In vivo is the Latin word which means with in the living body.
When effects of various biological entities are tested on whole, living organism or cells, usually animals including humans and plants.
Animal testing and clinical trials are major elements of in-vivo research.
In vivo testing is often employed over in vitro because it is better suited for observing the overall effects of an experiment on a living subject in drug discovery.
example, verification of efficacy in vivo is crucial, because in vitro assays can sometimes yield misleading results with drug.
Harry Smith found that sterile filtrates of serum from animals infected with Bacillus anthracis were lethal for other animals, whereas extracts of culture fluid from the same organism grown in vitro were not.
In microbiology Once cells are disrupted and individual parts are tested or analyzed, this is known as in vitro.
In vitro studies within the glass, i.e., in a laboratory environment using test tubes, petri dishes, etc. Examples of investigations in vivo include: the pathogenesis of disease.
In vitro toxicology:-
The bridge exists between new drug discovery and drug development.-
Provide information on mechanism of action of a drug
Provides an early indication of the potential for some kinds of toxic effects, allowing a decision to terminate or to proceed further.
In vitro methods are widely used for:-
Screening and ranking chemicals
Get a platform for animal studies for physiological actions
Studying cell, tissue, or target specific effects
Improve subsequent study design
Advantages and Disadvantages:-
Faster than in vivo studies
Less expensive to run
Less predictive of toxicity in intact organisms
In vitro to in vivo extrapolation (IVIVE) refers to the qualitative or quantitative transposition of experimental results or observations made in vitro to predict phenomena in vivo, biological organisms.
The problem of transposing in vitro results is particularly acute in areas such as toxicology where animal experiments are being phased out and are increasingly being replaced by alternative tests.
Results obtained from in vitro experiments cannot often be directly applied to predict biological responses of organisms to chemical exposure in vivo.
Therefore, it is extremely important to build a consistent and reliable in vitro to in vivo extrapolation method.
Two solutions are now commonly accepted:
Increasing the complexity of in vitro systems where multiple cells can interact with each other in order recapitulate cell-cell interactions present in tissues (as in "human on chip" systems).
Using mathematical modeling to numerically simulate the behavior of a complex system, whereby in vitro data provides the parameter values for developing a model.
The two approaches can be applied simultaneously allowing in vitro systems to provide adequate data for the development of mathematical models. To comply with push for the development of alternative testing methods.
The document summarizes various screening methods used to evaluate immunomodulators. It discusses in vivo methods like acute systemic anaphylaxis in rats and delayed type hypersensitivity reaction in rats. It also discusses in vitro methods like inhibition of histamine release from mast cells and neutrophil locomotion assays. The document provides details of various protocols used for screening immunomodulators.
Introduction to Screening Models Of Anti Cancer Drugs
Need for novel anti cancer drugs, In - vitro methods, In - vivo methods, Advantages and disadvantages
Presented by
T. Niranjan Reddy
Department of Pharmacology
The document summarizes the immune system and how it distinguishes self from nonself through innate and adaptive immunity. It then discusses immunomodulators which can suppress or stimulate the immune response, dividing them into immunosuppressants and immunostimulants. Several screening methods for evaluating immunomodulatory activity are also presented, including acute systemic anaphylaxis in rats, anti-anaphylactic activity, passive cutaneous anaphylaxis, Arthus type hypersensitivity, delayed type hypersensitivity, and carbon clearance tests for phagocytic response measurement. Modifications to these screening methods are also noted.
Assignment on Limitation of animal experimentation
This document discusses 5 key causes for why animal studies do not reliably predict human outcomes: 1) Interspecies differences in disease susceptibility, drug metabolism, and other factors; 2) Stressful laboratory environments and common procedures that alter animal physiology; 3) False positives from chronic high-dose rodent studies that overwhelm natural defenses; 4) Poor methodological quality in many animal experiments lacking randomization, blinding, and other controls; 5) Publication and other biases that skew available data.
This document describes various pre-clinical screening methods for anti-asthmatic drugs, including in vitro, isolated organ, and in vivo models. In vitro methods include the CULTEX technique using bronchial epithelial cell cultures and histamine receptor binding assays using guinea pig brain membranes. Tests in isolated organs involve measuring spasmolytic activity in guinea pig lung strips. In vivo models include tests in anesthetized guinea pigs to evaluate bronchospasmolytic effects and protection against anaphylactic shock or serotonin/histamine-induced asphyxia. Overall, the document outlines the most common pre-clinical tests used to evaluate potential anti-asthmatic effects prior to clinical trials.
Pharmacological screening of Anti-psychotic agents
This document provides information on screening models used to evaluate potential antipsychotic drugs. It begins with an introduction to psychosis and classification of antipsychotic agents. It then describes several in vivo and in vitro models used for screening including tests measuring catalepsy in rodents, inhibition of amphetamine-induced stereotypy, and D2 receptor binding assays. The in vivo models assess behaviors relevant to antipsychotic effects while the in vitro assays measure binding to specific receptors like the D2 receptor that contribute to antipsychotic mechanisms of action.
Screening methods for anti-anginal agents include in vivo and in vitro models. In vivo models involve inducing ventricular failure in animals through repeated injections of plastic microspheres into the left ventricular artery. In vitro models screen agents using isolated tissues like heart muscle to assess effects on coronary blood flow, oxygen consumption, and mechanical activity. Common classifications of anti-anginal agents are nitrates, beta-blockers, calcium channel blockers, potassium channel openers, and others like dipyridamole and trimetazidine.
