It has been estimated by the World Health Organization (WHO) that over 71 million people were infected with the hepatitis C virus (HCV) in 2015. Since then, a number of highly effective direct-acting antiviral (DAA) regimens have been licensed for the treatment of chronic HCV infection: sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, elbasvir/grazoprevir, sofosbuvir/ velpatasvir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir. With these treatment regimens, almost all chronic HCV-infected patients, even including prior DAA failures, can be treated effectively and safely. It is therefore likely that further development of DAAs will be limited. In this descriptive review we provide an overview of the clinical pharmacokinetic characteristics of currently available DAAs by describing their absorption, distribution, metabolism, and excretion. Potential drug-drug interactions with the DAAs are briefly discussed. Furthermore, we summarize what is known about the pharmacodynamics of the DAAs in terms of efficacy and safety. We briefly discuss the relationship between the pharmacokinetics of the DAAs and efficacy or toxicity in special populations, such as hard to cure patients and patients with liver cirrhosis, liver transplantation, renal impairment, hepatitis B virus or HIV co-infection, bleeding disorders, and children. The aim of this overview is to educate/update prescribers and pharmacists so that they are able to safely and effectively treat HCV-infected patients even in the presence of underlying co-infections or co-morbidities.

During pregnancy, the pharmacokinetics of an antiepileptic drug is altered because of changes in the clearance capacity and volume of distribution. These changes may have consequences for the frequency of seizures during pregnancy and fetal exposure to antiepileptic drugs. In 2009, a review was published providing guidance for the dosing and therapeutic drug monitoring of antiepileptic drugs during pregnancy. Since that review, new drugs have been licensed and new information about existing drugs has been published. With this review, we aim to provide an updated narrative overview of changes in the pharmacokinetics of antiepileptic drugs in women during pregnancy. In addition, we aim to formulate advice for dose modification and therapeutic drug monitoring of antiepileptic drugs. We searched PubMed and the available literature on the pharmacokinetic changes of antiepileptic drugs and seizure frequency during pregnancy published between January 2007 and September 2018. During pregnancy, an increase in clearance and a decrease in the concentrations of lamotrigine, levetiracetam, oxcarbazepine's active metabolite licarbazepine, topiramate, and zonisamide were observed. Carbamazepine clearance remains unchanged during pregnancy. There is inadequate or no evidence for changes in the clearance or concentrations of clobazam and its active metabolite N-desmethylclobazam, gabapentin, lacosamide, perampanel, and valproate. Postpartum elimination rates of lamotrigine, levetiracetam, and licarbazepine resumed to pre-pregnancy values within the first few weeks after pregnancy. We advise monitoring of antiepileptic drug trough concentrations twice before pregnancy. This is the reference concentration. We also advise to consider dose adjustments guided by therapeutic drug monitoring during pregnancy if the antiepileptic drug concentration decreases 15-25% from the pre-pregnancy reference concentration, in the presence of risk factors for convulsions. If the antiepileptic drug concentration changes more than 25% compared with the reference concentration, dose adjustment is advised. Monitoring of levetiracetam, licarbazepine, lamotrigine, and topiramate is recommended during and after pregnancy. Monitoring of clobazam, N-desmethylclobazam, gabapentin, lacosamide, perampanel, and zonisamide during and after pregnancy should be considered. Because of the risk of teratogenic effects, valproate should be avoided during pregnancy. If that is impossible, monitoring of both total and unbound valproate is recommended. More research is needed on the large number of unclear pregnancy-related effects on the pharmacokinetics of antiepileptic drugs.

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Abstract:It is always a strong motivation for aeronautic researchers and engineers to reduce the aircraft emissions or even to achieve emission-free air transport. In this paper, the impacts of different game-changing technologies together on the reduction of aircraft fuel consumption and emissions are studied. In particular, a general tool has been developed for the technology assessment, integration and also for the overall aircraft multidisciplinary design optimization. The validity and robustness of the tool has been verified through comparative and sensitivity studies. The overall aircraft level technology assessment and optimization showed that promising fuel efficiency improvements are possible. Though, additional strategies are required to reach the aviation emission reduction goals for short and medium range configurations.

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Antidepressant use has increased in the last decade. Several studies have suggested a possible association between maternal antidepressant use and teratogenic effects. In a review of the pharmacologic literature we showed that antidepressant exposure might disturb the development of the enteric nervous system. WHAT THIS STUDY ADDS • In utero exposure to selective serotonin re‐uptake inhibitors (SSRIs) in the second and third trimester or to tricyclic antidepressants (TCAs) in the first trimester leads to a significant increase in laxative use compared with non‐exposed children. SSRI exposure was not associated with significant increased antidiarrhoeal medication use, but TCA exposure was. AIMS Antidepressant use has increased in the last decade. Several studies have suggested a possible association between maternal antidepressant use and teratogenic effects. METHODS The pharmacy prescription database IADB.nl was used for a cohort study in which laxative and antidiarrhoeal medication use in children after in utero exposure to antidepressants (TCA, SSRI, fluoxetine or paroxetine exposed) was compared with no antidepressant exposure. Laxatives and antidiarrhoeal medication use were applied as a proxy for constipation and diarrhoea respectively, which may be associated with disturbed enteric nervous system (ENS) development. RESULTS Children exposed in utero to SSRIs (mainly fluoxetine and paroxetine) in the second and third trimester or to TCAs in the first trimester, more often received laxatives. Combined exposure to TCAs and SSRIs in pregnancy was associated with a 10‐fold increase in laxative use. In utero exposure to SSRIs is not associated with antidiarrhoeal medication use compared with non‐exposed children. In contrast, antidiarrhoeal medication use was significantly higher in children exposed to TCAs anytime in pregnancy. CONCLUSIONS The increased laxative use after second and third trimester exposure to SSRIs might be explained through the inhibitory effect of the serotonin re‐uptake transporter (SERT) and because of selectivity for the 5‐HT2B receptor which affects the ENS. TCA exposure during the first trimester leads to increased laxative use probably through inhibition of the norepinephrine transporter (NET). Exposure of TCAs anytime in pregnancy leads to increase diarrhoeal use possibly through down‐regulation of α2‐adrenoceptors or up‐regulation of the pore forming α1c subunit.

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