Mometasone furoate: efficacy and safety in moderate asthma compared with beclomethasone dipropionate.

BACKGROUND: Mometasone furoate (MF) is a new inhaled glucocorticoid administered by dry powder inhaler (DPI). OBJECTIVE: MF-DPI was evaluated for safety and efficacy and compared with placebo DPI and beclomethasone dipropionate (BDP) administered by metered dose inhaler (MDI) in the treatment of patients with moderate persistent asthma. METHODS: Eligible patients (n = 227), 13 to 75 years of age, maintained on inhaled glucocorticoids before entering the trial, were randomized to receive: MF-DPI, 100 microg, twice daily, MF-DPI, 200 microg, twice daily, BDP MDI, 168 microg, twice daily, or placebo in a 12-week, multicenter, double-blind study. RESULTS: At endpoint, FEV1 (primary efficacy variable) significantly improved for all three active treatments compared with placebo (P < .01, all comparisons). The response to MF-DPI, 200 microg, twice daily treatment was approximately twice as large as the response to MF-DPI, 100 microg, twice daily or BDP MDI treatment, although the differences between these groups did not reach statistical significance. Secondary efficacy variables including PEFR, asthma symptoms, nocturnal awakenings, and albuterol use showed similar trends. The MF-DPI, 100 microg, twice daily and BDP MDI, 168 microg, twice daily treatment groups produced comparable results for all efficacy variables. CONCLUSIONS: MF-DPI, 100 microg and 200 microg, twice daily were well-tolerated and significantly improved lung function and symptom control in the treatment of patients with moderate persistent asthma. In this study, MF-DPI, 200 microg, twice daily seemed to be the most effective dosage.

Comparison of once-daily to twice-daily treatment with mometasone furoate dry powder inhaler.

BACKGROUND: Once-daily dosing with an effective inhaled corticosteroid (ICS) would likely enhance compliance and, therefore, aid in the management of asthma. OBJECTIVE: Several once-daily dosing regimens of mometasone furoate (MF) administered by dry powder inhaler (DPI) were compared with a twice-daily dosing regimen in 286 patients with mild to moderate persistent asthma who were previously being treated with ICS. METHODS: During a 2-week open-label phase, patients received MF-DPI, 200 microg twice daily. They were then randomized to continue MF-DPI, 200 microg twice-daily treatment or to receive MF-DPI, 200 microg once daily in the morning (AM), 200 microg once daily in the evening (PM), 400 microg once daily AM, or placebo as part of the 12-week, double-blind phase. The primary efficacy variable was the mean change from the baseline to endpoint (last evaluable observation) for FEV1. RESULTS: Once-daily MF-DPI, 400 microg, AM maintained FEV1, and morning peak expiratory flow rate, FVC, FEF25%-75%, and asthma symptom scores, at levels similar to those for MF-DPI, 200 microg twice daily and significantly better than placebo. Once-daily MF-DPI, 200 microg, PM was effective in maintaining pulmonary function, but was less effective on other efficacy measures. In comparison to the other MF-DPI groups, once-daily MF-DPI, 200 microg, AM was not as effective overall. The incidence of local adverse events, including oral candidiasis, was low with all dosages. CONCLUSIONS: Once-daily MF-DPI, 400 microg, AM was as effective as MF-DPI, 200 microg twice daily, whereas once-daily MF-DPI, 200 microg, was more effective when administered in the evening compared with morning, for patients receiving ICS therapy. Once-daily dosing offers an effective and convenient treatment that could aid compliance in the treatment of asthma.

Inhaled mometasone furoate reduces oral prednisone requirements while improving respiratory function and health-related quality of life in patients with severe persistent asthma.

BACKGROUND: Inhaled corticosteroid therapy in severe persistent asthma has been shown to reduce or eliminate oral corticosteroid (OCS) use while retaining effective asthma control. OBJECTIVE: We sought to evaluate the ability of mometasone furoate (MF) delivered by means of dry powder inhaler to reduce daily oral prednisone requirements in OCS-dependent patients with severe persistent asthma. METHODS: We performed a 12-week, double-blind, placebocontrolled trial (21 centers, 132 patients) comparing 2 doses of MF (400 and 800 microg administered twice daily) with placebo, followed by a 9-month open-label phase in which 128 patients received treatment with MF. RESULTS: At the endpoint of the double-blind trial, MF 400 and 800 mg twice daily reduced daily OCS requirements by 46.0% and 23.9%, respectively, whereas placebo increased OCS requirements by 164.4% (P <.01). Oral steroids were eliminated in 40%, 37%, and 0% of patients in the MF 400 and 800 mg twice daily and placebo groups, respectively. Pulmonary function and quality of life significantly increased for MF-treated patients. Further reductions in OCS requirements were achieved with long-term MF treatment in the open-label phase. CONCLUSION: MF inhaled orally as a dry powder is an effective alternative to systemic corticosteroids in patients with severe persistent asthma.

