RESUMEN

BACKGROUND: Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases in children. Studies on costs related to T1DM are scarce and focused primarily on the costs directly related to diabetes. We aimed to investigate both the overall healthcare costs and the more specific costs related to the management of diabetes. METHODS: This is a retrospective and observational, nationwide cohort study of all Dutch children (aged 0-18 years) with T1DM. Data were collected from the national registry for healthcare reimbursement, in which all Dutch insurance companies combine their reimbursement data. In the Netherlands for all Dutch citizens health care is covered by law and all children are treated by hospital-based paediatricians. RESULTS: We analysed 6710 children distributed over 81 hospitals: 475 children in 6 university hospitals and 6235 children in 75 general hospitals. Total reimbursement for all children with T1DM over the period 2009 to 2011 was € 167,494,732 corresponding to an annual mean of € 55,831,577 of total costs and € 8326 euros per child. When comparing small (between 26 and 54 patients), medium (57-84 patients) and large (88-248 patients) general hospitals, costs per patient were highest in the hospitals with the highest number of T1DM patients. The costs for devices, secondary care and pharmaceutics had most impact on total expenditures. Over the study period, there was a slight decrease in per person costs. CONCLUSION: The overall health expenditure of a child with T1DM is more than € 8000 per patient per annum. Given the move towards more device-intensive multidisciplinary care for these patients, the costs of treating T1DM in children are likely to increase further in the coming years.

Asunto(s)

Asunto(s)

RESUMEN

OBJECTIVE: Adolescents with type 1 diabetes mellitus (DM1) often have problems in achieving optimal glycaemic control. We investigated whether there is evidence of the beneficial effect of the addition of metformin to insulin therapy in adolescents with DM1. DESIGN: Systematic literature study. METHOD: Medline and Embase were searched for randomised double-blind trials in adolescents with DM1 up to May 2011 inclusive. Two reviewers selected relevant articles based on title, summary and, if necessary, the full text. The quality of the methodology was also assessed. RESULTS: We found 2 studies in adolescents, of limited scope and duration. On this basis, it was decided that the search of the literature should be extended to adults with DM1, whereby 4 studies were found. All six trials were of good methodological quality, and included 196 patients in total. Clinical and statistical heterogeneity precluded pooling the results in a meta analysis. In one study in adolescents metformin treatment showed a reduction of HbA1c by 0.6% (95% CI: -1.16-0.04) and a slight decrease in daily total insulin dose. However, the treatment groups were not comparable at baseline. In the other studies, no significant changes in HbA1c were found. All studies showed decreased daily insulin dose; in four studies this was significant. Two studies showed a beneficial effect on weight or BMI. No serious side effects were recorded. One study showed an increase in hypoglycaemic episodes during metformin treatment. CONCLUSION: The possible benefit of adding metformin to insulin in adolescents and adults with type 1 diabetes remains unclear. A well-designed double-blind randomised trial carried out over a longer time period is required to assess whether metformin is of added value.

Asunto(s)

RESUMEN

The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of [(14)C]-asenapine to healthy male volunteers. Mean total excretion on the basis of the percent recovery of the total radioactive dose was ∼90%, with ∼50% appearing in urine and ∼40% excreted in feces; asenapine itself was detected only in feces. Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.

Asunto(s)

RESUMEN

OBJECTIVE: The objectives of this study were to assess the effect of mirtazapine on steady-state pharmacokinetics of phenytoin and vice versa and to assess tolerability and safety of the combined use of mirtazapine and phenytoin. METHODS: This was an open-label, randomised, parallel-groups, single-centre, multiple-dose pharmacokinetic study. Seventeen healthy, male subjects completed either treatment A [nine subjects: daily 200 mg phenytoin for 17 days plus mirtazapine (15 mg for 2 days continuing with 30 mg for 5 days) from day 11 to day 17] or treatment B [eight subjects: mirtazapine, daily 15 mg for 2 days continuing with 30 mg for 15 days plus phenytoin 200 mg from day 8 to day 17]. Serial blood samples were taken for kinetic profiling on the 10th and 17th days of treatment A and on the 7th and 17th days of treatment B. Induction of CYP 3A by phenytoin was evaluated by measuring the ratio of 6 beta-hydroxycortisol over cortisol on the 1st, 7th and 17th days of treatment B. RESULTS: Co-administration of mirtazapine had no effect on the steady-state pharmacokinetics of phenytoin, i.e. the area under the plasma concentration-time curve (AUC)(0-24) and peak plasma concentration (C(max)) remained unchanged. The addition of phenytoin to an existing daily administration of mirtazapine resulted in a mean (+/-SD) decrease of the AUC(0-24) from 576+/-104 ng h/ml to 305+/-81.6 ng h/ml and a mean decrease of C(max) from 69.7+/-17.5 ng/ml to 46.9+/-10.9 ng/ml. Induction of CYP 3A by phenytoin is confirmed by the significantly ( P=0.001) increased 6beta-hydroxycortisol/cortisol ratio from 1.74+/-1.00 to 2.74+/-1.64. CONCLUSION: Co-administration of mirtazapine did not alter the steady-state pharmacokinetics of phenytoin. The addition of phenytoin to an existing daily administration of mirtazapine results in a decrease of the plasma concentrations of mirtazapine by 46% on average, most likely due to induction of CYP 3A3/4.

Asunto(s)

RESUMEN

We have experimentally quantified exposure to dichloromethane during non-professional paint stripping and validated the mathematical paint exposure model of van Veen et al. (1999). The model innovates the prediction of the dichloromethane evaporation rate and room concentration by accounting for transport in the paint stripper matrix. The experiments show that peak concentrations range from 600 to 1600 mg/m3, increasing to 2000 mg/m3 when direct sun radiation increases evaporation. A naive model prediction, using a priori parameter values from the experimental set-up and a previous experiment with alkanes, accurately predicts the upper range of the experimental values, but overpredicted four out of six experiments. Statistical fit of the two paint stripper layer parameters to the experimental data resulted in a good coincidence of predicted and experimental data. Model and experiment indicate that 10-30% of dichloromethane is immediately available for evaporation.

Asunto(s)

RESUMEN

Quite often physicians contact the Dutch Poisons Control Centre for information on patients with increased lead exposure. The most important questions raised by physicians dealing with these patients are how to estimate the lead exposure and the total lead body burden, how to interpret blood lead concentrations and whether the patient needs treatment. In order to answer these questions we need knowledge of the toxicokinetics of lead in the human body. To achieve insight and to make this knowledge accessible to physicians a biokinetic model for lead metabolism in the human body was developed. A four-compartment model with first-order kinetics, based on the concept of Kneip, was used. A biokinetic model uses a mathematical approach to translate the complex biological and kinetic behaviour of lead. In order to develop this biokinetic model two computer programmes were used. At the moment the model is tested with clinical data from patient treated at the medical toxicology outpatient clinic of the Utrecht University Hospital (this department cooperates very closely with the National Poisons Control Centre). Especially with regard to chelation therapy for elevated blood lead levels due to chronic exposure, the model is very helpful in visualising the toxicokinetics of lead in the human body. Toxicokinetic model might help improve knowledge of lead toxicokinetics, leading to well-considered guidelines for treatment of lead intoxications.

Asunto(s)