Malcolm R. Hill

Plasma histamine, epinephrine, cortisol, and leukocyte β‐adrenergic receptors in nocturnal asthma

Plasma histamine, cortisol, epinephrine, cyclic adenosine monophosphate (cAMP), and leukocyte β‐adrenergic receptors were measured in asthmatic patients with (n = 7) and without (n = 10) nocturnal asthma at 4 PM and 4 AM and compared with those of normal subjects (n = 10). A twofold higher plasma histamine concentration was observed at 4 AM compared with 4 PM in all groups, with no change in plasma cortisol, epinephrine, and cAMP concentrations. At 4 AM compared with 4 PM, only patients with nocturnal asthma had a significant 33% decrease (p < 0.05) in mononuclear and polymorphonuclear leukocyte β‐adrenergic receptor density, with no difference in binding affinity in all three groups. Polymorphonuclear leukocytes from patients with nocturnal asthma had significantly impaired response to iso‐proterenol at 4 AM (17% ± 7.3% SEM increase in cAMP; p < 0.05) compared with those of patients without nocturnal asthma (69.4% ± 13.7%) and normal (80.2% ± 21.3%) subjects. A significant change in β‐adrenergic receptor density and function occurs at night in patients with nocturnal asthma.

Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma

BACKGROUND Troleandomycin (TAO), a macrolide antibiotic, was studied as an alternative treatment in 18 children with severe, steroid-requiring asthma. METHODS In this investigation three treatment arms were used in randomized, double-blind, parallel fashion: combination TAO and methylprednisolone (MPn), combination TAO and prednisone, and MPn alone. RESULTS All groups tolerated a considerable reduction in glucocorticoid dose over the 12 weeks of the study: 80% +/- 6% for TAO-MPn, 55% +/- 8% for TAO-prednisone, and 44% +/- 14% for MPn alone. These reductions are all statistically significant (p < 0.05) within groups, and the differences between groups were statistically significant between the TAO-MPn and MPn alone groups. The concentration of methacholine required to induce a 20% decrease in forced expiratory volume in 1 second and pulmonary function were not significantly improved in any treatment group. Safety parameters including blood chemistry and hematology, adrenal function assessment; bone densitometry, and muscle strength testing, were not altered significantly. Two patients who received TAO had elevated liver enzyme levels; one required discontinuation of TAO and one experienced spontaneous resolution without intervention. Lack of statistically significant changes in the efficacy parameters were likely a result of small sample size and effects of the glucocorticoid dose taper. CONCLUSIONS TAO is safe and may be a reasonable treatment alternative in a limited trial for patients who are unable to tolerate tapering of their glucocorticoid dosage. Therapy should be guided by the goal of treatment, that is, glucocorticoid dose reduction or improvement of pulmonary function with appropriate monitoring of pulmonary function and adverse effects.

Monitoring glucocorticoid therapy: a pharmacokinetic approach.

Although glucocorticoid therapy is essential for the treatment of severe inflammatory disorders, there is no systematic approach to patient variables that may affect availability of a steroid dose. After the development of a data base of pharmacokinetic parameters, we examined glucocorticoid pharmacokinetics in 54 patients between 2 and 70 years of age using 70 pharmacokinetic studies after administration of intravenous methylprednisolone (n = 25), oral methylprednisolone (n = 15), intravenous prednisolone (n = 18), and oral prednisone (n = 12). Eleven patients had unusually rapid methylprednisolone elimination (clearance, 565 to 837 ml/min/1.73 m2; population mean, [±SD] 380 ± 100 ml/min/1.73 m2) without an identifiable cause. Incomplete absorption of methylprednisolone and prednisone was observed in three patients and one patient, respectively. Evaluation of glucocorticoid pharmacokinetics in children aged 1 year 8 months to 18 years demonstrated a significant inverse correlation (r = 0.88; p < 0.001) between prednisolone clearance and age. It is therefore important to consider age in the interpretation of pharmacokinetic data. To simplify measurement of prednisolone clearance, a single‐dose single‐point method was developed. This was based on a highly significant relationship between the 6‐hour postdose prednisolone concentration and prednisolone clearance (log prednisolone clearance = 2.66 + [6‐hour postdose concentration] [‐0.00167]; r2 = 0.96; p < 0.0001). Evaluation of glucocorticoid pharmacokinetics in the clinical setting can be used to identify abnormalities in absorption, elimination, and patient compliance. This technique can be used to individualize glucocorticoid dosing regimens.

