Calcium channel blocking agents in the prophylaxis of asthma.

Asthma is a state of reversible airway obstruction caused by the activation and response of different cell types (smooth muscle cells, mast cells, mucous gland secretory cells, and inflammatory cells) in various combinations. Recent evidence has demonstrated that all these cells require calcium-dependent reactions for their activation, which suggests that mobilization of calcium from extracellular and intraorganelle storage depots to the cytoplasmic matrix may be one possible underlying mechanism for asthma. Numerous agents have been developed to prevent this flow of calcium to the intracellular cytoplasmic matrix. Although their exact mechanism of action is not always clear, it has been shown that they can be effective in preventing muscle spasm and release of chemical mediators from mast cells following antigen and exercise challenges. Studies indicate that one calcium channel blocking agent, ketitofen, is effective as a prophylactic agent in the treatment of mild to moderate asthma. Other calcium channel blockers, including nifedipine, verapamil, and diltiazem, are now being actively investigated.

Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children.

OBJECTIVE: To compare the benefits and adverse reactions of theophylline and beclomethasone (BDP) in the long-term control of mild to moderate chronic asthma in children. DESIGN: Multicentered, double-blind, double-placebo, randomized, controlled trial. PATIENTS: One hundred ninety-five children between the ages of 6 and 16 years with mild to moderate asthma. INTERVENTION: Treatment with either BDP, 84 micrograms four times a day, or sustained-release theophylline administered twice daily in doses adjusted for optimum control of symptoms. MAIN OUTCOME MEASURES: Daily diary record of symptoms, peak flow rates, supplemental bronchodilator and glucocorticoid treatment, doctor and hospital visits, absence from work and school, and side effects. RESULTS: Aerosol BDP and sustained-release theophylline were effective primary treatments for mild to moderate chronic asthma. Beclomethasone resulted in comparable symptom control with less bronchodilator use and fewer courses of systemic steroids than did theophylline. Side effects were observed significantly more frequently with theophylline than with BDP. Growth velocity suppression was noted with BDP and was more pronounced in boys. Suppression was not associated with alterations in cortisol measurements either at baseline or following stimulation. CONCLUSION: Both theophylline and BDP are effective therapy for mild to moderate asthma. Caution must be used with the administration of BDP in children because of possible growth velocity suppression.

Terbutaline and ephedrine in asthmatic children.

The effects of terbutaline, ephedrine, and placebo on the cardiovascular and pulmonary systems have been compared in 24 asthmatic children. Ephedrine and terbutaline were both found to be effective bronchodilators, with onset of action within 30 minutes. The bronchodilator effect of ephedrine was maintained for three hours, while terbutaline was active for five hours. Terbutaline caused significantly greater improvement in pulmonary functions than did ephedrine. Both terbutaline and ephedrine were associated with clinically insignificant changes in blood pressure and pulse rate. The only significant side effect observed was hand tremor in children receiving terbutaline and this appeared only early in the course of drug treatment. There was no evidence of tolerance to the bronchodilator effect of ephedrine or terbutaline after eight weeks of therapy.

Dose-response study of nebulized bitolterol mesylate solution in asthmatic patients.

Bitolterol mesylate, a new beta 2 adrenergic bronchodilator, is a "pro-drug" which is activated by esterases in the lung. In order to determine the optimal bronchodilator dose of bitolterol, six doses, (0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg and 3.0 mg), were administered by closed-port, intermittent-flow nebulization (CPIF) to asthmatic patients on different days. For most patients, the onset of bronchodilator activity (FEV1 increase of at least 15 percent above baseline) occurred within 5 minutes and lasted at least 8 hours. Maximum mean increases in FEV1 were 46-50 percent at the 1.0 mg to 3.0 mg doses. Beyond the 1.0 mg dose, there was no significant improvement in bronchodilator effect, but adverse effects, particularly tremor, increased at higher doses. The optimal dose of bitolterol administered by CPIF was determined to be 1.0 mg which is similar to the dose of bitolterol recommended for use by metered-dose inhaler (MDI) which is 0.7 mg to 1.1 mg. If continuous-flow nebulization is used, two-three times more drug may be needed for a comparable effect. Bitolterol appears to be a safe, effective and long-lasting bronchodilator when administered by jet nebulization.

