Paul Beringer - Academia.edu (original) (raw)
Papers by Paul Beringer
Neuro-Oncology
Background The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted the... more Background The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability of the blood-brain barrier (BBB). NEO100 is a high-purity version of the natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open the BBB in rodent models. Here we investigated whether NEO100 could enable brain entry of trastuzumab to achieve greater therapeutic activity. Methods An in vitro BBB, consisting of human astrocytes and brain endothelial cells, was used to determine trastuzumab penetration in the presence or absence of NEO100. For in vivo studies, we administered intravenous (IV) trastuzumab or the trastuzumab-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla®, Roche), to mouse models harboring intracranial HER2...
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Neuro-Oncology
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Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy
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PloS one, 2017
θ-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkey... more θ-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkeys. The peptides are pleiotropic effectors of innate immunity, possessing broad spectrum antimicrobial activities and immunoregulatory properties. Here we report that rhesus θ-defensin 1 (RTD-1) is highly effective in arresting and reversing joint disease in a rodent model of rheumatoid arthritis (RA). Parenteral RTD-1 treatment of DA/OlaHsd rats with established pristane-induced arthritis (PIA) rapidly suppressed joint disease progression, restored limb mobility, and preserved normal joint architecture. RTD-1 significantly reduced joint IL-1β levels compared with controls. RTD-1 dose-dependently inhibited fibroblast-like synoviocyte (FLS) invasiveness and FLS IL-6 production. Consistent with the inhibition of FLS invasiveness, RTD-1 was a potent inhibitor of arthritogenic proteases including ADAMs 17 and 10 which activate TNFα, and inhibited matrix metalloproteases, and cathepsin K. RTD-...
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American journal of respiratory cell and molecular biology, Mar 27, 2017
Acute lung injury (ALI) is a clinical syndrome characterized by acute respiratory failure and is ... more Acute lung injury (ALI) is a clinical syndrome characterized by acute respiratory failure and is associated with substantial morbidity and mortality. Rhesus theta defensin-1 (RTD-1) is an antimicrobial peptide with immunomodulatory activity. As airway inflammation and neutrophil recruitment and activation are hallmarks of ALI, we evaluated the therapeutic efficacy of RTD-1 in pre-clinical models of the disease. We investigated the effect of RTD-1 on neutrophil chemotaxis and macrophage-driven pulmonary inflammation with human peripheral neutrophils and LPS-stimulated murine alveolar macrophage (MH-S) cells. Treatment and prophylactic single escalating doses were administered subcutaneously in a well-established murine model of direct endotoxin induced ALI. We assessed lung injury by histopathology, pulmonary edema, inflammatory cell recruitment, and inflammatory cytokines/chemokines in the bronchoalveolar lavage fluid. In vitro studies demonstrated that RTD-1 suppressed CXCL8 induce...
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Antimicrobial Agents and Chemotherapy
Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increase... more Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several beta-lactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds t...
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Antimicrobial agents and chemotherapy, Aug 30, 2017
Rationale: Chronic airway infection and inflammation contribute to the progressive loss of lung f... more Rationale: Chronic airway infection and inflammation contribute to the progressive loss of lung function and shortened survival of patients with cystic fibrosis (CF). Rhesus theta (θ) defensin-1 (RTD-1) is a macrocyclic host defense peptide with antimicrobial and immunomodulatory activities. Combined with favorable preclinical safety and peptide stability data, RTD-1 warrants investigation to determine its therapeutic potential for treatment of CF lung disease.Objectives: We sought to evaluate the therapeutic potential of RTD-1 for CF airway infection and inflammation using in vitro, ex vivo, and in vivo models.Methods: We evaluated RTD-1's effects on basal and P. aeruginosa induced inflammation in CF sputum leukocytes and CF bronchial epithelial cells. Peptide stability was evaluated by incubation with CF sputum. Airway pharmacokinetics, safety and tolerance studies were performed in naïve mice. Aerosolized RTD-1 treatment effects were assessed by analyzing lung bacterial burde...
