No abstract

Gentamicin intrapatient pharmacokinetics variations were studied in 40 critically ill medical patients, suffering gram-negative sepsis. These patients were studied in two phases throughout gentamicin treatment: firstly, on the second day of treatment, when aggressive fluid therapy was required, and secondly, five days later, when patients had achieved a more stable clinical condition. Pharmacokinetic parameters were determined using least squares linear regression analysis assuming a one-compartment model using the Sawchuk-Zaske method. The apparent volume of distribution (Vd) in the first phase of the study was 0.43 +/- 0.12 L/kg, while on the seventh day of treatment it was 0.29 +/- 0.17 L/kg (p less than 0.001). Statistically significant differences were also observed for peak serum concentration (p less than 0.001), total dosage recommended (p less than 0.001) and half-life (p less than 0.05), whilst differences were not found for trough levels. From the analysis of the results obtained, we recommend increasing the initial dosage and monitoring plasma levels within the first days of therapy in critically ill patients treated with gentamicin, since important variations in aminoglycoside Vd related to disease, fluid balance and renal function, commonly occur in these patients.

Background Orphan medicines show some characteristics that hinder the evaluation of their clinical added value. The often low level of evidence available for orphan drugs, together with a high budget impact and an incremental cost-effectiveness ratio many times higher than drugs used for non-orphan diseases, represent challenges in their appraisal and effective access to clinical use. In order to explore how to handle these hurdles, the Catalan Health Service (CatSalut) began an initiative on a multidimensional assessment of drugs value during the appraisal process. Reflective multicriteria decision analysis (MCDA) using analytical methods was chosen, since it may help to standardise and contextualize all the relevant data related with the drug that could contribute to a decision. The aim of the study was to determine whether the implementation of reflective MCDA methodology could support the decision-making process about orphan medicines in the context of CatSalut. Methods The assessment and decision-making process for orphan drugs in the Programa d’Harmonització Farmacoterapeutica (PHF) of CatSalut was prioritized to test the implementation of the reflective MCDA both a qualitative and quantitatively. A staged approach was used with the following main steps: selection and structuration of quantitative criteria (Core Model) and qualitative criteria (Contextual Tool), framework scoring and assessment of three orphan drug case studies. This proof-of-concept would grant a continued refinement of the methodology and, if and when validated, its potential integration to other therapeutic areas of the PHF. Results The final framework was composed by 10 quantitative criteria (Core Model) and 4 qualitative criteria (Contextual Tool) according to the PHF goals being the most important criteria “disease severity”, “unmet need”, “comparative effectiveness” and “comparative safety /tolerability”. The matrix developed for the case studies served as a guide for the selection of the essential information that the decision-makers were expected to include in a framework. The reflective discussion was considered the most relevant phase of the approach to support inputs for health decision-making processes reflecting both drug value and place in therapy. Conclusions The study showed that reflective MCDA methodology could be implemented to complement the decision-making process in CatSalut, as an aid to determine the clinical added value for orphan medicines. MCDA provided transparency and a structured discussion during the committee meetings, thus increasing transparency and predictability of the relevant items supporting the agreements adopted on orphan drugs access.

1. The dynamic and kinetic interactions of alcohol and caffeine were studied in a double‐blind, placebo controlled, cross‐over trial. Treatments were administered to eight healthy subjects in four experimental sessions, leaving a 1 week wash‐out period between each, as follows: 1) placebo, 2) alcohol (0.8 g kg‐1), 3) caffeine (400 mg) and 4) alcohol (0.8 g kg‐1) + caffeine (400 mg). 2. Evaluations were performed by means of: 1) objective measures: a) psychomotor performance (critical flicker fusion frequency, simple reaction time and tapping test), b) long latency visual evoked potentials ('pattern reversal'); 2) subjective self‐rated scales (visual analogue scales and profile of mood states); 3) caffeine and alcohol plasma concentration determinations. 3. The battery of pharmacodynamic tests was conducted at baseline and at +0.5 h, +1.5 h, +2.5 h, +4 h and +6 h. An analysis of variance was applied to the results, accepting a P < 0.05 as significant. The plasma‐time curves for caffeine and alcohol were analysed by means of model‐independent methods. 4. Results obtained with caffeine in the objective measures demonstrated a decrease in simple reaction time and an increase in the amplitude of the evoked potentials; the subjects' self‐ratings showed a tendency to be more active. Alcohol increased simple reaction time and decreased amplitude of the evoked potentials, although the subjects rated themselves as being active. The combination of alcohol + caffeine showed no significant difference from placebo in the objective tests; nevertheless, the subjective feeling of drunkenness remained. The area under the curve (AUC) for caffeine was significantly higher when administered with alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)