Pharmaceuticals Exam 4

How can efficient targeted drug delivery be achieved?

• the delivery system must avoid the host’s defense mechanisms (immune system)

• circulate to its intended site

• taken up by target cells or released in close proximity to target cells

systemic effect

drug acts throughout the entire body

systemic delivery

• oral/IV routes

• distributed through whole body

local delivery

• topical, some injections

• enteral for some gastro targets 

• directly to organ/tissue

local effect

drug affects area in which it was administered

targeted delivery

• is generally systemic but drug is forumlated to where it isn’t active everywhere

targeted effect

• can occur through tissue/cell-specific delivery 

• can occur through secondary activation (radiation, heat, light)

• can occur through other targeting processes

active targeting

• highly specific delivery

• precise targeting capability

• enhanced delivery efficiency

i.e. organelle targeting, small molecules, antibodies and peptides, aptamer-based, targeting tumor

passive targeting

uses natural physiological processes such as the enhanced permeability and retention (EPR) effect, to gather nanocarriers in diseased tissues (e.g., tumors)

• improves bioavailability

• selective accumulation

• reduces toxic effects

i.e., liposome, polymer, magnetic nano-material, mesoporous silica

target destination

where the drug molecules have to approach to be taken up or exert effects

• outside of cell

• inside of cell

• extracellular structures

target - outside of the cell

• changing a signal that is being relayed inside the cell

• blocking a signal you dont want transmitted

• setting off a signal thats not going off often enough

potential targets- outside of the cell

Any chemical bound to embedded proteins/lipids in cell membrane

• Receptors

• Ion channels (exterior port)

• Channel protein (exterior port)

• Membrane-bound enzymes

What are some pre-uptake considerations when it comes to nanoparticles?

• Spherical, larger NPs circulate more easily
• Uncoated/charged NPs quickly cleared by macrophages
• Rod-shaped NPs extravasate more easily
• Rod-shaped, targeted, neutral NPs penetrate tumors best
• Leaky vessels allow larger NPs into tissue
• Positively charged, smaller, coated NPs penetrate mucus more
easily

What is it like to cross the cell membrane as a drug?

Phospholipid bilayer = hydrophobic core (tails) with hydrophilic surfaces (heads)

• Challenge: Balance between water solubility
  (to dissolve) and lipid solubility (to cross membrane)
  • For oral drugs: Must cross intestinal epithelium
  • For CNS drugs: Must cross blood-brain barrier

• Key Principle:

  • Too hydrophilic → can't cross lipid membrane

  • Too lipophilic → poor water solubility, can't dissolve/reach membrane

  • there needs to be a perfect of balance of
    properties

Lipinski's Rule of Five (Ro5) - The
Classic Framework

Rule of thumb to evaluate drug-likeness or determine if a chemical compound has
properties that would likely make it an orally active drug in humans
• Formulated by Christopher A. Lipinski in 1997
at Pfizer, based on observation that most
medication drugs are relatively small and
lipophilic molecules

The Four Rules (all multiples of 5)

Poor absorption is more likely when there are:
• LogP (lipophilicity) greater than 5

Rule Interpretation:
• More than 5 hydrogen-bond donors (NH and OH groups)
• More than 10 hydrogen-bond acceptors (N and O atoms)
• Molecular weight greater than 500 Daltons
• A compound can violate ONE of these and still be orally bioavailable
• Violate 2+ rules →possible poor membrane permeability

Understanding LogP - The Lipophilicity Parameter

LogP is directly related to the drug lipophilicity

• a key property for the solubility, absorption, membrane
  penetration, plasma protein binding, distribution, and tissue penetration
  • Partition coefficient (P) measures ability of
  compound to differentially dissolve in
  mixture of water and lipids/organic solvents
  • P = [concentration in organic phase] / [concentration in aqueous phase]
  • LogP = log₁₀(P)

LogP Values and Meaning

N-octanol is a fatty alcohol – lipid solution
• Negative LogP = hydrophilic (prefers water)
• Positive LogP = lipophilic (prefers lipids)
• LogP = 0 = equal solubility in both phases

Optimal LogP Values by Drug Type

Oral drugs: LogP <5, ideally between 1.35-1.8 for good oral and intestinal
absorption
• CNS drugs (crossing blood-brain barrier): LogP should be around 2
• Sublingual absorption drugs: LogP should be >5
• LogP value exceeding 5 may exhibit poor absorption or limited membrane
permeability, leading to poor solubility, unpredictable absorption, and
potential accumulation in fatty tissues

How does the presence of hydrogen bonding affect drug delivery across the cell membrane?

