Adequacy of recommended aminophylline loading doses in children.

The adequacy of a loading dose of aminophylline 6 mg/kg i.v. in hospitalized pediatric patients with reactive airway disease was studied. Children six months to 14 years of age were studied to determine their serum theophylline concentrations after they were given an aminophylline loading dose of 5-7 mg/kg i.v. and to see whether they had to receive additional bolus doses. Bolus doses were infused over 20-30 minutes and were followed by a continuous infusion. Additional bolus doses were administered if the patient's serum theophylline concentration and clinical condition indicated they were necessary. Data from two separate phases of the study were combined for analysis. Phase 1 was designed for estimating population pharmacokinetic values. Some 72% of the 64 patients studied had subtherapeutic serum theophylline concentrations (< 10 mg/L) within 5.5 hours of the loading dose, and 78% required at least one additional bolus dose. Males had significantly lower serum theophylline concentrations than females; of the patients with subtherapeutic concentrations, 67% were males. Patients five years of age or younger were more likely than older children to have subtherapeutic theophylline concentrations. A 6-mg/kg loading dose of i.v. aminophylline did not produce adequate serum theophylline concentrations or eliminate the need for a second bolus dose in most pediatric patients with acute exacerbations of asthma.

Cefpodoxime proxetil: a new, broad-spectrum, oral cephalosporin.

OBJECTIVE: To discuss the chemistry, pharmacokinetics, spectrum of activity, clinical trials, adverse effects, drug interactions, and dosage guidelines of cefpodoxime proxetil. DATA SOURCES: Literature was identified through a MEDLINE search from 1988 to the present and from review of bibliographies in that literature. STUDY SELECTION: Data were limited to comparative trials published in the English literature. Although many studies were conducted in Japan, the results often were available only in Japanese or partly in English. As these studies could not be completely evaluated, they are not included in this review. DATA SYNTHESIS: Cefpodoxime exhibits good activity against many gram-positive and gram-negative organisms. In clinical trials, cefpodoxime was similar in both clinical and bacteriologic efficacy to amoxicillin, cefaclor, amoxicillin/clavulanate, and penicillin in the treatment of respiratory and urinary tract infections. It also appeared effective in the treatment of skin and soft tissue infections, although no comparative trials have been performed. Cefpodoxime is well tolerated by children and is effective in the treatment of otitis media and pharyngitis. It has a similar adverse effect profile to that of other penicillins and cephalosporins, with gastrointestinal effects being most common. CONCLUSIONS: Cefpodoxime demonstrates good in vitro activity against pathogens frequently associated with respiratory tract, urinary tract, and skin and tissue infections. It has not demonstrated greater efficacy than the other antibiotics to which it has been compared. The available published clinical trials are fraught with methodologic, statistical, and evaluative flaws. Thus, further trials comparing cefpodoxime with established treatments, as well as the newer cephalosporins, are needed before its place in therapy can be established.

Effects of ethanol and delta 9-tetrahydrocannabinol on phencyclidine disposition in dogs.

A three-way crossover study was performed to determine the influence of delta 9-tetrahydrocannabinol (THC) and ethanol (EtOH) separately upon phencyclidine (PCP) disposition in dogs. Seven dogs were given three single dose treatments: 1.5 mg PCP kg-1 i.v., 1.5 mg PCP kg-1 i.v. with 0.4 mg kg-1 THC i.v., and 1.5 mg PCP kg-1 i.v. with 1.25 g EtOH kg-1 i.v. PCP was measured in plasma samples collected for 24 h after administration of each treatment, with several pharmacokinetic parameters calculated from the plasma concentration vs time data. The PCP serum Cls values were significant change in V beta or t1/2. EtOH did not induce significant changes in any PCP pharmacokinetic parameter, although mean Cls and V beta were increased. These results confirm the observed THC inhibition of PCP metabolism, and suggest that the enhanced pharmacologic action of PCP by THC may result from higher serum PCP concentrations. These results further suggest that enhanced PCP actions by acute EtOH administration may result from increased PCP distribution to the CNS.

Evaluation of three theophylline dosing methods in pediatric patients.