Once-daily mometasone furoate dry powder inhaler in the treatment of patients with persistent asthma.

BACKGROUND: Although inhaled glucocorticoids are recommended for all stages of persistent asthma, compliance with long-term therapy is often poor, leading to significant morbidity and mortality. A simplified, once-daily dosing regimen may foster improved compliance. OBJECTIVE: To compare the efficacy and safety of once-daily (AM) administration of mometasone furoate dry powder inhaler (MF DPI) 200 microg and 400 microg with placebo in patients with asthma previously maintained only on short-acting inhaled beta-adrenergic receptor agonists. METHODS: This was a 12-week, double-blind, placebo-controlled, parallel group study. The mean change from baseline to endpoint (last treatment visit) for FEV1 was the primary efficacy variable. RESULTS: At endpoint, both doses of MF DPI were significantly more effective than placebo (P < or = .05) in improving FEV1. Based on morning peak expiratory flow rate, once-daily MF DPI 400 microg was more effective than placebo (P < or = .001) at endpoint. Both active treatments also demonstrated improvement at endpoint in asthma symptom scores, physician-evaluated response to therapy and use of rescue medication. Although both MF DPI dosages were efficacious, MF DPI 400 microg provided additional improvement in some measures of pulmonary function (eg, morning PEFR) when these agents were administered once daily in the morning. Both doses of MF DPI were well tolerated and treatment-related adverse events occurred at a similar incidence among the three treatment groups. CONCLUSIONS: The results of this study indicate that once-daily (AM) MF DPI provides a convenient and effective treatment option for patients with mild or moderate persistent asthma.

Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray.

OBJECTIVE: Intranasal corticosteroids are used widely for the treatment of allergic rhinitis because they are effective and well tolerated. However, their potential to suppress growth of pediatric subjects with allergic rhinitis continues to be a concern, particularly in light of reports of growth suppression after treatment with intranasal beclomethasone dipropionate or intranasal budesonide (see the article by Skoner et al in this month's issue). A 1-year study of prepubertal patients between 3 and 9 years of age with perennial allergic rhinitis was conducted to assess the effects on growth of mometasone furoate aqueous nasal spray (MFNS), a new once-daily (QD) intranasal corticosteroid with negligible bioavailability. METHODS: This was a randomized, placebo-controlled, double-blind, multicenter study. Ninety-eight subjects were randomized to treatment with either MFNS 100 microg QD or placebo for 1 year. Each subject's height was required to be between the 5th and 95th percentile at baseline, and skeletal age at screening was required to be within 2 years of chronological age, as determined by left wrist x-rays. Washout periods for medications that affect either childhood growth or allergic rhinitis symptoms were established based on estimated period of effect, and these medications were prohibited during the study. However, short courses of either oral prednisone lasting no longer than 7 days or low-potency topical dermatologic corticosteroids lasting no longer than 10 days were permitted if necessary. Height was measured with a calibrated stadiometer at baseline and at 4, 8, 12, 26, 39, and 52 weeks, and the primary safety variable was the change in standing height. The rate of growth was also calculated for each subject as the slope (linear regression) of the change in height from baseline using data from all visits of subjects who had at least 2 visits. Hypothalamic-pituitary-adrenocortical- (HPA)-axis function was assessed via cosyntropin stimulation testing at baseline and at 26 and 52 weeks. All analyses were based on all randomized subjects (intent-to-treat principle). The change from baseline in standing height was analyzed by a 2-way analysis of variance that extracted sources of variation attributable to treatment, center, and treatment-by-center interaction. RESULTS: Demographic characteristics were similar at baseline. Eighty-two subjects completed the study (42 in the MFNS group and 40 in the placebo group), and 93% of subjects achieved at least 80% compliance with therapy. After 1 year of treatment, no suppression of growth was seen in subjects treated with MFNS, and mean standing heights were similar for both treatment groups at all time points. For the primary safety variable (change in height from baseline), both treatment groups were similar at all time points except for weeks 8 and 52. Subjects treated with MFNS had a slightly greater mean increase in height than subjects treated with placebo at these time points: the change in height was 6.95 cm versus 6.35 cm at the 1-year time point. However, the rate of growth (.018 cm/day) averaged for all time points over the course of the study was similar for both treatment groups. Additional analyses found that MFNS did not retard growth in any sex or age subgroup of subjects. The use of exogenous corticosteroids other than the study drug was also similar among the 2 treatment groups. Results from cosyntropin stimulation testing confirmed the absence of systemic effects of MFNS. The change from baseline in the difference between prestimulation and poststimulation levels was similar for both treatment groups after 1 year of treatment, with no evidence of HPA-axis suppression in MFNS-treated subjects at any time point. Incidences of treatment-related adverse events were similar for both treatment groups, with 16% of MFNS-treated subjects reporting adverse events, compared with 22% of placebo-treated subjects. CONCLUSIONS: (ABSTRACT TRUNCATED)

