the presentation give complete explanantion on OECD guideline 403 of acute toxicity study for inhalation and the test subject used in the studies. the presentation give complete explanation of the guideline 403 and also describe the observation result and data reporting of the guideline
Regulatory guidelines for conducting toxicity studies by ichAnimatedWorld
ICH is the “International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for
Human Use”
ICH is a joint initiative involving both regulators and research based industry representatives of the EU, Japan and the US in
scientific and technical discussions of the testing procedures required
to assess and ensure the safety, quality and efficacy of medicines
Dermal Irritation and Dermal Toxicity Studies Dinesh Gangoda
Dermal irritation and Corrosion test guidelines 204.
Dermal irritation is the production of reversible damage of the skin following the application of a test chemical for up to 4 hours.
Corrosive reactions are typified by ulcers, bleeding, bloody scabs, and, by the end of observation at 14 days, by discolouration due to blanching of the skin, complete areas of alopecia, and scars. Histopathology should be considered to evaluate questionable lesions. [1]
Dermal corrosion is the production of irreversible damage of the skin; namely, visible necrosis through the epidermis and into the dermis, following the application of a test chemical for up to four hours.[2]
REFERENCES
OECD/OCDE, Test No. 404: ‘‘Acute Dermal Irritation/Corrosion’’, 28 July 2015 OECD Publishing, peris, Page no, 1- 8.
Robert A., Turner., Screening Methods in Pharmacology; 1st edition; Academic press an imprint of Elsevier, pp, 279- 281.
OECD Guideline for testing of chemicals (1981). ‘‘Repeated Dose Dermal Toxicity’’, 21/28- day Study.
Regulatory guidelines for conducting toxicity studies by ichAnimatedWorld
ICH is the “International Conference on Harmonization of
Technical Requirements for Registration of Pharmaceuticals for
Human Use”
ICH is a joint initiative involving both regulators and research based industry representatives of the EU, Japan and the US in
scientific and technical discussions of the testing procedures required
to assess and ensure the safety, quality and efficacy of medicines
Dermal Irritation and Dermal Toxicity Studies Dinesh Gangoda
Dermal irritation and Corrosion test guidelines 204.
Dermal irritation is the production of reversible damage of the skin following the application of a test chemical for up to 4 hours.
Corrosive reactions are typified by ulcers, bleeding, bloody scabs, and, by the end of observation at 14 days, by discolouration due to blanching of the skin, complete areas of alopecia, and scars. Histopathology should be considered to evaluate questionable lesions. [1]
Dermal corrosion is the production of irreversible damage of the skin; namely, visible necrosis through the epidermis and into the dermis, following the application of a test chemical for up to four hours.[2]
REFERENCES
OECD/OCDE, Test No. 404: ‘‘Acute Dermal Irritation/Corrosion’’, 28 July 2015 OECD Publishing, peris, Page no, 1- 8.
Robert A., Turner., Screening Methods in Pharmacology; 1st edition; Academic press an imprint of Elsevier, pp, 279- 281.
OECD Guideline for testing of chemicals (1981). ‘‘Repeated Dose Dermal Toxicity’’, 21/28- day Study.
Dear Friends,
This is my 3rd presentation, which will help you to understand the depth knowledge of acute eye irritation/corrosion (OECD-405) study in rabbit.
Toxicity is the science dealing with properties, action, toxicity, fatal dose detection or interpretation of result of toxicological analysis & treatment of poison.
Toxicity studies helps to avoid adverse effect and enhance the safety of drug.
This slide provides the information about toxicity screening on experimental animals.
OECD Test Guideline 420: Acute Oral Toxicity - Fixed Dosepp_shivgunde
OECD Test Guideline 420: Acute Oral Toxicity - Fixed Dose
Guideline 420 was adopted in July 1992 as the first alternative to the conventional acute toxicity test.
