Management of acute severe asthma.
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Acute Disease↗
Biomedical subjects
H W Kelly
Publications and source records attributed to H W Kelly.
Interaction of chloramphenicol and rifampin.
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Animals↗
Effect of patent ductus arteriosus on gentamicin pharmacokinetics in very low birth weight (less than 1,500 g) babies.
The effect of patent ductus arteriosus (PDA) and its therapy on the pharmacokinetic disposition of gentamicin in very low birth weight neonates was studied. Twenty-four neonates weighing less than 1,500 g with PDA were compared to 16 patients without PDA. Patients with PDA had significantly greater apparent volumes of distribution (0.64 +/- 0.20 vs. 0.41 +/- 0.08 l/kg; p less than 0.001) and serum half-life (8.49 +/- 2.69 vs. 6.23 +/- 1.92 h; p less than 0.01). The total body clearance was not significantly different between the two groups (56 +/- 20 ml/kg/h with PDA vs. 50 +/- 24 ml/kg/h without PDA). In addition, 7 patients were studied before and after PDA closure. The apparent volume of distribution fell in every case (p = 0.02). A statistically significant effect on clearance and half-life was not found. These findings suggest that PDA increases extracellular fluid volume, but does not affect glomerular filtration rate adversely. Additionally, serum gentamicin concentrations must be reevaluated after PDA closure in premature neonates.
Ductus Arteriosus, Patent↗
Cromolyn sodium: a review of mechanisms and clinical use in asthma.
The cellular and clinical pharmacology of cromolyn sodium are reviewed. Cromolyn sodium inhibits the release of mediators of inflammation, induced by specific antigens as well as nonspecific mechanisms, such as exercise, from mast cells. Cromolyn may also inhibit the activity of other cell types that produce inflammation. It is the only antiasthmatic that blocks both early and late asthmatic responses induced by allergen inhalation and exercise. Consequently, cromolyn therapy can block the increase in bronchial hyperreactivity induced by chronic allergen exposure. Cromolyn is effective for controlling the symptoms of mild to moderate chronic asthma in 60 to 70 percent of patients. In comparative studies, cromolyn has been as effective as theophylline for controlling symptoms of chronic asthma with fewer side effects, and may be particularly suited for asthmatic patients with learning or behavioral problems. The combination of theophylline and cromolyn is often more effective than either agent alone. Because of the convenience of administration, cromolyn is preferred over theophylline for exercise-induced asthma. Cromolyn may allow the corticosteroid dosage to be reduced in severe steroid-dependent asthmatics, but it is primarily indicated for the prophylaxis of mild to moderate disease. Adverse reactions to cromolyn are uncommon to rare. Cromolyn is now available in a Spinhaler, a metered-dose aerosol, and a nebulizer solution. If taken properly all preparations appear to be equally effective. Attention to proper inhalation technique and appropriate education of the patient is essential to ensure a good outcome with cromolyn.
Asthma↗
Pharmacotherapy of pediatric lung disease: differences between children and adults.
Drug dosages for infants and children differ significantly from those used in adults (Table 5). This is due to normal developmental physiologic differences that affect absorption, distribution, and clearance. In general, infants and children require higher dosages of many therapeutic agents on a weight basis. Parenteral drug administration difficulties are complicated by the slow fluid infusion rates often used in infants and young children. The use of syringe infusion pump devices is critical for accurate therapeutic drug monitoring and dosage adjustment in pediatrics than in adults. Aerosol administration in pediatrics is more complicated and is poorly studied. Difficulty with coordinating metered-dose aerosols with inhalation and drug raining out on small endotracheal tubes of ventilated patients are two significant problems. Chronic and acute pulmonary disease can significantly affect drug disposition and metabolism, but has been poorly studied in children. The pharmacokinetics of a number of drugs have been evaluated in cystic fibrosis and may provide insight into the effect of disease states on drug disposition.
Administration, Inhalation↗
Ranitidine at very large doses does not inhibit theophylline elimination.