Comparison of the efficacy and safety of mometasone furoate dry powder inhaler to budesonide Turbuhaler.

Mometasone furoate (MF) administered by dry powder inhaler (DPI) was composed with budesonide (BUD) Turbuhaler in the treatment of moderate persistent asthma. The patients were randomized to one of four treatment groups: MF DPI (100, 200, 400 microg b.i.d) or BUD Turbuhaler. 400 microg b.i.d in a 12-week, active-controlled, evaluator-blind, multicentre international trial. The primary efficacy variable was the mean change from baseline to endpoint (last treatment visit) in forced expiratory volume in one second (FEV1). Changes in FEV1 showed a statistically significant superiority (p<0.05) of MF DPI 200 and 400 microg b.i.d compared with the BUD Turbuhaler 400 microg b.i.d treatment. Significant superiority (p<0.05) was also seen in scores for several secondary efficacy variables when MF DPI was compared with BUD Turbuhaler treatment. MF DPI 200 microg b.i.d was comparable to MF DPI 400 microg b.i.d in therapeutic benefit. The incidence of oral candidiasis was no more than 3% in any group. All treatments were well tolerated. A total daily dose of 400 microg of mometasone furoate administered by dry powder inhaler provides a well-tolerated treatment for patients with moderate persistent asthma and results in a significantly greater improvement, when compared to a daily dose of 800 microg BUD Turbuhaler in the parameters measured in this study.

Dose-ranging study of a new steroid for asthma: mometasone furoate dry powder inhaler.

A new formulation of mometasone furoate (MF) for administration by dry powder inhaler (DPI) was evaluated for the treatment of asthma. A 12-week, double-blind, placebo-controlled dose-ranging study compared the efficacy and safety of three doses of MF DPI (100, 200 and 400 mcg b.i.d) with beclomethasone dipropionate (BDP) 168 mcg b.i.d. administered by metered dose inhaler in 365 adult or adolescent patients being treated with inhaled glucocorticoids. The mean change from baseline to endpoint (last treatment visit) for forced expiratory volume in 1 sec (FEV1) was the primary efficacy variable. Secondary efficacy variables included other objective measures of pulmonary function [forced vital capacity (FVC), forced expiratory flow 25-75% (FEV25-75%.) and peak expiratory flow rate (PEFR)] as well as subjective measures of therapeutic response (patients' daily evaluation of asthma symptoms and physicians' evaluation). At endpoint, all four active treatments were significantly more effective than placebo (P < 0.01) in improving FEV1 (MF DPI 5 to 7%, BDP 3%, placebo -6.6%) and all other measures of pulmonary function (FVC: MF DPI 4 to 5%, BDP 2%, placebo -4.7%; FEF25-75%: MF DPI 6 to 18%, BDP 7.5%, placebo -9.5%; PEFR (AM): MF DPI 5 to 10%, BDP 5.7%, placebo -7%). A consistent trend was observed for better improvement in patients treated with MF DPI 200 mcg b.i.d. than with MF DPI 100 mcg b.i.d., with no apparent additional benefit of MF DPI 400 mcg b.i.d. Results for the MF DPI 100 mcg b.i.d. and BDP 168 mcg b.i.d. treatment groups were similar. Patients' and physicians' subjective evaluations of symptoms found similar improvement in the MF DPI 200 and 400 mcg b.i.d. treatment groups, which were slightly better than that in the MF DPI 100 mcg b.i.d. group. Symptoms tended to worsen in the placebo group. MF DPI was well tolerated at all dose levels and the most frequently reported treatment-related adverse effects were headache, pharyngitis and oral candidiasis. No evidence of HPA-axis suppression was detected in any treatment group. In summary, all doses of MF DPI were well tolerated and significantly improved lung function and MF DPI 400 mcg (200 mcg b.i.d.) was the optimal dose in this study of patients with moderate persistent asthma.

