Combined Administration of Carbamazepine and Phenobarbital: Effect on Anticonvulsant Activity and Neurotoxicity

Despite the trend towards single drug therapy of epilepsy, patients resistant to monotherapy are commonly treated with more than one antiepileptic drug. As part of an investigation on the experimental background for antiepileptic drug combinations, the effect of the pharmacodynamic interactions between carbamazepine and phenobarbital on the toxicity/efficacy ratio was studied in mice. All results were expressed in terms of drug concentrations in the brain to exclude possible pharmacokinetic interactions from the analysis. A purely additive interaction was found for the anticonvulsant as well as for the neurotoxic effect of the drugs. The combination of carbamazepine and phenobarbital has therefore no advantage over each drug alone in this model. Based on these and previous results, there is no experimental evidence in favor of any combination between the four main drugs against partial seizures, i.e., carbamazepine, phenytoin, phenobarbital, and primidone.     

Antiepileptic drug regimens and major congenital abnormalities in the offspring.

To assess the risk of major congenital abnormalities associated with specific antiepileptic drug regimens, a large retrospective cohort study was performed. The study comprised 1,411 children born between 1972 and 1992 in four provinces in The Netherlands who were born to mothers with epilepsy and using antiepileptic drugs during the first trimester of pregnancy, and 2,000 nonepileptic matched controls. We found significantly increased risks of major congenital abnormalities for carbamazepine and valproate monotherapy, with evidence for a significant dose-response relationship for valproate. The risk of major congenital abnormalities was nonsignificantly increased for phenobarbital monotherapy when caffeine comedication was excluded, but a significant increase in risk was found when caffeine was included. Phenytoin monotherapy was not associated with an increased risk of major congenital abnormalities. Regarding polytherapy regimens, increased risks were found for several antiepileptic drug combinations. Clonazepam, in combination with other antiepileptic drugs, showed a significantly increased relative risk. Furthermore, there were significantly increased relative risks for the combination of carbamazepine and valproate and the combination of phenobarbital and caffeine with other antiepileptic drugs. This study shows that most antiepileptic drug regimens were associated with an increased risk of major congenital abnormalities in the offspring, in particular valproate (dose-response relationship) and carbamazepine monotherapy, benzodiazepines in polytherapy, and caffeine comedication in combinations with phenobarbital.     

Selection of drugs for the treatment of epilepsy

Antiepileptic drug selection is based on efficacy for specific seizure types and epileptic syndromes. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the drug of choice is valproate. Secondary generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single drug or combination of drugs. The drugs of choice for absence seizures are ethosuximide and valproate. For control of tonic-clonic seizures, any of the other major antiepileptic drugs can be effective. If valproate cannot be used, carbamazepine, phenobarbital, phenytoin, or primidone is effective, but ethosuximide or a benzodiazepine needs to be added to control associated absence or myoclonic seizures. The drugs of first choice for partial epilepsies with partial and secondarily tonic-clonic seizures are carbamazepine and phenytoin. Increasing evidence suggests that valproate may be a third alternative. Phenobarbital and primidone are second choice selections because of side effects. A combination of two of these five major antiepileptic drugs may be necessary for inadequately controlled patients. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, and alcoholic epilepsy require specific drug treatment. For all these seizure types and epilepsy syndromes, treatment ultimately must be selected to provide maximal efficacy and minimal adverse effect for each individual patient.     

Isobolographic and subthreshold methods in the detection of interactions between oxcarbazepine and conventional antiepileptics--a comparative study