Hydrogen-bond donors (HBD) reduce permeability of compounds into lipophilic
environments
• Hydrogen-bond acceptors (HBA) affect permeability by interacting favorably with strongly hydrogen bonding solvents such as water
• Too many H-bond donors/acceptors → molecule becomes "too comfortable" in water
• High desolvation energy required to leave aqueous environment
• Cannot shed water molecules easily to enter lipid bilayer
• Result: Stuck outside the cell

What is the cellular balance when it comes to hydrogen bonding as a factor in drug delivery?

• Hydrogen bond acceptors and donors can form interactions with water,
  enhancing solubility, but excessive hydrogen bonding can reduce
  permeability by increasing energy required to desolvate the molecule
  • Need enough for solubility but not so much that membrane crossing is
  impossible

Why is it important to keep the molecular weight lower than 500 Daltons?

Larger molecules have:
• More surface area to desolvate
• Increased molecular complexity
• Greater steric hindrance
• Lower diffusion rates

What is the relationship between molecular size and permeability across the cellular membrane?

• Small molecules (MW 150-350 Da) → generally cross membranes well

• Medium molecules (MW 350-500 Da) → cross if other properties favorable

• Large molecules (MW >500 Da) → increasingly difficult to cross passively

• May require active transport or endocytosis

• Some successful drugs violate MW rule, often require special transport
  mechanisms

• Examples: Cyclosporine (MW 1203), many antibiotics

What are some compounds that cross membranes easily?

• small, lipophilic molecules

• molecules that have a small MW 250-350 Daltons (enables better diffusion)

• few H-bond donors: 0-2 

• Few H-bond acceptors: 2-5

• uncharged at physiological pH

• LogP of 1-3 (balanced lipophilicity)

What are some examples of drugs with great membrane permeability?

 Aspirin
• MW = 180.16 g/mol, log P = 1.2, hydrogen bond
acceptors = 4, hydrogen bond donors = 1
• All parameters well within Ro5

Ibuprofen
• MW = 206.29 g/mol, log P = 3.97, hydrogen bond
acceptors = 2, hydrogen bond donors = 1
• Highly lipophilic but still balanced

Caffeine
• Small, lipophilic, crosses BBB easily
• MW ~194 Da, LogP ~0

Steroid Hormones (testosterone, estrogen)
• Very lipophilic
• Cross membranes by passive diffusion
• Can enter nucleus

What are some special cases of membrane permeability?

• Uncharged molecules cross membranes much better than charged molecules

• Ionized molecules = trapped (can't cross lipid bilayer) (K+, Ca+, etc)

Drug Classes That Exploit This
• Weak Acids (aspirin, ibuprofen)
• Uncharged in acidic stomach (pH 1-3)
• Absorbed in stomach
• Weak Bases (morphine, codeine)
• Uncharged in basic intestine (pH 7-8)
• Absorbed in small intestine

What are some membrane permeability enhancers?

1. Formulation Strategies:
   • Lipid-based formulations (micelles, liposomes)
   • Nanoparticles to facilitate endocytosis
   • Permeation enhancers (surfactants, bile salts)

2. Chemical Modifications:
   • Prodrugs - Add lipophilic groups temporarily
   • Cleaved off after absorption
   • Example: Ester prodrugs
   • Masking polar groups
   • Intramolecular H-bonds reduce effective polarity

3. Cell-Penetrating Peptides (CPPs):
   • Arginine-rich sequences
   • TAT peptide from HIV
   • Can carry larger, polar cargo

4. Design substrates for influx transporters
   • Amino acid transporters (L-DOPA)
   • Glucose transporters
   • Peptide transporters (some antibiotics)

Is Ro5 Still Relevant?

