Withdrawal symptoms from phenytoin, carbamazepine and sodium valproate.

A prospective, double-blind, placebo-controlled investigation of possible withdrawal symptoms from phenytoin, carbamazepine and sodium valproate is reported in patients with active epilepsy, on combination therapy. There was an increase in seizures on reduction and withdrawal of carbamazepine, but there was no convincing evidence of withdrawal symptoms from any of these drugs.     

Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine

OBJECTIVE: To evaluate plasma homocysteine (Hcy) concentrations in children receiving sodium valproate (VPA) and carbamazepine (CBZ), monotherapy, in comparison with healthy control subjects and to determine the possible relationship between Hcy levels and dosage and plasma concentrations of the antiepileptic drugs. METHODS: We measured levels of fasting and post-methionine Hcy, plasma pyridoxal 5'-phosphate (PLP, active vitamin B6), serum folate, erythrocyte folate and serum vitamin B12 in 60 epileptic patients (29 females, 31 males), aged from 14.2 to 17.9 years, subdivided into two groups according to their therapy. Sixty-three healthy sex- and age-matched children served as controls. These measurements have been performed before the beginning of therapy and after 1 year of therapy with VPA or CBZ. RESULTS: Before the beginning of therapy, there were no significant differences in fasting and post-methionine Hcy, plasma PLP, serum folate, erythrocyte folate and serum vitamin B12 values between the control group and the two groups of epileptic children. After 1 year of therapy, patients treated with VPA and CBZ showed a significant increase of the plasma concentrations of Hcy when compared to baseline data and controls values. Moreover, was observed a significant decrease of serum folate and plasma PLP. On the contrary, serum vitamin B12 and erythrocyte folate levels remained in the normal range. CONCLUSIONS: Our study demonstrates that prolonged treatment with VPA and CBZ increases plasma concentrations of Hcy.     

Capillary microscopy and hemorheology in children during antiepileptic monotherapy with carbamazepine and valproate

The interactions of epilepsy and antiepileptic therapy an one hand and cardiovascular system on the other hand are multiple and complex. Antiepileptic drugs (AEDs) cause alterations of serum lipids and of the fatty acid composition of the membranes. Homocystein, known to induce vascular endothelial damage was found to be elevated in patients on valproate (VPA) and carbamazepine (CBZ) therapy. Marked coronary artherosclerosis and myocardial infarction may already occur in children treated with CBZ. Community based studies corroborated a higher incidence of myocardial infarction, peripheral vascular diseases hypercholesterinemia, left ventricle hypertrophy and stroke in patients with epilepsy. In this context, we wanted to elevate changes of microcirculation related to AEDs commonly prescribed such as VPA and CBZ. Capillary microscopy is a non-invasive technique for measuring the velocity of red blood cells and for determining nutritional blood flow in the capillaries of the skin. It can easily be performed in children. The aim of this study was to look for possible effects an antiepileptic monotherapy with carbamazepine or valproate has on the peripheral microcirculation in epileptic children. We were able to examine 14 children with CBZ and 24 children with VPA, recruited in our neuropediatric Unit. The results were compared to normative values, determined in former analyses of 207 healthy children. We found significant differences in capillary density, tortuous index of the capillaries, capillary diameter and flow rate of erythrocytes for both antiepileptic drugs. Additionally, there were changes in plasma viscosity and the aggregation of erythrocytes. These microcapillary effects could be of special interest in the relationship of a long-term antiepileptic therapy and the development of vascular diseases. We suggest that the influence of AEDs on microcirculation should also be considered in further studies on cardiovascular changes in patients with antiepileptic long-term medication.     