Until now, a character of interactions among the antiepileptic drugs (AEDs), in some experimental models of epilepsy, has been determined alternatively with subthreshold and isobolographic methods. In order to elicit the precise and adequate method for evaluating two drug interactions, the comparative study was performed in the maximal electroshock-induced seizure test in mice. In this experimental model, the exact types of interactions among oxcarbazepine (OXC) and conventional AEDs (diphenylhydantoin, phenobarbital, valproate, carbamazepine, and clonazepam) were determined with both methods. Results from the subthreshold method showed a considerable reduction of ED(50) values of clonazepam, diphenylhydantoin and valproate (after administration of OXC at the highest subthreshold dose of 2.5 mg/kg), whilst ED(50)s of carbamazepine or phenobarbital were almost unchanged when OXC (2.5 mg/kg) was co-administered with these AEDs. Results from the 2-dimensional (2-D) isobolographic analysis of interactions for a 50% anticonvulsant effect, for three fixed drug dose ratio combinations of 1:2, 1:1, and 2:1, indicate antagonism between OXC and diphenylhydantoin as regards their anticonvulsant (protective) activity. Furthermore, the interactions between OXC and clonazepam occurred either antagonistic (for the fixed-ratios of 1:4 and 1:3) or synergistic (for the fixed-ratio combinations of 1:1 and 2:1) depending on the proportions of used drugs. Remaining interactions between OXC and carbamazepine, OXC and valproate, or OXC and phenobarbital (for the fixed-ratios of 1:3, 1:1, and 3:1) were isobolographically additive for a 50% anticonvulsant effect tested. The 3-dimensional (3-D) isobolographic analysis of interactions between OXC and CZP revealed that the dual character of interactions (antagonistic and synergistic) observed for a 50% anticonvulsant effect (ED(50)) was also present for additional drug-dose effects tested, i.e. ED(16) and ED(84). The 3-D isobologram for the combination of OXC with CZP clearly visualized either synergy or antagonism between the drugs in combinations.Distinct differences resulting from two experimental methods prove evidently the superiority of isobolographic analysis over the subthreshold method. The former clearly and adequately detects the exact types of interactions between two AEDs, becoming a potent and powerful paradigm for further studies evaluating the character of interactions among AEDs.     

Phenytoin and carbamazepine, alone and in combination: anticonvulsant and neurotoxic effects

Comedication with phenytoin and carbamazepine is frequently used in patients with refractory seizures, although the benefit of this strategy has not been established. To assess whether the combination is a rational anticonvulsant treatment, we determined the therapeutic index (toxicity:efficacy ratio) for the drugs, alone and together, in mice, The individual agents were virtually identical in anticonvulsant and neurotoxic activity, and combined use had no additional therapeutic advantage. Analysis of drug concentrations in brain showed an additive pharmacodynamic interaction for phenytoin and carbamazepine, indicating that the combination is unlikely to be superior to either drug alone. Thus, we find no experimental justification for the simultaneous use of phenytoin and carbamazepine in the treatment of epilepsy.     

Isobolographic analysis of interactions between remacemide and conventional antiepileptic drugs in the mouse model of maximal electroshock

Using the mouse maximal electroshock-induced seizure model, indicative of tonic-clonic seizures in humans, the present study was aimed at characterizing the interaction between remacemide and valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis indicated additive interactions between remacemide and valproate, carbamazepine, and phenytoin (for all fixed ratios of tested drugs: 1:3, 1:1, and 3:1). Additivity was also observed between remacemide and phenobarbital applied in proportions of 1:1 and 3:1. In contrast, the combination of remacemide and phenobarbital at the fixed-ratio of 1:3 resulted in antagonism. Neither motor performance nor long-term memory was impaired by remacemide or by carbamazepine, phenobarbital, phenytoin, and valproate whether or not these drugs were administered singly or in combination. In combination with remacemide, brain concentrations of carbamazepine, phenobarbital, and phenytoin were increased by 71, 21, and 16%, respectively. Although brain valproate concentrations were unaffected by remacemide co-administration, brain concentrations of remacemide and its active metabolite, desglycinyl-remacemide, were increased by 68 and 162%, respectively. In contrast, phenobarbital co-administration was associated with decreases in brain remacemide (27%) and desglycinyl-remacemide (9%) concentrations, whereas only remacemide concentrations (increased by 131%) were affected by carbamazepine co-administration. In conclusion, significant and desirable pharmacodynamic interactions were observed between remacemide and valproate, carbamazepine, phenytoin, and phenobarbital. However, the concurrent pharmacokinetic interactions associated with remacemide complicate these observations and do not make remacemide a good candidate for adjunctive treatment of epilepsy.     

