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Mefenamic Acid Introduction Mefenamic acid is a prototypical nonsteroidal anti-inflammatory agent (NSAIA) that also exhibits analgesic and

d antipyretic activity !ses "ain Mefenamic acid is used to relieve mild to moderate pain #hen the duration of therapy #ill not exceed $ #ee% $&' (he drug has been used in the management of postoperative pain and pain follo#ing insertion of an intrauterine contraceptive device (here are fe# published studies comparing the effectiveness of mefenamic acid #ith other analgesics) and longterm safety and efficacy of the drug have not been established (herefore) determination of the relative value of mefenamic acid must a#ait further studies In the treatment of nonspecific pain associated #ith cancer) &'*-mg oral doses of mefenamic acid appear to be at least as effective as +'*-mg oral doses of acetaminophen) +'*-mg oral doses of aspirin) +'-mg oral doses of codeine) or '*-mg oral doses of penta,ocine "atient response to oral NSAIAs is variable- patients #ho do not respond to or cannot tolerate one NSAIA might be treated successfully #ith a different agent .o#ever) NSAIAs are generally contraindicated in patients in #hom sensitivity reactions (e g ) urticaria) bronchospasm) severe rhinitis) are precipitated by aspirin or other NSAIAs (See /autions0 "recautions and /ontraindications ) 1ysmenorrhea Mefenamic acid is used in the management of primary dysmenorrhea $&' 2hen used to relieve dysmenorrhea in one study) &'*-mg doses of mefenamic acid administered 3 times daily beginning #ith the onset of menses or pain #ere more effective than placebo In a controlled study of #omen #ith menorrhagia) administration of '** mg of mefenamic acid 4 times daily resulted in a reduction in blood loss of up to 5*6 and #as accompanied by a reduction in duration of dysmenorrhea and menstrually related headache 7ther !ses Mefenamic acid has been used for its antipyretic effect in the management of fever associated #ith infection in children In one study) the antipyretic effect of usual dosages of mefenamic acid #as about e8ual to that of usual dosages of aspirin (he drug) ho#ever) should not be used routinely as an antipyretic because of its potential adverse effects 1osage and Administration Administration Mefenamic acid is administered orally) preferably #ith food 1osage "ain and 1ysmenorrhea 9or relief of acute) mild to moderate pain or primary dysmenorrhea in adults or children older than $3 years of age) the usual initial dose of mefenamic acid is '** mg) follo#ed by &'* mg every + hours as necessary $&' 9or relief of acute pain) the drug should not be administered for longer than $ #ee% $&' 9or relief of primary dysmenorrhea) mefenamic acid therapy should be initiated #ith the onset of bleeding and associated symptoms and should not be necessary for more than &-4 days $&' /autions :I ;ffects Adverse reactions to mefenamic acid mainly involve the :I tract and may include diarrhea) nausea #ith or #ithout vomiting) abdominal pain) dyspepsia) heartburn) flatulence) constipation) gross bleeding<:I perforation) and peptic ulcer #ith or #ithout bleeding 1ry mouth)$&' esophagitis)$&' gastritis)$&' glossitis)$&' stomatitis)$&' #eight changes)$&' appetite changes)$&' eructation)$&' and hematemesis$&' have occurred in patients receiving mefenamic acid $&' Adverse :I effects may be minimi,ed by administering mefenamic acid #ith food In one study) the amount of :I bleeding as determined by fecal blood loss #as reported to be less #ith & g of mefenamic acid daily than #ith & + g of aspirin daily Although a causal relationship has not been directly determined) one case-control analysis suggests that NSAIAs may contribute to the formation of esophageal stricture in patients #ith gastroesophageal reflux Serious adverse :I effects (e g ) bleeding) ulceration) perforation) can occur at any time in patients receiving chronic NSAIA therapy) and such effects may not be preceded by #arning signs or symptoms $**) $*$) $*3 Minor upper :I effects (e g ) dyspepsia)) #hich usually develop early) occur commonly during NSAIA therapy) but the absence of such early :I manifestations does not preclude the development of serious :I toxicity in patients receiving chronic NSAIA therapy $**) $*$ (herefore) clinicians should remain alert to the possible development of serious :I effects (e g ) bleeding) ulceration) in any patient receiving chronic NSAIA therapy) and such patients should be follo#ed chronically for the development of manifestations of such effects and advised of the importance of this follo#-up $**) $*$ In addition) patients should be advised about the signs and symptoms of serious NSAIAinduced :I toxicity and #hat action to ta%e if they occur $**) $*$

