CNPR, NAPSR Exam
Secondary wholesale distributors
Buy from a primary and other secondary wholesalers as well as manufacturers but are not considered authorized distributors of the manufacturers within the meaning of the PDMA
Generic drugs are not regulated by the Food & Drug Administration.
False
Patents are applied for with, and granted by the FDA.
False
The Hatch-Waxman Act made it more difficult for generic manufacturers to manufacture and distribute off-patent drugs and compete with R & D companies.
False
The PDMA is the Prescription Drug Manufacturers Association.
False
The federal government does not regulate the drug sampling for a pharmaceutical representative
False
QD
Once a day
ophthamology therapy
Oral Glaucoma Therapy is classified as:
Absorption methods
Oral, Buccal, sublingual, rectal, subcutaneous, intramuscular, transdermal, topical, inhalation, intravenous
The most reliable source of information for determining therapeutically equivalent drug products are
Orange Book
ex vivo
Outside a living body:
The acronym for pharmacokinetics is:
PK
Used when referring to medication dosage, means "as needed":
PRN
Traits of Pharma sales Rep
Passion, Go the extra mile, be a resource, be creative, invest in yourself, authentic and real, love what they do, focus on service, cultivate support, believe, focus, macro-thinking, KIT, ask, keep accurate records
Transport Mechanisms
Passive diffusion, facilitated diffusion, active transport, pinocytosis
Home-Based Care
Patients/consumers and their families and friends home health nurses and aides
Cmax
Peak plasma concentration on a measuring curve
Upcharge
Percentage fee that is paid by the dispenser to the wholesaler for the cost of distribution
Half-life
Period of time it takes for a specific amount of drug in the body to be reduced, through the excretion or elimination process, to exactly one-half that original amount
Vaccines
Pg 108
Stem Cells
Pg 114
Managed Care
Pg 117
Regulatory Requirement terms
Pg 126
Gifts
Pg 162
AMA Gift guidelines
Pg 165
PhRMA Code on relationships
Pg 167
PhRMA FAQ
Pg 174
Nursing Structures
Pg 200
Organizing your day
Pg 239
Routes of drug administration
Pg 26-29
Drug Forms
Pg 35-38
Pharmaceutical Ingredients
Pg 54
Distribution Terminology
Pg 60-61
Package Insert Info
Pg 63
Drug Patents
Pg 65 Terms pg 67
Sales Team
Pg 7
E-sampling
Pg 72
Benefits of Government-Industry Partnerhsips
Pg 79
Four phases of clinical trials
Pg 90
Regulatory Requirement terms
Pg 92
Gifts
PhRMA Code prohibits no educational items pg 228
Basic clinical pharmacology involves 3 main concepts
Pharmacodynamics, Pharmacokinetics, drug distribution and elimination.
PBM
Pharmacy Benefit Manager act as intermediaries between pharmaceutical companies and large drug purchasers
What has fueled the recent growth in the pharmaceutical industry?
Population growth and recent life expectancies
Therapeutic equivalence
Production of the same medicinal effect
Section 503
Prohibits sale, purchase, or trade of drug samples
The "engine of innovation," focused on discovering or inventing promising new product.
Research & Development
Gene Therapy types
Retrovirus, adenovirus, adeno-associated virus, liposomes, naked DNA
gene therapy types
Retrovirus, adenovirus, adeno-associated virus, liposomes, naked DNA
5 rights of drug administration
Right dose, right patient, right medication, right route of administration, right time of delivery
2nd right of drug administration
Right medication
Pathology
The practice of medicine dealing with the causes and nature of disease/death
pathology
The practice of medicine dealing with the causes and nature of disease/death
Sponsor
The organization or individual that initiates the trial and finances the study
Sponsor
The organization or individual that initiates the trial and finances the study,
Investigator
The person who conducts the trial. This person is normally an expert in the field. They should not be employed by the sponsor
A sample closet or cabinet is essentially similar to a grocery store shelf. The more visibility you can give your drug, the more likely it will be used.
True
Any gifts accepted by physicians individually should entail a benefit to the patient and not be of substantial value
True
CL= rate of drug elimination/drug concentration in blood
True
Cytokines are produced mainly by the leukocytes (white blood cells)
True
DEA regulates the distribution and use of narcotics and other controlled substances
True
Drug recalls are almost always negotiated with the FDA beforehand.
True
Hormones are intercellular messengers.
True
In 2012, FDA regulators approved 39 new drugs for use in the U.S.
True
In some situations, a physician may sign the paperwork before the number of samples has been recorded
True
In vitro assays are increasingly being see because they are usually less expensive, offer more rapid results, and are not as prone to negative publicity.
True
Individual gifts of minimal value (Under $100) are permissible as long as the gifts are related to the work
True
It is important not to change the order of a sample closet
True
It takes about 10 years for a drug to hit the market
True
Manufacturers and distributors are required to have systems to monitor and audit the distribution of their drug samples
True
Many pharmaceutical manufacturers set expiration dates every six months (June, December)
True
Meticulous records must be kept of sample inventories and reps are required to account for their samples periodically.
True
Patent last 20 years
True
Pharma companies must submit extensive data to the FDA demonstrating the safety and effectiveness of new drugs before receiving approval for sale.
True
Pharmaceutical representatives must always record the amount of drug samples left and obtain signature for that amount.
True
Pharmaceutical representatives will typically store and secure their own drug samples
True
Pharmacological studies using animals are regulated under Good Laboratory Practice.
True
Patents expire after how many years from the date of filing?
20 years
Glossary
271
_____ new medicines are in development for diabetes
281
The pivotal trial is Phase ______ of the clinical trial.
3
Other Exclusivity
3 years for a change if criteria are met
______ medicines are in development for cancer
3070
new meds are in development for cancer
3070
In 2012 the FDA approved _____ new drugs for use in the US (highest number since 1996)
39
How many days does a brand name company have to sue
45
New Chemical entity
5 years exclusivity
Among the biotechnology medications under development, about _____ target cancer.
50%
The US accounts for about ____ of all the world's pharmaceutical revenues.
50%
Pediatric Exclusivity (PED)
6 months added to existing Patents/exclusivity
Exclusivity is granted for an orphan drug for _______ years.
7
Exclusivity is granted for an orphan drug for
7 years
Exclusivity is granted for an orphan drug for ____
7 years
Orphan Drug (ODE) `
7 years exclusivity
How many territories are in a district?
8 to 12
Orange Book ratings
A AA AN AO AP AT B
Therapeutic
Antibodies
Group purchasing organization (GPO)
An entity consisting of two or more hospitals or other healthcare entities that is formed to offer its members access to purchasing contracts for health supplies
6 stages of brand strategy
Brand positioning, brand personality, brand values, unique values of the brand that support the values, how the brand appears to its audience, internal commitment
Patients with leukemia have a condition in which the stem cells in the bone marrow malfunction and produce an excessive number of immature white blood cells, which interfere with normal blood cell production
true
The more a patient is asked to pay for his/her medication, the greater likelihood that he/she will refuse to fill the prescription, pr will not take the medication properly.
true
Representatives are required to store samples in a secure area where people cannot access them without permission and where they will not be subjected to extremes of temperature, moisture, and contamination
True
Storage conditions for drug products are based on data and information supplied by the manufacturer
True
Subjects should be informed about the aims, methods, risks, and benefits of the trial
True
Subsidies should not be accepted to pay for the costs of travel, lodging, or other personal expenses. Paying for a modest meal is OK
True
The FDA approves storage conditions for drug products.
True
The FDA regulates the introduction of new drugs and enforces U.S. drug laws.
