Nonsteroidal Anti- inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Dr. Florencia D. Munsayac.
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Nonsteroidal Anti-inflammatory Drugs, Disease-Modifying
Antirheumatic Drugs, Nonopioid Analgesics, &
Drugs Used in Gout
Dr. Florencia D. Munsayac
The Inflammatory Response
3 Phases of Inflammation:- Acute Inflammation
- The Immune Response
- Chronic Inflammation
Some of the mediators of acute inflammation & their effects
Mediators Vasodilation Vascular
PermeabilityChemotaxis Pain
Histamine ++ - -
Serotonin +/- - -
Bradykinin +++ - +++
Prostaglandins +++ +++ +
Leukotrienes - +++ -
Some of the Mediators of Chronic Inflammation
Mediators Sources Primary Effects
Interleukins-1,-2, and -3
Macrophages, T lymphocytes
Lymphocyte activation, PG production
GM-CSF T lymphocytes, endothelial cells, fibroblast
Macrophage & granulocyte activation
TNF-alpha Macrophages PG production
Interferons Macrophages, endothelial cells, T lymphocytes
Many
PDGF Macrophages, endothelial cells, fibroblasts, platelets
Fibroblast chemotaxis, proliferation
Therapeutic Strategy
2 Primary Goals:- The relief of pain
- NSAIDs - Nonopioid analgesics
- Corticosteroids- The slowing or--in theory--arrest of the
tissue damaging process- SAARDs or DMARDs
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
8 Groups of NSAIDs:1. Salicylic acid derivatives (Aspirin, Na salicylate, choline Mg+
+ trisalicylate, salsalate, diflusinal, sulfasalazine)2. Para-aminophenol (Acetaminophen)3. Para-chlorobenzoic acid derivatives or indoles (Indomethacin,
Sulindac)4. Pyrazolone derivatives (Phenylbutazone)5. Arylpropionic acid (Ibuprofen, Flurbiprofen, Ketoprofen,
Fenoprofen, Naproxen, Oxaprozin)6. Fenamates/Anthranilic acids (Mefenamic Acid, Meclofenamic
acid)7. Enolic acids/Oxicams (Piroxicam, Meloxicam)8. Heteroaryl/Penylacetic acids (Diclofenac Sodium, Tolmetin,
ketorolac)9. Alkalones (Nabumetone)10. Selective COX-2 inhibitors (Celecoxib, Rofecoxib, Etodolac,
Nimesulide)
SALICYLATES
• Aspirin or Acetylsalicylic Acid (ASA)– Comes from the family of salicylates
derived from salicylic acid– Prototype drug– Developed in 1899 by Adolph Bayer– The oldest anti-inflammatory agent
SalycilatesPharmacokinetics
• Rapidly absorbed from the stomach & upper small intestine
• Peak plasma level: 1-2 hrs• 80-90% protein bound• t1/2: 3-5 hrs• Cross BBB & placental barrier • Undergoes hepatic metabolism• Excretion: kidneys
SalycilatesPharmacodynamics
. MOA:- Inhibits prostaglandin synthesis- Irreversibly blocks the enzyme
cyclooxygenase (PG synthase). Pharmacological Properties & Therapeutic
indications: - anti-inflammatory effects- analgesic effects - antipyretic effects- Platelet effects- Uricosuric effects
. Dosage: children: 50-75mg/kg/day adult: 325-650mg p.o. q 4 hrs
SalicylatesAdverse Effects
• Gastric upset • Salicylism vomiting, tinnitus, decreased
hearing, & vertigo• Hyperpnea• Respiratory alkalosis later acidosis
supervenes• Glucose intolerance• Carditoxicity• Increases uric acid levels• Elevation of liver enzymes, hepatitis, decreased
renal function, bleeding, rashes, asthma• Reye’s syndrome
SalicylatesContraindications
• Pregnancy• Severe hepatic damage• Vitamin K deficiency• Hypoprothrombinemia• Hemophilia• PUD• Viral (chickenpox & influenza)
Special Drug Characteristics or NonAcetylated Salicylates
• Sodium salicylate, sodium thiosalicylate, Mg salicylate & choline salicylate
