Deck 15: Drug Delivery to the Cns: Breaking Down the Barrier

Question 1

_______________ circulates within the cavities of the CNS between two meningeal layers,the pia matter and the arachnoid.

A) The Blood
B) The amniotic fluid
C) The cerebrospinal fluid
D) The pleural fluid

Answer 1

C

Question 2

A fatty material called __________ coats nerve cells to insulate them and to facilitate rapid communication.

A) eyosin
B) myelin
C) ergosterol
D) structured triacylglycerols

Answer 2

B

Question 3

The ________________ restricts the passive diffusion of hydrophilic and charged compounds from inside the capillary into brain. It has a unique anatomical structure compared to other blood vessels.

A) Blood cerebrospinal fluid barrier
B) Phospholipid bilayer structure
C) Efflux transport proteins system
D) Blood brain barrier (BBB)

Answer 3

D

Question 4

The brain capillaries generally have _________.

A) high pinocytic activity
B) a lack of fenestration
C) low transendothelial electrical resistance
D) moderate paracellular diffusion

Question 5

Factors limiting drug penetration into the brain include:

A) efflux transport proteins
B) tight junction protein complexes
C) enzymatic proteins
D) All of the above

Question 6

Occludin,claudins and intercellular junctional adhesion molecules are the main building blocks of _____________.

A) efflux transport proteins
B) tight junction protein complexes
C) tight Phospholipid bilayer structures
D) dystrophin-associated protein complex

Question 7

While there are restrictions for compounds to gain access to brain,there are mechanisms that can be exploited to facilitate brain penetration,which include:

A) efflux transporters
B) influx transporters
C) receptor mediated transporters
D) enzymatic proteins
E) A & B
F) A & C
G) A & D
H) B & C
I) B & D
J) C & D

Question 8

____________ is a common measure of lipophilicity that shows the where the molecule prefers to exist,in either the aqueous (blood) or lipid membrane environments.

A) Aqueous solubility
B) Polar surface area
C) The octanol/water partition coefficient
D) Hydrogen bonding

Question 9

Lipinski "Rule of Five" aims to correlate a drug candidate's physico-chemical parameters with its absorption,permeability,and pharmacologic efficacy. According to Lipinski's "Rule of Five",Oil/water distribution coefficient (LogP) has to be:

A) ≤ 1
B) ≥ 1
C) ≤ 5
D) ≥ 5

Question 10

According to Lipinski's "Rule of Five",the number of hydrogen bond donors has to be:

A) ≤ 1
B) ≥ 1
C) ≤ 5
D) ≥ 5

Question 11

According to Lipinski's "Rule of Five",the number of hydrogen bond acceptors has to be:

A) ≤ 10
B) ≥ 10
C) ≤ 5
D) ≥ 5

Question 12

For successful CNS therapy,the Active Pharmaceutical Ingredient (API) has to have Polar Surface Area (PSA) smaller than _____ Ų according to Pajouhesh.

A) 50
B) 100
C) 500
D) 1000

Question 13

For successful CNS therapy,the Active Pharmaceutical Ingredient (API) should be _____________.

A) a weak CYP3A4 inducer
B) a potent CYP3A4 inducer
C) an efficient P-glycoprotein substrate
D) a weak P-glycoprotein substrate
E) A & B
F) A & C
G) A & D
H) B & C
I) B & D
J) C & D

Question 14

For successful CNS therapy,the Active Pharmaceutical Ingredient (API) has to have aqueous solubility higher than ____ µg/ml according to Pajouhesh.

A) 10
B) 60
C) 100
D) 600

Question 15

Unlike the first generation antihistamines,the second-generation antihistamines (e.g. Loratidine (Claritin)),are more ____________ and therefore lack the ability to appreciably cross the BBB thus failing to produce adverse effects in the CNS.

A) hydrophobic
B) hydrophilic
C) lipophobic
D) lipophilic
E) water-soluble

Question 16

______________ delivery is an invasive technique,which involves administration of therapeutic agents directly into the brain interstitium. This delivery strategy helps a drug to bypass the BBB and will theoretically yield high intracranial drug concentrations while reducing systemic toxicity.

