Difference in bronchoprotective effects of bronchodilators on postallergic propranolol-induced bronchoconstriction.

Administration of propranolol provokes bronchoconstriction only in asthmatic patients. It is unknown whether bronchodilator therapy can prevent the propranolol-induced bronchoconstriction (PIB). We previously reported an animal model of PIB in which bronchoconstriction is caused by propranolol when inhaled 20 minutes after an antigen provocation in passively sensitized guinea pigs. Our goal was to evaluate the bronchoprotective effects of bronchodilators on the PIB in our animal model. Propranolol was inhaled 20 minutes after an antigen challenge in passively sensitized, anesthetized, and artificially ventilated guinea pigs. Atropine (5 mg/kg) and equipotent doses of salbutamol (0.6 microgram/kg) and aminophylline (25 mg/kg), which were determined by the dose-response curves for inhibition of histamine-induced bronchoconstriction, were intravenously administered 5 minutes before the propranolol inhalation. Treatment of the animals with 25 mg/kg of aminophylline, but not with 0.6 microgram/kg of salbutamol or 5 mg/kg of atropine, significantly prevented the PIB. These results show that our animal model is an experimental model of PIB which is resistant to beta 2-agonists or anticholinergics and suggest that aminophylline may be useful to prevent and treat PIB resistant to beta 2-agonists.

Role of leukotrienes in post-allergic propranolol-induced bronchoconstriction in guinea-pigs.

BACKGROUND: Administration of propranolol can provoke bronchoconstriction only in asthmatic patients. Recently we developed an animal model for propranolol-induced bronchoconstriction (PIB). Our working hypothesis is that such bronchoconstriction may result from the inflammatory mediators released by an allergic reaction. OBJECTIVES: Our goal in this study was to determine which products of arachidonate 5-lipoxygenase pathway are involved in the PIB. METHODS: Propranolol at a concentration of 10 mg/mL was inhaled 20 min after antigen challenge in passively sensitized, anaesthetized and artificially ventilated guinea-pigs. Two different sulfidopeptide leukotriene (s-LT) antagonists, ICI198 615 in the doses of 0.03 and 0.3 mg/kg and vehicle and KCA757 in the doses of 1 and 5 mg/kg and vehicle, and a LTB4 antagonist ONO4057 in the doses of 1 and 10 mg/kg and vehicle were injected intravenously 15 min after antigen challenge. Effects of an anticholinergic agent atropine sulphate (5mg/kg) and an alpha-adrenergic blocker phentolamine (0.3 and 3 mg/kg) were examined in the same way. RESULTS: Bronchoconstriction occurred when 10 mg/mL of propranolol was inhaled 20 min after antigen challenge. Both ICI198 615 and KCA757 administered intravenously 15 min after antigen challenge reduced the PIB in a dose-dependent manner while ONO4057 did not alter the PIB. Atropine or phentolamine did not change the PIB. CONCLUSIONS: These results suggest that mediator mechanism, but not cholinergic or alpha-adrenergic nerve, is important in the PIB which developed after the allergic bronchoconstriction in our guinea-pig model and that s-LTs but not LTB4 have an important role in the pathophysiology of the PIB.

Effect of beclomethasone dipropionate inhalation on eosinophilic bronchitis in patients with silicosis.

The efficacy of beclomethasone dipropionate (CAS 5534-09-8, BDP, beclomethasone) inhalation therapy over the course of 12 months were evaluated in 42 patients with established chronic silicosis. Their pulmonary functions were monitored every 3 months and volume of sputum production was established daily. Subjects were divided randomly into two groups; 21 patients (BDP group) were treated with BDP (400 micrograms/day) by way of a metered-dose inhaler, while the 21 controls did not receive the BDP inhalation therapy. Although FVC (forced vital capacity), FEV1 (forced expiratory volume in 1 s), MMEF (maximal mean expiratory flow) and arterial blood oxygen tension did not improve significantly, sputum production significantly decreased in the BDP group. The patients who responded most dramatically to the treatment presented with sputum eosinophilia and elevated serum IgE levels prior to therapy. Pulmonary tuberculosis or exacerbation of chronic airway infection was not observed in any of the patients. These results suggest that corticosteroid inhalation therapy is helpful in the management of chronic silicosis, especially in patients with sputum eosinophilia. Positive atopic factors may be related to the pathogenesis of eosinophilic bronchitis, a complication of chronic silicosis.

Effect of a 5-lipoxygenase inhibitor, AL-3264, on propranolol-induced bronchoconstriction in guinea-pigs.

The administration of propranolol can provoke bronchoconstriction in asthmatic patients. We hypothesized that such bronchoconstriction may result from the inflammatory mediators released by an allergic reaction. We investigated the effect of AL-3264, a 5-lipoxygenase inhibitor, on propranolol-induced bronchoconstriction (PIB) after antigen inhalation in passively sensitized and artificially ventilated guinea-pigs. Our goal was to determine whether products of arachidonate 5-lipoxygenase are involved in such PIB. Bronchoconstriction occurred when 10 mg/ml of propranolol was inhaled 20 min after antigen challenge. Pretreatment with AL-3264 given in intravenous doses of 0.01 and 0.1 mg/kg 15 min after the antigen challenge significantly reduced PIB in a dose-dependent manner. Pretreatment with 0.1 mg/kg of AL-3264 10 min before antigen challenge significantly inhibited both the immediate allergic bronchoconstriction and PIB, although the effect was minimal. Results suggest that arachidonate 5-lipoxygenase products (such as leukotriene B4, C4, D4 or E4) are involved in the pathophysiology of PIB but their contribution may be small. Further studies using selective antagonists for each of these leukotrienes are needed to clarify their role.

[A case of miliary tuberculosis with high-grade fever that remitted without antituberculosis therapy].

