Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
50 Cards in this Set
- Front
- Back
|
Types of prodrugs
|
-Carrier-linked
-Bi-precursor |
|
|
Examples of Carrier-linked prodrugs
|
-Bipartate
-Tripartate -mutual |
|
|
Why are Most common prodrug form is an ester
|
-Esterases are abundant across the body
-Easily modifiable hydrophilicity-phobicity -Esters are stable |
|
|
How to accelerate hydrolysis rate
|
-Base hydrolysis? Attach electron withdrawing group
-Acid hydrolysis? Attach electron donating group -Acetals or ketals can be made for rapid hydrolysis in the acidic medium of the GI tract -Intramolecular hydrolysis of succinate esters |
|
|
How to slow down hydrolysis rate
|
-Make sterically shielded esters
-Make long chain fatty acid esters |
|
|
pKa of amines can be lowered by
(also increas log d ie lipophilicity) |
conversion to N-Mannich bases
Schiff base |
|
|
How to increase water solubility of sulfonamides?
|
Draw it right now , don't complain just do it
|
|
|
Bipartate Prodrugs?
|
Carrier linked drugs
|
|
|
For aqueous injection or opthalmic use
|
PO3Na2
|
|
|
Criteria for Success with Enzyme-Prodrug Therapies
|
-The prodrug should have low cytotoxicity and the drug high cytotoxicity
-target enzyme must have high catalytic activity -must be able to cross membrane |
|
|
How to increase water solubility through skin for hormones?
|
Draw it now!
|
|
|
ADEPT
|
-Antibody-Directed Enzyme Prodrug Therapy
-An approach for site-specific delivery of cancer drugs |
|
|
Clinical Trial explore and confirm?
|
efficacy and safety
|
|
|
Objectives of a Phase I Trial
|
Safety , tolerability , and characterization of pk properties
|
|
|
NOEL?
|
no observable effect level, calculates dose
|
|
|
Allometric scaling ?
|
Animal Scalling
|
|
|
Requirements for Allometric Scalling
|
intravenous pharmacokinetic data in at least two animal species
|
|
|
What can you deduce from Allometric Scalling?
|
- clearance (hepatically and renally)
- pharmacokinetic parameters (volume of distribution) |
|
|
What studies are used to deduce first dose in humans?
|
Allometric scaling + Noel/Notl (Pharmacology/toxicology studies)
|
|
|
Benefits of Parallel Group Design?
|
- Quicker than crossover design
- No problems with “washout” - Statistical analysis not affected by dropouts (opposite to crossover) |
|
|
Draw backs of Parallel Group Design?
|
- Generally requires fairly large numbers of patients/subjects
|
|
|
What are Parallel Group Design used for?
|
- efficacy and safety trials
|
|
|
What are crossover design used for?
|
Commonly used for bioavailability/bioequivalence
|
|
|
The main shortcomings of isolated tissue pharmacology are?
|
- not human samples
- Tissue has a short life span (1 day) so only acute experiments can be conducted |
|
|
Animal Models can be used for:
|
- hypertension
- endocrine systems - *not* psychiatric |
|
|
limitation of Genetic Models
|
- process takes 1-2 years
|
|
|
Regulatory toxicology studies in group (a) includes:
|
- 28-day repeated-dose toxicology studies in two species (including one non-rodent, usually dog),
- In vitro and in vivo genotoxicity tests -safety pharmacology - reproductive toxicity assessment |
|
|
Regulatory Toxicology studies in group (b) includes:
|
-Chronic 3-12-month toxicological studies in two or more species
- long-term (18-24 months) carcinogenjcity tests - reproductive toxicology - Interaction studies involving other drugs that are likely to be used for the same indications |
|
|
Types of Safety Pharmacology tests:
|
- core battery (cns, cardio, resp)
- follow up (Cns, cardio, resp) - supplementary (renal, gastro, ANS, other) |
|
|
Cause of QT interval prolongation ?
|
The main mechanism responsible appears to be inhibition of the potassium channel, termed the hERG channel, which plays a major role in terminating the ventricular action potential
|
|
|
Proposed standard tests for QT interval prolongation comprises of?
|
(a) testing for inhibition of hERG channel currents in cell lines expressing the hERG gene;
(b) measurements of action potential duration in myocardial cells from different parts of the heart in different species; (c) measurements of QT interval in ECG recordings in conscious animals |
|
|
Ames test?
|
The induction of revertant colonies indicates that some his- bacteria have mutated (reverted) to his+ , and therefore that substance X is a mutagen
|
|
|
An in vivo test for chromosomal damage (genotoxicity)
|
Animals are treated with the test compound for 2 days, after which immature erythrocytes in bone marrow are examined for micronuclei, representing fragments of damaged chromosomes.
|
|
|
NTEL?
|
No toxic effect level
the largest dose in the most sensitive species in a toxicology study of a given duration which produced no observed toxic effect; |
|
|
NOAEL
|
No observed adverse effect level
the largest dose causing neither observed tissue toxicity nor undesirable physiological effects |
|
|
MTD
|
Maximum tolerated dose
|
|
|
NOEL
|
No observed effect level
|
|
|
ICH
|
International Conference Harmonization
|
|
|
Three standards in GCP?
|
Design, conduct , monitoring
|
|
|
New principles (2000) for Helsinki decleration
|
- protocol/results to be made public
- competitor product preferred over placebo - Best treatment to be given to subjects after |
|
|
Deceleration of helsinki
|
Ethical principles for medical reasearch involving human test subjects
|
|
|
Three principles of the Belmont report
|
- Respect of persons
- Beneficial outcomes - Justice |
|
|
CRF
|
Case report form . Protocol required information on each test subject to be handed in to the sponsor.
|
|
|
EMEA
|
European Medicines Agency
|
|
|
IND
|
Investigational New Drug. Required for all clinical studies
|
|
|
NDA
|
New drug application. Before going to market
|
|
|
IRB
|
Institutional Review Board . Responsibility for reviewing and approving any study involving human subjects within the institution they serve
|
|
|
CDRH
|
Center for Devices and Radiological Health . medical devices including and especially electromagnetic radiation emitters
|
|
|
Conventional Strategies for finding New Drug Targets
|
- Analysis of pathophysiology
- Analysis of mechanism of action of existing therapeutic drugs |
|
|
Why do people object?
|
- strong relationship with competitors
- need for more info - bad mood - not authorized - hard to change habits |
