NASAL RATHER THAN RECTAL
`BENZODIAZEPINES IN THE MANAGEMENT
`OF ACUTE CHILDHOOD SEIZURES?
`
`Mary E O'Regati
`./oh Keith Bro\vti
`Midge Clarke
`
`A recent report by Latson el crl. (1991)
`recommended
`intranasal midazolam
`sedation for children undergoing outpa-
`tient echocardiography. The ages of the
`15 children studied ranged from 4 to 30
`months, and satisfactory sedation was
`achieved in 13 of them.
`Benzodiazepines are routinely used by
`the rectal route for the treatment of acute
`epileptic seizures. Teachers are reluctant
`to use this method in schools. and older
`children find the procedure very embar-
`rassing.
`We felt that if benzodiazepine was
`absorbed from nasal
`instillation
`this
`could provide a more acceptable alterna-
`tive to rectal administration.
`We have previously described the use
`of EEG monitoring to assess the use of
`benzodiazepines given intravenously and
`it was felt that a similar method could be
`used to assess the effectiveness of nasal
`midazolam (Livingston et al. 1987).
`Patients and method
`PATIENTS
`A series of 19 consecutive children (one
`child was assessed twice) was chosen
`from those attending the Department of
`Neurophysiology. Royal Hospital for
`Sick Children. Edinburgh.
`All the children were known to suffer
`from epilepsy (Table I). All had seizures
`that were difficult to control and all had
`an EEG that showed unequivocal activity
`of seizure type (i.e. paroxysmal slow
`
`spike
`activity, usually associated with
`andor polyspike component).
`This
`abnormal paroxysmal aciivity persisted
`throughout a normal 20 minute recording.
`Two 20 second epochs were chosen pre-
`and post-medication and the spike rate
`was quantified. The post-medication
`epoch was always chosen when benzodi-
`azepine-induced fast activity, if present,
`was at its maximum. The children were
`being considered
`for benzodiazepine
`medication as part of their clinical man-
`agement. It is routine in this Department
`to assess sensitivity, habituation or a
`paradoxical response to benzodiazepines
`by monitoring the effects of an acute dose
`under EEG control.
`MIDAZOLAM
`To ensure correct dosage all the children
`were weighed before the procedure. The
`dosage of midazolam was 0.2 mgkg of
`the intravenous solution (5 mg/ml). It
`was dripped slowly into the nose. If a
`patient did not respond in 10 minutes the
`dose was repeated. The patient's oxygen
`saturation and ECG were continuously
`monitored in addition to EEG.
`Full
`resuscitation equipment was
`available, and a doctor was present dur-
`ing the administration of the drugs. The
`procedure was explained in detail to the
`parents. who in most cases were present
`throughout the procedure, and a full
`explanation was made to the child when
`appropriate.
`
`AQUESTIVE EXHIBIT 1136 Page 0001
`
`

