Aspirin and Antiinflammatory Agents

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Aspirin and Antiinflammatory Agents

• Chapter 17

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History of Aspirin

• Hippocrates ( 460 - 377 B.C.) historical
  records of pain relief treatments, including
  powder made from willow tree bark, leaves to help
  heal headaches, pains and fevers
• The Royal Society of London publishes an article
  by the Rev. Edward Stone, "Account of the success
  of the Bark of the Willow in the Cure of Agues,"
  officially reporting what had been folklore for
  centuries

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• 1826 Brugnatelli and Fontana (Italians)
  obtained salicin in impure form
• 1828 Johann Buchner, University of Munich
  professor of pharmacy, isolated tiny amount of
  bitter tasting yellow, needle-like crystals,
  which he called salicin from willow bark

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• 1829 Henri Leroux (French chemist) improved
  extraction procedure ? 30g from 1.5kg of bark
• 1838 Raffaele Piria (Italian chemist) purified
  salicylic acid
• BUT salicylic acid tough on stomachs so
  searched for 'buffering
• 1853 Charles Frederic Gerhardt (French chemist)
  neutralized salicylic acid by buffering w/ sodium
  (sodium salicylate) and acetyl chloride ?
  acetylsalicylic acid
• Worked, but Gerhardt did not market it and
  abandoned his discovery

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• 1899 Felix Hoffmann (German chemist worked for
  Bayer) rediscovered Gerhardt's formula
• Admind to his father who was suffering from
  arthritis w/ good results
• Convinced Bayer to market the new wonder drug
• Aspirin patented March 6, 1889

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• Aspirin A" in acetyl chloride, "spir" in
  spiraea ulmaria (plant from which salicylic acid
  derived), in familiar name ending for medicines
• Aspirin and Heroin were once trademarks
  belonging to Bayer
• Aspirin first sold as powder
• First Aspirin tablets made in 1915
• After Germany lost World War I, Bayer forced to
  give up both trademarks as part of the Treaty of
  Versailles in 1919
• Reduces "aspirin" to generic word for any brand
  of acetylsalicylic acid

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• 1950 Dr. Lawrence L. Craven (US) describes
  aspirin's action as a blood-thinner, begins
  prescribing daily doses to his patients as a
  means of preventing heart attacks
• 1971 John R. Vane (British pharmacologist)
  discovers aspirin's mechanism of action inhibits
  prodn prostaglandins -- hormone-like substances
  in the body
• 1982 Sir John R. Vane is co-winner of the Nobel
  Prize in Medicine for his discoveries concerning
  prostaglandins
• 1990s Studies show regular use of aspirin may
  reduce risk of colon cancer.
• 2005 Research shows aspirin reduces risk of
  stroke in healthy women, although no clear
  benefit is seen for prevention of heart attack

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Acute Inflammatory Rxn

• Response of mammalian host to invading pathogen
  or noxious agent
• If deficient, suppressed ? opportunistic
  infections
• If inappropriate ? autoimmune dysfunctions
• Many, varied biochem mediators
• Interactions w/ each other, immune response
  biochems/cells

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Eicosanoids

• Generated de novo from membr phospholipids
• From esterified fa
• Eicosa20 C tetraenoic4 dbs
• History 1930s substance in semen ? uterine
  contractions
• Believed originated in prostate (so
  prostaglandin)
• Now recognize family of mols in most tissues,
  derd from arachidonic acid

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• Biosynthesis
• PLA2 cleaves arachidonic acid from membr
  phospholipid
• Also cleaves lyso-PAF precursor of another
  mediation of inflammn (PAF)

Rang 15.6
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• Not stored, but synthd when needed
• Stimuli for PLA2 activity vary w/ tissue
• Ag-Ab rxns on mast cells
• Bradykinin binding on fibroblasts
• Thrombin binding on platelets
• Free fa further metabd by
• Fatty acid cylooxygenases 1 and 2
• Lipoxygenases
• CYPs
• Primarily locally-active
• Commonly work at cell/tissue/structure from which
  synthd (autocoids)
• Blood concent very low
• Efficient pulmonary degradation

