Biomedical subjects

M Laviolette

Publications and source records attributed to M Laviolette.

At least 37 records · Page 2Linked to original sources

PubMed2000

Airway hyperresponsiveness, inflammation, and subepithelial collagen deposition in recently diagnosed versus long-standing mild asthma. Influence of inhaled corticosteroids.

This study aimed at documenting airway inflammation and subepithelial collagen deposition in patients using only inhaled beta(2)-agonists with either recently diagnosed asthma (RDA: </= 2 yr, n = 16) or long-standing asthma (LSA: >/= 13 yr, n = 16) and at the influence of an intense inhaled corticosteroid (ICS) treatment on these parameters, in relation to changes in airway responsiveness. Patients had a methacholine inhalation test and a bronchoscopy with bronchial biopsies before and after an 8-wk treatment with inhaled fluticasone propionate (FP), 1,000 microgram/day. Baseline FEV(1) (mean +/- SEM) was normal and similar in both groups (RDA: 98.1 +/- 2.7, LSA: 94.5 +/- 4.6%). Geometric mean methacholine PC(20) was lower in LSA than in RDA (0.44 versus 3.37 mg/ml) at baseline and improved similarly by 1.85 and 1.86 double concentrations with FP treatment. PC(20) normalized (>/= 16 mg/ml) in five patients with RDA and two patients with LSA. Baseline mean bronchial cell counts (per mm(2) connective tissue surface) for CD3(+), CD4(+), CD8(+), CD25(+), EG1(+), CD45ro(+), and AA1(+) cells were similar in both groups. With FP, EG1(+) (p < 0.001), EG2(+) (p = 0.018), and AA1(+) counts (p = 0.009) decreased significantly in both groups while CD45ro(+) (p = 0.02) counts decreased only in LSA. Baseline type 1 and type 3 collagen deposition underneath the basement membrane was similar in RDA and LSA and did not change significantly after FP. This study shows that recent compared to long-standing mild asthma is associated with a similar degree of airway inflammation and subepithelial fibrosis, and a similar improvement in airway hyperresponsiveness after 8 wk on high-dose ICS. It also indicates that once asthma becomes symptomatic, airway responsiveness cannot normalize in most subjects over such a time period, even with a high dose of ICS.

Administration, Inhalation↗

PubMed1999

3'-Phosphoadenosine 5'-phosphosulfate binding site of flavonol 3-sulfotransferase studied by affinity chromatography and 31P NMR.

The function of Lys-59, Arg-141, and Arg-277 in PAPS binding and catalysis of the flavonol 3-sulfotransferase was investigated. Affinity chromatography of conservative mutants with PAPS analogues allowed us to determine that Lys-59 interacts with the 5' portion of the nucleotide, while Arg-141 interacts with the 3' portion, confirming assignments deduced from the crystal structure of mouse estrogen sulfotransferase [Kakuta, Y., Pedersen, L. G., Carter, C. W. , Negishi, M., and Pedersen, L. C. (1997) Nat. Struct. Biol. 4, 904-908]. The affinity chromatography method could be used to characterize site-directed mutants for other types of enzymes that bind nucleoside 3',5'- or 2',5'-diphosphates. 31P NMR spectra of enzyme-PAP complexes were recorded for the wild-type enzyme and K59R and K59A mutants. The results of these experiments suggest that Lys-59 is involved in the determination of the proper orientation of the phosphosulfate group for catalysis.

Adenosine Diphosphate↗

PubMed1999

Skin bruising, adrenal function and markers of bone metabolism in asthmatics using inhaled beclomethasone and fluticasone.

