The document discusses targeted drug delivery systems to the brain. It describes three key points:
1. Traditional drug delivery methods like direct injection into cerebrospinal fluid or disrupting the blood-brain barrier are invasive and have toxic side effects.
2. A better approach is to use chemical delivery systems (CDS) that exploit properties of the blood-brain barrier. CDS are designed to be lipophilic to cross the barrier then undergo enzymatic changes within the brain to increase retention and decrease peripheral distribution.
3. Dihydropyridine is proposed as a "redox targeter" functional group on a CDS that can be enzymatically oxidized within the brain to a charged, water soluble form
Prodrug approaches for cns delivery ppt finished copyAtul Thakur
This document discusses prodrug approaches for central nervous system (CNS) drug delivery. It covers various prodrug concepts including increasing lipophilicity to enhance passive diffusion across the blood-brain barrier (BBB), utilizing endogenous transporters for carrier-mediated delivery, overcoming efflux transport, and antibody or gene-directed targeted therapies. The key roles of prodrug bioconversion kinetics and competing elimination processes are also addressed. Overall, the document provides an overview of rational chemistry and biology-based strategies to improve brain delivery of CNS therapeutics.
Drug targeting aims to selectively deliver drugs to pathological sites to increase efficacy and reduce side effects. Current drug administration leads to non-specific distribution and requires high doses. Drug targeting strategies include direct application to affected areas, passive targeting of leaky vasculature, physical targeting of abnormal pH/temperature, magnetic targeting, and use of targeting moieties like antibodies. Challenges to brain targeting include the blood-brain barrier. Approaches involve going through or behind the barrier using invasive methods, carrier systems, prodrugs, or chemical delivery systems exploiting enzyme pathways.
This document provides an overview of pharmacology concepts including:
- Pharmacokinetics describes what the body does to drugs through absorption, distribution, metabolism and excretion.
- Pharmacodynamics describes what drugs do to the body through receptor interactions and clinical effects.
- Key pharmacokinetic processes like absorption, distribution, metabolism and elimination are influenced by drug and body factors and determine drug availability at target sites.
The document discusses various approaches for targeted drug delivery to the brain. It begins by describing the different barriers in the brain, including the blood-brain barrier, blood-cerebrospinal fluid barrier, and blood-tumor barrier. Both invasive and non-invasive approaches are then outlined. Invasive approaches involve direct administration into the brain or cerebrospinal fluid, while non-invasive approaches utilize drug modifications or colloidal carriers like nanoparticles and liposomes to cross the blood-brain barrier. The techniques each have benefits but also limitations around toxicity, stability, and production costs that must be considered for effective brain-targeted drug delivery.
Brain Targeted Drug Delivery System
Prepared by :
Surbhi
M.Pharmacy II sem
Submitted to :
Dr. Anupama Diwan
MAGIC BULLET : CONCEPT OF PAUL EHRLICH
Brain Targeting: Challenges
Blood brain barrier (BBB): Brain is tightly segregated from the circulating blood by a unique membranous barrier.
The brain and spinal cord are lined with a layer of special endothelial cells that lack fenestrations and are sealed with tight junctions that greatly restrict passage of substances from the bloodstream.
These endothelial cells, together with perivascular elements such as astrocytes and pericytes, constitute the BBB.
Rate-limiting factor in determining permeation.
The factors affecting particular substance to cross BBB
Drug related factors at the BBB
Concentration at the BBB and the size,
Flexibility,
Conformation,
Ionization (nonionized form penetrates BBB)
Lipophilicity of the drug molecule,
Cellular enzyme stability and cellular sequestration,
Affinity for efflux mechanisms (i.e. P-glycoprotein),
Hydrogen bonding potential (i.e. charge),
Affinity for carrier mechanisms, and
Effect on all of the above by the existing pathological conditions
Transport Mechanisms
Several specialized transport mechanisms of solute transfer across endothelial cells and into the brain interstitium are also present within the BBB Carrier system for monosaccharides, monocarboxylic acid, neutral amino acids, basic amino acid, acidic amino acids, amines, purine bases, nucleosides, vitamins and hormones.
The more lipophilic substances that are present in the blood can diffuse passively directly through the lipid of the cell membrane and enter the endothelial cells and brain by this means.
Strategies for Brain Targeting Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB.
Neurosurgical or Invasive Strategies
BBB disruption :Disruption of BBB by osmotic means (Hyperosmolar solutions),
Intraventricular drug infusion
Intracerebral Implants: Biodegradable implants,
Physiologic based Strategies
Psuedo nutrients eg L-dopa
Cationic antibodies.These undergo Absorption mediated trancytosis through BBB owing to positive charge.
Chimeric peptides.
Drug distribution refers to the reversible transfer of drugs from the bloodstream to tissues throughout the body. Once absorbed, drugs diffuse from areas of high concentration (blood) to areas of lower concentration (tissues). This process continues until equilibrium is reached.
The rate and extent of distribution is influenced by several factors. These include a drug's physicochemical properties like size and solubility, tissue permeability, blood flow to organs, and binding of drugs to plasma proteins and tissues. Physiological barriers like the blood-brain barrier also control distribution to certain tissues. The non-uniform distribution of drugs throughout the body is due to tissues absorbing drugs at different rates and to varying extents based on these distribution factors.
This document discusses various approaches for delivering drugs to the brain by bypassing the blood-brain barrier (BBB). It describes invasive approaches like convection-enhanced delivery which involves inserting a catheter into the brain. It also discusses pharmacological, physiological, and prodrug approaches. Various carrier systems are covered like liposomes, nanoparticles, monoclonal antibodies, and colloidal carriers. The mechanisms of transport through the BBB like endocytosis, receptor-mediated transcytosis, and adsorption are also summarized. Overall, the document provides a comprehensive overview of the challenges of brain drug delivery and different strategies researchers are exploring to enhance transport of therapeutics across the BBB.
This document provides an overview of pharmacokinetics, which is the study of what the body does to a drug. It discusses the key processes of absorption, distribution, metabolism, and excretion (ADME). Absorption refers to how a drug enters the bloodstream from the site of administration. Distribution is the movement of drug between tissues. Metabolism involves chemical modification of drugs by the body. Excretion is the removal of drugs and metabolites from the body, mainly through the kidneys and liver. Understanding these pharmacokinetic processes is important for optimizing drug dosing and minimizing toxicity.
