Efficacy of Uniphyl, salbutamol, and their combination in asthmatic patients on high-dose inhaled steroids.

A group of 32 patients with moderately severe, chronic asthma (mean FEV1 55% of predicted), maintained on moderately high doses of inhaled corticosteroids (mean dose 1,100 micrograms/d), participated in this double-blind, placebo-controlled crossover study. The effect on pulmonary function of adding theophylline (U, once daily Uniphyl), inhaled salbutamol (S, 200 micrograms four times per day), and their combination (C) or placebo (P) was assessed on Day 14 of each treatment phase. Patients recorded peak expiratory flow, asthma symptom severity (morning and evening), and use of rescue salbutamol inhaler in daily diaries. Mean FEV1 between 0730 and 1800 h and maximum FEV1 between 0730 and 1300 h were significantly higher on U, S, and C compared with P (p < 0.006). Morning peak flow and FEV1 (0730 h) were significantly higher on U and C compared with S and P (p < 0.01). Evening peak flow was higher on U than P (p < 0.001), and C was higher than S and P (p < 0.01). Rescue salbutamol inhaler use was significantly higher on P than on U, C, or S (p = 0.0001). Patient rating of asthma symptoms during C was significantly better than on S or P (p < 0.05). Patient rating of asthma control and study phase preference was significantly higher on combination and Uniphyl alone than on placebo, the combination also being superior to salbutamol alone. Addition of Uniphyl or a combination of Uniphyl and salbutamol significantly improves pulmonary function and asthma symptoms in patients treated with high doses of inhaled corticosteroids and as-needed beta agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

How will we treat asthma in the year 2000?

Expansion of the understanding of the mechanism of asthma progressed dramatically in the past decade. With this new information, therapeutic emphasis switched from primarily bronchodilator therapy to anti-inflammatory therapy. Concurrently, drugs with different delivery systems as well as higher dose agents were released, simplifying therapy for many patients. The result is a fairly dramatic reexamination of traditionally used medications and attempts to develop newer medications aimed at reducing asthma based on the newer proposed pathophysiological mechanisms. Future management of asthma likely will involve some newer medications as well as the education of the patient and his/her family concerning the behavior of asthma and appropriate steps to take when there is loss of usual asthma control.

The effectiveness of immediate feedback during the objective structured clinical examination.

Using eight different physical examination or technical stations, 400 examinations were conducted to evaluate the effectiveness of immediate feedback during the Objective Structured Clinical Examination (OSCE). The test group comprised 50 medical students who underwent a standard 4-minute examination followed by 2 minutes of feedback. Immediately following feedback the students repeated an identical 4-minute examination scored by the same examiners. The control group consisted of 50 students from the same class who underwent an identical testing sequence, but instead of receiving feedback, they were instructed to continue their examinations for an additional 2 minutes before repeating the stations. Simple repetition of the task did not significantly improve score (mean increase 2.0%, NS). Extending the testing period from 4 to 6 minutes resulted in a small but significant increase in score (mean 6.7%, P less than 0.001). However, there was a much larger increase in the scores obtained following 2 minutes of immediate feedback compared to pre-feedback performance (mean 26.3%, P less than 0.0001). The majority of students and examiners felt that feedback, as administered in this study, was valuable both as a learning and teaching experience. Short periods of immediate feedback during an OSCE are practical and can improve competency in the performance of criterion-based tasks, at least over the short term. In addition, such feedback provides students with valuable self-assessment that may stimulate further learning.

The clinical significance of food-induced changes in the absorption of theophylline from Uniphyl tablets.

To determine the effects of food on the absorption of theophylline from Uniphyl tablets (a once-daily sustained-release theophylline formulation), we performed a crossover evaluation in 20 adults with asthma. After 5 days of continuous dosing (at 6 PM), all patients received their regular Uniphyl dose under specified fasting conditions, and serum theophylline concentrations were measured sequentially during the following 24 hours. The patients' next Uniphyl dose was administered immediately after ingestion of a standardized high-fat meal, and theophylline concentrations were again measured during 24 hours. Five days later, the procedure was repeated in the opposite order. The patients' mean daily theophylline dose was 890.0 +/- 229.2 mg. We found relatively minor, but in some cases statistically significant, differences in pharmacokinetic parameters between food and fasting administration. When Uniphyl was administered with food, bioavailability was increased by 10% (p less than 0.01), the time of maximum concentration occurred 3 hours later (p less than 0.01), and the minimum or "trough" theophylline concentration was 0.7 mg/L greater (p less than 0.01), as compared to administration while patients were fasting. There was no evidence of "dose dumping" after either food or fasting administration of Uniphyl, and there was no significant difference in the maximum theophylline concentration attained between the two dosing conditions. There was no evidence of a difference in therapeutic efficacy between the two dosing conditions. All patients tolerated the drug well throughout the trial.

