autonomic pharmacology and cholinergic drugs


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A Power point presentation on "Autonomic Pharmacology and Cholinergic Drugs" suitable for undergraduate Medical Students.


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Presentation Transcript

Slide 1: 

2011 Wish you

Autonomic Nervous System - “Autonomic Pharmacology” : 

Autonomic Nervous System - “Autonomic Pharmacology” Department of Pharmacology NEIGRIHMS, Shillong

Goal : 

Goal To Learn about the drugs affecting the autonomic nervous system Be prepared to link mechanism of drug action with knowledge mainly of cardiovascular anatomy, physiology and neurobiology to predict effects of drugs –

The autonomic nervous system maintains the internal environment of the body – clled HOMEOSTASIS : 

The autonomic nervous system maintains the internal environment of the body – clled HOMEOSTASIS Role of ANS in homeostasis links to target organs - (Cardivascular System , smooth muscle of GI and glands)

Slide 5: 

+ Drug A decreases activity of organ Y Autonomic Pharmacology is Practical Nerves to organ Y release neurotransmitter X, and X increases the activity of organ Y Mimic or Block transmitters Drug A blocks receptors for neurotransmitter X

Slide 6: 

+ Atropine blocks muscarinic receptors and decreases intestinal motility Atropine blocks muscarinic cholinergic receptors that respond to ACh Parasympathetic nerves release ACh and increase intestinal motility Understanding actions of drugs that influence the autonomic nervous system allows prediction of their effects!

Slide 7: 

Autonomic Drugs are very much Clinically Relevant

Slide 8: 

Autonomic drugs are used for the treatment of Angina

Slide 9: 

Autonomic drugs are used for the treatment of Heart Failure

Slide 10: 

Autonomic drugs are used for the treatment of High Blood Pressure Autonomic drugs also used for treatment of - Anaphylactic shock - Septic shock - Benign prostatic hypertrophy - Alzheimer’s disease - Asthma

Objectives : 

Objectives Review the anatomy of the autonomic nervous system Know the neurotransmitters at autonomic synapses Understand the mechanism of neurotransmission in the autonomic nervous system Be able to describe the distribution of adrenergic and cholinergic receptors Describe general mechanisms by which drugs interact with the autonomic nervous system

Autonomic Pharmacology : 

Autonomic Pharmacology I. Anatomy of Peripheral Nervous System

Organization of The Nervous System : 

Organization of The Nervous System Central Nervous System “Brain and spinal cord” Peripheral Nervous System Autonomic Nervous System Somatic Nervous System Afferent Division Efferent Division Sympathetic “thoracolumbar” Parasympathetic “craniosacral”

Differences Between Somatic and ANS : 

Differences Between Somatic and ANS

Slide 15: 

Controls skeletal muscle Controls smooth & cardiac muscle & glands Peripheral Nervous System Somatic Nervous System Autonomic Nervous System One Neuron Efferent Limb Two Neuron Efferent Limb Postganglionic Preganglionic

Slide 16: 

Skeletal Muscle Peripheral Nervous System Somatic Nervous System Autonomic Nervous System Parasympathetic Nervous System Sympathetic Nervous System Selective Activation Diffuse Activation Glands, Smooth Muscle & Cardiac Muscle



Slide 18: 

Parasympathetic Nervous System (Craniosacral Outflow) Genitalia Bladder Large Intestines Kidney Bile Ducts Gallbladder Small Intestines Stomach Bronchi/Bronchial Glands SA & AV Node Sphincter Muscle of Iris Ciliary Muscle Lacrimal Gland Submaxillary & Sublingual Glands Parotid Gland

Slide 19: 

Radial Muscle of Iris Ciliary Muscle SA & AV Nodes His-Purkinje System Myocardium Bronchi/Bronchial Glands Stomach Kidneys Intestines Bladder//Genitalia Sublingual/Submaxillary & Parotid Gland Pilomotor Muscles Sweat Glands Blood Vessels Sympathetic Nervous System (Thoracolumbar Outflow) Paravertebral Ganglia Prevertebral Ganglia

Slide 20: 

Epinephrine (+) Fatty Acid Release (-) Intestinal Motility (+) Glycogenolysis (+) ACTH & TSH (+) Mental Alertness (+) Muscle Contraction & Efficiency (+) Dilates Airways (+) Cardiac Output ADRENAL MEDULLA Chromaffin Cells

