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the blood-brain barrier (BBB) serves to protect and regulate the cnS microenvironment. the development of an in-vitro mimic of the BBB requires recapitulating the correct phenotype of the invivo BBB, particularly for drug permeation studies. However the majority of widely used BBB models demonstrate low transendothelial electrical resistance (TEER) and poor BBB phenotype. The application of shear stress is known to enhance tight junction formation and hence improve the barrier function. We utilised a high teeR primary porcine brain microvascular endothelial cell (pBMec) culture to assess the impact of shear stress on barrier formation using the Kirkstall QuasiVivo 600 (QV600) multi-chamber perfusion system. the application of shear stress resulted in a reorientation and enhancement of tight junction formation on both coverslip and permeable inserts, in addition to enhancing and maintaining TEER for longer, when compared to static conditions. Furthermore, the functional consequences of this was demonstrated with the reduction in flux of mitoxantrone across PBMEC monolayers. The QV600 perfusion system may service as a viable tool to enhance and maintain the high teeR pBMec system for use in in-vitro BBB models. The blood-brain barrier (BBB) represents an insidious barrier for the delivery of therapeutic agents for a wide range of central nervous system (CNS) disorders. Penetration of the restrictive brain microvascular endothelial cell barrier is often hindered by the presence of a network of intra-cellular tight junction proteins, in addition to a network of membrane localised active transporter proteins and enzymatic metabolism processes. The development and maintenance of an appropriate restrictive in-vitro BBB model is critical when assessing the potential for small molecule transport. Despite the rise in the use of in-vivo models for assessing BBB structure and function, in-vitro models are still widely used and have been developed from a range of species. However, a consensus on the most appropriate cellular system has still not been achieved, particularly in the context of assessing drug permeation and inherent barrier properties. For example, the human immortalised hCMEC/D3 cell, when grown in co-culture with astrocytes, yields low TEER values of approximately 140 Ω.cm 2 1 , and those from primary endothelial cells from rodents yield TEER values of approximately 300 Ω.cm 2 2. Higher TEER values have been obtained with stem cell based systems (iPSC-derived endothelial cells) and neuronal progenitor cells, when exposed to chemical treatment, resulting in values of 3000-4000 Ω.cm 2 3 to promote BBB formation, although these often require specialised and costly methods to culture. Although human brain tissue derived in-vitro BBB models are idealised for BBB studies, the lack of appropriate monolayer formation and reproductively, in-vitro, has led to other cellular models being attractive options. The use of a porcine primary cell culture system (PBMEC) reporting high TEER without the need for co-culture with as...

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Drugs can have harmful effects on the embryo or fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of nonpregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester.This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions.For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Three examples were described to show how pregnancy PBPK can facilitate and guide dose assessment throughout gestation.

The aim of this study was to develop and characterise an intranasal delivery system for amantadine (AMT). Optimal formulations (F) consisted of a thermosensitive polymer Pluronic ® 127 (P127) and either carboxy methyl cellulose (CMC) or chitosan (CS) which demonstrated gel-transition at nasal cavity temperatures (34 °C ± 1 °C). Rheologically, the loss tangent (Tan δ) confirmed a three-stage gelation phenomena at 34 °C ± 1 °C and nonNewtonian behaviour. Storage of FCMC and FCS at 4 °C for 8 weeks resulted in repeatable release profiles at 34 °C when sampled, with a Fickian mechanism earlier on but moving towards anomalous transport by week 8. Polymers (P127, CMC and CS) demonstrated no significant cellular toxicity to human nasal epithelial cells up to 4 mg/mL and up to 1 mM for AMT (IC50: 4.5 mM ± 0.05 mM). FCMC and FCS demonstrated slower release across an in-vitro human nasal airway model (43-44 % vs 79 % ± 4.58 % for AMT). Using a human nasal cast model, deposition into the olfactory regions (potential nose-to-brain) was demonstrated upon nozzle insertion (5 mm) whereas tilting of the head forward (15°) resulted in greater deposition in the bulk of the nasal cavity. KEYWORDSParkinson's disease; rheology; nasal; RPMI 2650; nose to brain; thermoresponsive; 3 INTRODUCTION Parkinson's disease (PD) is an ageing associated progressive neurological disorder and affects 1.5 % of the population over 65-years of age 1 , with age-adjusted prevalence rates thought to be around 150 per 100,000 with a suggested mean onset in the 70's 1 . Ageing is the largest single risk factor for the development of PD and the pathogenesis of PD is composed of a range of events leading towards neuronal apoptosis, primarily of degradation of dopamine neurones in the sustantia nigra. The mainstay of clinical drug therapy focuses on increases the levels of dopamine (DA) in the brain, with oral dosing of levodopa being the most commonly used to pharmacological intervention treatment to reverse the symptoms of PD. It is also common to use adjunct therapies in conjunction with levodopa, such as the weak NMDA-type receptor antagonist amantadine, which can aid in blocking dopamine reuptake.