scholarly journals O19 Development of a paediatric brain PBPK model in children with and without meningitis

2019 ◽  
Vol 104 (6) ◽  
pp. e8.3-e9 ◽  
Author(s):  
LFM Verscheijden ◽  
JB Koenderink ◽  
K Allegaert ◽  
SN de Wildt ◽  
FGM Russel
Keyword(s):  
Blood Brain Barrier ◽  
Pbpk Model ◽  
Plasma Concentrations ◽  
Model Performance ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Pbpk Models ◽  
Blood Brain ◽  
Age Related ◽  
Drug Concentrations

BackgroundSeveral paediatric physiologically-based pharmacokinetic (PBPK) models have been developed that incorporate developmental changes affecting plasma drug concentrations. Disposition into cerebrospinal fluid (CSF) is also age-related and influenced by physiological factors, including CSF production rate, but also by brain diseases, such as meningitis, which are associated with impaired blood-brain barrier integrity. Our aim was to develop a paediatric brain PBPK model to predict CSF drug concentrations in children with and without meningitis.MethodsA paediatric PBPK model was developed incorporating age-appropriate parameters and associated inter-individual variability. The model was validated for paracetamol, ibuprofen, flurbiprofen and naproxen, and for a paediatric meningitis population by estimating meropenem blood-brain barrier penetration using sensitivity analysis. Plasma and CSF drug concentrations derived from literature were used to perform visual predictive checks and to calculate ratios between simulated and observed AUCs in order to evaluate model performance.ResultsSimulated data were comparable to observed over a broad age range (1 day - 15 y postnatal age), for all drugs investigated. The ratios between observed and simulated AUCs were within 2-fold difference both in plasma and in CSF, indicating acceptable model performance. Disposition of meropenem into the brain was slow and CSF concentrations were lower compared to plasma concentrations. In addition, several days were needed to achieve CSF steady-state concentration.ConclusionsOur paediatric brain PBPK model provides a new tool to predict CSF concentrations in children with and without meningitis and can be used as a template model for other drugs acting in the CNS.Disclosure(s)Nothing to disclose

Nose to Brain Drug Delivery System

2021 ◽  
pp. 335-340
Author(s):  
Gayatri D Patil ◽  
Aditya R Nikam ◽  
Paresh A. Patil ◽  
Aakash D. Sonar
Keyword(s):  
Blood Brain Barrier ◽  
Plasma Concentrations ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Post Traumatic Stress ◽  
Brain Drug Delivery ◽  
Blood Brain ◽  
Drug Concentrations ◽  
Post Traumatic ◽  
The Brain

The treatment of brain disorders is particularly challenging due to the presence of a variety of formidable obstacles to deliver drugs selectively and effectively to the brain. Blood-brain-barrier (BBB) constitutes the major obstacle to the uptake of drugs into the brain following systemic administration. An intranasal delivery provides some drugs with short channels to bypass the blood-brain barrier (BBB), especially for those with fairly low brain concentrations after a routine delivery, thus greatly enhancing the therapeutic effect on brain diseases. The nasal mucosa is nearby the brain, cerebrospinal fluid (CSF) and the drug concentrations can exceed plasma concentrations. a longer retention time at the nasal mucosal surface, penetration enhancement of the active through the nasal epithelia, and a reduction in drug metabolism in the nasal cavity. Indications where nose-to-brain products are likely to emerge first include the following: neurodegeneration, post-traumatic stress disorder, pain, and glioblastoma.

scholarly journals Photodynamic Opening of the Blood–Brain Barrier Using Different Photosensitizers in Mice

2019 ◽  
Vol 10 (1) ◽  
pp. 33 ◽  
Author(s):  
Oxana Semyachkina-Glushkovskaya ◽  
Ekaterina Borisova ◽  
Vanya Mantareva ◽  
Ivan Angelov ◽  
Ivelina Eneva ◽  
...  
Keyword(s):  
Tight Junction ◽  
Blood Brain Barrier ◽  
Confocal Imaging ◽  
Brain Barrier ◽  
Zinc Phthalocyanine ◽  
Brain Diseases ◽  
Blood Brain ◽  
Age Related ◽  
Dextran 70 ◽  
The Brain

In a series of previous studies, we demonstrated that the photodynamic therapy (PDT), as a widely used tool for treatment of glioblastoma multiforme (GBM), also site-specifically opens the blood–brain barrier (BBB) in PDT-dose and age-related manner via reversible disorganization of the tight junction machinery. To develop the effective protocol of PDT-opening of the BBB, here we answer the question of what kind of photosensitizer (PS) is the most effective for the BBB opening. We studied the PDT-opening of the BBB in healthy mice using commercial photosensitizers (PSs) such as 5-aminolevulenic acid (5-ALA), aluminum phthalocyanine disulfonate (AlPcS), zinc phthalocyanine (ZnPc) and new synthetized PSs such as galactose functionalized ZnPc (GalZnPc). The spectrofluorimetric assay of Evans Blue albumin complex (EBAC) leakage and 3-D confocal imaging of FITC-dextran 70 kDa (FITCD) extravasation clearly shows a revisable and dose depended PDT-opening of the BBB to EBAC and FITCD associated with a decrease in presence of tight junction (TJ) in the vascular endothelium. The PDT effects on the BBB permeability, TJ expression and the fluorescent signal from the brain tissues are more pronounced in PDT-GalZnPc vs. PDT-5-ALA/AlPcS/ZnPc. These pre-clinical data are the first important informative platform for an optimization of the PDT protocol in the light of new knowledge about PDT-opening of the BBB for drug brain delivery and for the therapy of brain diseases.