Fluticasone propionate (FP) is generally considered to have twice the efficacy of beclomethasone dipropionate (BDP) on a weight-to-weight basis for the control of asthma, and may have lesser effects on adrenal function. However, the effects of FP and BDP on skin integrity and bone metabolism markers require further examination. Sixty-nine asthmatic subjects were enrolled in a double-blind crossover study in which, after a baseline period, they received BDP or FP (at half the dose of BDP) for two 4-month periods each. A questionnaire on skin bruising, a skin examination, tests of adrenal function and of markers of bone metabolism were performed after 2 months of each period. The number of asthma exacerbations was not significantly different for the two treatment periods (eight for BDP and nine for FP), nor were various indices of asthma control. Whereas the frequency of bruising reported by the questionnaire was not different, there were more bruises on examination for BDP (1.6+/-2.5) than for FP (1.2+/-2.3) (p=0.04). Although baseline serum cortisol was not significantly different for the two drugs, the increase in cortisol after cortrosyn was lower for BDP (357+/-158 micromol x dL(-1)) than for FP (422+/-144 micromol x dL(-1)) (p<0.01). Serum osteocalcin levels were significantly lower in subject on BDP (2.8+/-1.7 microg x mL(-1)) than on FP (3.5+/-1.9 ng x mL(-1)) (p=0.003). Other markers of bone metabolism were not significantly altered. The three major side-effects were loosely, but significantly correlated with the periods on BDP and FP. However, skin bruises, increase in cortisol after Cortrosyn and osteocalcin were not significantly correlated for the period on either BDP or FP. In conclusion, whereas fluticasone propionate used at half the dose of beclomethasone dipropionate has a comparable effect on the control of asthma, fluticasone propionate demonstrated fewer side-effects in terms of skin bruising, adrenal suppression and bone metabolism.

Administration, Inhalation↗

PubMed1999

Asymptomatic airway hyperresponsiveness: relationships with airway inflammation and remodelling.

To study the physiopathology and significance of asymptomatic airway hyperresponsiveness (AHR), the clinical and bronchial immunohistological parameters were evaluated in subjects with asymptomatic and symptomatic AHR. Asymptomatic subjects with AHR (eight females/two males, no respiratory symptoms, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (PC20) <8 mg x mL(-1) and no treatment) were compared with asthmatic subjects paired for age, sex and PC20, and with nonatopic, nonasthmatic controls paired for age and sex. All three groups were evaluated once at baseline, whilst the asymptomatic AHR subjects were re-evaluated after 1 and 2 yrs. Measurements included spirometry, methacholine challenge, serum immunoglobulin (Ig)E, blood eosinophils, and bronchoscopy (at baseline and after 2 yrs only). At first evaluation, the mean blood eosinophil count, total serum IgE level, atopic index, baseline forced expiratory volume in one second (FEV1) and the degree of bronchial epithelial desquamation of the asymptomatic AHR subjects were similar to those of asthmatic subjects. However, they presented focal rather than the continuous bronchial subepithelial fibrosis observed in asthmatics. Their mucosal CD3, CD4, CD25, EG1 and EG2-positive cell counts were intermediate between those of the control subjects and asthmatics. At the end of the 2-yr follow-up, four of them had developed asthma symptoms. At this time, bronchial biopsies revealed an increase in the extent of subepithelial fibrosis and in the number of CD25 and CD4-positive cells, and a decrease in the number of CD8+ cells, particularly in subjects who developed asthma symptoms. These data suggest that asymptomatic airway hyperresponsiveness is associated with airway inflammation and remodelling, and that the appearance of asthma symptoms is associated with an increase in these features, particularly the CD4/CD8 ratio and airway fibrosis. Consequently, this study proposes an association between asymptomatic airway hyperresponsiveness and airway inflammation, structural changes and asthma although these relationships remain to be further evaluated.

Adolescent↗

PubMed1999

Serum matrix metalloproteinase-9:Tissue inhibitor of metalloproteinase-1 ratio correlates with steroid responsiveness in moderate to severe asthma.

