(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Seizures

The aim of this study was to determine the influence of acute (single) and chronic (once daily for 7 consecutive days) treatments with atorvastatin and fluvastatin on the anticonvulsant potential of three antiepileptic drugs: carbamazepine, phenytoin and valproate in the mouse maximal electroshock-induced seizure model. Additionally, the effects of acute and chronic administration of both statins on the adverse effect potential of three antiepileptic drugs were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). To evaluate the pharmacokinetic characteristics of interaction between antiepileptic drugs and statins, the total brain concentrations of antiepileptic drugs were estimated with the fluorescence polarization immunoassay technique. Results indicate that atorvastatin at doses up to 80mg/kg in chronic experiment attenuated the anticonvulsant potential of carbamazepine by increasing its ED(50) value against maximal electroconvulsions. Acute fluvastatin (80mg/kg) enhanced the anticonvulsant potential of carbamazepine and valproate by decreasing their ED(50) values. Acute fluvastatin (80mg/kg) also markedly increased the total brain carbamazepine concentration by 61% in a pharmacokinetic reaction. Atorvastatin (acute and chronic) and fluvastatin (chronic) in combinations with valproate impaired long-term memory in mice. Both statins in combinations with all three antiepileptic drugs had no impact on their adverse effects in the chimney test. Based on this preclinical study, one can conclude that chronic administration of atorvastatin reduces the anticonvulsant action of carbamazepine and acute fluvastatin can enhance the anticonvulsant potency of the carbamazepine and valproate. The former interaction was pharmacokinetic in nature.

Topics: Animals; Anticonvulsants; Atorvastatin; Brain; Carbamazepine; Disease Models, Animal; Drug Interactions; Electroshock; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Indoles; Male; Memory; Mice; Motor Activity; Phenytoin; Pyrroles; Seizures; Valproic Acid

We report a 36-year-old woman with the occurrence of painful focal seizures of her left hand and the left leg. She also had focal motor seizures at the left corner of her mouth. The duration and frequency of the episodes increased over four days from a few seconds once a day to frequent intervals lasting more than four hours at a time. The symptoms appeared one day after start of the treatment with fluvastatin (40 mg) administered in order to diminish the endothelial activation induced by antiphospholipid antibodies (aPL). The patient suffered from severe manifestations of the antiphospholipid syndrome (APS) including Catastrophic Antiphospholipid Syndrome (CAPS, Asherson's syndrome). In this case a single 40 mg dose of oral fluvastatin was linked to seizures. After discontinuation of this treatment, the seizures immediately disappeared and the patient fully recovered without evidence of permanent neurological damage. This data links statins to seizures in patients with compromised blood brain barrier such as APS.

Topics: Adult; Antiphospholipid Syndrome; Blood-Brain Barrier; Brain; Epilepsies, Partial; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Magnetic Resonance Imaging; Seizures