Influence of body mass index on the response to asthma controller agents.

The incidence of asthma has been positively associated with obesity. Asthma comprises diverse "phenotypes" reflecting heterogeneity in a number of characteristics, including response to therapy. The present authors examined whether body mass index (BMI) influenced the response to placebo, as well as to two asthma controller medications. A post hoc analysis was performed, pooling data from four double-blind, placebo-controlled studies randomising 3,073 moderate asthmatic adults to montelukast (n=1,439), beclomethasone (n=894) or placebo (n=740). The primary end point was asthma control days; other end points were forced expiratory volume in one second, beta-agonist use and nocturnal awakening. Analyses were conducted using BMI classification into normal (<25.0 kg.m-2; 52% of patients), overweight (25-29.9 kg.m-2; 32%) and obese (>or=30.0 kg.m-2; 16%) categories, as well as BMI as a continuous variable. The treatment groups were balanced for BMI, demographic characteristics and parameters of asthma control. The placebo response for all end points was generally lower with increasing BMI. Similarly, the response to the inhaled corticosteroid decreased, whereas the response to the leukotriene antagonist remained stable. In conclusion, post hoc data from the present study suggested that body mass index may influence the natural history of asthma control (as reflected by response to placebo) and may differentially influence response to the two active agents, warranting explicit testing in future prospective studies.

Population impact of losartan use on stroke in the European Union (EU): projections from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study.

The Losartan Intervention for Endpoint reduction in hypertension (LIFE) study was designed to compare losartan- vs atenolol-based antihypertensive treatment on cardiovascular morbidity and mortality in a population of 9193 hypertensive patients with left ventricular hypertrophy (LVH). In LIFE, the losartan-based treatment further reduced the primary composite end point (cardiovascular death, myocardial infarction, or stroke) by 13% (risk reduction (RR) 0.87, 95% confidence interval (CI) 0.77-0.98, P=0.021). The further reduction in stroke with losartan (RR 0.75, 95% CI 0.63-0.89, P=0.001) was the major contributing factor to the reduction in the primary end point. Our objective was to project the reduction in stroke observed with a losartan- vs an atenolol-based antihypertensive treatment regimen in the LIFE study to the European Union (EU) population. The number of stroke events averted was estimated by identifying the number of persons in the EU expected to meet the LIFE inclusion criteria, and multiplying this figure by the cumulative incidence risk difference in stroke from LIFE at 5.5 years. The age- and gender-specific prevalence of hypertension, electrocardiographically (ECG)-diagnosed LVH among those with hypertension (inclusion criteria), and heart failure among those with LVH and hypertension (exclusion criteria) were applied to the EU census estimates. We conservatively projected that an estimated 7.8 million individuals aged 55-80 years in the EU are affected by hypertension and ECG-diagnosed LVH. Use of a losartan-based antihypertensive treatment in this population is projected to prevent approximately 125 000 first strokes over a 5.5-year period. A population-wide prevention strategy of using losartan in patients with LVH and hypertension has the potential to have a major public health impact by reducing the morbidity and mortality of stroke in the EU.

Distribution of therapeutic response in asthma control between oral montelukast and inhaled beclomethasone.

The distribution of responses in study populations provides a novel method of comparing the benefit of two treatments. This 6-week, randomised, placebo-controlled, double-blind study compared the effectiveness of oral montelukast with inhaled beclomethasone in chronic asthma by assessing the distribution and overlap of patient responses to therapy, as measured by a clinical outcome (asthma control days). A total of 730 adult patients with asthma, age 15-65 yrs, with a forced expiratory volume in one second (FEV1) at baseline of 50-85% of predicted and > or = 15% improvement in FEV1 after inhaled beta-agonist were enrolled. After a 2-week placebo run-in period, patients were randomly allocated to receive montelukast (10 mg once daily), inhaled beclomethasone (200 microg twice daily) or placebo. The primary end-point (per cent of asthma control days) was compared between treatments as the overlap in the response distributions. The overlap of the distribution of responses between the montelukast and beclomethasone groups was 89% for per cent asthma control days and 96% for change from baseline in FEV1. The mean (+/-SD) per cent asthma control days in the montelukast and beclomethasone groups was significantly higher than that in the placebo group (placebo 40.0+/-35.8, montelukast 50.7+/-37.1, beclomethasone 57.9+/-36.1). The mean differences between montelukast and placebo, beclomethasone and placebo, and montelukast and beclomethasone were significant. The mean per cent change (+/-SD) from baseline in FEV1 was 12.1+/-18.7 and 13.9+/-20.8 in the montelukast and beclomethasone groups, respectively, and significantly greater than that in the placebo group (6.4+/-20.1); there was no significant difference between the montelukast and beclomethasone groups in mean values or response distribution. There was also no difference among treatment groups in the frequency of adverse experiences. A comparison of the response distribution is an important approach to comparing therapies; montelukast and beclomethasone provided similar response distributions for the end-point of per cent asthma control days over a 6-week treatment period.

