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PubMed1984

Drug utilization study of antiepileptics in Hungary.

This paper describes drug utilization review activities on anticonvulsant drugs in Hungary. Data on the use of phenytoin, carbamazepine, primidone, and sulthiam in the 20 administrative regions of the country are presented. From 1971 to 1980, consumption of these anticonvulsants doubled, and most of them were used in combination therapy. Estimates of the numbers of epileptics in the country were calculated from data on the international incidence of epilepsy and from total drug consumption data in Hungary.

Anticonvulsants↗
PubMed1976

[Paroxysmal epileptic headache].

Epileptic paroxystic headache consists of an episode of pain that starts suddenly, in a varying area that is usually the same for the same patient, of medium to high intensity, lasting from a few seconds to minutes and, rarely, hours; the episode subsides spontaneously and tends to recur. This was found in 32 of 125 patients studied by the author. Average age of onset was 11 years, with 80% of cases presenting it in the first or second decade of life. Once diagnosed, the condition was present a maximum of 41 years and a minimum of one month, with an average of six years. Headache lasted from 30 seconds to 4 hours; in 62% of cases it was 15 minutes or less. Pain was severe in 24 patients and moderate in 8. Epileptic paroxystic headache can be the only epileptic symptom (31%) or be associated with other ictal manifestations, independently (56.2%) or simultaneously (12.5%). EEG studies showed focalization in temporal lobe (56%), in the midbrain (12.5%) or in other areas. Treatment with hydantoine, primidone and methylsuccimide gave excellent results. Differential diagnosis with other paroxystic headaches is noted.

Adolescent↗
PubMedDate not supplied

[Pharmacological basis for withdrawal of antiepileptic drugs].

OBJECTIVE: To review the pharmacological basis for withdrawal of antiepileptic drugs: the mechanisms by which seizures reappear, aspects of treatment which affect relapses and procedures for withdrawal of medication. DEVELOPMENT: Antiepileptic drugs are not curative, so when they are withdrawn the natural course of the condition becomes evident. Reappearance of seizures may be due to lack of protection and/or an abstinence syndrome. Seizures due to lack of protection occur following withdrawal of any antiepileptic drug when the epilepsy is not cured; they may not reappear for years (although over 80% occur within a year) and treatment then has to be restarted. They seem to be less frequent after withdrawal of carbamazepine or phenytoin than after withdrawing valproate, although the reason for this is not understood. Seizures due to an abstinence syndrome only occur after withdrawing benzodiazepines, phenobarbitone and primidone; they are seen in patients with both active and inactive epilepsy whilst the drug is being withdrawn and tend to be self-limiting. It is not necessary to reintroduce the drug when epilepsy is cured. Felbamate and vigabatrin cause seizures related to their withdrawal, but the mechanism of this is not clear. There is no scientifically established guideline for withdrawing antiepileptic drugs, but it is considered important to stop one at a time, starting with those which may cause abstinence syndromes, followed by the more toxic, less effective antiepileptic drugs, which cause more drug interactions and are more awkward to take. CONCLUSION: Further specific studies are necessary to establish the mechanisms of relapses and the scientific basis for withdrawal of antiepileptic drugs.

Adult↗
PubMed2000

Pharmacokinetic properties of current antiepileptic drugs: what improvements are needed?

The pharmacokinetics of antiepileptic drugs (AEDs) largely determine their ability to achieve and maintain concentrations that maximize their efficacy and safety. The term "pharmacokinetics" encompasses the quantitative assessment of changes of drug concentrations over time as a function of absorption, distribution, and elimination. Interaction among AEDs, and between AEDs and other classes of drugs, can result in undesirable drug levels. The pharmacokinetic properties of AEDs considered to be clinically most relevant include complete or constant bioavailability, availability of a parenteral formulation, elimination half-life or preparation suitable for once- or twice-daily dosing, linear elimination kinetics, no autoinduction of enzymatic biotransformation, and lack of pharmacokinetic interactions with other drugs. Both established AEDs (carbamazepine, phenytoin, valproate, phenobarbital, and primidone) and newer AEDs (oxcarbazepine, felbamate, gabapentin, lamotrigine, topiramate, tiagabine) are evaluated in terms of these properties. None of the currently marketed AEDs combines all of these desirable pharmacokinetic characteristics. However some of the newer AEDs have more favorable pharmacokinetic profiles. The main improvements needed are limited or no pharmacokinetic interactions, preparations suitable for once- or twice-daily administration, and availability of parenteral formulations.