A) Superficial Light
B) Intrathecal
C) Spinal
D) Interstitial

Question 17

_____________ involves chemically transforming the active drug,which does not have the ability to cross the BBB,to an inactive chemical derivative through chemical modifications.

A) Bioconjugation technique
B) Prodrug approach
C) Polymeric decorations technique
D) Encapsulation technique
E) Lipidization technique

Question 18

The _____________ involves the introduction of a lipophilic moiety,which facilitates BBB penetrance and the trapping drugs in the brain.

A) bioconjugation technique
B) prodrug approach
C) polymeric decorations technique
D) encapsulation technique
E) lipidization technique

Question 19

Heroin,the diacetylated form of morphine,exhibits a permeability coefficient that is 100-fold higher than morphine across the BBB because it is more ____________.

A) hydrophobic
B) hydrophilic
C) lipophobic
D) lipophilic
E) water-soluble

Question 20

Glycosylation strategies are also utilized to increase the permeability of dopamine across the BBB through the use of a galactose dopamine conjugate via the ______ influx transporter.

A) ENT
B) OAT
C) LAT1
D) GLUT1

Question 21

Angiopep-2 targets the ____________.

A) glucose transporter
B) transferrin receptor
C) low-density lipoprotein receptor
D) large neutral amino acid transporter
E) diphtheria toxin receptor

Question 22

COG-133 targets the ___________.

A) glucose transporter
B) transferrin receptor
C) low-density lipoprotein receptor
D) large neutral amino acid transporter
E) diphtheria toxin receptor

Question 23

Conventional liposomes grafted with _____________ are considered to be sterically stable and safe from degradation.

A) a PEG layer
B) a targeting antibody
C) a cell-penetrating peptide
D) a stimuli-sensitive moiety

Question 24

___________ consist of one or more concentric spheres of lipid bilayers separated by water or aqueous buffer compartments. Many studies use them as drug carriers in treating diseases of the central nerve system.

A) Liposomes
B) Solid Lipid Nanoparticles (SLNs)
C) Nanocapsules
D) Niosomes

Question 25

____________ are spherical solid particles of a lipid core matrix that can solubilize lipophilic molecules. The lipid core is stabilized by surfactants (emulsifiers).

A) Liposomes
B) Solid Lipid Nanoparticles (SLNs)
C) Nanocapsules
D) Niosomes

Question 26

_____________ is natural polymer and is classified as a linear polysaccharide composed of randomly distributed β-(1-4)-linked D-glucosamine and N-acetyl-D-glucosamine. It has a positive charge under acidic conditions coming from protonation of its free amino groups.

A) Poly(lactic-co-glycolic acid) copolymer (PLGA)
B) Polyethylene glycol
C) Polyethylenimine
D) Chitosan

Question 27

The mechanism of action of drug delivery by polymeric/lipid carrier systems across the BBB could be attributed to:

A) the increased retention of the carrier system in the brain capillaries along with sustained adsorption of the capillary walls creating a higher concentration gradient that would enhance the transport of drug across the endothelial cell layer and as a result its delivery to the brain.
B) the use of surfactants,which could aid in the solubilization of endothelial cell membrane lipids leading to membrane fluidisation and enhanced drug permeability at the BBB
C) the ability of the carrier system to facilitate an opening of the tight junctions between the endothelial cells. The drug could then permeate through the tight junctions either in free form or together with the nanoparticles.
D) the engulfment of the whole carrier system into the cell. The nanoparticles may be endocytosed by the endothelial cells followed by the sustained and/or controlled release of the drug within these cells
E) Any of the above

Question 28

The novel drug carrier systems for drug targeting to brain have to be:

A) non-toxic
B) biocompatible
C) biodegradable
D) of a particle size ranging from 10 - 100 nm
E) stable in-vivo
F) All of the above
G) None of the above

Question 29

The BBB defense mechanisms in controlling the trafficking of various chemical moieties in and out of the brain,include:

