The effect of inhaled salmeterol on methacholine responsiveness in subjects with asthma up to 12 hours.

The duration of the protective effect of 50 and 100 micrograms of inhaled salmeterol against methacholine-induced bronchoconstriction was compared with that of 200 micrograms of inhaled salbutamol in 12 patients with asthma with a baseline FEV1 of at least 70% and a provocative concentration of inhaled methacholine causing a 20% fall in FEV1 (PC20) greater than or equal to 8 mg/ml. The study was placebo controlled, double blind, randomized, and crossover. The bronchodilating effect was no longer significant 4 hours after inhalation of salbutamol, whereas the effect was still present 12 hours after administration of 50 and 100 micrograms of salmeterol. All active treatments caused PC20 to increase at 1 hour (p less than 0.05). PC20 (milligrams per milliliter) thus reached 3.7 +/- 0.8 after placebo, 13.8 +/- 3.0 after 50 micrograms of salmeterol, 23.2 +/- 4.7 after 100 micrograms of salmeterol, and 13.9 +/- 3.4 after 200 micrograms of salbutamol. The protective effect of 200 micrograms of salbutamol was no longer significant at 4 hours, whereas both doses of salmeterol protected against methacholine challenge up to 12 hours after inhalation (p less than 0.01). An increased incidence of tremor (2/12) and palpitations (2/12) was recorded after inhalation of 100 micrograms of salmeterol. We conclude that inhalation of 50 or 100 micrograms of salmeterol causes a long-lasting bronchodilatation and protects against methacholine-induced bronchoconstriction for at least 12 hours.

Changes in lymphocyte subpopulations in patients treated with cefodizime for acute lower respiratory tract infections.

The influence of cefodizime (CDZ) on CD4 and CD8 lymphocytes was investigated in patients with lower respiratory tract infection and underlying respiratory diseases. Ten men and one woman were treated with CDZ 1 g i.m. b.i.d. for ten days. The infecting organisms were Haemophilus influenzae (5), Streptococcus pneumoniae (2) and Escherichia coli (1). No adverse events were reported. Nine patients were clinically cured; two required further antibiotic therapy. Leucocyte counts decreased significantly during treatment. Lymphocyte counts and CD4 cells both increased significantly in absolute and relative numbers, while there was a much smaller increase in CD8 cells. This resulted in a significant increase in the CD4/CD8 ratio. These effects of CDZ might be of benefit for immunocompromised patients with bacterial infections.

Thymoma: a clinicopathological comparative study of 25 cases.

We reviewed 25 patients with thymoma for clinical symptoms at presentation, X-ray findings and outcome. The tumours of all patients were classified using 3 different pathologic classification systems and each system was evaluated for its predictive power with respect to survival. The recent classification system by Müller-Hermelink allowed to distinguish thymomas with associated systemic syndromes from those without. However, no good prediction with respect to outcome could be made by any of the 3 systems.

MK-571, a potent antagonist of leukotriene D4-induced bronchoconstriction in the human.

MK-571 is a novel leukotriene D4/E4 (LTD4/E4) receptor antagonist. The ability of MK-571 to inhibit LTD4-induced bronchoconstriction was examined both in six healthy volunteers and in six asthmatic subjects in a double-blind, placebo-controlled, randomized crossover study design. LTD4 challenges were performed during a constant infusion with placebo or the active compound. The provocative concentration of LTD4 causing a 35% decrease in SGaw (PC35 SGaw) was 4.8 +/- 0.6 x 10(-5) M (mean +/- SEM) in healthy volunteers and 1.8 +/- 0.7 x 10(-6) M in asthmatic subjects during placebo treatment. Intravenous MK-571 (1,500, 86, or 28 mg) inhibited the LTD4-induced bronchoconstriction completely in healthy volunteers, up to an inhaled concentration of 10(-4) M LTD4. In asthmatic subjects, 28 mg MK-571 caused a significant, at least 44-fold, rightward shift of the dose-response curve to LTD4, whereas 277 mg shifted the dose-response curve at least 84-fold to the right. MK-571 is therefore a potent antagonist of LTD4-induced bronchoconstriction in both normal volunteers and asthmatic patients. MK-571 also caused a small but significant increase in baseline airway caliber in asthmatic patients, suggesting the presence of LTD4 in asthmatic airways and thus providing further support to a role for sulfidopeptide leukotrienes in the pathogenesis of asthma.

Fibrotic stage of allergic bronchopulmonary candidiasis.

Since its first description in 1952, ABPA has been recognized with increasing frequency. More recently fungi other than Aspergillus fumigatus, in particular Candida albicans, have been implicated in a similar disease process. The following case report illustrates the possibility of finding a fibrotic stage 5 ABPM caused by C albicans.

