PCL 102 terms and important concepts for finals!

“First-in-class“ or “Pioneer drugs”

A drug that targets a protein that has never been targeted before by other drugs

General pipeline of drug development

Preclinical testing → file to FDA → Phase I → Phase II → Phase III → file and approved by FDA → Phase IV (post-marketing testing required)

Can you go to the next phase before completing the one before?

NO. In general, you MUST complete phase I to proceed to Phase II, and so on. However, during the time of emergency such as COVID-19, there may be an exception (in fact, during COVID, phase I and 2 overlapped, as well as phase 2 and 3).

Phase I

• Small number of HEALTHY volunteers

• Trials for SAFETY and DOSAGE

  • Determines a safe drug dose (the provided dosage are low at first and increase. Ascending)dosages

  • Pharmacokinetics

• In some cases, actual patients of the disease are used as volunteers

• Usually, money is given

Phase II

• 100-500 PATIENT volunteers

• Trials for EFFECTIVENESS and looks for SIDE EFFECTS

• Efficacy

• Compares TREATED individuals to CONTROLLED groups

  • placebo

• Single-blind/doubleblind

Phase III

• 1000-5000 PATIENT volunteers

• CONFIRMS effectiveness and monitors adverse reactions for long-term use

The World Health Organization (WHO)

• Creates the List of Essential Medicines every two years

• over 500 medicines including 361 for children

• They take into account

  • The commonality of the disease

  • Seirousness of the disease

  • whether or not the drugs are cost-effective (affordable)

  • The drug has evidence of efficacy

  • The drug has evidence of safety

  • Public and community health

What percentage of the drugs are made by Pharma?

100%!!!

Medical needs are decided by

• Therapeutic needs

• The global burden of the disease

  • also considers the ‘trend‘ of how much that disease can become a burden

• Patient voices are also a driving force that influences drug development (i.e. in the case of AIDS)

DALYs (Disability-Adjusted Life Years)

• used to calculate how much of a burden the disease will cause

1 DALYs =

1 Lost Year of Healthy life

Efficacy

• How well a Drug do in treating the disease

Discovery/preclinical testing

• Target identification + validation

  • Is the target druggable?

  • Targets are usually a protein

• At least TWO animal species saftey tests are REQUIRED by the FDA

Pharmacokinetics

• What happens to the drug in the body

• How the drug moves in the body

Placebo

• ‘CONTROLLED‘ groups

• are not given actual drugs during the trial

  • given fake pills that look real—-inactive pills

• related to expectation

  • response to taking what you expect and think is a drug. Very subjective and important for mental illnesses, especially.

Single-blind

• when the subjects/volunteers do not know whether they are in the controlled group or the treatment group

double-blind

When BOTH the investigators or the subjects do NOT know which groups they are treated with.

• The computer records who received which treatment

Drug development is?

A business!!

Patent protection

gives manufacturer of the drug a monopoly for a given amount of time (i.e. for 20 years)

Costs to get a SINGLE drug to the market

• Approximately 15 Years in time

• More than 2 billion dollars in cost (this doubles every 9 years or so)

  • Includes the cost of failures. In fact, most of the cost is of failure

The selection of medicines on the model list by WHO leads to

• Improved supply

• improved prescribing practices

• improved affordability (lower costs)

drug acts on many proteins at the

plasma membrane

Genes are organizational units of

DNA

Protein structure

• huge chains of AA

• chains are folded

• protein shape crucial for function

RNA

• single strand

• AUCD

mechanism of cancer

• diseases of uncontrolled growth

• can spread to

  • normal tissues and other parts of the body

  • forming tumors

• Normal growth control mechanisms are dysregulated

• Cancer cells are IMMATURE

metastatic cancers

• Cancers that spread to other parts of the body

• cancer cells spread through the blood

is cancer a single disease?

NO. Cancer is a group of over 100 different diseases

Is there a single drug to treat cancers?

NO

How to organize cancers

• Tissue/organ of origin (i.e. breast cancer, brain cancer)

• which pathways of growth dysregulation

Growth control in a normal cell

resting state → Grow Now (signals) → active growth machinery →Grow → stop now (signal) → activate stop machinery → stop

loops

Growth control lost in cancer: disables grow now signal

Resting state → (grow now signals are broken) → activated growth machinery → grow → stop now signal → activate stop machinery → stop

Since the grow now signals are broken, the cell has activated growth machinery on the WHOLE time, leading to rapid cloning of cancer cells.

