The effect of theophylline and beta 2 agonists on airway reactivity.

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.

Disposable jet nebulizers. How reliable are they?

We studied the frequency of malfunction, variability in rate of nebulization, and effect of this variability on aerosol particle size of eight disposable jet nebulizer models produced by six manufacturers. Four of eight models showed visual signs of malfunction, including spraying of large, individually visible droplets, leaking of nebulizer solution, and air leaks that completely prevented nebulization. Variability of nebulization rate within specific models ranged from 57 to 129 percent. The model with the largest variability of nebulization rate was also associated with an unacceptably large variability in particle size. In contrast, two models with smaller variability in nebulization rate had greater consistency of particle size. These results indicate poor quality control by some manufacturers in the disposable nebulizer industry. The data suggest that purchasing agents should consider reliability as well as cost before selecting a specific nebulizer model and that their evaluation should include physical testing of multiple units of each model under consideration.

Demonstration of in vivo bioequivalence of a generic albuterol metered-dose inhaler to Ventolin.

STUDY OBJECTIVE: To use histamine bronchoprovocation and bioassay statistical procedures to evaluate the in vivo bioequivalence of a generic albuterol metered-dose inhaler (MDI). DESIGN: A randomized, double-blind, balanced, crossover design was used to determine the potency of each generic albuterol MDI actuation relative to Ventolin (Glaxo Wellcome; Research Triangle Park, NC) administration. One treatment was administered on each of 4 study days. A histamine bronchoprovocation procedure was initiated 1.25 h before and 15 min after administration of the study treatment. PATIENTS: Twenty-four nonsmoking subjects with mild-to-moderate asthma were studied (18 to 65 years of age; FEV(1), > 60% of predicted; and provocative concentration of histamine causing a 20% fall in FEV(1) [PC(20)], < or = 8 mg/mL at screening). INTERVENTIONS: One and four actuations (90 and 360 microg, respectively) of the generic MDI and of Ventolin MDI. Placebo inhalers were used to maintain blinding of inhaler and doses. MEASUREMENTS AND RESULTS: The primary outcome variable was histamine PC(20) measured after study treatment administration. A significant dose-effect relationship was present (p < 0.0001). Deviation from parallelism of the generic and Ventolin dose-response curves (p = 0.95) and differences in overall mean response between the two formulations (p = 0.68) were not significant. Using Finney 2 x 2 bioassay statistical procedures, we estimated that one actuation of the generic albuterol MDI was equivalent to 1.01 puffs of Ventolin (90% confidence interval, 0.69 to 1.50). CONCLUSION: The generic albuterol MDI delivers a quantity of albuterol to the beta(2)-receptor site in the lung that is the bioequivalent to Ventolin. Further, this study reinforces the validity of this statistical methodology for determining in vivo bioequivalence.

Bilateral simultaneous lung lavage utilizing membrane oxygenator for pulmonary alveolar proteinosis in an 8-month-old infant.

Pulmonary alveolar proteinosis can result in severe hypoxemia. Treatment of symptomatic patients using unilateral or lobar staged lung lavage often results in improved oxygenation and functional capacity. Lung lavage is technically difficult in infants and small children because of inability to ventilate part of the lung safely and adequately during lavage of other areas. We used extracorporeal membrane oxygenation to facilitate adequate gas exchange during lung lavage for severe respiratory failure in a 3.7 kg, 8-month-old child with pulmonary alveolar proteinosis. Oxygenation was markedly improved immediately following the procedure. Extracorporeal membrane oxygenation permits satisfactory respiratory support in the setting of severe respiratory failure and should be considered an adjunct for treatment of pulmonary alveolar proteinosis when lung lavage cannot be otherwise safely accomplished.

Albuterol: an adrenergic agent for use in the treatment of asthma pharmacology, pharmacokinetics and clinical use.

