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Odanacatib

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https://www.readbyqxmd.com/read/28377978/long-term-treatment-with-odanacatib-maintains-normal-trabecular-biomechanical-properties-in-ovariectomized-adult-monkeys-as-demonstrated-by-micro-ct-based-finite-element-analysis
#1
Antonio Cabal, Donald S Williams, Richa Y Jayakar, Jingru Zhang, Swanand Sardesai, Le T Duong
The cathepsin K inhibitor odanacatib (ODN) is a potent and reversible inhibitor of osteoclastic resorption activity. This drug is currently under development for the treatment of postmenopausal osteoporosis. Previously, we described data on the treatment efficacy of ODN in a preclinical estrogen-deficient model of an ovariectomized (OVX) rhesus monkey using HR-pQCT based finite element analysis (FEA) in vivo estimates of bone strength on the distal radius. To support the bone safety profile of ODN, we report ex vivo data on the apparent and hard tissue biomechanical properties of the trabecular bone of vertebrae of animals after 20 months of dosing in three treatment groups: Vehicle (VEH), ODN (2 mg/kg/day), and ALN (30 μg/kg/week)...
June 2017: Bone Reports
https://www.readbyqxmd.com/read/28326348/effects-of-odanacatib-on-bone-matrix-mineralization-in-rhesus-monkeys-are-similar-to-those-of-alendronate
#2
Barbara M Misof, Paul Roschger, Charles Chen, Maureen Pickarski, Phaedra Messmer, Klaus Klaushofer, Le T Duong
Odanacatib (ODN) is a selective and reversible inhibitor of cathepsin K which is an important enzyme for the degradation of collagen I. Aim of the present work was the head-to-head comparison between the effects of ODN and alendronate (ALN) on bone mineralization density distribution (BMDD), based on quantitative backscattered electron imaging in relation to changes in histomorphometric mineralizing surface per bone surface (MS/BS) in 12-22 years old ovariectomized rhesus monkeys. Trabecular and cortical BMDD derived parameters from vertebrae and proximal tibiae were compared among vehicle (VEH, n = 8), odanacatib low dose (ODN-L, n = 8), odanacatib high dose (ODN-H, n = 8), and alendronate (ALN, n = 6) treated animals...
December 2016: Bone Reports
https://www.readbyqxmd.com/read/28304382/inhibition-of-cathepsin-k-promotes-osseointegration-of-titanium-implants-in-ovariectomised-rats
#3
Chun Yi, Ke-Yi Hao, Ting Ma, Ye Lin, Xi-Yuan Ge, Yu Zhang
The bone mineral deficiency in osteoporosis poses a threat to the long-term outcomes of endosseous implants. The inhibitors of cathepsin K (CatK) significantly affect bone turnover, bone mineral density (BMD) and bone strength in the patients with osteoporosis. Therefore, we hypothesised that the application of a CatK inhibitor (CatKI) could increase the osseointegration of endosseous implants under osteoporotic conditions. Odanacatib (ODN), a highly selective CatKI, was chosen as the experimental drug. Sixteen rats were randomised into 4 groups: sham, ovariectomy (OVX) with vehicle, OVX with low-dose ODN (5 mg/kg) and OVX with high-dose ODN (30 mg/kg)...
March 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28286990/the-quest-for-new-drugs-to-prevent-osteoporosis-related-fractures
#4
REVIEW
T J de Villiers
There is a need for the development of new drugs to prevent osteoporosis-related fractures. Fractures are projected to increase and the present drugs have modest efficacy, significant side-effects and poor compliance. To illustrate the difficulties in the development of new drugs, the author reviews the fate of several drugs that have failed to gain regulatory approval. These drugs include arzoxifene, lasofoxifene, MK-5442, roncalceret and odanacatib. Romosozumab and abaloparatide are the only new drugs presently in phase-3 development...
April 2017: Climacteric: the Journal of the International Menopause Society
https://www.readbyqxmd.com/read/28255336/bone-modeling-and-remodeling-potential-as-therapeutic-targets-for-the-treatment-of-osteoporosis
#5
REVIEW
Bente Langdahl, Serge Ferrari, David W Dempster
The adult skeleton is renewed by remodeling throughout life. Bone remodeling is a process where osteoclasts and osteoblasts work sequentially in the same bone remodeling unit. After the attainment of peak bone mass, bone remodeling is balanced and bone mass is stable for one or two decades until age-related bone loss begins. Age-related bone loss is caused by increases in resorptive activity and reduced bone formation. The relative importance of cortical remodeling increases with age as cancellous bone is lost and remodeling activity in both compartments increases...
December 2016: Therapeutic Advances in Musculoskeletal Disease
https://www.readbyqxmd.com/read/28217533/role-of-odanacatib-in-reducing-bone-loss-due-to-endodontic-disease-an-overview
#6
REVIEW
Rachana Bahuguna, Atul Jain, Suleman Abbas Khan, M S Arvind
AIMS AND OBJECTIVES: Through a comprehensive literature review, this article provides an overview of the potential role of odanacatib (ODN) in reducing bone loss due to endodontic disease. MATERIALS AND METHODS: A literature review was performed in PubMed Central, MEDLINE, Cochrane Library, and EBSCO databases. The articles identified included those published between 2002 and 2016. Based on the predetermined inclusion and exclusion criteria, out of 237 articles found, 50 were selected for this review...
