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is a significant approach to the overall advancement of the healthcare community. broad and complex. is the process through which potential new medicines are identified.

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Drug Discovery and Development (DDD)

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DRUG DISCOVERY DEVELOPMENT (DDD) - Details

Levels:

1) Chapter 1 View
2) Unit II View
3) Ethical Considerations View
4) Clinical Trials View
5) Clinical-Trials_-IND-Applications.pptx View
6) Drug Discovery-CLINICAL TRIALS.pptx View
7) Unit VII-PCT700.pptx View

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235 questions

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Is a significant approach to the overall advancement of the healthcare community. broad and complex. is the process through which potential new medicines are identified.

Drug Discovery and Development (DDD)

Any chemical that produces a change in the body agent intended for use in diagnosis, mitigation, tx, cure or prevention of disease in humans or animals

Drug

3 main routes by which drugs were discovered

1 Chemistry- driven approaches 2 Target-directed approaches 3 Accidental clinical discoveries

The Regulatory Process concern was poisonous or addictive, not with efficacy and possible harmful effects

Mid-19th century ( 1906 Food and Drugs Act)

3 main phases of creation of a New Drug:

1 Drug Discovery - from therapeutic concept to molecule 2 Drug Development - from molecule to registered product 3 Commercialization - from product to therapeutic application to sales

The Regulatory Process safety must be demonstrated, inspection of manufacturing facilities

1937 - Diethylene glycol in sulfonamide cause 107 deaths in USA

A process which aims at identifying a compound therapeutically useful in curing and treating disease. This process involves the identification of candidates, synthesis, characterization, validation, optimization, screening and assays for therapeutic efficacy.

Drug discovery

The Regulatory Process proven efficacy and safety

1962: Kefauver-Harris amendment

Entire process of taking a newly discovered compound or drug through regulatory approval to the point of marketing. new drug or compound should adhere to high standards in the conduct, analysis and interpretation of preclinical and clinical studies

Drug Development

A highly diversified approach for drug discovery which involves the observation, description and experimental investigation of indigenous drugs and their biologic activities that is based on botany, chemistry, biochemistry, pharmacology, and other disciplines (anthropology, archaeology, history, and linguistics) contributing to the discovery of natural products with biologic activity. 'the interdisciplinary scientific exploration of biologically active agents traditionally employed or observed by man’. The subject is mainly concerned with the observation, description and experimental investigation of biological activity and the active substance of plants and animals used in traditional medicine of past and present cultures

Ethnopharmacology

Resulting in the isolation of psilocybin from psychoactive mushrooms.

Robert Gordon Wasson [1898–1986] and Albert Hofmann [1906–2008] Wass up Hofmann?

Resulting in the isolation of psilocybin from psychoactive mushrooms.

Robert Gordon Wasson [1898–1986] and Albert Hofmann [1906–2008]

They established Molecular Ethnopharmacology.

Luis Lewin [1850–1929], Carl Hartwich [1851–1917], Alexander Tschirch [1856– 1939], Richard Evans Schultes [1915–2001] CARL

Drugs developed based on ethno pharmacological studies

1 Aspirin (Bark of willow tree) 2 Artemisinin (Artemisia annua L.; Chinese plant) 3 Quinine (Cinchona; first antimalarial)

NATURAL PRODUCT DRUG DISCOVERY This involves screening mixtures of compounds obtained from plant extracts or from microbial broths.

Activity profiling of extracts

NATURAL PRODUCT DRUG DISCOVERY natural products act as a starting point for the search of active agents in new medicines. In order to match the natural material to its corresponding enzyme, scientists mimic nature by either introducing chemical residues into areas of biological relevance

Biology-oriented synthesis

A term used generally to describe the legal practice by pharmaceutical companies exploiting the indigenous people’s traditional knowledge of medicine

Pharmaceutical biopiracy

A state of complete physical, mental and social well-being and not merely the absence of sickness or infirmity. is a dynamic state of wellbeing characterized by physical, mental and social potential which satisfies the demands of life commensurate with age, culture and personal responsibility.