Influence of levetiracetam on the anticonvulsant efficacy of conventional antiepileptic drugs against audiogenic seizures in DBA/2 mice

Levetiracetam (LEV, [S]-alpha-ethyl-2-oxo-1-pyrrolidine acetamide) is a new antiepileptic that has been used as adjunctive therapy to treat patients with intractable epilepsy. Systemic administration of levetiracetam (2.5-30 mg/kg, intraperitoneally (i.p.)) was able to produce a dose-dependent decrease in DBA/2 audiogenic seizure severity score. In combination with conventional antiepileptic drugs, levetiracetam, 5mg/kg, i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of some antiepileptic drugs studied against sound-induced seizures in DBA/2 mice. The degree of potentiation induced by levetiracetam was greater, approximately twice, for carbamazepine, diazepam, felbamate, topiramate, gabapentin, and valproate, less for lamotrigine, phenobarbital and phenytoin. This increase was associated with a comparable impairment in motor activity; however, the therapeutic index of combined treatment of antiepileptic drugs with levetiracetam was more favourable than the combination with saline with the exception of lamotrigine, phenytoin and phenobarbital. Since levetiracetam did not significantly influence the total and free plasma and the brain levels of antiepileptics studied. In addition, levetiracetam did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, levetiracetam showed an additive anticonvulsant effect when administered in combination with some classical anticonvulsants, most notably carbamazepine, diazepam, felbamate, gabapentin, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations.     

Problems of Combination Drug Therapy in Children

Summary: Despite the current trend toward monotherapy, polytherapy in children with epilepsy is still common. A drug combination is advantageous only if it achieves a higher efficacy: toxicity ratio (therapeutic index) or if its antiepileptic spectrum is wider. Studies of brain concentrations of antiepileptic drugs have so far shown that a higher efficacy toxicity ratio is not achieved by most combinations. Problems are associated with drug combinations. First, numerous pharmacokinetic interactions are documented. These interactions, which can be associated with significant changes in blood levels at a given dose, make frequent measurements and dosage readjustments necessary. They can also alter the concentration of active metabolites or the free fraction of a drug. Second, toxicity can be assumed to be at least partially cumulative, since reduction in polytherapy has been shown to be associated with a reduction in side effects. Third, the therapeutic range appears to depend on whether a drug is taken alone or in combination, so that polytherapy confuses the interpretation of serum drug measurements. Fourth, the presence of more than one drug will add to the difficulty in evaluating the efficacy or side effects of any single drug. Finally, a pharmacodynamic interaction between valproate and several other antiepileptics, particularly the barbiturates, can lead to a stuporous state. Transition from polytherapy to monotherapy is much more difficult to achieve than the opposite.     

Combination of carbamazepine and valproate in different dose proportions in maximal electroshock seizure model in mice

Rational polypharmacy of antiepileptic drugs is one of the treatment strategies for refractory epilepsy. To investigate whether it may be rational to combine carbamazepine (CBZ) and valproate (VPA), we tested both the anti-convulsant effect and the toxicity of combinations of CBZ and VPA in different dose proportions. CBZ/VPA dose ratios were, respectively, 1:6.66, 1:10, 1:13.3 and 1:20. The median effect doses of monotherapy and polytherapy in maximal electroshock seizure test and the median lethal (within 3 days after administration) doses were determined. These parameters were analyzed with the isobologram method. We found that the anti-convulsant effect of all combinations was additive. The toxicity of combination 1, 2 and 3 (CBZ/VPA, 1:6.66, 1:10, 1:13.3) was additive, but the toxicity of combination 4 (CBZ/VPA, 1:20) was infra-additive. Thus, in mice, using this model, a combination of CBZ/VPA 1:20 has an advantage over each of the drugs alone.     

