Adenosine receptors: novel targets for drug development in allergic rhinitis.
Explore the source record for details and available documents.
Adenosine↗
Biomedical subjects
M G Matera
Publications and source records attributed to M G Matera.
Comparison of the acute effect of tiotropium versus a combination therapy with single inhaler budesonide/formoterol on the degree of resting pulmonary hyperinflation.
In 20 COPD patients (FEV(1) < or =65% predicted, IC<80% predicted), we evaluated changes in the degree of pulmonary hyperinflation after acute administration of tiotropium 18 microg or budesonide/formoterol 320/9 microg. The study consisted of a screening visit and two study days separated by at least one week. Functional parameters were measured before and 30, and 120 min after inhalation of single study drug. Both tiotropium and budesonide/formoterol induced significant changes in functional parameters after 30 and 120 min. However, the impact of tiotropium on the degree of pulmonary hyperinflation was larger than that of budesonide/formoterol, although only differences in IC and TGV between the two treatments were significant (P<0.05), at least after 120 min, whereas those in RV were not significant. The documentation that tiotropium is able to modify IC even after an acute administration indicates its capacity of influencing expiratory flow limitation in a very fast manner and this is an important finding. In fact, changes in IC after bronchodilators in patients with COPD with expiratory flow limitation at rest may represent an objective tool for prescribing these drugs to attain symptomatic improvement and better quality of life, even in the absence of a significant increase in FEV(1).
Aged↗
Immune sensitization of equine bronchus: glutathione, IL-1beta expression and tissue responsiveness.
BACKGROUND: Increasing clinical epidemiological and experimental evidence indicates that excess of production of reactive oxygen free radicals (ROS) induced by an oxidative stress is involved in the pathogenesis of a number of human airway disorders, as well as equine recurrent airway obstruction. Free-radicals modulate the activation of transcription factors, such as nuclear factor-(NF)-kappaB and activator protein (AP)-1, in several different cells. This activation leads to expression of many pro-inflammatory cytokines, including interleukin (IL)-1beta. We have hypothesized that equine airway sensitization might induce an oxidative stress and increase the ROS production, which in turn might enhance a production of IL-1beta and airway hyperresponsiveness. METHODS: We have examined the effect of passive sensitization on IL-1beta mRNA expression and electrical field stimulation (EFS)-induced contraction in equine isolated bronchi, and the potential interference of reduced-glutathione (GSH), an antioxidant, with these responses. Bronchi passively sensitized with serum from animals suffering from heaves and having high total level of IgE, and control tissues, either pretreated or not with GSH (100 microM), were used to quantify IL-1beta mRNA. Other tissues were used to study the effect of EFS (3-10-25 Hz). RESULTS: Mean IL-1beta mRNA expression was higher in passively sensitized than in control rings. GSH significantly (p < 0.05) reduced the IL-1beta mRNA expression only in passively sensitized bronchi. ELF induced a frequency-dependent contraction in both non-sensitized and passively sensitized tissues, with a significantly greater response always observed in sensitized tissues. GSH did not modify the EFS-induced contraction in non-sensitized bronchi, but significantly (p < 0.05) decreased it in passively sensitized tissues. CONCLUSION: Our data indicate that the passive sensitization of equine bronchi induces inflammation and hyperresponsiveness. These effects might be due to an oxidative stress because a pretreatment with GSH decreased the increased IL-1beta mRNA expression and responsiveness to EFS of passively sensitized bronchi.
Animals↗
Effect of formoterol/budesonide combination on arterial blood gases in patients with acute exacerbation of COPD.
