Should we abandon the notion that calcium channel blockers are potentially useful for asthma?
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Asthma↗
Biomedical subjects
L Hendeles
Publications and source records attributed to L Hendeles.
Individualizing gentamicin dosage in patients with cystic fibrosis: limitations to pharmacokinetic approach.
Gentamicin serum concentrations were measured in 15 children and seven adults with cystic fibrosis and in eight children with other diseases. Potentially toxic trough concentrations occurred in three of the first nine patients studied, in whom the dose and a 4-hour dosing interval were prescribed on the basis of one-compartment pharmacokinetic calculations (Sawchuck-Zaske method). In contrast, final concentrations were within the accepted target ranges for the remaining 13 patients with cystic fibrosis, in whom the dose and interval were adjusted empirically on the basis of a single pair of "peak" and trough values. The mean +/- SD final dosage required to achieve target concentrations was 13.8 +/- 2.9 mg/kg/d for children and 11.8 +/- 1.1 mg/kg/d for adults (P greater than 0.05), generally divided into four doses at 6-hour intervals. Mean half-life and incremental increase in serum concentration from previous trough to subsequent "peak," an indirect measurement of volume of distribution, were not significantly different between children or adults with cystic fibrosis and pediatric control subjects; there was little interpatient variability in these values. Thus the high dosage requirements were related more to the higher target concentrations than to altered pharmacokinetic disposition in patients with cystic fibrosis. We conclude that the initial dose of gentamicin to achieve a peak of 8 to 12 micrograms/mL and a trough of less than 2.0 micrograms/mL in patients with cystic fibrosis should be 3 mg/kg administered every 6 hours in children and every eight hours in adults. Subsequent dosage adjustment should be made on the basis of a pair of peak and trough serum concentration measurements obtained after the fifth dose. Dosing intervals in this patient population generally should be no shorter than every 6 hours, even if the initial trough concentration is less than 1 microgram/mL.
Adolescent↗
The effect of oral diltiazem on airway reactivity to methacholine and exercise in subjects with mild intermittent asthma.
The effect of increasing doses of oral diltiazem on airway reactivity to methacholine was evaluated in 10 volunteers with mild asthma. Then the highest tolerated dose was compared with placebo in preventing exercise-induced bronchoconstriction. Methacholine challenges were performed 1 h before and 100 min after placebo or after 30, 60, 90, 120, or 180 mg of oral diltiazem, given in a single-blind, crossover manner on different days within 2 wk. Diltiazem, at doses above 60 mg prolonged the P-R interval of the electrocardiograph but had no significant effect on FVC, FEV1, or FEF25-75. The mean +/- SEM ratio of the dose of methacholine required to produce a 20% decrease in FEV1 (PD20) after diltiazem to the PD20 before diltiazem, i.e., the fold increase in PD20, was not significantly different from placebo at any dose: 0.93 +/- 0.11 after placebo, 1.2 +/- 0.1 after 30 mg, 1.3 +/- 0.3 after 60 mg, 1.2 +/- 0.2 after 90 mg, 1.1 +/- 0.1 after 120 mg, and 1.0 +/- 0.1 after 180 mg. One hundred minutes before a standardized exercise challenge, 120 to 180 mg of oral diltiazem and identically appearing placebo tablets were administered in a randomized, double-blind, crossover design on separate days at least 48 h apart. The mean +/- SEM maximal postexercise decrease in FEV1 was 25.5 +/- 3.3% after placebo and 17.0 +/- 4.8% after diltiazem (p less than 0.01). There was no correlation between change in FEV1 and serum concentrations of diltiazem or its active metabolite desacetyldiltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Calcium antagonists in the management of asthma: breakthrough or ballyhoo?
Research demonstrating the importance of intracellular calcium regulation in each of the pathophysiologic events of asthma has lead to speculation that calcium antagonists may be beneficial in the treatment of reactive airways disease. A plethora of data has been generated on the effects of verapamil, diltiazem, nifedipine, and several investigational agents on experimentally induced asthma, indicating that none of these agents significantly affects resting bronchomotor tone, and their efficacy in preventing bronchospasm is a function of the drug, dose, route of administration and method of bronchoprovocation. Most studies have demonstrated calcium antagonists have only modest and highly variable effects on airway smooth muscle contraction. Additional studies are needed to define the effects on the inflammatory component of airways obstruction, steroid requirements in steroid-dependent patients, and on the alteration of the pharmacodynamics of other agents used for the management of chronic asthma.