While most controlled studies in humans indicate that ranitidine does not alter drug metabolism, there is some evidence that ranitidine may have this property. If ranitidine does inhibit drug metabolism in a predictable manner, such an effect might be expressed at higher ranitidine doses. Our study was designed to contrast the effects of large doses of ranitidine (1200 and 4200 mg/day) and cimetidine (1200 mg/day) on theophylline elimination. Whereas cimetidine decreased theophylline clearance in 11 of 12 subjects by a mean of 19.4%, neither ranitidine dose affected theophylline disposition. While case reports indicate ranitidine may inhibit theophylline metabolism specifically and drug metabolism in general, we were not able in our controlled study to detect any effect of ranitidine on theophylline elimination even at ranitidine doses up to fourteenfold greater than are generally prescribed.
Administration, Oral↗
Comparison of the effects of intravenously administered aminophylline and inhaled isoproterenol on normal airways.
Although beta-agonists and anticholinergics have been well documented to alter the resting tone in normal airways, the effects of aminophylline on normal airway function is controversial. We therefore studied the effects of intravenously administered placebo and aminophylline, inhaled isoproterenol, and intravenously administered aminophylline plus inhaled isoproterenol in 8 nonasthmatic subjects using full and partial flow-volume curves, plethysmography, and respiratory resistance as measured by forced oscillation. Isoproterenol, as has been demonstrated previously, caused improvement in FEV1 FEF50, and the flow of a partial flow-volume curve at 75% of the VC (PFEF75). Intravenously administered aminophylline at therapeutic concentrations (17.0 to 22.4 mg/L) resulted in improvement in FEV1, PFEF75, and the total respiratory resistance. Aminophylline and isoproterenol administered together produced additive effects. Thus, contrary to other studies, intravenously administered aminophylline produced a small but significant effect on normal basal airway tone that was less than that seen after an adrenergic agent but proportionally similar to the effects seen in asthmatic subjects.
Adult↗
Lack of significant arrhythmogenicity from chronic theophylline and beta-2-adrenergic combination therapy in asthmatic subjects.
We monitored 14 asthmatic subjects (aged 18 to 60 years), with multiple 24-hour electrocardiogram (Holter) recordings, who were taking continuous sustained-release theophylline and beta-2-adrenergic therapy for control of their symptoms. All of the patients were enrolled in an efficacy study for the antiasthmatic drug lodoxamide. No patient demonstrated intrinsic cardiac disease by history or by a standard 12-lead electrocardiogram recording prior to entry into the study. All of the patients were stable at the beginning of the study while on therapeutic theophylline concentrations and inhaled and oral beta-2-adrenergics. Attempts were made to decrease the theophylline dosage by sequentially reducing the dose each week to one-half, one-quarter, and discontinuation. Holter monitoring was repeated at the end of each week of a new dose level. Five patients were able to reduce dosage and eight were able to discontinue theophylline completely. Theophylline therapy was associated with a higher mean heart rate (85.4 vs 79.9 bpm). The combination of theophylline and beta-2-adrenergics therapy was not associated with quantitative or qualitative changes in atrial or ventricular ectopic activity over beta-2-adrenergic therapy alone.
Adolescent↗
Controlled-release transdermal drug delivery.
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Administration, Topical↗
Effects of theophylline on inhaled methacholine and histamine in asthmatic children.
The effects of a therapeutic serum theophylline concentration on inhaled methacholine and histamine were studied in 8 stable, moderately severe asthmatic children 8 to 15 yr of age. Placebo or theophylline in a hydroalcoholic solution was administered in a double-blind fashion, and standard histamine and methacholine challenges were performed following both placebo and theophylline. Serum theophylline concentration averaged 13 mg/L (range 4.0 to 22.1). Theophylline caused a significant increase (p less than 0.01, paired t test) in provocative dose for a 20% drop in FEV1 (PD20 FEV1) for both methacholine (from a mean of 19.1 to 57.5) and histamine (75.9 to 144.5). This effect did not correlate with the small (7.6% increase in FEV1) but significant bronchodilatation produced by theophylline. We conclude that theophylline in doses that achieve serum concentrations in the usual therapeutic range produces significant attenuation of the bronchoconstrictor response to methacholine and histamine challenges in asthmatic children. The mechanism and therapeutic implications of this remain undefined.