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Annals of Pharmacotherapy, Feb 1, 1998
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Therapeutic Drug Monitoring, Sep 1, 1995
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Therapeutic Drug Monitoring, Dec 1, 2000
The authors evaluated the predictive performance of four methods used to estimate creatinine clea... more The authors evaluated the predictive performance of four methods used to estimate creatinine clearance (Cl(cr)) in patients with metastatic ovarian cancer. Methods described by Cockcroft and Gault, Jelliffe, and two equations derived from cancer patients by Robinson and Tsubaki, were evaluated. Estimated Cl(cr) values obtained by each method using actual weight (ABW), ideal weight (IBW) and lower of ABW and IBW were compared with measured values determined by a 12- or 24-hour urine collection for 14 patients enrolled in a controlled clinical trial. The mean prediction errors (ME) and mean absolute errors (MAE) were calculated to evaluate the bias and precision, respectively, of each method. The relationship between predicted and measured Cl(cr) is poor (r = 0.38 to 0.54). Cockcroft and Gault using ABW (p = 0.21), Robinson using ABW (p = 0.44), and Jelliffe (p = 0.17) were equally unbiased predictors of measured Cl(cr). All other methods significantly underestimated measured Cl(cr). All methods appeared to be equally imprecise (p<0.05). The use of standard equations for estimating Cl(cr) in patients with ovarian cancer is predictive of the measured 24-hour value. The use of oncology specific equations does not improve the accuracy or precision of these estimates.
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Journal of Antimicrobial Chemotherapy, 2015
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Background: Once-daily dosing (ODA) of aminoglycosides is now advocated due to ease of administra... more Background: Once-daily dosing (ODA) of aminoglycosides is now advocated due to ease of administration and improved toxicity profile. However, the optimal sampling times (OST) for this new dosing regimen have not been clearly established. A recent pharmacokinetic (PK) study in healthy volunteers demonstrated a prolonged distribution phase and reduced clearance using a 7mg/kg dose compared with the traditional 2 mg/kg dose (Demczar, Antimicrob. Agents Chemother., 1997; 41:1115-19). Due to the altered PK in patients with CF, higher daily doses are administered (10-15 mg/kg). The purpose of this study is to evaluate the PK of once-daily tobramycin administration in CF patients. The specific objectives are to compare the distribution and elimination patterns of traditional (3.3mg/kg q8h) dosing versus high dose (10mg/kg q24h) tobramycin, and to determine the OST to facilitate dosage individualization in the clinical setting. Methods: Six adult CF patients were enrolled in this prospectiv...
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Purpose: Chronic Pseudomonas aeruginosa infection causes an inflammatory response in the airways ... more Purpose: Chronic Pseudomonas aeruginosa infection causes an inflammatory response in the airways of CF patients. Accumulation of neutrophils and release of proteolytic enzymes (i.e. matrix metalloproteinase-9) causes airway destruction. We determined the effect of doxycycline on airway inflammation by measuring proteolytic enzyme levels (i.e. MMP-9) in induced sputum, correlated level changes with patient pulmonary function, and evaluated safety with short-term administration. Methods: A prospective, open-label, randomized controlled study was conducted to determine effects of doxycycline on inflammatory biomarkers. Eight of 24 patients have been stratified according to pulmonary function: mild (FEV1>70%) or moderate (FEV1 40-70%) and randomized in block to receive no drug, 40 mg, 100 mg, or 200 mg for 28 days. The first dose was administered intravenously. All subsequent doses were given orally. Induced sputum and spirometry were obtained during the 28-day treatment period and a...
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Purpose: Cystic Fibrosis is characterized by an intrinsic hyper-immune state. This primary inflam... more Purpose: Cystic Fibrosis is characterized by an intrinsic hyper-immune state. This primary inflammatory condition prior to bacterial infection is supported by clinical observations in CF neonates and young children. Mounting evidence also suggests an exaggerated and prolonged inflammatory response to foreign invaders of the airways. The aim of this work was to evaluate the anti-inflammatory activity of doxycycline on the CF phenotypic bronchial airway epithelium. Methods: The CF compound heterozygote IB3-1 and rescued isogenic S9 cell lines were used to characterize doxycycline's effects on lung parenchyma inflammation and remodeling. Biological markers IL-8 and MMP-9 were analyzed by ELISA and qRT-PCR following stimulation with IL-1β, TNF-α, or Pa-LPS at varying time points. Cytotoxicity was quantified by LDH assays. Results: Diminution of IL-8 release upon doxycycline treatment in a dose dependent manner was observed in both IB3 and S9 cell lines after immune activation with I...
