Cognitive and behavioral findings in children taking theophylline

In a prior pilot study involving six children, we noted improved memory and concentration and improved behavior when these children were switched from theophylline to cromolyn sodium therapy. We now report the findings in 29 children (24 boys and five girls), aged 7 to 12 years. In this study, a double-blind, double-dummy randomized design was used so that half the subjects continued to receive theophylline and the other half was actually switched from theophylline to cromolyn sodium therapy. Assessment again consisted of the revised Wechsler Intelligence Scale for Children, the Selective Reminding test, the Benton Visual Retention test, Stroop tests I and II, and the Child Behavior Checklist. The group receiving placebo theophylline/active cromolyn sodium therapy demonstrated greater improvement on all tests of memory and concentration, with greatest significance for the Stroop test (p less than 0.03 by analysis of covariance). There were also significant correlations between length of time theophylline was taken and scores on the depression (p less than 0.03) and the obsessive-compulsive (p less than 0.04) subscales of the Child Behavior Checklist. These results support the findings of the previous pilot study but, in addition, raise concern about depression and anxiety as possible long-term side effects of long-term theophylline therapy.     

Clinical effects of theophylline in the therapy of intractable asthmatic children. II. Theophylline therapy and behavior problems in children with asthma

This study examined the relationship between long-term theophylline therapy and behavior problems in 14 asthmatic children that includes 5 intractable cases and 24 non-asthmatic children. Asthmatic children have received theophylline therapy and cromolyn inhalation for 3.6 +/- 3.8 years. Subjects were tested on neuropsychologic batteries; behavior problems and personality of children questionnaire, child behavior checklist, caffeine-like side effects questionnaire, manifest anxiety scale, visual attention test, Uchida-Kraepelin test and soft neurological signs. These tests were repeated with an interval of 1 to 12 weeks. Parents noted caffeine-like side effects, stomach ache and difficulty in sleeping, in their child during the theophylline therapy. The caffeine-like side effects decreased after stopping theophylline therapy. The rate of mistake in Uchida-Kraepelin test for the asthmatic group and for the intractable cases was significantly higher than that of the control group. Time of the sequential finger thumb opposition of the soft neurological signs was significantly prolonged in asthmatic group. There was no significant change in the other tests between asthmatic and non-asthmatic children and before and after stopping theophylline therapy. It seems that behavior problems and learning disability observed in the asthmatic children are due to the pathogenesis or symptoms of asthma rather than the effect of long-term theophylline therapy.     

The effect of metaproterenol in chronic asthmatic children receiving therapeutic doses of theophylline.

The effect of metaproterenol added to therapeutic doses of theophylline was compared with a combination of placebo and theophylline by measurement of the forced expiratory volume in 1 sec (FEV₁), forced vital capacity (FVC), and maximum midexpiratory flow rate (MMEFR) in 17 asthmatic children in a double-blind crossover study. Plasma theophylline levels were measured at 1.5 hr (peak) and 6 hr (trough) after drug administration on all test days. Children weighing less than 60 pounds received 10 mg of metaproterenol (1 tsp), while those weighing more than 60 pounds received 20 mg every 6 hr. The mean peak theophylline level for both metaproterenol and placebo treatment days was approximately 10 μg/ml, while the trough was 6 μg/ml. Metaproterenol caused a significantly greater increase in FEVI (p < 0.05) of 17% at 1.5 hr when given with theophylline than the placebo- theophylline combination. The metaproterenol effect on MMEFR was even greater with increases over placebo of more than 80% at 1.5 hr and 2 hr (p < 0.0025) and 30% at 3 hr and 4 hr (p < 0.05). No increase in adverse effects with the metaproterenol-theophylline combination compared with placebo-theophylline was observed. This study suggests that metaproterenol can improve pulmonary function of both large and small airways when added to moderate theophylline doses without risking increased side effects in asthmatic children.     

