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     

42.

Inappropriate antibiotic use in a tertiary care center in Thailand: an incidence study and review of experience in Thailand.     

Anucha Apisarnthanarak  Somwang Danchaivijitr  Thomas C Bailey  Victoria J Fraser 《Infection control and hospital epidemiology》2006,27(4):416-420

The incidence and patterns of and factors associated with inappropriate antibiotic use were studied in a tertiary care center in Thailand. The incidence of inappropriate antibiotic use was 25%. Admission to the surgical department (adjusted odds ratio, 2.0; P=.02) and to the obstetrics and gynecology department (adjusted odds ratio, 2.0; P=.03) were associated with inappropriate antibiotic use, whereas consultation with an infectious diseases specialist was protective against inappropriate antibiotic use (adjusted odds ratio, 0.15; P=.01).     

43.

DRY AFTER-TREATMENT OF INFECTED HANDS     

Hamilton Bailey  F.R.C.S. 《Lancet》1941

     

44.

Surgical Repair of Lacerations and Fistulas of the Parotid Duct          下载免费PDF全文

Bailey HA  Skaff V 《Annals of surgery》1949,129(1):103-108

     

45.

Epidermal growth factor receptor inhibition modulates the nuclear localization and cytotoxicity of the Auger electron emitting radiopharmaceutical 111In-DTPA human epidermal growth factor.     

Kristy E Bailey  Danny L Costantini  Zhongli Cai  Deborah A Scollard  Zhuo Chen  Raymond M Reilly  Katherine A Vallis 《Journal of nuclear medicine》2007,48(9):1562-1570

(111)In-DTPA-human epidermal growth factor ((111)In-DTPA-hEGF [DTPA is diethylenetriaminepentaacetic acid]) is an Auger electron-emitting radiopharmaceutical that targets EGF receptor (EGFR)-positive cancer. The purpose of this study was to determine the effect of EGFR inhibition by gefitinib on the internalization, nuclear translocation, and cytotoxicity of (111)In-DTPA-hEGF in EGFR-overexpressing MDA-MB-468 human breast cancer cells. METHODS: Western blot analysis was used to determine the optimum concentration of gefitinib to abolish EGFR activation. Internalization and nuclear translocation of fluorescein isothiocyanate-labeled hEGF were evaluated by confocal microscopy in MDA-MB-468 cells (1.3 x 10(6) EGFRs/cell) in the presence or absence of 1 microM gefitinib. The proportion of radioactivity partitioning into the cytoplasm and nucleus of MDA-MB-468 cells after incubation with (111)In-DTPA-hEGF for 24 h at 37 degrees C in the presence or absence of 1 microM gefitinib was measured by cell fractionation. DNA double-strand breaks caused by (111)In were quantified using the gamma-H2AX assay, and radiation-absorbed doses were estimated. Clonogenic survival assays were used to measure the cytotoxicity of (111)In-DTPA-hEGF alone or in combination with gefitinib. RESULTS: Gefitinib (1 microM) completely abolished EGFR phosphorylation in MDA-MB-468 cells. Internalization and nuclear translocation of fluorescein isothiocyanate-labeled EGF were not diminished in gefitinib-treated cells compared with controls. The proportion of internalized (111)In that localized in the nucleus was statistically significantly greater when (111)In-DTPA-hEGF was combined with gefitinib compared with (111)In-DTPA-hEGF alone (mean +/- SD: 26.0% +/- 5.5% vs. 14.6% +/- 4.0%, respectively; P < 0.05). Induction of gamma-H2AX foci was greater in MDA-MB-468 cells that were treated with (111)In-DTPA-hEGF (250 ng/mL, 1.5 MBq/mL) plus gefitinib (1 microM ) compared with those treated with (111)In-DTPA-hEGF alone (mean +/- SD: 35 +/- 4 vs. 24 +/- 5 foci per nucleus, respectively). In clonogenic assays, a significant reduction in the surviving fraction was observed when (111)In-DTPA-hEGF (5 ng/mL, 6 MBq/microg) was combined with gefitinib (1 microM ) compared with (111)In-DTPA-hEGF alone (42.9% +/- 5.7% vs. 22.9% +/- 3.6%, respectively; P < 0.01). CONCLUSION: The efficacy of (111)In-DTPA-hEGF depends on internalization and nuclear uptake of the radionuclide. Nuclear uptake, DNA damage, and cytotoxicity are enhanced when (111)In-DTPA-hEGF is combined with gefitinib. These results suggest a potential therapeutic role for peptide receptor radionuclide therapy in combination with tyrosine kinase inhibitors.     

