Childhood epilepsy uncontrolled by phenytoin: clinical and electroencephalographic study.

Nine cases of childhood epilepsy manifesting motor convulsions uncontrolled despite high levels of phenytoin (PHT) were studied clinically and electroencephalographically. These cases consisted of five cases of partial seizures without impairment of consciousness, two cases of partial seizures (occasionally generalized seizures beginning locally), one case of predominantly unilateral seizures, and one case of generalized tonic-clonic seizures. the onset of seizures was at a rather early age, between 3 months and 9 years, and under 3 years of age in eight cases. All cases had single or multiple, cortical epileptic foci in EEG. The projection of spikes was localized to a rather limited area. Seizures of these patients were frequent. All cases, except one, did not respond to other medication. Convulsive seizures with cortical focal spike foci in EEG uncontrolled despite high levels of PHT were thought to have poor responsiveness to not only PHT itself, but also to other anticonvulsants.     

The Influences of Phenytoin on the Fundamental Electrical Properties of Simple Neural Systems

The effects of phenytoin on some neurophysiological properties of simple neuronal systems are reviewed. From all the available data phenytoin decreases or has no effect on post- tetanic hyperpolarization, which is interpreted as an expression of the electrogenic pump. Al- though in some neurons the membrane conduc- tance is increased, the resting membrane poten- tial is minimally affected. The effect on the action potential varies with different preparations and with different neurons of the same ganglion. If an effect is present, the overshoot is decreased or the falling phase is prolonged, or both. Post- synaptic potentials are also affected by pheny- toin. EPSPs are decreased in size, while the chloride-dependent, GABA-mediated IPSPs of the crayfish stretch receptor are prolonged. No effect was seen on chloride-dependent, ACh- mediated IPSPs in the abdominal ganglion of the Aplysia. Finally, phenytoin arrests endogenous or pharmacologically induced bursting. Most of the described effects are consistent with the an- tiarrhythmic and antiepileptic properties of the drug.     

Paradoxical Intoxication,:A Complication of Anticonvulsant Administration

A new syndrome, paradoxical intoxication, has been defined in which high levels of hydantoins, and in one instance carbamazepine, produced an increase in seizures with little or no evidence of intoxication; a decrease in these levels produced an improvement in seizure control. This syndrome occurs often but not exclusively in those people who are less astute in assessing their neurologic status and therefore may experience unexpectedly higher blood levels of their anticonvulsants. Instances have been documented with serum levels above 40 mugm/ml for phenytoin or mephenytoin alone, or above 50 mugm/ml of combined hydantoins phenytoin and mephenytoin, and when the level is in the range of 20 mugm/ml and above for carbamazepine. Possible mechanisms underlying the syndrome are reviewed. Appropriate therapy is a reduction of the dose of the drug in question.     

Significant induction of cyclophosphamide and thiotepa metabolism by phenytoin

Patient and method A 42-year-old male patient with relapsing germ-cell cancer was enrolled in a salvage protocol that employed two 4-day courses of CTC high-dose chemotherapy with cyclophosphamide (1,500 mg m^–2 day^–1), thiotepa (120 mg m^–2 day^–1), and carboplatin, followed by peripheral blood progenitor cell support. From five days before the start of the second CTC course the patient received phenytoin for generalized epileptic seizures. Blood samples were collected on day 1 of both CTC courses and analyzed for cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide, and for thiotepa and its main active metabolite tepa.Results Exposure (expressed as area under the plasma concentration vs time curve) to 4-hydroxycyclophosphamide and tepa in the second CTC course was increased by 51% and 115%, respectively, compared with the first CTC course, whereas exposure to cyclophosphamide and thiotepa was significantly reduced (67% and 29%, respectively). Because high exposure to 4-hydroxycyclophosphamide and tepa correlates with increased toxicity, the treatment risk of this patient was significantly increased. Therefore doses were reduced on the third day of the second course.Conclusion It was concluded that phenytoin significantly induces both cyclophosphamide and thiotepa metabolism, most probably by induction of the cytochrome p450 enzyme system. This potential clinical significant interaction should be taken into account when phenytoin is administered in combination with cyclophosphamide and thiotepa in clinical practice.     

