A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. CAP Study Group.

Because of the critical role of neutrophils in host defenses, it was hypothesized that stimulation of neutrophil production and function with Filgrastim would improve the outcome of hospitalized patients with community-acquired pneumonia. To test this hypothesis, a randomized, placebo-controlled, multicenter trial of Filgrastim (300 micrograms/day up to 10 days) as an adjunct to antibiotics was conducted for these patients. Outcome measures included time to resolution of morbidity (TRM, a composite measure of temperature, respiratory rate, blood oxygenation, and chest radiograph), 28-day mortality, length of stay, and adverse events. Filgrastim increased blood neutrophils 3-fold, but TRM, mortality, and length of hospitalization were not affected. Treatment, however, accelerated radiologic improvement and appeared to reduce serious complications (e.g., empyema, adult respiratory distress syndrome, and disseminated intravascular coagulation). Filgrastim administration was safe and well tolerated in these patients. Additional trials are needed to establish the value of this approach to treatment of infectious diseases.

Time to resolution of morbidity: an endpoint for assessing the clinical cure of community-acquired pneumonia.

Clinical trials of new therapeutics for community-acquired pneumonia (CAP) have typically used a subjective endpoint of clinical response. However, as this endpoint is not quantitative, it is subject to observer bias and renders the conduct of multicenter trials difficult. For the purposes of conducting a clinical trial of filgrastim, as an adjunct to antibiotics for the treatment of CAP, a set of clinical criteria were developed prospectively to determine the time when a clinical cure was achieved, based on respiratory rate, temperature, oxygenation and roentgenographic findings, which was termed the time to resolution of morbidity (TRM). The TRM was evaluated on the first 100 patients entered in this clinical trial. As no clear reference standard exists, the predictive value for the duration of parenteral antibiotics (AB) and the length of hospital stay (LOS) was compared with that provided by a widely used classification system for severity of disease, APACHE II. The TRM was found to correlate significantly better with AB or LOS than APACHE II (P < 0.001). Furthermore, TRM offers the benefit over the endpoints of LOS and AB of being specifically designed to measure the patient's response to therapy, and, in fact, may aid physicians in determining the duration of parenteral antibiotic therapy. Hence, TRM is relevant to the clinician and is a useful tool to ensure uniformity in the assessment of the response to a new therapeutic in a multicenter clinical trial.

Pharmacokinetics of cefepime after single and multiple intravenous administrations in healthy subjects.

The pharmacokinetics of cefepime in 31 young, healthy volunteers were assessed after the administration of single and multiple 250-, 500-, 1,000-, or 2,000-mg intravenous doses. Each subject received a single dose of cefepime via a 30-min intravenous infusion on day 1 of the study. Starting from day 2, subjects received multiple doses of cefepime every 8 h for 9 days, and on the morning of day 11, they received the last dose. Serial blood and urine samples were collected after administration of the first dose and on days 1, 6, and 11. Cefepime concentrations in plasma and urine were assayed by using reverse-phase high-performance liquid chromatography with UV detection. Data were evaluated by noncompartmental methods to determine pharmacokinetic parameters. The mean half-life of cefepime was approximately 2 h and did not vary with the dose or duration of dosing. The regression analyses of peak levels (Cmax) in plasma at the end of the 30-min intravenous infusion and the area under the plasma concentration-versus-time curve (AUCo-infinity) showed a dose-proportional response. The steady-state volume of distribution (Vss) was approximately 18 liters and was independent of the administered dose. The multiple-dose pharmacokinetic data are suggestive of a lack of accumulation or change in clearance of cefepime on repeated dosing. Cefepime was excreted primarily unchanged in urine. The recovery of intact cefepime in urine was invariant with respect to the dose and accounted for over 80% of the dose. The values for renal clearance ranged from 99 to 132 ml/min and were suggestive of glomerular filtration as the primary excretion mechanism. It is concluded that cefepime linear pharmacokinetics in healthy subjects.

High-performance liquid chromatographic method for the determination of etoposide in plasma using electrochemical detection.

