Allopurinol as adjunctive therapy in intractable epilepsy A double blind and placebo controlled trial

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Slide 1 : IN THE NAME OF GOD
Slide 2 : Allopurinol as adjunctive therapy in intractable epilepsy: A double blind and placebo controlled trial. Archives of Medical Research 38 (2007) 313e316 Mansoureh Togha,a Shahin Akhondzadeh,b Mahmood Motamedi,a Babak Ahmadi,a and Soodeh Razeghia aNeurology, Tehran University of Medical Sciences, Sina Hospital, Tehran, Iran bPsychiatric Research Center, Tehran University of Medical Sciences, Roozbeh Hospital, Tehran, Iran
Slide 3 : The idea came from Adenosine has been proposed to be an endogenous anticonvulsant agent, inhibiting glutamate release from excitatory neurons and inhibiting neuronal firing .
Slide 4 : Adenosine receptors Adenosine receptors are widely distributed throughout the body. There are increasing therapeutic applications for adenosine receptor agonists and antagonists that act at the four adenosine receptor subtypes AI, A2A, A2B and A3(1). Adenosine has been proposed to be an endogenous anticonvulsant agent, inhibiting glutamate release from excitatory neurons and inhibiting neuronal firing.
Slide 5 : Adenosine agonists therefore have potential Clinical application as anti epileptic. Recently the xantine oxidase inhibitor allopurinol,which inhibits purine degradation, was suggested for treatment of refractory epilepsy(2, 3). It has been reported that allopurinol exerts its anticonvulsant effect through inhibiting the synthesis of quinolic acid and kynurenine, two endogenous excitatory neurotransmitters(2).
Slide 6 : allopurinol is an inhibitor of the enzyme xantine oxidase The final step in purine metabolism, converting hypoxanthine and xantine into uric acid. The accumulation of hypoxanthine and xantine may favor the action of the enzyme hypoxantine-guanine-phosphorybosil-transferase, which is responsible for purine salvage, possibly increasing the levels of the neuromudulators adenosine and guanosine. Activation of adenosine receptors results anti epileptic effects in animal models.
Slide 7 : The Study In this double blind raomndomized, placebo controlled trial in 38 patients with refractory epilepsy; we assessed the antiepileptic effect of allopurinol as adjuvant agent.
Slide 8 : Methods Thirty eight patients were randomly allocated equally to allopurinol +preexisting antiepileptic (Group A) or placebo + preexisting antiepileptic (Group B) for a 6-month, double-blind, placebo-controlled study. The dose of allopurinol was titrated up to 300 mg/day (three times per day). The dose of preexisting medications was maintained without changed over the trial. The effect of allopurinol was evaluated by reduction in the total number of seizure per month and duration of seizures.
Slide 9 : Participants Participants were epileptic patients between the ages of 18 and 55 years. Patients who met the following criteria were admitted to the trial: clearly recognizable and reliably documented epileptic seizure; seizure frequency not less than 3 per month; not response to two or more standard medications; antiepileptic drug regimen optimized by adjustment of serum level, and no evidence of non-compliance
Slide 10 : Participants Patients were excluded if they had any serious illness other than epilepsy and non-progressive encephalopathy; receiving regularly medications other than antiepileptic drugs and pregnancy or risk of conception in females
Slide 11 : Treatment 38 patients were randomly allocated equally to allopurinol + preexisting antiepileptic (Group A) or placebo + preexisting antiepileptic (Group B) for a 6-month, double-blind, placebo-controlled study. The dose of allopurinol was titrated up to 300 mg/day (three times per day)
Slide 12 : Methods of evaluation The effect of allopurinol was evaluated by reduction in the total number of seizure per month and duration of seizures. The data were presented as mean:%: SD using Student t test and Chi square .
Slide 13 : Baseline data At baseline, mean?SD number of seizure in the allopurinol was 13.90 :I?10.20 and in the placebo group was 14.80:1?11.70 and duration of seizure was 1.30:1?0.60 (min) and 1.20?0.6 respectively. There were no significant differences between the two group regarding total number and duration of seizures. Mean ?SD reduction in the number and duration of seizure compared to baseline in 1, 2, 3, 4, 5 and six months after medications