Safety and efficacy of once-daily Uniphyl tablets compared with twice-daily Theo-Dur tablets in elderly patients with chronic airflow obstruction.

Oxygen desaturation and subclinical coronary artery disease may predispose older patients with chronic airflow obstruction to cardiac arrhythmias, especially when high concentrations of theophylline are present in the blood. To assess the safety and efficacy of Uniphyl tablets, an oral theophylline preparation formulated for once-daily dosing, in elderly patients with chronic airflow obstruction, we conducted a randomized, three-phase, double-blind crossover study comparing evening dosing with Uniphyl tablets, Theo-Dur tablets administered twice daily, and placebo. The patients in the study were scheduled to receive each treatment for two weeks. Each day, symptoms, side effects, peak expiratory flow rates, and use of metered-dose inhalers were recorded. Near the end of each phase, serum theophylline concentrations were measured every two hours between 8:00 A.M. and 8:00 P.M. on two consecutive days. The patients underwent ambulatory Holter monitoring during the final 48 hours of each phase. Twelve patients completed the active-drug phases of the study, but seven of the 12 were removed from the placebo phase because of increasing symptom severity. The difference between the number of patients completing the active-drug and placebo phases was statistically significant (p less than 0.001). Treatment with Uniphyl tablets resulted in a significantly (p less than 0.05) greater increase in peak expiratory flow rate than Theo-Dur tablet therapy, and both active drugs increased peak expiratory flow rate more than placebo. Circadian variation in peak expiratory flow rate was seen during the placebo and Theo-Dur tablet phases but not during the Uniphyl tablet phase. Symptoms and side effects were similar during the two active-drug phases. Cardiac ectopy was observed in most of the patients, but it was not significantly greater during the theophylline phases than during the placebo phase. Furthermore, ectopic activity was not directly related to the times of maximal serum theophylline concentration.

Positive skin tests and Prausnitz-Küstner reactions in metabisulfite-sensitive subjects.

Sulfiting agents have been reported to cause anaphylaxis, asthma, urticaria/angioedema, seizure, nausea, abdominal pain and diarrhea, and death. There is no consensus regarding the pathogenesis of these reactions. The possible role of IgE-mediated mechanism has been debated. To clarify the pathogenesis of these reactions, we studied 53 patients with a variety of symptoms related to either restaurant meals or alcoholic beverages. Food allergy was excluded as a cause of their symptoms by means of skin testing and elimination diet. Symptoms included urticaria/angioedema (32), asthma (nine), headache (eight), rhinoconjunctivitis (two), and abdominal pain (one), and one patient with anaphylaxis. Twenty normal control subjects were studied as well. Prick and intradermal skin testing with potassium metabisulfite (K2S2O5, 1 mg/ml) were carried out on all subjects. Single-blind oral provocative challenge tests were conducted with placebo (lactose) and with 1, 5, 10, 25, and 50 mg of K2S2O5 in all nine subjects with asthma, nine patients with urticaria/angioedema (excluding one subject with severe coronary insufficiency and positive skin testing to 1 mg of K2S2O5), four subjects with headache, one subject with rhinoconjunctivitis, and one patient with anaphylaxis. Pulmonary function tests (FEV1 and FVC) were measured in all subjects with asthma. Five patients had positive skin tests. One subject with asthma had a positive prick test. Four positive intradermal tests occurred (two subjects with asthma, one subject with urticaria/angioedema, and one subject with anaphylaxis). Single-blind oral provocative challenge testing was positive in the subject with anaphylaxis, as was intradermal skin testing, and also in three subjects with asthma, two of whom had positive skin testing.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of morning versus evening dosing with a new once-daily oral theophylline formulation.

A double-blind, cross-over comparison of morning (8 A.M.) versus evening (10 P.M.) dosing regimens with a new once-daily oral theophylline (Uniphyl, Purdue Frederick) was performed. The comparison was based upon steady-state theophylline pharmacokinetics, spirometric measurements over 24 hours, the patients' quantitative reporting of asthmatic symptoms, and medication side effects. No statistically significant differences were observed in any theophylline parameter between the dosing regimens. Evening dosing, but not morning dosing, resulted in a significant attenuation of the early morning dip in pulmonary function. The morning severity of wheezing, chest tightness, and shortness of breath was significantly reduced after evening dosing. Overall no difference in the incidence of symptoms was noted. No significant differences in side effects were noted. Evening dosing with Uniphyl produced a significant improvement in morning pulmonary function, and this benefit was subjectively noted by the patients. No decline in this benefit was noted later in the day. Evening dosing with Uniphyl clearly is superior to morning dosing.

