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     

52.

American Society of Nuclear Cardiology review of the ACCF/ASNC appropriateness criteria for single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI)     

R. Parker Ward MD  Mouaz H. Al-Mallah MD  Gabriel B. Grossman MD  PhD  Christopher L. Hansen MD  Robert C. Hendel MD  Todd C. Kerwin MD  Benjamin D. McCallister Jr MD  Rupa Mehta MD  Donna M. Polk MD  MPH  Peter L. Tilkemeier MD  Aseem Vashist MD  Kim Allan Williams MD  David G. Wolinsky MD  Edward P. Ficaro PhD 《Journal of nuclear cardiology》2007,14(6):911-e38

     

53.

American Society of Nuclear Cardiology review of the ACCF/ASNC appropriateness criteria for single-photon emission computed tomograph myocardial perfusion imaging (SPECT MPI)     

R. Parker Ward  Mouaz H. Al-Mallah  Gabriel B. Grossman  Christopher L. Hansen  Robert C. Hendel  Todd C. Kerwin  Benjamin D. McCallister  Rupa Mehta  Donna M. Polk  Peter L. Tilkemeier  Aseem Vashist  Kim Allan Williams  David G. Wolinsky  Edward P. Ficaro 《Journal of nuclear cardiology》2007,14(6):e26-e38

Conclusion  The ACCF/ASNC AC for SPECT MPI provides recommendations for the appropriate use of SPECT MPI. After the publication of the AC document in 2005, the AC has been used by nuclear cardiology practices with many clinical studies evaluating the list of indications in routine clinical practice. From these data. ASNC recommends minor but important changes to the indication list, suggesting the addition of 6 new indications and the modification of the definitions for “chest pain syndrome” and “CHD high risk.”. An objective review of existing indications focused on only those indications that had significant variability among the reviewers (n=20). These indications were reviewed in the presence of existing and new evidence-based data, and ASNC recommends that the grades for 6 indications be re-evaluated. The AC for SPECT MPI will require periodic review as new evidence becomes available or as clinical practice evolves. ASNC recognizes the importance of these criteria to improve the quality of patient care, and it will continue to play a key role in assembling the information for this ongoing review. From the current summary of evidence, ASNC consensus opinions, and ASNC recommendations in this document, ASNC strongly recommends that the AC guidelines be reviewed Prepared by the American Society of Nuclear Cardiology Quality Assurance Subcommittee for Quality in Imaging Standards. Reviewed by members of the American Society of Nuclear Cardiology Quality Assurance Committee. Approved by the American Society of Nuclear Cardiology Board of Directors, September 6, 20.     

54.

A hypertensive response to exercise is associated with transient ischemic dilation on myocardial perfusion SPECT imaging.     

Matthew P Smelley  Daniel E Virnich  Kim A Williams  R Parker Ward 《Journal of nuclear cardiology》2007,14(4):537-543

BACKGROUND: A hypertensive response to exercise (HRE) is associated with false-positive stress echocardiograms and myocardial perfusion single photon emission computed tomography (myocardial perfusion imaging [MPI]) defects even in the absence of coronary artery disease (CAD). Transient ischemic dilation (TID) of the left ventricle on stress MPI is a marker of severe CAD and future cardiac events. This study evaluated the association between an HRE and TID. METHODS AND RESULTS: Blinded quantitative TID assessment was performed in 125 patients who had an HRE and a summed stress score (SSS) of less than 4, as well as 125 control patients with an SSS of less than 4 and without an HRE matched for age, gender, and resting systolic blood pressure. Cardiac comorbidities, pretest Framingham risk, and exercise results were recorded. TID was defined as a stress-to-rest volume ratio of 1.22 or greater. An HRE was associated with a high prevalence of TID and significantly more TID than no HRE (25.6% vs 11.2%; odds ratio, 3.00 [95% confidence interval, 1.41-6.38]). TID was more prevalent even in subgroups with a low pretest probability CAD, including those without diabetes mellitus or angina. On conditional logistic regression analysis, an HRE was found to be independently associated with TID after consideration of other clinical and exercise MPI variables (odds ratio, 2.72 [95% confidence interval, 1.01-7.31]). CONCLUSION: An HRE is associated with a high prevalence of TID in patients without other significant perfusion defects, possibly as a result of global subendocardial ischemia induced by the HRE.     

55.

The Phosphodiesterase Type IV Inhibitor Cilomilast Decreases Pro-inflammatory Cytokine Production From Primary Bronchial Epithelial Cells in Lung Transplantation Patients     

Des M. Murphy MRCP  Chris Ward PhD  Ian A. Forrest MRCP  Gail Pritchard FIBMS  Debbie Jones BSc  Rachel Stovold BSc  Andrew J. Fisher MRCP  Tim E. Cawston PhD  Jim L. Lordan MRCP  Paul A. Corris FRCP 《The Journal of heart and lung transplantation》2006,25(12):1436-1440

     

56.

Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors.     

J Gits  D van Leeuwen  H P Carroll  I P Touw  A C Ward 《Leukemia》2006,20(12):2111-2118

     

57.

Visual disorders in children: international comparison of screening programs,: by A. Neugebauer, M. Reier, J. Fricke, W. Rüssmann. Ophthalmologe 99:32-7, 2002     

Charlotte M Poloschek  MD 《Survey of ophthalmology》2003,48(5):562

     

58.

Mortality and morbidity in gastro-oesophageal cancer surgery: initial results of ASCOT multicentre prospective cohort study     

Peter McCulloch  Jeremy Ward  Paris P Tekkis    for the ASCOT group of surgeons 《British medical journal》2003,327(7425):1192-1197

     

59.

