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Biomedical subjects

A N Payne

Publications and source records attributed to A N Payne.

At least 19 recordsLinked to original sources
PubMed1999

A comparison of the inhibitory effects of budesonide, beclomethasone dipropionate, dexamethasone, hydrocortisone and tixocortol pivalate on cytokine release from leukocytes recovered from human bronchoalveolar lavage.

OBJECTIVE: The potency of budesonide, beclomethasone dipropionate (BDP), dexamethasone, hydrocortisone and tixocortol pivalate as inhibitors of interleukin-5 (IL-5) and interferon-gamma (IFNgamma) release from human bronchoalveolar lavage cells in vitro were compared. METHODS: BAL leukocytes were obtained from patients undergoing bronchoscopy for diagnostic purposes. BAL leukocytes were activated with PHA (10 microg/ml) and PMA (10 ng/ml) and cultured for 48 h in the presence or absence of glucocorticoids. Culture supernatants were assayed for cytokines by ELISA. RESULTS: Budesonide (10(-9) to 10(-7) M) and BDP (10(-8) to 10(-6) M) were the most potent glucocorticoids tested. Dexamethasone (10(-7) to 10(-5) M) was less potent, and the maximum inhibitory effect of dexamethasone was less than that produced by than budesonide or BDP. Tixocortol pivalate (10(-6) to 3 x 10(-5) M) caused a concentration-related inhibition of IL-5 release but only the highest concentration tested inhibited the release of IFNgamma. Hydrocortisone (10(-4) M) inhibited IL-5 and IFNgamma release. CONCLUSION: We conclude that, unlike the other glucocorticoids tested, tixocortol pivalate appeared to be a selective inhibitor of IL-5 release. Possible mechanisms for this selectivity are discussed.

Anti-Inflammatory Agents↗
PubMed1996

Differential inhibition by selective phosphodiesterase inhibitors of antigen, LTC4 and histamine-induced contraction of guinea-pig isolated trachea.

Antigen (ovalbumin)-induced contraction of guinea-pig isolated trachea, which largely resulted from the endogenous release of peptidoleukotrienes, was strongly inhibited by the non-selective phosphodiesterase (PDE) inhibitor theophylline and, more potently, by the selective PDE type IV inhibitors rolipram and Ro 20-1724. It was also strongly inhibited by the PDE type V inhibitor zaprinast, but much less so by the PDE type III inhibitor siguazodan and milrinone. Similar results were obtained in trachea minus epithelium. In contrast to their effects vs. allergic airway smooth muscle contraction, both milrinone and siguazodan potently relaxed leukotriene C4 (LTC4)-induced contraction in isolated trachea from non-sensitized animals. In this assay, rolipram, Ro 20-1724 and zaprinast were less active compared to their effects vs. ovalbumin-induced contraction, whereas theophylline had equivalent potency in the two tests. The relative potencies of rolipram and siguazodan in relaxation of trachea were similar when added prior to or after either LTC4 or histamine. These results suggest that the higher potency of selective PDE type IV & V inhibitors compared with PDE type III inhibitors vs. ovalbumin-induced contraction is due to their greater inhibition of anaphylactic mediator release. The converse is true if we consider their bronchodilator actions, although the superior efficacy of selective PDE type III inhibitors over PDE type IV inhibitors may vary in sensitized vs. non-sensitized animals. The present results are in agreement with a previous study showing that low concentrations of a beta 2-agonist increased the relaxant effect of selective PDE type IV inhibitors in guinea-pig trachea. The present data indicate that prophylactic use of selective PDE type IV inhibitors combined with therapeutic use of low dose inhaled beta-agonist might represent an alternative to the use of antiallergic or steroid therapy in asthma.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1996

Salbutamol potentiates the relaxant effects of selective phosphodiesterase inhibitors on guinea pig isolated trachea.

The ability of low concentrations of salbutamol to potentiate the relaxant effects of the phosphodiesterase (PDE) inhibitors, rolipram, Ro 20-1724 (PDE type IV inhibitor), siguazodan and milrinone (PDE type III inhibitor) was studied on guinea pig isolated trachea. These PDE inhibitors were strong relaxants of guinea pig trachealis under basal tone, but had only a weak activity on tissues precontracted with histamine (10(-5) M). In both cases, PDE type IV inhibitors showed a relaxant effect composed of two phases. The first phase represented 20 and 40% and the second, 90 and 140%, respectively, of relaxation of basal tone and histamine-induced tone. A second characteristic of PDE type IV inhibitors was the very fast and partially reversible relaxation observed at concentrations greater than 3 x 10(-8) M (for histamine-induced tone) at the first addition of inhibitor, followed by a residual relaxant activity. The latter relaxant effect was stable at concentrations of 3 x 10(-8)-10(-5) M and was equivalent to a 20% relaxation (for histamine-induced tone). In the presence of low concentrations (10(-9) and 10(-8) M) of salbutamol, there was a significant concentration-dependent potentiation of the effects of PDE inhibitors on trachea precontracted with histamine. Salbutamol, at a concentration of 10(-9) M, potentiated the effects of PDE inhibitors between 1.4- and 3.6-fold. In the presence of salbutamol 10(-8) M, the potentiation was more marked for siguazodan (37.9-fold), milrinone (11.0-fold) and Ro 20-1724 (14.5-fold) than for rolipram (4.3-fold). These results suggest that low concentrations of salbutamol can potentiate the relaxant effects of both PDE type III and PDE type IV inhibitors. Thus, PDE type IV inhibitors, which have antiinflammatory properties, could also provide adequate bronchodilation when used in combination with lower than usual doses of beta 2-agonists.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1995