• Many chemists think of rule of 5 as guardrails
  rather than rules

• Successful Drugs That Break Ro5

• Cyclosporine (immunosuppressant) - MW
  1203

• Venetoclax (cancer) - MW 868

• Many antibiotics

• Macrocyclic drugs

• As more molecules that break rule of 5 have
  become oral drugs, researchers have begun to
  question its value

• Can use computational tools for shape/interaction
  predictions

What are some ways that drugs can cross cellular barriers?

• Uptake through cell membrane

• Endocytosis

• Exiting vesicular compartments

• Crossing additional intracellular
  membranes

What are the basic types of membrane transport?

Passive transport- Diffusion

• Cross the cell membrane towards the lowest
  concentration

Passive transport - Facilitated diffusion

• Travel through ion channel

• Transport protein which does not use ATP

Active transport

• Carrier protein uses ATP to pull drug against the concentration gradient

Endocytosis

• Cell “engulfs” ligands which have attached
  to receptors on the outside of the cell
  

What are the four types of endocytosis?

• caveolin-mediated endocytosis

• clathrin-mediated endocytosis

• independent endocytosis

• pinocytosis

Pinocytosis

Non-specific uptake of extracellular fluid and dissolved solutes

• "Cell drinking" - continuous process in most cells

• Forms small vesicles (typically <100
  nm)

• Does NOT require specific receptors

• Constitutive process (always occurring at low levels

Mechanism:

• Plasma membrane invaginates to form small pockets

• Pockets pinch off to form fluid-filled vesicles

• Vesicles contain whatever was in the surrounding fluid (non-selective)

• Vesicles delivered to early endosomes

How can pinocytosis be used for drug delivery?

• Allows uptake of small molecules
  and nutrients

• Can be exploited for non-targeted
  drug delivery

• Less efficient than receptor-
  mediated pathways

• Useful for drugs that don't have
  specific cellular targets

• Limited control over uptake amount

receptor-independent endocytosis (macropinocytosis)

Non-specific, large-scale uptake mechanism

• Forms large vesicles called
  macropinosomes (0.5-5 μm - MUCH larger than other types)

• Does NOT require specific receptors

• Can be enacted on its own OR induced by growth factors/stimuli

• causes "Ruffling" of plasma membrane

Macropinocytosis mechanism

How does it work?

• Stimulus triggers actin polymerization at cell surface

• Membrane extends outward forming lamellipodia or "ruffles"

• Ruffles fold back and fuse with plasma membrane

• Large vesicle (macropinosome) engulfs
  extracellular fluid

• Macropinosomes mature and can fuse with lysosomes OR recycle back

Triggers/Stimuli:

• Growth factors (EGF, PDGF)

• Bacterial toxins

• Viruses (some hijack this pathway)

• Tumor cells often have increased macropinocytosis

What are the advantages of macropinocytosis when it comes to drug delivery?

• No receptor required - useful when target cells lack specific receptors

• Large cargo capacity - can internalize large nanoparticles, aggregates

• High fluid uptake - can deliver more drug molecules

• Exploited by some viruses and bacteria (can learn from nature)

What are the drug design considerations when using drug delivery systems that utilize macropinocytosis?

• Can be enhanced with cell-penetrating
  peptides (CPPs)

• Useful for large nanoparticles (>200 nm)
  that don't fit in clathrin/caveolin vesicles

• Arginine-rich peptides and proteins can trigger macropinocytosis

What are the cell types that use macropinocytosis?

• Cancer cells - particularly RAS-mutated tumors (use for nutrient scavenging

• Immune cells (macrophages, dendritic cells) - antigen sampling

• Epithelial cells

What are the challenges of macropinocytosis drug delivery?

• Less predictable than receptor-mediated pathways

• Variable between cell types and conditions

• Cargo still may end up in lysosomes

• Need to ensure sufficient uptake in target cells

Clathrin-mediated endocytosis

• Most common and well-studied form of endocytosis

• Receptor-mediated process (highly specific)

• Forms clathrin-coated pits → clathrin-coated vesicles

• Vesicle size: ~100-150 nm diameter

How does clathrin-mediated endocytosis work?

