Anticonvulsant Effects Of Carbamazepine Research Articles

Pharmacodynamic and pharmacokinetic interactions between common antiepileptic drugs and acetone, the chief anticonvulsant ketone body elevated in the ketogenic diet in mice

Acetone is the principal ketone body elevated in the ketogenic diet (KD), with demonstrated robust anticonvulsant properties across a variety of seizure tests and models of epilepsy. Because the majority of patients continue to receive antiepileptic drugs (AEDs) during KD treatment, interactions between acetone and AEDs may have important clinical implications. Therefore, we investigated whether acetone could affect the anticonvulsant activity and pharmacokinetic properties of several AEDs against maximal electroshock (MES)-induced seizures in mice. Effects of acetone given in subthreshold doses were tested on the anticonvulsant effects of carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), topiramate (TPM) and valproate (VPA) against MES-induced seizures in mice. In addition, acute adverse effects of acetone-AEDs combinations were assessed in the chimney test (motor performance) and passive avoidance task (long-term memory). Pharmacokinetic interactions between acetone and AEDs were also studied in the mouse brain tissue. Acetone (5 or 7.5 mmol/kg, intraperitoneally [i.p.]) enhanced the anticonvulsant activity of CBZ, LTG, PB, and VPA against MES-induced seizures; effects of OXC, PHT, and TPM were not changed. Acetone (7.5 mmol/kg) did not enhance the acute adverse-effect profiles of the studied AEDs. Acetone (5 or 7.5 mmol/kg, i.p.) did not affect total brain concentrations of the studied AEDs. In contrast, VPA, CBZ, LTG, OXC, and TPM significantly decreased the concentration of free acetone in the brain; PB and PHT had no effect. Acetone enhances the anticonvulsant effects of several AEDs such as VPA, CBZ, LTG, and PB without affecting their pharmacokinetic and side-effect profiles.

Anticonvulsant Effects of Carbamazepine on Spontaneous Seizures in Rats with Kainate‐induced Epilepsy: Comparison of Intraperitoneal Injections with Drug‐in‐food Protocols

The present study evaluated the effectiveness of intraperitoneal (IP) injections and oral administration of carbamazepine (CBZ) in food on the frequency of spontaneous motor seizures in rats with kainate-induced epilepsy. The purpose was to develop a convenient drug-in-food approach for continuous, long-term administration of potential antiepileptic drugs (AEDs). Single IP injections of CBZ (10-100 mg/kg) were compared to vehicle injections via six AED-versus-vehicle tests using a repeated-measures, crossover protocol. Similar protocols were used with CBZ-containing or control food pellets. CBZ significantly reduced motor seizure frequency at 30 and 100 mg/kg after single IP injections, and these doses completely blocked motor seizures during a 6-h postdrug epoch in 25% and 70% of the animals, respectively. Single administrations of 30 mg/kg and 100 mg/kg CBZ in food also significantly reduced motor seizures, and blocked seizures in 33% and 89% of the rats, respectively. CBZ administered in food three times per day (100 mg/kg x3 CBZ in food) continuously blocked nearly all motor seizures over a 5-day period, and completely suppressed motor seizures in 50% of the animals tested. CBZ strongly suppresses spontaneous motor seizures, and single doses of CBZ in food are as effective as IP injections in rats with kainate-induced epilepsy. CBZ administered regularly in food continuously blocks nearly all motor seizures, and may provide a relatively simple method to test AEDs in chronic models of epilepsy.

Seizure susceptibility of neuropeptide-Y null mutant mice in amygdala kindling and chemical-induced seizure models