Oral cromolyn in food allergy: in vivo and in vitro effects

The results obtained in vivo in a group of 24 patients treated with oral cromolyn and compared to a group of 10 patients treated with placebo are reported. All patients were affected by adverse clinical reactions (urticaria and/or angioedema) related to food ingestion. A significant reduction of signs and symptoms were observed after oral cromolyn therapy only in the patients affected by true food allergy (FA), i.e., IgE mediated reactions. No adverse reactions appeared in the treated patients. Because we found an enhancing effect exerted in vitro by cromolyn (SCG) on T-cell responsiveness in previous studies, in the present investigation we analyzed in more detail in vitro effects of SCG on T lymphocytes [i.e., phytohemagglutinin-induced interleukin-2 (IL-2) production] and IL-2 receptor expression on T cells. No significant effect was induced by SCG on IL-2 production, whereas IL-2 receptor expression on surface of T cells appeared significantly increased (P less than 0.001) by adding SCG in cultures. These clinical and immunological results are analyzed and discussed in relation to a possible in vivo effect(s) of cromolyn in allergic diseases.     

Nebulisead Sodium Cromoglycate in the Treatment of Wheezy Bronchitis A Multicentre Double-Blind Placebo Controlled Study

The efficacy of nebulised sodium cromoglycate (SCG) used as a prophylactic treatment of wheezy bronchitis in children aged 1 to 4 years was evaluated in a multicentre double-blind placebo controlled, group comparative study. Fifty-four patients completed the 10-week trial (29 treated with SCG and 25 treated with placebo), preceded by 4-8 weeks baseline. Nebulised SCG did not prove significantly superior to placebo in reducing day wheezing, day coughing, or sleep disturbance due to wheezing or coughing at night. Neither was there significant difference in the use of supportive medicine (beta 2-agonist and theophylline) between the groups. Extra doctor visits, hospital admissions, and parental preference did not show significant difference either.     

Immunoglobulin E-mediated anaphylaxis with inhaled cromolyn sodium

Adverse reactions to cromolyn sodium inhalation are rare and evidence to document IgE mediation is meager. We report a case of a 7-yr-old, timothy-sensitive, asthmatic girl with severe anaphylaxis after inhaled cromolyn sodium. After 1 wk of attempted cromolyn sodium inhalation, a demonstration dose was administered in the physician's office. Within 1 min of a single inhalation, the patient became cyanotic, hypotensive, and suffered cardiopulmonary arrest. Resuscitation successfully revived the patient, who remained in status asthmaticus requiring intravenous therapy for 36 hr. Sera obtained at anaphylaxis and 3 mo later were negative for IgG anti-cromolyn sodium antibodies by the Farr technique. IgE involvement was investigated by passive transfer of the patient's 2-mo serum to the mother; 48 hr after transfer, both passively sensitized and nonsensitized skin sites were challenged intradermally with 0.02 ml of 1% aqueous cromolyn sodium, 1% lactose solution, and 100 PNU/ml timothy extract. Markedly positive reactions occurred to cromolyn sodium (44/110 mm², wheal/flare area) and timothy (44/80 mm²) at sensitized sites, with negative reactions in nonsensitized areas. Challenge with 1% cromolyn sodium solution at a site sensitized with heat-inactivated patient serum (56° C, 3 hr) produced mild induration (5 mm²), and lactose induced a small area of induration without flare. In vitro studies with the patient's basophils, obtained 11 mo after the systemic reaction, failed to demonstrate enhanced histamine release in the presence of cromolyn sodium. This case represents the worst reported adverse reaction to cromolyn and suggests that the mechanism was the result of IgE-mediated anaphylaxis. Physicians using this medication should be aware that clinically significant immune sensitization to cromolyn can occur.     

