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PubMed2002

Use of anticonvulsants for treatment of neuropathic pain.

Emerging evidence from animal models of neuropathic pain suggests that many pathophysiologic and biochemical changes occur in the peripheral and central nervous system. Similarities between the pathophysiologic phenomena observed in some epilepsy models and in neuropathic pain models justify the use of anticonvulsants in the symptomatic management of neuropathic pain. Positive results from laboratory and clinical trials further support such use. Carbamazepine was the first of this class of drugs to be studied in clinical trials and has been longest in use for treatment of neuropathic pain. Clinical trial data support its use in treating trigeminal neuralgia, but data for treatment of painful diabetic neuropathy are less convincing. Use of newer anticonvulsants has marked a new era in the treatment of neuropathic pain. Gabapentin has demonstrated efficacy, specifically in painful diabetic neuropathy and postherpetic neuralgia. Lamotrigine has been reported to be effective in relieving pain from trigeminal neuralgia refractory to other treatments, HIV neuropathy, and central post-stroke pain. Results from clinical trials of phenytoin are equivocal. Zonisamide's mechanisms of action suggest that it would be effective in controlling neuropathic pain symptoms. Other anticonvulsants, including lorazepam, valproate, topiramate, and tiagabine, have also been under investigation. Anecdotal experience provides support for studies with oxcarbazepine and levetiracetam for treating neuropathic pain. Evidence supporting the efficacy of anticonvulsants in treatment of such pain is evolving. Additional clinical trials should provide information that will better define their role in neuropathic pain.

Acetates↗
PubMed2004

Influence of coadministered antiepileptic drugs on serum phenobarbital concentrations in epileptic patients: quantitative analysis based on a suitable transforming factor.

This study investigated most suitable transforming factor related to the daily Phenobarbital dose (D) providing a steady-state serum concentration (Ct) and analyzed the influences of concomitant antiepileptic drugs on Ct quantitatively. Data obtained by routine therapeutic drug monitoring from a total of 326 epileptic patients treated with multiple oral administrations of phenobarbital (PB) as a powder, were used for the analysis. A total of 156 patients were administered PB alone, and 92, 57, and 21 patients were coadministered one, two, and three different antiepileptic drugs, respectively. Valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), zonisamide (ZNS), clonazepam, and ethosuximide were coadministered with PB. For administration of PB alone, four types of transforming factor corresponding to clearance, i.e., total body weight, total body water volume, body surface area and extracellular water volume (VECW) were proposed. With VECW as a transforming factor, the level/dose (L/D) ratio (:Ct/(D/VECW)) was independent of the patient's age and gender. Ct was dependent on only one variable regarding D/VECW and expressed as Ct=0.989 x (D/VECW). The coadministration of one drug caused a difference in the gradient of the regression line of PB alone, and the influence of each drug was detected by dividing each mean L/D ratio of PB plus one other drug by that of PB alone. VPA, CBZ, and PHT significantly increased (p<0.01) the L/D ratio to 1.48, 1.35, and 1.23 of the value for PB alone, respectively. With coadministration of multiple drugs, the L/D ratio rose significantly (p<0.05) as the number (< or =2) of drugs coadministered increased regardless of the type, and also increased with the concomitant use of 3 drugs compared with 2 drugs. For a more detailed analysis, we defined the parameter eta(i) (i=1, 2, ..., 6) and an alteration ratio Ri, representing the influence of each antiepileptic drug on the L/D ratio of PB alone. A model based on the assumption that each coadministered drug competitively inhibited PB-metabolizing enzyme, was adopted. The analysis clarified that VPA, CBZ, and PHT significantly increased (p<0.05) the L/D ratio of PB to 1.466, 1.177, and 1.186, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated L/D ratios were calculated using the value of each Ri and compared with the measured value. The mean of prediction error was calculated as 23.1%. Our results appear valid and Ri should be available for clinical use.

Adolescent↗
PubMed2004

Newer anticonvulsants in the treatment of bipolar disorder.

