The influence of cytokines on the integrity of the blood-brain barrier in vitro

The effects of the cytokines tumour necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 on the permeability of monolayers of rat cerebral endothelial cells (RCEC) were investigated to assess potential changes in the integrity of the blood-brain barrier (BBB). RCEC were cultured to tight monolayers with a trans endothelial electrical resistance (TEER) of 100-150 Ω · cm2 on polycarbonate filters. Exposure of the RCEC to TNF-α, IL-1β and IL-6 induced a decline in the TEER, which could be completely abolished by 1 μM of indomethacin, a cyclooxygenase inhibitor. In addition, the effect of IL-1β on TEER across monolayers of RCEC could be completely inhibited by IL-1 receptor antagonist. In conclusion, cytokines induce a disruption of the BBB in vitro. In this process, cyclooxygenase activation within the endothelial cells seems to play a key role

Integration of PKPD relationships into benefit-risk analysis

AIM: Despite the continuous endeavour to achieve high standards in medical care through effectiveness measures, a quantitative framework for the assessment of the benefit–risk balance of new medicines is lacking prior to regulatory approval. The aim of this short review is to summarise the approaches currently available for benefit–risk assessment. In addition, we propose the use of pharmacokinetic–pharmacodynamic (PKPD) modelling as the pharmacological basis for evidence synthesis and evaluation of novel therapeutic agents. METHODS: A comprehensive literature search has been performed using MESH terms in PubMed, in which articles describing benefit–risk assessment and modelling and simulation were identified. In parallel, a critical review of multi-criteria decision analysis (MCDA) is presented as a tool for characterising a drug's safety and efficacy profile. RESULTS: A definition of benefits and risks has been proposed by the European Medicines Agency (EMA), in which qualitative and quantitative elements are included. However, in spite of the value of MCDA as a quantitative method, decisions about benefit–risk balance continue to rely on subjective expert opinion. By contrast, a model-informed approach offers the opportunity for a more comprehensive evaluation of benefit–risk balance before extensive evidence is generated in clinical practice. CONCLUSIONS: Benefit–risk balance should be an integral part of the risk management plan and as such considered before marketing authorisation. Modelling and simulation can be incorporated into MCDA to support the evidence synthesis as well evidence generation taking into account the underlying correlations between favourable and unfavourable effects. In addition, it represents a valuable tool for the optimization of protocol design in effectiveness trials

Drug metabolism for the perplexed medicinal chemist.

Two related and significant issues may elicit perplexity in medicinal chemists and are discussed here. First, a broad presentation of the pharmacological and toxicological consequences of drug metabolism should justify the significance of drug metabolism and serve as an incentive to further study. When comparing the pharmacological activities of a drug and its metabolite(s), a continuum is found which ranges from soft drugs (no active metabolites) to prodrugs (inactive per se, as illustrated here with clopidogrel and prasugrel). Innumerable intermediate cases document drugs whose activity is shared by one or more metabolites, as exemplified with tamoxifen. The toxicological consequences of metabolism at the molecular, macromolecular, and macroscopic levels are manyfold. A brief overview is offered together with a summary of the reactions of toxification and detoxification of the antiepileptic valproic acid. The second issue discussed in the review is a comparison of the relative significance of cytochromes P450 and other oxidoreductases (EC 1), hydrolases (EC 3), and transferases (EC 2) in drug metabolism, based on a 'guesstimate' of the number of drug metabolites that are known to be produced by them. The conclusion is that oxidoreductases are the main enzymes responsible for the formation of toxic or active metabolites, whereas transferases play the major role in producing inactive and nontoxic metabolites

Associations of maternal folic acid supplementation and folate concentrations during pregnancy with foetal and child head growth: the Generation R Study

Purpose Folic acid supplementation during pregnancy \nhas been associated with a reduced risk of common neurodevelopmental delays in the offspring. However, it is \nunclear whether low folate status has effects on the \ndeveloping brain. We evaluated the associations of \nmaternal folic acid supplementation and folate concentrations during pregnancy with repeatedly measured prenatal \nand postnatal head circumference in the offspring. \nMethods Within a population-based prospective cohort, \nwe measured maternal plasma folate concentrations at \napproximately 13 weeks of gestation (90 % range \n10.5\xe2\x80\x9317.2) and assessed folic acid supplementation by \nquestionnaire (2001\xe2\x80\x932005). Up to 11 repeated measures of \nhead circumference were obtained during foetal life (20 \nand 30 weeks of gestation) and childhood (between birth \nand age 6 years) in 5866 children (2002\xe2\x80\x932012). \nResults In unadjusted models, foetal head growth was \n0.006 SD (95 % CI 0.003; 0.009, P\\0.001) faster per \nweek per 1-SD higher maternal folate concentration. After \nadjustment for confounders, this association was attenuated \nto 0.004 SD per week (95 % CI 0.000; 0.007, P = 0.02; \nestimated absolute difference at birth of 2.7 mm). The \nassociation was independent of overall foetal growth. No \nassociations were found between maternal folate concentrations and child postnatal head growth. Preconceptional \nstart of folic acid supplementation was associated with \nlarger prenatal head size, but not with prenatal or postnatal \nhead growth. \nConclusions Our results suggest an independent, modest \nassociation between maternal folate concentrations in early \npregnancy and foetal head growth. More research is needed \nto identify whether specific brain regions are affected and \nwhether effects of folate on foetal head growth influence \nchildren\xe2\x80\x99s long-term functioning