`

`TABLE I
`Summary of patient details
`
`Rasmu\sen syndrome Generaiizcd tonic
`cionic
`Polymorphic
`
`Mental retardation.
`epilepsy. autistic
`spcctrom disorder
`Lissencephaly
`
`Tonic
`
`First presentation in
`status
`Polymorphic
`
`St urge-- Weber
`syndrome
`Cerebral palsy
`secondary to HSV'
`cncephalitis
`Intracerebral fungal
`abscess, shunted
`hydrocephalus,
`cyanotic heart disease
`Shunted hydrocephatus, Generalized tonic
`epilep\y
`c h i c
`Myoclonic epilepsy
`Myoclonic
`
`Generalized tonic
`clonic
`
`M
`1 JMH 3,7
`2 CF
`5.0 M
`
`3 DC
`4 AF
`5 JC
`
`8.0 M
`6.5 M
`5.0 M
`
`6SR
`
`6.6 M
`
`F
`7HMD 1.16
`5.0 M
`8 DA'
`9 LL
`3.0
`F
`5.5 M
`t o RB
`3.0 M
`8.0
`F
`
`11 LS
`12TR
`
`13 HA
`F
`1.0
`IJCB 0.5 M
`I5 DH 14.0 M
`16 CF' sec case 2
`F
`3.0
`17 BC
`
`18 CMG43.0 M
`M
`M
`
`I9WI
`
`'OJB
`
`10
`
`7
`
`Lennox-Gastaut
`syndrome
`Cortical dysplasia,
`epileptic dysphasia
`Lennox-Gastaut
`syndrome
`Cerebral palsy,
`microcep~aiy, epilepsy
`Cryptogenic infantile
`spasms
`Cerebral palsy,
`microcephal y
`Tuberous sclerosis
`
`Epileptic aphasia
`
`Polymorphic
`
`Atonic
`
`Polymorphic
`Tonic
`
`Salaam attacks
`Generalized tonic
`clonic
`Generalized tonic
`clonic
`Aphasia, behavioural
`problems
`P ~ l y m o ~ ~ i c
`
`Lennox-Gastaut
`syndrome
`Primary epilcpsy
`Gencralired tonic
`clonic
`Cervical meningocele Generalized tonic
`clonic
`with shunted
`hydroccphalus.
`conical dysplasia and
`cerebral palsy
`
`Phen~toin.
`phenobarbitonc
`Sodium valproate.
`phenytoin
`Lamotrigine. clobazam
`pre-test
`Phenytoin
`
`Lamotriginc.
`sodium valproate,
`clobazam post-test
`Phenytoin
`.
`
`Sodium valproate
`
`Carbamazepine and
`clobazain post-test
`Sodium valproate.
`phenytoin
`ACTH. clobaram
`
`Phenytoin, sodium
`valproate, nitrazepam
`Carbamazepine
`
`Nitrazepam post-test
`
`Phenytoin,
`phenob~rbitone
`Phenytoin, clctbazam
`pre-test, lamotriginc
`Nitrazepam. ACTH
`
`Lamotrigine. clobazam
`post-test
`.
`Carbaniazepine
`
`Carbamazepine
`
`'HSV = herpes simplex virus. 'See Fig. 1. 'Cases 2 and 16 are same patient. .'See Fig. 2.
`
`AQUESTIVE EXHIBIT 1136 Page 0002
`
`

`

`Fig. 1. A 5- wtrr-old 1x1~ (iww 8) in rirwcloriic .miti:.\ lirtrl ( I j m i t i w diiiicd rc~vporr.se to irrtrrrricisd
`riri~l~i:oltrrri+
`
`EEG
`Silver/silver khloridc electrodes were
`applied by paste using the conventional
`10-20 system and a routine baseline
`recording was made using a standard 16
`channel EEG niachinc.
`
`ANALYSIS
`The following factors were assessed:
`I ) Sedative effects as seen clinically or
`with appropriate EEG changes.
`2) Any changes noted in the heart rate
`or oxygen saturation.
`
`1039
`
`AQUESTIVE EXHIBIT 1136 Page 0003
`
`

`

`3) Appearance of beta activity in the
`EEG.
`4) Time of appearance of beta activity
`following medication.
`5) Number of spikes seen before med-
`ication. The number of spikes per minute
`was counted in a representative part of
`
`the EEG. As soon as the count reached
`100 it was terminated.
`6) Number of spikes after medication.
`This was counted in exactly the same way
`as for before medication.
`7) Effects on background EEG.
`Background abnormalities were divided
`
`AQUESTIVE EXHIBIT 1136 Page 0004
`
`