Antiallergic drugs and the immune response

Since the pharmacological treatment of allergic diseases is used in patients with alteration of the immune response due to atopy and possible concomitant infections, we have investigated the possible effects of such drugs as cromolyn, theophylline, ketotifen, oxatomide, astemizole, fenoterol, pirenzepine, and rosaprostol on the in vitro immune response, in order to obtain experimental data and, as a consequence, clinical conclusions. In a series of investigations by our group and other authors the following immunological parameters have been considered: T cell activation induced by different pathways (i.e. autologous stimulation, PHA, anti-CD3, -CD2 and -CD28 monoclonal antibodies), and lymphokine production (i.e. IL-1, IL-2 and gamma-IFN). For a more detailed experimental model the experiments have been performed both in bulk culture and by using T cell clones derived from the peripheral blood. The results show cromolyn to have an enhancing effect, theophylline and ketotifen a suppressing effect, whereas the remainder show no effect on the immune response. These data are considered and discussed from the aspect of their possible clinical relevance and also in light of the in vivo data previously reported.     

Combination drug therapy in children with exercise-induced bronchospasm

Fifty-three children with moderately severe asthma were studied to determine the capacity of drugs to block exercise-induced bronchospasm (EIB). All 53 children demonstrated EIB (as defined by a 20% fall in FEV1 or 30% fall in FEF25-75) while receiving therapeutic theophylline (serum level 10-20 micrograms/ml). EIB was completely blocked in 47 children by an inhaled metaproterenol 10 minutes prior to exercise, in addition to the theophylline. In six children, EIB was only partially blocked when either metaproterenol or cromolyn was added to the theophylline, but was completely blocked when all three drugs were used. A small group of children may benefit from combination therapy for EIB.     

Clinical, physiologic, and psychologic comparison of treatment by cromolyn or theophylline in childhood asthma

Treatment of chronic perennial childhood asthma with cromolyn sodium (CS) or long-acting theophylline (LAT) was compared in 13 children by a double-blind, cross-over trial in which each drug was administered for 4 wk. LAT was administered twice daily in individual doses to elicit adequate blood levels (mean 14.0 +/- 1.6 SEM, micrograms per milliliters). Powdered CS was administered by inhalation in a dose of 20 mg four times daily. The patients were followed by means of a daily symptom and drug consumption diary and twice daily peak flow measurements. A series of psychologic studies were performed in the third week of each month. Exercise and histamine bronchial provocation tests were performed at the end of each month. There were no significant differences between the month in which CS was taken and the month in which LAT was taken in terms of diary scores, peak flow rates, additional drug consumption, or in bronchial reactivity to exercise or histamine at the end of each month. The results of psychologic tests reflecting visual-spatial planning were significantly better for the four children receiving CS with lower IQ scores (87 to 105) but not for the nine children with higher IQ scores (111 to 134). The possibility that the psychologic performance of children with lower intelligence may be adversely affected by theophylline requires further evaluation.     

Cromolyn sodium nasal solution in the prophylactic treatment of pollen-induced seasonal allergic rhinitis.

A large-scale multicenter investigation was undertaken in 3 cities with comparable pollen seasons and atmospheric pollen concentrations in order to obtain more definite information about the safety and efficacy of cromolyn sodium in the treatment of pollen-induced seasonal rhinitis. The 9-wk double-blind study was conducted in 104 patiets in Pittsburgh, Pa., Cleveland, Ohio, and Louisville, Ky., during the 1975 ragweed season. It indicated that a nebulized 4% aqueous solution of cromolyn sodium is effective in reducing sneezing, rhinorrhea, nasal congestion, and ocular irritation in ragweed hay fever patients. The efficacy of the drug was notable despite the fact that patients used an average of 52 mg instead of the recommended 62.4 mg daily. Cromolyn sodium did not appear to have a significant effect on transseasonal antiragweed IgE (IgEAR) levels. Patients acceptance of the cromolyn nasal solution was good, and there were no significant adverse reactions. The side effects, which were distributed equally between the drug and placebo groups, were mild and of limited duration.     