Adolescent↗
Antibiotic use in cystic fibrosis.
Chronic pulmonary infections contribute significantly to the morbidity and mortality of patients with CF. The primary pathogens are Pseudomonas aeruginosa (PA) and Staphylococcus aureus. Hemophilus influenzae has been isolated from a significant number of patients also. A number of the beta-lactam and aminoglycoside antibiotics reportedly have altered pharmacokinetic variables in CF. Therapy of acute pulmonary deterioration consists of intravenous antibiotics for two weeks. Antibiotic selection is based on culture and sensitivity results. Currently, the combination of a broad-spectrum penicillin and an aminoglycoside seems to provide the best results. Prophylactic antibiotics are effective if the primary isolates are sensitive to the agents used. Chronic PA infections are problematic because effective oral agents are not available. Aerosolized antibiotics do not improve results over adequate systemic therapy for acute exacerbations. Questions regarding optimal dosages, frequency, and duration of therapy remain.
Aerosols↗
Sustained-release theophylline. Pharmacokinetic and therapeutic comparison of two preparations.
The serum theophylline concentration profiles and clinical efficacy of two sustained-release theophylline tablets (Quibron-T/SR and Theo-Dur) were compared in 13 asthmatic children requiring continuous theophylline therapy. Quibron-T/SR and Theo-Dur, administered every 12 hours in the same dose for one week, were evaluated in a multiple-dose randomized crossover study. At the end of each week, serial serum theophylline concentrations were measured and spirometry and body plethysmography were performed. No significant differences between treatments were found in bioavailability, adverse effects, clinical symptom scores, or pulmonary function in spite of the fact that Quibron-T/SR and Theo-Dur produced significantly different serum theophylline concentration profiles as measured by a mean percent of fluctuation in serum theophylline levels of 143 for Quibron-T/SR and 65.7 for Theo-Dur. Over the short term of the study the pharmacokinetic differences did not produce significant differences in clinical efficacy.
Adolescent↗
Monitoring children on sustained-release therapy by salivary theophylline levels.
The serum-saliva theophylline level ratio was measured in 19 chronically asthmatic children after their conditions were stabilized on a sustained-release theophylline preparation. Simultaneous serum and saliva samples were collected at 0, 4, 6, and 10 hours after theophylline dose and measured by high-pressure liquid chromatography. The mean ratio for the group of 1.52 +/- 0.64 approximated the mean ratio from previous reports. However, the correlation coefficient (r = .80) was lower, and the interpatient and intrapatient variability (25% and 23%) much higher, than in previous reports. The possible mechanism of these findings in relation to sustained-release preparations are discussed. These data question the use of salivary theophylline determinations to monitor therapy. Dosage should be based on serum measurements.
Adolescent↗
Efficacy of a 12-hour sustained-release preparation in maintaining therapeutic serum theophylline levels in asthmatic children.
The purpose of this study was to determine whether a new sustained-release theophylline preparation TheoDur could maintain therapeutic serum theophylline levels in asthmatic children on a 12-hour dosage regimen. Twenty asthmatic children aged 6 to 18 years with a mean of 11.4 years who required continuous theophylline therapy for control of their asthma were enrolled in the study. Each patient's dosage was titrated to achieve a six-hour postdose serum theophylline level between 10 and 20 microgram/ml. The patients required a mean +/- SEM dose of 10.0 +/- 0.54 mg/kg every 12 hours which gave a mean +/- SEM six-hour postdose serum theophylline level of 15.65 +/- 0.72 microgram/ml. At the end of five days on this dosage, the patients were admitted and serum theophylline levels were determined every three hours for 24 hours. The mean +/- SEM difference between maximum and minimum serum theophylline levels (delta TL) for the group was 4.5 +/- 0.3 microgram/ml. There was not a significant difference in the delta TL between the two age groups (6 to 9 years, 4.5 +/- 0.5 microgram/ml and 10 to 18 years 4.5 +/- 0.4 microgram/ml). In conclusion, TheoDur will maintain therapeutic serum theophylline levels with minimal fluctuations in asthmatic children on a 12-hour dosing schedule.
