The ADMET SIG meeting at SLAS2014, January 21 in San Diego, featured a presentation by SIG Chair David M. Stresser, Ph.D., of Corning® GentestSM Contract Research Services. View his presentation, Time-Dependent Inhibition of Cytochrome P450: A Deep Dive Into Methods for Abbreviated Testing, here.
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 is a PRESENTATION just to help students to easily understand one of the method of drug designing i.e. QSAR.. this is a combination of many slides and books..this is not my personal.
Quantitative structure - activity relationship (QSAR)
Why QSAR?
costs – 800M$ to bring a new drug to market
Patent life time is limited (generic drugs)
Synthesis / Purification of compounds is expensive and time consume-able
It is like find a needle in the haystack
QSAR helps for focusing most promising drug candidates
QSAR is a mathematical relationship between a “biological activity of a molecular system” and its “geometric and chemical characteristics”.
Such relationships holds – Equations can be drawn up- some confidence
to which should be Fit to the target
QSAR what actually do?
IDENTIFY AND QUANTIFY the Physico-chemical properties effect on Drug’s Biological activity
Aims
To relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula
Requirements
Quantitative measurements for biological and physicochemical properties
Physicochemical Properties
Hydrophobicity of the molecule
Hydrophobicity of substituents
Electronic properties of substituents
Steric properties of substituents
QSAR equations are only applicable to compounds in the same structural class (e.g. ethers)
However, log Po is similar for anaesthetics of different structural classes (ca. 2.3)
Structures with log P ca. 2.3 enter the CNS easily
(e.g. potent barbiturates have a log P of approximately 2.0)
Can alter log P value of drugs away from 2.0 to avoid CNS side effects
Physical properties are measured for the molecule as a whole
Properties are calculated using computer software
No experimental constants or measurements are involved
Properties are known as ‘Fields’
Steric field - defines the size and shape of the molecule
Electrostatic field - defines electron rich/poor regions of molecule
Hydrophobic properties are relatively unimportant
No reliance on experimental values
Can be applied to molecules with unusual substituents
Not restricted to molecules of the same structural class
Predictive capability
Comparative molecular field analysis (CoMFA) - Tripos
Build each molecule using modelling software
Identify the active conformation for each molecule
Identify the pharmacophore
THANKING YOU
In Vitro ADMET Considerations for Drug Discovery and Lead GenerationOSUCCC - James
This document provides an overview of in vitro ADMET (absorption, distribution, metabolism, excretion, toxicity) assays that are used during drug discovery and development. Key points:
- In vitro assays are designed to mimic what happens to a compound in vivo and provide early data on absorption, distribution, metabolic transformations, potential toxicity, and more.
- Common assays examine solubility, permeability, protein binding, metabolic stability, metabolism pathways, toxicity, and effects of transporters and drug-drug interactions.
- The data generated from these assays are used throughout the drug development process to inform compound selection, design better candidates, and identify liabilities early. Understanding a compound's properties helps optimize the likelihood of success
Lecture 8 drug targets and target identificationRAJAN ROLTA
This document provides an overview of drug targets and target identification. It discusses the types of biological targets including proteins, nucleic acids, and small molecules. Common protein drug targets are G protein-coupled receptors, enzymes, ion channels, nuclear hormone receptors, structural proteins, and membrane transport proteins. The document describes characteristics of drug targets and examples of current drug targets such as receptors, enzymes, ion channels, nuclear hormone receptors, and membrane transport proteins. It also discusses the process of target identification including direct biochemical methods, computational inference methods, and genetic interaction methods as well as tools used for target identification like microarrays, antisense technologies, chemical genomics, and proteomics.
This document summarizes recent advances in the treatment of diabetes mellitus. It discusses improved methods for monitoring blood glucose levels and diagnosing diabetes. New therapies described include insulin sensitizers, inhibitors of intestinal carbohydrate absorption, various methods of insulin administration including pumps, and immunotherapy approaches. The document concludes that future treatment will depend on ongoing clinical trials of immunomodulation and immunosuppressive therapies to help preserve pancreatic beta cell function and reduce insulin requirements.
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 is a PRESENTATION just to help students to easily understand one of the method of drug designing i.e. QSAR.. this is a combination of many slides and books..this is not my personal.
Quantitative structure - activity relationship (QSAR)
Why QSAR?
costs – 800M$ to bring a new drug to market
Patent life time is limited (generic drugs)
Synthesis / Purification of compounds is expensive and time consume-able
It is like find a needle in the haystack
QSAR helps for focusing most promising drug candidates
QSAR is a mathematical relationship between a “biological activity of a molecular system” and its “geometric and chemical characteristics”.
Such relationships holds – Equations can be drawn up- some confidence
to which should be Fit to the target
QSAR what actually do?
IDENTIFY AND QUANTIFY the Physico-chemical properties effect on Drug’s Biological activity
Aims
To relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula
Requirements
Quantitative measurements for biological and physicochemical properties
Physicochemical Properties
Hydrophobicity of the molecule
Hydrophobicity of substituents
Electronic properties of substituents
Steric properties of substituents
QSAR equations are only applicable to compounds in the same structural class (e.g. ethers)
However, log Po is similar for anaesthetics of different structural classes (ca. 2.3)
Structures with log P ca. 2.3 enter the CNS easily
(e.g. potent barbiturates have a log P of approximately 2.0)
Can alter log P value of drugs away from 2.0 to avoid CNS side effects
Physical properties are measured for the molecule as a whole
Properties are calculated using computer software
No experimental constants or measurements are involved
Properties are known as ‘Fields’
Steric field - defines the size and shape of the molecule
Electrostatic field - defines electron rich/poor regions of molecule
Hydrophobic properties are relatively unimportant
No reliance on experimental values
Can be applied to molecules with unusual substituents
Not restricted to molecules of the same structural class
Predictive capability
Comparative molecular field analysis (CoMFA) - Tripos
Build each molecule using modelling software
Identify the active conformation for each molecule
Identify the pharmacophore
THANKING YOU
In Vitro ADMET Considerations for Drug Discovery and Lead GenerationOSUCCC - James
This document provides an overview of in vitro ADMET (absorption, distribution, metabolism, excretion, toxicity) assays that are used during drug discovery and development. Key points:
- In vitro assays are designed to mimic what happens to a compound in vivo and provide early data on absorption, distribution, metabolic transformations, potential toxicity, and more.