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Brody 17-1 flowchart
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Cyclooxygenase (COX)

• Two forms COX-1, COX-2
• Exploited by drug designers
• COX-1
• Constitutive enz (always present) in most cells
• Housekeeping protein
• Prostanoids prodd impt to normal homeostasis
  (ex regulation vascular responses)

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• COX-2
• Induced in inflammatory cells by inflammation
  stimuli
• Inhibited by NSAIDs
• Arach acid further metabd differently in diff
  cells
• Platelets ? TXA2
• Vasc endothelium, macrophages ? PGI2
• Most impt PGE2, PGI2, PGD2, PGF2a, TXA2

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Prostanoid Receptors

• Five main classes
• Typical G-protein coupled receptors
• DP-receptors
• FP-
• IP-
• TP-
• EP-, based on 5 classes prostanoids TXA2

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• Modulate adenylyl cyclase
• Stimulators DP, EP2, EP4, IP
• Inhibitors EP2
• Modulate phosphlipase C ? DAG/IP3 and Ca2
  mobilization
• Many cells have gt1 PG receptor subtype
• Eicosanoids do not enter cells except w/
  transport system intake
• Lung, renal prox tubules, thyroid plexus, ciliary
  body

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Actions of Prostanoids

• PGD2 ? vasodilation, inhibn platelet aggregn,
  relaxation gi muscle, uterine relaxation, modn
  release hypothl/ pituitary hormones
• PGF2a ? contraction myometrium (humans)
  luteolysis (cattle) vasoconstriction (dogs, cats)

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• PGI2 ? vasodilation inhibn platelet aggregn
• TXA2 ? vasoconstriction platelet aggregn
• PGE2 ? contraction bronchial gi smooth muscle
  (EP1 receptor) relaxation bronchial, vascular,
  gi smooth muscle (EP2) contractn intest smooth
  muscle and pregnant human uterus, inhibn gastric
  acid secrn, inhibn lipolysis and autonomic
  neurotransmitter release (EP3)

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Prostanoids and Inflammn

• PGE2 -- Predom prostanoid w/ inflamm response
  PGI2 also generated
• Prodd by local tissues, blood vessels w/ acute
  inflammn
• PGD2 released by mast cells
• With chronic inflammn, PGE2 and TXA2 released by
  monocytes/macrophages
• Powerful vasodilators
• Synergize w/ histamine, bradykinin

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• Redness w/ inflammn due to dilation precapillary
  arterioles by prostaglandins
• ? Incrd blood flow
• Histamine bradykinin also required
• Sensitize afferent neurons to bradykinin ? pain
• PGEs impt to fever
• Found in high concent in csf
• Prodd in hypothalamus in response to pyrogen
  (IL1) reld by bacteria
• ? Elevation temp set-point

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Leukotrienes

• Prodd from membr phospholipids by 5-lipoxygenase
• Adds hydroperoxy grp to C5 of arach acid (?
  HPETE)
• Further metab ? LTA4 ? LTs B4-F4
• LTC4,D4,E4 Slow Reacting Substance of
  Anaphylaxis
• Cysteinyl-leukotrienes

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Actions of Leukotrienes

• LTB4 powerful chemotactic for neutrophils,
  macrophages
• On neutrophils ? upregn membrane adhesion mols
  incrd prod toxic O2 prods release granule
  enzs
• On macrophages ? stimn prolifn cytokine
  release
• Receptor of phosphatidylinositol/DAG type ?
  incrd cell Ca

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• LTD4 impt to respiratory system
• Spasmogens
• Incrd mucous secrn
• Redd airway conductance
• LTD4 impt to cardiovascular system
• Decr bp (constrictn small coronary vessels)
• Wheal/flare w/ subcu dose
• LTB4 impt to bronchial hyperreactivity in
  asthmatics role in cardiovascular changes w/
  acute anaphylaxis

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Drugs Inhibiting Prostanoid Prodn