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Background: Time above MIC (T>MIC) is the pharmacodynamic parameter that best correlates with ... more Background: Time above MIC (T>MIC) is the pharmacodynamic parameter that best correlates with bacterial killing for CFP. CFP via CI achieves T>MIC throughout the dosing interval. The purpose of this study is to determine whether CFP exhibits sufficient stability and antibacterial (ABX) activity to be given by 24-hour CI using portable infusion pumps (PIP). Methods: The stability of CFP in D5W solns. was determined in ten replicates for a simulated CI using a PIP (Microject 30, Sorensen Medical) worn over a period of 24-36 hours. The temp. in the bags were measured every ½ hr using a device placed adjacent to the drug-reservoir. CFP concs. were measured by HPLC. Mass spectrometry (MS) was used to identify the major degradation products by comparing mass ions signatures of fresh with degraded solns. The ABX activity of the CFP solns. were measured by comparing the MICs and MBCs of fresh and degraded solns against a reference strain of P. aeruginosa according to NCCLS. The degrad...
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Journal of Chemical Information and Modeling, 2015
The chemokine receptor CXCR2 is expressed on various immune cells and is essential for neutrophil... more The chemokine receptor CXCR2 is expressed on various immune cells and is essential for neutrophil recruitment and angiogenesis at sites of acute and chronic inflammation caused by tissue injury or infection. CXCR2 and its ligand, CXCL8, are implicated in a number of inflammation-mediated diseases such as chronic obstructive pulmonary disease, cystic fibrosis, and cancer. Though the development of CXCR2-specific small-molecule inhibitors as anti-inflammatory agents has been pursued by pharmaceutical companies within the past decade, there are currently no clinically approved CXCR2 inhibitors. A pharmacophore model based on previously reported CXCR2 antagonists was developed to screen a database of commercially available compounds. Small-molecule compounds identified from the pharmacophore screening were selected for in vitro screening in a cell-based CXCR2-mediated β-arrestin-2 recruitment assay and further characterized in several cell-based assays and lipopolysaccharide (LPS)-induced lung inflammation studies in mice. CX compounds identified from pharmacophore modeling inhibited cell migration, lung and colon cancer cell proliferation, and colony formation. Mechanistic studies of CX4152 showed that this compound inhibits CXCR2 signaling through downregulation of surface CXCR2. Additionally, CX4152 significantly inhibits CXCL8-mediated neutrophil migration and LPS-induced lung inflammation in mice. Using a CXCR2-inhibitor-based pharmacophore model, we identified a novel set of sulfonamides from a diverse library of small molecules. These compounds inhibit CXCR2/β-arrestin-2 association, cell migration and proliferation, and acute inflammation in mouse models. CX compounds identified from our pharmacophore models are potential leads for further optimization and development as anti-inflammatory and anticancer agents.
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Journal of Cystic Fibrosis, 2014
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Clinical Pharmacology & Therapeutics, 2005
Background: Azithromycin (AZM) significantly improves pulmonary function in patients with cystic ... more Background: Azithromycin (AZM) significantly improves pulmonary function in patients with cystic fibrosis (CF). Our hypothesis is that the absorption of AZM may be altered in CF due to pancreatic insufficiency. Additionally, MDR1 and CFTR are coordinatley regulated which may alter the intracellular disposition of P-gp substrates. The objective is to compare the bioavailability and intracellular (IC) concentrations of AZM in
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Current opinion in pulmonary medicine, 2001
Colistin is a cationic polypeptide antibiotic from the polymyxin family that was first introduced... more Colistin is a cationic polypeptide antibiotic from the polymyxin family that was first introduced in 1962 but abandoned in the early 1970s because of initial reports of severe toxicities. However, a recent increase in the prevalence of multidrug resistant (MDR) Pseudomonas aeruginosa and the lack of novel agents in development calls for a need to re-examine the role of colistin therapy in patients with cystic fibrosis. Current data supports the use of intravenous colistimethate for the treatment of acute pulmonary exacerbations involving MDR P. aeruginosa and inhaled therapy for initial colonization. The frequency of nephrotoxicity and severity of neurotoxicity seem to be substantially less than previously believed. In addition, recent pharmacokinetic and pharmacodynamic data suggests new intravenous dosing regimens may enhance efficacy while minimizing toxicities; such regimens deserve further evaluation. Pre- and post-treatment spirometry is recommended at initiation of inhaled co...