Adolescent↗
Serum theophylline levels in asthmatic children receiving sustained-release theophylline tablets.
Serum theophylline levels produced in asthmatic children by sustained-release theophylline tablets (TheoDur) were studied. Nineteen patients received for 14 days a dose of 5.5 to 13.1 mg/kg (mean 9.1 mg/kg) of amhydrous theophylline (as sustained-release TheoDur tablets) every 12 hours. Theophylline serum levels were assayed, by cation-exchange high-performance liquid chromatography, immediately before and at 4, 6 and 10 hours after the first day-five dose. Symptoms of asthma and theophylline toxicity were recorded. Mean peak-trough difference for the 6-to-10-years age group (4.5 +/- 1.6 microgram/ml) was not significantly different than that of the 11-to-17-year age group (5.2 +/- 3.2 micrograms/ml) (p greater than 0.1). Therapeutic serum theophylline levels (8 to 20 micrograms/ml) were maintained throughout a 12-hour period in 12 patients. Two patients had side effects possibly attributable to theophylline. Four patients reported asthamtic symptoms on two or more evenings; none required emergency treatment. The study suggests that sustained-release theophylline tablets administered every 12 hours can maintain therapeutic serum levels in children.
Adolescent↗
New beta 2-adrenergic agonist aerosols.
The beta 2-adrenergic agonists are reviewed in terms of their dose-response characteristics, and two newer agents, fenoterol hydrobromide and bitolterol mesylate aerosols, are reviewed in relation to older agents. The fenoterol aerosol contains a more potent beta 2-adrenergic agonist dose per puff than the other aerosols but, when given in equipotent doses, offers no advantage over available agents. Bitolterol mesylate is a prodrug that is hydrolyzed to the active beta 2-adrenergic agonist colterol by lung esterases. Bitolterol demonstrates an improved bronchoselectivity in animals, but there are insufficient comparative data in humans. Tachycardia is the dose-limiting toxicity for all beta 2-adrenergic agonists. Currently available data do not suggest an important improvement in duration of action for the newer agents over terbutaline or albuterol. Aerosol administration improves bronchoselectivity of all the agents. Optimal use of beta 2-adrenergic agonist aerosols requires understanding of the variable dose-response characteristics. The type of delivery system and patient technique are important variables in determining the dose delivered. Tube-spacer devices attached to aerosol canisters can significantly improve delivery of the beta 2-adrenergic agonists to the lungs in patients unable to synchronize actuation and inspiration. They provide minimal to no improvement in patients who can perform the appropriate technique. Aerosol administration is the route of choice for beta 2-adrenergic agonists for prophylaxis of exercise-induced bronchospasm; albuterol and terbutaline provide a prolonged duration of action with excellent beta 2-adrenergic selectivity. Patients should be carefully instructed in the optimal use of metered-dose inhalers, and some patients may benefit from use of tube-spacers.
Adrenergic beta-Agonists↗
Controversies in asthma therapy with theophylline and the beta 2-adrenergic agonists.
The pharmacology and clinical use of the beta 2-adrenergic agonists and theophylline, singly and in combination, are reviewed. The beta 2-adrenergic agents produce bronchodilation by stimulating production of intracellular cyclic adenosine monophosphate, while theophylline's mechanism of action is unknown. The primary differences between various beta 2-adrenergic agents are in specificity and duration of action. In acute asthma attacks, greater reversal of bronchospasm results from beta 2-adrenergic agents than from theophylline. Inhalation of beta 2-adrenergic agents is as effective as injection of these drugs and produces fewer side effects. Inhaled beta 2-adrenergic agents also produce the greatest degree of prevention of exercise-induced bronchospasm. In hospitalized patients with severe acute bronchospasm, the combination of intravenous aminophylline and inhaled beta 2-adrenergic agents appears to provide optimal therapy with the greatest margin of safety. For long-term bronchodilator therapy, there is no clear treatment of choice; combination therapy with inhaled beta 2-adrenergic agents and oral theophylline appears to be safe and effective.
Acute Disease↗