• Salisalicylate• Methylsalicylate (oil of wintergreen)• Diflunisal
ACETAMINOPHEN
• Active metabolite of phenacetine• A weak PG inhibitor• No significant anti-inflammatory
effect• For the treatment of mild to
moderate pain• Antipyretic effect
AcetaminophenPharmacokinetics
• Administered orally• Absorption: related to rate of gastric emptying• Peak blood conc: 30-60 min• Slightly protein bound• Partially metabolized by hepatic microsomal
enzyme acetaminophen SO4 & glucuronide• Excretion: unchanged < 5%• A minor but highly active metabolite (N-acetyl-p-
benzoquinone) is important liver & kidney toxicity
• t1/2: 2-3 hrs
AcetaminophenIndications
• HA, myalgia, postpartum pain• ASA allergy, hemophilia or hx of PUD,
bronchospasm precipitated by ASA, & children with viral infection
• Analgesic adjunct to anti-inflammatory therapy
• Gout
AcetaminophenAdverse Effects
• Mild increase in hepatic enzymes• Dizziness, excitement & disorientation• Ingestion of 15gm: fatal death caused by
hepatotoxicity with centrilobular necrosis & sometimes with acute renal tubular necrosis
• Symptoms of early hepatic damage: N/V, diarrhea, abdominal pain
• Antidote: acetylcysteine (sulfhydryl groups)• Caution: liver disease• Dosage: 325-500mg q.i.d.
INDOMETHACIN
• Introduced in 1963• An indole derivative• A more potent analgesic, antipyretic
& anti-inflammatory agent than ASA • Nonselective COX inhibitor• May also inhibit phospholipase A & C• Reduce PMN migration• Decrease T & B cells proliferation
IndomethacinPharmacokinetics
• Rapidly & almost completely absorbed from GIT
• Peak concentration: 2 hrs• Metabolism: liver & extensive
enterohepatic circulation • Excretion: bile, urine, feces
IndomethacinTherapeutic Uses
• Rheumatic conditions• Gout & ankylosing spondylitis• Patent ductus arteriosus• Sweet’s syndrome• Juvenile rheumatoid arthritis• Pleurisy• Nephrotic syndrome• Tocolytic agent
IndomethacinAdverse Effects
• Gastrointestinal effects (abdominal pain, diarrhea, GI hemorrhage, pancreatitis)
• Headache, dizziness, confusion, depression
• Psychosis with hallucination• Thrombocytopenia• Aplastic anemia• hyperkalemia
IndomethacinContraindications
• Nasal polyps• Angioedema• Asthma• Renal failure• Enterocolitis• hyperbilirubinemia
SULINDAC
• A sulfoxide prodrug• An acetic acid derivative• Reversibly metabolized to active
metabolite sulfide more potent as cyclooxygenase inhibitor , enterohepatic recycling prolongs DOA: 12-16 hrs, excreted in bile
• Metabolized to an inactive sulfone
SulindacPharmacokinetics
• 90% absorbed after oral administration
• Peak concentration: 1 hr• t1/2: 7 hrs• First pass kinetics
SulindacTherapeutic Indications
• Rheumatoid arthritis• Suppresses familial intestinal
polyposis• Ankylosing spondylitis• Osteoarthritis• Acute Gout• Tocolytic agent
SulindacAdverse Effects
• GI side effects: abdominal pain & nausea
• CNS side effects: drowsiness, dizziness, HA, nervousness
• Skin rash & pruritus• Transient elevations of hepatic
enzymes
TOLMETIN
• A nonselective COX inhibitor• Effective anti-inflammatory with
analgesic & antipyretic effects• Has a short half-life: 5 hrs• Given frequently not often used• Ineffective in gout unknown• SE: allergic IgM-related
thrombocytopenic purpura, GI & CNS effects
DICLOFENAC
• A simple phenylacetic acid derivative• A potent nonselective
cyclooxygenase inhibitor• Decreases arachidonic acid
bioavailability• Has the usual anti-inflammatory,
antipyretic & analgesic properties
DiclofenacPharmacokinetics