This document summarizes screening methods for potential antiparkinson agents. It describes several in vivo and in vitro models used to test compounds. The key in vivo models discussed are:
1. Tremorine and oxotremorine antagonism in mice, which tests a compound's ability to reduce tremors induced by these muscarinic agonists.
2. The MPTP model in monkeys and mice, which uses MPTP to damage dopaminergic neurons and induce Parkinson's-like symptoms that can be reversed or reduced by test compounds.
3. Reserpine antagonism in rats, which tests if a compound can reduce sedation and motor impairment caused by reserpine depletion of cate
This document summarizes preclinical screening models of chronic obstructive pulmonary disease (COPD). It describes exposing mice to cigarette smoke over both acute (6 weeks) and chronic (5 days, 3 cigarettes/day) periods to model the effects of cigarette smoke, the main cause of COPD. For the acute study, mice are divided into groups exposed to air, smoke, or smoke with low- or high-dose test drugs. For the chronic study, groups are exposed to air, drugs and air, smoke, or smoke with low- or high-dose drugs. After exposure, the mice are sacrificed and their lungs examined to measure emphysema and macrophage volume as indicators of COPD pathology.
The document discusses various screening methods for evaluating potential anxiolytic drugs, including in vitro receptor binding assays and in vivo behavioral tests in animals like the elevated plus maze test, light-dark box test, and social interaction test, which measure anxiety-like behaviors that can be reduced by anxiolytic drug administration. Classification of anxiolytics and theories of anxiety involving neurotransmitters like GABA, serotonin and norepinephrine are also covered.
Screening Methods for behavioural and muscle Coordination
Screening Methods for behavioural and muscle Coordination
A. Motor activity and behaviour
1. Method of intermittent observation
2.Open field test
3.Hole board test
4.Combined open field test
B.Test for muscle coordination
1.Inclined plane method
2.Chimny test
3.Grip strength
4.Rotarod method
This document summarizes pre-clinical screening models for atherosclerosis. It discusses several in vivo and in vitro models, including triton wistar rat induced hyperlipidemia, cholesterol diet induced atherosclerosis in rabbits, and hereditary hyperlipidemia in rats. The triton model involves inducing hyperlipidemia in rats through triton injection and evaluating changes in serum lipid levels. The cholesterol diet model feeds rabbits a high cholesterol diet for 10-12 weeks then examines the aorta for lesions. The hereditary model uses rabbits genetically predisposed to hyperlipidemia to study the effects of potential drugs.
This document discusses several alternative methods that can be used instead of animal experiments for pharmacological and toxicological screening. It describes the full thickness skin model method which uses skin tissue to evaluate the effects of substances instead of live animals. It also mentions in silico methods which use computer programs and knowledge of similar substances to predict properties without testing. The document outlines the cell line technique using continuous cell lines to screen for effects like anticancer drugs. Finally, it explains the patch clamp technique which studies individual ion channels in isolated cells and kidney tubules as an alternative to testing on whole animals.
The document discusses immunoassay of digoxin. It provides an overview of immunoassays including the basic principles of competitive and non-competitive immunoassays. It describes how digoxin works to treat conditions like congestive heart failure and its mechanisms of action. The document also outlines the procedure for performing an immunoassay to measure digoxin levels and lists several analytical methods used like enzyme immunoassay, cloned enzyme donor immunoassay, and fluorescence polarization immunoassay.
The document describes several in vitro and in vivo methods used to study anti-allergic and anti-inflammatory drugs. In vitro methods include inhibition of histamine release from mast cells and inhibition of T cell proliferation. In vivo methods include a rat anaphylaxis model, guinea pig Schultz-Dale reaction, and passive cutaneous anaphylaxis in rats. One method involves sensitizing rats with ovalbumin, then challenging them to induce shock, which can be counteracted by test drugs. Another involves sensitizing guinea pigs to egg albumin to study contractions in response to ovalbumin.
1) The document discusses various in vitro and in vivo models used to study immunomodulatory activity, including inhibition of histamine release from mast cells, lymphocyte proliferation assays, and animal models of autoimmune diseases and hypersensitivity reactions.
2) Test protocols are provided for studying immunomodulation using assays such as mixed lymphocyte reactions, lymphocyte stimulation and cytokine production.
3) Animal models described include adjuvant-induced arthritis in rats and various spontaneous autoimmune disease models in mice and other species. Standard protocols are given for evaluating compounds in these disease models.
The document summarizes various screening methods used to evaluate immunomodulators. It discusses in vivo methods like acute systemic anaphylaxis in rats and delayed type hypersensitivity reaction in rats. It also discusses in vitro methods like inhibition of histamine release from mast cells and neutrophil locomotion assays. The document provides details of various protocols used for screening immunomodulators.
Introduction to Screening Models Of Anti Cancer Drugs
Need for novel anti cancer drugs, In - vitro methods, In - vivo methods, Advantages and disadvantages
Presented by
T. Niranjan Reddy
Department of Pharmacology
The document summarizes the immune system and how it distinguishes self from nonself through innate and adaptive immunity. It then discusses immunomodulators which can suppress or stimulate the immune response, dividing them into immunosuppressants and immunostimulants. Several screening methods for evaluating immunomodulatory activity are also presented, including acute systemic anaphylaxis in rats, anti-anaphylactic activity, passive cutaneous anaphylaxis, Arthus type hypersensitivity, delayed type hypersensitivity, and carbon clearance tests for phagocytic response measurement. Modifications to these screening methods are also noted.