Onset of action of mometasone furoate nasal spray (NASONEX) in seasonal allergic rhinitis.

BACKGROUND: Mometasone furoate nasal spray (MFNS, NASONEX ), is a new synthetic corticosteroid with considerable efficacy in the treatment of seasonal and perennial rhinitis and less than 0.1% systemic absorption. This study was designed to evaluate the time of onset of action of MFNS. The subjects were evaluated over the course of 2 weeks during the spring allergy season. METHODS: The effects of MFNS 200 microg given once daily for 2 weeks were evaluated in a randomized, multicenter, double-blind, placebo-controlled study in 201 patients with seasonal allergic rhinitis. Clinically significant onset of action was assessed prospectively by special patient diary cards kept during the first 3 days of treatment. RESULTS: By 12 h after initial dosage (the earliest evaluation), 28% of patients in the MFNS group experienced clinically significant relief, compared with 13% of those given placebo (P = 0.01). Median time to at least moderate symptom relief in patients who received MFNS was 35.9 h, compared with more than 72 h in patients given placebo (P<0.01). By 72 h, 64% of the patients receiving MFNS experienced at least moderate relief, compared with 40% of those treated with placebo (P<0.01). Both patient and physician ratings of symptom severity, response to treatment, and overall condition of rhinitis indicated significant (P<0.01) superiority of MFNS over placebo. MFNS was well tolerated, with adverse events comparable to placebo. CONCLUSIONS: MFNS provided rapid onset of clinically significant symptom relief in patients with seasonal allergic rhinitis.

Effect of mometasone furoate on early and late phase inflammation in patients with seasonal allergic rhinitis.

BACKGROUND: Mometasone furoate is a potent glucocorticoid that can markedly inhibit proinflammatory Th2 cytokines in vitro. An aqueous nasal spray formulation has been shown to be clinically active in reducing the symptoms of perennial and seasonal allergic rhinitis. OBJECTIVE: To determine whether pretreatment with mometasone furoate 200 microg once daily decreases specific indices of early and late phase nasal inflammation compared with placebo. METHODS: A randomized, double-blind, placebo-controlled crossover study was conducted using nasal provocation with ragweed antigen in 21 patients with ragweed-induced allergic rhinitis out of the ragweed season; the treatment period was 2 weeks. Symptom scores, rhinoprobe cytology, and nasal lavage fluid were collected during early and late phase periods for nasal cytokines (interleukin, 1, 4, 5, 6, and 8) and leukotriene B4 determinations using ELISA and RIA. RESULTS: Mean nasal symptom scores and sneezing frequency were consistently lower with mometasone furoate compared with placebo. Treatment was associated with a statistically significant early phase (30-minute time point) reduction in nasal lavage histamine levels compared with placebo (14.3 versus 20.2 ng/mL, P = .02). Within-treatment comparisons suggested that mometasone furoate reduced the antigen-induced late-phase response for IL-6, IL-8, and eosinophils compared with pretreatment. There were similar, but smaller, changes seen in the placebo group for these measurements. There were no statistically significant changes following antigen challenge in IL-1, IL-4, IL-5, LTB4, or in other nasal cytology parameters. CONCLUSION: These results suggest that the clinical activity of mometasone furoate nasal spray in seasonal allergic rhinitis is likely due, in part, to a reduction in the levels of histamine in nasal secretions related to the early phase response, and reductions in IL-6, IL-8, and eosinophils during the late phase response.

The responsiveness of disease-specific and generic health measures to changes in the severity of asthma among adults.

