Publications by authors named "Elizabeth C M de Lange"

Drug-target binding determines a drug's pharmacodynamics but can also have a profound impact on a drug's pharmacokinetics, known as target-mediated drug disposition (TMDD). TMDD models describe the influence of drug-target binding and target turnover on unbound drug concentrations and are frequently used for biologics and drugs with nonlinear plasma pharmacokinetics. For drug targets expressed in tissues, the effect of TMDD may not be detected when analyzing plasma concentration curves, but it might still affect tissue concentrations and occupancy.

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Chemically-induced seizures, as a result of exposure to a neurotoxic compound, present a serious health concern. Compounds can elicit seizure activity through disruption of neuronal signaling by neurotransmitters, either by mimicking, modulating or antagonizing their action at the receptor or interfering with their metabolism. Benzodiazepines, such as diazepam and midazolam, and barbiturates are the mainstay of treatment of seizures.

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Background And Purpose: Morphine is important for treatment of acute and chronic pain. However, there is high interpatient variability and often inadequate pain relief and adverse effects. To better understand variability in the dose-effect relationships of morphine, we investigated the effects of its non-linear blood-brain barrier (BBB) transport on μ-receptor occupancy in different CNS locations, in conjunction with its main metabolites that bind to the same receptor.

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Neurotropic viruses may cause meningitis, myelitis, encephalitis, or meningoencephalitis. These inflammatory conditions of the central nervous system (CNS) may have serious and devastating consequences if not treated adequately. In this review, we first summarize how neurotropic viruses can enter the CNS by (1) crossing the blood-brain barrier or blood-cerebrospinal fluid barrier; (2) invading the nose via the olfactory route; or (3) invading the peripheral nervous system.

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Drug metabolism is one of the critical determinants of drug disposition throughout the body. While traditionally associated with the liver, recent research has unveiled the presence and functional significance of drug-metabolizing enzymes (DMEs) within the brain. Specifically, cytochrome P-450 enzymes (CYPs) and UDP-glucuronosyltransferases (UGTs) enzymes have emerged as key players in drug biotransformation within the central nervous system (CNS).

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Article Synopsis
  • The study analyzes the steady-state transport of drugs across the blood-brain barrier (BBB) using the LeiCNS-PK3.0 physiological-based pharmacokinetic (PBPK) model in mice, given that mouse and human brain pharmacokinetics differ due to variations in central nervous system (CNS) physiology.
  • The researchers utilized data on the brain pharmacokinetics of 10 drugs across various mouse strains, estimating key parameters to predict drug behavior in mouse brain extracellular fluid.
  • Results showed that the model accurately predicted brain pharmacokinetics for 7 out of 10 drugs within acceptable error limits, indicating it can effectively bridge the gap in understanding drug transport from mouse models to potential human
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Alzheimer's disease (AD) is an aging-related neurodegenerative disease, leading to the progressive loss of memory and other cognitive functions. As there is still no cure for AD, the growth in the number of susceptible individuals represents a major emerging threat to public health. Currently, the pathogenesis and etiology of AD remain poorly understood, while no efficient treatments are available to slow down the degenerative effects of AD.

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Drug combination therapy is a promising strategy to enhance the desired therapeutic effect, while reducing side effects. High-throughput pairwise drug combination screening is a commonly used method for discovering favorable drug interactions, but is time-consuming and costly. Here, we investigate the use of reaction network topology-guided design of combination therapy as a predictive in silico drug-drug interaction screening approach.

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SARS-CoV-2 was shown to infect and persist in the human brain cells for up to 230 days, highlighting the need to treat the brain viral load. The CNS disposition of the antiCOVID-19 drugs: Remdesivir, Molnupiravir, and Nirmatrelvir, remains, however, unexplored. Here, we assessed the human brain pharmacokinetic profile (PK) against the EC values of the antiCOVID-19 drugs to predict drugs with favorable brain PK against the delta and the omicron variants.

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The bidirectional pulsatile movement of cerebrospinal fluid (CSF), instead of the traditionally believed unidirectional and constant CSF circulation, has been demonstrated. In the present study, the structure and parameters of the CSF compartments were revisited in our comprehensive and validated central nervous system (CNS)-specific, physiologically based pharmacokinetic (PBPK) model of healthy rats (LeiCNS-PK3.0).

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Background: Very little knowledge exists on the impact of Alzheimer's disease on the CNS target site pharmacokinetics (PK).

Aim: To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer's patients using the physiologically based LeiCNS-PK3.0 model.