Analysis of montelukast in mild persistent asthmatic patients with near-normal lung function.

Few studies have specifically evaluated controller therapy in patients with mild persistent asthma. We used a subgroup analysis to investigate the effects of montelukast, a potent cysteinyl leukotriene receptor antagonist, on adult patients on the milder end of the asthma severity spectrum. We have identified seven double-blind, randomized, placebo-controlled studies of adult patients with mild-to-moderate chronic asthma in which montelukast was investigated. Subsets of patients with baseline forced expiratory volume in 1 sec (FEV1) > 80% and > 75% predicted or further restricted by less than daily rescue beta-agonist use were included as four cohorts (A, B, C, D), and efficacy measures, including change in FEV1 rescue-free days, beta-agonist use, nocturnal awakenings and blood eosinophil counts were evaluated. Cohorts A to D comprised 21%, 8%, 11%, and 4%, respectively, of patients from these studies. Mean pretreatment FEV1 ranged from 81% to 84% predicted and daily beta-agonist use from 2.4 to 4.5 puffs day(-1) in the four cohorts. Pooled results demonstrated a treatment effect for montelukast over placebo in all cohorts, for all endpoints. There was a significant improvement in FEV1 in montelukast-treated patients (7-8% over baseline) compared with placebo (1-4% over baseline, between-group difference P < or = 0.02) for all cohorts. Similarly, the percentage of rescue-free days increased substantially more with montelukast (22-30%) than with placebo (8-13%). This subgroup analysis indicates that montelukast produced improvements in parameters of asthma control in patients with milder persistent asthma that should be confirmed in additional prospective trials.

Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. A randomized, double-blind trial. Exercise Study Group.

BACKGROUND: Montelukast, an oral, once-daily leukotriene receptor antagonist, provides protection against exercise-induced bronchoconstriction. OBJECTIVE: To evaluate the effect of 8 weeks of therapy with salmeterol aerosol or montelukast on exercise-induced bronchoconstriction in adults with asthma. DESIGN: 8-week multicenter, randomized, double-blind study. SETTING: 17 asthma treatment centers in the United States. PATIENTS: 191 adults with asthma who had documented exercise-induced bronchoconstriction. INTERVENTION: Qualified patients were randomly assigned to double-blind treatment with montelukast (10 mg once in the evening) or salmeterol (50 microg [2 puffs] twice daily). MEASUREMENTS: Changes in pre-exercise and postexercise challenge values; percentage inhibition in the maximal percentage decrease in FEV1; the area above the FEV1-time curve; and time to recovery of FEV1 at days 1 to 3, week 4, and week 8 of treatment. RESULTS: By day 3, similar and statistically significant reductions in maximal percentage decrease in FEV1 were seen with both therapies. Sustained improvement occurred in the montelukast group at weeks 4 and 8; at these time points, the bronchoprotective effect of salmeterol decreased significantly. At week 8, the percentage inhibition in the maximal percentage decrease in FEV1 was 57.2% in the montelukast group and 33.0% in the salmeterol group (P = 0.002). By week 8, 67% of patients receiving montelukast and 46% of patients receiving salmeterol had a maximal percentage decrease in FEV1 of less than 20%. CONCLUSIONS: The bronchoprotective effect of montelukast was maintained throughout 8 weeks of study. In contrast, significant loss of bronchoprotection at weeks 4 and 8 was seen with salmeterol. Long-term administration of montelukast provided consistent inhibition of exercise-induced bronchoconstriction at the end of the 8-week dosing interval without tolerance.