Assignment on Limitation of animal experimentationDeepak Kumar
This document discusses 5 key causes for why animal studies do not reliably predict human outcomes: 1) Interspecies differences in disease susceptibility, drug metabolism, and other factors; 2) Stressful laboratory environments and common procedures that alter animal physiology; 3) False positives from chronic high-dose rodent studies that overwhelm natural defenses; 4) Poor methodological quality in many animal experiments lacking randomization, blinding, and other controls; 5) Publication and other biases that skew available data.
pre clinical Screening for anti asthmatic drugsDHINESHKUMAR V
This document describes various pre-clinical screening methods for anti-asthmatic drugs, including in vitro, isolated organ, and in vivo models. In vitro methods include the CULTEX technique using bronchial epithelial cell cultures and histamine receptor binding assays using guinea pig brain membranes. Tests in isolated organs involve measuring spasmolytic activity in guinea pig lung strips. In vivo models include tests in anesthetized guinea pigs to evaluate bronchospasmolytic effects and protection against anaphylactic shock or serotonin/histamine-induced asphyxia. Overall, the document outlines the most common pre-clinical tests used to evaluate potential anti-asthmatic effects prior to clinical trials.
Pharmacological screening of Anti-psychotic agentsAbin Joy
This document provides information on screening models used to evaluate potential antipsychotic drugs. It begins with an introduction to psychosis and classification of antipsychotic agents. It then describes several in vivo and in vitro models used for screening including tests measuring catalepsy in rodents, inhibition of amphetamine-induced stereotypy, and D2 receptor binding assays. The in vivo models assess behaviors relevant to antipsychotic effects while the in vitro assays measure binding to specific receptors like the D2 receptor that contribute to antipsychotic mechanisms of action.
Screening methods for anti-anginal agents include in vivo and in vitro models. In vivo models involve inducing ventricular failure in animals through repeated injections of plastic microspheres into the left ventricular artery. In vitro models screen agents using isolated tissues like heart muscle to assess effects on coronary blood flow, oxygen consumption, and mechanical activity. Common classifications of anti-anginal agents are nitrates, beta-blockers, calcium channel blockers, potassium channel openers, and others like dipyridamole and trimetazidine.
This document summarizes screening methods for potential antiparkinson agents. It describes several in vivo and in vitro models used to test compounds. The key in vivo models discussed are:
1. Tremorine and oxotremorine antagonism in mice, which tests a compound's ability to reduce tremors induced by these muscarinic agonists.
2. The MPTP model in monkeys and mice, which uses MPTP to damage dopaminergic neurons and induce Parkinson's-like symptoms that can be reversed or reduced by test compounds.
3. Reserpine antagonism in rats, which tests if a compound can reduce sedation and motor impairment caused by reserpine depletion of cate
This document summarizes preclinical screening models of chronic obstructive pulmonary disease (COPD). It describes exposing mice to cigarette smoke over both acute (6 weeks) and chronic (5 days, 3 cigarettes/day) periods to model the effects of cigarette smoke, the main cause of COPD. For the acute study, mice are divided into groups exposed to air, smoke, or smoke with low- or high-dose test drugs. For the chronic study, groups are exposed to air, drugs and air, smoke, or smoke with low- or high-dose drugs. After exposure, the mice are sacrificed and their lungs examined to measure emphysema and macrophage volume as indicators of COPD pathology.
The document discusses various screening methods for evaluating potential anxiolytic drugs, including in vitro receptor binding assays and in vivo behavioral tests in animals like the elevated plus maze test, light-dark box test, and social interaction test, which measure anxiety-like behaviors that can be reduced by anxiolytic drug administration. Classification of anxiolytics and theories of anxiety involving neurotransmitters like GABA, serotonin and norepinephrine are also covered.
Screening Methods for behavioural and muscle Coordinationpradnya Jagtap
Screening Methods for behavioural and muscle Coordination
A. Motor activity and behaviour
1. Method of intermittent observation
2.Open field test
3.Hole board test
4.Combined open field test
B.Test for muscle coordination
1.Inclined plane method
2.Chimny test
3.Grip strength
4.Rotarod method
Pre clinical screening of atherosclerosispavanreddy292
This document summarizes pre-clinical screening models for atherosclerosis. It discusses several in vivo and in vitro models, including triton wistar rat induced hyperlipidemia, cholesterol diet induced atherosclerosis in rabbits, and hereditary hyperlipidemia in rats. The triton model involves inducing hyperlipidemia in rats through triton injection and evaluating changes in serum lipid levels. The cholesterol diet model feeds rabbits a high cholesterol diet for 10-12 weeks then examines the aorta for lesions. The hereditary model uses rabbits genetically predisposed to hyperlipidemia to study the effects of potential drugs.
This document discusses several alternative methods that can be used instead of animal experiments for pharmacological and toxicological screening. It describes the full thickness skin model method which uses skin tissue to evaluate the effects of substances instead of live animals. It also mentions in silico methods which use computer programs and knowledge of similar substances to predict properties without testing. The document outlines the cell line technique using continuous cell lines to screen for effects like anticancer drugs. Finally, it explains the patch clamp technique which studies individual ion channels in isolated cells and kidney tubules as an alternative to testing on whole animals.
Screening model of antidiarrheal activity Presented by ABDUL HAMEEDAbdul Hameed
This document presents an overview of a screening model used to evaluate the anti-diarrheal properties of the petroleum ether extract of Swietenia macrophylla seeds. The screening model involves testing the extract on several in vivo models in rats, including castor oil-induced diarrhea to test the effects on defecation rate and stool consistency, gastrointestinal motility tests using charcoal meals, castor oil-induced enteropooling to measure intestinal fluid accumulation, and magnesium sulfate-induced diarrhea. The extract is tested at different doses and compared to standard anti-diarrheal drugs to validate the traditional use of the plant for treating diarrhea.
