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R L Bell

Publications and source records attributed to R L Bell.

At least 55 records · Page 3Linked to original sources
PubMed1994

Stereoselective metabolism of the 5-lipoxygenase inhibitor A-78773.

Based on the knowledge that glucuronidation was a major route of metabolism of the N-hydroxyurea class of 5-lipoxygenase inhibitors, a simple in vitro glucuronidation assay was established using liver microsomes from various species, including man. Compounds that were potent inhibitors of 5-LO and showed a reduced metabolic liability in vitro were then characterized more extensively in experimental animals. This prudent usage of in vitro glucuronidation proved to be highly efficient and was indispensable in the identification of A-78773, a potent new long-acting 5-LO inhibitor. Further studies with liver microsomes revealed that glucuronidation of A-78773 was stereoselective and that the R(+) enantiomer was considerably more resistant to conjugation than the S(-) stereoisomer. Pharmacokinetic studies in experimental animals and humans confirmed the greater metabolic stability of the R(+) enantiomer. A single 400-mg oral dose of A-78773 inhibited ex vivo leukotriene biosynthesis for more than 24 hours. Since 78% of the drug plasma AUC following A-78773 administration was accounted for by the R(+) enantiomer, it is reasonable to assume that the majority of the leukotriene inhibition caused by the racemate is attributable to the R(+) enantiomer, A-79175, particularly at the later times. The equivalent 5-lipoxygenase inhibitory potency coupled with the superior pharmacokinetic profile of the R(+) enantiomer, A79175, compared to the S(-) enantiomer, A-79176, indicate that the development of this compound may be preferable to the racemate A-78773.

Animals↗
PubMed1994

The 5-lipoxygenase inhibitory activity of zileuton in in vitro and in vivo models of antigen-induced airway anaphylaxis.

Leukotrienes are biologically active lipid mediators capable of producing airway inflammation, hyperresponsiveness and bronchoconstriction. The first enzyme in the metabolic pathway of arachidonic acid leading to the leukotrienes is 5-lipoxygenase (5-LO). A selective and potent 5-LO inhibitor, zileuton (N-1(1-benzo[b]thien-2-ylethyl)-N-hydroxyurea, A-64077) was evaluated in models of airway anaphylaxis, where leukotrienes are a major component. In vitro, zileuton inhibited antigen-induced contractions of guinea-pig tracheal strips (GPTS) from actively sensitized animals with an IC50 of 6 microM. Similar results were obtained in human bronchial strips passively sensitized to IgE. Zileuton had little or no effect on contractions elicited by acetylcholine, prostaglandin D2 (PGD2), or the thromboxane agonist, U-44069. In anesthetized sensitized guinea-pigs pretreated with meclofenamic acid and mepyramine, a single aerosol exposure of antigen produced a substantial decrease in dynamic lung compliance (Cdyn). These profound changes in lung function were dose-dependently inhibited by orally administered zileuton (ED50 = 12 mg/kg). These results demonstrate that zileuton is a potent, selective inhibitor of in vitro contraction of GPTS and antigen-induced bronchoconstriction in vivo. These data also confirm the participation of 5-LO products in these models of airway anaphylaxis and suggest the usefulness of the guinea-pig for identifying and characterizing the pulmonary effects of 5-LO inhibitors.

Anaphylaxis↗
PubMed1994

An inversion algorithm for determining area-source emissions from downwind concentration measurements.

Measuring emissions from nonuniform area sources, such as waste repository sites, has been a difficult problem. A simple but reliable method is not available. An objective method of inverting downwind concentration measurements, utilizing an assumed form of atmospheric dispersion to reconstruct total emission rate and distribution, is described in this study. The Gaussian dispersion model is compared to a more realistic model based on K-theory and similarity expressions. A sensitivity analysis is presented indicating the atmospheric conditions under which a successful application of the method could be anticipated. Field releases of sulfur hexafluoride (SF6) from a simulated area source in flat terrain were conducted to check the method, ability to reconstruct source distribution, and total emission rate. The sensitivity analysis and the field study confirm that a few ground-level concentration measurements and a simple determination of the atmospheric dispersion characteristics are sufficient, under neutral to stable conditions, to obtain the total emission rate accurately. Reconstruction of the spatial pattern of the source is possible by utilizing concentration information from samplers located on two separate ground-level receptor lines, if a shift in the wind direction occurs and if it can be assumed that the total emission rate is time invariant. A method of cross-checking the accuracy of the reconstruction, using a simultaneous tracer release, is presented.

