Determining allergic versus nonallergic drug reactions.

Drug sensitivity is a major clinical problem that is incompletely understood. Much effort continues in identifying patients at risk for developing drug sensitivities, predicting the various immune mechanisms most likely to be activated by a specific drug, and developing more reliable tests to identify the drug-allergic patient.

Asthma: the irreversible airways disease.

Chronic inflammation of the asthmatic airway leads to epithelial desquamation, goblet cell hyperplasia, mucosal and submucosal inflammation, prominent smooth muscle, and collagen deposition below the basement membrane. The changes in the airway are attributed to chronic inflammation, the healing process and subsequent remodeling. These changes contribute to three predominant mechanisms of increased airway resistance in asthma: decreased elastance of airways; increased smooth muscle in the airway which may cause increased narrowing during bronchospasm; and collagen deposition beneath the basement membrane resulting in airway wall thickening. Destruction and subsequent remodeling of the normal bronchial architecture are manifested by a progressive decline in FEV1. In an attempt to decrease the progressive decline in FEV1, studies on proper therapy have been undertaken. Antiinflammatory medications, such as inhaled corticosteroids, have been shown to decrease this rate of decline in lung function, while the effect of bronchodilators is less conclusive. Beginning treatment with inhaled corticosteroids early produces a better clinical response compared to initiating treatment late, and early treatment may prevent airway remodeling and development of irreversible structural changes.

Intranasal fluocortin butyl in patients with perennial rhinitis: a 12-month efficacy and safety study including nasal biopsy.

Fluocortin butyl (FCB) is a recently developed topical intranasal corticosteroid that is inhaled as a powder and has been demonstrated to be well tolerated and to improve symptoms and signs of perennial rhinitis in previous short-term studies. This multicenter, open-label study evaluated the efficacy and safety of FCB during a 12-month treatment period in patients with perennial rhinitis. Treatment was initiated with one inhalation of FCB in each nostril three times a day (total dosage, 3 mg/day). In subsequent months, one third of the patients was maintained at the dosage of 3 mg/day, one third at a lower dosage of 2 mg/day, and the remaining one third of the patients at a larger dosage of 4 to 8 mg/day. Of 109 patients enrolled in the study, 90 patients (82.6%) completed all 12 months of treatment. Symptom and sign scores decreased significantly (p less than 0.001) at the 2-month evaluation compared to scores at baseline, and the improvement was maintained throughout the 12-month study period. After 12 months, greater than 80% of the patients had substantial control of symptoms. Specimens of nasal biopsies, performed at the beginning and end of treatment, revealed a decrease in eosinophils and other cellular infiltrates, a slight tendency of an increase in mast cell counts, and a trend toward normalization of the nasal mucosa. There were few adverse effects. Mean plasma cortisol levels were normal before and after corticotropin stimulation at baseline and after 12 months of FCB therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of three pretreatment protocols to prevent anaphylactoid reactions to radiocontrast media.

Three pretreatment regimens were compared for prevention of anaphylactoid reactions in 149 patients who previously had reacted to radiocontrast media (RCM) administration. From 1976 to 1980, 52 patients were treated with 50 mg of oral prednisone 13, 7, and 1 hour before and 50 mg intramuscular diphenhydramine 1 hour before procedures (group I). From 1980 to 1984, 48 patients received 300 mg oral cimetidine one hour before procedure in addition to the other regimen (group II). From 1984 to 1989, 49 patients received the three drugs and 25 mg oral ephedrine one hour before procedures (group III). Previous reactions were similar in each group, consisting of urticaria and/or angioedema in all patients, hypotension in some (groups I, 5; II, 6; III, 4), and wheezing in two (group I). Readministration of RCM was intraarterial (groups I, 18; II, 20; III, 20) or intravenous. Generalized reactions upon readministration of RCM occurred in 4 (8%) of group I and 3 (6%) of both groups II and III. All reactions consisted of urticaria and/or angioedema, were mild, and required no specific treatment. In a separate group of ten patients whose previous reactions to RCM were life threatening (shock), pretreatment was accompanied by a provocative dosing regimen. Two patients (20%) experienced systemic reactions that resulted in termination of the procedure. All our pretreatment regimens were equally effective; however, we favor a more comprehensive pretreatment protocol (regimen III) based upon our lack of demonstrated adverse effects and a possible therapeutic advantage as reported by other investigators.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of mononuclear cell-derived histamine release enhancing factor.

Histamine release enhancing factor (HREF) is a product of phytohemagglutinin-stimulated mononuclear cells that substantially augments in vitro IgE-mediated basophil histamine release. The factor is stable at 56 degrees C and has a molecular weight in the 10,000 to 30,000 dalton range. The magnitude of HREF activity produced is dependent on the concentration of mononuclear cells cultured and the final concentration of HREF during basophil challenge. The HREF phenomenon could not be attributed to phytohemagglutinin, alpha- or gamma-interferon, arachidonic acid metabolites, or interleukin-1 or 2. HREF appears to be a unique cytokine of potential importance in the immunology of inflammatory and atopic processes.

Characteristics of diatrizoate-induced basophil histamine release.

Factors influencing the release of histamine by basophils exposed to the radiocontrast agent diatrizoate were investigated in vitro by use of cells from healthy adult subjects with no history of radiocontrast reactions. Diatrizoate-induced release shared similarities with calcium ionophore-induced release. The response to both agents is dose dependent, enhanced by deuterium oxide, optimal at 37 degrees C, calcium dependent, and enhanced with longer reaction times. Unlike calcium ionophore, however, pretreatment of basophils with diatrizoate may also induce dose-dependent inhibition of reactivity during subsequent challenges with anti-IgE, N-formyl methionine peptide, and calcium ionophore. These findings suggest that diatrizoate may induce histamine release via a calcium ionophore-like mechanism, but other effects on cellular function probably account for its ability to inhibit basophil responsiveness.