Growth control lost in cancer: stop now signal and activated stop machinery ignored

Resting state → grow now signal → activate growth machinery → (stop now signal ignored) → (activated stop machinery ignored) → stop

The cells do NOT listen or pay attention to the stop signals, therefore continuous growth of cells leading to cancer

Cancers (dysregulated control mechanisms) are caused by …

MUTATIONS!

Some causes of cancers are

• heredity

• UV radiation (i.e. skin cancer)

• Chemicals

• viruses

• Smoking (i.e. lung cancer)

• cells dividing

Age related to cancer

• Mutations are inevitable in humans

  • Thus, more mutations as time proceeds (ages)

• When an individual lives longer, they are more exposed to the cancer-triggering factors (i.e. chemicals, UV radiation, etc)

Mutations can be

• neutral (no effect) which is most common

Inherited mutations

• inherited mutations are present in sex cells (egg or sperm cells)

• passed on to the next generation

Acquired mutations

• somatic mutation

• is NOT passed on

• Much more common than inherited mutations

• MOST CANCERS ARE CAUSED BY ACQUIRED MUTATIONS

Chemo therapy

• kills fast-growing cells

• chemicals

• very powerful

• ALSO kills fast-growing HEALTHY Cells

• 無差別killing ★★★

Targeted therapy

• Aimed at proteins that are only in cancer cells

• Or, aimed at proteins that are far more abundant in cancer cells than in healthy cells

• matching the corrct drug to the correct protein/DNA of the tumor

examples of a targeted cancer drug

• HERCEPTIN

  • Stopes the signal started by the HER2 protein

The immune system

• white blood cells

  • In the blood and lymphatic system

  • attacks viruses and bacteria

  • can also attack cancer cells (as long as it recognizes the cancer cells as foreign)

• Innate immunity

• Acquired immunity (i.e. vaccines, when you are exposed to micro-organisms like influenzaとかね？？)

specialized types of immune cells

T cells

• bind to foreign peptieds

• kills viruses

B cells

• makes antibodies

• antibodies bind to surfaces of the foreign cells

Cancer cells can avoid being destroyed by our immune systems

• The genetics of the cancer result in a cancer cells that cannot be sensed by our immune systems (擬態)

• The cancer cell might have proteins on the surface that turn of the immune system

• the cancer cells changes the healthy cells in the tissue around the tumor

Immunotherapy

helps our immune system to act better against the cancer

Sickle cell disease

• 2 copies of mutation in the hemoglobin B gene

• deformed blood cells, sticky and do not carry oxygen when they are supposed to

• causes pain

Recurrence

When cancer comes back after treatment

cancer can grow even if

there is only 1 cell left in the body. to cure, you must kill ALL cancer cells to prevent recurrence

Do cancer cells mutate?

yes. they mutate and can become resistant to the treatment

Enzyme

• active or catalytic site

  • lock and key mechanism

  • substrates bind and undergo chemical reaction

substrate enters the active site of enzyme → fromation of enzyme/substrate complex(converts substrate to products) → enzyme/products complex → products leave the zite of enzyme (as they no longer fit the lock and key mechanism)

substrates

fit into the active site

receptor

type of protein involved in cellular communication

Drug-receptor interaction model

R + D → DR → EFFECT

Pharmacodynamics

The effect of a drug on ligand-target interaction

While targets are usually proteins,

we use GENOMES to identify targets as they are less complex

Genomics

the study of all genes in the genome and the interactions among them and their environment ge

genetics

the study of single genes in isolation

genome-wide association studies

• compares genomes of healthy a people and the people with teh disease

• identify differences between the two groups

SNP (single nucleotide polymorphism) =

sites of variation in our genomes

• many SNPs have no apparent effect

Analysis of genome-wide data

computer power

data analysis experts

collaboration

genetic disease can be caused by

single genes and or multiple genes

Human genome project

reference genome of about 20 different people with some ehtnic diversity

1000 genomes project

DNA from 1000 different people across the world

All of Us Research Program

• DNA from 1 million people

  • still present

The Silent Genomes project

Indigenous populations in Canada (still present)

library pf DNA from indigenous people

goal:

• to reduce health care disparities

• improving diagnostic success

• for children with genetic diseases in indigenous populations

Target validation

• does the identified protein target actually matter to the mechanism of the disease?