- Common assays examine solubility, permeability, protein binding, metabolic stability, metabolism pathways, toxicity, and effects of transporters and drug-drug interactions.
- The data generated from these assays are used throughout the drug development process to inform compound selection, design better candidates, and identify liabilities early. Understanding a compound's properties helps optimize the likelihood of success
Lecture 8 drug targets and target identificationRAJAN ROLTA
This document provides an overview of drug targets and target identification. It discusses the types of biological targets including proteins, nucleic acids, and small molecules. Common protein drug targets are G protein-coupled receptors, enzymes, ion channels, nuclear hormone receptors, structural proteins, and membrane transport proteins. The document describes characteristics of drug targets and examples of current drug targets such as receptors, enzymes, ion channels, nuclear hormone receptors, and membrane transport proteins. It also discusses the process of target identification including direct biochemical methods, computational inference methods, and genetic interaction methods as well as tools used for target identification like microarrays, antisense technologies, chemical genomics, and proteomics.
This document summarizes recent advances in the treatment of diabetes mellitus. It discusses improved methods for monitoring blood glucose levels and diagnosing diabetes. New therapies described include insulin sensitizers, inhibitors of intestinal carbohydrate absorption, various methods of insulin administration including pumps, and immunotherapy approaches. The document concludes that future treatment will depend on ongoing clinical trials of immunomodulation and immunosuppressive therapies to help preserve pancreatic beta cell function and reduce insulin requirements.
1) De novo drug design involves generating new drug molecules from scratch based on the 3D structure of the target receptor.
2) It uses molecular modeling tools to modify lead compounds to better interact with the receptor's binding site.
3) The process involves defining interaction sites on the receptor, generating potential drug molecules, scoring them based on their fit with the receptor, and using search algorithms to refine candidates.
This document provides a history of quantitative structure-activity relationship (QSAR) studies from 1868 to the present. It discusses early relationships found between molecular properties like molecular weight and physiological activity. Key developments include Hammett's equation from 1937 relating chemical reactivity to substituents, Hansch analysis from the 1960s correlating biological activity to electronic, steric and hydrophobic descriptors, and the development of 2D and 3D QSAR models incorporating molecular structure information. QSAR aims to correlate biological activity to physicochemical properties using mathematical models.
De novo drug design is a computer-assisted process that uses the 3D structure of a receptor target to design new drug molecules. It involves determining the structure of existing drug-target complexes, designing modifications to existing lead compounds, and generating new chemical classes of compounds. The goal is to design drugs with the correct shape and functional groups to properly fit and interact within the target's binding site in order to produce the desired pharmacological effect. However, de novo design is challenging and rarely produces ideal compounds on its own. Software tools aim to automate and speed up the process by fitting and linking together molecular fragments to fill interaction sites in the binding pocket.
The document summarizes recent advances in understanding and treating Alzheimer's disease. It discusses both non-modifiable and modifiable risk factors for the disease. The major signs and symptoms include progressive memory loss and cognitive decline. Alzheimer's is confirmed through neuronal plaques and tangles seen in the brain. Recent treatment strategies aim to reduce amyloid plaques through vaccines, antibodies, and inhibitors of beta- and gamma-secretase. Other approaches include tau phosphorylation inhibitors, therapies for mitochondrial dysfunction, and cholinesterase inhibitors. Animal models continue to be important for studying the human APP, ApoE, and presenilin genes involved in Alzheimer's pathology.
Regulatory guidelines for conducting toxicity studies by ichAnimatedWorld
The document outlines regulatory guidelines for conducting toxicity studies established by the International Council on Harmonization (ICH). ICH provides guidelines on quality, safety, and efficacy for pharmaceutical registration. The safety guidelines cover areas like carcinogenicity studies, genotoxicity testing, toxicokinetics, duration of chronic toxicity testing, reproductive toxicity testing, immunotoxicity studies, phototoxicity evaluation, and nonclinical safety testing to support pediatric medicine development. Expert working groups establish the guidelines to ensure a consistent approach to nonclinical safety assessment is applied across regions.
This document discusses various quantitative structure-activity relationship (QSAR) methods including physicochemical parameters, Hansch analysis, and Free-Wilson analysis to correlate biological activity of compounds to their chemical structure. It describes measuring hydrophobicity using partition coefficients and electronic effects using Hammett constants. Hansch analysis relates biological activity to multiple physicochemical properties through linear or parabolic equations. Free-Wilson analysis quantifies the contribution of individual substituents to activity without needing physicochemical constants. Both approaches aim to predict new compounds' activities based on structural attributes.