Adenosine-induced bronchoconstriction in asthma: Role of mast cell-mediator release

Adenosine, when it is administered by inhalation to asthmatic subjects, is a potent bronchoconstrictor, although its mechanism of action is not known. Since adenosine has been demonstrated to potentiate IgE-dependent mediator release from mast cells, we have investigated the possible relationship between adenosine-induced bronchoconstriction and release of mast cell mediators in 14 asthmatic subjects. In the first study the effect of the putative mast cell-stabilizing drug cromolyn sodium (SCG) was observed on the dose-related changes in SG_aw and FEV₁ produced by inhaled adenosine and histamine in seven subjects. Inhaled SCG (20 mg) had no effect on the airway responses to histamine. In contrast SCG significantly protected against adenosine-induced bronchoconstriction in four of the seven subjects as reflected by a decrease in the airway response to the highest concentrations of adenosine, from 65 ± 8% to 12 ± 3% (mean ± SEM) for SG_aw and 31 ± 7% to 8 ± 3% for FEV,. Those three subjects whose adenosine response was unaffected by SCG had received regular SCG until 12 hr before the studies. In a separate study on eight subjects, a single inhalation of adenosine, causing a maximum 61 ± 4% fall in SG_aw at 10 min, had no significant effect on circulating levels of histamine, neutrophil chemotactic factor, or cyclic AMP. Together these two studies suggest that bronchoconstriction produced by adenosine is not a consequence of enhanced mast cell-mediator release and that the inhibitory effects of SCG occur by a mechanism other than through mast cell stabilization.     

Study on cockroach antigen as a probable causative agent in bronchial asthma

Bronchial provocative test (BPT) with cockroach (CR) antigen was performed in 22 asthmatic subjects. Sixteen had positive reaction (CR-positive) and 6 had negative reaction (CR-negative) to CR antigen by skin test. Immediate bronchoconstrictive response was noted following the antigen inhalation in 14 of 16 CR-positive asthmatics, while none of 6 CR-negative asthmatics showed bronchospasm. Late asthmatic responses also were noted in 13 of 16 CR-positive asthmatic individuals following BPT with CR antigen. The dual asthmatic reactions in CR-positive individuals were mostly inhibited by the prior administration of cromolyn sodium. Three-fold increases in peripheral eosinophil counts were noted 24 hr following BPT with CR antigen. Results indicate that CR-induced asthmatic responses are allergen-specific and CR plays a causative role in allergic asthma in the population studied.     

Preseasonal IgE ragweed antibody level as a predictor of response to therapy of ragweed hay fever with intranasal cromolyn sodium solution.

Intranasal administration of a 4% solution of cromolyn sodium for the treatment of ragweed hay fever was tested in an 8-week double-blind matched-pair study involving 66 patients. Patients on active drug received 5.2 mg into each nostril 6 times daily; control patients received a placebo spray. The treated group showed a significant reduction in mouth breathing (p less than 0.001), stuffy nose (p less than 0.002), runny nose (p less than 0.003), and postnasal drip (p less than 0.035). Patients receiving the active drug also reported fewer sneezing episodes (p less than 0.003) and nose blowing episodes (p less than 0.015). One patient using cromolyn solution developed nasal ulceration, tongue swelling, coughing, and wheezing. Other side effects were minimal and occurred with equal frequency in both groups. In the treated group relief of symptoms was most marked in patients with high preseasonal levels of IgE ragweed antibody. Intranasal 4% cromolyn solution appears to be an effective drug for the treatment of ragweed hay fever; measurement of the preseasonal level of IgE ragweed antibody is a useful screening test to identify patients most likely to achieve a maximal beneficial response to treatment.     

Topical ocular administration of cromolyn sodium for treatment in seasonal ragweed conjunctivitis.