Neuropeptide Y (NPY) administered exogenously is anticonvulsant, and, NPY null mutant mice are more susceptible to kainate-induced seizures. In order to better understand the potential role of NPY in epileptogenesis, the present studies investigated the development of amygdala kindling, post-kindling seizure thresholds, and anticonvulsant effects of carbamazepine and levetiracetam in 129S6/SvEv NPY(+/+) and NPY(−/−) mice. In addition, susceptibility to pilocarpine- and kainate-induced seizures was compared in NPY(+/+) and (−/−) mice. The rate of amygdala kindling development did not differ in the NPY(−/−) and NPY(+/+) mice either when kindling stimuli were presented once daily for at least 20 days, or, 12 times daily for 2 days. However, during kindling development, the NPY(−/−) mice had higher seizure severity scores and longer afterdischarge durations than the NPY(+/+) mice. Post-kindling, the NPY(−/−) mice had markedly lower afterdischarge thresholds and longer afterdischarge durations than NPY (+/+) mice. Carbamazepine and levetiracetam increased the seizure thresholds of both NPY (−/−) and (+/+) mice. In addition, NPY (−/−) mice had lower thresholds for both kainate- and pilocarpine-induced seizures. The present results in amygdala kindling and chemical seizure models suggest that NPY may play a more prominent role in determining seizure thresholds and severity of seizures than in events leading to epileptogenesis. In addition, a lack of NPY does not appear to confer drug-resistance in that carbamazepine and levetiracetam were anticonvulsant in both wild type (WT) and NPY null mutant mice.

Frontal versus transcorneal stimulation to induce maximal electroshock seizures or kindling in mice and rats.

Frontal stimulation, i.e. electrical stimulation where electrodes are pressed on the skin of the intact frontal skull of mice or rats, may represent a more humane alternative to the widely used transcorneal stimulation to induce electroshock seizures. The aim of this work was to directly compare transcorneal and frontal stimulation in eliciting maximal electroshock-induced seizures (MES) in mice and the anticonvulsant effect of carbamazepine (CBZ) and phenytoin (PHT) on thus produced seizures. In addition, we stimulated mice and rats repeatedly via transcorneal and frontal electrodes to see whether kindling is produced by this procedure. Two electroshock tests were used in mice, i.e. maximal electroshock seizure threshold (MEST) test and MES generated by supramaximal stimulation (50 mA). Frontal stimulation resulted in lower convulsive threshold than in the case of corneal stimulation. Both CBZ and PHT produced dose-dependent increases in seizure threshold for both sites of stimulation, i.e. transcorneal and frontal. As regards type of electrodes, higher doses of PHT were required to increase seizure threshold in the case of frontal than transcorneal stimulation. Supramaximal stimulation (50 mA) yielded comparable ED50 values regardless of the site of stimulation. Furthermore, once-daily stimulation of mice, regardless of the placement of electrodes, did not induce any changes in convulsive threshold. We also attempted to kindle mice and rats via corneal and frontal electrodes by repetitive electrical stimulation using currents which initially did not produce generalized clonic seizures. Mice were stimulated once daily for 2 s with 3 mA (corneal electrodes) or 2 mA (frontal electrodes) and rats were stimulated twice daily for 4 s at 8 mA (corneal electrodes) or 5 mA (frontal electrodes). With corneal stimulation in rats there was a clear progression of kindling development which was not the same in nature when compared with corneally-stimulated mice. Frontal stimulation did not produce kindling. Moreover, corneal stimulation was better tolerated by rats, while in mice high mortality was seen after either method of current delivery. Our data indicate that frontal electrodes can be used as an alternative to transcorneal stimulation to produce MES by supramaximal or threshold current intensities as screening procedures in antiepileptic drug (AED) development. Nevertheless, this type of stimulation cannot be used to produce minimal electroshock seizures and seems not to be useful to produce kindling in rats and mice.

Corticotropin-releasing hormone: potentiation of cocaine-kindled seizures and lethality.

Carbamazepine (CBZ) blocks the development of local anesthetic seizures kindled by cocaine and lidocaine. Cocaine and lidocaine release corticotropin-releasing hormone (CRH) in hypothalamic cell cultures, and this effect is also blocked by CBZ. Because CRH administered intracerebroventricularly (i.c.v.) can produce seizures, its potential role in the development of cocaine seizures and in the anticonvulsant effects of CBZ was studied. CRH (at doses of 5, 10, and 100 micrograms) potentiated cocaine-kindled seizure development and lethality in a dose-related fashion. CRH also reversed the effects of CBZ on cocaine kindling and lethality, but only at the highest doses, which also affected cocaine kindling. Thus, a selective role for CRH in the anticonvulsant effects of CBZ was not demonstrated. The findings suggest a potentially important role for CRH in exacerbating cocaine-seizure evolution and its associated lethality and confirm the inhibition of cocaine kindling and lethality by CBZ.