A quantitative analytical method has been established for the determination of a semi-synthetic epipodophyllotoxin, etoposide, in plasma. The method employs reversed-phase high-performance liquid chromatography and electrochemical detection. Sample preparation consisted of extraction with 1,2-dichloroethane followed by phase separation, evaporation of the organic phase, and reconstitution of the residue. Observed recoveries were 76.8 and 87.5% for 50 and 500 ng/ml, respectively. The method had a linear range of 10-1000 ng/ml. Correlation coefficients of 0.997 or greater were obtained during validation experiments and study sample analysis.

Liquid chromatographic procedure for the quantitative analysis of megestrol acetate in human plasma.

A simple, sensitive, and reproducible high-performance liquid chromatographic (HPLC) procedure was developed for the quantitative analysis of megestrol acetate in human plasma. An internal standard, 2,3-diphenyl-1-indenone, was added to 0.5 mL of plasma followed by extraction with hexane. The residue remaining after evaporation of hexane was reconstituted in methanol and injected onto a mu-Bondapak C18 column. The column was eluted with acetonitrile:methanol:water:acetic acid (41:23:36:1), and the eluant was monitored at 280 nm. Megestrol acetate and the internal standard eluted at 6-7 and 12-14 min, respectively. The peak height ratio (megestrol acetate/internal standard) versus plasma concentration was linear over a range of 10-600 ng of megestrol acetate/mL of plasma, and the limit of detection was 5 ng/mL. The mean intra- and interassay accuracies were within 3% of the actual values. The mean intra- and interassay precision, as estimated by RSD, were 4 and 6%, respectively. Constituents in human plasma and megestrol, a possible degradation product, did not interfere in the assay. The procedure was applied to the analysis of plasma samples from subjects receiving 40 mg of Megace q.i.d.

Evidence of nonlinearity in digoxin pharmacokinetics.

Six normal male volunteers received 0.5 mg label doses of digoxin as (a) a bolus intravenous injection over 2 min, (b) a constant rate intravenous infusion over 1 hr, (c) a constant rate intravenous infusion over 3 h, and (d) a solution in 5% dextrose given orally. Plasma concentrations of digoxin were measured by radioimmunoassay for a 4 day period and urinary excretion for a 6 day period after the single doses. The mean (coefficient of variation) total areas under the plasma concentration-time curves per 0.5 mg of digoxin were (a) 35.55 (14.8%), (b) 30.20 (27.7%), (c) 25.80 (35.5%), and (d) 15.47 (49.9%); the means differed significantly (0.01 greater than p greater than 0.005). The mean (coefficient of variation) total amounts excreted in the urine as a fraction of the dose were (a) 0.689 (6.31%), (b) 0.517 (20.4%), (c) 0.588 (16.8%), and (d) 0.374 (23.4%); the means differed significantly (p less than 0.001). Both the total clearance and the nonrenal clearance of digoxin differed significantly with the method of intravenous administration. The slower the rate of input of digoxin to the body, the greater were both the total clearance and the nonrenal clearance of the drug, which strongly suggests nonlinear pharmacokinetics.

Pharmacokinetics of digoxin in the cat and comparisons with man and the dog.

Digoxin doses of 14.3, 5.72 or 1.43 mcg/kg were administered to 8 cats and the plasma digoxin concentrations (concns) were measured as a function of time for 96 hr. Pharmacokinetic linearity was evidenced by: (1) mean plasma clearance (Clp) of 4.05 ml/(kg x min) with a coefficient of variation of 34.6% and a range of 2.69-6.71; (2) linear relationship between total area under the plasma concn-time curve and the administered dose. Further evidence for linearity was the lack of dose-dependence of apparent elimination half-life (beta). The volume of distribution and beta for cats were respectively (mean +/- s.d.) 20.4 +/- 5.35 L/kg and 0.0120 +/- 0.0030 hr-1. Results from cats were compared with literature data for dogs and man. The order of Clp in units of ml/(kg x min) were: infant greater than dog greater than cat greater than adult man.