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.

A pharmacokinetic comparison of two oral liquid glucocorticoid formulations.

To compare pharmacokinetics of liquid prednisolone and prednisone solutions and to assess relative bioavailability, six healthy adult men were administered 15 mg of each formulation. Blood samples were obtained and assayed for plasma prednisolone concentrations by high-performance liquid chromatography. Peak concentration was significantly higher with liquid prednisolone (mean +/- SD 430.3 +/- 62.5 vs 333.0 +/- 27.8 ng/ml, p = 0.013), with similar times to peak concentration. Prednisolone liquid gave higher concentrations at every time point (statistically significant for all except 0.25 hrs after the dose), resulting in a significantly greater total area under the curve (2029.8 +/- 246.9 vs 1633.3 +/- 221.1 ng/ml.hour, respectively, p = 0.002). Clearance was slower for prednisolone (128.3 +/- 15.1 vs 149.1 +/- 17.6 ml/min/1.73 m2, p = 0.01), and the relative bioavailability of the prednisolone liquid using prednisone liquid as the reference standard was 116 +/- 14%. Thus, prednisolone liquid has similar pharmacokinetic characteristics as prednisone liquid, with improved bioavailability.

Chamber challenges: the necessity of objective observation.

the specialty of Allergy-Immunology has used human challenge testing procedures to test theories of causal relationships for decades. This includes highly characterized airborne allergens and chemicals with allergic sensitization potential. The utility of such testing to establish allergic sensitivity is well accepted. The causal relationship of chemical exposure and myriad clinical syndromes is a very contentious issue. The completion of the challenge chamber facility at EPA's Human Exposure Research Facility presents a grand opportunity for government investigators to work harmoniously with other government investigators in an effort to bring the redeeming spotlight of scientific discipline to the testy considerations of multiple chemical sensitivity, chronic fatigue, and Gulf War illness phenomena.

Effectiveness of fluticasone propionate in patients with moderate asthma: a dose-ranging study.

This study was undertaken to evaluate the efficacy and safety of fluticasone propionate, an inhaled corticosteroid, in adolescents and adults with moderate asthma who were previously taking inhaled corticosteroids. After a 2-week, open-label screening period, a double-masked, randomized, parallel-group, dose-ranging study was conducted over 12 weeks in 21 outpatient centers throughout the United States. Patients (N = 304) > or = 12 years of age with moderate asthma previously treated with inhaled corticosteroids and beta-sympathomimetic bronchodilators were enrolled. Patients were assigned to receive placebo or fluticasone propionate 100, 250, or 500 micrograms twice daily via a metered-dose inhaler without a spacer device. These doses refer to the amount of fluticasone propionate released from the valve of the metered-dose inhaler; the corresponding doses released from the activator of the metered-dose inhaler are 88 micrograms, 220 micrograms, and 440 micrograms, respectively. Between baseline and end point, mean values of forced expiratory volume in 1 second decreased 0.31 L in the placebo group and improved 0.39 L, 0.30 L, and 0.43 L in patients receiving 100-micrograms, 250-micrograms, and 500-micrograms fluticasone propionate, respectively. The differences between placebo and all treatment groups were statistically significant. More patients were withdrawn from placebo (72%) than from fluticasone propionate (13% to 16%) because of failure to meet predetermined asthma stability criteria. Differences in baseline-to-end point changes in morning peak expiratory flow rate, physician overall assessments and patient-rated assessment of symptoms, and albuterol use for symptom control also significantly favored each fluticasone propionate group over placebo. There were essentially no differences in efficacy among the three fluticasone propionate groups. Treatment-related adverse events occurred in 8% of placebo-treated patients and 13% to 15% of fluticasone propionate-treated patients; these events were mainly localized to the oropharynx/ larynx. A 12-week course of fluticasone propionate (100, 250, and 500 micrograms twice daily) was well tolerated and more effective than placebo based on maintenance of asthma stability, pulmonary function tests, physician and patient assessments, and rescue bronchodilator use. No dose-related effects were observed with the dosages of fluticasone propionate used in this study.

Onset of action of aqueous beclomethasone dipropionate nasal spray in seasonal allergic rhinitis.