46.

Analysis of radionuclide arthrograms, radiographic arthrograms, and sequential plain radiographs in the assessment of painful hip arthroplasty   总被引：2，自引：0，他引：2  

A Miniaci  W H Bailey  R B Bourne  A C McLaren  C H Rorabeck 《The Journal of arthroplasty》1990,5(2):143-149

An analysis of sequential plain radiographs (XR), radionuclide arthrography, (RNA), and radiographic arthrography (RGA) was performed to determine the efficacy and usefulness of each study in the diagnosis of loosening of prosthetic hip components. Over a 2-year-period, 65 hip prostheses were assessed before operation using each type of study; these results were compared to the intraoperative assessment of the status of the components. Of the three studies, sequential plain radiographs were overall the most accurate, sensitive, and specific. Radionuclide arthrography was of no use on the acetabular side but quite useful on the femoral side, especially in cases with only minimal femoral component loosening. Radiographic arthrography was overall the least accurate or sensitive of the three studies performed.     

47.

Effect of propranolol on nitrogen and energy metabolism in sepsis     

R N Dickerson  R C Fried  P M Bailey  T P Stein  J L Mullen  G P Buzby 《The Journal of surgical research》1990,48(1):38-41

Pharmacologic therapy designed to block adrenergic activity or alter hormonal milieu may modulate energy and protein metabolism in stress. The metabolic effects of propranolol (beta adrenergic receptor blocker) in sepsis was investigated in 22 well-nourished rats that underwent superior vena caval cannulation, cecal ligation, and puncture. Animals were randomly assigned to receive either a continuous infusion of 0.7 mg/day of propranolol combined with parenteral nutrition (n = 11) or parenteral nutrition alone (n = 11). Both groups received isocaloric, isonitrogenous, isovolemic, parenteral nutrition post-operatively for 24 hr. Nitrogen balance was better for the propranolol group than for the control group (+743 +/- 84 mg/kg/day versus +300 +/- 63 mg/kg/day, respectively, P less than 0.05). A significant difference between the pharmacologic therapy and control groups was noted for urinary 3-methylhistidine excretion versus control (0.99 +/- 0.08 micrograms/kg/day versus 7.5 +/- 0.37 micrograms/kg/day, respectively, P less than 0.01). Measured energy expenditure was similar for both pharmacologic therapy and control groups (149 +/- 20 kcal/kg/day versus 134 +/- 11 kcal/kg/day, respectively, P = N.S.). No statistically significant difference was demonstrated for 24-hr survival between propranolol and control groups (73 and 64%, respectively). Continuous, low-dose propranolol promotes nitrogen retention and decreases 3-methylhistidine excretion without altering energy expenditure in parenterally fed septic rats.     

48.

Analysis of Various Creatinine Clearance Formulas in Predicting Gentamicin Elimination in Patients With Low Serum Creatinine     

Mr. Richard M. Reichley B.S. Pharm.  Dr. David J. Ritchie Pharm.D.  Dr. Thomas C. Bailey M.D. 《Pharmacotherapy》1995,15(5):625-630

Predicted gentamicin elimination rate constants (k_els) using creatinine clearance (C1_cr) estimates from seven equations were compared with k_els calculated from steady-state serum gentamicin concentrations in 186 hospitalized patients. In predicting k_el, the equations varied significantly in precision (mean absolute percentage error), and were particularly imprecise among patients with serum creatinine values of 71 μmol/L or less. Significant differences in bias (mean prediction error) were also observed. All equations using serum creatinine as an element showed improved precision, and most showed reduced bias when a minimum value of 71 μmol/L was used. The Cockcroft-Gault normalized to 72 kg and the Hull equations are among the simplest to calculate and, when using a minimum serum creatinine of 71 μmol/L, had significantly greater precision and less bias than several of the equations. We recommend one of these two methods for predicting gentamicin k_el in patients with low serum creatinine values.     

49.

Effect of inhaled fluticasone propionate on BAL TGF-beta(1) and bFGF concentrations in clinically stable lung transplant recipients.     