`

`Yes
`Ycs
`Yes
`YCS
`Ycs
`Yes
`Yes
`Yes
`Yes
`YCS
`YCS
`Yes
`YC.4
`YCS
`Yes
`Yes
`Ycs
`YCS
`Ycs
`YCS
`
`I JMH
`2 CF
`3 DC
`4 AF
`5 JC
`6 SR
`7 HMD
`8 DA
`9 LL
`10 RR
` KS
`12 TR
`13 HA
`I4 CB
`15 DH
`16' CF
`17 BC
`18CMG
`19 WI
`20 JB
`Mctirr
`SD
`
`0
`0
`0
`0
`0
`0 I
`0
`I
`0
`0
`0
`0
`, 0
`0
`0
`I
`I
`I
`I
`0.2
`0.47
`
`I00
`100
`I00
`I00
`' 65
`100
`41
`60
`25
`50
`24
`5
`34
`23
`21
`53
`46
`42
`30
`46
`53.2
`31.13
`
`3
`5 0
`I00
`I 0
`61
`66 6
`5
`0
`24
`3 -
`16
`14
`25
`3
`27
`0
`0
`21
`6
`2 I .95
`27.15
`3.8
`co.0 1
`Spike couiit
`prc and pwt-
`M DZ
`
`'Caw I6 is thc sanic paticnt ax caw 2.
`
`-
`
`3
`3
`0
`3
`3
`3
`0
`2
`0
`2
`3
`2
`3
`I
`2
`0
`3
`I
`0
`I
`I .75
`1.25
`
`0
`2
`0
`3
`2
`0
`3
`3
` 3
`3
`3
`2
`7
`3
`I
`3
`0
`2
`I
`2
`I .9
`1.16
`
`0
`I
`I
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`I
`0
`0
`0.15
`0.36
`
`I
`0
`0
`I
`0
`I
`I
`I
`I
`1
`0
`. 0
`0 0
`0
`I
`0
`0
`I
`I
`' 0.5
`0.5 I
`
`0
`3
`0
`I
`3
`0
`0
`0
`I
`I
`2
`I
`0 I
`I
`0
`0
`0
`0
`0
`0.75
`1.01
`2.77
`<0.02
`Slow wiive
`independcnt
`
`0
`2
`0
`0
`2
`I
`I
`0
`2
`7
`2
`I
`1
`3
`0
`2
`0
`0
`I
`0
`0.85
`0.98
`4.3
`<0.0 I
`Slow wave
`and spike
`
`~~~
`
`I
`I
`I
`0
`0
`1
`I
`0
`0
`0
`0
`I
`I
`I
`0
`I
`I
`I
`I
`I
`0.7
`0.47
`4.12
`<0.00 I
`for the
`appearance
`of beta post-
`M DZ
`
`I 11.5s
`95.32
`
`AQUESTIVE EXHIBIT 1136 Page 0005
`
`

