Comparing a mass-balance algorithm with a Bayesian regression analysis computer program for predicting serum phenytoin concentrations.

The ability of a mass-balance algorithm to predict non-steady-state phenytoin concentrations in neurosurgery patients was compared with that of Phenda, a computerized Bayesian regression analysis program. Fifty neurosurgery patients who had had two or more initial phenytoin serum concentrations measured at least 60 hours apart and at least 1 hour after any i.v. doses, with the second concentration being not more than twice and not less than half of the first, and who had had a third or final phenytoin measurement (for use in a prediction analysis) were evaluated. The patients' maximum rates of metabolism were calculated by using the two initial phenytoin concentrations and a mass-balance algorithm, and the third phenytoin concentration was predicted. The patients' demographics and phenytoin dosages and concentrations were entered into Phenda, which was used to predict the third phenytoin concentration. The ability of the two methods to predict the third concentration was evaluated by the method of Sheiner and Beal. Fifty observations from 48 patients were evaluated. The mass-balance algorithm had a positive prediction bias of 2.52 mg/L and a precision error of 5.08 mg/L, compared with 2.30 and 5.30, respectively, for Phenda. The difference in the results between the two methods was not significant. There was no significant difference between the mass-balance algorithm and Phenda in the ability to predict phenytoin concentrations.

Clinical pharmacokinetic pearls: bolus versus infusion equations.

Using a nonprogrammed calculator to solve lengthy pharmacokinetic equations is time consuming and carries the potential for entry error. Shorter equations reduce both the time and the risk. The aminoglycosides and vancomycin are usually administered as short infusions. The pharmaco-kinetic equation describing multiple-dose administration of short infusions is much longer than the corresponding equation for bolus dosing. This study examined the percentage errors that would occur using the bolus equation instead of the infusion equation at various drug half-lives. When the half-life is 5 or more times the duration of infusion, the error in predicting concentration is 6.8% or less. Although clinicians should make their own decisions on how much error is acceptable and whether introducing guaranteed error is appropriate to save time and reduce risk of potential error, it appears that the simpler bolus equation may be used safely when the half-life is at least 5 times the duration of the infusion.

Effect of clenbuterol on athletic performance.

Unlike inhaled beta 2-agonists, more studies need to be performed before the action of systemic beta 2-agonists on athletic performance can be assessed accurately. Experiments in animals with oral clenbuterol have shown augmentation in muscle bulk across numerous species, but human studies cannot confirm similar muscle mass enlargement in healthy men. Although the human studies demonstrate the potential for long-acting systemic beta 2-agonists to increase muscle strength in certain muscle fiber types, it is difficult to judge the drugs' effects on overall athletic performance, because athletic skill is more than strength, speed, and endurance. The effect of oral clenbuterol on athletic performance cannot be evaluated from its actions on muscle strength alone. However, as evidence stands now, sports regulatory agencies are correct to ban systemic beta 2-agonists until the following 2 points can be proven: (1) oral forms provide a therapeutic benefit that cannot be obtained with aerosol or inhaled forms; and (2) oral forms do not give any unfair advantage to the competitor in muscle strength, power output, or endurance. Provided they are administered as prescribed, aerosol or inhaled beta-agonists do not impart an unfair advantage or enhance athletic performance and can continue to be used in competition by athletes with EIA.

Iodine toxicity secondary to continuous povidone-iodine mediastinal irrigation in dogs.

Mediastinitis is a devastating complication following median sternotomy. Continuous povidone-iodine (PVP-I) irrigation has been advocated as therapy because of its broad antimicrobial spectrum and its apparent safety. However, several recent clinical reports have warned of suspected local and systemic iodine toxicity. The purpose of this study is to determine if significant amounts of iodine can be absorbed systemically via the mediastinum, and if so, what toxicity (local and/or systemic) may result. PVP-I (0.5%) was continuously irrigated into the pericardial sacs of three dogs via catheters for 48 hr. Serial serum and urine iodine levels were determined. The serum steady-state concentration (Css), the rate elimination constant (k), the urinary clearance (Cl), and the serum half-life (t 1/2) for iodine were assessed. Serum electrolytes, Bun, Cr, and arterial pH were measured to assess systemic iodine toxicity. Tissue samples of the heart, pericardium, liver, and kidney were examined histologically for evidence of local or end-organ iodine toxicity. This study demonstrated that the absorption of iodine during continuous mediastinal irrigation with PVP-I follows zero-order pharmacokinetics, just as if it were being given by continuous intravenous infusion. The baseline serum iodine concentration was 145.9 +/- 64.3 micrograms/dl, Css was 29,290 +/- 101.4 micrograms/dl, k was 0.0996 +/- 0.009/hr, Cl was 872.4 +/- 119.3 ml/hr, and t1/2 was 6.22 hr. Urinary excretion of iodine increased in proportion to the serum iodine. Measured serum chloride increased in a linear manner (r = 0.949), while serum Na, K, Bun, Cr, and pH were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Time for phenytoin concentration to peak: consequences of first-order and zero-order absorption.

An increase in the time required to achieve the peak plasma concentration is observed following the oral administration of increasing doses of phenytoin. Zero-order absorption is the usual explanation for this observation. The presence of Michaelis-Menten elimination also increases the peak time when absorption is first order. The contribution of each of these mechanisms in vivo is unknown.

Impact of decentralized pharmacokinetics consultation service.