• Rapidly absorbed following oral administration
• 99% protein bound• 30-70% systemic bioavailability first
pass hepatic metabolism• t1/2: 1-2 hrs• Accumulates in synovial fluid t1/2 of 2-6
hrs• Metabolized by CYP3A4 & CYP2C9• 30% biliary clearance, urine (65%)
DiclofenacAdverse Effects
• GI distress• Occult GI bleeding• Gastric ulceration• Elevates serum aminotransferases
Preparations: ophthalmic, dermatologic, IM administration
ETODOLAC
• A racemic acetic acid derivative • Slightly more COX-2 selective, with
COX-2:COX-1 activity ratio of 10• Clinical uses: postoperative
analgesia, osteoarthritis, rheumatoid arthritis
• SE: GI irritation & ulceration (less)
EtodolacPharmacokinetics
• Rapidly well absorbed• 80% bioavailability• Strongly bound to plasma proteins
(99%)• Enterohepatic circulation• t1/2: 7 hrs• Dosage: 400-1600mg/d• Excreted in the urine
KETOROLAC
• Potent analgesic with moderate anti-inflammatory & antipyretic effects
• Inhibits platelet aggregation • Promotes gastric ulceration & renal
impairment• Indications: postsurgical pain,
chronic pain, inflammatory conditions of the eye, seasonal allergic conjunctivitis topical
Pharmacokinetics
• Rapidly absorbed after oral or IM administration
• Also given IV• Peak concentration: 30-50 min.• 80% oral bioavailability• Almost totally protein bound• t1/2: 4-6 hrs• Metabolized to active & inactive forms• Excreted in the urine (90%)
FENOPROFEN
• A propionic acid derivative• t1/2: 2-4 hrs• Given q.i.d.• Toxic effect: interstitial nephritis• Adverse effects: nephrotoxicity,
nausea, dyspepsia, peripheral edema, rash, pruritus, CNS & CVS effects and tinnitus
FLURBIPROFEN
• A propionic acid derivative• Inhibits COX nonselectively• Also affect TNF-a & nitric oxide synthesis• t1/2: 0.5-4 hrs• Extensive hepatic metabolism• Dosages: 200-400mg/day• Ophthalmic formulation inhibition of
intraoperative miosis• SE: GI symptoms, cogwheel rigidity,
ataxia, tremor & myoclonus
IBUPROFEN• A simple derivative of phenylpropionic acid• Dose: 2400mg daily• 99% protein bound• Rapidly cleared• Terminal t1/2: 1-2 hrs• Extensively metabolized in CYP2C8 & CYP2C9 in
the liver• SE: GI irritation & bleeding• CI: nasal polyps, angioedema, bronchospastic
reactivity to ASA, rash, pruritus, tinnitus, dizziness, HA, aseptic meningitis, fluid retention, agranulocytosis, aplastic anemia, ARF, interstitial nephritis, nephrotic symdrome
KETOPROFEN
• A propionic acid derivative • Inhibits both cyclooxygenase
(nonselective) & lipoxygenase• Rapidly absorbed• Elimination t1/2: 1-3 hrs• Metabolized in the liver (glucuronide)• DI: probenicid• Dosage: 100-300mg/day• Indication: RA, OA, GA, dysmenorrhea• AE: GIT & CNS
NAPROXEN
• Is a naphthylpropionic acid• A nonselective COX inhibitor• Elimination serum t1/2: 12 hrs• High albumin binding• Metabolism: CYP2C9, less in CYP1A2 &
CYP2C8• Prep: SR formulation, oral susp• AE: UGIB, allergic pneumonitis,
leukocytoclastic vasculitis, & pseudoporphyria
OXAPROZIN
• a propionic acid derivative• t1/2: 50-60 hrs• Does not undergo enterohepatic
circulation• Given o.d.• Is a mild uricosuric agent
PIROXICAM
• An oxicam• A nonselective COX inhibitor• Also inhibits PMN leukocyte
migration, decreases O2 radical production, & inhibits lymphocyte function
• Mean t1/2: 50-60 hrs• Dosing: o.d. or every other day
PiroxicamPharmacokinetics
• Rapidly absorbed from the stomach & upper intestine
• Peak plasma concentration: 1 hr• Extensively metabolized to inactive