scholarly journals Blood-brain Barrier Crossing using Magnetic Stimulated Nanoparticles

2021 ◽  
Author(s):  
Jingfan Chen ◽  
Muzhaozi Yuan ◽  
Caitlin Madison ◽  
Shoshana Eitan ◽  
Ya Wang
Keyword(s):  
Blood Brain Barrier ◽  
Pbpk Model ◽  
Superparamagnetic Iron Oxide ◽  
Brain Barrier ◽  
Control Group ◽  
Pbpk Models ◽  
Blood Brain ◽  
The Impact ◽  
The Brain

Due to the low permeability and high selectivity of the blood-brain barrier (BBB), existing brain therapeutic technologies are limited by the inefficient BBB crossing of conventional drugs. Magnetic nanoparticles (MNPs) have shown great potential as nano-carriers for efficient BBB crossing under the external static magnetic field (SMF). To quantify the impact of SMF on MNPs' in vivo dynamics towards BBB crossing, we developed a physiologically based pharmacokinetic (PBPK) model for intraperitoneal (IP) injected superparamagnetic iron oxide nanoparticles coated by gold and conjugated with poly(ethylene glycol) (PEG) (SPIO-Au-PEG NPs) in mice. Unlike most reported PBPK models that ignore brain permeability, we first obtained the brain permeabilities with and without SMF by determining the concentration of SPIO-Au-PEG NPs in the cerebral blood and brain tissue. This concentration in the brain was simulated by the advection-diffusion equations and was numerically solved in COMSOL Multiphysics. The results from the PBPK model after incorporating the brain permeability showed a good agreement (regression coefficient R2 = 0.825) with the in vivo results, verifying the capability of using the proposed PBPK model to predict the in vivo biodistribution of SPIO-Au-PEG NPs under the exposure to SMF. Furthermore, the in vivo results revealed that the brain bioavailability under the exposure to SMF (4.01%) is slightly better than the control group (3.68%). In addition, the modification of SPIO-Au-PEG NPs with insulin (SPIO-Au-PEG-insulin) showed an improvement of the brain bioavailability by 24.47 % in comparison to the non-insulin group. With the SMF stimulation, the brain bioavailability of SPIO-Au-PEG-insulin was further improved by 3.91 % compared to the group without SMF.

scholarly journals Modulation of the Blood–Brain Barrier for Drug Delivery to Brain

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2024
Author(s):  
Liang Han
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Active Efflux ◽  
Safety Issues ◽  
Blood Brain ◽  
Drug Concentrations ◽  
Preclinical And Clinical Studies ◽  
The Brain ◽  
Systemic Therapies

The blood–brain barrier (BBB) precisely controls brain microenvironment and neural activity by regulating substance transport into and out of the brain. However, it severely hinders drug entry into the brain, and the efficiency of various systemic therapies against brain diseases. Modulation of the BBB via opening tight junctions, inhibiting active efflux and/or enhancing transcytosis, possesses the potential to increase BBB permeability and improve intracranial drug concentrations and systemic therapeutic efficiency. Various strategies of BBB modulation have been reported and investigated preclinically and/or clinically. This review describes conventional and emerging BBB modulation strategies and related mechanisms, and safety issues according to BBB structures and functions, to try to give more promising directions for designing more reasonable preclinical and clinical studies.

scholarly journals Probable Causes of Alzheimer’s Disease

Sci ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 16
Author(s):  
James David Adams
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lactic Acid ◽  
Blood Brain Barrier ◽  
Transient Receptor Potential ◽  
Brain Barrier ◽  
Folate Intake ◽  
Blood Brain ◽  
Age Related ◽  
The Brain

A three-part mechanism is proposed for the induction of Alzheimer’s disease: (1) decreased blood lactic acid; (2) increased blood ceramide and adipokines; (3) decreased blood folic acid. The age-related nature of these mechanisms comes from age-associated decreased muscle mass, increased visceral fat and changes in diet. This mechanism also explains why many people do not develop Alzheimer’s disease. Simple changes in lifestyle and diet can prevent Alzheimer’s disease. Alzheimer’s disease is caused by a cascade of events that culminates in damage to the blood–brain barrier and damage to neurons. The blood–brain barrier keeps toxic molecules out of the brain and retains essential molecules in the brain. Lactic acid is a nutrient to the brain and is produced by exercise. Damage to endothelial cells and pericytes by inadequate lactic acid leads to blood–brain barrier damage and brain damage. Inadequate folate intake and oxidative stress induced by activation of transient receptor potential cation channels and endothelial nitric oxide synthase damage the blood–brain barrier. NAD depletion due to inadequate intake of nicotinamide and alterations in the kynurenine pathway damages neurons. Changes in microRNA levels may be the terminal events that cause neuronal death leading to Alzheimer’s disease. A new mechanism of Alzheimer’s disease induction is presented involving lactic acid, ceramide, IL-1β, tumor necrosis factor α, folate, nicotinamide, kynurenine metabolites and microRNA.

scholarly journals Can Natural Products Exert Neuroprotection without Crossing the Blood–Brain Barrier?