Albuterol is a long-acting beta 2-adrenergic receptor-selective drug that relaxes airway smooth muscle. It is currently available in the United States in oral and metered-dose inhaler forms. Nebulizer solutions and parenteral preparations are likely to be marketed here in the future. The chemical modifications that make albuterol beta 2-selective also promote oral bioavailability and increased duration of action by decreasing sensitivity to degradative enzymes. Albuterol can also produce undesirable dose-related effects: metabolic effects including decreased levels of plasma potassium, phosphate, calcium and magnesium; increased levels of plasma glucose, insulin, renin, lactate and ketones; peripheral vasodilation and perhaps some direct cardiac stimulation resulting in decreased systemic and pulmonary vascular resistance, increased pulse pressure and tachycardia; and skeletal muscle tremor. These side effects are most common with parenteral administration and much less prominent with aerosol administration, which yields lower systemic concentrations. Limited pharmacokinetic data suggest a long distribution phase, a terminal half-life of 3-8 hours, and 10-20% oral bioavailability. Aerosolization of albuterol or a similar agent with a compressed-air nebulizer appears to be best first-line management of the patient with acute dyspneic asthma, but appropriate preparations for this kind of therapy are currently missing from the United States market. Intravenous albuterol has also been employed in acutely dyspneic patients, but produces more side effects than carefully administered intravenous theophylline, is impaired by lack of sufficient pharmacokinetic information to guide dosing, and is of uncertain efficacy in the asthmatic with respiratory failure. However, it appears to lack the potentially life-threatening side effects that can result when theophylline is used carelessly . In the ambulatory patient, aerosolized albuterol (or a similar agent) administered by metered-dose inhaler is an excellent agent for treatment as needed and/or for prevention of acute bronchospasm triggered by exercise or other predictable cause. Advantages include a high degree of efficacy, rapid onset and long duration of effect, and minimal side effects. Regularly scheduled administration of albuterol by metered-dose inhaler is a widely used and effective maintenance medication for patients requiring long-term prophylactic therapy. However comparisons of the ability of this regimen and the other common maintenance regimens (cromolyn and theophylline) to control chronic symptoms of asthma are needed.

The delivery of therapeutic aerosols through endotracheal tubes.

We used an in vitro model system to examine the sites of deposition of aqueous therapeutic aerosols administered through 3-mm, 6-mm, and 9-mm endotracheal tubes (commonly used in infants, children, and adults) at clinically relevant inspiratory flow rates. Aerosol was delivered to the endotracheal tube via a "T" piece and a 90 degree elbow. Aerosol exiting the endotracheal tube passed through an appropriately sized Plexiglas model of the trachea and mainstem bronchi, and then into an 80-liter bag. Aerosol deposited in the "T" and elbow, endotracheal tube, large airway model, and collection bag was quantitated separately using 0.1% uranine as a tracer. Study of a conventional aerosol typical of those in common clinical use (aerodynamic mass median diameter = 3.95 microns) showed that most of the aerosol delivered into each endotracheal tube was deposited before leaving the mainstem bronchi. Substitution of an alternative nebulizer that produced a much smaller aerosol particle size (aerodynamic mass median diameter = 0.54 micron) dramatically decreased aerosol deposition in the "T" and elbow, endotracheal tube, and large airway model, and increased the quantity of aerosol penetrating beyond the mainstem bronchi up to ninefold. The mass median particle diameter of the conventional aerosol was reduced during endotracheal tube and large airway passage by poorly defined aerodynamic mechanisms that selectively removed larger particles. The smaller submicron aerosol was not similarly affected. Thus, conventional therapeutic aerosols appear to penetrate poorly through endotracheal tubes. Use of smaller particle size aerosols in treatment of intubated patients may be an effective way to circumvent this problem.

Exercise-induced laryngomalacia.

Exercise-induced laryngomalacia (EIL) is characterized by severe dyspnea, stridor, and mild wheezing unresponsive to prophylactic treatment with beta-agonists and cromolyn sodium. Symptoms develop with extreme exertion, but resolve quickly as the degree of exercise is decreased. Diagnosis requires flexible fiberoptic laryngoscopy before, during, and after exercise. If the diagnosis of EIL is confirmed by laryngoscopy during maximal exercise, laser epiglottoplasty is effective in alleviating symptoms and improving the airway. However, because symptoms develop only during maximal exertion, EIL is unlikely to produce symptoms or functional disability in persons who lead relatively sedentary lives.