This document describes various methods for screening anti-anginal drugs, including both in vivo and in vitro techniques. The isolated heart (Langendorff) preparation is discussed in detail, where a heart is removed and retrogradely perfused to evaluate drug effects on contractility, coronary flow, and other parameters. The isolated heart-lung preparation and coronary artery ligation in isolated rat hearts are also presented as options to study anti-anginal drugs and model ischemia/reperfusion. Various evaluation criteria are provided such as measurements of left ventricular pressure, contractility, coronary flow, and more.
This presentation discusses methods for extrapolating preclinical drug testing data to estimate human drug doses. It describes two common extrapolation methods: linear extrapolation/simple scaling, which directly scales dosage based on weight, and allometric scaling, which accounts for how physiological processes change with body size. The presentation also outlines the process for extrapolating in vitro data to estimate first-in-human doses, including determining the no-observed-adverse-effect level, converting it to a human equivalent dose using body surface area, selecting the most appropriate animal species, applying a safety factor, and considering the pharmacologically active dose.
This document discusses extrapolating data from in vitro studies to preclinical and human trials. It defines extrapolation as estimating conclusions based on known facts. Two main methods of extrapolation are described: linear scaling and allometric scaling. When estimating a first human dose, the no-observed adverse effect level from animal studies is determined and converted to a human equivalent dose using body surface area. A safety factor is then applied to determine the maximum recommended starting dose. The document also discusses other approaches like using the minimum anticipated biological effect level.
Dose determination in preclinical and clinical studiesDrSahilKumar
This document discusses approaches for determining appropriate doses in preclinical and clinical studies. It covers considerations for in vitro, in vivo animal, and first-in-human clinical doses. For animal studies, a maximum tolerated dose is determined through dose range finding studies and acute toxicity studies. Regulatory toxicology studies use doses including a low dose at the no-observed-adverse-effect level, intermediate doses, and a high dose close to the maximum tolerated dose. For first-in-human studies, the estimated dose is typically 1/10 of the human equivalent dose calculated from the no-observed-adverse-effect level in the most appropriate animal species. Pharmacokinetic modeling and other drug properties may further inform safe starting doses
Toxicological Approach to Drug DiscoverySuhas Reddy C
This document outlines the toxicological approach to drug development. It discusses the importance of conducting various toxicity studies at different stages of drug development to ensure safety. These include single dose, repeated dose, fertility, reproductive, developmental and genotoxicity studies in animals. It describes the typical safety program involving staged approach and discusses factors to consider in designing toxicity studies. The goal is to obtain sufficient non-clinical safety data to support clinical trials and assess safety for human use.
Phase 1 clinical trials are the first studies done in humans of a new drug or treatment. They aim to determine the drug's safety and side effects, identify the maximum tolerated dose, and understand how the body processes the drug through pharmacokinetic evaluation. Phase 1 trials typically involve small groups of healthy volunteers or patients and start with low doses that are gradually increased. The results of phase 1 trials provide information needed to design subsequent clinical trial phases that further evaluate efficacy.
This document provides guidelines for safety pharmacology and toxicology studies for pharmaceutical products. It outlines the objectives and types of studies recommended at different stages of clinical development, including safety pharmacology core battery studies, follow-up studies, reproductive and developmental toxicity studies, and human studies. Test systems, dose levels, durations, endpoints, and good laboratory practice standards are discussed for each type of nonclinical study.
clinical and preclinical approaches to drug discovery.Here we mainly deals with preclinical approaches, ie. Pharmacological approach and toxicological approach
This phase 1 clinical trial protocol aims to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of a new investigational bronchodilator drug, CF-021, in healthy adult volunteers. The study is a randomized, open-label, single ascending oral dose trial. It will enroll approximately 30 subjects in sequential dose cohorts to determine the maximum tolerated dose of CF-021. Safety monitoring, pharmacokinetic profiling and bronchodilator effects will be assessed after single oral doses. The study aims to establish a safe clinical dosing range to enable further evaluation of CF-021 in phase 2 trials for chronic obstructive pulmonary disease.
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery, as with penicillin. More recently, chemical libraries of synthetic small molecules, natural products or extracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as classical pharmacology. After sequencing of the human genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease-modifying in a process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals for efficacy
Drug development involves basic research to identify drug targets and applied research to develop treatments. Preclinical trials test drug safety and efficacy in animals prior to human trials. They involve pharmacokinetic, pharmacodynamic and toxicology studies in two animal species. This provides data on effective and toxic doses, screens the drug's activity, and identifies formulation. Preclinical trials help determine if a drug warrants further development or should be terminated. They aim to predict potential human adverse effects and provide guidance for initial human clinical trials. However, extrapolating animal data to humans has limitations due to interspecies differences.
Toxicity studies in animals are conducted to identify any toxic effects of a substance prior to clinical use in humans. The document outlines various types of toxicity studies including acute, subacute, chronic, and lethality studies. Acute studies involve a single high dose to determine toxic effects over 14 days, while repeated dose studies like subacute and chronic studies administer multiple lower doses over weeks to years to identify target organ toxicity. Lethality studies determine the lethal dose for 50% of animals (LD50). Systemic toxicity parameters evaluated include effects on liver, kidney, heart and other organs. Toxicity studies provide safety information required for approval to conduct human clinical trials.
This document provides guidelines for safety pharmacology studies for human pharmaceuticals from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The guidelines discuss the objectives, scope, general principles, test systems, experimental design, dose levels/concentrations, duration of studies, and studies on metabolites for safety pharmacology evaluations. The goal is to help protect clinical trial participants and patients by identifying potential adverse effects of pharmaceuticals early in development.