Asthma↗
Selection of a slow-release theophylline product.
Slow-release formulations of theophylline, if absorbed completely, consistently, and at a sufficiently slow rate, provide more stable serum concentrations at longer dosing intervals than plain uncoated tablets or liquids and thus have the potential to improve efficacy, safety, and compliance. However, clinically important differences in extent and rate of absorption exist among the 15 slow-release formations available under 29 different brand names or as generic products in the United States. Moreover, food has different effects on the various formulations. Whereas some formulations are little affected by food with only a slight delay in absorption, others undergo malabsorption in either the presence or absence of food, depending on as yet unidentified but specific formulation factors. Because fluctuations in serum concentrations at any selected dosing interval are a function of the rate of elimination of theophylline from the patient and the rate of absorption of theophylline from the formulation, selection of a product and dosing interval needs to be an individualized clinical decision independent of marketing or regulatory influences. Most formulations with claims for twice-daily dosing cannot reliably maintain fluctuations in serum concentration whereby the peak will not exceed twice the trough. Moreover, of the three products approved for once-a-day dosing, fluctuations in serum concentration are more likely to be larger than are clinically optimal, and malabsorption occurs with two of the three approved formulations unless taken after food; one, in fact, has such a large increase in rate and extent of absorption when taken with food that its postprandial absorption characteristics are aptly described as "dose-dumping."
Delayed-Action Preparations↗
Therapeutic effect and dosing strategies for theophylline in the treatment of chronic asthma.
Theophylline has demonstrated a very high degree of clinical efficacy as a prophylactic maintenance drug for chronic asthma when dose levels maintain serum concentrations of 10 to 20 micrograms/ml. Once established, such doses appear to be well tolerated and free of clinically apparent side effects, although minor neuropsychological and physiologic abnormalities can be detected. In general, while there appears to be little clinical effect from these minor side effects, the possibility of bothersome symptoms in selected patients cannot be excluded and requires further study. The data argue strongly that formulations and dosage intervals should aim for the most stable serum concentrations practically attainable, even though clinicians will certainly make justifiable compromises in individual clinical situations. The wide variability in theophylline elimination rate and the relationship between effect and serum concentration dictate that dosage be individualized and that final dosage is best guided by measurement of serum concentration. Slow clinical titration decreases the frequency of caffeine-like side effects from greater than 50% of patients when therapeutic levels are rapidly attained to only 1% or 2%. Finally, although some physiologic variables and drug interactions may alter theophylline elimination and thus pose clinical risks, it is reassuring that dosage requirements generally remain stable over extended periods.
Asthma↗
Evaluation of a scheme for establishing and maintaining dosage of theophylline in ambulatory patients with chronic asthma.
To assess the utility of a dose-titration scheme for determining maintenance theophylline requirements, dose requirements and stability of serum concentrations were examined using 3537 serum determinations from 1073 patients with chronic asthma during a 5-year period. When the dosing scheme was followed, 78% of initial serum concentrations were within the target range of 10 to 20 micrograms/ml; the mean number of measurements to attain this range was 1.3. Among 404 of these patients prospectively questioned, adverse effects were not present in all 41 whose initial serum concentration was less than 10 micrograms/ml, occurred in eight of 296 patients when serum concentrations were between 10 and 20 micrograms/ml, and were present in 21 of 67 when concentrations were greater than 20 micrograms/ml. After final dose adjustment, mean dose requirements among those who attained serum concentrations of 10 to 20 micrograms/ml averaged 22 mg/kg/day in 1- to 9-year-old children, 20 mg/kg/day in 9- to 12-year-old children, 18 mg/kg/day in 12- to 16 year-old children, and 13 mg/kg/day in the 94 patients older than 16 years of age. Repeat serum concentrations after 3 months to 2 years showed 66% remaining within the 10 to 20 micrograms/ml range and another 15% between 7.5 and 10 micrograms/ml; 9% were greater than 20 micrograms/ml, and none greater than 30 micrograms/ml. Thus the dosing scheme produces serum concentrations in the usual therapeutic range with a minimum of samples and few side effects; most patients maintained acceptably stable blood levels.