Skeletal muscle tremor and the influence of adrenergic drugs.

Physiologic postural skeletal muscle tremor is enhanced by beta 2 receptor agonist such as those used in the treatment of asthma. This is a peripheral response rather than one occurring at the central nervous system level. It is greatest when drugs are administered by the oral or parenteral routes, and is the most important dose-limiting factor for oral administration. Clinically important tremor is minimal after aerosolized administration of clinically recommended doses of aerosolized beta 2 receptor agonists, but can be significant when larger doses are administered. Sympathomimetic drugs which can selectively stimulate airway beta 2 receptors, as opposed to skeletal muscle beta 2 receptors, do not currently exist. Combining orally administered beta 2 agents with theophylline potentiates the effects on muscle tremor. There does not seem to be a clinical advantage, in terms of reduced side effects such as muscle tremor, to combining "small doses" of oral beta agonists and theophylline as opposed to using either agent alone in optimal doses. Tolerance to the tremoregenic effects of beta 2 agonists appears to occur when these agents are administered on a chronic basis. Thus, there may be some rationale for beginning oral beta agonists initially with lower doses and progressively increasing to full doses over a period of days to weeks.

Bioequivalence of a generic slow-release theophylline tablet in children.

OBJECTIVE: To determine whether a generic slow-release theophylline tablet (manufactured by Sidmak Laboratories, Inc.) is therapeutically equivalent to a proprietary theophylline tablet, Theo-Dur, in children. DESIGN: Prospective, randomized, double-blind, crossover trial. SETTING: Multicenter clinics. PATIENTS: 38 children, 6 to 16 years of age, with asthma. INTERVENTIONS: Individualized doses of Theo-Dur or generic tablet every 12 hours for 5 days. MEASUREMENTS AND MAIN RESULTS: During the last 24 hours of each regimen, theophylline serum concentrations were measured serially and a standardized exercise stress test was performed at 24 hours (trough serum concentration). Neither formulation effectively blocked the response to exercise; the maximum decrease in forced expiratory volume in the first second was 26.1% +/- 18.9% with Theo-Dur and 24.8% +/- 19.7% with the generic product (p = 0.68; beta = 0.08). The mean +/- SD peak serum concentrations were 18.0 +/- 3.0 micrograms/ml with Theo-Dur and 18.7 +/- 3.7 micrograms/ml with the generic tablet; the trough serum concentration was < 10 micrograms/ml in 15 subjects after administration of Theo-Dur and in 20 subjects after administration of the generic product. There were no significant differences in relative extent of absorption or the time to reach peak serum concentration. CONCLUSIONS: This generic formulation and Theo-Dur are bioequivalent in children. However, these results cannot be extrapolated to slow-release theophylline formulations that have not been approved by the U.S. Food and Drug Administration as equivalent to Theo-Dur.

Relative efficacy of maintenance therapy with theophylline, inhaled albuterol, and the combination for chronic asthma.

The relative benefit of maintenance therapy with theophylline, inhaled albuterol, and the combination was examined in 18 adolescents and adults with chronic asthma during a 3-month, randomized, double-blind, crossover trial. Theophylline and combination regimens were associated with significantly fewer days with symptoms (52% and 55%) than albuterol (72%). The greater frequency of symptoms during the albuterol regimen was increasingly apparent more than 4 hours after albuterol doses and was greatest between 4 and 8 A.M. Albuterol transiently inhibited histamine-induced bronchospasm to a much greater degree than did theophylline, and combining the drugs produced at least an additive effect. The effect of albuterol was completely absent by 4 hours, however, whereas that of theophylline persisted. Thus, in spite of greater acute effects on the airways, the transient duration of effect from inhaled albuterol appears to limit its usefulness as maintenance therapy, especially for patients with nocturnal symptoms.

