Drug therapy reviews: drug therapy of status epilepticus.

Drug treatment of status epilepticus is reviewed. Tonic-clonic, focal motor, complex partial and absence status epilepticus are discussed. In managing tonic-clonic status epilepticus one should: (1) maintain vital functions at all times, (2) identify and treat precipitating factors and (3) administer an intravenous loading dose of phenytoin sodium or phenobarbital sodium. Careful use of i.v. diazepam sometimes helps to achieve these objectives. Intravenous phenytoin sodium and phenobarbital sodium provide definitive, long-term control of tonic-clonic seizures but must be administered slowly and require time to reach peak brain concentrations. Intravenous diazepam appears to enter and exit from the brain rapidly and may control seizures while therapeutic brain concentrations of long-acting drugs are being achieved. Phenytoin, phenobarbital and diazepam should not be administered intramuscularly in treating status epilepticus. Treatment of focal motor and complex partial status epilepticus is similar to that of tonic-clonic status epilepticus, but i.v. diazepam is required less frequently and loading doses of phenytoin and phenobarbital sometimes can be given more slowly. Status epilepticus of the absence type is managed with i.v. acetazolamide sodium or diazepam. Paraldehyde, muscle relaxants, general anesthesia and lidocaine may be tried when conventional therapies fail.     

Plasma levels of lidocaine during combined treatment with phenytoin and procainamide

Summary The effects of phenytoin and procainamide on plasma concentrations of lidocaine have been studied in patients and dogs receiving continuous intravenous infusions of the latter drug. All drugs were given in doses that produced therapeutic plasma concentrations. In the patients, no changes were observed in plasma lidocaine levels after intravenous or intramuscular phenytoin, or after intravenous or oral procainamide. Similarly, in the dogs, intravenous phenytoin had no effect on plasma lidocaine concentrations. However, in both patients and dogs a high incidence of CNS side-effects was recorded during lidocaine — phenytoin combination therapy, which suggests a potential pharmacodynamic interaction between them. The absorption of phenytoin administered intra-muscularly was impaired, probably because of pH-dependent crystallization. This route of administration should be avoided in acute treatment with phenytoin.Dedicated to the late Balzar Alexanderson, M.D.     

Effect of lidocaine on the absorption,disposition and tolerance of intramuscularly administered cefoxitin

Summary The use of lidocaine HCl solution at concentrations of 0.5 and 1.0% to reconstitute sodium cefoxitin relieves the pain associated with intramuscular injections of the antibiotic. Cefoxitin absorption by the intramuscular route is initially rapid and is virtually complete. Peak serum concentrations, corresponding to about one-half those of a comparable intravenous infusion, are achieved in 30 min. Continuing absorption tends to maintain higher serum concentrations for longer times. Renal clearance and serum half-life of cefoxitin do not appear to be affected by lidocaine at its effective anaesthetic concentrations.     

Serum lidocaine concentrations following application to the oropharynx: effects of cimetidine

Solutions of lidocaine hydrochloride are widely used for anesthesia of the oropharynx and respiratory tract prior to endoscopic procedures. It is commonly believed that this route of administration is not associated with clinically significant systemic absorption of the drug, and large doses of topical lidocaine are routinely used in this setting. Serious adverse effects, including seizures, occasionally occur. The extent of absorption of lidocaine from the oropharynx was studied in eight healthy volunteers. Wide variation in serum lidocaine concentrations was observed. A 14-fold range of peak lidocaine concentrations occurred following identical, accurately metered doses of a lidocaine aerosol spray preparation. The effects of cimetidine on lidocaine pharmacokinetics were also studied. Therapeutic doses of oral cimetidine significantly increased the area under the lidocaine time-concentration curve (p = 0.019), but no effect on the terminal-phase elimination rate constant was observed. Serum concentrations of alpha 1-acid glycoprotein, a major binding protein of lidocaine, were significantly elevated following cimetidine (p = 0.030). Maximum lidocaine concentration, time to reach maximum concentration, and mean residence time of lidocaine were unchanged following cimetidine. These observations suggest an effect of cimetidine on the volume of distribution of lidocaine. Because of the wide variability in lidocaine pharmacokinetics and the potentially serious nature of adverse reactions, caution is advised in the use of topical lidocaine solutions in "standard" doses.     