The effects of anesthesia and surgery on metabolic homeostasis in infancy and childhood   总被引：2，自引：0，他引：2  

M P Ward Platt  M J Tarbit  A Aynsley-Green 《Journal of pediatric surgery》1990,25(5):472-478

In order to test the hypothesis that the metabolic response to surgery in childhood varies with the age of the child and the severity of the surgery, 46 children, aged 1 month to 10 years and undergoing a variety of operations under a standard general anesthetic, were studied. Blood samples were drawn for analysis preoperatively, postoperatively, and at 6, 12, 24, and 48 hours after surgery. Severity of surgery was scored using the Oxford surgical stress scale (SSS). Surgery caused significant increases in the concentrations of lactate, pyruvate, and ketone bodies that were related to SSS, but not to age. Increases in blood glucose and insulin were also related to SSS. Total gluconeogenic substrate concentrations were markedly depressed 24 hours after surgery; this was well predicted by SSS but not by age. Older children tended to have a slightly more prolonged elevation of blood glucose and prolonged elevation of the insulin:glucose ratio postoperatively. The metabolic response of children to surgery, although different from both adults and neonates, is generally stable over a wide age range. The Oxford scale predicts the degree of metabolic displacement due to surgery and may thus prove a useful instrument in trials of anesthesia and analgesia in infants and children.     

60.

Day surgery: the concept, practice and implications          下载免费PDF全文

C M Ward 《Journal of the Royal Society of Medicine》1988,81(4):237-239

     

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American Society of Nuclear Cardiology review of the ACCF/ASNC appropriateness criteria for single-photon emission computed tomograph myocardial perfusion imaging (SPECT MPI)

Conclusion  The ACCF/ASNC AC for SPECT MPI provides recommendations for the appropriate use of SPECT MPI. After the publication of the AC document in 2005, the AC has been used by nuclear cardiology practices with many clinical studies evaluating the list of indications in routine clinical practice. From these data. ASNC recommends minor but important changes to the indication list, suggesting the addition of 6 new indications and the modification of the definitions for “chest pain syndrome” and “CHD high risk.”. An objective review of existing indications focused on only those indications that had significant variability among the reviewers (n=20). These indications were reviewed in the presence of existing and new evidence-based data, and ASNC recommends that the grades for 6 indications be re-evaluated. The AC for SPECT MPI will require periodic review as new evidence becomes available or as clinical practice evolves. ASNC recognizes the importance of these criteria to improve the quality of patient care, and it will continue to play a key role in assembling the information for this ongoing review. From the current summary of evidence, ASNC consensus opinions, and ASNC recommendations in this document, ASNC strongly recommends that the AC guidelines be reviewed Prepared by the American Society of Nuclear Cardiology Quality Assurance Subcommittee for Quality in Imaging Standards. Reviewed by members of the American Society of Nuclear Cardiology Quality Assurance Committee. Approved by the American Society of Nuclear Cardiology Board of Directors, September 6, 20.     

A hypertensive response to exercise is associated with transient ischemic dilation on myocardial perfusion SPECT imaging.

BACKGROUND: A hypertensive response to exercise (HRE) is associated with false-positive stress echocardiograms and myocardial perfusion single photon emission computed tomography (myocardial perfusion imaging [MPI]) defects even in the absence of coronary artery disease (CAD). Transient ischemic dilation (TID) of the left ventricle on stress MPI is a marker of severe CAD and future cardiac events. This study evaluated the association between an HRE and TID. METHODS AND RESULTS: Blinded quantitative TID assessment was performed in 125 patients who had an HRE and a summed stress score (SSS) of less than 4, as well as 125 control patients with an SSS of less than 4 and without an HRE matched for age, gender, and resting systolic blood pressure. Cardiac comorbidities, pretest Framingham risk, and exercise results were recorded. TID was defined as a stress-to-rest volume ratio of 1.22 or greater. An HRE was associated with a high prevalence of TID and significantly more TID than no HRE (25.6% vs 11.2%; odds ratio, 3.00 [95% confidence interval, 1.41-6.38]). TID was more prevalent even in subgroups with a low pretest probability CAD, including those without diabetes mellitus or angina. On conditional logistic regression analysis, an HRE was found to be independently associated with TID after consideration of other clinical and exercise MPI variables (odds ratio, 2.72 [95% confidence interval, 1.01-7.31]). CONCLUSION: An HRE is associated with a high prevalence of TID in patients without other significant perfusion defects, possibly as a result of global subendocardial ischemia induced by the HRE.     

The effects of anesthesia and surgery on metabolic homeostasis in infancy and childhood

In order to test the hypothesis that the metabolic response to surgery in childhood varies with the age of the child and the severity of the surgery, 46 children, aged 1 month to 10 years and undergoing a variety of operations under a standard general anesthetic, were studied. Blood samples were drawn for analysis preoperatively, postoperatively, and at 6, 12, 24, and 48 hours after surgery. Severity of surgery was scored using the Oxford surgical stress scale (SSS). Surgery caused significant increases in the concentrations of lactate, pyruvate, and ketone bodies that were related to SSS, but not to age. Increases in blood glucose and insulin were also related to SSS. Total gluconeogenic substrate concentrations were markedly depressed 24 hours after surgery; this was well predicted by SSS but not by age. Older children tended to have a slightly more prolonged elevation of blood glucose and prolonged elevation of the insulin:glucose ratio postoperatively. The metabolic response of children to surgery, although different from both adults and neonates, is generally stable over a wide age range. The Oxford scale predicts the degree of metabolic displacement due to surgery and may thus prove a useful instrument in trials of anesthesia and analgesia in infants and children.