Choice of comparator in active control trials of new drugs.

BACKGROUND: When choosing the active control group in a randomized trial, it is important to maintain standard treatment for the therapeutic indication for which a medicine is studied. This choice is relevant not only for demonstrating the efficacy and safety of a new drug, but also for assessing its place in therapy in comparison with existing medicines. Comparative information is important for decisions on prescribing and reimbursement. However, choosing the most suitable comparator is difficult when recommendations on drugs of first choice vary depending on clinical settings and times. OBJECTIVE: To evaluate the choice of comparator in premarketing randomized active control trials (RaCTs) in comparison with recommendations for standard treatment. METHODS: We evaluated drugs that were authorized for use in the European Union market between 1999 and 2005. Information on active comparators in RaCTs was extracted from the European Public Assessment Reports and information on recommendations regarding standard treatment was retrieved from the annual editions of the Dutch reference book on pharmacotherapy. Data on prescribing and indications at the time of authorization and 3 years before authorization were included. The comparator was considered to be in line with standard treatment if there was a similarity in both active substance or therapeutic class and the dosage. RESULTS: For 58 new medications identified, treatment in the active control group was in line with the recommended standard treatment in 108 of 153 (71%) RaCTs at the time of the drug's authorization; 47 (81%) of the new drugs had been compared with the recommended standard treatment in at least one trial. When dissimilarities occurred, none of the comparators had been recommended as standard treatment 3 years earlier (the supposed time of defining the trials' protocol). CONCLUSIONS: Most comparators in the premarketing RaCTs of new medicines were in line with the recommended standard treatment at the moment of marketing authorization. In view of this similarity, most of these trials are also fit for postmarketing decision-making on prescribing and on inclusion in clinical guidelines and reimbursement systems.

Population plasma pharmacokinetics of 11C-flumazenil at tracer concentrations.

OBJECTIVE: The objectives of the study were to develop a population pharmacokinetic model for (11)C-flumazenil at tracer concentrations, to assess the effects of patient-related covariates and to derive an optimal sampling protocol for clinical use. METHODS: A population pharmacokinetic model was developed using nonlinear mixed effects modelling (NONMEM) with data obtained from 51 patients with either depression or epilepsy. Each patient received approximately 370 MBq (1-4 microg) of (11)C-flumazenil. The effects of selected covariates (gender, weight, type of disease and age) were investigated. The model was validated using a bootstrap method. Finally, an optimal sampling design was established. RESULTS: The population pharmacokinetics of tracer quantities of (11)C-flumazenil were best described by a two compartment model. Type of disease and weight were identified as significant covariates (P < 0.002). Mean population pharmacokinetic parameters (percent coefficient of variation) were: CL 1530 mL min(-1) (6.6%), V(1) 24.8 x 10(3) mL (3.8%), V(2) 27.3 x 10(3) mL (5.4%), and Q 2510 mL min(-1) (6.5%). CL was 20% lower in patients with epilepsy, and the influence of weight on V(1) was 0.55% kg(-1). For the prediction of the AUC, a combination of two time points at t = 30 and 60 min post injection was considered optimal (bias -0.7% (95% CI -2.2 to 0.8%), precision 5.7% (95% CI 4.5-6.9%)). The optimal sampling strategy was cross-validated (observed AUC = 296 MBql(-1) min(-1) (95% CI 102-490), predicted AUC = 288 MBql(-1) min(-1) (95% CI 70-506)). CONCLUSIONS: The population pharmacokinetics of tracer quantities of (11)C-flumazenil are well described by a two-compartment model. Inclusion of weight and type of disease as covariates significantly improved the model. Furthermore, an optimal sampling procedure may increase the feasibility and applicability of (11)C-flumazenil PET.

Boron neutron capture therapy for glioblastoma multiforme.

AIM: Glioblastoma multiforme (GBM) is an incurable disease that can only be managed in a palliative way. The GBM accounts for approximately half of all newly diagnosed primary brain tumors with an incidence of 2-3 cases per 100,000 people each year. Surgery and radiation are the standard options for palliation, and whether there is a place for chemotherapy is still discussed. Boron neutron capture therapy (BNCT) is a promising and possibly curative method of treating GBM. The purpose of this article is to provide an updated review on the current management and future possibilities of treating GBM with BNCT. METHOD: Use was made of computerized searches and of checking cross-references of articles and book chapters. RESULTS: The principle of BNCT uses the high ability of 10B to capture thermal neutrons and to disintegrate immediately into a He nucleus (alpha-particle) and a Li nucleus. To reach a sufficient concentration of 10B in the malignant cells compared to the surrounding healthy tissue, 10B-carriers must be highly tumor-selective. At present, the 10B carriers boronophenylalanine (BPA) and sodium borocaptate (BSH) are used in clinical trials to perform BNCT. CONCLUSION: The BNCT is a promising and possibly curative method of treating GBM, but at present this procedure is far from perfect. Because of the lack of selectivity of the boron carriers, it appears so far that radiation toxicity limits the radiation dose, so that tumor damage is modest. Current investigations and developments are aimed at targeting the boron carriers to the tumor, in order to limit the damage to the healthy, surrounding tissue.

Intrathecal administration of high-dose morphine solutions decreases the pH of cerebrospinal fluid.

Terminally ill patients suffering from intractable cancer pain are treated in our hospital on an outpatient basis with a percutaneous intrathecal (i.t.) catheter and a portable pump delivering morphine continuously. In a patient showing an increased demand of morphine the dose was raised from 1.5 to 2 mg/h, but pain intensity did not decrease. Subsequently a 1.5 ml dose of 5% lidocaine was administered; however, no motor or sensory block was observed. After controlling the catheter position and passage through the catheter, a sample of cerebrospinal fluid (CSF) was taken and the pH was measured. It was found to be outside the physiological range of 7.19 (normal range: 7.27-7.37), possibly explaining the decreased activity of the local anesthetic. The purpose of this study was to determine the influence of morphine, with or without sodium metabisulfite, on pH in vitro, using artificial CSF (ACSF) and on pH in vivo during i.t. administration of morphine. An in vitro model was used to measure pH changes by adding a morphine solution (concentrations of 0.5, 2, 5 and 10 mg/ml) with and without sodium metabisulfite to ACSF solutions (Elliott B). Fourteen patients were consecutively selected for continuous administration of morphine. An i.t. catheter was inserted, tunnelled and connected with an external pump (Provider 5500, Abbott, Chicago, IL). CSF was aspirated and pH was measured with a blood-gas system (Ciba-Corning 288, Medfield, USA). In vitro, morphine solutions with or without sodium metabisulfite added to an Elliott B solution (pH = 7.47, 37 degrees C) caused a concentration-related decrease in pH.(ABSTRACT TRUNCATED AT 250 WORDS)