Term
| Name 3 key components of clinical pharmacology. |
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Definition
1. Clinical pharmacokinetics
2. Population pharmacokinetics
3. Pharmacodynamics |
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Term
| Drug metabolism is caused by these 2 factors. |
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Definition
1. Host internal and external environment
2. Host disease-causing genes or proteins |
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Term
| Name 6 systems for the study of pharmacogenomic target validations. |
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Definition
1. Cell-free invitro
2. Cell
3. Organs (in-vitro and in-vivo)
4. Small animals
5. Primates
6. Humans |
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Term
| Pharmacogenomics plays a major role during ___ stage of drug R & D. |
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Definition
Development phase:
phase I - IV |
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Term
| Inheritance of a ____allele of a drug-metabolizing gene(s) results in a favorable drug response (responders not at risk of toxicity; metabolizers). |
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Definition
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Term
| T/F: Patients with a profoundly inactive allele of a drug metabolizing gene, are at a higher risk of life-threatening toxicity that could be avoided by tailoring drug dosage and could be classified as responders at risk of toxicity |
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Definition
False: patients with a profoundly inactive allele, are at a higher risk of life-threatening toxicity that could not be avoided by tailoring drug dosage and could be classified as nonresponders at risk of toxicity
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Term
| WHat is the average time for the preclinical phase? |
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Definition
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Term
| WHat is the average time for the clincal, research and development phase? |
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Definition
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Term
| WHat is the average time for the NDA review? |
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Definition
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Term
| What is the goal of phase I? |
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Definition
1. Measure drug toxicity and safety
2. Drug respone
3. Minimum tolerated dose |
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Term
| ____ of genome is “junk DNA |
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Definition
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Term
Only ___% of the genome codes for proteins
–30,000 “genes” |
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Definition
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Term
| What is the difference between chromosome and chromatin? |
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Definition
| Chromosome is an actively dividing DNA wrapped tightly around a histone, while chromatin is an inactive DNA loosely wrapped around a histone. |
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
| There are only __ amino acids, ___ combinations of codons. |
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Definition
20 amino acids
64 combinations |
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Term
| What does it mean when one amino acid is made by multiple codons? |
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Definition
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Term
| ___ is an amino acid coded by stop codons. |
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Definition
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Term
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Definition
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Term
___strand is used to make mRNA (Complementary to coding strand except uracil replace thymine in mRNA). |
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Definition
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Term
•___ mutations over a lifetime. |
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Definition
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Term
| Only DNA mutations in ___are inherited |
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Definition
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Term
| The most common type of mutation is ___ |
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Definition
| Single nucleotide polymorphism (SNP) = 80-90% |
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Term
| What is another name for single nucleotide polymorphism (the most common type of mutation)? |
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Definition
| Point/Substitution mutation |
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Term
| Insertion or deletion of a nucleotide. |
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Definition
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Term
| ___ mutation leads to shift in reading frame and causes most functional changes. |
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Definition
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Term
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Definition
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Term
Give one example of each:
1. Dominant vs. recessive
2. Incomplete dominance
3. Co-dominant |
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Definition
1. Dominant vs. recessive - curly vs straight hair
2. Incomplete dominance (blended phenotype) - sickle cell
3. Co-dominant (equally expressed) - AB blood antigen |
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Term
| other genes may affect the phenotype |
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Definition
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Term
•___ genetic disorders have been characterized |
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Definition
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Term
•A mutation in a single gene can lead to many effects |
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Definition
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Term
mutations at several genetic loci may produce the same trait |
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Definition
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Term
•Each person is estimated to carry __ deleterious genes |
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Definition
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Term
–Triplet repeat on chromosome 4
–Dysfunctional protein builds up àtoxic to GABA neurons
–Manifestations: hyperkinesis, parkinsonian rigidity, bradykinesia, death within 15 years |
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Definition
| Huntington's disease - Autosomal Dominant |
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Term
–>150 mutations identified
–Defective LDL receptor à inability to bind LDL and transport to liver
–Manifestations: atherosclerosis, MI by age 20 yrs |
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Definition
| Familial hypercholesteremia - Autosomal Dominant |
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Term
–Mutation in fibrillin protein à weak extracellular matrix
–Manifestations: connective tissue disease affecting heart valves, aorta, skeletal system, eyes, lungs |
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Definition
| Marfan syndrome - Autosomal dominant |
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Term
–Defective phenylalanine hydroxylase
–Phenylalanine is not catabolizedà build-up in CNS causes severe mental retardation in infants |
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Definition
| Phenylketonuria - Autosomal Recessive |
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Term
–Defective chloride ion channel à thickened mucus secretions
–Respiratory infections, pancreatic dysfunction, impaired male fertility |
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Definition
| Cystic fibrosis - Autosomal Recessive |
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Term
–Defective hemobglobin (HbS) which precipitates at low O2 tension
–Sickling of RBC’s à blockage of blood vessels à tissue hypoxia |
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Definition
| Sickle Cell - Autosomal Recessive |
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Term
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Definition
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Term
| Variable gender patterns and depends on degree of penetrance ex. Retts syndrome |
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Definition
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Term
–Triplet repeat in FMR1 gene
–Affects brain development |
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Definition
| Fragile X syndrome - X- linked Recessive |
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Term
–Mutation in AVPR2 gene à defective vasopressin (V2) receptor |
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Definition
Diabetes insipidus - X-linked recessive |
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Term
–Most common enzyme defect in humans
