The use of bronchodilators in stable chronic obstructive pulmonary disease.
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Adrenergic beta-Agonists↗
Biomedical subjects
M G Matera
Publications and source records attributed to M G Matera.
Nitric oxide regulatory role in sensitized guinea pig trachea.
Nitric oxide (NO) has been cited to play an important regulatory role in airway function. Moreover, the NO synthase expression in models of inflammation is documented. The aim of this study was to investigate, in vitro, the NO modulation of cholinergic responses in sham-sensitized and ovalbumin-sensitized guinea pig trachea by using L-arginine (L-ARG), a precursor of NO synthesis, and L-Ng-nitro-arginine-methyl-ester (L-NAME), an inhibitor of NO synthase. Our results showed that NO's ability to modulate cholinergic responses in ovalbumin-sensitized guinea pig trachea is lost. Indeed L-ARG and L-NAME modify acetylcholine sensitivity in sham-sensitized guinea pig but not in ovalbumin-sensitized guinea pig.
Acetylcholine↗
Physiological and pharmacological properties of an endogenous sodium pump inhibitor.
To investigate on Na+, K+-ATPase behavior in chronic uremia, pre and postdialysis serum from 10 chronic dialysis patients and 10 healthy subjects was pooled and subjected to reverse phase C-18 HPLC. Only one fraction, isolated from pre and postdialysis sera, eluting at 28 min (F1), was found to display significant effects on electrophysiological and transepithelial 22Na flux pattern of rabbit distal colon mucosa mounted in Ussing type chambers; indeed, serosal addition of uremic F1 to colonic mucosa resulted in a slow, but constant, decline in short-circuit current (Isc) (deltaIsc = 1.55+/-0.16 microEq h(-1) cm(-2), mean +/- S.E.M., n=12, p<0.01) and transepithelial conductance (G(T)) (from 4.50+/-0.23 to 3.71+/-0.33 mS cm(-2), p<0.01, n=12). Measurement of transepithelial 22Na fluxes in the presence of pre or postdialysis sera also showed a significant Na+ absorption rate decrease (from 1.3+/-0.22 to 0.48+/-0.30 microEq h(-1) cm(-2), mean +/- S.E.M., n=4, p<0.01), mainly due to a decrease in mucosal-to-serosal Na+ flux. By contrast, assays of peaks isolated from healthy sera did not inhibit Isc and transepithelial Na+ transport. The incubation of highly purified basolateral membranes with F1 for 1 min produced a approximately 26% inhibition of Na+, K+-ATPase. These findings are consistent with the presence of an endogenous inhibitor of sodium pump activity in uremic plasma; it is of pharmacological interest in that it may participate in the development of unpredictable responsiveness to digitalis therapy in pathophysiologic states.
Adult↗
Pulmonary concentrations of dirithromycin and erythromycin during acute exacerbation of mild chronic obstructive pulmonary disease.
We compared the concentrations of dirithromycin and erythromycin at steady state in serum and the intrapulmonary region in patients suffering from acute exacerbation of mild chronic obstructive pulmonary disease. Twenty patients received dirithromycin, 500 mg given orally once daily for five consecutive days. The other 20 patients were treated with erythromycin base, which was administered orally four times daily at a total daily dose of 1000 mg for seven days. All patients were divided into eight groups, with five subjects in each group, according to sampling times (2, 4, 8, and hrs after the last dose) and treatment. After the erythromycin treatment mean serum concentrations were higher than those of dirithromycin treatment mean serum concentrations were higher than those of dirithromycin for upto 4 hours, but they were undetectable 24 hours after the last dose. At all time periods, the concentrations of dirithromycin in bronchial secretion, bronchial mucosa and epithelial lining fluid were greater than the concentration in serum. Concentrations of erythromycin were always lower than those of dirithromycin in the explored pulmonary sites. Our data demonstrated that a five day course of 500 mg of dirithromycin once daily induced higher concentrations and longer persistence in the various potential sites of pulmonary infection than a seven day course of 250 mg of erythromycin every 6 hrs. The shorter duration of therapy and the once daily dosing with good efficacy against common respiratory pathogens would be advantageous for patients and would be likely to promote better patient compliance and acceptability.