• Is it worth developing a drug against the identified protein target?

Model organism

• budding yeast

• Zebrafish

• roundworm

• fruit fly

Zebrafish

• similar drug metabolism between zebrafish and humans

Human Cell cultures

measures behaviours that can be measured in cells (cell growth and cell death)

Principles of Animal Research

• Use of animals in research is a privilege

• The research must be justified

• Animals must be treated with respect and care

• Animal research is highly regulated

• There must be a compelling BENFIT to human health or animal health in order to conduct animal research

3 R’s principles in animal research

• Replacement

  • Can you use otehr models? (i.e. computer models or invertebrates instead of other vertebrates)

• Reduction

  • The least possible number of animals used while still having a meaningful outcome

• Refinement

  • Improved experimental design and husbandry

  • minimize pain and distress

xenograft mouse models

mouse with human tumor grown for research

ALS (Amyotrophic lateral sclerosis)

• progressive and fatal

• causes motor neurons to break down

Worms has been genetically engineered to mimic one type of genetic cause of human motor neuron disease

ALS

Anxiety models in mice

• mice prefers darks and enclosed spaces (nocturnal)

• some models assess social interactions between mice

Drug safety

is the drug safe?

is a central question before giving drug to humans

DO NO HARM

or non-maleficence

Test for toxicity

• death of proportion of cells/organisms

• pathology (microscope)

• surrogate measures of organ toxicity by measuring the blood or urine

In VIVO =

in living organism

In VITRO =

In glass

biomarkers

A characteristic that is objectively measured and evaluated as an indicator of normal biological processes

Any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease

Ethics

JUSTICE (fairness and equality)

NONMALEFICENCE

• DO NO HARM

• Does the BENFIT OUTWEIGH the burdens/harm?

Beneficence

Actively doing good things

Important ethical values

• Beneficence

• Nonexploitation

• Respect

• Autonomy

Sources of guidance on the ethical conduct on the Ethical Conduct of Clinical Research

• Several international documents

• Nuremberg Code

• Declaration of Helsinki

• Many of these were written in response to certain specific ethical events, and have the purpose of avoiding future scandals

7 requirements

• Value

• Scientific validity

• Fair subject selection

• Favourable risk-benefit ratio

• Independent review

• Informed consent

• Respect

How does the drug move in the body?

Absorption

Distribution

Metabolism

Elimination

Adverse Events (AEs)

The serious and must be reported to the FDA when the patient outcome is:

• death

• life-threatening

• hospitalization

• disability or permanent damage

• birth defect

Sensitivity

• The fraction of persons WITH DISEASE characterized as SICK by the test

• Detecting ALL the people with the disease

Specificity

• the fraction of persons WITHOUT DISEASE characterized as HEALTHY by the test

• Specificity is EXCLUDING HEALTHY people

Medical signs

objective (i.e. biomarkers)

Medical symptoms

• subjective

• indication of health or illness perceived by patients themselves

biomarker for HIV/AIDs

viral load (high means virus replicating quickly)

CD4 cell count (low means disease progressing)

lurasidone

clinical trial for bipolar disorder and schizophrenia

Phase 4

• Any study performed after drug approval and related to the approved indication

• assessment in real-world setting

The FDA can recall drugs due to

• drug manufacturing/purity

• drug cases mild side effect

• drug causes major side effects, including death

FDAs Emergency Use Authorization (EUA)

• during emergencies (i.e. pandemic)

  • increases the availability of an unapproved medication for unapproved uses

Off-label use of medications

• prescribing a drug product in a way that is inconsistent with the approved label

  • outside the condition/indication

  • different population

  • diffrent dosages or frequencies

  • modifying duration of treatments

  • using alternate routes of administration

• DIFFERS from experimental use

• common in

  • oncology

  • pediatrics

  • elderly