We studied topical ocular administration of a 4% solution of cromolyn sodium (CS)for treatment of 112 patients with ragweed conjunctivitis in two 8-wk, double-blind, matched-pair studies. During the 1977 and 1978 ragweed seasons, patients instilled a daily total of 12.8 or 19.2 mg CS into each eye, control patients received placebo drops. Treatment efficacy was assessed by daily symptom score diaries, ophthalmic examinations, and a subjective report by the patient at the end of the trials. In the 1977 trial, CS pair members whose preseasonal immunoglobulin E antibody level was <99 ng/ml showed a significant reduction in eye itching (p < 0.01), eye irritation (p < 0.02), visual blurring (p < 0.025), and nasal congestion (p < 0.025) and required less supplemental medication (p < 0.02) during the peak pollen period. In the 1978 trial all patients had IgE antibody levels >100 ng/ml. CS pair members showed a significant reduction in rhinorrhea (p < 0.004) and nasal congestion (p < 0.007) only; no significant reduction in eye symptoms was noted. Transient eye burning was noted by a total of 38 CS and 39 placebo patients from both studies; ophthalmic examinations were unremarkable; and no other side effects were noted. The 4% CS ophthalmic solution provided significant relief of nasal symptoms in both the 1977 and 1978 trials, but significant relief of ocular symptoms was noted only in the 1977 trial and only in those patients with lower preseasonal IgE ragweed antibody levels.     

Allergic mucociliary dysfunction

This brief summary of several studies relating to allergic mucociliary dysfunction suggests that (1) mucociliary transport in the lower airways (and possibly in the nose) is impaired in subjects with allergic airway disease, (2) acute antigen challenge causes a further impairment of mucociliary transport that is related to chemical mediators, and (3) the elaboration of abnormal respiratory secretions is, at least in part, responsible for acute allergic mucociliary dysfunction. It is apparent from the currently available information that some of the in vivo and in vitro studies carried out in patients with allergic asthma would have to be applied to patients with allergic rhinitis. With respect to the management of patients with allergic rhinitis and asthma, the use of antiallergic agents such as cromolyn sodium or specific mediator antagonists (as they become available) seems to be justified when considering the important role of mucociliary dysfunction in the manifestations of allergic airway disease.     

Double-blind evaluation of nebulized cromolyn, terbutaline, and the combination for childhood asthma

To evaluate whether the potency of a long-acting selective beta 2-agonist negates the need for cromolyn, 27 children, aged 6 to 12 years, with mild to moderate asthma requiring long-term medication, were assessed for the therapeutic effects of cromolyn and/or terbutaline by jet nebulizer. Patients received either cromolyn, 20 mg, terbutaline, 0.1 mg/kg up to 4 mg, or the combination, three times daily. The study design was double-blind, crossover with each patient receiving the three treatment regimens in randomized order for a period of 8 weeks each. Daily diary mean scores generally demonstrated best symptom control with cromolyn or the combination than with terbutaline alone. Cough was significantly less with cromolyn than with terbutaline (p less than 0.05). Morning peak flow measures were higher with combination therapy than with terbutaline (p less than 0.05). Evening peak flow measures were higher with the combination and cromolyn alone than with terbutaline alone (p less than 0.01). Methacholine challenge demonstrated less bronchial hyperreactivity with the combination or cromolyn alone than with terbutaline alone (p less than 0.02). The effectiveness of the nebulizer regimen for children with chronic asthma is better when cromolyn is used alone or in combination with terbutaline than when the beta-agonist is used alone.     

A comparison of cromolyn and bronchodilators in patients with mild to moderately severe asthma in an office practice

The efficacy and safety of two treatment regimens, based in the one case on cromolyn and in the other on bronchodilators, were compared in an eight week study in predominantly young, mild to moderate asthmatics in an office practice. We utilized subjective and objective measures of assessment. Cromolyn was as effective as the bronchodilator regimen except in terms of asthmatic cough, which was better controlled by cromolyn. An equal number of patients could not tolerate each regimen and were dropped from the study. Among those who continued and completed the study cromolyn was devoid of adverse effects whereas 62% of the patients maintained on theophylline with or without a concomitant beta-agonist reported side effects. The results of this preliminary study and of our subsequent broader clinical experience suggest that a re-evaluation of the current approach to managing the symptoms of chronic asthma is indicated, at least in pediatric patients.     

