This document provides a summary of platelet activating factor (PAF):
1) PAF is a potent biological mediator that is synthesized by platelets, endothelial cells, and macrophages and is involved in platelet aggregation, inflammation, and anaphylaxis.
2) PAF was discovered in the 1970s and stimulates platelet activation and aggregation at extremely low concentrations.
3) PAF has many physiological and pathophysiological effects including thrombosis, acute inflammation, and shock, and excessive PAF has been implicated in several diseases.
4) Several PAF receptor antagonists have been developed that inhibit the actions of PAF and have shown efficacy in animal models of inflammation and anaphylaxis.
By Dr. Vishal Pawar, MD pharmacology
considering the complex nature of this topic, i am hereby providing a comprehensive review of prostaglandins and its various effects in the body, which after a through go through should be enough for simplifying the understanding of prostaglandins
Seretonin (5HT) and Its Antagonists PharmacologyPranatiChavan
Serotonin is a chemical that has a wide variety of functions in the human body. It is sometimes called the happy chemical, because it contributes to wellbeing and happiness.
The scientific name for serotonin is 5-hydroxytryptamine, or 5-HT. It is mainly found in the brain, bowels, and blood platelets.
Serotonin is used to transmit messages between nerve cells, it is thought to be active in constricting smooth muscles, and it contributes to wellbeing and happiness, among other things. As the precursor for melatonin, it helps regulate the body’s sleep-wake cycles and the internal clock.
It is thought to play a role in appetite, the emotions, and motor, cognitive, and autonomic functions. However, it is not known exactly if serotonin affects these directly, or if it has an overall role in co-ordinating the nervous system.
(Eicosanoids) Prostaglandins, leucotrienes, and platelet activating factorsPranatiChavan
Prostaglandins (PGs) and Leukotrienes (LTs) are biologically active derivatives of 20 carbon atom polyunsaturated essential fatty acids that are released from cell membrane phospholipids. They are the major lipid derived autacoids.
By Dr. Vishal Pawar, MD pharmacology
considering the complex nature of this topic, i am hereby providing a comprehensive review of prostaglandins and its various effects in the body, which after a through go through should be enough for simplifying the understanding of prostaglandins
Seretonin (5HT) and Its Antagonists PharmacologyPranatiChavan
Serotonin is a chemical that has a wide variety of functions in the human body. It is sometimes called the happy chemical, because it contributes to wellbeing and happiness.
The scientific name for serotonin is 5-hydroxytryptamine, or 5-HT. It is mainly found in the brain, bowels, and blood platelets.
Serotonin is used to transmit messages between nerve cells, it is thought to be active in constricting smooth muscles, and it contributes to wellbeing and happiness, among other things. As the precursor for melatonin, it helps regulate the body’s sleep-wake cycles and the internal clock.
It is thought to play a role in appetite, the emotions, and motor, cognitive, and autonomic functions. However, it is not known exactly if serotonin affects these directly, or if it has an overall role in co-ordinating the nervous system.
(Eicosanoids) Prostaglandins, leucotrienes, and platelet activating factorsPranatiChavan
Prostaglandins (PGs) and Leukotrienes (LTs) are biologically active derivatives of 20 carbon atom polyunsaturated essential fatty acids that are released from cell membrane phospholipids. They are the major lipid derived autacoids.
A Powerpoint presentation on the basics of Eicosanoids which includes Prostaglandins, Leukotrienes (LTs) ad Platelete Activating Factors (PAF) suitable for Undergraduate level Medical students.
Hypolipidemic agents, also known as cholesterol-lowering drugs or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of high levels of fats (lipids), such as cholesterol, in the blood (hyperlipidemia). They are also called lipid-lowering drugs.
Sulfonyl ureas pharmacology Presented by arjumandPARUL UNIVERSITY
Sulfonylureas are most commonly used Oral Hypoglycemic drugs helpful in treating Diabetes Mellitus .
They show their effects on beta cells of the pancreas to release insulin which maintains the blood sugar level.