The effects of pharmacokinetics consultation by a pharmacist on the quality of drug therapy were studied in a 500-bed teaching hospital. Data were collected retrospectively for three time periods: three months before, four months during, and three months after a period of intervention by a pharmacist with special responsibilities for pharmacokinetic monitoring of patients on a medical team. For the four-month intervention period, data were also collected for a parallel group of patients managed by another medical team that included pharmacy residents and students. Patients were included in the study if they had received either an aminoglycoside or a theophylline preparation. The preintervention, postintervention, and parallel groups were random samples of patients on the study ward, and the intervention group included all patients admitted to the pharmacist intervener's medical team who had received a drug covered by the study. Of serum drug concentration determinations (SDCDs) in the pharmacist intervention phase, 54% were appropriate, compared with 16% before intervention, 21% in the postintervention phase, and 46% in the patients of the other medical team. In the pharmacist intervention group, greater numbers of SDCDs were obtained appropriately and used appropriately in making therapeutic decisions, as evidenced by more subsequent measurements in the therapeutic range. Pharmacist intervention did not affect the number of adverse drug reactions or medical specialty consultations or the average length of stay. Decentralized pharmacokinetics services can have a positive effect on the quality of serum drug concentration determinations, dosage adjustments, and drug therapy.

A quantitative test for xerostomia. The Saxon test, an oral equivalent of the Schirmer test.

We describe a simple, reproducible, and low-cost test for xerostomia, which involves chewing on a folded sterile sponge for 2 minutes. Saliva production is quantitated by weighing the sponge before and after chewing. Normal control subjects produced greater than or equal to 2.75 gm of saliva in 2 minutes. Three of 32 consecutive, unselected outpatients in allergy-immunology clinics and 9 of 38 patients in rheumatology clinics had decreased saliva production, which was significantly different compared with controls (P less than 0.01). The presence of sicca symptoms was highly correlated with quantitatively abnormal tear and saliva production, according to the results of the Saxon and Schirmer's tests.

Appropriateness of sampling times for therapeutic drug monitoring.

Serum sampling for drug concentration was evaluated for usefulness in pharmacokinetic calculations and dosage adjustment. The prospective study included serum samples for 11 drugs in hospital inpatients during a four-week period. Appropriateness of sampling regarding (1) time of drug administration and (2) steady state was determined. Both of these evaluations were used in the final rankings of appropriateness of the samples with regard to ease of interpretation and clinical usefulness. Digoxin, theophylline, tobramycin, and phenytoin accounted for 81% of the 466 samples evaluated. Sampling time was recorded for 56% of all samples. Based on time of dose administration, 54% of samples were obtained at the recommended time; 38% of samples were obtained at steady state. Basic pharmacokinetic methods could be used to interpret 15% of samples, while 44% required complex pharmacokinetic methods, 34% required assumptions about sampling time versus dosing history, and 7% should not have been used in dosage adjustment. The majority of plasma drug samples required more than basic pharmacokinetic methods for evaluation. For assessment of therapeutic drug regimens by monitoring serum drug concentrations, sophisticated pharmacokinetic consultation services are needed.

Renal function and therapeutic concentrations of phenytoin.

The plasma protein binding of phenytoin was studied in 40 adult patients with varying degrees of renal function impairment. The patients had stable renal function and no other condition known to alter phenytoin binding. Binding was measured by equilibrium dialysis, and the apparent affinity constant was calculated using the binding data and the measured serum albumin concentration. The apparent affinity of the drug decreased with a decrease in renal function. The decrease was most apparent in patients with creatinine clearances below 25 ml/min. The importance of altered binding on the therapeutic range is discussed, and a method of calculating equivalent therapeutic phenytoin concentrations from serum albumin and renal function is described.

Spironolactone-associated digoxin radioimmunoassay interference.

Apparent digoxin was measured in the serum of 21 patients receiving spironolactone and in 21 controls, by use of a sequential-saturation 3H-radioimmunoassay (RIA) and an equilibrium 125I-RIA. No patient had been given digoxin for at least four weeks. "Digoxin" values in the former group were significantly (p less than 0.05) higher than in the control group, and often were in or near the "therapeutic" range by the equilibrium 125I-RIA, but not by the sequential-saturation 3H-RIA. Canrenone (a major active metabolite of spironolactone) in the serum of the former group was measured by a newly developed liquid-chromatographic technique and correlated (r = 0.73) with "digoxin" concentrations by the 125I-RIA. However, external addition of canrenone to control serum in comparable concentrations did not cause appreciable "digoxin" values by the 125I-RIA. These findings suggest that other metabolites of spironolactone are responsible for the assay interference, the degree of which appears to depend on antibody specificity. Therefore, assay specificity should be established in clinical laboratories by using digoxin-free serum from patients ingesting spironolactone, and not by using spironolactone- or canrenone-fortified digoxin-free serum.

Measurement of procainamide and N-acetylprocainamide in serum by high-performance liquid chromatography.

We measured procainamide (I) and its metabolite, N-acetylprocainamide (II), in human serum samples by solvent extraction, high-performance liquid chromatography on a reverse phase column, and detection at 280 nm, with use of external standards. The method requires 0.2 ml of serum and is sensitive to 0.3 mg of I and 0.6 mg of II per liter of serum, with intra-assay standard deviations of 0.22 and 0.24 mg/liter, respectively, at 5 mg/liter (N=10) and inter-assay standard deviations of 0.63 and 0.81 mg/liter, respectively, at 7.5 mg/liter (CV 8.4 and 10.5%, respectively, n = 20). Concentrations measured by high-performance liquid chromatography and by an established fluorescence technique correlated well (r = 0.98 for I and 0.97 for II). No interfering substances were found in 20 randomly selected sera from patients receiving a large number of other drugs. Of the pure drug substances tested only sulfathiazole interfered with the assay of II. The method is therefore suitable for routinely monitoring these compounds in serum in a clinical laboratory. The high concentrations of the metabolite in a significant number of patients demonstrate the need to consider it as well as the parent drug as guides in optimizing dosage regiments for I.