BACKGROUND: Patients with severe chronic airway obstruction might suffer dangerous hypoxemia after administration of a beta-agonist despite bronchodilation. METHODS: We first compared the acute effects on gas exchange of two doses of formoterol Turbuhaler (9 and 18 microg) in 10 patients with acute exacerbation of COPD. Afterwards, we compared the acute effects of formoterol Turbuhaler 9 microug with those of formoterol/budesonide combination in a single inhaler (Turbuhaler) 9/320 microg in 10 other patients with acute exacerbation of COPD. Finally, we compared the changes in PaO(2) induced by formoterol Turbuhaler 9 microg or formoterol/budesonide combination in a single inhaler (Turbuhaler) 9/320 microg with those in FEV(1) in 10 other patients with acute exacerbation of COPD. Each agent was given on separate days, and the patients' arterial blood gases were measured at baseline and at intervals of 120 min. RESULTS: Small but statistically significant declines in PaO(2) were found after administration of both formoterol 9 and 18 microg. In the second group of patients, formoterol 9 microg alone again induced a significant decrease in PaO(2). However, the simultaneous administration of budesonide 320 microg significantly reduced the acute effect of formoterol on PaO(2). In a third group of 10 patients we confirmed a small but significant decrease in PaO(2) after formoterol alone and the reduction of this effect when budesonide was administered simultaneously. Moreover, we also documented that addition of budesonide amplified the fast onset of action of formoterol. CONCLUSIONS: These results suggest that when treating patients suffering from acute exacerbation of COPD with formoterol, it is prudent to check their arterial blood gases. In any case, combined administration of formoterol and budesonide reduces the potential for acute effects of formoterol on blood-gas tensions.
Acute Disease↗
Alzheimer disease risk associated with APOE4 is modified by STH gene polymorphism.
The association of the STH gene polymorphism with Alzheimer disease (AD) is debated. In the analysis of two genetically and diagnostically distinct groups of Alzheimer patients from the USA and Italy, the authors did not find an association with the STH polymorphism. However, the APOE-4-associated risk of AD greatly increased if the STH-G allele was also present. The STH-G allele appears to be a risk modifier for AD.
Aged↗
Onset of action of formoterol/budesonide in single inhaler vs. formoterol in patients with COPD.
Formoterol is a beta(2)-agonist bronchodilator that combines a fast onset of action with a long duration of broncholytic effect. An increasing documentation is showing that the combination of a long acting beta(2)-adrenoceptor agonist bronchodilator and an inhaled corticosteroid targets the airways obstruction in patients with COPD. In this study, we have explored whether the acute addition of an inhaled corticosteroid influences the fast bronchodilator response to formoterol. A total of 20 patients with stable COPD were randomized. Single doses of formoterol/budesonide 2 x (4.5/160)microg or formoterol 2 x 4.5 microg were given via Turbuhaler. Serial measurements of FEV(1) were performed over 60 min. Formoterol/budesonide elicited a significantly larger mean FEV(1)-AUC(0-15 min) than formoterol alone. Also the change in FEV(1) 15 min after inhalation of formoterol/budesonide combination (0.197 l; 95% CI: to 0.142-0.252) was greater than that induced by formoterol alone (0.147 l; 95% CI: to 0.092-0.201). The mean increases in FEV(1) were always higher after budesonide/formoterol than formoterol alone, although both treatments induced a significant improvement over baseline at each explored time point. Even the FEV(1)-AUC(0-60 min) after formoterol/budesonide was significantly larger than that after formoterol. Both treatments induced a significant reduction in VAS score but did not modify heart rate in a statistically significant manner. This study indicates that the addition of budesonide influences the fast onset of action of formoterol, but does not induce systemic effects, in patients with stable COPD.
Adrenal Cortex Hormones↗
The functional impact of adding salmeterol and tiotropium in patients with stable COPD.
The aim of this double-blind, double-dummy, crossover, randomised, pilot study was to explore the acute effects of adding salmeterol and tiotropium in patients with stable COPD. A total of 20 outpatients with stable COPD were enrolled. Single doses of 18-microg tiotropium, 50-microg salmeterol, and 18-microg tiotropium+ 50-microg salmeterol were given. Serial measurements of forced expiratory volume in 1 s (FEV1) were performed over 24h. The mean maximum increases in FEV1 from pre-dosing value on each of the dosing days were 0.165l (95% CI: 0.098-0.232) for tiotropium, 0.241 l (95% CI: 0.151-0.332) for salmeterol, and 0.290 l (95% CI: 0.228-0.353) for the combination and occurred 4 h after inhalation of tiotropium or salmeterol and 3 h after the combination. At 12h, the mean increases in FEV1 from pre-dosing value were 0.071 l (95% CI: 0.001-0.141; P = 0.047) for tiotropium, 0.069 l (95% CI: 0.018-0.120; P = 0.010) for salmeterol, and 0.108 l (95% CI: 0.047-0.170; P = 0.001) for the tiotropium + salmeterol combination. Only the difference between salmeterol and tiotropium + salmeterol was statistically significant (P = 0.009). At 24h, the mean FEV1 value was still higher than the mean pre-dosing value for tiotropium (0.042 l; 95% CI: -0.012-0.097; P=0.119) and the tiotropium+salmeterol combination (0.051 l; 95% CI: 0.01 5-0.087; P = 0.007), but not for salmeterol alone (-0.013 l; 95% CI: -0.041-0.014; P = 0.324). The FEV1 area under the curve (AUCs0-12h) were 1.657 l (95% CI: 1.152-2.162) for tiotropium, 2.068 (95l CI: 1.385-2.752) for salmeterol, and 2.541 l (95% CI: 1.954-3.129) for tiotropium + salmeterol. Only the difference between tiotropium and the tiotropium +salmeterol combination was statistically significant (P = 0.01). The FEV1 AUCs0-24h were 2.854 l (95% CI: 1.928-3.780) for tiotropium, 2.786 l (95% CI: 1.913-3.660) for salmeterol, and 3.640 l (95% CI: 2.674-4.605) for tiotropium + salmeterol. ALL differences between treatments were not statistically significant (P> 0.05). These results seem to indicate that the use of the tiotropium + salmeterol combination is more efficacious than the single agents alone, but the once-daily administration of the two drugs is inadvisable due to the broncholytic profile of salmeterol.
