Differential effect of antiepileptic and non-antiepileptic drugs on the reticular formation

The effect of the antiepileptic drugs carbamazepine and phenytoin, and of the non-antiepileptic drug baclofen, was compared on various inhibitory and excitatory mechanisms in the feline trigeminal nucleus. Baclofen resembled carbamazepine and phenytoin in depressing segmental excitatory and facilitating segmental inhibitory mechanisms. However, baclofen facilitated the periventricular and periaqueductal inhibition of the trigeminal nucleus, while carbamazepine and phenytoin depressed these descending inhibitory mechanisms. Baclofen also resembles carbamazepine and phenytoin in its effectiveness in trigeminal neuralgia, but baclofen is not a clinically effective antiepileptic agent. Our experiments indicate that the ability to depress the reticular formation of the diencephalon and midbrain is an important characteristic of antiepileptic drugs. This suggests that the reticular core is involved in the spread and generalization of seizures.     

Influence of Ivabradine on the Anticonvulsant Action of Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice

Although the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in neuronal excitability and synaptic transmission is still unclear, it is postulated that the HCN channels may be involved in seizure activity. The aim of this study was to assess the effects of ivabradine (an HCN channel inhibitor) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) against maximal electroshock-induced seizures in mice. Tonic seizures (maximal electroconvulsions) were evoked in adult male albino Swiss mice by an electric current (sine-wave, 25 mA, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles of the combinations of ivabradine with classical antiepileptic drugs were measured in mice along with total brain antiepileptic drug concentrations. Results indicate that ivabradine (10 mg/kg, i.p.) significantly enhanced the anticonvulsant activity of valproate and considerably reduced that of phenytoin in the mouse maximal electroshock-induced seizure model. Ivabradine (10 mg/kg) had no impact on the anticonvulsant potency of carbamazepine and phenobarbital in the maximal electroshock-induced seizure test in mice. Ivabradine (10 mg/kg) significantly diminished total brain concentration of phenytoin and had no effect on total brain valproate concentration in mice. In conclusion, the enhanced anticonvulsant action of valproate by ivabradine in the mouse maximal electroshock-induced seizure model was pharmacodynamic in nature. A special attention is required when combining ivabradine with phenytoin due to a pharmacokinetic interaction and reduction of the anticonvulsant action of phenytoin in mice. The combinations of ivabradine with carbamazepine and phenobarbital were neutral from a preclinical viewpoint.     

三种抗癫痫药对癫痫患者脑电图的背景影响比较研究

目的：研究对比三种抗癫痫药（苯妥因钠、丙戊酸钠、卡马西平）对癫痫患者脑电图的背景影响。方法：选取我院于2009年3月至2011年2月收治的60例癫痫患者,随机分为苯妥因钠（PHT）、卡马西平（CBZ）和丙戊酸钠（SVP）组各20例,动态观察各组患者于治疗期间痫样波放电的频度和EEG背景的变化。结果：EEG痫样波放电的抑制率以SVP最为明显,而CBZ在EEG背景活动影响方面均比其他两组显著。结论：三种药物对癫痫波放电的抑制顺序是SVP〉PHT〉CBZ,SVP组明显优于其他两组。     

Mexiletine and its Interactions with Classical Antiepileptic Drugs: An Isobolographic Analysis

Using the mouse maximal electroshock test, the reference model of tonic–clonic seizures, the aim of the present study was to determine the type of interaction between mexiletine (a class IB antiarrhythmic drug) and classical antiepileptics: valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis of obtained data indicated antagonistic interactions between mexiletine and valproate (for fixed ratio combinations of 1:1 and 3:1). Additivity was observed between mexiletine and valproate applied in proportion of 1:3 as well as between mexiletine and remaining antiepileptics for the fixed ratios of 1:3, 1:1, and 3:1. Neither motor performance nor long-term memory were impaired by mexiletine or antiepileptic drugs regardless of whether they were administered singly or in combination. Mexiletine did not significantly affected brain concentrations of carbamazepine, phenobarbital or phenytoin. In contrast, the antiarrhythmic drug decreased by 23 % the brain level of valproate. This could be, at least partially, the reason of antagonistic interaction between the two drugs. In conclusion, the observed additivity suggests that mexiletine can be safely applied in epileptic patients treated with carbamazepine, phenytoin or phenobarbital. Because of undesirable pharmacodynamics and pharmacokinetic interactions with valproate, mexiletine should not be used in such combinations.