A 1-week dose-ranging study of inhaled salmeterol in patients with asthma.

STUDY OBJECTIVE: A dose-ranging study was conducted to evaluate the efficacy and safety of a new long-acting, selective beta 2-adrenoceptor agonist, salmeterol. DESIGN: Adolescents and adults (N = 160) with mild-to-moderate asthma received salmeterol (10.5, 21, 42, or 84 micrograms) or placebo by metered-dose inhaler twice daily for 1 week. Twelve-hour serial spirometry measurements were performed on the first and last days of treatment, and patients recorded their peak expiratory flow (PEF) twice daily on diary cards. RESULTS: On day 1, salmeterol produced greater bronchodilation than placebo (p = 0.001), and both the 42-micrograms and 84-micrograms doses of salmeterol were significantly more effective in improving FEV1 responses than the two lower doses of salmeterol (p < 0.05). After 1 week of treatment, all but the 21-micrograms dose of salmeterol remained statistically superior to placebo (p < 0.01), but significant differences between salmeterol doses were no longer evident, despite an apparent dose-response effect. Only the 42-micrograms and 84-micrograms doses of salmeterol sustained bronchodilation for 12 h in the majority of patients at both treatment days. The degree of improvement in morning and evening PEF was also found to be dose related. There was no significant difference among treatment groups in the overall incidence of adverse events; however, pharmacologically predictable events (eg, tremor) occurred significantly more often with salmeterol, 84 micrograms. CONCLUSIONS: Salmeterol, 42 micrograms, was similar in efficacy to 84 micrograms but was associated with a lower incidence of adverse events. Salmeterol, 42 micrograms twice daily, is a safe and effective dosage for patients with mild-to-moderate asthma who are persistently symptomatic and require maintenance bronchodilator therapy.

Proventil HFA and ventolin have similar safety profiles during regular use.

OBJECTIVE: As a secondary objective to a long-term study evaluating the bronchodilator effectiveness of Proventil HFA (albuterol), to assess the safety of Proventil HFA, Ventolin, and hydrofluoroalkane 134a (HFA-134a) placebo over 12 weeks of regular dosing. DESIGN: Randomized, double-blind, double-dummy parallel group, placebo-controlled, multicenter trial of asthmatics requiring inhaled beta-adrenergic bronchodilators for symptom control. INTERVENTIONS: Treatment with Proventil HFA, Ventolin, or HFA-134a placebo, qid, for 12 weeks. MEASUREMENTS: Adverse events were reviewed at biweekly clinic visits. Between clinic visits, patients recorded morning and evening peak expiratory flow (PEF), asthma symptom and nighttime asthma sleep disturbance scores, and use of rescue beta-adrenergic bronchodilator on diary cards daily. Investigators provided a global assessment of asthma control at weeks 0, 4, 8, and 12. Vital signs were recorded over 6 h after dosing with study drug at weeks 0, 4, 8, and 12. Standard laboratory tests, CBC count, serum chemistries, and urinalysis were obtained at study start and end. RESULTS: Adverse event reporting rates were similar for the three treatment groups. The morning PEF tended to be lower for the Proventil HFA and Ventolin groups than the HFA-134a placebo group, but the evening PEF tended to be higher for the active treatment groups. Daytime asthma symptom scores tended to be lower (better) with active treatment than placebo, but nighttime asthma sleep disturbance scores were similar for all three treatment groups. Use of Ventolin Rotacaps as rescue medication was significantly greater for the HFA-134a placebo group than the Proventil HFA and Ventolin groups. Diary card data did not change within groups over time. Investigator global assessments of asthma scores clustered between fair and good for all three treatment groups throughout the study. Changes in heart rate and BP were small after dosing with study drug and tended to be similar for the active treatments and HFA-134a placebo groups. No clinically meaningful changes in results of standard laboratory tests were found in any treatment group during this study. CONCLUSIONS: Proventil HFA had a similar safety profile as Ventolin during regular use. A dosage of 16 puffs per day of propellant HFA-134a was well tolerated by asthmatics. Regular use of either Proventil HFA or Ventolin did not cause asthma control to deteriorate.