A study of losartan, alone or with hydrochlorothiazide vs nifedipine GITS in elderly patients with diastolic hypertension.

We conducted a randomised, double-blind, parallel design study comparing the efficacy and tolerability of the angiotensin II receptor antagonist, losartan, alone or with low-dose hydrochlorothiazide (HCTZ) to the dihydropyridine calcium channel blocker, nifedipine GITS (gastro-intestinal therapeutic system), in elderly patients (> or =65 years old) with a diastolic blood pressure (DBP) between 95 and 115 mm Hg. After a placebo wash out period, 140 patients were randomly assigned to receive either losartan 50 mg or nifedipine GITS 30 mg. Patients were evaluated at 4-week intervals during a 12-week treatment period. Patients receiving losartan had HCTZ 12.5 mg added and increased to 25 mg to reduce DBP <90 mm Hg. Patients receiving nifedipine GITS had their dose increased to 60 mg and 90 mg to reduce DBP <90 mm Hg. Efficacy, tolerability and quality of life were assessed during the 12 weeks on each regimen. Patients treated with the losartan regimen (n = 73) had reductions in trough sitting DBP of -10, -13, and -13 mm Hg after 4, 8, and 12 weeks of therapy, respectively. Patients receiving the nifedipine GITS regimen (n = 67) had DBP reductions of -14, -15, and -15 mm Hg, respectively. There were no significant differences in the DBP response between the treatment groups except at week 4 (P < 0.05). Similar reductions in systolic BP (SBP) between the two treatment groups were observed at all time points. The percentages of patients in the two treatment groups reaching goal DBP (<90 mm Hg or DBP > or =90 mm Hg with a reduction from a baseline of > or =10 mm Hg) were comparable (81% on the losartan regimen and 90% on the nifedipine GITS regimen). There were significantly more adverse events reported in patients receiving nifedipine GITS when compared to the losartan regimen (54% vs 36%, P < 0.05). A patient-reported symptom inventory also showed that swollen ankles was bothersome in significantly more patients treated with the nifedipine GITS regimen when compared to the losartan regimen (24% vs 5%, P = 0.001). Thus, in elderly patients with diastolic hypertension, a regimen of losartan alone or with HCTZ has similar efficacy to a regimen of nifedipine GITS with greater tolerability and less symptom bother due to swollen ankles.

Expression patterns of adhesion receptors in the developing mouse lung: functional implications.

A detailed, immunohistological study of mouse lung development from the first appearance of primary lung buds off the laryngo tracheal groove through the formation of the mature, adult lung has been carried out using monoclonal antibodies specific for endothelial cells, smooth muscle cells, adhesion receptors and markers of mature endothelial cell function. These included mAbs specific for PECAM-1, alpha-smooth muscle actin, ICAM-1, ICAM-2, VCAM-1, alpha 4 and alpha 6 integrin subunits, thrombomodulin and factor VIII. The results document a dynamic pattern of receptor expression and indicate that the expansion of the pulmonary vascular system may take place by both angiogenic and vasculogenic processes. They further document differences in receptor expression by vascular and airway smooth muscle. ICAM-1 expression was primarily extravascular during development. The expression patterns of alpha 4 integrin and its counter receptor VCAM-1 lacked the complementarity that might be expected if they were functioning as a receptor/counter-receptor pair in lung development. Thrombomodulin expression patterns support a major role for the thrombin/ thrombomodulin system in lung development. The expression of thrombomodulin only at sites of airway branching suggests that the thrombin/thrombomodulin system could play a pivotal, regulatory role in branching morphogenesis.

Efficacy, tolerability, and quality of life of losartan, alone or with hydrochlorothiazide, versus nifedipine GITS in patients with essential hypertension.

