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`
`
`03 Lyon
`
`E
`
` Syndrome psychiatrique aigu
`
`et quinolones
`
`
`J. -F. DEFOlN ('), T. DEBONNE ("), M. -O. RAMBOUHG (7.
`J.£%¥MPHW¥?AJBUH¥W£?,AIJME%MUDF1
`*)f?FAYF% DflEUWY"?
`liBERDMfl.
`SAMUSt/CentreAnfi-Poisons. ServiceduDocteurGASEYS- 0....HFIU -51092HEIRBCédex.
`f Lmolatoh‘edeToxicologie-~ServiceduProiosseurH. OHOISYO....-HRU510928EIMSCédex.
`
`‘flPéd‘atrieA--ServiceduProtesseurF. PENNAFOHTE- CHHRJJ. -5109238m6édex.
`
`RESUME : Psychiatric syndrome and quinoione
`Les auteurs rapportent un syndrome psychiatrique aigu complique' d'uun étatde
`mal convulsif et de troubles me'taboliques majeurs nécessitant anticonvulsivantsm-
`traveineux et vena'lation artificialle.
`
`L'évolution était favorable en quelques heures. Le bilan e’tioiogique restait né-
`gatif at scale la spectrometrie de masse permetmit d'identifier une intoxication a la
`Fluméquine. Ceci démom‘re une nouvelle fois la trés grands prudence ne'cessaire
`event do retenir un diagnostic psychiatrique chez l’eniant, ainsi que le faible index
`thérapeutique des quinolones.
`
`Mots-clés : Psychiatric, Intoxication, Fluméquine, Qu'nolones.
`
`SUMMARY
`
`A case of Flumequine poisoning is described ,' a 13-year-old girl was admitted
`for a psychiatric syndrome.
`
`3 hours after, seizures, coma, and metabolic disorders were observed. Infec-
`tious, encephalitic or diabetic diseases were suspected, but not confirmed.
`
`After 12 hours ofa symptomatic treatment, the clinical status improved and the
`patient was discharged. At that time a mblet was foundin herbedroom anda mas
`spectrographic analysis was positive for Flumequine.
`
`This case report is in agreement with previous observations and confirms the
`small therapeutic index ofquinolone, and the absolute necessity to assess carefully
`a psychiatric diagnosis.
`
`' us at Expe'rimentale
`Journal de Toxicologie Cli
`1990, T. 10, n' 7—8—469-4 2
`
`ALCON 2102
`Apotex Inc. v. Alcon Pharmaceuticals, Ltd.
`Case |PR2013-00012
`
`

`

`Syndrome psychiatrique aigu et quinolones
`470
`_____________________._.__..—————-————
`
`Key-words : Psychiatric, Poisoning, Flumequine, Quinolone.
`
`.“a---“
`
`
`
`Le 5 avril 1990, dans l’apres- midi, unejeune fille agée de 13 ans est ad-
`mise aux Urgences pour des episodes itératifs d’agitation avec revulsion
`OCulaire évoluant depuis une heure ; entre ceux-ci, aucun contact ne s’avere
`possible malgré un état de conscience apparemment conserve.
`Elle est transferee dans le service de Pédialrie on elle fait une chute,
`sans signe de localisation on myoclonies associés. Une discrete hyperpnée
`est notée. L’interrogatoire familial ne renouve qu’une notion de dispute ré—
`cente sans prise médicamenteuse. L’intensité du tableau clinique conduit a
`son transfert en Pédopsychiatne u’ois heures apres son admission.
`Elle fait alors une crise comitiale dc type grand mal et an décours, un
`coma, persistant, aréactif a la stimulation douloureuse et sans anomalie pu-
`pillaire (Glasgow 3). Apres sedation des crises par diazépam, intubation et
`ventilation artificielle, elle est transferee dans l’unité de réanimation, tandis
`que sont signalées durant l’apres-midi des mictions volontaires anormale-
`ment fréquentes.
`La persistance de myoclonies avec hyperventilation nécessite rapide—
`ment 1e recours an Nesdonal (30 cg puis 10 cg/h) alors que l’état hémodyna-
`mique. est conserve et que le bilan biologique met en evidence une acidose
`mélabolique majeure (pl-I = 7,04 ; R.A. = 7 mnol/l) avec acidose lactique
`(4,1 mnol/l) et une hyperglycémie (20,1 mnol/l) sans cétose. La nanémie et
`la fonction rénale sont normales et l’hématose sans alteration hypoxémique.
`Un traitement symptomatique est poursuivi (alcalinisation, insulinothé—
`rapie) et le bilan étiologique comportant recherche toxicologique (Salicylés,
`Phénothiazines‘, Imipraminiques, Benzodiazépines, Carbamates), recherche
`d’un accident cerebral (tomodensitographie et artériographie cérébrales) et
`bilans infectieux (ponction lombaire et prélevements bactériologiques) s’a-
`verent négatifs.
`Au milieu de la nuit, soit 10 heures apms son admission, on observe le
`retour a un état de conscience satisfaisant avec une discrete agitation persi—
`stante. Dans la matinee du 6 avril 1990 (16 heures apres l‘admission), l’ex-
`tubation est réalisée. L’examen neurologique est alors sn'ictement normal.
`Elle quitte l’unité de reanimation pour-[e service'de Pediatric ; ses pa-
`rents nous apportent alors un comprimé non identifié retrouvé dans sa cham-
`bre.
`
`L’analyse en spectrometric de masse identifiera la fluméquine avec une
`concentration de 61 mg/l (dosage bacteriologique) sur le prélevement san-
`gain effectue a l‘acmé de la symptomatologie clinique (En dosage chroma.
`tographique une prise de 400 mg entraine un pic plasmatique de 16,9 rug/l)-
`
`
`
`

