The pharmacokinetics and bioavailability of 3 oral dyphylline preparations, solution (S), regular (R) and sustained release (SR), were studied in 8 healthy subjects (mean age 25 years). A single dose of each preparation, 20 mg X kg-1, was given at one week intervals and multiple serum samples obtained over 24 h. Drug levels were measured by high performance liquid chromatography. No adverse effects were found. The dyphylline half-life for the solution was 2.16 +/- 0.18 h and for the tablet 2.59 +/- 0.56 h. The mean clearance rate for S was 13.6 +/- 1.7 h-1 and volume of distribution 43.0 +/- 3.91. Peak concentration (Cmax, micrograms X ml-1), time of peak (Tmax, h), area under the curve (AUC, micrograms X ml-1 X h) and relative bioavailability (RB, %), were determined for three preparations: Cmax S, 33.7 +/- 3.7; R, 27.7 +/- 4.2; SR, 10.4 +/- 1.5 Tmax: S, 0.33 +/- 0.0; R, 0.66 +/- 0.0; SR, 2.13 +/- 1.1 AUC: S, 108.4 +/- 12.1; R, 113.9 +/- 25.2; SR, 104.0 +/- 30.8 RB: Reference Product R, 105.00 +/- 16.00; SR, 100.00 +/- 25.00 The data confirm the short half-life of dyphylline, demonstrate a lack of toxicity for the 20 mg X kg-1 dose and establish bioequivalence for the products studied.

Serum IgE (total and five specific) and eosinophil cationic protein (ECP) levels were compared in elderly physician-diagnosed patients with asthma with non-asthmatic controls matched by age and gender to ascertain whether elevated levels are indicators of asthma in the elderly. All subjects and controls were non-smokers. The subjects were participants in the Florida Geriatric Research Program (FGRP), a longitudinal aging study that tracks the health status of people 65 years and older. Frozen sera from 33 randomly selected asthmatic patients and 21 controls, none of whom had any other chronic respiratory disease, such as chronic obstructive pulmonary disease (COPD), all between the ages of 65 and 90, were assessed for total IgE; five specific IgE concentrations (for cat, ragweed, German cockroach, Dermatophagoides pteronyssinus (Dp) and live oak); and ECP levels using the Pharmacia Unicap System. The odds of an elderly asthmatic patient having a total IgE of > 100 KU/L were higher than that for a non-asthmatic patient (odds ratio (OR) = 13.0; Mantel-Haenszel (MH) p = 0.005). The odds of elderly asthmatic patients having at least one positive serum specific IgE compared to elderly age-matched non-asthmatic patients were higher (OR = 21.2; MH p = 0.001). Among the five specific IgE concentrations, only IgE for Dp was higher in asthmatic than in non-asthmatic patients (OR = 13.00; MH p = 0.005). The ECP level was not significantly different between elderly asthmatic and non-asthmatic patients (asthmatic mean = 20.7 microg/L, SE = 0.48; control mean = 19.5 microg/L. SE = 0.76) (mean for younger adults 4.4 microg/L, Pharmacia Diagnostics). The serum of elderly asthmatic patients is more likely to have elevated total IgE and a positive specific IgE to Dp. ECP is elevated in elderly subjects but is not an indicator of asthma.

Symptomatic gastroesophageal reflux disease (GERD) is characterized by a wide spectrum of symptoms. The variance of GERD symptoms may be due to a decreased threshold for symptom elicitation/perception described as "visceral sensitivity." In this study GERD symptoms were scored for presence/frequency. The symptom score was weighted for the presence/frequency of typical reflux symptoms: heartburn, retrosternal pain, and regurgitation. The weighted GERD symptom score was used to assess symptom expansion and the hypothesis of GERD visceral sensitivity. One hundred five subjects with heartburn/retrosternal pain underwent esophageal pH studies. Subjects with abnormal esophageal pH studies reported more GERD-related symptoms, occurring more frequently, compared to subjects with normal esophageal pH studies. Symptom scores correlated with the number of reflux episodes but not with the length of time of mucosal exposure to acid. Therefore, aggregation of symptoms in gastroesophageal reflux is associated with frequent alternation between low and normal pH values in the distal esophagus.