Variation in theophylline clearance rate with time in chronic childhood asthma

Wide theophylline clearance rate (TCR) range between different individuals has been reported, but little is known about its change with the passage of time. Optimal theophylline therapy for asthma aimed at plasma or serum levels of 10 to 20 μg/ml is now strongly recommended. Significant TCR variability with time might easily result in theophylline levels in the toxic or subtherapeutic ranges. Thirty severe asthmatics (mean age, 13 yr) received 24 hr constant intravenous infusion of 1 mg/kg/hr aminophylline USP. TCR was determined after a steady state was reached. Twelve of these patients with persisting poorly controlled asthma underwent repeat infusion for TCR determination at intervals of 1 to 8 mo (mean, 4.7 mo). When these results were compared to the initial individual TCR, the mean absolute change was 28 ± 24% (mean ± SD). Thus, this significant individual variation in TCR with the passage of time (p < 0.01) requires periodic monitoring of plasma theophylline levels in severe asthma treated by optimized theophylline dosage.     

Effect of inhaled lodoxamide tromethamine in prevention of antigen-induced bronchospasm

Lodoxamide tromethamine, a new cromolyn-like drug, was studied to determine its effectiveness and duration of action in preventing antigen-induced bronchospasm in 15 subjects with clinically stable extrinsic asthma. All subjects underwent antigen inhalation challenge 15 min after inhalation of an aerosolized solution of 0.1 mg of lodoxamide in saline or of saline solution alone (placebo) administered on separate days according to a double-blind, random-allocation protocol. Those subjects demonstrating a protective effect of lodoxamide subsequently underwent antigen inhalation challenges at various time intervals (2 to 8 hr) after lodoxamide treatment. Thirteen of 15 subjects (87%) showed a protective effect of lodoxamide administered 15 min prior to antigen challenge. Six of the 13 subjects who were protected initially remained protected 4 hr after lodoxamide treatment and one of these six subjects was also protected at 6 to 8 hr. One additional subject not protected at 4 hr was protected at 3 hr. Lodoxamide exhibited no bronchodilator activity and was not associated with any significant side effects. Further studies are warranted to compare the effectiveness of lodoxamide with that of cromolyn sodium in protection against antigen-induced bronchospasm and to evaluate the relative efficacy and safety of lodoxamide in long-term clinical trials.     

Clinical benefits of cromolyn sodium aerosol (MDI) in the treatment of asthma in children

A double-blind, placebo-controlled study was performed to determine the efficacy and safety of cromolyn sodium (Intal) administered to children by metered dose inhaler (MDI). Prior to entry, subjects were well controlled on cromolyn sodium capsules by Spinhaler turbo-inhaler plus beta 2 agonists. An active control interval of 2 weeks on cromolyn sodium capsules was followed by a 4-week single-blind period on placebo capsules. Those subjects whose asthma worsened significantly on placebo entered a 10-week double-blind phase, randomized to receive either cromolyn sodium (2 mg per dose) or placebo by MDI. Diary data, physician evaluation, and pulmonary function tests were used to assess efficacy, and scores were compared with the baseline value at 2-week intervals. Forty children with asthma, 8 to 20 years of age, entered the study and 32 qualified for the randomized phase. No significant differences existed between the treatment groups at baseline. Most comparative data favored the cromolyn sodium group over the course of the study. Significant differences (p less than .05) were noted for diary scores of breathlessness and overall asthma severity. There was significant improvement at the final visit favoring the cromolyn sodium group in restriction on normal activity, FEV1, and PEFR. The cromolyn sodium group also experienced a decreasing need for concomitant bronchodilators. Both groups preferred pressurized aerosol by MDI over powdered capsules by Spinhaler. (Intal and Spinhaler are registered trademarks of Fisons Corporation.)