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Sample records for adverse antiepileptic drug

  1. Cutaneous Adverse Drug Reactions in Dogs Treated with Antiepileptic Drugs

    PubMed Central

    Koch, Tina; Mueller, Ralf S.; Dobenecker, Britta; Fischer, Andrea

    2016-01-01

    Epilepsy is one of the most common neurologic disorders in dogs and life-long treatment with antiepileptic drugs (AED) is frequently required. Adverse events of AED targeting the skin are only rarely reported in veterinary medicine and the true incidence and spectrum of cutaneous reactions in epileptic dogs remains unknown. In this study, we hypothesized that cutaneous reactions commonly occur in epileptic dogs and are related to AED treatment. A retrospective case review of 185 dogs treated for epilepsy identified 20.0% with simultaneous appearance of dermatologic signs. In a subsequent prospective case investigation (n = 137), we identified newly appearing or distinct worsening of skin lesions following initiation of AED therapy in 10.9% of dogs treated for epilepsy (95% CI 6.8–17.7%). Cutaneous lesions were classified as probably drug-induced in 40.0% of these cases. Patch testing and intradermal testing were further investigated as potential diagnostic methods to confirm AED hypersensitivity. They were of high specificity but sensitivity and positive predictive value appeared inappropriate to recommend their routine use in clinical practice. PMID:27148543

  2. Patterns in spontaneous adverse event reporting among branded and generic antiepileptic drugs.

    PubMed

    Bohn, J; Kortepeter, C; Muñoz, M; Simms, K; Montenegro, S; Dal Pan, G

    2015-05-01

    Spontaneous adverse event reports constitute an important source of information on previously unknown adverse reactions to marketed medicines. However, the dynamics of such reporting following generic introduction are poorly understood. Using adverse event reports on five antiepileptic drugs from the US Food and Drug Administration's Adverse Event Reporting System, we describe temporal trends in adverse event reporting before and after generic introduction, and survey the quality of product-identifying information contained therein. The majority of reports were sent by innovator drug manufacturers while few were sent by generic manufacturers, even when generics accounted for >90% of dispensed prescriptions. We manually reviewed narratives from 2,500 reports and found that the suspect product type (brand or generic) could not be determined in 84% of reports, while generic products (16%) were identified more often than brand-name products (<1%). These results suggest that pharmacovigilance stakeholders should act to promote more detailed reporting practices. PMID:25670505

  3. Antiepileptic drug hypersensitivity syndrome.

    PubMed

    Schlienger, R G; Shear, N H

    1998-01-01

    The antiepileptic drug hypersensitivity syndrome (AHS) is an adverse drug reaction associated with the aromatic antiepileptic drugs (AEDs) phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), and primidone. The syndrome is defined by the triad of fever, skin rash, and internal organ involvement. It can also be caused by other drugs, such as sulfonamides, dapsone, minocycline, terbinafine, azathioprine, and allopurinol. Diagnosis of AHS may be difficult because of the variety of clinical and laboratory abnormalities and manifestations and because the syndrome may mimic infectious, neoplastic, or collagen vascular disorders. The incidence is approximately 1 in 3,000 exposures. AHS starts with fever, rash, and lymphadenopathy, within the first 2-8 weeks after initiation of therapy. Internal manifestations include, among others, agranulocytosis, hepatitis, nephritis, and myostitis. AHS is associated with a relative excess of reactive oxidative metabolites of the AED. Insufficient detoxification may lead to cell death or contribute to the formation of antigen that triggers an immune reaction. Crossreactivity among PHT, CBZ, and PB is as high as 70-80%. PMID:9798755

  4. Antiepileptic drugs in migraine prevention.

    PubMed

    Mathew, N T

    2001-01-01

    Migraineurs may continue to experience attacks, despite daily use of one or more agents from a wide range of drugs, including beta-blockers, calcium channel blockers, serotonin antagonists, tricyclic antidepressants, monoamine oxidase inhibitors, and antiepileptic agents. Divalproex sodium is the only antiepileptic drug approved for migraine prevention. Gabapentin, topiramate, and other antiepileptic agents are being evaluated for migraine prevention and treatment. Prospective, double-blind, placebo-controlled clinical trials of divalproex, gabapentin, and topiramate for migraine prevention generally were composed of a prospective baseline period, a dose titration period, and a fixed-dose treatment period. The primary efficacy variable was a reduction in the 28-day frequency of migraine headache. Patients receiving divalproex for 12 weeks at doses up to 1500 mg/day achieved significant decreases in the migraine frequency (P<.05), corresponding to reductions of 30% to 40% compared with baseline. Nearly half of the divalproex-treated patients had a 50% or more reduction from baseline in headache frequencies (P< or =.05). Asthenia, vomiting, somnolence, tremor, and alopecia were common adverse events associated with divalproex. Significant reductions in migraine frequency were also observed with gabapentin (1800 to 2400 mg/day) when compared with placebo (P<.01), and nearly half of all patients treated at the highest dose experienced a reduction in headache rate of 50% or more. Somnolence was the most commonly reported adverse event among the gabapentin-treated patients. Two single-center, double-blind, placebo-controlled clinical trials evaluated topiramate for migraine prevention. A lower 28-day migraine frequency was seen during 18 weeks of administration at a maximum daily dose of 200 mg (P =.09). In a second study, a significantly lower mean 28-day migraine frequency was observed during 16 weeks of treatment with topiramate (P =.0015). Mean reduction in migraine

  5. Use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to Help Predict the Occurrence of Idiosyncratic Cutaneous Adverse Drug Reactions Associated with Antiepileptic Drug Usage.

    PubMed

    Chan, Rosa; Wei, Chun-Yu; Chen, Yuan-Tsong; Benet, Leslie Z

    2016-05-01

    Cutaneous adverse reactions (CARs) from antiepileptic drugs (AEDs) are common, ranging from mild to life-threatening, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The identification of subjects carrying the HLA-B*15:02, an inherited allelic variant of the HLA-B gene, and the avoidance of carbamazepine (CBZ) therapy in these subjects are strongly associated with a decrease in the incidence of carbamazepine-induced SJS/TEN. In spite of the strong genetic associations, the initiation of hypersensitivity for AEDs is still not very well characterized. Predicting the potential for other AEDs to cause adverse reactions will be undoubtedly beneficial to avoid CARs, which is the focus of this report. Here, we explore the use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to distinguish AEDs associated with and without CARs by examining the binding relationship of AEDs to HLA-B*15:02 and data from extensive reviews of medical records. We also evaluate the lack of benefit from a Hong Kong population policy on the effects of screening for HLA-B*15:02 and previous incorrect structure-activity hypotheses. Our analysis concludes that BDDCS class 2 AEDs are more prone to cause adverse cutaneous reactions than certain BDDCS class 1 AEDs and that BDDCS Class 3 drugs have the lowest levels of cutaneous adverse reactions. We propose that BDDCS Class 3 AEDs should be preferentially used for patients with Asian backgrounds (i.e., Han Chinese, Thai, and Malaysian populations) if possible and in patients predisposed to skin rashes. PMID:26951484

  6. Newer anti-epileptic drugs.

    PubMed

    Aneja, S; Newton, R W

    1996-01-01

    During the past few years, a number of drugs have been added to the anti-epileptic arsenal. This review focusses on five of these drugs which have undergone extensive trials: Vigabatrin, Lamotrigine, Gabapentin, Felbamate and Oxcarbazepine. Some of these antiepileptic drugs appear to be helpful for treatment of catastrophic childhood epilepsies. Vigabatrin appears promising in children with infantile spasms who do not respond to ACTH or Prednisolone. Children with Lennox-Gastaut syndrome may respond to treatment with Lamotrigine or Vigabatrin. Gabapentin and vigabatrin have proved to be effective in refractory partial seizures. Oxcarbazepine, a ketoderivative of carbamazepine, is as effective as Carbamazepine but has a better safety profile. Lesser neurotoxicity and fewer drug interactions is another advantage with these drugs. However monitoring is required to determine the long term safety with their usage. These drugs have a definite role in childhood epilepsies refractory to conventional antiepileptic drugs. PMID:10829995

  7. The new antiepileptic drugs: clinical applications.

    PubMed

    LaRoche, Suzette M; Helmers, Sandra L

    2004-02-01

    In the past decade, 8 new antiepileptic drugs have been approved for use in the United States, offering many new treatment options to patients with epilepsy. With expanding use of these newer agents, primary care clinicians are challenged with understanding the roles that each new agent plays in the treatment of patients with epilepsy as well as possible interactions with other pharmacological therapies. Each new medication provides a unique profile of pharmacokinetics, adverse effects, and mechanisms of action, making an appreciation of how these agents are best utilized even more difficult. Despite well-performed trials evaluating the safety and efficacy of specific antiepileptic drugs, the lack of head-to-head comparisons among them makes it difficult to endorse a single therapeutic regimen. Limited studies have compared the new antiepileptic drugs with more traditional medications and found similar efficacy but improved tolerability of the newer agents. There remains no well-established guidelines for choosing a particular antiepileptic drug or for choosing a newer agent over a traditional one. However, careful consideration of seizure type, patient comorbidities, and specific medication toxicities aids in prescribing the most appropriate medication. This article aims to familiarize the general practitioner with the appropriate roles and effective uses of the new antiepileptic drugs in specific clinical scenarios. PMID:14762041

  8. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs.

    PubMed

    Zaccara, Gaetano; Perucca, Emilio

    2014-12-01

    Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P-glycoprotein) and can reduce the efficacy of co-administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥ 200 mg/day) and perampanel (at doses ≥ 8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen-containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of

  9. [Endocrine effects of antiepileptic drugs].

    PubMed

    Leśkiewicz, Monika; Budziszewska, Bogusława; Lasoń, Władysław

    2008-01-01

    Both seizures and antiepileptic drugs may induce disturbances in hormonal system. Regarding endocrine effects of anticonvulsants, an interaction of these drugs with gonadal, thyroid, and adrenal axis deserves attention. Since majority of antiepileptic drugs block voltage dependent sodium and calcium channels, enhance GABAergic transmission and/or antagonize glutamate receptors, one may expect that similar neurochemical mechanisms are engaged in the interaction of these drugs with synthesis of hypothalamic neurohormones such as gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH) and growth hormone releasing hormone (GHRH). Moreover some antiepileptic drugs may affect hormone metabolism via inhibiting or stimulating cytochrome P-450 iso-enzymes. An influence of antiepileptic drugs on hypothalamic-pituitary-gonadal axis appears to be sex-dependent. In males, valproate decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) but elevated dehydroepiandrosterone sulfate (DHEAS) concentrations. Carbamazepine decreased testosterone/sex-hormone binding globulin (SHBG) ratio, whereas its active metabolite--oxcarbazepine--had no effect on androgens. In females, valproate decreased FSH-stimulated estradiol release and enhanced testosterone level. On the other hand, carbamazepine decreased testosterone level but enhanced SHBG concentration. It has been reported that carbamazepine, oxcarbazepine or joined administration of carbamazepine and valproate decrease thyroxine (T4) level in patients with no effect on thyrotropin (TSH). While valproate itself has no effect on T4, phenytoin, phenobarbital and primidone, as metabolic enzyme inducers, can decrease the level of free and bound thyroxine. On the other hand, new antiepileptics such as levetiracetam, tiagabine, vigabatrine or lamotrigine had no effect on thyroid hormones. With respect to hormonal regulation of metabolic processes, valproate was

  10. Risk factors for seizures and antiepileptic drug-associated adverse effects in high-grade glioma patients: A multicentre, retrospective study in Hong Kong

    PubMed Central

    Woo, Peter Yat-Ming; Chan, Danny Tat-Ming; Chan, Kwong-Yau; Wong, Wai-Kei; Po, Yin-Chung; Kwok, John Ching-Kong; Poon, Wai-Sang

    2015-01-01

    Aim The aim of this present study was to determine the frequency, as well as risk factors, for seizures and antiepileptic drug (AED)-associated adverse effects among high-grade glioma (HGG) patients. Patients and Methods A multicentre, retrospective study of adult Chinese Hong Kong patients from three neurosurgical centres diagnosed with supratentorial HGG between 1 January 2001 and 31 December 2010 was performed. Results A total of 198 patients, with a mean age of 55 years (range: 18–88) and a mean follow up of 15 months, was recruited. Most suffered from glioblastoma multiforme (GBM) (63 per cent) followed by anaplastic astrocytoma (25 per cent). Median overall survival for patients with GBM was 8 months, and 11 months for those with grade III gliomas. Prophylactic AED was prescribed in 165 patients (83 per cent), and 64 per cent of patients were continued until end of life or last follow up. A total of 112 patients (57 per cent) experienced seizures at a mean duration of 8 months postoperatively (range: 1 day–75 months). Independent predictors for seizures were a diagnosis of GBM [adjusted odds ratio (OR): 2.33, 95 per cent confidence interval (CI): 1.21–4.52] and adjuvant radiotherapy (adjusted OR: 2.97, 95 per cent CI: 1.49–6.62). One-fifth of patients (21 per cent) experienced AED adverse effects, with idiosyncratic cutaneous reactions and hepatotoxicity most frequently observed. An independent predictor for adverse effects was exposure to aromatic AED, such as phenytoin, carbamazepine and phenobarbital (adjusted OR: 3.32, 95 per cent CI: 1.32–8.40). Conclusions Antiepileptic drug prescription for primary seizure prophylaxis is both pervasive and prolonged for HGG patients. Seizures occur frequently, but most were delayed and none were life threatening. Judicious prescription of AED is required, especially when a significant proportion of patients experience adverse effects. Patients with a diagnosis of GBM and exposure to radiotherapy

  11. Antiepileptic drugs and Tourette syndrome.

    PubMed

    Cavanna, Andrea E; Nani, Andrea

    2013-01-01

    Tourette syndrome is a neurodevelopmental disorder characterized by the chronic presence of multiple motor tics and at least one vocal/phonic tic for the duration of 1 year. The clinical picture of patients with Tourette syndrome is often complicated by tic-related behavioral problems and associated psychopathology. The pathophysiology of Tourette syndrome is not thoroughly understood, however converging evidence from neuroimaging studies suggests abnormalities within the frontostriatal pathways which are mediated by several neurotransmitters. The pharmacological management of the tic symptoms focuses on the dopaminergic and noradrenergic pathways and aims to improve the health-related quality of life of patients. The most common medications are neuroleptics and atypical antipsychotics, which have a strong D2 blocking action. Also, preliminary studies have documented the efficacy of antiepileptic drugs in controlling tics. Thus far, two anticonvulsants (topiramate and levetiracetam) have been tested with a randomized, double-blind, placebo-controlled procedure in the treatment of tics. A study has reported an improvement in the control of tics with topiramate. This pharmacological agent was also reported to be well tolerated by the patients. However, the most frequent observed topiramate side effects (such as somnolence, cognitive problems, and weight loss) could not have manifested because of the short trial duration. Levetiracetam has shown conflicting results. A study found significant improvements in the control of tics, also associated with improvement in school performance. These results, however, were not replicated in other studies. Further investigations are therefore needed to assess the real efficacy of antiepileptic drugs in the treatment of tics. PMID:24295627

  12. Antiepileptic Drug Withdrawal in Dogs with Epilepsy

    PubMed Central

    Gesell, Felix Kaspar; Hoppe, Sonja; Löscher, Wolfgang; Tipold, Andrea

    2015-01-01

    Epilepsy is one of the most common neurological disorders in dogs and is treated by chronic administration of antiepileptic drugs (AEDs). In human beings with epilepsy, it is common clinical practice to consider drug withdrawal after a patient has been in remission (seizure free) for three or more years, but withdrawal is associated with the risk of relapse. In the present study, the consequences of AED withdrawal were studied in dogs with epilepsy. Therefore, 200 owners of dogs with idiopathic or presumed idiopathic epilepsy were contacted by telephone interview, 138 cases could be enrolled. In 11 cases, the therapy had been stopped after the dogs had become seizure free for a median time of 1 year. Reasons for AED withdrawal were appearance or fear of adverse side effects, financial aspects, and the idea that the medication could be unnecessary. Following AED withdrawal, four of these dogs remained seizure free, seven dogs suffered from seizure recurrence, of which only three dogs could regain seizure freedom after resuming AED therapy. Due to the restricted case number, an exact percentage of dogs with seizure recurrence after AED withdrawal cannot be given. However, the present study gives a hint that similar numbers as in human patients are found, and the data can help owners of epileptic dogs and the responsible clinician to decide when and why to stop antiepileptic medication. PMID:26664952

  13. Advances in anti-epileptic drug testing.

    PubMed

    Krasowski, Matthew D; McMillin, Gwendolyn A

    2014-09-25

    In the past twenty-one years, 17 new antiepileptic drugs have been approved for use in the United States and/or Europe. These drugs are clobazam, ezogabine (retigabine), eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. Therapeutic drug monitoring is often used in the clinical dosing of the newer anti-epileptic drugs. The drugs with the best justifications for drug monitoring are lamotrigine, levetiracetam, oxcarbazepine, stiripentol, and zonisamide. Perampanel, stiripentol and tiagabine are strongly bound to serum proteins and are candidates for monitoring of the free drug fractions. Alternative specimens for therapeutic drug monitoring are saliva and dried blood spots. Therapeutic drug monitoring of the new antiepileptic drugs is discussed here for managing patients with epilepsy. PMID:24925169

  14. Antiepileptic Drug Treatment in Children with Epilepsy.

    PubMed

    Rosati, Anna; De Masi, Salvatore; Guerrini, Renzo

    2015-10-01

    Most children with new-onset epilepsy achieve seizure freedom with appropriate antiepileptic drugs (AEDs). However, nearly 20 % will continue to have seizures despite AEDs, as either monotherapy or in combination. Despite the growing market of new molecules over the last 20 years, the proportion of drug-resistant epilepsies has not changed. In this review, we report the evidence of efficacy and safety based on phase III randomized controlled clinical trials (RCTs) of AEDs currently used in the paediatric population. We conducted a literature search using the PubMed database and the Cochrane Database of Systematic Reviews. We also analysed the RCTs of newer AEDs whose efficacy in adolescents and adults might suggest possible use in children. Most of the phase III trials on AEDs in children have major methodological limitations that considerably limit meaningful conclusions about comparative efficacy between old and new molecules. Since the efficacy of new drugs has only been reported versus placebo, the commonly held opinion that new and newer AEDs have a better safety profile than old ones does not appear to be supported by evidence. Despite limited solid evidence, pharmacological management has improved over the years as a consequence of increased awareness of some degree of specificity of treatment in relation to different epilepsy syndromes and attention to adverse events. Future research should be directed taking these factors, as well as the diversity of epilepsy, into consideration. PMID:26400189

  15. Interactions between antiepileptic and antipsychotic drugs.

    PubMed

    Besag, Frank M C; Berry, David

    2006-01-01

    Antiepileptic and antipsychotic drugs are often prescribed together. Interactions between the drugs may affect both efficacy and toxicity. This is a review of human clinical data on the interactions between the antiepileptic drugs carbamazepine, valproic acid (sodium valproate), vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine, oxcarbazepine, levetiracetam, pregabalin, felbamate, zonisamide, phenobarbital and phenytoin with the antipsychotic drugs risperidone, olanzapine, quetiapine, clozapine, amisulpride, sulpiride, ziprasidone, aripiprazole, haloperidol and chlorpromazine; the limited information on interactions between antiepileptic drugs and zuclopenthixol, periciazine, fluphenazine, flupenthixol and pimozide is also presented. Many of the interactions depend on the induction or inhibition of the cytochrome P450 isoenzymes, but other important mechanisms involve the uridine diphosphate glucuronosyltransferase isoenzymes and protein binding. There is some evidence for the following effects. Carbamazepine decreases the plasma concentrations of both risperidone and its active metabolite. It also decreases concentrations of olanzapine, clozapine, ziprasidone, haloperidol, zuclopenthixol, flupenthixol and probably chlorpromazine and fluphenazine. Quetiapine increases the ratio of carbamazepine epoxide to carbamazepine and this may lead to toxicity. The data on valproic acid are conflicting; it may either increase or decrease clozapine concentrations, and it appears to decrease aripiprazole concentrations. Chlorpromazine possibly increases valproic acid concentrations. Lamotrigine possibly increases clozapine concentrations. Phenobarbital decreases clozapine, haloperidol and chlorpromazine concentrations. Phenytoin decreases quetiapine, clozapine, haloperidol and possibly chlorpromazine concentrations. There are major gaps in the data. In many cases there are no published clinical data on interactions that would be predicted on theoretical grounds. PMID

  16. Methods of assessment of antiepileptic drugs.

    PubMed Central

    Milligan, N; Richens, A

    1981-01-01

    Epilepsy is a symptom with protean manifestations and as such it is a difficult disease in which to carry out a therapeutic trial. The methods available to research workers for the assessment of new antiepileptic drugs are hampered by the fact that epilepsy is a fluctuant condition. Although it is a chronic disorder open to study using cross-over trials and within-patient comparisons, accurate assessment cannot be easily made at any one point in time. Research workers are therefore automatically placed at a time factor disadvantage and this is especially so for those searching for quick methods of evaluating new compounds. The need for a quick and reliable method of assessing a new antiepileptic drug has long been appreciated. This article will discuss the methods currently available and we will begin by considering the most commonly used method of assessment with particular reference to some of the problems involved in conducting a controlled clinical trial in epilepsy. PMID:7272157

  17. Antiepileptic Drug Therapy in Migraine Headache.

    PubMed

    Wheeler, Steve D.

    2002-09-01

    Severe migraine affects more than 28 million Americans. It is associated with episodic as well as long-term disability and suffering, yet it is underdiagnosed and undertreated. Acute treatments have advanced considerably, ignited by sumatriptan and the subsequent triptans; unfortunately migraine prevention has lagged far behind. There are no great migraine preventives! No migraine preventive agent studied in good randomized, double blind, placebo-controlled trials proved to be 50% better than placebo. Migraine trials typically focus on episodic migraine, a milder, gentler type of migraine that is selected for low frequency, lack of daily headaches, no preventive need, and previous failure to no more than a few preventive agents. These features are not typical of the usual migraine patient seen in most neurologic practices, thus the results of clinical trials may not carryover to real world situations. Treatment of frequent, chronic, or pervasive migraine is inadequate, and never has been studied in randomized controlled trials. Traditional migraine preventives, eg, beta-blockers, calcium channel blockers, and tricyclic antidepressants, are often ineffective in difficult or complicated populations. The antiepileptic drugs represent a category of pharmaceutics that target the neuronal instability and central hyperexcitability of migraine, and, through these actions, may be more effective than traditional preventives. Episodic migraine attacks are associated with peripheral and central sensitization; however, if attacks are frequent, severe, or long lasting, this sensitization may increase the risk of developing daily headaches. If antiepileptic drugs have an effect on central sensitization, perhaps mediated via glutamate inhibition or gamma-aminobutyric acid potentiation, it is appropriate to use these agents early in migraine treatment, particularly in the highly comorbid patient, possibly in conjunction with agents that antagonize the 5HT2 receptor. This report

  18. The New Antiepileptic Drugs: Their Neuropharmacology and Clinical Indications.

    PubMed

    Hanaya, Ryosuke; Arita, Kazunori

    2016-05-15

    The administration of antiepileptic drugs (AEDs) is the first treatment of epilepsy, one of the most common neurological diseases. Therapeutic guidelines include newer AEDs as front-line drugs; monotherapy with new AEDs is delivered in Japan. While about 70% of patients obtain good seizure control by taking one to three AEDs, about 60% experience adverse effects and 33% have to change drugs. Compared to traditional AEDs, the prolonged administration of new AEDs elicits fewer adverse effects and fewer drug interactions and their teratogenicity may be lower. These characteristics increase drug compliance and allow combination therapy for drug-resistant epilepsy, although the antiepileptic effects of the new AEDs are not greater than of traditional AEDs. Comorbidities are not rare in epileptics; many adult patients present with stroke and brain tumors. In stroke patients requiring risk control and in chemotherapy-treated brain tumor patients, their fewer drug interactions render the new AEDs advantageous. Also, new AEDs offer favorable side benefits for concurrent diseases and conditions. Patients with stroke and traumatic brain injury often present with psychiatric/behavioral symptoms and cognitive impairment and some new AEDs alleviate such symptoms. This review presents an outline of the new AEDs used to treat adult patients based on the pharmacological activity of the drugs and discusses possible clinical indications from the perspective of underlying causative diseases and comorbidities. PMID:26935782

  19. The New Antiepileptic Drugs: Their Neuropharmacology and Clinical Indications

    PubMed Central

    HANAYA, Ryosuke; ARITA, Kazunori

    2016-01-01

    The administration of antiepileptic drugs (AEDs) is the first treatment of epilepsy, one of the most common neurological diseases. Therapeutic guidelines include newer AEDs as front-line drugs; monotherapy with new AEDs is delivered in Japan. While about 70% of patients obtain good seizure control by taking one to three AEDs, about 60% experience adverse effects and 33% have to change drugs. Compared to traditional AEDs, the prolonged administration of new AEDs elicits fewer adverse effects and fewer drug interactions and their teratogenicity may be lower. These characteristics increase drug compliance and allow combination therapy for drug-resistant epilepsy, although the antiepileptic effects of the new AEDs are not greater than of traditional AEDs. Comorbidities are not rare in epileptics; many adult patients present with stroke and brain tumors. In stroke patients requiring risk control and in chemotherapy-treated brain tumor patients, their fewer drug interactions render the new AEDs advantageous. Also, new AEDs offer favorable side benefits for concurrent diseases and conditions. Patients with stroke and traumatic brain injury often present with psychiatric/behavioral symptoms and cognitive impairment and some new AEDs alleviate such symptoms. This review presents an outline of the new AEDs used to treat adult patients based on the pharmacological activity of the drugs and discusses possible clinical indications from the perspective of underlying causative diseases and comorbidities. PMID:26935782

  20. Treatment of hypopituitarism in patients receiving antiepileptic drugs.

    PubMed

    Paragliola, Rosa Maria; Prete, Alessandro; Kaplan, Peter W; Corsello, Salvatore Maria; Salvatori, Roberto

    2015-02-01

    Evidence suggests that there may be drug interactions between antiepileptic drugs and hormonal therapies, which can present a challenge to endocrinologists dealing with patients who have both hypopituitarism and neurological diseases. Data are scarce for this subgroup of patients; however, data for the interaction of antiepileptic drugs with the pituitary axis have shown that chronic use of many antiepileptic drugs, such as carbamazepine, oxcarbazepine, and topiramate, enhances hepatic cytochrome P450 3A4 (CYP3A4) activity, and can decrease serum concentrations of sex hormones. Other antiepileptic drugs increase sex hormone-binding globulin, which reduces the bioactivity of testosterone and estradiol. Additionally, the combined oestrogen-progestagen contraceptive pill might decrease lamotrigine concentrations, which could worsen seizure control. Moreover, sex hormones and their metabolites can directly act on neuronal excitability, acting as neurosteroids. Because carbamazepine and oxcarbazepine can enhance the sensitivity of renal tubules, a reduction in desmopressin dose might be necessary in patients with central diabetes insipidus. Although the effects of antiepileptic drugs in central hypothyroidism have not yet been studied, substantial evidence indicates that several antiepileptic drugs can increase thyroid hormone metabolism. However, although it is reasonable to expect a need for a thyroxine dose increase with some antiepileptic drugs, the effect of excessive thyroxine in lowering seizure threshold should also be considered. There are no reports of significant interactions between antiepileptic drugs and the efficacy of human growth hormone therapy, and few data are available for the effects of second-generation antiepileptic drugs on hypopituitarism treatment. PMID:24898833

  1. Emerging Antiepileptic Drugs for Severe Pediatric Epilepsies.

    PubMed

    Mudigoudar, Basanagoud; Weatherspoon, Sarah; Wheless, James W

    2016-05-01

    The medical management of the epilepsy syndromes of early childhood (eg, infantile spasms, Dravet syndrome, and Lennox-Gastaut syndrome) is challenging; and requires careful evaluation, classification, and treatment. Pharmacologic therapy continues to be the mainstay of management for these children, and as such it is important for the clinician to be familiar with the role of new antiepileptic drugs. This article reports the clinical trial data and personal experience in treating the severe epilepsies of childhood with the recently Food and Drug Administration-approved new antiepileptic drugs (vigabatrin, rufinamide, perampanel, and clobazam) and those in clinical trials (cannabidiol, stiripentol, and fenfluramine). Genetic research has also identified an increasing number of pediatric developmental and seizure disorders that are possibly treatable with targeted drug therapies, focused on correcting underlying neural dysfunction. We highlight recent genetic advances, and how they affect our treatment of some of the genetic epilepsies, and speculate on the use of targeted genetic treatment (precision medicine) in the future. PMID:27544474

  2. Interactions between antiepileptic drugs and hormones.

    PubMed

    Svalheim, Sigrid; Sveberg, Line; Mochol, Monika; Taubøll, Erik

    2015-05-01

    Antiepileptic drugs (AEDs) are known to have endocrine side effects in both men and women. These can affect fertility, sexuality, thyroid function, and bone health, all functions of major importance for well-being and quality of life. The liver enzyme inducing antiepileptic drugs (EIAEDs), like phenobarbital, phenytoin, and carbamazepine, and also valproate (VPA), a non-EIAED, are most likely to cause such side effects. AED treatment can alter the levels of different sex hormones. EIAEDs increase sex hormone binding globulin (SHBG) concentrations in both men and women. Over time, this elevation can lead to lower levels of bioactive testosterone and estradiol, which may cause menstrual disturbances, sexual problems, and eventually reduced fertility. VPA can cause weight gain in both men and women. In women, VPA can also lead to androgenization with increased serum testosterone concentrations, menstrual disturbances, and polycystic ovaries. Lamotrigine has not been shown to result in endocrine side effects. The newer AEDs have not yet been thoroughly studied, but case reports indicate that some of these drugs could also be suspected to cause such effects if endocrine changes commence after treatment initiation. It is important to be aware of possible endocrine side effects of AEDs as they can have a major impact on quality of life, and are, at least partly, reversible after AED discontinuation. PMID:25797888

  3. [New antiepileptic drugs, and therapeutic considerations].