Seizures following oral lidocaine for esophageal anesthesia

Lidocaine is absorbed from mucous membranes of the oropharynx, gastrointestinal tract, and tracheobronchial tree. First-pass hepatic metabolism of the drug greatly reduces the amount reaching the general systemic circulation in the normal individual. In patients whose hepatic metabolism is reduced by disease or drugs, or in whom liver blood flow is reduced, this first-pass effect is decreased and lidocaine concentrations may be higher than those produced by the same dose in normal patients. We report an elderly man taking cimetidine with congestive heart failure in whom the accidental ingestion of lidocaine solution for esophageal anesthesia was followed by seizures and elevated serum lidocaine concentrations.     

Antiarrhythmic drugs and epilepsy

For a long time it has been suspected that epilepsy and cardiac arrhythmia may have common molecular background. Furthermore, seizures can affect function of the central autonomic control centers leading to short- and long-term alterations of cardiac rhythm. Sudden unexpected death in epilepsy (SUDEP) has most likely a cardiac mechanism. Common elements of pathogenesis create a basis for the assumption that antiarrhythmic drugs (AADs) may affect seizure phenomena and interact with antiepileptic drugs (AEDs).Numerous studies have demonstrated anticonvulsant effects of AADs. Among class I AADs (sodium channel blockers), phenytoin is an established antiepileptic drug. Propafenone exerted low anti-electroshock activity in rats. Lidocaine and mexiletine showed the anticonvulsant activity not only in animal models, but also in patients with partial seizures. Among beta-blockers (class II AADs), propranolol was anticonvulsant in models for generalized tonic-clonic and complex partial seizures, but not for myoclonic convulsions. Metoprolol and pindolol antagonized tonic-clonic seizures in DBA/2 mice. Timolol reversed the epileptiform activity of pentylenetetrazol (PTZ) in the brain. Furthermore, amiodarone, the representative of class III AADs, inhibited PTZ- and caffeine-induced convulsions in mice. In the group of class IV AADs, verapamil protected mice against PTZ-induced seizures and inhibited epileptogenesis in amygdala-kindled rats. Verapamil and diltiazem showed moderate anticonvulsant activity in genetically epilepsy prone rats. Additionally, numerous AADs potentiated the anticonvulsant action of AEDs in both experimental and clinical conditions. It should be mentioned, however, that many AADs showed proconvulsant effects in overdose. Moreover, intravenous esmolol and intra-arterial verapamil induced seizures even at therapeutic dose ranges.     

利多卡因红花液外用在手背静脉穿刺中的应用研究

目的:探讨利多卡因红花液外用在手背静脉穿刺中的作用.方法:选取静脉输液2次以上的100例我院门诊患者为研究对象,采用自身对照的类实验性研究方法,即将第1次静脉输液(2％利多卡因50ml加红花饮片10 g)和第2次静脉输液(2％利多卡因)分别作为实验组和对照组.采用疼痛评定量表法测量患者疼痛程度,采用秒表测量进针时间和扎止血带时间,采用游标卡尺测量手背浅静脉直径,然后采用SPSS统计较件比较两组间静脉穿刺时血管扩张程度、静脉穿刺时疼痛程度、静脉穿刺进针时间和扎止血带时间、一次穿刺成功率的差异.结果:实验组的静脉穿刺时血管扩张程度、静脉穿刺时疼痛程度、静脉穿刺进针时间、扎止血带时间和一次穿刺成功率等指标值均显著优于对照组(P＜0.01).结论:利多卡因红花液外用能明显提高手背静脉穿刺工作效率.     