Exercise testing in evaluation of patients for lung resection.

We studied, in a prospective fashion, whether exercise testing selected candidates for lung resection and predicted postoperative morbidity and mortality better than "standard" lung function tests. We confirmed that a low preoperative FEV1 and VC had prognostic significance for the development of postoperative complications. Poor exercise performance did not. Likewise, analysis of exercise performance did not discriminate in patients rejected for surgery from those in whom resection was successfully completed.

Control of breathing in chronic obstructive pulmonary disease. The effect of histamine inhalation.

In 7 normocapnic and 6 hypercapnic patients with chronic obstructive pulmonary disease (COPD), we confirmed the recently reported observation that hypercapnic and/or hypoxemic patients with COPD breathe with a shorter inspiratory time (TI) and a smaller tidal volume (VT) than normocapnic and/or normoxemic patients with COPD. Both hypercapnic and normocapnic groups were exposed to doubling concentrations of aerosolized histamine, and FEV1 was measured 30 and 90 s after each 2-min exposure. A provocative concentration (PC20) of histamine was defined as that which produced a 20% decrease in FEV1. At PC20, minute ventilation and VT decreased in both groups. The decrease in VT was significantly greater in the normocapnic patients. Inspiratory flow (VT/TI) did not change in either group. Although breathing frequency (f) and inspiratory time (TI) did not change in the hypercapnic group, f increased and TI decreased significantly in the normocapnic patients. The same results were obtained when patients were separated into hypoxemic and "normoxemic" groups. At PC20, therefore, the pattern of breathing of the hypercapnic and/or hypoxemic patients showed only small variations, whereas in the normocapnic and/or "normoxemic" patients, the breathing pattern showed greater changes, becoming similar to that of the hypercapnic and/or hypoxemic patients during control breathing. We speculated, therefore, that activation of histamine-sensitive receptors in the airways could be involved in the pathophysiology of the rapid shallow breathing present at rest in hypercapnic and/or hypoxemic patients with COPD.

Inspiratory muscle training compared with physiotherapy in patients with chronic airflow limitation.

The effects on exercise performance of physiotherapy (PT) (8 patients) were compared with those of inspiratory muscle training (IMT) (9 patients) in severe chronic airflow limitation. Exercise performance was measured by 3 tests: the distance walked in 12 min, peak oxygen uptake on a progressive multistage exercise test, and endurance time at two thirds of maximal power output. Measurements were repeated after a 1-month control period during which no change was observed apart from an increase in the distance walked in 12 min in the PT group. The PT patients then performed graded exercise in a physiotherapy program 3 times weekly, whereas the IMT patients trained for 30 min daily, inspiring against a resistance. Measurements were repeated after 1 and 2 months of training. Physiotherapy was associated with insignificant increases in exercise performance, whereas IMT produced both an increase in endurance time and in the distance walked in 12 min. We concluded that a simple at-home training program of inspiratory muscles was more effective than this particular physiotherapy program in improving exercise performance of some patients with severe chronic airflow limitation.

The effects of inspiratory muscle training on exercise performance in chronic airflow limitation.

Using a simple, inexpensive, at-home program, 12 patients with moderate-to-severe chronic air flow limitation trained their inspiratory muscles. All showed increased inspiratory muscle endurance with no change in inspiratory muscle strength. Seven of the twelve patients increased their endurance time for submaximal exercise beyond the 90% confidence limits determined by 2 pretraining tests (i.e., a more than 40% increase in endurance time). The same group of 7 patients increased the maximal power output (p less than 0.005) and peak oxygen uptake (p less than 0.05) on a progressive exercise test after 2 months of training and increased the distance walked in 12 min after both 1 (p less than 0.005) and 2 (p less than 0.005) months of training. In 6 of the 7 patients in this group, the pretraining submaximal exercise tests were accompanied by electromyographic changes heralding inspiratory muscle fatigue. Their increased endurance time post-training was associated with a delay or absence of these changes. In the other group of 5 patients, who showed no change in exercise performance with training, electromyographic changes heralding inspiratory muscle fatigue were never observed in submaximal exercise tests. We concluded that although the endurance of the inspiratory muscles of patients with chronic airflow limitation is increased, specific training of the inspiratory muscles is usually associated with improved exercise performance only in those who demonstrate electromyographic changes heralding inspiratory muscle fatigue during exercise.