Discovery of potent and selective inhibitors of procollagen C-proteinase for the treatment of fibrotic disorders

Introduction   Fibrosis is a component of many tissue pathologies leading to loss of normal tissue function, primarily due to excessive collagen deposition. Collagen is deposited following cleavage of the C- and N- terminal peptides from the pro-collagen molecule. The cleavage of the globular C-peptide by PCP reduces solubility of the fibrillar collagen molecule, resulting in deposition of insoluble collagen. Increased insoluble collagen deposition is a feature of all organ fibroses, with inhibition of this process, a key potential anti-fibrotic mechanism. The aim of this work was to discover potent and selective PCP inhibitors as experimental, topically applied, anti-fibrotic drugs for clinical evaluation.
Materials and methods   PCP was cloned from human osteosarcoma cells and enzymatic activity demonstrated using a PCP-specific peptide cleavage assay. Activities were confirmed by measuring cleavage of [³H]C-peptide from type-I pro-collagen. A cell-based fibroplasias model was employed to demonstrate compound efficacy using collagen deposition, liberated C-peptide and histological endpoints. The activities of PCP inhibitors in fibroblast and epithelial in vitro cell proliferation and migration assays, and selectivity vs. a panel of MMPs were also determined.
Discussion   In summary, we have identified and characterized potent and selective inhibitors of PCP for progression to clinical studies for investigation as a treatment paradigm for fibrotic disease.  

  Results     

83.

From the Editors     

Richard S. Laskin  C. Ronald MacKenzie  Carolyn Sofka  Timothy Wright 《HSS journal》2007,3(1):1-1

     

84.

Predicting work status following interdisciplinary treatment for chronic pain.     

Kevin E Vowles  Richard T Gross  John T Sorrell 《European Journal of Pain》2004,8(4):351-358

The effectiveness of interdisciplinary treatments for chronic pain is well established. In general, these treatments decrease psychosocial distress and increase physical abilities. Further, return to work rates following interdisciplinary treatment tend to be quite high. Previous studies have highlighted a number of factors that individually influence return to work rates; however, there is a need for more comprehensive and unified models that allow an evaluation of the inter-relations among these factors. The present investigation examined how demographic and treatment outcome variables interacted to influence post-treatment return to work rates in a sample of individuals with chronic pain following interdisciplinary treatment. Results indicated that patient age, lifting ability, pain duration, depression level, and reported disability were individually related to return to work; however, when these variables were evaluated relative to one another, level of depression and patient age had the best ability to predict post-treatment work status. These results add to the literature by specifically highlighting post-treatment factors that best discriminate patients who had returned to work from those that had not. Furthermore, they provide evidence that general emotional distress is perhaps the most important predictor of work status following treatment.     

85.

Reply     

Toshio Sasajima  Ronald G. Blasberg 《European journal of nuclear medicine and molecular imaging》2005,32(3):371-371

     

86.

Campaigning the way it should be     

Ronald B. Marks DDS 《Journal of oral and maxillofacial surgery》2004,62(12)

     

87.

Occlusion in implant dentistry. A review of the literature of prosthetic determinants and current concepts     

MD Gross 《Australian dental journal》2008,53(S1):S60-S68

     

88.

Über die Brauchbarkeit Einiger Neueren Trübungs- und Flockungs-Reaktionen für die Serodiagnose der Syphilis     

H. Gross  L. Oelrichs 《Journal of molecular medicine (Berlin, Germany)》1929,8(33):1537-1538

Zusammenfassung Auf Grund unserer vergleichenden Versuche empfehlen wir, neben der WaR. stets mehrere Trübungs- und Flockungsreaktionen auszuführen. Als recht brauchbar haben sich uns die Kahn-, Citochol- und Meinicke-Trübungs-Reaktion erwiesen, da sie schnell und leicht anzustellen und abzulesen und hinsichtlich Empfindlichkeit und Spezifität der WaR. gleichgestellt, in manchen Fällen sogar überlegen sind.     

89.

The development and introduction of anti-oxytocic tocolytics   总被引：1，自引：0，他引：1  

Ronald F. Lamont 《BJOG : an international journal of obstetrics and gynaecology》2003,110(S20):108-112

     

90.

Special issue: MR safety     

Penny A. Gowland PhD  Walter Kucharczyk MD  FRCPC  Georg Bongartz MD  Ronald R. Price PhD  Martin R. Prince MD  PhD 《Journal of magnetic resonance imaging : JMRI》2007,26(5):1177-1178

     

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Predicting work status following interdisciplinary treatment for chronic pain.

The effectiveness of interdisciplinary treatments for chronic pain is well established. In general, these treatments decrease psychosocial distress and increase physical abilities. Further, return to work rates following interdisciplinary treatment tend to be quite high. Previous studies have highlighted a number of factors that individually influence return to work rates; however, there is a need for more comprehensive and unified models that allow an evaluation of the inter-relations among these factors. The present investigation examined how demographic and treatment outcome variables interacted to influence post-treatment return to work rates in a sample of individuals with chronic pain following interdisciplinary treatment. Results indicated that patient age, lifting ability, pain duration, depression level, and reported disability were individually related to return to work; however, when these variables were evaluated relative to one another, level of depression and patient age had the best ability to predict post-treatment work status. These results add to the literature by specifically highlighting post-treatment factors that best discriminate patients who had returned to work from those that had not. Furthermore, they provide evidence that general emotional distress is perhaps the most important predictor of work status following treatment.     

Über die Brauchbarkeit Einiger Neueren Trübungs- und Flockungs-Reaktionen für die Serodiagnose der Syphilis

Zusammenfassung Auf Grund unserer vergleichenden Versuche empfehlen wir, neben der WaR. stets mehrere Trübungs- und Flockungsreaktionen auszuführen. Als recht brauchbar haben sich uns die Kahn-, Citochol- und Meinicke-Trübungs-Reaktion erwiesen, da sie schnell und leicht anzustellen und abzulesen und hinsichtlich Empfindlichkeit und Spezifität der WaR. gleichgestellt, in manchen Fällen sogar überlegen sind.