    PubMed

    Szupera, Zoltán

    2011-09-30

    Epilepsy is not a singular disease, but a variety of disorders. It affects up to 0.5% of the population. Over the past decade, researchers have made great advances in the field of epilepsy. These have been accompanied by the licensing of a great number of antiepileptic drugs. However, despite these efforts, up to 15-20% of patients have refractory epilepsy. The novel antiepileptic drugs must suit several requirements: higher efficacy, especially in resistant cases, better tolerability, and improved pharmacokinetic properties. Recently, three new drugs have been introduced to the market. Retigabine is a carbamic derivate, and its anticonvulsive properties are largely due to its ability to prolong the opening of neuronal voltage-gated potassium Kv7.2 and Kv7.3 channels. Lacosamide is a functionalized amino acid, and selectively enhances voltage-gated sodium channel slow inactivation. Eslicarbazepine acetate is a new member of the dibenzazepine family, and blocks the fast inactivated voltage-gated sodium channel. All three of them differ from the foregoing agents in several important ways, including new mechanism of action (retigabine, lacosamide), or pharmacokinetics (eslicarbazepine acetate). These novel anticonvulsants appear to be a safe and effective addition to the armamentarium for the treatment of patients with refractory epilepsy. However, it will take the consideration of new concepts in shaping the new therapeutic algorithm. PMID:22059370

  4. Assessing suicidal risk with antiepileptic drugs

    PubMed Central

    Mula, Marco; Bell, Gail S; Sander, Josemir W

    2010-01-01

    Recently, the US Food and Drug Administration issued an alert about an increased risk for suicidality during treatment with antiepileptic drugs (AEDs) for different indications, including epilepsy. We discuss the issue of suicide in epilepsy with special attention to AEDs and the assessment of suicide in people with epilepsy. It has been suggested that early medical treatment with AEDs might potentially reduce suicide risk of people with epilepsy, but it is of great importance that the choice of drug is tailored to the mental state of the patient. The issue of suicidality in epilepsy is likely to represent an example of how the underdiagnosis of psychiatric symptoms, the lack of input from professionals (eg, psychologists, social workers, and psychiatrists), and the delay in an optimized AED therapy may worsen the prognosis of the condition with the occurrence of severe complications such as suicide. PMID:20957120

  5. Chemical properties of antiepileptic drugs (AEDs).

    PubMed

    Bialer, Meir

    2012-07-01

    Between 1990 and 2011 the following fifteen new antiepileptic drugs (AEDs) were approved: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. These AEDs (except felbamate) offer appreciable advantages in terms of their favorable pharmacokinetics, improved tolerability and lower potential for drug interactions. All AEDs introduced after 1990 that are not second generation drugs (with the exception of vigabatrin and tiagabine) were developed empirically (sometimes serendipitously) utilizing mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of new AEDs in the last three decades coupled with their multiple mechanisms of action explains their diverse chemical structures. The availability of old and new AEDs with various activity spectra and different tolerability profiles enables clinicians to better tailor drug choice to the characteristics of individual patients. With fifteen new AEDs having entered the market in the past 20years the antiepileptic market is crowded. Consequently, epilepsy alone is not attractive in 2011 to the pharmaceutical industry even though the clinical need of refractory epilepsy remains unmet. Due to this situation, future design of new AEDs must also have a potential in non-epileptic CNS disorders such as neuropathic pain, migraine prophylaxis and bipolar disorder or fibromyalgia as demonstrated by the sales revenues of pregabalin, topiramate and valproic acid. This review analyzes the effect that the emerging knowledge on the chemical properties of the old AEDs starting from phenobarbital (1912) has had on the design of subsequent AEDs and new therapeutics as well as the current approach to AED discovery. PMID:22210279

  6. Antiepileptic Drug Interactions - Principles and Clinical Implications

    PubMed Central

    Johannessen, Svein I; Landmark, Cecilie Johannessen

    2010-01-01

    Antiepileptic drugs (AEDs) are widely used as long-term adjunctive therapy or as monotherapy in epilepsy and other indications and consist of a group of drugs that are highly susceptible to drug interactions. The purpose of the present review is to focus upon clinically relevant interactions where AEDs are involved and especially on pharmacokinetic interactions. The older AEDs are susceptible to cause induction (carbamazepine, phenobarbital, phenytoin, primidone) or inhibition (valproic acid), resulting in a decrease or increase, respectively, in the serum concentration of other AEDs, as well as other drug classes (anticoagulants, oral contraceptives, antidepressants, antipsychotics, antimicrobal drugs, antineoplastic drugs, and immunosupressants). Conversely, the serum concentrations of AEDs may be increased by enzyme inhibitors among antidepressants and antipsychotics, antimicrobal drugs (as macrolides or isoniazid) and decreased by other mechanisms as induction, reduced absorption or excretion (as oral contraceptives, cimetidine, probenicid and antacides). Pharmacokinetic interactions involving newer AEDs include the enzyme inhibitors felbamate, rufinamide, and stiripentol and the inducers oxcarbazepine and topiramate. Lamotrigine is affected by these drugs, older AEDs and other drug classes as oral contraceptives. Individual AED interactions may be divided into three levels depending on the clinical consequences of alterations in serum concentrations. This approach may point to interactions of specific importance, although it should be implemented with caution, as it is not meant to oversimplify fact matters. Level 1 involves serious clinical consequences, and the combination should be avoided. Level 2 usually implies cautiousness and possible dosage adjustments, as the combination may not be possible to avoid. Level 3 refers to interactions where dosage adjustments are usually not necessary. Updated knowledge regarding drug interactions is important to predict

  7. The Controversy over Generic Antiepileptic Drugs

    PubMed Central

    Shaw, Susan J.; Hartman, Adam L.

    2010-01-01

    As patent protection ends for the next generation of antiepileptic drugs (AEDs), a complex debate continues over generic substitution of AEDs. On one hand, generic drug formulations provide cost savings for patients and society. On the other hand, patients with epilepsy and physicians are wary about the adequacy and efficacy of the Food and Drug Administration's (FDA) standards for generics. This article reviews current and proposed bioequivalence test procedures, summarizes new generic AED formulations and their costs, and discusses potential pitfalls in the current standards. These shortcomings include certain pharmacokinetic factors and clinical pharmacologic factors that may affect bioequivalence of generic AEDs, and statistical limitations of the standards. While the drug concentration differences between the brand name drug and each generic formulation are unlikely to be substantial, the differences with generic-to-generic switches will be greater and potentially clinically significant. Conversely, owing to their more favorable pharmacokinetic profile, newer AEDs may be less prone to problems with generic substitution than older ones. Unfortunately, very few data are available to guide decisions regarding what is best for an individual patient. Based on new prediction methods, generic substitution should be safe for many patients but identifying them ultimately requires more rigorous study. PMID:22477799

  8. The Impact of Psychoactive Drugs on Seizures and Antiepileptic Drugs.

    PubMed

    Habibi, Mitra; Hart, Felecia; Bainbridge, Jacquelyn

    2016-08-01

    Psychiatric comorbidities are very common in patients with epilepsy, and in fact, a bidirectional relationship between epilepsy and some psychiatric disorders have been identified. However, despite their high prevalence, these comorbidities are not routinely recognized or adequately treated causing a significant burden for these patients. Atypical presentations of some of these psychiatric comorbidities in epilepsy, the concern that some psychotropic drugs may lower seizure threshold worsening frequency of seizures, possibility of many drug-drug interactions, and the negative impact of some antiepileptic drugs on psychiatric conditions are some of the challenges faced by clinicians. Although the main focus in epilepsy has remained on treatment of seizures, acknowledgment of these comorbidities and their timely diagnosis and appropriate treatment not only can impact patients' quality of life but also may improve their response to antiepileptic therapies. PMID:27315249

  9. Old and new anti-epileptic drugs in pregnancy.

    PubMed

    Regesta, G; Tanganelli, P

    2000-01-01

    During the recent years, a significant number of anti-epileptic drugs have been approved for prescription in different countries. In addition, some other promising drugs are in various stages of development. Soon after each drug has found its place in the therapeutic arsenal, pregnancies with exposure occur, with an increased risk of birth defect and developmental disturbances. As regards the possible teratogenic effect of the new anti-epileptic drugs, apart some individual reports we have only the results of pre-clinical toxicological studies which are difficult to extrapolate to the human situation, because of the well-known interspecies differences in pharmacokinetics and pharmacodynamics. Furthermore, combinations of anti-epileptic drugs are not tested pre-clinically while these new drugs are prescribed as add-on medication. So, metabolic interactions between individual components of such drug combinations may induce unexpected teratogenic effects. Also as for the teratogenic effects of the old drugs many questions have still to be defined. The most common and more important are which anti-epileptic drugs or combination of drugs is most safe for a particular woman with epilepsy and if there is an association between single anti-epileptic drugs and specific malformations. The reason is that none of the available reports to date have studied a sufficient number of women with epilepsy exposed to anti-epileptic drug monotherapy during pregnancy. Other questions concern dose-effect relationships, a universally accepted definition of major and minor malformations, and the lack of a thorough, exhaustive evaluation of the other risk factors, apart from the drugs. All these questions need to be ascertained for both the old and the new anti-epileptic drugs. Owing to these considerations, in 1998 an European Register of anti-epileptic drugs and pregnancy was instituted. The primary objective of the study is to evaluate and determine the degree of safety, with respect to

  10. Sodium channels, inherited epilepsy, and antiepileptic drugs.

    PubMed

    Catterall, William A

    2014-01-01

    Voltage-gated sodium channels initiate action potentials in brain neurons, mutations in sodium channels cause inherited forms of epilepsy, and sodium channel blockers-along with other classes of drugs-are used in therapy of epilepsy. A mammalian voltage-gated sodium channel is a complex containing a large, pore-forming α subunit and one or two smaller β subunits. Extensive structure-function studies have revealed many aspects of the molecular basis for sodium channel structure, and X-ray crystallography of ancestral bacterial sodium channels has given insight into their three-dimensional structure. Mutations in sodium channel α and β subunits are responsible for genetic epilepsy syndromes with a wide range of severity, including generalized epilepsy with febrile seizures plus (GEFS+), Dravet syndrome, and benign familial neonatal-infantile seizures. These seizure syndromes are treated with antiepileptic drugs that offer differing degrees of success. The recent advances in understanding of disease mechanisms and sodium channel structure promise to yield improved therapeutic approaches. PMID:24392695

  11. Antiepileptic drug treatment strategies in neonatal epilepsy.

    PubMed

    Hernan, A E; Holmes, G L

    2016-01-01

    The highest risk of seizures across the lifespan is in the neonatal period. The enhanced excitability of the immature brain compared to the mature brain is related to the sequential development and expression of essential neurotransmitter signaling pathways. During the neonatal period there is an overabundance of excitatory receptors, and γ-amino-butyric acid (GABA) is potentially depolarizing, as opposed to hyperpolarizing in the older brain. While this enhanced excitability is required for regulation of activity-dependent synapse formation and refining of synaptic connections that are necessary for normal brain development, enhanced excitability predisposes the immature brain to seizures. In addition to being common, neonatal seizures are very difficult to treat; antiepileptic drugs used in older children and adults are less efficacious, and possibly detrimental to brain development. In an effort to target the unique features of neurotransmission in the neonate, bumetanide, an NKCC1 inhibitor which reduces intraneuronal Cl(-) and induces a significant shift of EGABA toward more hyperpolarized values in vitro, has been used to treat neonatal seizures. As the understanding of the pathophysiology of genetic forms of neonatal epilepsy has evolved there have been a few successful attempts to pharmacologically target the mutated protein. This approach, while promising, is challenging due to the findings that the genetic syndromes presenting in infancy demonstrate genetic heterogeneity in regard to both the mutated gene and its function. PMID:27323943

  12. Neurodevelopmental effects of fetal antiepileptic drug exposure.

    PubMed

    Velez-Ruiz, Naymee J; Meador, Kimford J

    2015-03-01

    Many studies investigating cognitive outcomes in children of women with epilepsy report an increased risk of mental impairment. Verbal scores on neuropsychometric measures may be selectively more involved. While a variety of factors contribute to the cognitive problems of children of women with epilepsy, antiepileptic drugs (AEDs) appear to play a major role. The mechanisms by which AEDs affect neurodevelopmental outcomes remain poorly defined. Animal models suggest that AED-induced apoptosis, altered neurotransmitter environment, and impaired synaptogenesis are some of the mechanisms responsible for cognitive and behavioral teratogenesis. AEDs that are known to induce apoptosis, such as valproate, appear to affect children's neurodevelopment in a more severe fashion. Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains, and these appear to persist at least until the age of 6. Some studies have shown neurodevelopmental deficiencies associated with the use of phenobarbital and possibly phenytoin. So far, most of the investigations available suggest that fetal exposures to lamotrigine or levetiracetam are safer with regard to cognition when compared with other AEDs. Studies on carbamazepine show contradictory results, but most information available suggests that major poor cognitive outcomes should not be attributed to this medication. Overall, children exposed to polytherapy prenatally appear to have worse cognitive and behavioral outcomes compared with children exposed to monotherapy, and with the unexposed. There is an increase risk of neurodevelopmental deficits when polytherapy involves the use of valproate versus other agents. PMID:25693658

  13. Availability of antiepileptic drugs across Europe.

    PubMed

    Baftiu, Arton; Johannessen Landmark, Cecilie; Nikaj, Valent; Neslein, Inger-Lise; Johannessen, Svein I; Perucca, Emilio

    2015-12-01

    Europe consists of 53 countries with widely different economic conditions and different political, educational, and health care systems. This study was aimed at determining the availability of antiepileptic drugs (AEDs) across Europe. An electronic questionnaire was submitted to all 43 European chapters of the International League Against Epilepsy (ILAE). Outcome measures were availability of older, newer, and newest AEDs, generic products, indications, reimbursement rules, and reasons for lack of availability of AEDs. Countries were divided according to economic status as defined by the World Bank. Thirty-four chapters (79%) provided data. There were large differences in AED availability across countries, especially between high-income countries and the other countries. The newest AEDs were not available in any of the 12 non-high-income countries. Availability was higher in countries with public reimbursement systems. Reimbursement policies ranged from full reimbursement for all AEDs to complete lack of reimbursement. Main hurdles for poor access to AEDs included lack of regulatory approval, high prices and reimbursement restrictions. The availability of AEDs differs across European countries, with many hurdles hampering access to epilepsy medicines, particularly to new medications. These findings raise major concerns on the quality of epilepsy care in many countries. PMID:26477534

  14. Molecular Targets for Antiepileptic Drug Development

    PubMed Central

    Meldrum, Brian S.; Rogawski, Michael A.

    2007-01-01

    Summary This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the α subunits of voltage-gated Na+ channels and also T-type voltage-gated Ca2+ channels) or influence GABA-mediated inhibition. Recently, α2–δ voltage-gated Ca2+ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na+ channels and GABAA receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca2+ channel subunits and auxiliary proteins, A- or M-type voltage-gated K+ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABAB and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current Ih; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na+ channels underlying persistent Na+ currents or GABAA receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the

  15. Challenges in the clinical development of new antiepileptic drugs.

    PubMed

    Franco, Valentina; French, Jacqueline A; Perucca, Emilio

    2016-01-01

    Despite the current availability in the market of over two dozen antiepileptic drugs (AEDs), about one third of people with epilepsy fail to achieve complete freedom from seizures with existing medications. Moreover, currently available AEDs have significant limitations in terms of safety, tolerability and propensity to cause or be a target for clinically important adverse drug interactions. A review of the evidence shows that there are many misperceptions about the viability of investing into new therapies for epilepsy. In fact, there are clear incentives to develop newer and more efficacious medications. Developing truly innovative drugs requires a shift in the paradigms for drug discovery, which is already taking place by building on greatly expanded knowledge about the mechanisms involved in epileptogenesis, seizure generation, seizure spread and development of co-morbidities. AED development can also benefit by a review of the methodology currently applied in clinical AED development, in order to address a number of ethical and scientific concerns. As discussed in this article, many processes of clinical drug development, from proof-of-concept-studies to ambitious programs aimed at demonstrating antiepileptogenesis and disease-modification, can be facilitated by a greater integration of preclinical and clinical science, and by application of knowledge acquired during decades of controlled epilepsy trials. PMID:26611249

  16. New avenues for anti-epileptic drug discovery and development.

    PubMed

    Löscher, Wolfgang; Klitgaard, Henrik; Twyman, Roy E; Schmidt, Dieter

    2013-10-01

    Despite the introduction of over 15 third-generation anti-epileptic drugs, current medications fail to control seizures in 20-30% of patients. However, our understanding of the mechanisms mediating the development of epilepsy and the causes of drug resistance has grown substantially over the past decade, providing opportunities for the discovery and development of more efficacious anti-epileptic and anti-epileptogenic drugs. In this Review we discuss how previous preclinical models and clinical trial designs may have hampered the discovery of better treatments. We propose that future anti-epileptic drug development may be improved through a new joint endeavour between academia and the industry, through the identification and application of tools for new target-driven approaches, and through comparative preclinical proof-of-concept studies and innovative clinical trials designs. PMID:24052047

  17. Hypoactive sexual desire disorder caused by antiepileptic drugs

    PubMed Central

    Singh, M.; Bathla, Manish; Martin, A.; Aneja, J.

    2015-01-01

    Female sexual dysfunction is common but poorly understood sexual problem in women. Sexual dysfunction in female is multi-factorial in origin and also observed with intake of drug acting on central nervous system. This case report describes a female epileptic patient who developed sexual dysfunction with intake of antiepileptic drugs. PMID:26157303

  18. Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs.

    PubMed

    Spina, Edoardo; Perucca, Emilio

    2002-01-01

    As antiepileptic drugs (AEDs) and psychotropic agents are increasingly used in combination, the possibility of pharmacokinetic interactions between these compounds is relatively common. Most pharmacokinetic interactions between AEDs and psychoactive drugs occur at a metabolic level, and usually involve changes in the activity of the cytochrome P450 mixed-function oxidases (CYP) involved in their biotransformation. As a consequence of CYP inhibition or induction, plasma concentrations of a given drug may reach toxic or subtherapeutic levels, and dosage adjustments may be required to avoid adverse effects or clinical failure. Enzyme-inducing AEDs, such as carbamazepine (CBZ), phenytoin (PHT), and barbiturates, stimulate the oxidative biotransformation of many concurrently prescribed psychotropics. In particular, these AEDs may decrease the plasma concentrations of tricyclic antidepressants, many antipsychotics, including traditional compounds, i.e., haloperidol and chlorpromazine, and newer agents, i.e., clozapine, risperidone, olanzapine, quetiapine, and ziprasidone, and some benzodiazepines. Conversely, new AEDs appear to have a lower potential for interactions with all psychotropic drugs. While antipsychotics and anxiolytics do not significantly influence the pharmacokinetics of most AEDs, some newer antidepressants, such as viloxazine, fluoxetine, and fluvoxamine, may lead to higher serum levels of some AEDs, namely CBZ and PHT, through inhibition of CYP enzymes. No significant pharmacokinetic interactions have been documented between AEDs and lithium. Information about CYP enzymes responsible for the biotransformation of individual agents and about the effects of these compounds on the activity of specific CYP enzymes may help in predicting and avoiding clinically significant interactions. Apart from careful clinical observation, serum level monitoring of AEDs and psychotropic drugs can be useful in determining the need for dosage adjustments, especially if

  19. The Effects of Antiepileptic Drugs on Classroom Performance

    ERIC Educational Resources Information Center

    Titus, Jeffrey B.; Thio, Liu Lin

    2009-01-01

    Epilepsy is one of the most common neurological disorders in children, and it has been associated with an increased risk of cognitive, psychiatric, and learning problems. Although side effects of antiepileptic drugs (AEDs) have been long studied in adults, an understanding of how they manifest in children is only beginning to emerge. Careful…

  20. Epilepsy, Antiepileptic Drugs, and Aggression: An Evidence-Based Review.

    PubMed

    Brodie, Martin J; Besag, Frank; Ettinger, Alan B; Mula, Marco; Gobbi, Gabriella; Comai, Stefano; Aldenkamp, Albert P; Steinhoff, Bernhard J

    2016-07-01

    Antiepileptic drugs (AEDs) have many benefits but also many side effects, including aggression, agitation, and irritability, in some patients with epilepsy. This article offers a comprehensive summary of current understanding of aggressive behaviors in patients with epilepsy, including an evidence-based review of aggression during AED treatment. Aggression is seen in a minority of people with epilepsy. It is rarely seizure related but is interictal, sometimes occurring as part of complex psychiatric and behavioral comorbidities, and it is sometimes associated with AED treatment. We review the common neurotransmitter systems and brain regions implicated in both epilepsy and aggression, including the GABA, glutamate, serotonin, dopamine, and noradrenaline systems and the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and temporal lobes. Few controlled clinical studies have used behavioral measures to specifically examine aggression with AEDs, and most evidence comes from adverse event reporting from clinical and observational studies. A systematic approach was used to identify relevant publications, and we present a comprehensive, evidence-based summary of available data surrounding aggression-related behaviors with each of the currently available AEDs in both adults and in children/adolescents with epilepsy. A psychiatric history and history of a propensity toward aggression/anger should routinely be sought from patients, family members, and carers; its presence does not preclude the use of any specific AEDs, but those most likely to be implicated in these behaviors should be used with caution in such cases. PMID:27255267

  1. Epilepsy, Antiepileptic Drugs, and Aggression: An Evidence-Based Review

    PubMed Central

    Besag, Frank; Ettinger, Alan B.; Mula, Marco; Gobbi, Gabriella; Comai, Stefano; Aldenkamp, Albert P.; Steinhoff, Bernhard J.

    2016-01-01

    Antiepileptic drugs (AEDs) have many benefits but also many side effects, including aggression, agitation, and irritability, in some patients with epilepsy. This article offers a comprehensive summary of current understanding of aggressive behaviors in patients with epilepsy, including an evidence-based review of aggression during AED treatment. Aggression is seen in a minority of people with epilepsy. It is rarely seizure related but is interictal, sometimes occurring as part of complex psychiatric and behavioral comorbidities, and it is sometimes associated with AED treatment. We review the common neurotransmitter systems and brain regions implicated in both epilepsy and aggression, including the GABA, glutamate, serotonin, dopamine, and noradrenaline systems and the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and temporal lobes. Few controlled clinical studies have used behavioral measures to specifically examine aggression with AEDs, and most evidence comes from adverse event reporting from clinical and observational studies. A systematic approach was used to identify relevant publications, and we present a comprehensive, evidence-based summary of available data surrounding aggression-related behaviors with each of the currently available AEDs in both adults and in children/adolescents with epilepsy. A psychiatric history and history of a propensity toward aggression/anger should routinely be sought from patients, family members, and carers; its presence does not preclude the use of any specific AEDs, but those most likely to be implicated in these behaviors should be used with caution in such cases. PMID:27255267

  2. Breastfeeding in Children of Women Taking Antiepileptic Drugs

    PubMed Central

    Meador, Kimford J.; Baker, Gus A.; Browning, Nancy; Cohen, Morris J.; Bromley, Rebecca L.; Clayton-Smith, Jill; Kalayjian, Laura A.; Kanner, Andres; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael; Loring, David W.

    2014-01-01

    IMPORTANCE Breastfeeding is known to have beneficial effects, but concern exists that breastfeeding during maternal antiepileptic drug (AED) therapy may be harmful. We previously noted no adverse effects of breastfeeding associated with AED use on IQ at age 3 years, but IQ at age 6 years is more predictive of school performance and adult abilities. OBJECTIVES To examine the effects of AED exposure via breastfeeding on cognitive functions at age 6 years. DESIGN, SETTING, AND PARTICIPANTS Prospective observational multicenter study of long-term neurodevelopmental effects of AED use. Pregnant women with epilepsy receiving monotherapy (ie, carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled from October 14, 1999, through April 14, 2004, in the United States and the United Kingdom. At age 6 years, 181 children were assessed for whom we had both breastfeeding and IQ data. All mothers in this analysis continued taking the drug after delivery. MAIN OUTCOMES AND MEASURES Differential Ability Scales IQ was the primary outcome. Secondary measures included measures of verbal, nonverbal, memory, and executive functions. For our primary analysis, we used a linear regression model with IQ at age 6 years as the dependent variable, comparing children who breastfed with those who did not. Similar secondary analyses were performed for the other cognitive measures. RESULTS In total, 42.9% of children were breastfed a mean of 7.2 months. Breastfeeding rates and duration did not differ across drug groups. The IQ at age 6 years was related to drug group (P italic> .001 [adjusted IQ worse by 7–13 IQ points for valproate compared to other drugs]), drug dosage (regression coefficient, −0.1; 95% CI, −0.2 to 0.0; P = .01 [higher dosage worse]), maternal IQ (regression coefficient, 0.2; 95% CI, 0.0 to 0.4; P = .01 [higher child IQ with higher maternal IQ]), periconception folate use (adjusted IQ 6 [95% CI, 2–10] points higher for folate, P = .005), and breastfeeding

  3. Idiopathic (primary) generalized epilepsy. Traditional versus new antiepileptic drugs.

    PubMed

    Yadegari, Samira; Bahrami, Parviz

    2013-04-01

    Idiopathic generalized epilepsies (IGE) are genetic based seizures with normal neurologic exam, intelligence, and imaging studies. Based on the age of onset and prominent seizure type, different syndromes were identified. The purpose of this study is to summarize the characteristics, prognosis, and choices of antiepileptic drugs (AED) in common syndromes of IGE. In addition, we review the updated role of new AEDs in specific syndromes of IGE. The first choice AED is usually valproate. Most drug trials on the effects of new AEDs compared them with placebo and not valproate. However, some of the broad spectrum new AEDs may be considered as the first choice in specific conditions. In true refractory patients, combination therapy and vagal nerve stimulation could be the next option. In the proper management of IGE, neurologists should consider the predominant seizure type, patient gender, co-morbidities, and antiepileptic drugs that may aggravate a specific seizure type. PMID:23545607

  4. Analysis of nocebo effects of antiepileptic drugs across different conditions.

    PubMed

    Zaccara, Gaetano; Giovannelli, Fabio; Giorgi, Filippo Sean; Franco, Valentina; Gasparini, Sara

    2016-07-01

    The aim of this study was to assess the nocebo effect in all randomised controlled trials (RCTs) exploring the effect of antiepileptic drugs (AEDs) in the clinical conditions in which these compounds have been studied with the exception of epilepsy. We searched for all double-blind, placebo-controlled trials performed in adult patients, testing AEDs in any clinical condition except epilepsy. The following data were extracted from the placebo arms: the number of randomized patients, the number of patients withdrawing because of adverse effects (AEs), and the number of patients with 11 predefined AEs (dizziness, ataxia/coordination abnormal, diplopia, somnolence, fatigue, headache, memory impairment, tremor, abnormal thinking, anxiety and depression). Outcome measures were the percentages of patients whithdrawing due to AEs and reporting the selected AEs. RCTs included in the analysis were grouped in six main categories of clinical conditions (pain, movement disorders, psychiatric disorders, substance abuse, obesity and binge eating disorders, and miscellanea). Proportions of patients with 95 % confidence intervals (CIs) have been calculated for all reported outcome measures. Thirteen AEDs were studied and the total number of selected RCTs was 157. Significant percentages of placebo-treated patients withdrawing due to AEs and with specific AEs were observed in several cases. Significant differences emerged across different conditions. Comparisons with results of a previous meta-analysis on all RCTs in patients with drug-resistant epilepsies showed that ataxia, diplopia and fatigue were significantly more frequent, and patients withdrawing were significantly less frequent, in placebo-treated epileptic patients. Significant differences have been identified in the AEDs-induced nocebo effect across different conditions. Placebo-treated epilepsy patients have significantly more frequent neurological AEs. PMID:26810717

  5. The Role of Reactive Species in Epileptogenesis and Influence of Antiepileptic Drug Therapy on Oxidative Stress

    PubMed Central

    Martinc, Boštjan; Grabnar, Iztok; Vovk, Tomaž

    2012-01-01

    Epilepsy is considered one of the most common neurological disorders. The focus of this review is the acquired form of epilepsy, with the development process consisting of three major phases, the acute injury phase, the latency epileptogenesis phase, and the phase of spontaneous recurrent seizures. Nowadays, an increasing attention is paid to the possible interrelationship between oxidative stress resulting in disturbance of physiological signalling roles of calcium and free radicals in neuronal cells and mitochondrial dysfunction, cell damage, and epilepsy. The positive stimulation of mitochondrial calcium signals by reactive oxygen species and increased reactive oxygen species generation resulting from increased mitochondrial calcium can lead to a positive feedback loop. We propose that calcium can pose both, physiological and pathological effects of mitochondrial function, which can lead in neuronal cell death and consequent epileptic seizures. Various antiepileptic drugs may impair the endogenous antioxidative ability to prevent oxidative stress. Therefore, some antiepileptic drugs, especially from the older generation, may trigger oxygen-dependent tissue injury. The prooxidative effects of these antiepileptic drugs might lead to enhancement of seizure activity, resulting in loss of their efficacy or apparent functional tolerance and undesired adverse effects. Additionally, various reactive metabolites of antiepileptic drugs are capable of covalent binding to macromolecules which may lead to deterioration of the epileptic seizures and systemic toxicity. Since neuronal loss seems to be one of the major neurobiological abnormalities in the epileptic brain, the ability of antioxidants to attenuate seizure generation and the accompanying changes in oxidative burden, further support an important role of antioxidants as having a putative antiepileptic potential. PMID:23730257

  6. Therapeutic drug monitoring of antiepileptic drugs by use of saliva.

    PubMed

    Patsalos, Philip N; Berry, Dave J

    2013-02-01

    Blood (serum/plasma) antiepileptic drug (AED) therapeutic drug monitoring (TDM) has proven to be an invaluable surrogate marker for individualizing and optimizing the drug management of patients with epilepsy. Since 1989, there has been an exponential increase in AEDs with 23 currently licensed for clinical use, and recently, there has been renewed and extensive interest in the use of saliva as an alternative matrix for AED TDM. The advantages of saliva include the fact that for many AEDs it reflects the free (pharmacologically active) concentration in serum; it is readily sampled, can be sampled repetitively, and sampling is noninvasive; does not require the expertise of a phlebotomist; and is preferred by many patients, particularly children and the elderly. For each AED, this review summarizes the key pharmacokinetic characteristics relevant to the practice of TDM, discusses the use of other biological matrices with particular emphasis on saliva and the evidence that saliva concentration reflects those in serum. Also discussed are the indications for salivary AED TDM, the key factors to consider when saliva sampling is to be undertaken, and finally, a practical protocol is described so as to enable AED TDM to be applied optimally and effectively in the clinical setting. Overall, there is compelling evidence that salivary TDM can be usefully applied so as to optimize the treatment of epilepsy with carbamazepine, clobazam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, topiramate, and zonisamide. Salivary TDM of valproic acid is probably not helpful, whereas for clonazepam, eslicarbazepine acetate, felbamate, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin, the data are sparse or nonexistent. PMID:23288091

  7. [Cutaneous adverse drug reactions].