Extrapulmonary effects of maintenance therapy with theophylline and inhaled albuterol in patients with chronic asthma.

The extrapulmonary effects of slow-release theophylline and an inhaled beta 2-agonist (albuterol) were examined separately and in combination among 18 adults and adolescents with asthma during a 3-month randomized, double-blind, crossover trial. Although neither global impressions nor daily diaries revealed differences in adverse effects, a structured questionnaire completed at the end of each regimen suggested a small but statistically significant increase in nausea and depressive and caffeine-like symptoms during the theophylline-containing regimens. Theophylline was also associated with improved verbal learning but decreased motor steadiness. Metabolic effects associated with theophylline included lower serum bicarbonate, greater urinary calcium excretion, and higher serum calcium, uric acid, and creatinine. Albuterol was associated with lower neutrophil counts and lower serum theophylline concentrations. There were no drug-induced effects on cardiac rhythm.

Use of bronchial provocation with histamine to compare the pharmacodynamics of inhaled albuterol and metaproterenol in patients with asthma.

Because measurement of effects on airway responsiveness may have advantages over the study of bronchodilatation for the evaluation of the effects of inhaled beta 2-agents, we developed a method using airway responsiveness for the independent quantitation of the relative potencies and rates of decline in effect of these drugs. This methodology was applied to the evaluation and comparison of inhaled metaproterenol and albuterol. The effects of two different doses of each drug (one and two inhalations of albuterol and two and four inhalations of metaproterenol from commercially available metered-dose inhalers) were compared with a double-blind, randomized, placebo-controlled, crossover study of 13 subjects. The effects of metaproterenol and albuterol declined at rates that were not significantly different. However, based on the effects on activity ratio at 30 minutes, each puff of metaproterenol was an estimated 0.37 times as potent as each puff of albuterol (95% confidence limits, 0.22 to 0.52). In recommended two puff doses, measurable effects of albuterol persisted longer than effects of metaproterenol. However, this appears to be because of a greater initial effectiveness of two puffs of albuterol rather than differences in the rates at which the effects of the two drugs declined with time. Airway responsiveness thus appears to be a useful tool for evaluating inhaled beta 2-agonists and designing beta 2-agonist dosing regimens.

Chronic cough in childhood: approach to diagnosis and treatment.

Chronic cough in childhood has many possible causes. The two most common are asthma and viral upper respiratory infection. Although usually associated with wheezing, dyspnea, or both, cough may be the sole manifestation of asthma ("cough-variant asthma"). Most important to initial evaluation are physical examination, patient history, and chest radiograph. Bronchial provocation testing may also prove helpful but is usually unnecessary. A trial of antiasthma therapy is appropriate when the pattern of symptoms is typical of asthma (excepting the lack of wheezing) and when nothing incompatible with asthma is present in the clinical picture. Drug therapy for cough-variant asthma is the same as that for more typical asthma. A vigorous trial of antiasthma therapy should not be considered complete unless a short course of high oral doses of corticosteroids has been included. The presence of clinical signs or symptoms atypical or incompatible with asthma and the failure of symptoms to respond to aggressive antiasthma therapy both warrant a more aggressive and complete diagnostic study.

A method for comparing the peak intensity and duration of action of aerosolized bronchodilators using bronchoprovocation with methacholine.

The effects of aerosolized metaproterenol (1.30 mg) and isoetharine (1.02 mg) on nonspecific airway responsiveness to inhaled methacholine were quantitated and compared in 6 asthmatic subjects for 4 h after dosing. Both metaproterenol and isoetharine demonstrated bronchodilatation and reduced airway responsiveness during the first hour. Isoetharine had lost its bronchodilator effects and its effects on airway responsiveness by 2.25 h. The effects of metaproterenol on airway responsiveness had decreased by half at 2.25 h, while its bronchodilator effect remained maximal. Metaproterenol had no effect on airway responsiveness by 4 h, despite persisting bronchodilatation. Thus, for metaproterenol, there is disparity between duration of bronchodilation and suppression of airway responsiveness. Because methacholine sensitivity is a measure of nonspecific airway responsiveness, which appears to correlate with the severity of asthma, this methodology may provide more relevant information for assessment of duration of effect and estimation of appropriate dosing intervals for maintenance therapy than do more traditional methods.