• Cargo binding: Ligand (drug, protein, nanoparticle) binds to
  specific cell surface receptor

• Coat assembly: Receptors cluster in clathrin-coated pits

• Vesicle formation: Membrane invaginates, clathrin lattice forms
  cage-like structure

• Pinching off: Dynamin (GTPase) pinches vesicle from membrane

• Uncoating: Clathrin coat removed, vesicle fuses with early
  endosome

What are the advantages of clathrin-mediated endocytosis for drug delivery?

• Highly specific targeting - can design ligands for specific
  receptors

• Efficient uptake - receptor-mediated = high affinity

• Well-characterized pathway - predictable intracellular
  trafficking

• Natural pathway for many proteins (transferrin, LDL,
  growth factors)

Common Targets/Receptors Used:

• Transferrin receptor (iron uptake) - often overexpressed in cancer

• LDL receptor (cholesterol uptake)

• Folate receptor (overexpressed in many cancers)

• EGF receptor (epidermal growth factor)

What are the considerations for drug delivery that utilizes clathrin mediated endocytosis?

• conjugate drugs/NPs with ligands for specific receptors

• Vesicles traffic to acidic endosomes (pH ~5-6)

• Must plan for endosomal escape if cytoplasmic delivery needed

  • Example: Antibody-drug conjugates often use this pathway

caveolin-mediated endocytosis

• Receptor-mediated endocytosis via caveolae ("little caves")

• Caveolae = small flask-shaped invaginations (50-80 nm)

• Enriched in cholesterol and sphingolipids (lipid rafts)

• Less common than clathrin-mediated (~30% of cell types have abundant caveolae)

• Often avoids lysosomal degradation* (difference from
  clathrin!)

How does caveolin-mediated endocytosis?

• Ligand binds to receptor in caveolae

• Caveolin-1 protein (main structural component) forms coat

• Dynamin pinches off vesicle

• Vesicle traffics to caveosomes (NOT early endosomes)

• Often bypasses lysosomes → can deliver to ER, Golgi, or
  cytoplasm

What are the advantages to caveolin-mediated endocytosis drug delivery?

• Avoids lysosomal degradation - major benefit for sensitive cargo (proteins, nucleic acids)

• It has less acidic compartments than the clathrin pathway

• It can deliver directly to specific organelles

• Important for uptake of some toxins, viruses, and signaling molecules

What are some cell types with high caveolae expression?

• Endothelial cells (critical for transcytosis across blood vessels)

• Adipocytes

• Smooth muscle cells

• Fibroblasts

What are some design considerations when using drug delivery systems that utilize caveolin-mediated endocytosis?

• Target ligands: Albumin, folate, cholera toxin B subunit

• Good for pH-sensitive drugs (less acidification)

• Useful for delivering cargo that needs to avoid degradation

• Can exploit for crossing endothelial barriers (BBB, tumor vessels)

  • Examples: Albumin-bound paclitaxel (Abraxane®) may use this pathway

What are the challenges to using caveolin-mediated endocytosis drug delivery?

• Not all cell types express caveolae

• Slower process than clathrin-mediated

• Less well-characterized than clathrin pathway

What are some drug targets inside of the cell?

• Intracellular receptors

• Enzymes

• Everything involved with protein synthesis/respiration

• Ion channels (interior port)

• Channel protein (interior port)

• Organelles

• Vesicles

• Nucleic acids

What are some drug targets outside of the cell?

Extracellular matrix (ECM)

• Non-cellular, three-dimensional network of macromolecules among cells in tissues

• Composed of collagens, elastin, proteoglycans (including hyaluronan), and non-collagenous glycoproteins

• Provides structural support AND generates signaling to control cell behavior

How do molecules exit vesicular compartments?

• NPs or drugs remain trapped within vesicular compartments, or endosomes, that feature various characteristics such as internal or external receptors.

• To achieve functional delivery, most NPs must escape from these compartments before they acidify.

• Thus, responsive NPs — such as ionizable NPs that become charged in low- pH environments aid in endosomal escape and allow for intracellular delivery

• Unresponsive NPs often remain trapped and are destroyed by lysosome acidity and proteolytic enzymes

Why do drugs target the extracellular matrix?