    PubMed

    Lebrun-Vignes, B; Valeyrie-Allanore, L

    2015-04-01

    Cutaneous adverse drug reactions (CADR) represent a heterogeneous field including various clinical patterns without specific features suggesting drug causality. Exanthematous eruptions, urticaria and vasculitis are the most common forms of CADR. Fixed eruption is uncommon in western countries. Serious reactions (fatal outcome, sequelae) represent 2% of CADR: bullous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), DRESS (drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome) and acute generalized exanthematous pustulosis (AGEP). These forms must be quickly diagnosed to guide their management. The main risk factors are immunosuppression, autoimmunity and some HLA alleles in bullous reactions and DRESS. Most systemic drugs may induce cutaneous adverse reactions, especially antibiotics, anticonvulsivants, antineoplastic drugs, non-steroidal anti-inflammatory drugs, allopurinol and contrast media. Pathogenesis includes immediate or delayed immunologic mechanism, usually not related to dose, and pharmacologic/toxic mechanism, commonly dose-dependent or time-dependent. In case of immunologic mechanism, allergologic exploration is possible to clarify drug causality, with a variable sensitivity according to the drug and to the CADR type. It includes epicutaneous patch testing, prick test and intradermal test. However, no in vivo or in vitro test can confirm the drug causality. To determine the cause of the eruption, a logical approach based on clinical characteristics, chronologic factors and elimination of differential diagnosis is required, completed with a literature search. A reporting to pharmacovigilance network is essential in case of a serious CADR whatever the suspected drug and in any case if the involved drug is a newly marketed one or unusually related to cutaneous reactions. PMID:25458866

  8. Access to antiepileptic drug therapy in children in Camagüey Province, Cuba

    PubMed Central

    Arencibia, Zeina Bárzaga; Leyva, Alberto López; Peña, Yordanka Mejías; Reyes, Alba Rosa González; Nápolez, Maurilys Acosta; Carbonell Perdomo, Demetrio; Manzano, Edita Fernández; Choonara, Imti

    2012-01-01

    Objective To describe access to antiepileptic drug therapy and estimate the prevalence of epilepsy in children in Camagüey Province, Cuba. Methods All the community pharmacies in the province were visited and information collected about the number of children receiving antiepileptic drugs in 2009. Availability and cost of each antiepileptic drug were determined. The prevalence of epilepsy was estimated by determining the number of children receiving antiepileptic drugs. Results There were 923 children who received a total of 977 antiepileptic drugs in Camagüey Province. The estimated prevalence of epilepsy was 5.18 per thousand children which is lower than previously reported rates in other low and lower-middle income countries. Most of the children (871, 94%) received a single antiepileptic drug. Carbamazepine and valproate were the two most frequently prescribed antiepileptic drugs. Antiepileptic drugs were available from the local pharmacy on 76% of occasions. If the antiepileptic drug was not available from the local pharmacy, the parent had to travel to another pharmacy to obtain the medicine. Conclusions The estimated prevalence of epilepsy in children in Cuba is lower than that estimated in other lower-middle income countries. Access to drug therapy in children with epilepsy can be achieved in lower-middle income countries. PMID:23134098

  9. Adverse antibiotic drug interactions.

    PubMed

    Bint, A J; Burtt, I

    1980-07-01

    There is enormous potential for drug interactions in patients who, today, often receive many drugs. Antibiotics are prominent amongst the groups of drugs commonly prescribed. Many interactions take place at the absorption stage. Antacids and antidiarrhoeal preparations, in particular, can delay and reduce the absorption of antibiotics such as tetracyclines and clindamycin, by combining with them in the gastrointestinal tract to form chelates or complexes. Other drugs can affect gastric motility, which in turn often controls the rate at which antibiotics are absorbed. Some broad spectrum antibiotics can alter the bacterial flora of the gut which may be related to malabsorption states. The potentiation of toxic side effects of one drug by another is a common type of interaction. Antibiotics which are implicated in this type of interaction are those which themselves possess some toxicity such as aminoglycosides, some cephalosporins, tetracyclines and colistin. Some of the most important adverse interactions with antibiotics are those which involve other drugs which have a low toxicity/efficacy ratio. These include anticoagulants such as warfarin, anticonvulsants such as phenytoin and phenobarbitone and oral antidiabetic drugs like tolbutamide. Risk of interaction arises when the metabolism of these drugs is inhibited by liver microsomal enzyme inhibitors such as some sulphonamides and chloramphenicol, or is enhanced by enzyme inducers such as rifampicin. PMID:6995091

  10. ADVERSE CUTANEOUS DRUG REACTION

    PubMed Central

    Nayak, Surajit; Acharjya, Basanti

    2008-01-01

    In everyday clinical practice, almost all physicians come across many instances of suspected adverse cutaneous drug reactions (ACDR) in different forms. Although such cutaneous reactions are common, comprehensive information regarding their incidence, severity and ultimate health effects are often not available as many cases go unreported. It is also a fact that in the present world, almost everyday a new drug enters market; therefore, a chance of a new drug reaction manifesting somewhere in some form in any corner of world is unknown or unreported. Although many a times, presentation is too trivial and benign, the early identification of the condition and identifying the culprit drug and omit it at earliest holds the keystone in management and prevention of a more severe drug rash. Therefore, not only the dermatologists, but all practicing physicians should be familiar with these conditions to diagnose them early and to be prepared to handle them adequately. However, we all know it is most challenging and practically difficult when patient is on multiple medicines because of myriad clinical symptoms, poorly understood multiple mechanisms of drug-host interaction, relative paucity of laboratory testing that is available for any definitive and confirmatory drug-specific testing. Therefore, in practice, the diagnosis of ACDR is purely based on clinical judgment. In this discussion, we will be primarily focusing on pathomechanism and approach to reach a diagnosis, which is the vital pillar to manage any case of ACDR. PMID:19967009

  11. Teratogenic potential of antiepileptic drugs in the zebrafish model.

    PubMed

    Lee, Sung Hak; Kang, Jung Won; Lin, Tao; Lee, Jae Eun; Jin, Dong Il

    2013-01-01

    The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs) arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ), ethosuximide (ETX), valproic acid (VPN), lamotrigine (LMT), lacosamide (LCM), levetiracetam (LVT), and topiramate (TPM)) in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf)) to termination of hatching (72 hpf) which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI) of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data. PMID:24324971

  12. Cognitive/behavioral teratogenetic effects of antiepileptic drugs

    PubMed Central

    Meador, Kimford J.; Baker, Gus; Cohen, Morris J.; Gaily, Eija; Westerveld, Michael

    2009-01-01

    The majority of children of mothers with epilepsy are normal, but they are at increased risk for developmental delay. Antiepileptic drugs (AEDs) appear to play a role. Our current knowledge is reviewed, including research design issues and recommendations for future research. In animals, exposure of the immature brain to some AEDs can produce widespread neuronal apoptosis and behavioral deficits. The risks of AEDs in humans are less clear, but recent studies raise concerns, especially for valproate. There is a critical need for well-designed systematic research to improve our understanding of AED effects on the fetal brain. PMID:17996637

  13. Antiepileptic drug use in women of childbearing age

    PubMed Central

    Meador, Kimford J.; Penovich, Patricia; Baker, Gus A.; Pennell, Page B.; Bromfield, Edward; Pack, Alison; Liporace, Joyce D.; Sam, Maria; Kalayjian, Laura A.; Thurman, David J.; Moore, Eugene; Loring, David W.

    2009-01-01

    Research on antiepileptic drug (AED) teratogenesis has demonstrated an increased risk for valproate. The impact of these findings on current AED prescribing patterns for women of childbearing age with epilepsy is uncertain. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective multicenter observational investigation that enrolled pregnant women with epilepsy on the most common AED monotherapies from October 1999 to February 2004 (carbamazepine, lamotrigine, valproate, and phenytoin). A 2007 survey of AED use in women of childbearing age at eight NEAD centers found a total of 932 women of childbearing age with epilepsy (6% taking no AED, 53% monotherapy, 41% polytherapy). The most common monotherapies were lamotrigine or levetiracetam. Since 2004, prescriptions of carbamazepine, phenytoin, and valproate have decreased, whereas those for levetiracetam have increased. Except for the top two AED monotherapies, there were marked differences in other monotherapies and in polytherapies between U.S. and UK centers. Future investigations are needed to examine reasons for drug choice. PMID:19410654

  14. Antiepileptic drug use in women of childbearing age.

    PubMed

    Meador, Kimford J; Penovich, Patricia; Baker, Gus A; Pennell, Page B; Bromfield, Edward; Pack, Alison; Liporace, Joyce D; Sam, Maria; Kalayjian, Laura A; Thurman, David J; Moore, Eugene; Loring, David W

    2009-07-01

    Research on antiepileptic drug (AED) teratogenesis has demonstrated an increased risk for valproate. The impact of these findings on current AED prescribing patterns for women of childbearing age with epilepsy is uncertain. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective multicenter observational investigation that enrolled pregnant women with epilepsy on the most common AED monotherapies from October 1999 to February 2004 (carbamazepine, lamotrigine, valproate, and phenytoin). A 2007 survey of AED use in women of childbearing age at eight NEAD centers found a total of 932 women of childbearing age with epilepsy (6% taking no AED, 53% monotherapy, 41% polytherapy). The most common monotherapies were lamotrigine or levetiracetam. Since 2004, prescriptions of carbamazepine, phenytoin, and valproate have decreased, whereas those for levetiracetam have increased. Except for the top two AED monotherapies, there were marked differences in other monotherapies and in polytherapies between U.S. and UK centers. Future investigations are needed to examine reasons for drug choice. PMID:19410654

  15. ISMP Adverse Drug Reactions

    PubMed Central

    2013-01-01

    The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration’s (FDA’s) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA’s MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner. PMID:24421544

  16. [Influence of coadministered antiepileptic drugs on serum antiepileptic drug concentrations in epileptic patients -quantitative analysis based on suitable transforming factor].

    PubMed

    Fukuoka, Noriyasu

    2004-07-01

    We conducted a study to clarify the most suitable transforming factor related to the daily dose of antiepileptic drugs (D) providing a steady-state serum concentration (C(t)) and analyzed the influences of the concomitant use of antiepileptic drugs on C(t) quantitatively. Data obtained by routine therapeutic drug monitoring from epileptic patients treated with the multiple oral administration of valproic acid (VPA), carbamazepine (CBZ), zonisamide (ZNS), phenobarbital (PB), and phenytoin (PHT) were used for the analysis. Employing the ideal body weight or the extracellular water volume as a transforming factor, allowed the level/dose (L/D) ratio to be independent of the patient's age and gender for monotherapy with VPA or CBZ, ZNS, PB, and PHT, respectively. Each C(t) was revealed to be dependent on only one variable in terms of the transformed daily dose (D'). C(t) was proportional to the power function of D' for VPA and CBZ and was linearly proportional to D' for ZNS and PB. The L/D ratio is expressed as a linear function of C(t) for PHT. For a detailed analysis of the influences of the coadministered antiepileptic drugs, we defined the parameter as an alteration ratio, representing the influence of each antiepileptic drug on the C(t) of VPA and CBZ alone, and on the L/D ratio of ZNS and PB alone, respectively. A model based on the assumption that each value of an alteration ratio was independent from one other and multiplicative for VPA, CBZ, and ZNS, and that the coadministered drug inhibited the drug-metabolizing enzyme competitively for PB, was adopted. The Michaelis-Menten kinetic model was adopted for PHT. The analysis clarified that CBZ, PB, and PHT significantly lowered (P<0.05) C(t) to 0.81, 0.88, and 0.83 compared with the value of VPA alone, that PB and PHT significantly lowered C(t) to 0.77 and 0.71 compared with the value of CBZ alone, and that VPA, CBZ, PB, and PHT significantly lowered the L/D ratio of ZNS alone to 0.87, 0.85, 0.85, and 0

  17. The challenges of treating epilepsy with 25 antiepileptic drugs.

    PubMed

    Santulli, Lia; Coppola, Antonietta; Balestrini, Simona; Striano, Salvatore

    2016-05-01

    Nowadays a substantial armamentarium of antiepileptic drugs (AEDs) is available, including drugs with different mechanisms of action, pharmacokinetics, efficacy and tolerability; therefore the choice for the right treatment is often challenging. The specific characteristic of the drug, the epileptic syndrome, seizure types and the patient's features need to be taken into consideration driving the choice through available evidence-based studies, which are often lacking for older AEDs. Besides, study conditions in registered clinical trials (RCTs) are quite different from daily clinical practice, which is more complex and various. When dealing with first diagnosed epilepsy, monotherapy is widely accepted as the gold standard option. Likewise, alternative monotherapy should be considered when the first drug treatment fails. However, the association of different AEDs in polytherapy is a common practice. The choice of AEDs used in association is often based on clinical experience or anecdotal observations or small clinical studies. Polytherapy should be as "rational" as possible and consider the mechanism of action, the pharmacokinetic characteristics and the safety of each drug. When dealing with drug resistant patients, clinicians should never give up and consider the use of AEDs acting on new targets. An attempt to come back to a monotherapy or simpler therapeutic regimen should be pursued even in patients who were previously drug resistant. This review will focus on the strategies to treat epilepsy by choosing among 25 available drugs. PMID:26995307

  18. Brain Graph Topology Changes Associated with Anti-Epileptic Drug Use

    PubMed Central

    Levin, Harvey S.; Chiang, Sharon

    2015-01-01

    Abstract Neuroimaging studies of functional connectivity using graph theory have furthered our understanding of the network structure in temporal lobe epilepsy (TLE). Brain network effects of anti-epileptic drugs could influence such studies, but have not been systematically studied. Resting-state functional MRI was analyzed in 25 patients with TLE using graph theory analysis. Patients were divided into two groups based on anti-epileptic medication use: those taking carbamazepine/oxcarbazepine (CBZ/OXC) (n=9) and those not taking CBZ/OXC (n=16) as a part of their medication regimen. The following graph topology metrics were analyzed: global efficiency, betweenness centrality (BC), clustering coefficient, and small-world index. Multiple linear regression was used to examine the association of CBZ/OXC with graph topology. The two groups did not differ from each other based on epilepsy characteristics. Use of CBZ/OXC was associated with a lower BC. Longer epilepsy duration was also associated with a lower BC. These findings can inform graph theory-based studies in patients with TLE. The changes observed are discussed in relation to the anti-epileptic mechanism of action and adverse effects of CBZ/OXC. PMID:25492633

  19. Rufinamide: A Novel Broad-Spectrum Antiepileptic Drug

    PubMed Central

    Wheless, James W; Vazquez, Blanca

    2010-01-01

    The last 20 years have witnessed a tremendous explosion in the number of antiepileptic drugs (AEDs) as well as the introduction of AEDS developed for specific epilepsy syndromes. The study of the efficacy and side effect profile of AEDs for unique epilepsy syndromes has allowed neurologists to utilize evidence-based medicine when treating patients. In late 2008, the Food and Drug Administration approved rufinamide for adjunctive use in the treatment of seizures associated with Lennox–Gastaut syndrome. This unique chemical compound is also the first new AED to reach the market in the United States having a pediatric indication prior to approval for adults. Rufinamide appears to have a broad spectrum of efficacy, is well tolerated, and may be rapidly initiated—properties that will likely extend its use outside of Lennox–Gastaut syndrome. PMID:20126329

  20. Drug interactions involving antiepileptic drugs: assessment of the consistency among three drug compendia and FDA-approved labels.

    PubMed

    Ekstein, Dana; Tirosh, Matanya; Eyal, Yonatan; Eyal, Sara

    2015-03-01

    Interactions of antiepileptic drugs (AEDs) with other substances may lead to adverse effects and treatment failure. To avoid such interactions, clinicians often rely on drug interaction compendia. Our objective was to compare the concordance for twenty-two AEDs among three drug interaction compendia (Micromedex, Lexi-Interact, and Clinical Pharmacology) and the US Food and Drug Administration-approved product labels. For each AED, the overall concordance among data sources regarding existence of interactions and their classification was poor, with less than twenty percent of interactions listed in all four sources. Concordance among the three drug compendia decreased with the fraction of the drug excreted unchanged and was greater for established inducers of hepatic drug-metabolizing enzymes than for the drugs that are not inducers (R-square=0.83, P<0.01). For interactions classified as contraindications, major, and severe, concordance among the four data sources was, in most cases, less than 30%. Prescribers should be aware of the differences between drug interaction sources of information for both older AEDs and newer AEDs, in particular for those AEDs which are not involved in hepatic enzyme-mediated interactions. PMID:25771206

  1. Antiepileptic drugs influences on body weight in people with epilepsy.

    PubMed

    Hamed, Sherifa Ahmed

    2015-01-01

    Data from clinical trials, retrospective and cross-sectional studies have quantified the metabolic changes associated with long-term use of antiepileptic drugs (AEDs). AEDs can be associated with weight gain or weight loss, although most are weight neutral. Weight gain is not only a cosmetic problem but also a risk for obesity-related vascular disorders. Weight loss may compromise growth in children/adolescents. This review discusses the possible contribution of peripheral and central hormones/neuropeptides (as leptin, insulin, adiponectin, neuropeptide-Y, ghrelin and galanin) and pathways that influence energy balance in the pathogenesis of weight changes with AEDs. As AEDs may influence weight, physicians have to properly select and characterize the suitable AED as an initial step or modify the existing AED if it compromises patient's health. PMID:25487080

  2. Modifications of Antiepileptic Drugs for Improved Tolerability and Efficacy

    PubMed Central

    Landmark, Cecilie Johannessen; Johannessen, Svein I.

    2008-01-01

    Introduction A large number of antiepileptic drugs (AEDs) are available today, but they may not be satisfactory regarding clinical efficacy, tolerance, toxicity or pharmacokinetic properties. The purpose of this review is to focus upon the rationale behind the chemical modifications of several recently marketed AEDs or drugs in development and to categorize them according to the main purposes for the improvements: better efficacy or tolerability accompanied by improved pharmacokinetic properties. Material and Method AEDs that have been chemically modified to new derivatives during the last years are reviewed based on recent publications and PubMed-searches. Results and Discussion Improvement in pharmacokinetic parameters may affect both tolerability and efficacy. Modifications to improve tolerability include various valproate analogues, divided into aliphatic amides, cyclic derivatives or amino acid conjugates. Furthermore, there are the carbamazepine analogues oxcarbazepine and eslicarbazepine, the felbamate analogues fluorofelbamate and carisbamate (RWJ 33369), and the lamotrigine analogue JZP-4. The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds. Other new drugs have new mechanisms of action related to GABA and glutamate receptors; the glutamate antagonists like topiramate (talampanel and NS-1209), and GABAA receptor agonists, benzodiazepine or progesterone analogues (ELB-139 and ganaxolone). Conclusion Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity. These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders. PMID:19787095

  3. New antiepileptic drugs: focus on ezogabine, clobazam, and perampanel.

    PubMed

    Rudzinski, Leslie A; Vélez-Ruiz, Naymeé J; Gedzelman, Evan R; Mauricio, Elizabeth A; Shih, Jerry J; Karakis, Ioannis

    2016-08-01

    Ezogabine, clobazam, and perampanel are among the newest antiseizure drugs approved by the Food and Drug Administration between 2011 and 2012. Ezogabine and perampanel are approved for adjunctive treatment of partial epilepsy. Perampanel is also approved for adjunctive treatment of primary generalized tonic-clonic seizures. Ezogabine and perampanel have novel mechanisms of action. Ezogabine binds to voltage-gated potassium channels and increases the M-current thereby causing membrane hyperpolarization. Perampanel is a selective, non-competitive 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid receptor antagonist, which reduces neuronal excitation. Clobazam has been used worldwide since the 1970s and is approved for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. Clobazam is the only 1,5-benzodiazepine currently in clinical use, which is less sedating than the commonly used 1,4-benzodiazepines. Phase III multicenter, randomized, double-blind, placebo-controlled trials demonstrated efficacy and good tolerability of these 3 new antiepileptic drugs. These drugs represent a welcome addition to the armamentarium of practitioners, but it remains to be seen how they will affect the landscape of pharmacoresistant epilepsy. PMID:27252470

  4. Diverse Mechanisms of Antiepileptic Drugs in the Development Pipeline

    PubMed Central

    Rogawski, Michael A.

    2006-01-01

    There is a remarkable array of new chemical entities in the current antiepileptic drug (AED) development pipeline. In some cases, the compounds were synthesized in an attempt improve upon the activity of marketed AEDs. In other cases, the discovery of antiepileptic potential was largely serendipitous. Entry into the pipeline begins with the demonstration of activity in one or more animal screening models. Results from testing in a panel of such models provide a basis to differentiate agents and may offer clues as to the mechanism. Target activity may then be defined through cell-based studies, often years after the initial identification of activity. Some pipeline compounds are believed to act through conventional targets, whereas others are structurally novel and may act by novel mechanisms. Follow-on agents include the levetiracetam analogs brivaracetam and seletracetam that act as SV2A-ligands; the valproate-like agents valrocemide, valnoctamide, propylisopropyl acetamide, and isovaleramide; the felbamate analog flurofelbamate, a dicarbamate, and the unrelated carbamate RWJ-333369; the oxcarbazepine analog licarbazepine, which probably acts as a use-dependent sodium channel blockers, and its prodrug acetate BIA 2-093; and various selective partial benzodiazepine receptor agonists, including ELB139, which is a positive allosteric modulator of α3-containing GABAA receptors. A variety of AEDs that may act through novel targets are also in clinical development: lacosamide, a functionalized amino acid; talampanel, a 2,3-benzodiazepine selective noncompetitive AMPA receptor antagonist; NS1209, a competitive AMPA receptor antagonist; ganaxolone, a neuroactive steroid that acts as a positive modulator of GABAA receptors; retigabine, a KCNQ potassium channel opener with activity as a GABAA receptor positive modulator; the benzanilide KCNQ potassium channel opener ICA-27243 that is more selective than retigabine; and rufinamide, a triazole of unknown mechanism. PMID

  5. Evidence for epistatic interactions in antiepileptic drug resistance.

    PubMed

    Kim, Myeong-Kyu; Moore, Jason H; Kim, Jong-Ki; Cho, Ki-Hyun; Cho, Yong-Won; Kim, Yo-Sik; Lee, Min-Cheol; Kim, Young-Ok; Shin, Min-Ho

    2011-01-01

    To investigate the epistatic interactions involved in antiepileptic drug (AED) resistance, 26 coding single-nucleotide polymorphisms (SNPs) were selected from 16 candidate genes. A total of 200 patients with drug-resistant localization-related epilepsy and 200 patients with drug-responsive localization-related epilepsy were genotyped individually for the SNPs. Rather than using the traditional parametric statistical method, a new statistical method, multifactor dimensionality reduction (MDR), was used to determine whether gene-gene interactions increase the risk of AED resistance. The MDR method indicated that a combination of four SNPs (rs12658835 and rs35166395 from GABRA1, rs2228622 from EAAT3 and rs2304725 from GAT3) was the best model for predicting susceptibility to AED resistance with a statistically significant testing accuracy of 0.625 (P < 0.001) and cross-validation consistency of 10/10. This best model had an odds ratio of 3.68 with a significant 95% confidence interval of 2.32-5.85 (P < 0.0001). Our results may provide meaningful information on the mechanism underlying AED resistance and, to the best of our knowledge, this is the first report of evidence for gene-gene interactions underlying AED resistance. PMID:21124337

  6. Antiepileptic Drugs with Mood Stabilizing Properties and Their Relation with Psychotropic Drug Use in Institutionalized Epilepsy Patients with Intellectual Disability

    ERIC Educational Resources Information Center

    Leunissen, C. L. F.; de la Parra, N. M.; Tan, I. Y.; Rentmeester, Th. W.; Vader, C. I.; Veendrick-Meekes, M. J. B. M.; Aldenkamp, A. P.

    2011-01-01

    A large number of patients with epilepsy and intellectual disability take medication, amongst which antiepileptic and psychotropic drugs, often simultaneously. Certain antiepileptic drugs have mood-stabilizing properties, e.g. carbamazepine, valproic acid and lamotrigine. The aim of this study was to investigate whether the use of these…

  7. Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6years.

    PubMed

    Cohen, Morris J; Meador, Kimford J; Browning, Nancy; May, Ryan; Baker, Gus A; Clayton-Smith, Jill; Kalayjian, Laura A; Kanner, Andres; Liporace, Joyce D; Pennell, Page B; Privitera, Michael; Loring, David W

    2013-11-01

    The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate). In this report, we examine fetal AED exposure effects on adaptive and emotional/behavioral functioning at 6years of age in 195 children (including three sets of twins) whose parent (in most cases, the mother) completed at least one of the rating scales. Adjusted mean scores for the four AED groups were in the low average to average range for parent ratings of adaptive functioning on the Adaptive Behavior Assessment System-Second Edition (ABAS-II) and for parent and teacher ratings of emotional/behavioral functioning on the Behavior Assessment System for Children (BASC). However, children whose mothers took valproate during pregnancy had significantly lower General Adaptive Composite scores than the lamotrigine and phenytoin groups. Further, a significant dose-related performance decline in parental ratings of adaptive functioning was seen for both valproate and phenytoin. Children whose mothers took valproate were also rated by their parents as exhibiting significantly more atypical behaviors and inattention than those in the lamotrigine and phenytoin groups. Based upon BASC parent and teacher ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy were at a significantly greater risk for a diagnosis of ADHD. The increased likelihood of difficulty with adaptive functioning and ADHD with fetal valproate exposure should be communicated to women with epilepsy who require antiepileptic medication. Finally, additional research is needed to confirm these findings in larger prospective study samples, examine

  8. Adverse Reactions to Hallucinogenic Drugs.

    ERIC Educational Resources Information Center

    Meyer, Roger E. , Ed.