Health

A condition which alters or interferes with the normal state of an organism and is usually characterized by the abnormal functioning of one or more of the host’s systems, parts or organs (Churchill’s Medical Dictionary, 1989). A morbid entity characterized usually by at least two of these criteria: recognized aetiologic agents, identifiable groups or signs and symptoms, or consistent anatomical alterations 9stedman’s Medical Dictionary, 1990). Potential insufficient to satisfy the demands of life as outlined by Bircher.

Disease

Models for Studying Diseases

1 Cell cultures 2 Cross-species studies 3 Bioinformatics 4 Biomarkers 5 Proteomics

The Regulatory Process concern was poisonous or addictive, not with efficacy and possible harmful effects

Mid-19th century ( 1906 Food and Drugs Act)

The Regulatory Process safety must be demonstrated, inspection of manufacturing facilities

1937 - Diethylene glycol in sulfonamide cause 107 deaths in USA

The Regulatory Process proven efficacy and safety

1962: Kefauver-Harris amendment

Thalidomide tragedy- Europe

1960

All new drugs has to be submitted for approval before clinical trials could begin, and before they can proceed to market

1963: Committee on the Safety of Drugs

Illegal to proceed with trials without approval

1968: Medicines Act

Evidence of efficacy was added to the criteria; evidence of safety, efficacy and chemical purity

1970

By growing both diseased and healthy cells in cell cultures, researchers can study differences in cellular processes and protein expression.

Cell cultures

Genes and proteins found in humans may also be found in other species. The functions of many human genes have been revealed by studying parallel genes in other organisms.

Cross-species studies:

These are substances, often proteins, that can be used for measuring a biological function, identifying a disease process, or determining responses to a therapy. They also can be used for diagnosis, for prognosis, and for guiding treatment.

Biomarkers

The study of protein activity within a given cell, tissue or organism. Changes in protein activity can shed light on the disease process and the impact of medicines under study.

Proteomics

Initiates because there is a disease or clinical condition without suitable medical products available. - Examples are rare diseases or orphan diseases.

Drug Discovery and Development

Various processes in drug discovery:

- Target Identification and Validation - Lead Identification and Optimization - Computer Aided Drug Design - Pre-formulation Studies-include the Challenges TLC P

It is a cellular or molecular structures involved in pathology which are responsible for disease. - Receptors -gene/protein - Enzyme - Nucleic acid - Hormone - Ion channel Interacts w/ a potential drug compound>>>> clinical effect

Target

It is the process of identifying the direct molecular target i.e. protein, nucleic acid. - It is aimed to finding the efficacy target of a drug. - It is the first step in drug discovery, “druggable”

Target Identification

It is the study of genes and their function -aims to understand the structure of the genome, including the mapping genes and sequencing the DNA. - Seeks to exploit the finding from sequencing of the human and other genomes to find new drug targets.

Genomics

Tools for Target Identification

- Genomics - Proteomics - Bioinformatics

- it is the study of the proteome, the complete set of proteins produced by a species, using the technologies of large - scale protein separation and identification.

Proteomics

- is a branch of molecular biology that involves extensive analysis of biological data using computers, for the purpose of enhancing biological research. - It plays a key role in various stages of the drug discovery process including target identification, computer screening of chemical compounds, and pharmacogenomics.

Bioinformatics

- Is the process by which the predicted molecular target for example protein or nucleic acid - of a small molecule is verified. - Can include knockdown or overexpression of the presumed target. - During this, its association with a specific disease and its ability to regulate biological processes is tested in the body. It confirms that interactions with the target produce the desired change in the behavior of diseased cells

Target Validation

1 Is the most commonly used for RNA interference tool for including short-term silencing of protein coding genes 2 Antisense technology prevent the synthesis of specific protein

1 siRNA- Small Interfering RNA 2 Antisense Oligonucleotides

Tools for Target Validation

- siRNA - Antisense Oligonucleotides

- defined as a new chemical entity that could potentially be developed into a new drug by optimizing its beneficial effects and minimizing its side effects. - a chemical compound that shows desired pharmacological activity and may initiate the development of new chemical entity, relevant compound.