True
The liver is the major organ for metabolizing drugs. Secondary is kidney
True
Water is NOT a nutrient
True
Adjuvants
a substance that enhances the actions of drug antigen; second form of treatment in addition to primary care examples: chemo in addition to surgery
self warehousing
a type of distribution system where the retailer of the institutional dispenser takes on the task of distribution itself
out of state wolesaler
a wholesaler that distributes drug products in a state in which it is not physically located
ANDA
abbreviated new drug application
lipid-soluble
ability to dissolve in lipids or fat tissue
The "road map" for a clinical research paper is called the _______.
abstract
API
active pharmaceutical ingredient two basic categories: chemical and biological
Glidants(flow enhancers)
added to powdered materials used in pill production to aid movement through tabletting machinery
A substance that enhances the action of a drug or antigen:
adjuvant
Which of the following is not a part of the Seven Step Cascade of Emotion?
be a consultant, not a rep
The meaning of subcutaneous is:
beneath outer skin
The costs for all phases of R&D for drug companies are rising, with the increase particularly acute for _____.
clinical trials
The ___________ is used to determine appropriate medical reimbursement.
coding system
Dividing a group of physicians and other potential prescribers for a certain category of drugs based on anticipated prescription volume:
declining
What do retail pharmacists do?
dispense pharmaceuticals
Because pharmaceutical sales reps work mostly out of their home it is not important for a rep to work well in a team environment.
false
Generic drugs are not regulated by the FDA.
false
Generic drugs are not regulated by the Food & Drug Administration.
false
Most drugs that are administered to patients typically contains just one active pharmaceutical ingredient.
false
Most visits by pharmaceutical reps are to pharmacies.
false
One of the most disappointing results of the pharmaceutical industry's continued investment in R & D is the few number of new drugs being approved and in development.
false
One of the oldest and least effective pharmaceutical marketing techniques is the direct-to-consumer advertising.
false
PBM's tend to serve a local market through a network of pharmacies.
false
Patents are applied for with, and granted by the FDA.
false
Specialty care products are often prescribed by generalist physicians.
false
The Hatch-Waxman Act made it more difficult for generic manufacturers to manufacture and distribute off-patent drugs and compete with R & D companies
false
The Hatch-Waxman Act made it more difficult for generic manufacturers to manufacture and distribute off-patent drugs and compete with R & D companies.
false
The aim of the Phase IV clinical trial is to examine the safety and effectiveness of the drug in the targeted disease group.
false
The chief motivating force in mergers and acquisitions within the pharmaceutical industry is the desire of one company to acquire and exploit more successfully the brands of another.
false
The federal government does not regulate the drug sampling for a pharmaceutical representative
false
The heart of a pharmaceutical sales team is the Regional Manager.
false
There are more white blood cells than red blood cells for the same volume in the human body.
false
Typically it only takes 1-2 calls to an individual physician before you can successfully get a physician to commit to prescribing your drug or product.
false
With the global need for new drugs, pharmaceutical brand names are not subject to regulatory approval.
false
The substances comprising all active and inert pharmaceutical ingredients, including fillers, colors, and other excipients used to prepare dosage forms:
formulation
QID
four times a day
Brand values
functional values, expressive values, central value
"Pull through" refers to:
generating demand for your company's product
What are some specialties of biotechnology companies?
generesearch, genetically-altered drugs, and molecular biology.
GMP guidelines
good manufacturing practices
Refers to medication dosage, means "hour":
h
Which one of the below terms is not a route for excreting a drug from the body?
heart
disintegrates (excipient class)
help break up tablets in the gastrointestinal tract to ensure full release of the pharmaceutical active ingredient
disintegrants
help break up the tablets int the GI tract
compression aids (excipient class)
help pills hold their shape when compressed
IDN
integrated delivery network
Injection routes
intramuscular, intrathecal, intravenous, subcutaneous
Parenteral
intravenous, intramuscular, subcutaneous
A patent owner has the right to exclude others from making, using, selling or importing into the US the ____ it describes.
invention
Type A (augmented adverse reaction)
involves an exaggeration of the drug's therapeutic effects
internist
is a physician that practices internal medicine
HW Act
made it easier to bring generic drugs to the market by requiring the FDA to only look at bioavailability studies in order to approve an ANDA
suspending/ dispersing agents (excipient class)
maintain a consistent concentration of the active ingredient through a drug product
suspending/dispersing agents
maintain consistent concentration of the active ingredients throughout the drug product
Primary wholesale distributors buy most of their drugs directly from ______
manufacturers
The best way to deliver health care is through a ________ system.
market based
Exclusivity gives exclusive ______, which is granted by the FDA, and can run concurrently with a patent or not.
marketing rights
New prescription drug benefits covered under the Medicare Prescription Drug Improvement & Modernization Act:
medicare part d
MAR
medication administration record
Capsules
medication dosage form in which the drug is contained in an external shell; can be pulled apart for access to contents
Pharmaceuticals
medicines and vaccines for human and animal use. products may have a brand name or be generic, and they may be prescription or OTC
First pass effect
metabolizing process in the liver that suppresses the amount of drug that eventually reaches the systemic circulation and the site of action
ML stands for:
milliliter
chemical equivalents
multi-source products which contain essentially the same amounts of identical active ingredients in identical dosage forms which meet existing physical chemical standards
Oral Glaucoma Therapy is classified as:
ophthalmology therapy
tablet
pharmaceutical preparation made by compressing the powdered for of a drug and bulk filling material under high pressure; commonly used for anti acids and antiflatulents
Multi-source drug prodcuts
pharmaceutically equivalent products are available from more than one manufacturer
The study of the effects, both beneficial and toxic, of drugs and chemicals on living cells, tissues, organisms:
pharmacology
The key areas in hospitals that require special selling tactics are ______, formulary committee, and the medical education department.
pharmacy department
A _____ is an inactive medication with no treatment value, used in experimental studies.
placebo
emulsion
preparation in which two agents cannot be ordinarily combined or mixed
PDMA
product development and management association
Therapeutic equivalence
production of the same medicinal effects
A OBR
products for which there are no known or suspected bioequivalence problems
AA OBR
products in conventional dosage forms with no bioequivalence problems
alteration
one drug may alter how the body absorbs, distributes, metabolizes, or excretes another drug
Section 503 of Federal food drug and cosmetic act
prohibits the sale, purchase, trade or offer to sell, purchase or trade prescription drug samples and coupons
film former/coatings (excipient class)
protect against physical breakup, mask taste, etc.
Package insert
provide practitioners with essential information they need to prescribe the drug safely and effectively for the care of patients
AMA
provides ethical guidelines to physicians about appropriate interactions with pharmaceutical companies
Average whole price (AWP)
published whole sale price or list price suggested by the manufacturer
A site in the body which generally resides on a cell surface or within the cytoplasm. When stimulated or occupied, a biological change/activity takes place:
receptor
strength
refers to the amount of active pharmaceutical ingredient in the drug
potency
refers to the amount of drug needed to produce an effect
caplet
shaped like a capsule but has the form of a tablet
caplets
shaped like a capsule but has the form of a tablet the shape and file make swallowing easier
End-stage care
skilled nursing facilities hospitals hospices
A term used to refer to drugs that are non-biological (that is, chemical) in nature:
small molecule
granules
small pill, usually accompanied by many others encased within a gelatin capsule
AN OBR
solutions and powders
Secondary Care (specialized outpatient consults)
specialists
According to the text, which of the following is considered "going to the next level?"