PLASMA LEVEL AND EFFECT OF CARBAMAZEPINE IN GRAND MAL AND PSYCHOMOTOR EPILEPSY

In 117 patients with grand mal and psychomotor epilepsy the effect of carbamazepine alone or in combination with phenobarbital and diphenylhydantoin was registered and correlated to the plasma level of carbamazepine.
Carbamazepine was found to be an effective anticonvulsant in the treatment of grand mal epilepsy. The therapeutic level was higher than 4 mg/l.
Carbamazepine given alone was rather ineffective in the treatment of psychomotor seizures.
The concentration of plasma carbamazepine epoxide, one of the metabolites of carbamazepine, was increased when the patients were treated with carbamazepine, in combination with phenobarbital or diphenylhydantoin or both. This may explain the better clinical effect of this combined medication, as the epoxide has an independent antiepileptic effect. The side-effects may be partly caused by the epoxide.     

Pharmacodynamic interaction studies with topiramate in the pentylenetetrazol and maximal electroshock seizure models.

There is emerging evidence to support the efficacy of some antiepileptic drug (AED) combinations in refractory epilepsy. Definitive clinical studies are, however, difficult to perform. Experimental seizure models can be employed to identify potentially useful combinations for subsequent clinical evaluation. We have investigated the anticonvulsant effects of topiramate (TPM) in combination with 13 other AEDs in the pentylenetetrazol (PTZ) and maximal electroshock (MES) seizure models. Single drugs and combinations were administered by intraperitoneal injection and anticonvulsant effects determined at 1-hour post-dosing. TPM was without significant effect in the PTZ test. In contrast, phenobarbital, primidone, ethosuximide, sodium valproate, felbamate and tiagabine all increased the latency to the first generalised seizure. Combinations of TPM and active adjunctive drug were universally effective. Combinations of TPM with clobazam, lamotrigine and levetiracetam were also anticonvulsant, despite the inactivity of the constituent compounds when administered alone. TPM reduced the incidence of MES-induced seizures in a dose-dependent manner, as did phenobarbital, phenytoin, primidone, carbamazepine, sodium valproate, clobazam, lamotrigine, felbamate and tiagabine. All combination treatments were similarly effective. These findings suggest that combinations of TPM with lamotrigine and levetiracetam may demonstrate anticonvulsant synergism and merit further investigation in additional model systems and with recourse to more quantitative mathematical analysis.     

Teratogenicity of antiepileptic drug combinations with special emphasis on epoxidation (of carbamazepine)

A higher rate of congenital anomalies has been found after prenatal exposure to some combinations of antiepileptic drugs than to the separate drugs. In an earlier study a rate of 58% congenital anomalies was found among infants exposed to carbamazepine plus phenobarbitone plus valproate. In this study an attempt was made to determine whether this specific combination of drugs has teratogenic activity due to metabolic interaction. The epidemiological data were analyzed further. The high rate of congenital anomalies after prenatal exposure to this combination could not be explained by the effects of one or two of these drugs only, nor by additional exposure to phenytoin. Assuming that metabolic interaction in the arene oxide pathway resulting in accumulation of epoxide intermediates of antiepileptic drugs could be responsible for teratogenesis, the ratio of carbamazepine to carbamazepine-10, 11-epoxide concentrations in serum was determined in adult patients with epilepsy who were treated with carbamazepine only and with different combinations of phenobarbitone, valproate, and/or phenytoin. For carbamazepine monotherapy the mean ratio was 8.19. For all combinations lower ratios were found, indicating accumulation of carbamazepine-10,11-epoxide. The combination of carbamazepine, phenobarbitone, valproate, and phenytoin showed the lowest ratio (1.94), followed by carbamazepine, valproate, and phenytoin and by carbamazepine, phenobarbitone, and valproate (2.81 and 3.18, respectively). These results give rise to the question of whether the combination of carbamazepine, phenobarbitone, valproate, and/or phenytoin has teratogenic activity by accumulation of carbamazepine-10,11-epoxide or other epoxide intermediates, and stress the need to take metabolic interactions into account when investigating the teratogenic activity of antiepileptic drugs.     