Role of nuclicacid microarray &protein micro array for drug discovery processmohamed abusalih
role of nuclic acid microarray and protein microarray for drug discovery process
1.introduction about microarray technique and genomics
2.process of drug discovery
3.microarray techiques
4.microarray analysis in drug discovery
5.steps involved in the micro array analysis
This document summarizes various virtual screening techniques used in drug discovery. It discusses ligand-based methods like similarity searching using 2D and 3D fingerprints, pharmacophore mapping. It also discusses structure-based methods like protein-ligand docking to predict binding poses and scores. Hybrid methods combining different techniques are also used. The document provides an overview of key virtual screening methods and their applications to enrich hit rates and select compounds for further testing from large libraries in an efficient manner during the drug discovery process.
Pharmacotherapy of asthma and copd 1.pptxAbhinav Singh
This document discusses asthma and COPD medications. It describes several classes of drugs used to treat asthma, including bronchodilators like beta-2 agonists that work quickly to relieve symptoms, and anti-inflammatory drugs like corticosteroids that are used long-term to prevent symptoms. Beta-2 agonists work by binding to beta-2 receptors and relaxing airway smooth muscle. Corticosteroids reduce inflammation through various mechanisms. Other discussed drug classes include muscarinic antagonists, methylxanthines, mast cell stabilizers, and leukotriene receptor antagonists.
Domainex has contributed to three clinical candidates through its drug discovery programs for clients. It uses a variety of technologies like combinatorial domain hunting, LeadBuilder for virtual screening, and integrated medicinal and computational chemistry. Domainex has a highly experienced team of drug discovery scientists and has successfully delivered ion-channel blockers, kinase inhibitors, and anti-thrombotics into clinical trials for clients. It provides concise drug discovery services from hit identification to candidate selection through its expertise in computational chemistry, library synthesis, and medicinal chemistry.
This document discusses the pharmacotherapy of asthma. It begins by defining asthma as a condition characterized by airway hyperresponsiveness and inflammation. It then discusses the various mediators involved in asthma pathology like histamine, prostaglandins, and leukotrienes. It covers the different drug classes used to treat asthma, including bronchodilators like beta-agonists, methylxanthines, and anticholinergics. It also discusses anti-inflammatory drugs like corticosteroids, mast cell stabilizers, and leukotriene receptor antagonists. The document provides details on specific drugs within these classes and their mechanisms of action and side effects. It concludes by discussing approaches to treating asthma based on severity and persistence
Autophagy is a normal cellular process that maintains homeostasis through degradation and recycling of cellular components. It plays a dual role in cancer and other diseases. The document discusses three main types of autophagy and the steps of autophagosome formation. It explores the link between autophagy and diseases like cancer, diabetes, and neurodegenerative disorders. Specifically, it examines the role of autophagy in diabetic neuropathy and potential interventions that target the autophagy process.
This document provides guidance on IND (Investigational New Drug) regulations for initial Phase 1 clinical trials. It clarifies that Phase 1 IND submissions require basic information to ensure safety rather than detailed development plans. For protocols, manufacturing information, and other sections, flexibility is allowed to adapt to early study results. The focus should be on safety aspects like monitoring and dose adjustments rather than predetermined experimental designs. This guidance aims to help sponsors provide sufficient information without being overly burdensome for early phase trials.
Recent advancement in parkinson's diseaseRajesh Yadav
The document discusses recent advancements in Parkinson's disease. It provides an introduction to Parkinson's, including its symptoms and characteristics like dopamine neuron loss. It then outlines current drug treatments that act on the dopaminergic and cholinergic systems, such as Levodopa. New drug treatments and surgical options like deep brain stimulation are also discussed. The document concludes by mentioning gene therapy and stem cell therapy as potential future treatment methods.
Fragment-based drug discovery is a process that begins with identifying low molecular weight fragments that weakly bind to the target of interest. These fragment hits are then optimized into lead compounds with higher affinity and selectivity. This approach has successfully identified several drug candidates, including Venetoclax which treats chronic lymphocytic leukemia by inhibiting BCL-2. Key techniques for fragment screening include differential scanning fluorimetry, isothermal titration calorimetry, NMR spectroscopy and X-ray crystallography. Hit optimization is achieved through fragment growing, linking or hopping to develop potent inhibitors.
The document discusses systems and assays that can be implemented by academic groups for central nervous system (CNS) drug discovery. It focuses on absorption, distribution, metabolism, and excretion (ADME) assays including solubility tests, pharmacokinetic studies, and metabolism experiments. It also covers toxicology assays such as in vitro safety tests and rodent tolerability studies. The level of characterization required depends on whether the compound is being developed as a research probe or as a potential investigational new drug (IND) candidate.
QSP is defined as an approach to translational medicine that combines computational and experimental methods to elucidate, validate, and apply new pharmacological concepts to the development an use of small molecule and biologic drugs.
1) De novo drug design involves generating new drug molecules from scratch based on the 3D structure of the target receptor.
2) It uses molecular modeling tools to modify lead compounds to better interact with the receptor's binding site.
3) The process involves defining interaction sites on the receptor, generating potential drug molecules, scoring them based on their fit with the receptor, and using search algorithms to refine candidates.
This document provides a history of quantitative structure-activity relationship (QSAR) studies from 1868 to the present. It discusses early relationships found between molecular properties like molecular weight and physiological activity. Key developments include Hammett's equation from 1937 relating chemical reactivity to substituents, Hansch analysis from the 1960s correlating biological activity to electronic, steric and hydrophobic descriptors, and the development of 2D and 3D QSAR models incorporating molecular structure information. QSAR aims to correlate biological activity to physicochemical properties using mathematical models.
De novo drug design is a computer-assisted process that uses the 3D structure of a receptor target to design new drug molecules. It involves determining the structure of existing drug-target complexes, designing modifications to existing lead compounds, and generating new chemical classes of compounds. The goal is to design drugs with the correct shape and functional groups to properly fit and interact within the target's binding site in order to produce the desired pharmacological effect. However, de novo design is challenging and rarely produces ideal compounds on its own. Software tools aim to automate and speed up the process by fitting and linking together molecular fragments to fill interaction sites in the binding pocket.