Anticonvulsants↗
PubMedDate not supplied

Prolonged anticonvulsant hypersensitivity syndrome related to lamotrigine in a patient with human immunodeficiency virus.

Anticonvulsant hypersensitivity syndrome (AHS) is a rare, potentially life-threatening allergic disorder, which is well described in relation to many aromatic anticonvulsants. Lamotrigine is a relatively new aromatic anticonvulsant agent that is thought to act on voltage-dependent sodium channels. Initially, it was licensed as add-on therapy for seizures inadequately controlled by other medications. However, its use has been broadened to other indications, including stand-alone therapy for seizures as well as for bipolar disorder. There is extensive experience with hypersensitivity syndromes related to phenytoin, carbomazepine, primidone, and phenobarbital, but fewer reactions have been reported to lamotrigine because of its relatively recent release. Patients with human immunodeficiency virus (HIV) have a higher rate of adverse reactions to many medications. It is unknown if they react more commonly to anticonvulsants such as lamotrigine. It is also unknown if the syndrome lias a tendency to be more severe or prolonged in such patients. The diagnosis of AHS may be particularly elusive in patients with HIV because its common features can easily be confused with an infectious etiology. We report the occurrence of a prolonged hypersensitivity syndrome likely related to lamotrigine in a 32-year-old female with HIV and review the literature regarding this condition.

Adult↗
PubMed2003

Clinical features, assessment and treatment of essential tremor.

Essential tremor is the most common of the movement disorders, being 20 times more common than Parkinson's Disease. It is characterised by postural and kinetic tremor which maximally affects the hands. It can be assessed by physiological techniques, subjective clinical methods, objective clinical methods and handicap/disability scales. Accelerometry, spirography and handwriting assessment, volumetry and handicap/disability questionnaires are commonly used methods. Primidone and propranolol are the first-line drugs. Several second-line drugs have been identified. Surgical techniques include lesioning or stimulation of the ventral lateral thalamus. Alcohol and botulinum toxin A are found to reduce tremor amplitude as well.

Essential Tremor↗
PubMed2003

Orthostatic tremor: report of a case and review of the literature.

Orthostatic tremor is a rare movement disorder characterized by tremulousness of the lower limbs on standing that disappears on walking, sitting or on lying down and a distinctive electromyographic burst of 14 to 16 Hz. On inspection, fine ripples can sometimes be seen over the quadriceps on standing. The tremor has a tendency to reappear even in the supine posture if the lower limb muscles are put to an isometric contraction state, indicating thereby that in spite of the fact that the tremor occurs on standing, it is essentially 'orthostasis independent' and the central factor is the contraction of the muscles. As a matter of fact, the tremor is abolished if the subject is suspended by harness, thus relieving him of muscle contraction. Doubts are being cast whether it is a variant of essential tremor since a number of families are being reported to be suffering from this disease as well. Positron emission tomography reveals hyperactivity of cerebellum in orthostatic tremor as it shows in essential tremor, therefore lending credence to such a hypothesis. However, lack of response to alcohol, propranolol and primidone in orthostatic tremor stands out as a serious challenge to such a view. Lack of positive family history, synchrony of contracting group of muscles and negative 'resetting' of the tremor by increasing peripheral load-phenomena consistently observed in orthostatic tremor and not in essential tremor, are other features that often help to distinguish between the two conditions. We report a case of orthostatic tremor that presented with the classical clinical and electromyographic features. Relevant literature in this regard is also being reviewed.

Aged↗
PubMed2000

[Establishment of ELISA for measuring phenytoin in serum].

OBJECTIVE: To develop a solid phase, competitive enzyme immunoassay for the measurement of serum phenytoin. METHODS: The chemical modified phenytoin combined with human serum albumin and then conjugated with horseradish peroxidase (HRP) to produce the enzyme labeled phenytoin (DPH-HSA-HRP). The anti-phenytoin antibody was prepared in this lab. RESULTS: The working range and sensitivity of this method were 2.9-30 micrograms/ml and 2.87 micrograms/ml respectively. The intra-assay coefficient of variation (CV) was 3.3%-10.2% (n = 15) and inter-assay CV was 5.1%-13.2%. The recovery of this method was 90%-96%. No significant interference was observed with phenobarbital, primidone, carbamazepine, and valproic acid. The new assay method was compared with HPLC method. A linear regression analysis yielded a slope of 1.03, an intercept 1.38 and a correlation coefficient 0.97. CONCLUSIONS: This solid phase enzyme immunoassay for serum phenytoin appears to be simple, precise, and accurate. It may be readily adopted in clinical laboratory for therapeutic monitoring of phenytoin level in serum.