Three methods used for individualizing theophylline dosing were prospectively evaluated in 34 pediatric patients to compare the methods' ability to accurately predict steady-state serum theophylline concentrations (STCs) from non-steady-state data. Methods evaluated included a Bayesian weighted sum of squares regression program, an algebraic method developed by Chiou, and a commonly used population-based pediatric dosing algorithm. An expanded retrospective evaluation was also done to further compare the Bayesian and Chiou methods. Patients (aged 1-11 y) admitted to the hospital for acute bronchospasm refractory to inhaled beta agonists and with physician's orders to receive intravenous aminophylline were eligible for participation. Study patients received a 6-mg/kg loading dose aminophylline, followed by a 0.8-1.0 mg/kg/h constant aminophylline infusion. STCs were obtained 0.5 and 5.5 hours postinfusion. Subjects were randomized to one of three dosing method groups (Bayesian, Chiou, or pediatric algorithm). Doses were calculated using the assigned method to attain a target steady-state STC. Predictions from each dosing method were compared with actual serum concentrations for bias and precision. Additionally, analysis of fit-to-the-line-of-identity for predicted versus observed STCs was evaluated for each method. Precision of methods was also compared with regard to their ability to predict within 20 percent of their observed steady-state STC. Results from the prospective evaluation showed no significant difference between the three methods tested. Predicted STCs fell within 20 percent of their observed steady-state concentrations for 18 percent (2/11) of patients in the algorithm group, and 45 percent (5/11) of patients in the Chiou group and 17 percent (2/12) of the patients in the Bayesian group met this criterion. Retrospective analysis of all 34 patients demonstrated that the Bayesian and Chiou methods had similar bias and precision and no statistical difference was found between them. The results from this evaluation suggest that the pediatric dosing algorithm is equivalent in predictive bias and precision to the Bayesian and Chiou methods as well as in its ability to identify doses that result in steady-state STCs within 20 percent of their target values. Given the relative inaccuracy of these methods, cautious use of these techniques is recommended when evaluating non-steady-state STCs obtained from children during the acute stages of reactive airway disease.

Postinduction carbamazepine clearance in an adult psychiatric population.

The objective of this study was to describe the postinduction clearance of carbamazepine (CBZ) in adult psychiatric patients by population pharmacokinetic analysis using the NONMEM program. Specifically, an estimate of CBZ clearance and insight into the effect of common patient characteristics on clearance were sought. Steady-state trough CBZ serum concentrations, CBZ dosing history, concomitant drug administration, and other data from 45 patients were collected retrospectively. A one-compartment model with first-order absorption and first-order elimination was used, with absorption rate, bioavailability, and volume of distribution fixed to literature values. No evidence was found that race, sex, age, ethanol use, smoking, and concomitant lithium significantly affected CBZ clearance. In the final model, clearance was based on lean body weight. The coefficient of variation for clearance estimates was 16.5%. Residual variability was modest. Estimates for volume of distribution, rates of absorption and elimination, and bioavailability could not be pursued rigorously. Although these results may assist in understanding CBZ disposition in this population, their general clinical application should be approached with caution.

Estimation of theophylline clearance during continuous arteriovenous hemofiltration.

Pharmacologic agents and other non-protein-bound compounds smaller than 5,000 daltons have the potential to be removed by continuous arteriovenous hemofiltration (CAVH). A proposed method for estimating drug clearance by CAVH (ClCAVH) equates ultrafiltrate clearance to the product of the sieving coefficient and the average ultrafiltration rate. This simplified approach for estimating ClCAVH would be a clinically useful method for calculating replacement doses, as it economizes on the sampling and analytical requirements associated with the conventional method. Presented are some theoretical considerations and a brief evaluation of the accuracy of this proposed method. The evaluation was conducted using an animal model whereby CAVH was performed in four male beagles. During the hemofiltration period, an i.v. bolus of theophylline, 6 mg/kg, was administered over 15 s. Samples for analysis of theophylline were collected from the arterial, venous, and ultrafiltrate ports at 0, 5, 15, 30, 45, 60, 90, 120, 180, 240, 360, and 480 min following dosage administration. The volume of ultrafiltrate produced during each collection interval was measured. Theophylline serum concentrations were determined by a high performance liquid chromatography assay. Statistically, the simplified method was found to result in significantly (p less than 0.05) larger estimates of ultrafiltrate clearance when compared to the conventional method. However, the average magnitude of difference was only 9% and does not constitute a clinically significant margin between the two methods.

Sodium loading treatment for amphotericin B-induced nephrotoxicity.