`

`inolones
`
`J.—F. Defoin at Coll.
`
`.
`
`471
`
`Cette jeune fille quittera le service de Pédiatrie apres qu’un electroen-
`céphalogramme ait formellement éliminé un terrain comitial sons-Jaceut et
`apres avoir, lors d’un entretien medical, confnmé l’ingestion de 5 compri-
`més de fluméquine.
`
`COMMENTAIRES
`
`La littérature fait état de quelques cas d’intoxications a la fluméquine
`avec des doses massives dans un but suicidaire (2-3-5) ou par simple surdo—
`sage (1-5) ; ceci le plus souvent chez dejeunes patientes de moins de 30 ans.
`A postériori, 1e tableau clinique et biologique apparait comme patho-
`gnomonique (les surdosages aigus a la fluméquine qui associent habituelle—
`ment des signes neuropsychiatriques, une acidose metabolique, une hyper-
`-
`pnée, des troubles de la regulation glycémique avec ou sans cétose, et des
`vomissements frequents.
`Le traitement de ces intoxications est symptomatique (anticonvulsi~
`vants, alcalinisation, insulinothérapie, ventilation artificielle) et l’évolution
`le plus souvent rapidement favorable sans séquelle.
`None observation est en accord avec les données de la linérature bien
`que les vomissements et la cétose soient absents ici.
`Elle permet cependant d’attirer l’attention sur quelques points :
`— la nécessité d’unbilan biologique minimum devant tout tableau psy-
`chiatrique aigu (1’installation brutale,
`— l’aide au diagnostic que represente la recherche minitieuse, notam—
`ment dans l’entourage, (1e médicaments ou toxiques devant des tableaux cli-
`niques inexpliqués,
`-
`— l’apport indiscutable, pour l’identification, _de la spectrometric de
`masse,
`,
`'
`:
`—.- 1e faible index thérapeutique, ainsi que l'extréme sensibilité indivi-
`duelle vis-a-vis de cette classe thérapeutique.
`'
`Ce dernier point, déja souligné par les publications antérieures (4-5-6),
`est corroboré d’une part par ce nouveau cas avec une prise équivalente a tune
`double posologie journaliere ; on observe pourtant une concentration plas-
`matique a pres de quatre fois la normale (16,9 mg/l apres 400 mg pour un
`dosage chromatographique). Les autres cas recensés par notIe Centre Anti-
`Poisons confirment ces données.
`'
`En effet, depuis 1983, dix autres cas ont été répertoriés ; cinq furent
`symptomatiques avec presence dc signes neuropsychiatriques pour des
`doses ingérées allant de 1,6 g a 8 g.
`
`A
`
`s est ad-
`Evulsion
`s’avere
`
`e chute,
`perpnée
`pute ré-
`)nduit a
`
`)urs, un
`alie pu—
`Iation et
`
`1, tandis
`ormale-
`
`rapide—
`iodyna—
`acidose
`actique
`emie et
`
`Emique.
`
`iinothé-
`licylés,
`:herche
`
`ales) et
`es) s’a-
`
`serve le
`
`n persi-
`t), l’ex-
`)rmal.
`
`sec pa—
`1cham_
`
`V60 une
`2m San.
`
`throma-
`9mg/1).
`
`l
`
`