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Neuro-Oncology
Background The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted the... more Background The antitumor efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as humanized monoclonal antibody trastuzumab (Herceptin®, Roche), in patients with breast-to-brain cancer metastasis is hindered by the low permeability of the blood-brain barrier (BBB). NEO100 is a high-purity version of the natural monoterpene perillyl alcohol, produced under current good manufacturing practice (cGMP) regulations, that was shown previously to reversibly open the BBB in rodent models. Here we investigated whether NEO100 could enable brain entry of trastuzumab to achieve greater therapeutic activity. Methods An in vitro BBB, consisting of human astrocytes and brain endothelial cells, was used to determine trastuzumab penetration in the presence or absence of NEO100. For in vivo studies, we administered intravenous (IV) trastuzumab or the trastuzumab-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla®, Roche), to mouse models harboring intracranial HER2...
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Neuro-Oncology
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Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy
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PloS one, 2017
θ-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkey... more θ-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkeys. The peptides are pleiotropic effectors of innate immunity, possessing broad spectrum antimicrobial activities and immunoregulatory properties. Here we report that rhesus θ-defensin 1 (RTD-1) is highly effective in arresting and reversing joint disease in a rodent model of rheumatoid arthritis (RA). Parenteral RTD-1 treatment of DA/OlaHsd rats with established pristane-induced arthritis (PIA) rapidly suppressed joint disease progression, restored limb mobility, and preserved normal joint architecture. RTD-1 significantly reduced joint IL-1β levels compared with controls. RTD-1 dose-dependently inhibited fibroblast-like synoviocyte (FLS) invasiveness and FLS IL-6 production. Consistent with the inhibition of FLS invasiveness, RTD-1 was a potent inhibitor of arthritogenic proteases including ADAMs 17 and 10 which activate TNFα, and inhibited matrix metalloproteases, and cathepsin K. RTD-...
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American journal of respiratory cell and molecular biology, Mar 27, 2017
Acute lung injury (ALI) is a clinical syndrome characterized by acute respiratory failure and is ... more Acute lung injury (ALI) is a clinical syndrome characterized by acute respiratory failure and is associated with substantial morbidity and mortality. Rhesus theta defensin-1 (RTD-1) is an antimicrobial peptide with immunomodulatory activity. As airway inflammation and neutrophil recruitment and activation are hallmarks of ALI, we evaluated the therapeutic efficacy of RTD-1 in pre-clinical models of the disease. We investigated the effect of RTD-1 on neutrophil chemotaxis and macrophage-driven pulmonary inflammation with human peripheral neutrophils and LPS-stimulated murine alveolar macrophage (MH-S) cells. Treatment and prophylactic single escalating doses were administered subcutaneously in a well-established murine model of direct endotoxin induced ALI. We assessed lung injury by histopathology, pulmonary edema, inflammatory cell recruitment, and inflammatory cytokines/chemokines in the bronchoalveolar lavage fluid. In vitro studies demonstrated that RTD-1 suppressed CXCL8 induce...
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Antimicrobial Agents and Chemotherapy
Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increase... more Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several beta-lactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds t...
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Antimicrobial agents and chemotherapy, Aug 30, 2017
Rationale: Chronic airway infection and inflammation contribute to the progressive loss of lung f... more Rationale: Chronic airway infection and inflammation contribute to the progressive loss of lung function and shortened survival of patients with cystic fibrosis (CF). Rhesus theta (θ) defensin-1 (RTD-1) is a macrocyclic host defense peptide with antimicrobial and immunomodulatory activities. Combined with favorable preclinical safety and peptide stability data, RTD-1 warrants investigation to determine its therapeutic potential for treatment of CF lung disease.Objectives: We sought to evaluate the therapeutic potential of RTD-1 for CF airway infection and inflammation using in vitro, ex vivo, and in vivo models.Methods: We evaluated RTD-1's effects on basal and P. aeruginosa induced inflammation in CF sputum leukocytes and CF bronchial epithelial cells. Peptide stability was evaluated by incubation with CF sputum. Airway pharmacokinetics, safety and tolerance studies were performed in naïve mice. Aerosolized RTD-1 treatment effects were assessed by analyzing lung bacterial burde...