staying focused
Branding
strengthens bond between buyer and seller; competition differentiation pg 198
preclinical studies
studies in which drugs are tested in vitro and on animals
pharmacokinetics
study of how a drug is processed by the body
Rectal
suppository
Edema
swelling
edema
swelling
Oral
tablet, capsule, liquid
PRN
take as needed
Type D (delayed adverse reaction)
take some time to develop
The heart of a pharmaceutical sales team is the
territory sales rep
drop shipment
the drug manufacturer directly delivers the drugs to a dispenser but the order and payments are made through a wholesaler
USP US pharmacopoeia
the first comprehensive publication of drug standards
Generic drug first to file exclusivity
the first generic drug manufacturer to file an ANDA with the FDA on a new off-patent drug receives a six-month marketing exclusivity
pharmacogenetics
the study of genetic differences in the response to drugs
physiology
the study of how those body structures function
anatomy
the study of the basic structures of the body
clinical pharmacology
the study of the effects and movement of drugs in the human body
pharmacodynamics
the study of what a drug does to the body
Float
the time differential between when a wholesaler receives payment from its customer and when the payment is due to its supplier
onset of action
the time it takes for a drug to start having any intended affect after it is administered
manufacturer direct sale
the type of sale that bypasses the need for any intermediary distributor
The three major areas in which biologics are used are prophylactic, _______, and replacement therapy.
therapeutic
A formulary is a list of prescription drugs approved by insurance coverage.
true
Acute medications, such as antibiotics, are used to address short-term illnesses or symptoms.
true
Any gifts accepted by physicians individually should entail a benefit to the patient and not be of substantial value
true
Carcinogenicity studies are carried out to identify the tumor-causing potential of a drug.
true
Cytokines are produced mainly by the leukocytes (white blood cells)
true
DTC advertising has become a required tactical consideration for most pharmaceutical brands in the U.S.
true
DTC advertising has become a required tactical consideration for most pharmaceutical brands in the U.S..
true
DUR programs involve retrospective monitoring of physicians' prescribing patterns.
true
Diffusion is the random movement of molecules in fluid
true
Drug labels must include indications and usage information, as well as contraindications.
true
Drug recalls are almost always negotiated with the FDA beforehand.
true
Effective drug therapy typically is a cost-effective and highly valuable means of controlling total healthcare expenditures and improving quality of life.
true
Hormones are intercellular messengers.
true
In 2012, FDA regulators approved 39 new drugs for use in the U.S.
true
In some medical cases, a therapy may be initiated by a specialist and monitored and maintained by a primary care physician.
true
In vitro assays are increasingly being see because they are usually less expensive, offer more rapid results, and are not as prone to negative publicity.
true
Individual gifts of minimal value (Under $100) are permissible as long as the gifts are related to the work
true
It is rare for pharmaceutical companies to explore, develop and promote expressive values with which patients might identify
true
It is rare for pharmaceutical companies to explore, develop and promote expressive values with which patients might identify.
true
Manufacturers and distributors are required to have systems to monitor and audit the distribution of their drug samples
true
Many pharmaceutical manufacturers set expiration dates every six months (June, December)
true
Opportunity Cost refers to the value of a sacrificed alternative, when making a choice using resources.
true
To be competitive, pharmaceutical brands must be distinctive. They must possess defining characteristics that are perceived by customers to be unique, attractive and relevant to their needs.
true
Toxicity information in preclinical studies provides confidence about a drugs safety aspect.
true
Unlike the small molecule drugs (pharmaceuticals) described, large molecule drugs (biopharmaceuticals) are mainly protein-based.
true
Water is NOT a nutrient
true
BID
twice a day
Emulsion
two agents that cannot ordinarily be combined or mixed
opposition (antagonism)
two drugs with opposing actions (drug-drug interaction)
drug sample
unit of drug not intended to be sold but to promote the sale
Fillers
used to make the drug sufficiently large for easy manufacture and consumption
fillers (excipient class)
used to make the drug sufficiently large for easy manufacture/patient consumption
Adenovirus
vector for gene therapy has large capacity for foreign genes • Disadvantage is that it has transient fxn of genes
drug kinetics
what the body does to the drug
central values
what the brand and I share at a fundamental level
Functional values
what the brand does for me
Expressive values
what the brand says about me
drug dynamics
what the drug does to the body
Bioequivalent
when drugs contain not only the same active ingredients but also produce virtually the same blood levels over time
Bioequivalent
when they contain the same active ingredients and proceed virtually the same blood levels over time.
duplication
when two drugs with the same effect are taken (a drug-drug interaction)
A type of blood cell that helps the body fight infection and disease:
white blood cell
The AWP is a published ______ price, suggested by drug manufacturers.
wholesale
dock to dock delivery
wholesaler obtains the drugs to a dispenser own warehouse without taking the drugs into its own inventory
sell-side margin
wholesaler revenues that are generated from fees and other charges obtained from dispensers
In-state wholesaler
wholesaler that distributes drug products in a state in which it is physically located
ASAP order
within 30 minutes of written order
asymptomatic
without signs or symptoms of disease
Which is not a rule in making the most out of your sales call?
your agenda not theirs
Clinical Trials
pg 89
Types of drug despensing
OTC and prescription
Benefits of Government-Industry Partnerhsips
pg 90
sustained release
several doses of a drug in special coatings that dissolve at different rates
5th right of drug administration
right time of delivery
The most important benefit of electronic prescribing is related to patient ______.
safety
Subjects for clinical trials are selected on the basis of _____
scientific objectives
SS is an abbreviation for:
semi doses
SS is an abbreviation for:
semis
gels or jellies
semisolid substances in non fatty bases that may be used for topical application
The US accounts for about ____ of all the world's pharmaceutical revenues.
1/2
_______ new treatments for Alzheimer's disease are in development
125
Average review time for a new drug
18 months
What is the average review time for a new drug?
18 months
Patent Challenge
180 days for ANDAs only
____ new medicines are developed for HIV/AIDS
185
______ new treatments have been approved for Hep C
2
Duration of a patent
20 years
Institutional review Board (IRB)
A committee of physicians, staticians, community advocated, and others which ensure that a clinical trial is ethical and that the rights of the study participants are protected. All clinical trials must be approved by an IRB before they begin.
Proteins
A nutrient made up of of chains of amino acids
Minerals
A nutrient necessary for bodily purposes such as the balance of body fluid
Fats
A nutrient stored in special body tissues as a great source of reserve energy
Vitamins
A nutrient substance necessary for growth, development, and normal regulation of metabolic processes. Must be taken from outside the body.
Carbohydrates
A nutrient that is the body's immediate source of energy. It's broken down to glucose and used for immediate metabolic reactions.
smalle molecule
A term used to refer to drugs that are non-biological (that is, chemical) in nature:
Inactive ingredients
Added to provide bulk, strength, aid dissolving, color, taste, etc. IAs do not affect the body
What does AMA stand for?
American Medical Association
PRN
As needed
Vaccine Preparations
Attenuated Vaccines Killed or Inactivated Vaccines Toxoids
Director of nursing
BSN MSN
What industry is having a profound impact on medicine?
Biotechnology
Nucleus
Brain of the cell that regulates all activities.
The agency which regulates the distribution and use of narcotics and other controlled substances is _______.
DEA
Primary wholesale distributors
Buy most of their drugs directly from manufacturers. Legally considered authorized distributors within the meaning of the PDMA because they usually have ongoing relationships with manufacturers
Monoclonal antibodies are created in laboratories to target the ________ of patients to kill cancer.
Cancer cells
Body's Major Systems
Cardiovascular, Respiratory, nervous, musculoskeletal, reproductive, immune
Peptide Vaccines
Chemically synthesized and normally consist of 8-24 amino acids
Medical supplies
Commodity, high-volume supplies such as surgical gowns and gloves
Chain drug store
Company that owns and operates four or more pharmacies
mass merchandiser
Department stores with a pharmacy
Toxoids
Derived from toxins secreted by a pathogen.Examples are diphtheria and tetnus vaccines.
Drug distribution & elimination
Drug delivery systems, route of administration , modes of excretion.
Drop shipment
Drug manufacturer directly delivers the drugs to a dispenser, but order and payments are made through a wholesaler
Generic drugs are not regulated by the FDA.
