Samenvatting
Summary blood-brain-barrier
- Vak
- HER901
- Instelling
- Universiteit Leiden (UL)
Summary of 12 pages for the course HER901 at UL (blood-brain-barrier)
[Meer zien]Voorbeeld 2 van de 12 pagina's
Voorbeeld 2 van de 12 pagina's
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Voorbeeld van de inhoud
BBB012024年9月16日 21:25
Factors in CNS effects
Dose
Plasma PK
homeostatic feedback Plasma exposure
Target tissue (site) distribution (BBB transport)
Target tissue exposure
Target binding kinetics effects transduction
Cellular response & homeostatic feedback
Body response & body homeostatic feedback
Approval time for new drugs for CNS drugs is the longest
Take on average 18 yrs from lab to the patients
Success rate is lowest
Failures in Phase 3
The most common reason for discontinuation was failure to demostrate efficacy
Central issues in CNS delivery
Optimal pharmacology in a patient
Therapeutic effect is mainly required on long-term basis, i.e. repeated dosing, which means:
High enough concentration at the site of action during a long enough time
Sometimes acute effects wanted
The unbound drug concentration is the driving force for drug effect
CNS drug delivery (PKPD)
High enough dose will always give effect, buy peripheral side effects may limit possible dose(brain
tumor and cardiotoxicity)
Molecules are too hydrophilic to penetrate the BBB (fast enough)
Molecules are too large to penetrate the BBB(fast enough and/ or in enough quantities)
Effect in preclinical models but not in the clinic*PK or PD)
Species difference?
Model not relevant for clinical condition?
分区 morphodology 的第 1 页
, BBB02
2024年9月17日 9:15
History Paul Ehrlich
Edwin Goldmann
Broman
Reese and Karnovsky, Brightman
BBB function is to control the Protect the brain from variations in external biochemical environment so that it functions optimally
brain environment Take up nutrients and other necessary components for brain function
Discard waste products from brain activity
Data on brain physiology
Barriers of the brain
“There are three principal barrier sites between blood and brain:
The BBB, which is created at the level of the cerebral capillary endothelial cells by tight junction
formation. It is by far the largest surface area for exchange and in the adult human is between 12 and 18
m2 in surface area. No brain cell is further than about 25 μm from a capillary, so once the BBB is
crossed, diffusion distances to neurons and glial cell bodies for solutes and drugs are short. Targeting a
drug across the BBB is therefore the favoured route for global delivery of drugs to all brain cells.
The blood–CSF barrier (BCSFB) lies at the choroid plexuses in the lateral, third and fourth ventricles of
the brain where tight junctions are formed between the epithelial cells at the CSF -facing surface (apical
surface) of the epithelium. Some drugs and solutes enter the brain principally across the choroid
plexuses into CSF, while others enter via both the BBB and BCSFB.
The arachnoid barrier. The brain is enveloped by the arachnoid membrane lying under the dura. The
arachnoid is avascular but lies close to the superior sagittal sinus and is separated from it by the dura.
The arachnoid is a multi-layered epithelium with tight junctions between cells of the inner layer that
form an effective seal. Arachnoid villi project into the sagittal sinus through the dura and a significant
amount of CSF drains into the sinus through these valvelike villi which only allow CSF movement out of
the brain to blood. Transport across the arachnoid membrane is not an important route for the entry of
solutes into brain.”
NVU
the neurovascular unit
A functional unit composed of groups of neurons and their associated astrocytes, interacting with smooth muscle cells and
endothelial cells on the microvessels (arterioles) responsible for their blood supply, and capable of regulating the local blood flow.
The glycocalyx of the neurovascular unit
A negatively charged, surface coat of proteoglycans, glycosaminoglycans, and adsorbed plasma proteins lining the luminal
surface of the endothelium
分区 morphodology 的第 2 页
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