Pulmonary pharmacology最新文献

{"title":"Effects of Endothelin Receptor Selective Antagonists, BQ-123 and BQ-788, on IRL 1620 and Endothelin-1 Responses of Airway and Vascular Preparations from Rats","authors":"S.R. O'Donnell,&nbsp;C.S. Kay","doi":"10.1006/pulp.1995.1002","DOIUrl":"10.1006/pulp.1995.1002","url":null,"abstract":"<div><p>Summary: IRL 1620 (Suc-[Glu⁹, Ala^11,15]ET-1(8-21), a selective ET_B receptor agonist) contracted rat trachea and bronchus. The maximum response to IRL 1620 was less than that to endothelin-1 (ET-1) and, compared with ET-1 responses, IRL 1620 responses reached equilibrium more quickly. IRL 1620 responses were antagonized by the selective ET_B antagonist, BQ-788 (3 μM), but not by the selective ET_A antagonist, BQ-123 (3 μM). ET-1 concentration-response curves were shifted only in the presence of both BQ-123 and BQ-788 (3 μM). In the presence of BQ-123, the time course of ET-1 responses changed from being slow and sustained (ET_A, see below) to being more like that to IRL 1620 (ET_B). IRL 1620 did not contract pulmonary artery preparations from rats but ET-1 produced slow and sustained contractile responses which were antagonized by BQ-123 but not by BQ-788. Thus, ET-1 contracts rat pulmonary artery and aorta predominantly via ET_A receptors (responses blocked by BQ-123) and functional ET_B receptors are unlikely to be present (no responses to IRL 1620). In contrast, ET-1 contracts rat trachea and bronchus via ET_A and ET_B receptors (tissues contracted to IRL 1620, ET-1 responses were blocked by a combination of BQ-123 and BQ-788 and ET-1 responses resembled ET_B in character when ET_A receptors were blocked).</p></div>","PeriodicalId":74618,"journal":{"name":"Pulmonary pharmacology","volume":"8 1","pages":"Pages 11-19"},"PeriodicalIF":0.0,"publicationDate":"1995-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/pulp.1995.1002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19516963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allergen-induced Glycoconjugate Secretion in Guinea-pig Trachea in vivo: Modulation by Indomethacin, BW B70C and ZD-2138","authors":"M. Yeadon,&nbsp;R.C. Price,&nbsp;Adrian N. Payne","doi":"10.1006/pulp.1995.1008","DOIUrl":"10.1006/pulp.1995.1008","url":null,"abstract":"<div><p>Summary: 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.</p></div>","PeriodicalId":74618,"journal":{"name":"Pulmonary pharmacology","volume":"8 1","pages":"Pages 53-63"},"PeriodicalIF":0.0,"publicationDate":"1995-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/pulp.1995.1008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19516861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Angiotensin Converting Enzyme Inhibition on Airway Conductance during Hypocapnic Hyperventilation in Normal Subjects","authors":"J.P. Jamison,&nbsp;P.J. Glover","doi":"10.1006/pulp.1995.1007","DOIUrl":"10.1006/pulp.1995.1007","url":null,"abstract":"<div><p>Summary: In nine normal subjects, specific airway conductance was measured by whole body plethysmography before and immediately after hypocapnic hyperventilation. This procedure, forced expiratory manoeuvres and arterial blood pressure measurements were carried out before and 4 h after placebo and the angiotensin converting enzyme inhibitor, enalapril, in a double-blind, randomized study design.</p><p>Bronchoconstriction to hypocapnic hyperventilation was shown by a reduction in specific airway conductance on all occasions (<em>P</em>&lt;0.001).</p><p>A reduction in mean blood pressure was obtained after enalapril compared to placebo (<em>P</em>&lt;0.05).</p><p>No significant change attributable to enalapril was observed in any lung function measurement either at rest or immediately after hypocapnic hyperventilation, despite an expected enhancement of endogenous angiotensin converting enzyme activity by alkalosis.</p><p>Inhibition of angiotensin converting enzyme revealed no effect of the endogenous activity of this enzyme on airway calibre either at rest or during the bronchoconstrictor response to hypocapnic hyperventilation.