Increased bronchial responsiveness has been reported at various time points following allergen challenge (AC), and may be related to the magnitude of the late response (LAR). We have studied 20 mild asthmatics, who were known to develop a late asthmatic response to inhalation of house dust mite extract (fall of > 15% from post-diluent baseline FEV1 from 2 to 7h after AC). The provocation concentration of methacholine causing a 20% fall in FEV1 (PC20 FEV1) was measured before and 24 h after challenge with house dust mite extract (HDM). The mean (SEM) change in log(PC20) was 0.08 (0.09) mg ml-1, and was not significant (P = 0.38; paired t-test). The change in PC20 for each subject was not significantly correlated with the size of LAR (r = -0.33; P > 0.05), but was significantly correlated with the absolute change from baseline FEV1 at 24 h (r = 0.67; P < 0.01). Our subjects had a high baseline responsiveness, when compared with previous studies. We suggest they may have been approaching a maximally responsive state prior to study, and allergen challenge may have had little effect in further increasing responsiveness. Exposure to allergen in late responders is not necessarily followed by an increase in non-specific bronchial responsiveness.

A modified formulation of inhaled salbutamol and a new inhaler device were studied in a group of 11 moderate-to-severe asthmatic patients. Changes in airway calibre (FEV1, Vmax30) were measured before and after inhalation of the new formulation, and compared with changes following inhalation of conventional salbutamol. A standard Rotahaler was used as a reference for the new inhaler. The study was conducted as a two-part randomized, double-blind cross-over trial. We found a significantly greater bronchodilatation of the larger airways using the modified drug in the Rotahaler. The new inhaler did not show any superiority over the Rotahaler, contrary to expectations from in vitro work. A slightly shorter model may better reflect the in vitro results. The study has implications for inhalation therapy in general.

Annals of the New York Academy of SciencesVolume 629, Issue 1 p. 430-431 The Effects of a 5-Lipoxygenase Inhibitor, BW A4C, on the Acute Response to Inhaled PAF in Man D. A. SPENCER, Corresponding Author D. A. SPENCER Department of Thoracic Medicine King's College Hospital London SE5, EnglandDepartment of Paediatrics, Birmingham Children's Hospital, Ladywood Middleway, Birmingham, England, B16 8ET.Search for more papers by this authorA. P. SAMPSON, A. P. SAMPSON Department of Pharmacology Royal College of Surgeons London WC2, EnglandSearch for more papers by this authorJ. M. EVANS, J. M. EVANS Department of Thoracic Medicine King's College Hospital London SE5, EnglandSearch for more papers by this authorL. G. GARLAND, L. G. GARLAND Wellcome Research Laboratories Beckenham, Kent, EnglandSearch for more papers by this authorP. J. PIPER, P. J. PIPER Department of Pharmacology Royal College of Surgeons London WC2, EnglandSearch for more papers by this authorJ. F. COSTELLO, J. F. COSTELLO Department of Thoracic Medicine King's College Hospital London SE5, EnglandSearch for more papers by this author D. A. SPENCER, Corresponding Author D. A. SPENCER Department of Thoracic Medicine King's College Hospital London SE5, EnglandDepartment of Paediatrics, Birmingham Children's Hospital, Ladywood Middleway, Birmingham, England, B16 8ET.Search for more papers by this authorA. P. SAMPSON, A. P. SAMPSON Department of Pharmacology Royal College of Surgeons London WC2, EnglandSearch for more papers by this authorJ. M. EVANS, J. M. EVANS Department of Thoracic Medicine King's College Hospital London SE5, EnglandSearch for more papers by this authorL. G. GARLAND, L. G. GARLAND Wellcome Research Laboratories Beckenham, Kent, EnglandSearch for more papers by this authorP. J. PIPER, P. J. PIPER Department of Pharmacology Royal College of Surgeons London WC2, EnglandSearch for more papers by this authorJ. F. COSTELLO, J. F. COSTELLO Department of Thoracic Medicine King's College Hospital London SE5, EnglandSearch for more papers by this author First published: July 1991 https://doi.org/10.1111/j.1749-6632.1991.tb38007.xCitations: 5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume629, Issue1Advances in the Understanding andTreatment of AsthmaJuly 1991Pages 430-431 RelatedInformation

Summary The reproducibility of acute effects of inhaled PAF on airway calibre, circulating neutrophil count and any subsequent increase in bronchial responsiveness has been studied in six normal subjects and compared to the effects of inhaled lyso‐PAF, the inactive precursor and metabolite of PAF. PAF caused acute bronchoconstriction and a transient fall in neutrophil count on two separate occasions in five out of six subjects (minimum percentage of baseline values (mean): first PAF challenge; sGaw 69%, V̇max 30 72%; neutrophil count 70%; second PAF challenge; sGaw 61 %, V̇max 30 74%, neutrophil count 63%). In one subject inhaled PAF caused bronchoconstriction and a transient fall in neutrophil count once, but a second challenge resulted in no detectable changes. There was no significant increase in bronchiai responsiveness to methacholine in any subject studied on five occasions over a 2‐week period following each PAF challenge. Challenge with lyso‐PAF did not cause acute effects or any subsequent changes in bronchial responsiveness. These findings demonstrate that any effects of inhaled PAF on bronchial responsiveness in normal man are small and probably not of clinical significance. It would also be inappropriate to use this human model to study the mechanisms of bronchial hyperresponsiveness or for the preliminary assessment of potential new anti‐asthma drugs.

