Molecular therapy
Inhoudsopgave
Week 1 Pharmacodynamics and pharmacokinetics................................................................................ 4
LE Personalized healthcare (Alain van Gool) ....................................................................................... 4
LE Pharmacology and Pharmacokinetics (Jan Koenderink) ................................................................. 5
Further reading interactive clinical pharmacology (catch-up on toxicology course BA) .................... 8
LE Drug transporters & metabolism .................................................................................................. 14
Transporters .................................................................................................................................. 14
LE Biotransformation......................................................................................................................... 16
E-learning Biotransformation of Xenobiotics .................................................................................... 18
General principles.......................................................................................................................... 18
Phase I reactions............................................................................................................................ 19
Phase II reactions........................................................................................................................... 21
E-learning transporters ..................................................................................................................... 24
Introduction ................................................................................................................................... 24
Week 2 Drug delivery & development .................................................................................................. 29
LE Drug Targeting and Delivery (Part I) (Rik Oude Egberink) ............................................................ 29
LE Drug Targeting and Delivery (Part II) ............................................................................................ 34
Antibody drug conjugates (ADCs) = antibody with cytotoxic conjugate ....................................... 34
Factors that influence tissue targeting: ......................................................................................... 35
Targeted Cytokines ........................................................................................................................ 35
Targeting:....................................................................................................................................... 35
Cellular molecule import: .............................................................................................................. 35
Oligonucleotides ............................................................................................................................ 36
Cellular uptake............................................................................................................................... 37
Oligonucleotide-based therapeutics ............................................................................................. 37
LE Drug Development ........................................................................................................................ 38
History of therapeutics .................................................................................................................. 38
Current small molecule drug development pipeline: different stage & assays ............................ 38
Small molecule drugs vs biologics (protein therapeutics) ............................................................. 40
Week 3 Genetic therapy for retinal disease .......................................................................................... 43
LE Genetic Therapy for inherited Retinal Disease ............................................................................. 43
LE Gene Augmentation Therapy........................................................................................................ 44
LE Splicing modulation / RNA therapy .............................................................................................. 45
, LCA ................................................................................................................................................. 45
Stargardt disease ........................................................................................................................... 46
LE Genome editing therapy ............................................................................................................... 47
Types of genome editing methods ................................................................................................ 47
Partly removing intron .................................................................................................................. 48
Base editing ................................................................................................................................... 48
PRIME editing ................................................................................................................................ 48
RNA editing .................................................................................................................................... 48
Week 4 Therapy of renal tubulopathies (jojanneke huck phd, neurophysiologist department of
medical biosciences RUMC) .................................................................................................................. 49
Renal Physiology................................................................................................................................ 49
Current studies and therapy of renal tubulopathies ......................................................................... 50
How to test the 3 functional defects in channels/transporters: ................................................... 50
Proximal tubule ............................................................................................................................. 51
Thick ascending lis of Henle (TAL) ................................................................................................. 52
Distal convoluted tubule ............................................................................................................... 52
Collecting duct (principle cell) ....................................................................................................... 53
Collecting duct (a-intercalated cell) .............................................................................................. 53
Drug-induced renal pathologies ........................................................................................................ 54
Classification Drug-induced renal failure: ..................................................................................... 54
Diagnosis of acute renal failure: .................................................................................................... 55
Week 5 Modern cancer therapies ......................................................................................................... 56
Tutorial Lecture Receptor Tyrosine Kinases ...................................................................................... 56
Cytokine receptors ........................................................................................................................ 56
Receptor tyrosine kinases (RTKs) .................................................................................................. 57
Cancer therapeutics .......................................................................................................................... 62
Molecular mechanisms of cancer.................................................................................................. 62
Common therapeutics ................................................................................................................... 62
Novel therapies targeting signaling molecules ............................................................................. 63
Lung cancer mechanisms/treatment ............................................................................................ 65
Modern cancer therapeutics Clinical aspects in lung cancer treatment........................................... 65
Week 6 Modern pain management ...................................................................................................... 67
LE GPCRs mediated signaling ............................................................................................................ 67
Signaling molecules ....................................................................................................................... 67
Intracellular receptors ................................................................................................................... 67
Cell-surface ion channels............................................................................................................... 68
, Cell-surface GPCRs......................................................................................................................... 68
Activation mechanism of GPCRs ................................................................................................... 68
Heterotrimeric G proteins ............................................................................................................. 69
Different effector systems............................................................................................................. 70
Common concepts in signaling ...................................................................................................... 72
De-activation ................................................................................................................................. 72
Crosstalk ........................................................................................................................................ 73
LE GPCRs and pain management....................................................................................................... 73
Opioid receptors ............................................................................................................................ 78
GPCR oligomerization ........................................................................ Error! Bookmark not defined.