• There is presumably no disease without quantitative and/or qualitative changes in the ECM

• In tumors, ECM acts as a barrier shielding cells from therapeutic agents

• Dense ECM network causes high interstitial fluid pressure, hypoxia, and reduced effectiveness of chemotherapy, radiotherapy, and immunotherapy

Two Main Strategies:

• Direct ECM targeting - Modify/degrade ECM components to improve drug penetration

• ECM-based drug delivery - Use ECM molecules or ligands as targeting systems

What are the components in the extracellular matrix that are targeted and present in cancer cells?

Collagen

• Most abundant structural protein

• Excessive collagen deposition increases ECM stiffness and impairs drug penetration

• Target for degradation to improve access
  

Hyaluronic Acid (HA)

• Highly expressed in tumor extracellular matrix

• Creates dense, hydrated barrier

• Can be targeted by hyaluronidase enzymes
  

Fibronectin Cell

• adhesion protein

• Promotes tumor invasion and metastasis

Integrins (ECM receptors)

• Transmembrane receptors whose primary role is to recognize and bind

• Target for drug delivery via ECM ligands

Strategy 1 to combat ECM barrier for drug targeting - Use enzymes or other agents to degrade ECM and improve drug penetration

• Overcome physical barrier to drug delivery

• Reduce interstitial fluid pressure

• Improve oxygenation (better radiation therapy response)

• Hyaluronidase (HAase) - Targeting Hyaluronic Acid:

• Nanoparticles modified with hyaluronidase on the surface can degrade hyaluronic acid in tumor ECM

• Allows deeper penetration of chemotherapy drugs

Collagenase:

• Degrades collagen fibers

• Reduces tissue stiffness

• Improves drug distribution

• Sequential Drug Release System

Strategy 2 to combat ECM barrier for drug targeting - Use ECM-binding ligands for targeting

Targeting Through ECM Receptors:

Integrin Targeting (αvβ3, αvβ5)

• RGD peptides (Arg-Gly-Asp) bind to integrins

• c(RGDyK) peptide targets integrin αvβ3 expressed on tumor cells

Hyaluronic Acid Receptor Targeting (CD44)

• CD44 overexpressed on many cancer cells

• HA-conjugated drugs bind to CD44

• Triggers receptor-mediated endocytosis

Collagen Receptor Targeting

• Discoidin domain receptors (DDRs)

• Integrins that bind collagen

Strategy 3 to combat ECM barrier for drug targeting - Tumor Penetrating Peptides (TPPs)

• Peptides that bind to ECM components and trigger trans-tissue transport

• Help drugs penetrate through dense tumor stroma

  • Key Example - iRGD Peptide:

Mechanism:

• Binds to αv integrins on tumor endothelium

• Proteolytically cleaved in tumor

• Exposed CendR binds neuropilin-1 receptor

• Triggers transcytosis through tissue

• Enhances drug penetration into tumor core

What are some current drugs that act on the extracellular matrix indirectly?

Angiotensin Receptor Blockers (ARBs):

• Examples: Losartan, valsartan

• Block angiotensin II type 1 receptor, showing antifibrotic action by reducing ECM
  accumulation

• Clinical use: Significantly slow the rate of progressive aortic-root dilation in Marfan's syndrome patients

TGF-β Inhibitors:

• Target key pro-fibrotic signaling

• Prevent excessive ECM deposition

Calcium Channel Blockers:

• Examples: Nifedipine, amlodipine

• Act on ECM via suppressing TGF-β, resulting in reduced matrix accumulation

• Key Point: These drugs weren't designed to target ECM, but ECM modulation contributes to their therapeutic benefit

What are the advantages of extracellular matrix-targeted therapy?

Universal tumor targeting

• Potential to affect all tumor cell types, including tumor stem cells and cancer-associated fibroblasts

• Not limited to cells expressing specific markers
  

Overcome drug resistance

• ECM doesn't mutate like cancer cells

• More stable target

• improve penetration

• Breaking down ECM allows better drug distribution

• Enhances effectiveness of other therapies

Reduce side effects

• ECM-drug conjugates showed significant reduction in doxorubicin-induced cardiotoxicity

• More targeted delivery = less systemic toxicity

What are the challenges of extracellular matrix-targeted therapy?