The generation and metabolism of leukotrienes (LTs) B4, C4, D4, and E4 were studied in vitro in the A23187-stimulated whole blood of normal (N) and atopic asthmatic (AA) human subjects. Using a combination of reversed-phase high performance liquid chromatography and radioimmunoassay, we have demonstrated that the blood cells of atopic asthmatic patients have an enhanced ability to release LTB4 and LTC4 when compared to those of normal subjects. The release of LTB4 and LTC4 in response to ionophore is dose- and time-dependent. Half-maximal doses of ionophore caused the generation of high, sustained levels of LTB4, which are significantly higher in the AA blood than in N blood. Incubations of 3H-LTB4 in ionophore-stimulated N and AA blood revealed a slow metabolism to 20-OH-LTB4 and 20-COOH-LTB4. LTC4 is generated in smaller amounts than LTB4, with an early peak after 10 min which is significantly higher (p less than 0.01) in the AA blood compared to the N blood. Subsequent metabolism of LTC4 elicits significantly greater amounts of LTD4, and consistently higher levels of LTE4, in the AA blood. Parallel incubations of 3H-LTC4 in ionophore-stimulated N and AA blood demonstrated rapid metabolism of LTC4 by the glutathione detoxification pathway. The elevated production of LTB4 and LTC4 in AA blood was not accounted for by differences in leukocyte sub-type counts in the two groups, nor by differences in their rates of catabolism. The novel, selective 5-lipoxygenase inhibitor BW A4C [N-(3-phenoxycinnamyl) acetohydroxamic acid] caused dose-dependent inhibition of LTB4 and LTC4 generation and was equipotent in N and AA blood.

The metabolism of exogenous leukotriene C4 (LTC4), LTD4 and LTE4 (10−8M) was studied in vitro in blood of normal and asthmatic subjects for up to 2 hr by reverse-phase high performance liquid chromatography.

The formation of leukotrienes (LTs) from arachidonic acid derived from phospholipids of the cell membrane is initially catalysed by 5-lipoxygenasel. Metabolism of the unstable epoxide LTA4 leads to the formation of LTB4 and the cysteinyl-containing LTs C4, D4 and E4. All these LTs have potent, although different, biological activities. LTB4 is a powerful chemotactic agent for leukocytes whereas LTs C4, D4 and E4 have potent smooth muscle stimulating actions and account for the biological activity of the allergic mediator previously known as slow-reacting substance of anaphylaxis (SRS-A)2. Leukotriene B4 has pro-inflammatory actions but little smooth muscle stimulating activity of its own whereas cysteinyl-containing LTs have potent actions in the cardiovascular system and in the airways in vitro and in vivo (see3,4).

1. We have studied some of the pharmacological properties of inhaled L-648,051 which has been shown to be a selective cysteinyl-leukotriene (LT) antagonist in vitro and in vivo in various animal models. 2. The effects of three different doses (1.6, 6.0 and 12.0 mg) on the bronchoconstriction induced by inhaled LTD4 have been investigated in normal male subjects in a series of double-blind, placebo controlled studies. Furthermore, the specificity of the drug has been investigated by challenging subjects with histamine after pre-inhalation of 12.0 mg L-648,051. 3. At all doses L-648,051 partially blocked the bronchoconstriction induced by LTD4 inhalation in a dose related manner. At a dose of 12.0 mg, L-648,051 decreased the maximum fall in specific airways conductance (sGaw) (placebo, 49% vs L-648,051, 21%, P less than 0.01) and shortened the time to recovery from LTD4-induced bronchoconstriction (placebo, 41 min vs L-648,051, 19 min, P less than 0.01). 4. There was no evidence of partial agonist activity, and no effect on histamine-induced bronchospasm. Inhaled L-648,051 at all doses was well tolerated. 5. We conclude that LT antagonism is possible by the inhaled route in man. Inhaled L-648,051 is an active and selective LT-antagonist in man which is well tolerated and may prove to be a useful drug for assessing the role of leukotrienes in asthma and other lung diseases.

The metabolism of exogenous leukotriene B4 (LTB4) was investigated in venous blood obtained from normal and asthmatic subjects. Using specific radioimmunoassay (RIA) and reverse-phase high performance liquid chromatography (RP-HPLC) techniques we have demonstrated that LTB4 is relatively stable during a 2 hr incubation period at 37 degrees C in our system in vitro. Nevertheless, chromatographic analysis revealed the presence of two products which had retention times identical to 20-hydroxy LTB4 (20-0H LTB4) and 20-carboxy LTB4 (20-C00H LTB4) in which the dicarboxylic derivative was the main metabolite present after 15 min incubation. The amount of LTB4 and its w-oxidation products observed after a 2 hr incubation period was 73% and 24% respectively. There was no basal release of LTB4 from blood. The appearance of these oxidative products was totally suppressed at 4 degrees C and with incubations performed with either venous plasma or Hartmann's control. No significant difference was observed in substrate metabolism between normal and asthmatic subjects. Our results demonstrate that LTB4 is slowly degraded in human whole blood through a cellular dependent process of w-oxidation which may be an important pathway for regulating the availability of this potent biologically active substance.