Optimal duration of nebulized albuterol therapy.

The output from a jet nebulizer was analyzed for aerosol profile, solution output, and delivery of albuterol at three different initial volume fills to determine the changes that occur during the course of nebulization. Increasing diluent volume led to significantly greater delivery of the albuterol initially placed in the nebulizer. Albuterol delivery from the nebulizer ceased completely following the onset of inconsistent nebulization (sputtering) as determined audibly and by laser particle analysis. Aerosol output rate declined by one-half within 20 s of the onset of sputtering. The albuterol concentration in the nebulizer solution increased significantly once the aerosol output declined. The weight of solution delivered as determined by change in weight of the nebulizer could not be fully accounted for as aerosol volume. It appeared that this discrepancy represented loss of water by evaporation. Aerosolization past the point of initial jet nebulizer sputtering is unproductive.

Pharmacokinetics of low-dose methotrexate in adult asthmatics.

Several reports have been published on the disposition of methotrexate (MTX) when given in low dosages, but none in asthmatic patients. To address this matter, pharmacokinetic studies were performed in nine patients with severe, steroid-requiring asthma (ages 18-76 yrs) after the sixth weekly intramuscular dose of MTX. Theophylline pharmacokinetic studies were also performed at baseline prior to the start of MTX treatment and at the time of the MTX studies. Total systemic clearance of MTX, given as mean (SD), was 122.6 (25.1) ml/minute, volume of distribution at steady state 0.49 (0.2) L/kg, half-life 3.1 (0.3) hours, mean residence time 5.0 (0.6) hours, and renal clearance 89.1 (36.3) ml/minute. These values are similar to those previously reported for other patient populations receiving low-dose MTX. Eight of these patients were evaluated for changes in theophylline pharmacokinetics. Theophylline clearance at week 6 decreased an average of 19% from baseline and correlated inversely with total MTX clearance. Percentage change in theophylline clearance from baseline was inversely correlated with MTX nonrenal clearance, but was not statistically significant. This finding may indicate competition for clearance pathways between MTX and theophylline.

Effect of low-dose methotrexate on the disposition of glucocorticoids and theophylline.

Low-dose methotrexate (MTX) therapy has been recently proposed as alternative therapy for patients with severe steroid-requiring asthma. Several questions have been raised regarding the mechanism of action, including alteration of pharmacokinetics of two medications used in these patients, specifically, glucocorticoids and theophylline. To address this question, pharmacokinetic studies were performed at baseline and after 6 weeks of treatment with either intramuscular MTX or placebo (folic acid). Plasma concentrations of theophylline were measured by fluorescence polarization immunoassay (TDx, Abbott Diagnostics, Abbott Park, Ill.). Prednisolone, methylprednisolone, and cortisol concentrations were measured by high-performance liquid chromatography. Fifteen adults were enrolled in the double-blind, placebo-controlled trial. No change in prednisolone pharmacokinetic parameters was found. Theophylline clearance decreased an average of 19% in patients randomized to receive MTX, from 48.0 +/- 2.0 ml/hr/kg to 38.9 +/- 3.6 ml/hr/kg (p less than 0.05). This change resembles change observed with theophylline and phenobarbital clearance in which a high degree of interpatient variability is observed. The most likely explanation for the change in theophylline clearance is inhibition of hepatic microsomal enzyme activity. Three patients complained of adverse effects, and dosage was reduced in one patient. The variable effect of MTX on theophylline clearance indicates that theophylline concentration monitoring should be performed in patients receiving both drugs.

Variability in the disposition of intraventricular methotrexate: a proposal for rational dosing.

Despite the clinical experience with Ommaya reservoir-facilitated intraventricular methotrexate (MTX) therapy, established age-related dosage guidelines do not exist. In an attempt to design such a schedule, 49 courses of intra-Ommaya MTX (median dose, 6 mg) administered to 12 patients were studied. Using a fluorescence polarized immunoassay (TDx; Abbott, Dallas, TX), the median peak intraventricular CSF MTX concentration (CSF [MTX]) was 423 mumol/L. Median CSF [MTX] at 24 hours was 4.6 mumol/L, and at 48 hours was 1.05 mumol/L. Median MTX half-life (t1/2) was 5.7 hours. A CSF [MTX] greater than 1 mumol/L was maintained for 24 hours in all but one course and for 48 hours in half of the courses. No correlations were found between MTX dose, patient age, [MTX], t1/2 or prior therapy. Considerable intra- and interpatient variability was seen in MTX disposition, emphasizing the need to monitor [MTX] with each course. A schedule for intraventricular MTX with an initial dose of 6 mg and supplemental doses of 6, 4, or 2 mg at 24 and 48 hours according to serial measurements of intraventricular [MTX] should be initiated to provide a minimum CSF [MTX] of 1 mumol/L for 72 hours.

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

Theophylline 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 individualization 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 individualize the theophylline dose, with an analysis of available techniques to monitor theophylline.

Pharmacokinetics of anticancer drugs in children.

Interpatient pharmacokinetic variability normally observed in adults is often of even greater magnitude in paediatric patients because of age-related maturation of physiological processes responsible for drug disposition. Several antineoplastic agents have shown age-related changes, including alterations in volume of distribution, hepatic (doxorubicin, cyclophosphamide), and renal (bleomycin, methotrexate) clearances. These differences in pharmacokinetics as a function of age alter systemic exposure to chemotherapy, and may alter the efficacy and toxicity profile for standard doses of antineoplastic drugs. The relationship of systemic exposure to toxicity has been most clearly defined for methotrexate. Clinical monitoring of methotrexate serum concentrations, and adjustment of folinic acid dosages and duration of rescue based on methotrexate disposition is now routine. More recently, pharmacodynamic data have been published for high-dose methotrexate, epipodophyllotoxins, cisplatin, and cytarabine (cytosine arabinoside), indicating a relation between drug disposition and toxicity or efficacy. Collectively, these data suggest that the pharmacokinetics of many anticancer drugs in children is different from adults, and that variability in drug disposition may have an important influence on toxicity or efficacy.