Aged↗
Bronchodilator effect of an inhaled combination therapy with salmeterol + fluticasone and formoterol + budesonide in patients with COPD.
In the present trial, we compared the broncholytic efficacy of the combination therapy with 50 microg salmeterol + 250 microg fluticasone and 12 microg formoterol + 400 microg budesonide, both in a single inhaler device, in 16 patients with moderate-to-severe COPD. The study was performed using a single-blind crossover randomized study. Lung function, pulse oximetry (SpO2) and heart rate were monitored before and 15, 30, 60, 120, 180, 240, 300, 360, 480, 600, and 720 min after bronchodilator inhalation. Both combinations were effective in reducing airflow obstruction. FEV1 AUC(0-12 h) was 2.83 l (95% CI: 2.13-3.54) after salmeterol/fluticasone and 2.57 l (95% CI: 1.97-3.2) after formoterol/budesonide. Formoterol/budesonide elicited the mean maximum improvement in FEV1 above baseline after 120 min (0.29 l; 95% CI: 0.21-0.37) and salmeterol/fluticasone after 300 min (0.32 l; 95% CI: 0.23-0.41). At 720 min, the increase in FEV1 over baseline values was 0.10 l (95% CI: 0.07-0.12) after salmeterol/fluticasone and 0.10 l (95% CI: 0.07-0.13) after formoterol/budesonide. The mean peak increase in heart rate occurred 300 min after formoterol/budesonide (1.5 b/min; 95% CI--2.3 to 5.3) and 360 min after salmeterol/fluticasone (2.6 b/min; 95% CI--1.9 to 7.0). SpO2 did not change. All differences between salmeterol/fluticasone and formoterol/budesonide were not significant (P > 0.05) except those in FEV1 at 120 and 360 min. The results indicate that an inhaled combination therapy with a long-acting beta2-agonist and an inhaled corticosteroid appears to be effective in improving airway limitation after acute administration in patients suffering from COPD.
Adrenergic beta-Agonists↗
A single high dose of formoterol is as effective as the same dose administered in a cumulative manner in patients with acute exacerbation of COPD.
Several clinical trials have shown that the inhaled beta2-agonists with long-acting properties, formoterol and salmeterol, may be effective in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, there is a great deal of controversy regarding the timing and optimal dose of inhaled beta2-agonists in this pathologic condition. In this double-blind, randomised, crossover study, we have compared the bronchodilating effect and the safety of inhaled formoterol administered via Turbuhaler using either a cumulative dose regimen or the equivalent single dose in 16 patients with acute exacerbations of COPD. On the two consecutive days, the patients received, in a randomised order, each of the following active dose regimens: (A): 9 + 9 + 18 microg of formoterol via Turbuhaler (36 microg cumulative delivered dose) or (B): 36 + 0 + 0 microg of formoterol via Turbuhaler. The three doses on each treatment day were administered at 30-mm intervals, with measurements being made 5 and 30 min after each dose. Contemporaneously, we also measured oxygen saturation by pulse oximetry (SpO2) and pulse rate. Both the high dose and the cumulative one induced a significant bronchodilation expressed as change in FEV1. The difference between the two regimens was significant (P=0.0332) only 60 min after the first inhalation. The trend of FVC and IC was similar to that of FEV1. All treatment regimens were well tolerated and no adverse events were reported. Neither the administration ofthe high dose nor that of the cumulative one modified heart rate in a significant manner. Also they did not influence SpO2. This study indicates that a single high dose offormoterol is as effective as the same dose administered in a cumulative manner in patients with acute exacerbation of COPD.
