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Asher Mullard
No abstract text is available yet for this article.
September 29, 2016: Nature Reviews. Drug Discovery
Le T Duong, Randy Crawford, Kevin Scott, Christopher T Winkelmann, Gouxin Wu, Pete Szczerba, Michael A Gentile
Odanacatib (ODN) a selective and reversible cathepsin K inhibitor, inhibits bone resorption, increases bone mass and reduces fracture risk in women with osteoporosis. A 16-month (~7-remodeling cycles) study was carried out in treatment mode to assess the effects of ODN versus ALN on bone mass, remodeling status and biomechanical properties of lumbar vertebrae (LV) and femur in ovariectomized (OVX) rabbits. This study also evaluated the impact of discontinuing ODN on these parameters. Rabbits at 7.5months post-OVX were dosed for 16-months with ODN (7...
September 15, 2016: Bone
Anna Cline-Smith, Jesse Gibbs, Elena Shashkova, Zachary S Buchwald, Deborah V Novack, Rajeev Aurora
A number of studies in model animal systems and in the clinic have established that RANKL promotes bone resorption. Paradoxically, we found that pulsing ovariectomized mice with low-dose RANKL suppressed bone resorption, decreased the levels of proinflammatory effector T cells and led to increased bone mass. This effect of RANKL is mediated through the induction of FoxP3(+)CD25(+) regulatory CD8(+) T cells (TcREG) by osteoclasts. Here, we show that pulses of low-dose RANKL are needed to induce TcREG, as continuous infusion of identical doses of RANKL by pump did not induce TcREG...
August 18, 2016: JCI Insight
Stefan Zajic, Stefaan Rossenu, David Hreniuk, Filippos Kesisoglou, Jacqueline McCrea, Fang Liu, Li Sun, Rose Witter, Don Gauthier, Roy Helmy, Darrick Joss, Tong Ni, Randall Stoltz, Julie Stone, S Aubrey Stoch
A stable-label i.v./oral study design was conducted to investigate the pharmacokinetics (PK) of odanacatib. Healthy, postmenopausal women received oral doses of unlabeled odanacatib administered simultaneously with a reference of 1 mg i.v. stable (13)C-labeled odanacatib. The absolute bioavailability of odanacatib was 30% at 50 mg (the phase 3 dose) and 70% at 10 mg, which is consistent with solubility-limited absorption. Odanacatib exposure (area under the curve from zero to infinity) increased by 15% and 63% when 50 mg was administered with low-fat and high-fat meals, respectively...
September 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Jon J Vermeire, Brian M Suzuki, Conor R Caffrey
Hookworm infection is chief among soil-transmitted helminthiases (STHs) for the chronic morbidly inflicted. Deworming via mass drug administration (MDA) programs most often employs single doses of benzimidazole drugs to which resistance is a constant threat. To discover new drugs, we employ a hamster model of hookworm infection with Ancylostoma ceylanicum and use albendazole (ABZ; 10 mg/kg orally) as the gold standard therapy. We previously showed that a single oral 100 mg/kg dose of the cathepsin cysteine protease (CP) inhibitor, K11777, offers near cure of infection that is associated with a 95% reduction in the parasite's resident CP activity...
2016: Pharmaceuticals
S Aubrey Stoch, Jeanine Ballard, Christopher Gibson, Filippos Kesisoglou, Rose Witter, Kelem Kassahun, Stefan Zajic, Anish Mehta, Christine Brandquist, Cynthia Dempsey, Daria Stypinski, Marc L Reitman
This open-label, 2-period study assessed the effect of multiple-dose administration of rifampin, a strong cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) inducer, on the pharmacokinetics of odanacatib, a cathepsin K inhibitor. In Period 1, 12 healthy male subjects (mean age 30 years) received a single dose of odanacatib 50 mg on Day 1 followed by a 28-day washout. In Period 2, subjects received rifampin 600 mg/day for 28 days; odanacatib 50 mg was co-administered on Day 14. Blood samples for odanacatib pharmacokinetics were collected at predose and Day 1 of Period 1 and Day 14 of Period 2...
June 20, 2016: Journal of Clinical Pharmacology
L T Duong, M Pickarski, T Cusick, C M Chen, Y Zhuo, K Scott, R Samadfam, S Y Smith, B L Pennypacker
The objectives here were to evaluate the effects of odanacatib (ODN) at doses exceeding the clinical exposure on biomechanical properties of lumbar vertebrae (LV), hip and central femur (CF), and compare ODN to alendronate (ALN) on bone remodeling/modeling in ovariectomized (OVX) monkeys. Ten days post-surgery, animals were treated with vehicle (VEH), ODN-L (2mg/kg/day, p.o.), ODN-H (8/4mg/kg/day), or ALN (30μg/kg/week, s.c.) for 20months. An intact group was also included. ODN-L provided systemic exposures of 1...