Administration, Oral↗
Effects of hyperbaric oxygen exposure on non-adrenergic non-cholinergic responses of rat trachea.
The effects of prolonged (20 day) hyperbaric exposure (HBO) to oxygen on non adrenergic non cholinergic (NANC) contractile and relaxant responses of rat trachea were examined. The electrical field stimulation (EFS) of rat tracheal rings was performed at 30 Hz and contractile and relaxant responses were assessed in the absence or in the presence of pretreatment with L-nitro-arginine-methyl-ester (L-NAME), an inhibitor of NO synthase, and L-Arginine (L-ARG), a precursor of NO synthesis, plus L-NAME. Our data demonstrated that L-NAME significantly (p < 0.05) enhanced the contractile responses induced by EFS (controls 30.6 +/- 0.99%; L-NAME 76.07 +/- 2.00%) and statistically (p < 0.05) reduced the relaxant component of EFS (controls 31.10 +/- 0.46; L-NAME 15.00 +/- 0.12); these effects were reversed when tissues were pretreated with L-ARG plus L-NAME, suggesting that NO plays a modulatory role in cholinergic neurotransmission and participates in EFS relaxant responses. Moreover, prolonged HBO exposure (20 days) at 202.6 and 303.9 kPa did not modify the contractile or relaxant responses induced by EFS, nor modify the L-NAME or L-ARG effects on EFS responses.
Animals↗
Effects of in vitro 5-HT1 receptor activation in guinea pig trachea.
5-hydroxytryptamine (5-HT) has been reported to show some effects in respiratory tissues by activation of different subtype receptors. It has been demonstrated that 5-HT2 receptor activation causes in vivo and in vitro airways contraction and enhances effects of cholinergic nerve-mediated responses, whereas 5-HT1 receptor activation seems to be related to a relaxant effect. Moreover, in isolated guinea pig ascendens colon preparations 5-HT1 activation causes relaxation by involvement of nitric oxide (NO). The aim of this study was to investigate the effects of 5-HT1 receptor activation in guinea pig trachea as well as NO probable role in this activation. In tissues pretreated with both ketanserin (10 microM), an antagonist of 5-HT2 receptors, and ondansetron (10 microM), an antagonist of 5-HT3 receptors, 5-HT (from 10 nM to 10 mM) relaxed guinea pig trachea precontracted with acetylcholine (ACh, 100 microM). Carboxamidotryptamine (5-CT, from 10 nM to 10 mM), an agonist of 5-HT1 receptors, as well relaxed guinea pig trachea precontracted with ACh (100 microM). A pretreatment with NAN-190 (from 10 nM to 100 microM), a 5-HT1A selective antagonist, reduced the 5-HT and 5-CT relaxant effects but only at very high concentrations. Finally, a pretreatment with L-nitro-arginine-methyl-ester (L-NAME, 1 mM), an inhibitor of NO-synthase, and L-arginine (L-ARG, 1 mM), a precursor of NO synthesis, did not modify 5-HT and 5-CT responses in guinea pig trachea. In conclusion, this study suggests a 5-HT relaxant activity in guinea pig trachea via a 5-HT1 receptor activation without any NO pathway involvement. However, further investigations are needed to clarify which 5-HT1 receptor subtype is involved in 5-HT relaxant effect.
Acetylcholine↗
A combination with clinical recommended dosages of salmeterol and ipratropium is not more effective than salmeterol alone in patients with chronic obstructive pulmonary disease.
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Adrenergic beta-Agonists↗
Characterization of adenosine receptors involved in adenosine-induced bronchoconstriction in allergic rabbits.