False
Brands should be:
Easy to pronounce, easy to write and read, memorable, distinctive and different from competition
Functional Values
Efficacy, safety, convenience, cost-effectiveness
The origin, or cause, of a disease or a patient's symptoms:
Etiology
Biologics
FDA definition is: o Biological product subject to licensure under Public Health Service Act is any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, a blood component or derivative, allergenic produce, or analogous product, applicable to prevention, treatment or cure of diseases or injuries to humans. Biological products include, but are not limited to, bacterial and viral vaccines, human blood and plasma and their derivatives, and certain products produced by biotechnology, such as interferons and erythropoietins. Biologics encompass many different protein-based drugs, and include blood products such as clotting factors extracted from blood.
Pinocytosis
Involves the engulfing of fluids by a cell.
QID
Four times a day
Values
Function, Expressive, Central
What kind of companies are pharmaceutical companies joining with for a significant research advantage?
Genomic companies
HMO
Health Maintenance Organization
Which one of the below terms is not a route for excreting a drug from the body?
Heart
tertiary care
Highly specialized medical and surgical care for unusual or complex medical problems provided by a large medical center
Metabolism
How the active part of a drug is metabolized into a more water-soluble compound that can be readily excreted by the kidneys
Distribution
How the drug is dispersed among the organs after absorption into the blood
Excretion
How the drug is eliminated from the body. Usually drugs are eliminated via urine. They can also be excreted through the lungs, skin, or breast milk.
Absorption
How the drug passes from its side of administration into the bloodstream
STAT
Immediately
Placebo
Inactive pill, liquid, or powder that has no treatment value aka sugar pill
AO OBR
Injectable oil solutions
Retrovirus
Integrates genes to hose chromosomes, change of long term stability
Retrovirus
Integrates genes to hose chromosomes, change of long term stability.
Oral medication
LPN
Smaller than ever before, what fraction of health care are prescriptive drug costs?
Less that 8% of total healthcare in this country
formulary
List of prescription drugs approved by insurance coverag
Formulary
List of prescription drugs approved by insurance coverage pg 118
First pass metabolism occurs when a drug administered orally is metabolized in the ________.
Liver
Areas of drug elimination and excretion
Lungs, breast milk, sweat tears urine feces, bile, saliva, and exhaled air
Primary wholesale distributors buy most of their drugs directly from ______
Manufacturers
This includes supply chain, manufacturing, trade, and distribution functions of the business.
Manufacturing & Operations
medicare part D
New prescription drug benefits covered under the Medicare Prescription Drug Improvement & Modernization Act:
PhRMA Code
Now prohibits pens, mugs, objects with company logo
Primary Care (checkups and general health issues)
OB/GYN family/general practitioners internists
The most reliable source of information for determining therapeutically equivalent drug products are
ORange Book
Average wholesale price (AWP)
Published wholesale price of list price suggested by the manufacturer.
Charge Nurse oversees shift in unit
RN
Clinical Care
RN
House supervisor, works off shift
RN
Case Manager risk manager/infection control
RN, BSN
Unit manager with 24 hour responsibility for unit
RN, BSN
FTC
Regulates general business practices to protect consumers against misleading claims and anticompetitive behavior
Organs
Specialized cells and tissues grouped together to perform specific body function for a common purpose. (Kidney, heart, intestines, and skin)
Pharmacokinetics
Study of how a drug is processed by the body, with emphasis on the time required for absorption, duration of action, distribution, and method of excretion. The study of how the body affects drugs.
Pharmacodynamics
Study of the biochemical and physiological effects of drugs and their mechanisms of action i.e. the study of what a drug does to the body. It describes the therapeutic effects of drugs (pain relief, blood pressure reduction, their side effects and their sites of action.
Edema
Swelling
Toxicity
The extent, quality, or degree to which a substance is poisonous or harmful to the body
PLasma
The liquid portion of the blood that carries proteins and other substances
Plasma
The liquid portion of the blood that carries proteins and other substances
What influences the number of districts in a region?
The region's population
clinical effect
The response produced by a medication
Anatomy
The study of basic structures of the body
Epidemiology
The study of how factors influence disease and health in human populations
Epidemiology
The study of how factors influence disease and health in human populations.
Physiology
The study of how those body structures function
physiology
The study of how those body structures function
Clinical Pharmacology
The study of the effects and movement of drugs in the human body
formulation
The substances comprising all active and inert pharmaceutical ingredients, including fillers, colors, and other excipients used to prepare dosage forms:
Type E end of use
These occur during drug withdrawal
Type C (continuing or chronic)
These persist for a long time
Protocol
This document sets out how a trial is to be conducted
Adendovirus
This vector has a large capacity for foreign genes.
Tmax
Time of peak plasma concentration on a measuring curve
Stem Cell Categories
Totipotent Pluripotent Multi-potent
(T/F) Pharmaceutical development is a high risk undertaking that often proves disappointing.
True
3,070 new meds are in development for cancer.
True
intramuscular
drugs given by direct injection into muscle tissue
According to the text, there are ___ classes of therapeutic drugs
US federal govt
According to the text, there are ___ classes of therapeutic drugs.
US federal govt
Define Off-label
Usage of a medication for purposes other than the specific ones appearing on the label
Off-Label
Usage of a medication for purposes other than the specific ones appearing on the label
Risk Factors
Use of several drugs, age, Pregnancy and breast feeding
SS
Used when referring to medication dosage, means "one-half":
Liposomes
Vector does not have viral genes so they do not cause disease.
QD
once a day
Vector-based vaccines
Viruses and bacteria are detoxified and used as vehicles to carry vaccines. Example is the use of canary pox (a virus that infects birds but not humans) to carry envelope proteins for HIV treatment.
travel time
What is one of the biggest time wasters for a pharmaceutical sales rep?
Asymptomatic
Without signs or symptoms
IRB (institutional review board)
a committee of physicians, statisticians, community advocates, and others which ensures that a clinical trial is ethical and the rights of study participants are protected
chain drug store
a company that owns and operates four or more pharmacies
independent drug store
a company that owns and operates three or fewer pharmacies
Powders
a drug that is dried and ground into fine particles
elixir
a drug vehicle that contains water, alcohol, and sugars
Integrated Delivery Network IDN
a financial management structure that unites hospitals, physicians ambulatory care site and managed care plans through ownership or exclusive formal agreements to provide a system to deliver a continuum of healthcare services
Managed Care
a largely but not exclusively private health insurance sector made up of organizations (MCOs) that emphasize controls to ensure cost-effective care.
N-acetyl transferase
a liver enzyme that metabolizes certain drugs (for half of the people in the US works slowly)
receptor
a molecule with a specific three dimensional structure to which only very specific substances can fit and attach
Mail order pharmacy
a pharmacy that dispenses prescriptions to patients who submit their prescriptions by mail or fax
pills
a single dose unit of medicine made by mixing the powdered drug with liquid such as syrup and rolling it into a round or oval shape
granules
a small pill usually accompanied usually accompanied by many others encased within a gelatin capsule; quite often releasing medication over time
Medical devices
advanced instrumentation and appliances used for medical therapy, such as joint replacements, implantable defibrillators, and pacemakers. Also includes drug delivery devices such as syringes, infusion pumps, metered dose inhalers, and trans-dermal patches
AEs
adverse events
Hatch-Waxman Act
aka Drug Price Competition and Patent Term Restoration Act of 1984. Considered the most significant drug-related legislation affecting pharma and healthcare. H-W made it easier to bring generics to the marker by requiring FDA to only look at bioavailability studies in order to approve. Also gave protection to the research based manu's by providing a 30 months automatic cooling off period
spirits/essences
alcohol-containing liquids that may be used pharmaceutically as solvents
tinctures
alcoholic preparations of a soluble drug
Pharmaceutical reps should thoroughly read _______ sections of clinical studies when results are released.
