Abnormal mucociliary transport is improvement by the action of theophylline, and this effect can be attributed to several mechanisms. The drug may directly and indirectly mediate the increase in the secretory output of bronchial glands, and this effect is enhanced by the vagal gastropulmonary reflex which is stimulated by the irritant action of theophylline on the stomach. Theophylline can increase the transepithelial secretion of fluid into the respiratory tract lumen by stimulating the chloride pump which is controlled by cyclic AMP. Ciliary motility is stimulated by theophylline; most of this effect is confined to the proximal part of the respiratory tree. However, much of the improvement in mucociliary clearance may be a consequence of the bronchodilation induced by theophylline, since the improved airway patency is generally a prerequisite for enhanced mucokinesis. Nevertheless, the multiple sites of action of theophylline in the respiratory tract suggests that this drug should be considered to be of significant value in any disorder characterized by mucostasis.

One of the important modes of action of theophylline in asthma and chronic obstructive airway disease may be the inhibition of airway inflammation. This hypothesis is based on in vitro and in vivo studies demonstrating that theophylline at therapeutic concentrations has an inhibitory activity on airway inflammation induced by allergic and nonallergic stimuli. Indirect evidence suggests that airway inflammation is an important determinant in the long-term outcome of chronic obstructive airway disease. The effect of theophylline on the long-term evolution of chronic obstructive lung disease remains to be proven.

Dyspnea is influenced by both physiologic and psychologic factors. Breathlessness is common in patients with chronic obstructive pulmonary disease (COPD) and often is the reason that the individual patient seeks medical attention. In order to evaluate the different clinical studies involving the use of theophylline in COPD patients, it is important to consider the three distinct approaches for measuring dyspnea--psychophysical testing, clinical methods, and ratings during exercise. Four randomized, double-blind, placebo-theophylline trials from one to four weeks in duration have evaluated the impact of theophylline on lung function and breathlessness. In these studies, the overall improvement in forced expiratory volume in one second was quite consistent for theophylline compared with placebo therapy. When appropriate clinical methods for measuring dyspnea were used, theophylline showed a positive reduction in breathlessness. These reports suggest that theophylline provides modest objective and subjective improvement in patients with symptomatic chronic air flow obstruction.

Thirty-four otherwise healthy patients having to undergo elective upper abdominal surgery were randomly assigned to two equal groups. In the treatment group, constant positive airway pressure (CPAP) with an expiratory pressure of 12 cm H2O was applied at one hour following extubation, and at daily intervals for the first five days following surgery for a continuous period of three hours. The control group received no CPAP treatment. All patients were given postoperative physiotherapy. In patients who received postoperative CPAP with an end-expiratory pressure of 12 cm H2O, marked normalization of pulmonary function was noted.

The bronchodilating action of theophylline in COPD has been examined, with emphasis on its combined use with inhaled beta 2 agonists. The suggestion is made that failure to recognize the nonlinearity of the dose-response curves for bronchodilators has resulted in underestimating their combined action. Recent studies suggest that systemic theophylline has somewhat different actions on the airways in COPD than inhaled beta agonists, and that more bronchodilation may be possible when the two are used together than large doses of either one. By analogy, with asthma the suggestion is also made that the addition of theophylline is also likely to provide a more constant bronchodilation, reducing peak-trough variations in flow. The most complete clinical comparison to date suggests that, in currently sanctioned doses, a regimen containing both theophylline and an inhaled beta 2 agonist provides significantly greater bronchodilation than either drug alone, with fewer patient withdrawals. Further carefully designed studies are needed to resolve this issue, and particularly, to identify those patients who will derive the greatest benefit from a combined regimen.

Increased airway responsiveness occurs in asthma, chronic bronchitis, cystic fibrosis, and other diseases. Theophylline and beta 2 agonists commonly are used as maintenance therapy for symptoms associated with the increased responsiveness. Both drugs can reduce airway responsiveness to a variety of provocational stimuli. With currently used dosing regimens, theophylline appears to produce relatively constant levels of effect on airway responsiveness and clinical efficacy around the clock, while inhaled beta 2 agonists appear to have insufficient effects at the end of longer dosing intervals. Improved dosing strategies for beta 2 agonists may improve the efficacy of these agents in the future.