Biased agonism .................................................................................. Error! Bookmark not defined.
,Week 1 Pharmacodynamics and pharmacokinetics
SMDs
LE Personalized healthcare (Alain van Gool)
,LE Pharmacology and Pharmacokinetics (Jan Koenderink)
Pharmacology is the science that is concerned with the uses, effects and modes of action of
chemicals on the function of living system
Pharmacokinetics what does the patient/body do with the drug (movement through the body) =
absorption, distribution, metabolism, excretion (ADME).
Pharmacodynamics what does the drug do with the patient = therapeutic or adverse effects
(action/interaction)
Pharmacokinetics + Pharmacodynamics = Rational Pharmacotherapy
- Mechanism-based pharmacotherapy (rational pharmacotherapy) or
- Evidence-based pharmacotherapy (no clue how it works (like paracetamol)
- Agonist = stimulates receptor
- Partial agonist
- Antagonist = inhibitor blocking receptor
Receptor types:
Binding sites:
,Inside cell lot of K (potassium) outside lot of Na (sodium) = mnemonic: the cell possess potassium,
and is surrounded by sodium.
Relation concentration – receptor occupation. Lower concentration for more binding
Receptor-antagonism
- Competitive: if agonist binds and antagonist is added, you need more agonist for the same
receptor occupation (graph moves to the right)
- Non-competitive: when antagonist is covalently bound (permanently bound) to the receptor
at another binding site as the agonist, it inhibits the biological response of the receptor to
the agonist without competing for the binding site
- Allosteric antagonist/agonist binds to different location called allosteric site and doesn’t
effect the affinity of the orthosteric antagonist/agonist
, Plasma travels through body and can be taken from anywhere to see if it contains toxins
Uptake from quick to slow (pharmacodynamics)
- Intravenous
- Intramuscular
- Subcutaneous (fatty layer under skin)
- Oral
Drug from small intestines through enterocyte cells into the portal vein to the liver. Function liver is
to detoxify (modify drugs, excrete in bile).
Vd = F x D / C0
- Vd= Volume of distribution
- F= bioavailability
- D = dose
- C0 = concentration at time 0 in the blood
Inhoudsopgave
Week 1 Pharmacodynamics and pharmacokinetics................................................................................ 4
LE Personalized healthcare (Alain van Gool) ....................................................................................... 4
LE Pharmacology and Pharmacokinetics (Jan Koenderink) ................................................................. 5
Further reading interactive clinical pharmacology (catch-up on toxicology course BA) .................... 8
LE Drug transporters & metabolism .................................................................................................. 14
Transporters .................................................................................................................................. 14
LE Biotransformation......................................................................................................................... 16
E-learning Biotransformation of Xenobiotics .................................................................................... 18
General principles.......................................................................................................................... 18
Phase I reactions............................................................................................................................ 19
Phase II reactions........................................................................................................................... 21
E-learning transporters ..................................................................................................................... 24
Introduction ................................................................................................................................... 24
Week 2 Drug delivery & development .................................................................................................. 29
LE Drug Targeting and Delivery (Part I) (Rik Oude Egberink) ............................................................ 29
LE Drug Targeting and Delivery (Part II) ............................................................................................ 34
Antibody drug conjugates (ADCs) = antibody with cytotoxic conjugate ....................................... 34
Factors that influence tissue targeting: ......................................................................................... 35
Targeted Cytokines ........................................................................................................................ 35
Targeting:....................................................................................................................................... 35
Cellular molecule import: .............................................................................................................. 35
Oligonucleotides ............................................................................................................................ 36
Cellular uptake............................................................................................................................... 37
Oligonucleotide-based therapeutics ............................................................................................. 37
LE Drug Development ........................................................................................................................ 38
History of therapeutics .................................................................................................................. 38
Current small molecule drug development pipeline: different stage & assays ............................ 38
Small molecule drugs vs biologics (protein therapeutics) ............................................................. 40
Week 3 Genetic therapy for retinal disease .......................................................................................... 43
LE Genetic Therapy for inherited Retinal Disease ............................................................................. 43
LE Gene Augmentation Therapy........................................................................................................ 44
LE Splicing modulation / RNA therapy .............................................................................................. 45
, LCA ................................................................................................................................................. 45
Stargardt disease ........................................................................................................................... 46
LE Genome editing therapy ............................................................................................................... 47
Types of genome editing methods ................................................................................................ 47
Partly removing intron .................................................................................................................. 48
Base editing ................................................................................................................................... 48
PRIME editing ................................................................................................................................ 48