They are also called as ATP sensitive Potassium[K] channel blockers
Immunosuppressants are drugs or medicines that lower the body's ability to reject a transplanted organ. Another term for these drugs is anti-rejection drugs. There are 2 types of immunosuppressants:
Induction drugs: Powerful antirejection medicine used at the time of transplant
Maintenance drugs: Antirejection medications used for the long term.
The slides describe concept of distribution, Volume of distribution, factors affecting volume of distribution and the barriers to distribution. Blood brain barrier and placental barrier.
A Powerpoint presentation on the basics of Eicosanoids which includes Prostaglandins, Leukotrienes (LTs) ad Platelete Activating Factors (PAF) suitable for Undergraduate level Medical students.
Hypolipidemic agents, also known as cholesterol-lowering drugs or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of high levels of fats (lipids), such as cholesterol, in the blood (hyperlipidemia). They are also called lipid-lowering drugs.
Sulfonyl ureas pharmacology Presented by arjumandPARUL UNIVERSITY
Sulfonylureas are most commonly used Oral Hypoglycemic drugs helpful in treating Diabetes Mellitus .
They show their effects on beta cells of the pancreas to release insulin which maintains the blood sugar level.
They are also called as ATP sensitive Potassium[K] channel blockers
Immunosuppressants are drugs or medicines that lower the body's ability to reject a transplanted organ. Another term for these drugs is anti-rejection drugs. There are 2 types of immunosuppressants:
Induction drugs: Powerful antirejection medicine used at the time of transplant
Maintenance drugs: Antirejection medications used for the long term.
The slides describe concept of distribution, Volume of distribution, factors affecting volume of distribution and the barriers to distribution. Blood brain barrier and placental barrier.
presentation about Nutraceutical
The term “nutraceutical” combines the word “nutrient” (a nourishing food or food component) with “pharmaceutical”(a medical drug). The word “nutraceutical” has been used to describe a broad list of products sold under the premise of being dietary supplements (i.e. a food), but for the expressed intent of treatment or prevent of disease.
For More Medicine Free PPT - http://playnever.blogspot.com/
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Different types of receptors can drugs affect the body through interacting with these receptors.
this presentation is a part from special course in basics of pharmacology .. deep and simple
Phosphodiesterase inhibitors; Could they be used for the treatment of COVID 19?Anjela Ahuja
Role and use of phosphodiesterase inhibitors in the treatment of COVID 19. DISCLAIMER: This is only a brief version of research studies conducted. Not to be taken as a piece of medical advice.
To be able to describe:
Cholesterol synthesis, source & metabolism
Hyperlipidemia – definition & normal values.
Anti hyperlipidemic drugs: its classification, mechanism of action & side effects.
The natural history of atherosclerosis might involve coronary plaque rupture / erosion, thrombus formation and vessel lumen occlusion, clinically recognized as acute coronary syndrome (ACS). International guidelines strongly recommend early statin administration in patients admitted for ACS. In addition to lowering circulating levels of low-density lipoprotein cholesterol (LDL-c), statin treatment was shown to promote plaque stabilization or regression in several ways, including reduction in necrotic lipid core, anti-inflammatory effects and improvement in endothelial function.
Update on the efficacy of statin treatment in acute coronary syndromes by Rosa, Gian Marco; Carbone, Federico; Parodi, Antonello; Massimelli, Elena A; Brunelli, Claudio; Mach, François (more...) European journal of clinical investigation, 05/2014, Volume 44, Issue 5, 501 - 515
HIF-1 Gene is transcribed in the nucleus with the help of specific protein .HIF-1 protein with DNA binding activity. Functional HIF transcription factors comprise 2 different subunits, that is, alpha (α) and beta (β). The α subunit, of which there are 3 forms ( HIF-1α, HIF-2α and HIF-3α) out of which HIF-1α and HIF-2α are main, HIF-1α is oxygen sensitive, HIF-1α is expressed in almost all cell types, and transcriptionally upregulates a large number of genes, including those encoding Vascular endothelial growth factor (VEGF), Glucose transporters, Glycolytic pathway enzymes , Insulin-like growth factor-2, Endothelin-1, transferrin, HIF-2 is the primary regulator of EPO production and also plays an important role in enterocyte iron uptake.