Effect of experimental renal failure on the pharmacodynamics of cefoselis-induced seizures in rats

We investigated the effect of infusion rate and experimental renal failure on the pharmacodynamics of cefoselis (CFSL)-induced seizures. As an animal model of CFSL-induced seizures, male Wistar rats received an intravenous infusion of CFSL at one of three different rates (1.4-5.8 g/h/rat) until the onset of maximal seizures (which occurred after 8.0 to 36.0 min of infusion). Samples of cerebrospinal fluid (CSF), blood (for serum), and brain were obtained immediately after stopping infusion of CSFL. The serum concentration of CFSL at the onset of seizures increased with increasing infusion rate, but brain and CSF concentrations of CFSL at the onset of seizures were not affected by the infusion rate. Ureter-ligated (UL) and control rats received an intravenous infusion of CFSL at 1.4 g/h/rat until the onset of seizures. Then the same procedure as used to determine the effect of infusion rate on the concentrations of CFSL was carried out. Renal failure was associated with a significant decrease in the amount of CFSL required to induce seizures. Serum, brain, and CSF concentrations of CFSL in UL rats were significantly lower than those in control rats. These results indicate that the experimental strategy and animal model in this investigation would be useful to assess the effects of diseases and other variables on the pharmacodynamics of CFSL-induced seizures and that renal failure is one of the risk factors for neurotoxicity of CFSL.     

Zonisamide: review of its use in epilepsy therapy

Zonisamide is an antiepileptic drug used as adjunctive therapy for refractory partial seizures in adults. Because of the multiple mechanisms of action, it shows a broad spectrum of anticonvulsant activity and has been effective in several types of seizures, including partial and generalized seizures, tonic-clonic seizures and absence seizures in patients unresponsive to other anticonvulsants. Myoclonic epilepsy, Lennox-Gastaut syndrome and infantile spasms have also been treated effectively with zonisamide. Recent clinical studies have demonstrated additional potential for therapeutic use in neuropathic pain, bipolar disorder, migraine, obesity, eating disorders and Parkinson's disease. Despite adverse events, zonisamide is relatively safe and well tolerated in patients, and shows low discontinuation rate. It has a good pharmacokinetic profile and a low drug interaction potential. Zonisamide is considered as a drug that effectively reduces the frequency of partial seizures.     

Levetiracetam. A review of its adjunctive use in the management of partial onset seizures

Levetiracetam, the S-enantiomer of alpha-ethyl-2-oxo-1-pyrollidine acetamide, is approved for use as adjunctive therapy in adult patients with partial onset seizures. Oral levetiracetam 1000, 2000 and 3000 mg/day administered as adjunctive therapy for up to 18 weeks significantly increased responder rates and reduced seizure frequency compared with placebo in 3 well designed pivotal trials in adults with treatment-refractory partial seizures with or without secondary generalisation. Levetiracetam 3000 mg/day also significantly increased the number of seizure-free patients, but the effects of levetiracetam 1000 and 2000 mg/day on this end-point were unclear. Effects on seizure severity were not assessed in these trials. Although not yet approved as monotherapy or for use in paediatric patients, efficacy was observed with levetiracetam 3000 mg/day as monotherapy in adult patients with refractory partial seizures with or without secondary generalisation and with the 10 to 40 mg/kg/day dosage as adjunctive therapy in children with refractory partial seizures. However, these data are limited. Oral levetiracetam 1000, 2000 and 3000 mg/day as adjunctive therapy is generally well tolerated with an overall incidence of adverse events similar to that observed with placebo. The most commonly reported events in individual clinical trials were CNS-related and included somnolence, asthenia, headache and dizziness. Levetiracetam administered as adjunctive therapy does not appear to interact with other anticonvulsant drugs, and no clinically relevant interactions were observed between levetiracetam and digoxin, warfarin or probenecid; oral contraceptive protective efficacy was also not affected by levetiracetam. CONCLUSIONS: Levetiracetam is a new anticonvulsant agent with a favourable tolerability profile and a low potential for drug interactions. It has shown efficacy as adjunctive therapy in patients with treatment-refractory partial onset seizures with or without secondary generalisation in clinical trials. Direct comparative trials with other anticonvulsant agents are not yet available, but placebo-controlled clinical evidence to date suggests that levetiracetam (1000, 2000 and 3000 mg/day) is a useful option as adjunctive therapy in patients with this subtype of epilepsy.     

