RESUMEN

BACKGROUND: Real-world studies of the emergency reversal of warfarin using 4-factor prothrombin complex concentrate (PCC) report unwarranted delays. The delay to receiving PCC was ≥ 8 h in 46·7% of patients with warfarin-associated bleeding (PWAB) treated with a variable PCC dosing protocol in our retrospective audit. OBJECTIVE: To report the impact of a simplified PCC dosing protocol on the interval to reversal of anticoagulation. METHODS: We developed a PCC dosing protocol standardising the initial PCC dose and simplifying dosing calculations. Study end points were the proportion of PWAB achieving international normalised ratio (INR) ≤1·5 and treated within 8 h of presentation, respectively. RESULTS: Of 17, 15 (88·2%) PWABs achieved a post-treatment INR ≤ 1·5; 14 of 17 (82·4%) PWABs were reversed within 8 h. Median intervals between triage and PCC request and PCC request and start of infusion (administration interval) were 126 min (range 39-520) and 30 min (range 5-100), respectively. Compared with the retrospective cohort, RAPID is associated with an improved administration interval (mean 37·7 vs 76 min, P = 0·031) and the proportion of PWABs treated within 30 min (58·8 vs 6·7%, P = 0·009). CONCLUSION: The RAPID protocol reduces unwarranted delays without compromising efficacy.

Asunto(s)

RESUMEN

The authors examined the effect of tamoxifen (TAM), a multiple-drug resistance modulator, on the pharmacokinetics of doxorubicin (DOX) in patients with non-Hodgkin's lymphoma treated according to the CHOP-protocol which included DOX, cyclophosphamide, vincristine, and prednisone. The dose of DOX was 50 mg/m2, but was reduced 25% if the patient was older than 60 years. Of these, 10 randomly-selected patients received a daily dose of 480 mg of TAM (Group-1) and 10 others did not (Group-2). Blood samples were collected at different time intervals, and DOX was measured in plasma by liquid chromatography. The concentration-time data of DOX exhibited the characteristics of the two-compartment open model well. The mean (SEM) values of alpha, beta, k12, k21, k10, Vc, Vss, AUC, total clearance, and mean residence time observed in Group-1 were 4.06 (0.96) hr(-1), 0.0395 (0.0068) hr(-1), 3.13 (0.79) hr(-1), 0.264 (0.052) hr(-1), 0.708 (0.19) hr(-1), 525 (156) l/m2, 1060 (163) l/m2, 1145 (234) microg x hr/l, 49.3 (8.5) l/hr x m2, and 26.8 (6.6) hours, respectively. Those in Group-2 were 4.99 (1.13) hr(-1), 0.0432 (0.0073) hr(-1), 2.46 (0.63) hr(-1), 0.111 (0.026) hr(-1), 2.46 (0.86) hr(-1), 231 (53) l/m2, 812 (149) l/m2, 1690 (276) microg x hr/l, 30.3 (4.1) l/hr x m2, and 29.7 (5.1) hours, respectively. Of these parameters, the difference between the two groups was significant (p < or = 0.0169) only in k21. Thus, the coadministration of TAM at the earlier-mentioned dose appears generally to have no significant influence on the pharmacokinetics of doxorubicin when used in the CHOP-protocol.

Asunto(s)

RESUMEN

The authors examined the activity of N-acetyltransferase and that of microsomal P-450 isoenzymes in health and hepatic disease state by determining the acetylation phenotype and the total (CLAP) and metabolic clearances of antipyrine to form norantipyrine or N-demethylantipyrine (MCLnora), 3-hydroxymethylantipyrine (MCLhma), and 4-hydroxyantipyrine (MCLha) in 21 healthy subjects and in 33 patients with chronic liver diseases (CLD) and investigated the relationship between the activities of these two enzyme systems. The acetylation phenotype was determined according to the urinary caffeine metabolites test. The mean and (SEM) of CLAP, MCLhma, MCLha, and MCLnora in healthy subjects were 2.42 (0.264), 0.193 (0.031), 0.322 (0.045), and 0.288 (0.04) L/h, and those observed in patients with CLD were 0.98 (0.1), 0.076 (0.015), 0.131 (0.026), 0.103 (0.022) L/h, respectively. The prevalence of fast acetylation among the healthy subjects and patients with CLD was 38% and 39%, respectively. Although all metabolic clearances appear to be reduced in healthy slow acetylators, the reduction was only significant in MCLnora, indicating a direct association between the activity of N-acetyltransferase and that of P-450 IIIA3 responsible for the N-demethylation of antipyrine. Conversely, slow acetylators with CLD exhibited significantly higher CLAP and near-significantly larger metabolic clearances including MCLnora, which suggests that P-450 activity in fast acetylators is more sensitive to chronic liver diseases than in slow acetylators.

Asunto(s)

RESUMEN

The pharmacokinetics of azathioprine (AZN) were examined in 28 renal transplant patients treated orally with 25 to 150 mg AZN once daily in combination with cyclosporin A and prednisone, and after single intravenous (IV) injection of 5 mg/kg AZN using the rabbit as an in vivo model. The steady-state concentrations of AZN observed in these patients ranged from 6 to 583 micrograms/L, and the interday coefficients of variation of the concentration in three randomly selected patients were 38%, 12%, and 4.6%. The frequency distribution pattern of the apparent oral clearance (TCLor) of AZN separates the patients almost equally into poor (TCLor = 0.126 to 4 L/hour.kg) and extensive metabolizers (TCLor = 5 to 12 L/hour.kg). The data obtained from the IV administration displayed the two-compartment model characteristics with mean (standard error of the mean) of alpha, beta, Vc, and total body clearance of 15.3 (2)/hour, 2.38 (.64)/hour, 1.05 (.3) L/kg, and 8.12 (1.26) L/hour.kg, respectively. The large variability in the pharmacokinetic parameters of AZN in patients and even in rabbits under carefully controlled conditions that may be ascribed to the complexity of its metabolism necessitates a careful approach to its dose selection.

Asunto(s)

Asunto(s)