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Annals of Pharmacotherapy, Feb 1, 1998
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Therapeutic Drug Monitoring, Sep 1, 1995
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Therapeutic Drug Monitoring, Dec 1, 2000
The authors evaluated the predictive performance of four methods used to estimate creatinine clea... more The authors evaluated the predictive performance of four methods used to estimate creatinine clearance (Cl(cr)) in patients with metastatic ovarian cancer. Methods described by Cockcroft and Gault, Jelliffe, and two equations derived from cancer patients by Robinson and Tsubaki, were evaluated. Estimated Cl(cr) values obtained by each method using actual weight (ABW), ideal weight (IBW) and lower of ABW and IBW were compared with measured values determined by a 12- or 24-hour urine collection for 14 patients enrolled in a controlled clinical trial. The mean prediction errors (ME) and mean absolute errors (MAE) were calculated to evaluate the bias and precision, respectively, of each method. The relationship between predicted and measured Cl(cr) is poor (r = 0.38 to 0.54). Cockcroft and Gault using ABW (p = 0.21), Robinson using ABW (p = 0.44), and Jelliffe (p = 0.17) were equally unbiased predictors of measured Cl(cr). All other methods significantly underestimated measured Cl(cr). All methods appeared to be equally imprecise (p<0.05). The use of standard equations for estimating Cl(cr) in patients with ovarian cancer is predictive of the measured 24-hour value. The use of oncology specific equations does not improve the accuracy or precision of these estimates.
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Journal of Antimicrobial Chemotherapy, 2015
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Background: Once-daily dosing (ODA) of aminoglycosides is now advocated due to ease of administra... more Background: Once-daily dosing (ODA) of aminoglycosides is now advocated due to ease of administration and improved toxicity profile. However, the optimal sampling times (OST) for this new dosing regimen have not been clearly established. A recent pharmacokinetic (PK) study in healthy volunteers demonstrated a prolonged distribution phase and reduced clearance using a 7mg/kg dose compared with the traditional 2 mg/kg dose (Demczar, Antimicrob. Agents Chemother., 1997; 41:1115-19). Due to the altered PK in patients with CF, higher daily doses are administered (10-15 mg/kg). The purpose of this study is to evaluate the PK of once-daily tobramycin administration in CF patients. The specific objectives are to compare the distribution and elimination patterns of traditional (3.3mg/kg q8h) dosing versus high dose (10mg/kg q24h) tobramycin, and to determine the OST to facilitate dosage individualization in the clinical setting. Methods: Six adult CF patients were enrolled in this prospectiv...
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Purpose: Chronic Pseudomonas aeruginosa infection causes an inflammatory response in the airways ... more Purpose: Chronic Pseudomonas aeruginosa infection causes an inflammatory response in the airways of CF patients. Accumulation of neutrophils and release of proteolytic enzymes (i.e. matrix metalloproteinase-9) causes airway destruction. We determined the effect of doxycycline on airway inflammation by measuring proteolytic enzyme levels (i.e. MMP-9) in induced sputum, correlated level changes with patient pulmonary function, and evaluated safety with short-term administration. Methods: A prospective, open-label, randomized controlled study was conducted to determine effects of doxycycline on inflammatory biomarkers. Eight of 24 patients have been stratified according to pulmonary function: mild (FEV1>70%) or moderate (FEV1 40-70%) and randomized in block to receive no drug, 40 mg, 100 mg, or 200 mg for 28 days. The first dose was administered intravenously. All subsequent doses were given orally. Induced sputum and spirometry were obtained during the 28-day treatment period and a...
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Purpose: Cystic Fibrosis is characterized by an intrinsic hyper-immune state. This primary inflam... more Purpose: Cystic Fibrosis is characterized by an intrinsic hyper-immune state. This primary inflammatory condition prior to bacterial infection is supported by clinical observations in CF neonates and young children. Mounting evidence also suggests an exaggerated and prolonged inflammatory response to foreign invaders of the airways. The aim of this work was to evaluate the anti-inflammatory activity of doxycycline on the CF phenotypic bronchial airway epithelium. Methods: The CF compound heterozygote IB3-1 and rescued isogenic S9 cell lines were used to characterize doxycycline's effects on lung parenchyma inflammation and remodeling. Biological markers IL-8 and MMP-9 were analyzed by ELISA and qRT-PCR following stimulation with IL-1β, TNF-α, or Pa-LPS at varying time points. Cytotoxicity was quantified by LDH assays. Results: Diminution of IL-8 release upon doxycycline treatment in a dose dependent manner was observed in both IB3 and S9 cell lines after immune activation with I...