The modulation of IL-6 and TNF-alpha release by nitric oxide following stimulation of J774 cells with LPS and IFN-gamma.

Lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) induced nitric oxide synthase (NOS) activity, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and prostaglandin (PG)E2 release in J774 cells, a murine macrophage cell line. The role of endogenous NO in modulating TNF-alpha and IL-6 release was investigated using N-iminoethyl-L-ornithine (L-NIO), a specific inhibitor of NOS. L-NIO (10-1000 microM) produced a concentration-dependent potentiation of LPS and IFN-gamma induced IL-6 release. Time-course studies demonstrated a significant potentiation of IL-6 release at 12 h with a maximum effect at 48 h. By contrast to its effects on IL-6, L-NIO significantly attenuated TNF-alpha release, and at 48 h reduced PGE2 release. The NO-donor S-nitroso-N-acetyl-penicillamine (SNAP,300 microM), significantly inhibited LPS and IFN-gamma induced IL-6 release, but potentiated TNF-alpha release. In addition, SNAP prevented the potentiation of IL-6 and the inhibition of TNF-alpha release by L-NIO. Stimulation of J774 cells with a combination of LPS and IFN-gamma for 24 h or 48 h reduced cell viability which was prevented by L-NIO. Furthermore, SNAP also reduced cell viability determined after 24 h incubation. These results indicate that NO can differentially modulate LPS and IFN-gamma-induced cytokine release from J774 cells, up-regulating TNF-alpha but down-regulating IL-6, and that NO is cytotoxic to these cells.

Analysis of Variance↗
PubMed1995

Allergen-induced glycoconjugate secretion in guinea-pig trachea in vivo: modulation by indomethacin, BW B70C and ZD-2138.

A method has been established for measurement of tracheal secretions in anaesthetized, ventilated guinea-pigs. The upper trachea was cannulated and perfused with saline. The perfusate was analysed for protein using the Lowry assay and for glycoconjugates ('mucus') by a procedure generating a fluorophore from fucose moieties in the sample. Intravenously infused acetylcholine (ACh) stimulated an increase in glycoconjugate secretion which was maximal after 75 min of ACh administration. Total protein concentration was not increased. Intravenously infused 15-HETE produced a similar increase in glycoconjugate secretion also without increasing protein concentration, but the time of maximal effect was earlier (30 min) than with ACh. Intravenous infusion of allergen (ovalbumin) in antihistamine pretreated, sensitized animals induced a dose-related glycoconjugate secretion which was maximal at 30 min after challenge. Indomethacin potentiated allergen-induced glycoconjugate secretion. The reportedly specific inhibitor of 5-lipoxygenase, ZD-2138, substantially inhibited allergen-induced pulmonary bronchoconstriction but did not influence glycoconjugate secretion. In contrast, the selective 5-, 15-lipoxygenase inhibitor BW B70C significantly attenuated both allergic airway closure and glycoconjugate secretion. These studies demonstrate the practicability of measuring glycoconjugate secretion in guinea-pig trachea in vivo, and that ACh and 15-HETE are potent secretagogues in this species. Further, they suggest that allergic glycoconjugate secretion is mediated, at least in part, via the release of lipid mediators from pathways other than via 5-lipoxygenase.

Acetylcholine↗
PubMed1993

Effect of BW B70C, a novel inhibitor of arachidonic acid 5-lipoxygenase, on allergen-induced bronchoconstriction and late-phase lung eosinophil accumulation in sensitised guinea-pigs.