The anticonvulsants valproate and carbamazepine have efficacy in treating acute mania, but their efficacy in treating acute bipolar depression and preventing mood episodes remains uncertain. Despite this, and given their utility and widespread use, both are widely accepted as standard treatments for bipolar disorder. All the newer anticonvulsants that have become available during the last decade have been or are being assessed to determine their efficacy in the treatment of various phases of bipolar disorder. Among the newer anticonvulsants, some appear to have efficacy in treating core bipolar symptoms, while others have efficacy in treating psychiatric comorbidity such as substance abuse or an anxiety disorder. Lamotrigine is the most widely studied and is effective in treating and preventing bipolar depression, and it is the only anticonvulsant approved by the U.S. Food and Drug Administration as a maintenance treatment for bipolar disorder. Other newer anticonvulsants, levetiracetam, oxcarbazepine, phenytoin, and zonisamide offer promise, but further studies are required before they can be recommended for routine use to treat bipolar disorder. Gabapentin and topiramate do not appear to have efficacy in treating acute mania, but their utility in bipolar depression and prevention of mood episodes has not been studied in double-blind trials. Pregabalin has utility in treating generalized anxiety disorder, but it has not been studied in bipolar disorder. Given the success of lamotrigine in treating bipolar disorder, further double-blind controlled trials of the newer anticonvulsants in treating bipolar disorder are warranted. This article summarizes current evidence from trials of anticonvulsants in bipolar disorder and makes recommendations for their clinical use.

Acetates↗
PubMedDate not supplied

Antiepileptic drugs in migraine prophylaxis: state of the art.

Antiepileptic drugs have proven their efficacy in the prophylactic treatment of migraine. Our study comprises a clinical trial that examines the efficacy of gabapentin and topiramate and a description of the pharmacologic characteristics and the efficacy of tiagabine, lamotrigine, levetiracetam and zonisamide. Antiepileptic drugs have multiple modes of action which can explain their efficacy in reducing neuronal excitability which is proven in epilepsy and postulated in migraine. The relationship between epilepsy and migraine has, in fact, been much debated but never convincingly proven. Antiepileptic drugs could be useful in migraine prophylaxis as some of these have determined a reduction in the monthly frequency and intensity of crises in subjects suffering from migraine with and without aura. These are the aims that have been proposed by the U.S. Headache Consortium Evidence-Based Guidelines. Further double-blind placebo-controlled studies are necessary in order to assess their safety and efficacy.

Acetates↗
PubMed1992

[Effect of anticonvulsants upon experimental limbic seizure status and regional cerebral blood flow in the hippocampus].

Continuous monitoring of regional cerebral blood flow (rCBF) of the hippocampus was made during limbic seizure status in cats by means of a heat clearance method with a calibration method by an electrolytic hydrogen clearance method. A stereotaxic operation was made under Nembutal anesthesia. Local anesthetics were applied to the painful area. Femoral artery and vein were cannulated and served for arterial blood pressure monitoring and drug injection, respectively. Tracheostomy was made and ventilated artificially. A double cannula was inserted to the amygdala and fixed to the skull with a dental cement. Electrodes for heat clearance method, electrolytic hydrogen clearance method and EEG recording were inserted to the dorsal hippocampus. Limbic seizure status was induced by kainic acid microinjection (2 ug) into amygdala via implanted cannula. Baseline rCBF was measured in each cats. Continuous monitoring of rCBF was made before and after intravenous administration of anticonvulsants such as zonisamide (ZNS), valproic acid (VPA), diazepam (DZP), phenobarbital (PB) and phenitoin (PHT). Physiological saline (PHS) was injected for controls. Injection of DZP resulted in strong seizure suppression with decrease of arterial blood pressure and hippocampal rCBF. Intravenous PB demonstrated analogous action with DZP with a mild anticonvulsant effect. Intravenous ZNS or VPA resulted in inhibition of seizure propagation from limbic system to cortex. However, these drugs augmented rCBF of the hippocampus more than 2 hours after administration. PHT and PHS demonstrated no anticonvulsant effect nor rCBF change in the present study.

Animals↗
PubMed1995

[New antiepileptic medications].

Progress made in the development of new antiepileptics (AEs) is justified by the high percentage of refractory patients to the available medical therapy (25%), although only a minority of cases are deemed suitable for surgical therapy. Yet, the ideal AE, that is, with a well-known mechanism of action, effective in monotherapy for all epileptic fits, with a perfect pharmacokinetic profile, with no adverse or teratogenic effects, with no drug interactions and available under many formulations, is far from being developed. The new AEs arise either from modification of already marked drug molecules or clinical formulations or from the effectiveness on the excitatory/inhibitory balance of the major neurotransmitters involved in the pathogenesis of seizures, the gamma-amino-butyric acid (GABA) as the inhibitory, and the glutamate (GLU) as the excitatory one. However, the mechanism remains unknown in a few of them. Those new AEs already marketed in Portugal (Vigabatrin), soon to be (Lamotrigine, Oxcarbazepine) or available abroad only (Gabapentin, Zonisamide) are review with special emphasis on their pharmacokinetic profile, side effects, interaction with other AEs, and clinical use. In conclusion, these new drugs have brought a very important advancement in the management of refractory patients, but the development of well-designed comparative trials involving both monotherapy and polytherapy has become important in order to develop useful strategies in the drug management of epilepsy.