丙戊酸钠与卡马西平治疗躁狂发作临床观察

目的：评价丙戊酸钠与卡马西平对锂盐治疗无效的躁狂发作的疗效和副反应。方法：将符合CCMD－2－R躁狂发作诊断标准的5例患者随机分为丙戊酸钠组和卡马西平组,治疗6周。使用Bech-Rafaelsen躁狂量表及临床疗效总评量表的疗效总评评定疗效,用副反应量表及有关实验室检查评定副反应。结果：丙戊酸钠与卡马西平均能有效减轻躁狂症状,疗效相近,丙戊酸钠起效时间迟于卡马西平。丙戊酸钠的副反应主要为肠道反应、震颤等、而卡马西平以共济失调、头晕、嗜睡等多见。结论：丙戊酸钠与卡马西平均可用于锂盐治疗无效的躁狂发作。     

Anticonvulsant potency and neurotoxicity of valproate alone and in combination with carbamazepine or phenobarbital

Although single drug therapy of epilepsy has been increasingly advocated, patients whose epilepsy is not controlled by monotherapy are commonly treated with more than one antiepileptic drug. In order to investigate the experimental background for antiepileptic drug combinations, the effect of the pharmacodynamic interactions between valproate and carbamazepine and between valproate and phenobarbital on the efficacy/toxicity ratio was studied in mice. All results were expressed in terms of drug concentrations in the brain in order to exclude possible pharmacokinetic interactions from the analysis. Purely additive interactions were found for the anticonvulsant effect when valproate was combined with carbamazepine as well as with phenobarbital. With regard to the neurotoxic effect, however, the interaction was additive between valproate and phenobarbital but infra-additive for valproate and carbamazepine. Thus, in this model, the combination of valproate and phenobarbital has no advantage over each drug alone, but the combination of valproate with carbamazepine has a better efficacy versus toxicity ratio than either valproate alone or carbamazepine alone. Based on these and previous results, there can be experimental evidence in favor of combining certain antiepileptic drugs, but each combination needs to be studied separately.     

The effects of carbamazepine and sodium valproate on SEPs and BAEPs

SEPs and BAEPs were studied in 36 previously untreated epileptics receiving either carbamazepine (CBZ) or sodium valproate (VPA) monotherapy. CBZ prolonged central conduction times in SEPs and BAEPs. SEP latency prolongation correlated with serum CBZ levels. VPA had minimal effects on evoked potentials. The present study gives evidence of similar effects of carbamazepine and phenytoin on central neural conduction.     

Pregabalin effect on steady-state pharmacokinetics of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, and tiagabine

By reducing neuronal excitability through selective binding to the α(2)δ subunit of voltage-dependent calcium channels, pregabalin effectively treats epilepsy, chronic pain, and anxiety disorders. To evaluate if pregabalin coadministration affects pharmacokinetics of other antiepileptic drugs, population pharmacokinetic analyses using NONMEM software were performed on data from three epilepsy trials involving seven antiepileptic drugs with pregabalin as add-on therapy. Results demonstrated that pregabalin did not alter the steady-state plasma concentrations of carbamazepine, lamotrigine, phenobarbital, phenytoin, tiagabine, topiramate, and valproate. Furthermore, the small percent change in the population estimate of antiepileptic drug plasma clearance values (-2% to +7%) suggests that pregabalin coadministration exerted no significant effect on the pharmacokinetics of these antiepileptic drugs, with the possible exception of tiagabine (+34.9%). These findings are in agreement with those of previously published reports. A further clarification study is necessary for tiagabine. In conclusion, it appears that pregabalin can be coadministered with other antiepileptic drugs without concern for significantly altering their pharmacokinetic profiles.     

Effects of antiepileptic drugs on delivery and early childhood--comparison among mono-therapies of valproic acid, phenytoin, carbamazepine and phenobarbital

The effects of antiepileptic drugs (AED) on infants during pregnancy and delivery were studied in a total of 82 epileptic mothers on various monotherapies; 29 cases receiving valproic acid (VPA), 20 receiving phenytoin (PHT), 18 on carbamazepine (CBZ) and 15 on phenobarbital (PB). While AED serum concentrations were low in most cases of VPA, PHT and PB except for one case of VPA which exceeded therapeutic limits, concentrations were within therapeutic levels in many cases of CBZ. Conclusion: When compared with normal controls, abnormal deliveries such as caesarian section were seen more frequently in epileptic mothers under AED treatment. In addition, infants in PB cases were shown to have significantly lower mean birth length, weight and head circumference, suggesting that PB may retard fetal growth. The incidence of malformation in cases of VPA, PHT, CBZ and PB, was 10.3%, 5.0%, 0% and 6.7%, respectively. There were five types of malformation: in VPA cases, spina bifida, Siamese twins and ventricular septal defect tended to be severe, while in PHT and PB cases, cor biloculare and hypospadias respectively were observed. In cases of VPA, serum levels in the umbilical cord were found to be 150% higher than those in the mother.     

