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Randy L Bell - One of the best experts on this subject based on the ideXlab platform.
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the 5 Lipoxygenase Inhibitor zileuton blocks antigen induced late airway responses inflammation and airway hyperresponsiveness in allergic sheep
European Journal of Pharmacology, 1992Co-Authors: William M Abraham, C Lanni, A Ahmed, A Cortes, M W Sielczak, Wendy Hinz, Jennifer Bouska, Randy L BellAbstract:Abstract Leukotrienes are thought to be involved in allergen-induced airway responses. To test this hypothesis we used a newly described 5-Lipoxygenase Inhibitor, zileuton, and examined its effect on antigen-induced early and late bronchial responses, airway inflammation and airway hyperresponsiveness in allergic sheep. Early and late responses were determined by measuring specific lung resistance (SR L ) before and serially for 8 h after antigen challenge. Airway inflammation was assessed by bronchoalveolar lavage performed before, 8 h after and 24 h after antigen challenge. Airway responsiveness was measured before and 24 h after challenge by determining the dose of inhaled carbachol that caused a 400% increase in SR L (PD 400% ). The sheep (n = 8) were challenged with Ascaris suum antigen once after vehicle treatment (methylcellulose) and once after treatment with zileuton (10 mg/kg in methylcellulose, p.o.) given 2 h before antigen challenge. Trials were separated by at least 21 days. Zileuton had no effect on the early bronchoconstrictor response to antigen but the drug inhibited the late bronchial response by 55% (P 4 was inhibited over several hours after a single oral dose of zileuton, indicating that the compound was acting as a 5-Lipoxygenase Inhibitor in vivo. These results suggest that 5-Lipoxygenase metabolites contribute to allergen-induced late responses, airway inflammation and airway hyperresponsiveness in this animal model of asthma.
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the discovery and development of zileuton an orally active 5 Lipoxygenase Inhibitor
International Journal of Immunopharmacology, 1992Co-Authors: Randy L Bell, Cristina Lanni, James B Summers, Daniel H Albert, P. R. Young, Dee W. Brooks, P Rubin, George W CarterAbstract:Abstract The enzyme 5-Lipoxygenase is a key target in the effort to discover drugs which inhibit the pathophysiology associated with the formation of leukotrienes. The research efforts of these laboratories have focused on the discovery of direct enzyme Inhibitors of 5-Lipoxygenase. In particular, compounds with hydroxamate or N -hydroxyurea functionalities have proven to be potent Inhibitors of leukotriene biosynthesis in vitro and more importantly in vivo . One of these compounds, zileuton ( N -(1-benzo-[b]-thien-2-ylethyl)- N -hydroxyurea) has been shown recently to be an effective leukotriene Inhibitor in man. The critical approaches and breakthroughs in the discovery and development of zileuton are described. In addition, some recent results with zileuton in animals and man are detailed.
Allen T Segal - One of the best experts on this subject based on the ideXlab platform.
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the effect of inhibition of 5 Lipoxygenase by zileuton in mild to moderate asthma
Annals of Internal Medicine, 1993Co-Authors: Elliot Israel, P Rubin, John J. Murray, James P Kemp, Jay Grossman, William Pierson, Sheldon C Siegel, David G Tinkelman, William W Busse, Allen T SegalAbstract:Objective: To evaluate the effectiveness of inhibiting the formation of the 5-Lipoxygenase products of arachidonic acid by the 5-Lipoxygenase Inhibitor zileuton in the treatment of mild-to-moderate...
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the effect of inhibition of 5 Lipoxygenase by zileuton in mild to moderate asthma
Annals of Internal Medicine, 1993Co-Authors: Elliot Israel, John J. Murray, James P Kemp, Jay Grossman, William Pierson, Sheldon C Siegel, David G Tinkelman, William W Busse, Paul Rubin, Allen T SegalAbstract:Objective: To evaluate the effectiveness of inhibiting the formation of the 5-Lipoxygenase products of arachidonic acid by the 5-Lipoxygenase Inhibitor zileuton in the treatment of mild-to-moderate asthma. Design: Randomized, double-blind, placebo-controlled study. Setting: University hospitals and private allergy and pulmonary practices. Patients: A total of 139 persons with asthma who had a forced expiratory volume in 1 second (FEV,) of 40% to 75% of the predicted value and who were not being treated with inhaled or oral steroids. Intervention: Zileuton, 2.4 g/d or 1.6 g/d, or placebo for 4 weeks
John J. Murray - One of the best experts on this subject based on the ideXlab platform.