Beclomethasone dipropionate nasal spray is widely used in the treatment of seasonal allergic rhinitis; however, the time of onset of action has not been determined. This study assessed the onset of action, level of relief, and efficacy of beclomethasone nasal spray in patients with seasonal allergic rhinitis. In a double-blind, randomized, placebo-controlled, parallel-group, multicenter, 7-day study, symptomatic patients were administered two inhalations of beclomethasone dipropionate (n = 80) or placebo (n = 81) into each nostril twice daily. Patients assessed the onset of action and level of relief at 6, 24, and 48 hours and at days 3 and 7. Investigators evaluated symptoms at days 0, 3, and 7 and response to therapy at days 3 and 7. The difference in the cumulative number of patients reporting relief of symptoms was statistically significant in favor of beclomethasone dipropionate by hour 24 (P = 0.05). Patients in the beclomethasone dipropionate group experienced a greater level of relief than patients receiving placebo at hour 24, and improvement increased over the 7-day study compared with a decrease in relief in the placebo group. Beclomethasone dipropionate was significantly more effective than placebo in reducing symptoms (P < or = 0.02), and patients in the beclomethasone dipropionate group showed a more favorable response to treatment than did patients in the placebo group (P < 0.01). Adverse events were minor in both groups. Beclomethasone dipropionate nasal spray produced significant onset of relief of symptoms the first day of treatment; improvement was sustained and increased over the course of the study.

Failure to assess psychopathology in patients presenting with chemical sensitivities.

Mediating processes can be inferred from self-report data only if it can be assumed that the patient has a valid capacity for introspection. That assumption is invalid when beliefs can be shown to influence sensory perception and symptom reports. Another serious limitation of self-reporting is that the individual has only a limited awareness of his or her psychological state. Also, we cannot ignore the observations that come from the psychodynamic tradition, that unconscious or subconscious ideas also can affect and distort self-reporting. The lack of validity of self-reports is summarized by Brewin: "[T]he value of self-reports would appear to be more in their relation to intentional future actions than in any insight they might provide into complex feeling states or into the contingencies governing past behavior." A more objective procedure for obtaining information about EI/MCS patients' beliefs is clearly needed before their symptom reports can be taken at face value.

Latex allergen in respirable particulate air pollution.

OBJECTIVE: Urban air samples contain numerous irregular respirable black particles, which may be airborne tire fragments. A major component of tires is natural latex. Proteins of natural latex can act as adjuvants and as antigens capable of eliciting immediate hypersensitivity, making their presence in particulate air pollution an important clinical issue. METHODS: Particulate air pollutants were collected by volumetric sampling devices and characterized by optical microscopy, chemical solubility tests, and mass spectrometry. Extracts of rubber tire fragments were tested for elutable latex antigens by antibody inhibition assays. RESULTS: Identification of latex in air samples and milled material from automobile tires was supported by mass spectrometry results and was further confirmed by physical appearance and chemical solubility studies. Competitive immunoassay confirmed the presence of extractable latex antigens from rubber tire fragments. CONCLUSIONS: Latex antigens are extractable from rubber tire fragments, which are abundant in urban air samples. Given the adjuvant and sensitizing effects of latex, these airborne particles could contribute, through direct and indirect mechanisms, to the increase in both latex sensitization and asthma. The impact of these particles should be considered in the issue of morbidity and mortality rates associated with respiratory diseases and air pollution.

Adult sequelae of childhood abuse presenting as environmental illness.

Sixty-three patients with polysomatic complaints attributed to sensitivity to environmental chemicals had detailed clinical assessments and diagnostic psychologic evaluations. Objective medical parameters failed to substantiate their beliefs that multiple chemicals were the cause of their problems. A group of 64 patients with chronic medical conditions and defined psychologic disorders not attributed to chemical exposure served as controls. Approximately half the patients in each group underwent long-term psychotherapy, and in these patients, the prevalence of physical and sexual childhood abuse was significantly higher (P < .05) among the cohort of women who attributed their symptoms to environmental or chemically related illness. These data suggest that somatization may reflect sequelae of childhood abuse and may play an important role in the illness experienced by women who believe they are sensitive to environmental chemicals.

Intranasal flunisolide spray as an adjunct to oral antibiotic therapy for sinusitis.