    This reports a conference of psychologists, psychiatrists, geneticists and others concerned with the biological and psychological effects of lysergic acid diethylamide and other hallucinogenic drugs. Clinical data are presented on adverse drug reactions. The difficulty of determining the causes of adverse reactions is discussed, as are different…

  9. Selected pharmacokinetic issues of the use of antiepileptic drugs and parenteral nutrition in critically ill patients

    PubMed Central

    2010-01-01

    Objectives To conduct a systematic review for the evidence supporting or disproving the reality of parenteral nutrition- antiepileptic drugs interaction, especially with respect to the plasma protein-binding of the drug. Methods The articles related to the topic were identified through Medline and PubMed search (1968-Feburary 2010) for English language on the interaction between parenteral nutrition and antiepileptic drugs; the search terms used were anti-epileptic drugs, parenteral nutrition, and/or interaction, and/or in vitro. The search looked for prospective randomized and nonrandomized controlled studies; prospective nonrandomized uncontrolled studies; retrospective studies; case reports; and in vitro studies. Full text of the articles were then traced from the Universiti Sains Malaysia (USM) library subscribed databases, including Wiley-Blackwell Library, Cochrane Library, EBSCOHost, OVID, ScienceDirect, SAGE Premier, Scopus, SpringerLINK, and Wiley InterScience. The articles from journals not listed by USM library were traced through inter library loan. Results There were interactions between parenteral nutrition and drugs, including antiepileptics. Several guidelines were designed for the management of illnesses such as traumatic brain injuries or cancer patients, involving the use of parenteral nutrition and antiepileptics. Moreover, many studies demonstrated the in vitro and in vivo parenteral nutrition -drugs interactions, especially with antiepileptics. Conclusions There was no evidence supporting the existence of parenteral nutrition-antiepileptic drugs interaction. The issue has not been studied in formal researches, but several case reports and anecdotes demonstrate this drug-nutrition interaction. However, alteration in the drug-free fraction result from parenteral nutrition-drug (i.e. antiepileptics) interactions may necessitate scrupulous reassessment of drug dosages in patients receiving these therapies. This reassessment may be particularly

  10. Polycystic ovary syndrome in patients on antiepileptic drugs

    PubMed Central

    Viswanathan, Lakshminarayanapuram G.; Satishchandra, Parthasarathy; Bhimani, Bipin C.; Reddy, Janardhan YC; Rama Murthy, Batchu S.; Subbakrishna, Doddaballapura K.; Sinha, Sanjib

    2016-01-01

    Objective: This study aims to discuss the prevalence of polycystic ovary (PCO) and Polycystic ovary syndrome (PCOS) in women with epilepsy (WWE) on valproate (VPA), carbamazepine (CBZ), or phenobarbitone (PB), drug naive WWE and women with bipolar affective disorder (BPAD) on VPA. Materials and Methods: This prospective study included 190 women aged 18–45 years, who had epilepsy or BPAD (on VPA), and consented for study. Patients were grouped as Group 1 (n = 40): WWE on VPA, Group 2 (n = 50): WWE on CBZ, Group 3 (n = 50): WWE on PB, Group 4 (n = 30): drug naïve WWE, and Group 5 (n = 20): women with BPAD on VPA. All women were interviewed for medical, menstrual, drug and treatment history, nature of epilepsy, and seizure control. Chi-square test and Fisher's exact test were done to compare results between the groups. Results: Fifty-two women (52/190; 27.4%) had menstrual disturbances, in which oligomenorrhea was the most common (55.8%). There was a significant difference in the occurrence of PCOS in patients on VPA versus normal population (P = 0.05) and patients on other antiepileptic drugs (AEDs) (P = 0.02). There was, however, no significant difference in the occurrence of PCO between patients on VPA and the untreated epileptic women. VPA group (Epilepsy + BPAD) had a significantly higher occurrence of obesity than other treatment groups (P = 0.043, OR = 2.11). Conclusions: The study observed significantly higher occurrence of PCO in patients on VPA compared to other AEDs and the normal population. The importance of proper clinical evaluation before initiating VPA is highlighted. PMID:27570385

  11. Short-term use of antiepileptic drugs is neurotoxic to the immature brain

    PubMed Central

    Liu, Yu; Wang, Xue-ying; Li, Dan; Yang, Lin; Huang, Shao-ping

    2015-01-01

    Previous studies have shown that the long-term use of antiepileptic drugs can cause nervous system damage. However, short-term antiepileptic drug treatment is frequently given to infants, especially neonates, to control seizure. Whether the short-term use of antiepileptic drugs is neurotoxic remains unclear. In the present study, immature rats, 3–21 days of age, were intraperitoneally injected with phenobarbital and/or topiramate for 3 consecutive days. Hematoxylin-eosin and immunohistochemical staining revealed that phenobarbital and topiramate, individually or in combination, were cytotoxic to hippocampal CA1 neurons and inhibited the expression of GluR1 and NR2B, excitatory glutamate receptor subunits. Furthermore, the combination of the two drugs caused greater damage than either drug alone. The results demonstrate that the short-term use of antiepileptic drugs damages neurons in the immature brain and that the combined use of antiepileptic drugs exacerbates damage. Our findings suggest that clinicians should consider the potential neurotoxic risk associated with the combined use of antiepileptic drugs in the treatment of seizure. PMID:26170821

  12. Enhancing antiepileptic drug adherence: a randomized controlled trial.

    PubMed

    Brown, Ian; Sheeran, Paschal; Reuber, Markus

    2009-12-01

    Suboptimal adherence to antiepileptic drug (AED) treatment is commonplace, and increases the risk of status epilepticus and sudden unexplained death in epilepsy. This randomized controlled trial was designed to demonstrate whether an implementation intention intervention involving the completion of a simple self-administered questionnaire linking the intention of taking medication with a particular time, place, and other activity can improve AED treatment schedule adherence. Of the 81 patients with epilepsy who were randomized, 69 completed a 1-month monitoring period with an objective measure of tablet taking (electronic registration of pill bottle openings, Medication Event Monitoring System [MEMS]). Intervention participants showed improved adherence relative to controls on all three outcomes: doses taken in total (93.4% vs. 79.1%), days on which correct dose was taken (88.7% vs. 65.3%), and doses taken on schedule (78.8% vs. 55.3%) (P<0.01). The implementation intention intervention may be an easy-to-administer and effective means of promoting AED adherence. PMID:19864187

  13. Adverse Drug Interactions

    PubMed Central

    Becker, Daniel E.

    2011-01-01

    The potential for interactions with current medications should always be considered when administering or prescribing any drug. Considering the staggering number of drugs patients may be taking, this task can be daunting. Fortunately, drug classes employed in dental practice are relatively few in number and therapy is generally brief in duration. While this reduces the volume of potential interactions, there are still a significant number to be considered. This article will review basic principles of drug interactions and highlight those of greatest concern in dental practice. PMID:21410363

  14. Parent-reported subjective complaints in children using antiepileptic drugs: what do they mean?

    PubMed

    Carpay, Johannes A.; Vermeulen, Jan; Stroink, Hans; Brouwer, Oebele F.; Boudewyn Peters, A C.; Aldenkamp, Albert P.; van Donselaar, Cees A.; Arts, Willem F.M.

    2002-08-01

    We used a parent-completed 20-item "side effect scale" quantifying complaints that parents perceive to be caused by antiepileptic drugs (AEDs) in 108 children with active epilepsy. We studied the associations between parent-reported complaints, severity of seizures, and restrictions due to epilepsy, and clinical data including number and AED load. In 85% of the children at least one complaint was reported, in less than 20% complaints were perceived as a substantial problem. In a multivariate analysis, there was no significant relationship between the "side effect scale" score and AED load, or the number of AEDs. However, complaints were associated with parent-reported frequency and severity of seizures. We conclude that the adverse effects of seizures or parental concern about the severity and intractability of seizures in their children may have influenced the reported complaints. PMID:12609329

  15. Adverse ocular reactions to drugs.

    PubMed Central

    Spiteri, M. A.; James, D. G.

    1983-01-01

    Drugs acting on various parts of the body may also affect the eye insidiously. Increased awareness of such drug toxicity by the prescribing doctor should encourage him to consider effects on the cornea, lens, retina, optic nerve and elsewhere when checking the patient's progress. The following review concerns adverse ocular effects of systemic drug administration. PMID:6356101

  16. Semi-automated continuous-flow enzyme immunoassay for antiepileptic drugs in serum.

    PubMed

    Hayashi, S; Kurooka, S; Arisue, K; Kohda, K; Hayashi, C

    1983-10-01

    We have developed a semi-automated method for measuring five kinds of antiepileptic drugs in serum by successfully adapting commercial competitive-binding enzyme immunoassay kits (MARKIT; Dainippon) for use with a continuous-flow analyzer (Technicon AutoAnalyzer II equipped with a dialyzer). The free enzyme-labeled drug is automatically separated by a microfilter from the competitive immunoreaction mixture between labeled and unlabeled drug for anti-drug immunoglobulin coupled to bacterial cell walls. The concentrations of the antiepileptic drugs in serum samples can be determined by automated measurement of enzyme activity of the enzyme-labeled drugs. Results of the semi-automated method correlated well with those obtained by manual enzyme immunoassay, gas-liquid chromatography, and "high-pressure" liquid chromatography. The correlation coefficients were all greater than 0.95, showing the practicality of this method for therapeutic monitoring of antiepileptic drugs. PMID:6352086

  17. Current Status of the New Antiepileptic Drugs in Chronic Pain

    PubMed Central

    Sidhu, Harpreet S.; Sadhotra, Akshay

    2016-01-01

    Antiepileptic drugs (AEDs) are extensively used worldwide to treat a wide range of disorders other than epilepsy, such as neuropathic pain, migraine, and bipolar disorder. Due to this situation more than 20 new third-generation AEDs have been introduced in the market recently. The future design of new AEDs must also have potential to help in the non-epileptic disorders. The wide acceptance of second generation AEDs for the management of various non-epileptic disorders has caused the emergence of generics in the market. The wide use of approved AEDs outside epilepsy is based on both economic and scientific reasons. Bipolar disorders, migraine prophylaxis, fibromyalgia, and neuropathic pain represent the most attractive indication expansion opportunities for anticonvulsant developers, providing blockbuster revenues. Strong growth in non-epilepsy conditions will see Pfizer’s Lyrica become the market leading brand by 2018. In this review, we mainly focus on the current status of new AEDs in the treatment of chronic pain and migraine prophylaxis. AEDs have a strong analgesic potential and this is demonstrated by the wide use of carbamazepine in trigeminal neuralgia and sodium valproate in migraine prophylaxis. At present, data on the new AEDs for non-epileptic conditions are inconclusive. Not all AEDs are effective in the management of neuropathic pain and migraine. Only those AEDs whose mechanisms of action are match with pathophysiology of the disease, have potential to show efficacy in non-epileptic disorder. For this better understanding of the pathophysiology of the disease and mechanisms of action of new AEDs are essential requirement before initiating pre-clinical and clinical trials. Many new AEDs show good results in the animal model and open-label studies but fail to provide strong evidence at randomized, placebo-controlled trials. The final decision regarding the clinical efficacy of the particular AEDs in a specific non-epileptic disorder should be

  18. Current Status of the New Antiepileptic Drugs in Chronic Pain.

    PubMed

    Sidhu, Harpreet S; Sadhotra, Akshay

    2016-01-01

    Antiepileptic drugs (AEDs) are extensively used worldwide to treat a wide range of disorders other than epilepsy, such as neuropathic pain, migraine, and bipolar disorder. Due to this situation more than 20 new third-generation AEDs have been introduced in the market recently. The future design of new AEDs must also have potential to help in the non-epileptic disorders. The wide acceptance of second generation AEDs for the management of various non-epileptic disorders has caused the emergence of generics in the market. The wide use of approved AEDs outside epilepsy is based on both economic and scientific reasons. Bipolar disorders, migraine prophylaxis, fibromyalgia, and neuropathic pain represent the most attractive indication expansion opportunities for anticonvulsant developers, providing blockbuster revenues. Strong growth in non-epilepsy conditions will see Pfizer's Lyrica become the market leading brand by 2018. In this review, we mainly focus on the current status of new AEDs in the treatment of chronic pain and migraine prophylaxis. AEDs have a strong analgesic potential and this is demonstrated by the wide use of carbamazepine in trigeminal neuralgia and sodium valproate in migraine prophylaxis. At present, data on the new AEDs for non-epileptic conditions are inconclusive. Not all AEDs are effective in the management of neuropathic pain and migraine. Only those AEDs whose mechanisms of action are match with pathophysiology of the disease, have potential to show efficacy in non-epileptic disorder. For this better understanding of the pathophysiology of the disease and mechanisms of action of new AEDs are essential requirement before initiating pre-clinical and clinical trials. Many new AEDs show good results in the animal model and open-label studies but fail to provide strong evidence at randomized, placebo-controlled trials. The final decision regarding the clinical efficacy of the particular AEDs in a specific non-epileptic disorder should be

  19. Effects of breastfeeding in children of women taking antiepileptic drugs(e–Pub ahead of print)(Patient Page)

    PubMed Central

    Meador, K.J.; Baker, G.A.; Browning, N.; Clayton-Smith, J.; Combs-Cantrell, D.T.; Cohen, M.; Kalayjian, L.A.; Kanner, A.; Liporace, J.D.; Pennell, P.B.; Privitera, M.; Loring, D.W.

    2010-01-01

    Background: Breastfeeding is known to have beneficial effects, but there is concern that breastfeeding during antiepileptic drug (AED) therapy may be harmful to cognitive development. Animal and human studies have demonstrated that some AEDs can adversely affect the immature brain. However, no investigation has examined effects of breastfeeding during AED therapy on subsequent cognitive abilities in children. Methods: The Neurodevelopmental Effects of Antiepileptic Drugs Study is an ongoing prospective multicenter observational investigation of long-term effects of in utero AED exposure on cognition. Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single AED (carbamazepine, lamotrigine, phenytoin, or valproate). We recently reported on differential AED effects on age 3 year cognitive outcomes. In this report, we focus on the effects of breastfeeding during AED therapy on age 3 cognitive outcomes in 199 children. Results: A total of 42% of children were breastfed. IQs for breastfed children did not differ from nonbreastfed children for all AEDs combined and for each of the 4 individual AED groups. Mean adjusted IQ scores (95% confidence intervals) across all AEDs were breastfed = 99 (96–103) and nonbreastfed = 98 (95–101). Power was 95% to detect a half SD IQ effect in the combined AED analysis, but was inadequate within groups. Conclusions: This preliminary analysis fails to demonstrate deleterious effects of breastfeeding during AED therapy on cognitive outcomes in children previously exposed in utero. However, caution is advised due to study limitations. Additional research is needed to confirm this observation and extend investigations to other AEDs and polytherapy. GLOSSARY AED = antiepileptic drug; NART = National Adult Reading Test; NEAD = Neurodevelopmental Effects of Antiepileptic Drugs; TONI = Test of Nonverbal Intelligence; WASI = Wechsler Abbreviated Scale of Intelligence. PMID:21106960

  20. Adverse drug reactions and organ damage: The skin.

    PubMed

    Marzano, Angelo V; Borghi, Alessandro; Cugno, Massimo

    2016-03-01

    Cutaneous adverse drug reactions are frequent, affecting 2-3% of hospitalized patients and in one twentieth of them are potentially life-threatening. Almost any pharmacologic agent can induce skin reactions, and certain drug classes, such as non-steroidal anti-inflammatory drugs, antibiotics and antiepileptics, have drug eruption rates ranging from 1% to 5%. Cutaneous drug reactions recognize several different pathomechanisms: some skin manifestations are immune-mediated like allergic reactions while others are the result of non immunological causes such as cumulative toxicity, photosensitivity, interaction with other drugs or different metabolic pathways. Cutaneous adverse drug reactions can be classified into two groups: common non-severe and rare life-threatening adverse drug reactions. Non-severe reactions are often exanthematous or urticarial whereas life-threatening reactions typically present with skin detachment or necrosis of large areas of the body and mucous membrane involvement, as in the Stevens-Johnson syndrome or toxic epidermal necrolysis. Clinicians should carefully evaluate the signs and symptoms of all cutaneous adverse drug reactions thought to be due to drugs and immediately discontinue drugs that are not essential. Short cycles of systemic corticosteroids in combination with antihistamines may be necessary for widespread exanthematous rashes, while more aggressive corticosteroid regimens or intravenous immunoglobulins associated with supportive treatment should be used for patients with Stevens-Johnson syndrome or toxic epidermal necrolysis. PMID:26674736

  1. A Study into the Possible Link between Anti-Epileptic Drugs and the Risk of Fractures in Muckamore Abbey Hospital.

    ERIC Educational Resources Information Center

    Tohill, Carmel

    1997-01-01

    A study investigated whether the effects of anti-epileptic drugs were (carbamazepine, phenobarbitone, and phenytoin) related, to the incidence of fractures in 85 Irish patients. If patients were only on one antiepileptic drug, there appeared to be no correlation; however, if patients were taking a combination of three drugs, they were more likely…

  2. The effects of antiepileptic drugs on the growth of glioblastoma cell lines.

    PubMed

    Lee, Ching-Yi; Lai, Hung-Yi; Chiu, Angela; Chan, She-Hung; Hsiao, Ling-Ping; Lee, Shih-Tseng

    2016-05-01

    To determine the effects of antiepileptic drug compounds on glioblastoma cellular growth, we exposed glioblastoma cell lines to select antiepileptic drugs. The effects of selected antiepileptic drugs on glioblastoma cells were measured by MTT assay. For compounds showing significant inhibition, cell cycle analysis was performed. Statistical analysis was performed using SPSS. The antiepileptic compounds selected for screening included carbamazepine, ethosuximide, gabapentin, lamotrigine, levetiracetam, magnesium sulfate, oxcarbazepine, phenytoin, primidone, tiagabine, topiramate, valproic acid, and vigabatrin. Dexamethasone and temozolomide were used as a negative and positive control respectively. Our results showed temozolomide and oxcarbazepine significantly inhibited glioblastoma cell growth and reached IC50 at therapeutic concentrations. The other antiepileptic drugs screened were unable to reach IC50 at therapeutic concentrations. The metabolites of oxcarbazepine were also unable to reach IC50. Dexamethasone, ethosuximide, levetiracetam, and vigabatrin showed some growth enhancement though they did not reach statistical significance. The growth enhancement effects of ethosuximide, levetiracetam, and vigabatrin found in the study may indicate that these compounds should not be used for prophylaxis or short term treatment of epilepsy in glioblastoma. While valproic acid and oxcarbazepine were effective, the required dose of valproic acid was far above that used for the treatment of epilepsy and the metabolites of oxcarbazepine failed to reach significant growth inhibition ruling out the use of oral oxcarbazepine or valproic acid as monotherapy in glioblastoma. The possibility of using these compounds as local treatment is a future area of study. PMID:26758059

  3. Developmental effects of antiepileptic drugs and the need for improved regulations.

    PubMed

    Meador, Kimford J; Loring, David W

    2016-01-19

    Antiepileptic drugs (AEDs) are among the most common teratogenic drugs prescribed to women of childbearing age. AEDs can induce both anatomical (malformations) and behavioral (cognitive/behavioral deficits) teratogenicity. Only in the last decade have we begun to truly discriminate differential AED developmental effects. Fetal valproate exposure carries a special risk for both anatomical and behavioral teratogenic abnormalities, but the mechanisms and reasons for individual variability are unknown. Intermediate anatomical risks exist for phenobarbital and topiramate. Several AEDs (e.g., lamotrigine and levetiracetam) appear to possess low risks for both anatomical and behavioral teratogenesis. Despite advances in the past decade, our knowledge of the teratogenic risks for most AEDs and the underlying mechanisms remain inadequate. Further, the long-term effects of AEDs in neonates and older children remain uncertain. The pace of progress is slow given the lifelong consequences of diminished developmental outcomes, exposing children unnecessarily to potential adverse effects. It is imperative that new approaches be employed to determine risks more expediently. Our recommendations include a national reporting system for congenital malformations, federal funding of the North American AED Pregnancy Registry, routine meta-analyses of cohort studies to detect teratogenic signals, monitoring of AED prescription practices for women, routine preclinical testing of all new AEDs for neurodevelopmental effects, more specific Food and Drug Administration requirements to establish differential AED cognitive effects in children, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms for AED-induced anatomical and behavioral teratogenesis. PMID:26519545

  4. Human placental perfusion method in the assessment of transplacental passage of antiepileptic drugs

    SciTech Connect

    Myllynen, Paeivi . E-mail: paivi.k.myllynen@oulu.fi; Pienimaeki, Paeivi; Vaehaekangas, Kirsi

    2005-09-01

    Epilepsy is one of the most common neurological diseases, affecting about 0.5 to 1% of pregnant women. It is commonly accepted that older antiepileptic drugs bear teratogenic potential. So far, no agreement has been reached about the safest antiepileptic drug during pregnancy. It is known that nearly all drugs cross the placenta at least to some extent. Nowadays, there is very little information available of the pharmacokinetics of drugs in the feto-placental unit. Detailed information about drug transport across the placenta would be valuable for the development of safe and effective treatments. For reasons of safety, human studies on placental transfer are restricted to a limited number of drugs. Interspecies differences limit the extrapolation of animal data to humans. Several in vitro methods for the study of placental transfer have been developed over the past decades. The placental perfusion method is the only experimental method that has been used to study human placental transfer of substances in organized placental tissue. The aim of this article is to review human placental perfusion data on antiepileptic drugs. According to perfusion data, it seems that most of the antiepileptic drugs are transferred across the placenta meaning significant fetal exposure.

  5. Psychotropic and Antiepileptic Drug Treatment in Early Childhood Special Education. Final Report.

    ERIC Educational Resources Information Center

    Gadow, Kenneth D.

    The effectiveness of psychotropic and antiepileptic drug treatment was investigated with approximately 2500 children receiving educational services in early childhood special education programs. The study consisted of three phases: phase 1 in which all teachers were surveyed to determine the prevalence of drug therapy and patterns of usage, phase…

  6. Adjusting to a seizure-free "new normal" life following discontinuation of antiepileptic drugs during adolescence.

    PubMed

    Chiu, Ya-Ping; Lee, Tzu-Ying; Lin, Kuang-Lin; Laadt, Virginia L

    2014-04-01

    This qualitative study sought to understand how children in adolescence adjust to their newly acquired normal life without epilepsy, following discontinuation of antiepileptic drugs during this dynamic period of growth and development. Three major themes with subthemes were identified: 1) setting the body and mind free; 2) engaging in self-regulation; and 3) protection by significant others. A sense of relief from constraints related to treatment schedules, special diets, and avoiding seizure-provoking activities was expressed by all participants. Freedom from side effects of the antiepileptic drugs improved life at home and school. Most of the participants said that they were not worried about seizure recurrence but would use caution against a possible relapse. Family members also must adjust to a new lifestyle. Medical staff needs to provide support and adequate care to adolescents during their period of identity adjustment following antiepileptic drug discontinuation. PMID:24632354

  7. Antiepileptic drugs for the treatment of neuropathic pain: A systematic review

    PubMed Central

    Vargas-Espinosa, Maríam L.; Sanmartí-García, Gemma; Vázquez-Delgado, Eduardo

    2012-01-01

    Many therapies have been proposed for the management of neuropathic pain, and they include the use of different antiepileptic drugs. However, the lack of high quality studies indicates that results on the different neuropathic disorders under study do not recommend a particular drug treatment. This study makes a systematic review of the published literature on the use of several antiepileptic drugs to treat neuropathic pain, and has the objective of considering both its clinical characteristics and pharmacological use, which will depend on their level of scientific evidence and will follow the principles of evidence-based dentistry. The articles were stratified according to their scientific evidence using the SORT criteria (Strength of Recommendation Taxonomy), and it included those articles that only have level 1 or 2. Randomized clinical trials were stratified according to their level of quality using the JADAD scale, an instrument described by Jadad et al. (7). to assess the quality of clinical trials, while studies with a level below 3 were discarded. Recently, type A or B recommendations are given in favor or against the use of antiepileptic drugs to treat neuropathic pain on the basis of their scientific quality. Key words:Neuropathic pain, antiepileptic drugs (AEDs), trigeminal neuralgia, glossopharyngeal neuralgia, post- herpetic neuralgia, burning mouth syndrome, persistent idiopathic facial pain. PMID:22549682

  8. Cutaneous adverse drug reactions in Indian population: A systematic review

    PubMed Central

    Patel, Tejas K; Thakkar, Sejal H; Sharma, DC

    2014-01-01

    Background: Epidemiological data is limited for cutaneous adverse drug reactions (CADRs) in India. Most of the Indian studies have small sample size and are of limited duration. Aims: The aim of this study is to analyze CADRs with reference to the causative drugs and their clinical characteristics in Indian population. Materials and Methods: As per selection criteria, electronic databases were searched for publications describing CADRs from January-1995 to April-2013 by two independent investigators. Data of the causative drugs and clinical characteristics were extracted and summarized by absolute numbers, percentages, ranges, and means as presented by the authors. The subgroup analysis of causative drugs was performed for causality assessment, severe or nonsevere reactions and occurrence of common CADRs. Studies showing “definite” and “probable” categories of causality analysis were labeled as “definite and probable causality (DPC) studies”. The other included studies were labeled as “non-DPC studies”. Results: Of 8337 retrieved references, 18 prospective studies were selected for analysis. The pooled incidence was 9.22/1000 total among outpatient and inpatient cases. Commonly observed reactions were maculopapular rash (32.39%), fixed drug eruptions (FDEs) (20.13%), urticaria (17.49%) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) (6.84%). The major causative drug groups were antimicrobials (45.46%), nonsteroidal anti-inflammatory drugs (NSAIDs) (20.87%) and anti-epileptic drugs (14.57%). Commonly implicated drugs were sulfa (13.32%), β-lactams (8.96%) and carbamazepine (6.65%). High frequency of CADRs is observed with anti-epileptic drugs in DPC studies only. Carbamazepine, phenytoin and fluoroquinolones had higher severe to nonsevere cutaneous reaction ratio than other drugs. Antimicrobials were the main causative drugs for maculopapular rash, FDEs and SJS/TEN, and NSAIDs for the urticaria. The mortality for overall CADRs, SJS

  9. New generation antiepileptic drugs: what do they offer in terms of improved tolerability and safety?

    PubMed Central

    Gazzola, Deana M.

    2011-01-01

    Over the last two decades a total of 11 antiepileptic drugs (AEDs) have been introduced to the US market. Randomized, placebo-controlled trials have yielded information about each drug’s efficacy, tolerability, and safety profile; however, few studies have compared the newer generation AEDs directly with the older generation. Comparative studies are not always straightforward in their interpretation, as many characteristics of drugs, both favorable and unfavorable, may not be highlighted by such studies. In general, findings from the literature suggest that the newer generation AEDs (including vigabatrin, felbamate, gabapentin, lamotrigine, tiagabine, topiramate, levetiracetam, oxcarbazepine, zonisamide, pregabalin, rufinamide, and lacosamide) enjoy both improved tolerability and safety compared with older agents such as phenobarbital, phenytoin, carbamazepine, and valproate. This is partially supported by some of the findings of the QSS and the TTA Committee of the American Academy of Neurology (AAN), whose review of four AEDs (gabapentin, lamotrigine, topiramate, and tiagabine) is discussed. Briefly, when compared with carbamazepine, lamotrigine was better tolerated; topiramate adverse events (AEs) were fairly comparable to carbamazepine and valproate; and tiagabine compared with placebo was associated with a higher discontinuation rate due to AEs. The findings of the SANAD trial are also presented; when administered to patients with partial epilepsy, carbamazepine was most likely to fail due to AEs, and lamotrigine and gabapentin were least likely to fail due to AEs. When administered to patients with idiopathic generalized epilepsy, topiramate was most frequently associated with AE-related discontinuation, followed by valproate; and while valproate was the most efficacious drug in this arm of the study, lamotrigine was more tolerable. What makes the SANAD study valuable and somewhat unique is its head-to-head comparison of one drug with another. Such

  10. Hepatic adenomas associated with anti-epileptic drugs: a case series and imaging review.

    PubMed

    Lee, Peter U Y; Roberts, Lewis R; Kaiya, Joseph K; Lee, Christine U

    2010-04-01

    We report four patients on long-term antiepileptic drugs, without any history of anabolic steroid or oral contraceptive use, who had path-proven hepatic adenomas at our institution. Imaging review of one case is presented here. An exhaustive literature search reveals only four other such case reports, none from the North American continent. PMID:19283429

  11. Foetal Antiepileptic Drug Exposure and Verbal versus Non-Verbal Abilities at Three Years of Age

    ERIC Educational Resources Information Center

    Meador, Kimford J.; Baker, Gus A.; Browning, Nancy; Cohen, Morris J.; Clayton-Smith, Jill; Kalayjian, Laura A.; Kanner, Andres; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael; Loring, David W.

    2011-01-01

    We previously reported that foetal valproate exposure impairs intelligence quotient. In this follow-up investigation, we examined dose-related effects of foetal antiepileptic drug exposure on verbal and non-verbal cognitive measures. This investigation is an ongoing prospective observational multi-centre study in the USA and UK, which has enrolled…

  12. Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs

    PubMed Central

    Meador, Kimford J.; Baker, Gus A.; Browning, Nancy; Clayton-Smith, Jill; Combs-Cantrell, Deborah T.; Cohen, Morris; Kalayjian, Laura A.; Kanner, Andres; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael; Loring, David W.

