midterm 1 - drug safety evaluation (toxicity studies)

``` Drug safety evaluation

Is a critical process in the development of pharmaceuticals

Drug safety evaluation

It involves assessing the safety profile of a drug from its preclinical stages through to post-marketing surveillance

Drug safety evaluation

Its goal is to identify, characterize, and mitigate potential risks associated with the drug’s use

Globally harmonized system (GHS)

According to the __________, toxicity is defined as “those adverse effects occurring following oral or dermal administration of a single dose of a substance, or multiple doses given within 24 hours, or an inhalation exposure of 4 hours

Toxicity

According to the Globally Harmonized System (GHS), __________ is defined as “those adverse effects occurring following oral or dermal administration of a single dose of a substance, or multiple doses given within 24 hours, or an inhalation exposure of 4 hours”

Toxicology

Is a branch of science that deals with toxins and poisons and their effects and treatment

Toxicological screening

Screening that is essential for the development of new drugs and for extending the therapeutic potential of existing molecules

Toxicokinetics

An extension of pharmacokinetics that deals with the kinetic patterns of higher doses of chemicals/toxins/xenobiotics

Toxicokinetics

Helps study the metabolism and excretion pattern of xenobiotics

Animal toxicokinetic data

__________ help extrapolate physiologically based pharmacokinetics in humans

Toxicological testing

In __________, pharmacokinetic studies are usually carried out in rodents, rabbits, dogs, nonhuman primates, and swine using many routes of administration

Blood samples

__________ are collected at various time points to analyze pharmacokinetic data such as AUC, drug distribution ratio, Cmax, tmax, and other pharmacokinetic parameters

OECD guidelines for the testing of chemicals

The __________ are a set of internationally agreed testing methods used to assess the safety and environmental impact of chemicals

Organization for economic cooperation and development

Meaning of OECD

Standardized methods

The guideline provides standardized methods for testing the physical and chemical properties of substances, their effects on health, and their environmental impact (OECD guidelines)

In vitro and in vivo tests

They include in vitro (test tube or culture dish) and in vivo (live animal) tests to evaluate toxicity, mutagenicity, and other effects (OECD guidelines)

Environmental testing

Specific tests are designed to assess the impact of chemicals on the environment, including aquatic toxicity, biodegradability, and bioaccumulation (OECD guidelines)

Human health

Guidelines cover tests for acute and chronic toxicity, carcinogenicity, reproductive toxicity, and more (OECD guidelines)

In vivo toxicity studies

Studies that are essential for evaluating the safety of new drugs and chemicals by testing them on live animals (Types of toxicity studies)

In vivo toxicity studies

Studies that help determine the potential adverse effects, toxic doses, and target organs affected by the substance (Types of toxicity studies)

Acute toxicity test

Determine the immediate harmful effects of a substance after a single dose (Types of in vivo toxicity studies)

Acute toxicity test

Example: testing a new pesticide on rats to see if it causes any immediate health issues (Types of in vivo toxicity studies)

Chronic/Sub-chronic toxicity test

Assesses the effects of long-term exposure to a substance (Types of in vivo toxicity studies)

Chronic/Sub-chronic toxicity test

Example: studying the impact of a new food additive on the health of mice over several months (Types of in vivo toxicity studies)

14

In acute toxicological testing, the investigational product is administered at different dose levels, and the effect is observed for __________ days

LD50

Acute toxicity testing permits the 50% lethal dose (__________) of the investigational product to be determined

LD50

The __________ was used as an indicator of acute toxicity

Fixed dose procedure

Meaning of FDP (Other methods of acute toxicity testing)

Acute toxic category method

Meaning of ATC (Other methods of acute toxicity testing)

Up-and-down method (Staircase design)

Meaning of UDP (Other methods of acute toxicity testing)

Genotoxicity test

Evaluates the potential of a substance to cause genetic mutations or damage (Types of in vivo toxicity studies)

Genotoxicity test

Example: testing a new industrial chemical on zebrafish to see if it causes DNA damage (Types of in vivo toxicity studies)

Reproductive and developmental toxicity test