all
Hatch Waxman act
also known as the drug price competition and patent tem restoration act of 1984 most significant drug related legislation affecting pharmaceutical and healthcare industries since 1962
mixtures/suspensions
an agent is mixed with a liquid but not dissolved
Office of inspector general
an arm of the department of health and human services that investigates regulatory infractions, provides compliance advice and bring enforcement actions
Group Purchasing Organization GPO
an entity consisting of two or more hospitals or other healthcare entities that is formed to offer its members access to purchasing contracts for health supplies
pharmacy benefit management group
an entity that administers the prescription drug part of health insurance plans on behalf of plan sponsors such as self insured employers, insureance companies, and health maintenance organizations
gel caps
an oil based medication that is enclosed in soft gelatin capsule
stem cells
an undifferentiated cell with the potential to become any cell
Authorized distributor
any distributor of a prescription drug that has a written agreement with the manufacturers of the prescription drug and conducts at least two transactions with the manufacturer of the prescription drug within any 24-month period
AUC
area under the curve, represents the extent of drug absorption or the quantity of a drug that appears in the bloodstream following oral administration
PRN
as needed
Which is a step to becoming an indispensable pharmaceutical sales rep?
asking feedback
A generic drug is ______ to the originator brand-name drug in dosage, strength, safety, and quality.
bioequivalent
A generic drug is ______ to the originator brand-name drug in dosage, strength, safety, and quality.
bioevuivalent
printing inks (excipient class)
biologically safe dyes used for printing information on the exterior of tablets or capsules
non-stock sales
brokerage sales, dock to dock sales, drop shipments, and any form of sale not placed in inventory
Monoclonal antibodies are created in laboratories to target the ________ of patients to kill cancer.
cancer cells
Binders
cement the active and inert components of tablets
binders (excipient class)
cement the active and inert components of tablets together to maintain cohesive proportions
According to the text, depression is a disease that attacks the:
central nervous system
CNS
central nervous system
CSF
cerebrospinal fluid
Biological equivalents
chemical equivalents which when administered in the same amount will provide same biological or physiological availability as measured by blood and urine levels
therapeutic equivalents
chemical equivalents which when administered in the same amount will provide same therapeutic effect as measured by the control of a symptom or disease
Discovery of Pharmaceuticals
commences w/ scanning hundreds of compounds, whether w/ actual materials (irrational approach) or virtual simulations (rational approach) • Pharmaceuticals are new chemical entities (NCE) and are produced (synthesized) in manufacturing plants using techniques based on chemical reactions of reactants
Tertiary Care (inpatient)
community hospitals academic medical centers skilled nursing facilities
The most effective method for grabbing market share is:
comparative selling
fluid extracts
concentrated solution of a drug removed from a plant source by mixing ground parts of a plant with a suitable solvent, and then separating the plant residue from the solvent
otic drugs
control localized infections or inflammation and require very low dosages to be effective
Which is not a step to plan for rumors?
counter attack
enteric coating
covering that keeps drugs from dissolving in the stomach and do not dissolve until they reach the intestine
Where the tolerance of one medication may result in increased tolerance of another medication?
cross tolerance
USP-UF US Pharmacopoeia - National Formulary
current annual publication of certified drug standards verifying purity and ingredients
DM
district manager
Enteric Coating
dosage in special coating that doesn't digest in the stomach; only starts to digest in the intestines
drug distribution and elimination
drug delivery systems, routes of administration, modes of excretion
capsule
drug is contained in an external shell
Therapeutic alternatives
drug products containing different therapeutic moieties but of the same pharmacological or therapeutic class can be expected to have similar therapeutic effects when administered in therapeutically equivalent doses
B
drug products requiring further FDA investigation and review to determine equivalence
pharmaceutical alternatives
drug products that have the same therapeutic effect and strength but differ in the salt, ester or dosage form and are administered by the same rout
agonist
drugs that activate receptors
slow acetylators
drugs that are metabolized by this enzyme (N-acetyl) tend to reach higher levels and remain in the body longer than fast acetyls
antagonist
drugs that block receptors
lubricants (excipient class)
ease the release of tablets from the dyes that stamp them during the manufacturing process
Lubricants
ease the release of the tablets from the dies that stamp them during the manufacturing process
The acronym for effective dose is:
ed
Diagnostic
equipment and supplies used in screening, detecting, and monitoring disease. can range from simple home testing kits to sophisticated imaging technologies
The Orange Book is considered the most authoritative manual on therapeutic ______.
equivalence
The origin, or cause, of a disease or a patient's symptoms:
etiology
Outside a living body:
ex vivo
Type A (Augmented) drug reaction
exaggeration of the drug's therapeutic effects
medication error
failure to administer drug in the correct form
Almost 98% of employed Americans are now covered by a HMO, a preferred provider organization, or a point-of-service plan.
false
Bioavailability
how quickly and how much of a drug reaches its intended target site of action
Bioavailablility
how quickly and how much of a drug reaches its intended target site of action
Pharmetrics
impact, pronunciation, scriptability, confusion, symbolism and communication, fit, appeal
Pharmetrics
impact, pronunciation, scriptability, confusion, symbolism and communication, fit, appeal pg 144
indication
in terms of drug approval, the exact cause of purpose for which the FDA has approved that a drug can be prescribed
Excipients
inactive ingredients
Three primary entities fund pharmaceuticals: employer, government (Medicare and Medicaid), and ______.
individuals
exicipents
inert ingredients in a drug formulation includes fillers, dyes, and flavors
AP
injectable aqueous solutions
intravenous
injected directly into the veins
A low supply of oxygen due to low blood flow is
ischemia
A low supply of oxygen due to low blood flow is:
ischemia
Another name for biologic compound is:
large molecule
The Hatch-Waxman Act is considered the most significant drug-related ______ affecting the pharmaceutical industry since 1962.