Asthma presents a variable clinical response to corticosteroids (CS). Because CS more likely act on inflammation than on tissue remodeling, the presence of bronchial structural changes in certain asthmatics may explain their limited clinical response to CS. Matrix metalloproteinase-9 (MMP-9) and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), are, respectively, involved in tissue inflammatory processes and fibrogenic processes. Previous reports have suggested that MMP-9:TIMP-1 ratio may reflect the balance between these two processes in various diseases. This study evaluated the relation of this ratio and the response to CS in severe asthma. Twenty asthmatics with low baseline FEV1 (59 +/- 4% predicted) and >/= 30 % increase with beta2-agonist were recruited. Serum MMP-9 and TIMP-1 levels were measured and correlated with response to an oral CS trial (methylprenisolone 40 mg/d for 14 d). With oral CS, FEV1 changes (DeltaFEV1) ranged from -15 to +43%. The DeltaFEV1 closely correlated with the MMP-9:TIMP-1 ratios (rho = 0. 79, p = 0.0006). In conclusion, serum MMP-9: TIMP-1 ratio could predict the response of oral CS therapy in asthma. The low MMP-9:TIMP-1 ratio observed in subjects with little or no FEV1 improvement with CS supports the hypothesis that, in these asthmatic subjects, bronchial fibrogenesis predominates over inflammation.

Adrenergic beta-Agonists↗

PubMed1999

Expression of costimulatory molecules on alveolar macrophages in hypersensitivity pneumonitis.

To verify whether alveolar macrophages (AM) of patients with hypersensitivity pneumonitis (HP) increase their antigen-presenting capacity by upregulating the expression of B7 costimulatory molecules (CD80, CD86), and whether a viral infection enhances this expression whereas cigarette smoking abrogates it, we performed bronchoalveolar lavage (BAL) on 18 patients with HP; 10 asymptomatic, virus-exposed subjects (AS); 18 nonsmokers; and 12 smokers. Influenza virus infection of AM from nonsmokers and smokers was induced in vitro. Expression of CD80 and CD86 on AM, and of CD28 and CTLA4 on T cells, was evaluated. The percentage of CD80(+) AM was greater in HP patients (34.6 +/- 7.7) and in AS (23.9 +/- 7.6) than in nonsmokers (6.7 +/- 1.6) or smokers (2.5 +/- 0.3). An increase in CD86(+) cells (62.3 +/- 5.9) was found in HP patients as compared with nonsmokers (24.2 +/- 3.8) and smokers (4.5 +/- 1.0). CD28 and CTLA4 molecules were highly expressed on all T cells. In vitro virus infection upregulated CD80 and CD86 expression in AM of normal nonsmoking subjects but not on those of smokers. These results suggest that: (1) an upregulation of B7 molecule expression is involved in the lymphocytic alveolitis of HP; (2) a viral infection could enhance HP by increasing B7 expression; and (3) the protective effect of cigarette smoking in HP may be due to the low level of expression of costimulatory molecules on AM from smokers, and to their resistance to further upregulation.

Adolescent↗

PubMed1999

Montelukast added to inhaled beclomethasone in treatment of asthma. Montelukast/Beclomethasone Additivity Group.

The primary objective of this study was to determine whether montelukast, an oral leukotriene receptor antagonist, provides additional clinical benefit to the effect of inhaled corticosteroids. A total of 642 patients with chronic asthma (FEV(1) 50 to 85% of predicted value and at least a predefined level of asthma symptoms) incompletely controlled with inhaled beclomethasone, 200 microg twice daily using a spacer device, during the 4-wk run-in period were randomly allocated, in a double-blind, double-dummy manner to one of four treatment groups: (1) montelukast 10 mg plus continuing inhaled beclomethasone; (2) placebo tablet plus continuing inhaled beclomethasone; (3) montelukast 10 mg and inhaled placebo (after blind beclomethasone removal); and (4) placebo tablet and inhaled placebo (after blind beclomethasone removal). The primary endpoints were FEV(1) and daytime asthma symptoms score. Montelukast provided significant (p < 0.05) clinical benefit in addition to inhaled beclomethasone by improving FEV(1), daytime asthma symptom scores, and nocturnal awakenings. Blind removal of beclomethasone in the presence of placebo tablets caused worsening of asthma control, demonstrating that patients received clinical benefit from inhaled corticosteroids. Blind removal of beclomethasone in the presence of montelukast resulted in less asthma control but not to the level of the placebo group. All treatments were well tolerated; clinical and laboratory adverse experiences were generally similar to placebo treatment in this study. In conclusion, montelukast provided additional asthma control to patients benefitting from, but incompletely controlled on, inhaled beclomethasone.