L Zheng  E H Walters  N Wang  H Whitford  B Orsida  B Levvey  Michael Bailey  T J Williams  G I Snell 《The Journal of heart and lung transplantation》2004,23(4):446-455

BACKGROUND: Inhaled fluticasone propionate (FP) therapy decreases inflammation and sub-basement membrane thickness in asthmatic airways. Bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTRs) involves progressive airway fibrosis and obliteration. Therefore, augmented immunosuppression may be of some benefit in treating BOS. In this study, we examined the effect of 3 months of treatment with high-dose inhaled FP on the concentrations of 2 fibrogenic factors, transforming growth factor (TGF)-beta(1) and beta fibrogenic growth factor (bFGF) in bronchoalveolar lavage (BAL) fluid from clinically stable LTRs. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel group study with inhaled FP (750 microg, twice/day for 3 months) in 28 LTRs (15 FP and 13 placebo). We recruited 23 healthy controls. We performed spirometry, bronchoscopy, and bronchoalveolar lavage procedures before treatment and after 3 months of treatment. We used commercially available enzyme-linked immunosorbent assay kits to measure BAL fluid TGF-beta(1) and bFGF concentrations. RESULTS: In LTRs before treatment, BAL TGF-beta(1) concentrations (but not bFGF concentrations), total cell counts, and neutrophil percentage increased compared with controls (p < 0.05). We found no significant differences between FP and placebo groups at baseline measurements. After treatment, BAL TGF-beta(1) concentrations significantly increased in the FP group (p = 0.03), but we found no difference between FP and placebo groups; BAL bFGF concentrations increased during treatment in both groups compared with controls (p < 0.05), but not significantly within either patient group (p > 0.05). We found a reverse correlation between forced expiratory volume in 1 second (FEV(1)) and BAL TGF-beta(1) concentration in the FP group (r = -0.53, p = 0.04), and between FEV(1) and BAL TGF-beta(1) concentration in the placebo group (r = -0.74, p = 0.004). Multivariable analysis indicated no significant independent effects of inhaled FP in either BAL TGF-beta(1) or bFGF concentrations. CONCLUSIONS: Bronchoalveolar fluid TGF-beta(1) concentrations increased in LTRs after transplantation and may correlate with the decrease in lung function. Inhaled FP added to conventional immunosuppression had no effect on TGF-beta(1) or bFGF production in BAL fluid.     

50.

Continuous arteriovenous haemofiltration in the treatment of tumour lysis syndrome     

D. Heney  A. Essex-Cater  J. T. Brocklebank  C. C. Bailey  I. J. Lewis 《Pediatric nephrology (Berlin, Germany)》1990,4(3):245-247

The management of tumour lysis syndrome remains problematic despite the rigorous use of preventative measures. Continuous arteriovenous haemofiltration (CAVH) is well suited to its use in both the prevention and treatment of metabolic abnormalities and renal insufficiency associated with tumour lysis. We report the successful use of CAVH in the treatment of a patient with tumour lysis syndrome.     

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Inappropriate antibiotic use in a tertiary care center in Thailand: an incidence study and review of experience in Thailand.

The incidence and patterns of and factors associated with inappropriate antibiotic use were studied in a tertiary care center in Thailand. The incidence of inappropriate antibiotic use was 25%. Admission to the surgical department (adjusted odds ratio, 2.0; P=.02) and to the obstetrics and gynecology department (adjusted odds ratio, 2.0; P=.03) were associated with inappropriate antibiotic use, whereas consultation with an infectious diseases specialist was protective against inappropriate antibiotic use (adjusted odds ratio, 0.15; P=.01).     

Epidermal growth factor receptor inhibition modulates the nuclear localization and cytotoxicity of the Auger electron emitting radiopharmaceutical 111In-DTPA human epidermal growth factor.