A) complete sealing of the luminal vascular endothelial cells by tight junction protein complexes such as occludin,claudins
B) lack of fenestration in the BBB vasculature
C) astrocytic foot processes
D) efflux transport proteins ("pumps")
E) enzymatic proteins in the BBB vascular endothelia
F) All of the above
G) None of the above

Question 30

The best successful strategy to deliver therapeutic agents to the CNS is:

A) the use of targeting moieties
B) the use of pegylation
C) the use of chemical modification
D) nterstitial delivery
E) the use of prodrugs
F) All of the above
G) None of the above

Question 31

Match the following:
Term
___ TEER

A) a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system B. facilitates the transport of glucose across the blood brain barrier.
C) a measure of how tight a capillary is sealed
D) facilitates the transport of organic anions across the blood brain barrier.
E) a highly selective permeability barrier that separates the circulating blood from the cerebrospinal fluid in the central nervous system
F) the part of the nervous system consisting of the brain and spinal cord.
B) facilitates the transport of glucose across the blood brain barrier.
C) a measure of how tight a capillary is sealed
D) facilitates the transport of organic anions across the blood brain barrier.
E) a highly selective permeability barrier that separates the circulating blood from the cerebrospinal fluid in the central nervous system
F) the part of the nervous system consisting of the brain and spinal cord.

Question 32

Match the following:
Term
___ BBB

A) a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system B. facilitates the transport of glucose across the blood brain barrier.
C) a measure of how tight a capillary is sealed
D) facilitates the transport of organic anions across the blood brain barrier.
E) a highly selective permeability barrier that separates the circulating blood from the cerebrospinal fluid in the central nervous system
F) the part of the nervous system consisting of the brain and spinal cord.
B) facilitates the transport of glucose across the blood brain barrier.
C) a measure of how tight a capillary is sealed
D) facilitates the transport of organic anions across the blood brain barrier.
E) a highly selective permeability barrier that separates the circulating blood from the cerebrospinal fluid in the central nervous system
F) the part of the nervous system consisting of the brain and spinal cord.

Question 33

Match the following:
Term
___ CNS

A) a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system B. facilitates the transport of glucose across the blood brain barrier.
C) a measure of how tight a capillary is sealed
D) facilitates the transport of organic anions across the blood brain barrier.
E) a highly selective permeability barrier that separates the circulating blood from the cerebrospinal fluid in the central nervous system
F) the part of the nervous system consisting of the brain and spinal cord.
B) facilitates the transport of glucose across the blood brain barrier.
C) a measure of how tight a capillary is sealed
D) facilitates the transport of organic anions across the blood brain barrier.
E) a highly selective permeability barrier that separates the circulating blood from the cerebrospinal fluid in the central nervous system
F) the part of the nervous system consisting of the brain and spinal cord.

Question 34

Match the following:
Term
___ BCSFB

A) a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system B. facilitates the transport of glucose across the blood brain barrier.
C) a measure of how tight a capillary is sealed
D) facilitates the transport of organic anions across the blood brain barrier.
E) a highly selective permeability barrier that separates the circulating blood from the cerebrospinal fluid in the central nervous system
F) the part of the nervous system consisting of the brain and spinal cord.
B) facilitates the transport of glucose across the blood brain barrier.
C) a measure of how tight a capillary is sealed
D) facilitates the transport of organic anions across the blood brain barrier.
E) a highly selective permeability barrier that separates the circulating blood from the cerebrospinal fluid in the central nervous system
F) the part of the nervous system consisting of the brain and spinal cord.

Question 35

Match the following:
Term
___ OAT

A) a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system B. facilitates the transport of glucose across the blood brain barrier.
C) a measure of how tight a capillary is sealed
D) facilitates the transport of organic anions across the blood brain barrier.
E) a highly selective permeability barrier that separates the circulating blood from the cerebrospinal fluid in the central nervous system
F) the part of the nervous system consisting of the brain and spinal cord.
B) facilitates the transport of glucose across the blood brain barrier.
C) a measure of how tight a capillary is sealed
D) facilitates the transport of organic anions across the blood brain barrier.
E) a highly selective permeability barrier that separates the circulating blood from the cerebrospinal fluid in the central nervous system
F) the part of the nervous system consisting of the brain and spinal cord.