The objective of the study was to compare the validity of asthma-specific and generic health outcome measures in relation to changes in the severity of asthma and to treatment. Adult patients (n = 142) participating in a randomized placebo-controlled trial at six clinics were assessed at baseline, prior to the withdrawal (placebo) or continuation of treatment with Vanceril and again after 8 weeks. The criterion measures of change in severity included pulmonary function expressed as the percent predicted FEV1, five physician-assessed asthma severity measures (cough, chest tightness, wheezing, shortness of breath and overall condition) and two patient-assessed severity measures (night-time symptoms and overall symptoms). The 8 week change scores were estimated for all generic and specific measures and the results were compared across groups of patients who did and did not change in terms of clinical criteria of disease severity and across treatment groups. The responsiveness of each generic and specific measure was estimated independently using the relative validity (RV) methodology, which compares F-ratios for the mean change scores across measures in analyses of the same comparison groups. RV coefficients estimate how much worse each measure discriminated between comparison groups, relative to the best measure (RV = 1.0). Four standardized asthma-specific measures and a total scale score (based on the Marks questionnaire), an individualized asthma-specific scale measuring limitations in activities most important to each patient (based on the Juniper method) and two newly-developed scales measuring physical and psychosocial symptoms were used as outcome measures, generic health outcome measures included eight functional health and well-being scales as well as the physical and mental health summary scales from the SF-36 health survey. A standardized asthma-specific scale was most valid in discriminating between groups of patients who did and did not change according to all of the clinical criterion variables studied and in discriminating between treated and untreated groups. Different scales performed best, depending on the clinical criterion. The asthma-specific Marks breathlessness scale was significant in all nine comparisons (RV = 0.62-1.0) and was most valid in discriminating between groups in six of nine tests. The overall scale also performed well in all comparisons (RV = 0.58-1.0). The newly-developed physical symptoms scale was significant in discriminating between groups in eight out of nine tests (RV = 0.52-1.0) and was most valid in three of the nine, including the treatment comparison. The psychosocial impact scale discriminated significantly in eight of the nine comparisons (RV = 0.16-0.38), but was less valid than other specific measures. The asthma-specific individualized activities scale discriminated significantly in seven of the nine tests, but performed less well than the other specific measures (RV = 0.21-0.35) and was not significant in the treatment comparison. One or more SF-36 scales discriminated significantly between groups in all nine comparisons. Two of those scales (physical functioning and role-physical) were consistently more valid than the others (RV = 0.17 and 0.58, respectively) and were the only two generic scales that discriminated between groups of patients defined in terms of changes in FEV1 (RV = 0.26-0.58). The SF-36 physical summary scale discriminated significantly between groups in all nine comparisons (RV = 0.19-0.61) and was the most valid generic measure in the treatment comparison (RV = 0.55). The SF-36 mental summary scale was significant only for the two patient-assessed changes in disease severity (RV = 0.31 and 0.32) and for physician-assessed overall severity (RV = 0.12). A comprehensive battery of generic and specific measures is likely to be most useful in understanding the impact of changes in disease severity on the functional health and well-being of adults with asthma, a

Dose ranging study of mometasone furoate (Nasonex) in seasonal allergic rhinitis.

BACKGROUND: Topical nasal corticosteroids are rapidly gaining acceptance as first-line therapy for seasonal allergic rhinitis, but there is a desire for effective corticosteroids with an improved safety profile over existing products. OBJECTIVE: A multicenter, double-blind dose ranging study was conducted to compare the activity and tolerance of four doses of mometasone furoate nasal spray (tradename Nasonex) and placebo in adult patients with seasonal allergic rhinitis. METHODS: Four hundred eighty patients with seasonal allergic rhinitis were enrolled and randomized to receive mometasone furoate nasal spray 50 micrograms (n = 96), 100 micrograms (n = 95), 200 micrograms (n = 98) or 800 micrograms (n = 95), or placebo vehicle (n = 95) once daily for 28 days. RESULTS: All of the doses of mometasone furoate nasal spray showed activity in reducing the severity of rhinitis. The 200-microgram dose reduced total nasal symptom scores and total symptom scores throughout the study (P < .05 versus placebo vehicle). The 50-microgram dose and the 100-microgram dose showed less consistent activity at early timepoints (days 3 and 7), while the 800 microgram dose did not provide significant additional benefits over the 200-microgram dose. All dose levels were well tolerated CONCLUSION: The results of this trial indicate that 200 micrograms once daily is the optimum dose of mometasone furoate nasal spray for the treatment of seasonal allergic rhinitis.

A comparison of double-strength beclomethasone dipropionate (84 microg) MDI with beclomethasone dipropionate (42 microg) MDI in the treatment of asthma.

