQA measurements assess the most important attributes that directly impact the clinical mechanism of action or have known implications for safety, while the moderate- to low-risk characteristics may have a lower direct impact and thereby may have a broader range to establish similarity...
October 5, 2016: AAPS Journal
Masato Fukae, Yoshimasa Shiraishi, Takeshi Hirota, Yuka Sasaki, Mika Yamahashi, Koichi Takayama, Yoichi Nakanishi, Ichiro Ieiri
PURPOSE: Docetaxel is used to treat many cancers, and neutropenia is the dose-limiting factor for its clinical use. A population pharmacokinetic-pharmacodynamic (PK-PD) model was introduced to predict the development of docetaxel-induced neutropenia in Japanese patients with non-small cell lung cancer (NSCLC). METHODS: Forty-seven advanced or recurrent Japanese patients with NSCLC were enrolled. Patients received 50 or 60 mg/m(2) docetaxel as monotherapy, and blood samples for a PK analysis were collected up to 24 h after its infusion...
October 5, 2016: Cancer Chemotherapy and Pharmacology
Xi-Ling Jiang, Hong-Wu Shen, Donald E Mager, Stephan Schmidt, Ai-Ming Yu
We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI), potentiates serotonin (5-HT) receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control...
September 2016: Acta Pharmaceutica Sinica. B
Cara C Schafer, Yong Wang, Kenneth P Hough, Anandi Sawant, Stefan C Grant, Victor J Thannickal, Jaroslaw Zmijewski, Selvarangan Ponnazhagan, Jessy S Deshane
Indoleamine 2,3-dioxygenase (IDO) has been implicated in immune evasion by tumors. Upregulation of this tryptophan (Trp)-catabolizing enzyme, in tumor cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME), leads to Trp depletion that impairs cytotoxic T cell responses and survival; however, exact mechanisms remain incompletely understood. We previously reported that a combination therapy of gemcitabine and a superoxide dismutase mimetic promotes anti-tumor immunity in a mouse model of lung cancer by inhibiting MDSCs, enhancing polyfunctional response of CD8+ memory T cells, and extending survival...
September 26, 2016: Oncotarget
Amélie Le Bihan, Ruben de Kanter, Iñigo Angulo-Barturen, Christoph Binkert, Christoph Boss, Reto Brun, Ralf Brunner, Stephan Buchmann, Jeremy Burrows, Koen J Dechering, Michael Delves, Sonja Ewerling, Santiago Ferrer, Christoph Fischli, Francisco Javier Gamo-Benito, Nina F Gnädig, Bibia Heidmann, María Belén Jiménez-Díaz, Didier Leroy, Maria Santos Martínez, Solange Meyer, Joerg J Moehrle, Caroline L Ng, Rintis Noviyanti, Andrea Ruecker, Laura María Sanz, Robert W Sauerwein, Christian Scheurer, Sarah Schleiferboeck, Robert Sinden, Christopher Snyder, Judith Straimer, Grennady Wirjanata, Jutta Marfurt, Ric N Price, Thomas Weller, Walter Fischli, David A Fidock, Martine Clozel, Sergio Wittlin
BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented...
October 2016: PLoS Medicine
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