Use of antiepileptic drugs in the treatment of epilepsy in people with intellectual disability

The main principles of antiepileptic drug treatment of epilepsy in patients with intellectual disability are basically the same as for other patients with epilepsy. However, some specific issues need to be taken into account These are primarily associated with the diagnostic difficulties of epilepsy in this population. In addition, a number of other relevant issues, including the degree and location of brain lesion, the nature of the underlying disease, the higher frequency of difficult-to-treat epilepsies, the additional intellectual impairment caused by inappropriate antiepileptic medication, or by frequent and prolonged seizures, the appropriate use of monotherapy versus rational polytherapy, and the use of broad-spectrum antiepileptic drugs will be discussed in the present paper. Although the goals of treatment are to keep the patient seizure-free and alert while preventing possible mental deterioration, we have to accept compromises between these primary goals in many cases. Some people with epilepsy and intellectual disability are very vulnerable to insidious neurotoxic effects; for example, sedative effects caused by phenobarbital, or cognitive and/or cerebellar dysfunction caused by long-term phenytoin, especially together with other drugs. Because of the adverse effects of phenobarbital and phenytoin, these drugs are no longer recommended as a first-choice drugs when long-term antiepileptic medication is required. In primary generalized tonic-clonic seizures, valproate, oxcarbazepine/carbamazepine and lamotrigine are recommended in this order of preference. The corresponding recommendations are: in typical absences, valproate, ethosuximide and lamotrigine; in atypical absences, valproate and lamotrigine; in juvenile myoclonic epilepsy, valproate, lamotrigine and clobazam; in infantile spasms vigabatrin, ACTH and valproate; in Lennox-Gastaut syndrome, valproate, lamotrigine and vigabatrin; in atonic seizures, valproate and lamotrigine; in simple and complex partial seizures with or without secondary generalization, oxcarbazepine/carbamazepine, valproate/ vigabatrin and lamotrigine; and in status epilepticus lorazepam, diazepam and clonazepam together with phenytoin or fosphenytoin. In cases of poor response to the monotherapy recommended above, the following combinations may be indicated: in primary generalized tonic-clonic epilepsy, valproate and oxcarbazepine/ carbamazepine, or valproate and lamotrigine; in typical absences, valproate and lamotrigine, or valproate and ethosuximide; in juvenile myolonic epilepsy, valproate and lamotrigine, or valproate and clonazepam; and in partial epilepsies, add to the monotherapy one of the following drugs, vigabatrin, lamotrigine, gabapentin, tiagabine, topiramate, zonisamide or clobazam. So far, the order of preference of these new drugs remains undetermined. More data are needed on the efficacy and adverse effects of the new drugs based on controlled studies on patients with intellectual disability and epilepsy.     

Results of a Nationwide Veterans Administration Cooperative Study Comparing the Efficacy and Toxicity of Carbamazepine,Phenobarbital, Phenytoin,and Primidone

Summary: : In 1985 a 5-year multicenter Veterans Administration Cooperative Study was completed that compared the efficacy and toxicity of phenobarbital, carbamazepine, phenytoin, and primidone in a double-blind prospective study design. A total of 622 patients, either previously untreated or undertreated, were entered into the study. Strict exclusion criteria limited confounding factors such as drug or alcohol abuse. Results showed that each of the four drugs used as monotherapy were similarly effective in the treatment of generalized tonic-clonic seizures, but carbamazepine was significantly more effective in the treatment of complex partial seizures as measured by 100% control. When the results for all four drugs were combined, the data showed that approximately 80% of the patients were adequately managed on monotherapy. Differences in toxicity were the most significant factor that discriminated between these four drugs. Both carbamazepine and phenytoin were associated with significantly lower incidences of intolerable side effects than were primidone or phenobarbital. A behavioral toxicity battery was performed whenever possible prior to administration of any antiepileptic drug and at 1, 3, 6, and 12 months after initiation of monotherapy. Significant differences in performance on all subtests of the battery were found between patients with epilepsy and a control group matched by age, sex, and education. When the differential effects of all four drugs on behavioral toxicity were compared, few statistically significant differences emerged. However, carbamazepine consistently produced fewer adverse effects on tests of attention/concentration and motor performance than did the other three antiepileptic drugs.     

