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Biomedical subjects

A F Harralson

Publications and source records attributed to A F Harralson.

10 recordsLinked to original sources
PubMed1999

The effects of grapefruit juice on sertraline metabolism: an in vitro and in vivo study.

Grapefruit juice is an inhibitor of cytochrome P-450 3A4 (CYP3A4). This study was designed to assess the in vitro and in vivo effects of grapefruit juice on sertraline metabolism. The in vitro assay involved analysis of sertraline metabolism by CYP3A4 using CYP3A4-expressed human beta-lymphoblast microsomes. The in vivo study involved high-performance liquid chromatographic analysis of serum trough levels of sertraline and desmethylsertraline in 5 patients who had been taking their usual dose of sertraline for > or =6 weeks, followed by concurrent use of sertraline with grapefruit juice for 1 week. The in vitro assay demonstrated that grapefruit juice inhibited the formation of desmethylsertraline in a dose-dependent manner. In the in vivo study, mean serum sertraline levels were determined in 5 patients with a history of depression (4 males and 1 female). The mean age of the patients was 68.6 years, their mean weight was 69.6 kg, and their mean sertraline dosage was 55 mg/d. The results of the in vivo study appeared to be consistent with the in vitro findings, in that mean (+/- SD) serum sertraline trough levels increased significantly from 13.7+/-4.9 microg/L before to 20.2+/-4.4 microg/L (P = 0.047) after administration of grapefruit juice. Thus the in vitro study demonstrated that grapefruit juice can inhibit the metabolism of sertraline. A larger study is warranted to substantiate the clinical significance of the in vivo findings.

Administration, Oral↗
PubMed1996

Effect of ranitidine on theophylline metabolism in healthy Koreans living in China.

OBJECTIVE: To evaluate the effect of concurrent ranitidine therapy on theophylline metabolism in healthy Koreans. DESIGN: A 4-week, double-blind, randomized, placebo-controlled, crossover study. SETTING: The Clinical Research Unit, Department of Pharmaceutical Sciences, Yanbian Medical College, Yanji, China. SUBJECTS: Six young, healthy, nonsmoking Korean volunteers residing in China with no known factors that would alter theophylline metabolism. INTERVENTIONS: Subjects received extended-release oral theophylline at a constant dosage over 4 weeks to yield a serum concentration (Cp) between 5 and 10 micrograms/mL. Week 1 was the dosage titration phase. During week 2 subjects randomly received either ranitidine or a matching placebo. Week 3 was a washout phase, and during week 4 subjects were crossed over to receive either placebo or ranitidine. At the end of each treatment week, serum and urinary metabolite concentrations were measured. OUTCOME MEASURES: Theophylline serum concentrations and urinary concentrations of 1-methylxanthine, 1-methyluric acid, 3-methylxanthine, and 1,3-dimethyluric acid were measured. Estimates of clearance (Cl), volume of distribution (Vd), and half-life (t1/2) were determined. RESULTS: Concurrent administration of ranitidine with theophylline did not significantly alter theophylline Cp, Cl, Vd, or t1/2. Urinary concentrations of major theophylline metabolites also were not changed. CONCLUSIONS: Ranitidine does not significantly alter the metabolism of theophylline in healthy Koreans residing in China.

Adolescent↗
PubMed1994

Sources of prediction error when using a Bayesian method to evaluate nortriptyline serum concentrations.

A Bayesian method was used to evaluate nortriptyline (NTP) serum concentrations (Cps) and predict future Cps in two populations: five simulated groups (n = 20 each) with known clearance (CL) and volume of distribution (Vd), and an actual inpatient group (n = 20). The effects of weight, CL, Vd, and magnitude of Cps on absolute prediction error (APE) were evaluated. In simulated groups, Cps after two doses of NTP and for steady-state were calculated for normal, increased, and decreased Vd and CL. In the actual patient group, Cps were measured in the first few days after starting NTP administration and again during maintenance therapy. The first Cps were used in the Bayesian program to estimate CL and Vd to predict the second Cps. In the simulated group, PE and APE differed significantly between normal and decreased values of CL. A large Vd resulted in less of a change in PE or APE in these subjects, but when combined with low CL led to the largest errors. In the actual patient group, PE was -5.9 +/- 19.2 ng/mL and APE was 15.4 +/- 12.6 ng/mL. In these patients, only body weight was correlated with the percent APE (r = 0.607, P = 0.005). The Bayesian method performs well clinically, but increased Vd and decreased CL can lead to higher PE. Clinically, the only factor that predicted higher APE was obesity. This may reflect an effect on Vd, and in these patients, a high APE may occur.

Adult↗
PubMed1991

Early individualization of tricyclic antidepressant dosing using a Bayesian pharmacokinetic model.