Prevention of recurrent febrile convulsions--a randomized therapeutic assay: sodium valproate, phenobarbital and placebo

The purpose of this study was to compare three different modes of treatment in the prevention of relapses of febrile convulsions (Phenobarbital = PH, Sodium Valproate = SV, Placebo = PO) in a randomized therapeutic trial. The patients included in the study had shown their first generalized convulsive seizure during a bout of fever (greater than or equal to 38.5 degrees C) and were aged between 6 months and 4 years. They were subsequently followed up as outpatients, and Phenobarbital and sodium valproate levels were measured regularly to ascertain compliance with the treatment and to adjust the dosage accordingly. The patients' families were questioned with respect to the occurrence of feverish bouts and convulsive seizures during the interval between visits, as well as possible adverse reactions. An EEG was carried out yearly. Results were as follows: - 69 patients - 35 boys and 34 girls - with an average age of 24 months were divided into 3 groups according to treatment: 21 cases on PH, 22 cases on SV, and 26 cases on PO. - they were followed up for an average duration of 21 months. - the average number of feverish bouts per child and per year was evaluated at 2.5, no statistically significant difference being noticeable between the various modes of prophylaxis. - 15 relapses of febrile seizures were noted in 14 children, over an average duration of 23 months; on average, relapses occurred after 9 months; among the 14 children who had relapsed, one had been treated with SV, 4 with PH and 9 with PO, leading to estimated relapse rates of 4%, 19%, and 35% respectively. There is a statistically significant difference in the relapse rates between the treated groups (SV and PH) and the Placebo group, and a particularly significant difference between Sodium Valproate and Placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative study of valproic acid and sodium valproate (author's transl)

The action of valproic acid prescribed instead of sodium valproate in strictly identical conditions was analysed in 11 epileptic children and 24 adults. No change in therapeutic effect was observed in a large proportion of cases. However, blood tests showed an increase in serum levels in most cases. Thus, valproic acid can be of help in cases hitherto treated with sodium valproate, on the same basis as diphenylhydantoin; the acid form sometimes offers an advantage over the use of the sodium salt.     

卡马西平联合丙戊酸钠治疗额叶癫痫的疗效研究

目的 研究丙戊酸钠和卡马西平联合治疗对额叶癫痫的临床疗效和安全性.方法 将额叶癫痫患者随机分为联合用药组(86例)和对照组(83例),联合用药组给予丙戊酸钠和卡马西平联合治疗,剂量分别为20mg(kg·d)-1、10 mg(kg·d)-1;对照组给予卡马西平治疗,随访半年.结果 联合用药组的疗效为:显效率54.7%、有效率30.2%、无效率15.1%;对照组的疗效为:显效率42.2%、有效率14.5%、无效率43.3%.两组的疗效有统计学差异.结论 丙戊酸钠和卡马西平联合治疗额叶癫痫能够明显地提高疗效,并且不良反应无明显增加,值得临床作为首选治疗方案推广应用.     

Effects of dextroamphetamine,lithium chloride,sodium valproate and carbamazepine on intraplatelet Ca2+ levels