A randomized, double-masked, parallel-group, multicenter clinical trial was conducted to compare the efficacy, tolerability, and effects on quality of life associated with the angiotensin II receptor antagonist losartan, alone or with hydrochlorothiazide (HCTZ), and the dihydropyridine calcium channel blocker nifedipine gastrointestinal therapeutic system (GITS) in patients whose sitting diastolic blood pressure measurements were between 95 and 115 mm Hg, inclusive, while receiving placebo. Patients were randomized to receive either losartan or nifedipine GITS in a double-masked, double-dummy fashion. A 4-week placebo washout period established baseline untreated blood pressure measurements and was followed by a 12-week active treatment period. Patients receiving losartan (n = 110) were initially given 50 mg once a day (QD) and could be titrated to losartan/HCTZ 50 mg/12.5 mg QD after 4 weeks followed by losartan/HCTZ 50 mg/25 mg QD after 8 weeks, as necessary. Patients in the nifedipine GITS group (n = 113) received 30 mg QD, which could titrated to 60 mg QD after 4 weeks followed by 90 mg QD after 8 weeks. Medication was titrated upward as necessary to achieve a sitting trough diastolic blood pressure < 90 mm Hg. Efficacy, tolerability, and quality-of-life scores were assessed after 12 weeks of each therapy. Trough sitting diastolic blood pressure reductions after 4, 8, and 12 weeks of therapy were clinically comparable: losartan, -8.9, -11.6, and -12.7 mm Hg, respectively, and nifedipine GITS, -9.3, -11.0, and -11.1 mm Hg, respectively, with the mean reduction in sitting diastolic blood pressure at 12 weeks in the losartan group 1.6 mm Hg lower (95% confidence interval, 3.4 mm Hg lower to 0.3 mm Hg Higher) than the mean reduction in sitting diastolic blood pressure in the nifedipine GITS group. Similarly, reductions in systolic blood pressure between the two treatment groups were comparable at all time points. The percentage of patients reaching the goal trough sitting diastolic blood pressure was comparable for the two treatment groups, with 74% of patients in the losartan regimen and 68% of patients in the nifedipine GITS regimen reaching the goal. Of patients reporting adverse events in the two groups (75 patients receiving losartan and 69 receiving nifedipine GITS), there was significantly more edema in the nifedipine GITS group (15% vs 4%; P = 0.005). Fourteen (12%) patients in the nifedipine GITS group were withdrawn due to an adverse event (eight of these were for edema). Six patients (5%) in the losartan group were withdrawn due to an adverse event (none of these patients had edema). There were significant differences in the patient-reported quality-of-life symptom bother inventory with respect to edema, with nifedipine GITS therapy causing significantly more bother due to edema in patients, regardless of whether that symptom was present at baseline (27% vs 9%; P = 0.0004). No statistically significant differences for bother due to the other symptoms in the inventory were noted. Of note, while the incidence of patient-reported symptom bother due to edema in the nifedipine GITS group was 27%, the incidence of physician-reported drug-related edema was 12%. This difference points to the need for improved physician-patient communication regarding adverse effects and their impact of patients' quality of life. In conclusion, a regimen of losartan, when compared with a regimen of nifedipine GITS, provides comparable efficacy, and with respect to edema, superior tolerability, less bother to patients, and fewer therapy dropouts.

Efficacy and tolerability of losartan versus enalapril alone or in combination with hydrochlorothiazide in patients with essential hypertension.