Prodrug approaches for cns delivery ppt finished copyAtul Thakur
This document discusses prodrug approaches for central nervous system (CNS) drug delivery. It covers various prodrug concepts including increasing lipophilicity to enhance passive diffusion across the blood-brain barrier (BBB), utilizing endogenous transporters for carrier-mediated delivery, overcoming efflux transport, and antibody or gene-directed targeted therapies. The key roles of prodrug bioconversion kinetics and competing elimination processes are also addressed. Overall, the document provides an overview of rational chemistry and biology-based strategies to improve brain delivery of CNS therapeutics.
Drug targeting aims to selectively deliver drugs to pathological sites to increase efficacy and reduce side effects. Current drug administration leads to non-specific distribution and requires high doses. Drug targeting strategies include direct application to affected areas, passive targeting of leaky vasculature, physical targeting of abnormal pH/temperature, magnetic targeting, and use of targeting moieties like antibodies. Challenges to brain targeting include the blood-brain barrier. Approaches involve going through or behind the barrier using invasive methods, carrier systems, prodrugs, or chemical delivery systems exploiting enzyme pathways.
This document provides an overview of pharmacology concepts including:
- Pharmacokinetics describes what the body does to drugs through absorption, distribution, metabolism and excretion.
- Pharmacodynamics describes what drugs do to the body through receptor interactions and clinical effects.
- Key pharmacokinetic processes like absorption, distribution, metabolism and elimination are influenced by drug and body factors and determine drug availability at target sites.
The document discusses various approaches for targeted drug delivery to the brain. It begins by describing the different barriers in the brain, including the blood-brain barrier, blood-cerebrospinal fluid barrier, and blood-tumor barrier. Both invasive and non-invasive approaches are then outlined. Invasive approaches involve direct administration into the brain or cerebrospinal fluid, while non-invasive approaches utilize drug modifications or colloidal carriers like nanoparticles and liposomes to cross the blood-brain barrier. The techniques each have benefits but also limitations around toxicity, stability, and production costs that must be considered for effective brain-targeted drug delivery.
Brain Targeted Drug Delivery System
Prepared by :
Surbhi
M.Pharmacy II sem
Submitted to :
Dr. Anupama Diwan
MAGIC BULLET : CONCEPT OF PAUL EHRLICH
Brain Targeting: Challenges
Blood brain barrier (BBB): Brain is tightly segregated from the circulating blood by a unique membranous barrier.
The brain and spinal cord are lined with a layer of special endothelial cells that lack fenestrations and are sealed with tight junctions that greatly restrict passage of substances from the bloodstream.
These endothelial cells, together with perivascular elements such as astrocytes and pericytes, constitute the BBB.
Rate-limiting factor in determining permeation.
The factors affecting particular substance to cross BBB
Drug related factors at the BBB
Concentration at the BBB and the size,
Flexibility,
Conformation,
Ionization (nonionized form penetrates BBB)
Lipophilicity of the drug molecule,
Cellular enzyme stability and cellular sequestration,
Affinity for efflux mechanisms (i.e. P-glycoprotein),
Hydrogen bonding potential (i.e. charge),
Affinity for carrier mechanisms, and
Effect on all of the above by the existing pathological conditions
Transport Mechanisms
Several specialized transport mechanisms of solute transfer across endothelial cells and into the brain interstitium are also present within the BBB Carrier system for monosaccharides, monocarboxylic acid, neutral amino acids, basic amino acid, acidic amino acids, amines, purine bases, nucleosides, vitamins and hormones.
The more lipophilic substances that are present in the blood can diffuse passively directly through the lipid of the cell membrane and enter the endothelial cells and brain by this means.
Strategies for Brain Targeting Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB.
Neurosurgical or Invasive Strategies
BBB disruption :Disruption of BBB by osmotic means (Hyperosmolar solutions),
Intraventricular drug infusion
Intracerebral Implants: Biodegradable implants,
Physiologic based Strategies
Psuedo nutrients eg L-dopa
Cationic antibodies.These undergo Absorption mediated trancytosis through BBB owing to positive charge.
Chimeric peptides.
Drug distribution refers to the reversible transfer of drugs from the bloodstream to tissues throughout the body. Once absorbed, drugs diffuse from areas of high concentration (blood) to areas of lower concentration (tissues). This process continues until equilibrium is reached.
The rate and extent of distribution is influenced by several factors. These include a drug's physicochemical properties like size and solubility, tissue permeability, blood flow to organs, and binding of drugs to plasma proteins and tissues. Physiological barriers like the blood-brain barrier also control distribution to certain tissues. The non-uniform distribution of drugs throughout the body is due to tissues absorbing drugs at different rates and to varying extents based on these distribution factors.
This document discusses various approaches for delivering drugs to the brain by bypassing the blood-brain barrier (BBB). It describes invasive approaches like convection-enhanced delivery which involves inserting a catheter into the brain. It also discusses pharmacological, physiological, and prodrug approaches. Various carrier systems are covered like liposomes, nanoparticles, monoclonal antibodies, and colloidal carriers. The mechanisms of transport through the BBB like endocytosis, receptor-mediated transcytosis, and adsorption are also summarized. Overall, the document provides a comprehensive overview of the challenges of brain drug delivery and different strategies researchers are exploring to enhance transport of therapeutics across the BBB.
This document provides an overview of pharmacokinetics, which is the study of what the body does to a drug. It discusses the key processes of absorption, distribution, metabolism, and excretion (ADME). Absorption refers to how a drug enters the bloodstream from the site of administration. Distribution is the movement of drug between tissues. Metabolism involves chemical modification of drugs by the body. Excretion is the removal of drugs and metabolites from the body, mainly through the kidneys and liver. Understanding these pharmacokinetic processes is important for optimizing drug dosing and minimizing toxicity.
Liposomes are spherical vesicles composed of phospholipid bilayers that can be used to deliver drugs. They can encapsulate both hydrophobic and hydrophilic drugs within their bilayers or aqueous core. This allows for sustained release and targeted delivery of many therapeutic agents. However, liposomes also have limitations including stability issues, difficulty sterilizing, incomplete drug encapsulation, challenges with active targeting, and lysosomal degradation breaking down gene therapy.