Comparison of the intensity and duration of effects of inhaled bitolterol and albuterol on airway caliber and airway responsiveness to histamine.

Inhaled beta-agonists can produce bronchodilatation and reduce airway hyperreactivity in patients with asthma. Using these two measures, we compared inhaled bitolterol (three puffs, 1110 micrograms), albuterol (two puffs, 180 micrograms), and placebo administered by metered-dose inhaler in a blinded, crossover study of 40 subjects with chronic asthma. On each study day, subjects underwent histamine challenges at 1 1/2 hours before, and 1/2, 2, 4, 6, and 8 hours after inhaling one of the three test-drug treatments. Both drugs produced significant bronchodilatation at 30 minutes through 4 hours and significant effects on airway reactivity at 30 minutes through 2 hours (p less than 0.05). Bitolterol also produced small but significant bronchodilator effects at 6 hours and effects on airway reactivity at 4 hours (p less than 0.05). Effects of bitolterol on airway reactivity diminished significantly more slowly than effects of albuterol in subjects with baseline provocative concentration causing a 20% fall in FEV1 greater than or equal to 1.0 mg/ml of histamine (half-life of biologic effect 1.37 versus 0.92 hours; p less than 0.05) but not in subjects with baseline provocative concentration causing a 20% fall in FEV1 less than or equal to 1.0 mg/ml (half-life of biologic effect of 1.01 versus 1.00 hours; p greater than 0.05).

Aerosol delivery and safety of recombinant human deoxyribonuclease in young children with cystic fibrosis: a bronchoscopic study. Pulmozyme Pediatric Broncoscopy Study Group.

The purpose of this study was to assess the delivery to the lungs and the short-term safety of recombinant human deoxyribonuclease (rhDNase, Pulmozyme) in children with cystic fibrosis younger than 5 years of age compared with older children. Patients between the ages of 3 months and 10 years had bronchoscopic examination with bronchoalveolar lavage (BAL) after administration of an aerosol dose of 2.5 mg of rhDNase. After recovery from the procedure, patients were discharged home for an additional 13 days of rhDNase therapy. During this time adverse events were recorded to assess short-term safety. A total of 98 patients were enrolled, 65 (66%) aged 3 months to 5 years and 33 (34%) aged 5 years to 10 years. Deoxyribonuclease concentrations in BAL fluid were variable (interquartile range, 752 to 3943 micrograms/mL epithelial lining fluid [ELF]) and did not depend on patient age, weight, or height or differ when delivered through a mouthpiece or mask. The median value for the BAL DNA concentration in the younger group was 432 micrograms/mL ELF compared with 703 micrograms/mL ELF in the older patients. This study demonstrates the value of bronchoscopy and BAL for assessing nebulized medication delivery in young children and shows that aerosolized medications can be delivered to and are present in comparable amounts in the lower airways of younger and older children. Exposure to rhDNase appears to be safe over 2 weeks in infants and young children with cystic fibrosis.

Asthma stability after oral prednisone: a clinical model for comparing inhaled steroid potency.