Chromatography, High Pressure Liquid↗
PubMed2003

The ideal pharmacokinetic properties of an antiepileptic drug: how close does levetiracetam come?

The pharmacokinetic properties of a drug are the primary deter-minant of the extent and duration of drug action, and influence susceptibility to clinically important drug interactions. Most of the older-generation antiepileptic drugs (AEDs) are far from ideal in terms of pharmacokinetics and interaction potential. For example, phenytoin, carbamazepine, and valproic acid exhibit non-linear kinetics; carbamazepine and valproic acid have relatively short half-lives; and most of these drugs cause either enzyme induction (phenytoin, phenobarbital, primidone, carbamazepine) or enzyme inhibition (valproic acid). Compared with older agents, certain new-generation AEDs offer a num-ber of pharmacokinetic advantages, particularly in terms of reduced inter-patient variability in drug clearance and a lower interaction potential. One of the most recently developed of these drugs, levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED: (1) it has a high oral bioavailability, which is unaffected by food; (2) it is not significantly bound to plasma proteins; (3) it is eliminated partly in unchanged form by the kidneys and partly by hydrolysis to an inactive metabolite, without involvement of oxidative and conjugative enzymes; (4) it has linear kinetics; and (5) it is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Although its half-life is relatively short (6 to 8 hours), its duration of action is longer than anticipated from its pharmacokinetics in plasma, and a twice-daily dosing regimen is adequate to produce the desired response.

Acetates↗
PubMed1992

Binding parameters of phenytoin during monotherapy and polytherapy.

The present in vivo study elucidated the effect of other commonly comedicated drugs on the phenytoin (PHT) Scatchard binding parameters. Specimens of 150 epileptic patients chronically treated with anticonvulsant drugs were analyzed. The results of covariance analysis suggest that phenobarbitone, ethosuximide, diazepam and folic acid do not alter binding of PHT to serum albumin. The contribution of carbamazepine and medazepam to the free fraction of PHT (decrease of about 0.4%) and/or Scatchard binding capacity (increase of about 1/3) is ambiguous and not statistically significant at the p less than 0.05 level. On the contrary, we found a statistically significant decrease of PHT binding in patients comedicated with valproic acid (VPA) and primidone (PRM). The decrease of about 25% in binding capacity evoked an increase of about 1% (VPA), and 1.5% (PRM), respectively in PHT free fraction.

Adult↗
PubMedDate not supplied

[Oxcarbazepine induced interstitial nephritis in a patient with drug hypersensitivity syndrome].

INTRODUCTION: Antiepileptic drugs (AED) have long been known to have a series of side effects and descriptions of drug hypersensitivity syndrome (DHS) have often linked it with these agents. This is more especially so in the case of those with an aromatic ring, but also in those that lack such a structure. CASE REPORT: We describe a case of DHS related to the administration of oxcarbazepine (OXC), a ketoanalogue of carbamazepine (CBZ) that has recently appeared on the market in our country, which coursed with interstitial nephritis as the most important clinical manifestation. Our patient developed fever, vomiting, itchy exanthema, kidney failure and biochemical anomalies in the liver after two weeks treatment with this drug. After stopping administration of this anticonvulsant and giving the patient corticoids, the clinical manifestations disappeared and the analytical anomalies began to improve. CONCLUSIONS: OXC can give rise to DHS in the same way as other AED with an aromatic ring structure (phenytoin, phenobarbital, primidone, CBZ and probably also lamotrigine) or without an aromatic ring structure (valproic). Interstitial nephritis may be the most significant and serious clinical manifestation of DHS produced by OXC. According to the review of the literature we carried out, to date no descriptions of this association of nephritis caused by OXC in the context of DHS have been reported.

Anticonvulsants↗
PubMed2004

Antiepileptic drugs: indications other than epilepsy.