Acetates↗
PubMed1997

[A case of cortical reflex myoclonus manifesting tremor].

A 58-year-old woman developed slowly progressive tremulous myoclonus provoked mainly by action and posture. She had neither seizure nor dementia. No one in her family had similar symptoms. The presence of giant somatosensory evoked potentials (SEP) with enhanced long loop reflex and premovement cortical spikes demonstrated by the jerk-locked averaging method suggest that the involuntary movement is cortical reflex myoclonus. Magnetoencephalogram revealed that the generator sources of giant SEPs were the post-central somatosensory cortex and probably also the pre-central motor cortex. Symptoms improved after treatment with zonisamide, clonazepam and valpolate. This kind of involuntary movement might be called cortical myoclonic tremor.

Anticonvulsants↗
PubMed1998

[Experience in managing refractory status epilepticus caused by viral encephalitis under long-term anesthesia with barbiturate: a case report].

This is a case study in managing refractory status epilepticus under long-term usage of secobarbital (SB). The patient is a 26-year-old woman with viral encephalitis. Fifteen days after the onset of the disease, status epilepticus with complex partial seizures began. The seizures were so refractory to conventional anti-epileptic drugs, such as valproate, carbamazepine, phenytoin, phenobarbital, clonazepam, lorazepam and lidocaine, that we had to put her on anesthesia with SB for approximately 10 months. Finally, we stopped the administration of SB and support for ventilation; we reduced the dose of SB extremely slowly, using zonisamide at the same time. After trial and error, we found that a reduction of the dosage after long-term anesthesia with high-dose administrations of barbiturate should be made very slowly.

Adjuvants, Anesthesia↗
PubMed2000

Treatment of epilepsy in the multiply handicapped.

The medical management of epilepsy in the multi-handicapped patient requires careful evaluation, classification, and pharmacologic treatment. It is estimated that 20-40% of patients with mental retardation and cerebral palsy have epilepsy. This review reports the clinical trial data and personal experience related to the use of newer AEDs in the chronic management of epilepsy syndromes in children and adults, as well as information available on the treatment of seizures in individuals with mental retardation and associated handicaps. Furthermore, clusters of seizures, prolonged seizures and status epilepticus are more commonly seen in the multiply handicapped and mentally retarded population and require special attention. The new antiepileptic drugs felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide show specific advantage in some multiply handicapped patients, be it for seizure control or medication tolerance. Furthermore, new modalities of treatment for prolonged seizures allow better efficacy both outside of hospital and within hospital facilities. The treatment of epilepsy in multi-handicapped and retarded adults and children has significantly advanced in the past few years, and much of this improvement can be attributed to improved knowledge and monitoring of new antiepileptic drugs. Conventional anticonvulsants remain first line therapy for most clinicians, but newer AEDs must broaden the therapeutic option and do allow improved therapy for some multiply handicapped patients.

Anticonvulsants↗
PubMed2000

The effect of alcohol on convulsions and nitric oxide levels in seizure-susceptible el mice.

To evaluate the influences of ethanol intake on convulsive seizures and brain nitric oxide (NO) production, EL mice, a strain highly susceptible to seizures, were given a 10% ethanol solution ad libitum. In mice consuming ethanol for 4, 8, and 12 weeks, seizures were not suppressed by zonisamide (75 mg/kg ip). Brain NO metabolite levels in mice after 12 weeks of consumption were significantly lower than those in control mice and those consuming ethanol for 4 weeks. Numbers of NADPH diaphorase-positive neurons in the hippocampal formation and parietal cortex of mice consuming for 4 and 12 weeks were significantly higher than in controls. These results suggested that increasing of numbers of NADPH diaphorase-positive neurons in the hippocampal formation and parietal cortex were assumed to develop in compensation for reduction in whole-brain NO metabolite levels of EL mice exposed to ethanol.

Journal Article↗
PubMed1993

The clinical pharmacology of the new antiepileptic drugs.