=esults of studies to date are inconclusive concerning the relative ris% of various prototypical NSAIAs in causing serious :I effects $**) $*$ In patients receiving NSAIAs and observed in clinical studies of several months> to & years> duration) symptomatic upper :I ulcers) gross bleeding) or perforation appeared to occur in approximately $6 of patients treated for 4-+ months and in about &-36 of those treated for $ year $**) $*$ .igh dosages of any NSAIA probably are associated #ith increased ris% of such effects) although controlled studies documenting this probable association are lac%ing for most NSAIAs $**) $*$ (herefore) #henever use of relatively high dosages (#ithin the recommended dosage range) is considered) sufficient benefit to offset the potential increased ris% of :I toxicity should be anticipated $**) $*$ Studies have sho#n that patients #ith a history of peptic ulcer disease and<or :I bleeding #ho are receiving NSAIAs have a substantially higher ris% of developing :I bleeding than patients #ithout these ris% factors $&3) $&+ In addition to a history of ulcer disease) pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the ris% for :I bleeding) including concomitant administration of oral corticosteroids or anticoagulants) longer duration of NSAIA therapy) smo%ing) alcoholism) older age) and poor general health status $&3) $&+) $&5 Most spontaneous reports of fatal :I effects have been in geriatric or debilitated patients $&' 9or patients at high ris% for complications from NSAIA-induced :I ulceration (e g ) bleeding) perforation)) concomitant use of misoprostol can be considered for preventive therapy $&3) $&? (See Misoprostol '+0@& ) Alternatively) some clinicians suggest that a proton-pump inhibitor (e g ) omepra,ole) may be used concomitantly to decrease the incidence of serious :I toxicity associated #ith NSAIA therapy $&3 .ematologic ;ffects (he most common adverse hematologic effect of mefenamic acid is a decrease in hematocrit) principally in patients #ho have received the drug for prolonged periods Aeu%openia) eosinophilia)$&' agranulocytosis)$&' pancytopenia)$&' ecchymosis) $&' melena)$&' purpura) $&'rectal bleeding)$&' thrombocytopenia)$&' hemolytic anemia) $&' aplastic anemia) $&' and lymphadenopathy$&' have also been reported occasionally $&' Since mefenamic acid can inhibit platelet aggregation) patients #ho may be adversely affected by a prolongation of bleeding time should be carefully observed during mefenamic acid therapy Nervous System ;ffects Adverse nervous system effects occur occasionally in patients receiving mefenamic acid and may include dro#siness)$&' di,,iness)$&' nervousness$&') headache)$&' anxiety)$&' asthenia)$&' confusion)$&' depression)$&' dream abnormalities)$&' malaise)$&' paresthesia)$&' somnolence)$&' tremors)$&' vertigo)$&' and insomnia $&' Sei,ures)$&' coma)$&' hallucinations)$&' or meningitis$&' has occurred rarely in patient receiving mefenamic acid $&' 7cular and 7tic ;ffects Blurred vision) $&' tinnitus)$&' conCunctivitis)$&' and hearing impairment$&' have occurred in patients receiving mefenamic acid "atients #ho experience visual disturbances during therapy #ith the drug should have an ophthalmologic examination =enal ;ffects Abnormal renal function)$&' edema)$&' cystitis)$&' dysuria)$&' hematuria)$&' interstitial nephritis)$&' oliguria<polyuria)$&' proteinuria)$&' and renal failure$&' have been reported in mefenamic acid-treated patients $&' Aong-term mefenamic acid therapy has resulted in renal papillary necrosis and other renal medullary changes $&' .epatic ;ffects Mild hepatotoxicity has been reported during mefenamic acid therapy Borderline elevations of one or more liver function test results may occur in up to $'6 of patients treated #ith NSAIAs- meaningful (4 times the upper limit of normal) elevations of serum AA( (S:"() or AS( (S:7() concentration have occurred in less than $6 of patients receiving NSAIAs in controlled clinical studies (hese abnormalities may progress) may remain essentially unchanged) or