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Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Adv. biopharm. APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMSAkankshaAshtankar
MIP 201T & MPH 202T
ADVANCED BIOPHARMACEUTICS & PHARMACOKINETICS : UNIT 5
APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMS By - AKANKSHA ASHTANKAR
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
2. Contents
What is platelet activating factor ?
Discovery of PAF.
Synthesis of PAF.
Physiological and Pathophysiological effects of PAF.
Platelet aggregation.
Thrombus formation.
Recent research.
Pharmacological actions of PAF.
PAF antagonists.
2
3. What is platelet activating factor..??
Platelet-activating factor is a potent biological mediator
that exerts its effects in a variety of cells and tissues.
Platelet-activating factor, also known as
PAF, PAF- acether or AGEPC (acetyl-glyceryl-ether-phosphorylcholine), is a
potent phospholipid activator and mediator of many leukocyte functions, including
platelet aggregation and degranulation, inflammation, and anaphylaxis.
3
4. It is also involved in changes to vascular permeability, the oxidative burst,
chemotaxis of leukocytes, as well as augmentation of arachidonic acid metabolism
in phagocytes. PAF is produced by a variety of cells, but especially those involved
in host defense, such as , platelets, endothelial cells, neutrophils,monocytes,
and macrophages.
4
5. 5
Discovery of PAF.
In 1970, during a study of immunological mechanisms involving
histamine and serotonin release from platelets in immunized rabbits,
Henson proposed that 'a soluble factor' was released from leukocytes
which stimulated platelets to release vasoactive amines.
This observation was confirmed independently by
Siraganian and Osler in 1971.
6. 6
In 1972, Benveniste, Henson and Cochrane demonstrated that the antibody
involved in the immunological reaction described was an IgE class antibody and
coined the term 'platelet-activating factor (PAF)' for the soluble factor released
from basophils following IgE stimulation.
However, it was not until 1979 that Demopoulos, Pinckard and Hanahan
demonstrated that a semisynthetic phosphoacylglycerol, l-O-alkyl-2-acetyl-sn-
glycero-3-phosphocholine (AGEPC), had physiochemical as well as biological
properties (i.e. aggregation of platelets and secretion of serotonin)
indistinguishable from those of naturally-generated PAF.
7. Synthesis of PAF
The major pathway by which PAF is generated involves the precursor 1-O-alkyl-2-
acyl-glycerophosphocholine.
PAF is synthesized from this substrate in two steps .
Involves the action of phospholipase A2, with the formation of 1-O-alkyl-2-lyso-
glycerophosphocholine (lyso-PAF) and a free fatty acid (usually AA) . Eicosanoid
and PAF biosynthesis thus is closely coupled, and deletion of cPLA2 in mice leads
to an almost complete loss of both prostanoid and PAF generation.
The second, rate-limiting step is performed by the acetyl coenzyme-A-lyso-PAF
acetyltransferase.
PAF synthesis also can occur de novo;
a phosphocholine substituent is transferred to alkyl acetyl glycerol by a distinct
lysoglycerophosphate acetylcoenzyme-A transferase.
7
8. This pathway may contribute to physiological levels of PAF for
normal cellular functions.
8
1-The synthesis of PAF may be stimulated during antigen–antibody reactions or
by a variety of agents, including chemotactic peptides, thrombin, collagen, and
other autacoids.
2- PAF also can stimulate its own formation. Both the phospholipase and
acetyltransferase are Ca2+
-dependent enzymes; thus, PAF synthesis is regulated
by the availability of Ca2+
.
3- The inactivation of PAF also occurs in two steps .
1)Initially, the acetyl group of PAF is removed by PAF acetyl hydrolase to form
lyso-PAF
2)Lyso-PAF is then converted to a 1-O-alkyl-2-acyl-glycerophosphocholine by
an acyltransferase.
9. 1-In addition to these enzymatic routes. PAF-like molecules can be formed from
the oxidative fragmentation of membrane phospholipids (oxidized phospholipids).