The antihypertensive effects and the tolerability of losartan and enalapril given alone or in combination with hydrochlorothiazide (HCTZ) were compared in a multicenter, double-blind, randomized, parallel-group, 16-week clinical trial. The study consisted of a 4-week placebo washout phase and a 12-week active treatment phase. Patients with mild-to-moderate, uncomplicated essential hypertension were considered for participation in the study. To enter the treatment phase of the study, a mean sitting diastolic blood pressure (SiDBP) > or = 95 and < or = 115 mm Hg was required. Patients received either 50-mg losartan once daily or 5-mg enalapril once daily at randomization. The dose of enalapril could be titrated to 10 mg after 4 weeks and 25 mg of HCTZ could be added after 8 weeks, based on measurements of SiDBP at clinic visits. The dose of losartan remained at 50 mg; 12.5 mg of HCTZ could be added after 8 weeks. Changes in the treatment regimen at each step were required if SiDBP remained > or = mm Hg. Doses of the diuretic were chosen based on commercially available forms of the test agents in combination with HCTZ. Trough blood pressure, heart rate, and safety parameters were measured at 4-week intervals during the treatment phase of the study. Significant reductions in mean SiDBP and mean sitting systolic blood pressure (SiSBP) were achieved at all time points (4, 8, and 12 weeks) with both treatments. No significant differences between treatment groups for mean changes in SiDBP or SiSBP were observed overall. At study end, patients receiving the losartan regimen had a mean reduction in SiDBP of 10.3 mm Hg, whereas patients in the enalapril regimen had a mean reduction of 9.8 mm Hg. Likewise, the percentage of patients reaching goal blood pressure reduction was not significantly different between groups. The mean reduction in SiDBP-- but not SiSBP--in black patients was slightly greater in the losartan group than in the enalapril group (SiDBP, 10.0 mm Hg losartan vs 8.0 mm Hg enalapril; P = 0.02). Similarly, losartan patients aged 65 years and older had a slightly greater decrease in SiDBP than comparable enalapril patients (12.7 mm Hg vs 8.7 mm Hg; P = 0.03). The importance of these differences between subgroups must be clarified by additional studies. Overall, both treatments were well tolerated. A regimen of losartan alone or in combination with HCTZ was effective in treating patients with essential hypertension and was comparable to a regimen of enalapril alone or in combination with HCTZ. However, treatment with losartan was associated with a lower incidence of cough.

The mouse VLA-2 homologue supports collagen and laminin adhesion but not virus binding.

Human VLA-2 (alpha 2 beta 1) mediates cellular adhesion to collagen and laminin and cell attachment by the human pathogen echovirus 1. We report here the cloning, sequencing and functional expression of the mouse VLA-2 alpha subunit homologue. This integrin subunit is closely related to its human counterpart, with 84% amino acid identity between the human and murine proteins. Conserved structural features include an identical number of amino acids, the presence of an I domain, and identity in the number and position of N-linked glycosylation sites and putative divalent cation binding regions. Murine and human alpha 2 show 30% amino acid divergence within the cytoplasmic tail, a difference that can be detected with antisera directed against the C-terminal peptides. Functionally, mouse alpha 2 was capable of mediating cell attachment to collagen and laminin, and responded to both intra- and extracellular signals with changes in its ligand affinity. In contrast, unlike its human homologue, mouse alpha 2 did not promote binding of echovirus 1. Comparison of the primary structure of the homologues leads us to predict that echovirus 1 may bind in the region of the first two thirds of the human alpha 2 I domain, where the sequences are most divergent, whereas more conserved flanking regions, and the conserved terminal one third of the I domain, may be involved in adhesion to collagen and laminin.

Structure/function analysis of the integrin beta 1 subunit by epitope mapping.

Monoclonal antibodies (mAbs) have been produced against the chicken beta 1 subunit that affect integrin functions, including ligand binding, alpha subunit association, and regulation of ligand specificity. Epitope mapping of these antibodies was used to identify regions of the subunit involved in these functions. To accomplish this, we produced mouse/chicken chimeric beta 1 subunits and expressed them in mouse 3T3 cells. These chimeric subunits were fully functional with respect to heterodimer formation, cell surface expression, and cell adhesion. They differed in their ability to react with a panel anti-chicken beta 1 mAbs. Epitopes were identified by a loss of antibody binding upon substitution of regions of the chicken beta 1 subunit by homologous regions of the mouse beta 1 subunit. The identification of the epitope was confirmed by a reciprocal exchange of chicken and mouse beta 1 domains that resulted in the gain of the ability of the mouse subunit to interact with a particular anti-chicken beta 1 mAb. Using this approach, we found that the epitopes for one set of antibodies that block ligand binding mapped toward the amino terminal region of the beta 1 subunit. This region is homologous to a portion of the ligand-binding domain of the beta 3 subunit. In addition, a second set of antibodies that either block ligand binding, alter ligand specificity, or induce alpha/beta subunit dissociation mapped to the cysteine rich repeats near the transmembrane domain of the molecule. These data are consistent with a model in which a portion of beta 1 ligand binding domain rests within the amino terminal 200 amino acids and a regulatory domain, that affects ligand binding through secondary changes in the structure of the molecule resides in a region of the subunit, possibly including the cysteine-rich repeats, nearer the transmembrane domain. The data also suggest the possibility that the alpha subunit may exert an influence on ligand specificity by interacting with this regulatory domain of the beta 1 subunit.

