Comparison of azelastine and chlorpheniramine in the treatment of mastocytosis.

BACKGROUND: Azelastine, a novel antiallergic medication, was compared with chlorpheniramine maleate for efficacy and safety in the treatment of systemic mastocytosis. METHODS: Fifteen subjects with mastocytosis participated in a double-blind, randomized, three-period, crossover trial, which compared an azelastine regimen of 4 mg or 8 mg every 12 hours with a chlorpheniramine regimen of 12 mg every 12 hours. Response to therapy was assessed by daily symptom scores, extinction dilution skin tests, plasma histamine levels, and global evaluations. RESULTS: Subjects' mean wheal area responses provoked by histamine or morphine sulfate were significantly lowered by azelastine when compared with chlorpheniramine. Plasma histamine levels in subjects receiving azelastine or chlorpheniramine were not significantly different. There were no significant differences between azelastine and chlorpheniramine in individual symptom scores or global evaluations except that azelastine at both doses significantly relieved pruritus and at 4 mg significantly relieved abdominal pain and that chlorpheniramine was associated with less fatigue in comparison to azelastine at 8 mg. CONCLUSIONS: It thus appears that azelastine is superior to chlorpheniramine in suppressing skin responses to histamine and morphine sulfate and in suppressing pruritus in patients with mastocytosis. However, when all parameters are considered, neither drug is clearly superior for the treatment of patients with mastocytosis.

Recruitment and screening experience for a clinical trial involving tear concentrations of a new drug.

The process of recruitment and screening of volunteers for clinical research studies has not been thoroughly evaluated in the ophthalmic literature. The data for the current report were derived from a double-masked randomized clinical trial designed to evaluate and compare the effective tear level concentrations of three topical ophthalmic medications. Subjects were recruited from the general population and were healthy volunteers on no medications. Tear volume was measured by the Schirmer test with anesthesia; acceptable results were in the range of 10-25 mm/5 min. Study enrollment was limited to 32 subjects per week, with a total sample size goal of 320. The study population, 18-45 years of age, consisted primarily of white male college students. Nine hundred fifty-seven volunteers were recruited. Of the 498 of these subjects that reported for screening (52%), 459 (48%) were actually screened, and 320 (33%) were enrolled. The overall prevalence of an abnormal Schirmer test (< 10 or > 25 mm/5 min in either eye) in the screened population was 22%. The frequency of decreased tear production (13%) was slightly greater than that of increased tear production (9%). An abnormal Schirmer test was the primary reason for ineligibility. The completion rate for those enrolled was 96%. This type of information is valuable when designing a clinical trial, especially with regard to budgetary, time table, and sample size estimations.

The effect of IL-4 on human nasal mucosal responses.

Interleukin (IL)-4 causes the dose limiting sensation of nasal congestion when administered systematically at doses of 3 micrograms/kg or higher thrice daily to humans. This side effect was observed in a group of patients treated as part of an immunotherapy protocol for cancer management. To determine the source of this congestion, nasal secretions were collected prospectively in a group of patients at baseline and after provocation with normal saline, methacholine (which stimulates glandular secretion), and histamine (which causes increased vascular permeability). Nasal lavages obtained at baseline and after provocation were analyzed for the presence of these glandular and vascular proteins and inflammatory mediators. Washings and provocations were performed before IL-4 administration, after 24 hours of IL-4 treatment, and after 3 days of treatment, at a time when nasal congestion was maximal. Compared with histamine challenge before IL-4 treatment, the secretion of the plasma proteins albumin and IgG were significantly decreased after 3 days of IL-4 treatment. IL-4 treatment had no apparent effect on methacholine-induced responses. Thus systemically administered IL-4 causes the subjective sensation of nasal congestion, increased histamine in nasal lavages, and the development of vascular unresponsiveness to histamine, without affecting parasympathetic responses to histamine. The relationships among increases in nasal lavage histamine, vascular unresponsiveness to histamine, and the sensation of nasal congestion are unclear.

A combined single-blind, double-blind, placebo-controlled study to determine the reproducibility of hypersensitivity reactions to aspartame.