Liposomes are spherical vesicles composed of lipids that can be used to deliver drugs in the body. They encapsulate drugs inside an aqueous core surrounded by a lipid bilayer membrane. This allows drugs both hydrophilic and hydrophobic drugs to be delivered. Liposomes have several applications including improving drug solubility, increasing intracellular drug delivery, providing sustained release, and reducing toxicity to healthy tissues by altering biodistribution. However, stability, sterilization, encapsulation efficiency, targeting ability, and lysosomal degradation limit their effectiveness. Doxil and AmBisome are two liposomal drug formulations that are approved and able to deliver higher doses of drugs while reducing toxicity compared to free drug formulations.
Liposomes are spherical vesicles composed of phospholipid bilayers that can be used to deliver drugs. They can encapsulate both hydrophobic and hydrophilic drugs and target delivery to specific sites. Some advantages include improved drug solubility, sustained release, reduced toxicity, and increased intracellular delivery. However, stability, sterilization, encapsulation efficiency, targeting, and lysosomal degradation present challenges. Doxorubicin and amphotericin B liposome formulations are approved to treat cancer and fungal infections by reducing toxicity compared to free drug formulations.
The document discusses drug distribution, which refers to the reversible transfer of drugs from the blood compartment to other tissue compartments. Several factors affect drug distribution, including tissue permeability, organ size/perfusion rate, and binding to tissue components. Drugs move from areas of high concentration (blood) to low concentration (tissues) until equilibrium is reached. The apparent volume of distribution is a measure relating the amount of drug in the body to its plasma concentration. Physiological barriers like the blood-brain barrier can restrict distribution of some drugs to certain tissues. Disease states and drug interactions can also impact a drug's distribution profile in the body.
This document discusses drug distribution, which refers to the reversible transfer of drugs between compartments, primarily between blood and extravascular tissues. It describes the steps in drug distribution, from permeation of blood vessels into interstitial fluid and intracellular fluid. Factors that affect distribution include tissue permeability, organ perfusion rates, protein binding, and physiological barriers like the blood-brain barrier. Methods for studying distribution patterns include using specific tracers to measure fluid compartment volumes and microdialysis to sample extracellular fluids.
Presentation covers the basics of pharmacokinetic. Mechanism for the transport of drug molecule. Absorption, factors affecting on absorption of drugs. Concept of bioavailability. Distribution, plasma protein binding, tissue binding, barriers.
Liposomes are spherical vesicles that can be used to deliver drugs in the body. They consist of lipid bilayers that encapsulate an aqueous core, allowing both hydrophilic and hydrophobic drugs to be carried. Liposomes have several applications in drug delivery such as improving drug solubility, providing sustained release, and increasing intracellular drug levels. However, stability, sterilization, and drug leakage pose challenges to their use. Currently, liposomal formulations of doxorubicin and amphotericin B are approved to deliver these drugs while reducing toxicity.
The document summarizes various approaches for brain targeted drug delivery to bypass the blood-brain barrier (BBB). It discusses the invasive approach using intracerebroventricular infusion and convection-enhanced delivery. The pharmacological approach modifies drug properties for passive diffusion. The physiological approach uses receptor-mediated transcytosis. Non-invasive approaches include prodrugs, drug conjugates, monoclonal antibodies, receptor-mediated transport, liposomes, nanoparticles, and colloidal carriers coated with surfactants to mimic LDL transport across BBB. The goal is to develop safe and effective strategies for delivering therapeutics to the brain.
This document provides an overview of general pharmacology and pharmacokinetics, with a focus on drug distribution. It defines drug distribution and describes how various factors influence it, including tissue permeability, organ size and perfusion rate, binding to blood and tissue components, and other miscellaneous factors like age and disease state. Specific barriers to drug distribution like the blood-brain barrier are also explained. The role of plasma and tissue protein binding in determining a drug's volume of distribution is discussed.
Several methods making drugs overcome blood-brain barier obstacle .Abeer Abd Elrahman
The blood-brain barrier represents a major obstacle to delivering drugs to the central nervous system. Several methods have been attempted to overcome this barrier, including using exosomes, prodrugs, polymer encapsulation, receptor-mediated transport, modifying surface charge, and transiently disrupting the barrier using chemical agents, focused ultrasound, or magnetic fields. Encapsulating drugs within biodegradable polymers like PLGA allows them to accumulate in brain tumors at higher levels compared to healthy brain tissue.
This document discusses factors that affect drug distribution in the body. It explains that drug distribution involves drugs leaving the bloodstream and entering tissues, and is determined by a drug's physicochemical properties and ability to cross membranes. Key factors discussed include lipid solubility, plasma protein binding, tissue binding, cardiac output, tissue perfusion, and barriers like the blood-brain and placental barriers. The concepts of volume of distribution and its implications for dosage are also introduced.
This document describes five physicochemical groups of drugs based on their properties. Lipid soluble drugs are highly absorbed, rapidly distribute throughout the body including into tissues and the brain limited by blood flow, are highly protein bound in plasma and tissues, have low concentrations in the glomerular filtrate which are reabsorbed, and can be eliminated unchanged in expired air or through hepatic metabolism to more polar metabolites.
This document describes five physicochemical groups of drugs based on their solubility properties and how they are handled by the body. It provides Gentamicin, an aminoglycoside antibiotic, as an example of a water soluble drug that is restricted to extracellular fluid, eliminated unchanged in urine, and not affected by plasma protein binding. Digoxin is presented as an intermediate drug that is absorbed from the gut, distributes to tissues including intracellular fluid, is influenced by protein binding, and eliminated through both urine and metabolism. Phenytoin is used to illustrate lipid soluble drugs that are readily absorbed, rapidly distribute throughout the body including into the brain, are highly protein bound, and extensively metabolized in the liver.
Distribution involves the movement of drugs through the body via absorption, transport through capillaries, penetration of cells, and excretion. The main compartments that the body's water is distributed in are the extracellular, interstitial, intracellular, transcellular, and blood compartments. Factors that affect a drug's distribution include its binding to plasma proteins, the blood flow to different organs, its ability to bind to cells, its concentration in fatty tissues, redistribution from tissues to plasma, and its ability to cross tissue barriers like the blood-brain barrier. A drug's fat-water partition coefficient determines how much it will distribute to fatty tissues versus water-based tissues.