Enteric Nervous System : 

Enteric Nervous System Considered 3rd Division of ANS Auerbach`s plexus or myenteric plexus Meissner`s plexus or submucous plexus Stimulation of these neurones causes release of – Ach, NE, VIP, ATP, Substance P, 5-HT etc. May be excitatory or inhibitory in Nature

Enteric Nervous System : 

Enteric Nervous System

Neurohumoral Transmission : 

Neurohumoral Transmission Neurohumoral transmission means the transmission of message across synapse and neuroeffector junctions by release of humoral (chemical) messages Initially junctional transmission was thought to be Electrical But, Dale (1914) and Otto Loewi (1921) provided direct proof of humoral transmission – vagusstoff and acceleranstoff Many Neurohumoral transmitters re identified: Acetylcholine, noradrenalin, Dopamine, 5-HT, GABA, Purines, Peptides etc.

Neurohumoral Transmission - Steps : 

Neurohumoral Transmission - Steps Impulse Conduction Tetrodotoxin and saxitoxin Transmitter Release Transmitter release on postjunctional membrane EPSP and IPSP Postjunctional activity Termination of transmitter action NET, SERT, DT

What is a synapse? : 

What is a synapse? A synapse is a junction between two neurones across which electrical signals pass. The human body contains up to 500 trillion synapses.

Release of neurotransmitters : 

Release of neurotransmitters When a nerve impulse arrives at the end of one neurone it triggers the release of neurotransmitter molecules from synaptic vesicles.

Continuing the impulse : 

Continuing the impulse The neurotransmitters diffuse across the synaptic cleft and bind with receptors on the next neurone, triggering another impulse.

Slide 29: 

Ach Ach Ach Ach NE Ach EPI/NE Ach Ach Somatic Sympathetic Sympathetic Sympathetic Para- sympathetic Postganglionic Fiber: Adrenergic Postganglionic Fiber: Cholinergic Adrenal Gland Motor Fiber Sweat Glands Smooth Muscle Cardiac Cells Gland Cells Smooth Muscle Cardiac Cells Gland Cells Skeletal Muscle Preganglionic Fiber: Cholinergic Ganglion Ganglion Ganglion

Cholinergic and Adrenergic System : 

Cholinergic and Adrenergic System Accordingly: Cholinergic Drugs, i.e., they act by releasing acetylcholine But also utilize nitric oxide (NO) or peptides for transmission Noradrenergic (commonly called "adrenergic") Drugs - act by releasing norepinephrine (NA)

Cotransmission : 

Cotransmission Peripheral and central Neurones release more than one active substance when stimulated In ANS, besides Ach and NA – neurones elaborate Purines (ATP, adenosines), Peptides (VIP) or NPY, substance P, NO, enkephalins etc. ACH and VIP, ATP with both Ach and NA Stored in same neurones, but distinct vesicles – ATP and NA in same vesicle NANC – gut, vas deferens, urinary tract, salivary glands and certain blood vessels.

Cholinergic System and Drugs : 

Cholinergic System and Drugs

Cholinergic Transmission : 

Cholinergic Transmission Acetylcholine (Ach) is major neurohumoral transmitter at autonomic, somatic and central nervous system: The important sites of Acetylcholine as Neurohumoral transmitters are: All Postganglionic and few postganglionic sympathetic to sweat glands and some blood vessels – Muscarinic All preganglionic (Para and sympathetic) i.e. ganglia and Adrenal medulla - Nicotinic (NN) Skeletal Muscle – Nicotinic (NM) Central Nervous System (cortex, basal ganglia and spinal chord) – Muscarinic and Nicotinic

Slide 35: 

Cholinergic Transmission: Cholinergic neurons contain large numbers of small membrane-bound vesicles (containing ACh) concentrated near the synaptic portion of the cell membrane ACh is synthesized in the cytoplasm from acetyl-CoA and choline by the catalytic action of acetyltransferase (ChAT) Acetyl-CoA is synthesized in mitochondria, which are present in large numbers in the nerve ending Choline is transported from the extracellular fluid into the neuron terminal by a sodium-dependent membrane carrier (carrier A). This carrier can be blocked by a group of drugs called hemicholiniums The action of the choline transporter is the rate-limiting step in ACh synthesis