Aspartame is an O-methyl ester composed of phenylalanine and aspartic acid. After its final approval as a sweetener in 1981, a number of reports of adverse reactions to aspartame appeared in the literature. To explore the pathogenesis of such reactions, we initiated a study in July 1986 to identify subjects with hypersensitivity reactions to aspartame with blinded challenge procedures. The study was closed after 32 months. During that time, we advertised in local newspapers and worked closely with the local community of allergists and dermatologists in an attempt to recruit subjects with hypersensitivity reactions to aspartame. A total of 61 self-referrals and physician referrals were screened, with 20 referrals evaluated in clinic. After this evaluation, 12 patients underwent single- and double-blind challenge with up to 2000 mg of aspartame. No subject with a clearly reproducible adverse reaction to aspartame was identified. In summary, we found that it is difficult to recruit study subjects with a history of hypersensitivity reactions to aspartame and that subjects who believed themselves allergic to aspartame did not have reproducible reactions.

Human nasal glandular secretion of novel antioxidant activity: cholinergic control.

Exposure of the respiratory mucosa to oxygen-enriched air contributes to the generation of the lung damage in both adult respiratory distress syndrome and bronchopulmonary dysplasia. Recent work has identified the nasal submucosal gland as the source of diverse molecules important in mucous membrane host defense. We searched for the presence of antioxidant activity in nasal glandular secretions, the absence of which could possibly predispose to oxygen-induced injury. Employing a low molecular weight preparation of nasal secretions (a pooled concentrate passed over a 10,000-dalton molecular sieve), antioxidant activity capable of inhibiting both horseradish peroxidase and Fenton reagent reactions was discovered. The following lines of evidence suggest that submucosal glands are the source of this activity. (1) Antioxidant activity present in resting, baseline nasal washings is significantly increased after cholinergic stimulation either in response to topical methacholine or induced by a gustatory reflex. (2) Application of atropine reduced the antioxidant activity to baseline levels after either of the cholinergic stimuli. (3) Levels of antioxidant activity correlated very closely with the secretion of lactoferrin, a recognized product secreted solely from the serous cell of the submucosal gland. The antioxidant activity is due to novel, previously unrecognized molecules. This activity is found in nasal secretions containing molecules less than 10,000 daltons, is unaffected by N-ethyl maleimide (which inactivates glutathione, another low molecular weight antioxidant), is not associated with the capacity to reduce cytochrome c (as seen with ascorbic acid), and resides in the water soluble pool of secretions (in contrast to vitamin E, another putative antioxidant).(ABSTRACT TRUNCATED AT 250 WORDS)

Airway hyperresponsiveness in patients with microvascular angina. Evidence for a diffuse disorder of smooth muscle responsiveness.

Anginal chest pain in patients with angiographically normal coronary arteries may be caused by a limited coronary flow response to stress because of abnormal function of the coronary microcirculation (microvascular angina). Studies of forearm arterial function suggested that patients with microvascular angina may have a diffuse disorder of smooth muscle tone. Because dyspnea is common in these patients and seems disproportionate to the severity of myocardial ischemia, we studied air flow (forced expiratory volume in 1 second, or FEV1) in the basal state and after methacholine inhalation to determine whether bronchial smooth muscle is affected in this syndrome. Five of 36 patients with microvascular angina had a basal FEV1 of less than 70% of that predicted and did not receive methacholine. Of the remaining 31 patients, 14 (45%) had a more-than-20% reduction in FEV1 after methacholine inhalation (as much as 25 mg/ml), a response significantly greater than that of nine patients with heart disease (0%, p less than 0.025) and 24 normal volunteers of similar age and gender distribution (13%, p less than 0.025). Furthermore, the product of the methacholine dose inhaled and the magnitude of decline in FEV1 from baseline (methacholine response score) was significantly lower in patients with microvascular angina than in normal volunteers (16 +/- 8.6 versus 22.2 +/- 3.7, p = 0.026). We conclude that airway hyperresponsiveness is frequently demonstrable in patients with microvascular angina; these findings are consistent with our hypothesis that this syndrome may represent a more generalized abnormality of vascular and nonvascular smooth muscle function.

Uric acid is a major antioxidant in human nasal airway secretions.

Airway mucosal surfaces are potentially subjected to a variety of oxidant stresses. Airway submucosal glands secrete a variety of compounds that may protect the airways from injury. Cholinergically induced nasal submucosal gland secretion has recently been found to contain a low molecular weight nasal antioxidant. In this report, the isolation and identification of this nasal secretory antioxidant are described. Concentrated, cholinergically induced human nasal secretions were fractionated through a 10-kDa sieve and subjected to DEAE anion-exchange chromatography. Fractions containing antioxidant activity were subjected to gel filtration with Bio-Gel P-2 gel (resolution range, 200-2000 Da). The resultant antioxidant fractions were then desalted by gel filtration over the same column equilibrated in HPLC-grade water, yielding only a single peak with antioxidant activity. The absorption spectrum of the purified antioxidant revealed peaks at 238 and 292 nm at pH 7. These peaks shifted to 230 and 280 nm in 0.1 M HCl and 226 and 296 nm in 0.1 M NaOH. Sodium borohydride reduction of the antioxidant had no effect on the UV absorption, whereas platinum-catalyzed hydrogenation ablated all absorption peaks. Uric acid had identical absorption peaks and showed the same chromatographic behavior as the nasal antioxidant activity on both gel filtration and DEAE columns. Uricase (which degrades uric acid) metabolized both uric acid and the purified antioxidant. Uric acid was shown to have antioxidant activity at concentrations greater than 1.5 microM. These data indicate that nasal secretions contain uric acid that serves as an antioxidant.