legislation
approvable letter
letters sent by the FDA to the applicant indicating whether the new drug application meets necessary requirements
Customers purchase products from people they like, trust, and respect. This is the:
likeability
liniments
liquid suspensions for external application to the skin to relieve pain and swelling
Orange Book
list of approved drug products with therapeutic equivalence
tablet
made by compressing the powdered form of a drug and bulk-filling material under high pressure
NAM
national account manager
subcutaneous
needle inserted into the fatty tissue just beneath the skin
intrathecal
needle is inserted between to vertebrea in the lower spine an into space around the spinal cord
Gene Therapy Techniques
o In vitro method • Some of patients tissues which have genetic fault are removed • Cells are selected from these tissues and normal genes are loaded into cells w/ vectors • Modified cells are then returned to patient to correct genetic fault o In situ method • Genes encapsulated by vectors are injected directly into tissues to be treated • w/ both methods, genes are first loaded onto vectors and a number of vectors are used
Avenues for Stem Cell Research
o Pluripotent • Obtained by 2 methods: • Harvest clusters of cells from blastocysts of human embryos • Isolation of pluripotent cells from fetuses in terminated pregnancies o Multi-potent • Derived from umbilical cords or adult stem cells • Because of specialization of these cells, their potential to develop into myriad of different cells is limited o Burning issue is ethics of obtaining pluripotent stem cells from embryos and fetuses o Federal gov't acted on issue and declared federal funds for stem cell research meet certain criteria • Requires that funding will only be provided to research w/ stem cells obtained before 9 Aug 2001 as a cut-off date to limit research to preexisting stem cells
Type E (end of use adverse reaction)
occur during drug withdrawal
Literally "disease producer":
pathogen
Autologous Transplant
patient donates bone marrow or stem cells before treatment for reinfusion later. This happens when patient is receiving radiotherapy or chemo in such high dose that bone marrow is destroyed. Bone marrow stem cells collected previously are reinjected into patient to reinforce immune system
Cmax
peak plasma concentration on a measuring curve
cmax
peak plasma concentration on a measuring curve
Type C (chronic adverse reaction)
persists for a long time
Syngeneic Transplant
person donating bone marrow or stem cell is identical twin
Unrelated Allogeneic Transplant
person donating marrow is unrelated to patient
Allogeneic Transplant
person giving bone marrow or stem cells is genetically matched family member (usually brother or sister)
Adjuvants
pg 110
Branding
pg 113
Opportunity cost
pg 124
Four phases of clinical trials
pg 125
Direct-to-consumer (DTC)
pg 152
Factors that influence DTC
pg 153
Sales techniques
pg 207
Medicare part D
pg 225
AMA gift Guidelines
pg 231
PhRMA Code on relationionships
pg 233
PhRMA FAQ
pg 240
Nursing Structures
pg 268
Seven rights of drug administration
pg 30
Organizing your Day
pg 307
Drug elimination and Excretion
pg 34
Preclinical studies
pg 81
Buy-side margin
refers to the early payment discounts and other earned or negotiated rebates and discounts received by wholesalers from drug manufacturers; increase in the value of wholesalers' inventories ad manufacturers' prices rise
efficacy
refers to the potential maximum therapeutic response a drug can produce
drug-disease
refers to the worsening of a disease by a drug
RM
regional manager
Federal trade commision
regulates general business practices to protect consumers against misleading and anti-competitive behavior
Drug enforcement administration
regulates the distribution and use of narcotics and other controlled substances
AUC
represents the extent of the drug absorption or the quantity of the drug that appears in the bloodstream following oral administration
clinical trials
research study conducted with human patients
Discovery of Biopharmaceuticals
researchers have to examine compounds w/in humans o Ex. Hormones or other biological response modifiers and how they affect biological processes o In some cases, study pathogens such as influenza virus or bacteria to derive vaccines o In other cases, researchers copy these biological response modifiers and use them as replacement therapy o Protein-based drugs are manufactured in biological systems, such as living cells, producing desired protein molecules in large reaction vessels or by extraction from animal serum o Becoming increasingly important • More potent and specific—more similar to proteins w/in body therefore more effective in treating our diseases
Type B (idiosyncratic)
results from mechanisms that are not currently understood; largely unpredictable
Type B (idiosyncratic adverse reaction)
results from mechanisms that can not currently understood ex. skin rashes, jaundice, anemia, etc.
Durable medical equipment
reusable products for health-related use in the home such as walkers, wheelchairs, oxygen equipment, prosthetics, hospital beds
3rd right of drug administration
right dose
1st right of drug administration
right patient
Rights of drug administration
right patient, right medication, right does, right route of administration, and right time of delivery
4th right of drug administration
right route of administration
ADME
testing that measures the rate at which the body absorbs the drug, distributes it to the organs necessary to produce the desired effect, metabolizes it into waste material, and then excretes it from the body
Protein Binding
the ability of certain drugs to bind to plasma protein
Protein binding
the ability of certain drugs to bind to plasma protein.
generic substitution
the act of dispensing a different brand for the product prescribed
pharmaceutical substitution
the act of dispensing a pharmaceutical alternative for the product prescribed
rebate
the amount that the manufacturer of the drug pays to an insurer or health plan for each unit of drug dispensed
Brokerage
the combination of -drop ship and dock to dock delivery services provided by wholesalers. Wholesalers do not bring the product into their warehouses
Margin of safety
the difference between the usual effective dose and the dose that induces severe or life threatening side effects
Factors that influence DTC
the growth of managed care organizations, A more hollistic prevention-oriented definition of health, More mainstream acceptance, AIDs activism and patients rights movement, the availability of OTCs, the direct and targeted marketing revolution, the emergence of the internet, the heightened competitive arena, aging baby boomers
first pass effect
the metabolizing process in the liver that suppresses the amount of drug that eventually reaches the systemic circulation and the site of action
Upcharge
the percentage fee that is paid by the dispenser to the wholesaler for the cost of distribution
titration
the process of adjusting drug doses to achieve maximum positive therapeutic effects while minimizing adverse/side effects
Titration
the process of adjusting drug doses to achieve the max positive therapeutic effects while minimizing adverse or side affects
Bioavailability
the rate and extent to which the active ingredient or therapeutic ingredient is absorbed from a drug product and becomes available at the intended site of drug action
Single-source drug products
there is only one approved product available for that active ingredient and dosage form
Type D delayed
these take some time to develop
Naked DNA
they do not have viral genes and do not cause disease
manufacturing & operations
this includes the supply chain, manufacturing trade, and distribution functions of the business
TID
three times a day
Transdermal
through the skin via creams or patches
duration of action
time interval within which a given dose of a drug is expected to have a therapeutic effect
Tmax
time of peak plasma concentration on a measuring curve
tmax
time of peak plasma concentration on a measuring curve
AT
topical products
The extent, quality, or degree to which a substance is poisonous or harmful to the body.
toxicity
Which of the below terms means "to apply the drug on the skin surface"?
transdermal
What is one of the biggest time wasters for a pharmaceutical sales rep?
travel time
Patients with leukemia have a condition in which the stem cells in the bone marrow malfunction and produce an excessive number of immature white blood cells, which interfere with normal blood cell production.
true
Pharma companies must submit extensive data to the FDA demonstrating the safety and effectiveness of new drugs before receiving approval for sale.
true
Pharmaceutical representatives must always record the amount of drug samples left and obtain signature for that amount.
true
Rebates are also referred to as after-market arrangements.
true
Side effects that might be considered merely minor annoyances in acute treatment can be a powerful barrier to adoption in chronic therapies.
true
Subjects should be informed about the aims, methods, risks, and benefits of the trial
true
Subsidies should not be accepted to pay for the costs of travel, lodging, or other personal expenses. Paying for a modest meal is OK
true
The FDA approves storage conditions for drug products.
true
The FDA regulates the introduction of new drugs and enforces U.S. drug laws.
true
The aim of pharmacological studies is to obtain data on the safety and effectiveness of the lead compound.
true
The duration for Phase III of the clinical trial can typically last 3-5 years.
true
The greatest challenge for a generics manufacturer is to replicate drug formulation factors that affect the pharmacokinetic and pharmacodynamic characteristics of the original drug.