LEAD COMPOUND

- use sophisticated computer modeling to predict what type of molecule may work - utilizing the 3D structure of the receptor to come up with new molecules that can bind or suit the receptor - involves structural determination of the lead target complexes using molecular modeling tools.

De Novo “scratch”

- most common way that leads are usually found - This is a key process used in drug discovery to identify hits from compound libraries that may become leads for medicinal chemistry optimization.

High-throughput Screening(HTS)

- Scientists can also genetically engineer living systems to produce disease-fighting biological molecules. - important tool in pharmaceutical drug research and development.

Biotechnology

Early Safety Test for the Lead Compound performed in living cells, in animals and via computational models.

ADME/ Tox properties

Process by which a drug candidate is designed after an initial lead compound is identified, ” or altered to make them more effective and safer. Relevant aspects like affinity, selectivity, mode of action, synthesizability and ADMET-properties are typically improved Aims to maximize bonded and non-bonded interactions with the active site of selected drug targets to increase selectivity, reduce side effects and diminish toxicity, through a dedicated screening funnel of both in vitro and in vivo assays

Lead optimization

➔ deliver information on the structure of the protein-ligand complex ➔ providing insights into spatial orientation of the ligand which is essential to rationally design more selective or potent ligands

X-ray Methods

An X ray method 1 used to determine nanoparticle size distributions, pore sizes, the shape of macromolecules, and characterize distances in materials 2 a non-destructive analytical technique which provides detailed information about the internal lattice of crystalline substances, including unit cell dimensions, bond-lengths, bond-angles, and details of site-ordering

. 1 Small Angle X-ray Scattering (SAXS) 2 Single-crystal X-ray diffraction

- Smaller proteins - gives structural information about binding and dynamics in physiological conditions

NMR (Nuclear Magnetic Resonance)

- inventive process of finding new medications based on the knowledge of a biological target. - It involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it.

Drug Design

Computational Tools for Drug Designing 1 Categories of software

❖ Databases & Draw Tools ❖ Molecular Modeling & Homology Modeling ❖ Binding site prediction & Docking ❖ Ligand design Screening -QSAR ❖ Binding free energy estimation ❖ ADME Toxicity

Types of Drug Design

1. Ligand-based drug design 2. Structure-based drug design

★ relies on the knowledge of the three dimensional structure of the biological target obtained through: - X-ray crystallography - Nuclear Magnetic Resonance (NMR) spectroscopy

Structure-based drug design (Direct)

Also known as comparative modeling of protein, refers to constructing an atomic resolution model of the "target" and an experimental three-dimensional structure of a related homologous protein (the "template").

Homology modeling

Relies on knowledge of other molecules that bind to the biological target of interest. -used to derive a pharmacophore model that defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target

Ligand-based drug design (Indirect)

It can be defined as an investigation of physical and chemical properties of a drug substance alone and when combined with excipients. • generate information useful to the formulator in developing stable and bioavailable dosage forms that can be mass produced. • designed to deliver all necessary data especially physicochemical, physico- mechanical and bio pharmaceutical properties of drug substances, excipients and packaging materials.

Preformulation studies

- aspects that can be experienced through one’s senses like taste, smell, sight, and touch. - Thus, it includes a recording of the colour, odour, and taste of the drug.

Organoleptic properties of the drug

- It is needed to identify all the solid forms that may exist as a consequence of the synthetic stage such as the presence of polymorphs.

Bulk characters of the drug

1 refers to the outer appearance and internal structure of the drug molecule and can affect its physicochemical properties 2 is the ability of a compound to crystallise in different shapes with different internal structure.