• Must distinguish tumor ECM from normal tissue ECM
• Risk of affecting healthy connective tissue

• ECM composition varies between tumor types
• Multiple components need simultaneous targeting

• Getting large enzymes (like hyaluronidase) into tumors is hard
• Ensuring sustained activity at tumor site is also hard

• ECM degradation might facilitate tumor cell escape (which is really bad)

antibody drug conjugate

A type of biopharmaceutical that enables the targeted delivery of cytotoxic agents to tumor sites by recognizing target antigens by antibody while minimizing dmage to healthy tissues

Components:

• the antibody part

• the cytotoxic chemo/payload/warhead - binds to intracellular target to disrupt cellular process to promote cell death

• the linker protein that connects the antibody and chemo

Example:

• Trastuzumab emtansine (Kadcyla®): This ADC treats metastatic HER2-positive breast cancer.

What are some targeted drug delivery methods that utilizes antibodies?

• Antibody-Drug Conjugates (ADCs)

• Targeted therapy and
  chemotherapy

• Traditional chemotherapy is
  systemic

red blood cell

• Erythrocyte – erytho = red, ctye =
cell
• Largest population of cells
• No nucleus
• Packed with hemoglobin
• Biconcave shape allows for passage
through narrow capillaries
• Live in bloodstream for 100-120
days

What are some drug loading methods for red blood cells?

• Drugs attached to surface

• Drugs incorporated into cell

  • Multiple methods

  • Electric pulse/ultrasound – disrupt cell membrane to let in
    particles

  • Endocytosis – cell engulfs a drug-containing particle

  • Osmotic – change the water balance of the cell to push or pull drug inside

What are some benefits to red blood cell drug delivery?

• Ease of cell isolation in large quantities and the ability to scale production

• Biocompatibility

  • autologous and donor erythrocytes are used to treat patients

• Biodegradability

  • old or damaged erythrocytes
    removed by spleen

• Long life in the bloodstream

  • RBCs protect drug from the immune
    system and plasma proteases

  • Cells survive in the body for a long time

  • Pharmacokinetics and pharmacodynamics of the drug in RBCs can significantly increase the desired therapeutic effect

• Decreasing side effects of drugs

  • preventing allergic reactions

  • the decrease in the peak concentrations of free drug in the blood to safer levels

What were some advancements made in the 2010s?

HIV

• Antiretroviral Dovato 1-2 pills a day vs 4-6

• Fostemsavir – for multi-drug resistant HIV infection

• PrEP (pre-exposure prophylaxis) to prevent transmission

• HPV vaccine approved to prevent HPV infections and cervical

cancer

• First chimeric antigen receptor (CAR) T-cell therapies were

approved by the FDA

• First gene therapy to receive U.S. approval, Luxturna (Spark Therapeutics) 2017 for a rare, inherited eye disease that causes

blindness

• Approval of Zolgensma (Novartis) in 2019 for spinal muscular

atrophy, a deadly muscle-wasting disease which cost $2.1

million

• CRISPR- based medicines launch

Which US war prompted an outcry from the public on how many soldiers died due to adulterated drugs, and led to the passage of the first federal drug law?

Mexican-American War

Mexican-American War (1846-1848)

• During the course of the war, 1,773 Americans were killed in action
with an additional 13,271 dying from other causes.
• This high number of collateral casualties shocked the nation, and
calls came from across America for an investigation —> pharmaceuticals/drugs

What was the conclusion after the investigation of miscellaneous deaths in the Mexican-American War?

It was concluded that adulterated drugs supplied to the Army
had caused the large numbers of deaths among soldiers.

Drug Importation Act (1848)

The outcry led Congress to pass the Drug Importation Act of 1848,
the first federal drug law.

• It was very limited in scope and addressed only
  the purity of drugs imported into the United States.

• Congress charged Customs with enforcing the law.

The publication of what book helped fuel the support for the Food and Drug Act of 1906?

The Jungle - Upton Sinclair

Sherley Amendment of 1912

• coupled the Amendment of Food and Drug Act of 1906

• Regulates manufacturers’ claims of benefits

• Prohibits false claims of therapeutic effect

• Made it illegal to sell drugs the manufacturer knew to be worthless

What happened during the investigation of sulfanilamide?

• Harold Watkins, the chief pharmacist, committed suicide whilst awaiting trial.