`

`into two categories: independent slow
`waves and slow waves with spikes. These
`abnormalities were absent (01, present
`(I), present in moderate amounts (2), or
`present in gross amounts (3).
`The EEGs were reported independently
`by a senior technician (MC) who was not
`involved in the clinical study.
`The data were analysed using the t test
`of statistical significance.
`Results
`There were 19 children treated whose
`ages ranged from 7 months to 14 years
`(mean 5.24 years). There were 14 males
`and five females.
`One patient (CF) had midazolam
`administered twice as there was clinical
`concern about the sensitivity to benzodi-
`azepines.
`All children had intractable seizures.
`They had a wide range of neurological
`lesions as outlined in Table I.
`The child with epileptic aphasia was
`the only one who did not exhibit spikes.
`The abolition of bilateral frontal slow
`waves by the midazolarn strongly sug-
`gested that these were of seizure type.
`All 19 children had epileptic activity
`on their EEGs. Fifteen had a positive
`response, i-e. a dramatic improvement in
`the EEG or cessation of fits. Of these 15,
`three who had clinicai seizures will now
`be discussed in greater detail.
`Case 4 (Sturge-Weber syndrome) pre-
`sented in clinical tatus and midazolam
`effectively termina ed his seizure activ-
`ity. Subsequently he was maintained
`seizure free on anficonvutsants.
`Case 6 was a 7-month-old infant who
`had intracerebral bleeding secondary to
`streptokinase and subsequently devel-
`oped a fungal intracerebral abscess,
`hydrocephalus and seizures. As he had
`profuse diarrhoea, rectal administration
`of diazepam was not an option. Intranasal
`midazolam provided effective relief of
`his seizure in a terminal care situation.
`The third patient, case 8 (Fig. I), pre-
`sented in myoclonic status. Intranasal
`midazolam terminated his myoclonic
`jerks. He was then given clobazam with
`good effect.
`Following administration of midazo-
`lam 14 patients had drug-induced beta
`activity, which is statistically significant
`
`I
`
`(t = 4.12, Pc0.001). The mean time to the
`appearance of drug-induced beta activity
`was 1 11.5 s & 95.3 s.
`The reduction in spike count per
`minute before and after midazolam was
`also statistically significant
`(1’2.9,
`pc0.01). The improvement in the back-
`ground in respect to slow waves (PcO.OI )
`and to slow waves with spike wave
`(pc0.01) was also statistically significant.
`The results are outlined in more detail in
`Table 11. Only one child demosstrated
`sleep changes (sleep spindles) on EEG
`following the intranasal midazolam.
`SIDE EFFECTS
`The only side effect noted in this series
`was that in one patient oxygen saturation
`fell to 87% of normal, but self corrected
`spontaneous1 y .
`None of the I9 children suffered from
`apnoea or bradycardia, or were abnor-
`mally drowsy. One patient had a paradox-
`ical response, in keeping with the study
`of Livingston ef 01. (1987).
`The intranasal administration of mida-
`zolam is not painful, though none of the
`children enjoyed it. The older children
`commented that they had a strange sensa-
`tion at the back of their nose and throat
`but felt this was preferable to intravenous
`administration and definitely better than
`rectal administration, which the older
`children would not even contemplate.
`Discussion
`M~dazolam, a water-soluble benzodi-
`azepine, was introduced into clinical
`practice in 1982. It is extensively used in
`anaesthetic practice and its pharmacology
`and pharmacokinetics are well known
`(Dundee et cil. 1984). It is an imidazo-
`benzodiazepine drug. At physiological
`pH the ring structure closes. becomes
`lipid-soluble and crosses the blood-brain
`barrier readily. Midazolam does not
`cause any significant haemodynamic or
`respiratory changes. It may be safely
`administered as a bolus dose. The elimi-
`nation haif-life of midazolam and its
`metabolites is usually about 1.5 to 3.5 h
`in healthy subjects.
`Benzodiazepines enhance the action of
`gamma-aminobutyric acid
`(GABA).
`GABA is the main inhibitory neurotrans-
`mitter in the brain and increases chloride
`
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`
`AQUESTIVE EXHIBIT 1136 Page 0006
`
`