The document summarizes recent advances in understanding and treating Alzheimer's disease. It discusses both non-modifiable and modifiable risk factors for the disease. The major signs and symptoms include progressive memory loss and cognitive decline. Alzheimer's is confirmed through neuronal plaques and tangles seen in the brain. Recent treatment strategies aim to reduce amyloid plaques through vaccines, antibodies, and inhibitors of beta- and gamma-secretase. Other approaches include tau phosphorylation inhibitors, therapies for mitochondrial dysfunction, and cholinesterase inhibitors. Animal models continue to be important for studying the human APP, ApoE, and presenilin genes involved in Alzheimer's pathology.
Regulatory guidelines for conducting toxicity studies by ichAnimatedWorld
The document outlines regulatory guidelines for conducting toxicity studies established by the International Council on Harmonization (ICH). ICH provides guidelines on quality, safety, and efficacy for pharmaceutical registration. The safety guidelines cover areas like carcinogenicity studies, genotoxicity testing, toxicokinetics, duration of chronic toxicity testing, reproductive toxicity testing, immunotoxicity studies, phototoxicity evaluation, and nonclinical safety testing to support pediatric medicine development. Expert working groups establish the guidelines to ensure a consistent approach to nonclinical safety assessment is applied across regions.
This document discusses various quantitative structure-activity relationship (QSAR) methods including physicochemical parameters, Hansch analysis, and Free-Wilson analysis to correlate biological activity of compounds to their chemical structure. It describes measuring hydrophobicity using partition coefficients and electronic effects using Hammett constants. Hansch analysis relates biological activity to multiple physicochemical properties through linear or parabolic equations. Free-Wilson analysis quantifies the contribution of individual substituents to activity without needing physicochemical constants. Both approaches aim to predict new compounds' activities based on structural attributes.
Role of nuclicacid microarray &protein micro array for drug discovery processmohamed abusalih
role of nuclic acid microarray and protein microarray for drug discovery process
1.introduction about microarray technique and genomics
2.process of drug discovery
3.microarray techiques
4.microarray analysis in drug discovery
5.steps involved in the micro array analysis
This document summarizes various virtual screening techniques used in drug discovery. It discusses ligand-based methods like similarity searching using 2D and 3D fingerprints, pharmacophore mapping. It also discusses structure-based methods like protein-ligand docking to predict binding poses and scores. Hybrid methods combining different techniques are also used. The document provides an overview of key virtual screening methods and their applications to enrich hit rates and select compounds for further testing from large libraries in an efficient manner during the drug discovery process.
Pharmacotherapy of asthma and copd 1.pptxAbhinav Singh
This document discusses asthma and COPD medications. It describes several classes of drugs used to treat asthma, including bronchodilators like beta-2 agonists that work quickly to relieve symptoms, and anti-inflammatory drugs like corticosteroids that are used long-term to prevent symptoms. Beta-2 agonists work by binding to beta-2 receptors and relaxing airway smooth muscle. Corticosteroids reduce inflammation through various mechanisms. Other discussed drug classes include muscarinic antagonists, methylxanthines, mast cell stabilizers, and leukotriene receptor antagonists.
Domainex has contributed to three clinical candidates through its drug discovery programs for clients. It uses a variety of technologies like combinatorial domain hunting, LeadBuilder for virtual screening, and integrated medicinal and computational chemistry. Domainex has a highly experienced team of drug discovery scientists and has successfully delivered ion-channel blockers, kinase inhibitors, and anti-thrombotics into clinical trials for clients. It provides concise drug discovery services from hit identification to candidate selection through its expertise in computational chemistry, library synthesis, and medicinal chemistry.
This document discusses the pharmacotherapy of asthma. It begins by defining asthma as a condition characterized by airway hyperresponsiveness and inflammation. It then discusses the various mediators involved in asthma pathology like histamine, prostaglandins, and leukotrienes. It covers the different drug classes used to treat asthma, including bronchodilators like beta-agonists, methylxanthines, and anticholinergics. It also discusses anti-inflammatory drugs like corticosteroids, mast cell stabilizers, and leukotriene receptor antagonists. The document provides details on specific drugs within these classes and their mechanisms of action and side effects. It concludes by discussing approaches to treating asthma based on severity and persistence
Autophagy is a normal cellular process that maintains homeostasis through degradation and recycling of cellular components. It plays a dual role in cancer and other diseases. The document discusses three main types of autophagy and the steps of autophagosome formation. It explores the link between autophagy and diseases like cancer, diabetes, and neurodegenerative disorders. Specifically, it examines the role of autophagy in diabetic neuropathy and potential interventions that target the autophagy process.
This document provides guidance on IND (Investigational New Drug) regulations for initial Phase 1 clinical trials. It clarifies that Phase 1 IND submissions require basic information to ensure safety rather than detailed development plans. For protocols, manufacturing information, and other sections, flexibility is allowed to adapt to early study results. The focus should be on safety aspects like monitoring and dose adjustments rather than predetermined experimental designs. This guidance aims to help sponsors provide sufficient information without being overly burdensome for early phase trials.
Recent advancement in parkinson's diseaseRajesh Yadav
The document discusses recent advancements in Parkinson's disease. It provides an introduction to Parkinson's, including its symptoms and characteristics like dopamine neuron loss. It then outlines current drug treatments that act on the dopaminergic and cholinergic systems, such as Levodopa. New drug treatments and surgical options like deep brain stimulation are also discussed. The document concludes by mentioning gene therapy and stem cell therapy as potential future treatment methods.
