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.

From the Editors     

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

     

53.

Reply     

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

     

54.

Campaigning the way it should be     

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

     

55.

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

     

56.

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

     

57.

How doctors think          下载免费PDF全文

Ronald M. Epstein 《The Journal of clinical investigation》2007,117(10):2738

     

58.

Myoblast transfer in duchenne muscular dystrophy     

George Karpati  Djordje Ajdukovic  Douglas Arnold  Robert B. Gledhill  Ronald Guttmann  Paul Holland  Penelope A. Koch  Eric Shoubridge  Desmond Spence  Michel Vanasse  Gordon V. Watters  Michael Abrahamowicz  Catherine Duff  Ronald G. Worton 《Annals of neurology》1993,34(1):8-17

One biceps muscle of 8 patients with Duchenne muscular dystrophy was injected at 55 sites with a total of 55 million viable, purified, and contamination-free normal myoblasts (myoblast transfer). The other biceps of each patient was injected with a placebo to serve as a control. The procedure was blinded to the patients, parents, and investigators. Myoblasts derived from a biopsy specimen of the fathers were cultured and purified under strict conditions and carefully screened for microbial contamination. All patients received cyclophosphamide for immunosuppression for 6 or 12 months. No serious complications were observed after myoblast transfer, indicating that the procedure is safe. The overall therapeutic efficiency of myoblast transfer was poor as judged by the results in maximal voluntary force generation, dystrophin content of the muscle, magnetic resonance imaging of the muscle, and the lack of donor-derived DNA and dystrophin messenger RNA in the injected muscle. An improved efficiency of the take of myoblasts might be achieved by using younger cells and injecting the myoblasts with a myonecrotic agent (to increase the prevalence of regeneration) and a basal laminal fenestrating agent.     

59.

A review of HIV-1 in Africa.     

A R Ronald  J O Ndinya-Achola  F A Plummer  J N Simonsen  D W Cameron  E N Ngugi  H Pamba 《Journal of urban health》1988,64(6):480-490

     

60.

Ergotamine/caffeine treatment of orthostatic hypotension in parkinsonism with autonomic failure     

Richard B. Dewey Jr    Surendra D. Rao  Stephanie L. Holmburg  Ronald G. Victor 《European journal of neurology》1998,5(6):593-599

Eight patients with parkinsonism who developed severe orthostatic sypotension, were treated with oral ergotamine/caffeine. Significant long-term improvement in standing systolic blood pressure and symptoms of syncope and light-headedness were observed in four of these patients. One patient in whom the drug was effective discontinued it because of nausea. Another lost benefit after 2 weeks of sucessful therapy. Significant supine systolic hypertension occureed in only one patient, which was easily managed by nifedipine given at night. Symptoms or signs of ergotism were not observed. Oral ergotamine/caffeine should be considered as a cost-effective teratment for refactory orthostatic hypotension in carefully selected patients with parkinsonism.     

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Myoblast transfer in duchenne muscular dystrophy

One biceps muscle of 8 patients with Duchenne muscular dystrophy was injected at 55 sites with a total of 55 million viable, purified, and contamination-free normal myoblasts (myoblast transfer). The other biceps of each patient was injected with a placebo to serve as a control. The procedure was blinded to the patients, parents, and investigators. Myoblasts derived from a biopsy specimen of the fathers were cultured and purified under strict conditions and carefully screened for microbial contamination. All patients received cyclophosphamide for immunosuppression for 6 or 12 months. No serious complications were observed after myoblast transfer, indicating that the procedure is safe. The overall therapeutic efficiency of myoblast transfer was poor as judged by the results in maximal voluntary force generation, dystrophin content of the muscle, magnetic resonance imaging of the muscle, and the lack of donor-derived DNA and dystrophin messenger RNA in the injected muscle. An improved efficiency of the take of myoblasts might be achieved by using younger cells and injecting the myoblasts with a myonecrotic agent (to increase the prevalence of regeneration) and a basal laminal fenestrating agent.     

Ergotamine/caffeine treatment of orthostatic hypotension in parkinsonism with autonomic failure

Eight patients with parkinsonism who developed severe orthostatic sypotension, were treated with oral ergotamine/caffeine. Significant long-term improvement in standing systolic blood pressure and symptoms of syncope and light-headedness were observed in four of these patients. One patient in whom the drug was effective discontinued it because of nausea. Another lost benefit after 2 weeks of sucessful therapy. Significant supine systolic hypertension occureed in only one patient, which was easily managed by nifedipine given at night. Symptoms or signs of ergotism were not observed. Oral ergotamine/caffeine should be considered as a cost-effective teratment for refactory orthostatic hypotension in carefully selected patients with parkinsonism.