Penetration of corticosteroids into the lung: Evidence for a difference between methylprednisolone and prednisolone

Little is known about the penetration of corticosteroids, such as methylprednisolone and prednisolone, into the lung, despite their common use in the treatment of inflammatory lung diseases. To compare methylprednisolone and prednisolone concentrations in the bronchoalveolar space, we administered these two corticosteroids in a randomized, crossover fashion to 17 adult rabbits. A loading dose was administered and was followed by a continuous infusion for 180 minutes to achieve steady-state plasma concentrations between 200 to 2000 ng/ml. Serial plasma samples were obtained during the infusions. Bronchoalveolar lavages (BAL) were performed at 180 minutes with sterile saline. Plasma and BAL fluid (BALF) were assayed for methylprednisolone and prednisolone concentration by high-performance liquid chromatography. Corticosteroid concentrations were normalized to urea concentrations in plasma and BALF. Generally, BALF corticosteroid concentration increased as plasma concentration increased. At plasma concentrations greater than 800 ng/ml, BALF methylprednisolone concentrations increased exponentially, whereas the increase for prednisolone remained linear. BALF methylprednisolone was five times as high as that of prednisolone when plasma corticosteroid concentration was in the 2000 ng/ml range. With this continuous infusion technique, methylprednisolone has a higher degree of bronchoalveolar penetration than prednisolone, and these differences are greater at higher plasma concentrations.

High-dose systemic glucocorticoid therapy in the treatment of severe asthma: A case of resistance and patterns of response

At some frequent interval, perhaps once a month, REFERENCES these would be reported to a central data collection 1. Yunginger JW. Sweeney KG. Stumer WQ. ct ,jl. Fatal i’ood center. Of course it would be ideal if each patient induced anaphylaxis. JAMA 1988;260: 1450-2 could be evaluated to determine if a food (and which 2. Sampson HA. Mendelson L, Rosen JP. Patal and trear-fatal food food) was actually responsible for the symptoms, but anaphylaxis reactions in children. N Engl J 2lcd 1992327:

Altered prednisolone pharmacokinetics in patients with cystic fibrosis

Prednisolone pharmacokinetics were evaluated in eight patients with cystic fibrosis (CF) (aged 1.8 to 20 years) by assessing absorption of orally administered prednisone (in its active form, prednisolone) and elimination of prednisolone after intravenous administration. After an overnight fast, subjects received intravenously administered doses of prednisolone or orally administered doses of prednisone, 40 mg/1.73 m2 body surface area, before a standardized breakfast. Serial blood samples were collected for 12 hours and analyzed for prednisolone concentration. Prednisolone pharmacokinetics were compared in eight age-matched patients with asthma who required steroids after intravenous administration of prednisolone. The prednisolone pharmacokinetic parameters derived demonstrated an increased total clearance (by 60%), an increased volume of distribution (by 46%), a lower peak concentration (by 35%), and no difference in elimination half-life in patients with CF compared with those with asthma. Bioavailability averaged 88.4% +/- 20.1% of the administered dose. Prednisolone clearance was markedly increased in those with CF. There was a proportional increase in nonrenal clearance, with no difference in renal clearance in those with asthma or CF. The plasma protein binding of prednisolone was only slightly decreased in patients with CF and did not account for the observed pharmacokinetic alteration. The marked increase in prednisolone clearance may necessitate the use of more frequent or higher doses of this steroid in the treatment of patients with CF, leading to a potentially less favorable benefit/risk ratio.

Are theophylline “levels” a reliable indicator of compliance?

Clinicians frequently rely on serum theophylline concentrations (STCs) as an indicator of compliance for asthma medications. Most patients with good compliance do not have excessive fluctuations during routine STC monitoring. However, our experience is that in certain patients, persistently low or erratic STCs may be a sign of abnormal theophylline disposition. With careful analysis of theophylline absorption (STC every 2 hours for 24 hours after oral theophylline doses) and elimination (serial STC for 12 hours after an intravenous dose of aminophylline), we identified several patients with previously unrecognized anomalies of theophylline pharmacokinetics. These include (1) a 16-year-old girl with consistent temporal fluctuation in STCs during administration of a sustained-release formulation every 8 hours because of delayed absorption and enhanced elimination of theophylline at night, (2) a 13-year-old girl with markedly delayed absorption of a once-daily preparation administered in the evening, (3) a 5-year-old boy with erratic absorption of a liquid theophylline preparation with significantly increased STCs during the night, and (4) a 49-year-old man with 60% bioavailability of aminophylline tablets. Based on these observations, we suggest that clinicians carefully consider the possibility of abnormalities in theophylline disposition before assuming unexpected deviations in STCs are solely the result of noncompliance.

