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     

24.

Soundings: Saving lives on the Silk Road     

James Owen Drife 《British medical journal》2004,329(7460):299

     

25.

GlaxoSmithKline to set up comprehensive online clinical trials register     

Owen Dyer 《British medical journal》2004,329(7466):590

     

26.

Women with breast cancer are more likely to have high blood levels of pesticides     

Owen Dyer 《British medical journal》2003,326(7396):952

     

27.

Soundings: Walking the walk     

James Owen Drife 《British medical journal》2003,326(7395):939

     

28.

Soundings: The king and I     

James Owen Drife 《British medical journal》2003,326(7389):607

     

29.

Relationship among level of distraction, evoked potentials, spinal cord ischemia and integrity, and clinical status in animals   总被引：1，自引：0，他引：1  

J H Owen  M Naito  K H Bridwell 《Spine》1990,15(9):852-857

Somatosensory evoked potentials (SEPs) and neurogenic-motor evoked potentials (NMEPs) were recorded after overdistraction of the spinal cord at T5-T6, T12-L1, or L3-L4. Measures of spinal cord perfusion and clinical status were also administered. Results indicated that stiffer spinal segments allowed less distraction than more flexible segments. SEPs and NMEPs were lost quickly after overdistraction in stiff segments and slowly in more flexible segments. However, SEPs were less sensitive than NMEPs to effects from overdistraction. Spinal cord perfusion and integrity were consistent with reduced perfusion and structural damage after overdistraction in stiff segments; extremely reduced perfusion but no structural changes in more flexible segments. The application of these results to the clinical situation was provided.     

30.

THE INTRODUCTION OF PATIENT-CONTROLLED ANALGESIA INTO AN ISOLATED RURAL HOSPITAL     

R. W. Watts  I. A. Fletcher  G. K. Kiroff  C. Weber  H. Owen  J. L. Plummer 《ANZ journal of surgery》1995,65(8):588-591

This study investigated the feasibility of using patient-controlled analgesia (PCA) effectively in a small 70 bed isolated rural hospital. The tirst 50 patients to use a Bard PCA 1, in the Port Lincoln Hospital, South Australia, were studied. The patients consumed morphine at a mean rate of 1.24 mg/h and used PCA for a mean of 48 h. Thirty-eight per cent of patients required treatment for nausea and other complications which is similar to the rate of those in other published series. Visual analogue pain scores showed excellent pain control, generally without evidence of oversedation; however, there was one episode of respiratory depression. Seventy-eight per cent of patients reported that their pain was relieved most or all of the time. The study demonstrated that a PCA service provided by nursing staff, the GP anaesthetist and rural surgeons is feasible in an isolated rural hospital.     

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Relationship among level of distraction, evoked potentials, spinal cord ischemia and integrity, and clinical status in animals

Somatosensory evoked potentials (SEPs) and neurogenic-motor evoked potentials (NMEPs) were recorded after overdistraction of the spinal cord at T5-T6, T12-L1, or L3-L4. Measures of spinal cord perfusion and clinical status were also administered. Results indicated that stiffer spinal segments allowed less distraction than more flexible segments. SEPs and NMEPs were lost quickly after overdistraction in stiff segments and slowly in more flexible segments. However, SEPs were less sensitive than NMEPs to effects from overdistraction. Spinal cord perfusion and integrity were consistent with reduced perfusion and structural damage after overdistraction in stiff segments; extremely reduced perfusion but no structural changes in more flexible segments. The application of these results to the clinical situation was provided.     

THE INTRODUCTION OF PATIENT-CONTROLLED ANALGESIA INTO AN ISOLATED RURAL HOSPITAL

This study investigated the feasibility of using patient-controlled analgesia (PCA) effectively in a small 70 bed isolated rural hospital. The tirst 50 patients to use a Bard PCA 1, in the Port Lincoln Hospital, South Australia, were studied. The patients consumed morphine at a mean rate of 1.24 mg/h and used PCA for a mean of 48 h. Thirty-eight per cent of patients required treatment for nausea and other complications which is similar to the rate of those in other published series. Visual analogue pain scores showed excellent pain control, generally without evidence of oversedation; however, there was one episode of respiratory depression. Seventy-eight per cent of patients reported that their pain was relieved most or all of the time. The study demonstrated that a PCA service provided by nursing staff, the GP anaesthetist and rural surgeons is feasible in an isolated rural hospital.