• Defense: there were no official standards for toxicity testing for them to violate

• Company only had to pay fine for calling it an “elixir” when it did not contain alcohol

• S. E. Massengill Company
  => Beecham Group
  => SmithKline Beecham
  => GlaxoSmithKline

Diethylene Glycol

• A very potent solvent

• Useful for many industrial applications

• When ingested or applied topically destroys:

  • Liver

  • Kidneys

  • Nerves

  • Effects were mostly unknown at the time

  • > 240 gal were distributed

  • 105 patients died

What happened after the investigation of diethylene glycol (DEG)?

Nothing.

• Continued to be used in drug manufacturing

• Many mass poisonings from contaminated drug

Federal Food, Drug, and Cosmetic Act of 1938

There was a huge public outcry over sulfanilamide
tragedy

• Prohibits distribution and use of any new drug or drug product without the filing of a New Drug Application (NDA) and approval of FDA

• Established the FDA - U.S. Food and Drug Administration

What does the US Food and Drug Administration do?

• It enforced and currently enforces the 1938 act

• Grant or denies permission to manufacture/distribute new products

• Reviews applicant’s data when considering drug manufacturating or distribution including:

  • Ingredients

  • Method of assay

  • Formulation and manufacturing processes

  • Preclinical (animal, toxicology) and clinical (human) trials

  • Required safety for human use

• BUT it does NOT address efficacy – whether it works or not because that part is more subjective

Durham-Humphery Amendment of 1951

• Amendment to Federal Food, Drug, and Cosmetic Act

• Legal distinction between prescription and over-the-counter (OTC) drug

• Prior to this, all drugs were classified as OTC

• ALL prescription drugs must be labeled

• RX Only

• “Caution: Federal Law Prohibits Dispensing
  Without Prescription”

• Refills only with consent of provider

Thalidomide

• Developed in the 1950s as a sedative/tranquilizer

• Used for cold, flu, nausea, morning sickness during pregnancy

• No lethal dose found while doing
  animal testing – “harmless to humans”

• Licensed for OTC use in 1956 in Germany

• World-wide production - 14 pharmaceutical companies were marketing thalidomide in 46 countries under at least 37 different trade names.

Who was Paracelsus? (ca. 1493-1541 CE)

Aureolus Theophrastus Bombastus von Hohenheim

• Swiss physician and chemist

• Away from botanical remedies, toward chemistry

• Specific medicinal ingredient to combat a specific

disease

• Importance of cleanliness, protection of wounds

• Toxicology

•  Psychosomatics – mental wellbeing => physical health

•  also made some prophecies about the future

What were some historical advances of medicine by the Romans?

Surgical instruments

• Forceps

• Scalpels

• Cross-bladed scissors

• Surgical needle

• Speculas

Who was Hippocrates? (ca. 460-733 BCE)

Hippocratic Oath – confidentiality and “do no harm”

•  Illness as an imbalance of internal factors

• Not external spirits or supernatural influences

• Descriptions of diseases and conditions

• Delineation of acute, chronic, endemic, epidemic

• Described 100s of drugs

• Pharmakon (Gr.) – remedy used for good only

What was ancient medicine?

Early written texts on diagnosing and treating illness in many cultures

• Mesopotamia (Bablyon, neo-Assyrian)

• Indian

• Atharvaveda – charms, spells, herbal remedies

• Ayurveda – “complete knowledge for long life”, medical system

• Chinese

• Traditional Chinese Medicine – herbal medicine, acupuncture, massage

• Pharmakon (Gr.) – charm or drug used for good or evil

The Great American Fraud

Gullible America will spend this year some 75 millions

of dollars in the purchase of patent medicines,” one of

Adams’ stories reported. “In consideration of this sum it

will swallow huge quantities of alcohol, an appalling

amount of opiates and narcotics, a wide assortment of

varied drugs ranging from powerful and dangerous

heart depressants to insidious liver stimulants; and far

in excess of all other ingredients, undiluted fraud. For

fraud, exploited by the skillfulest of advertising bunco

men, is the basis of the trade.”