Acetates↗

PubMed1999

5-Oxo-6,8,11,14-eicosatetraenoic acid induces important eosinophil transmigration through basement membrane components: comparison of normal and asthmatic eosinophils.

Basement membrane transmigration is an important step in tissue recruitment of eosinophils into inflamed tissue. Recent reports showed that this phenomenon is modulated by platelet-activating factor (PAF) in combination with cytokines and proteinases. We investigated the in vitro efficacy of 5-oxo-6,8,11, 14-eicosatetraenoic acid (5-oxo-ETE), a metabolite of arachidonic acid and known as a potent eosinophil chemotactic factor, in promoting the transmigration of blood eosinophils from normal and asthmatic subjects through a Matrigel basement membrane. 5-Oxo-ETE proved to be a more potent (> 10-fold) inducer of eosinophil transmigration than PAF, and this effect was similar in cells from normal and asthmatic subjects (82.0 +/- 3.7% and 88.1 +/- 3.7%, respectively). Moreover, 5-oxo-ETE was active in the absence of interleukin (IL)-5, although this cytokine amplified the effect of 5-oxo-ETE from 61.3 +/- 3.3% to 92.8 +/- 1.8% (p = 0.003). The membrane receptor for urokinase plasminogen activator (CD87), a serine protease, was observed on eosinophils, and its expression was increased by IL-5. The inhibition of both metalloproteinases (MMP) and plasmin/plasminogen complex with inhibitor or monoclonal antibodies decreased cell transmigration by about 50%. Combination of an MMP inhibitor with anti-CD87 antibodies had no additive effect. These data show that 5-oxo-ETE is an efficient promoter of eosinophil transmigration in vitro, and is much more potent in this respect than PAF. The data suggest that 5-oxo-ETE could play an important role in eosinophil recruitment in vivo. Moreover, they demonstrate that in addition to MMP, the plasmin/plasminogen system could be involved in eosinophil transmigration.

Adult↗

PubMed1998

Characteristics of leukotriene biosynthesis by human granulocytes in presence of plasma.

The formation of leukotriene B4 (LTB4) by neutrophils stimulated with the ionophore A23187 or physiological stimuli in heparinized plasma was investigated. In comparison with neutrophils stimulated (A23187) in a protein-free buffered salt solution, neutrophils stimulated in plasma produced only trace amounts of LTB4. The addition of human recombinant LTA4-hydrolase or erythrocytes to plasma prior to A23187 stimulation strongly and selectively stimulated (> 4-fold) the formation of LTB4 supporting that neutrophils activated in plasma with A23187 release in the extracellular milieu most of LTA4 formed by the cells, and indicating that plasma proteins drastically slow down the further metabolism of LTA4 released by neutrophils. The formation of LTB4 was then investigated in GM-CSF-primed neutrophils stimulated with fMLP in plasma; levels of synthesis were very low and the addition of erythrocytes prior to stimulation strongly enhanced LTB4 synthesis, demonstrating that agonist-stimulated neutrophils also release most of LTA4 generated in the extracellular milieu. Investigations on the fate of LTA4 in plasma revealed that LTA4 was slowly degraded through an unknown process, i.e. not through the previously described non-enzymic hydrolysis resulting in the formation of dihydroxy derivatives of LTA4. Using neutrophils labeled with tritiated arachidonate, we also demonstrated that neutrophils stimulated in plasma with fMLP or A23187, almost exclusively use endogenous arachidonate, as opposed to plasma arachidonate, to generate 5-lipoxygenase products. Finally, experiments performed with purified eosinophils indicated that contrary to neutrophils, the eosinophils do not release LTA4, but directly release LTC4.

Asthma↗

PubMed1998

Effect of route of breathing on response to exposure in a swine confinement building.