• Two main types
• Glucocorticoids
• Non-steroidal antiinflammatories (NSAIDs)
• NSAIDs
• Used worldwide
• gt 50 on market
• Many have unwanted effects
• Three major types of effects
• Modn inflammatory rxn (antiinflamm)
• Redn pain (analgesic)
• Lower body temp (antipyretic)

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Commonly Used NSAIDs

• Aspirin
• Ibuprofen
• Diflunisal
• Fenbufen
• Diclofenac
• Mefenamic Acid
• Nabumetone

• Acetaminophen
• Naproxen
• Sulindac
• Indomethacin
• Tolmetin
• Piroxicam
• Tenoxicam

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ibuprofen
Fenbufen
Indomethacin
Sulindac
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• Most traditional NSAIDs have sim antiinflammatory
  activity except
• Indomethacin, piroxicam may be stronger
• Aspirin has diff pharmacological actions
• Antipyresis activity relieves fever
• Analgesia effective against arthritis, bursitis,
  muscular/vascular pain, toothache, dysmenorrhea,
  postpartum pain
• Headache pain relieved by blocking cerebral
  vascular dilation w/ prostanoid decr

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NSAID Mechanism of Action COX Inhibn

• COX enzs bifunctional
• Main activity ? PGG2
• Peroxidase activity converts PGG2?PGH2
• Inhibitors block only main rxn
• COX enzs assocd w/ cell membr
• Active site hydrophobic, accepts arachidonic acid
• Rxn insertion 2 O, extraction free radical ? 5C
  ring

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COX-1 vs COX-2

• COX-2 active site slightly wider
• Aa523 differs
• COX-1 has leucine
• Rel bulky
• COX-2 has valine
• Smaller leaves gap
• Allows access to side-pocket
• COX-2 selective agents have side chain, interacts
  w/ pocket
• May be too large to fit COX-1 active site channel

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Celecoxib (Celebrex)
Rofecoxib (Vioxx)
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• Traditional NSAIDs
• H-bond polar arginine (120) half-way down channel
  ? blockage of channel
• COX-1 inhibn instantaneous, competitively
  reversible
• COX-2 inhibn incrs w/ time
• Also reversible (by competitively excluding arach
  acid)
• Aspirin
• Binds, acetylates serine530 ? irrev inactn of
  both enzs

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• NSAIDs may inhibit inflammation by other mechs
  also
• Some scavenge oxygen radiacls prodd by
  neutrophils, macrophages (ex sulindac)
• Aspirin inhbits exprn transcrn factor NF-kB
• Impt to transcrn genes for mediators of
  inflammn

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COX-1 vs COX-2

• COX-2 most responsible for prodn prostanoids
  impt to inflammation
• COX-2 inhibn predicts best antiinflamm response
• Most NSAIDs inhibit both COX enzs (diff extent
  inhibn)
• COX-1 inhibn predicts unwanted gi tract
  side-effects (irritation)
• Selective COX-2 inhibitors marketed
• Celecoxib (Drug Side Effect Lawyers incrd
  risk heart attack)
• Rofecoxib (Vioxx withdrawal)

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NSAID Adverse Reactions

• Numerous may cause death
• Elderly w/ joint diseases need fairly large
  doses, long-continued use
• High incidence side effects gi, liver, skin,
  kidney, spleen, blood, bone marrow

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• Gastrointestinal disturbances commonest
• Due to COX-1 inhibn
• Impt for PGS that inhibit acid secrn, protective
  of mucosa
• Side-effects include dyspepsia, diarrhea (or
  constipation), nausea, vomiting, gastric
  bleeding, ulceration
• May ? hemorrhage, perforation
• Can admin PGs to relieve
• Selective COX-2 inhibs ? decrd gi effects

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• Skin Reactions
• Second most common side-effect
• Mild rashes, urticaria, photosensitivity
• May be fatal
• Most frequently w/ mefenamic acid, sulindac
• Renal Effects
• Some pts susceptible
• Reversible w/ stopping drug
• PGs synthd here impt to vasodilation at kidney
  w/ angiotensin II, noradrenaline
• Can ? chronic nephritis, renal papillary necrosis
• Impt w/ paracetamol (now withdrawn)