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a controlled trial of the effect of the 5 Lipoxygenase Inhibitor zileuton on lung inflammation produced by segmental antigen challenge in human beings
The Journal of Allergy and Clinical Immunology, 1996Co-Authors: Gregory C Kane, Judith Cohn, M Pollice, Ryszard Dworski, James R. Sheller, John J. Murray, James E. Fish, Stephen P PetersAbstract:Abstract BACKGROUND: Segmental antigen challenge (SAC) and bronchoalveolar lavage (BAL) have been proven useful for investigating IgE-mediated lung inflammation in volunteers with allergies. OBJECTIVE: This model was used to evaluate the pulmonary antiinflammatory effects of an experimental 5-Lipoxygenase Inhibitor (zileuton) in subjects allergic to ragweed. We hypothesized that decreased generation of leukotrienes by inhibition of the 5-Lipoxygenase pathway of arachidonic acid metabolism would diminish the subsequent inflammatory response resulting from antigen challenge. METHODS: Ten subjects with allergies received zileuton or placebo, 600 mg administered orally four times a day for 8 days, and then underwent bronchoscopy, BAL of a control segment, and SAC in the contralateral lung followed by BAL of the challenged segment 24 hours later in a double-blind, placebo-controlled, crossover protocol. Urinary excretion of leukotriene E 4 induced by antigen challenge plus total and differential cell counts and the amount of total protein, albumin, urea, and eosinophil cationic protein in BAL fluid were determined. RESULTS: A significant inhibition of leukotriene production (approximately 86%) was observed in subjects receiving zileuton. In addition, there was a statistically significant increase in eosinophils after antigen challenge (0.6 ± 0.2 × 10 4 eosinophils/ml increasing to 49.0 ± 25.0 × 10 4 ) in subjects receiving placebo, whereas the influx of eosinophils in subjects receiving zileuton was not statistically different from baseline (1.1 ± 0.7 × 10 4 eosinophils/ml increasing to 16.5 ± 4.1 × 10 4 ; analysis of variance for repeated measures with post hoc comparisons). CONCLUSION: Treatment with zileuton altered the inflammatory response after antigen challenge. Products of the 5-Lipoxygenase pathway appear to be important in recruiting eosinophils to the lung after SAC. (J ALLERGY CLIN IMMUNOL 1996;97:646-54.)
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the effect of inhibition of 5 Lipoxygenase by zileuton in mild to moderate asthma
Annals of Internal Medicine, 1993Co-Authors: Elliot Israel, P Rubin, John J. Murray, James P Kemp, Jay Grossman, William Pierson, Sheldon C Siegel, David G Tinkelman, William W Busse, Allen T SegalAbstract:Objective: To evaluate the effectiveness of inhibiting the formation of the 5-Lipoxygenase products of arachidonic acid by the 5-Lipoxygenase Inhibitor zileuton in the treatment of mild-to-moderate...
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the effect of inhibition of 5 Lipoxygenase by zileuton in mild to moderate asthma
Annals of Internal Medicine, 1993Co-Authors: Elliot Israel, John J. Murray, James P Kemp, Jay Grossman, William Pierson, Sheldon C Siegel, David G Tinkelman, William W Busse, Paul Rubin, Allen T SegalAbstract:Objective: To evaluate the effectiveness of inhibiting the formation of the 5-Lipoxygenase products of arachidonic acid by the 5-Lipoxygenase Inhibitor zileuton in the treatment of mild-to-moderate asthma. Design: Randomized, double-blind, placebo-controlled study. Setting: University hospitals and private allergy and pulmonary practices. Patients: A total of 139 persons with asthma who had a forced expiratory volume in 1 second (FEV,) of 40% to 75% of the predicted value and who were not being treated with inhaled or oral steroids. Intervention: Zileuton, 2.4 g/d or 1.6 g/d, or placebo for 4 weeks
P Rubin - One of the best experts on this subject based on the ideXlab platform.
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the effect of inhibition of 5 Lipoxygenase by zileuton in mild to moderate asthma
Annals of Internal Medicine, 1993Co-Authors: Elliot Israel, P Rubin, John J. Murray, James P Kemp, Jay Grossman, William Pierson, Sheldon C Siegel, David G Tinkelman, William W Busse, Allen T SegalAbstract:Objective: To evaluate the effectiveness of inhibiting the formation of the 5-Lipoxygenase products of arachidonic acid by the 5-Lipoxygenase Inhibitor zileuton in the treatment of mild-to-moderate...
