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Unidirectional cross-tolerance from levetiracetam to carbamazepine in amygdala-kindled seizures.
- Source :
-
Epilepsia [Epilepsia] 2003 Dec; Vol. 44 (12), pp. 1487-93. - Publication Year :
- 2003
-
Abstract
- Purpose: Tolerance is a potential problem in long-term anticonvulsant therapy of epilepsy, bipolar disorder, and neuropathic pain. The present study was designed to determine whether cross-tolerance occurs between levetiracetam (LEV) and carbamazepine (CBZ) in amygdala-kindled rats.<br />Methods: Male Sprague-Dawley rats were implanted with an electrode into the left amygdala. While kindling stimulation was started, animals received repeated treatment (i.p.) with saline (n = 7) or LEV (150 mg/kg, n = 8). Saline-injected rats were subsequently challenged with a single dose of 150 mg/kg LEV when full kindling developed (stage > or =4). Both groups of rats were then administered long-term CBZ (5 mg/kg) until rats developed complete tolerance. All CBZ-tolerant rats were subsequently re-exposed to LEV (150 mg/kg) for an additional 10 consecutive days.<br />Results: Repeated LEV treatment significantly suppressed the increase in seizure stage, seizure duration, and afterdischarge duration induced by amygdala stimulation, markedly increasing the number of stimulations to achieve a kindling major motor seizure. The LEV challenge produced a more robust suppression of seizure stage in saline-injected rats compared with LEV-treated animals. CBZ treatment markedly suppressed fully kindled seizures in rats initially injected with saline, and then anticonvulsant tolerance rapidly developed after 3-4 days of repeated treatment. In contrast, rats that had initially received repeated LEV treatment did not show a response to treatment with CBZ (5 mg/kg). When CBZ-tolerant rats were subsequently exposed to LEV (150 mg/kg), noticeable anticonvulsant effects were observed; but these were gradually lost with increasing numbers of LEV exposures.<br />Conclusions: Whereas LEV shows potent antiepileptogenic and anticonvulsant effects in amygdala-kindled rats, its repeated treatment induces anticonvulsant tolerance and unidirectional cross-tolerance to CBZ. In contrast, anticonvulsant tolerance to CBZ does not transfer to LEV. The mechanistic implications of the present results for clinical therapeutics remain to be evaluated.
- Subjects :
- Animals
Electroencephalography drug effects
Injections, Intraperitoneal
Levetiracetam
Long-Term Care
Male
Rats
Rats, Sprague-Dawley
Amygdala drug effects
Anticonvulsants pharmacology
Carbamazepine pharmacology
Drug Tolerance
Kindling, Neurologic drug effects
Piracetam analogs & derivatives
Piracetam pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0013-9580
- Volume :
- 44
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Epilepsia
- Publication Type :
- Academic Journal
- Accession number :
- 14636317
- Full Text :
- https://doi.org/10.1111/j.0013-9580.2003.34803.x