Proventil HFA provides bronchodilation comparable to ventolin over 12 weeks of regular use in asthmatics.

OBJECTIVE: To compare the bronchodilator effectiveness of albuterol reformulated in the chlorofluorocarbon-free propellant hydrofluoroalkane (HFA)134a (Proventil HFA) to that of Ventolin and HFA placebo over 12 weeks of regular dosing. DESIGN: Randomized, double-blind, double-dummy, parallel group, placebo-controlled, multi-center trial of asthmatics requiring inhaled beta-adrenergic bronchodilators for symptom control. INTERVENTIONS: Treatment qid with Proventil HFA, Ventolin, or HFA-134a placebo for 12 weeks. MEASUREMENTS: At weeks 0, 4, 8, and 12, spirometry was performed predose and serially over 6 h after dosing with study drug. Bronchodilator efficacy variables, based on FEV1 response to study drug, were proportion of responders, time to onset of effect, peak percent change, time to peak effect, duration of effect, and area under the curve (AUC). RESULTS: Demographic and baseline characteristics were similar for patients randomized to Proventil HFA (193), Ventolin (186), and HFA-134a placebo (186). No significant differences were found between the Proventil HFA and Ventolin treatment groups for any FEV1 efficacy variable, either predose or during 6 h of serial spirometry, at weeks 0, 4, 8, and 12. For all efficacy variables, except time to onset of effect, the Proventil HFA and Ventolin results were significantly greater than placebo. Time to onset of effect for the HFA-134a placebo group is misleading; only 13 patients (7%) were found to be responders in the intent-to-treat database. These efficacy results were found to be consistent across subgroup analyses of inhaled and nasal corticosteroid use, age (18 to 35 and 36 to 66 years), sex, race, weight (<60, 60 to 100, and >100 kg), and baseline FEV1 (< or =55% and >55% predicted). The peak FEV1 effect, duration of FEV1 effect, and AUC for FEV1 were all significantly smaller at weeks 4, 8, and 12 than week 0 for both the Proventil HFA and Ventolin treatment groups. CONCLUSIONS: Proventil HFA provided bronchodilation comparable to Ventolin and superior effects to HFA-134a placebo over 12 weeks of regular dosing. There was a diminution in bronchodilator response to both Proventil HFA and Ventolin after 4 weeks of use.

Clinical evaluation of ketorolac tromethamine 0.5% ophthalmic solution for the treatment of seasonal allergic conjunctivitis.

We evaluated 148 patients with allergic conjunctivitis in a double-masked, paired comparison clinical trial comparing ketorolac 0.5% ophthalmic solution with vehicle. Patients received one drop of each study medication in preassigned eyes, four times a day, for seven days. Both treatments showed significant changes from baseline in the signs and symptoms associated with allergic conjunctivitis. Evaluations at the final visit (day 7 or 8) showed that ketorolac-treated eyes had a significant treatment response when compared to vehicle-treated eyes for conjunctival inflammation (p = 0.010), ocular itching (p = 0.006), swollen eyes (p = 0.002), discharge/tearing (p = 0.021), foreign body sensation (p = 0.035), and conjunctival injection (p = 0.016). Mean scores evaluating the overall therapeutic effect of the study treatments at the completion of the study were higher for ketorolac-treated eyes than for vehicle-treated eyes as rated by investigators (p = 0.004) and study patients (p < 0.001). Results of this study confirmed the trends of a previous study showing that ketorolac 0.5% ophthalmic solution applied topically is an effective therapy for allergic conjunctivitis.

Double-masked, paired-comparison clinical study of ketorolac tromethamine 0.5% ophthalmic solution compared with placebo eyedrops in the treatment of seasonal allergic conjunctivitis.