Drug hypersensitivity to previously tolerated phenytoin by carbamazepine-induced DRESS syndrome

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome associated with anticonvulsant drugs is a rare but potentially life-threatening disease that occurs in response to arene oxide producing anticonvulsant such as phenytoin and carbamazepine. There have been many reports of cross reactivity among the anticonvulsants upon first exposure to the offending drugs. However, there has been few data describing the development of DRESS syndrome after switching medication from previously well-tolerated phenytoin to carbamazepine, and the induction of hypersensitivity to phenytoin by DRESS to carbamazepine. We experienced a case of a 40-yr-old man who had uncontrolled seizure that led to the change of medication from the long-term used phenytoin to carbamazepine. He developed DRESS syndrome after changing the drugs. We stopped carbamazepine and restored phenytoin for seizure control, but his clinical manifestations progressively worsened and he recovered only when both drugs were discontinued. Patch tests with several anticonvulsants showed positive reactions to both carbamazepine and phenytoin. Our case suggests that hypersensitivity to a previously tolerated anticonvulsant can be induced by DRESS to another anticonvulsant, and that the patch test may be a useful method for detecting cross-reactive drugs in anticonvulsant-associated DRESS syndrome.     

药物联合应用在神经外科外伤性癫痫治疗中的临床研究

目的探讨丙戊酸镁联合苯妥英钠治疗外伤性癫痫的临床疗效。方法选择2010年3月至2013年3月外伤性癫痫患者150例,按照治疗方式分为丙戊酸铗治疗组（A组）50例、苯妥英钠治疗组（B组）50例和两药联合治疗组（c组）50例。观察三组患者的治疗效果。结果在控制癫痫发作频率和发作持续时间方面,三组患者治疗后均优于治疗前,差异有统计学意义（P〈O．05）;A组和B组差异无统计学意义（P〉0．05）;C明显优于A组和B组,差异有统计学意义（P〈0．05）。三组总有效率比较,C组明显优于A组和B组,差异有统计学意义（P〈0．05）;A组和B组差异无统计学意义（P〉0．05）。三组不良反应比较差异无统计学意义（P〉0．05）。结论丙戊酸镁联合苯妥英钠治疗外伤性癫痫具有显著的临床疗效,不增加药物的不良反应,患者的耐受性较好,值得临床推广应用。     

高效液相色谱法同时测定人血清中氨茶碱、苯巴比妥、苯妥英钠及卡马西平的浓度

目的：建立同时测定人血清中氨茶碱（APL）、苯巴比妥（PB）、苯妥英钠（DPH）和卡马西平（CBZ）的高效液相色谱（HPLC）法。方法：以Agilent TC-C18（250 mm×4.6 mm,5μm）为分析柱,甲醇-水（60∶40）为流动相,检测波长230 nm,流速1.0 ml/min,柱温35℃。结果：APL、PB、DPH、CBZ均能达到良好的分离,与相邻峰的分离度（R）均〉1.5;线性范围分别为1.01～40.34 mg/L（r=0.999 5）、1.24～59.52 mg/L（r=0.999 1）、2.60～31.20 mg/L（r=0.998 6）、1.09～32.61 mg/L（r=0.999 2）;平均回收率分别为98.15%、99.25%、98.86%、100.3%;日内和日间精密度的RSD均〈4.3%。结论：本法灵敏、准确、简便、快速,适用于临床血药浓度的检测。     

Should phenytoin or barbiturates be used as second-line anticonvulsant therapy for toxicological seizures?