Health status and disease activity in systemic lupus erythematosus.

The physical manifestations of disease activity and health status of patients with systematic lupus erythematosus (SLE) were measured in this study. Forty-nine patients completed the Arthritis Impact Measurement Scale (AIMS) and consented to examination for physical features of SLE documented by a Clinical Activity Index (CAI). Results showed a mean score of 22 on the AIMS and 6.6 on the CAI. The total scores for each measure were significantly correlated (r = 0.55, p less than 0.001), indicating a relationship between health status and clinical disease activity. The total score for CAI was significantly correlated with the physical activity, pain, and depression subscales of health status. The total score for health status was significantly correlated with mucocutaneous, musculoskeletal, and general features of CAI. Within scale correlations were also found. Mucocutaneous aspects of disease activity were significantly correlated with pain and depression. Musculoskeletal features were significantly correlated with physical activity and pain. General aspects of SLE, including fatigue, were significantly correlated with physical activity. The study concludes that there is a relationship between certain physical features of SLE and key components of health status.

A double-blind, placebo-controlled, crossover trial of ketotifen versus hydroxyzine in the treatment of pediatric mastocytosis.

To asses the efficacy of ketotifen (Zaditen; Sandoz Pharmaceuticals, Basel, Switzerland) for the treatment of pediatric mastocytosis, eight children who exhibited symptoms as a result of mastocytosis were enrolled in a 12-week, double-blind, placebo-controlled, crossover trial of ketotifen versus hydroxyzine (Atarax; Roerig, New York, N.Y.). Efficacy of each drug was assessed by daily symptom scores and plasma- and 24-hour urine-histamine levels. After completion of the study, symptom scores revealed that seven of the eight children exhibited a greater reduction in symptoms while they were receiving hydroxyzine (p less than 0.05). The symptoms most likely to improve with treatment with hydroxyzine were flushing and abdominal pain. Analysis of plasma- and 24-hour urine-histamine levels at the beginning and end of each trial period of each drug revealed no significant differences (p greater than 0.20). Changes in 24-hour urine-histamine levels, but not plasma-histamine levels, correlated with changes in symptom scores. We conclude that ketotifen offers no advantage over hydroxyzine in the treatment of pediatric mastocytosis.

Leukapheresis and pathogenetic mechanisms in rheumatoid arthritis.

Rheumatoid Arthritis is a chronic, usually progressive inflammatory disorder of joints in which the immune system plays a central role in the pathogenesis. In its classic form, the synovial tissues from severely affected joints are densely infiltrated with HLA-DR bearing T-lymphocytes (primarily OKT4+/Leu3+ subset) and macrophage-like cells. Moreover, these tissues, as demonstrated by ex vivo culture, spontaneously produce high levels of a multitude of inflammatory mediators, such as collagenase, PGE2, interleukin 1 and fibroblast activating factors, indicating that the cells infiltrating the synovium are "activated". The action of these various inflammatory mediators on different target substances or cells (collagen, fibroblasts, chondrocytes, osteoclasts, etc.) most likely produce the characteristic pattern of joint pathology. Recent data indicate that this classic form of synovitis tends to be associated with peripheral anergy and other qualitative and quantitative abnormalities in the peripheral blood mononuclear cells. Repeated leukapheresis can induce substantial, although transient, clinical improvement in patients with these classic features, probably as a consequence of disrupting T-lymphocyte traffic. Rheumatoid synovitis, however, is highly heterogeneous, but can be categorized into subsets. For example, a subset of patients with highly active clinical rheumatoid arthritis exists which do not exhibit the classic features of disease. Synovial tissues from this patient subset are sparsely infiltrated by T-lymphocytes but contain mainly macrophages and fibroblasts, as well as prominent lining layer fibrin deposition.(ABSTRACT TRUNCATED AT 250 WORDS)