`

`ion conduction into the cells. This causes
`hyperpolarization of the cells and reduces
`the chance of firing: hence the anticon-
`vulsant action. Benzodiazepines are
`regarded as the drugs of choice for the
`treatment of status epilepticus in children
`(Schmidt 1983, Tassinari et cil. 1983).
`Brown er 01. (1979) demonstrated that
`intravenous midazolam produced EEG
`changes identical to those seen with
`diazepam, i.e. widespread beta activity,
`attenuation and disappearance of the
`alpha rhythm. The effectiveness of intra-
`venous and intramuscular midazolam as
`an anticonvulsant has already been estab-
`lished, both as a single dose and as con-
`tinuous intravenous infusion (Elgi and
`Albani 198 I , Kaneko et 01. 1983, Crisp er
`nl. 1988, Kumar and Bleck 1992, Roberts
`and Eng-Bourquin 1995).
`The value of intravenous benzodi-
`azepines as the drugs of choice for status
`epilepticus in children is not in doubt.
`However,
`in. primary care, special
`schools and residential units for children
`with disabilities,
`immediate venous
`access may be difficult to obtain in the
`convulsing child, so that rectal adminis-
`tration of diazepam is widely used to end
`seizures. While the rectal administration
`of drugs is not a problem for mcdical or
`nursing staff,
`the same cannot be
`assumed for parents, teachers, nursery
`staff and foster parents.
`Many of
`the children who have
`intractable seizures also have many other
`neurological problems, and respite care is
`often required, which can be difficult to
`organize. One of the reasons for this is
`that foster parents may not accept rectal
`administration of drugs. Foster parents,
`day carers and teachers are very aware of
`the damage that allegations of sexual
`abuse could cause to their personal lives
`and careers. Intranasal preparations might
`be much more acceptable.
`The effect of rectal administration on
`older children and tcenagers has never
`been studied, but we know that children
`with epilepsy suffer from low self esteem
`(Hoare and Russell 1995). Colleagues in
`the community inform us that truancy and
`school refusal are a problem in older chil-
`dren and one of the reasons they cite is
`fear of rectal Valium administration if
`they have a prolonged seizure.
`
`L
`
`Diazepam, the benzodiazepine most
`commonly used as an anticonvulsant, is a
`very lipophilic substance and relatively
`insoluble in water. The parented solu-
`tion is prepared in propylene glycol and
`alcohol, or as an emulsion or as rectal
`tubes in cremophor EL. These prepara-
`tions are not suitable for intranasal
`administration. There have been two
`the intravenous
`recent studies using
`preparation of midazolam via the
`intranasal route for sedation. Wilton et al.
`(1988) used this route for the pre-anaes-
`thetic management of preschool children.
`In their study of 45 children they found it
`to be an effective mode of administration
`with no adverse side effects. Latson et al.
`(199 1) used intranasal midazolam for
`sedation in 15 children undergoing outpa-
`tient echocardiography. It provided com-
`petent sedation without unwanted side
`effects. It therefore seemed appropriate
`for us to use midazolam as the anticon,
`vulsant when testing the intranasal route.
`Nasal administration has the advantage
`of rapid absorption of the drug directly
`into the systemic circulation, from an
`area rich in blood supply, without the dis-
`advantage of passage through the portal
`circulation. Drugs with high hepatic
`clearance such as midazolam will have a
`much higher systemic availability follow-
`ing nasal rather than oral administration.
`It has been demonstrated that in chil-
`dren effective blood levels of diazepam
`are produced within 5 minutes after rectal
`administration (Shorvon 1994). However
`bioavailability is variable after rectal
`administration (Magnussen et 01. 1979).
`Remy er crl. (1992) have shown that the
`rectal route is not always totally reliable.
`In this small study it has been shown that
`midazolam penetrates the brain within 2
`to 5 min.
`The EEG technicians welcomed the
`intranasal administration of benzodi-
`azepines. Their time was no longer
`wasted in waiting for medical staff to
`achieve satisfactory intravenous access
`for the drugs. Often there is difficulty in
`siting a butterfly needle or cannula. caus-
`ing the child to cry. become very restless.
`or to pull the leads off.
`The study confirmed that midazolam is
`absorbed from the nasal mucosa. It took 2
`to 5 minutes to reach the cerebral cortex
`
`I z c
`d (f
`
`1043
`
`AQUESTIVE EXHIBIT 1136 Page 0007
`
`

