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81 Cards in this Set
- Front
- Back
Origin of HIVs
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- cross-species transmission on SIV/HIV genomic sequence comparison
- HIV-1 from chimpanzees (SIVcpz) - HIV-2 from sooty mangabeys (SIVsm) |
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HIV-1 genetic subtypes
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- aka clades
- Groups M, N, O, P represent 4 independent primate-human transmission events - Group M further classified into clades (A, B, C...); West-central Africa - Group N: Cameroon - Group O: West-central Africa - Group P: Cameroon (?) |
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Nucleocapsid contains
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- 2 copies of ssRNA - each strand a result of provirus
- viral enzymes (proteins that facilitate chemical reactions) - reverse transcriptase, integrase, protease |
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HIV virus classification
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- retrovirus
- lentivirus subfamily |
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"Simple" retrovirus genome
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- 7000-11000 ribonucleotides long
- encodes 3-4 viral genes: gag, pro, pol, env |
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Gag gene
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- encodes capsid proteins
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Pro gene
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- encodes protease
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Pol gene
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- encodes reverse transcriptase and integrase
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Env gene
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- encodes envelope (spike) proteins
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LTR (Long Terminal Repeat)
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- proviral sequence created by integration of provirus
- 5' LTR contains promoter region where cellular RNA polymerase binds to begin transcription of viral RNA; 3' LTR contains transcription termination sequences |
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Virion structure
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- enveloped virus
- capsid [p24] - matrix [p17] - spikes [gp120 + gp41] |
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HIV attachment
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- host cells must display 2 receptors: CD4 molecule + one of 2 chemokine receptors (CCR5 or CXCR4)
1. gp120 initiates attachment to CD4 receptor 2. binding to chemokineR changes shape of gp120; reveals gp41 - gp41 inserts into cell membrane, triggers membrane fusion |
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Chemokine receptors
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- small proteins synthesized and release by certain cells that communicate/activate other immune system cells
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Genetic mutation in CCR5 coreceptor
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- 1996: CCR5 coreceptor identified, CCR5 deletion mutant identified [CCR5Δ32] - Koup & Landau found mutant CCR5 allele in 2 homosexual, high-risk HIV- men
- genetic testing revealed mutation in Caucasian Americans (spec., Western European origin); <1% homozygous [both alleles mutated], ~20% heterozygous [one mutant allele, one wild-type (i.e., functional) allele] |
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Allele
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- variant form of a gene
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Mutation
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- change in nucleotide sequence within genome
- change in the code, deletion of nucleotide(s), insertion of new nucleotide(s) - can occur spontaneously (no outside influence) - can be 'induced' by influences outside the cell (chemicals, radiation) |
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Effect of mutation
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- no effect
- deleterious effect - advantageous effect |
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Potential effect of mutation on protein
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- change in DNA nucleotide sequence within a gene encoding a protein may:
- have no effect on amino acid sequence - result in a different amino acid (may or may not change protein function) - result in premature termination of protein synthesis which likely will produce a non-functional protein |
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Cellular targes for HIV infection
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- T-helper cells: CD4 and CCR5 (or CXCR4)
- Macrophage: CD4, CCR5 |
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Inside an HIV-infected cell
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- after partial uncoating, RT (carried inside the infecting virus capsid) begins synthesizing a dsDNA copy of HIV genome; process occurs in pre-integration complex (PIC); RT does not 'proofread'; RT can 'switch' between template RNA strands
- dsDNA genome transported across nuclear membrane in a complex containing viral integrase - integration of proviral DNA by action fo viral integrase & cellular DNA repair enzymes; IN chemically 'breaks' bond in each of the strands of chromosomal DNA; positions viral dsDNA into chromosome break; cellular DNA enzymes 'repair' the break, restoring integrity of host cell chromosome - expression of proviral DNA by cellular RNA polymerase; host cell RNA polymerase binds to promoter region in proviral LTR; RNA polymerases do not 'proofread'; HIV-1 genome encodes 15 viral proteins |
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Structural genes
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- gag (capsid & matrix proteins)
- pol (RT, RNase, IN, protease) - env (gp120, gp41) |
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Regulatory genes
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- tat (transcriptional activator)
- rev (nuclear export of viral RNAs) |
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Accessory genes
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- vif, vpr, vpu, nef
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-Static drugs
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- stop replication
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-Cidal drugs
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- kill microbe
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Chemoprophylaxis
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- attempt to prevent disease
- administer pre-exposure |
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Chemotherapy
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- attempt to treat disease
- administer after exposure (most often, symptomatic patient) |
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Reverse transcriptase
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- copies ssRNA into strand of DNA, then replicates DNA into its complement (reverse transcription)
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Integrase
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- breaks chemical bonds that makes up strands of chromosomes
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Protease
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- left over from when virus was released from its previous host cell
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Unique features of retrovirus replication
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- only way to kill viral DNA in the cell is to kill the cell itself
- viral info can be in a cell but not active - cellular enzyme copies provirus DNA |
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Tat
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- regulatory gene
- transcriptional activator |
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Rev
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- regulatory gene
- nuclear export of viral RNAs |
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Accessory genes
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- vif, vpr, vpu, nef
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From nonproductive to productive infection
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- activation of T-cell triggers HIV replications