This document discusses factors that influence drug absorption from various routes of administration. It begins by defining biopharmaceutics as the study of how drug properties, dosage forms, and administration routes affect drug absorption rate and extent. Several routes of administration are then described in detail, including oral, intravenous, intramuscular, subcutaneous, and topical. Key concepts like bioavailability, first-pass effect, and factors influencing membrane transport are also summarized. The goal of drug administration routes is to attain therapeutic drug concentrations in plasma or tissues.
The document discusses pharmacokinetics, which is the quantitative study of how drugs move through the body. It covers the key processes of absorption, distribution, metabolism, and excretion (ADME) that drugs undergo. Absorption governs how drugs enter circulation after administration. Distribution determines where drugs go in tissues. Metabolism, or biotransformation, alters drugs' chemical structures, often making them more water-soluble for excretion. These processes determine a drug's effects over time.
This document provides an overview of pharmacokinetic principles including definitions of pharmacology and pharmacokinetics. It describes how drugs are absorbed, distributed, and eliminated in the body. Key points include how drugs pass through membranes via passive diffusion, active transport, or vesicles. Distribution depends on plasma protein binding, tissue binding, and physicochemical properties. The liver and kidneys aid in drug metabolism and excretion from the body. Factors like pH, blood flow, dosage form, and route of administration influence drug absorption and disposition.
Pharmacokinetics and Pharmacodynamics -SandeepSandeep Kandel
This document discusses principles of pharmacokinetics and pharmacodynamics. Pharmacokinetics refers to what the body does to a drug, including absorption, distribution, metabolism and excretion. Absorption is the transfer of a drug from its site of administration into the bloodstream. Distribution is when a drug leaves the bloodstream and enters tissues. Metabolism biotransforms drugs in the liver or other tissues. Excretion eliminates drugs and metabolites through urine, bile or feces. Pharmacodynamics is what the drug does to the body, like its physiological effects and interactions with receptors or enzymes.
Liposomes are spherical vesicles composed of phospholipid bilayers that can be used to deliver drugs. They can encapsulate both hydrophobic and hydrophilic drugs within their bilayers or aqueous core. This allows for sustained release and targeted delivery of many therapeutic agents. However, liposomes also have limitations including stability issues, difficulty sterilizing, incomplete drug encapsulation, challenges with active targeting, and lysosomal degradation breaking down gene therapy.
Liposomes are spherical vesicles composed of lipids that can be used to deliver drugs in the body. They encapsulate drugs inside an aqueous core surrounded by a lipid bilayer membrane. This allows drugs both hydrophilic and hydrophobic drugs to be delivered. Liposomes have several applications including improving drug solubility, increasing intracellular drug delivery, providing sustained release, and reducing toxicity to healthy tissues by altering biodistribution. However, stability, sterilization, encapsulation efficiency, targeting ability, and lysosomal degradation limit their effectiveness. Doxil and AmBisome are two liposomal drug formulations that are approved and able to deliver higher doses of drugs while reducing toxicity compared to free drug formulations.
Liposomes are spherical vesicles composed of phospholipid bilayers that can be used to deliver drugs. They can encapsulate both hydrophobic and hydrophilic drugs and target delivery to specific sites. Some advantages include improved drug solubility, sustained release, reduced toxicity, and increased intracellular delivery. However, stability, sterilization, encapsulation efficiency, targeting, and lysosomal degradation present challenges. Doxorubicin and amphotericin B liposome formulations are approved to treat cancer and fungal infections by reducing toxicity compared to free drug formulations.
The document discusses drug distribution, which refers to the reversible transfer of drugs from the blood compartment to other tissue compartments. Several factors affect drug distribution, including tissue permeability, organ size/perfusion rate, and binding to tissue components. Drugs move from areas of high concentration (blood) to low concentration (tissues) until equilibrium is reached. The apparent volume of distribution is a measure relating the amount of drug in the body to its plasma concentration. Physiological barriers like the blood-brain barrier can restrict distribution of some drugs to certain tissues. Disease states and drug interactions can also impact a drug's distribution profile in the body.
This document discusses drug distribution, which refers to the reversible transfer of drugs between compartments, primarily between blood and extravascular tissues. It describes the steps in drug distribution, from permeation of blood vessels into interstitial fluid and intracellular fluid. Factors that affect distribution include tissue permeability, organ perfusion rates, protein binding, and physiological barriers like the blood-brain barrier. Methods for studying distribution patterns include using specific tracers to measure fluid compartment volumes and microdialysis to sample extracellular fluids.
Presentation covers the basics of pharmacokinetic. Mechanism for the transport of drug molecule. Absorption, factors affecting on absorption of drugs. Concept of bioavailability. Distribution, plasma protein binding, tissue binding, barriers.
Liposomes are spherical vesicles that can be used to deliver drugs in the body. They consist of lipid bilayers that encapsulate an aqueous core, allowing both hydrophilic and hydrophobic drugs to be carried. Liposomes have several applications in drug delivery such as improving drug solubility, providing sustained release, and increasing intracellular drug levels. However, stability, sterilization, and drug leakage pose challenges to their use. Currently, liposomal formulations of doxorubicin and amphotericin B are approved to deliver these drugs while reducing toxicity.
The document summarizes various approaches for brain targeted drug delivery to bypass the blood-brain barrier (BBB). It discusses the invasive approach using intracerebroventricular infusion and convection-enhanced delivery. The pharmacological approach modifies drug properties for passive diffusion. The physiological approach uses receptor-mediated transcytosis. Non-invasive approaches include prodrugs, drug conjugates, monoclonal antibodies, receptor-mediated transport, liposomes, nanoparticles, and colloidal carriers coated with surfactants to mimic LDL transport across BBB. The goal is to develop safe and effective strategies for delivering therapeutics to the brain.