2021 ◽  
Vol 22 (7) ◽  
pp. 3356
Author(s):  
Manon Leclerc ◽  
Stéphanie Dudonné ◽  
Frédéric Calon
Keyword(s):  
Natural Products ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Omega 3 ◽  
Indirect Pathway ◽  
Brain Functions ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Peripheral Metabolism

The scope of evidence on the neuroprotective impact of natural products has been greatly extended in recent years. However, a key question that remains to be answered is whether natural products act directly on targets located in the central nervous system (CNS), or whether they act indirectly through other mechanisms in the periphery. While molecules utilized for brain diseases are typically bestowed with a capacity to cross the blood–brain barrier, it has been recently uncovered that peripheral metabolism impacts brain functions, including cognition. The gut–microbiota–brain axis is receiving increasing attention as another indirect pathway for orally administered compounds to act on the CNS. In this review, we will briefly explore these possibilities focusing on two classes of natural products: omega-3 polyunsaturated fatty acids (n-3 PUFAs) from marine sources and polyphenols from plants. The former will be used as an example of a natural product with relatively high brain bioavailability but with tightly regulated transport and metabolism, and the latter as an example of natural compounds with low brain bioavailability, yet with a growing amount of preclinical and clinical evidence of efficacy. In conclusion, it is proposed that bioavailability data should be sought early in the development of natural products to help identifying relevant mechanisms and potential impact on prevalent CNS disorders, such as Alzheimer’s disease.

The complexity of the blood-brain barrier and the concept of age-related brain targeting: challenges and potential of novel solid lipid-based formulations

2021 ◽  
Author(s):  
Federica Sommonte ◽  
Ilaria Arduino ◽  
Giuseppe Francesco Racaniello ◽  
Antonio Lopalco ◽  
Angela Assunta Lopedota ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Solid Lipid ◽  
Blood Brain ◽  
Age Related

Age-Related Changes in Blood-Brain Barrier ( BBB )

1990 ◽  
pp. 701-703
Author(s):  
Masaki Ueno ◽  
Hironobu Naiki ◽  
Ichiro Akiguchi ◽  
Toshio Kawamata ◽  
Yasuhisa Fujibayashi ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
Age Related ◽  
Age Related Changes

scholarly journals Gastrodia-Uncaria Water Extract Inhibits Endoplasmic Reticulum Stress and Matrix Metalloproteinase in Protecting against Cerebral Ischemia

2021 ◽  
Author(s):  
Angus Y Choi ◽  
Jia Wen Xian ◽  
Sum Yi Ma ◽  
Zhixiu Lin ◽  
Chun Wai Chan
Keyword(s):  
Endoplasmic Reticulum ◽  
Cerebral Ischemia ◽  
Endoplasmic Reticulum Stress ◽  
Blood Brain Barrier ◽  
Neuroprotective Effect ◽  
Water Extract ◽  
Neuronal Cell ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Blood Brain

Stroke is the second leading cause of death in worldwide, in which cerebral ischemia accounts for 87% of all cases. The building up of endoplasmic reticulum stress in cerebral ischemia contributes to the disruption of blood brain barrier and neuronal cell death. The only FDA-approved drug, recombinant tissue plasminogen activator, is still of limited use due to the narrow window period and lack of neuroprotective effect. Therefore, it is necessary to explore alternative treatment on cerebral ischemia. Tianma-Gouteng decoction is a traditional Chinese Medicine prescription used to treat brain diseases in China. In this study, we investigated the neuroprotective effect of a water extract consisting of Gastrodia elata and Uncaria rhynchophylla, which are the two main herbs in the decoction. Cerebral ischemia was induced in rats using middle cerebral artery occlusion. GUW-treated rats have significantly reduced infarction volume and recovered neurological functions. The number of protein aggregates and caspase-12 positive cells were significantly inhibited. In vitro oxygen-glucose deprivation / reoxygenation stroke model demonstrated that the unfolded protein response proteins GRP78 and PDI were upregulated by GUW. Less ubiquitin puncta and normalized ubiquitin distribution indicated the reduction in endoplasmic reticulum stress. Furthermore, a lower Evan blue signal and MMPsense signal was observed, suggesting that GUW may preserve the blood brain barrier integrity through inhibiting MMP activity. Taken together, this suggested that GUW protected ischemic neurons and the blood brain barrier through inhibiting endoplasmic reticulum stress.

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