S3A: NOTE FOR GUIDANCE ON TOXICOKINETICS: THE ASSESSMENT OF SYSTEMIC EXPOSURE IN TOXICITY STUDIES
S3B: PHARMACOKINETICS: GUIDANCE FOR REPEATED DOSE TISSUE DISTRIBUTION STUDIES
Pre-discovery
Understand the disease
Target Identification
Choose a molecule to target with a drug
Target Validation
Test the target and confirm its role in the disease
Drug Discovery
Find a promising molecule (a “lead compound”)
that could become a drug
ICH guidelines provide standards for toxicity studies to ensure safe, effective, and high quality pharmaceutical products. Guideline S3A deals with conducting toxicity studies and quantifying exposure. General principles include quantifying exposure levels in different species and sexes using plasma concentration or area under the curve. Toxicokinetic studies should be performed to determine metabolite levels and justify dose levels. Reporting should include detailed toxicokinetic data and evaluation. Toxicokinetics are assessed in various toxicity studies including single dose studies, repeated dose studies, genotoxicity studies, carcinogenicity studies, and reproductive toxicity studies.
First dose size in humans and non linear pharmacokinetics.pptxABDULRAUF411
The document discusses estimating the first dose of a drug to be administered to humans during clinical trials. It describes three factors to consider for the first dose: safety, ensuring measurable drug concentrations, and pharmacokinetics. Several methods are provided for estimating the maximum recommended starting dose including using no observed adverse effect levels from animal studies, minimal anticipated biological effect levels, comparing to similar drugs, and considering pharmacokinetic and pharmacodynamic models. Non-linear pharmacokinetics are discussed where parameters like absorption, distribution, metabolism, and excretion can become saturated at higher doses.
INTRODUCTION
FACTORS EFFECTING STABILITY
OBJECTIVE
TYPES OF STABILITY
TYPES OF STABILITY THAT MUST BE CONSIDERED FOR ANY DRUG
REGULATORY REQUIREMENTS
STABILITY STUDIES FOR PHARMACEUTICAL PRODUCTS
DEGRADATIVE PATHWAYS
Stability studies are performed in life sciences, chemical, and food and beverage industries to determine the effects of environmental conditions on product quality. Environmental conditions can impact product shelf life, and the viability of product formulation.
DEFINATION
The capacity of a drug or product to remain within established specifications of identity, quality, purity in a specific period of time.
The capacity or the capability of a particular formulation in a specific container to remain with in particular chemical, microbiological, therapeutically, and toxicological specifications.
USP defines stability of pharmaceutical product as, "extent to which a product retains with in specified limits and throughout its period of storage and use (i.e. shelf life).
The capacity or the capability of a particular formulation in a specific container to remain with in particular chemical, microbiological, therapeutically, and toxicological specifications.
USP defines stability of pharmaceutical product as, "extent to which a product retains with in specified limits and throughout its period of storage and use (i.e. shelf life).
The primary factors effecting stability:
PH, Temperature, Moisture, humidity, light, Storage closure and containers Oxygen.
The major factors effecting drug stability are:
Particle size (suspension and emulsion), PH, additives and molecular binding and diffusion of drugs and excipients.
Immunomodulation is modulation (regulatory adjustment) of the immune system. It has natural and human-induced forms, and thus the word can refer to the following:
Homeostasis in the immune system, whereby the system self-regulates to adjust immune responses to adaptive rather than maladaptive levels (using regulatory T cells, cell signaling molecules, and so forth)
Immunomodulation as part of immunotherapy, in which immune responses are induced, amplified, attenuated, or prevented according to therapeutic goals
Immunosuppressants:-
Immunosuppressants stop your immune system from damaging healthy cells and tissues. People with organ transplants and stem cell transplants take these medicines to prevent transplant rejections. The drugs also treat autoimmune disease symptoms. Immunosuppressants are powerful drugs that require careful monitoring to avoid problems.
Introduction
Types of polymer
Classification of Polymer
Polymerization
Biodegradable Polymer
Application of biodegradable polymer
Natural polymer
They occur naturally and are found in plants and animals. For example, proteins, starch, cellulose, and rubber. To add up, we also have biodegradable polymers called biopolymers.
Semi-synthetic Polymers:
They are derived from naturally occurring polymers and undergo further chemical modification. For example, cellulose nitrate, and cellulose acetate.
Synthetic Polymers
These are man-made polymers. Plastic is the most common and widely used synthetic polymer. It is used in industries and various dairy products. For example, nylon-6, 6, polyether’s etc.
Thermosetting polymersThese polymers greatly improve the material’s mechanical properties. It provides enhanced chemical and heat resistance. For example, phenolics, epoxies, and silicones.Addition Polymerization: For Example, poly ethane, Teflon, Polyvinyl chloride (PVC)Condensation Polymerization: Example, Nylon -6, 6, perylene, polyesters.
Medicines and Healthcare products Regulatory Agency(MHRA)TMU
What are regulatory bodies:- In the present scenario, pharmaceuticals are considered as the most highly regulated industries worldwide. The regulatory body ensures compliances in various legal and regulatory aspects of a drug. Every country has its own regulatory authority, which is responsible to enforce the rules and regulations and issue the guidelines to regulate drug development process, licensing, registration, manufacturing. marketing and labeling of pharmaceutical products like:
USFDA(USA)
MHRA(UK)
TGA(Australia
AIMS:- Protecting public health through regulation, with acceptablebenefit-risk profiles for medicines and devices.