This presentation will help understanding the vast process of rat and mice handling and oral routes of drug administration through acute class method (OECD: 423).
Dear Friends,
This is my 3rd presentation, which will help you to understand the depth knowledge of acute eye irritation/corrosion (OECD-405) study in rabbit.
Toxicity is the science dealing with properties, action, toxicity, fatal dose detection or interpretation of result of toxicological analysis & treatment of poison.
Toxicity studies helps to avoid adverse effect and enhance the safety of drug.
This slide provides the information about toxicity screening on experimental animals.
OECD Test Guideline 420: Acute Oral Toxicity - Fixed Dosepp_shivgunde
OECD Test Guideline 420: Acute Oral Toxicity - Fixed Dose
Guideline 420 was adopted in July 1992 as the first alternative to the conventional acute toxicity test.
This presentation will help understanding the vast process of rat and mice handling and oral routes of drug administration through acute class method (OECD: 423).
Medical and Healthcare Professions:
Medical Doctors: Physiology forms the foundation for medical education. It is essential for diagnosing, treating, and preventing diseases. Doctors need a deep understanding of how the body's systems work to provide effective patient care.
Nurses: Nurses rely on physiology to monitor patients' vital signs, administer medications, and provide overall care. Understanding physiology is vital for patient safety.
Pharmacists: Pharmacists require knowledge of physiology to understand drug interactions, mechanisms of action, and potential side effects.
Biomedical Research:
Physiologists and researchers use knowledge of physiology to conduct experiments, develop new therapies, and advance medical science. This research is critical for discovering treatments for diseases.
Sports Science and Exercise Physiology:
Understanding how the body responds to exercise and physical activity is essential in sports science. Coaches, athletes, and fitness professionals rely on this knowledge to optimize training regimens and improve performance.
Nutrition and Dietetics:
Nutritionists and dietitians use physiology to understand how nutrients affect the body's various systems. This knowledge helps in designing diets to manage health conditions and promote overall well-being.
Pharmaceutical and Biotechnology Industries:
Professionals in these industries need to understand the physiological effects of drugs and biotechnological products to develop safe and effective treatments.
Biomechanics:
Physiological principles are fundamental in biomechanics, which is crucial in fields like orthopedics, physical therapy, and engineering to design prosthetics and improve mobility.
Environmental Science:
Environmental scientists study the physiological responses of organisms to changes in their environment, which is essential for understanding the impact of climate change and pollution on ecosystems.
Psychology and Neurobiology:
Understanding the physiological basis of behavior and cognition is critical in psychology and neuroscience. This knowledge helps in researching and treating mental health disorders.
Public Health:
Public health professionals need to comprehend the physiological aspects of disease transmission and prevention, especially in epidemiology and health policy development.
Education and Science Communication:
Educators and science communicators use physiology to teach students and the general public about the importance of health and wellness, disease prevention, and medical advancements.
Personal Well-Being:
Knowledge of physiology helps individuals make informed decisions about their health, leading to a healthier lifestyle, better disease prevention, and improved quality of life.
In summary, the study of physiology is a cornerstone of various disciplines and professions, impacting healthcare, research, sports, nutrition, industry, and more. It equips students with a deep understanding of how the human body functions, en
Skin sensitisation, OECD Test guideline 406 .pptxNikitaBankoti2
Skin Sensitisation: ( allergic contact dermatitis) is an immunologically mediated cutaneous reaction to a substance. In the human, the responses may be characterised by pruritis, erythema, oedema, papules, vesicles or a combination of these. In other species the reactions may differ and only erythema and oedema may be seen.
The small intestine and colon are parts of your digestive tract, which processes the foods you eat.
The intestines take nutrients from the foods. What isn't absorbed by the intestines continues along the digestive tract and is passed as stool during a bowel movement.
Intestinal obstruction is a blockage that keeps food or liquid from passing through your small intestine or large intestine (colon).