Acute Disease↗
Onset of action following formoterol Turbuhaler and salbutamol pMDI in reversible chronic airway obstruction.
Short-acting beta(2)-agonists are currently recommended for symptom relief in asthma and the treatment of mild, acute exacerbations in COPD. However, formoterol has as fast an onset of action as salbutamol with the additional benefit of longer-lasting bronchodilation (approximately 12 h). Furthermore, systemic side effects observed with formoterol are of a similar duration but less pronounced than with short-acting beta(2)-agonists. In this double-blind, randomized, cross-over study, 20 adult patients with reversible chronic airway obstruction (intrinsic asthma or COPD) inhaled single doses of formoterol 9 microg or salbutamol 100 microg (group A) or formoterol 18 microg or salbutamol 200 microg (group B). FEV(1) was measured prior to and 5, 10, 15, 20, 25 and 30 min following inhalation of study drug. No significant differences in FEV(1) values were observed between group A (P=0.704) or group B (P=0.270) at baseline, or at 5 (Group A: P=0.340; Group B: P=0.559) and 15 min (Group A: P=0.526; Group B: P=0.818) post dose. No adverse events were reported during the study. Formoterol Turbuhaler has as rapid an onset of action as salbutamol pMDI when given at the recommended doses.
Adult↗
The protective role of epithelium-derived nitric oxide in isolated bovine trachea.
Airway epithelial cells from bovine airways can release relaxant factors such as nitric oxide (NO) and prostaglandin E(2) and the removal of airway epithelium results in an increased responsiveness of smooth muscle to spasmogen stimuli. In this study, we assessed whether or not epithelial NO modulates the contractile response of bovine trachea in vitro.Cumulative concentration-response curves to acetylcholine (ACh), histamine (Hist) and 5-hydroxytryptamine (5-HT) were obtained in both intact and epithelium denuded tracheal strips in the presence of indomethacin (10 microM).In intact, but not in epithelium denuded strips, preincubation with the NO synthase inhibitor L-N((G))-Nitro-arginine methyl ester (L-NAME), but not with D-NAME, shifted to the left the concentration-response curve to ACh (pD(2) values in the absence and in the presence of L-NAME were 3.47+/-0.1 and 4.60+/-0.1, respectively; P<0.05) and to Hist (pD(2) in the absence and in the presence of L-NAME: 3.89+/-0.1 and 4.54+/-0.1, respectively; P<0.05). This effect was reversed by L-arginine (1mM), but not by D-arginine. The contractile response to 5-HT was not affected by L-NAME in either intact or epithelium denuded strips. These data suggest that NO is an epithelial relaxant factor modulating airway cholinergic and histaminergic contraction of bovine trachea and that the activation of the epithelial NO synthase is a mediator-specific process.
Acetylcholine↗
Innervation of equine airways.
Equine obstructive pulmonary disease (COPD), or heaves or recurrent airway obstruction, is a common equine pulmonary disease similar to human asthma and/or CODP. Since bronchospasm and inflammation are the key features in heaves, the purpose of this paper is to review the contribution of neural mechanism that may be relevant to this disease. Equine airway receive cholinergic and adrenergic innervation, as well as observed in many species. It was suggested that the autonomic neural control in asthma might be defective with an imbalance between excitatory and inhibitory pathways, resulting in excessively twitchy airways. Moreover, the recognition that, in addition to classical adrenergic and cholinergic pathway there are non-adrenergic-non-cholinergic inhibitory (iNANC) and excitatory (eNANC) innervation and many mediators, which have potent effects on airway function, has revived interest in neural control of airway.
Animals↗
Formoterol as dry powder oral inhalation compared with salbutamol metered-dose inhaler in acute exacerbations of chronic obstructive pulmonary disease.
BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (COPD) are managed with increased doses or frequency of the patient's existing bronchodilator therapy. The use of formoterol in the treatment of mild acute exacerbations of COPD has been suggested; however, a comparison of cumulative doses of formoterol with salbutamol, the gold standard bronchodilator agent for this pathologic condition, is still lacking. OBJECTIVE: The aim of the study was to compare the inhaled beta2-agonists salbutamol (rapid onset, short duration of action) and formoterol (rapid onset, long duration of action), both used as needed in patients attending outpatient clinics because of mild acute exacerbations of COPD (Anthonisen exacerbation type I or II). METHODS: A dose-response curve to formoterol via Turbuhaler or salbutamol via pressurized metered-dose inhaler (pMDI) was constructed. On 2 consecutive days, the patients received, in randomized order, both of the following active dose regimens: A = 12 + 12 + 24 microg formoterol via Turbuhaler (48-microg cumulative metered dose); B = 200 + 200 + 400 microg salbutamol via pMDI (800-microg cumulative metered dose). Dose increments were given at 30-minute intervals, with measurements made 25 minutes after each dose. The maximum forced expiratory volume in 1 second (FEV1) value during the dose-response curve to formoterol or salbutamol was chosen as the primary outcome variable to compare the 2 treatments. Oxygen saturation by pulse oximetry (SpO2) and pulse rate were also measured at each assessment period. Every adverse event, either reported spontaneously by the patients or observed by the investigators, was recorded. RESULTS: Sixteen patients (2 women, 14 men) aged 51 to 77 years (most older than 65 years) participated in the study. Both formoterol and salbutamol induced a large, significant, dose-dependent increase in FEV1, inspiratory capacity (IC), and forced vital ca- pacity (FVC). There was no significant difference between FEV1, IC, and FVC values after 48 microg formoterol and 800 microg salbutamol. There was no significant difference in FEV1 after 24 microg formoterol and 800 microg salbutamol; however, the difference in FEV1 after 24 and 48 microg formoterol was significant. Neither heart rate (mean differences from baseline after 48 microg formoterol, 1.9 beats/min [95% CI, -3.4, 7.2] and 800 microg salbutamol, 3.7 beats/min [95% CI, -1.1, 8.5]) nor SpO2 (mean percentage differences from baseline after 48 microg formoterol, -0.37% [95% CI, -1.22, 0.47] and 800 microg salbutamol, -0.75% [95% CI, -1.73, 0.23]) changed significantly. However, SpO2 decreased below 90% in 2 patients after the highest dose of formoterol and in 1 patient after the highest dose of salbutamol. CONCLUSIONS: In this small, selected group of patients with mild acute exacerbations of COPD, formoterol via Turbuhaler induced a fast bronchodilation that was dose dependent and not significantly different from that caused by salbutamol. Furthermore, formoterol appeared to be as well tolerated as salbutamol.
Administration, Inhalation↗
Addition of an extra dose of salmeterol Diskus to conventional dose of salmeterol Diskus in patients with COPD.
Patients experiencing dyspnoea can request an additional dose of salmeterol during the dose interval for the control of their symptoms, although under treatment with salmeterol. In this study we have explored the effects on respiratory function of an additive dose of salmeterol Diskus in 15 chronic obstructive pulmonary disease (COPD) patients in regular treatment with a conventional dose of 50 microg salmeterol. On two different days, patients inhaled 50 microg Diskus. After 240 min, they inhaled additional 50 microg salmeterol Diskus (salmeterol arm) or placebo Diskus (placebo arm). Lung function was controlled before first drug administration and 0.5, 1, 2, 3, 4, 4.5, 6, 8, 10, and 12 h thereafter. The mean (95% CI) peak increase in FEV1 from baseline was reached after 4 h in the salmeterol arm (0.174 L; 0.144-0204) and after 5 h (0.141 L; 0.115-0.168) inthe placebo arm; after 12 h, the mean (95% Cl) increase in FEV1 from basal values was still 0.149 L (0.119-0.179) in salmeterol arm, but only 0.041 L (0.017-0.064) in placebo arm. The mean (95% CI) FEV1 AUC0-12h for all patients were 2.01 (1.72-2.30) L when salmeterol was added and 1.30 (1.03-1.58) L when placebo was inhaled. The difference (mean; 95% CI) between the FEV1 AUC0-12h of the two arms (0.71 L; 0.47-0.95) was statistically significant (P<0.0001), although the difference (mean; 95% CI) between the FEV1 AUC0-4h of the two treatments (0.08 L; -0.02-0.18) was notstatistically significant (P=0.126). The addition of an extra dose of salmeterol did not significantly increase the heart rate or decrease the SpO2. This study suggests that the addition of an extra dose of salmeterol does not give room for further increase in peak FEV1, but the effect of adding salmeterol to salmeterol is largely additive when considering the duration of action and safe.