Exposure of naive subjects to swine buildings results in acute nasal, lung, and peripheral blood inflammatory responses with an increase in nonallergic airway responsiveness. Because nasal passages filter large particles and soluble gases and because swine building exposure results in an acute inflammatory response at this level, we questioned what effect breathing through or avoiding this route would have on local and systemic inflammation. Nine normal young men 23 to 37 yr of age were exposed for 5 h to a swine building, once breathing normally and once with the mouth occluded (n = 8) (Protocol 1) or the nose occluded (n = 4) (Protocol 2); three subjects participated in both protocols. For each protocol each subject underwent a methacholine challenge for PC20 measurement, a nasal lavage, venous blood puncture, and a bronchoalveolor lavage (BAL) once before and once after each swine building exposure. Bronchial responsiveness as measured by PC20 decreased in most subjects after swine building exposure and was not influenced by the route of breathing. Nasal lavage neutrophils increased tenfold after each swine exposure, except when the nose was occluded where no alteration was observed. Total BAL cells significantly increased after each exposure to the swine building, this increase was not modified by the route of breathing. In Protocol 1, white blood cells increased from a baseline level of 7.0 to 10.5 x 10(9) cells/L after exposure with normal breathing and to 10.7 x 10(9) cells/L during nasal breathing exclusively. For Protocol 2, these respective values were: 5.6, 11.7 and 10.4 x 10(9)/L. Interleukins 6 and 8 levels in BAL, nasal washes, and serum were increased by swine building exposure, except in the nasal wash when the nose was occluded. In conclusion, the lung and blood responses to exposure in a swine confinement building are not modified by the route of breathing, suggesting that nasal inflammation and filtration are not important in the process and that small respirable particles and/or gases may be responsible for these responses.

Adult↗

PubMed1998

Tolerance to the protective effects of salmeterol on methacholine-induced bronchoconstriction: influence of inhaled corticosteroids.

Long-acting beta2-adrenoceptor agonists such as salmeterol reduce airway responsiveness for at least 12 h, but this effect seems to decrease with regular use. We evaluated the time-course of the protective effects of salmeterol on methacholine-induced bronchoconstriction, its modulation by inhaled corticosteroids (ICS) and its influence on asthma control. Thirty two subjects (13 males and 19 females) with mild to moderate stable asthma were divided into two groups according to their medication needs: bronchodilators (BD) alone (n=16) or with ICS (n=16). After a 2 week run-in period, a double-blind crossover study was conducted. Subjects from both groups received salmeterol 50 microg b.i.d. or a placebo for 4 weeks each in random order, separated by a 2 week washout period. The provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (PC20) was measured before and after each treatment period, 1 h prior to inhalation of salmeterol or placebo and 1 and 12 h after. Baseline forced expiratory volume in one second (FEV1) increased significantly after salmeterol, both after the first dose and at 4 weeks (BD group: 19 and 17%; ICS: 22 and 13%). On the first day of administration, salmeterol provided significant protection in both groups up to 12 h with a PC20 before and 1 and 12 h postdose of 2.2, 21.7 and 12.4, mg x mL(-1), respectively, in the BD group and 2.1, 11.6 and 55 mg x mL(-1), respectively, in the ICS group. After 4 weeks, this effect was significantly attenuated in both groups with a PC20 before, 1 and 12 h postdose of 3.3, 10.9 and 7.1 mg x mL(-1), respectively, in the BD group and 2.1, 5.0 and 2.3 mg x mL(-1), respectively, in the ICS group. This loss of protective effect was of similar magnitude in both groups. Respiratory symptoms, rescue beta2-agonist use and baseline FEV1 did not change significantly throughout the study in both groups. In conclusion, the bronchoprotective effect of salmeterol decreased with regular use both 1 and 12 h postdose; inhaled corticosteroids did not prevent this reduction. However, the development of tolerance was not associated with loss of asthma control.

Administration, Inhalation↗

PubMed1998

Influence of beclomethasone and salmeterol on the perception of methacholine-induced bronchoconstriction.