Effect of antiepileptic drug polytherapy on crystalluria

Urolithiasis is a rare side effect of antiepileptic drugs. To clarify the risk factors for urolithiasis induced by antiepileptic drugs, the effect of antiepileptic drug monotherapy on crystalluria was studied, and zonisamide or sulthiame therapy and alkaline urine were demonstrated to be risk factors. In the next investigation, the effect of antiepileptic drug polytherapy on crystalluria was retrospectively studied in epilepsy patients treated for more than 1 month during the last 7 years. A total of 278 urine specimens from epilepsy patients aged between 7 months and 36 years were enrolled in this study. The mean age was 12.3 years. There were 109 samples from females and 169 from males. Antiepileptic drugs administered in this study were valproate (174 urinary samples), zonisamide (139), carbamazepine (138), phenobarbital (65), phenytoin (52), acetazolamide (17), clonazepam (15), sulthiame (6), ethosuximide (6), nitrazepam (4), and clobazam (4). Epilepsy patients treated with antiepileptic drug polytherapy were frequently found to have crystalluria in patients demonstrating alkaline urine and taking acetazolamide, zonisamide (particularly with high serum levels), or many antiepileptic drugs in combination. Regular urinalysis seems to be necessary in these patients, and the evaluation for urolithiasis should be performed if persistent crystalluria is demonstrated.     

A study on epileptic negative myoclonus in atypical benign partial epilepsy of childhood

Objective. To investigate the clinical and neurophysiological characteristics, particularly therapeutic considerations, of epileptic negative myoclonus (ENM) in atypical benign partial epilepsy (ABPE) of childhood. Methods. From 1998 to 2006, 14/242 patients with benign children epilepsy with centrotemporal spikes (BECTS) were diagnosed as having ABPE with ENM. In all 14 patients, we performed video-EEG monitoring along with tests with the patient’s arms outstretched; 6/14 patients were also simultaneously underwent surface electromyogram (EMG). ENM manifestations, electrophysiological features, and responses to antiepileptic drugs were analyzed. Results. In all cases, ENM developed after the onset of epilepsy and during antiepileptic drug therapy, and the appearance of ENM were corresponding to EEG findings of high-amplitude spikes followed by a slow wave in the contralateral motor areas with secondary generalization. This was further confirmed by time-locked silent EMG. During ENM occurrence or recurrence, habitual seizures and interictal discharges were exaggerated. In some patients, the changes in antiepileptic drug regimens in relation to ENM appearance included add-on therapy with carbamazepine, oxcarbazepine, and phenobarbital or withdrawal of valproate. ENM was controlled in most cases by administration of various combinations of valproate, clonazepam, and corticosteroids. Conclusion. The incidence of ENM or ABPE in our center was approximately 5.79%. A combination of video-EEG monitoring with the patient’s arms outstretched and EMG is essential to identify ENM. The aggravation of habitual seizures and interictal discharges indicate ENM. Some antiepileptic drugs, such as carbamazepine, oxcarbazepine, and phenobarbital, may be related to ENM occurrence during spontaneous aggravation of ABPE. Various combinations of valproate, benzodiazepines, and corticosteroids are relatively effective for treating ENM that occurs in ABPE.     

Bone and calcium metabolism and antiepileptic drugs

There is increasing evidence suggesting that epilepsy and its treatment can affect bone mineralization and calcium metabolism. Many studies have shown a significant reduction in bone mineral density in patients treated with classic (phenobarbital, carbamazepine, valproate, etc.) and with new (oxcarbazepine, gabapentin) antiepileptic drugs. In spite of data about the possible effects of the antiepileptic drugs on calcium metabolism, the mechanisms of this important side effect remain to be defined. The abnormalities of calcium metabolism were thought to result from the cytochrome P450 enzyme-inducing properties of some antiepileptic drugs and the resultant reduction in vitamin D levels, but the effect of many medications (e.g., valproate) cannot be readily explained by vitamin D metabolism.     