1. Recent work has suggested that adenosine may be involved in asthma via the activation of A1 receptors. However, the role of the recently cloned A3 receptor in airways is largely unknown. In the present study, we have investigated the role of the A3 receptor in adenosine-induced bronchoconstriction in allergic rabbits. 2. Aerosol challenge of antigen (Ag) immunized rabbits with the adenosine precursor, adenosine 5'-monophosphate (AMP), resulted in a dose-dependent fall in dynamic compliance (Cdyn). The maximum fall in Cdyn in these rabbits was significantly greater than that in litter matched, sham immunized animals (P < 0.05). However, there was no significant difference in the maximum increase in airways resistance (Rt) between Ag and sham immunized rabbits (P > 0.05). 3. Aerosol challenge of Ag immunized rabbits with cyclopentyl-adenosine (CPA) (A1-receptor agonist) elicited a dose-dependent fall in Cdyn in Ag immunized rabbits and the maximum fall in Cdyn in these rabbits was significantly greater than that observed in sham immunized rabbits (P < 0.05). Similarly, CPA induced dose-dependent increases in R1 in Ag immunized rabbits whereas sham immunized rabbits failed to respond to CPA within the same dose range. The maximum increase in RL in Ag immunized rabbits was significantly greater than that of sham immunized rabbits (P < 0.05). 4. Aerosol challenge of either Ag or sham immunized rabbits with the A3 agonist aminophenylethyladenosine (APNEA) did not elicit dose-dependent changes in either RL or Cdyn. Moreover, there was no significant difference in the maximum response, measured by either parameter, between the two animal groups (P > 0.05). 5. These data provide further evidence for a role of the A1 receptor in the airways, but do not support a role for the A3 receptor in adenosine-induced bronchoconstriction in the allergic rabbit.
Adenosine↗
Functional role of nitric oxide in guinea pig tracheal epithelium.
Nitric oxide (NO) may play an important regulatory role in airway function. We have, thus, investigated in vitro whether epithelium derived NO may modulate cholinergic neurotransmission, via release of NO in guinea pig trachea, by using L-arginine (L-ARG), a precursor of NO synthesis, and L-N(G)-nitro-arginine-methyl-ester (L-NAME), an inhibitor of NO synthase. Results show that L-ARG and L-NAME modify acetylcholine sensitivity in epithelium-intact smooth muscle preparations, suggesting a probable NO synthesis by tracheal guinea pig epithelium.
Acetylcholine↗
A comparison of the bronchodilating effects of salmeterol, salbutamol and ipratropium bromide in patients with chronic obstructive pulmonary disease.
Bronchodilator efficacy of salbutamol (200 micrograms), salmeterol (50 micrograms) and ipratropium bromide (40 micrograms) aerosols has been compared in 16 patients with stable chronic obstructive pulmonary disease (COPD) using a double-blind placebo controlled cross-over design. When absolute changes in FEV1 were used as the response criterion, efficacy of the three drugs was significantly better than placebo (P < 0.05). The onset of bronchodilatation after ipratropium bromide was slower than after salbutamol, but ipratropium induced more and longer-lasting bronchodilatation than the adrenergic drug. Salmeterol was slower but its duration was longer than salbutamol. The onset of the effect of salmeterol was slower than ipratropium bromide, but salmeterol showed, on average, superior bronchodilator efficacy compared with the anticholinergic agent, sustaining bronchodilation longer than ipratropium bromide (responses to salmeterol were significantly (P < 0.05) greater than those to ipratropium bromide from 4-12 h time period, but from 15 min to 1 h time periods response to ipratropium bromide exceeded salmeterol). The mean FEV1 area under the curve was significantly (P < 0.05) larger after salmeterol when compared to ipratropium bromide and salbutamol. Moreover, the mean FEV1 area under the curve after ipratropium bromide was significantly (P < 0.05) higher than that after salbutamol. In any case, our data showed individual differences in patient response. We conclude that salmeterol compares favourably with ipratropium bromide in terms of effects on lung function at clinically recommended doses because it has a longer duration of action than ipratropium bromide. The longer dosing intervals, which may enhance compliance, encourage its administration in patients with COPD.
Administration, Inhalation↗
Role of 5-hydroxytryptamine in mediating adenosine-induced airway contraction.