Causes of intestinal obstruction may include fibrous bands of tissue (adhesions) in the abdomen that form after surgery; hernias; colon cancer; certain medications; or strictures from an inflamed intestine caused by certain conditions, such as Crohn's disease or diverticulitis.
Without treatment, the blocked parts of the intestine can die, leading to serious problems. However, with prompt medical care, intestinal obstruction often can be successfully treated.
the presentation includes a definition of oral contraceptives, type of oral contraceptives, detail description of both types with its mode of action and potential beneficial and unwanted effects also include pharmacokinetics of oral contraceptives and knowledge of emergency contraceptives
the presentation is based on OECD guideline of chemical test on acute eye irritation guideline 403, it also give knowledge about why the guideline was updated and analgesic and anesthetic uses on the albino rabbit eye so to overcome the animal distress, and pain. the presentation explain the full guideline in detail
the above presentation contain the history of the thyroid disorder, including the definition of thyrotoxicosis, and its two main cause that are graves' disease and another toxic nodular goiter and the classification of drugs that are used in hyperthyroidism i.e. hormone sythesis inhibitor, hormone release inhibitors, destroy thyroid tissue, and inhibit ionic trapping with it's example including the adverse effect and side effect and marketted preparation of the same and the agents which cause hypothyroidism and the agents which are used to prescribe in the pregnancy
the presentation include the different type of mechanism used by cancer cells to protect them from anticancer agents lead to produce resistance. the slide include definition of cancer as per WHO, type of tumors, treatment of cancer, goal of treatment, problem associated with chemotherapeutic agents, need of studing mechanisms of resistance for anticancer agents, resistance, different mechanism of drug resistance, epigenetics, drug efflux, drug inactivation, DNA damage repair, drug target alteration and cell death inhibitiond
The above presentation consist of the definition of microarray, brief history, general principle of the same, the type of scanner that are used to read or to scan the microarray , type of DNA microarray and finally its various apliccation including the role of DNA microaarray in drug discovery.
the slideshare is been made to get knowledge about flow cytometry it's introduction, working, construction mainly components used in the flow cytometry and its application to use
This power point presentation include the definition of the peptic ulcer, formation of peptic ulcer, regulation of gastric acid secreation, sign and symptomes, etiology of chronic ulceration, acid- pepsin vs mucosal resistance, gastric hyper secreation, disease complication, infection and obstruction, different factors related to acid secreation, classification of drugs used in peptic ulcer animal models in experimental peptic ulcer in both in-vivo and in- vitro
This ppt gives information about the introduction to asthma disease its causes, pathophysiology and classification of antiasthmetic drugs with its stucture , the ppt is made for basic knowledge of antiasthemetic drugs on medicinal chemistry point of veiw for B. pharmacy students.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
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Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...
Acute toxicity study for inhalation
1. ACUTE TOXICITY STUDY FOR
INHALATION
OECD GUIDELINE 403
BY: PRIYA SHUKLA
DEPARTMENT OF PHARMACOLOGY
SSR COLLEGE OF PHARMACY
GUIDE: Dr. Chirag.A.Patel
2. Introduction
• Acute toxicity study for inhalation was
documented as document no. 39 as OECD
GUIDELINE FOR THE TESTING OF CHEMICALS
Acute Inhalation Toxicity.
• Guideline 403 ( 2009)
• Guideline 436 (2009)
• Guideline 433 (2017)
• The original acute inhalation Test Guideline
403 was adopted in 1981.
3. Introduction
• This revised Test Guideline 403 (TG 403) has
been designed to be more flexible, to reduce
animal usage, and to fulfil regulatory needs.
• The revised TG 403 features two study types:
• 1. a Traditional LC50 protocol and
• 2. a Concentration x Time (C x t) protocol.
4. Initial Consideration
• In accordance with this Test Guideline all
available information on the test article,
including existing studies (e.g. TG 436) whose
data would support not doing additional
testing should be considered by the testing
laboratory in order to minimize animal usage.