This document provides an overview of general pharmacology and pharmacokinetics, with a focus on drug distribution. It defines drug distribution and describes how various factors influence it, including tissue permeability, organ size and perfusion rate, binding to blood and tissue components, and other miscellaneous factors like age and disease state. Specific barriers to drug distribution like the blood-brain barrier are also explained. The role of plasma and tissue protein binding in determining a drug's volume of distribution is discussed.
Several methods making drugs overcome blood-brain barier obstacle .Abeer Abd Elrahman
The blood-brain barrier represents a major obstacle to delivering drugs to the central nervous system. Several methods have been attempted to overcome this barrier, including using exosomes, prodrugs, polymer encapsulation, receptor-mediated transport, modifying surface charge, and transiently disrupting the barrier using chemical agents, focused ultrasound, or magnetic fields. Encapsulating drugs within biodegradable polymers like PLGA allows them to accumulate in brain tumors at higher levels compared to healthy brain tissue.
This document discusses factors that affect drug distribution in the body. It explains that drug distribution involves drugs leaving the bloodstream and entering tissues, and is determined by a drug's physicochemical properties and ability to cross membranes. Key factors discussed include lipid solubility, plasma protein binding, tissue binding, cardiac output, tissue perfusion, and barriers like the blood-brain and placental barriers. The concepts of volume of distribution and its implications for dosage are also introduced.
This document describes five physicochemical groups of drugs based on their properties. Lipid soluble drugs are highly absorbed, rapidly distribute throughout the body including into tissues and the brain limited by blood flow, are highly protein bound in plasma and tissues, have low concentrations in the glomerular filtrate which are reabsorbed, and can be eliminated unchanged in expired air or through hepatic metabolism to more polar metabolites.
This document describes five physicochemical groups of drugs based on their solubility properties and how they are handled by the body. It provides Gentamicin, an aminoglycoside antibiotic, as an example of a water soluble drug that is restricted to extracellular fluid, eliminated unchanged in urine, and not affected by plasma protein binding. Digoxin is presented as an intermediate drug that is absorbed from the gut, distributes to tissues including intracellular fluid, is influenced by protein binding, and eliminated through both urine and metabolism. Phenytoin is used to illustrate lipid soluble drugs that are readily absorbed, rapidly distribute throughout the body including into the brain, are highly protein bound, and extensively metabolized in the liver.
Distribution involves the movement of drugs through the body via absorption, transport through capillaries, penetration of cells, and excretion. The main compartments that the body's water is distributed in are the extracellular, interstitial, intracellular, transcellular, and blood compartments. Factors that affect a drug's distribution include its binding to plasma proteins, the blood flow to different organs, its ability to bind to cells, its concentration in fatty tissues, redistribution from tissues to plasma, and its ability to cross tissue barriers like the blood-brain barrier. A drug's fat-water partition coefficient determines how much it will distribute to fatty tissues versus water-based tissues.
This document discusses factors that influence drug absorption from various routes of administration. It begins by defining biopharmaceutics as the study of how drug properties, dosage forms, and administration routes affect drug absorption rate and extent. Several routes of administration are then described in detail, including oral, intravenous, intramuscular, subcutaneous, and topical. Key concepts like bioavailability, first-pass effect, and factors influencing membrane transport are also summarized. The goal of drug administration routes is to attain therapeutic drug concentrations in plasma or tissues.
The document discusses pharmacokinetics, which is the quantitative study of how drugs move through the body. It covers the key processes of absorption, distribution, metabolism, and excretion (ADME) that drugs undergo. Absorption governs how drugs enter circulation after administration. Distribution determines where drugs go in tissues. Metabolism, or biotransformation, alters drugs' chemical structures, often making them more water-soluble for excretion. These processes determine a drug's effects over time.
This document provides an overview of pharmacokinetic principles including definitions of pharmacology and pharmacokinetics. It describes how drugs are absorbed, distributed, and eliminated in the body. Key points include how drugs pass through membranes via passive diffusion, active transport, or vesicles. Distribution depends on plasma protein binding, tissue binding, and physicochemical properties. The liver and kidneys aid in drug metabolism and excretion from the body. Factors like pH, blood flow, dosage form, and route of administration influence drug absorption and disposition.
Pharmacokinetics and Pharmacodynamics -SandeepSandeep Kandel
This document discusses principles of pharmacokinetics and pharmacodynamics. Pharmacokinetics refers to what the body does to a drug, including absorption, distribution, metabolism and excretion. Absorption is the transfer of a drug from its site of administration into the bloodstream. Distribution is when a drug leaves the bloodstream and enters tissues. Metabolism biotransforms drugs in the liver or other tissues. Excretion eliminates drugs and metabolites through urine, bile or feces. Pharmacodynamics is what the drug does to the body, like its physiological effects and interactions with receptors or enzymes.
The cost of acquiring information by natural selectionCarl Bergstrom
This is a short talk that I gave at the Banff International Research Station workshop on Modeling and Theory in Population Biology. The idea is to try to understand how the burden of natural selection relates to the amount of information that selection puts into the genome.
It's based on the first part of this research paper:
The cost of information acquisition by natural selection
Ryan Seamus McGee, Olivia Kosterlitz, Artem Kaznatcheev, Benjamin Kerr, Carl T. Bergstrom
bioRxiv 2022.07.02.498577; doi: https://doi.org/10.1101/2022.07.02.498577
Describing and Interpreting an Immersive Learning Case with the Immersion Cub...Leonel Morgado
Current descriptions of immersive learning cases are often difficult or impossible to compare. This is due to a myriad of different options on what details to include, which aspects are relevant, and on the descriptive approaches employed. Also, these aspects often combine very specific details with more general guidelines or indicate intents and rationales without clarifying their implementation. In this paper we provide a method to describe immersive learning cases that is structured to enable comparisons, yet flexible enough to allow researchers and practitioners to decide which aspects to include. This method leverages a taxonomy that classifies educational aspects at three levels (uses, practices, and strategies) and then utilizes two frameworks, the Immersive Learning Brain and the Immersion Cube, to enable a structured description and interpretation of immersive learning cases. The method is then demonstrated on a published immersive learning case on training for wind turbine maintenance using virtual reality. Applying the method results in a structured artifact, the Immersive Learning Case Sheet, that tags the case with its proximal uses, practices, and strategies, and refines the free text case description to ensure that matching details are included. This contribution is thus a case description method in support of future comparative research of immersive learning cases. We then discuss how the resulting description and interpretation can be leveraged to change immersion learning cases, by enriching them (considering low-effort changes or additions) or innovating (exploring more challenging avenues of transformation). The method holds significant promise to support better-grounded research in immersive learning.