Adolescent↗
Identification of children for whom routine monitoring of aminoglycoside serum concentrations is not cost effective.
On the basis of our clinical impression that aminoglycoside serum concentration measurements did not result in dosage changes in many children with normal renal function, data collected during pharmacokinetic consultations were evaluated to identify pediatric patients for whom routine serum concentration monitoring would not be cost effective. The frequency of peak or trough concentrations outside the desired ranges was related to age and duration of therapy in 88 children with normal renal function who were given recommended doses of gentamicin or tobramycin. Trough concentrations were outside the target range (greater than 2 micrograms/ml) in five of 26 patients who had received more than 10 days of therapy or were older than 18 years of age. In contrast, troughs were less than 2 micrograms/ml and did not significantly increase over the course of therapy in all patients who were younger than 18 years of age and had received less than 10 days of therapy. This latter group represented 36% of all aminoglycoside pharmacokinetic consultation requests to our service. In addition, when infusion technique and sample time were meticulously controlled, peak concentrations were greater than or equal to 4 micrograms/ml in all patients who had received a dose of approximately 2.5 mg/kg. We conclude that routine peak and trough measurements are unnecessary in patients between 3 months and 18 years of age unless duration of therapy extends beyond 10 days, renal function is impaired, there is a clinical need for higher doses or shorter dosing intervals, or a potential nephrotoxin has been administered in the previous 3 months.
Adolescent↗
Evaluation of the asthmogenicity of propafenone, a new antiarrhythmic drug. Comparison of spirometry with methacholine challenge.
Propafenone is a new membrane-stabilizing antiarrhythmic agent that structurally resembles the beta-adrenergic receptor antagonist, propranolol. To determine the potential asthmogenicity of this new drug, pulmonary function, airway reactivity to methacholine, blood pressure, the electrocardiogram, and plasma concentrations were measured in 12 patients with mild intermittent asthma after 48 to 72 hours of treatment with placebo and with oral propafenone in low dosage (150 mg every eight hours) and high dosage (300 mg every eight hours) in a double-blind crossover manner. The forced vital capacity (FVC), forced expiratory volume in one second (FEV1), forced expiratory flow over the middle half of the FVC (FEF25-75%), heart rate, and blood pressure during the three regimens of treatment were not significantly different; however, the QRS interval on the ECG was significantly widened with both dosages of active drug, and the mean provocative dose of methacholine (+/- SE) required to reduce FEV1 by 20 percent (PD20) decreased from 3.0 +/- 0.6 mg/ml with placebo to 2.1 +/- 0.7 mg/ml with the high dosage of propafenone (p less than 0.01). The mean PD20 on the low-dose regimen was not significantly different from placebo or high-dose therapy. A potentially relevant increase in airway reactivity, as measured by a ratio of less than 0.5 for PD20 after treatment to PD20 after placebo, occurred in seven subjects with high-dose and in one subject during low-dose treatment (p less than 0.01). These data suggest that propafenone should be used with caution in patients with asthma and that bronchial provocation will provide a more sensitive measure of the asthmogenicity of a drug with beta-adrenergic receptor antagonist activity than pulmonary function tests. Moreover, use of bronchial provocation allows the selection of subjects with mild disease, thus reducing the risk of potentially severe bronchospasm.
Adult↗
Current concepts in clinical therapeutics: asthma.
