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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.

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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.

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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.

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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)

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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.

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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.

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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.

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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.

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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.

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The inhalation of adenosine is known to cause bronchoconstriction in asthmatic patients. A thorough study of the possible role of this purine nucleoside in the pathogenesis of asthma has been hampered by the lack of a suitable animal model. We have studied the bronchial effects of adenosine in an in vivo rat model. The intravenous injection of 0.1 to 10 micromoles/kg body weight of adenosine causes in BDE-rats an increase in lung resistance and decrease in dynamic compliance. Study of the potency of various adenosine analogs suggests that the bronchial adenosine receptor belongs to the A2-type. The bronchoconstriction caused by adenosine is inhibited by atropine, methysergide, sodium cromoglycate, nedocromil sodium, and ketotifen. Xanthines in doses of 5 and 15 mg/kg body weight have no significant effect on the adenosine-induced bronchoconstriction. These results suggest that adenosine causes bronchoconstriction by stimulating postsynaptic vagal nerve endings and mast cells.

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The changes in arterial blood gas, pulmonary function tests, leukocyte counts and complement activation were evaluated during first use and subsequent reuse of cuprophan dialyzers. The dialysate buffer was bicarbonate. Reuse of cuprophan dialyzers significantly attenuated the fall in leukocyte counts and the rise in C3a des Arg seen during first use dialysis. First use dialysis also caused a drop in arterial paO2 from 93.0 +/- 12.4 mm Hg to a nadir of 82.8 +/- 12.6 mm Hg at 60 minutes (P less than 0.01). PaO2 levels did not change when reused dialyzers were employed (93.7 +/- 12.2 before dialysis and 96.4 +/- 15.2 mm Hg at 60 minutes, P greater than 0.05). Intradialytic paO2 curves obtained during first use and reuse were significantly different by variance analysis (P less than 0.001). There was also a significant decline in lung diffusion capacity (DLCO, from 30.70 +/- 8.89 to 23.77 +/- 7.76 ml/min X mm Hg, P less than 0.01) and transfer factor (KCO, from 6.07 +/- 1.97 to 5.65 +/- 2.13 ml/min X mm Hg, P less than 0.01), during first use at one hour after initiation of dialysis. This decrease was entirely prevented during reuse, (P less than 0.001 vs. first use by variance analysis). Percentual changes in leukocyte counts and C3a des Arg concentration on one hand, and in paO2, DLCO and KCO on the other were significantly correlated to each other. Other factors with a possible influence on intradialytic pulmonary function such as ultrafiltration volume, dialysate buffer composition, evolution of intradialytic blood pH and cardiac output, were all identical under both experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

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