RESULTS OF OTHER DRUG TRIALS: ITALIAN EXPERIENCE

1. Edvige VeneselliU.O. e Cattedra di Neuropsichiatria Infantile Dipartimento di Neuroscienze, Oftalmologia e Genetica Sezione di Neuroscienze dello SviluppoUniversità di Genova IRCCS G. Gaslini RESULTS OF OTHER DRUG TRIALS: ITALIAN EXPERIENCE

2. ITALIAN ASSOCIATION OF AHC REVIEW OF THERAPY  Data regarding24 patients 12 males 12 females Age 1yr 1m - 38yr (median 12yr 11m) METHODS  questionnaire for child neuropsychiatrists  interview of parents RESULTS  continuative therapy  intermittent therapy

3. CONTINUATIVE THERAPY- RESULTS Flunarizine Effectiveness reported for 14/24 pts on frequency 11 severity 6 duration 2 No significant effectiveness reported for 10 pts,with drop-out of 6 Mild benefits with 5HTP referred for 1/3 pts No effectiveness with nimodipine 2/2 clonidine 1/1 propanolol 1/1 Discrete but transitory (1 and 8 months each) benefits with GVG, in 2/3 pts Significant decrease of frequency with TPM referred by an adult pt in the first 2 years No effectiveness PB 11/11 GBP, PHT 3/3 CBZ 6/6 PRM, FBM, ESM, VPA, LTG 4/4 BARBESACLONE 1/1

4. BENZODIAZEPINES Decrease of severity and frequency of attacks by reducing anxiety and hyperexcitability; less discomfort CZP 2/3 delorazepam 1/3 CLB 1/5 DZ 0/1 OTHERS Acetazolamideeffectiveness 3/5 increase of severity of attacks 1/5 Mild reduction of frequency for 2 years withtrihexyphenidyl1/1 Cyproterone+ethinylestradiol number and severity of attacks during 6 mo of therapy in a pt  drop-out with relapse  re-treatment and improvement No effectiveness haloperidol 4/4 pimozide 2/2 niaprazine, trazodone, fluoxetine, biperiden, baclofen, Ldopa+carbidopa, piracetam, B6, B1, L-carnitine 1/1 NON CONVENTIONAL MEDICINE No effectiveness reflexology 2/2 homeopathy 3/3

5. INTERMITTENT THERAPY- RESULTS BENZODIAZEPINES5/15CHLORAL HYDRATE2/4 diazepam 2/10NIAPRAZINE3/8 nitrazepam 1/2 delorazepam 1/2 clonazepam 0/1 BENZODIAZEPINES Generally stop the attacks by inducing sleep (according to dose) After awakening, good general status in some pts, significant side effects (such as sedation and/or irritability) in others Paradoxal effects including insomnia and hyperexcitability in some cases ANECDOTAL REPORTS -paracetamol+codeinepain control, less discomfort, sleep -paracetamoladministered for fever, decrease of frequency of attacks -desamethazoneprompt interruption of major attacks

6. CHLORAL HYDRATE Sedative, hypnotic, and anticonvulsant Rapidly reduced to tricloethanol (half life of a few minutes), which is a central depressant metabolite with plasma half-life from 4 to 12 hours Conjugated with glucuronic acid, excreted in the urine It rapidly induces sleep, with good awakening AHC Rapid arrest of attacks, inducing sleep in 2/4 pts Single rectal dose of 600 to 1200 mg - not for sale in Italy oral dose of 40 mg/Kg - unstable galenic product Good in hospital, low manageability for parents  used for severe major attacks

7. NIAPRAZINE Piperazine derivative, histamine 1-receptor antagonist Widely used in children for its sedative and hypnotic properties Sedation reflects the disruption of the 5-hydroxytryptamine/ noradrenaline equilibrium as a result of specific short-lasting depletion of brain catecholamines Niaprazine reduces noradrenaline and dopamine concentrations in mouse brain with a dose-dependent effect AHC At a single oral dose of 10 to 20 mg interruption of attacks in 10 minutes in 3/8 pts, without inducing sleep The effect was obtained when administered at the onset Good manageability

8. ITALIAN ASSOCIATION AHC - Conclusions CONTINUATIVE THERAPY Flunarizineis confirmed as thedrug of choice, but not as the resolutive one. In few cases there is evidence of the usefulness of acetazolamide, 5HTP, GVG, TPM, trihexyphenidyl In some patientsbenzodiazepinesmay improve the quality of life by decreasing stressing factors such as anxiety and hyperexcitability: therefore it may be helpful asadjunctive therapyfor brief periods of time INTERMITTENT THERAPY This approach can be taken into consideration in prolonged major attacks Benzodiazepines, chloral hydrate, or niaprazine can arrest the attacks, usually inducing sleep The drug can be chosen on the basis of several factors.

9. ITALIAN ASSOCIATION AHC - Conclusions Because of their effectiveness, manageability and side effects chloral hydrate could be preferable for hospital use, while niaprazine could be suggested for home administration, and benzodiazepines are suitable for both. It is important to  administer the drug at the beginning of the attack  control possible adverse effects When the pain is particularly strong paracetamol  codeine may be useful Finally, new prospects are open through collaborative studies  trials with new drugs  further studies on the pathogenesis of this rare, peculiar disease not only to control the attacks but also to fight the neurological and intellectual impairment