Albuterol↗
Acute effects of higher than customary doses of salmeterol and salbutamol in patients with acute exacerbation of COPD.
Worsening of underlying bronchospasm may be associated with acute exacerbations of chronic obstructive pulmonary disease (COPD). As airway obstruction becomes more severe, the therapeutic option is to add salbutamol, but not salmeterol, as needed to cause rapid relief of bronchospasm. Unfortunately the most effective dosage of beta2-agonists may increase above that recommended during acute exacerbations. In this study, we compared the acute effects of higher than customary doses of salmeterol and salbutamol in 20 patients with acute exacerbation of COPD. A dose-response curve to salmeterol pMDI, 25 microg/puff or salbutamol pMDI, 100 microg/puff, was constructed using 1, 1, and 2 puff' i.e., a total cumulative dose of 100 microg salmeterol or 400 microg salbutamol on 2 consecutive days. After baseline measurements, dose increments were given at 30-min intervals with measurements being made 25 min after each dose. Hear rate (HR) and pulse-oximetry (SpO2) measurements were then taken. Both salmeterol and salbutamol induced a larg and significant (P < 0.05) dose-dependent increase in FEV1 [mean differences from baseline (L) = after 100 microg salmeterol 0.174 (95% CI: 0.112 to 0.237); after 400 microg salbutamol: 0.165 (95% CI: 0.080 to 0.249)], in IC [mean differences from baseline (L) = after 100 microg salmeterol: 0.332 (95% CI: 0.165 to 0.499); after 400 microg salbutamol: 0.281 (95% CI: 0.107 to 0.456)] (Fig. 2), and in FVC mean differences from baseline (L) = after 100 microg salmeterol: 0.224 (95% CI: 0.117 to 0.331); after 400 microg salbutamol: 0.242 (95% CI: 0.090 to 0.395)]. There was no significant difference between the FEV1 values (P=0.418), the ICvalues (P=0.585), and the FVCvalue (P=0.610) after 100 microg salmeterol and 400 microg salbutamol. HR [mean differences from baseline (beats/min) = after 100 microg salmeterol: 3.15 (95% CI: -0.65 to 6.96); after 400 microg salbutamol: 2.30 (95% CI: -0.91 to 5.51)] and SpO2 [mean differences from baseline (%) = after 100 microg salmeterol: -0.20 (95% CI: -1.00 to 0.60); after 400 microg salbutamol: -0.11 (95% CI: -1.00 to 0.79)] did not change significantly from baseline (P > 0.05). These data indicate that salmeterol is effective and safe in the treatment of acute exacerbation of COPD and support its use in this clinical condition.
Acute Disease↗
Ext-mutation analysis in Italian sporadic and hereditary osteochondromas.
Osteochondromas represent the largest group of benign tumors of bone. Multiple osteochondromatosis or hereditary multiple exostoses (EXT) is an autosomal dominant inherited disorder characterized by the presence of multiple benign cartilage-capped exostoses. EXT is genetically heterogeneous with at least 3 chromosomal loci: EXT1 (8q24.1), EXT2 (11p11-p13), and EXT3 (19p). In <5% of EXT patients, the inactivation of both copies of EXT alleles (LOH) is associated with malignant transformation. We have analyzed the EXT1 and EXT2 genes in 9 unrelated EXT families and in a patient with a sporadic osteochondroma, all originating from Italy. Four families show an EXT1 mutation, consisting of a small deletion in 3 of them and a small insertion in the 4th. All these mutations lead to premature termination of translation and thus a truncated EXT1 protein. Three families presented EXT2 mutations consisting of nucleotide substitutions leading to alterations of the third intron splice-site, to an amino acid substitution and to a nonsense mutation. All these mutations cosegregate with the disease phenotype. The sporadic osteochondroma patient carried a novel missense mutation in exon 11 of EXT2 gene, leading to an amino acid substitution. Seven of these mutations have never been described before. EXT2 missense mutations were also confirmed by amino acids conservation between human and mouse and by analysis of a healthy control population. In conclusion, our study provide further evidence that loss of function of the EXT1 or EXT2 gene is the main cause of EXT supporting the putative tumor-suppressor function of these genes.