     

Effect of carbamazepine and gabapentin on excitability in the trigeminal subnucleus caudalis of neonatal rats using a voltage-sensitive dye imaging technique

Background

The antiepileptic drugs carbamazepine and gabapentin are effective in treating neuropathic pain and trigeminal neuralgia. In the present study, to analyze the effects of carbamazepine and gabapentin on neuronal excitation in the spinal trigeminal subnucleus caudalis (Sp5c) in the medulla oblongata, we recorded temporal changes in nociceptive afferent activity in the Sp5c of trigeminal nerve-attached brainstem slices of neonatal rats using a voltage-sensitive dye imaging technique.

Results

Electrical stimulation of the trigeminal nerve rootlet evoked changes in the fluorescence intensity of dye in the Sp5c. The optical signals were composed of two phases, a fast component with a sharp peak followed by a long-lasting component with a period of more than 500 ms. This evoked excitation was not influenced by administration of carbamazepine (10, 100 and 1,000 μM) or gabapentin (1 and 10 μM), but was increased by administration of 100 μM gabapentin. This evoked excitation was increased further in low Mg²⁺ (0.8 mM) conditions, and this effect of low Mg²⁺ concentration was antagonized by 30 μM DL-2-amino-5-phosphonopentanoic acid (AP5), a N-methyl-d-aspartate (NMDA) receptor blocker. The increased excitation in low Mg²⁺ conditions was also antagonized by carbamazepine (1,000 μM) and gabapentin (100 μM).

Conclusion

Carbamazepine and gabapentin did not decrease electrically evoked excitation in the Sp5c in control conditions. Further excitation in low Mg²⁺ conditions was antagonized by the NMDA receptor blocker AP5. Carbamazepine and gabapentin had similar effects to AP5 on evoked excitation in the Sp5c in low Mg²⁺ conditions. Thus, we concluded that carbamazepine and gabapentin may act by blocking NMDA receptors in the Sp5c, which contributes to its anti-hypersensitivity in neuropathic pain.     

Characterization of Phenytoin,Carbamazepine, Vinpocetine and Clorgyline Simultaneous Effects on Sodium Channels and Catecholamine Metabolism in Rat Striatal Nerve Endings

The effects of two classic antiepileptic drugs (carbamazepine and phenytoin), a potential antiepileptic (vinpocetine) and a monoamine-oxidase inhibitor (clorgyline) on the simultaneous changes (detected by HPLC) on Glu, Asp, dopamine and DOPAC inside and outside striatal isolated nerve endings were investigated. Under resting conditions phenytoin, carbamazepine and clorgyline increased dopamine release. Phenytoin and clorgyline increased internal dopamine and decreased DOPAC formation. Carbamazepine decreased internal dopamine and practically did not change DOPAC formation. Glu and Asp release was unchanged. Neurotransmitter release induced by the Na⁺ channel opener veratridine was reduced by all the antiepileptic drugs tested, except phenytoin which, like clorgyline, facilitated veratridine-induced dopamine release. We conclude that besides the antagonism exerted by carbamazepine, phenytoin and vinpocetine on excitatory neurotransmitters release triggered by Na⁺ channel activation, that might importantly contribute to their anticonvulsant action, they exert different actions on striatal dopamine distribution, that might explain their different side effect profiles.     

Anticonvulsant drugs for management of pain: a systematic review.