`

`as shown by the appearance of beta activ-
`ity in the recording and the longest time
`to achieve a positive response was 8 min.
`It acts on the abnormal EEG electrical
`activity by suppression of spikes and abo-
`lition of seizure activity. It also acts as a
`clinical anticonvulsant when fits are pre-
`sent. The dose required to suppress spikes
`does not induce sleep, from which we
`deduce that the reduction in spikes is not
`a product of the sleep-wake state of the
`child. Furthermore. as excessive sedation
`is not a problem, extra nursing time or
`technician time is not spent in monitoring
`a heavily sedated child. It did not produce
`a significant change in oxygen saturation.
`ECG or heart rate.
`Further studics are now needed on a
`group of children with clinical seizures,
`to'ascertain if seizures are effectively ter-
`minated by intranasal midazolam and if it
`can provide an alternative route for the
`delivery of anticonvulsants in the man-
`agement of acute seizure.
`Conclusion
`Intranasal midazolam was administered
`to 19 children (20 tests) under EEG and
`cardiovascular monitoring. At a dose of
`0.2 mgkg the drug was absorbed into the
`b~oodstream, penetrated the brain in 2 to
`5 min, as shown by the appearance of
`beta activity in the EEG and suppressed
`epileptic activity, and produced an
`
`improvement in EEG background activ-
`ity. It did not produce changes secondary
`to sleep in the EEG in our small group.
`The adverse side effects were Iimited to a
`short-lived drop in oxygen saturation in
`one child, which self corrected very
`quickly.,
`This is. to our knowledge. the first
`reported
`study
`that has used
`the
`intranasal route for the administration of
`anticonvulsant drugs. Also this is the
`only clinical study with midazolam
`where its effects on the EEG in.chi1dren
`have been observed. We feel that this
`route has much potential but the formula-
`tian of the drug needs to be more accept-
`able and for .ease of administration it
`should be produced in two strengths with
`a nasal dropper.
`A ~ ~ i t r t t r / e t f . ~ t ? t e / t i ~
`We are grateful to thc Facdty of Mcdicinc George
`Guthrie Research Fellowship, Edinburgh University.
`for supporting MOR and for thc help and support
`given by
`the staff of
`the Department of
`Neurophysiology at the Royal Hospital for Sick
`Childrcn. Edinburgh.
`Accrprud,/rw ptiblircrriorr IJdt Fdwtrrwv 1996.
`Airrhors Appoiiifiiieiirs
`'"Mary ORegan. ME. DCH, MRCP. George Guthrie
`Research Fcllow. Depanment of Paediatric
`Neurology:
`John Keith Brown. MB. FRCPE. DCH. Consultant
`Paediatric Neurologist:
`Midge Clarke. Senior Chief Technician. Dcpartrncnt
`of Neurophysiology:
`Royal Hospital for Sick Childrcn. Edinburgh. UK.
`.
`'~C~~r~es/~uiitfrirc~i~
`to ritr fir.st triifhor.
`
`'
`
`SUMMARY
`Benzodiazepines arc routinely used by the rectal route for the treatmcnt of acute epileptic seizures:
`if a benzodiazepine was absorbed from nasal administration this could provide a more acceptable
`alternative to rectal administration.
`.
`Nineteen children (age range 7 months to 14 years) with 'intractable epilepsy were chosen. The
`EEG's showed unequivocal epileptic activity persisting during the recording. Thc midazolam was
`dripped slowly into the anterior nares.
`\ Fifteen had a positive response, a dramatic improvement in their EEG or cessation of fits. Drug
`induced beta activity occuired in 14 children. The mean time to appearance of beta activity was
`I 1 1.5 secs (SD = 95.3 secs). The reduction in spike count prc and post midazolam was statistically
`significant (pcO.01). The improvement in EEG background was also statistically significant.
`Midazolam is absorbed via the. i.n. route. With the dosages used it suppressed epileptic activity and
`produced an improvement in EEG background. The children and parents found the method
`acceptable. This is the first study to use the i.n. route for anti-convulsant drugs.
`RESUME
`Ln voie iiascile esr-elk prkfirnhle ii la w i e rectrile ckiris I 'eniploi h i
` itiidcixhrli (iii coiir.y tles crises
`coj~i~ti~les
`cle I'etzjiiitir?
`Les benzodiaztpines sont tris habituellcment u'tilisCes par voie rcctale dans Ie traitcment des crises
`absorbable par voic nasale con~tituerai~ une alternative plus
`cornitiales. Une ~ n z ~ i a z e p i n e
`acceptable B la voie rectale.Dix-neuf enfants SgCs de 7 mois h I4 ans avec dpilepsie incontrdldc ont
`ete selectionnis. Lcs EEGs montraient une activite epifeptique indiscutable persistant durant
`I'enregistrement. Le midazolam fut depose lentement par voie nasale dans les n a r k s antdncures,
`Chez 15 enfants. il y eu une reponse positive avec une ameiioralion spectacuIaire dans les EEG ct
`I'arrCt des crises. La midication fit apparaitre unc activitk beta chez 14 enfmts. Le temps moyen
`
`\
`
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`AQUESTIVE EXHIBIT 1136 Page 0008
`
`