STUDY OBJECTIVE: To compare the efficacy and safety of a double-strength formulation of beclomethasone dipropionate (BDP 84) metered-dose inhaler (MDI) with that of beclomethasone dipropionate (BDP 42) MDI in the treatment of chronic asthma. DESIGN: A 28-day, randomized, double-blind, double-dummy, placebo-controlled, multicenter study. SETTING: Outpatient. PATIENTS: A total of 423 patients aged 12 to 65 years (mean range, 34 to 36 years) with moderate asthma (FEV1, 50 to 80% of predicted) who required long-term inhaled corticosteroids were enrolled. INTERVENTIONS: Patients were randomized to receive BDP 84, two oral inhalations bid (336 microg/d), BDP 42, four oral inhalations bid (336 microg/d), or placebo. A fourth treatment arm administering BDP 84, eight oral inhalations bid (HD BDP 84; 1,344 microg/d) was also included to determine whether a dose-response relationship could be demonstrated. MEASUREMENTS: Spirometry, clinical observations. RESULTS: The three active treatments were significantly more effective (p < or = 0.01) than placebo at all time points in improving FEV1, the primary efficacy parameter; BDP 42 and BDP 84 were comparable to each other at every time point. Secondary pulmonary function tests (FVC, forced expiratory flow at 25 to 75% of FVC, and peak expiratory flow rate) showed similar results. All three active treatments were well tolerated. A dose response between 336 microg/d and 1,344 microg/d was demonstrated. CONCLUSION: In this well-controlled 28-day study, BDP 42 and BDP 84 were shown to be comparable in efficacy and safety on a microgram-for-microgram basis.

Microvascular and macrovascular endothelial cells produce different constrictor substances.

The media from cultured microvascular and macrovascular endothelial cells (conditioned media, CM) were collected and tested for constrictor activity in sheep coronary artery rings and tracheal smooth muscle strips in vitro (isometric force), expressed as percentage of contraction produced by 80 mM KCl. Both microvascular (micro) and macrovascular (macro) CM caused a sustained slow-onset contraction (P less than 0.05) of the coronary artery rings by 71 +/- 10% (micro; n = 7) and 67 +/- 8% (macro; n = 6) and tracheal smooth muscle strips by 33 +/- 14% (micro; n = 6) and 34 +/- 6% (macro; n = 11); the calcium antagonist gallopamil (10(-7) M) attenuated these effects by 25-55%. Unconditioned medium and medium conditioned by cultured tracheal smooth muscle cells had no constrictor activity on coronary artery rings or tracheal smooth muscle strips. Synthetic endothelin (ET-1) also produced contraction of coronary artery rings and tracheal smooth muscle strips. The mean levels of ET-1 measured by radioimmunoassay were 1,200 pg/ml in the macro CM and 33 pg/ml in the micro CM. Depleting macro CM of ET-1 by affinity columns constructed with protein A agarose and anti-ET-1 antibody removed the contractile activity for coronary artery rings and tracheal smooth muscle strips. Thus ET-1 did not appear to be the contractile substance in the micro CM. Preliminary characterization of the contractile substance in micro CM revealed that it was heat stable, had a molecular weight of less than 10,000, was inactivated by trypsin, and retained its activity after two cycles of freeze-thawing.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement of tumor necrosis factor-induced endothelial cell injury by cycloheximide.

Tumor necrosis factor (TNF), a potent polypeptide mediator released by activated monocytes and macrophages, has a number of proinflammatory effects on endothelial cells. TNF is cytotoxic to tumor cells in vivo and in vitro, but TNF-induced toxicity to endothelial cells is less well established. We now report that cycloheximide (CHX), an inhibitor of protein synthesis, renders endothelial cells highly susceptible to TNF-induced lysis. TNF alone did not change the overall rate of protein synthesis by endothelial cells, whereas the addition of CHX completely abolished protein synthesis. Endothelial cells incubated in TNF alone in high concentrations (up to 1,000 U/ml) showed minimal rounding up and release of 51Cr. Likewise, CHX alone (5 micrograms/ml) had no significant effect on endothelial cell morphology and release of 51Cr. However, incubation of endothelial cells in both CHX and TNF caused injury in a dose-dependent manner. Morphological evidence of cell retraction, rounding, and detachment began within 2 h, but specific 51Cr release did not begin to rise until after 4 h. These changes were not observed when endothelial cells were incubated with TNF/CHX at 4 degrees C. The combination of TNF/CHX was lethal to all endothelial cells tested (bovine pulmonary artery, human umbilical vein, and human aorta), with human aortic cells showing the most pronounced changes. We conclude that healthy endothelial cells are resistant to TNF-induced lysis, but inhibition of their ability to make protein renders them highly susceptible.