Polytherapy in epilepsy: the experimental evidence

Monotherapy is recommended preferentially among newly diagnosed epileptic patients. In monotherapy-resistant patients polytherapy may be necessary. Two antiepileptic drugs may produce antagonistic, additive, and supra-additive (synergistic) anticonvulsant effects. The drug combination providing the supra-additive effect seems of clinical significance. However, when the supra-additive anticonvulsant efficacy is also associated by a distinct increase in toxicity, the protective index may be not affected or even lowered. Synergistic interactions have been shown for the combinations of valproate-phenytoin/ethosuximide, topiramate-carbamazepine/phenobarbital and felbamate-all major conventional antiepileptics. In contrast, the protective action of conventional antiepileptics has not been affected by felbamate at subprotective doses against maximal electroshock in mice. This is indicative that synergism is evident at only some drug ratios. Potential antiepileptic drugs, excitatory amino acid antagonists and calcium channel inhibitors, generally enhanced the protection offered by antiepileptic drugs. The experimental data may be helpful for predicting which drug combinations may prove effective in epileptic patients.     

Serum hormones in male epileptic patients receiving anticonvulsant medication

Circulating sex and thyroid hormones, as well as the pituitary function, were assessed in 63 male patients with epilepsy receiving either a single medication of carbamazepine, phenytoin, or valproate or a combination of carbamazepine plus phenytoin or carbamazepine plus valproate. All therapeutic regimens, including carbamazepine and/or phenytoin were associated with low levels of circulating thyroxine (T4), free thyroxine (FT4), and dehydroepiandrosterone sulfate, and with low values for the free androgen index, and phenytoin and carbamazepine plus phenytoin were associated with high serum concentrations of sex hormone-binding globulin. These hormone parameters were unaffected by valproate monotherapy. It seems probable that accelerated hormone metabolism is responsible for the hormonal changes found in patients treated with carbamazepine and/or phenytoin. However, every drug regimen studied also had depressant and/or stimulatory effects on the function of the hypothalamic-pituitary axis. The diverse endocrine effects of different antiepileptic drug regimens should be considered when starting antiepileptic drug therapy.     

Efficacy and tolerability of conversion to monotherapy with lamotrigine compared with valproate and carbamazepine in patients with epilepsy

OBJECTIVE: This randomized, open-label study was designed to compare the efficacy and tolerability of lamotrigine monotherapy with those of valproate and carbamazepine monotherapy in patients with epilepsy whose seizures were uncontrolled on their prestudy antiepileptic drug monotherapy. METHODS: Patients meeting eligibility criteria were randomized 2:1 to lamotrigine:carbamazepine or lamotrigine:valproate. The treatment phase was divided into a 4-week dose-escalation phase (Weeks 1-4), during which lamotrigine, carbamazepine, or valproate was added to patient's prestudy monotherapy; an 8-week add-on phase (Weeks 5-12), during which patients were stabilized on both the study medication and their prestudy antiepileptic therapy; an 8-week withdrawal phase (Weeks 13-20), during which prestudy antiepileptic therapy could be withdrawn if clinically appropriate; and an 8-week monotherapy phase (Weeks 21-28), during which patients could be treated with study medication as monotherapy. RESULTS: The numbers of patients randomized to the carbamazepine and valproate arms of the study were 144 (98 lamotrigine, 46 carbamazepine) and 158 (105 lamotrigine, 53 valproate), respectively. Successful monotherapy sustained for at least 7 weeks was achieved in comparable percentages of patients in the lamotrigine group (56%) and the carbamazepine group (54%) and in more patients in the lamotrigine group (49%) than the valproate group (40%). Among monotherapy completers, the percentage of patients with zero seizures during the monotherapy phase was comparable for lamotrigine (41%) and carbamazepine (30%) and significantly higher (P<0.05) with lamotrigine (32%) than with valproate (11%). No differences between treatments were observed with respect to time to treatment failure or time to first seizure. Lamotrigine was also better tolerated than carbamazepine or valproate. CONCLUSION: Lamotrigine monotherapy was as effective as and better tolerated than carbamazepine or valproate monotherapy in patients whose seizures were uncontrolled on their prestudy antiepileptic drug monotherapy.