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72 Cards in this Set
- Front
- Back
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What is gene therapy?
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Approach to treat, cure, or prevent disease by repairing genes
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What is somatic therapy?
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Treatment of a gene that alters gene expression and is not passed to next generation
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What is gene vector?
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A carrier used to insert the gene therapy (Ex: virus)
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What is in vivo therapy?
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Adminstration of vector directly into living organism
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What is ex vivo therapy?
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Administration of vector into cells outside of body and then cells are transplanted into body
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What is gene vs. cell therapy?
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Gene - genetic material to manipulate cells
Cell - cells are altered and transplanted into patient for treatment |
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What are objectives of gene therapy?
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1. Complete repair or replacement of inherited faulty gene
2. Intervention of acquired disease to alter disease course 3. Alter pharmacokinetic or resistance to drugs 4. Inhibit the expression of select genes |
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What are some examples of vectors?
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Viral- modified to prevent replication
Non-viral - as the name says... *Either way, vector must get gene to right location |
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Viral table...in...the...notes...help...
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...I am...drowning...in steatorrhea
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Which virus can hold the most material? The least?
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Herpes followed by adenovirus
Adeno-associated virus |
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Which viruses do not integrate genome into the cells?
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Adenovirus
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Which viruses have high viral replication?
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Herpes, Adenovirus
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Which virus has a high immune response?
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Adenovirus
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Which virus uses cells to proliferate?
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Retrovirus
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How do you make a viral vector?
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Retroviruses copy RNA to DNA --> take DNA sequences that you want to keep and remove the rest
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What are the non-viral vectors?
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- Uncomplexed DNA
- Liposomes - DNA-protein conjugates - Electroporation - Gene gun |
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How do liposomes work?
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Fuse with cell membranes and their material then gets into cell. Based on what you put on the liposome (proteins, etc...) it will favor attachment to one cell over another
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What is a gene gun?
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Like a vaccine but you inject DNA
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What is ideal char. of a viral vector?
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- Superior to non-viral counterparts
- Low immunogenic response - Selective deliver - Non-toxic - Site-specific integration - Easy to prepare - Low cost - Stable BLAH BLAH BLAH |
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What is Fomiversin?
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Anti-sense genetic sequence which blocks the production of mRNA in viruses
Commonly used for CMV retinitis (opthalmic use only!) |
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What is Allovectin-7?
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Liposomal delivered gene therapy drug used to treat melanoma
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What major lung disorder can you use gene therapy to treat?
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CF
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What major cardiac disorder can you use gene therapy to treat?
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Myocardial Ischemia
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What is LCA?
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Leber's Congenital Amaurosis - inherited abnormality of photoreceptor formation
Surprise - you may be able to use gene therapy to correct |
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Is human gene therapy approved by the FDA?
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NO NO NO NO AHHHH NO
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What is an SNP?
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Single nucleotide polymorphism
Most important source of genomic variation |
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What is drug idiosyncracy?
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Unusual response to a drug (rare and usually unknown)
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What are nutrigenomics?
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How different foods interact with specific genes to increase risk of common chronic diseases such as diabetes
How food alters gene expression |
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Why study pharmacogenomics?
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Tailor individual drug therapies
Predict and control variability in response to drugs Development of better and safer drugs Reduce drugs developmental costs Useful in experimental study of normal drug responses |
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What should be done to the sample in pharmacogenomics?
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Screen the population and remove non-responders or toxic responders to traditional treatment
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Can pharmacogenomics decrease healthcare costs?
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Yes because decreases adverse drug reactions, failed drug trials, and a bunch of other unimportant shit
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What is the effect of SNP's?
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Some people express different levels of enzymes that may metabolize drugs differently
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What are thiopurines?
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Inactive prodrugs that require metabolism to thioguanine nucleotides to exert cytotoxicity
Toxicity varies depending on what SNP someone has |
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What are some examples of drug idiosyncracy?
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Glucocorticoid effect that is decreased (dexamethosone)
Androgen insensitiviity (testosterone) Estrogen insensitivity (estradiol) Vitamin D resistant rickets |
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Genetic differences that alter pharmacodynamics?
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P450 polymorphism
Genetic variations in drug metabolism Acetylation polymorphism Genetic variations in absorption, distribution, excretion of drugs |
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What is MDR1?
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Multidrug resistance gene
Protein product is P-glycoprotein which binds ATP-binding transporters Portein resides in the plasma membrane and is an efflux transporter for lipophilic xenobiotics **Well documented for multidrug resistance in cancer chemotherapy |
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What drugs does MDR1 mess up?
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Cancer drugs: nelfinavir and efavirenz
If know the genotype, can increase or lower the dose for different genotypes |
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What is the dibucaine number?
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Shows the percent inhibition of enzyme activity (shows cholinesterase activity)
In some cases, variants are not entirely the whole picture due to atypical enzymes Prolonged apnea if have low levels of enzyme |
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What is the problem in cholinesterase deficiency?
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Suxamethonium may cause prolonged effects and remain paralyzed
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What is the acetylation polymorphism?