In a multicenter, double-masked, clinical study, we compared the ocular safety and efficacy of ketorolac 0.5% ophthalmic solution with placebo in alleviating the signs and symptoms of allergic conjunctivitis. The study was conducted in 93 patients who received one drop of the appropriate treatments in each eye, four times a day, for seven days. Of these subjects, 74 were evaluated for efficacy. The principal clinical sign of allergic conjunctivitis, conjunctival inflammation, and six allergic symptoms (itching, swollen eyes, burning or stinging, discharge or tearing, foreign body sensation, and photophobia) were evaluated by the investigators at midweek (day 3 or 4) and at the end of the study (day 7 or 8). Ketorolac was superior to placebo in reducing conjunctival inflammation (p = 0.003) and itching (p = 0.020), the principal clinical symptom, at the final examination. In addition, ketorolac was favored over placebo in reducing the other five symptoms evaluated. On the day of final examination, overall therapeutic response evaluated by the investigators rated ketorolac as superior to placebo (p = 0.007). A significant placebo effect was noted in this study, as has been previously reported in clinical studies of allergic conjunctivitis patients. Results of this study demonstrate that 0.5% ketorolac ophthalmic solution used topically four times daily, for seven days, was effective in alleviating the principal sign and the symptoms associated with allergic conjunctivitis.

Alternative drug therapy for asthma.

Individualized management of asthma requires consideration of single or combined pharmacologic alternatives. This article reviews experimental and clinical data on the efficacy, safety, mode of action, and therapeutic indications for cromolyn and related inhalational compounds; ketotifen; alpha-adrenergic blockers; calcium-channel blockers; nonsteroidal anti-inflammatory drugs; and such diverse agents as immunosuppressive drugs, ether, alcohol, ascorbic acid, and other nutritional substances.

Analysis of breath sounds in normal and asthmatic children and adults using computer digitized airway phonopneumography (CDAP).

Analysis of breath sounds using the stethoscope is a major part of physicians evaluation of their patients. However, the use of a stethoscope is often inadequate to give quantitative measurements of the clinical state of the individual. In this study a modification of a previously described computer analysis of breath sounds was used to measure sound intensity levels in both normal and asthmatic children who, in most cases, were unable to perform pulmonary function. The intensity levels were derived using a microcomputer-based program that digitizes audio signals and calculates energy values at 25-ms intervals throughout each signal. There were statistical differences between mean intensity levels for normal breath sounds in children between 2 and 6 years and the mean intensity levels for wheezing sounds in the same age group, as well as wheezing sounds in asthmatic patients over the age of 8 years (P less than 0.002). Also, the mean intensity levels for normal breath sounds could be clearly differentiated from intensity levels for other sounds from the chest, including heart sounds and voice sounds. Thus, computer digitized airway phonopneumography (CDAP) proved to be a reproducible, quantifiable method for demonstrating airway obstruction in those children and patients unable to perform pulmonary function testing.

Disease management program improves asthma outcomes.

OBJECTIVE: To show that a disease management program that empowers patients with asthma to participate in the management of their condition can improve quality of life and reduce the use of medical services. STUDY DESIGN: Utilization and quality-of-life data were tracked to identify outcome changes in patients with moderate to severe asthma. Baseline measures were used as a control and were compared with measures taken at 6 and 12 months after enrollment. PATIENTS AND METHODS: Study participants were from a single Medicaid managed care plan in western Pennsylvania. Patients' quality of life during their participation in the program was tracked through an outside pharmacoepidemiologic research firm. Utilization data were updated with every interaction between a patient and case management nurse. RESULTS: Both quality-of-life and utilization data show statistically significant improvements at 6 months. Further, 12-month data show improvement that is statistically significant in all measures with the exception of the adult quality-of-life measure, where a small sample size limited the statistical results. CONCLUSIONS: A collaborative, proactive approach to asthma management improves patients' quality of life and reduces use of costly medical services.

Antigen bronchial challenges: uses, misuses, and problems.

The antigen bronchial challenge is a reliable tool for evaluating the efficacy of new treatment modalities and for increasing the basic understanding of asthma. However, because of the difficulty in interpreting test results and the potential for significant morbidity, this procedure is unlikely to be widely used in clinical practice. When it is performed in a clinical setting, patients must be carefully instructed in dealing with a late-phase reaction.