Fragment-based drug discovery is a process that begins with identifying low molecular weight fragments that weakly bind to the target of interest. These fragment hits are then optimized into lead compounds with higher affinity and selectivity. This approach has successfully identified several drug candidates, including Venetoclax which treats chronic lymphocytic leukemia by inhibiting BCL-2. Key techniques for fragment screening include differential scanning fluorimetry, isothermal titration calorimetry, NMR spectroscopy and X-ray crystallography. Hit optimization is achieved through fragment growing, linking or hopping to develop potent inhibitors.
The document discusses systems and assays that can be implemented by academic groups for central nervous system (CNS) drug discovery. It focuses on absorption, distribution, metabolism, and excretion (ADME) assays including solubility tests, pharmacokinetic studies, and metabolism experiments. It also covers toxicology assays such as in vitro safety tests and rodent tolerability studies. The level of characterization required depends on whether the compound is being developed as a research probe or as a potential investigational new drug (IND) candidate.
QSP is defined as an approach to translational medicine that combines computational and experimental methods to elucidate, validate, and apply new pharmacological concepts to the development an use of small molecule and biologic drugs.
The document discusses optimizing ADME and PK properties in drug development. It addresses common mistakes such as believing that intrinsic clearance cannot be optimized or that increasing plasma protein binding will always benefit PK. It emphasizes that intrinsic clearance, uptake clearance, and renal clearance all contribute to in vivo clearance. Good quality experimental data is important for accurate prediction of human PK. Formulation strategies can improve bioavailability when absorption is limited, but not if clearance is the dominant elimination pathway. The effects of plasma protein binding on free drug exposure are also explained.
Dr. Praveen Balimane, senior staff fellow, Division of Clinical Pharmacology-1 at OCP/OTS/CDER/FDA, spoke during the Society for Laboratory Automation and Screening ADMET Special Interest Group Meeting on “Transporter Evaluation in Drug Development.”
Transporters, like CYPs, are being recognized as proteins that can play a pivotal role in dictating the ADME properties of drugs. A thorough understanding of potential roles of transporters in drug interactions and toxicity is important in drug development. The talk provided a high level overview of various transporter evaluation initiatives at the agency. Some of the topics discussed:
• On-going efforts on decision trees within the DDI guidance
• Novel emerging transporters impacting ADME
• Inter-play of hepatic transporters and liver-toxicity
• Inter-play of renal transporters and renal function
- The CSRC has conducted a prospective study in collaboration with the IQ consortium to evaluate whether early QT assessment can replace a TQT study.
- The study assessed the effects of 6 marketed drugs on the QT interval using concentration-effect modeling in healthy volunteers.
- The results found that all 5 positive drugs met the criteria for demonstrating a drug-induced QT effect at the specified dose. The negative drug also met the criteria of excluding a QT effect above 10ms.
The document discusses immunosuppression in renal transplant patients. It explains that immunosuppression involves reducing the immune system's activation to prevent rejection of transplanted organs. Several immunosuppressive drug classes and agents are described, including corticosteroids, calcineurin inhibitors, mTOR inhibitors, antiproliferatives, and antibodies. The principles of immunosuppressive treatment include starting suppression before immunogen exposure, using multiple low-dose drugs to minimize toxicity risks from over-immunosuppression. Induction therapy provides potent initial suppression while maintenance therapy prevents long-term rejection.
This document provides an overview of the treatment of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). For AML, it discusses pre-treatment evaluation, induction therapy including various chemotherapy regimens, post-remission consolidation therapy stratified by risk factors, and management of relapsed or refractory disease. It also covers special situations in AML including differentiation syndrome, tumor lysis syndrome, and hyperleucocytosis. For CML, it outlines prognostic scoring, treatment goals, available tyrosine kinase inhibitors and their dosing and side effects, monitoring response levels, and options for treatment discontinuation or allogeneic stem cell transplant.
Exploring Compound Combinations in High Throughput Settings: Going Beyond 1D ...Rajarshi Guha
The document describes efforts to screen drug combinations in high throughput settings beyond traditional one-dimensional metrics. It discusses the infrastructure and workflows used to screen compound combinations against a library of over 2000 small molecules with diverse mechanisms of action. Quality control of combination screening experiments poses challenges due to the multi-dimensional nature of the data. The researchers are exploring various metrics and analytical approaches to characterize synergistic, additive and antagonistic combination responses across different cell lines and combinations.
This document provides an overview of various pathogen inactivation methods for blood components including plasma, platelets, red blood cells, and whole blood. It discusses both chemical and physical methods such as solvent-detergent treatment, methylene blue with light activation, amotosalen with UVA light, and riboflavin with UV light. The document outlines the mechanisms of action of these different methods and their effectiveness against various pathogens including viruses, bacteria, and parasites. It also notes some of the limitations of current pathogen inactivation technologies, such as potential damage to blood components and residual infectivity of some non-enveloped viruses.
1) The document discusses the use of protein and metabolite biomarkers in personalized healthcare, noting that over 100 biomarkers are now included in drug labels and 16 companion diagnostics are needed.
2) It describes how companion diagnostics can help determine a drug's metabolism, efficacy, or safety for a patient. Systems biology approaches that integrate multi-omic data are important for developing personalized treatment approaches.
3) The Radboud Center for Proteomics, Glycomics and Metabolomics performs various 'omics analyses including proteomics, glycoproteomics, metabolomics, and top-down proteomics to discover and validate biomarkers for personalized healthcare applications like diagnosing rare diseases, detecting inborn errors of metabolism, and characterizing
At the 7th World Congress of Diabetes Prevention and Its Complications, ISIC sponsored a session entitled, Good things in life: Can coffee help in diabetes prevention? Speakers at the conference session included Dr. Nathan Matusheski - Associate Principal Scientist, Mondelēz International.