true
The liver is the major organ for metabolizing drugs. Secondary is kidney
true
Multi-Potent
• Differentiated stem cells • They have potential to produce specialized cells
3 Mechanisms Adjuvants Help Immune Response
• Adjuvants help immune response by forming reservoirs of antigens and providing sustained release of antigens over long period • Adjuvants act as non-specific mediators of immune cell function by stimulating or modulating immune cells • Adjuvants can serve as vehicles to deliver antigen to spleen and/or lymph nodes where immune response is initiated
New Vaccines
• Advances in genomics, molecular biology and recombinant technology has provided new directions for discovery, development and manufacture of vaccines • Current approach is minimalist strategy to decouple virulence and immunity functions • Aim is to use only immunity part to confer protection, so vaccine is safe to be administered • Approach can be divided into subunit, vector-based, DNA and peptide vaccines
DNA Vaccines
• Aka nucleic vaccines or genetic immunization • Host (patient) is directly injected w/ selected viral genes which contain engineered DNA sequences that code for antigens • Hosts own cells take up these genes and express antigens which are then presented to immune cells and activate immune response
Vaccines
• Basis of vaccination is that administering small quantity of a vaccine (antigen that has been treated) stimulates our immune system and causes antibodies to be secreted to react against foreign antigen • Later in life, when we encounter another exposure to same antigen, our immune system will evoke a memory response and activate defense mechanisms by generating antibodies to combat invading antigen • Contains antigenic components that are obtained from or derived from pathogen o Include mainly viruses, bacteria, parasites and fungi o Research has shown that part of pathogen that causes disease (virulence) can be decoupled from protective part (immunity) • Development focuses on means to reduce virulence factor while retaining immunity stimulation • Oral or parenteral
Bone Marrow Transplant
• Bone marrow is spongy tissue inside cavities of bones • Bone marrow stem cells grow and divide into various types of blood cells: white blood cells (leukocytes) that fight infection, red blood cells (erythrocytes) that transport oxygen and platelets that are agents for clotting • Patient w/ leukemia have condition in which stem cells in bone marrow malfunction and produce and excessive number of immature white blood cells, which interfere w/ normal blood cell production • Aim of bone marrow transplant is to replace abnormal bone marrow stem cells w/ healthy stem cells from donor o Healthy stem cells are harvested using syringe to withdraw bone marrow from rear hip bone of donor o Then infused into patient via catheter in chest area o Before infusion, patient receives chemo or radiotherapy to destroy diseased bone marrow stem cells so that the infused stem cells have chance to grow free of complications from diseased cells
AIDS
• Caused by HIV infection • HIV belongs to large family of retroviruses, Lenti virus • HIV genome is w/in RNA • RNA genome of HIV is reverse-transcribed into DNA and integrated w/in human cell • HIV undergoes frequent mutation and therefore highly variable • Technique for producing AIDS vaccine is to reproduce, using recombinant technology, the surface proteins on HIV o 2 particular envelope proteins being investigated • gp120 and gp41 • trimeric protein and held together by 3 transmembrane gp41 proteins • Vaccines based on these proteins can induce antibody responses to different strains of HIV • Other AIDS treatments are use of antiviral (AZT, reverse transcriptase inhibitor) drugs, drugs (indinavir) that target and inhibit production of HIV protease, and enzyme required to assemble new virus particles and gene therapy—control of viral genome expression through use of synthetic oligonucleotides
Killed or Inactivated Vaccines
• Chemical and temperature treatment are normally used to kill or inactivate pathogen • Formaldehyde treatment most common method • Other chemicals used are phenol and acetone • Another method is to irradiate pathogen to render it inactive • Advantages are non-reversal to virulence and relatively stable shelf life • Disadvantages are higher cost of production, more control is required for production to ensure reliable processes for complete inactivation and there is possibility of reduced immunological response due to treatment processes so multiple booster vaccinations may be required
Peptide Vaccines
• Chemically synthesized and normally consist of 8-24 amino acids • Relatively small • Aka peptidomimetic vaccines as they mimic epitopes • Complex structures of cyclic components, branched chain or other configurations can be built into peptide chain • They possess conformations similar to epitopes and can be recognized by immune cells • An in silico vaccine design approach has been used to find potential epitopes • Critical aspect of peptide vaccines is to produce 3D structures similar to native epitopes of pathogen
Toxoids
• Derived from toxins secreted by pathogen • Advantages and disadvantages similar to killed or inactivated vaccines(advantages: non-reversal to virulence and relatively stable shelf life; disadvantages: higher cost of production, more control is required for production to ensure reliable processes for complete inactivation and there is possiblity of reduced immunological response due to treatment processes so multiple booster vaccinations may be required)
Gene Therapy
• Described as good genes for bad genes • Involves transfer of normal fxnal genes to replace genetically faulty ones so that proper control of protein expression and biochemical processes can take place • Transport system or vehicles used are called vectors (gene carriers) • Most common vectors used today are viruses, w/ retroviruses being preferred candidates, as they're efficient vectors for entering humans and replicating their genes w/in human cells o Disease-causing genes from viruses are removed and therapeutic genes are inserted o Retroviruses carrying desired therapeutic genes are placed in patients body o When viruses invade cells, they infect these host cells and therapeutic genes are added to host DNA • New genes fxn and take over from original faulty genes • Another hurdle surrounding gene therapy is identification of genes causing disease o Effective cures can only arise when theres good understanding of roles of particular genes in diseases • Gene therapy may be applicable to cancer, hemophilia, sickle cell anemia, cystic fibrosis, insulin-depended diabetes, emphysema, Alzheimer's, Huntington's disease and severe combined immune deficiency (SCID) o To date, FDA hasn't approved any gene therapy product o Number clinical trials are in progress o Ethical considerations for gene therapy
Gene Therapy Trials
• First gene therapy trial was conducted in Sept 1990 o 4 year old girl w/ SCID (Bubble Boy syndrome) treated in Cleveland, OH and is still doing well 10yrs after treatment o Another girl w/ same disorder underwent gene therapy and is also doing well • More than 400 gene therapy clinical trials have been conducted, mainly on cancer, but not many cases worked o in 1999, 18 yr old boy in Pennsylvania unexpectedly died from reaction to gene therapy when he was treated for metabolic disease • This trial raised many issues and many trials w/ discrepancies and unreported adverse events were suspended by FDA • FDA has since introduced tighter controls for gene therapy trials
Chicken Pox
• Highly contagious viral infection that causes rash-like blisters on skin surface and mucous membranes • mild and not normally life-threatening o can be deadly to pregnant women, people w/ leukemia, or immunosuppressed patients • Varivax from Merck tested on about 11,000 children and adults and was approved by FDA as chicken pox vaccine
Pneumococcal
• In Oct 2006, FDA approved use of Prevnar for immunization of infants and toddlers against otitis media middle ear infection o Prevnar is pneumococcal seven-valent conjugate vaccine • Formulated w/ sterile solution of saccharides conjugated to antigen
Cancer
• In cancer, immune system doesn't recognize changes in cancer cells • Cancer vaccines seek to mimic cancer-specific changes by using synthetic peptides to challenge immune system o When these peptides are taken up by T cells, immune system is activated o T cells search for cancer cells w/ specific markers and proceed to kill them • Vaccines being tested are peptide called B-defensin 2 which activates immune system against tumor activity and outer coat protein of human papilloma virus act as vaccine against cervical cancer
Hormones
• Intercellular messengers • Typically steroids (control level of water and salts excreted by kidney), polypeptides and amino acid derivatives • Maintain homeostasis
Malaria
• Major disease in tropical countries • According to WHO, 300-500million individuals are infected w/ malaria o Death tolls are 1.5-3.5million people yearly • 4 species of malaria parasites that infect humans o plasmodium falciparum • predominant malarial parasite found in Africa and most virulent o P. vivax o P. ovale o P. malariae • Vaccine strategies are of 3 types: o Pre-erythrocytic o Blood stage o Transmission-blocking stage
Diabetes Mellitus
• Occurs when human body doesn't produce enough insulin o This form of diabetes is called insulin-dependent diabetes mellitus (IDDM or juvenile diabetes or Type I Diabetes) o Autoimmune disease in which B cells are targeted by bodys own immune system and progressively destroyed o Once destroyed, unable to produce insulin • Production of insulin is triggered when theres rise in blood sugar>after meal • Most body cells have insulin receptors which bind to insulin secreted • When insulin binds to receptor, other receptors on cell are activated to absorb sugar from bloodstream into cell • When theres insufficient insulin to bind to receptors, the cells are starved because sugar cannot reach interior to provide energy for vital biological processes o Patients w/ Type I become sick when this happens, they depend on insulin injection for survival • Non-insulin dependent diabetes mellitus (Type II Diabetes) o Insulin is produced and normal insulin level is detected in blood but its effect is reduced o Caused by reduced number of insulin receptors on cells or reduced effectiveness in binding to these receptors o Cause is complex and may involve genetic makeup, changes in lifestyle, nutritional habits, and environmental factors