2-These compounds are increased in settings of oxidant stress such as cigarette
smoking.
3-They differ structurally from PAF in that they contain a fatty acid at the sn-1
position of glycerol joined through an ester bond and various short-chain acyl
groups at the sn-2 position.
4-Oxidized phospholipids mimic the structure of PAF closely enough to bind to
its receptor and elicit the same responses.
5-Unlike the synthesis of PAF, which is highly controlled, oxidized
phospholipids production is unregulated; degradation by PAF acetyl hydrolase,
therefore, is necessary to suppress the toxicity of oxidized phospholipids.
9
10. 6-Levels of PAF acetyl hydrolase (also known as lipoprotein-associated
phospholipase a2) are increased in colon cancer, cardiovascular disease & stroke.
7-Polymorphisms have been associated with altered risk of cardiovascular events.
Remodelling of cell membrane phospholipid denevo 1-0-alkyl-sn-glycero-3-phosphate
10
11. Physiological and pathophysiological effects of PAF
1-Platelet aggregation and secretion, thrombosis.
2-Stimulation of neutrophils and macrophages.
3-Acute inflammation.
4-Asthma and systemic anaphylaxis.
5-Endotoxin and immune factor-induced shocks.
6-Gastrointestinal ulceration.
7-Glycogenolysis and increased portal pressure.
8-Pancreatitis.
11
12. 12
9-Cardiac anaphylaxis (negative inotropic effect and increased heart
beating rate).
10-Pregnancy and ovoimplantation.
11-Ovulation.
12-Acute lung injury.
13. Platelet aggregation
1.Platelet aggregate or clump together using fibrinogen of vWF as a
connecting agent.
2.The most abundant platelet aggregation receptor is glycoprotein IIb/3A.
Activated platelets will adhere, via glycoprotein Ia to the collagen that is
exposed by endothelial damage.
3.Aggregation and adhesion act together to form platelet plug.
Platelet aggregation is stimulated by ADP,Thromboxane and a2 receptor-
activation but inhibited by other inflammatory products like PGI2 and
PGD2. Platelet aggregation is enhanced by exogenous administration of
anabolic steroids.
13
15. Initially, PAF was found to effect aggregation of platelets at concentrations as low
as 10^-11 M, and it induced a hypertensive response at very low levels also. More
generally, it is now recognised that its primary role is to mediate intercellular
interactions.
For example, by binding to its specific receptor, PAF activates the cytoplasmic
phospholipase A2 and phospholipase C. The result of the latter is an increase in
intracellular Ca2+ downstream of the cell and activation of protein kinase C.
15
It is now known to exert effects on many different types of non-inflammatory
biological events and functions, including glycogen degradation, reproduction,
brain function and blood circulation.
16. Thrombus formation.
The function of platelets is the maintainence of haemostasis,this is achievd by the
formation of thrombi when damage to endothelium of blood vessels occurs.
Conversely ,thrombus formation must be inhibited at times when there is no
damage to the endothelium,
Activation-the inner surface of blood vessel is lined with a thin layer of endothelial
cells,that in normal haemostasis acts to inhibit platelet activation by producing
endothelial ADPase, nor-adrenaline and PGI2.
Endothelial ADPase clears away ADP,a platelet activator,from platelet surface
receptors.
Endothelial cells produce a protein called von Willebrand factor,a cell adhesion
ligand,which helps endothelial cells adhere to collagen in the basement membrane.
Under physiological condition collgen does not pass into the bloodstream;however
vWF is secreted constitutively into the plasma by the Endothelial cells that
16
17. Produce it or otherwise is stored within the endothelial cells or in platelets. When
endothelial damage occurs platelets comes into contact with exposed collagen and
vWF,causing a reduction in secretion of endothelium platelet inhibitors the inner
surface of blood vessels is lined with a thin layer of endothelial cells. Under this is
a layer of collagen. When the endothelial layer is injured the collagen is exposed.
When platelets contact collagen they are activated.
17
19. 19
Recent research
Much recent work has been concerned with the function of PAF as a mediator of
inflammation, and in the mechanism of the immune response.