See presentation for details
This document discusses organs-on-chips technology for evaluating drug efficacy and activity in vivo. It describes how organs-on-chips can model the absorption, distribution, metabolism, and excretion (ADME) processes using microfluidic cell culture chips that simulate organ functions. Specifically, it outlines efforts to develop intestinal, kidney, and liver chips to evaluate absorption, metabolism, and clearance. Linked organ chips are also discussed as a way to model organ crosstalk and better understand systemic drug effects. The technology shows promise for reducing animal testing and aiding drug development but challenges remain around replicating full organ complexity and quantifying kinetics.
Introduction to drug metabolism case studies for its impacts on drug discover...SAPA-GP
2014/10/02 SAPA-GP Webinar:
Introduction to drug metabolism case studies for its impacts on drug discovery and development
Zhoupeng Zhang
Dept of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism
Merck Research Laboratories
Sino-American Pharmaceutical Professionals Association (SAPA)
– A lecture for Medicinal Chemists
(October 2, 2014)
academic / small company collaborations for rare and neglected diseasesv2Sean Ekins
This document discusses academic and small company collaborations for rare and neglected diseases. It provides background on rare diseases, noting they affect 6-7% of the population in the US and less than 1 in 2000 people in Europe. Many rare diseases have a genetic origin. The document then focuses on specific rare diseases, including Sanfilippo Syndrome, a lysosomal storage disorder caused by deficiencies in certain enzymes. Potential treatment approaches for Sanfilippo Syndrome are discussed such as enzyme replacement therapy, gene therapy, and substrate reduction therapy. The document also discusses machine learning models to identify potential drug candidates for other rare and neglected tropical diseases such as tuberculosis, Chagas disease, and Ebola virus.
Trials in secondary progressive multiple sclerosis: design & efficiencyMS Trust
- The NHS reforms have established new structures including NHS England which commissions clinical services and is accountable for improving outcomes as outlined in the NHS Outcomes Framework.
- The framework includes overarching indicators related to preventing premature death, enhancing quality of life for people with long-term conditions, helping people recover from episodes of ill health or injury, and ensuring that people have a positive experience of care.
- The new system aims to improve quality, outcomes and experience of care but also faces challenges in coordinating services across new organizational boundaries and ensuring the needs of patients with long-term conditions like MS remain a priority.
therapeutic drug monitoring of antibioticsPathKind Labs
Therapeutic drug monitoring (TDM) of antibiotics aims to maximize efficacy and minimize toxicity through personalized dosing. TDM involves analyzing drug concentrations in biological fluids to guide dosing. It is most useful for drugs with a narrow therapeutic index or those where concentration correlates with response or toxicity. Common antibiotics monitored include aminoglycosides, vancomycin, linezolid, and daptomycin. Pharmacokinetic/pharmacodynamic principles guide TDM by correlating drug exposure measures like Cmax/MIC and AUC/MIC with treatment outcomes.
Endotoxin Testing is performed to ensure that injectable preparations and medical devices are free from pyrogens and safe for human use.
Pyrogens constitute a heterogeneous group of fever causing substances which comprise both microbial and non-microbial substances. The most potent and most widely known are the endotoxins or lipopolysaccharides (LPS), which are cell wall components of gram-negative bacteria. Gram-positive bacteria are also sources of pyrogens, in particular lipoteichoic acid (LTA), as are particles from yeasts and viruses. Non-microbial pyrogens often emanate from production environments. Small particles of packaging materials are a typical example.
Adam Weinglass and Mary Jo Wildey from Merck & Co. share their winning presentation from SLAS2017 in Washington, DC. Join the conversation in the SLAS Screen Design and Assay Technology Special Interest Group LinkedIn group at https://www.linkedin.com/groups/3867725.
Timothy Dawes of Genentech and Elliot Hui of the University of California, Irvine share their well-received presentation from SLAS2017 in Washington, DC.
David A. Weil, Ph.D, senior applications scientist with Agilent Technologies, presented "Identification of Potential Bioactive Leachables and Extractables from Plastic Lab Ware by using GC and LC Separation Methods linked with MS Detection."
Deploying Automated Workstreams and Computational Approaches for Generation of Toxicity Data Used for Hazard Identification, by Robert T. Dunn, II, Ph.D., DABT
JALA Editor-in-Chief Edward Kai-Hua Chow, Ph.D., of National University of Singapore shared step-by-step advice on how to design and write scientific research papers more clearly and effectively to improve their chances for successful publication at the recently held conference in Washington, DC. Learn what editors want, what they don't want and how reviewers evaluate manuscripts by reviewing slides from the session.
The document discusses two scientific journals - the Journal of Laboratory Automation (JALA) and the Journal of Biomolecular Screening (JBS). It provides information on their editors, impact factors, indexing in databases, scientific advisors and editorial boards. The goal of both journals is to publish research applying technological advances to scientific exploration and discovery of new therapeutics. Authors are encouraged to submit their work to these peer-reviewed, MEDLINE-indexed journals.
The Screen Design and Assay Technology SIG meeting at SLAS2014, January 22 in San Diego, featured a presentation by Wayne J. Levin of Predictum titled Design of Experiment Challenges & Opportunities. The slides and supplementary material are provided here.
The Sample Management SIG for 2014 will focus on (3) group discussions. These discussion topics were chosen based on the feedback from our SLAS2013 SIG. Each discussion topic will be an open forum to allow participants to contribute their ideas and personal insights. See the slides for more.
