Ng K.W.,St. Vincents Institute
Clinical Interventions in Aging | Year: 2012
Cathepsin K is a key enzyme involved in the degradation of organic bone matrix by osteoclasts. Inhibition of bone resorption observed in human and animal models deficient for cathepsin K has identified this enzyme as a suitable target for intervention by small molecules with the potential to be used as therapeutic agents in the treatment of osteoporosis. Odanacatib (ODN) is a nonbasic selective cathepsin K inhibitor with good pharmacokinetic parameters such as minimal in vitro metabolism, long half-life, and oral bioavailability. In preclinical studies, ovariectomized monkeys and rabbits treated with ODN showed substantial inhibition of bone resorption markers along with increases in bone mineral density (BMD). Significant differences were observed in the effects of ODN treatment compared with those of other antiresorptive agents such as bisphosphonates and denosumab. ODN displayed compartment-specific effects on trabecular versus cortical bone formation, with treatment resulting in marked increases in periosteal bone formation and cortical thickness in ovariectomized monkeys whereas trabecular bone formation was reduced. Furthermore, osteoclasts remained viable. Phase I and II studies conducted in postmenopausal women showed ODN to be safe and well tolerated. After 5 years, women who received ODN 50 mg weekly continuously from year 1 (n = 13), showed BMD increases from baseline of 11.9% at the lumbar spine, 9.8% at the femoral neck, 10.9% at the hip trochanter, and 8.5% at the total hip. Additionally, these subjects maintained a low level of the urine bone resorption marker N-terminal telopeptide/creatinine (-67.4% from baseline) through 5 years of treatment, while levels of serum bone-specific alkaline phosphatase remained only slightly reduced relative to baseline (-15.3%). In women who were switched from ODN to placebo after 2 years, bone turnover markers were transiently increased and BMD gains reversed after 12 months off medication. Adverse experiences in the ODN-treated group were not significantly different from the placebo group. In conclusion, available data suggests that cathepsin K inhibition could be a promising intervention with which to treat osteoporosis. Ongoing studies are expected to provide information on the long-term efficacy in fracture reduction and safety of prolonged treatment with ODN. © 2012 Ng, publisher and licensee Dove Medical Press Ltd. Source
Martin J.T.,St. Vincents Institute
World Journal of Orthopaedics | Year: 2013
After it was suggested 30 years ago that the osteoblast lineage controlled the formation of osteoclasts, methods were developed that established this to be the case, but the molecular controls were elusive. Over more than a decade much evidence was obtained for signaling mechanisms that regulated the production of a membrane - bound regulator of osteoclastogenesis, in the course of which intercellular communication in bone was revealed in its complexity. The discovery of regulation by tumor necrosis factor ligand and receptor families was made in the last few years of the twentieth century, leading since then to a new physiology of bone, and to exciting drug development. © 2013 Baishideng. Source
St. Vincent's Institute | Date: 2011-08-04
The present disclosure relates generally to the field of diagnostic and prognostic assays for diseases and conditions of the systemic vasculature. The present disclosure teaches an assay for identifying such a disease or condition of the systemic vasculature as well as classifying and determining the state or stage of the disease or condition or the risk of developing the disease or condition. The assay enabled herein is also useful in the stratification of a subject with respect to a risk of developing various diseases and conditions of systemic vasculature. The assay taught herein is also capable of integration into pathology architecture to provide a diagnostic and reporting system.
Walter, Eliza Hall Institute of Medical Research and St. Vincent's Institute | Date: 2013-08-21
The present invention relates to a method for treating and/or preventing a disease associated with glucose toxicity in a subject which may comprise administering to the subject a compound that reduces the level of Bim, PUMA and/or Bax activity in a cell of the subject. Furthermore, provided is a method for culturing cells susceptible to exposure to high concentrations of glucose, which may comprise delivering to the cells, or progenitor cells thereof, a compound that reduces the level of Bim, PUMA and/or Bax activity in the cells.
St. Vincent's Institute and Howard Florey Institute | Date: 2013-02-06
The present invention relates to inhibitors of insulin-regulated aminopeptidase (IRAP) and methods for inhibiting same, as well as compositions comprising said inhibitors. In particular, the inhibitors of the present invention may be useful in therapeutic applications including enhancing memory and learning functions.