BACKGROUND: Patient evaluation of asthma severity and medication needs is mostly based on respiratory symptoms and may be influenced by changes in perception of bronchoconstriction-induced sensations. However, the influence of asthma medication on the ability to perceive symptoms is still to be documented. This study evaluated the effects of short-term and regular use of salmeterol on the perception of methacholine-induced bronchoconstriction (MIB) in subjects with mild asthma, using inhaled salbutamol on an "as required" basis (n=15), and in subjects with moderate asthma, using daily inhaled beclomethasone (mean daily dose, 640 microg; n=15) in addition to salbutamol to control their asthma. METHODS: Methacholine challenges (MC) were performed at entry into the study, and then before, 1, and 12 h following inhalation of 50 microg of salmeterol or a placebo, after a 15-day baseline period; and after 4 weeks of twice daily use of those treatments. The measurements were then repeated with the alternate treatment after a 15-day washout period. Finally, a last MC was performed after another 15-day washout period. For each MC, the perception score of bronchoconstriction-associated breathlessness at 20% fall in FEV1 (PS20) was evaluated on a modified Borg scale from 0 to 10. RESULTS: Subjects using regular beclomethasone had a higher baseline PS20 than those using only salbutamol (means: 3.06 0.06 and 2.01+/-0.07, p=0.0001). Short- and long-term use of salmeterol did not change significantly the PS20 compared with placebo (p>0.05) in either group (with or without corticosteroid). Although there were some intraindividual variations, mean PS20 did not vary significantly throughout the study. CONCLUSION: These observations show that the perception of bronchoconstriction-associated breathlessness is not influenced by regular use of salmeterol. Patients using inhaled corticosteroids show a greater perception of MIB.

Administration, Inhalation↗

PubMed1998

In vitro procollagen synthesis and proliferative phenotype of bronchial fibroblasts from normal and asthmatic subjects.

Asthma is characterized histologically by a bronchial subepithelial fibrosis. Cytokines and other mediators released in the asthmatic chronic inflammatory microenvironment can activate the repair process that leads to fibroblast proliferation and collagen synthesis. To our knowledge, there are no data regarding the effect of a chronic inflammatory microenvironment on the phenotype of human bronchial fibroblasts. In the present study, we address this issue by comparing bronchial fibroblasts isolated from normal and asthmatic subjects in terms of: (a) proliferation over cell passage; (b) in vitro lifespan; (c) proliferative response to transforming growth factor-beta 1, platelet-derived growth factor-BB, dexamethasone, and retinoic acid; and (d) base-line synthesis of procollagens I and III. Bronchial fibroblasts from asthmatic subjects demonstrated lower DNA synthesis with cell passage than bronchial fibroblasts from normals. The in vitro lifespan of asthmatic bronchial fibroblasts was lower than in those from normal subjects and was significantly correlated with airway responsiveness. Platelet-derived growth factor-BB and dexamethasone increased 3H-thymidine incorporation in asthmatic bronchial fibroblasts without having any significant effect on normal fibroblast proliferation. Transforming growth factor-beta 1 and retinoic acid had no significant effect on bronchial fibroblast proliferation. Base-line procollagens I and III synthesis measurements showed no differences between normal and asthmatic fibroblasts. Taken together, these results indicate that the chronic inflammatory microenvironment found in asthma can modulate some aspects of bronchial fibroblast phenotype.

Adult↗

PubMed1997

Identification and analysis of eosinophils by flow cytometry using the depolarized side scatter-saponin method.