Fosphenytoin and phenytoin in patients with status epilepticus: improved tolerability versus increased costs.

Tonic-clonic status epilepticus (TCSE) is the most common neurological emergency and affects approximately 60000 patients each year in the US. The risk of complications increases substantially as TCSE lasts longer than 60 minutes. Ideally, drugs used to treat this condition should be well tolerated when administered as rapid intravenous infusions and should not interfere with patients' state of consciousness or cardiovascular and respiratory functions. Because of its efficacy, absence of sedation or respiratory suppression, intravenous phenytoin has largely replaced phenobarbital (phenobarbitone) as the second agent of choice (following the administration of a benzodiazepine) in the treatment of TCSE. While the efficacy of phenytoin in the treatment of acute seizures and TCSE is well established, the parenteral formulation of phenytoin has several inherent shortcomings which compromise its tolerability and limit the rate of administration. Intravenous phenytoin has been associated with fatal haemodynamic complications and serious reactions at the injection site including skin necrosis and amputation of extremities. Fosphenytoin, a phenytoin prodrug, has the same pharmacological properties as phenytoin but none of the injection site and cardiac rhythm complications of intravenous infusions of phenytoin. While fosphenytoin costs more than intravenous phenytoin, treating the acute and chronic complications of TCSE itself, and the complications of intravenous phenytoin can also be costly. All other factors being equal, there is no doubt that fosphenytoin is better tolerated and can be delivered faster than intravenous phenytoin; 2 measures that clearly improve outcome in patients with TCSE. The tolerability of intramuscular fosphenytoin also extends its use to clinical situations where prompt administration of a nondepressing anticonvulsant is indicated but secure intravenous access and cardiac monitoring are not available, such as treatment of seizures by rescue squads in the field and serial seizures in the institutionalised, elderly and other patients with intractable epilepsy.     

Interactions of tiagabine with ethosuximide in the mouse pentylenetetrazole-induced seizure model: an isobolographic analysis for non-parallel dose-response relationship curves

The aim of this study was to characterize the interaction between tiagabine (TGB) and ethosuximide (ETS), two antiepileptic drugs, in pentylenetetrazole (PTZ)-induced clonic seizures in mice using isobolographic analysis. The nature of the interaction between the drugs administered in combination was ascertained by estimating plasma and brain concentrations of ETS and TGB using fluorescence polarization immunoassay (FPIA) and high-performance liquid chromatography (HPLC). The results indicated that both drugs produced clear anticonvulsant effects against PTZ-induced clonic seizures in mice, but that their dose-response relationship curves (DRRCs) were not parallel, consequently necessitating the isobolographic analysis for non-parallel DRRCs. The isobolographic analysis revealed that the combination of TGB with ETS at the fixed-ratio of 1:1 exerted an additive interaction against PTZ-induced clonic seizures in mice. FPIA documented that TGB significantly elevated brain ETS concentrations (by 64%), while having no effect on plasma ETS concentrations in experimental animals. In contrast, ETS had no significant impact on plasma and brain concentrations of TGB in mice, as measured by HPLC. It can be concluded that the additive interaction between TGB and ETS at the fixed-ratio of 1:1 in the PTZ test was complicated by a significant pharmacokinetic increase in total brain ETS concentrations. At present, there are no recommendations to use this drug combination in epileptic patients.     

Antiarrhythmic effect of aprindine on several types of ventricular arrhythmias.