We have investigated the role of 5-hydroxytryptamine (5-HT) on adenosine-induced guinea-pig trachea contraction. R-N6-phenylisopropyladenosine (R-PIA), an A1 receptor subtype agonist, induced a concentration-dependent contraction of tracheal rings. The pD2 values were 7.43 +/- 0.26. A 30-min pretreatment with 1,3-dipropyl-8-amino-4-clorophenylxantine (PACPX), a selective A1 receptor antagonist, shifted to the right the R-PIA concentration effect curves. Ketanserin (1 microM), a 5-HT2 receptor antagonist, also caused a rightward shift of the R-PIA concentration-effect curves. The changes for the pD2 values comparing the controls and the tissues incubated with ketanserin were statistically significant (P < 0.05). In the same experimental conditions, neither atropine (1 microM), nor diphenydramine (1 microM), nor indomethacin (5 microM) showed any effects. The challenge of R-PIA (1 microM) with said substances induced a release of 5-HT (4.8 +/- 0.20 fmol/ml) from guinea-pig trachea in presence or in absence of epithelium; in the same experimental conditions, this effect did not occur in the controls. Our data support the hypothesis that 5-HT plays a role in adenosine-induced airway contraction.
Analysis of Variance↗
Salmeterol and formoterol in partially reversible severe chronic obstructive pulmonary disease: a dose-response study.
When testing the response to beta 2-agonist drugs in severe chronic obstructive pulmonary disease (COPD), a dose-response assessment should be undertaken. This study compares the time course of inhaled salmeterol (25, 50 and 75 micrograms) and formoterol (12, 24 and 36 micrograms) at different doses in a group of 12 patients with partially reversible, but severe COPD (FEV1 of 12-32% of predicted values after beta 2-agonist drugs had been withheld for 24 h). All doses of salmeterol and formoterol induced a significant (P < 0.01) spirometric improvement over the 12-h monitoring period, when compared to the spirometric improvement after placebo, but while formoterol induced a dose-dependent increase of the FVC, FEV1 and FEF50, this was not the case for salmeterol. In fact, 75 micrograms salmeterol did not produce a further improvement of these parameters. Mean peak bronchodilation, expressed as the increase in FEV1 over baseline values, occurred 2 h after inhalation of the three doses of salmeterol, and 1 h after inhalation of the three doses of formoterol. A comparison of 50 micrograms salmeterol with 12 micrograms or 24 micrograms formoterol (clinically recommended doses), showed that improvement of FEV1 after salmeterol was statistically (P < 0.05) higher than that after the two doses of formoterol, although the mean peak bronchodilations were similar. This was because salmeterol has a longer duration of action than formoterol. These data demonstrate that salmeterol is equally effective as, but longer-acting than, formoterol at clinically recommended doses in patients suffering from COPD, with severe airway obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Agonists↗
Effects of serotonin on airways: recent developments.
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Allergy and Immunology↗
Effects of RO 5-4864 and PK 11195 on guinea pig trachea.
Previous reports have suggested a role played by peripheral benzodiazepine receptors (PBZ) in the regulation of calcium. The aid of this investigation was to evaluate the effects of Ro 5-4864 (PBZ agonist) and PK11195 (PBZ antagonist) in guinea pig trachea and their possible role in the regulation of calcium. Ro 5-4864 and PK 11195 showed spasmolytic effects on the contraction curve induced by acetylcholine. Moreover, Ro 5-4864, PK 11195 and diltiazem (a Ca2+ -antagonistic drug) shifted to the right the contraction curves induced by acetylcholine, potassium chloride (KCl), calcium chloride (CaCl2), or by Bay K 8644. These results demonstrate that the benzodiazepines and their antagonists may exhibit Ca2+ -antagonistic activity. Ro 5-4864 and PK 11195 may exert this effect at a site that is a component of, or is associated with, voltage operated calcium channels (VOC).
Acetylcholine↗
Effect of telenzepine, an M1-selective muscarinic receptor antagonist, in patients with nocturnal asthma.
Muscarinic M1-receptor antagonists can prevent the induction of a long-lasting excitatory postsynaptic potential in autonomic ganglia. As the prolonged occupation of M1-receptors is a possible protective mechanism against vagal overstimulation, M1-antagonists might prove to be effective in preventing nocturnal wheeze. The aim of the present study was to investigate whether telenzepine, an M1-selective muscarinic receptor antagonist, administered orally at different doses (1.5 mg, 3 mg, 5 mg) for one week, reduced airway obstruction in patients with nocturnal asthma in comparison with placebo. Peak expiratory flow rate (PEFR) difference between each study medication (arithmetic means from values on days 4, 5 and 6) and baseline at 6 a.m. and at midnight on day 5 did not differ significantly. Treatment with placebo nocte (at night, 9 p.m.), or telenzepine 1.5 mg nocte, telenzepine 3 mg nocte and telenzepine 5 mg nocte did not affect significantly the 24-h time course of PEFR. The results of this study indicate that the use of telenzepine via the oral route at a dose of up to 5 mg is not effective in preventing nocturnal asthma.