may be transient #ith continued therapy .epatitis)$&' Caundice)$&' and liver failure$&' have been reported in patients receiving mefenamic acid $&' Mefenamic acid should be discontinued if signs or symptoms of a severe hepatic reaction occur (See /autions0 "recautions and /ontraindications ) 7ther Adverse ;ffects !rticaria)$&' rash) $&' pruritus)$&' alopecia)$&' photosensitivity)$&' and perspiration$&' have been reported follo#ing mefenamic acid administration =arely reported adverse effects include death)$&' angioedema)$&' anaphylactoid reactions)$&' toxic epidermal necrosis)$&' erythema multiforme)$&' exfoliative dermatitis)$&' and Stevens-Dohnson syndrome $&' /ongestive heart failure)$&' hypertension)$&' tachycardia)$&' syncope)$&' arrhythmia)$&' hypotension)$&' myocardial infarction)$&' palpitations)$&' and vasculitis$&' have occurred in mefenamic acid-treated patients $&'

Asthma)$&' dyspnea)$&' respiratory depression)$&' and pneumonia$&' have been reported in patients receiving mefenamic acid $&' 7ther adverse effects reported in these patients include fever)$&' infection)$&' sepsis)$&' hyperglycemia)$&' and pancreatitis $&' "recautions and /ontraindications "atients should be advised that mefenamic acid) li%e other NSAIAs) is not free of potential adverse effects) including some that can cause discomfort) and that) rarely) more serious effects (e g ) :I bleeding)) #hich may re8uire hospitali,ation and may even be fatal) can occur $**) $*$ "atients also should be informed that) #hile NSAIAs may be commonly employed for conditions that are less serious) NSAIA therapy often is considered essential for the management of some diseases (e g ) rheumatoid arthritis)) and the drugs have a maCor role in the management of pain $**) $*$ /linicians may #ish to discuss #ith their patients the potential ris%s and li%ely benefits of NSAIA therapy) particularly #hen consideration is being given to use of these drugs in less serious conditions for #hich therapy #ithout a NSAIA may represent an acceptable alternative to both the patient and clinician $**) $*$ (he ris% of potentially serious adverse :I effects should be considered in patients receiving mefenamic acid) particularly in patients receiving chronic therapy #ith the drug $**) $*$ Mefenamic acid should be used #ith caution in patients #ith a history of :I disease and such patients should receive an appropriate ulcer preventive regimen $*@) $$3) $$') $$+ All patients considered at increased ris% of potentially serious adverse :I effects (e g ) geriatric patients) those receiving high therapeutic dosages of NSAIAs) those #ith a history of peptic ulcer disease) those receiving anticoagulants or corticosteroids concomitantly) should be closely monitored for signs and symptoms of ulcer perforation or :I bleeding $*@) $$3) $$') $$+ Mefenamic acid is contraindicated in patients #ith active ulceration or chronic inflammation of the upper or lo#er :I tract 9or additional information) see /autions0 :I ;ffects (he possibility that the antipyretic and anti-inflammatory effects of NSAIAs may mas% the usual signs and symptoms of infection or other diseases should be considered ;levations in serum AA( may be the most sensitive indicator of NSAIA-induced liver dysfunction "atients #ho experience signs and<or symptoms suggestive of liver dysfunction or an abnormal liver function test result #hile receiving mefenamic acid should be evaluated for evidence of the development of a severe hepatic reaction Severe reactions) including Caundice and<or fatal hepatitis) have occurred during therapy #ith other NSAIAs Although such reactions are rare) mefenamic acid should be discontinued if abnormal liver function test results persist or #orsen) if clinical signs and symptoms consistent #ith liver disease develop) or if systemic manifestations occur (e g ) eosinophilia) rash) Because renal prostaglandins may have a supportive role in maintaining renal perfusion in patients #ith prerenal conditions) administration of a NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation "atients at greatest ris% of this reaction include those #ith impaired renal function) heart failure) or hepatic dysfunction- those #ith extracellular fluid depletion (e g ) patients receiving diuretics)- those receiving a nephrotoxic drug concomitantly- those #ith elevated levels of angiotensin II or catecholamines- and geriatric patients =ecovery of renal function to pretreatment levels usually occurs follo#ing discontinuance of NSAIA therapy (he manufacturer states that mefenamic acid should not be administered to patients #ith substantial renal impairment) since the drug is eliminated principally by the %idneys (he manufacturer also states that the drug should be avoided in patients #ith preexisting renal disease !se of corticosteroids during NSAIA therapy may increase the ris% of :I ulceration) and the drugs should be used concomitantly #ith caution $*?) $$& Mefenamic acid is contraindicated in patients #ith %no#n hypersensitivity to the drug and in patients in #hom urticaria) bronchospasm) or allergic rhinitis is precipitated by aspirin or other NSAIAs NSAIAs generally are contraindicated in patients in #hom urticaria) angioedema) bronchospasm) severe rhinitis) or shoc% is precipitated by aspirin or other NSAIAs) although the drugs have occasionally been used in NSAIA-sensitive patients #ho have undergone desensiti,ation 9or further discussion of cross-sensitivity of NSAIAs) see /autions0 Sensitivity =eactions) in the Salicylates :eneral Statement &50*5 *3 &3 "ediatric "recautions Safety and efficacy of mefenamic acid in children younger than $3 years of age have not been established :eriatric "recautions /aution should be observed if mefenamic acid is used in geriatric individuals $&' :eriatric individuals appear to tolerate :I ulceration or bleeding less #ell than other individuals) and many of the spontaneous reports of fatal adverse :I effects in patients receiving NSAIAs involve geriatric individuals $&' (See /autions0 :I ;ffects ) "regnancy) 9ertitlity and Aactation Although there are no ade8uate and controlled studies to date in humans) mefenamic acid has been sho#n to have various adverse effects in animals during reproduction studies 1oses up to $* times the usual human dose have resulted in a decreased rate of fetal survival-to-#eaning in rats- these doses did not result in fetal abnormalities in rats or dogs In rabbits) doses up to & ' times the usual human dose resulted in an increase in the number of fetal

resorptions Mefenamic acid inhibits prostaglandin synthesis #hich may result in prolongation of gestation and interference #ith labor if the drug is given late in pregnancy Inhibitors of prostaglandin synthesis may have adverse effects on the fetal cardiovascular system (e g ) premature closure of the ductus arteriosus)- therefore) administration of the drug during late pregnancy should be avoided Mefenamic acid should be used during pregnancy only #hen the potential benefits Custify the possible ris%s to the fetus $&' 1oses of mefenamic acid up to $* times the usual human dose have resulted in decreased fertility in rats (he effect of the drug on fertility in humans is not %no#n Mefenamic acid is distributed into mil% Because of the potential for adverse effects from mefenamic acid on the cardiovascular system in infants) a decision should be made #hether to discontinue nursing or the drug) ta%ing into account the importance of the drug to the #oman 1rug Interactions "rotein-bound 1rugs Because mefenamic acid is highly protein bound) it theoretically could be displaced from binding sites by) or it could displace from binding sites) other protein-bound drugs such as oral anticoagulants) hydantoins) salicylates) sulfonamides) and sulfonylureas "atients receiving mefenamic acid #ith any of these drugs should be observed for adverse effects Anticoagulants and (hrombolytic Agents Mefenamic acid enhances the hypoprothrombinemic effect of #arfarin If the drugs must be used concurrently) prothrombin time should be determined fre8uently and anticoagulant dosage adCusted accordingly- the patient should be observed for adverse effects In addition) the ulcerogenic potential of mefenamic acid and the effect of the drug on platelet function may further contribute to the ha,ard of concomitant therapy #ith any anticoagulant or thrombolytic agent (e g ) strepto%inase) Aithium Mefenamic acid has been reported to reduce renal lithium clearance $*') $*+ (he mechanism involved in the reduction of lithium clearance by NSAIAs is not %no#n) but has been attributed to inhibition of prostaglandin synthesis) #hich may interfere #ith the renal elimination of lithium $*' If mefenamic acid and lithium are administered concurrently) the patient should be observed closely for signs