The epidemiology, etiology, pathophysiology, diagnosis, and treatment of asthma are reviewed, and the major drugs used in treating asthma are discussed in depth. In terms of morbidity, mortality, and economic impact, asthma is a serious disease. About nine million Americans suffer from it, and in a recent year nearly 2000 people died from it. The underlying mechanism of asthma appears to be a hyperreactivity of the airways to certain stimuli, including environmental irritants, exercise, and psychological factors. The symptoms of asthma are caused by spasm of airway smooth muscle, increased mucus secretion, and inflammation. Asthma may be classified as intermittent (patients with extended symptom-free periods) or chronic (patients with frequent exacerbations). Diagnosis of asthma relies heavily on a comprehensive patient history confirmed with objective physiologic data. Acute or intermittent asthma should be treated first with inhaled beta 2 agonists such as albuterol or terbutaline. Corticosteroids should be started if the response to the beta 2 agonists is inadequate, and theophylline may be used while waiting for the steroids to exert an effect. Adequate hydration, correction of metabolic acidosis, and oxygen are essential supportive measures. Theophylline appears to be the best noncorticosteroid for chronic asthma, although cromolyn is an acceptable alternative. Sympathomimetic bronchodilator therapy and corticosteroids may be needed adjunctively. Immunotherapy is indicated in patients with chronic asthma caused by specific allergens and poorly controlled on theophylline or cromolyn. Asthma is best managed using multiple pharmacologic agents in response to specific events and symptoms, making optimal therapy difficult to achieve and sometimes difficult to define.
Adrenal Cortex Hormones↗
Theophylline use: an overview.
Four critical issues related to theophylline are addressed: What is theophylline? Why use it? How should it be used? Who should receive it? Theophylline is a methylated xanthine with established clinical benefit as maintenance therapy for chronic asthma. In fact, evolution of our knowledge of the pharmacodynamics and pharmacokinetics of theophylline has made this drug the most effective nonsteroidal prophylactic used for chronic asthma. Theophylline has the potential for serious toxicity at excessive serum concentrations. Nonetheless, its major justification for use today, when so many other asthma medications have become available, is because of the high degree of efficacy that can be attained with appropriate use. The optimal likelihood of maximal safe effect is attained with maintenance of serum concentrations within the 10 to 20 micrograms/ml therapeutic range. Dosage should be individualized by clinical titration, guided by measurement of serum concentrations, and continued only if well tolerated; selection of appropriate products and dosing intervals permits maintenance of acceptably stable serum concentrations. Asthma in patients only intermittently symptomatic, regardless of severity, is probably best treated by intervention measures with inhaled bronchodilators, supplemented when necessary by short-term use of oral corticosteroids, rather than by long-term maintenance therapy. Theophylline therapy in patients with obstructive pulmonary disease other than asthma should generally be highly selective and based on clearly demonstrable clinical benefit.
Adrenergic beta-Agonists↗
Theophylline product and dosing interval selection for chronic asthma.
Unless they are taken at unacceptably frequent intervals, conventional rapid-release theophylline tablets and liquids produce excessive serum concentration fluctuations, particularly in patients with rapid elimination. Slow-release formulations provide more stable serum concentrations with longer dosing intervals if absorbed completely, consistently, and at a sufficiently slow rate and thus have the potential to improve efficacy and compliance. However, there are clinically important differences in the extent and rate of absorption among the 15 slow-release formulations available under 29 brand names in the United States. Fluctuations in steady-state serum concentrations are a function of the absorption rate of the product, the elimination rate of the patient, and the dosing interval. In patients with slow elimination, clinically relevant differences among formulations are not apparent with twice-daily dosing. Among patients with more rapid elimination, however, available data for only two products demonstrate sufficiently slow absorption to justify routine twice-daily use without excessive fluctuations. More rapidly absorbed formulations must be administered at 8-hour intervals in such patients to prevent breakthrough in asthmatic symptoms before the next dose, despite promotional claims to the contrary. Current products approved for "once-a-day" dosing are clinically inadequate because of incomplete or erratic absorption or excessive serum concentration fluctuations. Lastly, food intake induces dose dumping of potentially toxic amounts of theophylline from Theo-24 and greatly impairs absorption from Theo-Dur Sprinkle capsules but has no important effect on Theo-Dur tablets. The effects of food on most other theophylline products are not known.
Delayed-Action Preparations↗
Potentially dangerous theophylline dose recommendations in The Harriet Lane Handbook.