1 Crystallinity 2 Polymorphism

- It is the measure of the tendency to adsorb atmospheric moisture by the drug substance. - It characterizes the drug stability with respect to the environmental

Hygroscopicity

Types of Hygroscopicity 1 a substance which absorb sufficient moisture from the atmosphere to dissolve itself at higher extreme 2 a substance which loses water to form a lower hydrate or become anhydrous at lower level 3 a substance that exist in a dynamic equilibrium with water

. 1 Deliquescent 2 Efflorescent 3 Hygroscopic

The size of the drug particle can influence its dissolution rate, suspendability and other properties.

Fine particle characterization

Help you understand the ease with which the drug powder will flow under a set of specific conditions like humidity, pressure and etc

Powder flow properties

(elasticity, plasticity, fragment ability and punch filming propensity) for small quantities of a new drug candidate can be established. This property is used in proper selection of the formulation ingredients.

Compression properties

Methods of Solubility analysis include:

❏ Ionization constant ❏ pH solubility profile ❏ Common ion effect ❏ Thermal effects ❏ Solubilization ❏ Partition coefficient ❏ Dissolution

Is the measurement of the acidity of the compound. Its determination helps in understanding the solubility, protein binding and permeability of the drug substance to characterize its properties like absorption, distribution, metabolism and excretion from the body

Ionization constant

Helps to understand the influence of pH on drug solubility, stability, and absorption

PH solubility profile

Determines the solubility of the drug substance when a solution compound having a common ion with the drug is added to the test solution

Common ion effect

Helps to evaluate the drug solubility with respect to the changes in the drug temperature of the solvent

Thermal effects

Is the measurement of the drug lipophilicity or ability to cross a cell membrane.

Partition coefficient

Is the method of increasing the solubility of the sparingly soluble drug substance by various technique like adding co solvent, changing pH, and temp, adding surfactant, and reducing particle size

Solubilization

Is the process of resolving the drug substance into its individual components and characterizing their properties

Dissolution

These studies include the effect of pH, Ionic strength, Co-solvent, Light, Temperature and Oxygen. Usually these commence with probing experiments to confirm decay at the extremes of pH and temperature e.g., 0.1N HCl (Hydrochloric acid) , water and 0.1N NaOH (Sodium hydroxide) all at 90 deg C.

Solution stability:

The primary objective of this study is investigation and identification of stable storage condition for drug in the solid state and identification of compatible excipients for a formulation to ensure the efficacy, safety, quality of active drug substance and dosage forms, to establish shelf life or expiration period and to support label claims, to gain information about its packaging, assess the condition of the product on storage on prolong period of time, determine compatibility of drug with excipients and other additives and to determine the dosage form in which the drug is most suitable.

Solid state stability

Three R's in research

1 Replacement 2 Reduction 3 Refinement

The USE OF NON SENTIENT MATERIAL TO REPLACE METHODS which use conscious living vertebrates

Replacement

MINIMIZING THE NUMBER OF ANIMALS used to obtain information

Reduction:

DECREASE INCIDENCE or severity of INHUMANE PROCEDURES applied to the animals

Refinement

HUMAN RESPONSIBILITY that encompasses ALL ASPECTS OF ANIMAL WELL BEING, including proper housing. management, nutrition, disease prevention and treatment, humane handling, and when necessary, humane euthanasia; Well-being, characterized as the fulfillment of needs

Animal Welfare

ANIMALS HAVE THE SAME MORAL RIGHTS AS HUMAN BEINGS or in part because they have many of the same mental capabilities and activities as people.

Animal Rights

Has adopted an animal welfare policy, which includes the following statement: "We do not accept the view that animals have specialized rights as an entity on their own. We believe that animals can benefit more from the point of view that man is responsible for the provision of animal welfare, rather than from the view which promotes animal rights alone."

World Veterinary Association (WVA)

Freedom from pain or suffering The only very strong interest that nonhuman animals possess is an interest in not experiencing pain or suffering or, if they must undergo some pain or suffering in their use by people, in not experiencing unnecessary pain or suffering.