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zileuton a 5 Lipoxygenase Inhibitor in rheumatoid arthritis
The Journal of Rheumatology, 1992Co-Authors: Michael E Weinblatt, Agnes L Maier, Gayle F Petrillo, Simon M. Helfgott, Joel M Kremer, Jonathan S. Coblyn, Brian Henson, P Rubin, Rayne A SperlingAbstract:The effects of zileuton, a new 5-Lipoxygenase Inhibitor, on leukotriene generation and clinical response in rheumatoid arthritis (RA) was studied in a 4-week randomized double blind placebo controlled study at 2 academic rheumatology centers. Zileuton decreased the mean (± SEM) ionophore induced synthesis of leukotriene B 4 at Week 1 by 70% from 191.2±28.5 to 57.5±17.0 ng/ml. A parallel suppression of all major 5-Lipoxygenase pathway products was observed
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the discovery and development of zileuton an orally active 5 Lipoxygenase Inhibitor
International Journal of Immunopharmacology, 1992Co-Authors: Randy L Bell, Cristina Lanni, James B Summers, Daniel H Albert, P. R. Young, Dee W. Brooks, P Rubin, George W CarterAbstract:Abstract The enzyme 5-Lipoxygenase is a key target in the effort to discover drugs which inhibit the pathophysiology associated with the formation of leukotrienes. The research efforts of these laboratories have focused on the discovery of direct enzyme Inhibitors of 5-Lipoxygenase. In particular, compounds with hydroxamate or N -hydroxyurea functionalities have proven to be potent Inhibitors of leukotriene biosynthesis in vitro and more importantly in vivo . One of these compounds, zileuton ( N -(1-benzo-[b]-thien-2-ylethyl)- N -hydroxyurea) has been shown recently to be an effective leukotriene Inhibitor in man. The critical approaches and breakthroughs in the discovery and development of zileuton are described. In addition, some recent results with zileuton in animals and man are detailed.
Elliot Israel - One of the best experts on this subject based on the ideXlab platform.
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effect of treatment with zileuton a 5 Lipoxygenase Inhibitor in patients with asthma a randomized controlled trial
JAMA, 1996Co-Authors: Elliot Israel, Louise Dube, Judith Cohn, Arthur C. Degraff, W W Pleskow, Jeffrey M Drazen, Paul H Ratner, Paul Chervinsky, Stephen I Wasserman, Harold S NelsonAbstract:Objective. —To study the effect of 3 months of treatment with zileuton, an Inhibitor of the enzymatic pathway (5-Lipoxygenase) leading to leukotriene formation, on disease control in patients with mild to moderate asthma. Design. —Randomized, double-blind, parallel-group study in 401 patients. A 10-day placebo lead-in was followed by a double-blind treatment period of 13 weeks. Setting. —Asthma study clinics in university hospitals and private practices. Patients or Other Participants. —Patients with mild to moderate asthma (forced expiratory volume in the first second [FEV 1 ], 40% to 80% of predicted) whose only treatment was inhaled β-agonists. Interventions. —Treatment with 600 mg or 400 mg of zileuton or placebo (each taken four times daily). Main Outcome Measures. —Frequency of asthma exacerbation requiring treatment with corticosteroids, use of inhaled β-agonists, pulmonary function tests, asthma symptom assessment, and quality-of-life evaluation. Safety was evaluated by monitoring adverse events. Results. —Only eight (6.1%) of 132 patients receiving 600 mg of zileuton four times a day required corticosteroid treatment for asthma vs 21 (15.6%) of 135 patients receiving placebo ( P =.02), giving a relative risk of 2.6. At the time of expected peak drug concentration, the average FEV 1 improved 15.7% in the 600-mg zileuton group vs 7.7% in the placebo group ( P =.006). Quality-of-life assessments significantly improved in the 600-mg zileuton group and not in the placebo group ( P =.007 for the overall score). Elevations in liver function tests (more than three times normal), all of which reversed with drug withdrawal, occurred in five patients ( P =.03 vs placebo), three patients ( P =.12 vs placebo), and no patients treated with 600 mg of zileuton, 400 mg of zileuton, or placebo, respectively. Conclusions. —Three months of 5-Lipoxygenase inhibition produced a significant improvement in asthma control. These data indicate that 5-Lipoxygenase products of arachidonic acid metabolism are mediators of inflammation with an important role in the biology of asthma. ( JAMA . 1996;275:931-936)
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the effect of inhibition of 5 Lipoxygenase by zileuton in mild to moderate asthma
Annals of Internal Medicine, 1993Co-Authors: Elliot Israel, P Rubin, John J. Murray, James P Kemp, Jay Grossman, William Pierson, Sheldon C Siegel, David G Tinkelman, William W Busse, Allen T SegalAbstract:Objective: To evaluate the effectiveness of inhibiting the formation of the 5-Lipoxygenase products of arachidonic acid by the 5-Lipoxygenase Inhibitor zileuton in the treatment of mild-to-moderate...
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the effect of inhibition of 5 Lipoxygenase by zileuton in mild to moderate asthma
Annals of Internal Medicine, 1993Co-Authors: Elliot Israel, John J. Murray, James P Kemp, Jay Grossman, William Pierson, Sheldon C Siegel, David G Tinkelman, William W Busse, Paul Rubin, Allen T SegalAbstract:Objective: To evaluate the effectiveness of inhibiting the formation of the 5-Lipoxygenase products of arachidonic acid by the 5-Lipoxygenase Inhibitor zileuton in the treatment of mild-to-moderate asthma. Design: Randomized, double-blind, placebo-controlled study. Setting: University hospitals and private allergy and pulmonary practices. Patients: A total of 139 persons with asthma who had a forced expiratory volume in 1 second (FEV,) of 40% to 75% of the predicted value and who were not being treated with inhaled or oral steroids. Intervention: Zileuton, 2.4 g/d or 1.6 g/d, or placebo for 4 weeks