Endothelin-1 from pulmonary artery and microvessels acts on vascular and airway smooth muscle.

The conditioned medium (CM) from microvascular and macrovascular endothelial cell (EC) cultures was tested for constrictor activity. Sheep coronary artery rings, under 1 g tension, and sheep tracheal smooth muscle strips, under 2 g tension, were hung in organ baths containing Krebs-Henseleit solution (39 degrees C) and were equilibrated with 95% O2 and 5% CO2. Isometric force was measured in response to 80 mM KCl and constrictor responses to 100% CM were expressed as a percentage of maximum KCl response. Serum-free CM from confluent microvascular endothelial cells caused a sustained, slow-onset contraction of the coronary rings similar to that obtained with CM from macrovascular ECs. Indomethacin (5 microM) added to either the microvascular or macrovascular CM enhanced the constrictor responses by 1.6- and 1.8-fold, respectively, and the constrictor effects of both media were reduced by the calcium antagonist gallopamil (10 nM). CM from macrovascular EC caused a sustained contraction of tracheal strips similar to microvascular CM. In both cases, constriction was preceded by a brief relaxation as noted in vascular smooth muscle. Unconditioned medium had no constrictor activity on either vascular or airway smooth muscle. Microvascular-derived constrictor activity was heat stable. There was a slight loss of activity in the heat-treated CM from the macrovascular cells compared with control CM. Constrictor effects on tracheal smooth muscle were partially reversed by 1 microM gallopamil.

Glucose utilization in vivo by human pulmonary neoplasms.

Neoplastic tissue in general shows a high rate of glucose consumption under both anaerobic and aerobic conditions. Using positron emission tomography (PET) we measured the rate of uptake of the glucose analogue 18fluoro-2-deoxy-D-glucose (18FDG) in 12 patients with carcinoma of the lung. The tumor types were six squamous cell, two large cell, two oat cell, one adenocarcinoma, and one undifferentiated carcinoma. In each patient a transaxial plane was selected that contained the bulk of the tumor tissue. Regional density and blood volume were measured. Following the intravenous injection of 18FDG, the rates of uptake in the tumor and normal lung tissue were assessed from sequential scans over 1 hour. In each patient the rate of uptake of 18FDG in the tumor tissue was significantly increased relative to normal lung tissue. For the group the rate of uptake by the tumor was 211.4 +/- 69.4 ml/100 g/hr (mean +/- SD) compared to 31.9 +/- 13.2 in the contralateral lung (P less than 0.05). The tumor-to-normal tissue ratio of 6.6 (range, 2.7 to 14.6) was higher than previously reported ratios for brain and liver tumors. In contrast to brain tumors there was little correlation between tumor type and rate of 18FDG uptake. Measurements of glucose metabolism taken in vivo in human pulmonary tumors may lead to advances in screening, staging, and therapy.

A comparison of 99mTc-DTPA and 113mIn-DTPA aerosol clearances in humans. Effects of smoking, hyperinflation, and in vitro oxidation.

As an index of permeability of the alveolar epithelium, the clearance of an inhaled aerosol of 99mTc-DTPA is increased in several disease states. However, the usefulness of the test to assess the severity of disease is limited because healthy smokers also have abnormally rapid rates of clearance. Because the stability of the 99mTc-DTPA bond might be a contributory factor, we tested the affinity of 99mTc for DTPA in vitro, and in groups of healthy smokers (n = 13) and nonsmokers (n = 7) we measured the clearances of 99mTc-DTPA and 113mIn-DTPA, which have a similar molecular shape and charge. In vitro, sodium hypochlorite or hydrogen peroxide released as much as 98% of free 99mTc from the 99mTc-DTPA complex. When incubated with human neutrophils stimulated with phorbol myristate acetate, between 4 and 7% of free 99mTc-DTPA was released after 30 min, and 12% was released after 60 min. In vivo, the clearances of both 99mTc-DTPA and 113mIn-DTPA in the smokers (n = 13) were faster than in the nonsmokers (n = 7) (p less than 0.05). Within the smokers, the mean 99mTc-DTPA clearance (T1/2 25 +/- 4 min) was faster than the mean 113mIn-DTPA clearance (34 +/- 6 min), (p less than 0.05). For nonsmokers, the difference was smaller (T1/2 99mTc-DTPA, 56 +/- 6; T1/2 113mIn-DTPA, 62 +/- 6) and not significant. During hyperinflation, smokers (n = 8) and nonsmokers (n = 8) both demonstrated an increase in 113mIn-DTPA clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of aerosolised 99mTc DTPA clearance to predict outcome in patients with adult respiratory distress syndrome.