Anticruelty position

GOVERNMENT OFFICES

1 Bureau of Animal Industry (BAI) 2 Philippine Association for Laboratory Animal Science (PALAS) 3 Committee on Laboratory Animal Resources Development and Standardization (LARDS) 4 Protected Areas and Wildlife Bureau (PAWB) 5 Philippine Council for Health Research and Development (PCHRD)

1 Animal Welfare Act 2 Rules and Regulations on the Conduct of Scientific Procedures Using Animals

1) R.A. 8485 2) D.A. A.O. No. 40

➔ Justified statistically ➔ Alternatives (less invasive procedures, other species, isolated organ preparation, tissue culture, computer models)

Appropriate species, quality, number or animals

Are not normal methods of housing Not to be used simply as a convenience in handling Period should be minimum Train animals to adapt to these Observe animals at appropriate intervals Provide veterinary care in case of injury or illness due to this

PHYSICAL RESTRAINT

Multiple major of this on an animal are discouraged ➔ Permitted if scientifically justified ➔ Cost savings alone is not an adequate reason Pay attention to animal well-being through continuing evaluation of outcomes

SURGICAL PROCEDURES

➢ Should be scientifically justified ➢ Monitor physiologic or behavioral indexes ➢ Use least restriction to achieve scientific objective ➢ Use highly preferred food instead of restriction for positive reinforcement

FOOD OR FLUID RESTRICTION

OTHER CONSIDERATIONS

➢ Veterinary care ➢ Personnel qualifications and training ➢ Personal hygiene ➢ Occupational health and safety of personnel ➢ Hazard Identification and Risk Assessment ➢ Facilities, Procedures and Monitoring ➢ Personal protection ➢ Medical evaluation and preventive medicine for personnel

❖ Species, strain and breed of animals ❖ Sex, age, size ❖ Maintained singly or in groups ● Ability to form social groups through sight, smell, contact ❖ Design and construct of housing ❖ Availability and suitability of enrichments ❖ Project goals and experimental design ❖ Intensity of animal manipulation and invasiveness ❖ Presence of hazardous materials ❖ Duration of holding period

ANIMAL ENVIRONMENT, HOUSING AND MANAGEMENT

1 primary enclosure ● Immediate surroundings, temperature, humidity, air composition ● Can induce changes in metabolic and physiologic processes 2 secondary enclosure ● Room, barn, outdoor habitat

1 Microenvironment 2 Macroenvironment

❖ Naturalistic environments ❖ Sheltered or outdoor ❖ Primary enclosures

HOUSING

Type of research that studies new tests and treatments and evaluates their effects on human health outcomes Carefully designed, reviewed and completed, and need to be approved before they can start. People of all ages can take part in, including children. are conducted to collect data regarding the safety and efficacy of new drug and device development.

CLINICAL TRIALS

CONSIDERATIONS FOR CLINICAL TRIALS

1st: Pharmacologic profile is equal or better than existing competitors 2nd: Address unmet medical or improve therapy 3rd: Market potential sufficient to sustain profitability 4th: Risk factors are assessed 5th: Potential expenses 6th: Success in the marketplace

Refers to studies, or trials, that are done in people

Clinical research

TRIAL OBJECTIVES

Phase I- limited to determining toxicity at a range of dosages Terminal illnesses- efficacy assessment Phase Il and III- Clinical efficacy in large sample of patients Phase IV- Assess efficacy and side effects in specific patient population

COMPONENTS OF A TRIAL OBJECTIVE

1 Approach of the trial (to compare; asses and evaluate) 2 Specific disease 3 Types of patients 4 Drug therapy(ies) 5 Dosage

Used to compare different types and combinations of drug therapy Allows comparisons between single drug therapies and combination of two drugs combined

Factorial design

DRUG DISCOVERY DEVELOPMENT (DDD)