Low propensity of conventional antiepileptic drugs for interaction with felbamate against maximal electroshock-induced seizures in mice

Summary. The objective of this study was to evaluate an interaction of the novel antiepileptic drug felbamate (2-phenyl-1,3-propanediol dicarbamate) with conventional antiepileptic drugs against maximal electroshock-induced convulsions in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor performance) and passive avoidance task (long-term memory). Brain and plasma levels of antiepileptic drugs were measured by immunofluorescence. Felbamate (7.5–30 mg/kg) significantly increased the electroconvulsive threshold. Felbamate at the subprotective dose of 5 mg/kg did not affect the anticonvulsive action of antiepileptics studied. On the other hand, this drug used at the lowest protective dose of 7.5 mg/kg remained without effect upon the activity of valproate, carbamazepine or phenobarbital, but significantly potentiated the protective potential of diphenylhydantoin. No adverse effects were observed with combinations of felbamate with these antiepileptics. Neither brain nor free plasma levels of antiepileptic drugs were changed by felbamate. The results indicate that the combination of felbamate with conventional antiepileptic drugs is not promising from the experimental point of view. Received March 3, 1999; accepted September 28, 1999     

Captopril potentiates the anticonvulsant activity of carbamazepine and lamotrigine in the mouse maximal electroshock seizure model

Some studies suggest a higher risk of hypertension in people with epilepsy. Captopril, a potent and selective angiotensin-converting enzyme (ACE) inhibitor, is a well known antihypertensive drug. Besides the peripheral renin–angiotensin system (RAS), ACE inhibitors are also suggested to affect the brain RAS which might participate in the regulation of seizure susceptibility. The purpose of the current study was to evaluate the effect of captopril on the protective action of numerous antiepileptic drugs (carbamazepine [CBZ], phenytoin [PHT], valproate [VPA], phenobarbital [PB], oxcarbazepine [OXC], lamotrigine [LTG] and topiramate [TPM]) against maximal electroshock-induced seizures in mice. This study was accompanied by an evaluation of adverse effects of combined treatment with captopril and antiepileptic drugs in the passive avoidance task and chimney test. Captopril (25 and 50 mg/kg i.p.) did not influence the threshold for electroconvulsions. Among the tested antiepileptics, captopril (25 and 50 mg/kg i.p.) potentiated the antiseizure action of CBZ, decreasing its ED₅₀ value from 12.1 to 8.9 and 8.7 mg/kg, respectively. Moreover, captopril (50 mg/kg i.p.) enhanced the anticonvulsant activity of LTG. ED₅₀ value for LTG was lowered from 5.1 to 3.5 mg/kg. The observed interactions between captopril and CBZ or LTG were pharmacodynamic in nature as captopril did not alter plasma and total brain concentrations of these antiepileptics. The combinations of captopril with antiepileptic drugs did not lead to retention deficits in the passive avoidance task or motor impairment in the chimney test. Based on the current preclinical data, it is suggested that captopril may positively interact with CBZ and LTG in epileptic patients. The combinations of captopril with the remaining antiepileptics (PHT, VPA, PB, OXC and TPM) seem neutral.     

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.     

Influence of a potential anti-asthmatic drug,CR 2039, upon the anticonvulsive activity of conventional antiepileptics against maximal electroshock-induced seizures in mice

Summary CR 2039 [4-(1H-tetrazol-5-yl)-N-(4-(1H-tetrazol-5-yl]phenylbenzamide], in doses of 10, 50, and 100mg/kg i.p., significantly elevated the threshold for electroconvulsions, increasing the CS₅₀ (current strength 50% in mA) values from 6.3 to 7.2, 7.5, and 7.6 mA, respectively. When combined with carbamazepine, diphenylhydantoin, or valproate, CR 2039 (5 and 10mg/ kg) potentiated the anticonvulsive action of these antiepileptics against maximal electroshock-induced convulsions which was reflected by significant decreases in the respective ED₅₀s (in mg/kg). The protective efficacy of phenobarbital was not affected by the phenylbenzamide derivative. The potentiation of the anticonvulsive activity of three antiepileptics was not accompanied by increased adverse effects, evaluated in the chimney test (motor coordination) and passive avoidance task (long-term memory). Finally, CR 2039 (10 mg/kg) did not alter the plasma levels of the antiepileptic drugs studied which speaks against a pharmacokinetic mechanism in the observed results.It is concluded that CR 2039 may prove a safer anti-asthmatic drug for the use in epileptic patients than aminophylline which, either acutely or chronically, considerably impaired the anticonvulsive activity of conventional antiepileptics.     