Air Pollutants, Occupational↗
PubMed1993

Preclinical and clinical activity of zileuton and A-78773.

The importance of leukotrienes as mediators of inflammation and bronchoconstriction was examined with two recently described 5-lipoxygenase inhibitors, zileuton and A-78773. Preclinical evaluation of these two molecules indicates that they are potent, selective, direct, reversible inhibitors of 5-lipoxygenase with activity in a variety of purified cells and in more complex biological systems such as whole blood, lung fragments, and tracheal tissues. In various animals models of inflammation and allergy, the molecules inhibited edema, inflammatory cell influx, and bronchospasm. These observations are consistent with the recent clinical success of zileuton in treating asthma and inflammatory bowel disease. In all preclinical systems tested thus far, A-78773 is more potent and longer acting than zileuton, indicating that the molecule could be even more effective in the clinic than zileuton and that both molecules are useful tools in defining the role of leukotrienes in preclinical and clinical settings.

Animals↗
PubMed1993

The properties of A-69412: a small hydrophilic 5-lipoxygenase inhibitor.

A compound which inhibits leukotriene biosynthesis could be clinically useful in treating several allergic and inflammatory diseases. One site for such inhibition is at the enzyme 5-lipoxygenase. Most inhibitors of this enzyme thus far described are poorly bioavailable. A-69412 is a small, relatively hydrophilic compound of the N-hydroxyurea class, which exhibits minimal plasma protein binding (6-12%). The compound was found to be a potent long-acting inhibitor of leukotriene formation in vivo in the rat (oral ED50 = 5 mg/kg) and ex vivo in several species. In addition, the compound exhibits excellent bioavailability in dogs and monkeys with a relatively long elimination half-life in both the species (6 and 3 h, respectively). The biochemical activity and pharmacological profile of A-69412 indicates its potential utility in asthma and ulcerative colitis, and possibly other inflammatory and allergic conditions.

Anaphylaxis↗
PubMed1992

Visualization of extrastriatal dopamine D2 receptors in the human brain.

[123I]Epidepride, a potent and selective dopamine D2 radioligand, was administered to a 27 year old normal male volunteer. Single photon tomography revealed that peak striatal uptake occurred at 4 h after injection with a striatal:cerebellar ratio of 7.8 rising to over 100 at 18 h post injection. Uptake above the levels seen in cerebellum was also noted in the thalamus, pituitary, hypothalamus and temporal lobe, particularly medially. Single photon tomography with [123I]epidepride allows visualization of extrastriatal dopamine D2 receptors in man.

Adult↗
PubMed1992

The 5-lipoxygenase inhibitor zileuton blocks antigen-induced late airway responses, inflammation and airway hyperresponsiveness in allergic sheep.

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 (SRL) 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 SRL (PD400%). 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 less than 0.05). Unlike the control trial, there was no significant increase in bronchoalveolar lavage eosinophils at 8 h post challenge in the zileuton-treated sheep. Furthermore, zileuton treatment blocked (P less than 0.05) the airway hyperresponsiveness seen 24 h after challenge. Ex vivo formation of leukotriene B4 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.

Administration, Oral↗
PubMed1992

The discovery and development of zileuton: an orally active 5-lipoxygenase inhibitor.

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.

Animals↗
PubMed1991

Inhibition of leukotriene biosynthesis in the rat peritoneal cavity.

In the search for a model of leukotriene (LT) production to provide a method to determine in vivo 5-lipoxygenase (5-LO) inhibitory activity by various compounds, a passive anaphylactic reaction in the rat peritoneal cavity was examined, refined and characterized. The reaction, produced by passive sensitization with an i.p. injection of rabbit anti-bovine serum albumin (anti-BSA) followed by an i.p. injection of BSA, resulted in the biosynthesis of large amounts of sulfidopeptide LTs measurable by immunoassay or by reversed phase high performance liquid chromatography. The oral activity of several 5-LO inhibitors has been examined using this model. An example of these is zileuton (Abbott-64077), a potent 5-lipoxygenase inhibitor now under clinical evaluation. Zileuton inhibited sulfidopeptide LT biosynthesis in the rat peritoneal cavity in a dose-dependent manner (ED50 = 3 mg/kg). WY-49,232, MK-866, BW A4C and phenidone also produced good activity with ED50 values of 6, 8, 11 and 17 mg/kg, respectively. This modified rat peritoneal anaphylaxis model appears to be a valuable tool for establishing in vivo activity of 5-LO inhibitors.

Administration, Oral↗
PubMed1991

4-hydroxythiazole inhibitors of 5-lipoxygenase.