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Differential susceptibility to drug toxicity and cancer related to aromatic and heterocyclic amine exposures
N-acetylation detoxifies many carcinogenic drugs and initiates other carcinogens which can lead to cancer |
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What are slow acetylators susceptible to?
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Predisposing factor for allergic diseases and quite a few other things
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What drugs are problems with slow acetylators?
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Isoniazid - peripheral neuropathy
Procainamide - develop SLE Benzidine - high bladder cancer If rapid acetylators may need a higher dose |
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What are P450 polymorphisms?
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Largest phenotypical variability
Most important enzyme in drug metabolism |
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What are the consequences of the P450 CYP2D6 poor metabolizer phenotype?
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Codeine: less analgesia
Haloperidol: neurological problems Propranolol: no change |
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What is debrisoquine used for?
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Noradrenaline release by nerve cells and acts and then taken back up into nerve cells
Debrisoquine = taken up into nerve cells just like noradrenaline Thus when signal sent to nerve, release debrisoquine instead of noradrenaline Debrisoquinne has no effect so it causes a decrease in BP |
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What are bioinformatics?
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Gene expression arrays and genotyping techniques that give a shit ton of information in a single experiment
Software developed to compare trends and genomes Think human genome project |
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What is debrisoquine polymorphism?
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Lack of metabolism causes rapid decrease in BP
CYP2D6 problem |
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What are drug cocktails?
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Compounds that compensate for toxic side effects (like a combo therapy)
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What are the 2 limitations of pharmacogenmoic differences?
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Racial differences - prevent from making predictions about drug responses across patient population
Dynamic complexitiy of the human genome and involvement of multiple genes in drug responses |
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Challenges of elderly population
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1) Take many meds (polypharmacy)
2) Lots of chronic Dz states 3) Rare clinical trials |
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What is ADME?
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A - absorption
D - distribution M - metabolism E - excretion |
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What is bioavailability?
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Amount of drug reach systemic circ. after oral admin
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What is volume of distribution?
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Theoretical volume in which drug may distribute
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What is clearance?
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Amount of plasma from which drug is eliminated per unit time
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Common clearance mechanisms?
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- Metabolic (major route - esp. CYP3A4)
- *Renal (elderly like to have renal issues) - Bile |
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What does aging do to bioavailability?
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In general, can decrease...
Absorption (dec. gastric acid & dec. gastric emptying/GI motility) *Blood flow (Dec. blood flow) First pass metabolism (Dec. CYP3A4 function, Dec. liver mass, *Dec. blood flow) ***Decreased absorption and decreased metabolism could offset one another |
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What does aging do to volume of distribution?
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Amount of body water dec. = dec. Vd
Amount of lean body mass dec. & inc. fat = dec. Vd for water-loving drugs & inc. Vd for lipid drugs Plasma protein (albumin) binding dec. = Inc. unbound/active drug Plasma protein (Alpah 1 acid glycoprotein) = Dec. unbound/active drug |
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What are the clinical implications of decreased body mass?
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*Lower loading dose (b/c body wt. falls)
*Weight-base your doses |
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What does aging do to clearance?
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Overall, decreases w/ age (& therefore t1/2 increases)
*Renal clearance problematic |
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How is metabolic clearance effected?
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- CYPs thought to decrease (no change in CYP3A4...)
- Phase II may change in very frail |
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What are the clinical implications of metabolic clearance using CYP3A4?
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Don't need to adjust dose for CYP3A4s in an elderly patient b/c studies have showed CYP3A4s do not change
***Still, pay attention to drug interactions |
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What are the clinical implications of metabolic clearance using other CYPs?
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Drugs w/ lower therapeutic index should be reduced in older patients...(Ex: Warfarin & Phenytoin)
Monitor these drugs closely as well |
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What is the affect of aging on renal clearance?
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- Dec. renal wt.
- Dec. functional glomeruli - BM thickens - Dec. renal blood flow ***All these thing decrease renal clearance!!! |
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Is there a gender difference in renal clearance?
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Yes, females have lower clearance than males
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What is the most important factor in renal clearance in relation to elderly?
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***GFR decreases!!! - meaure by looking at the creatinine levels
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What is the Cockcroft-Gault equation?
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An equation in which you plug in creatinine to get GFR
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What is the MDRD?
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A modified equation for getting GFR not using just creatinine but also age, urine urea, serum urea
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What are the clinical implications of renal clearance?
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- Lower dose in elderly
- Lower dose in women than men - Monitor |
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What is the most common drug interaction?
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CYP3A4 altering drugs effect the metabolism of another drug that works thru CYP3A4
Could also induce CYP3A4 |
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Why do elderly have more drug interactions?
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Take multiple meds
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What are clinical implications of DDI in elderly?
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- Monitor
- Consider health changes may be due to drugs - Consider OTC drugs and prescription when dealing w/ DDI |
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What are pharmacodynamic changes in elderly?
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- Changes in Adrenergic system
- Dec. Ca+2 channels - *Inc. sensitivity to sedation/alcohol - Inc. sensitivity to anti-cholinergics |