metabolites• 99% protein bound• Elimination: renal – 5% unchanged• Toxicity: GI symptoms, dizziness, tinnitus,
HA & rash, increased incidence of PUD and bleeding
MELOXICAM
• An enolcarboxamide• Slightly COX-2 selective• Slowly absorbed• t1/2: 20 hrs• Clearance: 40% decreased in elderly• Dose: 7.5-15mg/d for RA & OA• Slightly less ulcerogenic
NABUMETONE
• The only nonacid NSAID• Converted to the active acetic acid
derivative in the body• Given as a ketone prodrug• t1/2: > 24 hrs• Deos not undergo enterohepatic
circulation• Cause less gastric damage• Cause pseudoporphyria & phosensitivity
PHENYLBUTAZONE
• A pyrazolone derivative• Withdrawn from the market in North
American & most European markets• Toxicity: aplastic anemia
agranulocytosis
MECLOFENAMATE & MEFENAMIC ACID
• Fenamic acid derivatives• Inhibit both COX & phospholipase A2• Peak plasma level: 30-60 min• t1/2: 1-3 hrs• SE: LBM, abdominal pain (meclofenamate)• CI: pregnancy, children• DI: oral anticoagulants
CELECOXIB
• Highly selective COX-2 inhibitor• Absorption: 20-30% decreased by food• t1/2: 11 hrs• Highly protein bound• Metabolized by CYP2C9• Clearance affected by hepatic impairment • Effective dose: 100-200mg b.i.d.• Does not affect platelet aggregation• DI: warfarin• AR: dyspepsia
ROFECOXIB• A furanose derivative• A potent highly selective COX-2 inhibitor• Well absorbed• Dosage range: 12.5-50mg/d• Slightly less protein-bound (87%)• t1/2: 17 hrs• Given o.d., for OA• Metabolized by cytosolic liver enzymes• Does not inhibit platelet aggregation• Have little effect on gastric mucosal PGs• Associated with fewer gastric or duodenal
gastroscopic ulcers
CORTICOSTEROID DRUGS
• Capable of slowing the appearance of new bone erosions
• Known to inhibit phospholipase A2• Shown to selectively inhibit the
expression of COX-2• SE: fracture, infections, cataracts• Prep: oral, intra-articular
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS)
• Might arrest or at least slow the progression of bone & cartilage destruction
• Effects may take 6 weeks to 6 months to become evident
• Include: methotrexate, azathioprine, penicillamine, hydroxychloroquine, chloroquine, organic gold compounds, sulfasalazine, leflunomide, TNF-blocking agents, & immunoadsorption apheresis
METHOTREXATE• A potent immunosuppressive drug• MOA: inhibition of aminoimidazolecarboxamide
ribonucleotide (AICAR) transformylase & thymidylate synthase, plus enhanced adenosine release
• Absorption: 70% after oral administration• Highly polyglutaminated• Excretion: urine & bile• Dose: 25mg/wk• Toxicities: nausea, mucosal ulcers, dose-related
hepatotoxicity, “hypersensitivity” lung reaction, pseudolymphomatous reaction
• Folic acid & leucovorin
ANKYLATING AGENTS(CHLORAMBUCIL)
• MOA: probably through its metabolic phenylacetic acid mustard, cross-links DNA, thereby preventing cell replication
• Bioavailability: 70%• Completely metabolized• Complete excretion within 24 hrs• Other indications: SLE, vasculitis,• Toxicities: BM suppression, infertility, risk
of neoplasia & leukemia
ALKYLATING AGENTS(CYCLOPHOSPHAMIDE)
• MOA: through it active metabolite, phosphoramide mustard, cross-links DNA & prevents cell replication, it suppresses T & B cell functions by 30-40%
• Metabolized in the liver• Given orally at 2mg/kg/d• Toxicities: infertility, BM suppression,
hemorrhagic cystitis, bladder Ca acrolein
• Other indications: SLE
CYCLOSPORINE
• Acts through IL-2 & TNF-a suppression• Its major actions in rheumatic diseases
