Mary H. H. Chandler

Premenstrual Asthma: The Effect of Estrogen on Symptoms, Pulmonary Function, and β2‐Receptors

Study Objectives. To characterize asthma symptoms, pulmonary function, and responsiveness to β2‐agonist stimulation, and in vitro β2‐receptor density and cyclic adenosine 3′,5′‐monophosphate (cAMP) response throughout the menstrual cycle in women with premenstrual asthma (PMA); and to examine the effect of exogenous estradiol administration on asthma symptoms, pulmonary function and responsiveness, and β2‐receptor density and function in these women.

Pharmacokinetic Optimisation of Vancomycin Therapy

SummaryRenewed interest in vancomycin over the past decade has led to an abundance of data concerning the pharmacokinetics of vancomycin, and its dosage selection and concentration-response relationships.No definitive data exist that correlate vancomycin serum concentrations with clinical outcomes. However, inconsistencies in sampling times for peak serum concentrations and differences in infusion times make interpreting vancomycin serum concentrations difficult. Furthermore, the evidence implicating vancomycin as a cause of oto- or nephrotoxicity is circumstantial, and these adverse effects may occur only in high-risk populations.Owing to the variability in its dose-serum concentration relationship and multicompartmental pharmacokinetics, several methodologies have been developed for instituting and adjusting vancomycin dosages. Nomograms rely on a fixed volume of distribution and the relationship between vancomycin clearance and creatinine clearance. Since both of these factors may be altered in certain populations, dosage methodologies (both traditional and Bayesian) that use population- or patient-specific pharmacokinetic data perform better than standard nomograms for initiating vancomycin therapy. Controversy still exists as to whether a 1- or a 2-compartment model is more appropriate for making dosage adjustments; however, steady-state rather than non-steady-state vancomycin serum concentrations should be used for dosage adjustments. Certain pathophysiological states such as age, bodyweight and renal function contribute to altered pharmacokinetics and may alter the design of the dosage regimen.Since no definitive relationship exists between vancomycin serum concentrations and either clinical outcome or adverse effects, considerable controversy surrounds the utility of monitoring serum vancomycin concentrations. Therefore, routine vancomycin serum concentration monitoring may be warranted only in specific populations, such as patients receiving concurrent aminoglycoside therapy or those receiving higher than usual dosages of vancomycin, patients undergoing haemodialysis and patients with rapidly changing renal function.

Age‐associated stereoselective alterations in hexobarbital metabolism

This clinical investigation was designed to study the influence of age on stereoselective drug disposition using hexobarbital as a model marker. The disposition of hexobarbital enantiomers was investigated in 10 young and 10 elderly, healthy male volunteers. Mean oral clearance (±SD) of d‐hexobarbital (1.9 ± 0.5 vs. 1.7 ± 0.3 ml/min/kg; P > 0.05) did not differ significantly between the young and elderly subjects, respectively. However, despite wide intersubject variability, l‐hexobarbital mean oral clearance (± SD) was approximately twofold greater in the young than in the elderly subjects (16.9 ±11.9 vs. 8.2 ± 3.2 ml/min/kg; P < 0.05). This resulted in a significantly greater enantiomeric oral clearance ratio in the young when compared with the elderly subjects (8.3 ± 3.4 vs. 4.7 ± 1.4; P < 0.01). No significant difference (P > 0.05) in pharmacologic response after hexobarbital administration was found between the two groups. Demonstration of an age‐related preferential decline in metabolism of one enantiomer over another has not been reported previously for any racemic drug in animals or humans.