Introduction. Seizures are a common sequela of self-poisoning. However, their mechanism differs from seizures of other etiologies. Toxicological seizures result from alterations in the excitatory and inhibitory balance of otherwise normal neurons. In contrast, idiopathic or trauma related seizures usually start with a focus of abnormal neurons. For both forms of seizures, benzodiazepines are recommended as first-line therapy; however, there is debate about the use of phenytoin or barbiturates for second-line therapy. Methods and Results. In this article, we systematically review the evidence for the use of these drugs as second-line therapy for toxicological seizures. Barbiturates complement the anticonvulsant effect of benzodiazepines at the GABAA receptor by increasing the duration of chloride channel opening; phenytoin blocks voltage-dependent sodium channels to inhibit propagation from active electrical foci, an effect more useful for nontoxicological seizures. We found no randomized controlled trial comparing phenytoin and barbiturates in toxicological seizures refractory to benzodiazepines; similarly no trial was found comparing the use of these drugs in nonpoisoned patients. Animal studies indicate that phenobarbital has greater effectiveness than phenytoin for many poisons; a few case reports suggest a better response in patients. Conclusion. Despite the lack of high-quality clinical trial data, pharmacological knowledge and animal studies suggest that phenobarbital or thiopentone should be second-line agents for controlling toxicological seizures. The role of newer agents such as propofol and levetiracetam in toxicological seizures is currently unclear because of a lack of clinical or animal studies.     

Levetiracetam compared to phenytoin for the prevention of postoperative seizures after craniotomy for intracranial tumours in patients without epilepsy

Anticonvulsant drugs are frequently given after craniotomy. Phenytoin (PHT) is the most commonly used agent; levetiracetam (LEV) is a new anticonvulsant drug with fewer side effects. To compare the incidence of seizures in patients receiving either prophylactic PHT or LEV perioperatively, 971 patients undergoing a craniotomy were analysed retrospectively during a 2-year period. PHT was used routinely and LEV was administered when PHT was contraindicated. Seizures documented during the first 7 days after craniotomy were considered. A total of 235 patients were treated with an antiepileptic drug: 81 patients received LEV, and 154 patients, PHT. Two patients receiving LEV (2.5%) and seven receiving PHT (4.5%) had a seizure despite this treatment. No patient had a documented side effect or drug interaction. The data show that LEV may be an alternative option in patients with contraindications to PHT.     

Several major antiepileptic drugs are substrates for human P-glycoprotein

One of the current hypotheses of pharmacoresistant epilepsy proposes that transport of antiepileptic drugs (AEDs) by drug efflux transporters such as P-glycoprotein (Pgp) at the blood-brain barrier may play a significant role in pharmacoresistance in epilepsy by extruding AEDs from their intended site of action. However, several recent in vitro studies using cell lines that overexpress efflux transporters indicate that human Pgp may not transport AEDs to any relevant extent. In this respect it has to be considered that most AEDs are highly permeable, so that conventional bi-directional transport assays as used in these previous studies may fail to identify AEDs as Pgp substrates, particularly if these drugs are not high-affinity substrates for Pgp. In the present study, we used a modified transport assay that allows evaluating active transport independently of the passive permeability component. In this concentration equilibrium transport assay (CETA), the drug is initially added at identical concentration to both sides of a polarized, Pgp-overexpressing cell monolayer instead of applying the drug to either the apical or basolateral side for studying bi-directional transport. Direct comparison of the conventional bi-directional (concentration gradient) assay with the CETA, using MDR1-transfected LLC cells, demonstrated that CETA, but not the conventional assay, identified phenytoin and phenobarbital as substrates of human Pgp. Furthermore, directional transport was determined for lamotrigine and levetiracetam, but not carbamazepine. Transport of AEDs could be completely or partially (>50%) inhibited by the selective Pgp inhibitor, tariquidar. However, transport of phenobarbital and levetiracetam was also inhibited by MK571, which preferentially blocks transport by multidrug resistance transporters (MRPs), indicating that, in addition to Pgp, these AEDs are substrates of MRPs. The present study provides the first direct evidence that several AEDS are substrates of human Pgp, thus further substantiating the transporter hypothesis of pharmacoresistant epilepsy.