OBJECTIVE: To explore the possible involvement of second-messenger pathways in the pathophysiology of bipolar disorder and the mechanism of action of mood stabilizers, we investigated the effects of dextroamphetamine (a model for mania) and the most widely used mood stabilizers, lithium chloride, sodium valproate and carbamazepine, on intraplatelet levels of calcium ion ([Ca2+). DESIGN: In the first part of the study, dextroamphetamine was administered in vivo in a double-blind, placebo-controlled, crossover design. In the second part of the study, platelets from untreated subjects were incubated in vitro with dextroamphetamine, lithium chloride, sodium valproate or carbamazepine. PARTICIPANTS: Fifteen healthy men between 18 and 45 years of age. OUTCOME MEASURES: Basal, thrombin-induced and serotonin- (5-HT) induced intraplatelet [Ca2+] determined by means of fura-2 fluorescent intensity. RESULTS: In vivo administration of dextroamphetamine had no effect on basal or agonist-induced intraplatelet [Ca2+]. However, in vitro basal platelet [Ca2+] was significantly higher in samples incubated with dextroamphetamine (86.8 nmol/L [standard error of the mean, SEM, 3.9], p < 0.001), lithium chloride (76.4 nmol/L [SEM 3.1], p < 0.002), sodium valproate (82.7 nmol/L [SEM 3.7], p < 0.001) and carbamazepine (84.8 nmol/L [SEM 3.3], p < 0.001) than in the controls (58.2 nmol/L [SEM 2.3]). Thrombin-induced and 5-HT-induced peak cytosolic [Ca2+] were significantly greater than control levels in samples incubated with carbamazepine (277.1 nmol/L [SEM 19.9] v. 195.8 nmol/L [SEM 12.2], p < 0.002; and 153.0 nmol/L [SEM 8.2] v. 115.4 nmol/L [SEM 5.7], p < 0.003, respectively). CONCLUSIONS: This study does not support the involvement of intraplatelet [Ca2+] in the dextroamphetamine model of mania; however, the modulation of intraplatelet [Ca2+] by the mood stabilizers lithium chloride, sodium valproate and carbamazepine implicates intracellular [Ca2+] in the therapeutic mechanisms of these drugs and the pathophysiological basis of mania.     

Comparative anticonvulsant activity and neurotoxicity of clobazam, diazepam, phenobarbital, and valproate in mice and rats

The 1.5-benzodiazepine (clobazam), the 1,4-benzodiazepine (diazepam), and two nonbenzodiazepine antiepileptic drugs (phenobarbital and valproate) were evaluated in mice and rats with a battery of well-standardized anticonvulsant test procedures. The results obtained indicate that clobazam and valproate exhibit a wider range of experimental anticonvulsant activity than either diazepam or phenobarbital. Except for clobazam by the maximal electroshock seizure (MES) test in rats, clobazam and valproate are effective in nontoxic doses against MES and all four chemically induced seizures (Metrazol, bicuculline, picrotoxin, and strychnine). Clobazam is effective by the MES test in rats only in doses that exceed the median minimal toxic dose. Phenobarbital is effective against all of the above tests, but minimal toxic doses must be employed to prevent strychnine seizures. Diazepam, on the other hand, is effective in nontoxic doses against seizures induced by Metrazol, bicuculline, and picrotoxin, but protects animals from maximal electroshock and strychnine seizures only when given in toxic doses. When compared on the basis of protective indices (PI = TD50/ED50) calculated from intraperitoneal data, the PIs for clobazam were 1.6 to 13 times higher than those for diazepam. Overall, except for the MES test in rats, the PIs for clobazam were from 1.5 to 44 times higher than those for any of the other three substances. With respect to the MES test in rats, the PI for clobazam was 10.8 times higher than that for diazepam; however, the PIs for phenobarbital and valproate were 3.5 and 4.4 times higher, respectively, than that for clobazam. These data suggest that the spectrum of anticonvulsant activity for the 1,5-benzodiazepine (clobazam) is superior to that for the 1,4-benzodiazepine (diazepam). Also, the broad experimental profile of anticonvulsant activity of clobazam agrees well with its reported broad clinical efficacy.     

Comparative study of lacosamide and classical sodium channel blocking antiepileptic drugs on sodium channel slow inactivation

