Effect of DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide], a human tumor necrosis factor alpha-converting enzyme inhibitor, on the disposition of methotrexate: a transporter-based drug-drug interaction case study.

DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] is a potent human tumor necrosis factor alpha-converting enzyme inhibitor with potential therapeutic implications for rheumatoid arthritis. Methotrexate (MTX), a drug for the treatment of rheumatoid arthritis, is eliminated primarily unchanged via renal and biliary excretion in humans as well as in rats and dogs. The objective of the present study was to investigate the potential effect of DPC 333 on the disposition of MTX. In dogs, DPC 333 administered orally at 1.7 mg/kg 15 min before the intravenous administration of [14C]MTX (0.5 mg/kg) did not alter the plasma concentration-time profile of MTX; however, the total amount of radioactivity excreted in urine increased from 58.7% to 92.2% of the dose, and the renal clearance increased from 1.8 ml/min/kg to 2.9 ml/min/kg, suggesting a decrease in MTX disposition via biliary excretion. The biliary excretion of MTX was investigated in isolated perfused livers prepared from wild-type and TR(-) [multidrug resistance-associated protein 2 (Mrp2)-deficient] Wistar rats in the absence and presence of DPC 333. Mrp2-mediated biliary excretion of MTX was confirmed with 95.8% and 5.1% of MTX recovered in the bile of wild-type and TR(-) Wistar rats, respectively. DPC 333 at an initial perfusate concentration of 50 microM completely blocked the biliary excretion of MTX, but not the clearance from perfusate, in both wild-type and TR(-) rats. These results suggest that the enhanced renal elimination of MTX may be due to the potent inhibition of biliary excretion and active renal reabsorption by DPC 333 and/or its metabolites.     

The effect of visual field defects on eye movements and practical fitness to drive

Eye movements of subjects with visual field defects due to ocular pathology were monitored while performing a dot counting task and a visual search task. Subjects with peripheral field defects required more fixations, longer search times, made more errors, and had shorter fixation durations than control subjects. Subjects with central field defects performed less well than control subjects although no specific impairment could be pinpointed. In both groups a monotonous relationship was observed between the visual field impairment and eye movement parameters. The use of eye movement parameters to predict viewing behavior in a complex task (e.g. driving) was limited.     

Urinary tract pathology attributed to Schistosoma haematobium: does parasite genetics play a role?

Disease outcome in persons infected with Schistosoma haematobium varies dramatically, ranging from mild symptoms to severe damage of the kidneys and/or bladder. We used ultrasonography to characterize the extent of urinary tract pathology of infected children in Zimbabwe, and random genetic markers to examine the relationship between genetic diversity of S. haematobium and clinical outcome. One hundred thirty-three parasite isolates from 12 students with mild lesions and 13 with severe lesions were compared. Using four randomly amplified polymorphic DNA (RAPD) markers, we scored parasite allelic frequencies at 53 loci. Although parasite heterogeneity did not differ, allelic frequencies at eight loci differed significantly between the mild and severe groups. Parasite isolates were analyzed further using a modified cluster analysis that segregated the population into 13 clusters of associated genotypes. Three clusters were significantly over-represented in children with severe lesions. Our findings, although preliminary, suggest that parasite genetic associations may be important in clinical outcome.     

(N-3) fatty acids do not affect electrocardiographic characteristics of healthy men and women