July 2016: Bone
Kakoli Mukherjee, Naibedya Chattopadhyay
Osteoporosis is a metabolic bone disease that is characterized by heightened state of bone resorption accompanied by diminished bone formation, leading to a reduction of bone mineral density (BMD) and deterioration of bone quality, thus increasing the risk of developing fractures. Molecular insight into bone biology identified cathepsin K (CatK) as a novel therapeutic target. CatK is a lysosomal cysteine protease secreted by activated osteoclasts during bone resorption, whose primary substrate is type I collagen, the major component of organic bone matrix...
October 1, 2016: Biochemical Pharmacology
Dieter Brömme, Preety Panwar, Serap Turan
INTRODUCTION: The osteoporosis market reached a value of more than $11 billion in 2015. Current treatments remain mostly antiresorptive and comprise of bisphosphonates, the anti-RANKL antibody, denusomab, and selective estrogen receptor modulators (SERMs). The most promising novel antiresorptives are cathepsin K inhibitors, which selectively target the bone matrix, degrading protease without interfering with osteoclast viability or formation as all other antiresorptives do. AREAS COVERED: This review analyses the current status of cathepsin K inhibitor development, its side effects, and compares the phenotypes of mouse and human cathepsin K deficiencies with drug treatment outcomes...
2016: Expert Opinion on Drug Discovery
Torben Harsløf, Bente L Langdahl
Efficient therapies are available for the treatment of osteoporosis, however, there are still unmet needs. Anti-resorptive therapies only increase bone mineral density to a certain extent and reduce the risk of non-vertebral fractures by 20%, only one anabolic option is available-the effect of which levels off over time, and the evidence for combination therapy targeting both resorption and formation is limited. The current review will focus on emerging treatments of osteoporosis with the potential of enhanced anabolic effects (romosozumab and abaloparatide) or uncoupling of resorption and formation (odanacatib and romosozumab) as well as the effect of combination therapy...
June 2016: Current Opinion in Pharmacology
Brigitte Uebelhart, René Rizzoli
Calcium intake shows a small impact on bone mineral density and fracture risk. Denosumab is a more potent inhibitor of bone resorption than zoledronate. Abaloparatide, PTHrP analog, increases bone mineral density and decreases fracture incidence. Teriparatide could be delivered via a transdermic device. Romosozumab and odanacatib improve calculated bone strength. Sequential or combined treatments with denosumab and teriparatide could be of interest, but not denosumab followed by teriparatide. Fibrous dysplasia, Paget disease and hypophosphatasia are updated, as well as atypical femoral fracture and osteonecrosis of the jaw...
January 13, 2016: Revue Médicale Suisse
R Rizzoli, C-L Benhamou, J Halse, P D Miller, I R Reid, J A Rodríguez Portales, C DaSilva, R Kroon, N Verbruggen, A T Leung, D Gurner
UNLABELLED: The efficacy and safety of weekly oral odanacatib (ODN) 50 mg for up to 8 years were assessed in postmenopausal women with low bone mineral density (BMD). Treatment with ODN for up to 8 years resulted in continued or maintained increases in BMD at multiple sites and was well tolerated. INTRODUCTION: ODN is a selective inhibitor of cathepsin K. In a 2-year phase 2b study (3/10/25/50 mg ODN once weekly [QW] or placebo) and extensions (50 mg ODN QW or placebo), ODN treatment for 5 years progressively increased BMD and decreased bone resorption markers in postmenopausal women with low BMD ( ClinicalTrials...
June 2016: Osteoporosis International
X X Wei, J P Chu, Y Z Zou, N Ru, S X Cui, Y X Bai
The aim of this study was to investigate the effect of local administration of odanacatib (ODN) on orthodontic root resorption and the status of alveolar bone metabolism in rat molars. All specimens were scanned using microcomputed tomography and then the raw images were reconstructed. The total volume of the root resorption craters of the 60 g-NS (normal saline) group was higher than in the 60 g-ODN group and the control group. In the 60 g-NS group, the bone volume fraction values of alveolar bone were significantly decreased compared with the other 2 groups...