of lithium toxicity) and serum lithium concentrations should be monitored carefully during initial stages of combined therapy $*' In addition) appropriate adCustment of lithium dosage may be re8uired #hen therapy #ith mefenamic acid is discontinued $*' 7ther 1rugs Mefenamic acid should be used cautiously) if at all) #ith other drugs that might potentiate the adverse :I effects Aaboratory (est Interferences Mefenamic acid may cause a false-positive reaction for urinary bile using the dia,o tablet test If biliuria is suspected) the finding should be confirmed by other diagnostic tests (e g ) .arrison spot test) Acute (oxcicity Aimited information is available on the acute toxicity of mefenamic acid "athogenesis /oma and tonic-clonic sei,ures (#hich resolved follo#ing treatment #ith IE dia,epam) occurred follo#ing ingestion of '-$* g of mefenamic acid by a $4-year-old girl Acute ingestion of large doses of mefenamic acid in animals has led to incoordination) depression) tonic sei,ures) and diarrhea In humans #ho reportedly ingested $ '-'* g of mefenamic acid) those #ith plasma drug concentrations ranging from $$-&$$ mcg<mA experienced tonic-clonic sei,ures) muscle t#itching) vomiting) and diarrhea Several other cases of sei,ures follo#ing ingestion of '-'* g of mefenamic acid have also been reported) although a causal relationship to the drug #as not established "athogenesis In acute overdosage) the stomach should be emptied immediately by inducing emesis or by gastric lavage) follo#ed by administration of activated charcoal 9orced diuresis) al%alini,ation of urine) or hemodialysis are probably of no value in enhancing elimination of mefenamic acid since the drug is highly bound to plasma proteins "harmacology Mefenamic acid has pharmacologic actions similar to those of other prototypical NSAIAs (he drug exhibits antiinflammatory) analgesic) and antipyretic activity (he exact mechanisms have not been clearly established) but many of the actions appear to be associated principally #ith the inhibition of prostaglandin synthesis Mefenamic

acid inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase- at least & isoen,ymes) cyclooxygenase-$ (/7F-$) and -& (/7F-&) (also referred to as prostaglandin :<. synthase-$ G":.S-$H and -& G":.S-&H) respectively)) have been identified that cataly,e the formation of prostaglandins in the arachidonic acid path#ay $$?) $$5) $$@) $&*) $&$) $&& Mefenamic acid) li%e other prototypical NSAIAs) inhibits both /7F-$ and /7F-& $$?) $$5) $$@) $&*) $&$) $&& Although the exact mechanisms have not been clearly established) NSAIAs appear to exert anti-inflammatory) analgesic) and antipyretic activity principally through inhibition of the /7F-& isoen,yme- /7F-$ inhibition presumably is responsible for the drugs> un#anted effects on :I mucosa and platelet aggregation $$?) $$5) $$@) $&*) $&$) $&& !nli%e most other NSAIAs) the fenamates) including mefenamic acid) appear to compete #ith prostaglandins for binding at the prostaglandin receptor site and thus potentially affect prostaglandins that have already been formed Anti-inflammatory) Analgesic) and Antipyretic ;ffects (he anti-inflammatory) analgesic) and antipyretic effects of mefenamic acid and other NSAIAs) including selective inhibitors of /7F-& (e g ) celecoxib) rofecoxib)) appear to result from inhibition of prostaglandin synthesis 2hile the precise mechanism of the anti-inflammatory and analgesic effects of NSAIAs continues to be investigated) these effects appear to be mediated principally through inhibition of the /7F-& isoen,yme at sites of inflammation #ith subse8uent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors $$?) $$5) $$@) $&*) $&$) $&& Mefenamic acid also has been reported to inhibit the biosynthesis of mucopolysaccharides through uncoupling of oxidative phosphorylation) a mechanism that may also contribute to the anti-inflammatory effect of the drug Mefenamic acid does not possess glucocorticoid or adrenocorticoid-stimulating properties (here is no evidence that long-term therapy #ith mefenamic acid results in tolerance to or physical dependence on the drug (he drug probably cannot suppress the abstinence syndrome in opiate-dependent patients Mefenamic acid lo#ers body temperature in patients #ith fever Although the mechanism of the antipyretic effect of NSAIAs is not %no#n) it has been suggested that suppression of prostaglandin synthesis