Clinical comparability of albuterol delivered by the breath-actuated inhaler (Spiros) and albuterol by MDI in patients with asthma

STUDY OBJECTIVE This study compares the efficacy and safety of one and two actuations of albuterol sulfate powder delivered via a breath-actuated, effort-assisted, investigational inhaler (Spiros, Dura Pharmaceuticals, Inc) and albuterol delivered via a conventional propellant-driven metered dose inhaler (Ventolin, Glaxo, Inc). DESIGN Randomized, double-blind, placebo-controlled, 5-way crossover study. PARTICIPANTS Sixty patients with mild-to-moderate asthma (FEV1 59% predicted) were enrolled and 44 completed the study. MEASUREMENTS AND RESULTS FEV1 values over 6 hours were analyzed by ANCOVA and the Finney relative potency model. The relative potency of the inhalers (albuterol MDI: albuterol DPI) was 1.132 (90% CI, 0.680 to 2.252) indicating 1.132 actuations of albuterol MDI provided the same bronchodilation as one actuation of albuterol DPI. ANCOVA analyses further indicated that there were no significant differences between the two delivery systems with respect to FEV1, FVC, FEF25-75%, or PEF. Both inhalers had similar effects on serum potassium levels, QTc interval, blood pressure, and heart rate. CONCLUSIONS In patients with mild-to-moderate asthma in this study, the albuterol DPI was determined to be therapeutically comparable to albuterol MDI in the delivery of one and two actuations of albuterol.

Delivery of glucocorticoids by jet nebulization: Aerosol characteristics and output

BACKGROUND Since inflammation has been identified as a critical factor in the pathogenesis of asthma, use of inhaled glucocorticoids has increased. Because young children are often unable to coordinate properly the use of metered-dose inhalers and no glucocorticoids preparations for nebulization have been approved in the United States, parenteral and intranasal glucocorticoids preparations are occasionally administered by nebulization. METHODS We examined whether a parenteral preparation (triamcinolone acetonide [TAA]; Kenalog) could be delivered by nebulization. TAA, 1000 micrograms (0.1 ml), was placed in the nebulizer bowl (MB5 [MeFar, Brescia, Italy] or Pari-Jet [Dura Pharmaceuticals, San Diego, Calif.]), then diluted with 2.9 ml normal saline solution for a total volume fill of 3 ml. Using a laser particle analyzer, high-performance liquid chromatography, and cascade impactor, we examined the percentage of aerosol volume produced with particles in the respirable range of 1 to 5 microns in diameter, actual TAA output (in micrograms) and concentration of TAA contained in the particles within the respirable range. RESULTS Laser particle analysis indicated that 34% +/- 3% (mean +/- SEM) (MB5) and 47 +/- 3% (Pari-Jet) of the total aerosol volume produced were within the respirable range of 1 to 5 microns in diameter, and this remained consistent throughout nebulization. The nebulizer was stopped serially for determination of TAA output with high-performance liquid chromatography. TAA output (1000 micrograms less the amount in micrograms remaining after nebulization) was essentially complete after 2 minutes with the Pari-Jet and within 4 minutes with the MB5 and totaled 352 +/- 19 micrograms and 367 +/- 9 micrograms, respectively. Finally, cascade impactor studies confirmed that 33.4% of the TAA aerosol generated by the MB5 nebulizer was contained in particles in the respirable range. CONCLUSION Approximately 35% (Pari-Jet) and 37% (MB5) of the initial 1000 micrograms of TAA was delivered with the two nebulizers tested. The particles generated within the respirable range were limited to 34% (MB5) and 47% (Pari-Jet) of the amount delivered. TAA was equally distributed in the particles generated. The theoretic amount delivered in the respirable range was approximately 12.5% for the MB5 nebulizer on the basis of the cascade impactor and 16.5% for the Pari-Jet (assuming TAA distribution equivalence) of the TAA placed in each of the nebulizers. Additional clinical studies are needed to define efficacy and safety in view of the excipients used in preparing the parenteral preparation.

Sustained release theophylline preparations. Practical recommendations for prescribing and therapeutic drug monitoring.

SummaryTheophylline is an important antiasthmatic medication which has bronchodilator properties. With increased understanding of the relationships of serum theophylline concentration and effect, both adverse and beneficial, oral dosage forms were developed to provide consistent serum theophylline concentrations with the benefit of convenient dosage intervals for long term use.Since factors such as concurrent disease states, drug interactions and age have a profound effect on theophylline disposition, relatively sophisticated dosage guidelines have evolved. Theophylline is in fact a model drug for the application of pharmacokinetic principles to the individualisation of a treatment regimen.The purpose of this discussion is to review the relationship of serum theophylline concentration and pharmacodynamic effect and the special properties of oral sustained release theophylline formulations, and to provide a practical approach to prescribing theophylline. Guidelines are provided on the use of serum theophylline concentrations to individualise the theophylline dose, with an analysis of available techniques to monitor theophylline.