The increased frequency and duration of antifungal treatment with amphotericin B in immunocompromised patients has stimulated a great deal of research into the mechanisms of its nephrotoxic effects and treatment modalities designed to attenuate these effects. A review of amphotericin B-induced nephrotoxicity, the underlying pathophysiologic mechanisms, and the role of salt loading as a means of minimizing renal impairment are described. Both animal and human studies regarding the efficacy of sodium loading are presented as well as a case report describing the use of salt supplementation over a prolonged course of therapy.

Procainamide-induced myasthenic crisis.

We describe a case of procainamide-induced respiratory failure in a myasthenic patient with no prior history of respiratory weakness. Respiratory failure was induced secondary to procainamide alone since no N-acetyl-procainamide level was detectable. The patient's strength rapidly improved and he was successfully extubated 12 h after the offending dose.

Sucralfate significantly reduces ciprofloxacin concentrations in serum.

The effect of sucralfate on the bioavailability of ciprofloxacin was evaluated in eight healthy subjects utilizing a randomized, crossover design. The area under the concentration-time curve from 0 to 12 h was reduced from 8.8 to 1.1 micrograms.h/ml by sucralfate (P less than 0.005). Similarly, the maximum concentration of ciprofloxacin in serum was reduced from 2.0 to 0.2 micrograms/ml (P less than 0.005). We conclude that concurrent ingestion of sucralfate significantly reduces the concentrations in serum produced by a 500-mg dose of ciprofloxacin. On the basis of these findings, ciprofloxacin and sucralfate should not be administered concurrently.

Marked digoxin-like immunoreactive factor interference with an enzyme immunoassay.

A case in which digoxin-like immunoreactive factors (DLIF) interfered with an enzyme immunoassay in a patient with renal insufficiency is reported. A 79-year-old woman was found to have a serum digoxin concentration (SDC) determined by enzyme immunoassay of 5.0 ng/ml. Although all subsequent SDC determined by the enzyme immunoassay system were elevated, identical samples run on a fluorescence polarization immunoassay revealed SDC within the therapeutic range. Marked DLIF-related assay interference has been reported to occur with some digoxin assays; however, the enzyme immunoassay methods have never been reported to cross-react to the magnitude seen in this case.

Continuous arteriovenous hemofiltration: an alternative to hemodialysis.

An introduction to the procedure of continuous arteriovenous hemofiltration (CAVH) for management of acute renal failure, as well as a review of hemodialysis, is presented. Initially developed for the management of hemodynamically unstable patients with acute renal failure, CAVH now is also used for management of fluid overload and acid-base disturbances resulting from conditions such as acute pulmonary edema, congestive heart failure, septic shock, and oliguric states in which pharmacologic or parenteral nutrition therapy necessitates administration of large volumes of fluids. CAVH, in contrast to hemodialysis, does not typically involve use of blood pumps but uses the patient's own mean arterial pressure to generate a driving force across the hemofilter membrane. CAVH, like hemodialysis, can remove excess fluid and uremic toxins; however, fluid removal by CAVH is characterized by the slow, continuous process of ultrafiltration and thus avoids the risk of hypotension, muscle cramps, or disequilibrium syndrome. Furthermore, CAVH does not require fluid restriction, allowing for increased administration of parenteral nutrition and intravenous medications; neither does it require expensive equipment or highly trained personnel. Although CAVH membrane materials may differ, they all permit the removal of plasma water and non-protein-bound solutes with molecular weights less than 10,000. To prevent blood from clotting in the hemofilter, most patients will require administration of heparin, which in some patients may increase the possibility of hemorrhaging. CAVH also can remove pharmacologic agents from the blood; however, only the non-protein-bound fraction of the drug has the potential to be cleared from the bloodstream by CAVH.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of a Bayesian program with three microcomputer programs for predicting gentamicin concentrations.