5. • Information that may assist in the selection of the
most appropriate
1. species
2. strain
3. sex
4. mode of exposure
• appropriate test concentrations include
• the identity, chemical structure, and
physicochemical properties of the test article;
results of any in vitro or in vivo toxicity tests;
anticipated uses and potential for human
exposure; available (Q)SAR data and toxicological
data on structurally related substance.
6. • Testing corrosive and/or irritating test articles
at concentrations that are expected to cause
severe pain and/or distress should be avoided
to the extent possible.
• The corrosive/irritating potential should be
evaluated by expert judgment using such
evidence as human and animal experience
(e.g. from repeat dose studies performed at
non-corrosive/irritant concentrations), existing
in vitro data, pH values, information from
similar substances or any other pertinent data,
for the purpose of investigating whether
further testing can be waived.
7. • The targeted concentrations should not
induce severe irritation/corrosive effects, yet
sufficient to extend the concentration-
response curve to levels that reach the
regulatory and scientific objective of the test.
These concentrations should be selected on a
case-by-case basis and justification for
concentration selection should be provided
8. PRINCIPLE OF THE TEST
• This revised TG 403 has been designed to
obtain sufficient information on the acute
toxicity of a test article to enable its
classification and to provide lethality data
(e.g. LC50, LC01 and slope) for one or both sexes
as needed for quantitative risk assessments.
9. • This Guideline offers two test methods.
1. The first method is a Traditional protocol in
which groups of animals are exposed to a
limit concentration (limit test) or a series of
concentrations in a stepwise procedure for a
predetermined duration of usually 4 hours.
Other durations of exposure may apply to
serve specific regulatory purposes.
2. The second method is a (C x t) protocol in
which groups of animals are exposed to one
(limit concentration) or a series of multiple
concentrations over multiple durations.
10. • Moribund animals or animals obviously in
pain or showing signs of severe and enduring
distress should be humanely killed and are
considered in the interpretation of the test
result in the same way as animals that died on
test.
• Criteria for making the decision to kill
moribund or severely suffering animals, and
guidance on the recognition of predictable or
impending death, are the subject of an OECD
Guidance Document No. 19 on Humane
Endpoints
11. DESCRIPTION OF THE METHOD
1. Selection of animal species:-
2. Preparation of animals
3. Animal husbandry
4. Inhalation chambers
12. 1. Selection of animal species:-
• Healthy young adult animals of commonly
used laboratory strains should be used.
• The preferred species is the rat and
justification should be provided if other
species are used.
13. 2. Preparation of animals
1. Females should be nulliparous and
nonpregnant.
2. On the exposure day, animals should be
young adults 8 to 12 weeks of age, and body
weights should be within ±20% of the mean
weight for each sex of any previously
exposed animals of the same age
14. 3. The animals are randomly selected and
marked for individual identification. The
animals are kept in their cages for at least 5
days prior to the start of the test to allow for
acclimatization to laboratory conditions.
4. Animals should also be acclimatised to the
test apparatus for a short period prior to
testing, as this will lessen the stress caused by
introduction to the new environment.
15. 3. Animal husbandry
1. The temperature of the experimental animal
maintenance room should be 22±3°C.
2. The relative humidity should ideally be
maintained in the range of 30 to 70%, though this
may not be possible when using water as a
vehicle.
3. Before and after exposures, animals generally
should be caged in groups by sex and
concentration, but the number of animals per
cage should not interfere with clear observation
of each animal and should minimize losses due to
cannibalism and fighting.
16. 4. When animals are to be exposed nose-only, it
may be necessary for them to be acclimated
to the restraining tubes. The restraining tubes
should not impose undue physical, thermal, or
immobilization stress on the animals.
5. Animals exposed whole-body to an aerosol
should be housed individually during exposure
to prevent them from filtering the test aerosol
through the fur of their cage mates.