Adolescent↗
Formoterol Turbuhaler for as-needed therapy in patients with mild acute exacerbations of COPD.
Worsening of underlying bronchospasm may be associated with acute exacerbations of chronic obstructive pulmonary disease (COPD). As airway obstruction becomes more severe, the therapeutic option is to add a short-acting inhaled beta2-agonist as needed to cause rapid relief of bronchospasm. Unfortunately however, the most effective dosage may increase above that recommended during acute exacerbations. Formoterol (Oxis) Turbuhaler has a rapid onset of action (within minutes) and demonstrates a maintained effect on a rway function. In this study, we examined the effects of formoterol used as needed in 20 patients with acute exacerbations of COPD. A dose response curve to inhaled formoterol (9 microg per inhalation) or placebo was constructed using three separate inhalations, i.e. a total cumulative dose of 27 microg. Dose increments were given at 20-min intervals, with measurements being made 15 min after each dose. Formoterol, but not placebo, induced a large and significant (P<0.001) dose-dependent increase in forced expiratory volume in 1 sec (FEV1) [mean differences from baseline = 0.1311 after 9 microg formoterol (95% CI: 0.096-0.167)] 0.1811 after 18 microg formoterol (95% CI: 0.140-0.2221) and 0.2081 after 27 microg formoterol (95% CI: 0.153-0.2631). However, 27 microg formoterol did not induce further benefit [0.0271 (95% CI: -0.008-0.0621); P=0.121] when compared wth 18 microg formoterol. Results of this study suggest the use of higher than customary dose of formoterol for as-needed therapy to provide rapid relief of bronchospasm in patients suffering from acute exacerbations of partially reversible COPD.
Acute Disease↗
Comparison of the bronchodilating effect of salmeterol and zafirlukast in combination with that of their use as single treatments in asthma and chronic obstructive pulmonary disease.
BACKGROUND: It has been suggested that the effect of a beta2-agonist is additive with that of a cysteinyl leukotriene 1 receptor antagonist. OBJECTIVES: The present study was designed to answer the question of whether combined administration of inhaled salmeterol and oral zafirlukast at the standard doses would result in greater bronchodilation in patients with chronic airway obstruction than the use of either drug alone. METHODS: The study was performed using a double-blind, double-dummy, crossover, randomised design, and was conducted on 4 non-consecutive days. Sixteen patients with moderate to severe chronic obstructive pulmonary disease (COPD) and 10 non-smoker asthmatic patients received 40 mg of oral zafirlukast, 50 microg of inhaled salmeterol, 50 microg of inhaled salmeterol plus 40 mg of oral zafirlukast of placebo. Lung function was assessed before drug administration and 30, 60, 120, 180 and 240 min thereafter. At the end of the 4-hour period, each patient received 400 microg of inhaled salbutamol and spirometric testing was performed 30 min later. RESULTS: In both asthmatic and COPD patients, the overall effect of salmeterol and zafirlukast on the forced expiratory volume in 1 s (FEV1) was considered extremely significant (p < 0.0001), with a maximum bronchodilation above baseline after 180 min (20.7 and 11.0%, respectively) in asthmatics and after 2 h (21.7 and 11.2%, respectively) in COPD subjects. Zafirlukast did not produce any further significant acute bronchodilation in addition to that achieved with salmeterol alone in either asthmatic or COPD patients. Nevertheless, 7 out of 16 COPD patients and 7 out of 10 asthmatic patients had a further improvement after the combination of salmeterol and zafirlukast. The mean difference in pre- and post-salbutamol FEV1 values in both asthmatic and COPD patients after zafirlukast was significant (p < 0.05), but that after salmeterol and the combination of the two drugs was not significant (p > 0.05). The difference between placebo and zafirlukast was not significant following inhaled salbutamol given 4 h after each treatment. CONCLUSIONS: Both salmeterol and zafirlukast induced a significant increase in FEV1, although salmeterol elicited a greater improvement in both asthmatic and COPD patients. Apparently, zafirlukast at the clinically recommended dose did not produce any further significant acute bronchodilation in addition to that achieved with salmeterol alone, either in asthma or COPD. In any case, evaluation of the effect of the combination over a 12-hour period is mandatory.
Adrenergic beta-Agonists↗