Contingent tolerance to carbamazepine is associated with lowering of amygdala-kindled seizure thresholds

Amygdala-kindled seizure thresholds were studied in animals which were or were not tolerant to the anticonvulsant effects of carbamazepine. The seizure threshold was defined as the lowest current that elicited a major motor seizure (stage 3 or greater). Amygdala-kindled rats received carbamazepine, once daily, either before each electrical stimulation (carba-before) or after each stimulation (carba-after). The rats given carbamazepine before, but not after, each once-daily kindling stimulation became tolerant to its anticonvulsant effects. Following this manipulation, seizure thresholds were redetermined in both groups of animals while medication-free. The carba-before (i.e., tolerant) animals showed a decreased seizure threshold, while the carba-after (i.e., nontolerant) animals showed no change. Tolerance to carbamazepine was reversed by giving the rats kindled seizures for a period of 7 days without drug; nontolerant animals received the same stimulation and seizures. When seizure thresholds were reevaluated, the carba-before animals (now not tolerant) had returned to their pretolerance values, while the carba-after group again showed no change. This effect of carbamazepine tolerance and its reversal being associated with respective decreases and increases in basal seizure threshold was replicated two more times. In each case the change in the generalized seizure threshold mirrored the change in responsivity of the animals to carbamazepine. These findings, consistent with the formulations of Siegel regarding conditioned compensatory response mechanisms mediating contingent drug tolerance, may have important clinical and theoretical implications.

Lack of Major Effects on Mouse Brain Adenosine A1Receptors of Oral Carbamazepine and Calcium Antagonists

Interaction with adenosine A1 receptors is a possible contributory mechanism to the anticonvulsant effects of carbamazepine (CBZ) and the dihydropyridine calcium antagonists. We measured the binding of [3H]cyclohexyladenosine to adenosine A1 receptors in mouse brain stem, cerebellum, and cortex after oral administration of nifedipine, nimodipine (NMD), and CBZ for 7 days and compared the results with binding in control mice. Equilibrium dissociation constant (Kd) and receptor numbers (Bmax) were calculated using Scatchard and saturation isotherm analyses. Mean Kds (SEM) in control brain stem, cerebellum, and cortex were 2.09 (0.31), 2.39 (0.2), and 3.12 (0.28) nM, respectively. Results of Bmax for the same areas were 188 (26), 280 (24), and 449 (54) fmol/mg protein. Nifedipine (p less than 0.005) and NMD (p less than 0.02) raised the Kd of A1 receptors only in the cerebellum, and CBZ increased cerebellar Bmax (p less than 0.05). These minor effects on A1 receptors in CF1 mice, when given in doses previously shown to have anticonvulsant properties in these animals, do not suggest that alteration in A1 receptor activity is an important mechanism for the anticonvulsant effects of these drugs.

Effects of carbamazepine on bicuculline- and pentylenetetrazol-induced seizures in developing rats

The anticonvulsant effect of carbamazepine (CBZ) was examined in 10-, 18- and 25-day-old Wistar albino rats into which bicuculline or pentylenetetrazol had been systemically injected to induce generalized epileptic manifestations typical for the specific age of the animals. The results showed that: a) in developing rats, CBZ appears to be more effective in the pentylenetetrazol than the bicuculline model of epilepsy; b) in both models of epilepsy the efficacy of CBZ increases with the age of the animals; and c) among the various epileptic manifestations, the tonic phase is the most sensitive to the anticonvulsant effect of CBZ. These conclusions are correlated with the different levels of cerebral maturation of the animals, and are discussed with reference to the mechanisms of action of CBZ and bicuculline or pentylenetetrazol.

Lack of Beneficial Effects of L-Baclofen in Affective Disorder

GABAB mechanisms have been implicated in the antinociceptive, but not anticonvulsant effects of carbamazepine. A variety of antidepressants have been reported to upregulate GABAB receptors after chronic administration. The GABAB agonist l-baclofen was studied in depressed patients based on two separate rationales. l-Baclofen, in doses ranging from 10-55 mg/day, was administered to five patients with primary affective disorder. No patient showed a positive clinical response, while three patients showed a pattern of increasing depression or cycling during treatment and improvement during withdrawal. These preliminary data suggest that GABAB agonism is unlikely to produce antidepressant effects and may be unrelated to the mechanism of carbamazepine's antidepressant action. These data, taken with a reinterpretation of other findings that antidepressant modalities upregulate GABAB receptors in brain following chronic administration, suggest that GABAB antagonism rather than agonism may be a fruitful clinical strategy to explore in depression.