Dr. Edward Kai-Hua Chow, JALA Associate Editor/Asia and National University of Singapore, shares his SLAS2013 JALA and JBS Authors Workshop presentation. Learn more about these leading peer-reviewed journals, and then see Ed's tips for publication beginning on slide 16.
Can target-based drug discovery be reconciled with phenotypic assays in the context of drug repurposing? One of the questions discussed at the SLAS Drug Repurposing SIG meeting at SLAS2013.
This file includes the SLAS2013 presentations of Paul A. Johnston of University of Pittsburgh; Douglas Auld of Novartis Institutes for Biomedical Research; and Lisa Minor of In Vitro Strategies, LLC.
The Allotrope Foundation led discussion on building an open framework for laboratory data - recommending a holistic approach to build upon & promote industry standards & best practices by providing software that instantiates them.
More from SLAS (Society for Laboratory Automation and Screening) (12)
GraphRAG for Life Science to increase LLM accuracyTomaz Bratanic
GraphRAG for life science domain, where you retriever information from biomedical knowledge graphs using LLMs to increase the accuracy and performance of generated answers
Introduction of Cybersecurity with OSS at Code Europe 2024Hiroshi SHIBATA
I develop the Ruby programming language, RubyGems, and Bundler, which are package managers for Ruby. Today, I will introduce how to enhance the security of your application using open-source software (OSS) examples from Ruby and RubyGems.
The first topic is CVE (Common Vulnerabilities and Exposures). I have published CVEs many times. But what exactly is a CVE? I'll provide a basic understanding of CVEs and explain how to detect and handle vulnerabilities in OSS.
Next, let's discuss package managers. Package managers play a critical role in the OSS ecosystem. I'll explain how to manage library dependencies in your application.
I'll share insights into how the Ruby and RubyGems core team works to keep our ecosystem safe. By the end of this talk, you'll have a better understanding of how to safeguard your code.
Building Production Ready Search Pipelines with Spark and MilvusZilliz
Spark is the widely used ETL tool for processing, indexing and ingesting data to serving stack for search. Milvus is the production-ready open-source vector database. In this talk we will show how to use Spark to process unstructured data to extract vector representations, and push the vectors to Milvus vector database for search serving.
Let's Integrate MuleSoft RPA, COMPOSER, APM with AWS IDP along with Slackshyamraj55
Discover the seamless integration of RPA (Robotic Process Automation), COMPOSER, and APM with AWS IDP enhanced with Slack notifications. Explore how these technologies converge to streamline workflows, optimize performance, and ensure secure access, all while leveraging the power of AWS IDP and real-time communication via Slack notifications.
This presentation provides valuable insights into effective cost-saving techniques on AWS. Learn how to optimize your AWS resources by rightsizing, increasing elasticity, picking the right storage class, and choosing the best pricing model. Additionally, discover essential governance mechanisms to ensure continuous cost efficiency. Whether you are new to AWS or an experienced user, this presentation provides clear and practical tips to help you reduce your cloud costs and get the most out of your budget.
Unlock the Future of Search with MongoDB Atlas_ Vector Search Unleashed.pdfMalak Abu Hammad
Discover how MongoDB Atlas and vector search technology can revolutionize your application's search capabilities. This comprehensive presentation covers:
* What is Vector Search?
* Importance and benefits of vector search
* Practical use cases across various industries
* Step-by-step implementation guide
* Live demos with code snippets
* Enhancing LLM capabilities with vector search
* Best practices and optimization strategies
Perfect for developers, AI enthusiasts, and tech leaders. Learn how to leverage MongoDB Atlas to deliver highly relevant, context-aware search results, transforming your data retrieval process. Stay ahead in tech innovation and maximize the potential of your applications.
#MongoDB #VectorSearch #AI #SemanticSearch #TechInnovation #DataScience #LLM #MachineLearning #SearchTechnology
How to Interpret Trends in the Kalyan Rajdhani Mix Chart.pdfChart Kalyan
A Mix Chart displays historical data of numbers in a graphical or tabular form. The Kalyan Rajdhani Mix Chart specifically shows the results of a sequence of numbers over different periods.
Ivanti’s Patch Tuesday breakdown goes beyond patching your applications and brings you the intelligence and guidance needed to prioritize where to focus your attention first. Catch early analysis on our Ivanti blog, then join industry expert Chris Goettl for the Patch Tuesday Webinar Event. There we’ll do a deep dive into each of the bulletins and give guidance on the risks associated with the newly-identified vulnerabilities.
Digital Marketing Trends in 2024 | Guide for Staying AheadWask
https://www.wask.co/ebooks/digital-marketing-trends-in-2024
Feeling lost in the digital marketing whirlwind of 2024? Technology is changing, consumer habits are evolving, and staying ahead of the curve feels like a never-ending pursuit. This e-book is your compass. Dive into actionable insights to handle the complexities of modern marketing. From hyper-personalization to the power of user-generated content, learn how to build long-term relationships with your audience and unlock the secrets to success in the ever-shifting digital landscape.
Driving Business Innovation: Latest Generative AI Advancements & Success StorySafe Software
Are you ready to revolutionize how you handle data? Join us for a webinar where we’ll bring you up to speed with the latest advancements in Generative AI technology and discover how leveraging FME with tools from giants like Google Gemini, Amazon, and Microsoft OpenAI can supercharge your workflow efficiency.
During the hour, we’ll take you through:
Guest Speaker Segment with Hannah Barrington: Dive into the world of dynamic real estate marketing with Hannah, the Marketing Manager at Workspace Group. Hear firsthand how their team generates engaging descriptions for thousands of office units by integrating diverse data sources—from PDF floorplans to web pages—using FME transformers, like OpenAIVisionConnector and AnthropicVisionConnector. This use case will show you how GenAI can streamline content creation for marketing across the board.