4-Hydroxythiazoles have been identified as potent inhibitors of 5-lipoxygenase in vitro exhibiting IC50's of less than 1 microM. An investigation of structure-activity relationships showed that the most potent inhibitors of this series are the 5-phenyl derivatives. The corresponding thiazolidin-4-one analogues were found to be relatively inactive. The 4-hydroxythiazoles were active inhibitors against 5-lipoxygenase in both intact rat polymorphonuclear leukocytes and human whole blood. The compounds were also selective inhibitors of 5-lipoxygenase, displaying only weak activity against other related enzymes, cyclooxygenase and 12- and 15-lipoxygenase.

Animals↗
PubMed1991

5-lipoxygenase inhibitory activity of zileuton.

Zileuton [N-(1-benzo[b]thien-2-ylethyl)-N-hydroxyure] inhibited 5-hydroxyeicosatetraenoic acid synthesis by rat basophilic leukemia cell 20,000 x g supernatant and rat polymorphonuclear leukocytes (PMNL) (IC50 = 0.5 and 0.3 microM) respectively. It also inhibited leukotriene (LT)B4 biosynthesis by rat PMNL (IC50 = 0.4 microM), human PMNL (IC50 = 0.4 microM) and human whole blood (IC50 = 0.9 microM). Inhibition of human PMNL LTB4 biosynthesis was removed readily by a simple wash procedure. At concentrations up to 100 microM, the compound produced little or no inhibition of several related enzymes, such as platelet 12-lipoxygenase, soybean and rabbit reticulocyte 15-lipoxygenase and sheep seminal vesicle cyclooxygenase. At p.o. doses from 0.5 to 5 mg/kg in the dog, zileuton produced a rapid and sustained inhibition of ex vivo blood LTB4 biosynthesis which correlated with the pharmacokinetic behavior of the compound. In a similar ex vivo study in the rat, the compound displayed an p.o. ED50 of 2 mg/kg. Zileuton was highly effective in preventing 6-sulfidopeptide LT formation in the rat peritoneal cavity triggered by an antigen-antibody reaction with an ED50 of 3 mg/kg. In experimental models of inflammation, zileuton significantly reduced arachidonic-acid induced mouse ear edema (ED50 = 31 mg/kg) and also attenuated inflammatory cell accumulation in the rat pleural Arthus reaction. The effectiveness of this compound for preventing LT formation in vitro, ex vivo and in vivo suggests its utility for preventing the pathophysiological effects of the LTs and other 5-lipoxygenase products in animals and in humans.

Administration, Oral↗
PubMed1987

Mediators of C5a-induced bronchoconstriction in the guinea pig.

The effect of intravenous injection of C5a on pulmonary resistance and dynamic lung compliance was determined in anesthetized, artificially respirated guinea pigs. A mixture of C5a plus C5ades arg was purified from yeast-activated guinea pig serum and is referred to as C5a. Intravenous injection of C5a caused a dose-related bronchoconstriction as evidenced by a decrease in compliance and increase in resistance. Conversion of the C5a in the mixture to C5ades arg by carboxypeptidase B digestion did not significantly alter the magnitude of the bronchoconstriction. Pharmacological antagonists were employed to determine if histamine, acetylcholine or products of the arachidonate metabolism were mediators of C5a-induced bronchoconstriction. The histamine H1 antagonist pyrilamine inhibited the C5a-induced bronchoconstriction, suggesting the involvement of histamine. The cholinergic receptor antagonist atropine in combination with pyrilamine caused an inhibition of the C5a-induced increase in resistance but not compliance, suggesting acetylcholine does not play a major role in C5a-induced bronchoconstriction beyond its known role in participating in histamine-induced bronchoconstriction. Involvement of arachidonate metabolites was suggested by the ability of the cyclooxygenase inhibitor, indomethacin, to prevent the C5a-induced bronchoconstriction. Because indomethacin also caused a delay in the leukotriene C4 (LTC4)-induced bronchoconstriction, the participation of peptidoleukotrienes in the C5a-induced bronchoconstriction could not be ruled out. The leukotriene antagonists FPL 55712 and L-649,923 were evaluated for their specificity in inhibiting LTC4-induced bronchoconstriction. FPL 55712 was nonselective since it inhibited prostaglandin D2 and histamine-induced bronchoconstriction as well as LTC4-induced bronchoconstriction. L-649,923 inhibited only the LTC4-induced bronchoconstriction and was without effect on the C5a-induced bronchoconstriction, suggesting that peptidoleukotrienes are not important mediators of C5a-induced bronchoconstriction. Using radioimmunoassay, the change in peptidoleukotriene levels detected in plasma during C5a-induced bronchoconstriction was not significantly different from 0. Thus, these studies have quantitated the C5a-induced decrease in dynamic lung compliance and increase in pulmonary resistance and suggest that histamine and cyclooxygenase products, but not peptidoleukotrienes, play a major role in C5a-induced bronchoconstriction.