    2009-01-01

    BACKGROUND Fetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain. METHODS Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis is a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in utero. This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age. RESULTS At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P = 0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P = 0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P = 0.04). The association between valproate use and IQ was dose dependent. Children’s IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate. CONCLUSIONS In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated

  13. Adverse drug reactions in dermatology.

    PubMed

    Ferner, R E

    2015-03-01

    Adverse drug reactions (ADRs) - that is, unintended and harmful responses to medicines - are important to dermatologists because many present with cutaneous signs and because dermatological treatments can cause serious ADRs. The detection of ADRs to new drugs is often delayed because they have a long latency or are rare or unexpected. This means that ADRs to newer agents emerge only slowly after marketing. ADRs are part of the differential diagnosis of unusual rashes. A good drug history that includes details of drug dose, time-course of the reaction and factors that may make the patient more susceptible, will help. For example, Stevens-Johnson syndrome with abacavir is much commoner in patients with HLA-B*5701, and has a characteristic time course. Newer agents have brought newer reactions; for example, acneiform rashes associated with epidermal growth factor receptor inhibitors such as erlotinib. Older systemic agents used to treat skin disease, including corticosteroids and methotrexate, cause important ADRs. The adverse effects of newer biological agents used in dermatology are becoming clearer; for example, hypersensitivity reactions or loss of efficacy from antibody formation and progressive multifocal leucoencephalopathy due to reactivation of latent JC (John Cunningham) virus infections during efalizumab treatment. Unusual or serious harm from medicines, including ADRs, medication errors and overdose, should be reported. The UK Yellow Card scheme is online, and patients can report their own ADRs. PMID:25622648

  14. Transplacental genotoxicity of antiepileptic drugs: animal model and pilot study on mother/newborn cohort.

    PubMed

    Fucic, Aleksandra; Stojković, Ranko; Miškov, Snježana; Zeljezic, Davor; Markovic, Darko; Gjergja, Romana; Katic, Jelena; Jazbec, Ana Marija; Bakulic, Tomislav Ivicevic; Demarin, Vida

    2010-12-01

    Antiepileptic drugs (AED) as transplacental agents are known to have adverse effects on fetal development. Genotoxicity of AEDs is still not fully understood. The aim of present study was to investigate the transplacental genotoxicity of valproate on animal model and in 21 mothers and their newborns receiving AED. In both studies, in vivo micronucleus (MN) assay was used. Pregnant dams were exposed to Na-valproate (100mg/kg) on gestational days 12-14. Dams and pups receiving Na-valproate showed a significantly increased MN frequency (5.17 ± 1.17/1000; 5.20 ± 1.48/1000) compared to the control (1.0 ± 0.58/1000; 1.67 ± 1.03/1000). In mother/newborn study a significant increase of MN frequency was detected in newborns of mothers taking AEDs (3.09 ± 0.49/10,000) compared to the referent newborns (1.56 ± 0.22/10,000). The results of this study suggest that AEDs may act as transplacental genotoxins. Launching the mother/newborn cohorts for genotoxicological monitoring may give a significant new insight in health effects of AEDs. PMID:20955786

  15. Recent and future antiepileptic drugs and their impact on cognition: what can we expect?

    PubMed

    Mula, Marco

    2012-06-01

    Cognitive problems are frequently observed in patients with epilepsy and the relative contribution of antiepileptic drugs (AEDs) in this respect is determinant. During the past few years, a number of new AEDs have been introduced, and new compounds will be probably available in the forthcoming years. The ideal AED would be the one characterized by good efficacy with no negative effects on cognitive functions, mood and behavior. This paper is aimed at discussing the potential impact on cognition of a number of new compounds, namely lacosamide, rufinamide, retigabine, eslicarbazepine acetate, brivaracetam, perampanel and ganaxolone. In almost all cases, specific data on cognitive functions are not yet available, and it is possible only to speculate on their potential impact considering the mechanism of action and the adverse event profile in placebo-controlled studies. Lacosamide, eslicarbazepine acetate and probably brivaracetam are promising and will probably exhibit very limited impact on cognition. Conversely, retigabine may be more problematic, needing low starting doses and slow titration rates to improve cognitive tolerability. Data on rufinamide are restricted to special populations such as Lennox-Gastaut syndrome. Perampanel and ganaxolone are still in Phase III development, but the mechanism of action of these compounds is in line with a more sedative than neutral profile. PMID:22650169

  16. Progress report on new antiepileptic drugs: a summary of the Tenth Eilat Conference (EILAT X).

    PubMed

    Bialer, Meir; Johannessen, Svein I; Levy, René H; Perucca, Emilio; Tomson, Torbjörn; White, H Steve

    2010-12-01

    The Tenth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT X, took place in Eilat, Israel from the 25th to 29th of April 2010. About 200 basic scientists, clinical pharmacologists and neurologists from 25 countries attended the conference, whose main themes included learning from the past: Lessons learnt after 18 years of Eilat Conferences and Detecting assessing and preventing adverse effects of AEDs. Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the previous EILAT (EILAT IX) manuscript, the current (EILAT X) manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, carisbamate, 2-deoxy-glucose, ganaxolone, huperizine A, ICA-105665, NAX-5055, retigabine, perampanel, T-2007, valnoctamide and YK3089. Since the previous Eilat Conference (EILAT IX-2008) two new AEDs; eslicarbazepine acetate and lacosamide have been marketed and three new AEDs in development not included in the EILAT IX manuscript were added: ICA-105665, perampanel and valnoctamide. The CNS efficacy of these compounds in anticonvulsant animal models as well as other disease model systems are presented in Tables 1 and 2 and their proposed mechanism of action at summarized in Table 3. PMID:20970964

  17. Severe cutaneous adverse drug reactions.

    PubMed

    Chung, Wen-Hung; Wang, Chuang-Wei; Dao, Ro-Lan

    2016-07-01

    The clinical manifestations of drug eruptions can range from mild maculopapular exanthema to severe cutaneous adverse drug reactions (SCAR), including drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which are rare but occasionally fatal. Some pathogens may induce skin reactions mimicking SCAR. There are several models to explain the interaction of human leukocyte antigen (HLA), drug and T-cell receptor (TCR): (i) the "hapten/prohapten" theory; (ii) the "p-i concept"; (iii) the "altered peptide repertoire"; and (iv) the "altered TCR repertoire". The checkpoints of molecular mechanisms of SCAR include specific drug antigens interacting with the specific HLA loci (e.g. HLA-B*15:02 for carbamazepine-induced SJS/TEN and HLA-B*58:01 for allopurinol-induced SCAR), involvement of specific TCR, induction of T-cell-mediated responses (e.g. granulysin, Fas ligand, perforin/granzyme B and T-helper 1/2-associated cytokines) and cell death mechanism (e.g. miR-18a-5p-induced apoptosis; annexin A1 and formyl peptide receptor 1-induced necroptosis in keratinocytes). In addition to immune mechanism, metabolism has been found to play a role in the pathogenesis of SCAR, such as recent findings of strong association of CYP2C9*3 with phenytoin-induced SCAR and impaired renal function with allopurinol SCAR. With a better understanding of the mechanisms, effective therapeutics and prevention for SCAR can be improved. PMID:27154258

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

    PubMed

    Borowicz-Reutt, Kinga K; Banach, Monika; Piskorska, Barbara

    2016-05-01

    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. PMID:26738990

  19. Antiepileptic drug use in a nursing home setting: a retrospective study in older adults

    PubMed Central

    Callegari, Camilla; Ielmini, Marta; Bianchi, Lucia; Lucano, Melissa; Bertù, Lorenza; Vender, Simone

    2016-01-01

    Summary The authors set out to examine qualitatively the use of antiepileptic drugs (AEDs) in a population of older adults in a nursing home setting, evaluating aspects such as specialist prescriptions and changes in dosage. This retrospective prevalence study was carried out in a state-funded nursing home that provides care and rehabilitation for elderly people. The first objective of the study was to determine the prevalence of AED use in this population. The second objective was to monitor AED dosage modifications during the fifteen-month study period, focusing on the safety and the tolerability of AEDs. In the period of time considered, 129 of 402 monitored patients received at least one anti-epileptic therapy. The prevalence of AED use was therefore 32%. Gabapentin was found to be the most commonly prescribed drug, with a frequency of 29%, and it was used mainly for anxiety disorders, psychosis, neuropathic pain and mood disorders. PMID:27358221

  20. Fluorination of an antiepileptic drug: A self supporting transporter by oxygen enrichment mechanism.

    PubMed

    Natchimuthu, V; Amoros, J; Ravi, S

    2016-03-01

    Drug therapy of seizures involves producing high levels of antiepileptic drugs in the blood. Drug must enter the brain by crossing from the blood into the brain tissue, called a transvascular route (TVR). Even before the drug can reach the brain tissue, factors such as systemic toxicity, macrophage phagocytises and reduction in oxygen content limit the success of this TVR. Encapsulating the drug within a nano scale delivering system, synthesising drugs with low molecular weight are the best mechanisms to deliver the drug to the brain. But through this article, we have explored a possibility of attaching a molecule 4-(trifluoromethyl) benzoic acid (TFMBA), that possess more number of fluorine atom, to benzodiazepine (BDZ) resulting in an ionic salt (S)-(+)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine5,11(10H,11aH)-dione with 4-(trifluoromethyl)benzoic acid. By this way, reducing the toxicity of BDZ than the conventional anti-epileptic drugs (AEDs), increasing the solubility, reducing the melting point, enriching the TVR with excess oxygen content with the support of fluorine. With all these important prerequisites fulfilled, the drug along with the attached molecule is expected to travel more comfortably through the TVR without any external support than any other conventional AEDs. FTIR, (1)H NMR, (13)C NMR, HRMS spectroscopy, HRTEM and In vitro cytotoxicity analysis supports this study. PMID:26708322

  1. Patterns of Nonadherence to Antiepileptic Drug Therapy in Children With Newly Diagnosed Epilepsy

    PubMed Central

    Modi, Avani C.; Rausch, Joseph R.; Glauser, Tracy A.

    2012-01-01

    Context Because of epilepsy’s common occurrence, the narrow therapeutic and safety margins of antiepileptic medications, and the recognized complications of medication nonadherence in adults with epilepsy, identifying the rates, patterns, and predictors of nonadherence in children with epilepsy is imperative. The onset and evolution of antiepileptic drug nonadherence in children with newly diagnosed epilepsy remains unknown. Objectives To identify and characterize trajectories of adherence in children with newly diagnosed epilepsy over the first 6 months of therapy and to determine sociodemographic and epilepsy-specific predictors of adherence trajectories. Design, Setting, and Patients Prospective, longitudinal observational study of antiepileptic drug adherence in a consecutive cohort of 124 children (2–12 years old) with newly diagnosed epilepsy at Cincinnati Children’s Hospital Medical Center. Patients were recruited from April 2006 through March 2009, and final data collection occurred in September 2009. Main Outcome Measure Objective adherence measured using electronic monitors. Results Fifty-eight percent of children with newly diagnosed epilepsy demonstrated persistent nonadherence during the first 6 months of therapy. Group-based trajectory models identified 5 differential adherence patterns (Bayesian information criterion=−23611.8): severe early nonadherence (13%; 95% confidence interval [CI], 8%–20%), severe delayed nonadherence (7%; 95% CI, 3%–12%), moderate nonadherence (13%; 95% CI, 8%–20%), mild nonadherence (26%; 95% CI, 19%–34%), and near-perfect adherence (42%; 95% CI, 33%–50%). The adherence pattern of most patients was established by the first month of therapy. Socioeconomic status was the sole predictor of adherence trajectory group status (χ42=19.3 [n = 115]; P < .001; partial r2 = 0.25), with lower socioeconomic status associated with higher nonadherence. Conclusion Five trajectory patterns were identified that captured the

  2. Adverse Drug Reactions in Dental Practice

    PubMed Central

    Becker, Daniel E.

    2014-01-01

    Adverse reactions may occur with any of the medications prescribed or administered in dental practice. Most of these reactions are somewhat predictable based on the pharmacodynamic properties of the drug. Others, such as allergic and pseudoallergic reactions, are less common and unrelated to normal drug action. This article will review the most common adverse reactions that are unrelated to drug allergy. PMID:24697823

  3. Comparing the effects of first-line antiepileptic drugs on the gait of dogs with idiopathic epilepsy.

    PubMed

    Suiter, E J; Packer, R M A; Volk, H A

    2016-06-25

    Idiopathic epilepsy (IE) is a common chronic neurological disease of the dog. Previous studies of anti-epileptic drug (AED) treatment have indicated that acceptable AED adverse effects are as important to owners as reductions in seizure frequency. AEDs in both dogs and human beings are frequently associated with the adverse-effect ataxia. The aim of this study was to compare ataxia levels in dogs with IE treated chronically with phenobarbitone or imepitoin, the two currently available first-line AED treatments. The gait of 6 imepitoin-treated dogs, 8 phenobarbitone-treated dogs and 10 age-matched healthy control dogs were compared. Fifty strides from a walking gait were analysed for each dog, quantifying ataxia via the variability in six established gait parameters. Three variables differed significantly between groups: lateral distance between (i) pelvic paw placements, (ii) thoracic paw placements and (iii) stance time, which were significantly more variable in the phenobarbitone-treated dogs than imepitoin-treated or control dogs. These results indicate that dogs treated with phenobarbitone experience ataxia compared with controls and imepitoin-treated dogs. Conversely, there was no difference between imepitoin-treated dogs and controls. These results along with further research are needed to quantify AEDs adverse effects, to help vets and owners make more informed drug-choices. PMID:27302918

  4. Adverse cutaneous drug eruptions: current understanding.

    PubMed

    Hoetzenecker, W; Nägeli, M; Mehra, E T; Jensen, A N; Saulite, I; Schmid-Grendelmeier, P; Guenova, E; Cozzio, A; French, L E

    2016-01-01

    Adverse cutaneous drug reactions are recognized as being major health problems worldwide causing considerable costs for health care systems. Most adverse cutaneous drug reactions follow a benign course; however, up to 2% of all adverse cutaneous drug eruptions are severe and life-threatening. These include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Physicians should be aware of specific red flags to rapidly identify these severe cutaneous drug eruptions and initiate appropriate treatment. Besides significant progress in clinical classification and treatment, recent studies have greatly enhanced our understanding in the pathophysiology of adverse cutaneous drug reactions. Genetic susceptibilities to certain drugs have been identified in SJS/TEN patients, viral reactivation in DRESS has been elucidated, and the discovery of tissue resident memory T cells helps to better understand the recurrent site-specific inflammation in patients with fixed drug eruption. PMID:26553194

  5. Clinically significant pharmacokinetic drug interactions of antiepileptic drugs with new antidepressants and new antipsychotics.

    PubMed

    Spina, Edoardo; Pisani, Francesco; de Leon, Jose

    2016-04-01

    Antiepileptic drugs (AEDs) are frequently co-prescribed with new antidepressants (ADs) or new antipsychotics (APs). A PubMed search with no time limit was used to update the review of the clinically significant pharmacokinetic (PK) drug interactions DIs (DIs) between AEDs with new ADs and APs. Our best interpretation of what to expect regarding dosing changes in the average patient after combining AEDs with new ADs or new APs is summarized on updated tables that integrate the information on in vitro metabolism studies, therapeutic drug monitoring (TDM) studies, case report/series and prospective studies. There will be a need to periodically update these dose correction factors as new knowledge becomes available. These tables will provide some orientation to clinicians with no TDM access and may also encourage clinicians to further study TDM. The clinical relevance of the inductive properties of carbamazepine, phenytoin, phenobarbital and primidone on new ADs and new APs and the inhibitory properties of valproic acid and some new ADs, are relatively well understood. On the other hand, PK DI studies combining new AEDs with weak inductive properties (particularly oxcarbazepine doses≥1200mg/day), topiramate doses≥400mg/day, clobazam, eslicarbazepine, and rufinamide), with new ADs and new APs are needed. Valproic acid may be 1) an inhibitor and/or inducer of clozapine and olanzapine with potential for clinically relevant DIs, 2) an inhibitor of paliperidone, and 3) a weak inducer of aripiprazole. Fluoxetine and fluvoxamine are relevant inhibitors of phenytoin and valproic acid and possibly of clobazam, lacosamide, phenobarbital, or primidone. PMID:26896788

  6. Prenatal Exposure to Antiepileptic Drugs and Dental Agenesis

    PubMed Central

    Jacobsen, Pernille E.; Henriksen, Tine B.; Haubek, Dorte; Østergaard, John R.

    2014-01-01

    Objective The aim of the study was to investigate the association between prenatal exposure to AEDs and the risk of dental agenesis and to differentiate between the possible effects of the different drugs used. Methods Data on 214 exposed and 255 unexposed children, aged 12–18 years, were extracted from the Prescription Database of the Central Denmark Region and North Denmark Region and the Danish Medical Birth Registry. The children's dental charts were examined for the presence of dental agenesis. Results Overall, children exposed to AED in utero had an increased risk of developing dental agenesis, but as a group, the difference was not significant (OR = 1.7; [95% CI: 0.8–3.6]). The risk of developing dental agenesis was three-fold increased (OR = 3.1; [95% CI: 1.3–7.4]) in children exposed to valproate in mono- or in poly-therapy with other AEDs than carbamazepine or oxcarbazepine. The risk was further increased (OR = 11.2; [95% CI: 2.4–51.9]) in children exposed to valproate and carbamazepine or oxcarbazepine in combination. Conclusions The present study shows that dental agenesis is a potential congenital abnormality that is related to prenatal exposure to valproate, and dental agenesis may be considered a sensitive marker for the teratogenicity of valproate. PMID:24416231

  7. Targeting pharmacoresistant epilepsy and epileptogenesis with a dual-purpose antiepileptic drug.

    PubMed

    Doeser, Anna; Dickhof, Gesa; Reitze, Margit; Uebachs, Mischa; Schaub, Christina; Pires, Nuno Miguel; Bonifácio, Maria João; Soares-da-Silva, Patrício; Beck, Heinz

    2015-02-01

    In human epilepsy, pharmacoresistance to antiepileptic drug therapy is a major problem affecting a substantial fraction of patients. Many of the currently available antiepileptic drugs target voltage-gated sodium channels, leading to a rate-dependent suppression of neuronal discharge. A loss of use-dependent block has emerged as a potential cellular mechanism of pharmacoresistance for anticonvulsants acting on voltage-gated sodium channels. There is a need both for compounds that overcome this resistance mechanism and for novel drugs that inhibit the process of epileptogenesis. We show that eslicarbazepine acetate, a once-daily antiepileptic drug, may constitute a candidate compound that addresses both issues. Eslicarbazepine acetate is converted extensively to eslicarbazepine after oral administration. We have first tested using patch-clamp recording in human and rat hippocampal slices if eslicarbazepine, the major active metabolite of eslicarbazepine acetate, shows maintained activity in chronically epileptic tissue. We show that eslicarbazepine exhibits maintained use-dependent blocking effects both in human and experimental epilepsy with significant add-on effects to carbamazepine in human epilepsy. Second, we show that eslicarbazepine acetate also inhibits Cav3.2 T-type Ca(2+) channels, which have been shown to be key mediators of epileptogenesis. We then examined if transitory administration of eslicarbazepine acetate (once daily for 6 weeks, 150 mg/kg or 300 mg/kg) after induction of epilepsy in mice has an effect on the development of chronic seizures and neuropathological correlates of chronic epilepsy. We found that eslicarbazepine acetate exhibits strong antiepileptogenic effects in experimental epilepsy. EEG monitoring showed that transitory eslicarbazepine acetate treatment resulted in a significant decrease in seizure activity at the chronic state, 8 weeks after the end of treatment. Moreover, eslicarbazepine acetate treatment resulted in a

  8. Cancer risk in people with epilepsy: the role of antiepileptic drugs.

    PubMed

    Singh, Gagandeep; Driever, Pablo Hernáiz; Sander, Josemir W

    2005-01-01

    There has been considerable debate about the relationship between epilepsy and cancer, in particular whether the incidence of cancer is increased in people with epilepsy and whether antiepileptic drugs promote or protect against cancer. We review available evidence from animal experiments, genotoxicity studies and clinico-epidemiological observations, and discuss proposed mechanisms underlying the association between epilepsy and cancer. A carcinoma-promoting effect has been seen unequivocally in rodent models for phenobarbital and phenytoin; phenobarbital promoted liver tumours and phenytoin caused lymphoid cell and liver tumours in rats. Early human epidemiological studies found an association between phenobarbital and hepatocellular carcinoma, and several subsequent studies suggested an association with lung cancer. An association with brain tumours has also been demonstrated. Phenytoin has been causally implicated in three human cancers: lymphoma, myeloma and neuroblastoma, the latter specifically in the setting of foetal hydantoin syndrome. However, despite considerable long-term pharmaco-epidemiological data being available for both antiepileptic drugs, evidence for human carcinogenicity is not consistent and both are considered only possibly carcinogenic to humans. Valproate, however, has been found to exert an antiproliferative effect on certain cancer cell lines both in vitro and in vivo. A corresponding cancer-suppressive effect has not been studied in human epidemiological studies, though there are now preliminary reports of the use of valproate in human haematological and solid tumours. The anticancer activity of valproate appears to be driven by histone deacetylase inhibition and to be independent of hormone or multidrug protein resistance dependent mechanisms. The newer antiepileptic drugs appear to be safe, as no carcinogenicity has been demonstrated either during regulatory testing or in post-marketing surveillance. Nevertheless, the subject of

  9. Economic evaluation of a behavior-modifying intervention to enhance antiepileptic drug adherence.

    PubMed

    Plumpton, Catrin O; Brown, Ian; Reuber, Markus; Marson, Anthony G; Hughes, Dyfrig A

    2015-04-01

    Between 35% and 50% of patients with epilepsy are reported to be not fully adherent to their medication schedule. We aimed to conduct an economic evaluation of strategies for improving adherence to antiepileptic drugs. Based on the findings of a systematic review, we identified an implementation intention intervention (specifying when, where, and how to act) which was tested in a trial that closely resembled current clinical management of patients with epilepsy and which measured adherence with an objective and least biased method. Using patient-level data, trial patients were matched with those recruited for the Standard and New Antiepileptic Drugs trial according to their clinical characteristics and adherence. Generalized linear models were used to adjust cost and utility in order to estimate the incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the National Health Service in the UK. The mean cost of the intervention group, £1340 (95% CI: £1132, £1688), was marginally lower than that of the control group representing standard care, £1352 (95% CI: £1132, £1727). Quality-adjusted life-year values in the intervention group were higher than those in the control group, i.e., 0.75 (95% CI: 0.70, 0.79) compared with 0.74 (95% CI: 0.68, 0.79), resulting in a cost saving of £12 (€15, US$19) and with the intervention being dominant. The probability that the intervention is cost-effective at a threshold of £20,000 per QALY is 94%. Our analysis lends support to the cost-effectiveness of a self-directed, implementation intention intervention for improving adherence to antiepileptic drugs. However, as with any modeling dependent on limited data on efficacy, there is considerable uncertainty surrounding the clinical effectiveness of the intervention which would require a substantive trial for a more definitive conclusion. PMID:25819948

  10. Antiepileptic Drug Discovery and Development: What Have We Learned and Where Are We Going?

    PubMed Central

    Gerlach, Aaron C.; Krajewski, Jeffrey L.

    2010-01-01

    Current marketed antiepileptic drugs (AEDs) consist of a variety of structural classes with different mechanisms of action. These agents typically have non-overlapping efficacy and side-effect profiles presenting multiple treatment options for the patient population. However, approximately 30% of seizure sufferers fail to respond to current therapies often because poorly tolerated side-effects limit adequate dosing. The scope of this review is to summarize selected advances in 2nd and 3rd generation AEDs as well as compounds in development with novel mechanisms of action.

  11. Drug interactions with the newer antiepileptic drugs (AEDs)--part 1: pharmacokinetic and pharmacodynamic interactions between AEDs.

    PubMed

    Patsalos, Philip N

    2013-11-01

    Since 1989 there has been an exponential introduction of new antiepileptic drugs (AEDs) into clinical practice and these include eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine (ezogabine), rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide; 16 in total. Because often the treatment of epilepsy is lifelong, and because patients are commonly prescribed polytherapy with other AEDs, AED interactions are an important consideration in the treatment of epilepsy and indeed can be a major therapeutic challenge. For new AEDs, their propensity to interact is particularly important because inevitably they can only be prescribed, at least in the first instance, as adjunctive polytherapy. The present review details the pharmacokinetic and pharmacodynamic interactions that have been reported to occur with the new AEDs. Interaction study details are described, as necessary, so as to allow the reader to take a view as to the possible clinical significance of particular interactions. The principal pharmacokinetic interaction relates to hepatic enzyme induction or inhibition whilst pharmacodynamic interactions principally entail adverse effect synergism, although examples of anticonvulsant synergism also exist. Overall, the new AEDs are less interacting primarily because many are renally excreted or not hepatically metabolised (e.g. gabapentin, lacosamide, levetiracetam, topiramate, vigabatrin) and most do not (or minimally) induce or inhibit hepatic metabolism. A total of 139 pharmacokinetic interactions between concurrent AEDs have been described. The least pharmacokinetic interactions (n ≤ 5) are associated with gabapentin, lacosamide, tiagabine, vigabatrin and zonisamide, whilst lamotrigine (n = 17), felbamate (n = 15), oxcarbazepine (n = 14) and rufinamide (n = 13) are associated with the most. To date, felbamate, gabapentin, oxcarbazepine, perampanel, pregabalin

  12. Nurses must report adverse drug reactions.

    PubMed

    Griffith, Richard

    There is renewed determination throughout the European Union (EU) to reduce the economic cost and high death rate associated with adverse drug reactions through better pharmacovigilance. Timely reporting and sharing of information concerning adverse drug reactions is vital to the success of this initiative. In the UK, the reporting of serious adverse drug reactions is facilitated by the Yellow Card Scheme, yet despite being well placed to monitor the effect of medicines on patients, nurses do not make full use of the scheme. This article sets out the impact of adverse drug reactions in the EU and argues that it is essential that nurses must be at the vanguard of adverse reaction reporting if the EU's pharmacovigilance initiative is to be a success. PMID:23905231

  13. Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications.

    PubMed

    Tomson, Torbjörn; Landmark, Cecilie Johannessen; Battino, Dina

    2013-03-01

    Pregnancy is a state where pharmacokinetic changes are more pronounced and more rapid than during any other period of life. The consequences of such changes can be far reaching, not least in the management of epilepsy where the risks with uncontrolled seizures during pregnancy need to be balanced against potential teratogenic effects of antiepileptic drugs (AEDs). This article aims to review the literature on gestational effects on the pharmacokinetics of older and newer generation AEDs and discuss the implications for the treatment of epilepsy in women during pregnancy. Pregnancy can affect the pharmacokinetics of AEDs at any level from absorption, distribution, metabolism, to elimination. The effect varies depending on the type of AED. The most pronounced decline in serum concentrations is seen for AEDs that are eliminated by glucuronidation (UGT), in particular lamotrigine where the effect may be profound. Serum concentrations of AEDs that are cleared mainly through the kidneys, for example, levetiracetam, can also decline significantly. Some AEDs, such as carbamazepine seem to be affected only marginally by pregnancy. Data on pharmacokinetics during pregnancy are lacking completely for some of the newer generation AEDs: pregabalin, lacosamide, retigabine, and eslicarbazepine acetate. Where data are available, the effects of pregnancy on serum concentrations seem to vary considerably individually and are thus difficult to predict. Although large-scale systematic studies of the clinical relevance of the pharmacokinetic alterations are lacking, prospective and retrospective case series have reported an association between declining serum concentrations and deterioration in seizures control. The usefulness of routine monitoring of AED serum concentrations in pregnancy and of dose adjustments based on falling levels, are discussed in this review. We suggest that monitoring could be important, in particular when women have been titrated to the lowest effective AED

  14. Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age

    PubMed Central

    Meador, Kimford J.; Baker, Gus A.; Browning, Nancy; Cohen, Morris J.; Clayton-Smith, Jill; Kalayjian, Laura A.; Kanner, Andres; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael

    2011-01-01

    We previously reported that foetal valproate exposure impairs intelligence quotient. In this follow-up investigation, we examined dose-related effects of foetal antiepileptic drug exposure on verbal and non-verbal cognitive measures. This investigation is an ongoing prospective observational multi-centre study in the USA and UK, which has enrolled pregnant females with epilepsy on monotherapy from 1999 to 2004. The study seeks to determine if differential long-term neurodevelopmental effects exist across four commonly used drugs (carbamazepine, lamotrigine, phenytoin and valproate). This report compares verbal versus non-verbal cognitive outcomes in 216 children who completed testing at the age of three years. Verbal and non-verbal index scores were calculated from the Differential Ability Scales, Preschool Language Scale, Peabody Picture Vocabulary Test and Developmental Test of Visual-Motor Integration. Verbal abilities were lower than non-verbal in children exposed in utero to each drug. Preconceptional folate use was associated with higher verbal outcomes. Valproate was associated with poorer cognitive outcomes. Performance was negatively associated with valproate dose for both verbal and non-verbal domains and negatively associated with carbamazepine dose for verbal performance. No dose effects were seen for lamotrigine and phenytoin. Since foetal antiepileptic drug exposure is associated with lower verbal than non-verbal abilities, language may be particularly susceptible to foetal exposure. We hypothesize that foetal drug exposure may alter normal cerebral lateralization. Further, a dose-dependent relationship is present for both lower verbal and non-verbal abilities with valproate and for lower verbal abilities with carbamazepine. Preconceptional folate may improve cognitive outcomes. Additional research is needed to confirm these findings, extend the study to other drugs, define the risks associated with drug treatment for seizures in the neonates, and

  15. Non-adenosine nucleoside inosine, guanosine and uridine as promising antiepileptic drugs: a summary of current literature.

    PubMed

    Kovacs, Zsolt; Kekesi, Katalin A; Juhasz, Gabor; Barna, Janos; Heja, Laszlo; Lakatos, Renata; Dobolyi, Arpad

    2015-01-01

    Adenosine (Ado) and some non-adenosine (non-Ado) nucleosides including inosine (Ino), guanosine (Guo) and uridine (Urd) are modulatory molecules in the central nervous system (CNS), regulating different physiological and pathophysiological processes in the brain such as sleep and epilepsy. Indeed, different drugs effective on adenosinergic system (e.g., Ado metabolism inhibitors, agonists and antagonists of Ado receptors) are being used in drug development for the treatment of epileptic disorders. Although (i) endogenous Ino, Guo and Urd showed anticonvulsant/antiepileptic effects (e.g., in quinolinic acid - induced seizures and in different epilepsy models such as hippocampal kindling models), and (ii) there is a need to generate new and more effective antiepileptic drugs for the treatment of drug-resistant epilepsies, our knowledge about antiepileptic influence of non-Ado nucleosides is far from complete. Thus, in this review article, we give a short summary of anticonvulsant/antiepileptic effects and mechanisms evoked by Ino, Guo, and Urd. Finally, we discuss some non-Ado nucleoside derivatives and their structures, which may be candidates as potential antiepileptic agents. PMID:25382017

  16. Standardizing drug adverse event reporting data.

    PubMed

    Wang, Liwei; Jiang, Guoqian; Li, Dingcheng; Liu, Hongfang

    2013-01-01

    Normalizing data in the Adverse Event Reporting System (AERS), an FDA database, would improve the mining capacity of AERS for drug safety signal detection. In this study, we aim to normalize AERS and build a publicly available normalized Adverse drug events (ADE) data source.he drug information in AERS is normalized to RxNorm, a standard terminology source for medication. Drug class information is then obtained from the National Drug File - Reference Terminology (NDF-RT). Adverse drug events (ADE) are aggregated through mapping with the PT (Preferred Term) and SOC (System Organ Class) codes of MedDRA. Our study yields an aggregated knowledge-enhanced AERS data mining set (AERS-DM). The AERS-DM could provide more perspectives to mine AERS database for drug safety signal detection and could be used by research community in the data mining field. PMID:23920875

  17. Effect of Anti-Epileptic Drugs on Serum Level of IgG Subclasses

    PubMed Central

    Ashrafi, Mahmoud-Reza; Hosseini, Seyed-Ahmad; Biglari, Mohammad; Abolmaali, Sarah; Azizi Malamiri, Reza; Mombeini, Hoda; Pourpak, Zahra; Saladjegheh, Narges; Rezaei, Nima; Samadian, Azam; Aghamohammadi, Asghar

    2010-01-01

    Objective There are some controversial studies on effects of anti-epileptic drugs (AEDs) on serum IgG subclasses; however, the role of these medications is still unclear. The aim of this study was evaluation the effects of anti-epileptic drugs on serum concentration of IgG and its subclasses Methods Serum IgG and IgG subclasses of 61 newly diagnosed epileptic patients were measured at the beginning of monotherapy with carbamazepine, sodium valproate, and phenobarbital, and 6 months later. Measurement of IgG and its subclasses was performed using nephlometry and ELISA techniques, respectively. Findings Reduction of at least one IgG subclass was found in 6 patients 6 months after treatment with AEDs. Among 27 patients receiving carbamazepine, decrease in at least one serum IgG subclass level was found in 5 patients. Among 20 patients using sodium valproate, only one patient showed decrease in IgG2 subclass. None of the 14 patients using phenobarbital revealed significant decrease in IgG subclasses. No infection was seen in the patients with reduction of subclasses. Conclusion Although in our study, children with selective IgG subclass deficiency were asymptomatic, assessment of serum immunoglobulin levels could be recommended at starting the administration of AEDs and in serial intervals afterward in epileptic patients. PMID:23056716

  18. Antiepileptic drugs with histone deacetylase inhibition activity and prostate cancer risk: a population-based case-control study.