Many antiepileptic drugs (AEDs) exert their therapeutic activity by modifying the inactivation properties of voltage‐gated sodium (Na_v) channels. Lacosamide is unique among AEDs in that it selectively enhances the slow inactivation component. Although numerous studies have investigated the effects of AEDs on Na_v channel inactivation, a direct comparison of results cannot be made because of varying experimental conditions. In this study, the effects of different AEDs on Na_v channel steady‐state slow inactivation were investigated under identical experimental conditions using whole‐cell patch‐clamp in N1E‐115 mouse neuroblastoma cells. All drugs were tested at 100 μM, and results were compared with those from time‐matched control groups. Lacosamide significantly shifted the voltage dependence of Na_v current (I_Na) slow inactivation toward more hyperpolarized potentials (by ?33 ± 7 mV), whereas the maximal fraction of slow inactivated channels and the curve slope did not differ significantly. Neither SPM6953 (lacosamide inactive enantiomer), nor carbamazepine, nor zonisamide affected the voltage dependence of I_Na slow inactivation, the maximal fraction of slow inactivated channels, or the curve slope. Phenytoin significantly increased the maximal fraction of slow inactivated channels (by 28% ± 9%) in a voltage‐independent manner but did not affect the curve slope. Lamotrigine slightly increased the fraction of inactivated currents (by 15% ± 4%) and widened the range of the slow inactivation voltage dependence. Lamotrigine and rufinamide induced weak, but significant, shifts of I_Na slow inactivation toward more depolarized potentials. The effects of lacosamide on Na_v channel slow inactivation corroborate previous observations that lacosamide has a unique mode of action among AEDs that act on Na_v channels. © 2012 Wiley Periodicals, Inc.     

Clorazepate and phenobarbital as antiepileptic drugs: a double-blind study

The antiepileptic effect of clorazepate when given with phenytoin was compared, in a randomized double-blind crossover study, to the effect of the standard regimen of phenobarbital plus phenytoin in patients with partial seizures. Thirty of 42 subjects preferred the clorazepate-phenytoin regimen (p less than 0.01). The same number of subjects had fewer seizures while taking clorazepate as had fewer seizures while taking phenobarbital. However, subjects had significantly more toxicity, objective and subjective, on the phenobarbital-phenytoin regimen (p less than 0.01 in both cases). In some subjects, increased toxicity due to phenobarbital outweighed better seizure control, so that clorazepate was preferred. As an add-on antiepileptic drug, clorazepate is well tolerated, effective, and preferred by most patients to phenobarbital.     

Differential effects of agents enhancing purinergic transmission upon the antielectroshock efficacy of carbamazepine,diphenylhydantoin, diazepam,phenobarbital, and valproate in mice

Summary L-phenylisopropyladenosine (L-PIA; a preferential A1 adenosine agonist—0.05 mg/kg) offered no protection against electroconvulsions in mice but potentiated the anticonvulsant action of diazepam and valproate against maximal electroshock-induced seizures, decreasing the respective ED₅₀ values from 9.5 to 4.0 mg/kg and from 250 to 185 mg/kg. However, it remained without effect on the protective activity of phenobarbital, carbamazepine and diphenylhydantoin. 5-N-ethylcarboxamidoadenosine (NECA; a preferential A2 adenosine agonist—0.5 mg/kg) potentiated the efficacy of valproate. On the other hand, NECA (1 mg/kg) diminished the anticonvulsant action of phenobarbital (ED₅₀ was elevated from 16.5 to 20.5 mg/kg), possessing no effect upon the protective action of carbamazepine. In addition, papaverine (20 mg/kg) significantly enhanced the protective efficacy of valproate and up to 40 mg/kg remained without influence upon the protective action of carbamazepine. However, papaverine (20 and 40 mg/kg) inhibited the anticonvulsive potential of phenobarbital.In the light of the results obtained A 1 and A 2 adenosine receptor-mediated events seem to possess different influences upon the protective effects of antiepileptic drugs.     

Complex partial seizures: EEG foci and response to carbamazepine and sodium valproate.

The EEG and clinical records were reviewed of 85 subjects who had been treated for complex partial seizures with carbamazepine alone or with a combination of carbamazepine and sodium valproate. There was a correlation between the site of the EEG abnormality and the therapeutic response to anticonvulsant therapy. Subjects who had a left sided temporal lobe EEG abnormality responded better to carbamazepine alone, while those who had an abnormality on the right responded to a combination of carbamazepine and sodium valproate.     

A prospective study between carbamazepine, phenytoin and sodium valproate as monotherapy in previously untreated and recently diagnosed patients with epilepsy.

One hundred and eighty one patients with previously untreated epilepsy were randomised to sodium valproate, phenytoin or carbamazepine as monotherapy and followed up for a median period which ranged from 14 to 24 months. All three drugs were highly effective in the control of generalised seizures but less effective for partial seizures. Excellent or good control was achieved with therapeutic levels of sodium valproate and carbamazepine, but with subtherapeutic levels of phenytoin.