Adamantinoma of the tibia with pulmonary metastases and hypercalcemia.

Adamantinomas of long bones are rare primary malignant bone tumors. A case of a woman who died of pulmonary metastases of an adamantinoma of the tibia is presented. A unique feature of this case is the association with hypercalcemia. The association of hypercalcemia, hypophosphatemia, decreased parathyroid hormone levels and increased urinary cAMP excretion suggests a humorally mediated hypercalcemia. Histologic and ultrastructural analysis of the pulmonary metastases demonstrated that the tumor was composed of a heterogeneous cell population with mesenchymal and epithelial differentiation.

The effect of aerosolized SK&F 104353-Z2 on the bronchoconstrictor effect of leukotriene D4 in asthmatics.

Leukotriene D4 (LTD4) is a potent bronchoconstrictor and vasoactive mediator that has been implicated in the pathogenesis of bronchial asthma. We have studied the effect of SK&F 104353-Z2, a specific LTD4 antagonist, on LTD4-induced bronchoconstriction in asthmatics. A total of 12 mild asthmatics (mean baseline FEV1 +/- SEM: 85.9% +/- 2.6) received on 2 separate days, double-blind and cross-over, 800 micrograms SK&F 104353-Z2 or placebo via aerosol. After 30 min, doubling concentrations of LTD4 (0.078 to 20.1 microM in the first 4 patients and up 80.4 microM in the other patients) were inhaled with intervals of 30 min. Specific airways conductance (sGaw) and forced expiratory volume in 1 s (FEV1) were measured. On the placebo-day LTD4 inhalation caused a concentration dependent bronchoconstriction. The effect of SK&F 104353-Z2 on baseline sGaw and FEV1 could be evaluated in 10 patients. After inhalation of SK&F 104353-Z2 a small, but significant increase, in sGaw (0.107 +/- 0.013 to 0.132 +/- 0.011 cm H2O-1s-1) and FEV1 (3.39 +/- 0.23 to 3.56 +/- 0.25 liter) was observed. The effect of SK&F 104353-Z2 on the dose-response curve for LTD4 was evaluated in the six patients who inhaled concentrations of LTD4 up to 80 microM. On the active treatment day, the dose-response curve for LTD4 was significantly shifted to the right.(ABSTRACT TRUNCATED AT 250 WORDS)

The penetration of aminoglycosides into the alveolar lining fluid of rats. The effect of airway inflammation.

The concentration-time profile of gentamicin and tobramycin in the alveolar lining fluid (ALF) of rats was determined after intravenous bolus injection using bronchoalveolar lavage (BAL). BAL can be used for evaluating the penetration of both aminoglycosides into the ALF if highly sensitive detection methods are used, and an endogenous marker (urea) can be applied to avoid the unpredictable dilutional effect of the lavage procedure. The concentration of gentamicin and tobramycin in ALF reached a peak after 5 and 10 min, respectively, and remained high when plasma concentrations were declining, suggesting an accumulation reservoir in the lung acini. The ratio of the AUC of the concentration-time profile in ALF and plasma was 0.67 and 0.45 for gentamicin and tobramycin, respectively. The penetration of both aminoglycosides into the ALF was significantly higher after induction of airway inflammation by inhalation of endotoxin. The ratio of the AUC in ALF and plasma in the endotoxin-exposed animals was 0.76 and 0.55 for gentamicin and tobramycin, respectively. The ratio of the AUC of the concentration-time profile of gentamicin in ALF to that of tobramycin was 1.27 without inflammation and 1.44 after endotoxin exposure. Thus, both with and without inflammation, gentamicin penetrates better into the ALF than does tobramycin.

Pharmacokinetics of antibiotics in the lungs.

This paper reviews current knowledge on the relationship between local penetration or antibiotics and therapeutic efficacy in pulmonary and bronchial infections. The antimicrobial drug concentration at the site of infection is supposedly determinative for the efficacy of the antibiotic treatment but the number of studies in respiratory infections supporting this hypothesis is limited. The mechanisms responsible for the pulmonary deposition or orally or systemically administered antibiotics include passive diffusion, active transport, bulk flow and permeation. The penetration of antimicrobial drugs into the respiratory tract is influenced by both host-related factors, such as inflammation or mechanical injury, and drug-related factors, such as molecular weight. In addition, local bio-inactivation can occur. The final bioactive antibiotic concentration at the site of the respiratory infection is, therefore, the result or a very complex dynamic process. Different sampling and measuring methods have been used for the assessment of antibiotic concentrations at the site of respiratory infections. Concentrations in sputum, bronchial secretions and biopsy specimens have been correlated with serum concentrations and clinical outcome. Bronchoalveolar lavage could be a promising technique for evaluating antibiotic drug concentrations in alveolar lining fluid. For many antibiotics, data concerning penetration and pharmacokinetic behaviour in the respiratory tract are lacking.