    PubMed

    Salminen, Jukka K; Tammela, Teuvo L J; Auvinen, Anssi; Murtola, Teemu J

    2016-05-01

    Previous studies suggest that antiepileptic drugs with histone deacetylase (HDAC) inhibitor properties may have prostate cancer preventive effects. We evaluated the association between antiepileptic drug use and prostate cancer risk in a population-based case-control study. The study included all new prostate cancer cases diagnosed in Finland in 1995-2002 and matched controls (24,657 case-control pairs) identified from the Finnish Cancer Registry and the Population Register Center, respectively. Information on antiepileptic drug purchases was obtained from the national prescription reimbursement database. Odds ratios and their 95 % confidence intervals were estimated using age-adjusted and multivariable-adjusted conditional logistic regression analysis. Compared to never-users of antiepileptic drugs, the overall prostate cancer risk was decreased among users of phenobarbital, carbamazepine, and valproic acid (multivariable-adjusted odds ratio (OR) 0.47, 95 % CI 0.24-0.92; OR 0.82, 95 % CI 0.71-0.94, and OR 0.62, 95 % CI 0.42-0.92, respectively), but not among users of other antiepileptic drugs. Overall prostate cancer risk decreased in a dose-dependent manner by cumulative amount, duration and yearly dosage (intensity) of HDAC inhibitors valproic acid and carbamazepine. The risk of advanced prostate cancer was decreased only among carbamazepine users (OR 0.65, 95 % CI 0.44-0.96). Our results support possible prostate cancer preventive effects of HDAC inhibitors. However, also phenobarbital use was associated with decreased prostate cancer risk, despite not having HDAC inhibiting activity. The mechanism of action for antiepileptic drugs in prostate cancer deserves further study. PMID:27038166

  19. [Adverse events of psychotropic drugs].

    PubMed

    Watanabe, Koichiro; Kikuchi, Toshiaki

    2014-01-01

    The authors discuss adverse events which are often missed but clinicians should pay attention to in order to preserve patients'quality of life(QOL). Among mood stabilizers, lithium may cause a urinary volume increase, hyperparathyroidism, and serum calcium elevation; sodium valproate possibly increases androgenic hormone levels and the risk of polycystic ovary syndrome (PCOS) as well as hypothyroidism. Moreover, in addition to teratogenesis, it has been reported that fetal exposure to a higher dose of valproate is associated with a lower intelligence quotient and higher incidence of autism spectrum disorders in children. Antidepressants with a higher affinity for serotonin transporters might induce gastrointestinal bleeding, and some antidepressants cause sexual dysfunction more frequently than others. Activation syndrome is still a key side effect which should be noted. Regarding the adverse events of antipsychotics, subjective side effects unpleasant to patients such as dysphoria and a lower subjective well-being should not be overlooked. We clinicians have to cope with adverse events worsening the QOL of patients with psychiatric disorders and, therefore, we need to adopt appropriate counter-measures. PMID:24864567

  20. Identifying Adverse Drug Events by Relational Learning

    PubMed Central

    Page, David; Costa, Vítor Santos; Natarajan, Sriraam; Barnard, Aubrey; Peissig, Peggy; Caldwell, Michael

    2013-01-01

    The pharmaceutical industry, consumer protection groups, users of medications and government oversight agencies are all strongly interested in identifying adverse reactions to drugs. While a clinical trial of a drug may use only a thousand patients, once a drug is released on the market it may be taken by millions of patients. As a result, in many cases adverse drug events (ADEs) are observed in the broader population that were not identified during clinical trials. Therefore, there is a need for continued, post-marketing surveillance of drugs to identify previously-unanticipated ADEs. This paper casts this problem as a reverse machine learning task, related to relational subgroup discovery and provides an initial evaluation of this approach based on experiments with an actual EMR/EHR and known adverse drug events. PMID:24955289

  1. Current status of the utilization of antiepileptic treatments in mood, anxiety and aggression: drugs and devices.

    PubMed

    Barry, John J; Lembke, Anna; Bullock, Kim D

    2004-01-01

    Interventions that have been utilized to control seizures in people with epilepsy have been employed by the psychiatric community to treat a variety of disorders. The purpose of this review will be to give an overview of the most prominent uses of antiepileptic drugs (AEDs) and devices like the Vagus Nerve Stimulator (VNS) and Transcranial Magnetic Stimulation (TMS) in the treatment of psychiatric disease states. By far, the most prevalent use of these interventions is in the treatment of mood disorders. AEDs have become a mainstay in the effective treatment of Bipolar Affective Disorder (BAD). The U.S. Food and Drug Administration has approved the use of valproic acid for acute mania, and lamotrigine for BAD maintenance therapy. AEDs are also effectively employed in the treatment of anxiety and aggressive disorders. Finally, VNS and TMS are emerging as possibly useful tools in the treatment of more refractory depressive illness. PMID:15112459

  2. Lamotrigine versus other antiepileptic drugs: a star rating system is born.

    PubMed

    Brodie, M J

    1994-01-01

    With the launching worldwide of a range of new antiepileptic drugs (AEDs), the prescriber has a much wider choice than ever before. Comparative studies between new and established AEDs are few, and those between new AEDs are rarely performed. This report considers the strengths and weaknesses of nine new and established AEDs. Scores ranging from -2 to +2 are given under six headings: mechanism of action, pharmacokinetics, efficacy, side effects, drug interactions, and a comfort factor. Perceived advantages and disadvantages in their clinical use are summarized and a final "star rating" produced for each. This process is illustrated by a detailed critique of lamotrigine (LTG). The star system is intended to stimulate dialogue among epileptologists in reaching a consensus in the pharmacologic management of the epileptic patient. PMID:8039470

  3. Genotoxic evaluation of antiepileptic drugs by Drosophila somatic mutation and recombination test.

    PubMed

    Yüksel, Muammer; Sarıkaya, Rabia; Bostanci, Neslihan

    2010-10-01

    The study examines the potential genotoxicity of three antiepileptic drugs (phenytoin sodium, pregabalin, gabapentin) using the wing somatic mutation and recombination test (SMART) in Drosophila melanogaster. Trans-heterozygous (two genetic markers mwh and flr) third-instar larvae of D. melanogaster were treated with different concentrations of the test compounds. A positive correlation was observed between total mutations and the number of wings with morphologically detectable mutations. The observed mutations were classified according to size and type of mutation per wing. Phenytoin clearly increased the frequency of total spots at all concentrations above 1.25 microg/ml. Gabapentin also increased the frequency of total spots at concentrations of 40 and 80 microg/ml. This study shows that phenytoin and gabapentin have genotoxic effects according to the SMART test; however, pregabalin displays lower genotoxicity in the SMAR assay when compared with the other two antiepileptics. The results also show that all AED concentrations lower the survival rate of the flies. PMID:20600525

  4. Pharmacogenomics and adverse drug reactions in children

    PubMed Central

    Rieder, Michael J.; Carleton, Bruce

    2014-01-01

    Adverse drug reactions are a common and important complication of drug therapy in children. Over the past decade it has become increasingly apparent that genetically controlled variations in drug disposition and response are important determinants of adverse events for many important adverse events associated with drug therapy in children. While this research has been difficult to conduct over the past decade technical and ethical evolution has greatly facilitated the ability of investigators to conduct pharmacogenomic studies in children. Some of this research has already resulted in changes in public policy and clinical practice, for example in the case of codeine use by mothers and children. It is likely that the use of pharmacogenomics to enhance drug safety will first be realized among selected groups of children with high rates of drug use such as children with cancer, but it also likely that this research will be extended to other groups of children who have high rates of drug utilization and as well as providing insights into the mechanisms and pathophysiology of adverse drug reactions in children. PMID:24795743

  5. Adverse Drug Reactions of the Lower Extremities.

    PubMed

    Adigun, Chris G

    2016-07-01

    Adverse drug reactions (ADRs) are a common cause of dermatologic consultation, involving 2 to 3 per 100 medical inpatients in the United States. Female patients are 1.3 to 1.5 times more likely to develop ADRs, except in children less than 3 years of age, among whom boys are more often affected. Certain drugs are more frequent causes, including aminopenicillins, trimethoprim-sulfamethoxazole, and nonsteroidal antiinflammatory drugs. Chemotherapeutic agents commonly cause adverse reactions to the skin and nails, with certain agents causing particular patterns of reactions. ADRs can involve any area of the skin; the appendages, including hair and nails; as well as mucosa. PMID:27215159

  6. The Portland Neurotoxicity Scale: Validation of a Brief Self-Report Measure of Antiepileptic-Drug-Related Neurotoxicity

    ERIC Educational Resources Information Center

    Salinsky, Martin C.; Storzbach, Daniel

    2005-01-01

    The Portland Neurotoxicity Scale (PNS) is a brief patient-based survey of neurotoxicity complaints commonly encountered with the use of antiepileptic drugs (AEDs). The authors present data on the validity of this scale, particularly when used in longitudinal studies. Participants included 55 healthy controls, 23 epilepsy patient controls, and 86…

  7. The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism

    PubMed Central

    Fan, Hueng-Chuen; Lee, Herng-Shen; Chang, Kai-Ping; Lee, Yi-Yen; Lai, Hsin-Chuan; Hung, Pi-Lien; Lee, Hsiu-Fen; Chi, Ching-Shiang

    2016-01-01

    Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities. PMID:27490534

  8. The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism.

    PubMed

    Fan, Hueng-Chuen; Lee, Herng-Shen; Chang, Kai-Ping; Lee, Yi-Yen; Lai, Hsin-Chuan; Hung, Pi-Lien; Lee, Hsiu-Fen; Chi, Ching-Shiang

    2016-01-01

    Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities. PMID:27490534

  9. Failure of antiepileptic drugs in controlling seizures in epilepsy: What do we do next?

    PubMed

    Galindo-Mendez, Brahyan; Mayor, Luis C; Velandia-Hurtado, Fernando; Calderon-Ospina, Carlos

    2015-01-01

    Medically intractable epilepsy is a clinical condition of concern that arises when a patient with epilepsy suffers seizures, despite a trial of two or more antiepileptic drugs (AEDs) suitable for the type of epilepsy that are prescribed at maximum tolerated doses, does not achieve control of seizures. This diagnosis could be related to cortical dysplasias. We report the case of a 5-year-old girl with a previous normal neurological development and no family history of epilepsy who presented with focal-type seizures at age 4. She started treatment by taking different AEDs for seizure control. She continued having frequent seizures that sometimes progressed to generalized seizures and status epilepticus. After a focal cortical resection performed in the area where interictal spikes were detected, the pathology confirmed a type IIb cortical dysplasia as the cause of the epilepsy. This article discusses cortical dysplasias as a cause of pharmacoresistant epilepsy and its treatment. PMID:26101746

  10. The treatment of epilepsy in pregnancy: The neurodevelopmental risks associated with exposure to antiepileptic drugs.

    PubMed

    Bromley, R

    2016-09-01

    A number of antiepileptic drugs (AEDs) have been confirmed as teratogens due to their association with an increased malformation rate. The majority of research to date does not find an association between prenatal exposure to monotherapy carbamazepine, lamotrigine or phenytoin and neurodevelopmental outcome in comparison to control children and noted higher abilities in comparison to children exposed to valproate; but further work is needed before conclusions can be drawn. Data for levetiracetam was limited to one study, as was the evidence for topiramate. Sodium valproate exposure appeared to carry a dose dependent risk to the developing brain, with evidence of reduced levels of IQ, poorer verbal abilities and increased rate of autistic spectrum disorder both in comparison to control children and children exposed to other AEDs. The severity of the neurodevelopmental deficits associated with prenatal exposure to valproate highlight the critical need to consider neurodevelopmental outcomes as a central aspect of teratological research. PMID:27312074

  11. Disorders of reproduction in patients with epilepsy: antiepileptic drug related mechanisms.

    PubMed

    Isojärvi, Jouko

    2008-03-01

    Epilepsy, antiepileptic drugs (AEDs), and the reproductive system have complex interactions. Fertility is lower in both men and women with epilepsy than in the general population. Moreover, reproductive endocrine disorders are more common among patients with epilepsy than among the population in general. These disorders have been attributed both to epilepsy itself and to AEDs. The use of the liver enzyme inducing AEDs phenobarbital, phenytoin and carbamazepine increases serum sex hormone binding globulin (SHBG) concentrations in both men and women with epilepsy. Over time the increase in serum SHBG levels leads to diminished bioactivity of testosterone and estradiol, which may result in diminished potency in men and menstrual disorders in some women, and, thus, to reduced fertility. Valproate (VPA) medication may have effects on serum androgen concentrations and it reduces serum follicle stimulating hormone levels in men with epilepsy. However, the clinical significance of the VPA related reproductive endocrine changes in men is unknown. On the other hand, in women the use of VPA is associated with a frequent occurrence of reproductive endocrine disorders characterized by polycystic changes in the ovaries, high serum testosterone concentrations (hyperandrogenism) and menstrual disorders. Young women with epilepsy seem to be especially vulnerable to the effects of VPA on serum androgen levels. The endocrine effects of the new AEDs have not been widely studied. However, it seems they may offer an alternative if reproductive endocrine problems emerge during treatment with the older antiepileptic drugs. On the other hand, it seems that in many cases the reproductive endocrine effects of the AEDs are reversible, if the medication is discontinued. PMID:18164216

  12. What clinical trial designs have been used to test antiepileptic drugs and do we need to change them?

    PubMed

    Perucca, Emilio

    2012-06-01

    Designs used to evaluate the efficacy and safety of antiepileptic drugs (AEDs) have evolved considerably over the years. A major impulse to develop methodologically sound randomised controlled trials dates back to the Kefauver-Harris Drug Amendment of 1962, through which the US congress introduced the requirement of substantial evidence for proof of efficacy in a new drug application. The mainstay for the initial approval of most new AEDs has been, and still is, the placebo-controlled adjunctive therapy trial, which evolved over the years from the cross-over to the parallel-group design. In the early days, when few AEDs were available, enrolment of patients into these trials was relatively easy and prolonged placebo exposure could be justified by lack of alternative treatment options. With more than 20 drugs now available to treat epilepsy, however, exposing patients to placebo or to a potentially ineffective investigational agent faces practical and ethical concerns. Recruitment difficulties have led sponsors to markedly increase the number of trial sites, but there is evidence that this may adversely affect the ability to differentiate between effective and ineffective treatments. Methodological and practical difficulties are also encountered with monotherapy trials. Because regulatory guidelines for monotherapy approval differ between Europe and the US, sponsors need to pursue separate and costly development programs on the two sides of the Atlantic. Moreover, the scientific validity of the monotherapy trial paradigms currently used in Europe (the non-inferiority design) and in the US (the conversion to monotherapy design with historical controls) has been questioned. This article will review these issues in some detail and discuss how trial designs and regulatory approval processes may evolve in the future to address these concerns. PMID:22977898

  13. Local anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated sodium channel.

    PubMed

    Boiteux, Céline; Vorobyov, Igor; French, Robert J; French, Christopher; Yarov-Yarovoy, Vladimir; Allen, Toby W

    2014-09-01

    Voltage-gated sodium (Nav) channels are important targets in the treatment of a range of pathologies. Bacterial channels, for which crystal structures have been solved, exhibit modulation by local anesthetic and anti-epileptic agents, allowing molecular-level investigations into sodium channel-drug interactions. These structures reveal no basis for the "hinged lid"-based fast inactivation, seen in eukaryotic Nav channels. Thus, they enable examination of potential mechanisms of use- or state-dependent drug action based on activation gating, or slower pore-based inactivation processes. Multimicrosecond simulations of NavAb reveal high-affinity binding of benzocaine to F203 that is a surrogate for FS6, conserved in helix S6 of Domain IV of mammalian sodium channels, as well as low-affinity sites suggested to stabilize different states of the channel. Phenytoin exhibits a different binding distribution owing to preferential interactions at the membrane and water-protein interfaces. Two drug-access pathways into the pore are observed: via lateral fenestrations connecting to the membrane lipid phase, as well as via an aqueous pathway through the intracellular activation gate, despite being closed. These observations provide insight into drug modulation that will guide further developments of Nav inhibitors. PMID:25136136

  14. Solid Dispersion Approach Improving Dissolution Rate of Stiripentol: a Novel Antiepileptic Drug

    PubMed Central

    Afifi, Samar

    2015-01-01

    Some drugs have low bioavailability due to their poor aqueous solubility and/or slow dissolution rate in biological fluids. Stiripentol (STP) is a novel anticonvulsant drug that is structurally unrelated to the currently available antiepileptics. It has poor aqueous solubility and its solubility has to be enhanced accordingly. Polyethyleneglycol 6000 (PEG-6000) is commonly utilized as a hydrophilic carrier for poorly water soluble drugs in order to improve their bioavailability. STP and PEG-6000 binary system was obtained by physical mixture, solvent evaporation, co-evaporation and melting methods using different weight ratios. The properties of the prepared binary systems were evaluated using dissolution rate, phase solubility, Fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and scanning electron microscope (SEM) studies. The FTIR spectroscopic studies showed the stability of STP and absence of STP-PEG-6000 interaction. The DSC and SEM studies indicated the amorphous state of STP in its binary systems with PEG-6000. Dissolution profile of STP was significantly improved via complexation with PEG-6000 as compared with the pure drug. The binary system which was prepared using melting method showed the highest dissolution rate. The promising results of the prepared binary systems open the avenue for further oral formulation of STP. PMID:26664367

  15. Adverse Effects of Common Drugs: Adults.

    PubMed

    Lewis, Peter R; Karpa, Kelly Dowhower; Felix, Todd Matthew

    2015-09-01

    Although drugs can be an essential and lifesaving component of the care of adult patients, their use frequently is accompanied by adverse effects and life-threatening adverse drug reactions that can result in significant disability and mortality. The potential for drug-related severe morbidity and mortality is compounded during periods of hospitalization, when high-risk drugs such as anticoagulants or insulin are used, and when care in an intensive care unit is required. Patient factors in adults that can increase the risk of drug harms include immunosuppression, cognitive impairment, depression, alcoholism and other substance abuse disorders, chronic kidney disease, hepatic dysfunction, coagulopathies, limited English proficiency, institutional/nursing home care, and underinsurance or lack of insurance. Physician factors that can increase the risk of drug harms include inappropriate prescribing of drugs (including to pregnant and breastfeeding women), failure to appropriately discontinue/deprescribe drugs, insufficient drug reconciliation, failure to coordinate care among multiple prescribing clinicians, and failure to elicit and incorporate into health histories and clinical decision-making the widespread use of nonprescription drugs, herbal products, and dietary supplements. PMID:26375995

  16. Adverse Effects of Common Drugs: General Concepts.

    PubMed

    Karpa, Kelly Dowhower; Lewis, Peter R; Felix, Todd Matthew

    2015-09-01

    Adverse drug reactions (ADRs) contribute to substantial morbidity and mortality and add to rising health care costs. Many ADRs are preventable with appropriate prescribing and monitoring because they often occur as an extension of a drug's mechanism of action or known drug interactions. Patients at higher risk of ADRs include those at the extremes of age, those with multiple comorbidities, those taking multiple drugs, and patients admitted to intensive care units or experiencing transitions of care. Because the risk of ADRs becomes greater as the number of drugs and dietary supplements taken increases, it is imperative that prescribers be vigilant about the prescribing cascade and take steps to discontinue drugs that are likely to be more harmful than helpful. Pharmacists serve as important partners in clinical care environments by conducting comprehensive drug reviews, aiding in drug/dosage selection, and developing therapeutic monitoring plans. Although the potential exists for clinicians to use electronic health record systems to aid in clinical decision making through drug safety decision support tools, computer systems should never replace clinical judgment. Clinicians also are encouraged to report ADRs to the Food and Drug Administration Adverse Event Reporting System. PMID:26375993

  17. Interactions between non-vitamin K oral anticoagulants and antiepileptic drugs.

    PubMed

    Stöllberger, Claudia; Finsterer, Josef

    2016-10-01

    Atrial fibrillation (AF) is a frequent cause of stroke. Secondary prophylaxis by oral anticoagulants (OAC) is recommended after stroke in AF-patients. OAC can be achieved by vitamin-K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) like dabigatran, rivaroxaban, apixaban or edoxaban. Seizures are frequent after stroke, and antiepileptic drugs (AEDs) are indicated. The review, based on a literature research, aims to give an overview about pharmacokinetic knowledge and clinical data about drug-drug interactions (DDIs) between NOACs and AED. Carbamazepine, levetiracetam, phenobarbital, phenytoin and valproic acid might decrease the effect of NOACs by inducing P-glycoprotein (P-gp) activity. Carbamazepine, oxcarbazepine, phenytoin, phenobarbital and topiramate might decrease the effect of NOACs by inducing CYP3A4 activity. Controversial data - inhibition as well as induction of CYP3A4 - were found about valproic acid. The relevance of these DDIs is largely unknown since there are only sporadic case reports available. To increase the knowledge about DDIs between NOACs and AEDs we suggest subgroup analyses addressing effects and safety of VKAs versus NOACs in patients with AF on AEDs, in case they have been included in previously completed or still ongoing trials or registries. This could be easily feasible and would be desirable in view of the large data already accumulated. PMID:27450623

  18. Practical Use of Newer Antiepileptic Drugs as Adjunctive Therapy in Focal Epilepsy.

    PubMed

    Brodie, Martin J

    2015-11-01

    This article lays the background for, and discusses the practical issues surrounding, the adjunctive use of the last four antiepileptic drugs (AEDs) to be licensed for the treatment of pharmacoresistant focal seizures in the UK and elsewhere. More than 30% of adolescent and adult patients will not be fully controlled on the currently available therapeutic armamentarium. After not responding to their first three AED schedules, only a handful of patients attained seizure freedom on subsequent regimens. To optimise the response to any new AED in this setting, it is often necessary to reduce the existing drug burden. The pharmacology, tolerability and safety, and everyday use of lacosamide, eslicarbazepine acetate, retigabine (ezogabine) and perampanel will be reviewed and discussed. This will be accompanied by data from prospective audits with each drug undertaken at the Western Infirmary in Glasgow, Scotland, and a report of their successful introduction in an illustrative case. Overall, there is a large variation in the course of refractory epilepsy and the effect of AED therapy on this process seems minimal. Nevertheless, a number of patients will benefit from the introduction of each new AED, with some becoming seizure-free. PMID:26507832

  19. Effect of antiepileptic drug therapy on thyroid hormones among adult epileptic patients: An analytical cross-sectional study

    PubMed Central

    Adhimoolam, Mangaiarkkarasi; Arulmozhi, Ranjitha

    2016-01-01

    Objective: The objective of the study was to evaluate and compare the effect of conventional and newer antiepileptic drugs (AEDs) on thyroid hormone levels in adult epileptic patients. Methods: A hospital-based, analytical cross-sectional study was conducted among the adult epileptic patients receiving conventional AEDs (Group 2) or newer AEDs (Group 3) for more than 6 months. Serum thyroid hormone levels including free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) were analyzed and the hormonal status was compared with healthy control subjects (Group 1). Findings: Sodium valproate and phenytoin were commonly used conventional AEDs; levetiracetam and topiramate were common among the newer drugs. There was a statistically significant decrease in serum fT4 and increase in serum TSH levels (P < 0.0001) in patients on long-term therapy with conventional antiepileptic agents than in the control group. No significant change in thyroid hormone levels (fT3, fT4, and TSH; P = 0.68, 0.37, and 0.90, respectively) was observed with newer antiepileptics-treated patients when compared to control group. One-way analysis of variance followed by post hoc Dunnett's test was performed using SPSS version 17.0 software package. Conclusion: The present study showed that conventional AEDs have significant alteration in the thyroid hormone levels than the newer antiepileptics in adult epileptic patients. PMID:27512707

  20. [Adverse drug effects in the community pharmacy].

    PubMed

    Arnet, Isabelle; Seidling, Hanna M; Hersberger, Kurt E

    2015-12-01

    Community pharmacists represent an important pillar for the identification and the reporting of adverse drug effects (ADE}. Thanks to their broad view on the pharmacotherapy, over-the-counter medication included, they contribute greatly to the improvement of drug safety. In principle, the community pharmacy will face three groups of ADE which require specific attention. This article deals with these specific ADE groups and presents some illustrative examples from daily practice. Furthermore, we suggest some solutions to identify potential relevant interactions - including herbal-drug interactions - and give tips for daily practice, along with some often overseen cutaneous ADE. PMID:26654812

  1. [Haematological adverse effects caused by psychiatric drugs].

    PubMed

    Mazaira, Silvina

    2008-01-01

    Almost all clases of psychiatric drugs (typical and atypical antipsychotics, antidepressants, mood stabilizers, benzodiazepines) have been reported as possible causes of haematological toxicity. This is a review of the literature in which different clinical situations involving red blood cells, white blood cells, platelets and impaired coagulation are detailed and the drugs more frequently involved are listed. The haematological adverse reactions detailed here include: aplastic anemia, haemolitic anemia, leukopenia, agranulocytosis, leukocytosis, eosinophilia, thrombocytosis, thrombocytopenia, disordered platelet function and impaired coagulation. The haematologic toxicity profile of the drugs more frequently involved: lithium, clozapine, carbamazepine, valproic acid and SSRI antidepressants is mentioned. PMID:19424521

  2. Effects of nucleosides on glia - neuron interactions open up new vistas in the development of more effective antiepileptic drugs.

    PubMed

    Kovacs, Zsolt; Kardos, Julianna; Kekesi, Katalin A; Juhasz, Gabor; Lakatos, Renata; Heja, Laszlo

    2015-01-01

    One-third of epileptic patients are drug refractory due to the limited efficacy of antiepileptic therapy. Thus, there is an immense need to find more effective, safer and well-tolerated antiepileptic drugs. A great deal of results suggests that adenosine (Ado), guanosine (Guo), inosine (Ino) or uridine (Urd) are endogenous antiepileptogenic modulators. Furthermore, nucleosides and their derivatives may be safe and effective potential drugs in the treatment of epilepsy. Conversely, nucleosidergic modulatory system implying nucleoside levels, metabolism, receptors and transporters may also be involved in seizure pathomechanisms. Application of Ado receptor agonists as well as antagonists, elevation of nucleoside levels (e.g., by nucleoside metabolism inhibitors, and Adoreleasing implants) or utilization of non-Ado nucleosides may also turn to be useful approaches to decrease epileptic activity. However, all drugs exerting their effects on the nucleosidergic modulatory system may affect the fine regulation of glia-neuron interactions that are intimately governed by various nucleosidergic processes. Perturbation of the complex, bidirectional communication between neurons and astrocytes through these nucleosidergic modulatory mechanisms may lead to pathological changes in the central nervous system (CNS) and therefore may cause significant side effects. Thus, a deeper understanding of the nucleosidergic modulatory control over glia-neuron interactions is essential in order to develop more effective and safe nucleoside-based antiepileptic drugs. In this review article we focus on the role of Ado and Urd in glia-neuron interactions, placing emphasis on their implications for the treatment of epilepsy. PMID:25666791

  3. Several major antiepileptic drugs are substrates for human P-glycoprotein.

    PubMed

    Luna-Tortós, Carlos; Fedrowitz, Maren; Löscher, Wolfgang

    2008-12-01

    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

  4. Standardizing adverse drug event reporting data

    PubMed Central

    2014-01-01

    Background The Adverse Event Reporting System (AERS) is an FDA database providing rich information on voluntary reports of adverse drug events (ADEs). Normalizing data in the AERS would improve the mining capacity of the AERS for drug safety signal detection and promote semantic interoperability between the AERS and other data sources. In this study, we normalize the AERS and build a publicly available normalized ADE data source. The drug information in the AERS is normalized to RxNorm, a standard terminology source for medication, using a natural language processing medication extraction tool, MedEx. Drug class information is then obtained from the National Drug File-Reference Terminology (NDF-RT) using a greedy algorithm. Adverse events are aggregated through mapping with the Preferred Term (PT) and System Organ Class (SOC) codes of Medical Dictionary for Regulatory Activities (MedDRA). The performance of MedEx-based annotation was evaluated and case studies were performed to demonstrate the usefulness of our approaches. Results Our study yields an aggregated knowledge-enhanced AERS data mining set (AERS-DM). In total, the AERS-DM contains 37,029,228 Drug-ADE records. Seventy-one percent (10,221/14,490) of normalized drug concepts in the AERS were classified to 9 classes in NDF-RT. The number of unique pairs is 4,639,613 between RxNorm concepts and MedDRA Preferred Term (PT) codes and 205,725 between RxNorm concepts and SOC codes after ADE aggregation. Conclusions We have built an open-source Drug-ADE knowledge resource with data being normalized and aggregated using standard biomedical ontologies. The data resource has the potential to assist the mining of ADE from AERS for the data mining research community. PMID:25157320

  5. Relationship of Child IQ to Parental IQ and Education in Children with Fetal Antiepileptic Drug Exposure

    PubMed Central

    Meador, Kimford J.; Baker, Gus A.; Browning, Nancy; Clayton-Smith, Jill; Cohen, Morris J.; Kalayjian, Laura A.; Kanner, Andres; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael; Loring, David W.

