CNPR, NAPSR Exam

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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


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