</p></div>","PeriodicalId":74618,"journal":{"name":"Pulmonary pharmacology","volume":"8 1","pages":"Pages 49-51"},"PeriodicalIF":0.0,"publicationDate":"1995-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/pulp.1995.1007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19516860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effect of Selective Phosphodiesterase Inhibitors in Comparison with other Anti-asthma Drugs on Allergen-induced Eosinophilia in Guinea-pig Airways","authors":"K.H. Banner,&nbsp;F. Marchini,&nbsp;A. Buschi,&nbsp;E. Moriggi,&nbsp;C. Semeraro,&nbsp;C.P. Page","doi":"10.1006/pulp.1995.1005","DOIUrl":"10.1006/pulp.1995.1005","url":null,"abstract":"<div><p>Summary: The effects of isoenzyme selective phosphodiesterase (PDE) inhibitors and other anti-asthma drugs on antigen-induced eosinophil recruitment and activation in guinea-pig airways was studied. Guinea-pigs were sensitized and subsequently challenged with aerosolized ovalbumin (OVA). Bronchoalveolar lavage (BAL) was performed 24 h later. A significant increase in eosinophils and eosinophil peroxidase (EPO) was detected in BAL fluid and BAL fluid supernatant respectively from OVA immunized guinea-pigs compared with sham treated animals.</p><p>Guinea-pigs were treated for 7 days prior to antigen challenge with either the following drugs or the appropriate vehicle (i.p.). The selective β₂ agonist, salbutamol (0.3 mg/kg), the PDE III inhibitor, milrinone (15 mg/kg) and the non-selective PDE inhibitor, trequinsin (1 mg/kg) had no effect on eosinophil number or EPO levels. The PDE IV inhibitor, rolipram (15 mg/kg), the mixed type III/IV PDE inhibitor, benzafentrine (15 mg/kg) and the nonselective PDE inhibitor, aminophylline (31.5 mg/kg) had no effect on eosinophil number but reduced the amount of EPO detected. The anti-inflammatory glucocorticosteroids, beclomethasone (10 mg/kg) and betamethasone (4 mg/kg) and the type IV PDE inhibitor, RP 73401 (5 mg/kg) reduced both eosinophil numbers and EPO levels. These results suggest a role for the type IV PDE isoenzyme in the control of eosinophil recruitment and possibly activation in the airways.</p></div>","PeriodicalId":74618,"journal":{"name":"Pulmonary pharmacology","volume":"8 1","pages":"Pages 37-42"},"PeriodicalIF":0.0,"publicationDate":"1995-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/pulp.1995.1005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19516966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implications of Genetic Variability of Human β2-adrenergic Receptor Structure","authors":"S.A. Green,&nbsp;J. Turki,&nbsp;I.P. Hall,&nbsp;S.B. Liggett","doi":"10.1006/pulp.1995.1001","DOIUrl":"10.1006/pulp.1995.1001","url":null,"abstract":"","PeriodicalId":74618,"journal":{"name":"Pulmonary pharmacology","volume":"8 1","pages":"Pages 1-10"},"PeriodicalIF":0.0,"publicationDate":"1995-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/pulp.1995.1001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"19516962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pulmonary Penetration of Dirithromycin in Patients Suffering From Acute Exacerbation of Chronic Bronchitis","authors":"M. Cazzola,&nbsp;M.G. Matera,&nbsp;M.A. Tufano,&nbsp;M. Polverino,&nbsp;P. Catalanotti,&nbsp;L. Varanese,&nbsp;F. Rossi","doi":"10.1006/pulp.1994.1044","DOIUrl":"10.1006/pulp.1994.1044","url":null,"abstract":"<div><p>Summary: The aim of this study was to evaluate the concentrations of dirithromycin, a new macrolide antibiotic, in bronchial secretions (BS), bronchial mucosa (BM), epithelial lining fluid (ELF) and serum in 25 patients with acute exacerbation of chronic bronchitis after a 5-day, once-daily, dirithromycin regimen. All patients received dirithromycin, 500 mg (two 250 mg tablets) given orally once daily at 08.00 fasted, for 5 consecutive days. They were divided into five groups (n=5 in each group) according to sampling time (24, 48, 72, 96 and 120 h after the last dose). Mean serum concentrations remained low throughout the study (0.44 μg/ml at 24 h, 0.31 μg/ml at 48 h, 0.33 μg/ml at 72 h, 0.12 μg/ml at 96 h and 0.11 μg/ml at 120 h, respectively), although they