`

`472
`
`Syndrome psychiatrique aigu at quinolones
`
`CONCLUSION
`_ _ .___
`Un bilan biologique minimum et un interrogatoire minutieux dc l’en—
`tourage apparaissent indispensablm devant tout tableau psychiatrique aigu
`(1’installation brutale chez un sujetjusque-la indemne dc tout trouble.
`De méme son: indiSpensablw avec cette classe thérapeutique un Strict
`reSpectdo: posologies etde leur repartitionjomnaliére, ainsiqu’une,adapta-
`tion de ces posologies au terrain.
`Un regain d’allention apparait
`nouvelles quinolones qui pounaientconduire a dc tels effets se
`Ion les susceptibilités individuelles, etced’autant quecettainesd’Ientreelles
`bénéficient de modalités d’administration particuliérw (monodose).
`
`BIBLIOGRAPHIE
`Acido-cétose ct hyperglycé—
`.,
`.,
`mic réversiblu apxés absorption dc Fluméquine. R616 dc font“ doses chez. l‘aclulte non
`diabétique. Presse Med, 1980. 9. 636.
`2 - BOLESJ.M., GEN1'RICA., Gm M., Comm 6.. WC,MIL:
`Intoxication massive i laFluméquine. Presse Med, 1985, 14. 1668.
`M., Gamma A., SCI-[EYDECKER 1L. :
`3 - Gown!) 6., Pannaz C., Roma 6.. Bows J.
`Apropos d’un nwveau cas d'intoxication ilaFluméquinc. Conv. Med, 1984, 3. 439—440.
`4 - GAILAND M.C., Dunn! F., LULLB 1.13.. 1011me I. : Fluméquine ct effets sc-
`condaircs nemologiqucs centraux. B. Med. Légale at Tmica, 1979, 22, 615-617.
`. Iouvs-Basrm M.H., Room B, JOUGLARD J. : Effets indésira-
`'
`antibactériens urinaires. Thérapie 1982, 37, 481—487.
`6 - HANNEDOUCHET., GODIM M.,m LP. : Les effets secondaires dcs médica—
`meats umpour 1c traitemcnt des infections admires. Magic 1983, 38, 281—293.
`
`
`
`NOTULE
`
`Concours Médical - 37 rue de Bailefond - 75441 Paris Cédex 09
`
`19janvier 1991
`
`[267]
`
`lectives dans lc cadre du tabac.-
`as, rapport: 25 a 30 milliaxds
`ll rappelle que ce secteur em loic 6.0)0 5 7.000
`dc francs par an au Minister: du udgct. lcs publicitau’es consacrcnt aujourd‘hui pies d‘un
`milliard dc francs par an au tabac, ct i1 montre la difficullé de faire passer unc idéc généralc
`de santé publique dams la population.
`
`
`
`** TOTAL PAGE. 06 **
`
`

`

`Acute
`
`Psychiatric
`
`Quinolones
`
`Syndrome
`
`and
`
`1—P1Luuuqu(n,it[MEBOAunE(n,A4—o.AMALBOLU«}(®,J;SERAiuqu(n,A4.BLUUUET(b
`M. JA USSA UD (*), R. BERTA ULT (*), R. FAY (* *), B. DIGEON (* * *)
`
`(*) SAMU 51/CentreAnti-Poisons [“Poison Control Center”] 7 Department of Dr. G.A. SEYS 7 C.H.R.U. 7 51092 REIMS CédeX.
`(**) Laboratory of Toxicology 7 Department of Professor H. CHOISY 7 C.H.R.U. 7 51092 REIMS CedeX.
`(***) Pediatrics A 7 Department of Professor F. PENNAFORTE 7 C.H.R.U. 7 51092 REIMS Cedex.
`
`SUMMARY: Psychiatric Syndrome and Quinolone
`The authors report an acute psychiatric syndrome complicated with convulsive status
`epilepticus and major metabolic disorders requiring intravenous anticonvulsants and mechanical
`ventilation.
`
`The outcome was favorable in a few hours. The etiological assessment was negative and only
`mass spectrometry allowed identification ofFlumequine intoxication. This demonstrates once again
`the extreme caution necessary before adopting a psychiatric diagnosis in children, as well as the
`low therapeutic index ofquinolones.
`
`Keywords: psychiatric, intoxication, flumequine, quinolones.
`
`SUMMARY
`
`Acmoffiumaqufizepoisarmgisdascrflndm 13-yaar-aidgfiwasadnitted
`farapsybmtficsyndmme.
`
`3hoursaftenseizums. commandmembaticcfisardersmabserwd. Infec-
`fious, emphaliticonfiabaficdisaammmsuspamd, burnotamfinnad.
`
`Altar fEhaumafa aymptmafic #aamm, the Wealmm mmwdandtha
`paflentwascfisdvarged Airbatflmaatabhtwasiuundmharbedrmnarflamas
`WOW was posifiw bf Flumoquina.
`miscase rapaflis inagreemon!‘ M'h‘rpravious obssmfions WW3 the
`small flurapwnb indsxoqumlano, and the absolute necessity a: assess mafidiy
`apsyehiarrlcdiagrmls
`
`Journal de Toxicologie Clinique et Expérimentale
`1990, Vol. 10, No. 7-8 — 469-472
`
`