OBJECTIVE--To determine effectiveness and adverse effects of anticonvulsant drugs in management of pain. DESIGN--Systematic review of randomised controlled trials of anticonvulsants for acute, chronic, or cancer pain identified by using Medline, by hand searching, by searching reference lists, and by contacting investigators. SUBJECTS--Between 1966 and February 1994, 37 reports were found; 20 reports, of four anticonvulsants, were eligible. MAIN OUTCOME MEASURES--Numbers needed to treat were calculated for effectiveness, adverse effects, and drug related withdrawal from study. RESULTS--The only placebo controlled study in acute pain found no analgesic effect of sodium valproate. For treating trigeminal neuralgia, carbamazepine had a combined number needed to treat of 2.6 for effectiveness, 3.4 for adverse effects, and 24 for severe effects (withdrawal from study). For treating diabetic neuropathy, anticonvulsants had a combined number needed to treat of 2.5 for effectiveness, 3.1 for adverse effects, and 20 for severe effects. For migraine prophylaxis, anticonvulsants had a combined number needed to treat of 1.6 for effectiveness, 2.4 for adverse effects, and 39 for severe effects. Phenytoin had no effect on the irritable bowel syndrome, and carbamazepine had little effect on pain after stroke. Clonazepam was effective in one study for temporomandibular joint dysfunction. No study compared one anticonvulsant with another. CONCLUSIONS--Anticonvulsants were effective for trigeminal neuralgia and diabetic neuropathy and for migraine prophylaxis. Minor adverse effects occurred as often as benefit.     

Micellar electrokinetic capillary chromatography for therapeutic drug monitoring of zonisamide

The simultaneous determination of zonisamide, a new type of antiepileptic drug, and the typical antiepileptic drugs phenobarbital, phenytoin and carbamazepine in human serum was developed using micellar electrokinetic capillary chromatography (MECC) with a diode array detector. A high correlation was revealed between the zonisamide levels in human serum obtained by MECC and those obtained by high-performance liquid chromatography (r=0.981). The serum levels of phenobarbital, phenytoin and carbamazepine determined by MECC were almost equal to those obtained by fluorescence polarization immunoassay. The reproducibility of separation and quantification with MECC analysis was appropriate for the intra- and inter-day assay coefficients. Therefore, the MECC method established here could provide a simple and efficient therapeutic drug monitoring method for antiepileptic drugs in patients, especially those treated with a combination of zonisamide and other antiepileptic drugs.     

Studies on the effects of acetylcholine and antiepileptic drugs on32Pi incorporation into phospholipids of rat brain synaptosomes

Studies were conducted on the effects of antiepileptic drugs on the acetylcholine-stimulated³²P labeling of phospholipids in rat brain synaptosomes. Of the four antiepileptic drugs investigated in the present study, namely phenytoin, carbamazepine, phenobarbital, and valproate, only phenytoin blocked the acetylcholine-stimulated³²P labeling of phosphatidylinositol and phosphatidic acid, and the acetylcholine-stimulated breakdown of polyphosphoinositides. Phenytoin alone, like atropine alone, had no effect on the³²P labeling of phospholipids nor on the specific radioactivity of [³²P]ATP. Omission of Na⁺ drastically reduced both the³²P labeling of synaptosomal phospholipids and the specific radioactivity of [³²P]ATP and furthermore it significantly decreased the phosphoinositide effect. It was concluded that certain antiepileptic drugs, such as phenytoin, could exert their pharmacological actions through their antimuscarinic effects. In addition the finding that phenytoin, which acts to regulate Na⁺ and Ca²⁺ permeability of neuronal membranes, also inhibited the phosphoinositide effects in synaptosomes, support the conclusions that Ca²⁺ and Na⁺ are probably involved in the molecular mechanism underlying this phenomenon in excitable tissues.Abbreviations used ACh Acetylcholine - PA phosphatidic acid - PI phosphatidylinositol - poly PI polyphosphoinositides (diphosphoinositide and triphosphoinositide) - PC phosphatidylcholine - PE phosphatidylethanolamine - PS phosphatidylserine - S.A. specific radioactivity     

Segregation of the growth slowing effects of valproic acid from phenytoin and carbamazepine on lymphoid tumor cells.

One human and six murine tumor cell lines of lymphoid origin were assessed for growth in the presence of three commonly used antiepileptic drugs (AEDs). All seven lines were sensitive to the growth slowing effects of phenytoin (PHT) and carbamazepine (CBZ). Six lines showed a similar effect when exposed to valproic acid (VPA), while one murine B cell line was resistant to inhibition of growth by VPA.     