Cell adhesion receptors and early mammalian heart development: an overview.

Cardiovascular development is the end result of a complex genetic program subject to regulation by signals transmitted between a cell and its extracellular environment. As cells encounter new extracellular matrices or establish new cell-cell interactions, new genes must be activated to accommodate the altered developmental situation within which the cell finds itself. This is likely reflected in a program of adhesion receptor and counter receptor expression on the surface of cells engaged in the morphogenesis. To understand the molecular basis of development, it is necessary to first determine if such a program exists and then to establish the role of various receptors and counter receptors in the particular morphogenetic process under investigation. To this end, we have initiated an investigation into expression of specific adhesion receptors during cardiovascular development in the mouse. Here, we demonstrate that platelet endothelial cell adhesion molecule (PECAM)-1 is an excellent marker for following vascular formation in the mammalian embryo. It is expressed during development in several alternatively spliced forms involving the cytoplasmic domain of the molecule. These forms differ in their ligand binding properties. Thus, a change in the cytoplasmic domain affects the folding of the molecule in such a way as to structurally alter the extracellular domain. Further, several receptors including the laminin receptor, the fibronectin receptor and a hyaluronic acid receptor, display specific expression patterns during heart development. These include differential expression in the endocardium and myocardium, down regulation during endocardial and myocardium, down regulation during endocardial cushion formation and cessation of expression in particular regions of the heart upon maturation. Interference with the function of one of these receptors (the fibronectin receptor) results in aberrant heart formation. These observations strongly support the concept that morphogenesis requires specific cell adhesion molecules that are expressed in precisely choreographed programs.

Cytoplasmic and transmembrane domains of integrin beta 1 and beta 3 subunits are functionally interchangeable.

Integrin beta subunits combine with specific sets of alpha subunits to form functional adhesion receptors. The structure and binding properties of integrins suggest the presence of domains controlling at least three major functions: subunit association, ligand binding, and cytoskeletal interactions. To more carefully define structure/function relationships, a cDNA construct consisting of the extracellular domain of the avian beta 1 subunit and the cytoplasmic and transmembrane domains of the human beta 3 subunit was prepared and expressed in murine 3T3 cells. The resulting chimeric beta 1/3 subunit formed heterodimers with alpha subunits from the beta 1 subfamily, could not interact with alpha IIb from the beta 3 subfamily, was targeted to focal contacts, and formed functional complexes within the focal contacts. A second cDNA construct was prepared that coded for an avian beta 1 subunit without a transmembrane or cytoplasmic domain. This subunit was not found in association with an accompanying alpha subunit, nor was it found expressed on the cell surface. Instead, it accumulated in vesicles within the cytoplasm and was eventually shed from the cell. The results from studies of the behavior of these two cDNA constructs demonstrate that the transmembrane and cytoplasmic domains play no role in alpha subunit selection, that the cytoplasmic domain of beta 3 is capable of functioning in the context of alpha subunits with which it is not normally paired, and that both integrin subunits must be membrane associated for normal assembly and transport to cell surface adhesive structures.

Cryptococcal pulmonary infection in patients with AIDS: radiographic appearance.

The clinical, laboratory, and radiographic findings in seven patients with acquired immunodeficiency syndrome (AIDS) and cryptococcal pulmonary infections were reviewed. The infection was most commonly seen on radiographs as lymphadenopathy, interstitial infiltrates, or both. Interstitial infiltrates were commonly nodular. Large nodules or alveolar infiltrates, the most common findings at presentation in both immunocompetent patients and immunocompromised patients without AIDS, were not present in our series. Isolated pleural effusion was seen as the only radiographic finding in one case. Meningitis was present in six of seven cases and was neurologically silent in five of six cases. Cryptococcal pneumonia in AIDS patients should prompt a search for neurologically silent cryptococcal meningitis.