PRE CLINICAL PHASE DRUG SAFETY

Toxicity study

is the investigation of either short or long-term toxic effects of a drug or chemical on animals

Hemlock

was used as Greek capital punishment

Aconite

was used in Chinese poison arrows

Amanita phalloides

caused the death of Pope Clement VII

Pedanius Dioscorides

• Greek physician and pharmacologist whose work De materia medica was the foremost classical source of modern botanical terminology and the leading pharmacological text for 16 centuries.

• gave the first classification of poisons and the use of emetics as a treatment

Paracelsus

concluded that toxic effects of poisons and therapeutic agents are dose dependent

• “All substances are poisons; there is non which is not a poison. The right dose differentiates a poison from a remedy”

King Mithridates VI

• of Pontus

• conducted an experiment on criminals including himself. He took increasing doses of poisons to develop tolerance.

• He died due to stabbed wounds upon his own request when the Romans attacked him.

mithridatism

administer lason to you to develop resistance

Maimonides

- Introduced the concept of bioavailability

• Full stomach delays absorption

• Fat content delays absorption

THE TREATISE ON POISON AND THEIR ANTIDOTE

• lason can absorb

Toffana

– She was known to sell arsenic-laced cosmetics

• mercury

• arsenic

• lead

• cadmium

HEAVY METAL - bawal sa gamot

Heironyma Spara

– She offered services for those who want to be widowed

• posion have ARSENIC - series

Catherine de Medici

– She conducted systematic study of poisons and deduced the following:

• Rapidity of toxic effect

• Effectiveness

• Degree and specificity of response

• Complaints of victims

1775

YEAR

• Soot in scrotal cancer in chimney sweeps identified polyaromatic hydrocarbons

Soot

WHAT INHALE CAUSE iscrotal cancer in chimney sweeps identified polyaromatic hydrocarbons

1825

YEAR

– Phosgene and mustard gas were used as chemical warfare

Phosgene gas

can cause edema in lungs

• no antidote

mustard gas

KING OF BATTLE GASSES

• glispering agent - DELAYED - ONION smell

• can cause BLISTER

Mathieu Orfila

FATHER OF MODER TOXICOLOGY

• fucos in FURENSIC

1783 to 1885

– Magendie detailed the absorption and distribution of several compounds in the body

Magendie

FATHER OF EXPERIMENTAL PHARMACOLOGY

1890s to 1900s

• Bioassays are conducted

• Development of neurotoxicity field due to methanol and lead toxicity (bootleg liquor byproducts)

• Bomb production led to metal toxicology

• Organophosphates as cholinesterase inhibitors (pesticides)

• Quinine as antimalarial drug

• Mixed-function oxidases were discovered

• bootleg liquor

SMOGGLE BEBERIGAS

• metal toxicology

• Bomb production led to

  • 3 SIKAT NA BUMBA

    • SUMAN

    • SARIN

    • TABUN

Casarett

1996

• defined Toxicology as a science that defines the limits of safety of chemical agents for human and animal population

  • THERAPEUTIC INDEX

TOXIC DOSE DIVIDED BY EFFECTIVE DOSE

FORMULA THERAPEUTIC INDEX

Lethal Doses/Concentrations, such as LD10, and LC50, which denote doses or concentrations that are expected to lead to death in specific percentages of a population

Effective Doses, such as ED50 and ED90, which denote doses that are effective in achieving a desired endpoint in specific percentages of a population.

Toxic Doses

, such as TD0 and TD50, denote doses that cause adverse toxic effects in specific percentages of a population.

No-Observed-Adverse-Effect Level

NOAEL

is the highest dose at which there is no observed toxic effect.

NOAEL

Lowest Observed Adverse Effect Level

LOAEL stands for

LOAEL

is the lowest dose at which there is an observed toxic effect

The therapeutic Index (TI)

compares the effective dose to the toxic dose of a drug.

Margin of Safety (MOS)

compares the toxic dose to 1% of the population to the effective dose to 99% of the population.

14 days

Acute toxicity

28 days

Sub-acute (repeated doses) Toxicity

ORGANIZATION FOR ECONOMIC COOPERATION AND DEVELOPMENT (OECD)

unique forum where the governments of 36 member states with market economies work with each other, as well as with more than 70 non-member economies to promote economic growth, prosperity, and sustainable development.