December 2016: Journal of International Society of Preventive & Community Dentistry
https://www.readbyqxmd.com/read/28117540/cathepsin-k-modulates-invasion-migration-and-adhesion-of-oral-squamous-cell-carcinomas-in%C3%A2-vitro
#7
K Yamashita, M Iwatake, K Okamoto, S-I Yamada, M Umeda, T Tsukuba
OBJECTIVE: Cathepsin K was initially discovered as an osteoclast-specific cysteine proteinase, but the enzyme is also expressed in various cancers including oral squamous cell carcinomas. This study aimed to clarify the function of cathepsin K in oral squamous cell carcinomas. MATERIALS AND METHODS: Expression levels of cathepsin K were examined in six types of cell carcinomas. Carcinomas overexpressing cathepsin K were constructed. Effects of cathepsin K overexpression and treatment with odanacatib, a specific cathepsin K inhibitor, on cell invasion, migration and adhesion were analysed...
January 24, 2017: Oral Diseases
https://www.readbyqxmd.com/read/28049758/identification-of-mouse-cathepsin-k-structural-elements-that-regulate-the-potency-of-odanacatib
#8
Simon Law, Pierre-Marie Andrault, Adeleke Aguda, Nham Nguyen, Natasha Kruglyak, Gary Brayer, Dieter Bromme
Cathepsin K (CatK) is the predominant mammalian bone-degrading protease and thus an ideal target for anti-osteoporotic drug development. Rodent models of osteoporosis are preferred due to their close reflection of the human disease and their ease of handling, genetic manipulation, and economic affordability.  However, large differences in the potency of CatK inhibitors for the mouse/rat versus the human protease orthologues have made it impossible to use rodent models. This is even more of a problem considering that the most advanced CatK inhibitors including odanacatib and balicatib failed in human clinical trials due to side effects and rodent models are not available to investigate the mechanism of these failures...
January 3, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28017956/-topics-for-clinical-research
#9
Seiji Fukumoto
Results from phase 3 study of a new drug along with effects of longer duration of a currently used drug for osteoporosis were presented. While there were several papers concerning odanacatib, the clinical development of this drug was announced to be terminated just before the meeting. In addition, low treatment rate for patients with osteoporosis because of fear for rare adverse events was emphasized to be a crisis in the treatment of osteoporosis. Finally, a new treatment for hypophosphatemic diseases was introduced...
2017: Clinical Calcium
https://www.readbyqxmd.com/read/27856662/therapeutic-implications-of-suppressing-osteoclast-formation-versus-function
#10
REVIEW
Steven L Teitelbaum
Anti-resorptive therapy is the principal means of treating osteoporotic disorders. The two families of presently available anti-resorptive drugs, namely bisphosphonates and denosumab, dampen activity of osteoclasts by reducing their number. In consequence, these agents also arrest bone remodelling eventuating suppressed formation as well as resorption. Evidence exists that osteoclasts recruit osteoblasts to sites of bone remodelling by mobilizing chemotactic proteins from matrix and direct secretion of such proteins that attract osteoblast precursors...
December 2016: Rheumatology
https://www.readbyqxmd.com/read/27681784/merck-co-drops-osteoporosis-drug-odanacatib
#11
Asher Mullard
No abstract text is available yet for this article.
September 29, 2016: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/27639811/odanacatib-effects-of-16-month-treatment-and-discontinuation-of-therapy-on-bone-mass-turnover-and-strength-in-the-ovariectomized-rabbit-model-of-osteopenia
#12
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
https://www.readbyqxmd.com/read/27570837/pulsed-low-dose-rankl-as-a-potential-therapeutic-for-postmenopausal-osteoporosis
#13
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
https://www.readbyqxmd.com/read/27402726/the-absolute-bioavailability-and-effect-of-food-on-the-pharmacokinetics-of-odanacatib-a-stable-label-i-v-oral-study-in-healthy-postmenopausal-women
#14
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
https://www.readbyqxmd.com/read/27384569/odanacatib-a-cathepsin-k-cysteine-protease-inhibitor-kills-hookworm-in-vivo
#15
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...
July 4, 2016: Pharmaceuticals
https://www.readbyqxmd.com/read/27321774/coadministration-of-rifampin-significantly-reduces-odanacatib-concentrations-in-healthy-subjects
#16
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 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 coadministered on day 14. Blood samples for odanacatib pharmacokinetics were collected at predose and on day 1 of period 1 and day 14 of period 2...
January 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27126999/effects-of-long-term-treatment-with-high-doses-of-odanacatib-on-bone-mass-bone-strength-and-remodeling-modeling-in-newly-ovariectomized-monkeys
#17
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
https://www.readbyqxmd.com/read/27106079/pharmacological-inhibition-of-cathepsin-k-a-promising-novel-approach-for-postmenopausal-osteoporosis-therapy
#18
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
https://www.readbyqxmd.com/read/27001692/cathepsin-k-osteoporosis-trials-pycnodysostosis-and-mouse-deficiency-models-commonalities-and-differences
#19
REVIEW
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
https://www.readbyqxmd.com/read/26989807/new-horizons-in-osteoporosis-therapies
#20
REVIEW
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
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