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There is growing evidence that membrane transporters expressed at the blood-brain barrier (BBB) and brain parenchymal cells play an important role in Alzheimer's disease (AD) development and progression. However, quantitative information about changes in transporter protein expression at neurovascular unit cells in AD is limited. Here, we studied the changes in the absolute protein expression of five ATP-binding cassette (ABC) and thirteen solute carrier (SLC) transporters in the isolated brain microvessels and brain cortical tissue of TgF344-AD rats compared to age-matched wild-type (WT) animals using liquid chromatography tandem mass spectrometry based quantitative targeted absolute proteomic analysis.

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Alzheimer's disease (AD) is the most common form of dementia and typically characterized by the accumulation of amyloid-β plaques and tau tangles. Intriguingly, there also exists a group of elderly which do not develop dementia during their life, despite the AD neuropathology, the so-called non-demented individuals with AD neuropathology (NDAN). In this review, we provide extensive background on AD pathology and normal aging and discuss potential mechanisms that enable these NDAN individuals to remain cognitively intact.

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Micrometastatic brain tumor cells, which cause recurrence of malignant brain tumors, are often protected by the intact blood-brain barrier (BBB). Therefore, it is essential to deliver effective drugs across not only the disrupted blood-tumor barrier (BTB) but also the intact BBB to effectively treat malignant brain tumors. Our aim is to predict pharmacokinetic (PK) profiles in brain tumor regions with the disrupted BTB and the intact BBB to support the successful drug development for malignant brain tumors.

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This review addresses questions on how to accomplish successful central nervous system (CNS) drug delivery (i.e., having the right concentration at the right CNS site, at the right time), by understanding the rate and extent of blood-brain barrier (BBB) transport and intra-CNS distribution in relation to CNS target site(s) exposure.

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Brain drug delivery may be restricted by the blood-brain barrier (BBB), and enhancement by liposome-based drug delivery strategies has been investigated. As access to the human brain is limited, many studies have been performed in experimental animals. Whereas providing interesting data, such studies have room for improvement to provide mechanistic insight into the rate and extent of specifically BBB transport and intrabrain distribution processes that all together govern CNS target delivery of the free drug.

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Predicting brain pharmacokinetics is critical for central nervous system (CNS) drug development yet difficult due to ethical restrictions of human brain sampling. CNS pharmacokinetic (PK) profiles are often altered in CNS diseases due to disease-specific pathophysiology. We previously published a comprehensive CNS physiologically-based PK (PBPK) model that predicted the PK profiles of small drugs at brain and cerebrospinal fluid compartments.

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Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting many individuals worldwide with no effective treatment to date. AD is characterized by the formation of senile plaques and neurofibrillary tangles, followed by neurodegeneration, which leads to cognitive decline and eventually death.

Introduction: In AD, pathological changes occur many years before disease onset.

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The blood-brain barrier (BBB) is equipped with unique physical and functional processes that control central nervous system (CNS) drug transport and the resulting concentration-time profiles (PK). In CNS diseases, the altered BBB and CNS pathophysiology may affect the CNS PK at the drug target sites in the brain extracellular fluid (brain) and intracellular fluid (brain) that may result in changes in CNS drug effects. Here, we used our human CNS physiologically-based PK model (LeiCNS-PK3.

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The development of drugs targeting the brain still faces a high failure rate. One of the reasons is a lack of quantitative understanding of the complex processes that govern the pharmacokinetics (PK) of a drug within the brain. While a number of models on drug distribution into and within the brain is available, none of these addresses the combination of factors that affect local drug concentrations in brain extracellular fluid (brain ECF).

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Purpose: We have developed a 3D brain unit network model to understand the spatial-temporal distribution of a drug within the brain under different (normal and disease) conditions. Our main aim is to study the impact of disease-induced changes in drug transport processes on spatial drug distribution within the brain extracellular fluid (ECF).

Methods: The 3D brain unit network consists of multiple connected single 3D brain units in which the brain capillaries surround the brain ECF.

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To diagnose and treat early-stage (preclinical) Alzheimer's disease (AD) patients, we need body-fluid-based biomarkers that reflect the processes that occur in this stage, but current knowledge on associated processes is lacking. As human studies on (possible) onset and early-stage AD would be extremely expensive and time-consuming, we investigate the potential value of animal AD models to help to fill this knowledge gap. We provide a comprehensive overview of processes associated with AD pathogenesis and biomarkers, current knowledge on AD-related biomarkers derived from on human and animal brains and body fluids, comparisons of biomarkers obtained in human AD and frequently used animal AD models, and emerging body-fluid-based biomarkers.

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Cognitive aging creates major individual and societal burden, motivating search for treatment and preventive care strategies. Behavioural interventions can improve cognitive performance in older age, but effects are small. Basic research has implicated dopaminergic signalling in plasticity.

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Background And Purpose: K 11.1 (hERG) channel blockade is an adverse effect of many drugs and lead compounds, associated with lethal cardiac arrhythmias. LUF7244 is a negative allosteric modulator/activator of K 11.

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