RNA editing .................................................................................................................................... 48
Week 4 Therapy of renal tubulopathies (jojanneke huck phd, neurophysiologist department of
medical biosciences RUMC) .................................................................................................................. 49
Renal Physiology................................................................................................................................ 49
Current studies and therapy of renal tubulopathies ......................................................................... 50
How to test the 3 functional defects in channels/transporters: ................................................... 50
Proximal tubule ............................................................................................................................. 51
Thick ascending lis of Henle (TAL) ................................................................................................. 52
Distal convoluted tubule ............................................................................................................... 52
Collecting duct (principle cell) ....................................................................................................... 53
Collecting duct (a-intercalated cell) .............................................................................................. 53
Drug-induced renal pathologies ........................................................................................................ 54
Classification Drug-induced renal failure: ..................................................................................... 54
Diagnosis of acute renal failure: .................................................................................................... 55
Week 5 Modern cancer therapies ......................................................................................................... 56
Tutorial Lecture Receptor Tyrosine Kinases ...................................................................................... 56
Cytokine receptors ........................................................................................................................ 56
Receptor tyrosine kinases (RTKs) .................................................................................................. 57
Cancer therapeutics .......................................................................................................................... 62
Molecular mechanisms of cancer.................................................................................................. 62
Common therapeutics ................................................................................................................... 62
Novel therapies targeting signaling molecules ............................................................................. 63
Lung cancer mechanisms/treatment ............................................................................................ 65
Modern cancer therapeutics Clinical aspects in lung cancer treatment........................................... 65
Week 6 Modern pain management ...................................................................................................... 67
LE GPCRs mediated signaling ............................................................................................................ 67
Signaling molecules ....................................................................................................................... 67
Intracellular receptors ................................................................................................................... 67
Cell-surface ion channels............................................................................................................... 68
, Cell-surface GPCRs......................................................................................................................... 68
Activation mechanism of GPCRs ................................................................................................... 68
Heterotrimeric G proteins ............................................................................................................. 69
Different effector systems............................................................................................................. 70
Common concepts in signaling ...................................................................................................... 72
De-activation ................................................................................................................................. 72
Crosstalk ........................................................................................................................................ 73
LE GPCRs and pain management....................................................................................................... 73
Opioid receptors ............................................................................................................................ 78
GPCR oligomerization ........................................................................ Error! Bookmark not defined.
Biased agonism .................................................................................. Error! Bookmark not defined.
,Week 1 Pharmacodynamics and pharmacokinetics
SMDs
LE Personalized healthcare (Alain van Gool)
,LE Pharmacology and Pharmacokinetics (Jan Koenderink)
Pharmacology is the science that is concerned with the uses, effects and modes of action of
chemicals on the function of living system
Pharmacokinetics what does the patient/body do with the drug (movement through the body) =
absorption, distribution, metabolism, excretion (ADME).
Pharmacodynamics what does the drug do with the patient = therapeutic or adverse effects
(action/interaction)
Pharmacokinetics + Pharmacodynamics = Rational Pharmacotherapy
- Mechanism-based pharmacotherapy (rational pharmacotherapy) or
- Evidence-based pharmacotherapy (no clue how it works (like paracetamol)
- Agonist = stimulates receptor
- Partial agonist
- Antagonist = inhibitor blocking receptor
Receptor types:
Binding sites:
,Inside cell lot of K (potassium) outside lot of Na (sodium) = mnemonic: the cell possess potassium,
and is surrounded by sodium.
Relation concentration – receptor occupation. Lower concentration for more binding
Receptor-antagonism
- Competitive: if agonist binds and antagonist is added, you need more agonist for the same
receptor occupation (graph moves to the right)
- Non-competitive: when antagonist is covalently bound (permanently bound) to the receptor
at another binding site as the agonist, it inhibits the biological response of the receptor to
the agonist without competing for the binding site
- Allosteric antagonist/agonist binds to different location called allosteric site and doesn’t
effect the affinity of the orthosteric antagonist/agonist
, Plasma travels through body and can be taken from anywhere to see if it contains toxins
Uptake from quick to slow (pharmacodynamics)
- Intravenous
- Intramuscular
- Subcutaneous (fatty layer under skin)
- Oral
Drug from small intestines through enterocyte cells into the portal vein to the liver. Function liver is
to detoxify (modify drugs, excrete in bile).
Vd = F x D / C0
- Vd= Volume of distribution
- F= bioavailability
- D = dose
- C0 = concentration at time 0 in the blood