were higher than the MICs for <em>Moraxella catarrhalis</em> for up to 72 h and than that for <em>Streptococcus pneumoniae</em> for up to 120 h after the last dose. By contrast, in all other samples, mean concentrations were higher than the MICs for many relevant respiratory pathogens for at least 3 days, and higher than that for <em>S. pneumonia</em> and <em>M. catarrhalis</em> for up to 120 h (mean concentrations measured 2.67, 2.15, 1.74, 0.27 and 0.17 μg/ml, respectively, in BS; 2.59, 2.59, 1.96, 0.41 and 0.27 μg/g, respectively, in BM; 2.21, 2.25, 1.57, 0.22 and 0.15 μg/ml, respectively, in ELF). These findings demonstrate that dirithromycin is concentrated in each of these potential sites of infection for up to 3 days after a 5-day course of therapy. Therefore, short-term therapy with dirithromycin may be useful for many respiratory infections.</p></div>","PeriodicalId":74618,"journal":{"name":"Pulmonary pharmacology","volume":"7 6","pages":"Pages 377-381"},"PeriodicalIF":0.0,"publicationDate":"1994-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/pulp.1994.1044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18556873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperresponsiveness of the Airways Following Exposure of Guinea-pigs to Racemic Mixtures and Distomers of β2-selective Sympathomimetics","authors":"L. Mazzoni,&nbsp;R. Naef,&nbsp;I.D. Chapman,&nbsp;J. Morley","doi":"10.1006/pulp.1994.1043","DOIUrl":"10.1006/pulp.1994.1043","url":null,"abstract":"<div><p>Summary: Allergic bronchospasm in sensitized guinea-pigs was totally suppressed by acute subcutaneous infusion of rac-salbutamol (0.69 μg/kg per min) for &lt;1 h. More prolonged infusion of rac-salbutamol induced a progressive susceptibility to inhaled antigen so that, by 48 h, animals collapsed and died following inhalation of antigen. In anaesthetized animals, acute infusion of rac-salbutamol (1.67 μg/kg per min) suppressed airway obstruction, an effect that can be attributed to β₂-adrenoceptor activation by the eutomer (R-salbutamol). Acute intravenous infusion of the distomer (S-salbutamol) (1.67 μg/kg per min) induced hyperresponsiveness to histamine without having any effect upon airway calibre. It is suggested therefore that subcutaneous infusion of rac-salbutamol initially abrogates the bronchoconstrictor response to antigen because the bronchodilator action of the eutomer predominates over hyperreactivity attributable to the distomer. Conversion from protection to susceptibility was not determined by reduced β₂-adrenoceptor activation since animals could be protected from a lethal response to antigen by inhalation of rac-isoprenaline or by subcutaneous injection of rac-salbutamol. The seeming progressive loss of efficacy of R-salbutamol may result from disproportionate accumulation of S-salbutamol if, as in man, there is stereospecific metabolism of R-salbutamol. The capacity of S-salbutamol to evoke hyperresponsiveness is shared by S-isoprenaline and S-terbutaline and, as has been shown previously for rac-isoprenaline, the capacity of S-salbutamol to elicit hyperresponsiveness was not evidenced following section of the vagus nerves. No mechanism has yet been established which might account for this property of S-salbutamol or for other S-enantiomers of sympathomimetics.</p></div>","PeriodicalId":74618,"journal":{"name":"Pulmonary pharmacology","volume":"7 6","pages":"Pages 367-376"},"PeriodicalIF":0.0,"publicationDate":"1994-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/pulp.1994.1043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18554504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Addition of a Bacterial Alginate Lyase to Purulent CF Sputum In Vitro Can Result in the Disruption of Alginate and Modification of Sputum Viscoelasticity","authors":"R.J. Mrsny,&nbsp;B.A. Lazazzera,&nbsp;A.L. Daugherty,&nbsp;N.L. Schiller,&nbsp;T.W. Patapoff","doi":"10.1006/pulp.1994.1042","DOIUrl":"10.1006/pulp.1994.1042","url":null,"abstract":"<div><p>Summary: Alginate is a large molecular weight exopolysaccharide present in the purulent airway secretions of cystic