The influence of L-NG-nitroarginine methyl ester, an inhibitor of nitric oxide synthase, upon the anticonvulsive activity of conventional antiepileptic drugs against maximal electroshock in mice

Summary. N^G-Nitro-L-arginine methyl ester (L-NAME, an unspecific nitric oxide synthase inhibitor), applied at 1 and 40 mg/kg, did not influence the electroconvulsive threshold, but impaired the anticonvulsant activity of valproate (at 40 mg/kg) and phenobarbital (at 1 and 40 mg/kg). No effect was observed in the case of carbamazepine and diphenylhydantoin. The effect of L-NAME upon the protective activity of phenobarbital was not reversed by L-arginine (500 mg/kg), a source of endogenous nitric oxide. Moreover, this nitric oxide synthase inhibitor did not alter the plasma levels of antiepileptic drugs studied, so a pharmacokinetic interaction is not probable. L-NAME per se (40 mg/kg) caused a moderate motor impairment but did not affect long-term memory. The combined treatment of L-NAME and antiepileptic drugs (providing a 50% protection against maximal electroshock) resulted in motor disturbances. On the other hand, mice performed the memory task better upon combined treatment of antiepileptic drugs with L-NAME compared to antiepileptic drugs alone. A 4-day administration of L-NAME, similarly to acute injections, decreased the protective action of phenobarbital but not that of diphenylhydantoin. The results indicate that L-NAME is able to reduce the protective activity of some conventional antiepileptics and this effect may be not associated with impaired synthesis of nitric oxide. Accepted November 19, 1997 / Received July 15, 1997     

Effects of piracetam alone and in combination with antiepileptic drugs in rodent seizure models

Summary. The nootropic drug piracetam was investigated in various experimental models of epilepsy. Generally, piracetam exhibits no or only moderate anticonvulsant properties against generalized tonic or clonic seizures. However, in many cases it did increase the anticonvulsant effectiveness of conventional antiepileptics, as shown in the maximal electroshock seizure (MES) threshold test, the traditional MES test or in DBA/2 mice. A pharmacokinetic interaction does not seem to be responsible for this effect. In lethargic mice, a model of absence seizures, piracetam significantly decreased the incidence and duration of spike-wave discharges. Furthermore, in the cobalt-induced focal epilepsy model piracetam reduced the number of spikes/min and in the hippocampal stimulation model it increased the anticonvulsant potency of phenobarbital and phenytoin after single and repeated administration. In conclusion, the well tolerated piracetam itself did not show marked anticonvulsant effects in most screening tests, however, its co-medication with antiepileptic drugs improved seizure protection in various models which may bear potential clinical significance.     

Response of kidney and bone to parathyroid hormone in children receiving anticonvulsant drugs

The response of kidney and bone to parathyroid extract (PTE) was investigated in 8 epileptic children on long-term treatment with primidone in combination with phenytoin or other anticonvulsant drugs. The results indicate a dissociation between normal and cyclic AMP excretion and disturbed renal handling of phosphate which resembles type II pseudohypoparathyroidism suggesting an anticonvulsant drug related inhibition of cyclic AMP-induced phosphaturia. It is speculated that antiepileptic drugs may provoke renal conservation of phosphate which may explain the relative low incidence of manifest rickets or osteomalacia in site of low 25-hydroxy-vitamin D levels in epileptic patients. A normal bone response of PTE indicates that antiepileptic treatment with phenobarbital and phenytoin does not affect PTH-stimulated bone resorption in the investigated patients.     