in the /NS (probably in the hypothalamus) may be involved :enitourinary and =enal ;ffects Mefenamic acid-induced inhibition of prostaglandin synthesis may result in decreased uterine tone and contractility "rostaglandins ;& and 9&a increase the amplitude and fre8uency of uterine contractions in pregnant #omen- current evidence suggests that primary dysmenorrhea is also mediated by these prostaglandins 2hether the increased production of prostaglandins associated #ith primary dysmenorrhea is mediated by /7F-$ or /7F-& remains to be determined $&4 In some patients #ith primary dysmenorrhea) mefenamic acid has produced an analgesic effect (herapy #ith mefenamic acid has been effective in relieving menstrual pain and has also reduced blood loss in #omen #ith menorrhagia) probably by inhibiting the formation and<or action of these prostaglandins Administration of mefenamic acid during late pregnancy may prolong gestation by inhibiting uterine contractions Mefenamic acid has been reported to adversely affect renal function (See /autions0 =enal ;ffects ) Eery little is %no#n about the mechanisms of adverse renal effects) although it has been suggested that papillary necrosis observed during therapy #ith mefenamic acid may be related to a reduction in renal blood flo# resulting from the inhibition of renal prostaglandin synthesis Mefenamic acid does not appear to have uricosuric activity :I ;ffects Mefenamic acid can cause gastric mucosal damage #hich may result in ulceration and<or bleeding (See /autions0 :I ;ffects ) (hese gastric effects have been attributed to inhibition of the synthesis of prostaglandins produced by /7F-$ $$?) $$5) $$@) $&*) $&$) $&&) $&3 7ther factors possibly involved in NSAIA-induced gastropathy include local irritation) promotion of acid bac%-diffusion into gastric mucosa) uncoupling of oxidative phsphorylation) and enterohepatic recirculation of the drugs $$@) $&3 ;pidemiologic and laboratory studies suggest that NSAIAs may reduce the ris% of colon cancer $&$ Although the exact mechanism by #hich NSAIAs may inhibit colon carcinogenesis remains to be determined) it has been suggested that inhibition of prostaglandin synthesis may be involved $&$ .ematologic ;ffects Mefenamic acid can inhibit platelet aggregation- in one study) the drug inhibited the platelet aggregation response induced by connective tissue particles Ai%e aspirin and other prototypical NSAIAs) the effects of mefenamic acid on platelets appear to be associated #ith the inhibition of the synthesis of prostaglandins produced by /7F-$ $&$ Pharmacokinetics Absorption Mefenamic acid appears to be rapidly absorbed from the :I tract 9ollo#ing oral administration of a single $-g dose of mefenamic acid to healthy adults) pea% plasma drug concentrations of approximately $*-&* mcg<mA are reached in &-3 hours 9ollo#ing oral administration of $ g of mefenamic acid 3 times daily) steady-state

concentrations of &* mcg<mA are reached by the second day of administration After multiple doses) plasma concentrations of mefenamic acid are proportional to the dose administered (he manufacturer states that there is no evidence of drug accumulation follo#ing multiple doses 1istribution Mefenamic acid is extensively bound to plasma proteins It is not %no#n if the drug or its metabolites cross the placenta (he drug is distributed into mil% in very small amounts ;limination (he plasma half-life of mefenamic acid has been reported to be & hours Mefenamic acid is metaboli,ed principally to the 4I-hydroxymethyl and 4I-carboxyl derivatives :lucuronic acid conCugates of the drug and its metabolites are also formed About '&6 of a dose of mefenamic acid is excreted in urine as glucuronic acid conCugates of the drug and its metabolites About &*6 of a dose is excreted in feces Mefenamic acid is apparently not dialy,able /hemistry and Stability /hemistry Mefenamic acid) an anthranilic acid derivative (fenamate)) is a prototypical nonsteroidal anti-inflammatory agent (NSAIA) (he drug is structurally and pharmacologically related to meclofenamate sodium Mefenamic acid occurs as a #hite to greyish-#hite po#der and is insoluble in #ater and slightly soluble in alcohol (he apparent pJa of the drug is 3 & Stability Mefenamic acid capsules should be stored in tight containers at a controlled room temperature of $'-4*K/ $&' "reparations Mefenamic Acid 7ral /apsules &'* mg "onstelL) 9irst .ori,on