Antiepileptic drugs (AEDs) are increasingly used for the treatment of several non-epileptic neurological conditions and psychiatric disorders. Most of the information available on the use of these agents in clinical disorders outside epilepsy is from case series, uncontrolled studies or small randomised clinical trials, and their apparent efficacy requires confirmation through well designed, large, phase III trials. With regard to neurological conditions other than epilepsy, experimental evidence for the efficacy of AEDs is only available for the treatment of patients with trigeminal neuralgia, neuropathic pain syndromes, migraine and essential tremor. Carbamazepine is commonly prescribed as first-line therapy for patients with trigeminal neuralgia. Gabapentin has been recently marketed for the management of neuropathic pain syndromes, particularly diabetic neuropathy and postherpetic neuralgia. Valproic acid (sodium valproate), in the form of divalproex sodium, is approved for migraine prophylaxis. Primidone can be considered a valuable option for the treatment of essential tremor. AEDs are also used to treat psychiatric conditions, in particular bipolar disorder. So far, the most commonly utilized AEDs in the treatment of this disorder have been carbamazepine and valproic acid, which have showed an antimanic efficacy and a probable long-term, mood-stabilizing effect in many bipolar patients, including those refractory or intolerant to lithium. The availability of a new generation of AEDs has broadened the therapeutic options in bipolar disorder. Lamotrigine, oxcarbazepine, gabapentin and topiramate appear to be promising in the treatment of refractory bipolar disorder, as a monotherapy as well as in combination with traditional mood stabilizers. In addition, newer AEDs appear to have a more favourable tolerability and drug interaction profile as compared to older compounds, so thus improving compliance to treatment.

Anticonvulsants↗
PubMed2004

When breastfeeding mothers need CNS-acting drugs.

BACKGROUND: Breastfeeding is the ideal method of infant nutrition. However, if mothers need medications such as the central nervous system (CNS) acting drugs, infant safety concerns arise. Summarized information on infant exposure levels to drugs in milk and associated side effect profiles will help clinicians to rationalize and justify important drug therapy for a breastfeeding patient. METHODS: Electronic searches of MEDLINE and PsycINFO from 1966-2003, and of EMBASE from 1980-2003, were conducted for studies on breastfeeding or breast milk and medications in the following categories: antidepressants, antipsychotics, antiepileptics (or anticonvulsants) and anxiolytics. The infant exposure level (%) was defined as follows: [Drug concentration in milk (mg/mL)] x [Daily milk intake (mL/kg/d)] x 100 / Maternal dose (mg/kg/d). RESULTS: A total of 129 papers were eligible for analyses. Our findings indicate that the majority of the CNS-acting drugs, if taken by nursing women, result in average exposure levels to their breast-fed infants of less than 10% of the therapeutic doses per kg body weight. Exceptions are lithium, ethosuximide, phenobarbital, primidone, lamotrigine and topiramate. Adverse effect profiles do not always correlate with a higher exposure level. Overall, most reported adverse effect profiles appear benign. Where adverse effects were reported, they were often confounded by intrauterine exposure. CONCLUSIONS: CNS-acting drugs taken by the mother do not appear to pose any major risks of immediate adverse effects to the breastfeeding infant, although with most of the newer drugs further research is needed to be conclusive.

Anticonvulsants↗
PubMedDate not supplied

[Population pharmacokinetics of carbamazepine in adults with epilepsy].

The aim of the present study was to determinate the factors affecting carbamazepine (CBZ) clearance (CL) in adults with epilepsy using a mixed-effect model and sparse data collected during routine clinical care. The patient population comprised 104 adults receiving CBZ. A total of 161 CBZ steady state serum concentration samples were analyzed. Population CL was calculated by using NONMEM with a one compartment model with first-order absorption and elimination. The following covariates were tested for their influence on clearance (CL): total body weight, age, dose/day, sex, surface area (SA) and comedication with primidone (PRIM), ualproic acid or phenytoin (DFH). The final regression model for carbamazepine clearance found best to describe the data was: CL = (0.614 SA + 0.0016 dose/day)(1 + 0.278 DFH)(1 + 0.326 PRIM).

Adolescent↗
PubMed1975

Determination of diphenylhydantoin in human serum by spin immunoassay.

A spinn immunoassay for diphenylhydantoin is reported, which appears to give an accurate and precise estimate of serum diphenylhydantoin concentrations, as judged by the disappearance of [14C]diphenylhydantoin from the serum of a rabbit. The assay also appears to be a reliable technique for routine diphenylhydantoin determinations, as judged from our experience with 28 patients. Serum diphenylhydantoin concentrations in the range of 1.0-50.0 mg/liter are easily determined on a 50-mul sample. Except for primidone, no significant cross reactivity was observed with eight drugs that are commonly used in conjunction with diphenylhydantoin therapy. This fast, simple, and precise method therefore appears to be readily applicable to routine determination of diphenylhydantoin.