The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy

Resistance to drug treatment is an important hurdle in the therapy of many diseases, including cancer, infectious diseases and brain disorders such as epilepsy. A phenotype that is referred to as multidrug resistance was first described for chemotherapy-resistant cancer cells that overexpressed the drug efflux transporter P-glycoprotein (P-gp). More recently, overexpression of P-gp has been found in capillary endothelial cells of epileptogenic brain tissue from patients with medically intractable epilepsy. Such regionally restricted P-gp overexpression in the blood-brain barrier is likely to reduce the concentration of antiepileptic drugs at epileptic neurons, which would be a plausible explanation for multidrug resistance in epilepsy. However, a definite proof-of-principle for this hypothesis is lacking. In the present study, we used a rat model of temporal lobe epilepsy that allows selecting drug-resistant and drug-responsive subgroups of epileptic rats by prolonged treatment with the antiepileptic drug phenobarbital at maximum tolerated doses. We have shown recently that drug-resistant rats selected from this model exhibit a marked overexpression of P-gp in the hippocampus and other limbic brain regions. This model is thus ideally suited to prove the multidrug transporter hypothesis of drug resistance. For this purpose, we selected a group of phenobarbital-resistant rats, which was subsequently treated by combinations of phenobarbital with the selective P-gp inhibitor tariquidar. Coadministration of tariquidar (15-20 mg/kg) fully restored the anticonvulsant activity of phenobarbital without altering plasma pharmacokinetics or neurotoxicity of the antiepileptic drug. These data demonstrate that inhibiting P-gp in epileptic rats with proven drug resistance counteracts resistance, providing the first proof-of-principle of the multidrug transporter hypothesis of medically refractory epilepsy.     

Effect of Aminophylline on the Protective Action of Common Antiepileptic Drugs Against Electroconvulsions in Mice

The increasing amount of data tends to suggest that adenosine-mediated inhibition may play a role in the anticonvulsant activity of a number of antiepileptic drugs. Consequently, we tried to reverse the protective action of acetazolamide [(40 and 80 mg/kg) i.p.; 60 min before the test]; carbamazepine (20 and 30 mg/kg i.p., 60 min); diazepam (5 and 10 mg/kg i.p., 60 min); diphenylhydantoin (8 and 12 mg/kg i.p., 120 min), phenobarbital (20 and 30 mg/kg i.p., 120 min) and valproate (200 and 300 mg/kg i.p., 30 min) with aminophylline (50 and 100 mg/kg i.p., 30 min) against electroconvulsions in mice. Aminophylline markedly decreased the anticonvulsant efficacy of almost all drugs studied, acetazolamide (40 and 80 mg/kg) and carbamazepine (30 mg/kg) being the only exceptions. The ethylenediamine component of aminophylline did not modify the anticonvulsant activity at all. These results seem to support the suggestion that aminophylline-induced blockade of adenosine receptors might be involved in the reversal of the protective action of at least some drugs studied. Regardless of the nature of the aminophylline-induced impairment in the anticonvulsant efficacy of a number of antiepileptic drugs, the use of methylxanthines in epileptic patients for the treatment of obstructive lung diseases should be avoided.     

Interactions between riluzole and conventional antiepileptic drugs – a comparison of results obtained in the subthreshold method and isobolographic analysis

Summary. The exact types of pharmacodynamic interactions between riluzole and conventional antiepileptic drugs were evaluated in two available ways, the subthreshold and isobolographic analysis. Maximal electroshock test in mice was used as an animal model for generalized tonic-clonic convulsions.In the first method, riluzole (1.25–2.5mg/kg) significantly raised the electroconvulsive threshold in mice. The drug administered at its subprotective dose of 0.3125mg/kg enhanced the antiseizure activity of carbamazepine and phenobarbital, while, when applied at the higher dose of 0.625mg/kg, it potentiated also the action of valproate and diphenylhydantoin. Riluzole (0.625) alone and in combinations with antiepileptic drugs did not produced any motor or log-term memory deficit.Results obtained from isobolographic analysis determined pure additive interaction between riluzole and all used conventional antiepileptic drugs. Since riluzole did not change plasma concentrations of co-administered antiepileptics, pharmacokinetic interactions, at least in terms of their free plasma levels, do not seem probable.The results of the present study confirm significant antiseizure properties of riluzole in the model of generalized tonic-clonic epileptic attacks. Moreover, comparison of effects obtained from both methods evaluating drug interactions strongly indicates a crucial role of the isobolographic analysis in verification and supplementation data achieved from the subthreshold method.     