The actions of BW B70C, an orally available, biologically persistent and selective inhibitor of arachidonic acid 5-lipoxygenase, have been examined in two systems of anaphylaxis in actively sensitised guinea-pigs in vivo. In anaesthetised, artificially ventilated animals pretreated with mepyramine and indomethacin to leave only the "peptidoleukotriene-dependent" component (leukotrienes C4, D4 and E4) of the anaphylactic response, direct inhalation of nebulised allergen resulted in a slowly developing bronchoconstriction which was prevented in a dose-dependent manner by BW B70C (2-50 mg/kg p.o.) administered 1 or 6 h before challenge. In conscious animals fasted overnight and then pretreated with mepyramine to prevent death due to acute bronchial anaphylaxis, exposure to nebulised allergen produced slight respiratory symptoms. When blood and lung samples were analysed 4-48 h after allergen provocation a sustained leukocytosis and pulmonary eosinophil accumulation were observed. In contrast, in food-replete conscious animals, the early respiratory symptoms were still observed upon allergen inhalation, but no significant blood leukocytosis or accumulation of eosinophils in the lungs occurred subsequently. The eosinophil influx induced by allergen in fasted animals was assessed both by histological examination and determination of tissue peroxidase content, two measures which demonstrated reasonable agreement. Administration of a single dose of BW B70C (10 mg/kg p.o.) 1 h prior to allergen challenge did not affect the subsequent eosinophil infiltration 24 h later, but 20 mg/kg given in divided doses (-1 and +12 h) produced 67% inhibition of cell accumulation. A single dose of 50 mg/kg (-1 h) had a similar effect (78% inhibition). The potent glucocorticosteroid betamethasone was used as a reference compound, and 4 mg/kg given as a divided dose (-1 and +7) fully inhibited lung inflammation assessed 24 h after provocation with allergen. BW B70C inhibited both acute and allergic bronchoconstriction and late-phase eosinophil accumulation subsequent to allergen inhalation in guinea-pigs. In view of the apparent requirement for sustained plasma levels of BW B70C in order to prevent late-phase eosinophil recruitment to the lung after a single challenge with allergen, it is unclear whether inhibition of 5-lipoxygenase underlies the observed anti-eosinophil accumulation effects of the compound, but the anti-bronchoconstrictor effects are consistent with the known inhibitory activity of BW B70C against 5-lipoxygenase.

Administration, Oral↗
PubMed1992

Mechanisms contributing to ozone-induced bronchial hyperreactivity in guinea-pigs.

The effect of ozone (3 ppm, 15-120 min) on bronchial reactivity in the guinea-pig was studied. Ozone induced marked (6-250-fold) bronchial hyperreactivity (BHR) to a range of inhaled, but not intravenous bronchoconstrictors. The degree of BHR was related to the duration of prior ozone exposure. The glutathione redox status was shifted to a more oxidized state in lung after 120 min ozone treatment, although no changes were found in the energy status of lung tissue, as judged by the concentrations of adenosine phosphates. Ascorbic acid pretreatment prevented BHR induced by 30 min ozone exposure. Neutral endopeptidase inhibitors elicited BHR to both substance P and histamine, but did not further enhance bronchoconstriction to substance P after ozone exposure for 120 min. Neither mepyramine, fentanyl, indomethacin nor a 5-lipoxygenase inhibitor (BW B70C), given prior to ozone exposure prevented the induction of BHR to histamine. Atropine or bilateral vagotomy reduced BHR after a 120-min, but not 30-min exposure to ozone. We conclude that in the guinea-pig, ozone induces non-specific, route-dependent BHR by oxidative injury, reducing airway NEP activity and enhancing the cholinergic and peptidergic component to bronchoconstriction. Neither cyclooxygenase nor 5-lipoxygenase products appear to play a role in ozone-induced BHR in this animal model.

Adenine Nucleotides↗
PubMed1991

Hydroxamic acids and hydroxyureas as novel, selective 5-lipoxygenase inhibitors for possible use in asthma.

Inhibition of 5-lipoxygenase (5-LO) is a potential target for therapeutic intervention in asthma. Acetohydroxamic acids such as BW A4C are potent and selective 5-LO inhibitors in vitro and also inhibit 5-LO activity in vivo following oral administration. In man, BW A4C is metabolised relatively rapidly (t1/2 = approx. 2h) but nevertheless inhibits 5-LO with reasonable persistence. Chemical modification of BW A4C has resulted in compounds, including the alpha-methyl analogues BW B218C and BW A360C and the hydroxyurea BW B70C, that retain high in vitro potency as selective 5-LO inhibitors and, compared to BW A4C, have a higher potency and longer duration of action in vivo. Members of both the hydroxamic acid and hydroxyurea series of 5-LO inhibitors are presently being considered as potential anti-asthma drugs.

Anaphylaxis↗
PubMed1990

The role of prostanoid TP- and DP-receptors in the bronchoconstrictor effect of inhaled PGD2 in anaesthetized guinea-pigs: effect of the DP-antagonist BW A868C.