The use of Nauplii and metanauplii artemia in aquaculture (brine shrimp).pptxMAGOTI ERNEST
Although Artemia has been known to man for centuries, its use as a food for the culture of larval organisms apparently began only in the 1930s, when several investigators found that it made an excellent food for newly hatched fish larvae (Litvinenko et al., 2023). As aquaculture developed in the 1960s and ‘70s, the use of Artemia also became more widespread, due both to its convenience and to its nutritional value for larval organisms (Arenas-Pardo et al., 2024). The fact that Artemia dormant cysts can be stored for long periods in cans, and then used as an off-the-shelf food requiring only 24 h of incubation makes them the most convenient, least labor-intensive, live food available for aquaculture (Sorgeloos & Roubach, 2021). The nutritional value of Artemia, especially for marine organisms, is not constant, but varies both geographically and temporally. During the last decade, however, both the causes of Artemia nutritional variability and methods to improve poorquality Artemia have been identified (Loufi et al., 2024).
Brine shrimp (Artemia spp.) are used in marine aquaculture worldwide. Annually, more than 2,000 metric tons of dry cysts are used for cultivation of fish, crustacean, and shellfish larva. Brine shrimp are important to aquaculture because newly hatched brine shrimp nauplii (larvae) provide a food source for many fish fry (Mozanzadeh et al., 2021). Culture and harvesting of brine shrimp eggs represents another aspect of the aquaculture industry. Nauplii and metanauplii of Artemia, commonly known as brine shrimp, play a crucial role in aquaculture due to their nutritional value and suitability as live feed for many aquatic species, particularly in larval stages (Sorgeloos & Roubach, 2021).
Or: Beyond linear.
Abstract: Equivariant neural networks are neural networks that incorporate symmetries. The nonlinear activation functions in these networks result in interesting nonlinear equivariant maps between simple representations, and motivate the key player of this talk: piecewise linear representation theory.
Disclaimer: No one is perfect, so please mind that there might be mistakes and typos.
dtubbenhauer@gmail.com
Corrected slides: dtubbenhauer.com/talks.html
ESA/ACT Science Coffee: Diego Blas - Gravitational wave detection with orbita...Advanced-Concepts-Team
Presentation in the Science Coffee of the Advanced Concepts Team of the European Space Agency on the 07.06.2024.
Speaker: Diego Blas (IFAE/ICREA)
Title: Gravitational wave detection with orbital motion of Moon and artificial
Abstract:
In this talk I will describe some recent ideas to find gravitational waves from supermassive black holes or of primordial origin by studying their secular effect on the orbital motion of the Moon or satellites that are laser ranged.
The debris of the ‘last major merger’ is dynamically youngSérgio Sacani
The Milky Way’s (MW) inner stellar halo contains an [Fe/H]-rich component with highly eccentric orbits, often referred to as the
‘last major merger.’ Hypotheses for the origin of this component include Gaia-Sausage/Enceladus (GSE), where the progenitor
collided with the MW proto-disc 8–11 Gyr ago, and the Virgo Radial Merger (VRM), where the progenitor collided with the
MW disc within the last 3 Gyr. These two scenarios make different predictions about observable structure in local phase space,
because the morphology of debris depends on how long it has had to phase mix. The recently identified phase-space folds in Gaia
DR3 have positive caustic velocities, making them fundamentally different than the phase-mixed chevrons found in simulations
at late times. Roughly 20 per cent of the stars in the prograde local stellar halo are associated with the observed caustics. Based
on a simple phase-mixing model, the observed number of caustics are consistent with a merger that occurred 1–2 Gyr ago.
We also compare the observed phase-space distribution to FIRE-2 Latte simulations of GSE-like mergers, using a quantitative
measurement of phase mixing (2D causticality). The observed local phase-space distribution best matches the simulated data
1–2 Gyr after collision, and certainly not later than 3 Gyr. This is further evidence that the progenitor of the ‘last major merger’
did not collide with the MW proto-disc at early times, as is thought for the GSE, but instead collided with the MW disc within
the last few Gyr, consistent with the body of work surrounding the VRM.
ESPP presentation to EU Waste Water Network, 4th June 2024 “EU policies driving nutrient removal and recycling
and the revised UWWTD (Urban Waste Water Treatment Directive)”
Unlocking the mysteries of reproduction: Exploring fecundity and gonadosomati...AbdullaAlAsif1
The pygmy halfbeak Dermogenys colletei, is known for its viviparous nature, this presents an intriguing case of relatively low fecundity, raising questions about potential compensatory reproductive strategies employed by this species. Our study delves into the examination of fecundity and the Gonadosomatic Index (GSI) in the Pygmy Halfbeak, D. colletei (Meisner, 2001), an intriguing viviparous fish indigenous to Sarawak, Borneo. We hypothesize that the Pygmy halfbeak, D. colletei, may exhibit unique reproductive adaptations to offset its low fecundity, thus enhancing its survival and fitness. To address this, we conducted a comprehensive study utilizing 28 mature female specimens of D. colletei, carefully measuring fecundity and GSI to shed light on the reproductive adaptations of this species. Our findings reveal that D. colletei indeed exhibits low fecundity, with a mean of 16.76 ± 2.01, and a mean GSI of 12.83 ± 1.27, providing crucial insights into the reproductive mechanisms at play in this species. These results underscore the existence of unique reproductive strategies in D. colletei, enabling its adaptation and persistence in Borneo's diverse aquatic ecosystems, and call for further ecological research to elucidate these mechanisms. This study lends to a better understanding of viviparous fish in Borneo and contributes to the broader field of aquatic ecology, enhancing our knowledge of species adaptations to unique ecological challenges.
The technology uses reclaimed CO₂ as the dyeing medium in a closed loop process. When pressurized, CO₂ becomes supercritical (SC-CO₂). In this state CO₂ has a very high solvent power, allowing the dye to dissolve easily.