Sensitization and Kindling Perspectives for the Course of Affective Illness: Toward a New Treatment with the Anticonvulsant Carbamazepine

Successive episodes of affective illness often show an accelerating frequency of recurrence. Two very different preclinical models (behavioral sensitization to psychomotor stimulants and electrophysiological kindling) may be used as indirect analogies or non-homologous models for conceptualizing mechanisms underlying the progressive and evolving aspects of manic-depressive illness. These models focus on phenomena involved in the longitudinal course of illness and on novel treatment implications. Literature is reviewed on the acute and long-term effectiveness of the anti-convulsant carbamazepine, particularly in treatment of lithium-refractory bipolar illness. Potential mechanisms of carbamazepine's acute anticonvulsant and antinociceptive and delayed psychotropic actions are discussed. alpha-2 adrenergic and peripheral-type benzodiazepine receptors, and stabilization of type-2 sodium channels are likely involved in the anticonvulsant effects of carbamazepine. GABAB mechanisms are thought to be related to the antinociceptive but not anticonvulsant or psychotropic effects of carbamazepine. A large number of neurotransmitters remain candidates for the psychotropic effects and a novel animal model requiring chronic administration of carbamazepine in order to show efficacy is reported (Weiss et al., 1989). It is hoped that further understanding of the mechanism of action of the anti-convulsant agents in comparison and contrast with traditional psychotropic agents will help in generating new treatments and in uncovering the basic defects of manic-depressive illness.

Clinical Pharmacokinetics of Carbamazepine

Carbamazepine seems to as effect as phenytoin in the treatment of grand mal and psychomotor epilepsy. It is the drug of first choice in trigeminal neuralgia. After single oral doses of carbamazepine, the absorption is fairly complete and the elimination half-life is about 35 hours (range 18 to 65 hours). During multiple dosing, the half-life is decreased to 10-20 hours, probably due to autoinduction of the oxidative metabolism of the drug. Phenytoin and barbiturates also induce the metabolism of carbamazepine. After single doses of carbamazepine, elimination follows dose-dependent first order kinetics. Carbamazepine is metabolised by oxidation before excretion in the urine. In experimental animals, the metabolite carbamazepine-10,11-epoxide has anticonvulsant activity comparable with that of the parent drug. The plasma concentration of the metabolite during long-term treatment of epileptic patients varies between 5 and 81% of that of the parent drug. The plasma protein binding of the metabolite is about 50% compared with about 75% for the parent drug. Less than 50% of a given carbamazepine doses has been identified as metabolites in the urine. The quantitatively most important metabolites is the trans-10,11-dihydro-10,11-diol. The kinetics of carbamazepine have been explored to some extent in pregnant women, newborns and children. Plasma levels of carbamazepine seem to decrease during pregnancy, possibly as a result of increased metabolism. The drug readily crosses the placenta and the levels measured in newborns are comparable with maternal plasma concentrations. In newborns exposed to the drug during fetal life, the plasma half-lives were relatively short (8.2 to 28.1 hours) indicating an induction of carbamazepine metabolism during gestation. The pharmacokinetics of carbamazepine in children aged 0.3 to 15 years are comparable with that in adults. A single daily dose of carbamazepine is insufficient; 2 doses per day are appropriate in most cases, but some patients may benefit from more frequent dosing to avoid side-effects. Compared with phenytoin, for example, very few controlled studies have been performed to establish the plasma level range of carbamazepine associated with the best therapeutic outcome. However, the best anticonvulsant effect of carbamazepine seems to be obtained at plasma levels of about 5 to 10microgram/ml (20 to 40mumol/L). Side-effects are most frequent at higher levels but may also be seen at lower levels.

Decreased anticonvulsant activity of carbamazepine in 6-hydroxydopamine-treated rats

An intraventricular injection of 6-hydroxydopamine, which produced a marked decrease of catecholamines in the forebrain, significantly lowered the electroconvulsive threshold in rats. The anticonvulsant effect of carbamazepine was also significantly reduced in the animals treated with 6-hydroxydopamine. The results are consistent with the hypothesis that brain catecholamines may play an important role in seizure susceptibility as well as in the anticonvulsant activity of carbamazepine in rats.