Comparison of 3 vancomycin dosage regimens during hemodialysis with cellulose triacetate dialyzers: post-dialysis versus intradialytic administration.

AIMS: Traditionally, vancomycin is administered following dialysis to minimize drug loss when high-flux membranes are employed. Unfortunately, this approach is extremely inconvenient for patients and staff, requiring the patients to remain in the unit for at least 1 hour following dialysis. This study was designed to evaluate the feasibility of administering vancomycin during hemodialysis. Specifically, this study was designed to compare the pharmacokinetics of vancomycin when administered during the last 1-2 hours of dialysis (i.e. intra-dialytic administration) to that administered after completion of dialysis. MATERIALS AND METHODS: In a randomized, 3-way crossover trial, the pharmacokinetics of vancomycin were evaluated in 9 hemodialysis patients, comparing vancomycin 15 mg/kg following dialysis (Phase I), vancomycin 15 mg/kg during the last hour of hemodialysis (Phase II) or vancomycin 30 mg/kg during the last 2 hours of hemodialysis (Phase III). Vancomycin plasma concentrations were obtained over an 8-day period and subsequent comparisons between the treatment approaches were made with paired t-tests or ANOVA, as appropriate. Dialysate vancomycin concentrations determined on Day 1 and Day 3 of Phases II and III were used to calculate the fraction of vancomycin dose removed, and were compared to plasma data using paired t-tests. RESULTS: Vancomycin was significantly removed (33.4 to 39.5%) during a 3- to 4-hour high-flux dialysis session occurring on Day 3 after vancomycin administration. Mean serum concentrations immediately following intradialytic vancomycin administration of 15 mg/kg over the last hour of dialysis or 30 mg/kg over the last 2 hours of dialysis were initially high (77.7 and 95.5 mcg/ml respectively), but fell to 25.9 and 40.5 mcg/ml, respectively, by 4 hours post-dialysis. Predialysis concentrations on Days 3, 5 and 8 were similar for vancomycin 30 mg/kg administered over the last 2 hours of dialysis as compared with a 15 mg/kg dose given after dialysis. Vancomycin 15 mg/kg over the last hour of dialysis resulted in significantly lower subsequent predialysis concentrations than the other dosing schemes. CONCLUSIONS: Vancomycin administration of 30 mg/kg over the last 2 hours of dialysis achieves serum concentrations similar to conventional dosing of 15 mg/kg after dialysis and would allow dosing on a weekly basis.

Protease inhibitor drug levels in the management of human immunodeficiency virus-1 antiretroviral therapy.

In order to evaluate the relationship between protease inhibitor (PI) plasma concentrations and viral suppression in individuals receiving highly active antiretroviral therapy (HAART), plasma concentrations and area under the time concentration curve (AUC(0.5-4)) for 35 HIV-infected adults receiving their initial (or first salvage) nelfinavir- (NFV) or indinavir (IDV)-based HAART were studied. Two groups were evaluated: those who had achieved HIV-RNA suppression (HIV-RNA <500 copies/mL, group 1, n=21) and those who had achieved incomplete HIV-RNA suppression (HIV-RNA>500 copies/mL, group 2, n=14) at the time of study entry. NFV one-hour pre-dose concentrations were significantly higher in group 1 compared to group 2 (P=0.023). The NFV AUC(0.5-4) for group 1 approached significance (P=0.068). No significant differences in IDV concentrations or AUC(0.5-4) were found between group 1 and group 2. It is feasible to use PI drug level monitoring in the outpatient setting.

Novel method to assess gastric emptying in humans: the Pellet Gastric Emptying Test.

To further validate the Pellet Gastric Emptying Test (PGET) as a marker of gastric emptying, a randomized, four-way crossover study was conducted with 12 healthy subjects. The study consisted of oral co-administration of enteric coated caffeine (CAFF) and acetaminophen (APAP) pellets in four treatment phases: Same Size (100 kcal), Fasted, Small Liquid Meal (100 kcal), and Standard Meal (847 kcal). The time of first appearance of measurable drug marker in plasma, t(initial), was taken as the emptying time for the markers. Co-administration of same size enteric coated pellets of CAFF and APAP (0.7 mm in diameter) revealed no statistically significant differences in t(initial) values indicating that emptying was dependent only on size and not on chemical make-up of the pellets. Co-administration of different size pellets indicated that the smaller 0.7-mm diameter (CAFF) pellets were emptied and absorbed significantly earlier than the larger 3.6-mm diameter (APAP) pellets with both the Small Liquid Meal (by 35 min) and the Standard Meal (by 33 min) (P<0.05). The differences in emptying of the pellets were not significant in the Fasted Phase. The results suggest that the pellet gastric emptying test could prove useful in monitoring changes in transit times in the fasted and fed states and their impact on drug absorption.

Determination of fluoxetine and norfluoxetine concentrations in cadaveric allograft skin.

Fluoxetine hydrochloride is the sixth most prescribed drug in the United States and is administered to treat major depression. A cadaveric skin donation was obtained from a 46-year-old woman who died as a result of a fluoxetine overdose. Due to the potential penetration of the drug and its major metabolite, norfluoxetine, into skin, the safety of using the skin as an allograft was questioned. Our evaluation showed that mean concentrations in skin were 2304+/-175 and 1353+/-102 ng/g of skin, respectively. The skin:plasma ratio was 0.41. Clinically, the amount of fluoxetine that can be transferred to an allograft recipient depends on many factors. Based on penetration of drug and metabolite into skin, one would have to evaluate carefully the risk:benefit ratio of using allografts from a donor who died from a fluoxetine overdose.

Indomethacin in the management of elevated intracranial pressure: a review.

Elevated intracranial pressure occurs frequently in patients with severe head injury. A number of studies in recent years suggest that indomethacin may be useful in the management of elevated intracranial pressure. Indomethacin acts primarily by reducing cerebral blood flow and decreasing cerebral edema following head injury. This review summarizes the basic and clinical studies of the effects of indomethacin on cerebral blood flow, brain edema, and intracranial pressure. The pharmacology of indomethacin, and issues for future investigation in the use of indomethacin in severe head injury, are discussed.

Intra-arterial urokinase versus surgery for acute peripheral arterial occlusion.

The outcomes of intra-arterial urokinase versus surgery for acute peripheral arterial occlusion (PAO) were compared. Patients at a university hospital who had received intraarterial urokinase for PAO were identified by computer and pair-matched on the basis of comorbidities, age, sex, and site of occlusion to computer-selected patients who had undergone surgery. Only patients with category I or II ischemia were considered. The study period for the urokinase group was February 1995 through January 1996, and the period for the surgery group was June 1993 through January 1996. Twenty-eight patients in each group met the selection criteria. Patients who had received urokinase had a significantly shorter median length of stay (8.5 days) than patients in the surgery group (13 days) and significantly fewer infectious complications (2 versus 10). No differences in amputation rates, total hospital costs, or mortality rates were detected. Patients who received intra-arterial urokinase for PAO had a shorter length of stay in the hospital and fewer infectious complications than those who underwent surgery.