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.

No abstract

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)

Discussão: A comparação entre os grupos demonstrou que as crianças com rinite alérgica e respiração oral apresentam maior altura facial inferior, maior ângulo entre o plano de Frankfurt e o plano mandibular e maior ângulo entre a linha Sela-Nasion e o plano oclusal. Este grupo apresentou também menor comprimento da maxila e da mandíbula, menor overbite e diminuição do espaço aéreo respiratório superior. Conclusões: As crianças com rinite alérgica e respiração oral têm faces mais longas, maxilas e mandíbulas mais curtas e espaço aéreo faríngeo menor. Não existem diferenças estatísticas significativas entre grupos nas bases ósseas (plano sagital) ou inclinações dentárias. Palavras-chave: Cefalometria; Criança; Portugal; Respiração Oral, Rinite Alérgica. ABSTRACT Introduction:Orthodontists frequently treat children with mouth breathing. The purpose of the present study was to examine dental positions, skeletal effects and the pharyngeal airway space of children with chronic allergic rhinitis, when compared with a control group exhibiting a normal breathing pattern. Comparison between the allergic rhinitis and control group showed that there is an increased lower facial height, larger Frankfurt -mandibular plane angle and Sela-Nasion oclusal plane angle in children with chronic allergic rhinitis. This group also had a shorter maxillary and mandibular length, less overbite and decreased upper airway space. Conclusions: Children with allergic rhinitis and mouth breathing have longer faces, shorter maxillas and mandibles and a narrowed pharyngeal airway space. No statistical differences between the groups in sagital relationships or in dental inclinations were found.

The pharmacokinetic profile of triflusal (2-acetoxy-4-trifluoromethyl benzoic acid) and its main metabolite HTB (2-hydroxy-4-trifluoromethyl benzoic acid) has been studied in 8 healthy subjects (4 males and 4 females), after a single oral dose of 900 mg of triflusal. Plasma concentrations were determined by a sensitive HPLC method. Sampling was performed up to 120 h post medication. Triflusal displays a Cmax of 11.6 +/- 1.7 micrograms/ml and a tmax of 0.88 +/- 0.26 h. The elimination half-life (t1/2) was 0.55 h with a clearance (Cl/F) of 45.5 +/- 11.0 l/h. HTB kinetic parameters were: tmax 4.96 +/- 1.37 h and Cmax 92.7 +/- 17.1 micrograms/ml, with an elimination t1/2 of 34.3 +/- 5.3 and a clearance of 0.18 +/- 0.04 l/h. The results obtained in this study show a rapid absorption of triflusal and an immediate biotransformation into HTB. The long lasting platelet anti-aggregatory effect of triflusal in spite of its short t1/2, could be explained by the irreversible inhibition of platelet cyclo-oxygenase and the sustained levels of HTB, which also possess anti-aggregant properties.

It has been argued that representative drugs of the main psychopharmacological classes induce similar pharmaco-EEG changes within groups but different changes between groups. The aim of this double-blind, cross-over, placebocontrolled study was to evaluate the effects of single oral doses of buspirone (BUS) 5, 15 and 30 mg in 15 healthy young subjects of both sexes on topographic maps of quantitative phannaco-EEG, using diazepam (DZP) 10 mg as reference compound. Sixteen lead recordings of three-minute vigilance-controlled EEG (V-EEG) and four-minute resting EEG (R-EEG) were assessed at 0, 1, 2, 4, 6 and 8 hours after drug intake. EOG activity (vertical and horizontal) was also recorded in order to minimize ocular artifacts before applying an automatic artifact rejection method. MANOVNHotelling T2 maps (multivariate analysis) showed a highly significant differentiation of DZP from placebo from the 1st until the 8th hour all over the brain. After BUS a clear dose-response was observed with effects being greater and longer lasting with increasing doses, the highest showing a peak effect in the 2nd hour which lasted until the 4th hour, mostly in central regions. Maps of drug-induced pharmaco-EEG changes as compared to placebo-induced alterations (univariate analysis) demonstrated typical 'anxiolytic pharmaco-EEG patterns' after DZP, characterized by a decrease of total power, attenuation of alpha activity and augmentation of beta activity, as well as by an increase of the centroid and centroid deviation of the total activity. Furthermore, a decrease of the centroid of the combined delta-theta activity and an increase of the centroid of alpha activity was seen. In contrast, BUS produced an increase of theta activity with an acceleration of the centroid of the combined delta-theta activity, no modification of alpha activity but a slowing down of its centroid and a tendency to reduce beta activity. The centroid of the total activity was also decreased. Although both compounds have proven their ability to reduce anxiety in patients, their different neurophysiological profiles suggest different neurobiological mechanisms of action after acute administration.

The influence of controlled mechanical ventilation (CMV) on the pharmacokinetic profile of gentamicin has been examined in 23 patients after elective open heart surgery. A parallel design was adopted in two groups of patients; 13 patients requiring CMV for at least 32 h after surgery, all of whom were able to breath spontaneously (SB) after 72 h (study group), and 10 patients who required CMV for only a brief period and who showed SB at 32 h postsurgery. Haemodynamic parameters remained stable throughout the study. Apparent volume of distribution (VZ), half-life (t1/2), total clearance (CL), peak (Cmax") and trough (Cmin") plasma levels at steady-state for target levels (6-8 microgram/ml), were measured. In the study group significant differences between CMV and SB conditions were found in VZ (mean 0.36 and 0.25 l/kg). t1/2 (mean 3.63 and 2.90 h) and Cmax" (mean 4.30 and 5.53 microgram/ml) while Cmin" (mean 1.06 microgram.ml-1 and 0.92 microgram.ml-1) did not change significantly. In contrast, the pharmacokinetics in the control group showed no differences. It appears that CMV leads to an increase in gentamicin Vz which accounts for the fall in Cmax" below the therapeutic dose range (less than 5 microgram/ml) recommended for gentamicin. It seems advisable to use a large dose of gentamicin in patients receiving CMV, even before the level is assessed.