Animals↗
PubMedDate not supplied

[Generic drugs in the treatment of epilepsy].

AIM: We discuss some controversial aspects with prescription of generic drugs (GD) and the problems concerning bioequivalence, mainly in the case of drugs with non-linear pharmacokinetics and/or narrow therapeutic rank, like the antiepileptic drugs (AED). DEVELOPMENT: There is considerable debate about GD in the treatment of epilepsy, with clearly advantages (cost saving) and disadvantages (loss of seizure control or drug toxicity) in prescribing generics anticonvulsants. We make a systematic review of the literature in primary (PubMed) and secondary (Tripdatabase and Cochrane Library) bibliographic databases in relation to GD and AED. The main information is about classical AED (phenytoin, carbamazepine, valproic acid and primidone) and we don't found studies in this area about the new AED. The level of evidence is, generally, weak, based on case-series and expert opinion without explicit critical appraisal (except in phenytoin with level of evidence moderate, based on some analytical studies). In Spain, at this moment, there are only two generic AED, one-classical (carbamazepine) and one-new (gabapentin). CONCLUSION: The American Academy of Neurology and Epilepsy Foundation maintains that the individual and physician should be notified and give their consent before a switch in antiepileptic medications is made, whether it involves generic substitution for brand name products, or generic to generic substitutions.

Anticonvulsants↗
PubMedDate not supplied

Management of epilepsy and pregnancy.

Epilepsy is recognized as the commonest serious neurological disorder in the world. Women with epilepsy (WWE) experience several gender-related physical and social problems. They constitute high obstetric risk because of reduced fertility, risk of seizures during pregnancy and complications of pregnancy. Hormonal and other factors can alter the pharmacokinetics of antiepileptic drugs (AED) during pregnancy and puerperium. Antenatal exposure to AEDs, particularly at higher dosage and in polytherapy, increases the risk of fetal malformation. Recent reports raise the possibility of selective developmental language deficits and neurocognitive deficits with antenatal exposure to AEDs. There are concerns regarding the effect of traces of AEDs that pass to the infant during breast-feeding. The pre conception management is the cornerstone for epilepsy care in WWE. A careful reappraisal of each case should ascertain the diagnosis, the need for continued AED therapy, selection of appropriate AEDs, optimization of the dosage and prescription of folic acid. During pregnancy, the fetal status needs to be monitored with estimation of serum a-feto-protein and ultrasound screening for malformations. The dosage of AEDs can be adjusted according to clinical requirement and blood levels of AEDs. Several institutions recommend oral vitamin K toward the end of pregnancy when enzyme-inducing AEDs are prescribed because the latter may potentially predispose the new born to hemorrhagic disease, but recent reports indicate that such a risk is practically negligible. WWE who are using enzyme-inducing AEDs (phenobarbitone, primidone, phenytoin, carbamazepine and oxcarbazepine) need to know that these AEDs may lead to failure of oral contraception.

Anticonvulsants↗
PubMedDate not supplied

[Carbamazepine-induced systemic lupus erythematosus--a case report].

Epileptic seizures may be an early symptom of systemic lupus erythematosus, while at the same time some of the epileptic drugs, namely carbamazepine (CBZ), phenytoin (PHT), valproic acid (VPA), ethosuximide (ETM), primidone (PRM), lamotrigine (LTG), zonisamide (ZNS) can cause lupus. A separate clinical problem is the fact that few cases of systemic lupus have as yet been identified by giving antiepileptic drug. We present the case of a 30-year-old woman with frequent simple partial seizures and few secondarily generalized seizures since the age of 18. She was treated with VPA for three years. Then, because of side effects the drug had to be withdrawn and was replaced by CBZ. After eight months duration of the treatment with CBZ, the dose was increased because a secondarily generalized seizure occurred again. After another two months, painful swelling of all joints and leucopenia were observed. During additional studies, LE cells and high titer of ANA antibodies were found. Systemic lupus erythematosus was diagnosed and prednisone therapy was introduced. In spite of the withdrawal of CBZ, the increased titer of ANA antibodies persisted for several years and skin and muscle biopsy performed five years from the onset of clinical symptoms disclosed inflammatory infiltration and presence of IgG and IgM deposits in skin and vessel walls. Control serological examinations, skin and muscle biopsy carried out after eight years of observation and lack of clinical manifestations permitted to exclude a connective tissue disease in our patient.

Adult↗