A recently developed Bayesian regression program was compared with three other aminoglycoside pharmacokinetic dosing programs available for clinical use. From 30 adult patients, 152 measured serum gentamicin concentrations (SGC) were evaluated retrospectively (78 peak and 74 trough). Predictive performance was compared for each method by using the first peak and trough SGC pair to predict subsequent serum concentrations, making a total of 92 predictions (48 peak and 44 trough). The two Bayesian programs (Brater and Koup) were further evaluated using only one initial peak or trough SGC to make the same predictions. Mean predicted error (ME), mean absolute error (MAE), and root mean squared error (RMSE) were calculated for each method. Prediction bias and precision were compared statistically, between each method, by calculating the 95% confidence intervals for the delta ME and delta MAE, respectively. No statistically significant differences were found in the MAEs among any of the methods for predicting peak SGCs, with the exception of the Brater program, using a single trough SGC, which was statistically less precise (less than 0.05). There were few statistically significant differences in the MAEs for trough SGCs; however, Koup's Bayesian program using a single trough concentration yielded statistically more precise predictions than the other methods. The ME was found to differ significantly (p less than 0.05) among estimates for peak and trough SGCs provided by some of the predictive methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Accuracy of Bayesian, Sawchuk-Zaske, and nomogram dosing methods for vancomycin.

The predictive performance of a Bayesian method for vancomycin dosing was compared with that of two nomogram-based methods and the Sawchuk-Zaske method. Prospectively collected serum concentration data were evaluated retrospectively in patients who had at least two steady-state peak and trough serum vancomycin concentrations obtained during two different dosage regimens. The methods evaluated were a Bayesian program that uses a one-compartment weighted-sum-of-squares expression; the nomogram methods of Moellering and Matzke, which derive vancomycin clearance from urinary creatinine clearance; and the Sawchuk-Zaske method, which uses equations for one-compartment, first-order elimination. The ability of each method to predict the second set of serum concentrations when given the first set of concentrations was evaluated using mean prediction error (ME), mean absolute error (MAE), and root mean squared error (RMSE). To compare the predictions made by each of the four methods, the differences in mean error and the differences in the natural logarithm of mean absolute error and their 95% confidence intervals were compared. No significant difference in ME (bias) or MAE (precision) was found between the Moellering and Matzke methods. The Sawchuk-Zaske method was significantly more precise than the Matzke method in predicting peak serum concentrations and more precise than the Moellering or Matzke method in predicting trough concentrations. The Bayesian program was significantly more precise and less biased than the Moellering and Matzke methods and less biased than the Sawchuk-Zaske method in predicting both peak and trough concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of a Bayesian regression-analysis computer program using non-steady-state phenytoin concentrations.

The predictive performance of a Bayesian regression-analysis computer program that uses non-steady-state phenytoin data was evaluated. Forty patients receiving phenytoin or phenytoin sodium who had two or more non-steady-state serum concentrations were selected for study. Additional serum concentrations and dosing data were collected as they became available, but no effort was made to control the number or timing of serum concentration determinations. Patients were categorized into four groups for evaluation of the effect of potential bioavailability problems and length of dosing history (time over which serum concentration-time data were collected) on the ability to predict subsequent phenytoin concentrations. Population parameters for phenytoin maximum rate of elimination (Vmax), apparent Michaelis-Menten constant (Km), volume of distribution (V), and bioavailability (F) were obtained from the literature. Predictions based on serum phenytoin concentrations and dosing histories (information intervals) of 5 or 10 days were compared with predictions based on naive (population-based) estimates using prediction-error analysis. In each patient group, the use of either 5-day or 10-day information intervals resulted in a significant increase in precision and a significant reduction in bias compared with naive estimates. For the group of patients who initially had two or more serum concentrations within the first five days of monitoring, predictions showed a marked increase in bias and a decrease in precision as the time interval from the last measured concentration to the time of prediction increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral antimicrobial therapy for adults with osteomyelitis or septic arthritis.

We conducted a retrospective review of 21 adult patients with osteomyelitis and septic arthritis who were treated with high doses of oral antimicrobial agents, usually after an initial course of intravenous therapy. The mean duration of parenteral and oral therapy was 3.6 days and 43.0 days, respectively. Absorption of oral antibiotics was assessed by determining the trough serum bactericidal titers for the infecting organism; whenever feasible, the dosages were adjusted to achieve trough titers greater than or equal to 1:8. The follow-up period ranged from six to 66 months (mean, 42.4 months). Eighteen of 21 patients had no clinical signs of recurrence after initial therapy. One patient with an infected joint prosthesis developed recurrent infection, and two patients had recurrences accompanied by sequestra. The mean duration of hospitalization was 13.4 days, and the mean duration of outpatient treatment was 31.9 days.