Conventional anticonvulsants have important limitations in terms of efficacy and tolerability, and there is a clear need for new agents to be developed. After a quiescent period which lasted for more than two decades, several promising new compounds have undergone clinical evaluation and a few of these (vigabatrin, lamotrigine, oxcarbazepine, zonisamide) are now commercially available in some countries. Some of the new agents represent structural analogues of pre-existing drugs in an attempt to improve the therapeutic index of the latter (e.g., oxcarbazepine), while others were rationally designed to interfere selectively with inhibitory (vigabatrin) or excitatory (NMDA receptor antagonists) neurotransmission in the brain. Many other compounds were discovered more or less serependitiously and their mode of action is poorly understood. The present article provides a concise review of the clinical pharmacology of the new anticonvulsants which have undergone most extensive clinical testing in patients with epilepsy. Topics discussed include clinical pharmacokinetics, drug interactions, efficacy data in selected epileptic syndromes or seizure types, and adverse effects profile. Although the precise role of these new agents in the overall management of epilepsy remains to be clearly defined, their availability already provides a valuable tool which can be usefully exploited to improve prognosis, especially in patients with the more severe forms of the disease.

Anticonvulsants↗
PubMed2005

Alteration of thyroid hormone homeostasis by antiepileptic drugs in humans: involvement of glucuronosyltransferase induction.

RATIONALE: The aim of this review article is to analyse which antiepileptic drugs (AEDs) alter thyroid hormone homeostasis in humans and when this can be explained, at least partially, by the induction of the glucuronoconjugation pathways. METHODS: Electronic databases were searched which have provided more than 300 articles. These have been integrated with fundamental books and personal information by experts in the different areas examined. RESULTS: Alteration of thyroid hormone homeostasis by phenobarbital/primidone, phenytoin, and carbamazepine clearly occurs in humans. However, it is not associated with thyroid-stimulating hormone (TSH) increase and the clinical significance of altered serum concentrations of thyroid hormones by these antiepileptic drugs has remained unclear. The published information on the effect of the other antiepileptic drugs examined in this review article on thyroid hormones is lacking (felbamate, pregabalin, zonisamide) or limited. Oxcarbazepine appears to have some effects. Topiramate would need further investigations as well as gabapentin. Levetiracetam, tiagabine, vigabatrine, and lamotrigine do not alter at all, or only minimally, thyroid hormone homeostasis. CONCLUSION: Concerning the antiepileptic drugs which alter thyroid hormone homeostasis, it is highly probable that the mechanism of induction of uridine diphosphate glucuronosyltransferases (UGT) is involved, at least partially, in such an alteration. However, it is not possible to estimate the relative contribution of the UGT induction by these drugs on the total alteration observed in thyroid hormone levels, as other mechanisms not investigated, or not examined in the present article, could contribute.

Anticonvulsants↗
PubMed2005

Effect of antiepileptic drug monotherapy on urinary pH in children and young adults.

OBJECTS: Since alkaline urine is a risk factor for urolithiasis, the relationship between antiepileptic drugs and urinary pH was retrospectively studied in epilepsy patients treated with antiepileptic drug monotherapy for more than 1 month. METHODS: A total of 913 urinary samples from antiepileptic drug-treated patients were compared with 780 age-matched control samples, and with 112 samples from epilepsy patients who had not been treated with antiepileptic drugs. The antiepileptic drugs administered were carbamazepine, valproate, phenobarbital, zonisamide, sulthiame, and phenytoin. CONCLUSIONS: The proportion of the acid urine in the valproate-treated patients was lower than that in controls. The proportion of the alkaline urine in the valproate-treated patients was higher than that in controls. This effect was independent of age, sex, and the serum valproate concentration. There was no significant difference in urinary pH among the epilepsy patients treated with other antiepileptic drugs, the epilepsy patients who had not been treated with antiepileptic drugs, and the controls.

Adolescent↗
PubMed2004

Drug selection for the newly diagnosed patient: when is a new generation antiepileptic drug indicated?

Treatment options in epilepsy have increased dramatically since the early 1990s with the introduction of nine new generation antiepileptic drugs (AEDs) (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide). This makes drug selection much more complicated and challenging. This review discusses drug selection in patients with newly diagnosed epilepsy and in particular the role of new AEDs in this population. The choice of treatment should always be based on a careful comparison of the risk-benefit ratio for the different treatment options and the outcome of such evaluation may be different in patients with new onset compared with chronic epilepsy. Efficacy, tolerability and safety are the main criteria for selection of AEDs and any first line drug for patients with newly diagnosed epilepsy must have demonstrated satisfactory efficacy as monotherapy in that patient population. So far, of the new AEDs only lamotrigine, oxcarbazepine and topiramate have documentation sufficient to be granted licence for use as monotherapy in most European countries. Because the new generation AEDs have failed to demonstrate improved effectiveness as monotherapy, old generation AEDs such as carbamazepine and valproate remain drugs of first choice for partial and generalised seizures, respectively. However, there are special situations and populations where a new AED may be a reasonable first line drug. These include vigabatrin in West syndrome associated with tuberous sclerosis, lamotrigine as alternative to valproate in idiopathic generalised seizures in women of childbearing potential and lamotrigine for the treatment of epilepsy in the elderly population. The role of the new generation AEDs is likely to become more prominent as more experience is gained.