Clinical studies comparing the potency of inhaled corticosteroids require steep dose-response slopes (b) and minimal response variability (s), as statistical power is inversely related to the s/b ratio. To evaluate a new study model, we performed a randomized, crossover study of 12 adult asthmatics who required 800 to 2,000 microg of inhaled corticosteroids daily, and calculated s/b for 21 raw clinical outcomes and 36 mathematically derived variables based on these raw outcomes. Each of two 21-d treatment periods was preceded by 4 to 7 d of oral prednisone to maximize asthma control and minimize carry-over of previous inhaled treatment. Treatments were 100 and 800 micron/d of an HFA-134a beclomethasone dipropionate formulation. Assessments included daily home spirometry, histamine challenge, inhaled albuterol use, and asthma symptom scores. Efficacy variables with the greatest power (lowest s/b values) were A.M.FEF25-75, A.M.FEV1, and A.M.PEF, (s/b = 0.46, 0.48, and 0.59). Carry-over between treatment periods was not significant. Crossover study sample size calculations using these ratios yielded samples of 23, 25, and 37 patients, respectively. Otherwise identical parallel studies would require sample sizes of 657, 1,438, and 2,261 patients. These results support the use of a crossover asthma stability model after a short course of oral prednisone as a clinical study model for comparing topical potency of inhaled corticosteroids.

Evaluation of particle size distribution of salmeterol administered via metered-dose inhaler with and without valved holding chambers.

BACKGROUND: Administration of inhaled medications to very young children is sometimes difficult. Administration of inhaled medications via metered dose inhalers (MDIs) to pediatric patients younger than 4 years of age requires use of a holding chamber/spacer with an attached facemask. OBJECTIVE: This in vitro study was conducted to determine the particle size distribution and overall dose of salmeterol delivered in conjunction with the use of various US-marketed valved holding chambers (VHCs) in comparison to the dose-delivered via MDI without VHCs. METHODS: Cascade impaction methodology with high-performance liquid chromatography was used to evaluate the fine particle mass (FPM) of salmeterol administered without and with the use of the following VHCs: Optichamber, medium and large Aerochambers, adult Aerochamber, and medium Aerochamber Plus. RESULTS: Particle size distributions for the Optichamber, various sizes of Aerochamber, and the Aerochamber Plus were very similar and the particle size distributions for all VHCs were similar to the distribution of the control. The FPM for particles ranging from 0.7 to <3.3 microm in diameter (in the range shown to provide the greatest lung dose to negotiate the small airways of infants) was similar across the various VHCs tested. Statistical comparison of the fine particle fraction for these stages shows a very similar profile when differences from the salmeterol MDI control were evaluated. CONCLUSIONS: In vitro results obtained under these test conditions demonstrate that all FPM values for the VHCs tested were within 15% of the control range, a difference that is unlikely to be clinically meaningful. These results indicate that the difference in FPM does not warrant a change in the recommended dosage of salmeterol administered when using the VHCs tested. Our results demonstrate that the use of an MDI and VHC provides a reasonable therapeutic approach for administration of salmeterol MDI to young children and other patients who have difficulties administering the MDI alone.

Therapeutic equivalence of Spiros dry powder inhaler and Ventolin metered dose inhaler. A bioassay using methacholine.

Because chlorofluorocarbons (CFCs) contribute to depletion of stratospheric ozone, CFC-containing metered-dose inhalers (MDIs) such as Ventolin and Proventil are being phased out of production. In terms of delivery of albuterol to the lungs, we compared an alternative delivery system, the Spiros dry-powder inhaler (DPI), with Ventolin, using a methacholine challenge-based clinical bioassay. Twenty-four adults and adolescents with asthma completed this double-blind, four-period crossover study. Doses evaluated were one and three actuations each of Spiros and Ventolin (90- and 270-microgram albuterol base). A methacholine challenge (Cockcroft method) was initiated 3 h before and 0.25 h after albuterol. Predose PC(20)FEV(1) values were not significantly different between study days. Postdose PC(20)FEV(1) results met standard bioassay study validity criteria: i.e., a significant dose-response relationship was present (p = 0.0002); tests for deviation from parallelism and overlap of dose-response curves were nonsignificant (p = 0.08, 0.69). By using Finney 2-by-2 bioassay analysis, we estimate that each Spiros actuation delivers 1.12 times as much albuterol to the airways as one Ventolin actuation (90% confidence interval, 0.68 to 1.94). There were no significant differences in markers of systemic effects (vital signs, potassium, and blood glucose concentrations). We conclude that Spiros and Ventolin inhalers deliver comparable quantities of albuterol to the airways.