Examines the effects on reproduction and development (Types of in vivo toxicity studies)

Reproductive and developmental toxicity test

Example: testing a new pharmaceutical on pregnant rabbits to see if it affects fetal development (Types of in vivo toxicity studies)

Micronucleus test

Is a test used in toxicological screening for potential genotoxic (OECD 474)

Carcinogenicity test

Determines if a substance has the potential to cause cancer (Types of in vivo toxicity studies)

Carcinogenicity test

Example: long term studies on rodents exposed to a new chemical to see if it induces tumors (Types of in vivo toxicity studies)

Cardiotoxicity studies

Evaluates the effects of a drug on the heart (Types of in vivo toxicity studies)

Cardiotoxicity studies

These studies are important for drugs that may affect cardiovascular function (Types of in vivo toxicity studies)

Nephrotoxicity and hepatotoxicity studies

Assess the effects of a drug on the kidneys and liver, respectively (Types of in vivo toxicity studies)

Nephrotoxicity and hepatotoxicity studies

These studies help identify any potential organ-specific toxicity (Types of in vivo toxicity studies)

In vitro toxicity studies

Studies that are conducted using isolated cells, tissues, or organs outside their normal biological context, typically in a lab setting (Types of toxicity studies)

In vitro toxicity studies

Studies that are crucial for understanding the potential toxic effects of substances without the ethical and logistical complexities of in vivo studies (Types of toxicity studies)

Skin/eye irritation tests

Assessing the potential of a substance to cause irritation to skin or eyes (Types of in vitro toxicity studies)

Skin/eye irritation tests

Example: testing a new cosmetic ingredient on cultured human skin cells to see if it causes inflammation or damage (Types of in vitro toxicity studies)

Skin sensitization test

Evaluating whether a substance can cause an allergic reaction (Types of in vitro toxicity studies)

Skin sensitization test

Example: testing a new textile dye on human-derived immune cells to check for allergic responses (Types of in vitro toxicity studies)

Acute dermal toxicity

__________ is the adverse effects occurring within a short time of dermal application of a single dose of a test substance

Acute dermal toxicity study

In __________, the test substance is applied to the skin in graduated doses to several groups of experimental animals, one dose being used per group

Genotoxicity tests

Determining if a substance causes genetic mutations or DNA damage (Types of in vitro toxicity studies)

Genotoxicity tests

Example: using cultured mammalian cells to test a new pharmaceutical for its potential to cause chromosomal aberrations (Types of in vitro toxicity studies)

Cytotoxicity tests

Measuring the toxicity of a substance to cells (Types of in vitro toxicity studies)

Cytotoxicity tests

Example: exposing cultured liver cells to a new industrial chemical to see if it causes cell death or other adverse effects (Types of in vitro toxicity studies)

Hepatotoxicity tests

Assessing the potential liver toxicity of a substance (Types of in vitro toxicity studies)

Hepatotoxicity tests

Example: using cultured liver cells to test a new drug for its effects on liver enzyme levels and cell viability (Types of in vitro toxicity studies)

Ethical consideration

__________ in human and animal experimentation are crucial to ensure the humane and responsible

Informed consent

Participants must be fully informed about the study’s purpose, procedures, risks, and benefits, and they must voluntarily agree to participate (Human experimentation)

Minimizing harm

Researches must take all possible steps to minimize physical and psychological harm to participants (Human experimentation)

Privacy and confidentiality

Participants’ personal information must be protected, and their privacy must be respected (Human experimentation)

Equitable selection

Participants should be selected fairly, without exploiting vulnerable populations (Human experimentation)

Right to withdraw

Participants should have the right to withdraw from the study at any time without any negative consequences (Human experimentation)

Justification of use

Researchers must justify the necessity of using animals and ensure that the potential benefits outweigh the harm caused to the animals (Animal experimentation)

Humane treatment

Animals should be treated humanely, with efforts to minimize pain and distress (Animal experimentation)

Refinement, reduction, and replacement (3Rs)

Researchers should aim to refine procedures to minimize suffering, reduce the number of animals used, and replace animal models with alternative methods whenever possible (Animal experimentation)