Epilepsy in the Elderly: Some Clinical and Pharmacotherapeutic Aspects

Summary: The majority of epileptic seizures and epilepsies are no longer manifested in childhood and adolescence; instead their incidence is higher at the age of 65 years or older than during the first two decades of life. After cerebrovascular disorders and dementias, epileptic seizures and epilepsies now constitute the third most frequent neurologic problem encountered in the elderly. Important clinical features of epilepsy in the elderly related to the diagnosis include the most common seizure types and causes. Special features of drug treatment for epilepsy in the elderly result not only from the physiologic changes in the elderly but also from the particular pharmacology of the respective drugs. Because elderly patients very often require other long-term medication in addition to antiepileptic therapy, drug interactions between different antiepileptic drugs and between antiepileptics and other drugs can be of major significance. Other special features of pharmacotherapy for epilepsy in the elderly include the presence of liver and kidney diseases.     

Anticonvulsant activity of carbamazepine and diphenylhydantoin against maximal electroshock in mice chronically treated with aminophylline

Summary The anticonvulsant activities of both carbamazepine and diphenylhydantoin alone (after a single intraperitoneal administration) or combined with aminophylline were studied against maximal electroshock-induced convulsions in male mice. Aminophylline (injected acutely at 50 mg/kg) significantly increased the ED₅₀ values of both antiepileptics. Given for three days, aminophylline (50 mg/kg, twice daily) still impaired the potency of both antiepileptics and after chronic aminophylline administration a further decrease in the protective activity of carbamazepine and diphenylhydantoin was found. Specifically, after 14 days of aminophylline treatment, ED₅₀s for carbamazepine and diphenylhydantoin were 26 and 19 mg/kg, respectively. These ED₅₀s were significantly elevated compared to values determined after acute aminophylline treatment (21.2 and 14.9 mg/kg, respectively). Plasma levels of both antiepileptics were unaffected by chronic aminophylline which seems to exclude a pharmacokinetic interaction in terms of total plasma levels at least.The present results clearly indicate that the aminophylline-induced impairment of the anticonvulsant activity of carbamazepine and diphenylhydantoin is enhanced over time. This may render aminophylline a hazardous drug to epileptic patients who are prescribed this smooth muscle relaxant.     

Influence of aminophylline and strychnine on the protective activity of excitatory amino acid antagonists against maximal electroshock-induced convulsions in mice

Summary Aminophylline reversed the protective action of both, D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (D-CPP-ene — a competitive NMDA antagonist) and valproate (used as a conventional antiepileptic drug for comparative purposes) against maximal electroshock-induced seizures. The respective ED₅₀ values of aminophylline were 55.7 and 98.4mg/kg i.p. However, aminophylline (up to 100mg/kg i.p.) did not influence the protective efficacy of 1-(4-aminophenyl)-4-methyl-7,8-methyl-enedioxy-5H-2, 3-benzodiazepine (GYKI 52466 — a non-NMDA antagonist). Strychnine affected the protection provided by D-CPP-ene, GYKI 52466, and valproate against maximal electroshock — the ED₅₀ values of strychnine for the reversal of the anticonvulsive effects of D-CPP-ene, GYKI 52466 or valproate were 0.082, 0.35 and 0.28mg/kg s.c., respectively.An involvement of strychnine sensitive glycinergic receptor-mediated events in the mechanism of the anticonvulsive activity of excitatory amino acid antagonists and valproate may be postulated. The ineffectiveness of aminophylline to reduce the anticonvulsive effects of GYKI 52466 may distinguish a new class of antiepileptic drugs offering an advantage over conventional antiepileptics in patients with epilepsy, requiring aminophylline for pulmonary reasons.     