Slide 36: 

Cholinergic Transmission: Synthesized, ACh is transported from the cytoplasm into the vesicles by an antiporter that removes protons (carrier B). This transporter can be blocked by vesamicol Release is dependent on extracellular Ca2+ and occurs when an action potential reaches the terminal and triggers sufficient influx of Ca2+ ions The increased Ca2+ concentration "destabilizes" the storage vesicles by interacting with special proteins associated with the vesicular membrane (VAMPs) Fusion of the vesicular membranes with the terminal membrane results in exocytotic expulsion of ACh into the synaptic cleft The ACh vesicle release process is blocked by botulinum toxin through the enzymatic removal of two amino acids from one or more of the fusion proteins. Black widow spider

Slide 37: 

Cholinergic Transmission: After release - ACh molecules may bind to and activate an ACh receptor (cholinoceptor) Eventually (and usually very rapidly), all of the ACh released will diffuse within range of an acetylcholinesterase (AChE) molecule AChE very efficiently splits ACh into choline and acetate, neither of which has significant transmitter effect, and thereby terminates the action of the transmitter. Most cholinergic synapses are richly supplied with AChE; the half-life of ACh in the synapse is therefore very short. AChE is also found in other tissues, eg, red blood cells. Another cholinesterase with a lower specificity for ACh, butyrylcholinesterase [pseudo cholinesterase], is found in blood plasma, liver, glial, and many other tissues

Differences between 2 AChEs : 

Differences between 2 AChEs

Cholinergic receptors - 2 types : 

Cholinergic receptors - 2 types Muscarinic (M) and Nicotinic (N) Muscarinic (M) - GPCR Nicotinic (N) – ligand gated

Sites of Cholinergic transmission : 

Sites of Cholinergic transmission

Cholinergic receptors– Muscarinic (M) and Nicotinic (N) : 

Cholinergic receptors– Muscarinic (M) and Nicotinic (N) Nicotinic receptors: nicotinic actions of ACh are those that can be reproduced by the injection of Nicotine and also can be blocked by tubocurarine and hexamethonium ligand-gated ion channels activation results in a rapid increase in cellular permeability to Na+ and Ca++ results in depolarization and initiation of action potential

Nicotinic (NM and NN) Receptor Locations : 

Nicotinic (NM and NN) Receptor Locations NM (Muscle type) and NN (Ganglion type) NM (Muscle type): at neuromuscular junctions of skeletal muscle: Postsynaptic and Excitatory (increases Na+ and K+ permeability) Stimulate skeletal muscle (contraction) Agonists: ACh, carbachol (CCh), suxamethonium Selective stimulation by phenyl trimethyl ammonium (PTMA) Antagonists: tubocurarine, hexamethonium NN type: In autonomic ganglia of all type (ganglion type) – Sympathetic, Parasympathetic and also Adrenal Medulla Depolarization and postganglionic impulse – stimulate all autonomic ganglia Excitatory – Na+, K+ and Ca+ channel opening Agonists: ACh, CCh, nicotine Selectively stimulated by phenyl piperazinium (DMPP) Antagonists: mecamylamine, trimetaphan

Muscarinic (M) Receptors : 

Muscarinic (M) Receptors Amanita muscaria

Acetylcholine (cholinergic receptors) – Muscarinic Receptors : 

Acetylcholine (cholinergic receptors) – Muscarinic Receptors Selectively stimulated by Muscarine nd blocked by Atropine G-protein coupled receptors Primarily located in heart, blood vessels, eye, smooth muscles and glands of GIT Subsidiary M receptors are also present in ganglia for modulation Autoreceptors (M type) are present in prejunctional cholinergic Nerve endings

Muscarinic Receptors - Subtypes : 

Muscarinic Receptors - Subtypes M1, M2, M3, M4 and M5 M1, M2 and M3 are major ones and present in effector cell and prejunctional nerve endings in CNS M4 and M5 are present in certain areas of Brain and regulate other neurotransmitters All subtypes have little agonist selectivity but selective antagonist selectivity

Slide 46: 

Muscarinic Receptor Subtypes

Acetylcholine (cholinergic receptors) – Muscarinic Receptors : 

Acetylcholine (cholinergic receptors) – Muscarinic Receptors Selectively stimulated by Muscarine and blocked by Atropine

Cholinergic Drugs or Cholinomimetic or Parasympathomimetics : 

Cholinergic Drugs or Cholinomimetic or Parasympathomimetics Drugs producing actions similar to Ach – by interacting with Cholinergic receptors or by increasing availability of Ach at these sites.