Acetylcholine↗
PubMed1986

Contribution of macrophages to immediate hypersensitivity reaction.

The interaction of mast cells with other leukocytes during immediate hypersensitivity reactions was tested by in vivo and in vitro experiments. Intraperitoneal challenge of passively sensitized rats with antigen caused the production of peptidoleukotrienes, leukotriene (LT)B4, thromboxane (TX)B2, and 6-keto-prostaglandin (PG) F1 alpha in the peritoneal cavity. Pretreatment of the rats with thioglycollate i.p. markedly changed the amount of eicosanoids formed. When polymorphonuclear leukocytes were the predominant cell type in the peritoneal exudate, both LTC4 and 6-keto-PGF1 alpha were decreased by 75% each and TXB2 by 50%. When elicited macrophages were predominant, there was an additional reduction in LTC4 by 68% as compared with 18 hr after thioglycollate treatment, but no additional change in the other arachidonic acid metabolites. In vitro antigen challenge of passively sensitized mouse bone marrow-derived mast cells caused the release of LTC4, LTB4, 6-trans-LTB4, 5-hydroxyeicosatetraenoic (5-HETE), and TXB2. Exposure to antigen of these mast cells in the presence of resident peritoneal macrophages markedly altered eicosanoid formation. Early in the time course (2 to 15 min), macrophages markedly enhanced all 5-lipoxygenase products. However, later in the time course (30 to 120 min), these products were decreased. This decrease was reversed by catalase and superoxide dismutase, which suggests the involvement of oxygen radicals. These active oxygen species also seemed to be generated by mast cells, because these enzymes caused an increase in 5-lipoxygenase products when mast cells were challenged alone. RIA of cyclooxygenase products showed that mast cells released only TXB2 when stimulated with antigen. When they were stimulated in the presence of macrophages, TXB2 and also PGE2 and 6-keto-PGF1 alpha were synthesized. Therefore, macrophages probably contribute the PGE2 and 6-keto-PGF1 alpha. Because the same amount of TXB2 was generated whether macrophages were present or not, the mast cells seem to be the major source of this compound. These data indicate that macrophages and possibly polymorphonuclear leukocytes participate in immediate hypersensitivity reactions.

Animals↗
PubMed1985

Enhancement of visit adherence in the national beta-blocker heart attack trial.

Efforts were made in the Beta Blocker Heart Trial (BHAT), a double-blind study of 3837 post-MI patients, to enhance visit adherence, a measure of compliance that is not subjective and can be easily monitored. Of the required visits, 93.9% were completed in the window, 3.9% of the patients were classified as dropouts and 12 persons were lost to follow-up. Methods used to enhance compliance varied with circumstances but included appointment reminders, assistance with transportation, minimal waiting times, newsletters, continuity of care, involvement of family members, and close contact with private physicians. Comparisons of the BHAT visit adherence rates to those from other clinical trials are difficult to make because there are few reports in the literature regarding follow-up in large multicenter clinical trials. However, data obtained through personal communications, as well as published reports, indicate that adherence in primary prevention trials was generally less than that of secondary prevention trials. Adherence rates in the BHAT tended to be slightly higher than those of comparable trials.

Adult↗
PubMed1985

Termination of clinical trials: the beta-blocker heart attack trial and the hypertension detection and follow-up program experience.

The close-out of clinical trials that end ahead of schedule often involves problems that differ from those of trials that end as planned. The Beta-Blocker Heart Attack Trial (BHAT), a double-blind study of 3837 post-myocardial infarction patients, was a multicenter clinical trial that ended early because therapeutic benefit had been demonstrated. The Hypertension Detection and Follow-up Program (HDFP), a randomized unblinded study of 10,940 hypertensive individuals, was a multicenter trial that ended as planned. Using these trials as illustrations, the issues arising in multicenter trials that end ahead of schedule are contrasted to those that arise in trials that end as scheduled. Close-out activities that are discussed include documentation of close-out procedures, release of trial information, preparation of trial participants and staff, ascertaining vital status, continuing patient care, data collection and coding, and publication of trial results. Because of the possibility a study might end early, advance planning for close-out is essential.

Adult↗