Promoting public health by helping people who use these productsto understand their benefits and risks.
Improving public health by encouraging and facilitating developments in products that will benefit people
GUIDELINES:- Guidelines for Manufacturers on Clinical Investigations to be carried out in the UK.
Inspected UK Contract GMP Quality Control Laboratories.
BLUE GUIDE: Advertising and Promotion of medicines in the UK.
ORANGE GUIDE: Rules and Guidelines for Pharmaceutical Manufacturers and Distributors.
Good Pharmacovigilance Practice Guide.
Guidelines on Process Validation
Guide to UK GLP Regulations 1999
Recommendations on the control and monitoring of storage and transportation temperatures of medicinal products.
Guide to defective medicinal products.
Introduction of a Risk Based Inspection Programme for GMP Labs.
SALIENT FEATURES, COMMITTEES/WORKING GROUPS:-
MHRA has the power to withdraw a product from market and suspend production of medicines.
A manufacturer or distributor can be prosecuted if the law has been broken.
Regulatory decisions are impartial D Different products are treated differently.
MHRA collaborates with :
US Food and Drug Administration
NPSA National Patient Safety Agency
NICE National Institute for Health and Clinical Excellence
INTRODUCTION
CLASSIFICATION: SEDATIVE AND HYPNOTICS
BARBITURATES
BENZODIAZEPINES
SITE OF ACTION
MECHANISM OF ACTION
NEWER NONBENZODIAZEPINES HYPNOTICS
PHARMACOKINETICS
SIDE EFFECTS
Mechanism of action
Benzodiazepines
Increase frequency of opening of cl- channels induced by GABA.
Increase binding of GABA to GABA® receptor.
Reduction of anxiety. Reduce anxiety by selectively enhancing GABAergic transmission in neurons having the α-2 subunit in their GABA® receptor.
The hypnotic effect are mediated by α1-GABA® receptor
Anticonvulsant effect is partially although not completely, mediated by α1-GABA® receptors.
REGULATORY REQUIRMENT FOR PRODUCT APPROVAL.pptxTMU
1.Introduction
2.API sourcing
3.API sourcing in other Countries
4.Regulatory filing
5.DMFs
6.Regulatory Guideline for API
7. Compression study of active pharmaceutical ingredients in different countries
8.Filling issue
WORKING PRINCIPLE AND APPLICATIONS OF GENOMIC AND PROTEOMIC TOOLS
DNA ELECTROPHORESIS
POLYMERASE CHAIN REACTION (PCR)
REVERSE TRANSCRIPTION PCR (RT-PCR)
MICROARRAY TECHINIQUE
ENZYME LINKED IMMUNOSORBENT ASSAY (ELISA)
WESTERN BLOTTING
30 – Hours Yogic Sukshma Vyayama Teacher Training Course
What is Sukshma Yoga?
Dhirendra Brahmachari formulated this system and wrote books to clearly formulate the ancient yogic science. This practice simple yet powerful series of specific exercises that improve health and enhance the strength of different organs and systems in the body, from top of head to toes.
Suksma means subtle prana, mind, and intellect: Vyayama means exercise. Suksma Vyayama is meant for the Subtle Body (Suksma Sarira), it is not meant for the Sthula Sarira (Gross Physical Body).
Need of Suksma Vyayama
In yoga, it is said that most pranic blockages start in our joints. Ayurveda says that ‘ama’ or the toxic and undigested waste material tends to settle in the empty spaces of our body, the joints. To remove these impurities we practice Suksma Vyayama, to release any such impurities in our subtle pranic body.
Three dimension of suksma Vyayama:
1.Breathing (slow or fast: Bhastrika/Bellows)
2.Point of concentration (mental concentration on Chakras)
3.Exercise (using Bandhas and Mudras)
Sukshma yoga purifies and recharges the body, mind, energy, and emotion. It prepares the well foundation for further means of Yoga practice. It includes Sukshma Vyayama (Subtle Exercise), and Vishram (Rest & Relaxation). It is itself complete package that fulfills the basic need of human being.
Sukshma Vyayama is one of the major parts for physical activity and the regulation of entire physiologies. Sukshma Vyayama is also known as a kind of warm up exercise or basic exercise or clinically anti-rheumatic group of exercise and also called body scan. The system of the physical and breathing exercise which help to sequentially work out all joints of a body, to warm it up. This system has a strong purifying effect on energy body of a human.
1.1. History of Sukshma Vyayama
We will observe visible Parampara of Sukshma Vyayama. Literal meaning of Parampara is the continuous chain of succession by Master to followers. In Parampara system, the knowledge is passed on without changes from generation to generation). Unfortunately because of the absence of enough information we are not able to find sources of this tradition.
System of Sukshma Vyayama knowledge which was unknown in the west before that was extended by one of outstanding yoga masters, Dhirendra Brahmachari (1925-1994). He received Initiation into Sukshma Vyayama techniques from Maharshi Kartikeya, the prophet and sacred great yogi who was his Master. In the preface to the book “Yogic Sukshma Vyayama” Dhirendra Brahmachari wrote about his precious Guru. Deep knowledge made him the unique expert of human characters, of their abilities and possibilities. From Maharshi Kartikeya, Dhirendra Brahmachari received a precept to spread knowledge about Sukshma Vyayama. The invaluable merit of Dhirendra Brahmachari is that he managed to accumulate knowledge in the convenient form, to make it open and understandable for the audience everywhere. The b
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EXTRAPOLATION OF IN VITRO DATA TO PRECLINICAL
1. EXTRAPOLATION OF IN VITRO DATA TO
PRECLINICAL
A
PRESENTATION
OF
MASTER OF PHARMACY
IN
PHARMACOLOGY
SUBJECT CODE - MPL103T
SUBJECT NAME- TOXICOLOGY 1
DEPARTMENT OF PHARMACOLOGY
TEERTHANKER MAHAVEER COLLEGE OF PHARMACY
TEERTHANKER MAHAVEER UNIVERSITY
MORADABAD
SESSION: 2022-2023
SUBMITTED TO
PROF. PHOOLCHANDRA
SUBMITTED BY
PRAKHAR VARSHNEY
2. In vivo studies
In vivo is the Latin word which means with in the living body.