    2011-01-01

    Clinical trial designs need to control for genetic and environmental influences when examining cognitive outcomes in children for whom clinical considerations preclude randomization. However, the contributions of maternal and paternal IQ and education to pediatric cognitive outcomes are uncertain in disease populations. The NEAD Study is an ongoing prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy to determine if differential long-term neurodevelopmental effects exist across four commonly used antiepileptic drugs (AEDs). Here, we examined the relationship of IQ and education in both parents to child IQ at age 3 years. IQ and education for both parents were statistically correlated to child IQ. However, paternal IQ and education were not significant after accounting for maternal IQ effects. Because maternal IQ and education are independently related to child cognitive outcome, both should be assessed in studies investigating the effects of fetal drug exposures or other environmental factors that could affect the child’s cognitive outcome. PMID:21546316

  6. Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons.

    PubMed

    Morte, Maria I; Carreira, Bruno P; Falcão, Maria J; Ambrósio, António F; Soares-da-Silva, Patrício; Araújo, Inês M; Carvalho, Caetana M

    2013-12-01

    In this study we evaluated the neurotoxicity of eslicarbazepine acetate (ESL), and of its in vivo metabolites eslicarbazepine (S-Lic) and R-licarbazepine (R-Lic), as compared to the structurally-related compounds carbamazepine (CBZ) and oxcarbazepine (OXC), in an in vitro model of cultured rat hippocampal neurons. The non-related antiepileptic drugs (AEDs) lamotrigine (LTG) and sodium valproate (VPA) were also studied. We assessed whether AEDs modulate pro-survival/pro-apoptotic pathways, such as extracellular-regulated kinase (ERK1/2), Akt and stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). We found that neither ESL nor its metabolites, CBZ or LTG, up to 0.3mM, for 24h of exposure, decreased cell viability. OXC was the most toxic drug decreasing cell viability in a concentration-dependent manner, leading to activation of caspase-3 and PARP cleavage. VPA caused the appearance of the apoptotic markers, but did not alter cell viability. ESL, S-Lic and OXC decreased the levels of phospho-ERK1/2 and of phospho-Akt, when compared to basal levels, whereas CBZ decreased phospho-SAPK/JNK and phospho-Akt levels. LTG and VPA increased the phosphorylation levels of SAPK/JNK. These results suggest that ESL and its main metabolite S-Lic, as well as CBZ, LTG and VPA, are less toxic to hippocampal neurons than OXC, which was the most toxic agent. PMID:24055897

  7. Generic products of antiepileptic drugs: a perspective on bioequivalence and interchangeability.

    PubMed

    Bialer, Meir; Midha, Kamal K

    2010-06-01

    Most antiepileptic drugs (AEDs) are currently available as generic products, yet neurologists and patients are reluctant to switch to generics. Generic AEDs are regarded as bioequivalent to brand AEDs after meeting the average bioequivalence criteria; consequently, they are considered to be interchangeable with their respective brands without loss of efficacy and safety. According to the U.S. Food and Drug Administration (FDA) the present bioequivalence requirements are already so rigorous and constrained that there is little possibility that generics that meet regulatory bioequivalence criteria could lead to therapeutic problems. So is there a scientific rationale for the concerns about switching patients with epilepsy to bioequivalent generics? Herein we discuss the assessment of bioequivalence and propose a scaled-average bioequivalence approach where scaling of bioequivalence is carried out based on brand lot-to-lot variance as an alternative to the conventional bioequivalence test as a means to determine whether switching patients to generic formulations, or vice versa, is a safe and effective therapeutic option. Meeting the proposed scaled-average bioequivalence requirements will ensure that when an individual patient is switched, he or she has fluctuations in plasma levels similar to those from lot-to-lot of the brand reference levels and thus should make these generic products safely switchable without change in efficacy and safety outcomes. PMID:20384761

  8. Risk of recurrence after discontinuation of antiepileptic drug therapy in children with epilepsy

    PubMed Central

    Incecik, Faruk; Herguner, Ozlem M.; Altunbasak, Sakir; Mert, Gulen; Kiris, Nurcihan

    2014-01-01

    Objectives: The numerous antiepileptic drug (AED) withdrawal studies published in the last 40 years have relied mainly on heterogeneous study groups. There is still no general agreement on the criteria to predict safe discontinuation. The goal of this study was to assess the outcome of AED withdrawal in epileptic children. Materials and Methods: Three hundred and eight children with epilepsy were enrolled, and these patients followed at least 1 year after drug withdrawal. Time to seizure relapse and predictive factors were analyzed by survival methods. Results: Among the 308 patients, 179 (58.1%) were boys and 129 (41.9%) were girls and the mean age at the seizure onset was 60.41 ± 36.54 months (2-144 months). The recurrence occurred in 73 (23.7%) patients. Mental retardation, history of febrile seizure, etiological of epilepsy, abnormal first electroencephalogram (EEG), abnormal neuroimaging findings, and total number of AED before remission were significantly associated with relapse risk according to univariate analysis. In the multivariate analysis, abnormal first EEG and number of AED before remission (polytherapy) were the risk factors influencing seizure recurrence. Conclusions: In our study, recurrence rate was 23.7% in children and most occurred during the 1st year. The potential risk factors of recurrence are history of febrile seizure, mental retardation, etiological of epilepsy, abnormal first EEG, abnormal neuroimaging findings, and total number of AED before remission. However, we found abnormal first EEG and polytherapy as risk factors of recurrence in multivariate analysis. PMID:25250060

  9. Antiepileptic drugs toxicity: A case of toxic epidermal necrolysis in patient with phenytoin prophylaxis post-cranial radiation for brain metastases

    PubMed Central

    AlQuliti, Khalid; Ratrout, Basem; AlZaki, Alaa

    2014-01-01

    Background Treatment of epilepsy with antiepileptic drugs (AED) is effective and remains the principal mode of management. A group of adverse effects and drug toxicity can develop immediately or later in the course of treatment. AEDs also have the potential of precipitating idiosyncratic adverse effects including serious cutaneous, hematological and hepatic events. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe cutaneous adverse reactions are related to or caused by a variety of medications including AEDs, they carry a high mortality and morbidity rate, accurate diagnosis and rapid treatment may improve the prognosis. Objective To characterize the clinical features and methods of differentiating Stevens–Johnson syndrome from toxic epidermal necrolysis using a case study and to identify other factors that may contribute to this critical illness. Conclusion Clinical knowledge of potential sever adverse reaction of AEDs is essential and may overcome treatment failure with major impact on health-related quality of life in people with epilepsy. PMID:25161384

  10. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age: an update.

    PubMed

    Italiano, Domenico; Perucca, Emilio

    2013-08-01

    Epilepsies occur across the entire age range, and their incidence peaks in the first years of life and in the elderly. Therefore, antiepileptic drugs (AEDs) are commonly used at the extremes of age. Rational prescribing in these age groups requires not only an understanding of the drugs' pharmacodynamic properties, but also careful consideration of potential age-related changes in their pharmacokinetic profile. The present article, which updates a review published in 2006 in this journal, focuses on recent findings on the pharmacokinetics of new-generation AEDs in neonates, infants, children, and the elderly. Significant new information on the pharmacokinetics of new AEDs in the perinatal period has been acquired, particularly for lamotrigine and levetiracetam. As a result of slow maturation of the enzymes involved in glucuronide conjugation, lamotrigine elimination occurs at a particularly slow rate in neonates, and becomes gradually more efficient during the first months of life. In the case of levetiracetam, elimination occurs primarily by renal excretion and is also slow at birth, but drug clearance increases rapidly thereafter and can even double within 1 week. In general, infants older than 2-3 months and children show higher drug clearance (normalized for body weight) than adults. This pattern was confirmed in recent studies that investigated the pediatric pharmacokinetics of several new AEDs, including levetiracetam, rufinamide, stiripentol, and eslicarbazepine acetate. At the other extreme of age, in the elderly, drug clearance is generally reduced compared with younger adults because of less efficient drug-metabolizing activity, decreased renal function, or both. This general pattern, described previously for several AEDs, was confirmed in recent studies on the effect of old age on the clearance of felbamate, levetiracetam, pregabalin, lacosamide, and retigabine. For those drugs which are predominantly eliminated by renal excretion, aging

  11. Dried blood spots for monitoring and individualization of antiepileptic drug treatment.

    PubMed

    Milosheska, Daniela; Grabnar, Iztok; Vovk, Tomaž

    2015-07-30

    Therapeutic drug monitoring (TDM) is a multi-disciplinary clinical specialty used for optimization and individualization of drug therapy in the general and special populations. Since most antiepileptic drugs (AEDs) are characterized by pronounced intra- and inter-individual variability, it can be especially valuable as an aid for dosing adjustments in patients with epilepsy. Dried blood spots (DBS) sampling technique is recognized as a suitable alternative for conventional sampling methods as TDM interventions should be applied in the most cost-effective, rational and clinically useful manner. In the present review we summarize the latest trends and applications of DBS in TDM of epilepsy. Quantification of AEDs in DBS was employed in various clinical settings and has been already reported for phenobarbital, phenytoin, valproic acid, clonazepam, clobazam, carbamazepine, topiramate, rufinamide, lamotrigine, 10-hydroxycarbazepine and levetiracetam. The major limitation of the published studies are restricted evaluation of critical parameters such as the impact of spotted blood volume, spot homogeneity and haematocrit effect, limited clinical validation and non-established correlations between the DBS and plasma concentrations of AEDs. Standardization of critical technical aspects for appropriate sampling, sample preparation and validation of the analytical procedures for quantification of the drugs, as well as appropriate interpretation of the results are the fields which should get more attention in upcoming studies. Limited data on clinical validation and the fact that this technique has been used in practice only for a few AEDs makes the routine implementation of TDM of AEDs using DBS method a big challenge that should be faced by the pharmaceutical scientists in the future. PMID:25896371

  12. Atherosclerotic effects of long-term old and new antiepileptic drugs monotherapy: a cross-sectional comparative study.

    PubMed

    El-Farahaty, Reham M; El-Mitwalli, Ashraf; Azzam, Hanan; Wasel, Yasser; Elrakhawy, Mohamed M; Hasaneen, Bothina Mohammed

    2015-03-01

    This work aimed to evaluate the metabolic and atherogenic effects of long-term antiepileptic drugs in a group of Egyptian epileptic patients. Sixty-nine epileptic patients on antiepileptic drug monotherapy for at least 2 years and 34 control subjects were recruited in this study. Patients were divided into 5 subgroups according to antiepileptic drugs used (valproate, carbamazepine, lamotrigine, topiramate, and levetiracetam). Fasting lipid profile (total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), lipoprotein(a), homocysteine, free thyroxine, thyroid-stimulating hormone, and common carotid artery intima-media thickness were measured for all subjects. Significant higher mean values of low-density lipoprotein cholesterol, low-density lipoprotein / high-density lipoprotein ratio, lipoprotein(a), homocysteine, significantly lower mean value of high-density lipoprotein cholesterol, and significantly larger diameter of common carotid artery intima-media thickness were observed in each drug-treated group versus control group. Our study supports that long-term monotherapy treatment with valproate, carbamazepine, lamotrigine, and topiramate had altered markers of vascular risk that might enhance atherosclerosis, whereas levetiracetam exerted minimal effect. PMID:25342306

  13. Effects of WIN 55,212-2 (a non-selective cannabinoid CB1 and CB 2 receptor agonist) on the protective action of various classical antiepileptic drugs in the mouse 6 Hz psychomotor seizure model.

    PubMed

    Florek-Luszczki, Magdalena; Wlaz, Aleksandra; Kondrat-Wrobel, Maria W; Tutka, Piotr; Luszczki, Jarogniew J

    2014-07-01

    The aim of this study was to characterize the influence of WIN 55,212-2 (WIN--a non-selective cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant effects of various classical antiepileptic drugs (clobazam, clonazepam, phenobarbital and valproate) in the mouse 6 Hz-induced psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), step-through passive avoidance task (assessing learning) and grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5 mg/kg, administered intraperitoneally) significantly enhanced the anticonvulsant action of clonazepam (P < 0.001), phenobarbital (P < 0.05) and valproate (P < 0.05), but not that of clobazam in the mouse 6 Hz model. Moreover, WIN (2.5 mg/kg) significantly potentiated the anticonvulsant action of clonazepam (P < 0.01), but not that of clobazam, phenobarbital or valproate in the 6 Hz test in mice. None of the investigated combinations of WIN with antiepileptic drugs was associated with any concurrent adverse effects with regard to motor performance, learning or muscular strength. Pharmacokinetic experiments revealed that WIN had no impact on total brain concentrations of antiepileptic drugs in mice. These preclinical data would suggest that WIN in combination with clonazepam, phenobarbital and valproate is associated with beneficial anticonvulsant pharmacodynamic interactions in the mouse 6 Hz-induced psychomotor seizure test. PMID:24549572

  14. Modern Methods for Analysis of Antiepileptic Drugs in the Biological Fluids for Pharmacokinetics, Bioequivalence and Therapeutic Drug Monitoring

    PubMed Central

    Park, Yoo-Sin; Kim, Shin-Hee; Kim, Sang-Hyun; Jun, Min-Young

    2011-01-01

    Epilepsy is a chronic disease occurring in approximately 1.0% of the world's population. About 30% of the epileptic patients treated with availably antiepileptic drugs (AEDs) continue to have seizures and are considered therapy-resistant or refractory patients. The ultimate goal for the use of AEDs is complete cessation of seizures without side effects. Because of a narrow therapeutic index of AEDs, a complete understanding of its clinical pharmacokinetics is essential for understanding of the pharmacodynamics of these drugs. These drug concentrations in biological fluids serve as surrogate markers and can be used to guide or target drug dosing. Because early studies demonstrated clinical and/or electroencephalographic correlations with serum concentrations of several AEDs, It has been almost 50 years since clinicians started using plasma concentrations of AEDs to optimize pharmacotherapy in patients with epilepsy. Therefore, validated analytical method for concentrations of AEDs in biological fluids is a necessity in order to explore pharmacokinetics, bioequivalence and TDM in various clinical situations. There are hundreds of published articles on the analysis of specific AEDs by a wide variety of analytical methods in biological samples have appears over the past decade. This review intends to provide an updated, concise overview on the modern method development for monitoring AEDs for pharmacokinetic studies, bioequivalence and therapeutic drug monitoring. PMID:21660146

  15. Adverse drug reactions: classification, susceptibility and reporting.

    PubMed

    Kaufman, Gerri

    2016-08-10

    Adverse drug reactions (ADRs) are increasingly common and are a significant cause of morbidity and mortality. Historically, ADRs have been classified as type A or type B. Type A reactions are predictable from the known pharmacology of a drug and are associated with high morbidity and low mortality. Type B reactions are idiosyncratic, bizarre or novel responses that cannot be predicted from the known pharmacology of a drug and are associated with low morbidity and high mortality. Not all ADRs fit into type A and type B categories; therefore, additional categories have been developed. These include type C (continuing), type D (delayed use), and type E (end of use) reactions. Susceptibility to ADRs is influenced by age, gender, disease states, pregnancy, ethnicity and polypharmacy. Drug safety is reliant on nurses and other healthcare professionals being alert to the possibility of ADRs, working with patients to optimise medicine use and exercising vigilance in the reporting of ADRs through the Yellow Card Scheme. PMID:27507394

  16. Ranking Adverse Drug Reactions With Crowdsourcing

    PubMed Central

    Gottlieb, Assaf; Hoehndorf, Robert; Dumontier, Michel

    2015-01-01

    Background There is no publicly available resource that provides the relative severity of adverse drug reactions (ADRs). Such a resource would be useful for several applications, including assessment of the risks and benefits of drugs and improvement of patient-centered care. It could also be used to triage predictions of drug adverse events. Objective The intent of the study was to rank ADRs according to severity. Methods We used Internet-based crowdsourcing to rank ADRs according to severity. We assigned 126,512 pairwise comparisons of ADRs to 2589 Amazon Mechanical Turk workers and used these comparisons to rank order 2929 ADRs. Results There is good correlation (rho=.53) between the mortality rates associated with ADRs and their rank. Our ranking highlights severe drug-ADR predictions, such as cardiovascular ADRs for raloxifene and celecoxib. It also triages genes associated with severe ADRs such as epidermal growth-factor receptor (EGFR), associated with glioblastoma multiforme, and SCN1A, associated with epilepsy. Conclusions ADR ranking lays a first stepping stone in personalized drug risk assessment. Ranking of ADRs using crowdsourcing may have useful clinical and financial implications, and should be further investigated in the context of health care decision making. PMID:25800813

  17. [Exalief as a newer antiepileptic drug for adjunctive therapy of refractory partial-onset seizures].

    PubMed

    Ermolenko, N A; Buchneva, I A

    2014-01-01

    Results of a multicenter international study on the efficacy of exalief (eslicarbazepine acetate (ESL)), a newer blocker of voltage-gated sodium channels and T-type voltage gated calcium channels, for adjunctive therapy of refractory partial-onset seizures are presented. A clinical program included phase II (BIA-2093-201) followed by three phase Ill studies (BIA-2093-301, -302 and-303), each of which was accompanied by an additional open one-year study (301 E, 302E, 303E). In three parallel phase Ill studies patients were randomized to receive ESL in single doses 400, 800, 1200 mg or placebo together with 1 - 3 antiepileptic drugs used in stable doses, with the exception of felbamate and oxcarbazepine. The design of the study included 8-week initial period, double-blind phase (2-week titration period, 12-week maintenance period), 4-week dose reduction period. The results of clinical phase II trials demonstrated the high efficacy and best tolerability profile for single dose titration regimen. Median changes in the frequency of partial-onset seizures were greater (p<0,0001) in patients receiving 800 and 1200 mg ESL (35 and 39%)compared to placebo (15%). The proportion of treatment responders was significantly higher in the groups treated with ESL indoses 800 mg (36%) and 1200 mg (44%) compared to the placebo group (22%). The aversive effects of the drug were of mild or moderate severity. Treatment retention was higher in patients receiving ESL (84,9% of patients completed the 6-month treatment period and 76,6% completed the one-year period). The use of ESL leads to the reduction in partial seizure frequency and the increase in the proportion of treatment responders. The drug has a good tolerability profile. PMID:25629136

  18. Inhibition of the enzyme, GABA-aminotransferase in human platelets by vigabatrin, a potential antiepileptic drug.

    PubMed Central

    Rimmer, E; Kongola, G; Richens, A

    1988-01-01

    1. The effect of the new antiepileptic drug, vigabatrin (gamma-vinyl GABA), on the platelet enzyme, GABA-aminotransferase (GABA-T) was investigated in volunteers and patients. Platelets GABA-T activity was assayed using a radioenzymic method. 2. Three single oral doses of vigabatrin (1 g, 2 g and 4 g) were given to six healthy male volunteers in an open randomised cross over study and compared with a baseline period preceding the three treatments. 3. Significant inhibition of the platelet GABA-T was produced by treatment with all three doses and a dose-response relationship was demonstrated. The minimum enzyme activities after 1 g, 2 g and 4 g doses were 43%, 30% and 21% respectively compared with the control values. 4. A significant depression of enzyme activity occurred at 30 min after drug administration and the values remained below control values for 72 h post-dose, outlasting the presence of the drug itself in the plasma. 5. Eight patients with chronic refractory epilepsy were treated with vigabatrin for 6 weeks. After taking the 2 g daily dose for 1 week there was a marked reduction in platelet enzyme activity in all subjects but the enzyme inhibition produced by the 3 g dose was not significantly different from that produced by the 2 g dose, even after 4 weeks treatment with the larger dose. The mean enzyme activity was approximately 30% throughout the active treatment period. One week after stopping vigabatrin, the enzyme levels were not significantly different from the baseline values.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3358887

  19. Does in utero exposure of antiepileptic drugs lead to failure to reach full cognitive potential?

    PubMed

    McCorry, D; Bromley, R

    2015-05-01

    A clinical scenario of a young female on 800 mg of sodium valproate (VPA) who has recently failed lamotrigine (LTG) and levetiracetam (LEV) and who is currently planning a pregnancy is presented. Currently available data pertaining to the longer-term development of children exposed to antiepileptic drugs (AEDs) are reviewed along with considerations around the methodology and interpretation of such research. There is an accumulation of data highlighting significant risks associated with prenatal exposed to VPA, with the level of risk being mediated by dose. The majority of published evidence does not find a significant risk associated with carbamazepine (CBZ) exposure in utero for global cognitive abilities however the evidence for more specific cognitive skills are unclear. Limited data indicate that LTG may be a preferred treatment to VPA in terms of foetal outcome but further evidence is required. Too little data pertaining to LEV exposure is available and a lack of evidence regarding risk of this and other new AEDs should not be interpreted as evidence of safety. PMID:25819874

  20. A computer-based intervention for improving the appropriateness of antiepileptic drug level monitoring.

    PubMed

    Chen, Philip; Tanasijevic, Milenko J; Schoenenberger, Ronald A; Fiskio, Julie; Kuperman, Gilad J; Bates, David W

    2003-03-01

    We designed and implemented 2 automated, computerized screens for use at the time of antiepileptic drug (AED) test order entry to improve appropriateness by reminding physicians when a potentially redundant test was ordered and providing common indications for monitoring and pharmacokinetics of the specific AED. All computerized orders for inpatient serum AED levels during two 3-month periods were included in the study. During the 3-month period after implementation of the automated intervention, 13% of all AED tests ordered were canceled following computerized reminders. For orders appearing redundant, the cancellation rate was 27%. For nonredundant orders, 4% were canceled when information on specific AED monitoring and pharmacokinetics was provided. The cancellation rate was sustained after 4 years. There has been a 19.5% decrease in total AED testing volume since implementation of this intervention, despite a 19.3% increase in overall chemistry test volume. Inappropriateness owing to repeated testing before pharmacologic steady state was reached decreased from 54% of all AED orders to 14.6%. A simple, automated, activity-based intervention targeting a specific test-ordering behavior effectively reduced inappropriate laboratory testing. The sustained benefit supports the idea that computerized interventions may durably affect physician behavior. Computerized delivery of such evidence-based boundary guidelines can help narrow the gap between evidence and practice. PMID:12645347

  1. Results of barbiturate antiepileptic drug discontinuation on antipsychotic medication dose in individuals with intellectual disability.

    PubMed

    Hanzel, T E; Bauernfeind, J D; Kalachnik, J E; Harder, S R

    2000-04-01

    Five individuals with intellectual disability prescribed both a barbiturate antiepileptic drug (AED) and an antipsychotic medication were identified in a public residential facility. It was hypothesized that antipsychotic medication was prescribed at doses higher than necessary as a result of inadvertent barbiturate AED behavioural side-effects thought to be part of the underlying psychiatric or behavioural condition. To test this hypothesis, barbiturate AEDs were gradually reduced, and replaced with either carbamazepine or valproic acid, and antipsychotic medication was gradually reduced as well. Challenging behaviours, such as physical aggression, self-injurious behaviour and property destruction, were measured with a frequency count or partial interval recording, and retrospectively analysed for time periods of approximately 60 days before phenobarbital reduction, after phenobarbital discontinuation and after the lowest antipsychotic medication dose. Challenging behaviour collectively decreased by 81.5% after barbiturate discontinuation, mean antipsychotic medication dose significantly decreased from 146 mg day(-1) (SD = 98) to 106 mg day(-1) (SD = 88) chlorpromazine equivalence, and antipsychotic medication was discontinued in the cases of two individuals. Compared to the prebarbiturate AED reduction period, challenging behaviour collectively decreased by 96.3% after the lowest antipsychotic medication dose, which confirmed that reduced antipsychotic medication was not achieved at the expense of behaviour deterioration. The data supported the hypothesis that discontinuation of barbiturate AEDs results in decreased challenging behaviour and less antipsychotic medication. PMID:10898379

  2. Temporal trends in new exposure to antiepileptic drug monotherapy and suicide-related behavior

    PubMed Central

    Hesdorffer, Dale; Wang, Chen-Pin; Amuan, Megan E.; Tabares, Jeffrey V.; Finley, Erin P.; Cramer, Joyce A.; Kanner, Andres M.; Bryan, Craig J.

    2013-01-01

    Objective: Because some recent studies suggest increased risk for suicide-related behavior (SRB; ideation, attempts) among those receiving antiepileptic drugs (AEDs), we examined the temporal relationship between new AED exposure and SRB in a cohort of older veterans. Methods: We used national Veterans Health Administration databases to identify veterans aged ≥65 years who received a new AED prescription in 2004–2006. All instances of SRB were identified using ICD-9-CM codes 1 year before and after the AED exposure (index) date. We also identified comorbid conditions and medication associated with SRB in prior research. We used generalized estimating equations with a logit link to examine the association between new AED exposure and SRB during 30-day intervals during the year before and after the index date, controlling for potential confounders. Results: In this cohort of 90,263 older veterans, the likelihood of SRB the month prior to AED exposure was significantly higher than in other time periods even after adjusting for potential confounders. Although there were 87 SRB events (74 individuals) the year before and 106 SRB events (92 individuals) after, approximately 22% (n = 16) of those also had SRB before the index date. Moreover, the rate of SRB after AED start was gradually reduced over time. Conclusions: The temporal pattern of AED exposure and SRB suggests that, in clinical practice, the peak in SRB is prior to exposure. While speculative, the rate of gradual reduction in SRB thereafter suggests that symptoms may prompt AED prescription. PMID:24174583

  3. A pilot randomized controlled clinical trial to improve antiepileptic drug adherence in young children with epilepsy.

    PubMed

    Modi, Avani C; Guilfoyle, Shanna M; Mann, Krista A; Rausch, Joseph R

    2016-03-01

    The primary aim was to examine the preliminary efficacy of a family tailored problem-solving intervention to improve antiepileptic drug (AED) adherence in families of children with new-onset epilepsy. Secondary aims were to assess changes in targeted mechanisms and treatment feasibility and acceptability. Fifty families (Mage = 7.6 ± 3.0; 80% Caucasian; 42% idiopathic localization related) completed baseline questionnaires and were given an electronic monitor to observe daily AED adherence. If adherence was ≤ 95% in the first 7 months of the study, families were randomized (Supporting Treatment Adherence Regimens (STAR): n = 11; Treatment as Usual (TAU): n = 12). Twenty-one families were not randomized due to adherence being ≥95%. The STAR intervention included four face-to-face and two telephone problem-solving sessions over 8 weeks. Significant group differences in adherence were found during active intervention (weeks 4-6; TAU = -12.0 vs. STAR = 18.1, p < 0.01; and weeks session 6-8: TAU = -9.7 vs. STAR = 15.3, p < 0.05). Children who received the STAR intervention exhibited improved adherence compared to children in the TAU group during active treatment. Significant changes in epilepsy knowledge and management were noted for the STAR group. Families expressed benefitting from the STAR intervention. Future studies should include a larger sample size and booster intervention sessions to maintain treatment effects over time. PMID:26693964

  4. Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT XII).