2015: Genetics and Molecular Research: GMR
Eric S Muise, Alexei A Podtelezhnikov, Maureen Pickarski, Andrey Loboda, Yejun Tan, Guanghui Hu, John R Thomspon, Le T Duong
Similar efficacy of the cathepsin K inhibitor odanacatib (ODN) and the bisphosphonate alendronate (ALN) in reducing bone turnover markers and increasing bone mineral density in spine and hip were previously demonstrated in ovariectomized (OVX)-monkeys treated for 20 months in prevention mode. Here, we profiled RNA from tibial metaphysis and diaphysis of the same study using Affymetrix microarrays, and selected 204 probe sets (p < 0.001, three-group ANOVA) that were differentially regulated by ODN or ALN versus vehicle...
April 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Preety Panwar, Kent Søe, Rafael Vc Guido, Renata V C Bueno, Jean-Marie Delaisse, Dieter Brömme
BACKGROUND AND PURPOSE: Cathepsin K (CatK) is a major drug target for the treatment of osteoporosis. Potent active site-directed inhibitors have been developed and showed variable success in clinical trials. These inhibitors block the entire activity of CatK and thus may interfere with other pathways. The present study investigates the antiresorptive effect of an exosite inhibitor that selectively inhibits only the therapeutically relevant collagenase activity of CatK. EXPERIMENTAL APPROACH: Human osteoclasts and fibroblasts were used to analyse the effect of the exosite inhibitor, ortho-dihydrotanshinone (DHT1), and the active site inhibitor, odanacatib (ODN), on bone resorption and TGF-ß1 degradation...
January 2016: British Journal of Pharmacology
Piet Geusens
For the prevention of fractures, antiresorptive drugs (bisphosphonates and denosumab) that decrease high bone resorption and, secondarily, also bone formation, are the mainstream of therapy. Osteoanabolic drugs, such as teriparatide, increase bone formation more than bone resorption, and are used in severe osteoporosis, including patients treated with antiresorptive drugs who still lose bone and have recurrent fractures. New potential drugs for fracture prevention that uncouple bone resorption from bone formation include odanacatib, a specific inhibitor of cathepsin-K, the enzyme that degrades bone collagen type I, that inhibits bone resorption and only temporarily bone formation, and monoclonal antibodies against sclerostin (romosozumab, blosozumab), that stimulate bone formation and decrease bone resorption...
2015: RMD Open
Shira D Halperin, Daniel Kwon, Michael Holmes, Erik L Regalado, Louis-Charles Campeau, Daniel A DiRocco, Robert Britton
Late-stage C-H fluorination is an appealing reaction for medicinal chemistry. However, the application of this strategy to process research appears less attractive due to the formation and necessary purification of mixtures of organofluorines. Here we demonstrate that γ-fluoroleucine methyl ester, an intermediate critical to the large-scale synthesis of odanacatib, can be accessed directly from leucine methyl ester using a combination of the decatungstate photocatalyst and N-fluorobenzenesulfonimide in flow...
November 6, 2015: Organic Letters
F Jakob, F Genest, G Baron, U Stumpf, M Rudert, L Seefried
Bone is continuously regenerated and remodeled as an adaptation to mechanical load. Bone mass and fracture resistance are maintained by a balanced equilibrium between bone formation and bone resorption. Regeneration and response to mechanical load are, however, impaired in osteoporosis and during aging. Bone resorption is enhanced by chronic inflammation while bone formation is altered by rising levels of inhibitors in the aging organism. Core molecular principles of the regulation of bone metabolism in health and disease have been characterized and developed as therapeutic targets...
November 2015: Der Unfallchirurg
Mohd Parvez Khan, Atul Kumar Singh, Abhishek Kumar Singh, Pragya Shrivastava, Mahesh Chandra Tiwari, Geet Kumar Nagar, Himangshu Kousik Bora, Venkitanarayanan Parameswaran, Sabyasachi Sanyal, Jayesh R Bellare, Naibedya Chattopadhyay
Cathepsin K (CK), a lysosomal cysteine protease, is highly expressed in mature osteoclasts and degrades type 1 collagen. Odanacatib (ODN) is a selective and reversible CK inhibitor that inhibits bone loss in preclinical and clinical studies. Although an antiresorptive, ODN does not suppress bone formation, which led us to hypothesize that ODN may display restorative effect on the osteopenic bones. In a curative study, skeletally mature New Zealand rabbits were ovarectomized (OVX) and after induction of bone loss were given a steady-state exposure of ODN (9 mM/d) for 14 weeks...
March 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
H G Bone, D W Dempster, J A Eisman, S L Greenspan, M R McClung, T Nakamura, S Papapoulos, W J Shih, A Rybak-Feiglin, A C Santora, N Verbruggen, A T Leung, A Lombardi
No abstract text is available yet for this article.
November 2015: Osteoporosis International
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