Administration, Oral↗
Effect of salmeterol and formoterol in patients with chronic obstructive pulmonary disease.
In the present trial we investigated the time course of inhaled salmeterol and formoterol bronchodilation in comparison with that of inhaled salbutamol and placebo in 16 patients with moderate to severe chronic obstructive pulmonary disease (COPD). The study was performed using a single-blind crossover randomized study. The bronchodilator activity of 200 micrograms salbutamol, 50 micrograms salmeterol, 24 micrograms formoterol and placebo, which were all inhaled from a metered dose inhaler, was investigated. Our results showed that salmeterol and formoterol are efficacious in reducing airflow obstruction in patients suffering from COPD. We found similar times of onset to improve FEV1 by 15% for salmeterol and formoterol (salbutamol behaving faster), while the duration of action showed the expected differences between the two long-acting drugs and salbutamol. The results indicate that long-acting beta 2-agonists appear to be very effective in improving airway limitation in patients suffering from COPD. Although the onset of bronchodilation after inhaling salmeterol and formoterol is slightly delayed compared with salbutamol, this is of little clinical importance since in these patients salmeterol and formoterol must be intended for maintenance treatment and not immediate symptomatic relief.
Administration, Inhalation↗
K+ channels and guinea-pig trachea: a possible functional modulation by GABAB receptors.
K+ channel activators represent a novel class of smooth muscle relaxant agents. There is now much evidence demonstrating that K+ channels, localized to prejunctional neurons and post-junctional smooth muscle membranes, can regulate airway smooth muscle activity, inducing smooth muscle cell membrane hyperpolarization. K+ channel activity may be influenced by some neurotransmitters, such as adenosine, serotonin and noradrenaline. More recently, it has been observed that the stimulation of GABAB receptors influences K+ channels in the hippocampus, dorsal rafe and spinal cord neurons. The aim of this study was to investigate the effects of levcromakalim in guinea-pig trachea at pre- and post-junctional sites and to evaluate whether GABAB receptors may modulate K+ channel activation. Levcromakalim (from 1 nM to 1 microM) relaxed guinea-pig trachea (IC50 10 +/- 0.9 nM) previously contracted by KCl (30 mM). This effect was reversed by a pretreatment with tetraethylammonium (10 mM) (IC50 120 +/- 0.7 nM). A 30-min pretreatment with baclofen (1 microM) or phaclofen (1 microM) failed to modify the effects of levcromakalim (IC50 18 +/- 1.0 nM and 14 +/- 0.6 nM, respectively). The contractile responses to electrical field stimulation (71.20 +/- 5.12% of acetylcholine--100 microM--contraction) was significantly (P < 0.05) reduced by a pretreatment with levcromakalim (10 nM) (54.00 +/- 6.68%). This reduction was antagonized by tetraethylammonium (10 nM) (72.20 +/- 14.27%).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Pulmonary penetration of dirithromycin in patients suffering from acute exacerbation of chronic bronchitis.
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 microgram/ml at 24 h, 0.31 microgram/ml at 48 h, 0.33 microgram/ml at 72 h, 0.12 microgram/ml at 96 h and 0.11 microgram/ml at 120 h, respectively), although they were higher than the MICs for Moraxella catarrhalis for up to 72 h and than that for Streptococcus pneumoniae 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 S. pneumonia and M. catarrhalis for up to 120 h (mean concentrations measured 2.67, 2.15, 1.74, 0.27 and 0.17 micrograms/ml, respectively, in BS; 2.59, 2.59, 1.96, 0.41 and 0.27 micrograms/g, respectively, in BM; 2.21, 2.25, 1.57, 0.22 and 0.15 micrograms/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.
Anti-Bacterial Agents↗