Rapid i.v. loading with phenytoin with subsequent dose adaptation using non-steady-state serum levels and a Bayesian forecasting computer program to predict maintenance doses.

OBJECTIVE: To evaluate the suitability of a phenytoin loading dose regimen; to assess whether dose-individualization was necessary and to investigate the reliability of a Bayesian forecasting method for phenytoin dose adaptation using non-steady-state levels in hospital-admitted patients. METHOD: An initial loading dose (15 mg phenytoin acid/kg BW) was given i.v. over 4 h, followed by standardized maintenance doses given i.v. in 12-h intervals from days 1 to 5 (175 mg 70 kg BW). The evening dose of day 5 was individualized based on three serum trough levels: L1 (after 16 h), L2 (morning day 4) and L3 (morning day 5). RESULTS: Ninety of 136 consecutive patients were evaluable in a prospective study for the standardized phase; 50 of them had additional serum levels in the individualized phase. There was no exclusion of patients with interacting co-medication. Seventy-seven per cent (L1) and 68% (L3) of patients showed therapeutic values (10-20 mg/L). The prediction error of the forecasting was 3.95 mg/L, the root mean squared error 6.27 mg/L (target trough level 11 mg/L). Seventy per cent of the levels (n=50) were within the 68% confidence interval. CONCLUSION: The effectiveness and safety of the regimen with rapid i.v. loading and the necessity to individualize phenytoin dosing after day 5 were demonstrated.

Stability of high-dose morphine chloride injection upon heat sterilization: comparison of UV-spectroscopy and HPLC.

The stability of a preservative-free morphine chloride solution for intravenous or intrathecal use manufactured at a concentration of 40 mg/ml, near the solubility limit in water, was studied. The influence of heat and oxygen on morphine content was measured with and without autoclaving, and after additional thermal and oxidative stress. The morphine injection was stable during steam sterilization at 121 degrees C for up to 180 min if the solution was adjusted to a pH of 3.2 and if oxygen was eliminated by saturating the solution and flushing the vial with nitrogen before sealing. By adding an oxidizing agent (200 microliters H2O2 3% per 20 ml vial) before 15 min of sterilization, a decomposition of approximately 20% of morphine resulted when compared to oxygen-free control samples (P < 0.01, n = 3) High-performance liquid chromatography with UV detection (HPLC) and direct UV spectroscopy (UV) (the latter available in most hospital pharmacies for analytical purposes) were compared for specificity, precision and appropriateness for content and stability assessment of morphine solutions. UV could only be used for quantification of undecomposed morphine. Morphine degradation products of stressed solutions interfered with the direct UV assay of morphine at 286 nm, whereas these interfering components were separated by the ion-pair reversed-phase HPLC used. The results demonstrate that even in the absence of stabilizers, morphine chloride solutions may safely be sterilized for 15 min at 121 degrees C. The HPLC method was shown to be sufficiently sensitive and specific for quality control and stability assessment of morphine preparations, and, therefore, appropriate for the validation of the manufacture of morphine injection solutions in hospital pharmacies, where morphine solutions are manufactured in special strengths and volumes for individual patients' needs.