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Synthetic drugs
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- manufactured from individual chemicals (chemists study reactions, components)
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Antibiotics
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- chemical compounds made by living microorganisms (usually by soil microorganisms)
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Semi-synthetic antibiotics
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- comes from naturally occurring compounds from microorganisms at its base, like antibiotics
- these naturally-occurring compounds are altered in a lab |
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Broad spectrum
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- used to treat a variety of infections
- usually antibiotics |
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Narrow spectrum
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- used to treat specific disease
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Selective toxicity
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- kill the pathogen, not the host
- least amount of damage to diseased person, most amount of damage to pathogen |
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In vivo drug stability
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- how stable is the drug in the body
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In vivo drug distribution
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- where does the drug go in the body
- can it go where it needs to go |
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Drug interactions
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- with other prescription drugs
- with OTC drugs - with herbal ("natural") drugs |
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Antagonism
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- one drug nullifies another's effect
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Synergism
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- two drugs work better together than separately
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Greatest selectivity found in antibacterial drugs
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- easiest to see differences between prokaryotic cells and human cells
- can stop synthesis of peptidoglycan/repairing cell wall (beta-lactam antibiotics - penicillins & vancomycin) - can target assembly of ribosomes - different ribosomes from humans (have 50S & 30S; humans have 60S & 40S) - chloramphenicol & tetracyclines |
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Selective toxicity in fungi & protozoa
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- much more problematic; must kill a eukaryotic pathogen inside a eukaryotic organism
- drugs with fewest side effects target ergosterol in plasma membranes of fungi - cyst stage in protozoans not susceptible to drugs (metabolically 'dormant') - pathogen must be actively growing in order to treat it - pathogens hard to treat once they are inside cells of the body |
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Antiviral synthetic drugs
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- nucleotide must have a phosphate group
- deoxyguanosine - ex. acyclovir: when acyclovir triphosphate is added into a growing DNA strand, no additional nucleotides can be added. No -OH for DNA polymerase to add on to; stops synthesis of DNA strand |
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Physician's Desk Reference
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- source for information on prescription, OTC, and herbal drugs
- also has basic information on a wide range of human diseases and conditions |
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Microbial drug resistance
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- mutations passed on to progeny (allows them to continue replicating) - bacteria, eukaryotic, viruses
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Drug resistance in bacteria through...
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- conjugation: direct contact between cells (DNA transferred)
- transduction: DNA carried into cell by a virus - transformation: extracellular DNA taken up by cell |
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Mechanisms of drug resistance
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- drug inactivation: inactivation of drug like penicillin by penicillinase, an enzyme that cleaves a portion of the molecule and renders it inactive
- decreased permeability: the receptor that transports the drug is altered, so that the drug cannot enter the cell - activation of drug pumps: specialized membrane proteins are activated and continually pump the drug out of the cell - use of alternate metabolic pathway: the drug has blocked the usual metabolic pathway, so the microbe circumvents it by using an alternate, unblocked pathway that achieves the required outcome |
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4 sectors of the pharmaceutical industry
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- research intensive pharmaceutical firms (Pfizer, Lilly, Merck, Glaxo Smith Kline)
- Generic drug manufacturing firms (Sandoz, Teva) - biotechnology firms (Amgen) - drug delivery firms (Alza, Inhale) |
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Pre-clinical drug development
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- lab and animal tests to establish pharmacology and toxicology in animal models
- pharmacokinetics (ADME) - provides data for dosing, drug formulation - pharmacodynamics - drug's positive and adverse effects in animals - toxicology - collect date on drug's safety in both high and low doses, including 24-month carcinogenicity of the product, impact on reproductive health - human tissue cultures are sometimes used |
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Goal of pre-clinical drug work
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- to provide data to support an Investigational New Drug Application (IND)
- IND provides evidence that human testing of the drug should be allowed - FDA has 30 days to request more info, deny, or approve IND |
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Contents of an IND
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- results of pre-clinical studies
- drug's chemical structure and how it is thought to work/mechanism of action - listing of adverse effects - manufacturing info - detailed clinical testing plan which lists how the drug will be tested, patient types, and where the testing will take place and by whom |
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Clinical development
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- process of testing a drug in humans
- goal = show the drug is safe and effective in treating specific conditions in certain patients - prior to 1962 only the safety of the drug needed to be proven, but with the passage of 1962 FDA amendments effectiveness is required |
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Phase 1 Trials
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- establishes safety of administration in humans and a range of safe doses
- trials conducted on young healthy male humans, who are put in a carefully controlled environment & are under observation for hours or day - # of subjects 20 to 100 |
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Phase 2 trials
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- first clinical test of drug on people with the disease
- 100-500 patients - determines if drug actually works ("proof of concept") - helps establish dosing (min & max), safety (adverse effects), and efficacy testing, or endpoints |
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Phase 3 trials
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- large scale randomized, blinded, placebo controlled trial (sometimes comparative product used instead of placebo)
- can take 3-6 years & cost millions - 1000-5000 patients with targeted disease or condition - goal = collect efficacy info about product to support New Drug Application to FDA (collect end-oint effectiveness data) - many times conducted by contract research organizations (CROs) |
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Placebo group
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- group of patients who are receiving the inactive, fake, or "sugar pill," but do not know it.