fibrosis (CF) patients. This polymer, produced by some of the opportunistic pathogens associated with the recurrent lung infections characteristic of CF, has been suggested to effect an increase in the viscoelastic properties of purulent CF airway secretions. We have investigated the use of an enzyme targeted at this exopolysaccharide, an alginate lyase obtained from a bacterial source, to disrupt its polymeric nature and effect a change in the rheological properties of CF sputum in vitro. Expectorated sputum samples obtained from hospitalized CF patients were found to contain 80-200 μg alginate per ml sputum with no measurable endogenous alginate lyase activity. Treatment with exogenous alginate lyase prepared from a mucoid strain of <em>Pseudomonas aeruginosa</em> resulted in the disruption of alginate and a decrease in sputum viscoelasticity in a small percentage of the samples tested. Similar treatment of these samples with recombinant human deoxyribonuclease I to cleave DNA present in purulent sputum and the use of alginate extracted from sputum as an alginate lyase assay substrate suggested that the inability of the exogenous alginate lyase to disrupt sputum alginate was not due to substrate inaccessibility or an unresponsive substrate. Concentrations of Ca²⁺ and Zn²⁺ in alginate lyase-resistant sputum samples, determined by metal ion analysis, were found to inhibit enzyme activity in studies using seaweed alginate as a substrate. High concentrations of Ca²⁺ and Zn²⁺ in sputum samples initially resistant to lyase activity could be reduced significantly in some samples by dialysis and these same samples acquired sensitivity to the lyase. Other sputum samples did not show reduced concentrations of Ca²⁺ and Zn²⁺ following dialysis and these samples remained lyase-insensitive. Together, these results suggest that bacterial alginate present within purulent CF sputum may be quite stable, that endogenous alginate lyase activities appear to be limited and that the in vitro addition of exogenous alginate lyase can lead to the disruption of alginate and a change in the viscoelastic properties of some purulent CF sputum samples.</p></div>","PeriodicalId":74618,"journal":{"name":"Pulmonary pharmacology","volume":"7 6","pages":"Pages 357-366"},"PeriodicalIF":0.0,"publicationDate":"1994-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/pulp.1994.1042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18554503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pinacidil-induced Relaxation in Pulmonary Arteries Isolated From Pulmonary Hypertensive and Normotensive Rats and Pre-contracted With Different Spasmogens","authors":"J.C. Wanstall,&nbsp;C.S. Kay,&nbsp;S.R. O'Donnell","doi":"10.1006/pulp.1994.1047","DOIUrl":"10.1006/pulp.1994.1047","url":null,"abstract":"<div><p>Summary: Vasorelaxant responses to the potassium channel opening drug, pinacidil, were obtained on preparations of pulmonary artery and aorta taken from rats with pulmonary hypertension (induced by chronic hypoxia or monocrotaline) and pre-contracted either submaximally with endothelin-1 (ET-1), PGF_2α, U46619 (thromboxane-mimetic) or noradrenaline (NA), or with 80 mM K⁺. In pulmonary artery, but not aorta, from pulmonary hypertensive rats the maximum relaxant response to pinacidil was increased, when compared with data in control rats, irrespective of the spasmogen used to precontract the tissues. The increase in maximum was associated with relaxation to below the tissue resting baseline and probably reflected the presence of inherent contractile tone in arteries from pulmonary hypertensive rats. In addition the potency (-log EC₅₀) of pinacidil was increased in pulmonary arteries from pulmonary hypertensive rats but this was seen only in preparations contracted with ET-1 (30-fold increase) or NA (seven-fold increase) and not in those contracted with PGF_2α, U46619 or K⁺. As a result, in ET-1-contracted preparations from pulmonary hypertensive rats pinacidil was 29-fold more potent on pulmonary artery than on aorta. To explain the increase in potency it is speculated that during the development of pulmonary hypertension the mechanism whereby ET-1 and NA contract pulmonary arteries may change from one in which Ca²⁺ influx plays only a minor role to one in which Ca²⁺ influx predominates, although no direct evidence to support this speculation has yet been obtained.