The rate of clearance of technetium-99m labelled diethylene triamine pentacetic acid (99mTc DTPA) was measured in 32 patients with adult respiratory distress syndrome to determine if a more rapid clearance rate, possibly reflecting a more severe abnormality of pulmonary function, was associated with a reduced likelihood of recovery from pulmonary failure. Although the mean rate of clearance from lung to blood (T1/2LB) of 99mTc DTPA was more rapid in the patients (T1/2LB = 29 (SEM 3.2) min than in 42 normal subjects (T1/2LB = 59 (1.8)min), there was no difference between the clearance rate in the 18 patients who recovered from respiratory failure (T1/2LB = 31 (5) min) and the 14 who died (T1/2LB = 27 (4) min). Additionally, not all patients studied had abnormally rapid clearance rates. In 12 of the 32 patients the T1/2 fell within the range for normal individuals; this was found more commonly in patients who were predisposed to develop adult respiratory distress syndrome by pancreatitis or massive blood transfusion. These data suggest that a single measurement of 99mTc DTPA clearance in patients with established respiratory failure and adult respiratory distress syndrome is of no value in assessing the likelihood of recovery from this condition.

Epithelial and endothelial flux after bypass in dogs: effect of positive end-expiratory pressure.

Cardiopulmonary bypass (CPB) causes lung injury that occasionally progresses to the adult respiratory distress syndrome (ARDS). We measured the effect of 10 cmH2O of positive end-expiratory pressure (PEEP) on small solute and protein flux in dogs 1 wk before and 2 h after the completion of CPB. As an index of alveolar epithelial permeability, the clearance from lung to blood of inhaled technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA) was measured. To assess microvascular endothelial integrity, the rate of accumulation in the lung interstitium of intravascular 113mIn-transferrin was measured. The clearance half time (t 1/2) for 99mTc-DTPA in the study dogs declined from 18.8 +/- 1.9 min (mean +/- SE) at base line to 9.4 +/- 2.0 min during PEEP (P less than 0.05). Two hours after CPB, the t 1/2 was 8.1 +/- 1.6 min at base line and unchanged during PEEP. The 113mIn-transferrin rate of accumulation was unchanged by PEEP before CPB. After CPB, the index was 3.25 +/- 0.95 slope/min X 10(-3) (P less than 0.05). Of the five dogs with a significant slope, four showed a decrease in microvascular flux during PEEP, although for the group the mean change in slope was not significant (P = 0.10). We conclude that the application of PEEP does not increase 99mTc-DTPA clearance in lungs already injured by CPB, and may actually decrease the apparent microvascular protein flux in some cases.

Positive end-expiratory pressure increases pulmonary clearance of inhaled 99mTc-DTPA in nonsmokers but not in healthy smokers.

Positive end-expiratory pressure (PEEP) is widely used in the treatment of severe pulmonary oedema, although its effects on the clearance of water and small solutes from alveolus to blood are not well characterized. We studied the effect of the application of 10 cmH2O of PEEP on the flux of inhaled 99mTc-diethylene-triamine-penta-acetic acid (DTPA) from lung to blood in six healthy smoking and six nonsmoking subjects. The rate of flux was corrected for possible changes in pulmonary blood volume during PEEP by use of an intravenous injection of 99mTc-DTPA. The baseline clearance rate (K, % X min-1) for nonsmokers was 1.48 +/- 0.12 (mean +/- SE) and increased to 2.40 +/- 0.29 during PEEP (p less than 0.05). In contrast, the mean clearance rate for smokers was 3.26 +/- 0.82 at baseline and 3.03 +/- 0.82 during PEEP (p = NS). The application of positive end-expiratory pressure appears to increase alveolar solute flux in nonsmokers but not in smokers, suggesting that the pathway for solute clearance in smokers is governed by different rate-limiting steps to those of nonsmokers.