(111)In-DTPA-human epidermal growth factor ((111)In-DTPA-hEGF [DTPA is diethylenetriaminepentaacetic acid]) is an Auger electron-emitting radiopharmaceutical that targets EGF receptor (EGFR)-positive cancer. The purpose of this study was to determine the effect of EGFR inhibition by gefitinib on the internalization, nuclear translocation, and cytotoxicity of (111)In-DTPA-hEGF in EGFR-overexpressing MDA-MB-468 human breast cancer cells. METHODS: Western blot analysis was used to determine the optimum concentration of gefitinib to abolish EGFR activation. Internalization and nuclear translocation of fluorescein isothiocyanate-labeled hEGF were evaluated by confocal microscopy in MDA-MB-468 cells (1.3 x 10(6) EGFRs/cell) in the presence or absence of 1 microM gefitinib. The proportion of radioactivity partitioning into the cytoplasm and nucleus of MDA-MB-468 cells after incubation with (111)In-DTPA-hEGF for 24 h at 37 degrees C in the presence or absence of 1 microM gefitinib was measured by cell fractionation. DNA double-strand breaks caused by (111)In were quantified using the gamma-H2AX assay, and radiation-absorbed doses were estimated. Clonogenic survival assays were used to measure the cytotoxicity of (111)In-DTPA-hEGF alone or in combination with gefitinib. RESULTS: Gefitinib (1 microM) completely abolished EGFR phosphorylation in MDA-MB-468 cells. Internalization and nuclear translocation of fluorescein isothiocyanate-labeled EGF were not diminished in gefitinib-treated cells compared with controls. The proportion of internalized (111)In that localized in the nucleus was statistically significantly greater when (111)In-DTPA-hEGF was combined with gefitinib compared with (111)In-DTPA-hEGF alone (mean +/- SD: 26.0% +/- 5.5% vs. 14.6% +/- 4.0%, respectively; P < 0.05). Induction of gamma-H2AX foci was greater in MDA-MB-468 cells that were treated with (111)In-DTPA-hEGF (250 ng/mL, 1.5 MBq/mL) plus gefitinib (1 microM ) compared with those treated with (111)In-DTPA-hEGF alone (mean +/- SD: 35 +/- 4 vs. 24 +/- 5 foci per nucleus, respectively). In clonogenic assays, a significant reduction in the surviving fraction was observed when (111)In-DTPA-hEGF (5 ng/mL, 6 MBq/microg) was combined with gefitinib (1 microM ) compared with (111)In-DTPA-hEGF alone (42.9% +/- 5.7% vs. 22.9% +/- 3.6%, respectively; P < 0.01). CONCLUSION: The efficacy of (111)In-DTPA-hEGF depends on internalization and nuclear uptake of the radionuclide. Nuclear uptake, DNA damage, and cytotoxicity are enhanced when (111)In-DTPA-hEGF is combined with gefitinib. These results suggest a potential therapeutic role for peptide receptor radionuclide therapy in combination with tyrosine kinase inhibitors.     

Analysis of radionuclide arthrograms, radiographic arthrograms, and sequential plain radiographs in the assessment of painful hip arthroplasty

An analysis of sequential plain radiographs (XR), radionuclide arthrography, (RNA), and radiographic arthrography (RGA) was performed to determine the efficacy and usefulness of each study in the diagnosis of loosening of prosthetic hip components. Over a 2-year-period, 65 hip prostheses were assessed before operation using each type of study; these results were compared to the intraoperative assessment of the status of the components. Of the three studies, sequential plain radiographs were overall the most accurate, sensitive, and specific. Radionuclide arthrography was of no use on the acetabular side but quite useful on the femoral side, especially in cases with only minimal femoral component loosening. Radiographic arthrography was overall the least accurate or sensitive of the three studies performed.     

Effect of propranolol on nitrogen and energy metabolism in sepsis

Pharmacologic therapy designed to block adrenergic activity or alter hormonal milieu may modulate energy and protein metabolism in stress. The metabolic effects of propranolol (beta adrenergic receptor blocker) in sepsis was investigated in 22 well-nourished rats that underwent superior vena caval cannulation, cecal ligation, and puncture. Animals were randomly assigned to receive either a continuous infusion of 0.7 mg/day of propranolol combined with parenteral nutrition (n = 11) or parenteral nutrition alone (n = 11). Both groups received isocaloric, isonitrogenous, isovolemic, parenteral nutrition post-operatively for 24 hr. Nitrogen balance was better for the propranolol group than for the control group (+743 +/- 84 mg/kg/day versus +300 +/- 63 mg/kg/day, respectively, P less than 0.05). A significant difference between the pharmacologic therapy and control groups was noted for urinary 3-methylhistidine excretion versus control (0.99 +/- 0.08 micrograms/kg/day versus 7.5 +/- 0.37 micrograms/kg/day, respectively, P less than 0.01). Measured energy expenditure was similar for both pharmacologic therapy and control groups (149 +/- 20 kcal/kg/day versus 134 +/- 11 kcal/kg/day, respectively, P = N.S.). No statistically significant difference was demonstrated for 24-hr survival between propranolol and control groups (73 and 64%, respectively). Continuous, low-dose propranolol promotes nitrogen retention and decreases 3-methylhistidine excretion without altering energy expenditure in parenterally fed septic rats.     