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Background: Time above MIC (T>MIC) is the pharmacodynamic parameter that best correlates with ... more Background: Time above MIC (T>MIC) is the pharmacodynamic parameter that best correlates with bacterial killing for CFP. CFP via CI achieves T>MIC throughout the dosing interval. The purpose of this study is to determine whether CFP exhibits sufficient stability and antibacterial (ABX) activity to be given by 24-hour CI using portable infusion pumps (PIP). Methods: The stability of CFP in D5W solns. was determined in ten replicates for a simulated CI using a PIP (Microject 30, Sorensen Medical) worn over a period of 24-36 hours. The temp. in the bags were measured every ½ hr using a device placed adjacent to the drug-reservoir. CFP concs. were measured by HPLC. Mass spectrometry (MS) was used to identify the major degradation products by comparing mass ions signatures of fresh with degraded solns. The ABX activity of the CFP solns. were measured by comparing the MICs and MBCs of fresh and degraded solns against a reference strain of P. aeruginosa according to NCCLS. The degrad...
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Journal of Chemical Information and Modeling, 2015
The chemokine receptor CXCR2 is expressed on various immune cells and is essential for neutrophil... more The chemokine receptor CXCR2 is expressed on various immune cells and is essential for neutrophil recruitment and angiogenesis at sites of acute and chronic inflammation caused by tissue injury or infection. CXCR2 and its ligand, CXCL8, are implicated in a number of inflammation-mediated diseases such as chronic obstructive pulmonary disease, cystic fibrosis, and cancer. Though the development of CXCR2-specific small-molecule inhibitors as anti-inflammatory agents has been pursued by pharmaceutical companies within the past decade, there are currently no clinically approved CXCR2 inhibitors. A pharmacophore model based on previously reported CXCR2 antagonists was developed to screen a database of commercially available compounds. Small-molecule compounds identified from the pharmacophore screening were selected for in vitro screening in a cell-based CXCR2-mediated β-arrestin-2 recruitment assay and further characterized in several cell-based assays and lipopolysaccharide (LPS)-induced lung inflammation studies in mice. CX compounds identified from pharmacophore modeling inhibited cell migration, lung and colon cancer cell proliferation, and colony formation. Mechanistic studies of CX4152 showed that this compound inhibits CXCR2 signaling through downregulation of surface CXCR2. Additionally, CX4152 significantly inhibits CXCL8-mediated neutrophil migration and LPS-induced lung inflammation in mice. Using a CXCR2-inhibitor-based pharmacophore model, we identified a novel set of sulfonamides from a diverse library of small molecules. These compounds inhibit CXCR2/β-arrestin-2 association, cell migration and proliferation, and acute inflammation in mouse models. CX compounds identified from our pharmacophore models are potential leads for further optimization and development as anti-inflammatory and anticancer agents.
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Journal of Cystic Fibrosis, 2014
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Clinical Pharmacology & Therapeutics, 2005
Background: Azithromycin (AZM) significantly improves pulmonary function in patients with cystic ... more Background: Azithromycin (AZM) significantly improves pulmonary function in patients with cystic fibrosis (CF). Our hypothesis is that the absorption of AZM may be altered in CF due to pancreatic insufficiency. Additionally, MDR1 and CFTR are coordinatley regulated which may alter the intracellular disposition of P-gp substrates. The objective is to compare the bioavailability and intracellular (IC) concentrations of AZM in
Bookmarks Related papers MentionsView impact
Current opinion in pulmonary medicine, 2001
Colistin is a cationic polypeptide antibiotic from the polymyxin family that was first introduced... more Colistin is a cationic polypeptide antibiotic from the polymyxin family that was first introduced in 1962 but abandoned in the early 1970s because of initial reports of severe toxicities. However, a recent increase in the prevalence of multidrug resistant (MDR) Pseudomonas aeruginosa and the lack of novel agents in development calls for a need to re-examine the role of colistin therapy in patients with cystic fibrosis. Current data supports the use of intravenous colistimethate for the treatment of acute pulmonary exacerbations involving MDR P. aeruginosa and inhaled therapy for initial colonization. The frequency of nephrotoxicity and severity of neurotoxicity seem to be substantially less than previously believed. In addition, recent pharmacokinetic and pharmacodynamic data suggests new intravenous dosing regimens may enhance efficacy while minimizing toxicities; such regimens deserve further evaluation. Pre- and post-treatment spirometry is recommended at initiation of inhaled co...
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