When effects of various biological entities are tested on whole, living organism or cells, usually animals
including humans and plants.
Animal testing and clinical trials are major elements of in-vivo research.
In vivo testing is often employed over in vitro because it is better suited for observing the overall effects of
an experiment on a living subject in drug discovery.
example, verification of efficacy in vivo is crucial, because in vitro assays can sometimes yield misleading
results with drug.
Harry Smith found that sterile filtrates of serum from animals infected with Bacillus anthracis were lethal
for other animals, whereas extracts of culture fluid from the same organism grown in vitro were not.
In microbiology Once cells are disrupted and individual parts are tested or analyzed, this is known as in
vitro.
In vitro studies
In vitro studies within the glass, i.e., in a laboratory environment using test tubes, petri dishes, etc.
Examples of investigations in vivo include: the pathogenesis of disease.
3. In vitro toxicology:-
The bridge exists between new drug discovery and drug development.-
Provide information on mechanism of action of a drug
Provides an early indication of the potential for some kinds of toxic effects, allowing a decision to terminate or to
proceed further.
In vitro methods are widely used for:-
Screening and ranking chemicals
Get a platform for animal studies for physiological actions
Studying cell, tissue, or target specific effects
Improve subsequent study design
Advantages and Disadvantages:-
Faster than in vivo studies
Less expensive to run
Less predictive of toxicity in intact organisms
4. Preclinical trials:-
A laboratory test of a new drug or a series of chemicals, usually done on animal subjects, to see if the hoped-for
treatment really works and if it is safe to test on humans.
Several steps of preclinical trials:-
Identify a Drug
Target
Develop
a Bioassay
Screen the
Drug in the
Assay
Establish
Effective and
Toxic Doses
File for
approval as an
Investigational
New Drug
(IND)
5. Preclinical studies
In vitro In vivo
Pharmacologica
l studies
Efficacy
Dose
conversion
Determination of
starting dose
Toxicological
studies
Safety
Receptor Characterization
Receptor binding assay
Enzyme inhibition
2° Messenger analysis
Cytotoxic activity
A route map of
preclinical studies
7. Preclinical Research can fall short in 3 ways:-
1. Failure to predict human risks
2. Clinical benefits that fail to materialize in humans
3. Prediction of non-existent risks in humans
Extrapolation of in vitro data to preclinical to humans:-
Estimating the first in human (FIH) dose is one of the initial steps in the clinical development of any molecule
that has successfully gone through all of the hurdles in preclinical evaluations.
8. MABEL is the ”anticipated dose level leading to minimal biological effect level in humans”. In general, MABEL can be
used to determined a starting dose when conventional toxicology testing may not be sufficient to predict serious adverse
reactions in clinical trials.
NOAEL No-Observed-Adverse-Effect Level:- The no observed adverse effect level is defined as the highest dose where the
effects observed in the treated group do not imply an adverse effect to the subject
LOAEL lowest observed adverse effect level is defined as the lowest dose where the effects observed in the treated group
imply an adverse effect to the subject
9. Calculations based on:
1) Animal pharmacokinetic
2) Administered doses
3) Observed toxicity
4) Algorithmic calculation
10. ESTIMATING THE MRSD-METHODS (maximum recommended starting dose)
1) NOAEL Method
2) MABEL Method.
3) Similar Drug Comparison Method
4) Pharmacokinetic Guided Approach
5) PK/PD Modelling Guided Approach
NOAEL method:- The NOAEL method is based on selecting a dose with minimal risk of toxicity, rather than
selecting one with minimal pharmacologic activity in humans
Steps using animal toxicology data:
1) Determine No Observed Adverse Effect Level (NOAEL) %0
2) Convert NOAEL to Human Equivalent Dose (HED) %0
3) Select most appropriate species %0
4) Apply Safety Factor %0
5) Consider Pharmacologically Active Dose
STEP 1:
NO OBSERVED ADVERSE EFFECT LEVEL DETERMINATION The NOAEL is a generally accepted benchmark for
safety when derived from appropriate animal studies
11. STEP 2:
HUMAN EQUIVALENT DOSE CALCULATION.
After the NOAELS in the relevant animal studies have been determined, they are converted to human equivalent doses
(HEDS) using appropriate scaling factors. The most appropriate method for extrapolating the animal dose to the
equivalent human dose should be decided.
doses scaled (1:1) between species when doses are normalized to body surface area (mg/m²).
These are recommended as the standard values to be used for interspecies dose conversions for NOAELS.
HED = Animal NOAEL x (W animal/W human)(1-b)
Conversion factors = (W animal/W human)(1-b)
Conventionally, for a mg/m² normalization b would be 0.67, but studies have shown that MTDs scale
best across species when b=0.75
Conversion factors are calculated over a range of animal and human weights using (W animal/W
human)0.330r (W animal/W human o.25 to assess the effect on starting dose selection of using b = 0.75
instead of b = 0.67
BASIS FOR USING Mg/Kg CONVERSIONS.