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Aspirin

• Acetylsalicylic acid
• Among most commonly consumed world-wide
• Rel insoluble Na and Ca2 salts readily soluble
• Many effects beyond antiinflammatory
• Antiplatelet for cardiovascular disorders
• Decrd colon, rectal cancer
• Decrd risk, later onset of Alzheimers

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• Weak acid, unionized in stomach
• ? good absn
• Most absn in ileium (more surface area)
• Metab by oxn (25) glucuronide or sulfate
  conjugation (50) excrd unchanged (25)
• Rate excrn incrd in alkaline urine
• Irreversible inhibitor of COX enzs
• Toxicity may be local or systemic
• Same side-effects as NSAIDs
• Salicylism tinnitis, vertigo, decrd hearing w/
  large, repeated doses
• Reyes syndrome in children liver and CNS
  disturbances
• May alter acid-base balanceby uncoupling oxve
  phosphn ? incrd blood O2 ? alteration
  breathing ? resp alkalosis

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Acetaminophen

• One of most common non-narcotic
  analgesic/antipyretic
• Rel weak (?) antiinflammatory activity
• Selective for COX-3 (recently described)
• Given orally well absorbed
• Peak plasma concents 30-60 mins
• Plasma ½ life 2-4 h
• Glucuronidated or sulfated in liver

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• Unwanted effects few at therapeutic doses
• Large doses over long period increases renal
  damage risk
• Toxic doses (2-3x max therapeutic) ?
  hepatotoxicity
• Potentially fatal
• Phase II enzs satd ? products of mfos (Phase I
  enzs) in incrd concent
• N-acetyl-p-benzoquinone imine
• Usually metabd by conjugation glutathione
• Depletion glutathione ? suff imine to react w/
  cellular nucleophiles ? necrosis liver, kidney
  tubules

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• Init symptoms poisoning nausea, vomiting
• Hepatotoxicity occurs 24-48 h later
• Treatment
• Gastric lavage, then
• Oral activated charcoal
• If early, acetylcysteine IV or methionine orally
  ? incrd glutathione in liver ? enhanced
  metab/excrn

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Drugs that Inhibit Leukotriene Synthesis/Activity

• Zileuton inhibits 5-lipoxygenase
• Antiasthmatic
• Zyflo
• Zarfirlukast, Montelukast
• Cys-LT receptor antagonists
• Antiasthmatic
• Accolate, Singulair

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(Zyflo)
Montelukast (Singulair)
Zafirlukast (Accolate)
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Glucocorticoids

• For antiinflammatory activity, work through both
  innate and adaptive responses
• Through induction/inhibn transcription of
  modulator proteins
• Innate via cyclooxygenase modulation, leukocyte
  mediators
• Adaptive via cytokines and pathogen-assocd prots

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Innate Responses via Leukocytes

• Mediators gend from both cells and plasma
• Modify, regulate vascular and cellular events
• Tissue macrophages recognize pathogen-assocd
  molec patterns on invading microorganisms
• Interaction triggers release cytokines (esp IL-1,
  TNF-a, chemokines)

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• IL-1, TNF-a ? vasc dilation, fluid exudation
• Exudate has enz cascade mols ? kinin system,
  complement system
• ? release histamine from mast cells ? local
  dilation arterioles
• W/ local tissue damage ? cytokines reld ?
  eicosanoids synthd (PGI2, PGE2 ? vasodilation,
  leukotrienes ? chemotaxis prots)
• Expression of adhesion mols on cell surfaces
• Draw leukocytes toward pathogen ? phagocytosis

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Adaptive Responses via Leukocytes

• Lymphocytes T cells, B cells
• Cloned for specific attack on partic invader
• Humoral response via B cells, Abs
• Cell mediated response via T cells
• Produce various prots to modulate, coordinate
  responses of other leukocytes (innate and
  adaptive)