`

`470
`
`Acute Psychiatric Syndrome and Quinolones
`
`Keywords: Psychiatric, Poisoning, Flumequine, Quinolone.
`
`In the afternoon of April 5, 1990, a 13-year-old girl was admitted to the ER for recurrent
`episodes of agitation with ocular revulsion lasting for one hour; between the episodes, no
`connection proved possible despite the fact she maintained an apparent state of consciousness.
`
`She was transferred to the Pediatric Department where she suffered a fall without an associated
`localization sign or myoclonus. Discrete hyperventilation was noted. Questioning of the family
`revealed only a glimpse into a recent dispute without the taking of any medication. The intensity of
`the clinical picture led to her transfer to Pediatric Psychiatry three hours after her admission.
`
`She then had a grand mal-type seizure that gave way to a persistent coma, unresponsive to
`painful stimulation and without a pupillary anomaly (Glasgow 3). Following sedation of the
`seizures with diazepam, intubation and mechanical ventilation, she was transferred to the ICU,
`while abnormally frequent voluntary urination in the afternoon was reported.
`
`The persistence of myoclonus with hyperventilation quickly required the use of Nesdonal (30
`cg then 10 cg/h), while her hemodynamic status was maintained and the biological assessment
`revealed major metabolic acidosis (pH = 704; RA. = 7 mnol/ 1) with lactic acidosis (4.1 mnol/ 1)
`and hyperglycemia (20.1 mnol/ 1) without ketosis. Plasma sodium and renal function were normal
`and hematosis without hypoxemic alteration.
`
`insulin therapy) and the etiological
`Symptomatic treatment was continued (alkalization,
`assessment entailing toxicological analysis (salicylates, phenothiazines, tricyclics, benzodiazepines,
`carbamates), search for a cerebrovascular accident (brain CT scan and cerebral angiography) and
`infectious assessments (lumbar puncture and bacteriological samples) proved negative.
`
`In the middle of the night, i.e., 10 hours after her admission, she was observed to return to a
`satisfactory state of consciousness with a discrete persistent agitation. In the morning of April 6,
`1990 (16 hours after admission), she was extubated. The neurological examination was then fully
`normal.
`
`She left the Pediatric ICU Department; her parents then brought us an unidentified pill found in
`her room.
`
`Mass spectrometry analysis identified flumequine with a concentration of 61 mg/l (bacterial
`assay) in the blood sample taken at the peak of the clinical symptoms (in chromatographic assay,
`taking 400 mg revealed a peak plasma concentration of 16.9 mg/l).
`
`

`

`J.-F. Defoin et al.
`
`471
`
`This young girl left the Pediatric Department after an electroencephalogram formally excluded
`an underlying epileptic condition and after a medical interview confirmed the ingestion of five
`tablets of flumequine.
`
`COWENTS
`
`The literature reports several cases of fiumequine intoxication with massive doses taken in a
`suicide attempt (2-3-5) or a mere overdose (1-5); this has occurred most often among young patients
`under the age of 30.
`
`In hindsight, the clinical and laboratory picture appears pathognomonic for acute fiumequine
`overdoses that generally combine neuropsychiatric signs, metabolic acidosis, hyperventilation,
`disorders of glucose regulation with or without ketosis, and frequent vomiting.
`
`The treatment of these intoxications is symptomatic (anticonvulsants, alkalization, insulin
`therapy, mechanical ventilation) and the outcome is most often quickly favorable without any
`sequelae.
`
`Our observation is in agreement with the data in the literature, although vomiting and ketosis
`are absent here.
`
`However, it serves to draw attention to several points:
`
`the need for a minimum biological assessment in the face of any acute psychiatric picture
`-
`with a brutal onset,
`
`assistance in the diagnosis represented by a painstaking inquiry, particularly in the
`-
`patient’s relations, for medications or toxins in the face of unexplained clinical pictures,
`
`-
`
`-
`
`the unquestionable contribution of mass spectrometry for identification purposes,
`
`the low therapeutic index and extreme individual sensitivity to this therapeutic class.
`
`further
`is
`(4-5-6),
`already underscored by previous publications
`latter point,
`This
`corroborated by this new case with the taking of a dose equivalent to a double daily dose; however,
`a plasma concentration nearly four times normal (16.9 mg/l after 400 mg for a chromatographic
`assay) was observed. The other cases identified by our Poison Control Center confirm these data.
`
`Indeed, since 1983, ten other cases were identified; five were symptomatic with the presence
`of neuropsychiatric signs for ingested doses ranging from 1.6 to 8 grams.
`
`Aside from these signs, no other symptoms were observed; it is also noted that a dose of 2.4
`grams taken by a 17-year-old girl did not cause any problem.
`
`

