Lecture 13 Part 2: Liver Disease- pharmaceutical perspectives Flashcards
What are interferons? (2 points)
Proteins made and released by host cells in response to the presence of pathogens.
They interfere with viral replication within host cells and have a MW >40 kDa
What is interferon therapy? (3 points)
- therapy which has been used for the treatment of chronic hepatitis B for many decades
- normalises alanine aminotransferase levels
- suppresses hepatitis b virus
What are the limitations of conventional interferon injections? (3 points)
- short half life
- high incidence of dose related side effects
- beneficial only in the short term
What are the advanced interferon injections? (3 points)
- PEGylated interferons approved by FDA for the treatment of hepatitis B and C
- slows down the rate of viral replication
- available as α2a (PEGIntron) and α2b (Pegasys)
What are the advantages of PEGylated interferons? (7 points)
- decreased immunogenicity of protein drugs
- optimised rate of absorption following SC injection
- reduced renal and cellular clearance –> extended blood circulating life
- increased AUC
- reduced injection frequency (3x week –> 1x week)
- increased solubility
- enhanced protease resistance
What is PEGylation?
- covalent coupling of a non toxic, hydrophilic polyethylene glycol to pharmaceutical ingredients such as proteins and phospholipids.
What is the history of PEGylation? (3 points)
- first developed from pioneering work carried out in 1970s
- in 1981: first PEG protein company was formed called Enzon
- in 1990: the first approved PEG drug conjugate was developed- PEG-adenosine deaminase
What are opsonins?
Molecules that act as a binding enhancer for the process of phagocytosis
How can opsonins be used? (3 points)
- can attach it onto a target such as bacteria or other foreign bodies
- can allow it to be recognised by the receptors on the macrophages
- makes the invading bacteria/foreign body more susceptible to destruction by phagocytes
What are examples of opsonins? (2 points)
- Antibodies e.g. IgG and IgA
- components of the complement system e.g. C3b
What is the liver designed to maintain?
The body’s chemical and metabolic homeostasis
What is opsonisation?
When particles or macromolecules are coated with opsonins
What kind of particles/macromolecules are more efficiently opsonised? (3 points)
- Those that have a hydrophobic surface.
- They are easily recognised by the macrophage and cleared rapidly.
- particles with a hydrophilic surface resist opsonisation and are cleared more slowly
What is the effect of PEGylation on opsonisation? (4 points)
- PEGylation on the surface of particles sterically inhibit hydrophobic and electrostatic interactions of opsonins and the particles
- Prevents adsorption of opsonins on the particles
- Slows recognition by phagocytic cells such as macrophages of the RES
- reduces immunogenicity to the particles
What is PEGylation also known as?
Stealth technology
What is stealth technology in drug delivery?
-When the surface of a carrier is coated with hydrophilic polymers
What are the different polymers used in stealth technology? (4 points)
- PEG
- Poloxamer
- Poloxamine
- Polysaccharides
What is doxil? (3 points)
- PEGylated liposomal doxorubicin
- consists of single lipid bilayer membrane with HSPC and cholesterol which separates the internal aqueous compartment from the external medium
- Drug is encapsulated in the aqueous compartment
What are the advantages of PEGylated doxil?
- more predictable PK
- Consistent release within therapeutic levels
- able to achieve sustained release
- less frequent administration
What are the advantages of PEGylation of nanoparticles/macromolecules? (5 points)
- reduces immunogenicity
- extends circulating life
- increases aqueous solubility
- improves PK profile
- offers opportunities for new delivery formats and dosing regimens, as well as extending the patent life.
What are the limitations of PEGylation? (2 points)
- May interfere with ability of a protein to bind to its receptors and decrease biologic effects
- high cost in formulation of products
What are the three main types of liver cells? (3 points)
- hepatocytes (hepatic parenchymal)
- Kupffer cells (nonhepatic parenchymal)
- endothelial cells (nonhepatic parenchymal)
What are kupffer cells? (5 points)
- Constitute about 15% of liver cells
- located along sinusoid
- accounts for 80-90% of resident macrophages in the body (part of RES)
- Life span of ~14 months
- only ~3% is responsible for cell population renewal in vivo
What are the two types of hepatocyte-directed delivery? (2 points)
- Passive targeting using colloidal carriers
- Receptor mediated (active) targeting