Penetration of ampicillin and sulbactam in the lower airways during respiratory infections.

We studied the penetration of ampicillin-sulbactam in the alveolar lining fluid (ALF) of eight patients after intravenous administration of 2,000 mg of ampicillin and 1,000 mg of sulbactam three times daily over 30 min. Bronchoalveolar lavage was performed on day 3, 30 min after the end of the morning drug administration. The mean penetration ratios (i.e., the ratios of the concentrations in ALF versus those in serum) were 53% (standard error, 12%) and 61% (standard error 31%) for ampicillin and sulbactam, respectively. The concentration ratio of ampicillin versus sulbactam in serum was not significantly different from that in ALF. From a pharmacokinetic point of view, ampicillin-sulbactam is a good choice for treatment of infectious exacerbation of chronic obstructive pulmonary disease and community-acquired bacterial pneumonia, since the concentrations of both drugs in ALF exceed the MICs for the respiratory pathogens responsible.

The effect of endotoxin inhalation on airway responsiveness and cellular influx in rats.

Studies in humans suggests that airway inflammation may modulate nonspecific airway responsiveness. We studied in a rat model the effect of the inhalation of endotoxin on the cellular composition of the bronchoalveolar lavage (BAL) fluid and airway responsiveness. The exposure to an aerosol of endotoxin caused a rapid influx of neutrophils in the airways. The neutrophils persisted up to 24 h after exposure. Elastase activity in lavage fluid became detectable 30 min after the endotoxin exposure and peaked 9 h later. The exposure to the endotoxin aerosol was followed 1 to 2 h later by a significant increase in the airway responsiveness to 5-hydroxytryptamine (5HT). However, the increase in responsiveness disappeared, and 9 to 12 h following the end of the exposure a significant decrease in airway 5HT responsiveness was observed at the moment that more than 80% of the cells contained in the BAL fluid were neutrophils. The effect of endotoxin on airway responsiveness and inflammation was dose dependent. We also compared in three different inbred rat strains the effect of endotoxin inhalation. The aerosol exposure induced in all three strains a comparable neutrophil influx in the airways, but only two of the three strains became hyperresponsive to 5HT. We conclude that the inhalation of endotoxin causes a neutrophilic airway inflammation in rats. The relationship between this airway inflammation and airway responsiveness is dependent on the time following the exposure and the animal strain used.

Scintigraphic, spirometric, and roentgenologic effects of radiotherapy on normal lung tissue. Short-term observations in 14 consecutive patients with breast cancer.

The effects of radiotherapy on lung function, ventilation/perfusion scans, and chest radiography were studied prospectively in 15 patients who underwent either modified radical mastectomy or tumorectomy, followed by radiotherapy for breast cancer. In all patients, pulmonary function studies, chest x-ray films, and lung scintigraphic studies were performed prior to and at the end of radiotherapy as well as three months later. No consistent or significant alteration in either parameter was detected. No patient developed clinical symptoms suggestive of radiation-induced lung changes, although in one of them, major radiologic features were found that were consistent with radiation pneumonitis; those changes disappeared completely in the course of the subsequent months. It is concluded that the tangential beam technique for postoperative irradiation as used in these patients is largely safe as regards pulmonary function, perfusion, and ventilation.

Synergistic mechanisms in the adenosine- and neuropeptide-induced bronchoconstriction.

Neuropeptides and purines are possible neurotransmitters of the nonadrenergic noncholinergic nervous system of the airways. We investigated possible synergistic mechanisms between these two bronchoconstricting agents in a rat model. We observed that both adenosine and tachykinins enhance histamine release in the airways and that adenosine and neurokinin A act synergistically both on airway narrowing and histamine release.

The effect of nedocromil sodium on the bronchoconstrictor effect of neurokinin A in subjects with asthma.

We have previously demonstrated that the neuropeptide, neurokinin A (NKA) (substance K), causes bronchoconstriction in subjects with asthma. In a double-blind, crossover study we investigated the effect of nedocromil sodium on NKA-induced bronchoconstriction in subjects with asthma. Twelve patients with mild asthma (mean FEV1 percent predicted +/- SE, 87.3 +/- 3.4) inhaled on 2 separate days either nedocromil sodium, 4 mg, or placebo, as two puffs from a metered-dose aerosol, 30 minutes before challenge with NKA. NKA was inhaled at three concentrations (10(-7), 3.10(-7), and 10(-6) mol/ml). The specific airway conductance (SGaw) and FEV1 were measured before and 5 and 15 minutes after each concentration step. On the placebo-treatment day, NKA caused a concentration-dependent decrease in SGaw and FEV1 (mean log for the provocative concentration of NKA causing a 35% fall in SGaw [10(-7) mol/ml], 0.49; mean log for the provocative concentration of NKA causing a 15% fall in SGaw [10(-7) mol/ml], 0.90). The inhalation of 4 mg of nedocromil sodium reduced the decrease in both SGaw and FEV1. The maximal percentage decrease in SGaw on the nedocromil sodium-treatment day was 27 +/- 5.2 (versus placebo, 53.3 +/- 5.4; p less than 0.05), and the maximal percentage decrease in FEV1 was 5.5 +/- 1.4 (versus placebo, 12.4 +/- 2.3; p less than 0.05). The dose-response curves for NKA after nedocromil sodium treatment were significantly shifted to the right compared to the curve after placebo-treatment. We conclude that nedocromil sodium protects against NKA-induced bronchoconstriction in subjects with asthma.