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Endogenous Glucocorticoids

• Steroids secrd by adrenal cortex
• Synthd, reld w/ ACTH from ant pit
• ACTH secrn regulated
• Corticotropin Releasing Factor from hypothal
• Blood glucocorticoid
• CRF secrn regulated
• Blood glucocorticoid
• CNS input
• Opioid peptides inhibitory
• Psych factors inhibitory or stimulatory
• Injury, infection

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• Basal glucocorticoids in blood
• Highest 8 a.m.
• Lowest midnight
• Metabolic actions
• Carbohydrate decrd uptake, utilization glu
  incrd gluconeogenesis ? hyperglycemia
• Proteins incrd catab decrd anab
• Fat permissive lipolysis fat redistn
• Regulation of inflammatory response

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Mechanism of Antiinflammatory Action

• Glucocorticoid receptors cytoplasmic
• Steroid hormones lipophilic
• Control gene transcrn
• Found in most cells
• 3000 to 10000 per cell, depending on tissue
• Receptor binding ? conforml change ? exposure
  DNA-binding domain and dimerization
• Bound dimer ? nucleus
• Bind steroid response elements on DNA
• ? Repression or induction partic genes

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Glucocorticoids Repress Transcrn

• Through inhibn transcrn factors AP-1, NF-kB
• ? Repression genes for COX-2
• So no prostanoids, leukotrienes
• ? Repression genes for cytokines, adhesion
  factors
• So lessens macrophage activity
• Others

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Glucocorticoids Induce Transcrn

• Annexin-1 ( lipocortin-1)
• Impt to neg faeedback control at hypothal/ant
  pit
• Antiinflammatory (inhibits PLA2?)
• Others
• Take sev hours

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Antiinflammatory Actions of Glucocorticoids

• Redd vasodilation, decrd fluid exudation
• At acute inflammn ? decrd influx, activity of
  leukocytes
• At chronic inflammn ? decrd activity
  macrophages, decrd angiogenesis
• Decrd prodn, action of cytokines (ILs, TNF),
  eicosanoids, IgG, complement components
• Overall redn chronic inflammn, autoimmune
  rxns BUT decrd healing, protections of inflamm
  responses

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• Decrd redness, heat, pain, swelling
• Decrd wound healing, repair
• Regardless of cause of inflammn
• Invaders, chem/phys stimuli, hypersensitivity/auto
  immunity
• Used to suppress graft rejection
• May prevent overshoot of endogenous responses

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Unwanted Effects

• Occur w/ large doses, prolonged admin
• Suppression of response to infection, injury
• Sudden withdrawal ? suppression ability
  synthesize endogenous hormones
• Metabolic, water/electrolyte effects w/
  endogenous hormones
• Swelling, Cushings syndrome

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• Calcium, phosphate regulation by endogenous
  hormones
• So osteoporosis
• Metabolic effects of endogenous hormones
• So growth inhibn in children

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Pharmacokinetics

• Various routes of admin
• Active orally
• IM/IV
• Topically
• Fewer side effects
• Binding to corticosteroid-binding globulin and
  albumin
• Bound forms inactive
• Hydrocortisone ½ life 90 mins (main biol effects
  in 2-8 h)

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Clinical Uses

• Replacement in adrenal failure (Addisons
  disease)
• Antiinflammatory for asthma skin/ear/ eye
  inflammn hypersensitivity disorders autoimmune
  disorders transplant pts
• Neoplastic disease for redn cerebral edema in
  combination w/ cytotoxic drugs antiemesis w/
  chemotherapy

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Corticosteroid Agents

• Hydrocortisone
• Cortisone
• Corticosterone
• Prednisolone
• Prednisone
• Methylprednisolone
• Triamcinolone

• Dexamethasone
• Betamethasone
• Beclometasone dipropionate
• Budesonide
• Deoxycortone
• Fludrocortisone
• Aldosterone

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Hydrocortisone
Corticosterone
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• http//opioids.com/heroin/heroinhistory.html
• www.library.ucla.edu
• inventors.about.com/library/inventors/blaspirin.ht
  m
• http//www.intelihealth.com/IH/ihtIH/WSIHW000/8124
  /23697/237089.html?ddmtContent