Objective: The primary objective of this review is to discuss systemic allergic reactions and risk factors associated with the injection of allergen vaccines. Data Sources: A review of the literature on anaphylactic reaction, adverse effects, and fatalities associated with allergen immunotherapy (TT) was conducted. Study Selection: The expert opinion of the author aias used to select relevant data. Results: Systemic allergic reactions associated with the injection of allergen vaccines usually begin within 20 minutes. However, on occasion, they begin 20 to 30 minutes or longer after an injection. Such reactions can also occur after allergen skin testing. Most reactions associated with skin testing and allergen IT are mild and readily respond to appropriate treatment. However, severe and even fatal reactions have been reported with both skin testing and IT. Conclusions: Risk factors for skin testing and allergen IT include: 1) patients, particularly asthmatic patients, suffering with seasonal exacerbation of their symptoms; 2) patients who demonstrate exquisite sensitivity to particular allergen(s); 3) patients on beta -blockers; 4) patients with asthma, especially if their asthma is unstable; 5) patients in whom rush IT is used; and 6) patients in whom high doses of potent standardized allergen vaccines are used. It is essential that strict attention be paid to the risk factors for systemic reactions, and that techniques and manage ment be initiated both before and after skin testing or IT to minimize these risks. Done properly, the risk of skin testing and IT is minimal.

Gastroesophageal reflux disease (GERD) occurs in up to one-third of the adult US population. Most affected individuals are either unaware of their condition or do not seek medical help, relying on nonprescription acid suppressants and antacids for relief. GERD, a common disorder of infancy, old age, and pregnancy, is particularly prevalent in patients with asthma. A causal relationship between the two diseases has been postulated by many investigators. The physiologic changes of asthma exacerbations and the actions of some of the medications used to treat asthma both aggravate GERD. The adverse effect of GERD on asthma and the pathophysiology of this relationship are still under debate. Some studies showed no objective improvement by spirometry of asthmatics treated for GERD, but recognized improvement in asthma symptoms and decreased use of asthma medication. Other studies, supporting GERD induction of asthma, have been performed to test two hypotheses: that asthma is exacerbated by endotracheal aspiration of gastric contents or by a reflex response to stimulation of esophageal receptors. Clinical experience has shown that early diagnosis and treatment of GERD often leads to better control of asthma.

Airway inflammation is a characteristic feature of asthma. After contact with a specific allergen on the surface of bronchial airway mast cells, IgE-dependent degranulation induces the early phase bronchial response, consisting of smooth muscle contraction and increased vascular permeability. The inflammatory LPR that begins 4 to 8 hours after the early phase is characterized by inflammatory cellular infiltrates in the bronchial mucosa and submucosa. The cells present in the bronchial airway wall and lumen, including mast cells, basophils, eosinophils, neutrophils, platelets, Tand B-lymphocytes, macrophages, and epithelial cells, are all involved in the pathogenesis of the inflammation in asthma. Although none of the cells can be identified as the primary effector cell, lymphocytes appear to have a critical role because of their immunoregulatory functions. Systemic glucocorticoids remain the cornerstone of the treatment of severe asthma in patients refractory to bronchodilator therapy. Their long-term use systemically, however, is associated with substantial and often irreversible adverse side effects. The favorable experience with nonsteroidal anti-inflammatory therapy of dermatologic and rheumatologic diseases has prompted studies of drugs in the treatment of severe asthma. Anti-inflammatory agents studied for their steroid-sparing capability include methotrexate, gold, nedocromil , colchicine, dapsone, hydroxychloroquine, and azathioprine, among other drugs. Only methotrexate, gold, and nedocromil have proven to

(1990). Asthma Mortality: It Needs a WHAM-TF. Hospital Practice: Vol. 25, No. 10, pp. 10-13.