While it is presumed to have evolved as part of a protective mechanism in the
innate host defence system, there is particular interest in its involvement in
uncontrolled pathological conditions.
For example, it has a number of proinflammatory properties, and in excess it has
been implicated in the pathogenesis of a number of disease states, ranging from
allergic reactions to stroke, sepsis, myocardial infarction, colitis and multiple
sclerosis.
20. 20
PAF can activate human inflammatory cells at concentrations as low as 10^-
14M.
In relation to asthma, platelet-activating factor is able to act directly as a
chemotactic factor and indirectly by stimulating the release of other
inflammatory agents.
Administration of PAF can produce many of the symptoms observed in asthma,
probably via the formation of leukotrienes as secondary mediators. However, the
amount of PAF produced by cellular stimuli of various kinds is dependent on the
nature of the cell and specific agonists. In essence it is a hormone that acts
locally, as it is found only on the surface of activated cells so restricting the
inflammatory response.
21. Pharmacological actions
CVS
1-PAF is a potent dilator in most vascular beds; when administered intravenously, it
causes hypotension in all species studied.
2-PAF-induced vasodilation is independent of effects on sympathetic innervation, the
renin–angiotensin system, or arachidonate metabolism and likely results from a
combination of direct and indirect actions.
3- PAF induces vasoconstriction or vasodilation depending on the concentration,
vascular bed, and involvement of platelets or leukocytes.
For example, the intracoronary administration of very low concentrations of PAF
increases coronary blood flow by a mechanism that involves the release of a platelet-
derived vasodilator.
21
22. 4-Coronary blood flow is decreased at higher doses by the formation of intravascular
aggregates of platelets and/or the formation of TXA2.
5-The pulmonary vasculature is also constricted by PAF and a similar mechanism is
thought to be involved.
6-Intradermal injection of PAF causes an initial vasoconstriction followed by a typical
wheal and flare.
7-PAF increases vascular permeability and edema in the same manner as histamine and
bradykinin. but PAF is more potent than histamine or bradykinin by three orders of
magnitude.
22
23. Platelets
1-PAF potently stimulates platelet aggregation in vitro.
2-While this is accompanied by the release of TxA2 and the granular contents of the
platelet, PAF does not require the presence of TxA2 or other aggregating agents
to produce this effect.
3-The intravenous injection of PAF causes formation of intravascular platelet
aggregates and thrombocytopenia.
23
24. Smooth Muscle
1-PAF generally contracts gastrointestinal, uterine, and pulmonary smooth muscle.
2- PAF enhances the amplitude of spontaneous uterine contractions; quiescent muscle
contracts rapidly in a phasic fashion.
3- These contractions are inhibited by inhibitors of PG synthesis.
4-PAF does not affect tracheal smooth muscle but contracts airway smooth muscle.
Most evidence suggests that another autacoid (e.g., LTC4 or TxA2) mediates this
effect of PAF.
5-When given by aerosol, PAF increases airway resistance as well as the
responsiveness to other bronchoconstrictors.
6-PAF also increases mucus secretion and the permeability of pulmonary
microvessels; this results in fluid accumulation in the mucosal and submucosal
regions of the bronchi and trachea.
24
25. Kidney
1-When infused intrarenally in animals, PAF decreases renal blood flow, glomerular
filtration rate, urine volume, and excretion of Na+
without changes in systemic
hemodynamics
2-These effects are the result of a direct action on the renal circulation.
3-PAF exerts a receptor-mediated biphasic effect on afferent arterioles, dilating them at
low concentrations and constricting them at higher concentrations.
4-The vasoconstrictor effect appears to be mediated, at least in part, by COX products,
whereas vasodilation is a consequence of the stimulation of NO production by
endothelium.
Stomach
1-In addition to contracting the fundus of the stomach, PAF is the
most potent known ulcerogen.
2-When given intravenously, it causes hemorrhagic erosions of the gastric mucosa that
extend into the submucosa.
25
27. Pathophysiological function of PAF
PAF generally is viewed as a mediator of pathological events.