This study describes a method for flow cytometric (FCM) identification and analysis of eosinophils (EOS) in mixed granulocyte populations without the need of further cell purification. Granulocytes were prepared from 10 ml blood samples obtained from 14 non-atopic healthy subjects and 16 hypereosinophilic subjects. The cells were fixed in paraformaldehyde (PFA) and permeabilized with either saponin or n-octyl-beta-D-glucopyranoside (OG) before FCM. Side scatter light (SS) and depolarized sideward light scatterings (dSS) were measured before and after granulocyte fixation and permeabilization. Based on autofluorescence of cells, EOS were depicted in forward scatter (FS)-SS and FS-dSS cytograms. FS-dSS analysis of PFA-saponin-treated cells provided the best discrimination between EOS (high dSS) and neutrophils (low dSS) in normal and hypereosinophilic blood samples (n = 22). Subsequent sorting and differential staining of the two populations further confirmed cell identity in high dSS (97.2 +/- 3.0% EOS) and low dSS (99.6 +/- 0.5% neutrophils) PFA-saponin-treated cells (n = 5). Similar FS-dSS profiles were obtained for hypodense (HBSS-1.082 g/ml interface) and normodense (1.082-1.100 g/ml interface) EOS separated by centrifugation on discontinuous Percoll gradients and treated with PFA-saponin. Using this method, we successfully detected the cytokines interleukin-2 (IL-2), IL-4, IL-5, and interferon gamma (IFN gamma) in blood EOS of normal and hypereosinophilic subjects (n = 12). In conclusion, this method allows the analysis of EOS intracellular antigens in mixed granulocyte populations obtained from small blood samples. This analysis is not affected by the buoyant density of eosinophils, and can therefore be applied for the analysis of blood EOS in various types and severities of diseases.

Cell Separation↗

PubMed1997

A twelve-week comparison of salmeterol and salbutamol in the treatment of mild-to-moderate asthma: a Canadian multicenter study.

BACKGROUND: A long-acting inhaled bronchodilator that is both well tolerated and effective could allow for improved control of both daytime and nighttime symptoms in patients with asthma who use frequent as-needed short-acting bronchodilators despite antiinflammatory treatment. OBJECTIVE AND METHODS: We compared the efficacy and safety of inhaled salmeterol, 50 micrograms twice daily, with inhaled salbutamol, 200 micrograms four times daily, delivered through a metered-dose inhaler for 3 months in a multicenter, randomized, double-blind, parallel-group study of 228 patients (aged 12 to 76 years) with mild-to-moderate asthma. RESULTS: A single morning dose of salmeterol produced improvement in FEV1 that was significantly greater (p < or = 0.012) than that produced by two doses of salbutamol (taken 6 hours apart) when patients were assessed 3 to 6 hours and 10 to 12 hours after the dose. This greater bronchodilation was present on day 1 of the study and after 4, 8, and 12 weeks of regular treatment. Over the 12 weeks, compared with salbutamol, salmeterol treatment was associated with a greater mean improvement in morning peak expiratory flow (35 L/min vs -3 L/min, p < 0.001), a higher percentage of days with no symptoms (29% vs 15%; p = 0.012), and a higher percentage of nights with no awakenings (14% vs -1%; p < 0.001). Adverse events were similar for both treatments. CONCLUSIONS: In this study salmeterol, 50 micrograms twice daily, was well tolerated and more effective than salbutamol, 200 micrograms four times daily, in improving symptoms and lung function in patients with mild-to-moderate asthma.

Administration, Inhalation↗

PubMed1997

Inhibitory effects of BAY x 7195, a CYS leukotriene 1 receptor antagonist, on allergen-induced asthmatic responses.

BACKGROUND: Leukotriene antagonists may inhibit bronchoconstrictive responses to a variety of stimuli. OBJECTIVE: To evaluate the efficacy and safety of a new CYS LTI antagonist, BAY x 7195, given as a single oral dose of 500 mg, in prevention of allergen-induced asthmatic responses. METHODS: This is a randomized, double-blind crossover, placebo-controlled study in mildly asthmatic non-smoking subjects (n = 10), aged 20 to 32 years (mean 24.8). Following an initial baseline allergen challenge, the subjects came back for two other challenges separated by at least a 2-week period, during which placebo or BAY x 7195 was administered two hours before allergen inhalation. Allergen challenges were preceded and followed by a methacholine inhalation test (24 hours before and 30 hours after). RESULTS: For each subject, the same allergen and doses were used throughout the study. In the randomized (intent-to-treat) population (n = 10), after BAY x 7195, the allergen induced % fall in FEV1 was less than after placebo, with mean between-treatment differences of 31.8 +/- 18.0% during the early asthmatic response, P = .03, and of 54.4 +/- 23.2% during the late asthmatic response (P = .04). The allergen-induced increase in methacholine responsiveness was reduced after BAY x 7195, with a change of -0.45 doubling concentrations of methacholine as compared with -1.77 after placebo; however, the change did not achieve statistical significance, P = .08. CONCLUSION: BAY x 7195 shows suppressive effects on allergen-induced responses, suggesting that it may be useful in the treatment of asthma.