Multi-Indication Carbamazepine and the Risk of Severe Cutaneous Adverse Drug Reactions in Korean Elderly Patients: A Korean Health Insurance Data-Based Study

Objective

To evaluate the risk of severe cutaneous adverse drug reactions (SCAR) after exposure to multi-indication antiepileptic drugs for in Korean elderly patients.

Methods

We used a nationwide database from the Korean Health Insurance Review and Assessment Service claims constructed for the monitoring of drug utilization among the entire Korean elderly population from January 2005 to June 2006. We identified cases of SCARs among inpatients aged ≥65 years and those newly diagnosed with erythema multiforme according to the International Classification of Diseases, 10th revision code (L51). Each case was matched to four controls for gender, age, and the first hospitalization date as the index date. The use of carbamazepine, gabapentin, lamotrigine, topiramate, phenobarbital, phenytoin, and valproate during a 60-day period before the index date was compared. A conditional logistic regression analysis was performed to calculate the odds ratios (OR) and 95% confidence intervals (CI) of SCARs for antiepileptic drug.

Results

We identified 286 cases of SCAR and 1,144 matched controls. Among the 25 patients who were prescribed antiepileptic drugs within 60 days of the index date. There were 11 cases (3.8%) of severe ocular manifestations, and most elderly patients were first-time or short-term users of antiepileptic drugs. Among the 10 cases of carbamazepine use, only 2 cases were prescribed carbamazepine for seizure. All antiepileptic drugs were associated with an increased SCAR risk (adjusted OR = 3.42, 95% CI: 1.75–6.63). The SCAR risk was highest in patients treated with carbamazepine (adjusted OR = 10.39, 95% CI: 2.64–40.86, for multi-indication; adjusted OR = 6.84, 95% CI: 1.55–30.10, for neuropathic pain).

Conclusion

Carbamazepine use was associated with a nearly 10-fold increase in severe cutaneous drug reactions in Korean elderly patients. This association was consistently high with SCAR patients who received carbamazepine for neuropathic pain.     

Effect of diazepam, carbamazepine, sodium valproate and their combinations with vitamin preparations on epileptic activity

The anticonvulsive action of diazepam, carbamazepine, sodium valproate and their combinations with pyridoxal-5-phosphate, nicotinamide, and alpha-tocopherol were investigated in acute experiments on mice with corazole-induced seizures. Diazepam (0.5 mg/kg), carbamazepine (50 mg/kg) and sodium valproate (200 mg/kg) were shown to reduce convulsive intensity and lethality. Vitamins nicotinamide (250 mg/kg), pyridoxal-5-phosphate (10 mg/kg) and alpha-tocopherol (100 mg/kg) potentiated anticonvulsive action of the above antiepileptic drugs. The results of the investigation suggest the efficacy of pathogenetic therapy and give new evidence of the advisability of using vitamins in combination with synthetic anticonvulsive drugs.     

Interaction of hydroalcoholic extract of Acorus calamus Linn. with sodium valproate and carbamazepine

Anticonvulsant property of Acorus calamus is known. Since combination therapy can lower the dose of individual drug and dose related toxicities, in this study, the effect of co-administration of hydroalcoholic extract of A. calamus (HAEAC) on conventional antiepileptic drugs (AEDs), sodium valproate and carbamazepine was determined using pentylenetetrazole-induced seizures model in rats. On combining the subanticonvulsant doses of HAEAC with sodium valproate and carbamazepine, greater protection as compared to either drug alone was observed. This was not related to change in levels of the AEDs. Thus, the results further substantiate anticonvulsant effect of HAEAC and suggest a potential for add on therapy with AEDs.     