(n-3) Fatty acids may reduce the risk of sudden death by preventing life-threatening cardiac arrhythmia. A standard electrocardiogram (ECG) may be used to detect clues as to the mechanism by which (n-3) fatty acids affect the electrophysiology of the heart. An earlier study showed that (n-3) fatty acids decreased the duration of the heart-rate corrected QT interval (QTc) in dogs. However, effects of (n-3) fatty acids on the standard ECG of humans have not been reported. Therefore, we investigated the effect of (n-3) fatty acids on QTc, QRS duration, apex-to-end-T duration, T-loop morphology and spatial QRS-T angle in apparently healthy men and women aged 50 to 70 y. Subjects (n = 42/group) received either capsules providing 1.5 g (n-3) fatty acids daily or placebo for 12 wk. ECG were recorded before and after intervention. None of the ECG characteristics were affected by (n-3) fatty acids. The QTc decreased by 0.8 ms or 0.2% (95% confidence interval, -6.1 to 4.4 ms) in subjects that consumed (n-3) fatty acids compared with the placebo group. These results do not support the hypothesis that (n-3) fatty acids prevent arrhythmia through electrophysiologic effects on heart cell membranes. However, an effect on the ECG in more susceptible populations can not be excluded.     

More care for a limited budget; a case for a better use of the efficiency criteria

A systematic consideration of the cost-effectiveness in decisions concerning the financing and implementation of healthcare technologies would contribute to the efficiency of the Dutch healthcare system. This consideration applies to the initial decision to finance a project, the periodic testing of this on the basis of practice data and the policy to promote a cost-effective approach in daily practice (via practice guidelines). Bearing in mind that the government has decided to allocate few additional resources to healthcare, it should undertake measures to ensure the systematic use of such information in these steps. The National Institute for Clinical Excellence (NICE) in the United Kingdom can serve as an example, where broadly supported guidelines are drawn up with systematic attention for the cost-effectiveness and the implications for healthcare. Within this context the question arises as to whether a Dutch variant of NICE is needed.     

The precautionary principle applied to lung cancer risk caused by residential radon

Residential radon seems to represent a major health hazard. The studies, which investigate the pulmonary risk of cancer caused by radon, are of different nature and their results are divergent. Thus, there persist scientific uncertainties concerning the real size of this risk. The application of the precautionary principle is based on an analysis of these uncertainties. Studies on miners, studies concerning residential radon (at individual and ecological level), as well as experimental data allow for the organisation of the uncertainty of each one of these specific approaches taking into account their proper limitations. The first risk that is linked to radon is the risk of pulmonary cancer. Miner occupational exposure studies appear compatible with the results of case-control studies concerning residential radon. However, the case-control studies, where the risk appears more present, are contradicted by ecological studies, often not very convincing about the existence of a risk. The case-control studies have an intrinsic advantage over the ecological studies because they limit the classification errors by the individualization of the relation-exposure effect. In addition, the experimental data are not in contradiction with the existence of effects for very small exposures. Consequently, the inherent scientific uncertainties of the totality of these data, can be classified and permit the application of the precautionary principle in a better proportioned way. The utilisation of the precautionary principle implies the necessity to limit, as far as possible, the exposure to residential radon. Precautionary principle is based on the debated hypothesis of no threshold linear relation between radon exposition and health consequences. This relation has been established on professional and residential exposures. The implementation of this epidemiological model shows the "residential radon" risk as the second cause of pulmonary cancer and responsible of about 10% of these specific cancers.     

The CarerQol instrument: A new instrument to measure care-related quality of life of informal caregivers for use in economic evaluations

The societal perspective in economic evaluations dictates that costs and effects of informal care are included in the analyses. However, this incorporation depends on practically applicable, reliable and valid methods to register the impact of informal care. This paper presents the conceptualisation and a first test of the CarerQol instrument, aimed at measuring care-related quality of life in informal caregivers. The instrument combines the information density of a burden instrument (encompassing seven important burden dimensions) with a valuation component (a VAS scale for happiness). The instrument was tested in a Dutch sample of heterogeneous caregivers (n = 175) approached through regional caregiver support centres. This first test describes the feasibility as well as convergent and clinical validity of the CarerQol instrument. The seven burden dimensions related well with differences in VAS scores. In all instances, the average CarerQol-VAS scores decreased as the severity of problems increased. Multivariate analyses showed that the seven burden dimensions explained 37–43% of the variation in CarerQol-VAS scores, depending on the model used. The CarerQol seems a promising new instrument to register the impact of informal caregivers in economic evaluations.