Elaine S. Waller

Pharmacokinetic Principles of Lidocaine Dosing in Relation to Disease State

Abstract: The pharmacokinetic parameters of lidocaine are pertinent to the determination of both appropriate loading doses and constant infusion rates that achieve a therapeutic plasma concentration while avoiding toxicity. Because lidocaine is used primarily in older patients who may have concurrent diseases, the effects of disease states on lidocaine disposition are important when calculating lidocaine doses. Patients with congestive heart failure and hepatic disease have pronounced changes in lidocaine clearance. Patients placed on prolonged lidocaine infusions have a change in disposition half‐life of the drug. Patients with renal disease do not have significant alterations in handling the parent compound but, because of the dependence of glycinexylidide elimination on renal function, may accumulate the metabolite and develop central nervous system toxicity. Even though there are differences in some of the pharmacokinetic variables for lidocaine in young and elderly patients, the clearance of the drug was not significantly different in the two patient groups. The effects of concurrently administered drugs on lidocaine pharmacokinetics remain to be more widely studied in patients.

The Effect of Probenecid on Nafcillin Disposition

Abstract: Five normal male volunteers participated in an open crossover study designed to examine the disposition of nafcillin given intravenously with and without probenecid. Each subject received two 500 mg iv doses of sodium nafcillin seven days apart, one dose without probenecid and another dose during oral probenecid administration of 1.0 Gm at bedtime prior to the study day and 1.0 Gm two hours before the nafcillin dose. Blood and urine samples were collected for 10 hours after nafcillin dosing. Assay for nafcillin concentrations was performed via the cup‐plate technique with M. Iuteus. Administration of probenecid significantly increased and prolonged circulating plasma concentrations of nafcillin. Probenecid administration significantly, decreased the per cent of nafcillin recovered in the urine (30% vs. 16.9%). Probenecid pretreatment increased the ana under the plasma drug concentration‐time curve (AUC) two‐fold and decreased the total body clearance significantly with decreases in both renal and non‐renal clearance. K12/k21 and Vc did not significantly change with probenecid. Because probenecid coadministration did not appear to change nafcillin distribution while increasing and prolonging plasma concentrations, probenecid can be recommended to be given concurrently when high nafcillin plasma concentrations are desirable. Changes in plasma concentrations are apparently due to alterations in both renal and non‐renal clearances of nafcillin.

Evaluation of New Indomethacin Dosage Forms

Indomethacin, an indole derivative nonsteroidal anti‐inflammatory drug, has been available since the early 1960s in gelatin capsules. In 1982, a sustained release product, Indocin® SR, was marketed. Awaiting marketing approval is a unique controlled release form of indomethacin, Indos.® The disposition of indomethacin includes enterohepatic cycling and extensive metabolism to inactive metabolites. Enterohepatic cycling makes interpretation of bioavailability estimates of indomethacin dosage forms difficult. The relationship of indomethacin plasma concentrations to therapeutic effects and side effects is inconclusive. It appears in vivo prostaglandin inhibition occurs at very low plasma concentrations that are achievable with all available dosage forms.

Tolmetin in Breast Milk

age tolmetin concentration of 0.075 /Lg/ml theoretically could ingest 18 /Lg of tolmetin. Based on the peak maternal plasma concentration in our patient of 20.99 /Lg/ml and a M:P ratio of 0.0055, an infant who consumed 240 ml of breast milk could ingest 27.7 /Lg of to1metin. Using either of the previous methods, it is determined that an infant would ingest a relatively small amount of the drug in one feedEq. 2 Eq. I AUC~~~ M:P = Aucg~s.;na

Influence of Food on the Bioavailability of Trental® (Pentoxifylline) in Man

AbstractPentoxifylline is an investigational drug shown to improve impaired blood flow in diseased microvasculature. The present study objective was to determine the influence of a single test meal on the bioavailability of pentoxifylline. Single 400 mg oral capsule doses of pentoxifylline were administered to 16 healthy adult male volunteers in a complete crossover design in which the subjects received the drug after fasting overnight or 15 minutes following a standard breakfast. The plasma concentrations of pentoxifylline and its major metabolite were determined as a function of time using a gas chromatographic procedure. The AUC values for both parent drug and metabolite for 0 to 10 hours showed no significant difference due to ingestion of food. A significant decrease in peak plasma concentration (p < .05) was shown for parent drug and metabolite when administered with food. The time-to-peak concentration was significantly delayed (p < .001) when the drug was administered with food. Food administered ...

Central Nervous System Toxicity Associated with Concurrent Use of Triazolam and Cimetidine

A 49-year-old woman treated with cimetidine 300 mg tid for more than 18 months for Zollinger-Ellison syndrome experienced lethargy, dizziness, ataxia, and auditory and visual hallucinations after receiving triazolam 0.375 mg hs for sleep. Triazolam plasma concentrations were measured, and a triazolam elimination half-life was calculated to be approximately 8 hours (reported range 1.7–3 h). Cimetidine has been reported to decrease the apparent oral clearance of triazolam, resulting in increased triazolam plasma concentrations with the potential for exaggerated triazolam pharmacologic effects. Cimetidine may have been responsible for the unusually large elimination half-life in this patient. Until the mechanisms and clinical significance of this potential drug interaction are determined, clinicians should use the combination of triazolam and cimetidine with caution.

Dapsone-Induced Hemolytic Anemia in a Patient with Relapsing Polychondritis:

A 53-year-old woman presented with bilateral auricular chondritis which was responsive to high doses of prednisone. After a diagnosis of relapsing polychondritis was confirmed, she was treated with dapsone. Her disease responded well to dapsone 200 mg daily. While on this regimen, she developed a dapsone-induced hemolytic anemia which was successfully managed by a reduction in dosage. The use of dapsone for relapsing polychondritis and dapsone-induced hemolytic anemia are reviewed.