One thousand four hundred ten (44%) of the 3236 subjects in the Hymenoptera venom study accepted venom immunotherapy (VIT). Time to maintenance averaged 95 days, and the largest number achieved maintenance (147 subjects, 10.4%) at day 56. Ninety-two percent of the treated subjects achieved maintenance, and 84% continued therapy, most subjects (91%) until the study was terminated. One hundred seventy-one subjects (12%) experienced 327 treatment systemic reactions (Srs). The incidence of pruritus and angioedema/urticaria was similar with mild, moderate, or severe SRs. The SR severity did not correlate with the severity of the most recent sting before entry into the Hymenoptera-venom study, the most severe historical sting SR, the most severe SR during venom skin tests, the total dose of venom, the degree of skin test reactivity, or the lowest concentration yielding a positive skin test. Most SRs occurred between 1 and 50 micrograms and at maintenance; honeybee or wasp venoms were most likely to produce SR. This study, the largest of its kind with the use of standardized extracts, demonstrates (1) that there was good compliance, (2) that various historical and diagnostic criteria did not predict SRs to VIT, (3) that SRs to VIT were most likely to occur between 1 and 50 micrograms and at maintenance, (4) that honeybee or wasp venoms were most likely to produce an SR, and (5) that VIT is relatively safe.

Data are summarized in this Hymenoptera venom study (HVS) article on the safety of skin testing with venom extracts. Of the 3236 subjects studied, 89% had experienced an historical sting systemic reaction (SSR). Seventy-four percent of all subjects and 76% of subjects who had experienced an historical SSR had a positive skin test to at least one venom. More subjects tested positive to yellow jacket venom (51.8%) than to any other venom. There were no significant differences of the wheal and erythema sizes associated with different venoms or different historical sting reactions. Forty-five percent of subjects with positive venom skin tests (VST) were positive to wasp, and 89% of these subjects were also positive to at least one of the following venoms: yellow jacket, yellow hornet, or white-faced hornet. Sixty-four of the 3236 subjects studied (2%) had a systemic reaction (SR) during VST; 13 of the SRs (0.4%) were severe. Thirteen of 64 adverse reactions (20%) were possibly vasovagal, and six other subjects (9%) demonstrated no symptoms of immediate-type hypersensitivity. Thus, 45 (1.4%) of the 3236 subjects tested had an SR that was considered to be a reaction of hypersensitivity, of which eight reactions (0.25%) were severe. Allergic SRs are associated with VST but are unusual and are rarely severe.

Thirty-eight subjects were challenged (25 nasal, 13 bronchial) with Bahia grass, Paspalum notatum, pollen extract. A positive Bahia intradermal skin test predicted a positive challenge to Bahia in all (11/11) of the nasal challenges and 75% (6/8) of the bronchial challenges. All 19 subjects with negative Bahia intradermal skin tests had negative challenges with Bahia. Specific IgE antibodies to Bahia pollen were detected by conventional RAST (greater than or equal to 2+) in 82% (14/17) of subjects with positive challenges and in 5% (1/20) of subjects with negative challenges. Eight subjects had positive intradermal skin tests to either Bahia (three) or timothy, Phleum pratense (five). Seven of the eight subjects reacted exclusively to either Bahia or timothy nasal challenge as predicted by their skin tests. Bahia grass is a significant aeroallergen, which in some subjects can be demonstrated not to cross-react with timothy.

The Hymenoptera venom study, a study based on case histories, skin test results and adverse reactions, immunotherapy and adverse reactions, and treatment efficacy, for 3236 Hymenoptera-allergic subjects, was begun in 1979 after the Food and Drug Administration approval of Hymenoptera venoms. Eighty-four Fellows and Members of the American Academy of Allergy and Immunology participated in the study. All subjects had a history of an adverse reaction to one or more Hymenoptera insects. The mean age was 30 1/2 years (range 1 to 83 years). Male subjects accounted for 61.5% and female subjects, 38.5%; 3.1% were beekeepers and 32.3% were atopic. Demographic data were similar for subgroups. There was an average of 2.7 history stings per subject. At least one systemic reaction (SR) was reported by 2866 subjects (89%); 2219 (69%) experienced an SR after their most recent sting before entry into the study, and 70% had experienced only a single SR. Moderate to severe SRs were equally likely after stings of yellow jacket, white-faced hornet, and yellow hornet (65%), honeybee (67%), or wasp (70%), although historical SRs were reported more often after stings of yellow jacket, white-faced hornet, or yellow hornet (30%) than after honeybee (19%) or wasp (14%) stings. No association was noted between the number of stings per episode and severity of the SR. Fifty-one percent of SRs were reported as occurring within 10 minutes of sting; however, the onset of a moderate to severe SR sometimes occurred at 301 or more minutes after a sting episode. Of 2219 subjects with an SR after their most recent sting before entry into the study, 68% received epinephrine for treatment.