Analysis of Various Creatinine Clearance Formulas in Predicting Gentamicin Elimination in Patients With Low Serum Creatinine

Predicted gentamicin elimination rate constants (k_els) using creatinine clearance (C1_cr) estimates from seven equations were compared with k_els calculated from steady-state serum gentamicin concentrations in 186 hospitalized patients. In predicting k_el, the equations varied significantly in precision (mean absolute percentage error), and were particularly imprecise among patients with serum creatinine values of 71 μmol/L or less. Significant differences in bias (mean prediction error) were also observed. All equations using serum creatinine as an element showed improved precision, and most showed reduced bias when a minimum value of 71 μmol/L was used. The Cockcroft-Gault normalized to 72 kg and the Hull equations are among the simplest to calculate and, when using a minimum serum creatinine of 71 μmol/L, had significantly greater precision and less bias than several of the equations. We recommend one of these two methods for predicting gentamicin k_el in patients with low serum creatinine values.     

Effect of inhaled fluticasone propionate on BAL TGF-beta(1) and bFGF concentrations in clinically stable lung transplant recipients.

BACKGROUND: Inhaled fluticasone propionate (FP) therapy decreases inflammation and sub-basement membrane thickness in asthmatic airways. Bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTRs) involves progressive airway fibrosis and obliteration. Therefore, augmented immunosuppression may be of some benefit in treating BOS. In this study, we examined the effect of 3 months of treatment with high-dose inhaled FP on the concentrations of 2 fibrogenic factors, transforming growth factor (TGF)-beta(1) and beta fibrogenic growth factor (bFGF) in bronchoalveolar lavage (BAL) fluid from clinically stable LTRs. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel group study with inhaled FP (750 microg, twice/day for 3 months) in 28 LTRs (15 FP and 13 placebo). We recruited 23 healthy controls. We performed spirometry, bronchoscopy, and bronchoalveolar lavage procedures before treatment and after 3 months of treatment. We used commercially available enzyme-linked immunosorbent assay kits to measure BAL fluid TGF-beta(1) and bFGF concentrations. RESULTS: In LTRs before treatment, BAL TGF-beta(1) concentrations (but not bFGF concentrations), total cell counts, and neutrophil percentage increased compared with controls (p < 0.05). We found no significant differences between FP and placebo groups at baseline measurements. After treatment, BAL TGF-beta(1) concentrations significantly increased in the FP group (p = 0.03), but we found no difference between FP and placebo groups; BAL bFGF concentrations increased during treatment in both groups compared with controls (p < 0.05), but not significantly within either patient group (p > 0.05). We found a reverse correlation between forced expiratory volume in 1 second (FEV(1)) and BAL TGF-beta(1) concentration in the FP group (r = -0.53, p = 0.04), and between FEV(1) and BAL TGF-beta(1) concentration in the placebo group (r = -0.74, p = 0.004). Multivariable analysis indicated no significant independent effects of inhaled FP in either BAL TGF-beta(1) or bFGF concentrations. CONCLUSIONS: Bronchoalveolar fluid TGF-beta(1) concentrations increased in LTRs after transplantation and may correlate with the decrease in lung function. Inhaled FP added to conventional immunosuppression had no effect on TGF-beta(1) or bFGF production in BAL fluid.     

Continuous arteriovenous haemofiltration in the treatment of tumour lysis syndrome

The management of tumour lysis syndrome remains problematic despite the rigorous use of preventative measures. Continuous arteriovenous haemofiltration (CAVH) is well suited to its use in both the prevention and treatment of metabolic abnormalities and renal insufficiency associated with tumour lysis. We report the successful use of CAVH in the treatment of a patient with tumour lysis syndrome.