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Randomization
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- subjects are randomly assigned to either the placebo or test group
- being assigned to the test group is by chance |
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Single blinded
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- subjects do not know if they are receiving the placebo or test drug, however the investigator knows
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Double blinded
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- subjects and caregiver or investigator do not know who is receiving test drug
- most common study |
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NDA (New Drug Application)
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- submitted to the FDA for review following completion of phase 3 & when company believes that sufficient efficacy and safety data were collected
- non-biological agents - NDA cent to FDA's Center for Drug Evaluation and Research (CDER) - biologicals: a BLA (Biological Application) is submitted to FDA's Center for Biological Evaluation and Research (CBER) |
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Draft package insert included in NDA
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- proposed package insert
- specifies: indications, explains dosages and dosing administration, includes key statement as to safety, risks, mechanism of action, adverse effects |
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FDA classifies NDAs
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- puts NDA into 2 categories based on: novelty of active ingredient, clinical improvement
- if product satisfies an unmet need or represents a significant therapeutic advancement, FDA may grant a priority review which takes 6 months or less - if it doesn't fit the above, then the drug fits the normal time frame of about 12 to 15 months for FDA review |
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Phase 4
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- "post-marketing surveillance" or "post-approval" studies - after drug has been approved and product is on the market
- not all products undergo phase 4 studies - used to monitor adverse effects & check on safety of drug product |
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Patents
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- granted anywhere along line of drug development, but normally occur early
- patent life is 20 years after patent is filed and approved - pharmaceutical companies file for drug patent once they think they have an innovative molecule; normally this occurs before preclinical studies |
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Exclusivity
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- exclusive marketing rights granted by FDA upon approval of the drug
- can run concurrently with patent time |
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Exclusivity times
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- orphan drugs: 7 years
- new chemical entity: 5 years - pediatric exclusivity: 6 months added to existing exclusivity or patent - patent challenge: 180 days (ANDAs only) |
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sterilization
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- process in which the end result is a sterile product - all infectious microorganisms that can replicate have been eliminated from that material
- only absolute term |
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disinfection
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- inanimate objects
- adding or using a chemical that will kill microorganisms but does not guarantee total elimination of microbes |
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sanitization
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- inanimate objects
- any process prescribed by a state health department designed to reduce the number of microbes on/in a specific material |
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antisepsis/asepsis
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- living tissue
- chemical safe enough to use on living tissue that reduces number of microbes |
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pasteurization
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- treating liquids - applying heat to kill microbes within that product thereby lessening the likelihood that there are harmful microbes in that product
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scale of most to least resistant microorganisms
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- bacterial endospores, protozoan cysts, gram-negative bacteria, viruses without envelopes, gram-positive bacteria, viruses with lipid envelopes
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factors affecting microbial inactivation
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- number of microbes
- nature of microbe - inhibition vs. death - pH - temperature (generally, cold doesn't kill) - presence of organic matter (it competes for the chemical that is supposed to be killing the microbe) |
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approaches to killing microbes
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- physical agents: temperature (heat kills, cold storage preserves, heat changes shape of protein); desiccation (drying); radiation (ionizing = high energy, non-ionizing (UV) = lower energy)
- mechanical removal: filtration (membrane filtration removes microbes, used for liquids & gases) - chemical methods: soaps, alcohols, halogens, hydrogen peroxide |
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microbes & hands
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- normal microflora (what is already on your body) vs. transient microflor (what you pick up during the day)
- ease of microbial transfer: from non-porous surface (no liquid absorbed), from porous or absorbant surface - lower ability for transfer of microbes to you, from finger to lip - hand washing: highly effective in preventing microbial speed |