Pharmacokinetics of Anti-Infective Agents in Paediatric Patients

SummaryVarious differences in drug disposition exist between children and adults. For example, the volume of distribution (Vd) for many drugs is larger in children than in adults. Other parameters, including excretion and elimination may be altered in children compared with adults.The penicillins and cephalosporins are used commonly for the treatment of infection in paediatric patients. The increased Vd in children contributes to the increased elimination half-life of these agents. Clearance of the acylureido-penicillins is increased in children with cystic fibrosis, a disease that decreases the elimination half-life for these drugs. Aminoglycosides distribute into extracellular fluid and their pharmacokinetic profile is affected by changes in Vd. The Vd for aminoglycosides is slightly higher in children than in adults. Children with cystic fibrosis, bums, or cancer have higher clearance rates and larger Vd values for aminoglycosides.Few data in the literature address the pharmacokinetics of other anti-infective agents, including vancomycin, teicoplanin, erythromycin, metronidazole, chloramphenicol, and cotrimoxazole (trimethoprim-sulfamethoxazole), in children. Similarly, there is little information regarding the pharmacokinetic profile of antivirals and antifungals in children.Dosage guidelines are available to enable the clinician to initiate anti-infective therapy in children. Subsequent dosage requirements may change based on the patient’s current clinical condition.Although several studies have investigated the pharmacokinetics of anti-infectives in neonates and adults, data for children are limited. Therefore, further studies are required so that the ever growing arsenal of anti-infectives can be administered appropriately to children.

Computers in pharmacokinetics : choosing software for clinical decision making

SummaryOver the past 20 years, pharmacokinetic programs have been developed for clinical decision making. These clinical pharmacokinetic software programs are designed to assist the clinician in the analysis, interpretation and reporting of serum drug concentration data for a variety of medications. The programs vary in the extent of features and range of medications supported and thus warrant careful review before selecting or purchasing such a program for routine use. A series of programs which are commercially available in the United States was reviewed for this article. The focus of the review is not to recommend a single program or to provide a ranked list of commercially available programs. Information is presented to clinicians to better their understanding of the features of these computer-based clinical resources. As an introduction to this topic, the information presented concentrates on the system and support features.Those programs that were reviewed demonstrate the ability to assist in the analysis of serum or plasma drug concentration data for most of the medications that warrant therapeutic drug monitoring. They provide both Bayesian and non-Bayesian methods for predicting serum drug concentrations. Standard personal computers were sufficient to run each of the programs reviewed. In addition, most programs offered technical and clinical support. However, the quality of the user manuals and training material varies among software programs. In-depth analytical comparisons are currently being conducted for future publication.

Severe Phenytoin Intoxication as a Result of Altered Protein Binding in Aids

Alterations in plasma protein binding may alter patient response to pharmaceutical agents because only free drug is considered to be pharmacologically active. Such alterations appear to be more significant with highly bound agents such as phenytoin. Traditionally, most drug assays monitor total drug concentrations and do not quantitate free drug. When binding alterations are present, total drug concentrations may mislead clinicians in evaluating patient response. We describe a case in which profound hypoalbuminemia (0.2 g/dL), associated with focal segmental glomerulosclerosis, produced toxic free phenytoin concentrations (4.9 μg/mL) in an HIV-positive 25-year-old black woman. At such a high serum concentration of free phenytoin, the patient exhibited seizure-like effects. Renal abnormalities and hypoalbuminemia associated with acquired immunodeficiency syndrome (AIDS) may place patients at risk for elevated free fractions of phenytoin and subsequent toxicity.

Dirithromycin increases ethinyl estradiol clearance without allowing ovulation

Objective To use a novel, sensitive study design to detect a potential oral contraceptive (OC) and dirithromycin drug interaction by assessing the pharmacokinetics of the ethinyl estradiol (E2) component of a common OC and the potential failure of OC effectiveness. Methods In this nonblinded study, 20 healthy women using Ortho Novum 7/7/7-28 were selected for a three-OC-cycle study. Baseline measures included E2 and progesterone serum levels on days 21, 23, 25, and 27 of cycle one and days 1, 3, 5, and 7 of cycle two. During cycle two, 24-hour blood sampling and radioimmunoassay analysis for ethinyl E2 pharmacokinetics were performed on day 8 and pelvic ultrasound on day 13. Oral dirithromycin 500 mg/day for 14 days began on day 21 of cycle 2. After starting dirithromycin, cycle two and three serum E2, progesterone, and serial ethinyl E2 levels and pelvic ultrasound replicated the baseline schedule. Ovulation was assumed if E2 concentration was greater than 50 pg/mL, progesterone concentration was greater than 3 ng/mL, or if an ovarian cyst greater than 10 mm was present on ultrasound. Results Pharmacokinetic analysis demonstrated a small (7.6%) but statistically significant decrease (P = .03) in the mean ethinyl E2 24-hour area under the curve and an increase in apparent oral clearance. No woman ovulated, based on E2 levels and progesterone concentrations or ultra sound. Conclusion Dirithromycin increased the apparent oral clearance of ethinyl E2. The clinical importance of the interaction may be negligible because no woman ovulated or had compromised OC effectiveness in this small series.