Adult↗

PubMed1997

Characteristics of bronchial asthma with incomplete reversibility of airflow obstruction.

BACKGROUND: Incomplete reversibility of airflow obstruction (IRAO) can be observed in some asthmatic patients without significant smoking history nor evidence of other respiratory condition. The characteristics of this group remain however to be defined. METHODS: We compared 18 asthmatic patients with persistent airflow obstruction, defined as an FEV1 < or = 75% predicted despite optimal corticosteroid treatment, to others with complete reversibility of airflow obstruction, paired for age and gender (CRAO, FEV1 > 80% of predicted). RESULTS: Mean duration of asthma was 31.6 years for IRAO patients and 17.7 for the CRAO group and mean baseline FEV1 was 48.6 +/- 2.6% and 89.3 +/- 3.4%, respectively. Patients with IRAO had more severe airflow obstruction and hyperinflation than those with CRAO, while lung compliance and CO diffusion were similar. Overall healthcare use was similar in the two groups, but those with IRAO had a greater global asthma-related discomfort, increased diurnal variation of airflow obstruction and used higher doses of inhaled corticosteroids than those with CRAO. Patients with IRAO had slightly increased airway wall thickness on high resolution chest tomography compared with CRAO. Baseline FEV1 however, was not correlated with the measured airway wall thickness. CONCLUSION: We found that asthmatic patients with IRAO have a more severe asthma and asthma of longer duration than asthmatic subjects with CRAO. Our data suggest that in asthma, IRAO may result from long-standing airway inflammation and associated structural changes, although this remains to be further documented.

Administration, Inhalation↗

PubMed1997

Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response.

Inhaled allergens, acting through IgE-dependent mechanisms, are important triggers of asthma symptoms and inducers of airway hyperresponsiveness and airway inflammation. The effect of anti-IgE recombinant humanized monoclonal antibody-E25 (rhuMAb-E25) on the provocation concentration of allergen causing a 15% fall in FEV1 (allergen PC15) during the allergen-induced early asthmatic response (EAR) was assessed in a multicenter, randomized, double-blind, parallel group study. Ten of 11 allergic asthmatic subjects randomized to receive intravenous rhuMAb-E25, 2 mg/kg on study day 0 and 1 mg/kg on Days 7, 14, 28, 42, 56, and 70 completed the study; nine received intravenous placebo. The allergen PC15 was measured on Days -1, 27, 55, and 77 and methacholine PC20 on Days -2, 42, and 76. rhuMAb-25 was well tolerated and only one patient (active group) was withdrawn because of a generalized urticarial rash after the first dose. Compared with baseline values (Day -1), the median allergen PC15 on Days 27, 55, and 77 were increased by 2.3, 2.2, and 2.7 doubling doses (delta log PC15/0.3) respectively with rhuMAb-E25 and -0.3, +0.1, and -0.8 doubling doses with placebo (p < or = 0.002). Methacholine PC20 improved slightly after rhuMAb-E25, this change becoming statistically significant on Day 76 (p < 0.05); no change was observed in the placebo group. Mean serum-free IgE fell by 89% after rhuMAb-E25 while there was no significant change after placebo. The inhibitory effects of rhuMAb-E25 on allergen-induced EAR suggest that it may be an effective, novel antiallergic treatment for asthma.

Adult↗