Clinical response and serum prostaglandin levels in aspirin idiosyncrasy. Effect of aspirin and a new nonsteroidal anti-inflammatory agent.

Clinical measurements and serum prostaglandin concentrations were monitored in three normal subjects, three asthmatic controls and five asthmatic patients with aspirin (ASA) idiosyncrasy before and after oral challenge with small doses of aspirin. Additionally, in the latter group, the effects of ASA were compared with those of piroxicam, a new nonsteroidal anti-inflammatory agent. Challenge with either agent caused bronchospasm in patients with aspirin idiosyncrasy, but was more severe after piroxicam. Nasal stuffiness and/or rhinorrhea preceded or accompanied the changes in pulmonary function with both agents. Serum prostaglandin concentrations, which reflect synthesis by platelets during the clotting of blood, revealed significant decreases in PGE1, PGE2, and PGF2 alpha and thromboxane B2 within two to four hours after drug administration in all subjects with or without ASA idiosyncrasy. The change in serum PG concentration was presented when bronchospasm developed in patients with ASA idiosyncrasy, but persisted for a longer time, reflecting the irreversible effect of these agents on the cyclo-oxygenase enzyme in platelets. The results demonstrate that administration of minute doses of ASA and other nonsteroidal anti-inflammatory drugs alters prostaglandin synthesis in normal and asthmatic subjects with or without ASA idiosyncrasy. Alteration in arachidonate metabolism may be responsible for the induction of bronchospasm, and cautious use of cyclo-oxygenase inhibitors in patients with known or suspected ASA idiosyncrasy is indicated.

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.

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.

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.

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.

Neuropsychophysiology during relaxation in generalized, universal 'allergic' reactivity to the environment: a comparison study.

Comparisons were made among a group of patients presenting with universal 'allergic' intolerance to environmental chemicals (universal reactor, n = 58), a group of control subjects without psychologic symptoms (control, n = 55) and a group of outpatients from a psychology practice (psychologic, n = 89) on neuropsychophysiological measures during relaxation. The measures were electroencephalographic (EEG) spectral category for frequencies below 15 Hz, EEG beta activity, scalp electromyography (EMG), peripheral temperature (TEMP), and skin resistance level (SRL). The distributions of subjects in each group across eight EEG spectral categories were significantly different, with the distribution for universal reactors the same as that of the psychologic patients (p = 0.22), and both different from the distribution of controls (p less than 0.001). High levels of EEG beta activity were observed in more universal reactors and psychologic patients than in controls (p = 0.04). High levels of EMG scalp activity were observed in a greater number of universal reactors than in subjects in the other two groups (p less than 0.001). The three groups did not differ in TEMP and SRL. Implications of neuropsychophysiologic stress profiling for the diagnosis and treatment of psychosomatic illness are discussed.

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.

Visualization techniques in the nasal airway: their role in the diagnosis of upper airway disease and measurement of therapeutic response.

Flexible fiberoptic rhinopharyngolaryngoscopy permits the examination of most areas of the upper airway that heretofore have not been easily visualized with other available techniques. Use of the flexible fiberscope is safe, convenient, quick, and cost efficient. Abnormalities can be easily seen relating to the septum, turbinates, and mucosa, as well as the nasopharynx, adenoids, eustachian orifice, tonsils, posterior tongue, epiglottis, glottis, and vocal cords. The origin of nasal polyps can also be identified. Furthermore, effects of treatment can be followed with the fiberscope as well. For example, when flunisolide is given to a patient with allergic rhinitis, the reduction of nasal obstruction and edema can be easily visualized.

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.

Rhinolaryngoscopy in the allergy office.

Rhinolaryngoscopy is a valuable diagnostic and treatment assessment tool for the allergist. We present a method for office use of the rhinolaryngofiberscope and review our experience with 400 consecutive examinations.

Parents' subjective evaluation of a self-help education-exercise program for asthmatic children and their parents.