appear to be mediated through T cell effects
• Absorption: erratic• Bioavailability: 30%• Metabolized in the liver• Dosage: 3-5mg/kg/d• Toxicities: nephrotoxicity, HTN,
hyperkalemia, hepatotoxicity, gingival hyperplasia, & hirsutism
AZATHIOPRINE
• Acts through its major metabolite, 6-thioinosinic acid, to suppress inosinic acid synthesis and B & T cell functions
• Dosage: 2mg/kg/d• Other indications: SLE, Behcet’s syndrome• Toxixcities: BM suppression, GI
disturbances, increased in risk for infections and malignancy
ANTIMALARIAL DRUGS(CHLOROQUINE,
HYDROXYCHLOROQUINE)• Used for the treatment of RA & SLE• MOA: unclear• They suppress the responsiveness of T
lymphocytes to nitrogens, decrease leukocyte chemotaxis, stabilize lysosomal membranes, inhibit DNA & RNA synthesis and trap free radicals
• Effects are seen after 12-24 weeks• Other indications: juvenile chronic arthritis,
Sjogren’s syndrome, SLE
GOLD
• Prep: auranofin – oral; aurothiomalate & aurothioglucose – parenteral
• 95% protein-bound• Concentrate in synovial membrane, liver,
kidney, spleen, adrenal glands, LN, & BM• Peak serum level: 2-6 hrs• Excretion: 40% within a week, 2/3-urine;
1/3-feces• Total body t1/2 (IM) – 1 year
GoldPharmacodynamics
• alters the morphology and functional capabilities of human macrophages
• inhibition of lysosomal enzyme activity• reduction of histamine release from mast cells• inactivation of the first component of complement• suppression of phagocytic activity of the PMN
leukocytes• inhibition of the Swartzman phenomenon• Aurothiomalate reduces the number of circulating
lymphocytes• Auranofin inhibits the release of PGE2 from
synovial cells and the release of leukotrienes B4 & C4 from PMN leukocytes
GoldIndications & Contraindications
• Active RA• Active inflammation & erosive
changes• RA with Sjogren’s syndrome • Juvenile RA• CI: hx of previous toxicity from the
drug, pregnancy, serious liver & renal impairment & blood dyscrasia
GoldAdverse Effects
• Dermatitis - 15-20% (most common)• Thrombocytopenia, leukopenia, pancytopenia – 1-
10%• Aplastic anemia – rare but fatal• Proteinuria nephrotic syn – 8-10%• Stomatitis, metallic taste, skin pigmentation,
enterocolitis, cholestatic jaundice, peripheral neuropathy, pulmonary infiltrates, & corneal deposition of gold
• Nitritoid reaction (sweating, faintness, flushing, & headache)
• GI disturbances (LBM), dermatitis
PENICILLAMINE
• A metabolite of penicillin• Is an analog of amino acid cysteine• Absorption: half of the orally
administered, enhanced after 1.5 hrs p.c.
• Excretion: urine & feces in 24 hrs
PenicillaminePharmacodynamics
• Interact with lymphocytes membrane receptors
• Interfere with the synthesis of DNA, collagen, & mucoplosaccharides
PenicillamineAdverse Effects
• Decrease RF titer• Impedes absorption of many drugs• Inhibition of wound healing• Muscle & blood vessel damage• Proteinuria – 20%• Immune complex nephritis – 4%• Leukopenia & thrombocytopenia aplastic anemia• Skin & mucosal membrane reactions• Drug fever associated with cutaneous eruption• Any of these maybe seen: myasthenia gravis, hemolytic
anemia, thyroiditis, Goodpasture’s syndrome & SLE• Loss of taste perception or metallic taste• Anorexia, N/V• Mammary hyperlasia, alopecia, & psychologic changes
PenicillamineContaindications & Drug Interactions
• Pregnancy• Renal insufficiency • DI: gold, cytotoxic drugs or
phenylbutazone• Dose: 125-250mg daily for 1-3
months, 1.5 hrs p.c.