Interactions between neurotransmitters and inflammatory cells in the airways.

Neuropeptides and purines are possible autonomic neurotransmitters. Both tachykinins (neurokinin A, substance P) and adenosine cause acute airway narrowing by synergistic activation of airway mast cells and postganglionic vagal nerve endings.

Effect of nedocromil sodium on the bronchoconstrictor effect of neurokinin A in asthmatics.

In a double-blind, crossover study we have investigated the effect of nedocromil sodium on neurokinin A (NKA)-induced bronchoconstriction in asthmatics. 12 patients with mild asthma inhaled either nedocromil sodium 4mg or placebo, on 2 separate days, as 2 puffs from a metered-dose aerosol 30 minutes before challenge with NKA. On the placebo treatment day, NKA produced a concentration-dependent decrease in basal specific airway conductance (sGaw) and forced expiratory volume in 1 second (FEV1). The inhalation of nedocromil sodium 4mg inhibited the decrease in both sGaw and FEV1. The maximal percentage decrease in sGaw on the nedocromil sodium day was 27.0 +/- 5.2 (vs placebo, 53.3 +/- 5.4; p less than 0.05) and the maximal percentage decrease in FEV1 5.5 +/- 1.4 (vs placebo, 12.4 +/- 2.3; p less than 0.05). We conclude that nedocromil sodium protects against NKA-induced bronchoconstriction in asthmatics.

Effect of nedocromil sodium on bronchoconstriction induced by adenosine and tachykinins.

Purines and neuropeptides may act as neurotransmitters of the local axon reflex in the airways. Nedocromil sodium has been shown to inhibit adenosine- and neurokinin A-induced bronchoconstriction both in the rat and in man. In this study we used the rat model for further investigation of the mechanism of action of nedocromil sodium in the adenosine- and neurokinin A-challenge. The animals were challenged intravenously, and immediately after maximal bronchoconstriction a bronchoalveolar lavage was performed and histamine was assayed in the supernatant of the lavage fluid. Nedocromil sodium significantly inhibited the adenosine- and the neurokinin A-induced increase in histamine concentration in the lavage fluid. Nedocromil sodium had no influence on the airway responsiveness to serotonin or carbachol. We therefore concluded that the inhibitory effect of nedocromil sodium on adenosine- and neurokinin A-induced bronchoconstriction can be explained by its activity on airway mast cells.

The mechanism of tachykinin-induced bronchoconstriction in the rat.

The mammalian tachykinins substance P (SP) and neurokinin A (NKA) are known to be present in sensory airway nerves of animals and humans. We studied the effect of mammalian and nonmammalian tachykinins on the conducting airways of anesthetized, mechanically ventilated Fisher 344 rats. Dose-dependent increases in lung resistance and decreases in dynamic compliance occurred after the intravenous administration of eledoisin (E), kassinin (K), NKA, and SP. E, K, and NKA were more potent bronchoconstrictors than was SP. Neurokinin B (NKB) caused a similar decrease in dynamic compliance, but had no effect on lung resistance. This order of potency suggests a predominance of NK-2 receptors in the rat airways. Both atropine and the 5-hydroxytryptamine antagonist methysergide largely reduced the bronchoconstriction induced by E and SP. Vagotomy did not change this reaction, whereas pretreatment with the ganglion blocker hexamethonium slightly enhanced the bronchoconstrictor action of E and SP. Sodium cromoglycate and nedocromil sodium, 2 drugs that can inhibit mediator release from inflammatory cells, significantly reduced the bronchoconstrictor action of NKA. Ketotifen, an antihistamine with mast-cell-stabilizing properties, significantly reduced the bronchoconstriction induced by E, whereas the H1-receptor antagonist clemastine had no effect. We conclude that tachykinins cause bronchoconstriction in rats largely by an indirect mechanism, involving both acetylcholine and 5-hydroxytryptamine. We suggest that tachykinins cause bronchoconstriction by stimulation of postganglionic vagal nerve endings and mast cells.