Classifiction - Direct-acting (receptor agonists ) : 

Classifiction - Direct-acting (receptor agonists ) Choline Esters Natural: Acetylcholine Synthetic: Methacholine, Carbachol and Bethanechol. Alkaloids: pilocarpine, muscarine, arecholine Synthetic: Oxotremorine

Cholinergic Drugs – Indirect acting : 

Cholinergic Drugs – Indirect acting Cholinesterase inhibitors or reversible anticholinesterases: Natural: Physostigmine Synthetic: neostigmine, pyridostigmine, distigmine, rivastigmine, donepezil, gallantamine, edrophonium, ambenonium, demecarium Irreversible anticholinesterases: Organophosphorous Compounds (OPC) – Diisopropyl fluorophosphate (DFP), Ecothiophate, Parathion, malathion, diazinon (insecticides and pesticides) Tabun, sarin, soman (nerve gases in war) Carbamate Esters Carbaryl and Propoxur (Baygon)

Question… : 

Question… What side effects might you expect to see in a patient taking a cholinergic drug? Hint… Cholinergic = “Colon-Urgent”

Ach actions - Muscarinic : 

Ach actions - Muscarinic Heart: M2 Hyperpolarization of SA node, reuction in impulse generation and Bradycardia Slowing of AV conduction and His-purkinje fibres – partial or complete block Atrial fibrillation and flutter – nonuniform vagal innervations Decrease in ventricular contractility Blood Vessels: M3 Cholinergic innervations is limited – skin of face and neck But, M3 present in all type blood vessel – Vasodilatation by Nitric oxide (NO) release Penile erection

Muscarinic action – contd. : 

Muscarinic action – contd. 3. Smooth Muscles: M3 Abdominal cramps, diarrhoea – due to increased peristalsis and relaxed sphincters Voiding of Bladder Bronchial SM contraction – dyspnoea, attack of asthma etc. Glands: M3 Increased secretions: sweating, salivation, lacrimation, tracheobronchial tree and gastric glands Eye: M3 Contraction of circular fibres of Iris – miosis Contraction of Ciliary muscles – spasm of accommodation, increased outflow and reduction in IOP

Ach actions - Nicotinic : 

Ach actions - Nicotinic Autonomic ganglia: Both Sympathetic and parasympathetic ganglia are stimulated After atropine injection Ach causes tachycardia and rise in BP Skeletal muscle IV injection – no effect Application causes contraction of skeletal muscle CNS: Does not penetrate BBB Local injection in CNS – complex actions (Acetylcholine is not used therapeutically)

Pilocarpine : 

Pilocarpine Alkaloid from leaves of Pilocarpus microphyllus Prominent muscarinic actions Profuse salivation, lacrimation, sweating Dilates blood vessels, causes hypotension On Eyes it produces miosis and spasm of accommodation Lowers intraocular pressure (IOP) in Glaucoma when applied as eye drops Too toxic for systemic use

Pilocarpine – contd. : 

Pilocarpine – contd. Used as eye drops in treatment of narrow angle and wide angle glaucoma to reduce IOP Used to reverse mydriatic effect of atropine To break adhesion between iris and cornea/lens alternated with mydriatic Pilocarpine nitrate eye drops ( 1 to 4% ) CNS toxicity after systemic use Atropine used as antidote in acute pilocarpine poisoning ( 1-2 mg IV 8hrly )

Pilocarpine – Mechanism in Eye : 

Pilocarpine – Mechanism in Eye Causes opening up of trabecular pores and increased drainage

Muscarine : 

Muscarine Alkaloid from mushroom Amanita muscaria Only muscarinic actions No clinical use Cause mushroom poisoning due to ingestion of poisonous mushroom = Early onset mushroom poisoning = Late onset mushroom poisoning (neurogenic)

Early Onset Mushroom Poisoning : 