1. In anaesthetized, pump-ventilated guinea-pigs, bolus intravenous injection of prostaglandin D2 (PGD2 5-160 micrograms kg-1) caused a dose-dependent rise in both heart rate and systemic mean arterial blood pressure with only a small monophasic rise in pulmonary inflation pressure (PIP). 2. In contrast, inhaled PGD2 (0.1-1 mg ml-1, 30s) provoked a substantial concentration-dependent biphasic rise in PIP. The bronchoconstrictor action of inhaled PGD2 was accompanied by minimal cardiovascular effects. 3. The 3-benzyl substituted hydantoin BW A868C (0.1-1 mg kg-1 i.v.) a novel prostanoid DP-receptor antagonist, had no significant effect on the cardiovascular or bronchoconstrictor effects of intravenously administered or inhaled PGD2. 4. However, BW A868C (0.1-1 mg kg-1 i.v.) did inhibit the hypotensive actions of the DP-receptor agonist, BW 245C (1-3 micrograms kg-1 i.v.). 5. The prostanoid TP-receptor antagonist BM 13.177 (2.5 mg kg-1 i.v.) strongly inhibited the bronchoconstrictor effect of inhaled PGD2, abolishing the first phase of this response and reducing the peak increase in PIP provoked by PGD2 (0.1 or 1 mg ml-1 for 30 s), by 67 +/- 16% and 44 +/- 5% respectively. 6. A combination of BW A868C (0.1 or 1 mg kg-1 i.v.) with BM 13.177 (2.5 mg kg-1 i.v.) produced no greater inhibition of the bronchoconstrictor effect of inhaled PGD2 than that seen with BM 13.177 (2.5 mg kg-1 i.v.) alone. 7. Neither bilateral vagotomy, nor selective inhibition of arachidonate cyclo-oxygenase with indomethacin or 5-lipoxygenase with the novel acetohydroxamic acid BW A4C, significantly reduced the bronchoconstrictor effect of inhaled PGD2. 8. These findings indicate that the bronchoconstrictor effect of inhaled PGD2 in guinea-pigs in vivo is mediated primarily through direct TP-receptor activation and not through actions on DP-receptors.

Administration, Inhalation↗
PubMed1989

Airway hyperreactivity follows anaphylactic microshock in anaesthetized guinea-pigs.

Actively sensitized guinea-pigs were challenged with a dose of ovalbumin aerosol (300 micrograms ml-1, 5 s) that caused submaximal bronchoconstriction (anaphylactic microshock). Airway reactivity to i.v. 5-hydroxytryptamine (5-HT), i.v. acetylcholine (ACh) and aerosolised 5-HT was assessed subsequently. In addition, histological studies were carried out to investigate possible pulmonary recruitment of inflammatory cells following anaphylactic microshock. Following antigen challenge, there was a significant (P less than 0.05) increase in airway reactivity. This phenomenon was temporally separated (60-120 min) from the initial anaphylactic bronchoconstriction, but occurred in the absence of detectable lung pathology other than minor epithelial necrosis. Whilst histamine aerosol (100 micrograms ml-1, 5 s) did not induce airway hyperreactivity, pretreatment with the histamine H1 receptor antagonist mepyramine (2 mg kg-1 i.v.) prevented that occurring following antigen challenge. These observations suggest that in the pathogenesis of airway hyperreactivity, mediator release from resident leukocytes is initially more important than pulmonary infiltration of circulating cells. Depletion of a putative epithelium-derived relaxant factor may also play a contributory role. The anaphylactic release of histamine may modulate the release of secondary mediators of airway hyperreactivity.

Acetylcholine↗
PubMed1989

Cardiopulmonary and gastric ulcerogenic actions of endothelin-1 in the guinea pig and rat.

The cardiovascular and bronchoconstrictor actions of endothelin-1 (ET-1) in the anesthetized guinea pig and the cardiovascular effects and gastric ulcerogenic actions in the anesthetized rat were investigated. In the guinea pig, ET-1 (0.05-1 nmol/kg i.v.) induced a dose-related increase in pulmonary inflation pressure, which was substantially inhibited by pretreatment with indomethacin and the thromboxane receptor antagonist BM 13.177. The concurrent vasopressor effects of ET-1 were attenuated but not abolished by these agents. In the rat, ET-1 (0.1-0.4 nmol/kg i.v.) induced a biphasic effect on arterial blood pressure (BP), with a transient fall being followed by a rise, which was unaffected by indomethacin pretreatment, whereas i.v. infusion of ET-1 induced only an increase in BP. Local intra-arterial infusion of ET-1 (0.04-0.1 nmol/kg/min) induced extensive macroscopically determined gastric mucosal damage in the rat, confirmed histologically. Thus, the pharmacological profile of ET-1 encompasses bronchoconstriction, vasopressor and vasodepressor actions, as well as potent gastric ulcerogenic properties.

Animals↗