An assessment of the in vitro antimicrobial effects of two antiepileptic drugs--sodium valproate and phenytoin

An incidental observation led to the evaluation of the antimicrobial properties of valproate and phenytoin. In vitro inhibition of Mycobacterium smegmatis, Candida albicans, and other standard test organisms by these two antiepileptic drugs was assessed using the broth microdilution procedure. Fluorescence microscopy (Viability Stains, Molecular Probes Inc.) and cultural techniques were employed to distinguish between microbicidal and microbistatic effects. Phenytoin showed no inhibitory activity against the microbes tested. Sodium valproate, on the other hand, was selectively potent against the yeast strains in a dose-dependent manner (MIC = 10–20 μg ml⁻¹). In vitro activity against Mycobacterium smegmatis (70% growth inhibition by 81 μg ml⁻¹) was moderate to low while Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli were not significantly affected. Viability data from fluorescent microscopy and plate cultures correlated well with absorbance (A_620nm) growth index, and showed that valproate was microbicidal against susceptible organisms. The mode of action may include blockage of calcium channels and perturbation of membrane potential. This report opens up yet another opportunity for further enquiry into the fundamental mechanisms of drug action and microbial resistance. This revised version was published online in June 2006 with corrections to the Cover Date.     

Hypothesis: An important role for R-verapamil in pharmacoresistant epilepsy

Drugs that block P-glycoprotein-modulated efflux of antiepileptic drugs in the brain, lead to increase their intracellular concentration. Addition of R-verapamil as one enantiomer of verapamil to antiepileptic drugs may facilitate the penetration of drugs to the brain and prevents their efflux from CNS without serious cardiovascular side effects.     

BK(Ca) channel agonist NS1619 and Kv channel antagonist 4-AP on the facial mechanical pain threshold in a rat model of chronic constriction injury of the infraorbital nerve

Trigeminal neuralgia is a paroxysmal disorder with severely disabling facial pain and thus continues to be a real therapeutic challenge. At present there are few effective drugs for treatment of this pain. The present study was aimed to explore the involvement of BK(Ca) channels and Kv channels in the mechanical allodynia in a rat model of trigeminal neuropathic pain. Here the effectiveness of drug target injection at the trigeminal ganglion through the infraorbital foramen was first evaluated by immunofluorescence and animal behavior test. Trigeminal neuropathic pain model was established by chronic constriction injury of the infraorbital nerve (ION-CCI) in rats. BK(Ca) channel agonist and Kv channel antagonist were administered into the trigeminal ganglion in ION-CCI rats and sham rats by the above target injection method, and the facial mechanical pain threshold was measured. The results showed that the drug could accurately reach the trigeminal ganglion by target injection which was more effective than that by the normal injection around infraorbital foramen. Rats suffered significant mechanical allodynia in the whisker pad of the operated side from 6 d to 42 d after ION-CCI. BK(Ca) channel agonist NS1619 significantly and dose-dependently attenuated the facial mechanical allodynia and increased the facial mechanical pain threshold in ION-CCI rats 15 d after operation. Kv antagonist 4-AP was able to reduce the threshold in ION-CCI rats when facial mechanical threshold was partly recovered and relatively stable on the 35th day after operation. These results suggest that BK(Ca) channel agonist NS1619 and Kv channel antagonist 4-AP can significantly affect the rats' facial mechanical pain threshold after ION-CCI. Activation of BK(Ca) channels may be related to the depression of the primary afferent neurons in trigeminal neuropathic pain pathways. Activation of Kv channels may exert a tonic inhibition on the trigeminal neuropathic pain.     

Effects of pregnancy on seizure threshold and the disposition and efficacy of antiepileptic drugs in the mouse

The effects of pregnancy on seizure excitability as well as antiepileptic drug disposition and efficacy were studied in the mouse during late gestation. Phenytoin and carbamazepine concentrations in brain were increased in pregnant animals, which was related to increased free concentrations in plasma. Little changes were observed for valproic acid and phenobarbital. The seizure threshold in untreated pregnant mice was significantly higher than in the nonpregnant group. The efficacy of carbamazepine and valproic acid in the pregnant animals was increased as compared to the control group; little changes were observed for phenobarbital and phenytoin. Our study indicates that - in contrast to the general clinical opinion - pregnancy has little influence or even a slight beneficial effect on the seizure propensity as well as the efficacy of antiepileptic drugs.     