Existing methods to prospectively dose tricyclic antidepressants (TCAs) require either specific test doses, precisely timed serum sampling, or both. We prospectively tested a new pharmacokinetic model that allows flexible dosing and sampling to determine maintenance requirements in patients receiving TCAs. Thirty-four patients entered the study. Drug concentrations were measured on the third day after starting TCA therapy. These values were analyzed using a Bayesian pharmacokinetic model to determine drug clearance and volume of distribution. This information was then used to predict the serum concentration resulting from a maintenance dose chosen by the psychiatrist. In phase I (n = 17), patients received imipramine without specific starting doses. Phase II (n = 17) was performed to provide a preliminary evaluation of the method in the usual clinical environment. In this phase, patients received either amitriptyline, imipramine, desipramine, doxepin (75 mg on day 1,100 mg on day 2), or nortriptyline (50 mg on day 1, 75 mg on day 2). Lower doses were allowed if clinically indicated. The predictability of future serum concentrations was then compared between the two phases. The mean prediction errors (model bias) in phases I and II were -15.5 +/- 27.3 and -12.3 +/- 21.8 ng/mL and were not different (p greater than 0.05). The absolute prediction errors (model precision) were 18.5 +/- 25.1 and 18.8 +/- 16.0 ng/mL and were not different (p greater than 0.05). Two slow metabolizers were identified (clearance less than 0.10 L/kg/h). This new method allows the determination of maintenance dose requirements early in therapy without standard test doses or specifically timed serum sampling.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Aminoglycoside inactivation by penicillins and cephalosporins and its impact on drug-level monitoring.

The degree of in vitro inactivation of gentamicin, tobramycin, and amikacin by various penicillins and cephalosporins was investigated. Serum samples were prepared that contained one aminoglycoside and one penicillin or cephalosporin. Each aminoglycoside was combined with each of the following: penicillin, ampicillin, nafcillin, carbenicillin, ticarcillin, cephapirin, cefazolin, cefoxitin, and cefamandole. Each sample contained a final concentration of 10 micrograms/ml of gentamicin or tobramycin, or 35 micrograms/ml of amikacin, with 400 micrograms/ml of the beta-lactam antibiotic. Control samples containing only the aminoglycoside were used for comparison. Half of each mixture was frozen at -20 degrees C and the remainder was left at room temperature for 24 hours. The samples were assayed for aminoglycoside content by a radioimmunoassay and each combination was compared with its control value. Based on the results, the beta-lactams can be divided into three groups: (1) cefazolin and cefamandole, which cause little inactivation; (2) nafcillin, cephapirin, and cefoxitin, which cause moderate inactivation; and (3) penicillin, ampicillin, carbenicillin, and ticarcillin, which cause marked inactivation. In general, tobramycin was the most reactive of the three aminoglycosides studied and amikacin the most stable. The frozen samples were much less affected than those left at room temperature. Freezing samples, if there will be a delay in assaying, and choosing aminoglycoside sampling times when the beta-lactam concentration is at a trough are recommended to minimize spurious aminoglycoside level determinations due to in vitro inactivation.

Amikacin↗
PubMed1983

I. Unbound serum gold: procedure for quantitation.

The unbound fraction of many drugs appears to be the therapeutically active component. However, the major problem encountered in following unbound serum gold (UBSG) concentration during chrysotherapy has been the ability to quantitate such a small quantity of gold reliably without matrix interference. The methodology detailed here overcomes these difficulties and provides an effective means of monitoring the UBSG fraction during chrysotherapy. We have observed that the unbound fraction of gold dissipates quickly after gold sodium thiomalate administration and constitutes less than 2% of the total serum gold concentration.

Arthritis, Rheumatoid↗
PubMed1983

II. Unbound versus total serum gold concentration: pharmacological actions on cellular function.

Unbound serum gold (UBSG) has received little attention, possibly because of rapid in vivo decay and in vivo concentration below the range of existing analytical procedures. We have recently developed a methodology enabling quantitation and study of UBSG during chrysotherapy to assess effects on cellular functions. UBSG after gold administration is labile, declining rapidly after attaining peak values at which lymphocyte mitogen response and polymorphonuclear phagocytosis were observed to be suppressed. Oral gold, i.e., auranofin, 3 mg BID as compared to systemic chrysotherapy 50 mg/wk, resulted in a higher percentage of UBSG to total serum gold.

Anti-Inflammatory Agents↗
PubMedDate not supplied

Direct determination of tobramycin clearance in patients with mild-to-moderate cystic fibrosis.

Studies performed in patients with cystic fibrosis (CF) have suggested altered pharmacokinetic parameters for aminoglycosides. Specifically, increased plasma clearance (Cl) of aminoglycosides and increased apparent volume of distribution have been noted. In the present study, tobramycin Cl is determined by both serum concentration data and direct renal clearance (Clren). Tobramycin Clren appeared to be directly correlated to the measured creatinine clearance (Clcr) (r = 0.93, p less than 0.01). The tobramycin Cl, by both methods of determination, was not elevated in comparison to the Clcr or expected values for patients without the disease. These results appear to corroborate a recent study in which the renal and plasma Cl of gentamicin was measured in patients with mild-to-moderate CF and were not noted to be elevated. It is suggested that standard doses of tobramycin be used initially in patients with mild-to-moderate CF with dosage adjustment based on serum concentration data to achieve the desired goals.

Adolescent↗