6. Lighting should be artificial, the sequence
being 12 hours light/12 hours dark.
17. 4. Inhalation chambers
• The nature of the test article and the objective
of the test should be considered when
Selecting an inhalation chamber.
• The preferred mode of exposure is nose-only
(which term includes head-only, nose-only or
snout-only).
• Nose-only exposure is generally preferred for
studies of liquid or solid aerosols and for
vapours that may condense to form aerosols.
18. • To ensure atmosphere stability when using a
whole-body chamber, the total volume of the
test animals should not exceed 5% of the
chamber volume.
20. Administration of Concentration
• Nose-only exposures may be any duration up
to 6 hours in rats. If mice are exposed nose-
only, exposures generally should not exceed 4
hours.
• Justification should be provided if longer
duration studies are needed.
21. • Animals are exposed to the test article as a
gas, vapour, aerosol, or a mixture thereof. The
physical state to be tested depends on the
physico-chemical properties of the test article,
the selected concentration, and/or the
physical form most likely present during the
handling and use of the test article.
• Hygroscopic and chemically reactive test
articles should be tested under dry air
conditions. Care should be taken to avoid
generating explosive concentrations.
22. Particle-size distribution
• Particle sizing should be performed for all
aerosols and for vapours that may condense to
form aerosols.
• Although a reasonable effort should be made to
meet this standard, expert judgment should be
provided if it cannot be achieved. For example,
metal fumes may be smaller than this standard,
and charged particles, fibres, and hygroscopic
materials (which increase in size in the moist
environment of the respiratory tract) may exceed
this standard.
23. Test article preparation in a vehicle
• A vehicle may be used to generate an
appropriate concentration and particle size of
the test article in the atmosphere.
• water should be given preference.
• Adequate care should be taken to not
contaminate the test material. It is not
necessary to test non-friable granular
materials which are purposefully formulated
to be un-inhalable.
24. Control animals
• A concurrent negative (air) control group is not
necessary.
• When a vehicle other than water is used to assist
in generating the test atmosphere, a vehicle
control group should only be used when historical
inhalation toxicity data are not available.
• If a toxicity study of a test article formulated in a
vehicle reveals no toxicity, it follows that the
vehicle is non-toxic at the concentration tested;
thus, there is no need for a vehicle control.
25. MONITORING OF EXPOSURE
CONDITIONS
• 1. Chamber airflow
• 2. Chamber temperature and relative
humidity
• 3. Test article: Nominal concentration
• 4. Test article: Actual concentration
• 5. Test article: Particle size distribution
26. 1. Chamber Airflow
• The flow of air should be carefully
- Controlled
- Continuously monitored
- Recorded
• For at least hourly during each exposure.
27. • The monitoring of test atmosphere
concentration (or stability) is an integral
measurement of all dynamic parameters and
provides an indirect means to control all
relevant dynamic atmosphere generation
parameters.
• Oxygen concentration should be at least 19%
and carbon dioxide concentration should not
exceed 1%.
• If there is reason to believe that these
standards cannot be met, oxygen and carbon
dioxide concentrations should be measured.
28. 2. Chamber temperature and relative
humidity
• Chamber temperature should be maintained
at 22±3°C.
• Relative humidity in the animals’ breathing
zone, for both nose-only and whole-body
exposures, should be monitored and recorded
at least three times for durations of up to 4
hrs, and hourly for shorter durations.
29. • The relative humidity should ideally be
maintained in the range of 30 to 70%, but this
may either be unattainable
• (e.g. when testing water based formulations)
or not measurable due to test article
interference with the test method.
30. 3. Test article: Nominal concentration
• The nominal exposure chamber concentration
should be calculated and recorded.
• The nominal concentration is the mass of
generated test article divided by the total
volume of air pass through the chamber
system.
31. 4. Test article: Actual concentration
• The actual concentration is the test article
conc at the animals breathing zone in an
inhalation chamber.