A self-help education-exercise program for asthmatic children and their parents was evaluated in Denver, Colorado. The objective of the program was to instill better self-care practices in the child which are expected to reduce utilization and cost of medical services and reduce the amount of interference in the child's normal activities. The program was designed to educate the family about the nature of asthma and its treatment, the importance of self-responsibility for the child, and the psychosocial aspects which may affect both the child and the parents in a family with an asthmatic child. The program also included specific lessons pertaining to self-care practices including general health exercises on land and in water, relaxation training, and diaphragmatic breathing. The results of subjective evaluations of the parents indicated that the program was successful in achieving its goals to: Reduce the number of severe attacks, reduce medication usage, improve compliance, reduce days of school missed, increase exercise activity, and control wheezing by the steps taught in the course. While the results are suggestive, a further, controlled evaluation of the program is recommended.

The practical approach to the evaluation of suspected environmental exposures: chemical intolerance.

The purpose of this article is to encourage allergists to expand their interest in environmental intolerance to include chemicals found in everyday exposure. By incorporating controlled challenge procedures into outpatient practice capabilities, the practicing allergist can expand both clinical interest and practice potential. By merging scientific principles of toxicology and psychology with the traditional investigative skills of the well-trained clinical allergist, we believe that discipline of allergy/immunology can realize a rather remarkable new dimension.

The hidden tonsils of Waldeyer's ring.

The visible and the hidden tonsils of Waldeyer's ring merit attention from specialists in allergy and clinical immunology not only because they are sites of antigen recognition and synthesis of antibody, including IgE, but also because they may produce a wide range of symptoms in the upper airway. Ordinarily, such symptoms may be differentiated from those of classic allergic rhinitis, but allergists commonly see patients with a variety of upper airway complaints that on investigation prove not to have an allergic basis. Use of flexible fiberoptic upper airway endoscopy, a simple office procedure that permits direct inspection of the recessed areas of the upper airway, will result in timely evaluation and treatment of pathology of these upper airway lymphatic structures, and identification of patients requiring referral to another specialist.

Presence of sulfur dioxide in commonly used bronchodilator solutions.

We detected a significant amount of SO2 released from commercially used bronchodilators, including isoproterenol (Isuprel; Breon Laboratories, Inc., New York, N. Y.), metaproterenol (Alupent; Boehringer Ingelheim, Ridgefield, Conn., or Metaprel; Dorsey Laboratories, Lincoln, Neb.), isoetharine (Bronkosol; Breon Laboratories, Inc., New York, N. Y.), and racemic epinephrine (Micronefrin; Bird Corp., Palm Springs, Calif.). During standard nebulization of these agents, SO2 concentration varied from 0.1 to 6.0 ppm. These levels are known to be bronchoconstrictive in asthmatic patients. We believe clinicians should be aware of this observation when sulfite-containing bronchodilators are used.

Evaluation of a self-help education-exercise program for asthmatic children and their parents: six-month follow-up.

A program evaluation was conducted on a sample of 40 families with asthmatic children who were managed in private practice and participated in a self-help education-exercise program in Denver. Baseline measures were collected for the six-month period before the program, and follow-up measures were collected for the six-month period following completion of the eight-week program. The results indicated that a significant number of children experienced less debilitation after completing the program and also had less need of medical services. The interpersonal relations between the child and the parents were judged to have improved in a significant number of families, and a significant number of mothers reported that they experienced less emotional distress in getting a significant number of parents to quit smoking. Additional evaluations are recommended with a sample of asthmatic children who are more severely debilitated and more difficult to manage.

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.

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.

Inhaled metabisulfite sensitivity.

Sensitivity to an inhaled sulfite-containing solution was evaluated in 13 asthmatics and ten nonasthmatic controls. Three of the 13 asthma patients were known to be sensitive to ingested sulfite and ten were not sensitive. All three sulfite-sensitive patients developed bronchospasm following sulfite inhalation challenges. Four of the ten asthmatics not sensitive to ingested sulfite developed bronchospasm following sulfite inhalation. The control subjects showed no reaction to inhaled sulfite. This study demonstrated that all asthmatics sensitive to ingested sulfite developed bronchoconstriction with inhaled sulfite. Furthermore, sensitivity to inhaled sulfite was more common than sensitivity to ingested sulfite in asthmatic patients. Possible reasons for this difference are discussed.