BACKGROUND: The diagnosis of sinusitis is difficult and there are few controlled studies of customary therapies. In particular, the possible role of topical intranasal steroid as an adjunct to antibiotic treatment has not been evaluated. METHODS: The study was a multicenter, double-blind, randomized, parallel trial in which patients aged 14 years or older were recruited from allergy practices. All patients had maxillary sinusitis documented by radiographs. Treatment consisted of amoxicillin/clavulanate potassium 500 mg combined with nasal spray of either 100 micrograms flunisolide or placebo to each nostril three times a day for 3 weeks (phase I) followed by administration of flunisolide or placebo nasal spray alone three times a day for 4 weeks (phase II). RESULTS: Clinical symptoms and signs decreased significantly in both treatment groups during phase I (p < 0.01). There was a trend to greater improvement in the patients treated with flunisolide, but only the decrease in turbinate swelling/obstruction was statistically significant at the end of phase I when compared with placebo (p = 0.041). Patients' global assessment of overall effectiveness of treatment was higher for flunisolide than placebo after phase I (p = 0.007) and after phase II (p = 0.08). Maxillary sinus radiographs showed improvement in both treatment groups during phase I (p < 0.004) with somewhat greater regression of abnormal findings in patients treated with flunisolide after phase II (p = 0.066). However, 80% of radiographs were still abnormal at the end of phase I. All types of inflammatory cells were significantly decreased in nasal cytograms in patients treated with flunisolide in comparison with those treated with placebo. Flare-up of sinusitis during phase II occurred in 26% of with those treated with placebo. Flare-up of sinusitis during phase II occurred in 26% of patients treated with flunisolide and 35% of those treated with placebo and tended to be more severe in the latter, although these differences were not statistically significant. Adverse events, mainly gastrointestinal symptoms and headache, were similar in both groups and more frequent in phase I than in phase II, (42 vs 15 patients); these side effects were probably due to the antibiotic. CONCLUSION: The addition of flunisolide topical nasal spray as an adjunct to antibiotic therapy was most effective in global evaluations, tended to improve symptoms, to decrease inflammatory cells in nasal cytograms, to normalize ultrasound scans, and to aid regression of radiographic abnormalities compared with placebo spray.

Double-blind provocation chamber challenges in 20 patients presenting with "multiple chemical sensitivity".

A clinical algorithm was used to discriminate verifiable chemical sensitivity from psychological disorders in patients referred for evaluation of polysomatic symptoms attributed to hypersensitivity to workplace and domestic chemicals. These patients believed that they were reactive or hypersensitive to low-level exposure to multiple chemicals. Some had previously been evaluated and managed by the tenets of "clinical ecology" and diagnosed as having "multiple chemical sensitivity." Double-blind provocation challenges with an olfactory masker were performed in an environmental chamber on each of 20 patients. A variety of chemicals was employed, one or more per subject, dependent on individual clinical history. Clean air challenges with the olfactory masker were used as placebo or sham controls. As a group, probability analyses of patient symptom reports from 145 chemical and clean air challenges failed to show sensitivity (33.3%), specificity (64.7%), or efficiency (52.4%). Individually, none of these patients demonstrated a reliable response pattern across a series of challenges. Implications for future research in assessment methodology incorporating neurophysiologic and neurobehavioral measures are discussed.

Immunoassay of specific IgE: low level assays require measurement of allergen specific assay background.

The allergen-specific backgrounds of a paper disk radioimmunoassay (RIA) system and a cellulose sponge fluorescent enzyme immunoassay (FEIA) system were evaluated using three inhalants, timothy, short ragweed, and cat, with reagents obtained from the same manufacturer. Radioimmunoassay was performed with Phadebas RAST reagents by the modified RAST method, and FEIA by the Pharmacia CAP System. Horse serum, 5% HSA, assay diluent, and serum pools from nonallergic and allergic patients, were assayed. The lower limit of detection (LLD) was defined using both the Z distribution (as is conventional) and the t distribution. The solid phases, analytes, and assays differed (p less than .001) in background results. For RIA, background was lowest for timothy and highest for cat; for FEIA, background was lowest for cat and highest for short ragweed. For RIA, background assessed with the allergic serum pool was higher than the other analytes; for FEIA, responses of the five analytes did not differ. For timothy and short ragweed, background of RIA was lower than FEIA. For FEIA, the highest LLD calculated using the Z distribution was 11 SD lower than the manufacturer's recommended quantitative cutoff; for RIA, the highest LLD calculated was 2.5 SD higher than the recommended analytic cutoff. The analytic false positive rate for RIA may differ between allergic and nonallergic patient populations. Laboratories reporting results near either assay's background should set LLD based on assay of allergen-specific negative controls in each assay run.

Immunoassay of specific IgE: use of a single point calibration curve in the modified radioallergosorbent test.