Antiepileptic Drugs Prevent Changes Induced by Pilocarpine Model of Epilepsy in Brain Ecto-Nucleotidases

Ecto-nucleotidases, one of the main mechanisms involved in the control of adenosine levels in the synaptic cleft, have shown increased activities after the pilocarpine model of epilepsy. Here we have investigated the effect of the antiepileptic drugs (AEDs) on ecto-nucleotidase activities from hippocampal and cerebral cortical synaptosomes of rats at seven days after the induction of the pilocarpine model. Expression of these enzymes were investigated as well. Our results have demonstrated that phenytoin (50 mg/kg) and carbamazepine (30 mg/kg) were able to prevent the increase in ecto-nucleotidase activities elicited by pilocarpine in brain synaptosomes. However, sodium valproate (at 100 mg/kg) was only able to avoid the increase on ATP and ADP hydrolysis in hippocampal synaptosomes. Increase on ATP hydrolysis in hippocampal synaptosomes was also prevented by sodium valproate at 286 mg/kg, which corresponds to ED50 for pilocarpine model. NTPDase1, NTPDase2, NTPDase3, and ecto-5′-nucleotidase expressions were not affected by pilocarpine in cerebral cortex. However, expressions of NTPDase2, NTPDase3, and ecto-5′-nucleotidase were increased by pilocarpine in hippocampus. Our results have indicated that previous treatment with AEDs was able to prevent the increase in hippocampal ecto-nucleotidases of pilocarpine-treated rats. These findings have shown that anticonvulsant drugs can modulate plastic events related to the increase of nucleotidase expression and activities in pilocarpine-treated rats.     

L-Histidine is a beneficial adjuvant for antiepileptic drugs against maximal electroshock-induced seizures in mice

Summary. Endogenous histamine has been reported to be involved in regulation of seizure susceptibility. Enhancement of histamine neurotransmission engendered by L-histidine treatment produces anticonvulsant effects in experimental animals. The present study investigated the influence of L-histidine on the protective effects of carbamazepine and phenytoin against maximal electroshock-induced seizures in mice.L-Histidine, administered at the doses that did not influence the threshold for electroconvulsions (250–500mg/kg), enhanced by nearly 30% the protective effects of carbamazepine against maximal electroshock-induced seizures. D-Histidine (1000mg/kg), an inactive isomer of histidine, was without any effect in this regard. L-Histidine (500mg/kg) also augmented the protective effects of phenytoin. Importantly, the enhancement of the anticonvulsant effects of these antiepileptic drugs produced by L-histidine co-administration was not associated with augmentation of their unwanted effects on memory and motor performance. A pharmacokinetic interaction was also excluded since the free plasma levels of these antiepileptics remained unchanged in the presence of L-histidine. It may be suggested that L-histidine could serve as a beneficial adjuvant for selected antiepileptic drugs.Present address: Integrative Neuroscience Section, Behavioral Neuroscience Branch, NIDA/NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224, U.S.A.     

Phenytoin-valproate interaction: importance of saliva monitoring in epilepsy.

Sodium valproate is often used with phenytoin when epilepsy cannot be controlled by a single drug. Sodium valproate depresses phenytoin protein binding and so invalidates plasma phenytoin monitoring as a means of determining precise phenytoin dosage requirements. Plasma and saliva phenytoin and plasma valproate concentrations were measured in 42 patients with epilepsy receiving both drugs. Phenytoin protein binding was also measured by ultrafiltration in 19 of these patients and 19 patients taking phenytoin alone. Saliva phenytoin concentration bore the same close correlation to unbound (therapeutically active) phenytoin in patients receiving both drugs as it did in patients receiving phenytoin alone, whereas plasma total phenytoin did not. The same therapeutic range for saliva phenytoin (4-9 mumol/1; 1-2 microgram/ml) was therefore valid in both groups. The depression of phenytoin binding was directly related to the plasma concentration of valproate both in random samples taken from the 42 patients and in samples taken throughout the day in two of these patients. This was confirmed in vitro. Even when the concentration of valproate is known the degree of binding cannot be predicted. Saliva rather than plasma monitoring of phenytoin treatment is therefore valuable in the presence of valproate and with reduced phenytoin binding from any cause.