Human Growth Hormone (hGH)
• Polypeptide w/ 191 amino acids • Secreted by pituitary gland • Stimulates production of insulin-like growth factor 1 (IGF-1) from liver • Positive effects of hGH are mediated by IGF-1 system which also includes specific binding proteins • Major fxn is promotion of anabolic activity due to increase in metabolic processes • Biological effects of hGH are stimulation of protein synthesis, elevation of blood glucose level and improvement of liver fxn • Overproduction of hGH during puberty leads to gigantism and deficiency during this period results in dwarfism • Main therapeutic use of hGH is for treatment of short stature • Used by athletes illegally to enhance performance • Sold w/out prescription w/ claims of improvement to body composition, bone strength, immune fxn, youthful vigor and general well being
Stem Cells
• Potential contribution of stem cells to medical treatment lies in their capability to differentiate and grow into normal, healthy cells • Using pluripotent stem cells, scientists are devising means to culture them in lab and coax them to grow into various specialized cells • Stem cells have potential of cell therapy to repair our disease tissues and organs o Circumvent problem of lack of donor organs o Provide possibility for healthy cells to cure disabilities such as strokes, Parkinson's, and diabetes • Drawback is problem of cell rejection due to hosts immune system recognizing the cells as foreign o Has to be overcome to ensure stem cell therapy as viable treatment • French scientists reported on research progress of stem cell transplants for curing children w/ sickle cell anemia o Mix of anti-rejection drugs was used to suppress rejection of new stem cells • Bone marrow transplant for patients w/ leukemia involves finding matching donor to harvest bone marrow stem cells and transfuse them to patient w/ leukemia
Insulin
• Produced in pancreas by B cells in region called islets of Langerhans • Polypeptide hormone consisting of 2 chains: A chain w/ 21 amino acids w/ internal disulfide bond and B chain w/ 30 amino acids • 2 disulfide bonds joining these 2 chains together • Molecular weight is around 6.8 kDa • Regulates blood glucose level w/in narrow range of 3.5-8mmol/L of blood • Originally obtained from porcine and bovine extracts o Bovine insulin differs from human insulin by 3 amino acids and it can elicit antibody response that reduces its effectiveness o Porcine insulin differs in only 1 amino acid • Enzymatic process can yield insulin identical to human form • Insulin is produced via rDNA process it was first recombinant biopharmaceutical approved by FDA (early 1980s) o Removes reliance on animal sources of insulin and ensures that reliable and consistent insulin is manufactured under controlled manufacturing processes
Cytokines
• Produced mainly by leukocytes (white blood cells) • Potent polypeptide molecules that regulate immune and inflammation fxns as well as hemopoesis (production of blood cells) and wound healing • 2 major classes o Lymphokines and monokines • Cytokines produced by lymphocytes are lymphokines • Interferons (IFN) and interleukins (IL) • Cytokines produced by monocytes are monokines • Other interleukins and tumor necrosis factor (TNF) • Different types of white blood cells o Growth factors
Areas of Biopharmaceuticals
• Prophylactic→ preventive as in vaccines • Therapeutic→ antibodies • Replacement therapy→ hormones, growth factors
Human Immune System
• Remarkable system for combating foreign substances that invade body • Protects us from infections by pathogens such as viruses, bacteria, parasite and fungi • Important aspect of immune system is self-non-self recognition fxn by means of markers present on protein called major histocompatibility complex (MHC) o Substances w/out such markers are discerned and targeted for destruction • For some, immune system lacks normal discrimination capability and revers to attack and destroy their own body cells as if they're foreign o Gives rise to autoimmune disease such as rheumatoid arthritis, diabetes, MS, and lupus o Also occasion when immune system response w/ undue sensitivities to innocuous substances such as airborne pollen leading to allergies as in case of asthma and hay fever • Immune responses are mediated through lymphocytes called B cells and T cells o Lymphocytes are particular type of white blood cells o White blood cells (leukocytes) are dividted into granulocytes (neutrophils 55-70%, esosinophils 1-3% and basophils .5-1%) and agranulocytes (lymphocytes {B and T cells} 20-40% and monocytes 1-6%) o There are 5000-10000 white blood cells per mL of blood compared w/ 5 million red blood cells in same volume • When pathogens enter human body, cells called macrophages (big eaters) engulf and ingest pathogens (antigens) o Antigens are processed by macrophages and parts of antigens are displayed on surface in form of short peptide chains bound to MHC protein o These antigen-presenting cells (APC) of macrophages and dendritic cells activate immune response by sensitizing B and T cells
Totipotent
• Stem Cells • Obtained from embryos that are less than 5 days old • Have full potential to develop into another individual and every cell type • After 5 days and several cycles of cell division, totipotent cells form hollow sphere of cells called blastocyst • Blastocyst has outer layer of cells surrounding clusters of cells • Those cells on outside continue to divide and grow into placenta and supporting tissues
Pluripotent
• Stem cells • Clusters of cells on inside divide and form virtually all cell types except placenta and supporting tissues which give rise to human being • Continue to develop, differentiate, and specialize into different cells • Become the specialized stem cells (blood, skin, and nerve stem cells)
Drug Discovery
• Unlike small molecule drugs (pharmaceuticals), large molecule drugs (biopharmaceuticals) are mainly protein-based o These protein-based drugs are similar to natural biological compounds found in human body or they're fragments that mimic active part of natural compounds
Subunit Vaccines
• Use only part of bacteria or virus instead of entire pathogen • Part is derived from outside envelope protein of pathogen • Requires knowledge of genome sequence of pathogen by identifying open reading frames (ORF) that potentially encode novel antigenic surface proteins known as epitopes, which bind to antibodies • When identified, ORFs are cloned to express protein epitopes using self-replicating plasmids • Binding properties of epitopes can be studied using enzyme linked immunosorbent assay (ELISA) or fluorescent activated cell sorter (FACS) • Leading candidates of epitopes are injected into animals to determine whether they elicit any antibody response o Those that work are selected and optimized to become vaccine candidates w/ further tests before human clinical trials o Also working on multiple epitope subunit vaccines which can provide different antigenic binding sites
Alzheimer's Disease
• Vaccine being tested contains small protein called B amyloid (AB) o This protein forms abnormal deposits or "plaques" in the brains of individuals w/ Alzheimer's o It's believed that AB deposition Causes loss of mental fxn by killing brain neurons o AB vaccination stimulates immune system to clean up plaques and prevent further AB deposits o Phase II clinical trial was halted because 15 of 360 patients developed severe brain inflammation • Studies showed that AB did generate desired antibody response • Acceptable vaccine may still be possible by modifying epitope to reduce inflammation effects
Adjuvant
• Vaccines formulated w/ certain substances to enhance immune response • Latin adjuvare→ to help • Most common adjuvants for humans are aluminum hydroxide, aluminum phosphate and calcium phosphate • Others include bacteria and cholesterol • Mineral oil emulsions normally adjuvants used in animal studies • Adjuvant known as Freund's Complete Adjuvant consists of killed tubercle bacilli in water-in-mineral oil emulsion • Freund's Incomplete Adjuvant is water-in-oil emulsion • Both effective in stimulating immune response but cause unacceptable side effects in humans
Attenuated Vaccines
• Virulence of pathogen that can be reduced in number of ways • By chemical treatment, by temperature adaptation, or by growing pathogen in specified other than natural host (passaging) • Advantages are low cost preparation, elicit desired immunological response, and normally single dose is sufficient • Disadvantages are potential to revert to virulence and limited shelf life
Vector-based Vaccines
• Viruses and bacteria are detoxified and used as vehicles to carry vaccines • Subunit vaccines are being delivered by carrier vehicles to elicit immune response • Multiple types of envelope proteins can be delivered w/ this method • Clinical trials w/ this type of vector-based vaccines are being investigated
Retrovirus
• preferred vector for gene therapy • integrates genes to host chromosomes, chance of long-term stability. • Major disadvantage is that integration is random, mostly on dividing cells
Naked DNA
• vector for gene therapy • do not have viral genes so do not cause disease • Major disadvantage is that its an inefficient gene transfer
Liposomes
• vector for gene therapy • doesn't have viral genes so they do not cause disease • Much less efficient than viruses
Adeno-associated virus
• vector for gene therapy • integrates genes to host chromosomes • Major disadvantage is that it has small capacity for foreign genes