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Drug Administration Schedule↗
Measurement of tobramycin concentrations in saliva.
Paired serum and saliva specimens were obtained from 16 patients and three volunteers who had received tobramycin. In addition, saliva was collected from ten controls who had not taken any drugs in the previous week. Tobramycin concentrations were measured in duplicate by the Emit assay modified to obtain precise results at concentrations greater than 0.25 microgram/ml. The drug was undetectable in 32 of 34 saliva specimens and only trace amounts were present in the other two, even though corresponding steady-state serum concentrations were greater than or equal to 4.0 micrograms/ml for 29 of 34 specimens. Tobramycin values were zero for all ten saliva specimens from controls. These results probably can be extrapolated to other aminoglycoside antibiotics since most are hydrophilic and ionized at physiologic pH, which disfavors penetration into saliva. We conclude that saliva cannot be used as a noninvasive indirect method of measuring aminoglycoside serum concentrations to guide dosage adjustments.
Adolescent↗
Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity.
Three slow-release preparations of theophylline have received approval from the U.S. Food and Drug Administration (FDA) for "once-daily" dosing indications, amid controversy regarding the appropriateness of this decision. Because of specific concerns regarding data submitted to the FDA in support of the first of these products to be approved, Theo-24, we examined the absorption characteristics of this newly marketed formulation. Eight healthy volunteers received, in a crossover manner, single doses of a theophylline reference solution and Theo-24, taken both fasting and after a breakfast of bacon and eggs. The concentrations of theophylline were measured up to 60 hours after the dose. Absorption of Theo-24 after an overnight fast was very slow, with only 71 +/- 6 percent (mean +/- SE) of the dose ultimately absorbed. In contrast, food caused precipitous "dose-dumping," resulting in dose-normalized peak levels in the serum that averaged 2.3 times higher than after a fasting dose. About half of the dose was absorbed in a four-hour period, generally beginning six to eight hours after the postprandial dose, and complete absorption was then attained within 24 hours (p less than 0.001). Toxic effects of theophylline occurred in four subjects when they took the dose with food whereas no toxic effects occurred during the fasting regimen. Consequently, doses of Theo-24 that would have attained a predicted peak concentration of 15 micrograms/ml after multiple dosing taken without food would, if taken with food, have resulted in larger fluctuations and in peak concentrations in the potentially toxic range for six of the eight subjects.
Adult↗
Update on the pharmacodynamics and pharmacokinetics of theophylline.
Theophylline has emerged as a major prophylactic agent for controlling the symptoms of chronic asthma, but it provides little if any relief of pulmonary symptoms caused by irreversible chronic airways obstruction. Although in vitro it inhibits phosphodiesterase and antagonizes adenosine receptors, theophylline's mechanism of action in asthma is unknown. Often, 10 to 20 micrograms/ml is used as the range of serum concentrations where there is the greatest likelihood of obtaining maximal benefit safely. Slow-release products have the potential to provide more stable serum concentrations with longer dosing intervals. However, clinically important differences in rate and sometimes extent of absorption exist between the 15 formulations sold under 29 brand names in this country. In patients with more rapid elimination, few products have sufficiently slow absorption to allow twice-daily use. Often these formulations must be administered every eight hours to prevent breakthrough in asthmatic symptoms despite promotional claims to the contrary. In patients with slower elimination, differences among products are unlikely to be clinically important with 12-hour dosing intervals. Current products approved for "once-a-day" dosing are clinically inadequate because of erratic absorption or excessive serum concentration fluctuations. Moreover, food induces dose dumping of potentially toxic amounts of theophylline from Theo-24, greatly increases the extent of absorption of theophylline from Uniphyl, decreases extent of absorption from Theo-dur-Sprinkle capsules, but has no clinically important effect on Theo-Dur tablets, Theobid, Slo-Bid, or Somophyllin-CRT. The effects of food or other factors that alter gastrointestinal physiology on theophylline absorption are unknown for most other products.
Asthma↗
Slow-release theophylline for the management of chronic asthma.
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Asthma↗
Food-induced dose dumping of Theo-24.
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Food↗