Dysregulation of PAF signaling or degradation has been associated with some human
diseases, aided by data from genetically modified animals.
Platelets
1-Since PAF is synthesized by platelets and promotes aggregation, it was proposed
as the mediator of cyclooxygenase inhibitor–resistant, thrombin-induced aggregation.
2-However, PAF antagonists fail to block thrombin-induced aggregation, even
though they prolong bleeding time and prevent thrombus formation in some
experimental models.
3-Thus, PAF does not function as an independent mediator of platelet aggregation
but contributes to thrombus formation in a manner analogous to TxA2 and ADP.
27
28. 1-The proinflammatory actions of PAF and its elaboration by endothelial cells,
leukocytes, and mast cells under inflammatory conditions are well characterized.
2-PAF and PAF-like molecules are thought to contribute to the pathophysiology of
inflammatory disorders, including anaphylaxis, bronchial asthma, endotoxic shock, and
skin diseases.
3-The plasma concentration of PAF is increased in experimental anaphylactic shock, and
the administration of PAF reproduces many of its signs and symptoms, suggesting a role
for the autacoid in anaphylactic shock.
4- In addition, mice overexpressing the PAF receptor exhibit bronchial hyperreactivity
and increased lethality when treated with endotoxin.
5-PAF receptor knockout mice display milder anaphylactic responses to exogenous
antigen challenge, including less cardiac instability, airway constriction, and alveolar
edema; they are, however, still susceptible to endotoxic shock.
28
29. 6-Despite the broad implications of these observations, the effects of PAF antagonists
in the treatment of inflammatory and allergic disorders have been disappointing.
7- Although PAF antagonists reverse the bronchoconstriction of anaphylactic shock
and improve survival in animal models, the impact of these agents on animal models
of asthma and inflammation is marginal.
8-Similarly, in patients with asthma, PAF antagonists partially inhibit the
bronchoconstriction induced by antigen challenge but not by challenges of exercise,
or inhalation of cold air.
9-These results may reflect the complexity of these pathological conditions and the
likelyhood that other mediators contribute to the inflammation associated with these
disorders.
29
30. PAF Antagonists.
1.Ginkgolide B
Biological Activity
Platelet-activating factor
(PAF) receptor antagonist.
Inhibits neutrophil degranulation
and superoxide production in vitro
and inhibits bronchoconstriction and
is neuroprotective following oral
administration in vivo.
2.PCA 4248
30
Biological Activity
A specific PAF antagonist, more potent
than the ginkolide BN-52021. Inhibits rabbit
platelet aggregation and has no significant
activity on Ca2+
channels. Active in vivo,
antagonizing PAF-induced systemic
hypotension and protein-plasma
extravasation in rats.
32. References
32
Stafforini, D.M. Cardiovasc. Drugs Ther. 23, 73-83 (2009).
Aponte, M., Jiang, W., Lakkis, M., et al. Cancer Res. 68, 5839-5848 (2008).
Pg. no.131, 287-304,254, 9355-9358,3-106, 1244-1251
Demopoulos, C. A., Pinckard, R. N. and Hanahan, D. J. (1979) J. Biol. Chem. Henson, P. M. (1970) J. Exp.
Med. Siraganian, R. P. and Osler, A. G. (1971) J. Immunol. Platelet activating factor and signal transduction.
,136,1356-1377.
Christie, W.W. and Han, X. Lipid Analysis - Isolation, Separation, Identification and Lipidomic Analysis
(4th edition). 446 pages (Oily Press, Woodhead Publishing and now Elsevier) (2010).
Yost, C.C., Weyrich, A.S. and Zimmerman, G.A. The platelet activating factor (PAF) signaling
cascade in systemic inflammatory responses. Biochimie, 92, 692-697 (2010).
Endotoxic shock is the shock state resulting from endotoxin in the blood. Endotoxin is a component of gram-negative bacterial cell walls, and is toxic in small amounts. A person can go into endotoxic shock when he/she has a gram-negative bacterial infection and the infection moves into the blood (sepsis). A vast rise in body temp would be evident, along with multi-organ failure possibly occurring if not treated.