The antiarrhythmic effect of aprindine was compared with those of lidocaine and propranolol on several ventricular arrhythmias-epinephrine arrhythmias in cats, ouabain arrhythmias in cats and guinea pigs, ischemic ventricular arrhythmias in coronary-ligated Beagle dogs. Antiarrhythmic effects of aprindine and lidocaine were observed both in ouagain and ischemic arrhythmias, but not in epinephrine arrhythmias. While propranolol had a strong antiarrhythmic effect against epinephrine and ouabain arrhythmias, it did not increase sinus beats in ischemic arrhythmias. Marked anti-arrhythmic effects of aprindine in ischemic arrhythmias were observed in dogs using either single intravenous administration (4 mg/kg) or intravenous infusion (200 mug/kg/min, 2 mg/kg). Antiarrhythmic activity of aprindine is considered to be about twice as strong as that of lidocaine, but lidocaine is less toxic in experimental animals.     

氟喹诺酮类药物引致癫痫发作54例的国内文献回顾

目的:了解氟喹诺酮类药物引致癫痫发作的发生情况及临床特点。方法:收集与分析中国生物医学文献数据库(1978-01-2006-06)及中国医院数字图书馆期刊全文库(1994-01-2006-06)中氟喹诺酮类药物所致癫痫发作病例。结果:氟喹诺酮类药物所致癫痫发作54例,男性31例,女性23例,其中5例有癫痫史。引起癫痫发作的常见药物依次为环丙沙星、氧氟沙星、左氧氟沙星、诺氟沙星等。静脉给药43例,口服7例,4例不明。6例合用茶碱制剂。54例中,47例为全面性强直阵挛发作,7例为部分发作,发作的开始时间在用药后10min至6d。发作持续时间为20s至10min,发作次数为1～5次。54例中除1例死于脑胶质瘤、脑梗死外,其余患者均在停药或对症治疗后好转出院。结论:静脉或口服应用氟喹诺酮类药物均可引致癫痫发作。临床医生应了解氟喹诺酮类药物所致癫痫发作的危害以利于安全用药。     

硫酸镁注射液对乌头碱中毒致室性心律失常的临床疗效观察

目的观察硫酸镁注射液用于乌头碱中毒致室性心律失常患者的临床疗效。方法回顾性分析我院收治的乌头碱中毒患者,共纳入64例患者,均常规静脉注射阿托品,静脉使用利多卡因。其中32例患者在以上基础上静脉使用硫酸镁注射液,32例未静脉使用硫酸镁注射液作为对照组,比较二组之间室性心律失常得到控制时间。结果静脉使用硫酸镁组患者平均室性心律失常控制时间为(1.1±0.5)h,对照组平均室性心律失常控制时间为(2.3±0.7)h,两组之间差异有统计学意义(P<0.05)。结论静脉使用硫酸镁注射液对乌头碱中毒所致室性心律失常有明显抑制作用。     

Target pharmacology of topiramate, a new antiepileptic drug

Topiramate is a novel antiepileptic drug, a fructopyranose derivative. In animal studies, topiramate suppresses maximal electroshock seizures, whereas it does not exert inhibitory effects on pentylenetetrazol-induced seizures. Since topiramate hardly affects the threshold of the seizure, topiramate has been believed to be a type of antiepileptic drug that blocks spread of seizures. Thus far, the mechanisms of its actions have been proven to include use-dependent inhibition of voltage-dependent Na+ channels in neurons, potentiation of GABA (gamma-amino-butyric acid)-induced Cl- influx, and inhibitory effects on inward currents by antagonizing kainate/alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. In clinical studies conducted overseas, topiramate has been demonstrated to be effective in the treatment of partial seizures etc. In 55 countries including UK and USA, topiramate has been already approved for the clinical use as a drug for partial seizures, while a phase III study has been planned in Japan, using patients with symptomatic localization-related epilepsies.     