Effects of long-term oral carvedilol on the steady-state pharmacokinetics of oral digoxin in patients with mild to moderate hypertension

The effect of multiple oral doses of carvedilol on steady‐state plasma digoxin pharmacokinetics was evaluated in 12 patients with mild to moderate hypertension. Area under the curve (AUC), mean maximum plasma concentration (Cmax), mean time to maximum concentration (Tmax), concentration at 24 hours after the dose (C24), creatinine clearance, renal digoxin clearance, and urinary digoxin excretion were determined after patients took oral digoxin 0.25 mg once/day for 2 weeks. Carvedilol was added to the regimen, and digoxin pharmacokinetics were assessed after 2 weeks of concurrent treatment. The AUC and Cmax for digoxin increased by 14% and 32%, respectively (p<0.05), with no change in Tmax. The 24‐hour urinary digoxin excretion and 24‐hour renal digoxin clearance increased by 45% and 26%, respectively (p<0.05), with no change in creatinine clearance. Carvedilol appears to increase digoxins oral bioavailability as well as renal elimination. The absolute change in digoxin pharmacokinetics was small and not clinically significant. The significance of the interaction in other patient populations remains to be studied.

Multiple dose pharmacokinetics of four different doses of nisoldipine in hypertensive patients.

This randomized double‐blind parallel group study characterized the pharmacokinetics of the calcium channel antagonist, nisoidipine (core‐coat tablets), administered once daily for 7 days in doses of 5 mg (n = 12), 10 mg (n = 13), 20 mg (n = 12), and 30 mg (n = 11) to patients with mild to moderate hypertension. Serial blood samples were obtained from 0 to 24 hours and from 0 to 48 hours after nisoidipine administration on days 1 and 7, respectively. Nisoldipine plasma concentrations were determined by gas chromatography with electron capture detection. No statistically significant difference was found in dose‐normalized area under the curve between the four groups. Area under the curve (standardized to body weight) correlated to dose (r = .74, P < .05). No significant difference existed in oral clearance (L/h/kg) when analyzed for equivalence across the four doses: 8.21 ± 3.47 (5 mg), 11.84 ± 13.85 (10 mg), 11.48 ± 7.49 (20 mg), and 10.36 ± 5.49 (30 mg). The present investigation characterizes the pharmacokinetics of nisoidipine core‐coat tablets in hypertensive patients and demonstrates the dose proportionality or linearity of nisoidipine plasma concentrations and area under the curve, measured over a dose range of 5 to 30 mg.

Home Monitoring of Theophylline Levels: A Novel Therapeutic Approach

This pilot clinical investigation was conducted to compare a home therapeutic drug‐monitoring (TDM) method for theophylline blood levels and a traditional TDM method with respect to various patient outcome factors. Outpatients with chronic obstructive pulmonary disease (COPD) or asthma who were receiving long‐term theophylline therapy were randomized to one of two groups: home TDM or traditional TDM (controls). Patients in the former group monitored their serum theophylline levels at home over 6 months. Patients in both groups completed survey instruments, including questionnaires, visual analog scales, and other psychosocial measures, at designated times throughout the study period. Pulmonary function tests and dyspnea index scores were evaluated at each clinic visit. Results indicated a significantly lower (p < 0.05) number of changes in concomitant drug therapy in the home TDM group compared with controls. Other indicators that showed a trend toward more favorable outcomes in the home TDM group included symptomology, percentage of levels within the therapeutic range, patient attitudes regarding participation in health care management, and pulmonary function test results. Home monitoring prevented unnecessary clinic visits in several instances when theophylline dosage adjustments were based on telephone reports from patients. The utility of a home TDM method for theophylline has not been reported previously despite potential for broad applications. Findings from this preliminary study may support the use and feasibility of state‐of‐the‐art methodologies in carefully selected subpopulations outside the confines of the hospital or clinic setting.