The "mg/kg" scaling will give a 12-,6- & 2-fold higher HED than the default mg/m² approach for
mice, rats, and dogs, respectively
mg/m² = km x mg/kg
where km = 100/K x W0.33 where K is a value unique to each species
12. STEP 3: MOST APPROPRIATE SPECIES SELECTION
Factors that could influence the choice of the most appropriate species. Differences in the absorption, distribution,
metabolism, and excretion (ADME) of the therapeutic between the species
STEP 4: APPLICATION OF SAFETY FACTOR
STEP 5: CONSIDERATION OF THE PHARMACOLOGICALLY ACTIVE DOSE(PAD)
Categories Evaluated in First In Human Trials:-
Local tolerance studies
Genotoxicity studies
Carcinogenicity studies
Reproduction toxicity studies
Photo safety testing
Nonclinical abuse liability
Other toxicity studies
Clinical trials in paediatric populations
Combination drug toxicity testing
Immunotoxicity
13. MABEL Method:-
• TheMABEListheanticipateddoselevelleadingto aminimal biological effect level in humans.
• In general, MABELcan be used to determined a starting dose when conventional toxicology testing may not
be sufficient to predict serious adverse reactions inclinical trials.
• Proposed by the Association of the British Pharmaceutical Industry (ABPI)/Bioindustry Association
(BIA) Early Stage Clinical Trial Task Force (2006)
• Relativelysafedosewithsomelevelofpharmacologyactivity
• No single method for calculation
• Use all available data
• Binding endpoints (e.g.,bindingaffinity, receptor occupancy)
• Functional endpoints (e.g., cytotoxicity, cytokine release, immune cell activation, intracellular
signaling)
14. MABEL General Factors to Consider:-
1. Mode of action
Novelty of pharmaceutical and target
Plausibility and extent of knowledge of MOA
Concentration/dose response
2. Pharmacology of the target
Tissue distribution and pharmacology of the target in normal and pathological states
3. Relevance of animal models
Compare available data in animals species to humans
Degree of species-selectivity for both target binding and FcyR binding
4.Patient population
Minimize dosing at sub-therapeutic levels in patients
15. Calculating aMABEL
• ThereisnouniversalapproachfordeterminingaFIHdosebasedona MABEL
• Examples for supporting data:
Invitropharmacologydatafromtargetcellsfromhumanandtoxicology species
Evaluation of MOA (agonistic vs antagonistic activity), potential for cytokine release, receptor occupancy,
concentration response data
If using animal data, then provide a comparison of
• Animal-human differences in exposure/drug distribution, differences in expressionlevelanddistributionoftarget,
andaffinityoftargetbinding and intrinsic efficacy
• Duration and reversibility of biologic effect
• Dose-exposure relationship (PK/PD)
Clinical ProtocolConsiderations:-
• Clinical trial population
• Number ofsubjects per cohort (e.g.,single-patientcohorts at potentially sub- therapeutic levels)
• Timeinterval between dosingsubjects withinthesame cohort (e.g., staggered enrollments within cohort)
• Doseescalationincrements(e.g.,acceleratedtitrationmaybeacceptableon a case-by-case basis)
• Criteria andtime interval for escalation tonext cohort (e.g.,extended observation period for dose limitingtoxicities)
• Clinicaltrialsite(availability oftreatments formedicalemergencies and intensive care unit facilities)
17. Methods of scaling drugs (methods of extrapolation of data)
1. Linear extrapolation/simple scaling/isometric scaling method
2. Non linear extrapolation/allometric scaling method
1. Linear extrapolation:-
mg/kg dose established for one species is applied across all species.
Advantage:-
• Simple
• Dosage and weight are directly (linearly) proportional.
• Problems arise when this method is applied to other species
• This method assumes that any differences in species PK/PD are not clinically relevant
Drawbacks:-
• This method tends to overdose large animals and underdose small animals, which may be very clinically significant.
• Typically, this method is only effective with drugs that have large margins of safety and wide therapeutic ranges.
18. 2. Allometric scaling:-
• Drug pharmacokinetics has a nonlinear (allometric) relationship to weight.
• Allometric scaling has become the method of choice for inter species extrapolation in drug discovery and
development.
• It is the study of size and its consequences Based on the principle that major physiologic processes are
related to body weight raised to allometric exponent
Interspecies difference between PK phase:-
Body metabolic rate
Species difference (size independent)
Rate of drug distribution
Protein binding
Drug metabolism
Drug elimination
19. In vitro to in vivo extrapolation (IVIVE) refers to the qualitative or quantitative transposition of experimental results or
observations made in vitro to predict phenomena in vivo, biological organisms.
The problem of transposing in vitro results is particularly acute in areas such as toxicology where animal experiments are
being phased out and are increasingly being replaced by alternative tests.
Results obtained from in vitro experiments cannot often be directly applied to predict biological responses of organisms to
chemical exposure in vivo.
Therefore, it is extremely important to build a consistent and reliable in vitro to in vivo extrapolation method.
Two solutions are now commonly accepted:
• Increasing the complexity of in vitro systems where multiple cells can interact with each other in order recapitulate cell-
cell interactions present in tissues (as in "human on chip" systems).
• Using mathematical modeling to numerically simulate the behavior of a complex system, whereby in vitro data provides
the parameter values for developing a model.
The two approaches can be applied simultaneously allowing in vitro systems to provide adequate data for the development
of mathematical models. To comply with push for the development of alternative testing methods, increasingly
sophisticated in vitro experiments are now collecting numerous, complex, and challenging data that can be integrated into
mathematical models