Question 36

Match the following:
Term
___ GULT

A) a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system B. facilitates the transport of glucose across the blood brain barrier.
C) a measure of how tight a capillary is sealed
D) facilitates the transport of organic anions across the blood brain barrier.
E) a highly selective permeability barrier that separates the circulating blood from the cerebrospinal fluid in the central nervous system
F) the part of the nervous system consisting of the brain and spinal cord.
B) facilitates the transport of glucose across the blood brain barrier.
C) a measure of how tight a capillary is sealed
D) facilitates the transport of organic anions across the blood brain barrier.
E) a highly selective permeability barrier that separates the circulating blood from the cerebrospinal fluid in the central nervous system
F) the part of the nervous system consisting of the brain and spinal cord.

Question 37

What is the BBB and what are its functions?

Question 38

What are the BBB defense mechanisms in controlling the trafficking of various chemical moieties in and out of the brain?

Question 39

What are the physico-chemical properties governing the uptake of CNS drugs into the brain across the BBB?

Question 40

Why does Benadryl causes drowsiness while Claritin doesn't?

Question 41

What are the current strategies for CNS drug delivery?

Question 42

What are the currently known targeting moieties that can be used to enhance CNS drug delivery?

Question 43

What are the current novel drug delivery carrier systems used in CNS delivery?

Question 44

How are novel drug delivery carrier systems (NDDS) beneficial in CNS drug delivery?

Question 45

How can liposomes or SLNs be tailor-designed to enhance CNS drug delivery?

Question 46

What is the best strategy to deliver therapeutic agents to the CNS?

Question 47

Fill in the blanks in the illustration of the central nervous system below.

Question 48

Label the figure below showing a cross-section of a brain capillary,which represents the structure of the blood- brain barrier (BBB). The BBB does not represent a distinct organ but rather is a functional concept.

Question 49

Add labels to the figure below. Liposomes as a novel colloidal drug delivery system. Liposomes can be tailor designed to adopt diverse grafting strategies on their surfaces or modifications within the liposomal composition to provide tissue specificity and targetability

Question 50

Fill in the blanks: Tight junction protein complexes are made up of multiple proteins including _______,_______,and _______. The sealing of the luminal endothelial cells of the BBB is so effective that __________ is orders of magnitude higher than that of the peripheral capillaries.

Question 51

Fill in the blanks: The ___________ represents one example of interstitial drug delivery to the CNS. It uses a solenoid (coil wound into a tightly packed helix) pumping mechanism. Another example is the ____________,which delivers drugs via a peristaltic mechanism.

Question 52

Fill in the blank: A more recent technique for interstitial drug delivery is the use of ____________. Such intracranial drug formulations bypass the BBB and locally release a therapeutic agent to establish a sustained concentration in the brain.

Question 53

Fill in the blanks: PEGylation improves the pharmacokinetic and pharmacodynamic profiles by increasing ________ and ________,decreasing _________,which protects it from _______.

Question 54

Fill in the blanks: Colloidal carrier systems grafted with ________ moieties are considered "smart" carrier systems,which alter and modify their chemical structure or configuration based on a change in the biological environment. Such technology is used to target diseased tissues by using cues specific to the targeted tissue or cell. For example,______,________,_______,_______,or ________ represent some of the currently used triggers to design smart bioresponsive colloidal carrier systems.

Question 55

Fill in the blanks: Neuronal survival requires the nutrient iron,which is predominantly delivered to the brain by __________. It is an iron-binding blood plasma glycoprotein that governs the level of free iron in biological fluids. It is the major source of iron delivery to neurons and satisfies the iron requirements for maintaining myelination. It has been widely explored as ___________ for brain drug delivery.

Question 56

Fill in the blanks: One of the predominant receptors found on BBB endothelium is the low-density lipoprotein receptor-related protein. The _________ can bind to the low-density-lipoprotein receptor-related protein. The critical binding region is a sequence called the ________.

Question 57

Fill in the blanks: Novel delivery carrier systems adopted in CNS drug delivery are usually based on _________,_________,or _________.