Bronchodilation from intravenous theophylline in patients with cystic fibrosis: results of a blinded placebo-controlled crossover clinical trial.

Most patients with cystic fibrosis (CF) eventually develop chronic obstructive pulmonary disease and theoretically could benefit from theophylline therapy. The purpose of this study was to investigate the pharmacologic response to intravenous theophylline by pulmonary function tests (PFT) and the theophylline pharmacokinetics in patients with CF. A randomized, double-blind, placebo-controlled, crossover trial was conducted in 10 ambulant patients with CF (5 females, 5 males), aged 11 to 21 years. Each patient received an intravenous dose of theophylline and normal saline over 1/2 hour on consecutive days. Spirometry and whole-body plethysmography were performed at baseline, 1, 3, 5, and 7 h after the theophylline dose, and 10 blood samples were collected over 9 h on both study days. The percent change of PFT from the baseline was recorded. Analysis of variance for balanced two-period crossover design was used to evaluate the effectiveness of theophylline therapy. The serum concentration (Conc.) vs. time data were fitted using nonlinear least-squares regression analysis. The theophylline dose administered was 7.9 +/- 0.4 (mean +/- SD) mg/kg, which produced a maximal Conc. (Cmax) of 14.6 +/- 2.7 microgram/ml. The half-life (T1/2), volume of distribution (Vd), and total body clearance (TBC) were 4.9 +/- 1.9 h, 537 +/- 124 mL/kg, and 80 +/- 16 ml/h/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased dosage requirements of tobramycin and gentamicin for treating Pseudomonas pneumonia in patients with cystic fibrosis.

The pharmacokinetic behavior of tobramycin and gentamicin was evaluated in 27 patients who had cystic fibrosis (CF). A previously studied, age-matched group of 334 patients who had been treated with gentamicin and who did not have CF served as controls. The CF patients, who ranged in age from 2 to 32 years and who had normal renal function, received 36 treatment courses with either tobramycin (19) or gentamicin (17) to treat Pseudomonas pneumonia. Serum concentrations were determined after a 1.5-mg/kg dose to compute half-life (t 1/2), elimination rate constant (k), and apparent volume of distribution (V). From these values, doses were calculated to produce steady-state peak concentrations of 8.0 micrograms/ml with a dosing interval of every six hours. For tobramycin the mean (+/- SD) t1/2 was 1.0 (0.4) hours, V was 0.18 (0.06) l/kg, total body clearance (TBC) was 2.19 (0.71) ml/min/kg, and the calculated dose was 8.2 (2.1) mg/kg/day. For gentamicin t1/2 was 1.1 (0.5) hours, V was 0.20 (0.06) l/kg, TBC was 2.28 (0.89) ml/min/kg, and the calculated dose was 8.8 (2.4) mg/kg/day. The pharmacokinetic parameters were not statistically different between the two drugs, but the mean values of t1/2 and TBC of CF patients differed significantly from those of the control group. The calculated doses were larger than the manufacturer's maximum recommended dose of 7.5 mg/kg/day for 63% of tobramycin and 71% of gentamicin treatment courses. A dosing interval change to every four hours would have been appropriate in 28 of the 36 treatment courses (78%).(ABSTRACT TRUNCATED AT 250 WORDS)

Value of computed tomographic scan in the evaluation of adult patients after their first seizure.

The role of the computed tomographic (CT) scan in evaluating adults after their first seizure(s) was determined by reviewing the hospital records of 148 patients studied within 30 days of their ictus. Patients with alcohol or drug intoxication or withdrawal or with known brain tumor, craniotomy, or open skull fracture were excluded. Type of seizure; neurological, CT, and electroencephalographic findings; final diagnosis; and hospital outcome were cross correlated. The cause of seizure was established in 71 patients (48%); a structural lesion was identified by CT in 55 (37%), and 16 (11%) had metabolic seizures. CT findings agreed with the results of neurological examination 82% of the time. Structural lesions (including three tumors) were found by CT in 14 patients (15%) with nonfocal findings and in 12 (22%) of those with generalized electroencephalographic abnormalities. Our findings are similar to those reported in adult epileptics and lead us to conclude that the CT scan is a valuable aid in establishing the cause of seizures and in disclosing early lesions.

Heparin kinetics: variables related to disposition and dosage.

A method to determine heparin kinetics and dosage requirements was examined in 20 patients with active thromboembolic disease. Pretreatment heparin sensitivities were determined to establish the relationship between heparin concentration and activated partial thromboplastin times (APTTs). After an initial bolus dose, serial APTTs were measured, heparin concentrations were estimated, and kinetic determinations followed. Heparin elimination rate, distribution volume, and clearance were used to calculate dosage requirements. There was a 500% range in pretreatment heparin sensitivities. Smokers had more rapid heparin elimination rates and t 1/2s than nonsmokers did. Men had more rapid drug clearances than women did. Body weight was related to heparin dosage requirements. Patients treated early after onset of symptoms required higher doses than patients in whom treatment was delayed. A multiple regression model was developed for heparin dosage requirements from body weight, sex, delay between onset of symptoms and treatment, and smoking. This statistical model explained 78% of the variance in heparin requirements.

Gentamicin dosage requirements: wide interpatient variations in 242 surgery patients with normal renal function.

Wide interpatient variations were demonstrated in gentamicin elimination rate and dosage requirements for 242 surgery patients with normal renal function. These patients' half-lives ranged from 0.4 to 13.4 hours as compared to previous reports of 2.5 to 4 hours. The distribution volumes ranged from 0.06 to 0.63 liter/kg, as compared of reported values of 0.20 to 0.25 liter/kg. These wide interpatient variations in kinetic parameters, combined with the need to obtain narrow ranges in serum concentrations, necessitated measuring serum concentrations and individually calculating each patient's dosage regimen early in the treatment course. Using this approach, optimal peak and trough serum levels were consistently produced in these patients. Their required dosage regimens demonstrated considerable variability--ranging from 0.7 to 12.4 mg/kg/day. Compared to the recommended regimen (3 to 5 mg/kg/day), 47% of these surgery patients required higher dosages, and 14% required lower dosages. The incidence of ototoxicity and nephrotoxicity were extremely low, with only three patients possibly having gentamicin-associated nephrotoxicity. These results further emphasize the need to measure serum concentrations and make necessary dosage adjustments to ensure therapeutic levels. However, because of the wide interpatient variation, these increased dosage regimens are not routinely suggested without previously measuring serum concentrations.