A 23-year-old man was admitted with a persistent high-grade fever of 20 days duration. Chest roentgenogram showed diffuse miliary shadows in both lung fields, highly suggestive of miliary tuberculosis. Sputum, gastric juice, and bronchoalveolar lavage fluid did not, however, reveal acid-fast bacilli on smears. A bone marrow aspirate and a transbronchial lung biopsy were also negative for caseating granulomas and tubercule bacilli. After admission, the high-grade fever remitted in several days without continuous antibiotic, antituberculosis or antipyretic therapy. Levels of inflammatory markers (CRP, ESR, alpha 2-globulin dropped simultaneously. Despite the atypical clinical course, miliary tuberculosis was suspected. We therefore carried out an open lung biopsy. The presence of caseating granulomas and acid-fast bacilli confirmed the diagnosis of miliary tuberculosis. The remission of miliary tuberculosis without treatment is very rare and the details of this case are presented herein with a discussion of the pertinent literature.

Effects of aerosol administration of a thromboxane receptor antagonist (S-1452) on experimental asthma in guinea pigs.

The importance of thromboxane A2 (TXA2), one of the arachidonate metabolites, in the pathogenesis of bronchial asthma has been emphasized recently. Because aerosolized administration of antiasthmatic drugs is effective and safe, this study examined the effect of aerosolized TXA2 receptor antagonist (S-1452) on allergic bronchoconstriction in passively sensitized and mechanically ventilated guinea pigs. Under the cover of antihistamine, antigen-induced bronchoconstriction was markedly inhibited by pretreatment with aerosolized S-1452 inhalation in a dose-dependent manner. Although aerosolized S-1452 itself provoked weak bronchoconstriction for its partial agonist effect, bronchial responsiveness to inhaled histamine did not change 10 min after S-1452 inhalation. These results indicate that aerosolized S-1452 may be useful in treating bronchial asthma.

Involvement of thromboxane A2 in propranolol-induced bronchoconstriction after allergic bronchoconstriction in guinea pigs.

Although it is well recognized that beta-blockers can induce bronchoconstriction only in patients with asthma, mechanisms of the bronchoconstriction are not well known. We hypothesize that bronchoconstriction induced by beta-blockers may result from inflammatory mediators released by allergic reactions. In this study, we developed a guinea pig model for propranolol-induced bronchoconstriction (PIB) after antigen inhalation and investigated the effect of specific thromboxane (TXA2) receptor antagonists, S-1452 and ONO NT-126, on PIB in passively sensitized and artificially ventilated guinea pigs to determine whether TXA2 is involved in PIB. Propranolol caused bronchoconstriction with 10 mg/ml of propranolol was inhaled 20 min after antigen challenge. On the other hand, propranolol did not produce bronchoconstriction after antigen provocation in nonsensitized guinea pigs or after saline provocation in sensitized animals. Pretreatment of the animals with S-1452 in doses of 0.01 and 0.1 mg/kg and ONO NT-126 in doses of 1.0 and 10 micrograms/kg injected intravenously 15 min after antigen challenge as well as before antigen challenge reduced PIB in a dose-dependent manner. Bronchoconstriction caused by methacholine did not induce PIB. These results suggest that TXA2 has an important role in the pathophysiology of the PIB that develops after the allergic bronchoconstriction.

Prothrombin fragment F1 + 2 and thrombin-antithrombin III complex are useful markers of the hypercoagulable state in atrial fibrillation.

It is well known that atrial fibrillation (AF) is one of the most important diseases that predispose patients to thrombosis. We have attempted to identify patients with AF in the hypercoagulable state by measuring molecular markers such as thrombin-antithrombin III complex (TAT) and prothrombin fragment 1 + 2 (PTF) and determining the effect of antithrombotic therapy on these markers; 83 patients with AF were studied. Increased levels of plasma TAT and PTF were more frequently observed in patients with AF and associated mitral stenosis than in patients with AF alone. In cases of AF without mitral stenosis, plasma levels of TAT and PTF were significantly lower in those patients receiving antithrombotic agents (aspirin or warfarin) than in those receiving no antithrombotic agents. Furthermore, plasma levels of PTF were significantly lower in patients given warfarin than in those receiving aspirin. These results suggest that (1) patients with AF and mitral stenosis who are not given warfarin are in an extremely hypercoagulable state and (2) some patients with AF without mitral stenosis who are not given antithrombotic agents are also moderately hypercoagulable. In vivo activation of blood coagulation was more effectively controlled in patients receiving warfarin than in those taking aspirin.

Interaction of thromboxane A2 and leukotrienes in guinea pig airways in vivo.

Effects of a thromboxane A2 receptor antagonist (S-1452) on bronchoconstriction induced by inhaled leukotriene C4 and a leukotriene receptor antagonist (AS-35) on bronchoconstriction caused by inhalation of a thromboxane A2 mimetic (STA2) were studied in anesthetized, artificially ventilated guinea pigs in order to examine the interaction of thromboxane A2 and leukotrienes in airways. 0.01-1.0 mu g/ml of leukotriene C4 and 0.1-1.0 mu g/ml of STA 2 inhaled from ultrasonic nebulizer developed for small animals caused dose-dependent increase of pressure at the airway opening (Pao) which is considered to be an index representing bronchial response. Pretreatment of the animals with inhaled S-1452 (0.01, 0.033 mg/ml) significantly reduced the airway responses produced by 0.01,0.033,0.1,0.33 and 1.0 mu g/ml of leukotriene C4 in a dose dependent manner. While pretreatment with inhaled AS-35 (1mg) did not affect the STA2 dose-response curve. These findings suggest that leukotriene C4 activates thromboxane A2 generation while thromboxane A2 does not influence 5-lipoxygenase pathway in the airways.