`

`I F-
`F.
`
`Cy) *
`c
`c
`m
`r+
`c a
`E
`...
`
`\
`
`- s
`\ - *
`9
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`d'apparition dc I'activite beta fut de I 1 1.5 secs, (E.T. = 95.3 secs). La reduction du compte de ;
`pointe pre et post midazolam etait significative au seuil de p >0.01. L'amelioration globale de
`I'EEG fut aussi statistiqucment significative. Les enfants et les parents trouvkrent la methode
`acceptable. C'est la premiere etude d'utilisation de la voie intra-nasale pour les medications
`anticornitiales.
`ZUSAMMENFASSUNG
`Nnscile C O I I I ~ N rektde Applikulioii voii Midc1:oIrrii Dei der Behniidlirrig voii Ailfiille~i irii Kiridesolter
`Zur Behandlung epilcptischer AnMlle werden Benzodiazepine routinemiiBig rektal appliziert. Wenn
`ein Benzodiazepin iiber die Nascnschleimhaut rekorbien wurde, konnte dies eine bessere
`Alternative zur rektalen Verabreichung darstellen. I9 Kinder im Alter zwischen sieben Monaten
`und 14 Jahren mit unkontrollierbarer Epilepsie wurden ausgewiihlt. Dic EEGs zeigten eindeutige
`epilcptiforme Aktivitiit wlhrend der gesarnten Ableitung. Das Midazolam wurdc langsam in die
`Nase eingetrlufelt. I5 Kinder zeigten eine positive Reaktion. cine dramatische Verbesserung ihres
`EEG oder die Beendigung der Krhpfe. Das Medikament induzierte bei 14 Kindern eine Beta-
`Aktivitlt. Die mittlere Zeit bis zum Auftreten der Beta-Aktivitlt betrug I I I .5 Sekunden (SD=95.3
`Sekunden). Nach Midazolarn fand sich eine statistisch signifikante Reduktion der Spikes. pc0.01.
`Die EEG Grundaktivitiit besserte sich ebenfalls. Kinder und Eltern fanden die Methode akzcptabel.
`Dies ist die erste Studie iiber die nasale Applikation von antikonvulsiven Medikameoten.
`RESUMEN
`iMidir:olaii ricrscil riiejur*qiie' rectctl cii el imiiejo de Iris coii~w1.sioiie.s iirftiritiles
`Las bcnzodiazepinas se usan rutinariamente por via rectal en el tratarniento de 10s ataques '
`epilepticos agudos. Si una benzodiacepina fuera absorbida px via nasal podria constiiuir una
`alternativa mis aceptablc que la administraci6n rectal. Fueron elegidos 19 niiios de siete meses a
`14 aiios con epilepsia intratable. El EEG mostraba una actividad epilCprica inequivoca que persistia
`durante la grabicion. El midazolan fue administrado lentamente a potas en las fosas nasales.
`Quince niiios tuvieron una respucsta positiva con una mejoria en el EEG o la cesaci6n del ataque.
`En 14 niiios two lugar una actividad beta inducida por el frirmaco. El prornedio de tiempo dc
`aparici6n de la actividad beta fue de 1 I I ,5 scgundos (SD=95'3 segundos). La reduction de espigas.
`antes y despues del midazolan fue estadisticamente significativa (pc0'01). La rnejoria en el EEG de
`fondo fue tambiCn estadisticamente significativa. Los niiios y 10s padres cncontraron el metodo
`aceptable. Este es el primer estudio de utilizacion de la via intranasal de firmacos anticonvulsivos.
`
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`Shorvon s. ( 1 9 4 ) ~ 1 t r r i r . s &pilc,plicrtr. /Is Cliiricol
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`
`AQUESTIVE EXHIBIT 1136 Page 0009
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