• Actual concentrations can be obtained by
specific methods (e.g. direct sampling,
adsorptive or chemical reactive methods, and
subsequent analytical characterisation) or by
nonspecific methods such as gravimetric filter
analysis.
32. • The use of gravimetric analysis is acceptable
only for single component powder aerosols or
aerosols of low volatility liquids and should be
supported by appropriate pre-study test
article-specific characterisations.
• Multi-component powder aerosol
concentration may also be determined by
gravimetric analysis. However, this requires
analytical data which demonstrate that the
composition of airborne material is similar to
the starting material.
33. • One lot of the test article should be used, if
possible, and the test sample should be stored
under conditions that maintain its purity,
homogeneity, and stability.
34. 5. Test article: Particle size distribution
• The particle size distribution of aerosols should
be determined at least twice during each 4 hour
exposure by using a cascade impactor or an
alternative instrument such as an aerodynamic
particle sizer.
• A second device, such as a gravimetric filter or an
impinger/gas bubbler, should be used in parallel
to the primary instrument to confirm the
collection efficiency of the primary instrument
35. • Particle sizing should be performed for
vapours if there is any possibility that vapour
condensation may result in the formation of
an aerosol, or if particles are detected in a
vapour atmosphere with potential for mixed
phase.
36. PROCEDURE
• Two study types are described below:
1. the Traditional protocol
2. and the C x t protocol
Both protocols may include a sighting study, a
main study, and/or a limit test or testing at
limit concentration.
37. • If one sex is known to be more susceptible,
the study director may choose to perform
these studies using only the susceptible sex.
• If rodent species other than rats are exposed
nose-only, maximum exposure durations may
be adjusted to minimise species-specific
distress.
38. 1. TRADITIONAL PROTOCOL
• General considerations: In a Traditional study,
groups of animals are exposed to a test article for
a fixed period of time (generally 4 hours) in either
a nose-only or whole-body exposure chamber.
• Animals are exposed to either a limit
concentration (limit test), or to at least three
concentrations in a stepwise procedure (main
study).
• A sighting study may precede a main study
unless some information about the test article
already exists, such as a previously performed TG
436.
39. 2. Sighting study
• A sighting study is used to estimate test article
potency, identify sex differences in
susceptibility, and assist in selecting exposure
concentration levels for the main study or
limit test.
• When selecting concentration levels for the
sighting study, all available information should
be used including available (Q)SAR data and
data for similar chemicals.
40. • No more than three males and three females
should be exposed at each concentration (3
animals/sex may be needed to establish a sex
difference).
• A sighting study may consist of a single
concentration, but more concentrations may
be tested if necessary.
41. • A sighting study should not test so many
animals and concentrations that it resembles
a main study. A previously performed TG 436
study (4) may be used instead of a sighting
study.
42. 3. Limit test
• A limit test is used when the test article is
known or expected to be virtually non-toxic,
i.e. eliciting a toxic response only above the
regulatory limit concentration.
• In a limit test, a single group of three males
and three females is exposed to the test
article at a limit concentration.
43. • Information about the toxicity of the test
material can be gained from knowledge about
similar tested compounds or similar tested
mixtures or products, taking into
consideration the identity and percentage of
components known to be of toxicological
significance.
• In those situations where there is little or no
information about its toxicity, or the test
material is expected to be toxic, the main test
should be performed
44. • The selection of limit concentrations usually
depends on regulatory requirements. When
the GHS Classification System is used, the limit
concentrations for gases, vapours, and
aerosols are 20000 ppm, 20 mg/L, and 5 mg/L,
respectively (or the maximum attainable
concentration)
45. 4. Main Test
• A main study is typically performed using five
males and five females (or 5 animals of the
susceptible sex, if known) per concentration
level, with at least three concentration levels.
• Sufficient concentration levels should be used
to obtain a robust statistical analysis.