Rapid estimation of unbound lidocaine clearance in cardiac patients: implications for reducing toxicity

The clearance (CL), volume of distribution (Vd) and elimination half-life (t1/2), based on unbound and total concentration-time data, were estimated using two serum lidocaine concentrations drawn approximately 6 and 12 hours after the initiation of continuous intravenous lidocaine therapy in nine patients with myocardial infarction (MI) (in the immediate postinfarct period) and in 12 patients with ventricular arrhythmias. No significant intergroup differences were found for any of the parameters based on unbound or total lidocaine concentration-time data. A significant (P less than .01) correlation was found between measured unbound lidocaine and unbound lidocaine concentrations predicted using alpha-1-acid glycoprotein (AAGP) and total serum lidocaine concentrations. However, the predicted values were significantly lower than the measured values for both groups (P less than .001). Significant correlations were found between total and unbound volumes of distribution and between total and unbound clearances. Coefficients of determination (r2) for these correlations were 0.6906 and 0.9178 respectively. The relationship between total and unbound clearance allows rapid estimation of unbound clearance from two total serum lidocaine concentrations. Unbound clearance can then be used to determine patient-specific maximum infusion rates and reduce the risk of central nervous system toxicity from lidocaine.     

A comparison of intravenous and subarachnoid lidocaine pharmacokinetics in the rhesus monkey

A comparative study between intravenous and subarachnoid lidocaine in the rhesus monkey was conducted in an effort to compare the kinetics of lidocaine in the monkey with reported intravenous human data, and to determine the rate and extent of systemic absorption of lidocaine following subarachnoid injection. Each animal received an intravenous and subarachnoid treatment in an effort to determine the fraction of drug absorbed. Pharmacokinetic parameters were calculated for each animal based on arterial blood concentrations of lidocaine. In the case of the intravenous data, a standard two- compartment model was used. Subarachnoid injections were evaluated by fitting data to an extravascular one-compartment model and by analog computer fitting of the blood level data to an extravascular two-compartment model. Data for both intravenous and subarachnoid injection were also analysed independent of compartment model.     

Treatment of partial seizures in childhood : an overview

The treatment of partial seizures in children is based on the use of first generation and recently introduced antiepileptic drugs as well as nonpharmacological treatments such as the ketogenic diet, vagus nerve stimulation and surgical therapy. The present review discusses the efficacy and tolerability of different treatment options for partial seizures in childhood. Few adjunctive or monotherapy, placebo-controlled or comparative trials of the first-generation antiepileptic drugs and some of the more recently introduced antiepileptic drugs have been performed in children. This can be explained by the fact that it is only relatively recently (1989) that the International League against Epilepsy proposed that randomised, controlled trials be included among the required criteria for assessing the efficacy and tolerability of an antiepileptic agent. This led to controlled, comparative trials among older antiepileptic drugs (phenobarbital, phenytoin, carbamazepine and valproic acid), both in adults and in paediatric patients, being performed relatively 'late', based on when these drugs were first introduced. Carbamazepine and valproic acid may still be considered as first-line antiepileptic therapies for children with partial seizures. Phenobarbital and phenytoin are mostly considered as last choice drugs because of their adverse event profiles. The new generation of antiepileptic agents has added to the first- and second-line treatment options for paediatric partial seizures. To date, there are sufficient data to support the clinical use of some of the recently introduced antiepileptic drugs (e.g. oxcarbazepine, topiramate, gabapentin and lamotrigine) as adjunctive or first-line monotherapy. Because of the risk of visual field constriction with vigabatrin, the use of this drug is currently limited to patients refractory to other medications. Tiagabine, felbamate, levetiracetam and zonisamide have been shown to be effective in adults with partial seizures; however, at present there are not yet enough data on the efficacy of these drugs in children to support consideration of their use as either first-line or add-on therapy in this patient population, although controlled studies are expected shortly. Furthermore, the use of felbamate is considerably limited by rare, but severe, hepatic and haematological toxicity. Controlled trials for paediatric partial seizures are still lacking for the ketogenic diet and vagus nerve stimulation, though they may represent, in given patients, useful adjunctive alternative treatments for refractory partial seizures. In conclusion, further trials are needed to determine an optimal sequence of first- and second-line therapies and to establish whether other newer antiepileptic drugs merit consideration as initial therapy in children with partial seizures.