The binding of cosmological structures by massless topological defectsSérgio Sacani
Assuming spherical symmetry and weak field, it is shown that if one solves the Poisson equation or the Einstein field
equations sourced by a topological defect, i.e. a singularity of a very specific form, the result is a localized gravitational
field capable of driving flat rotation (i.e. Keplerian circular orbits at a constant speed for all radii) of test masses on a thin
spherical shell without any underlying mass. Moreover, a large-scale structure which exploits this solution by assembling
concentrically a number of such topological defects can establish a flat stellar or galactic rotation curve, and can also deflect
light in the same manner as an equipotential (isothermal) sphere. Thus, the need for dark matter or modified gravity theory is
mitigated, at least in part.
Authoring a personal GPT for your research and practice: How we created the Q...Leonel Morgado
Thematic analysis in qualitative research is a time-consuming and systematic task, typically done using teams. Team members must ground their activities on common understandings of the major concepts underlying the thematic analysis, and define criteria for its development. However, conceptual misunderstandings, equivocations, and lack of adherence to criteria are challenges to the quality and speed of this process. Given the distributed and uncertain nature of this process, we wondered if the tasks in thematic analysis could be supported by readily available artificial intelligence chatbots. Our early efforts point to potential benefits: not just saving time in the coding process but better adherence to criteria and grounding, by increasing triangulation between humans and artificial intelligence. This tutorial will provide a description and demonstration of the process we followed, as two academic researchers, to develop a custom ChatGPT to assist with qualitative coding in the thematic data analysis process of immersive learning accounts in a survey of the academic literature: QUAL-E Immersive Learning Thematic Analysis Helper. In the hands-on time, participants will try out QUAL-E and develop their ideas for their own qualitative coding ChatGPT. Participants that have the paid ChatGPT Plus subscription can create a draft of their assistants. The organizers will provide course materials and slide deck that participants will be able to utilize to continue development of their custom GPT. The paid subscription to ChatGPT Plus is not required to participate in this workshop, just for trying out personal GPTs during it.
3. Targeted Delivery of the Drug
• Targeted drug delivery system have been desgined on the concept of
magic bullets given by Dr. Paul Ehrlich
• This concept is associated with the development if such systems which
when introduced in the body , dirct the drug only to its site of action
therpy providing maximum theraputic response with reduced toxic effect
to decrese distrbution of other body tissue .
• Targeted drug delivery may be achieved by physical, biological, and
molecular systems that provide high concentrations of the active agent at
the pathophysiologically relevant sites.
• Many drugs have poor receptor specifcity resulting in side-effects that
may or may not be due to the specifc.
• substrate±receptor interactions involved in the desired drug action. The
receptors also may be distributed throughout the body besides those
present at the target site. Consequently, drug targeting should include
many considerations other than the improvement of receptor±substrate
interactions by re®ning the molecular architecture, such as molecular
transport and other related processes
4. • The blood-brain barrier (BBB), an important biological membrane in
the body, has been a perennial obstacle to the development of
drugs that act directly on the central nervous system (CNS).
• The capillaries in more than 99% of the brain parenchyma possess
tight, high-resistance junctions between the endothelial cell.
• The capillaries in more than 99% of the brain parenchyma possess
tight, high-resistance junctions between the endothelial cells.1,2
The cells themselves lack ``pores'' for the diffusion of water soluble
molecules, and pinocytic vesicles are largely absent.3 Towards small
molecules, the brain capillary endothelium behaves like a
continuous lipid bilayer, and diffusion is largely dependent on the
lipid solubility of the solute. Intracellular or transcellular transport,
i.e., directly through the endothelial cell membrane, is the principal
route into and out of the CNS for most drugs.4 Therefore, the BBB is
generally permeable to lipophilic compounds, but excludes
hydrophilic molecules
5. • The physicochemical restrictions discussed above prevent
the entry of many potentially useful drugs into the CNS.
While a peripheral cancer, for instance, may be effectively
treated with a particular drug, central metastasis of this
cancer is usually refractory to similar treatment.
• The potential neuropharmaceutical use of biotechnology-
based therapies, such as various neuropeptides, is also
hampered. Transport of peptide molecules across the BBB
may occur, but it is unlikely that endogenous peptides pass
the BBB in physiologically signi®cant amounts. Although
peptide molecules may actually reach the cellular elements
of the tissue within the circumventricular organs, there is
no evidence of penetration to deeper layers.
• Most of the naturally occurring neuropeptides are
hydrophilic and, thus, do not cross the BBB in the absence
of a specifc transport system in the BBB
6. Method to improve the conc of the
drug in the brain
• General methods for improving the efflux of
medication into the brain have relied on various
approaches which have recently been reviewed
extensively.
• One method for selectively increasing brain
concentrations of therapeutic agents is by their
direct injection into the cerebrospinal fluid (CSF).
• Medication can be administered intrathecally (i.t.)
or intracerebroventricularly (i.c.v.) at one of three
sites including the lumbar area, the basal cistern,
or the ventricles
7. • In these indications, many drugs of choice are
highly water soluble, and are therefore excluded
from the brain. Unfortunately, i.t. administration
is associated with many medical risks, some of
which are unacceptably high,22 including
encephalitis, meningitis, and arachnoiditis. In
addition, the method itself is often ineffcient.
• Since polar drugs administered into the CSF are
restricted to this aqueous compartment, their
distribution is uneven and incomplete in the CNS.
Also, the rate of drug distribution is usually
dependent on the rate of CSF flow, and as such, it
is often slow.
8. • A second method involves the disruption of the BBB via
carotid infusions of hypertonic aqueous
nonelectrolytes.25,26 The mechanism of the transient BBB
disruption involves an osmotic shrinkage of endothelial
cells, which opens the normally tight junctions.27,28
Compounds that have been used include glucose, sucrose,
arabinose, and urea. This method results in an
indiscriminate delivery. The considerable toxic effects of
the procedure should also be taken into account.
Inflammation, encephalitis, and seizures (as high as 20% of
the applications) have been reported. Altogether, BBB
disruption and i.t. administration are invasive techniques,
and their use is only justifed in life-threatening medical
conditions
9. Classification of Noninvasive brain-
delivery systems
• 1- biological approaches
• 2- chemical approaches
Biological systems involve cellular drug carriers.