46. • The time interval between exposure groups is
determined by the onset, duration, and
severity of toxic signs. Exposure of animals at
the next concentration level should be
delayed until there is reasonable confidence
of survival for previously tested animals
47. C x t protocol
• General considerations: A step-wise C x t
study may be considered as an alternative to a
Traditional protocol when assessing inhalation
toxicity.
• This approach allows animals to be exposed to
a test article at several concentration levels
and for multiple time durations
48. • All testing is performed in a nose-only
chamber (whole-body chambers are not
practical for this protocol).
• Using 2 animals per sex per concentration and
time point may reduce bias and variability of
the estimates, increase the estimation success
rate, and improve confidence interval
coverage
49. 2. Sighting study
• A sighting study is used to estimate test article
potency and to assist in selecting exposure
concentration levels for the main study.
• 3 animal of per sex id used for test and exposure
of animal is done for single duration mainly 240
min.
• When selecting the initial target concentration in
a TG 403 study, the study director should
consider the mortality patterns observed in any
available TG 436 studies for both sexes and for all
concentrations tested
50. 3. Initial Concentration
• Group of 1 animal/sex is expose to the test article
initial conc for time interval of 15, 30, 60 , 120
and 240 min
• Total 10 animals are used in this test.
• The selection of limit concentrations usually
depends on regulatory requirements. When the
GHS Classification System is used, the limit
concentrations for gases, vapours, and aerosols
are 20000 ppm, 20 mg/L and 5 mg/L,
respectively.
51. • If mortality or moribundity is observed at the
initial concentration, the results at this
concentration can serve as a starting point for
further testing at other concentrations.
• When a test article’s physical or chemical
properties make it impossible to attain a limit
concentration, the maximum attainable
concentration should be tested.
• If less than 50% lethality occurs at the
maximum attainable concentration, no further
testing is necessary.
52. Main study
Exposure Session I –Testing at the limit concentration
• 1 animal/sex per concentration/time point; 10 animals in total a
• Target concentration = limit concentration.
• Expose five groups of animals at this target concentration for durations of
15, 30, 60, 120 and 240 minutes, respectively
Exposure Session II – Main Study
• 1 animal/sex per concentration/time point; 10 animals in total.
• Expose five groups of animals at a lower concentration d (1/2L) with slightly
lower duration of exposure.
53. Exposure Session III – Main Study
• 1 animal/sex per concentration/time point; 10 animals total.
• Expose five groups of animals at a lower concentration d (1/4L) with slightly
longer exposure durations.
Exposure Session IV′ – Main Study
• 1 animal/sex per concentration/time point; 10 animals total.
• Expose five groups of animals at a lower concentration d (1/8L) with slightly
longer exposure durations
Exposure Session IV – Main Study
• 1 animal/sex per concentration/time point; 10 animals total.
• Expose five groups of animals at a higher concentration e (2L) with slightly
shorter exposure durations
54. Observation
• The animals should be clinically observed
frequently during the exposure period.
• Once daily for 14 days.
• The length of the observation period is not
fixed, but should be determined by the nature
and time of onset of clinical signs and length
of the recovery period.
55. • The times at which signs of toxicity appear
and disappear are important, especially if
there is a tendency for signs of toxicity to be
delayed.
• All observations are systematically recorded
with individual records being maintained for
each animal.
• Animals found in a moribund condition and
animals showing severe pain and/or enduring
signs of severe distress should be humanely
killed for animal welfare reasons
56. • Cage-side observations should include
changes in the skin and fur, eyes and mucous
membranes, and also respiratory, circulatory,
autonomic and central nervous systems, and
somatomotor activity and behaviour patterns
• When possible, any differentiation between
local and systemic effects should be noted.