Nineteen patients (12 men) mean age, 63.4 years (range, 32 to 78), with stable chronic airflow limitation, mean FEV, 0.55 L (range, 0.3 to 1.05 L), completed an eight-week, double-blind, double cross-over study comparing nebulized salbutamol and salbutamol from a metered-dose inhaler (MDI). Salbutamol from both delivery systems produced bronchodilation. The doses of salbutamol inhaled via the nebulizer and MDI producing maximal bronchodilation were established by cumulative dose-response curves. The contents of the nebulizer and MDI were inhaled four times a day, one system containing salbutamol and the other a placebo. Cross-over of salbutamol from one system to the other occurred every two weeks. There was no significant difference between the two delivery methods in daily peak expiratory flow rate (PEFR), severity of symptoms, or extra bronchodilator usage. Two weekly laboratory assessments of spirometry, PEFR, and exercise tolerance also showed no significant differences. Careful assessment is recommended before the provision of domiciliary nebulizers.

We studied the antihistaminic property of a new compound, azelastine, on histamine-induced bronchoconstriction and compared it with ketotifen and placebo. In 12 patients with bronchial asthma we performed histamine bronchial challenges before and four hours after ingestion of placebo, 2.0 mg ketotifen, and 4.4 mg azelastine given in a double-blind, randomized, cross-over fashion. Ketotifen and azelastine provided significant protection compared with placebo. No statistically significant difference between ketotifen and azelastine could be detected. As the antihistaminic effect of azelastine does not predict the therapeutic usefulness in the maintenance therapy of bronchial asthma, further studies are indicated.

We conducted a single-bind placebo controlled study using 24-hour continuous ambulatory electrocardiographic recordings. The arrhythmogenic potential of the combination of salbutamol and theophylline was investigated in 25 ambulatory subjects with severe chronic airflow obstruction (mean age 65 +/- 8 SD, mean FEV1 31 percent +/- 13 SD predicted). Asymptomatic arrhythmias were very prevalent in the study population: 76 percent of the patients had runs of supraventricular tachycardia while 24 percent had runs of ventricular tachycardia. Individual arrhythmia frequency showed greater between-test variability than previously described in non-COPD subjects. The mode of administration of salbutamol may have affected arrhythmia frequency in that subjects using aerosol nebulizers had more ventricular extrasystoles than those using metered dose inhalers. Although the addition of theophylline to salbutamol significantly increased heart rate and supraventricular extrasystoles, there was no statistically significant increase in ventricular arrhythmias.

Changes in intrathoracic pressure can influence cardiac performance by altering ventricular loading conditions. Since ventricular loading, both from systemic venous return (preload) and from left ventricular wall stress (afterload), varies during the cardiac cycle, we reasoned that appropriately placed, phasic, cardiac cycle-specific (synchronous) increases in intrathoracic pressure might augment ventricular ejection in acute ventricular failure. Recent studies in animals suggest that synchronous increases in intrathoracic pressure during systole increase ejection. We compared the hemodynamic effect of synchronous increases in intrathoracic pressure with similar increases delivered at random in the cardiac cycle in patients with congestive cardiomyopathy (n = 9). Intrathoracic pressure was estimated by measuring esophageal pressure. High-frequency jet ventilation (HFJV) synchronized with the electrocardiogram (synchronous HFJV) was compared with HFJV at a fixed frequency within 15 percent of the heart rate (asynchronous HFJV) and with intermittent positive-pressure breathing (IPPB) (tidal volume = 10 ml/kg; f = 15). All forms of ventilation resulted in the same mean airway pressure and esophageal pressure. Mean pulmonary arterial occlusion pressure and arterial pressure were constant in all conditions. Cardiac output was greater with synchronous HFJV than with either IPPB or asynchronous HFJV (4.5 +/- 0.7 L/min compared with 3.5 +/- 0.7 and 3.4 +/- 0.6 L/min [mean +/- SE], respectively; p less than 0.05). Mixed venous oxygen saturation covaried with cardiac output (p less than 0.05), such that calculated oxygen consumption remained constant for all conditions. We conclude that synchronous HFJV augments cardiac output more efficiently than do similar increases in intrathoracic pressure delivered randomly in the cardiac cycle.

In order to study the dose-related effect of nifedipine on expiratory flow rates, 15 asthmatic patients were given sublingually 10 mg and 20 mg of the drug on two different days and the FVC and FEV1 were measured during 90 minutes. Then they received 2.5 mg albuterol (Salbutamol) by inhalation, and the two parameters were measured again after 30 minutes. It was found that the drug has a dose-related effect on expiratory flow rates. Indeed, 20 mg nifedipine produced a mild (less than 10 percent) but significant improvement in FVC (p less than 0.01) and FEV1 (p less than 0.05), while the response to 10 mg was mild, not significant and manifested rather by a decrease in both parameters. In three patients, the forced expiratory flow rates markedly worsened. No correlation could be established between the effect of nifedipine and the severity of the disease. In contrast, the improvement produced by albuterol was strongly related to the degree of airway obstruction (p less than 0.001). Nifedipine in both doses did not potentiate the bronchodilatation induced by albuterol.