Brain-targeting strategies have been proposed
based on specifc peptide transcytosis systems
that exist for various biomolecules in the BBB
10.
11. Chemical approaches
• Chemical apporaches to improve brain uptake
of a therapeutic agent rely on molecular
manipulations.
• Prodrug formation involves a transient
chemical modifcation of the pharmacologically
active species to improve the defcient
physicochemical properties.
12. • A prodrug is a pharmacologically inactive
compound that can be converted to the
parent drug usually by a single activating step.
In order to improve the entry of a hydroxy,
amino or carboxylic acid±containing drug,
esterifcation or amidation may be performed
to increase the lipophilicity of the target
compound.
13.
14. Limation
• Unfortunately, most prodrugs have several important limitations in
drug targeting. While increasing the lipophilicity of a molecule may
improve its movement through the BBB, the uptake of the
compound into other tissues is likewise increased leading to a
generally greater tissue burden. This nonselective delivery is
especially detrimental when potent drugs such as steroids or
cytotoxic agents are considered
• In addition, while the uptake of the prodrug into the CNS may be
facilitated by the increased lipophilicity, its ef¯ux is also enhanced
resulting in poor tissue retention (In general, lipid-soluble
compounds that are able to cross the BBB can maintain active
concentrations in the CNS only if their blood concentrations are
maintained at adequately high levels)
• Finally, while the only metabolism process involving the prodrug
should be its conversion to the parent drug, other routes can also
occur and may contribute to the toxicity of the compound.
15. • Some of the weaknesses of the prodrug approach
originate in the single chemical conversion
occurring in the activation of the compound.
Multiple conversions may not only lead to
selectivity in delivery under certain conditions,
but also decrease the toxicity of a drug and to
sustain its action.
• The recognition of this important aspect led to
the concept of chemical delivery systems (CDSs).
16. Desiging of CDS
• In designing a CDS for the CNS, the unique
architecture of the BBB can actually be turned
to an advantage. First, a CDS should be
suffciently lipophilic to enter the central
compartment. The molecule should then
undergo an enzymatic and/or chemical
conversion to promote retention in the CNS. It
is expected that, at the same time, peripheral
elimination of the entity is accelerated due to
facile conversion of the CDS in the body
17. • It is expected that, at the same time,
peripheral elimination of the entity is
accelerated due to facile conversion of the
CDS in the body. CDSs that possess these
attributes have been developed in which a
hydroxy, amino or carboxylic acid containing
drug is covalently linked to a functional group
containing a dihydropyridine unit that serves
as a redox ``targeter'' (T).
18. B R A I N - T A R G E T I N G B Y D I H Y
D R O P Y R I D I N E
19. Design and Mechanism of Action
• A CDS is defned as a biologically inert molecule that
requires several steps of chemical and/or enzymatic
conversion to the active drug and enhances drug
delivery to a particular organ or site.
• In designing a CDS for the CNS, the existence of the
BBB is actually exploited, as shown in Fig. 1. Tis a
specifc functional group attached to the molecule
which, in addition to enhancing BBB penetration by
virtue of its lipophilicity, can be converted by enzymatic
oxidation to a water soluble, lipid insoluble, quaternary
pyridinium salt (T‡
+).
20. • The drug molecule (D) may be further modi®ed to provide
increased lipophilicity through biolabile functional groups (F1,...,Fn)
which are susceptible to easy removal. Upon systemic
administration, the CDS can partition into several body
compartments due to its enhanced lipophilicity, some of which are
inaccessible to the unmanipulated compound. At this point, the
CDS is simply working as a lipoidal prodrug. However, the
dihydropyridine-type T moiety, undergoes an enzymatically-
mediated oxidation and converts to a membrane-impermeable
pyridinium salt. At this point, the CDS is simply working as a lipoidal
prodrug. However, the dihydropyridine-type T moiety, undergoes an
enzymatically-mediated oxidation and converts to a membrane-
impermeable pyridinium salt. This conversion occurs ubiquitously.
The mechanism of this oxidation has been extensively examined
21.
22.
23. Introduction
• The pyridine moiety has found a function in almost all aspects of organic
chemistry, as a solvent, base, ligand, functional group, and molecular scaffold.
• As a structural element, pyridine is considered a privileged pharmacophore in
medicinal chemistry.
• Each containing an intact pyridine moiety—Takepron, Nexium, Singulair, and Actos
produced billions of dollars in revenue in 2010. (Scheme 1).
24. • Modern C-H activation methods have confirmed pyridine as an essential functional
group with unique directing and activating utility.
• The crucial chelating ability of pyridine has given the molecule an important role in
metal organic frameworks and other supramolecular structures hJA10756,
JA14457, JA15814, CC8752i.
• Pyridinium salts are versatile reagents and important cationic structures in
nanodevices hCSR2203, EJO92i.
• Pyridines have found applications in organoelectronic materials hCEJ2392i, organic
light-emitting diodes technology hOL5534i, herbicides hJHC171i, and molecular
sensors hJA8544, CEJ1480i.
• Even as the forefront of nano- and biotechnology calls on chemists to prepare
innovative pyridine-derived structures, novel alkaloids containing the pyridine
moiety continue to be uncovered in nature.
25. • Polyaxibetaine (Scheme 2) is a modified tyrosine that contains a pyridine moiety
. Isolated from the skin of the poison arrow frog Epipedobates anthonyi,
phantasmidine is a tightly wound knot of fused ring systems containing a
chloropyridine, dihydrofuran, pyrrolidine, and cyclobutane.
* Dedicated to the late John Daly, this novel ring system shows activity as a nicotinic
acetylcholine receptor agonist but with different selectivity than Daly’s epibatidine.
*Lycoposerramine is a member of the pyridine-containing lycodine family of alkaloids
and was recently synthesized for the first time in 2010
26. • Isolated from the Australian colonial ascidian
Aplidiopsis confluata, aplidiopsamine
• A contains a fused pyrrolo[2,3-c]quinoline
linked to an adenine residue (Scheme 3).
• The compound shows significant anti-
plasmodial activity even against
chloroquineresistant parasites
27. Preparation of Pyridines
• Cyclocondensation-based syntheses have historically been the most commonly
used preparations of pyridine.