Evaluation of oral terfenadine for treatment of the common cold.

This study was a single center trial comparing the effects of the nonsedating antihistamine terfenadine, at a dose of 120 mg twice a day, with placebo in the treatment of rhinitis symptoms associated with the common cold. Forty-nine subjects were treated with terfenadine, 120 mg twice each day, and 48 subjects were treated with placebo twice each day for four or five days. Evaluations by both subjects and physicians suggest that terfenadine at 120 mg given twice daily marginally improved sneezing and total symptom scores at day 4. When comparing terfenadine to placebo, neither the symptoms nor signs of the common cold improved in a clinically or statistically significant manner. Terfenadine was well tolerated and had a low incidence of side effects. Terfenadine was found to be ineffective in the treatment of the signs and symptoms of the common cold.

Clinical and bacteriologic features of chronic sinusitis in children.

The clinical and bacteriologic aspects of chronic sinusitis in childhood were studied. Of 35 children who underwent surgical procedures for chronic sinusitis, 22 had positive bacteriologic cultures of aspirates from the sinus. The most common organisms isolated were Haemophilus influenzae, Streptococcus pneumoniae, and Branhamella catarrhalis. Five of eight S pneumoniae strains were relatively resistant to penicillin and resistant to sulfamethoxazole-trimethoprim. All of the B catarrhalis and 20% of the H influenzae organisms were beta-lactamase positive. Overall, 14 of 28 of the bacteria were penicillin resistant. In addition, all 12 children 2 years of age or younger had a positive bacterial culture as compared with much lower rates in older children. Although the incidence of S pneumoniae strains that are relatively resistant seems to be rising, to our knowledge we report the first description of these organisms as significant pathogens in chronic childhood sinusitis. These results indicate that chronic, difficult to manage sinusitis in very young children is frequently bacterial in origin, especially if the patient is 2 years old or younger. In light of the frequent failure of antibiotic therapy and considering the incidence of relatively resistant S pneumoniae strains, puncture of the sinus should be considered early in the course of chronic sinusitis to isolate pathogenic organisms and determine appropriate antimicrobial therapy.

A pilot study of pemirolast in patients with seasonal allergic rhinitis.

Pemirolast is a potent, long-acting, orally effective antiallergic agent evaluated for clinical activity in prevention of symptoms of seasonal allergic rhinitis. It was evaluated in a randomized, double-blind, placebo-controlled parallel group in season trials to test its safety, tolerance, and prophylactic activity. Thirty-one patients with a history of fall seasonal allergic rhinitis were treated for 6 weeks with pemirolast, 50 mg bid, or placebo beginning approximately 2 weeks before the onset of the ragweed season in Atlanta. Daily evaluation of symptom scores disclosed statistically significantly less sneezing, rhinorrhea, and stuffy nose during treatment with pemirolast. There was, however, no difference for other evaluated symptoms or for the use of rescue medicines. There were no side effects during this short study. This preliminary study indicates that pemirolast may warrant further evaluation for the treatment of allergic rhinitis.

Barriers to measuring and achieving optimal outcomes in pediatric asthma.

To measure the effectiveness of any therapeutic endeavor, a set of defined outcome measurements must be performed, or the task of determining the effectiveness of any therapeutic step becomes difficult. With asthma, however, in which case it is difficult to establish the initial diagnosis, beginning a program of outcome measurements regarding any therapeutic interaction is nearly impossible. Conventional means are thwarted at the outset. One way of approaching the problem of obtaining reproducible outcomes data is to examine those areas in which measurements can be made and determine the barriers to obtaining the data. Establishing a good medical history is a critical step that, in general, is especially difficult with very young children, and tools that provide objective measurements that are used in the normal evaluation of older children are of little use in the very young child with asthma. Parts of the physical examination are difficult to perform in very young children, and findings associated with asthma can be found in other clinical states. In this age group, diary keeping suffers from the same problems and issues that are related to obtaining an accurate medical history. Barriers also exist to obtaining the best outcomes. The choice of medications for the very young child is limited; there are several typical adherence problems, and information about adverse effects is limited.