Cognitive and behavioral effects of antiepileptic drugs

In managing epilepsy, drugs that offer the best seizure control to the patient should be used, but their influence on quality of life must also be considered. This must include any effects on mood and mental state, which should be minimal in order that these patients may achieve their full potential. Subtle behavioral and cognitive disadvantages may occur with anticonvulsant drug use. Behavioral changes with phenobarbital are both idiosyncratic and dose related. Carbamazepine and valproic acid can have adverse effects on mood and cognition, but do so less frequently than the other medications or combinations (Table 1). Cognitive dysfunction may relate to antiepileptic drug blood levels, but impairment of skills can occur in the nonintoxicated patient. Thus, office neurologic examinations are insufficient to detect these subtle mental impairments. Practical methods need to be developed to identify and monitor these problems so that in the future cognitive and behavioral dysfunction in epileptic patients can be minimized.     

Pharmacoresistance and expression of multidrug transporter P-glycoprotein in kindled rats

Multidrug transporter over-expression is considered to limit access of antiepileptic drugs to the epileptic focus region and to be one cause of intractable epilepsy. To reach further proof for this multidrug transporter hypothesis, we compared P-glycoprotein expression rates in subgroups of Wistar rats which are sensitive or resistant to the anticonvulsant effect of the antiepileptic drug phenytoin in the amygdala-kindling model of temporal lobe epilepsy. In the electrode-implanted amygdala of phenytoin-resistant rats, the area labelled for P-glycoprotein was more than twice as large than that in phenytoin-sensitive rats. The data indicate that P-glycoprotein expression levels in the kindled focus have a critical impact on the anticonvulsant response to antiepileptic drugs.     

Antiepileptic drugs and teratogenesis

The teratogenic risk of anticonvulsant drugs was established more than 15 years ago. Experimental and statistical studies, types of malformations, drugs incriminated, significance of epileptic seizures during pregnancy are reviewed. The percentage of congenital malformations among children from epileptic mothers is twice higher than in the general population. Such data, especially those about epidemiological investigations, can in fact be criticized. The origin of a congenital malformation is always multifactorial and genetic factors play a major role. A line of conduct may be proposed to women asking for advice before and during pregnancy. It is concluded that generally the teratogenic potential of an antiepileptic drug is low and does not contraindicate pregnancy in epileptic women.     

Influence of N-hydroxymethyl-p-isopropoxyphenylsuccinimide on the anticonvulsant action of different classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Experimental epileptology is mainly focused on searching for some active compounds suppressing seizures that could become efficacious antiepileptic drugs. Accumulating evidence indicates that succinimide derivatives would be good candidates for novel antiepileptic drugs. Therefore, the aim of this study was to determine the effects of N-hydroxymethyl-p-isopropoxyphenyl-succinimide (HMIPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the maximal electroshock-induced seizure test in mice. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. Results indicate that HMIPPS administered intraperitoneally at 100mg/kg significantly elevated the threshold for electroconvulsions in mice (P<0.05). HMIPPS at doses of 12.5, 25 and 50mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, HMIPPS (50mg/kg) significantly enhanced the anticonvulsant activity of phenobarbital and valproate in the mouse maximal electroshock-induced seizure model by reducing their median effective doses (ED(50) values) from 23.25mg/kg to 16.82 mg/kg (P<0.01; for phenobarbital) and from 259.3mg/kg to 189.7 mg/kg (P<0.001; for valproate), respectively. In contrast, HMIPPS (50mg/kg) had no impact on the protective action of carbamazepine or phenytoin in the maximal electroshock seizure test in mice. HMIPPS (25mg/kg) significantly potentiated the anticonvulsant action of valproate by reducing its ED(50) value from 259.3mg/kg to 210.6 mg/kg (P>0.05), but not that of phenobarbital, phenytoin and carbamazepine in the mouse maximal electroshock-induced seizure model. Pharmacokinetic experiments revealed that HMIPPS did not alter total brain concentrations of phenobarbital or valproate in mice. Moreover, none of the examined combinations of HMIPPS (50mg/kg) with carbamazepine, phenobarbital, phenytoin and valproate (at their ED(50) values from the maximal electroshock-induced seizure test) affected motor coordination in the chimney test, long-term memory in the passive avoidance task, and muscular strength in the grip-strength test in mice, indicating no possible acute adverse effects in animals. In conclusion, the enhanced anticonvulsant action of phenobarbital and valproate by HMIPPS in the mouse maximal electroshock-induced seizure model, lack of pharmacokinetic interactions and no potential acute adverse effects make the combinations of HMIPPS with phenobarbital and valproate worthy of consideration for further experimental and clinical studies. The combinations of HMIPPS with carbamazepine and phenytoin are neutral from a preclinical viewpoint.     

