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Tesi etd-10292010-075800


Thesis type
Tesi di laurea specialistica LC5
Author
LUPI, MARTA
URN
etd-10292010-075800
Title
ANTIEPILEPTIC MECHANISM OF CORTICOSTEROIDS: PHARMACOKINETIC OR PHARMACODYNAMIC?
Struttura
FARMACIA
Corso di studi
CHIMICA E TECNOLOGIA FARMACEUTICHE
Commissione
relatore Prof.ssa Martini, Claudia
relatore Marchi, Nicola
Parole chiave
  • corticosteroids
  • drug resistant patients
  • antiepileptic
Data inizio appello
17/11/2010;
Consultabilità
parziale
Data di rilascio
17/11/2050
Riassunto analitico
Background: the brain is protected by the blood brain barrier (BBB), a vascular system which maintains the proper environment surrounding the neurons. BBB damage is associated with several central nervous system (CNS) diseases including epilepsy. Recently a cause-effect link between BBB damage and seizures has been shown. However, it is still unclear whether pharmacological targeting of the BBB can reduce occurrence of seizure. We have tested the efficacy of anti-inflammatory glucocorticoids (GC) and adrenocorticotropic hormone (ACTH) in reducing seizures by a mechanism involving BBB repair. <br>Experimental approach. Efficacy of add-on GC or ACTH was determined in pediatric patients affected by drug resistant seizures. White blood cell (WBC) numbers were measured. Presence of edema was detected using FLAIR/MRI. We also evaluated the presence of albumin, an indication of BBB leakage, in brain tissue resected from drug-resistant patients. Finally, we studied the effects of dexamethasone on seizure onset in a rat model of epilepsy.<br> Key results: We found a significant reduction in seizure frequency after GC or ACTH add-on treatment. This reduction was associated with a significant increase of total WBC count in blood. In particular, neutrophils were significantly increased. MRI demonstrated a reduction of brain edema after GC or ACTH. We also found a significant reduction of seizures in an animal model of epilepsy when pretreated with dexamethasone.<br>Conclusions: Our results show an efficacy of add-on GC and ACTH for reducing seizure burden in pediatric subjects. The proposed mechanisms of action include BBB reparation and restoration of brain homeostasis, facilitating penetration of antiepileptic drugs (AEDs) into the brain. <br>
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