Efficacy and tolerance of fluocortin butyl administered twice daily in adult patients with perennial rhinitis.

Fluocortin butyl (FCB) is a newly developed corticosteroid drug with no detectable systemic corticosteroid activity when it is used topically. Previous studies have demonstrated the therapeutic efficacy of FCB applied topically to the nasal mucosa three to four times a day for perennial rhinitis. The therapeutic efficacy of FCB used only twice daily, with total daily dosages similar to those previously found to be effective when these were applied more frequently, was studied in a multicenter, double-blind, placebo-controlled trial. This was a 4-week study with a 1-week observation (baseline) period and a 3-week period during which the response to three dosage regimens (2 mg per day, 4 mg per day, and 8 mg per day) of FCB and placebo were compared to baseline observations of rhinitis. Two hundred thirty-five patients from six centers were studied. Patients had perennial rhinitis of allergic, nonallergic, or combined etiology. Patients who received FCB exhibited significant amelioration of signs and symptoms of rhinitis as assessed by patients and physicians and had a greater reduction in the use of concomitant antihistamine and/or decongestant therapy compared to placebo-treated patients. Relief tended to occur early and was progressive during the 3 wk of therapy. There were no significant differences in response between the various dosages of FCB used. Side effects were minimal and insignificant and did not differ between FCB-treated and placebo-treated patients. FCB appears to be an effective well-tolerated topical steroid useful in the treatment of perennial rhinitis.

Effect of rifampin on theophylline disposition.

The concentrations of theophylline from single 400-mg oral doses were evaluated both before and after 7 days of oral rifampin administration (600 mg/day) in six healthy, nonsmoking adults. The mean oral clearance of theophylline was significantly increased from 54.9 +/- 21.2 to 68.9 +/- 26.5 ml/h/kg. The elimination rate constant was significantly increased in five of the six subjects, with a mean increase of approximately 25%. Although intersubject variability was large, these data indicate the potential need to increase theophylline doses in some patients receiving rifampin.

Multi-center, double-blind, placebo-controlled trial of fluocortin butyl in perennial rhinitis.

Fluocortin butyl (FCB) is a newly synthesized corticosteroid with a high ratio of topical to systemic activity. FCB was studied in a multi-center, double-blind, placebo-controlled trial of therapy of perennial rhinitis. The study was conducted between January and May 1981. Patients evaluated suffered from either chronic allergic or chronic nonallergic rhinitis or both. A total of 306 patients from 16 investigative centers were evaluated by comparing FCB to placebo. Three separate dosage regimens were employed. Patients received a total daily dose of 2, 4, or 8 mg. FCB was found to be an effective therapeutic agent. It reduced symptoms of nasal congestion, rhinorrhea, postnasal drainage, and sneezing. It also markedly reduced the use of concomitant medications (chlorpheniramine maleate and/or pseudoephedrine). Relief of symptoms was noted as early as the first week of therapy, and the degree of improvement increased progressively during the study. There was little difference between the relief produced by the 4 mg and 8 mg regimens. Both of these were superior to the 2 mg regimen. The drug was well tolerated; no significant side effects were noted.

Efficacy of phenylephrine-phenylpropanolamine in the treatment of rhinitis.

A double-blind placebo-controlled crossover study was done to evaluate the efficacy of an oral decongestant preparation in the treatment of rhinitis. The preparation consisted of 5 mg of phenylephrine hydrochloride, 45 mg of phenylpropanolamine hydrochloride, and 200 mg of guaifenesin (Rymed). Subjects were selected for participation in the study on the basis of history, physical examination, and immediate hypersensitivity skin testing. Fourteen of 20 subjects (P less than .05) observed a reduction in the severity of nasal symptoms while taking the drug. The mean symptom score of the 20 subjects while taking the drug was 31.344 and while taking placebo, 42.979. This is a statistically significant difference (P = .009717). Side effects were minimal. We concluded that the oral decongestant preparation used in this study is effective in controlling symptoms of rhinitis.

Beclomethasone dipropionate aerosol: hematologic and immunologic effects.

Inhaled beclomethasone dipropionate aerosol is a topically active corticosteroid that has proved to be of great value in treating asthma. The authors have examined the effect of inhaled beclomethasone dipropionate aerosol on circulating leukocytes and on immunological measurements in normal adult subjects. Subjects inhaled either 400 micrograms or 1600 micrograms as a single dose. White blood cell counts, total neutrophil counts, total eosinophil counts and total lymphocyte counts were determined at 0, 2, 4 and 6 hours following an 8:00 a.m. inhalation. Among the 11 subjects who inhaled 400 micrograms, the total white blood cell count increased significantly at six hours (p less than 0.05). The total neutrophil count was increased significantly at 2, 4 and 6 hours (p less than 0.05). Total eosinophil counts and total lymphocyte counts were diminished but not significantly. Among the five subjects inhaling 1600 micrograms similar findings were observed. Seventeen volunteers inhaled 200 micrograms of beclomethasone dipropionate qid for 24 hours. In addition to the above studies, T and B cell numbers were determined and lymphocyte transformation studies were performed. Although trends similar to those observed with single larger dose inhalations were seen, the changes were not statistically significant. The results of these studies indicate that inhaled beclomethasone dipropionate does have the potential to affect circulating leukocytes.

Abnormal immunologic measurements in asthmatic children and adults.

Several immunologic measurements were evaluated in 128 asthmatic patients (81 pediatric and 47 adults) in an effort to examine the question of altered cell-mediated immunity in asthmatics. Both pediatric and adult patients showed alterations in some but not all measurements. The results indicate that there are differences among subgroups of asthmatics and in some cases between pediatric and adult patients.