Ethical review

Animal research should be reviewed and approved by an ethics committee to ensure compliance with ethical standards (Animal experimentation)

Proper care and housing

Animals should be provided with appropriate care, housing, and enrichment to ensure their well-being (Animal experimentation)

Institutional animal care and use committee

Meaning of IACUC

Institutional animal care and use committee (IACUC)

The __________ is responsible for oversight of the animal care and use program and its components as described in the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals and the Guide for the Care and Use of Laboratory Animals

5, 50, 300, 2000

Groups of animals of a single sex are dosed in a stepwise procedure using the fixed dose of _________, _________, _________, and _________ mg/kg (exceptionally an additional fixed dose of 5000 mg/kg may be considered) (OECD 420)

5000

Groups of animals of a single sex are dosed in a stepwise procedure using the fixed doses of 5, 50, 300, and 2000 mg/kg (exceptionally an additional fixed dose of _________ mg/kg may be considered) (OECD 420)

Sighting study

The initial dose level is selected on the basis of a _________ as the dose expected to produce some signs of toxicity without causing severe toxic effects or mortality (OECD 42)

Rat (female)

The preferred rodent species is the _________, although other rodent species may be used (OECD 420)

30, 24, 4, 14

Animals are observed individually after dosing at least once during the first _________ minutes, periodically during the first _________ hours, with special attention given during the first __________ hours, and daily thereafter for a total of __________ days (OECD 420)

Stepwise procedure

Acute toxic class method is based on a __________ with the use of a minimum number of animals per step (OECD 423)

3

The substance is tested using a stepwise procedure, each step using __________ animals of a single sex (usually females) (OECD 423)

3.2

If the animal survives, the dose for second animal is increased by a factor of __________ times the original dose and vice versa (OECD 425)

3.2

__________ is the default factor corresponding to a dose progression of one half log unit (OECD 425)

175

If no information available regarding lethality of drug than dosing start from __________ mg/kg bw (OECD 425)

2000, 5000

Limit test carryout at __________ mg/kg, orally (exceptionally __________ mg/kg) when information indicating test material is likely to be nontoxic or toxicity above regulatory limit dose (OECD 425)

3

The LD50 is less than the test dose (2000 mg/kg) when __________ or more animals die (OECD 425)

3

The LD50 is greater than the test dose (2000 mg/kg) when __________ or more animal survive (OECD 425)

14

Observation: __________ days same as OECD 423 (OECD)

10, 5, 5

Number of animals: __________ animals per group (__________ female and __________ male) (OECD 407)

3

At least __________ test groups and the control group should be used (OECD 407)

1000, 28

Limit test: __________ mg/kg/day for __________ days daily (OECD 407)

Once

General clinical observation at least _________ a day (OECD 407)

Twice

Morbidity and mortality - at least __________ daily (OECD 407)

ANS activity

__________ - lacrimation, piloerection, pupil size, respiratory pattern, grip strength, motor activity assessment (OECD 407)

Weekly

Body weight - __________ (OECD 407)

Weekly

Food consumption - __________ (OECD 407)

Weekly

Water consumption - __________ (OECD 407)

1 mL/100 gm, 2 mL/100 gm

Administration by gavages or via the diet or drinking water in volume of _________ for suspension and __________ bw for aqueous (OECD 408)

10, 5, 5

Number of animals: __________ animals per group (__________ female and __________ male) (OECD 408)

3

Dosage: At least __________ test groups and the control group should be used (OECD 408)

1000, 90

Limit test: __________ mg/kg/day for __________ days daily (OECD 408)

In vivo

The mammalian _________ micronucleus test is used for the detection of damage induced by the test substance to the chromosomes or the mitotic apparatus of erythroblasts by analysis of erythrocytes (OECD 474)

In vivo, In vitro

There are two major version of this test, one __________ and the other __________ (OECD 474)

In vivo

The __________ test normally uses mouse bone marrow or mouse peripheral blood (OECD 474)

24

__________ hours before the test, fur should be removed from the dorsal area of the trunk of the test animals by clipping or shaving (OECD 402)

10

Not less than __________ percent of the body surface area should be clear for the application of the test substance (OECD 402)