Competitive NMDA-Receptor Antagonists, LY 235959 and LY 233053, Enhance the Protective Efficacy of Various Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice

Purpose: The objective of this study was to evaluate an interaction of two competitive N-methyl-D-aspartate (NMDA)-receptor antagonists, LY 235959 [(-)-3R,4aS,6R,8aR-6-(phosphonomethyl)-decahydroiso-quinoline-3-carboxylic acid; 50.5 mgikg] or LY 233053 [cis-(±)-4–[(2H-tetrazol-5–yl) methyl] piperidine-2-carboxylic acid; 5 mg/kg] with carbamazepine, diphenylhydantoin, phenobarbital, or valproate magnesium against maximal electroshock-induced convulsions in mice. Methods: Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the end point) delivered by a Hugo-Sachs stimulator (Type 221, Freiburg, FRG). Adverse effects were evaluated in the chimney test (motor performance) and passive-avoidance task (long-term memory). Plasma levels of antiepileptic drugs were measured by immunofluorescence. Results: Both LY 235959 and LY 233053 (=0.5 and 5 mg/kg, respectively) did not influence the electroconvul sive threshold but potentiated the anticonvulsant action of all antiepileptics studied. The combined treatment of LY 233053 (5 mg/kg) with carbamazepine, diphenylhydan-toin, or phenobarbital (providing a 50% protection against maximal electroshock) resulted in the impairment of long-term memory. No adverse effects were observed with combinations of LY 235959 with these antiepileptics. The combined treatment of valproate with either LY 235959 or LY 233053 was superior to valproate alone, as regards motor impairment, but not the impairment of long-term memory. Neither NMDA-receptor antagonist elevated the total plasma levels of antiepileptic drugs studied. Conclusions: It may be concluded that NMDA-receptor blockade leads to the enhanced anticonvulsive action of conventional antiepileptics against maximal electroshock-induced seizures. A pharmacokinetic interaction does not seem probable.     

Problems and Management of the Pregnant Woman with Epilepsy

Summary: Pregnancies occurring in women who are epileptic are considered to be high risk. These women are at increased risk of seizures during pregnancy, labor, and delivery and of pregnancy complications and adverse pregnancy outcomes. Pregnancy alters the pharmacokinetics of anticonvulsant drugs, the levels of which decline as pregnancy advances. Not all drugs are altered in a similar manner, however. The rate of congenital malformations in infants of epileptic mothers is 2.4 times higher than in the general population. Malformations occur with all of the commonly used anticonvulsant drugs. The possible mechanisms of teratogenicity include folic acid antagonism, fetal tissue binding, and toxic effects of metabolic intermediates. Therapy with more than one drug increases the risk of congenital malformations. A unique hemorrhagic phenomenon in the infants of epileptic mothers has been reported and appears to be the result of a deficiency of vitamin K-dependent clotting factors. When taken by a pregnant woman, all antiepileptic drugs except valproic acid manifest themselves in breast milk, but only if the infant exhibits evidence of sedation should breastfeeding be discontinued. The dilemma for the physician treating the pregnant epileptic woman is to protect the mother from seizures and the fetus from unnecessary exposure to anticonvulsant medications.     

Cutaneous drug eruptions by current antiepileptics: case reports and alternative treatment options

Serious cutaneous drug eruptions due to antiepileptics have been defined for many drugs like carbamazepine, diphenylhydantoin, phenytoin and valproate. In recent years, adverse cutaneous reactions due to the current antiepileptic drugs have also been reported. In this paper, two cases are presented: a 48-year-old female receiving gabapentin for postherpetic neuralgia who developed leukocytoclastic vasculitis after 8 weeks and a 23-year-old male receiving lamotrigine for epileptic seizures who developed toxic epidermal necrolysis (TEN) in 15 days. Alternative therapy approaches with practical suggestions are also discussed.