• Attention should be directed to observations
of tremors, convulsions, salivation, diarrhoea,
lethargy, sleep and coma
57. Body weights
• Individual animal weights should be recorded
once during the acclimatization period, on the
day of exposure prior to exposure (day 0), and
at least on days 1, 3 and 7 (and weekly
thereafter), and at the time of death or
euthanasia if exceeding day 1.
58. Pathology
• All test animals, including those which die during
the test or are euthanized and removed from the
study for animal welfare reasons, should be
subjected to gross necropsy.
• If necropsy cannot be performed immediately
after a dead animal is discovered, the animal
should be refrigerated (not frozen) at
temperatures low enough to minimize autolysis.
• Necropsies should be performed as soon as
possible, normally within a day or two.
59. DATA AND REPORTING
• Data : Individual animal data on body weights
and necropsy findings should be provided.
• Clinical observation data should be
summarized in tabular form, showing for each
test group the number of animals used, the
number of animals displaying specific signs of
toxicity, the number of animals found dead
during the test or killed for humane reasons,
time of death of individual animals, a
description and time course of toxic effect
60. Test report
• The test report should include the following
information, as appropriate:
• Description of caging conditions, including:
number (or change in number) of animals per
cage, bedding material, ambient temperature
and relative humidity, photoperiod, and
identification of diet
61. • - Species/strain used and justification for
using a species other than the rat
• - Number, age and sex of animals
• - Method of randomization
• - Details of food and water quality (including
diet type/source, water source);
• - Description of any pre-test conditioning
including diet, quarantine, and treatment for
disease;
62. Test article
• Physical nature, purity and, where relevant,
physico-chemical properties (including
isomerization)
• Identification data and Chemical Abstract
Services (CAS) Registry Number, if known
63. vehicle
• Justification for use of vehicle and
justification for choice of vehicle (if other than
water)
• Historical or concurrent data demonstrating
that the vehicle does not interfere with the
outcome of the study
64. Inhalation chamber
• Description of the inhalation chamber including
dimensions and volume
• Source and description of equipment used for the
exposure of animals as well as generation of
atmosphere
• Equipment for measuring temperature, humidity,
particle-size, and actual concentration
• Source of air and treatment of air supplied/extracted
and system used for conditioning
• Methods used for calibration of equipment to ensure a
homogeneous test atmosphere
• Pressure difference (positive or negative);
65. • Exposure ports per chamber (nose-only)
• location of animals in the system (whole-body)
• Temporal homogeneity/stability of test atmosphere
• Location of temperature and humidity sensors and
sampling of test atmosphere in the chamber
• Air flow rates, air flow rate/exposure port (nose-only),
or animal load/chamber (wholebody)
• Information about the equipment used to measure
oxygen and carbon dioxide, if applicable
• Time required to reach inhalation chamber
equilibrium
• Number of volume changes per hour
• Metering devices (if applicable)
66. Test conditions
• Details of test article preparation, including
details of any procedures used to reduce the
particle size of solid materials or to prepare
solutions of the test article. In cases where
mechanical processes may have altered test
article composition, include the results of
analyses to verify the composition of the test
article
67. • A description (preferably including a diagram)
of the equipment used to generate the test
atmosphere and to expose the animals to the
test atmosphere
• Details of the chemical analytical method
used and method validation (including
efficiency of recovery of test article from the
sampling medium)
• The rationale for the selection of test
concentrations
68. Results
• Tabulation of chamber temperature, humidity,
and airflow; - Tabulation of chamber nominal
and actual concentration data
• Tabulation of particle size data including
analytical sample collection data, particle size
distribution
69. • Individual body weights of animals collected on
study; date and time of death if prior to
scheduled euthanasia, time course of onset of
signs of toxicity and whether these were
reversible for each animal
• Necropsy findings and histopathological findings
for each animal, if available
• Lethality estimates (e.g. LC50, LD01) including
95% confidence limits, and slope (if provided by
the evaluation method)
• Statistical relation, including estimate for the
exponent n (C x t protocol). The name of the
statistical software used should be provided