Early Onset Mushroom Poisoning Occurs ½ to 1 hour. Muscaria cause mild cholinergic symptoms like nausea, vomiting, salivation, lacrimation, headache, bronchospasm, diarrhoea ntidote is Atropine sulphate (0.5-I mg IM twice daily) Inocybe or Clitocybe – severe cholinergic symptoms like bradycardia, dyspnoea, hypotension, weakness, cardiovascular collapse, convulsions and coma Antidote is Atropine sulphate ( 2-3 mg IM hrly till improvement ) Volvariella volvacea

Late Onset Mushroom Poisoning : 

Late Onset Mushroom Poisoning Occurs within 6-15 hours Amanita phylloides – irritability, restlessness, nausea, vomiting, ataxia, hallucination, delirium, sedation, drowsiness and sleep. Maintain blood pressure, respiration Inj. Diazepam 5 mg IM Atropine contraindicated as it may cause convulsions and death Gastric lavage and activated charcoal

Cholinesterase inhibitors: : 

Cholinesterase inhibitors: Reversible anticholinesterases (Carbamates): Natural: Physostigmine Synthetic: Neostigmine, pyridostigmine, distigmine, rivastigmine, donepezil, gallantamine, edrophonium, ambenonium, demecarium Irreversible anticholinesterases: Organophosphorous Compounds (OPC) – Diisopropyl fluorophosphate (DFP), Ecothiophate, Parathion, malathion, diazinon (insecticides and pesticides) Tabun, sarin, soman (nerve gases in war) Carbamate: Carbaryl and Propoxur (Baygon)

AChEs - MOA : 

AChEs - MOA Acetylcholinesterase (AchE) is an enzyme, which hydrolyses Acetylcholine The active site of AChE is made up of two subsites – anionic and esteratic The anionic site serves to bind a molecule of ACh to the enzyme Once the ACh is bound, the hydrolytic reaction occurs at a second region of the active site called the esteratic subsite The AChE itself gets acetylated at serine site Acetylated enzyme reacts with water to produce acetic acid and choline Choline is then immediately taken up again by the high affinity choline uptake system on the presynaptic membrane

Hydrolysis of ACh : 

Hydrolysis of ACh

Anti-ChEs (MOA) – contd. : 

Anti-ChEs (MOA) – contd. Anticholinesterases also react with the enzyme ChEs in similar fashion like Acetylcholine Carbamates – carbamylates the active site of the enzyme Phosphates – Phosphorylates the enzyme Carbamylated (reversible inhibitors) reacts with water slowly and the esteratic site is freed and ready for action – 30 minutes (less than synthesis of fresh enzyme) But, Phosphorylated (irreversible) reacts extremely slowly or not at all – takes more time than synthesis of fresh enzyme Sometimes phosphorylated enzyme losses one alkyl group and become resistant to hydrolysis – aging Edrophonium and tacrine reacts only at anionic site while Organophosphates reacts only at esteratic site

Cholinesterase inhibitors – contd. : 

Cholinesterase inhibitors – contd.

Anticholinesterases – Individual Drugs : 

Anticholinesterases – Individual Drugs 2 (two) important clinically used drugs – Physostigmine – lipid soluble, ganglion acting and less action in skeletal muscle Also organophosphates Neostigmine – lipid insoluble, skeletal muscle acting

Physostigmine : 

Physostigmine Alkaloid from dried ripe seed (Calabar bean) of African plant Physostigma venenosum Tertiary amine, lipid soluble, well absorbed orally and crosses BBB Hydrolyzed in liver and plasma by esterases. Long lasting action (4-8 hours) Reversible anticholinesterase drug It indirectly prevents destruction of acetylcholine released from cholinergic nerve endings and causes ACh accumulation Muscarinic action on eye causing miosis and spasm of accommodation on local application Antagonises mydriasis and cycloplegia produced by atropine and anticholinergic drugs Salivation, lacrimation, sweating and increased tracheobronchial secretions. Increased heart rate & causes hypotension

Physostigmine - uses : 

Physostigmine - uses Used as miotic drops to decrease IOP in Glaucoma To antagonise mydriatic effect of atropine To break adhesions between iris and cornea alternating with mydriatic drops Belladonna poisoning, TCAs & Phenothiazine poisoning Alzheimer’s disease- pre-senile or senile dementia. Atropine is antidote in physostigmine poisoning. ADRs – CNS stimulation followed by depression.