Ollama Use Case: Learn how Scenario Specialist Dmitri Bagh has utilized Ollama within FME to input data, create custom models, and enhance security protocols. This segment will include demos to illustrate the full capabilities of FME in AI-driven processes.
Custom AI Models: Discover how to leverage FME to build personalized AI models using your data. Whether it’s populating a model with local data for added security or integrating public AI tools, find out how FME facilitates a versatile and secure approach to AI.
We’ll wrap up with a live Q&A session where you can engage with our experts on your specific use cases, and learn more about optimizing your data workflows with AI.
This webinar is ideal for professionals seeking to harness the power of AI within their data management systems while ensuring high levels of customization and security. Whether you're a novice or an expert, gain actionable insights and strategies to elevate your data processes. Join us to see how FME and AI can revolutionize how you work with data!
Monitoring and Managing Anomaly Detection on OpenShift.pdfTosin Akinosho
Monitoring and Managing Anomaly Detection on OpenShift
Overview
Dive into the world of anomaly detection on edge devices with our comprehensive hands-on tutorial. This SlideShare presentation will guide you through the entire process, from data collection and model training to edge deployment and real-time monitoring. Perfect for those looking to implement robust anomaly detection systems on resource-constrained IoT/edge devices.
Key Topics Covered
1. Introduction to Anomaly Detection
- Understand the fundamentals of anomaly detection and its importance in identifying unusual behavior or failures in systems.
2. Understanding Edge (IoT)
- Learn about edge computing and IoT, and how they enable real-time data processing and decision-making at the source.
3. What is ArgoCD?
- Discover ArgoCD, a declarative, GitOps continuous delivery tool for Kubernetes, and its role in deploying applications on edge devices.
4. Deployment Using ArgoCD for Edge Devices
- Step-by-step guide on deploying anomaly detection models on edge devices using ArgoCD.
5. Introduction to Apache Kafka and S3
- Explore Apache Kafka for real-time data streaming and Amazon S3 for scalable storage solutions.
6. Viewing Kafka Messages in the Data Lake
- Learn how to view and analyze Kafka messages stored in a data lake for better insights.
7. What is Prometheus?
- Get to know Prometheus, an open-source monitoring and alerting toolkit, and its application in monitoring edge devices.
8. Monitoring Application Metrics with Prometheus
- Detailed instructions on setting up Prometheus to monitor the performance and health of your anomaly detection system.
9. What is Camel K?
- Introduction to Camel K, a lightweight integration framework built on Apache Camel, designed for Kubernetes.
10. Configuring Camel K Integrations for Data Pipelines
- Learn how to configure Camel K for seamless data pipeline integrations in your anomaly detection workflow.
11. What is a Jupyter Notebook?
- Overview of Jupyter Notebooks, an open-source web application for creating and sharing documents with live code, equations, visualizations, and narrative text.
12. Jupyter Notebooks with Code Examples
- Hands-on examples and code snippets in Jupyter Notebooks to help you implement and test anomaly detection models.
In the rapidly evolving landscape of technologies, XML continues to play a vital role in structuring, storing, and transporting data across diverse systems. The recent advancements in artificial intelligence (AI) present new methodologies for enhancing XML development workflows, introducing efficiency, automation, and intelligent capabilities. This presentation will outline the scope and perspective of utilizing AI in XML development. The potential benefits and the possible pitfalls will be highlighted, providing a balanced view of the subject.
We will explore the capabilities of AI in understanding XML markup languages and autonomously creating structured XML content. Additionally, we will examine the capacity of AI to enrich plain text with appropriate XML markup. Practical examples and methodological guidelines will be provided to elucidate how AI can be effectively prompted to interpret and generate accurate XML markup.
Further emphasis will be placed on the role of AI in developing XSLT, or schemas such as XSD and Schematron. We will address the techniques and strategies adopted to create prompts for generating code, explaining code, or refactoring the code, and the results achieved.
The discussion will extend to how AI can be used to transform XML content. In particular, the focus will be on the use of AI XPath extension functions in XSLT, Schematron, Schematron Quick Fixes, or for XML content refactoring.
The presentation aims to deliver a comprehensive overview of AI usage in XML development, providing attendees with the necessary knowledge to make informed decisions. Whether you’re at the early stages of adopting AI or considering integrating it in advanced XML development, this presentation will cover all levels of expertise.
By highlighting the potential advantages and challenges of integrating AI with XML development tools and languages, the presentation seeks to inspire thoughtful conversation around the future of XML development. We’ll not only delve into the technical aspects of AI-powered XML development but also discuss practical implications and possible future directions.
TrustArc Webinar - 2024 Global Privacy SurveyTrustArc
How does your privacy program stack up against your peers? What challenges are privacy teams tackling and prioritizing in 2024?
In the fifth annual Global Privacy Benchmarks Survey, we asked over 1,800 global privacy professionals and business executives to share their perspectives on the current state of privacy inside and outside of their organizations. This year’s report focused on emerging areas of importance for privacy and compliance professionals, including considerations and implications of Artificial Intelligence (AI) technologies, building brand trust, and different approaches for achieving higher privacy competence scores.
See how organizational priorities and strategic approaches to data security and privacy are evolving around the globe.
This webinar will review:
- The top 10 privacy insights from the fifth annual Global Privacy Benchmarks Survey
- The top challenges for privacy leaders, practitioners, and organizations in 2024
- Key themes to consider in developing and maintaining your privacy program