Anticonvulsants↗
PubMed2004

Prophylactic migraine therapy: emerging treatment options.

In this paper, new treatment options for migraine prevention are reviewed. An overview about migraine pathophysiology is provided and current indications for migraine prevention and new and upcoming preventive medications are discussed briefly. Data are presented on topiramate, levetiracetam, zonisamide, botulinim toxin, tizanidine, nefazodone, lisinopril, candesartan, carabersat, petasites, and coenzyme Q.

Central Nervous System Agents↗
PubMed2006

New findings from the Bipolar Collaborative Network: clinical implications for therapeutics.

In this article, we highlight recent Bipolar Collaborative Network data. We found that childhood-onset bipolar illness is common, often goes untreated for more than a decade, and carries a poor prognosis. During randomized studies of adjunctive medications in depression: 1) Venlafaxine showed higher switch rates than bupropion or sertraline; 2) Tranylcypromine was as well tolerated as lamotrigine; and 3) Modafinil was more effective than placebo. Finally, in treatment of overweight and obesity, topiramate and sibutramine showed equal efficacy but poor tolerability, and zonisamide data showed that it may be useful for mood and weight loss.

Adult↗
PubMed2002

Progressive Myoclonic Epilepsies.

The treatment of progressive myoclonus epilepsy (PME) remains a major therapeutic challenge in neurology. Generalized convulsive seizures are often well controlled through classic antiepileptic drugs (AEDs) like valproate and clonazepam, whereas myoclonus, the main symptom that is affecting patients most in their daily life, is usually refractory to standard AEDs. Alternative therapy concepts have been and still are investigated. Among the new drugs, zonisamide and piracetam have shown the most promising results as add-on treatments. Other therapeutic approaches, like the use of antioxidants, 5-hydroxytryptophan (5-HTP), and baclofen should also be taken into consideration for the treatment of intractable cases of PME. Nonpharmacologic treatment options such as diet and physical therapy should always be considered, because they may save costs and side effects. In some instances, the occasional use of alcohol has shown beneficial effects.

Journal Article↗
PubMed2004

Single Unprovoked Seizures.

Unprovoked seizures are common, affecting approximately 4% of the population by age 80. Only approximately 30% to 40% of patients with a first seizure will have a second unprovoked seizure (ie, epilepsy). Treatment with antiepileptic drugs (AEDs) should not be initiated unless the diagnosis of a seizure is firm. Decisions regarding treatment of single unprovoked seizures must balance seizure recurrence risk, the potential impact of a recurrent seizure, the likelihood of adverse effects of treatment, and patient preference. Risk factors for seizure recurrence include a history of remote neurologic insult, epileptiform abnormalities on electroencephalogram, focal structural lesion on neuroimaging, and family history of epilepsy. Adult patients with these risk factors have a recurrence risk of 60% to 70% and usually should be treated with an AED to prevent seizure recurrence. Without risk factors, the recurrence risk is 20% to 30%, and treatment depends on individual risk-to-benefit ratios and patient preference. Treatment of a first unprovoked seizure is often not necessary in childhood, especially if the seizure is part of a benign self-limited syndrome, such as benign Rolandic epilepsy of childhood. Treatment with an AED reduces the risk of seizure recurrence after a single unprovoked seizure. This must be balanced against the risk of adverse effects of AEDs. Treatment of the first seizure does not appear to affect the long-term prognosis of epilepsy. The choice of an AED should be guided by the seizure type and likely epilepsy syndrome diagnosis. Monotherapy is preferable. Standard AED options include phenytoin, carbamazepine, valproate, and phenobarbital. The newer AED, including gabapentin, lamotrigine, topiramate, oxcarbazepine, levetiracetam, and zonisamide, have good efficacy, favorable pharmacokinetic profiles, and often fewer adverse effects, supporting their use early in treatment. Not all of the newer AEDs are approved for use as monotherapy. Patients with single seizures should be counseled about seizure first aid and general safety measures, including precautions regarding swimming alone, engaging in high-risk activities, driving, possible seizure precipitation by photic stimuli (in generalized epilepsy), sleep deprivation, and alcohol.

Journal Article↗