• $2.6 billion in 2024

• discusses how American medicine is fueled by dangerous and poisonous substances that keep you within the cycle of fraudulent healthcare, despite the large amount of money that is spent patenting and purchasing medicine. Wealthy corporations that advertise good health are also the ones that control the cycle that keep you sick and needy.

Drug Listing Act of 1972

• Compile a full list of marketed drugs

• National Drug Code

• One unique identifier per drug per package

type per manufacturer

• Permanently assigned

• Manufacturers and re-packagers must register

and supply information about their drug

• NDC must appear on all drug labeling

• Search online via Drug Code Directory

Poison Prevention Packaging Act (PPPA) - 1970

• This law was passed to require a number of household substances to be packaged in child-resistant packaging.

• According this Act, the packaging must be designed or constructed

to be significantly difficult for children under five years old to open within a reasonable time, and not difficult for normal adults to use properly.

FDA Black Box warning 1979

• Most serious type of warning mandated by FDA

• Prominently featured in the labeling of drugs to warn prescribers about:

• Serious adverse reactions, compared to potential benefit, that they should be considering when prescribing

• The risk can be prevented/reduced by careful use, FDA has restrictions on when drug can be used

Kefauver-Harris Amendments of 1962

• Amendment to Federal Food, Drug, and Cosmetic Act

• Passed without dissent

• Before clinical trials, manufacturers have to prove new drug is SAFE AND EFFECTIVE

• Investigational New Drug Application (IND) filed and approved

• Perform clinical trials on humans

• Then file an NDA for approval to market

Controlled Substances Act of 1970

• Combined existing federal drug laws and expanded their scope, but it also

• Changed the nature of federal drug law policies

• Expanded federal law enforcement pertaining to controlled substances

• Established new regulatory framework

• Drug Enforcement Administration (DEA) in Dept of Justice

• Established drug Schedules I-V

NY Herbal Supplement Investigation - 2016

• The investigation focused on a variety of herbal supplements from four major retailers:

GNC, Target, Walmart and Walgreen Co.

• Lab tests determined that only 21 percent of the products actually had DNA from the plants advertised on the labels.

• The investigation found supplements, including echinacea, ginseng, St. John's wort, garlic, ginkgo biloba and saw palmetto, were contaminated with substances including rice, beans, pine, citrus, asparagus, primrose, wheat, houseplant and wild carrot.

• In many cases, unlisted contaminants were the only plant

material found in the product samples.

Food and Drug Modernization Act of 1997

• Streamlined policies and new regulations

• Expanded access to investigational treatments for serious illnesses

• AIDS, Alzheimers, cancer

• Use drug user fees to hire more reviewers, use external reviewers

• Incentives for researching drugs for children

• Joint program with NIH to track clinical data

Late 2000s in the industry

 The average cost and time to develop a new drug continued to increase, often exceeding $1.3 billion and 12 years for a successful launch

• High-profile lawsuits and product withdrawals (such as Merck's Vioxx) led to greater public and regulatory scrutiny of drug safety.

• Pharmaceutical companies increasingly engaged in collaborative partnerships with academic institutions, smaller Biotech firms, and private foundations

• This "open innovation" model aimed to leverage external expertise and share the financial burden of early-stage research

• increased research focus on complex diseases, particularly central nervous system disorders and cancer (antineoplastic agents)

What were some key developments in medicine of the early 2000s?

• At Oregon Health and Science University, Shoukhrat Mitalipov and his team cloned a Rhesus Monkey and used the resulting embryo to create stem cells (2007) using somatic cell nuclear transfer (SCNT)

• Human Genome Project

• Launched in October 1990 and completed in April 2003

• Generated the first sequence of the human genome

Affordable Care Act

• Signed in 2010

• Brought healthcare coverage to ~ 20 million uninsured people

• Provided protections for ~ 50 million people who could otherwise have a hard time getting health coverage, thanks to past injuries or illnesses

• No annual or lifetime limits on coverage

• Pregnancy cannot be a “pre-existing condition” and denied coverage

• Center for Medicare and Medicaid Innovation focused on value-based care, or paying doctors and hospitals for making patients healthy, rather than for each visit or surgery

• Supreme Court ruled in 2012 that states could decide whether to expand Medicaid

• Fourteen states haven't, resulting in about 4.9 million more people in the US going without health insurance