Slide 14 : Table 1- Demographic data and seizure types. A= Allopurinol group; B= Placebo group; TCG= Tonic Clonic Generalized seizure; GT= Generalized Tonic; GA= Generalized Atonic; CPS= Complex Partial Seizure
Slide 15 : The Results Seizure reduction of more than 30% in 66%, more than 50% in 55% and more than 60% in 44% of cases in Allopurinol group were achieved after two months and persisted during the study. Nevertheless, only in month 4, there was a significant difference between the two groups regarding reduction in seizure duration. In the allopurinol group two patients had transient rashes, two mild nausea and two dizziness, but only one patient discontinued the drug, due to dizziness
Slide 16 : Reduction in the number and duration of seizure compared to baseline A= Allopurinol group B= Placebo group
Slide 17 : Discussion Our results are in line with previous studies that indicate the efficacy of allopurinol in refractory seizure(2,4,5). In addition, no severe side effects were observed with either treatments and there was no significant difference in the frequency of side effects
Slide 18 : Discussion (con.) In the study by De Marco and Zagnoni (11), on 64 epileptics decrease in seizure frequency of 50-100% in 68.74% of their patients was achieved and they did not report decline in Allopurinol positive effect at the end of one year follow up.
Slide 19 : Discussion (con.) In regard to the effect of the drug in various seizure types, the researches are limited. In the study by Zognoni (9), The zeisure reduction was 27.9% in secondary generalized seizures versus 10.5% reduction in total seizures. Tada et al (8) reported decrease in seizure frequency in 55% of patients and impressed that the effect was more pronounced in focal and especially in focal secondary generalized type seizures.
Slide 20 : Limitations The limitations of the present study, including the small number of patients and as a result of that lack of verification whether allopurinol exerted a differential effect on the various seizure types, requires that the results be confirmed in larger randomized controlled trials
Slide 21 : References 1. Stone TW. Physiological roles for adenosine and adenosine 5-triphosphate in the nervous system. Neuroscience 1981;6:523e550. 2. Stone TW. Purine receptor classification: a discussion point. Trends Pharmacol Sci 1985;5:492e493. 3. Guieu R, Couraud F, Pouget J, Sampieri F, Bechis G, Rochat H. Adenosine and the nervous system: clinical implications. Clin Neuropharmacol 1996;19:459e474. 4. Brundege JM, Dunwiddie TV. Role of adenosine as a modulator of synaptic activity in the central nervous system. Adv Pharmacol 1997;39:353e391. 5. Guieu R, Bussol B. Adenosine and the nervous system. Pharmacological data and therapeutic perspectives. Gen Pharmacol 1998;31:553e561. 6. Wada Y, Hasegawa H, Nakamura M, Yamaguchi N. Anticonvulsant effect of allopurinol on hippocampal-kindled seizures. Pharmacol. Biochem Behav 1992;42:899e901. 7. Marrosu F, Marrosu G. Allopurinol add-on treatment in intractable seizure. Acta Neural (Napoli) 1990;12:207e213. 8. Tada H, Morooka K. Clinical effects of allopurinal on intractable epilepsy. Epilepsia 1991;32:279e283. 9. Zagnoni PG, Bianchi A. Allopurinal as add-on therapy in refractory epilepsy: a double-blind placebo-controlled randomized study. Epilepsia 1994;35:107e112. 10. Coppola G, Pascotto A. Double-blind, placebo-controlled cross over trial of allopurinal as add-on therapy in childhood refractory epilepsy. Brain Dev 1996;18:50e52. 11. De Marco P, Zagnoni P. Allopurinol in severe epilepsy. A preliminary report. Neuropsychobiology 1988;19:51e53. 12. Guzeva VI, Gusel VA, Mikhailov IB. Allopurinol in the combined therapy of severe forms of epilepsy in children. Zh Nevropatol Psikhiatr Im S S Korsakova 1988;88:69e72. 13. World Medical Association. Declaration of Helsinki. Ethical principles for medical research involving human subjects. 2000. Available at: http://www.wma.net.
Slide 22 : Persepolis, IRAN

 


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