SULFASALAZINE
• Consists of sulfapyridine & 5-amino-salicylic acid connected by diazo bond
• Metabolized by bacteria in the colon• Have some anti-inflammatory action by O2
radical scavenging & inhibition of prostanoids and inhibit immune reactivity
• t1/2: 6-17 hrs• Dose: 2-3g/d• Uses: RA, reducing bone erosion, juvenile
arthritis & ankylosing spondylitis
ANTI-TNF-ALPHA DRUGS(INFLIXIMAB)
• Monoclonal Ab that binds with high affinity to human TNF-a
• Given IV infusion• Terminal t1/2: 8-12 days• Dose: 3 or 10 mg/kg at 0, 2, & 6 wks• SE: upper RTI, nausea, headache,
sinusitis, rash & cough with MTX
ANTI-TNF-ALPHA DRUGS(ETANERCEPT)
• A recombinant fusion protein that consists of 2 soluble TNF p75 receptor moieties linked to Fc portion of human IgG
• It binds 2 TNF-alpha molecules• Peak serum conc: 72 hrs• Dose: 25mg SC twice weekly• Uses: psoriatic arthritis, juvenile chronic
arthritis• SE: injection site reactions – pain,
erythema, swelling, itching (20-40%)
LEFLUNOMIDE
• A77-1726 (active metabolite) inhibits dihydroorotate dehydrogenase decrease de novo RNA synthesis and lower levels of rUMP translocation of p53 to nucleus inhibits autoimmune T cell proliferation & production of autoantibodies by B cells
• Increases the mRNA level of IL-10 receptor, decreases IL-8 receptor type A mRNA concs & blocks TNF-dependent nuclear factor-kappa B activation
LeflunomidePharmacokinetics
• Orally active molecule• MW: 270• Absorption: rapidly & nearly 100%plasma
t1/2: 15 days• Strong protein binding• Enterohepatic circulation• Excretion: bile• DI: cholestyramine• SE: diarrhea, elevation of liver enzymes
IMMUNOADSORPTION APHERESIS
• Contains staphylococcal protein A bound to silica matrix designed to remove IgG & IgG-containing immune complexes from plasma
• Median duration of response: 6 months
• SE: chills – 30%, musculoskeletal pain – 15%, HA & nausea – 20-30%, joint pains & swelling – 30%
DRUGS USED IN GOUT(COLCHICINE)
• An alkaloid from autumn crocus, Colchicum autumnale• Dramatically relieves pain, anti-inflammatory effects by
binding to IC protein tubulin preventing polymerization into microtubules inhibition of leukocyte migration & phagocytosis
• Absorption: readily absorb after oral administration• Peak serum level: 2 hrs• Excretion: intestinal tract & urine• Indication: gouty arthritis, acute mediterranean fever,
sarcoid arthritis, hepatic cirrhosis• Dosage: 0.5-1 mg q 2 hrs• SE: LBM, N/V, abd pain, hair loss, BM depression, peripheral
neuritis, myopathy• Acute intoxication: burning throat pain, bloody LBM, shock,
hematuria, oliguria, ascending CNS depression
NSAIDs in GOUT
• Inhibit urate crystal phagocytosis• Endomethacin is the agent most often
used – 50 mg q 6 hrs reduced to 25mg t.i.d or q.i.d. for 5 days
• ASA, salicylates, tolmetin are not effective for gouty episodes
• Oxaprozin, lowers serum uric acid, but not given to patients with uric acid stone
URICOSURIC AGENTS(Probenecid & Sulfinpyrazone)
• Are organic acids• Act at the anionic transport sites of
the renal tubule• Probenecid: completely reabsorbed
by renal tubules & metabolized slowly
• Sulfinpyrazone: rapidly excreted by the kidneys
Probenecid &SulfinpyrazonePharmacodynamics
• Employed to decrease the body pool of urates
• Reabsorption of uric acid in the proximal tubule is decreased
Probenecid & SulfinpyrazoneAdverse Effects, CI & Cautions
• AE: GI irritation, allergic dermatitis, nephrotic syndrome (probenecid), apalstic anemia
• CI & C: stone formation• Dosage: probenecid – 0.5 gm orally
in divided doses, sulfinpyrazone – 200 mg daily
ALLOPURINOL• Reduce uric acid synthesis by inhibiting xanthine
oxidase and increasing uric acid excretion• Absorption: 80% after oral administration• Metabolized by xanthine oxidase• Given o.d.• Indications: chronic tophaceous gout, uric acid
urine (24hrs) > 600-700mg, allergic reactions to probenecid & sulfinyrazone, renal impairment, grossly elevated serum uric acid levels
• AE: N/V, diarrhea, peripheral neuritis, necrotizing vasculitis, BM depression, aplastic anemia, hepatic toxicity, interstitial nephritis, allergic skin reaction, cataracts
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