Neostigmine : 

Neostigmine Synthetic reversible anticholinesterase drug. Quaternary ammonium compound and lipid soluble. Cannot cross BBB Hydrolysed by esterases in liver & plasma Short duration of action (3-5 hours) Direct action on nicotinic (NM) receptors present in neuromuscular junction (motor end plate) of skeletal muscle Antagonises (reverses) skeletal muscle relaxation (paralysis) caused by tubocurarine and other competitive neuromuscular blockers Stimulates autonomic ganglia in small doses Large doses block ganglionic transmission No CNS effects

Neostigmine – Uses and ADRs : 

Neostigmine – Uses and ADRs Used in the treatment of Myasthenia Gravis to increase muscle strength Post-operative reversal of neuromuscular blockade Post-operative complications – gastric atony paralytic ileus, urinary bladder atony Cobra snake bite Produces twitchings & fasciculations of muscles leading to weakness Atropine is the antidote in acute neostigmine poisoning

Physostigmine and Neostigmine - Summary : 

Physostigmine and Neostigmine - Summary

Therapeutic Uses – cholinergic drugs : 

Therapeutic Uses – cholinergic drugs Myasthenia gravis: Edrophonium to diagnose and Neostigmine, Pyridostigmine & Distigmine to treat To stimulate bladder & bowel after surgery: Bethanechol, Carbachol, Distigmine. To lower IOP in chronic simple glaucoma: Pilocarpine, Physostigmine To improve cognitive function in Alzheimer’s disease: Rivastigmine, Gallantamine, Donepezil. Physostigmine in Belladonna poisoning

Myasthenia gravis : 

Myasthenia gravis Autoimmune disorder affecting 1 in 10,000 population Causes: Development of antibodies directed to Nicotinic receptors in muscle end plate – reduction in number by 1/3rd of NM receptors Structural damage to NM junction Symptoms: Weakness and easy fatigability Treatment: Neostigmine – 15 to 30 mg orally every 6 hrly Adjusted according to the response* Pyridostigmine – less frequency of dosing Other drugs: Corticosteroids (prednisolone 30-60 mg /day) Azathioprin and cyclosporin also Plasmapheresis

Myasthenic crisis : 

Myasthenic crisis Acute weakness and respiratory paralysis Tracheobronchial intubation and mechnical ventilation Methylprednisolone IV with withdrawal of AChE Gradual reintroduction of AChE Thymectomy

Snake venom Poisoning : 

Snake venom Poisoning Asian Cobra Bite Symptoms are similar to Myasthenia gravis Atropine sulfate 0.6 mg IV slowly – to counteract Muscarinic action Edrophonium chloride (Tensilon) - 10 mg IV over 2 minutes – reversal of occulomotor and respiratory paralysis

AChE Poisoning (Organophopsphorous Poisoning) : 

AChE Poisoning (Organophopsphorous Poisoning) Poisoning may be – Occupational, accidental, Suicidal Symptoms: Fall in BP, bradycardia or tachycardia, cardiac arrhythmia and vascular collapse Irrittion of Eye, lacrimation, salivation, colic, involuntary defection, breathlessness, blurring of vision Muscular fasciculations and weakness Death due to respiratory paralysis – peripheral and central

Principles of Treatment : 

Principles of Treatment Remove soiled clothes Wash soiled skin and eyes Prone Positioning and clear mouth and throat Intubation of airway Gastric lavage Atropine: All cases of AChE poisoning, 2mg IV every `10 minutes – continue till atropinization occurs Cholinesterase reactivators: Oximes

Cholinesterase Reactivators - Oximes : 

Cholinesterase Reactivators - Oximes Pralidoxime (2-PAM), Obidoxime Diacetyl monoxime (DAM) Oximes have generic formula R-CH=N-OH Provides reactive group OH to the enzymes to reactivate the phosphorylated enzymes PAM: Quaternary Nitrogen of PAM gets attaches to Anionic site of the enzyme and reacts with Phosphorous atom at esteratic site Forms Oxime-phosphonate complex making esteratic site free Not effective in Carbamate poisoning Dose: 1-2 gm IV slowly

Slide 79: 

Khublei Shibun/Thank you

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