Interest in immunoassay standardization has prompted development of specific IgE assays reporting results related to the international IgE reference. To examine the single point calibration curve employed in the modified RAST assay (MRT) to convert MRT counts to IgE units, independent dilutions of a 25 kU/L total IgE reference and nine allergic sera (three each for short ragweed, cat, and timothy) were made in horse serum and assayed. In a log-log plot, the single point curve was, by definition, linear over its entire range; the dilution curve was curvilinear because of reagent system saturation, which was at 7 kU/L. Curves were not parallel (P less than .001). Allergen-specific dilution curves showed saturation points at values similar to or less than the total IgE system. The linear portions of these curves paralleled the total IgE dilution curve but not the single point curve. This lack of parallelism would have resulted in varying magnitudes of error in estimation of IgE antibody levels in the upper and lower assay ranges, and would imply a lower detection limit for IgE than that which the assay actually has. Modified RAST assay is not appropriate in research or a clinical situation in which accurate quantitative results are needed. Modified RAST assay would furthermore be an inappropriate means of assigning units to proposed reference preparations for standardization.

The histamine content of allergen extracts.

The histamine content of 108 inhalant, food, and venom extracts from four commercial sources was measured by chemical (glass fiber-based) and immunologic (competitive RIA) methods. Histamine was present in 64 of 76 inhalant extracts (range, 0.005 to 7.4 micrograms/ml), 20 of 26 food extracts (range, 0.16 to 23 micrograms/ml), and six of six venoms, 100 micrograms/ml (range, 1.0 to 38 micrograms/ml). Histamine was removed by treatment with diamine oxidase or dialysis of an extract. Repeat assay of selected extracts after addition of known amounts of histamine in the glass fiber-based method produced additive results, and glycerin- or phenol-extract preservatives did not affect assay performance. Timed extractions of dried-pollen grains demonstrated maximal histamine content at 30 seconds, suggesting that histamine is an inherent component of at least some pollens. Histamine found in some allergen extracts could, under extreme circumstances, produce false-positive results in skin testing and in basophil histamine release assays, and could affect the result of research that uses intact pollen or allergen extracts.

Comparison of skin testing and three in vitro assays for specific IgE in the clinical evaluation of immediate hypersensitivity.

A new assay, Pharmacia CAP System (PCS), for allergen-specific IgE (sIgE) was evaluated in 198 new patients presenting with respiratory symptoms to an urban allergy practice. An experienced allergist examined each patient and clinically assessed sensitivity to timothy, short ragweed, Alternaria tenuis, cat, or D. farinae. Puncture and selected intracutaneous skin tests (ST) with these inhalant extracts were then performed. The physician again rated the likelihood of clinical sensitivity to each inhalant, and serum was obtained for sIgE measurements by Phadebas RAST, modified RAST, and PCS. Results of the three in vitro tests (IVT) correlated well with each other and generally agreed with physician assessments and ST results. Individual differences for extracts and assay methods were identified. A few patients with negative ST had positive IVT, but more patients with positive ST were negative by IVT. Modified RAST had greater sensitivity but less specificity than the other two IVT. Analysis of receiver operating characteristic curves showed that sensitivity of the three assays when compared at the 95% level of specificity, did not differ. This result suggests that the cutoff criterion for a positive modified RAST result is too low and should be reevaluated. Skin tests remain the most sensitive and specific test available. The Pharmacia CAP System is a clinically useful assay for sIgE and appears to be a clear advancement for IVT technology.

The effect of repeat action albuterol sulfate (Proventil Repetabs) in nocturnal symptoms of asthma.

At four medical centers, 98 patients with stable asthma, histories of nighttime awakening at least three times weekly and nighttime declines of pulmonary function of at least 15%, who were not taking oral adrenergic agonists, were randomly treated with either oral repeat-action albuterol sulfate (Proventil Repetabs), 4 mg in the morning and 4-16 mg at bedtime, or a placebo for 2 weeks. All patients were required to have nocturnal symptoms of asthma, with prior use of bronchodilators other than oral adrenergic agonists to be eligible for the study. The patients maintained a diary of asthma symptom scores and recorded peak flow rates at home at bedtime and in the morning. They had spirometry (FEV1, FVC, and PEFR) after a 1-week baseline stabilization period, and after 1 and 2 weeks of double-blind oral therapy as noted above. Efficacy was evaluated by changes in the bedtime and morning peak flow rates, changes in the number of nighttime awakenings, results of office spirometry testing, and by physician and patient global evaluations of response to therapy. Of the 98 patients in the study, 47 received oral albuterol, and 51 received placebo. The patients on albuterol had a statistically significant reduction in the number of nighttime awakenings (p less than or equal to 0.01), as compared with the patients on placebo; this included both the average number of awakenings per week (p = 0.04), and the mean number of nights with awakenings per week (p = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)