`

`472
`
`Acute Psychiatric Syndrome and Quinolones
`
`C0NCL USION
`
`A minimum laboratory assessment and careful questioning of the patient’s relations appear
`indispensable in the face of any acute psychiatric picture with a brutal onset in an individual
`previously free of any disorder.
`
`Likewise, strict compliance with the doses and their daily distribution, as well as an
`adaptation of these doses to the circumstances, are indispensable.
`
`Renewed attention appears necessary with the marketing of new quinolones that might lead
`to such side effects according to individual susceptibilities, all the more so since some of them
`benefit from special administration methods (single dose).
`
`REFERENCES
`
`1. ARNAUDO J.P., MAHEUT H., MARTIN B., HESSE J.Y.: Ketoacidosis
`and
`Hyperglycemia Reversible After Absorption of Flumequine. Role of High Doses in Non-
`Diabetic Adults. Presse Med, 1980, 9, 636.
`
`2. BOLES JM GENTRIC A, GARRE M., COCHARD G, PERNEZ C, SCHEYDECKER J .L.:
`Massive Flumequine Intoxication. Presse Med, 1985, 14, 1668.
`3. COCHARD G, PERNEZ C, ROUE G, BOLES JM GENTRIC A, SCHEYDECKER J .L.:
`On a New Case of Flumequine Intoxication. Conv. Med, 1984, 3, 439-440.
`4. GALLAND M.C., DUPUY F, LULLE J.B., JOUGLARD J.: Flumequine and Central
`Secondary Effects. B. Med Le’gale el T0xic0., 1979, 22, 615-617.
`5. GALLAND M.C., JOUVE-BESTAGNE MH. RODOR F, JOUGLARD J.: Undesirable
`Neurological Effects of Urinary Antibacterial Quinolones. The’rapie 1982, 37, 481-487.
`6. HANNEDOUCHE T, GODIM M., FILLASTRE J.P.: The Side Effects of Medications
`Used for the Treatment of Urinary Infections. The’rapie 1983, 38, 281-293.
`
`SHORT NOTE
`
`Concours Medical — 37 rue de Bellefond — 75441 Paris Cedex 09
`
`[267]
`
`January 19, 1991
`
`During the proceedings of the SOCIETE FRANCAISE DE MEDECINE PREVENTIVE ET SOCIALE
`[“French Society of Preventive and Social Medicine”] (November 24, 1990), Albert HIRSCH showed
`the difficulties of changing collective mindsets when it comes to tobacco.
`
`He pointed out that this sector employs 6,000 to 7,000 persons, produces 25 to 30 billion francs
`a year for the Ministry of Budget, advertisers today devote nearly a billion francs a year to tobacco,
`and it shows the difficulty of communicating a general idea of public health to the general public.
`
`

`

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`
`CERTIFICATE OF ACCURACY
`
`l hereby certify that the attached is, to the best of my knowledge, ability and belief, a true
`and complete translation from French to English of the Journal Article tit/ed "Syndrome
`psychiatrique aigu et quinolones” by J.-F. DEFOIN et al. appearing in Journal de
`Toxicologie Clinique etExpérimenta/e, 1990, T. 10, No. 7—8— 469-472.
`
`Glenn Cain
`President
`
`Yndigo Translations
`
`Subscribed and sworn to before me this g” day ofm , 2013.
`
`
`
`otary Public
`My Commission Expires: fig] 0%]WE
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`DAVID SZETO
`Notary Public, State of New York
`Qualified in Kings County
`Reg No. 01826245871
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