–Usually asymptomatic until hemolysis is triggered (drugs, infection, fava beans) à RBCs unable to repair |
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Definition
| Glucose-6-phosphate dehydrogenase (G6PD) deficiency - X-linked Recessive |
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Term
–Defect in clotting factors (factor VIII or factor IX)
–Leads to prolonged bleeding due to inability to form a fibrin clot |
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Definition
Hemophilia A & B - X-linked Recessive
(remember, it is factors 8 & 9 that are affected) |
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Term
| Non-disjunction diseases occur at what stage of cell cycle? |
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Definition
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Term
| 2 hypothesis to why do genetic diseases exist? |
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Definition
•Hypothesis 1 - We are living longer now and natural selection may not have had time to select against these genes
•Hypothesis 2 – Mutations may help protect us from other diseases. Natural selection worked to select FOR these mutations |
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Term
•Heritable mutation which confers a survival advantage |
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Definition
| positive selection - alcohol and lactose tolerance |
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Term
What disease mutation do these protections come from:
1. Cholera
2. Malaria
3. Typhoid
4. Tuberculosis |
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Definition
1. Cholera - Type A & B blood
2. Malaria - sickle cell
3. Typhoid - Cystic fibrosis
4. Tuberculosis - Tay Sachs |
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Term
| T/F: Genotype predicts phenotype |
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Definition
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Term
Null alleles; no LDL receptors are made |
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Definition
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Term
Interferes with transport of LDL receptor from endoplasmic reticulum to Golgi apparatus |
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Definition
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Term
Interfere with cell surface binding of the receptor to LDL |
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Definition
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Term
Interferes with internalization of LDL-bound receptors |
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Definition
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Term
Interferes with recycling of LDL receptors |
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Definition
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Term
| The number one enzyme deficiency in the whole world. |
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Definition
| G6PD deficiency - X-linked recessive |
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Term
G6PD is the rate limiting step in ____. Only pathway for ____in RBCs
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Definition
hexose manophosphate pathway (HMP);
NADPH |
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Term
Drug induced oxidative stress |
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Definition
Primaquine
salicylates
sulfonamides
nitrofurans
vitamin K derivatives |
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Term
severe G6PD deficiency (<10% activity) leads to _____ |
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Definition
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Term
Overexpression of ___ causes tumor |
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Definition
| epidermal growth factor receptor (EGFR) |
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Term
| T/F: anti-EGFR antibodies work on K-ras mutants |
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Definition
False: anti-EGFR antibodies dont work on K-ras mutants (only on K-ras wildtype)
- so screen for wildtype or mutant k-ras, since you dont want to waste expensive antibodies |
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Term
| T/F: K-ras mutants benefit from tyrosine kinase ninhibitors |
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Definition
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Term
T/F: K-ras & EGFR (activating) mutations are mutually exclusive |
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Definition
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Term
EGFR activating mutations clearly benefit from ____ |
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Definition
| Tyrosine Kinase inhibitors |
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Term
K-ras mutation may benefit from TKI |
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Definition
| False: neither tyrosine kinase inhibitors nor anti-EGFR antibodies work on K-ras mutants |
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Term
In HIV patients:
–___% resistant to two drug classes
–____% resistant to three drug classes |
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Definition
50% - resistant to 2 drugs
13% - resistant to 3 drugs |
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Term
| T/F: Highly Active Anti-retroviral Therapy (HAART): 2 or more drugs from at least 2 classes is preferred. |
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Definition
| False: Highly Active Anti-retroviral Therapy (HAART): 3 or more drugs from at least 2 classes |
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Term
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Definition
•Phenotype is relatively common
•Accurate, reliable test is available
•Detection alters treatment & outcomes
•Narrow therapeutic window
•Serious toxicity/Lack of activity
•Marginal efficacy/Specific populations |
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Term
if drug metabolism is affected, will result in two major consequences
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Definition
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Term
| What does PK ADME stand for? |
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Definition
A- absorption
D - distribution
M - Metabolism
E - Excretion |
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Term
| T/F: majority of patients (90%) are classified as "responds at risk to toxicity." |
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Definition
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Term
| P-gp act as a biomarker for __and ___ in cancer patients |
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Definition
| drug resistance and progonosis |
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Term
P-gp act as a target for ___, especially for drug resistant cancers, in combination with coventional therapy. |
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Definition
| discovery of novel anticancer agents |
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Term
Metabolizes 45-60% of commonly used drugs |
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Definition
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Term
Conjugates drugs through formation of thioether linkage, targeting hydrophobic compounds with electrophilic atom. |
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Definition
Glutathione-S-Transferase (GST) - majority found in the liver |
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Term
NAT1 seen in most ___. NAT2 in the __and __. |
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Definition
tissues = NAT1
liver and gut = NAT 2 |
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Term
| Slow NAT acetylators show higher concentrations of ___ and ___ |
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Definition
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Term
An asthma patient with a genetic polymorphism which decreases expression of the ALOX5 enzyme will be:
a)More likely to respond to leukotriene inhibitor therapy
b)Less likely to respond to leukotriene inhibitor therapy
c)At increased risk for developing QT prolongation
d)At decreased risk for developing QT prolongation |
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Definition
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Term
define a biologic population based on genetics (i.e. DNA sequence) |
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Definition
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Term
define a biologic population based on an observable physicial or biochemical characteristic (e.g. probe metabolites) |
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Definition
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Term
A 72 year old breast cancer patient is about to start chemotherapy and you are consulted to help optimize her regimen. HER2 testing shows 1+ (FISH) and Oncotype DX recurrence score is 32 (high risk). Her cancer is estrogen receptor positive. Which of the following would be the best regimen for her?
a)Trastuzumab + cytotoxic chemotherapy
b)Trastuzumab + cytotoxic chemotherapy + tamoxifen
c)Cytotoxic chemotherapy
d)Cytotoxic chemotherapy + tamoxifen |
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Definition
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