</p></div>","PeriodicalId":74618,"journal":{"name":"Pulmonary pharmacology","volume":"7 6","pages":"Pages 401-408"},"PeriodicalIF":0.0,"publicationDate":"1994-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/pulp.1994.1047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18556876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Zatebradine, a Novel 'Sinus Node Inhibitor', on Pulmonary Function Compared to Placebo","authors":"F.P.V. Maesen,&nbsp;J.J. Smeets,&nbsp;J.A. van Noord,&nbsp;G. Nehmiz,&nbsp;F.D.M. Wald,&nbsp;P.J.G. Cornelissen","doi":"10.1006/pulp.1994.1041","DOIUrl":"10.1006/pulp.1994.1041","url":null,"abstract":"<div><p>Summary: Zatebradine, a member of a novel class of drugs called 'sinus node inhibitors', is a specific heart rate lowering drug suitable for the treatment of stable angina pectoris. Animal studies showed that relatively high intravenous doses of zatebradine contracted guinea-pig airways by a histamine-like mechanism. Therefore, the objective of the present study was to assess the bronchopulmonary effects in asthmatic patients who showed a moderate to severe bronchial hyperreactivity towards histamine (PC₂₀ FEV₁ ≤1 mg/ml). Moreover, it had to be established to what extent the bronchial responsiveness to inhaled salbutamol was retained and whether pulmonary effects were related to the severity of bronchial hyperreactivity. By means of a double-blind cross-over design, single oral doses of zatebradine (10 mg) or placebo were administered on two occasions with a washout phase of at least 3 days. Sixteen patients, four female and 12 male, with stable mild to moderate bronchial asthma (FEV₁ less than 80% predicted) were selected. Their mean age was 54 years and the mean FEV₁ was 1.831 (59% predicted). They showed a mean improvement in FEV₁ of 27% 15 min after inhaling 200 μg salbutamol; the mean PC₂₀ was 0.35 mg/ml. Following test drug intake, the respiratory and cardiac effects were assessed at regular time intervals up to 6 h after administration. In comparison to placebo, zatebradine induced small, but significant (<em>P</em>&lt;0.05), mean falls of 128 ml and 168 ml in FEV₁ at 3 h and 6 h after drug intake. A large inter-individual variation in response was noted. In two of the 16 patients a deterioration by more than 20% was observed 6 h after zatebradine intake: 21% and 38% below pre-dose FEV₁ (at 3 h the values were +2% and -14%, respectively). Analysis of the FVC data confirmed the FEV₁ findings. No significant differences were found between zatebradine and placebo for the pulmonary parameters PEF and <em>SG</em> AW. Compared to that on the placebo test day the salbutamol dose-response curve determined 6 h after zatebradine intake did not show a parallel shift to the right; the response to salbutamol was fully retained. No correlation was identified between PC₂₀ and the FEV₁ response observed in the individual patients. One patient reported severe visual disturbances and vomiting, which occurred rather late following zatebradine intake. On both test days no influence on blood pressure was observed, while zatebradine induced a small, but significant, decrease in heart rate at 3 h post-dosing. It is concluded that zatebradine has the potential to cause a deterioration of pulmonary function in asthmatic patients, regardless of the severity of their non-specific bronchial hyperreactivity towards histamine. However, the mean small decrease in pulmonary function as observed in the present study population did fully respond ","PeriodicalId":74618,"journal":{"name":"Pulmonary pharmacology","volume":"7 6","pages":"Pages 349-355"},"PeriodicalIF":0.0,"publicationDate":"1994-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/pulp.1994.1041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"18554502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}