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.

We compared two modes of aerosol bronchodilator delivery in 34 patients hospitalized with obstructive airways diseases. The standard mode, therapist-administered up-draft nebulization (UDN), is labor-intensive and therefore relatively costly. The alternative mode, self-administration by a metered dose inhaler (MDI), is less costly, but its efficacy over an entire hospitalization has heretofore not been established. Patients were enrolled after transfer to the pulmonary ward from the emergency room or intensive care units (ICU). We then randomized them to receive metaproterenol q4h either via MDI or UDN. Daily spirometry revealed that MDI and UDN were associated with equivalent bronchodilation initially and equivalent improvement at discharge. The duration of hospitalization for the two groups was also the same. Thus, the two delivery methods were equally effective. We could not attribute this equivalence to pretreatment intergroup differences or to differences in concomitant therapy with steroids, theophylline, other bronchodilators, or antibiotics. Routine use of MDI rather than UDN in all non-ICU adult patients would save $253,487 per year at our institution alone.

Many patients have incorrect aerosol inhalation technique with metered dose inhalers (MDI). Several inhalation aids have been developed and marketed for these patients. Even those who have correct inhalation technique may benefit from these devices. We compared bronchodilator efficacy of two puffs of albuterol aerosol administered either directly from a MDI mouthpiece, or from an inhalation aid (InspirEase, Aerochamber, Aerosol Bag) in 20 children who had previously demonstrated proper inhalation technique. The children received two puffs of aerosol from a MDI in each of two modalities tested each day on four different days (double blind). One modality contained albuterol aerosol and the other placebo. Pulmonary function was tested before and at 15, 30, 60, 120, and 180 minutes after treatment. Forced expiratory volume in 1 second (FEV1) increased similarly after all four modes of administration. Six patients who had incorrect inhalation technique benefited from the three inhalation aids. The aerosol bag and InspirEase produced slightly greater bronchodilator response than the Aerochamber. The inhalation aids are useful devices for those who have incorrect inhalation technique, but those who have correct technique do not derive any benefit from these devices.

Cough and wheezing are frequent side effects of inhaling beclomethasone dipropionate aerosol (BA) in patients with asthma. Twenty percent of our outpatient asthmatic subjects are unable to take BA due to these side effects. Twelve patients with history of severe cough and wheezing after inhaling BA were tested. Three puffs of either BA or placebo (Plc) were administered from a metered dose inhaler (MDI) in a double-blind crossover design. They coughed a mean of 31 times after BA and 19 times after Plc. Forced expiratory volume in one sec (FEV1) declined a mean of 22.6 percent after BA and 22.0 percent after Plc. Pretreatment with albuterol attenuated both the cough and the drop in FEV1. Follow-up study showed that regular pretreatment with bronchodilator enabled seven of 12 patients to tolerate BA therapy. The remaining five required a short course of increased dose oral steroid therapy. Cough and wheezing are frequent side effects of BA therapy that interfere with regular compliance. Pretreatment with a bronchodilator is effective in attenuating these side effects in some patients; in others, a short course of oral steroid therapy may be necessary.

The short-term effects of intravenously administered diltiazem on pulmonary and systemic hemodynamics were evaluated in patients with hypoxic pulmonary hypertension. Twelve patients were randomly assigned to two groups in a double-blind fashion. One group (eight patients) received diltiazem, and the other group (four patients) received a placebo. Three increasing doses of diltiazem (0.2, 0.3, and 0.4 mg/kg of body weight) were injected into each patient, followed each time by an infusion (2 micrograms/kg/min, 3 micrograms/kg/min, and 4 micrograms/kg/min). The effects of the drug were also compared with those of oxygen, and the combined effect of high oxygen and diltiazem was tested. The mean plasma concentrations of diltiazem were, successively, 64 +/- 4, 158 +/- 19, and 267 +/- 40 ng/ml with the three increasing doses. There was no significant effect of diltiazem on the pulmonary vascular resistance even when given with oxygen. Diltiazem was well tolerated even at high doses. The arterial oxygen pressure, systemic oxygen supply, and oxygen consumption were unchanged. We conclude that diltiazem does not seem to decrease acutely hypoxic pulmonary vasoconstriction in patients with chronic hypoxia; however, diltiazem may be given safely to these patients for other indications, such as angina pectoris.