    PubMed

    Bialer, Meir; Johannessen, Svein I; Levy, René H; Perucca, Emilio; Tomson, Torbjörn; White, H Steve

    2015-03-01

    The Twelfth Eilat Conference on New Antiepileptic Drugs (AEDs) - EILAT XII, took place in Madrid, Spain from August 31st to September 3rd 2014. About 130 basic scientists, clinical pharmacologists and neurologists from 22 countries attended the conference, whose main themes included "Conquering pharmacoresistant epilepsy", "Innovative emergency treatments", "Progress report on second-generation treatment" and "New methods and formulations". Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 2004. Like the EILAT X and EILAT XI reports, the current article focuses on the preclinical and clinical pharmacology of AEDs that are currently in development. These include adenosine-releasing silk, allopregnanolone (SAGE-547), AMP-X-0079, brivaracetam, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-glucose, everolimus, ganaxolone, huperzine A, imepitoin, minocycline, NAX 801-2, pitolisant, PRX 0023, SAGE-217, valnoctamide and its homologue sec-butyl-propylacetamide (SPD), and VLB-01. Since the previous Eilat conference, perampanel has been introduced into the market and twelve novel potential epilepsy treatments are presented for the first time. PMID:25769377

  5. Medicine possession ratio as proxy for adherence to antiepileptic drugs: prevalence, associations, and cost implications

    PubMed Central

    Jacobs, Karen; Julyan, Marlene; Lubbe, Martie S; Burger, Johanita R; Cockeran, Marike

    2016-01-01

    Objective To determine the adherence status to antiepileptic drugs (AEDs) among epilepsy patients; to observe the association between adherence status and age, sex, active ingredient prescribed, treatment period, and number of comorbidities; and to determine the effect of nonadherence on direct medicine treatment cost of AEDs. Methods A retrospective study analyzing medicine claims data obtained from a South African pharmaceutical benefit management company was performed. Patients of all ages (N=19,168), who received more than one prescription for an AED, were observed from 2008 to 2013. The modified medicine possession ratio (MPRm) was used as proxy to determine the adherence status to AED treatment. The MPRm was considered acceptable (adherent) if the calculated value was ≥80%, but ≤110%, whereas an MPRm of <80% (unacceptably low) or >110% (unacceptably high) was considered nonadherent. Direct medicine treatment cost was calculated by summing the medical scheme contribution and patient co-payment associated with each AED prescription. Results Only 55% of AEDs prescribed to 19,168 patients during the study period had an acceptable MPRm. MPRm categories depended on the treatment period (P>0.0001; Cramer’s V=0.208) but were independent of sex (P<0.182; Cramer’s V=0.009). Age group (P<0.0001; Cramer’s V=0.067), active ingredient (P<0.0001; Cramer’s V=0.071), and number of comor-bidities (P<0.0001; Cramer’s V=0.050) were statistically but not practically significantly associated with MPRm categories. AEDs with an unacceptably high MPRm contributed to 3.74% (US$736,376.23) of the total direct cost of all AEDs included in the study, whereas those with an unacceptably low MPRm amounted to US$3,227,894.85 (16.38%). Conclusion Nonadherence to antiepileptic treatment is a major problem, encompassing ~20% of cost in our study. Adherence, however, is likely to improve with the treatment period. Further research is needed to determine the factors influencing

  6. Inverse Association between Sodium Channel-Blocking Antiepileptic Drug Use and Cancer: Data Mining of Spontaneous Reporting and Claims Databases

    PubMed Central

    Takada, Mitsutaka; Fujimoto, Mai; Motomura, Haruka; Hosomi, Kouichi

    2016-01-01

    Purpose: Voltage-gated sodium channels (VGSCs) are drug targets for the treatment of epilepsy. Recently, a decreased risk of cancer associated with sodium channel-blocking antiepileptic drugs (AEDs) has become a research focus of interest. The purpose of this study was to test the hypothesis that the use of sodium channel-blocking AEDs are inversely associated with cancer, using different methodologies, algorithms, and databases. Methods: A total of 65,146,507 drug-reaction pairs from the first quarter of 2004 through the end of 2013 were downloaded from the US Food and Drug Administration Adverse Event Reporting System. The reporting odds ratio (ROR) and information component (IC) were used to detect an inverse association between AEDs and cancer. Upper limits of the 95% confidence interval (CI) of < 1 and < 0 for the ROR and IC, respectively, signified inverse associations. Furthermore, using a claims database, which contains 3 million insured persons, an event sequence symmetry analysis (ESSA) was performed to identify an inverse association between AEDs and cancer over the period of January 2005 to May 2014. The upper limit of the 95% CI of adjusted sequence ratio (ASR) < 1 signified an inverse association. Results: In the FAERS database analyses, significant inverse associations were found between sodium channel-blocking AEDs and individual cancers. In the claims database analyses, sodium channel-blocking AED use was inversely associated with diagnoses of colorectal cancer, lung cancer, gastric cancer, and hematological malignancies, with ASRs of 0.72 (95% CI: 0.60 - 0.86), 0.65 (0.51 - 0.81), 0.80 (0.65 - 0.98), and 0.50 (0.37 - 0.66), respectively. Positive associations between sodium channel-blocking AEDs and cancer were not found in the study. Conclusion: Multi-methodological approaches using different methodologies, algorithms, and databases suggest that sodium channel-blocking AED use is inversely associated with colorectal cancer, lung cancer, gastric

  7. Pharmacogenetics of idiosyncratic adverse drug reactions.

    PubMed

    Pirmohamed, Munir

    2010-01-01

    Idiosyncratic adverse drug reactions are unpredictable and thought to have an underlying genetic etiology. With the completion of the human genome and HapMap projects, together with the rapid advances in genotyping technologies, we have unprecedented capabilities in identifying genetic predisposing factors for these relatively rare, but serious, reactions. The main roadblock to this is the lack of sufficient numbers of well-characterized samples from patients with such reactions. This is now beginning to be solved through the formation of international consortia, including developing novel ways of identifying and recruiting patients affected by these reactions, both prospectively and retrospectively. This has been led by the research on abacavir hypersensitivity - its association with HLA-B*5701 forms the gold standard of how we need to identify associations and implement them in clinical practice. Strong genetic predisposing factors have also been identified for hypersensitivity reactions such as are associated with carbamazepine, allopurinol, flucloxacillin, and statin-induced myopathy. However, for most other idiosyncratic adverse drug reactions, the genetic effect sizes have been low to moderate, although this may partly be due to the fact that only small numbers have been investigated and limited genotyping strategies have been utilized. It may also indicate that genetic predisposition will be dependent on multiple genes, with complex interactions with environmental factors. Irrespective of the strength of the genetic associations identified with individual idiosyncratic adverse drug reactions, it is important to undertake functional investigations to provide insights into the mechanism(s) of how the drug interacts with the gene variant to lead to a phenotype, which can take a multitude of clinical forms with variable severity. Such investigations will be essential in preventing the burden caused by idiosyncratic reactions, both in healthcare and in industry

  8. Idiosyncratic Adverse Drug Reactions: Current Concepts

    PubMed Central

    Naisbitt, Dean J.

    2013-01-01

    Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they also markedly increase the uncertainty of drug development. The major targets are skin, liver, and bone marrow. Clinical characteristics suggest that IDRs are immune mediated, and there is substantive evidence that most, but not all, IDRs are caused by chemically reactive species. However, rigorous mechanistic studies are very difficult to perform, especially in the absence of valid animal models. Models to explain how drugs or reactive metabolites interact with the MHC/T-cell receptor complex include the hapten and P-I models, and most recently it was found that abacavir can interact reversibly with MHC to alter the endogenous peptides that are presented to T cells. The discovery of HLA molecules as important risk factors for some IDRs has also significantly contributed to our understanding of these adverse reactions, but it is not yet clear what fraction of IDRs have a strong HLA dependence. In addition, with the exception of abacavir, most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug. Interindividual differences in T-cell receptors and other factors also presumably play a role in determining which patients will have an IDR. The immune response represents a delicate balance, and immune tolerance may be the dominant response to a drug that can cause IDRs. PMID:23476052

  9. Induction of nuclear receptors and drug resistance in the brain microvascular endothelial cells treated with antiepileptic drugs.

    PubMed

    Lombardo, Laura; Pellitteri, Rosalia; Balazy, Michael; Cardile, Venera

    2008-05-01

    Our work contributes to the understanding of the mechanisms of drug resistance in epilepsis. This study aimed to investigate i) the levels of expression of P-glycoprotein (P-gp), and multidrug resistance-associated proteins (MRP)1 and 2, ii) the activation of the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), and iii) the relationship between increased P-gp and MRPs expression and PXR and CAR activation, in immortalized rat brain microvascular endothelial cell lines, GPNT and RBE4, following treatment with the antiepileptic drugs (AEDs), topiramate, phenobarbital, carbamazepine, tiagabine, levetiracetam, and phenytoin, using Western blotting and immunocytochemistry methods. Carbamazepine, phenobarbital and phenytoin induced the highest levels of P-gp and MPRs expression that was associated with increased activation of PXR and CAR receptors as compared to levetiracetam, tiagabine and topiramate. We conclude that P-gp and MRPs are differently overexpressed in GPNT and RBE4 by various AEDs and both PXR and CAR are involved in the drug-resistant epilepsy induced by carbamazepine, phenobarbital and phenytoin. PMID:18473823

  10. Antiepileptic Drugs: A Consideration of Clinical and Biochemical Outcome in Patients with Epilepsy

    PubMed Central

    Tolou-Ghamari, Zahra; Zare, Mohammad; Habibabadi, Jafar Mehvari; Najafi, Mohammad-Reza

    2013-01-01

    Background: The challenge of antiepileptic drugs (AEDs) management is to attain the best compromise between the desire to maximize seizure control and the need to keep side-effects within tolerable limits for the individual patient. To reduce devastation in Iranian epileptic patients, the aim of this study was to explore the overall outcome following AEDs prescription. Methods: A cross-sectional study of 36 patients located at the epilepsy ward, conducted to Isfahan Neurosciences Research Centre was carried out during the year 2011. Female (n = 17) and male subjects (n = 19) with a mean age of 27 years (range; 7-74 years) were studied. Variables including, sex, age, age of seizure onset, type, and number of AEDs, biochemical and hematological data were recorded in d-Base and statistical analyses were performed using SPSS (version 18) for windows. Results: The main drug to control seizure attack was carbamazepine and valproic-acid. The following tests were the most frequently influenced; alkaline phosphatase (AP), lymphocyte (Lymph), white blood cell (WBC) counts and hemoglobin (Hgb). There was a significant increase in (AP) (mean; 534.6 u/l↑; [P = 0.02] in three patients and (Lymph) (55%↑; [43-84] %↑; [P = 0.04] in seven patients. WBC was lower than 4400 mm3↓ (P = 0.02) in six patients. Hgb was significantly lower in 70.6% of women (11.8↓; [10-14.2] g/dl↓; [P = 0.04] and 68.4% of men population (12.3↓; [9.7-13.8] g/dl↓; [P = 0.01]. Mean age of epilepsy onset was 15.6 years (range: Birth-74 years). Analysis of drug prescriptions showed that the incidence of monotherapy and polypharmacy (2 up to six AEDs simultaneously) was 19.4% plus 80.6% respectively. Conclusions: In Iranian epileptic population, effectiveness of treatment should be attributed by the close supervising of AEDs in relation to clinical circumstance, laboratory data, and therapeutic drug monitoring. Any significant change in patients’ biochemical and hematological data may require

  11. [Use of antiepileptic drugs in schizophrenia: A review of recent evidence].

    PubMed

    Theochari, I; Boulas, C; Chaidemenos, A

    2007-07-01

    The treatment of schizophrenia has always been a challenge for clinicians. Neuroleptic monotherapy is not sufficient in all subtypes and all symptoms of schizophrenia. New treatment strategies have been developed including the combination of neuroleptics and antiepileptics. We summarize papers published on the efficacy and the action mechanism of antiepileptic agents in schizophrenia. We have searched the computer database system MEDLINE and COCHRANE for relevant articles. GABA and glutamate are involved in the symptom improvement of schizophrenia when antiepileptics are added in the main neuroleptic treatment. Augmentation treatment with valproate leads to a decrease in hostility, violent behavior, agitation and anxiety and is related to fewer days of hospitalization. Carbamazepine has been used as a calmative and is effective in controlling patients with psychomotor agitation. Whether both antiepileptics can reduce positive and negative symptoms in schizophrenia, still remains controversial. Oxcarbazepine has a very safe pharmaceutical profile in combination with neuroleptics but only a single study indicates its efficacy. Adjunctive lamotrigine appears effective when added to clozapine even in cases of treatment resistant schizophrenia. Both lamotrigine and clozapine share anti-glutamatergic actions. There have been reported few studies which support the use of topiramate in schizophrenia. Future studies on a great number of patients will provide more reliable evidence. Finally the potential role of new antiepileptics has to be evaluated using new clinical testing. PMID:22466630

  12. IQ at 6 years after in utero exposure to antiepileptic drugs

    PubMed Central

    Baker, Gus A.; Briggs, Maria; Cheyne, Christopher P.; Cohen, Morris J.; García-Fiñana, Marta; Gummery, Alison; Kneen, Rachel; Loring, David W.; Mawer, George; Meador, Kimford J.; Shallcross, Rebekah; Clayton-Smith, Jill

    2015-01-01

    Objective: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs. Methods: Children born to women with epilepsy (n = 243) and women without epilepsy (n = 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models. Results: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] −4.9 to −14.6; p < 0.001) for children exposed to high-dose (>800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5–19.7; p < 0.001). Valproate at doses <800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (−5.6, 95% CI −11.1 to −0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4–18.0; p = 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (−4.2, 95% CI −0.6 to −7.8; p = 0.02) and increased frequency of IQ <85. Conclusions: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine. PMID:25540307

  13. Use of antiepileptic drugs during pregnancy and lactation: Type of information provided by searching Google.

    PubMed

    Lavi-Blau, Tal; Ekstein, Dana; Neufeld, Miri Y; Eyal, Sara

    2016-02-01

    Surveys among women with epilepsy (WWE) show that they receive their essential pregnancy-related information from many sources, including the internet. Our aim was to assess the types of websites provided by searching Google for the use of four antiepileptic drugs (AEDs) during pregnancy and lactation. The search was performed on 40 computers used by health-care professionals, on 40 computers used by nonhealth-care professionals, and on 5 computers used by WWE in Israel and on 8 computers used by nonhealth-care professionals in the U.S. On each computer, a Google search was conducted for term combinations that included one AED name ("carbamazepine","valproic acid", "lamotrigine", "levetiracetam", or "Keppra") and "Pregnancy", "Lactation", or "Breastfeeding". The top three and top ten websites retrieved in every search were mapped (a total of 45 and 150 websites, respectively, from each computer). Across all searches in English, on both U.S. and Israeli computers, the majority of websites listed among the first three and first ten results were those of independent health portals. The representation of the Epilepsy Foundation website was 10% or less, and only a few results were obtained from the NIH's general public-oriented MedlinePlus. In Hebrew, results included almost exclusively Israeli or Hebrew-translated websites. As in English, results from public-oriented, professionally-written websites in Hebrew accounted for less than 50% of entries. Overall, the availability of readable and high-quality information on AEDs used by pregnant and breastfeeding women is limited. Guiding patients towards accurate web resources can help them navigate among the huge amount of available online information. PMID:26773680

  14. Comparison of body composition in persons with epilepsy on conventional & new antiepileptic drugs

    PubMed Central

    Sarangi, Sudhir Chandra; Tripathi, Manjari; Kakkar, Ashish Kumar; Gupta, Yogendra Kumar

    2016-01-01

    Background & objectives: Certain antiepileptic drugs (AEDs) such as valproic acid (VPA) are known to affect body weight, and lipid profile. However, evidences regarding effects of AEDs on the body composition are deficient. This cross-sectional study compared the body composition and lipid profile among patients with epilepsy on newer and conventional AEDs. Methods: The patients with epilepsy (n=109) on treatment with conventional and newer AEDs (levetiracetam, lamotrigine and clobazam) for > 6 months were enrolled. Of these, 70 were on monotherapy: levetiracetam (n=12), VPA (n=16), carbamazepine (n=20) and phenytoin (n=22) and the remaining on polytherapy. Their body composition [body fat mass, lean dry mass (LDM), total body water (TBW), intracellular water (ICW), extracellular water (ECW) and basal metabolic rate (BMR) was estimated and biochemical parameters were assessed. Results: Levetiracetam group had no significant difference with VPA, carbamazepine, phenytoin and control groups, except low LDM (17.8±2.4) than VPA groups (20.2±2.7, P<0.05). In comparison with control, AEDs monotherapy groups had no significant difference, except higher LDM and ECW in VPA group. Among groups based on conventional and newer AEDs, there was no significant difference in body composition parameters except for higher LDM (as % of BW) in conventional AEDs only treated group than control (P<0.01). Interpretation & conclusions: The alterations observed in body composition with valproic acid in contrast to other AEDs like levetiracetam, carbamazepine and phenytoin could affect treatment response in epilepsy especially in subjects with already altered body composition status like obese and thin frail patients, which needs to be established by prospective studies (CTRI/2013/05/003701). PMID:27241646

  15. Apgar-score in children prenatally exposed to antiepileptic drugs: a population-based cohort study

    PubMed Central

    Christensen, Jakob; Pedersen, Henrik Søndergaard; Kjaersgaard, Maiken Ina Siegismund; Parner, Erik Thorlund; Vestergaard, Mogens; Sørensen, Merete Juul; Olsen, Jørn; Bech, Bodil Hammer; Pedersen, Lars Henning

    2015-01-01

    Objectives It is unknown if prenatal exposure to antiepileptic drugs (AEDs) increases the risk of low Apgar score in offspring. Setting Population-based study using health registers in Denmark. Participants We identified all 677 021 singletons born in Denmark from 1997 to 2008 and linked the Apgar score from the Medical Birth Register with information on the women's prescriptions for AEDs during pregnancy from the Danish Register of Medicinal Product Statistics. We used the Danish National Hospital Registry to identify mothers diagnosed with epilepsy before birth of the child. Results were adjusted for smoking and maternal age. Results Among 2906 children exposed to AEDs, 55 (1.9%) were born with an Apgar score ≤7 as compared with 8797 (1.3%) children among 674 115 pregnancies unexposed to AEDs (adjusted relative risk (aRR)=1.41 (95% CI 1.07 to 1.85). When analyses were restricted to the 2215 children born of mothers with epilepsy, the aRR of having a low Apgar score associated with AED exposure was 1.34 (95% CI 0.90 to 2.01) When assessing individual AEDs, we found increased, unadjusted RR for exposure to carbamazepine (RR=1.86 (95% CI 1.01 to 3.42)), valproic acid (RR=1.85 (95% CI 1.04 to 3.30)) and topiramate (RR=2.97 (95% CI 1.26 to 7.01)) when compared to unexposed children. Conclusions Prenatal exposure to AEDs was associated with increased risk of being born with a low Apgar score, but the absolute risk of a low Apgar score was <2%. Risk associated with individual AEDs indicate that the increased risk is not a class effect, but that there may be particularly high risks of a low Apgar score associated with certain AEDs. PMID:26359281

  16. Comparative persistence of antiepileptic drugs in patients with epilepsy: A STROBE-compliant retrospective cohort study.

    PubMed

    Lai, Edward Chia-Cheng; Hsieh, Cheng-Yang; Su, Chien-Chou; Yang, Yea-Huei Kao; Huang, Chin-Wei; Lin, Swu-Jane; Setoguchi, Soko

    2016-08-01

    We compared persistence of antiepileptic drugs (AEDs) including carbamazepine, oxcarbazepine, gabapentin, lamotrigine, topiramate, valproic acid, and phenytoin in an Asian population with epilepsy.A retrospective cohort study was conducted by analyzing Taiwan's National Health Insurance Research Database (NHIRD). Adult epilepsy patients newly prescribed with AEDs between 2005 and 2009 were included. The primary outcome was persistence, defined as the treatment duration from the date of AED initiation to the date of AED discontinuation, switching, hospitalization due to seizure or disenrollment from databases, whichever came first. Cox proportional hazard models were used to estimate the risk of non-persistence with AEDs.Among the 13,061 new users of AED monotherapy (mean age: 58 years; 60% men), the persistence ranged from 218.8 (gabapentin) to 275.9 (oxcarbazepine) days in the first treatment year. The risks of non-persistence in patients receiving oxcarbazepine (adjusted hazard ratio [HR], 0.78; 95% CI, 0.74-0.83), valproic acid (0.88; 0.85-0.92), lamotrigine (0.72; 0.65-0.81), and topiramate (0.90; 0.82-0.98) were significantly lower than in the carbamazepine group. Compared with carbamazepine users, the non-persistence risk was higher in phenytoin users (1.10; 1.06-1.13), while gabapentin users (1.03; 0.98-1.09) had similar risk. For risk of hospitalization due to seizure and in comparison with carbamazepine users, oxcarbazepine (0.66; 0.58-0.74) and lamotrigine (0.46; 0.35-0.62) users had lower risk, while phenytoin (1.35; 1.26-1.44) users had higher risk. The results remained consistent throughout series of sensitivity and stratification analyses.The persistence varied among AEDs and was better for oxcarbazepine, valproic acid, lamotrigine, and topiramate, but worse for phenytoin when compared with carbamazepine. PMID:27583857

  17. Hepatic drug metabolism and adverse hepatic drug reactions.

    PubMed

    Schaffner, F

    1975-01-01

    Drugs and other chemicals are usually metabolized in the liver in the drug-metabolizing enzyme system. The metabolites sometimes bind with cellular macromolecules and injure the cell directly or serve as new antigens to create immunologic injury in a delayed fashion. The immediate or toxic injury is dose-dependent, predictable and zonal in the liver lobule, usually in the central region. Carbon tetrachloride intoxication and acetaminophen overdose are examples of injury resulting from microsomal metabolism. Other injuries related to microsomal metabolism are those produced by vinyl chloride in polymerization plant workers and by methotrexate in psoriatics or leukemic children. Most adverse drug reactions affecting the liver and producing jaundice are unpredictable, delayed in onset, and only hypothetically related to microsomal metabolism in some instances. The two main types are cholestasis and viral-hepatitis-like. The former may be in a pure form, in which case it may be partly dose-dependent, or in a form mixed with hepatitis. Many drugs produce cholestasis in a small percentage of persons, and because the reaction is benign, albeit prolonged at times, such drugs continue to be used. The viral-hepatitis-like reaction involves few drugs and affects few persons, but can be fatal. The recognition that chronic hepatitis can be caused by drugs such as oxyphenisatin, alpha-methyldopa, and isoniazid has added a new dimension to the clinical problem of adverse drug reactions, which may extend to widely used and commonly available agents like aspirin. PMID:171822

  18. Adverse immunologic effects of antithyroid drugs.

    PubMed Central

    Wing, S S; Fantus, I G

    1987-01-01

    Propylthiouracil and methimazole are frequently used in the management of hyperthyroidism. Two patients in whom adverse immunologic effects other than isolated agranulocytosis developed during treatment with propylthiouracil are described. A review of the literature revealed 53 similar cases over a 35-year period. Rash, fever, arthralgias and granulocytopenia were the most common manifestations. Vasculitis, particularly with cutaneous manifestations, occurs and may be fatal. The clinical evidence suggests that an immunologic mechanism is involved. A number of different autoantibodies were reported, but antinuclear antibodies were infrequent, and none of the cases met the criteria for a diagnosis of systemic lupus erythematosus. Thus, the reactions do not represent a true drug-induced lupus syndrome. Current hypotheses and experimental data regarding the cause of the reactions are reviewed. No specific clinical subgroup at high risk can be identified, and manifestations may occur at any dosage and at any time during therapy. Cross-reactivity between the two antithyroid drugs can be expected. Except for minor symptoms (e.g., mild arthralgias or transient rash), such reactions are an indication for withdrawal of the drug and the use of alternative methods to control the hyperthyroidism. In rare cases of severe vasculitis a short course of high-dose glucocorticoid therapy may be helpful. PMID:3539299

  19. Heterogeneous effects of antiepileptic drugs in an in vitro epilepsy model--a functional multineuron calcium imaging study.

    PubMed

    Hongo, Yoshie; Takasu, Keiko; Ikegaya, Yuji; Hasegawa, Minoru; Sakaguchi, Gaku; Ogawa, Koichi

    2015-07-01

    Epilepsy is a chronic brain disease characterised by recurrent seizures. Many studies of this disease have focused on local neuronal activity, such as local field potentials in the brain. In addition, several recent studies have elucidated the collective behavior of individual neurons in a neuronal network that emits epileptic activity. However, little is known about the effects of antiepileptic drugs on neuronal networks during seizure-like events (SLEs) at single-cell resolution. Using functional multineuron Ca(2+) imaging (fMCI), we monitored the activities of multiple neurons in the rat hippocampal CA1 region on treatment with the proconvulsant bicuculline under Mg(2+) -free conditions. Bicuculline induced recurrent synchronous Ca(2+) influx, and the events were correlated with SLEs. Other proconvulsants, such as 4-aminopyridine, pentetrazol, and pilocarpine, also induced synchronous Ca(2+) influx. We found that the antiepileptic drugs phenytoin, flupirtine, and ethosuximide, which have different mechanisms of action, exerted heterogeneous effects on bicuculline-induced synchronous Ca(2+) influx. Phenytoin and flupirtine significantly decreased the peak, the amount of Ca(2+) influx and the duration of synchronous events in parallel with the duration of SLEs, whereas they did not abolish the synchronous events themselves. Ethosuximide increased the duration of synchronous Ca(2+) influx and SLEs. Furthermore, the magnitude of the inhibitory effect of phenytoin on the peak synchronous Ca(2+) influx level differed according to the peak amplitude of the synchronous event in each individual cell. Evaluation of the collective behavior of individual neurons by fMCI seems to be a powerful tool for elucidating the profiles of antiepileptic drugs. PMID:25967117

  20. [Plasma levels of anti-epileptic drugs. Evaluation of determinations carried out in the years 1978-1979].

    PubMed

    Zagnoni, P; Cognazzo, A; Gerbino Promis, P C; Grasso, E

    1981-11-10

    The results of 701 determinations of antiepileptic drug plasma concentrations administered to 190 patients are described. It has been possible to reduce the number of prescribed drugs to 1.55 per patient, so that only 8.1% of subjects takes three or more drugs while 53% is on monotherapy. The use of the measurement of AEDs plasma concentrations resulted very useful: a) when Phenytoin (PHT) is prescribed; b) in epileptic children; c) when the patient takes two or more drugs; d) to evaluate the compliance. A significant increase (p less than 0.01) of the level/dose ratio of Phenobarbital (PB) when PHT is in, or over, the therapeutic range was observed, while at plasma concentrations of PHT below 10 micrograms/ml it does not influence the metabolism of PB. PMID:7301176

  1. Discovery of benzothiazine derivatives as novel, orally-active anti-epileptic drug candidates with broad anticonvulsant effect.

    PubMed

    Tanaka, Tomoyuki; Yajima, Nana; Tanitame, Akihiko; Kiyoshi, Tomoko; Miura, Yoshiki

    2015-10-15

    In order to develop novel anti-epileptic drugs that are effective for both general and partial seizure, we conducted in vivo screening of our chemical library in the mice MES and sc-PTZ models and found the benzothiazine 1 as lead compound. Optimization of this compound led to the discovery of compound 7b, which showed potent anticonvulsant effect in the MES, scPTZ and rat amygdala kindling models. Since the chemical structure of 7b is different from that of any existing AED, it is suggested that 7b may have unique mechanism of action for relieving both partial and generalized epilepsy. PMID:26364945

  2. Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy.

    PubMed

    Isojärvi, Jouko I T; Taubøll, Erik; Herzog, Andrew G

    2005-01-01

    It is well known that epilepsy, antiepileptic drugs (AEDs), and the reproductive system have complex interactions. Fertility is lower in both men and women with epilepsy than in the general population. Moreover, reproductive endocrine disorders are more common among patients with epilepsy than among the population in general. These disorders have been attributed both to epilepsy itself and to use of AEDs. The use of the liver enzyme-inducing AEDs phenobarbital, phenytoin and carbamazepine increases serum sex hormone-binding globulin (SHBG) concentrations in both men and women with epilepsy. Over time, the increase in serum SHBG levels leads to diminished bioactivity of testosterone and estradiol, which may result in diminished potency in men and menstrual disorders in some women, and thus to reduced fertility. Liver enzyme-inducing AEDs also reduce the efficacy of oral contraceptives. Valproic acid medication may have effects on serum androgen concentrations and it reduces serum follicle stimulating hormone levels in men with epilepsy. However, the clinical significance of valproic acid-related reproductive endocrine changes in men is unknown. On the other hand, in women, use of valproic acid appears to be associated with a frequent occurrence of reproductive endocrine disorders characterised by polycystic changes in the ovaries, high serum testosterone concentrations (hyperandrogenism) and menstrual disorders. These disorders are especially common among women who have gained weight during valproic acid treatment. There are some discrepancies regarding the reported occurrence of reproductive endocrine disorders in women taking valproic acid for epilepsy. However, most studies also including patients receiving valproic acid for other reasons than epilepsy, and studies in different non-epileptic animal models, have shown an association between valproic acid medication and hyperandrogenism and related reproductive endocrine disorders. From a practical point of view

  3. Comparative persistence of antiepileptic drugs in patients with epilepsy: A STROBE-compliant retrospective cohort study

    PubMed Central

    Lai, Edward Chia-Cheng; Hsieh, Cheng-Yang; Su, Chien-Chou; Yang, Yea-Huei Kao; Huang, Chin-Wei; Lin, Swu-Jane; Setoguchi, Soko

    2016-01-01

    Abstract We compared persistence of antiepileptic drugs (AEDs) including carbamazepine, oxcarbazepine, gabapentin, lamotrigine, topiramate, valproic acid, and phenytoin in an Asian population with epilepsy. A retrospective cohort study was conducted by analyzing Taiwan's National Health Insurance Research Database (NHIRD). Adult epilepsy patients newly prescribed with AEDs between 2005 and 2009 were included. The primary outcome was persistence, defined as the treatment duration from the date of AED initiation to the date of AED discontinuation, switching, hospitalization due to seizure or disenrollment from databases, whichever came first. Cox proportional hazard models were used to estimate the risk of non-persistence with AEDs. Among the 13,061 new users of AED monotherapy (mean age: 58 years; 60% men), the persistence ranged from 218.8 (gabapentin) to 275.9 (oxcarbazepine) days in the first treatment year. The risks of non-persistence in patients receiving oxcarbazepine (adjusted hazard ratio [HR], 0.78; 95% CI, 0.74–0.83), valproic acid (0.88; 0.85–0.92), lamotrigine (0.72; 0.65–0.81), and topiramate (0.90; 0.82–0.98) were significantly lower than in the carbamazepine group. Compared with carbamazepine users, the non-persistence risk was higher in phenytoin users (1.10; 1.06–1.13), while gabapentin users (1.03; 0.98–1.09) had similar risk. For risk of hospitalization due to seizure and in comparison with carbamazepine users, oxcarbazepine (0.66; 0.58–0.74) and lamotrigine (0.46; 0.35–0.62) users had lower risk, while phenytoin (1.35; 1.26–1.44) users had higher risk. The results remained consistent throughout series of sensitivity and stratification analyses. The persistence varied among AEDs and was better for oxcarbazepine, valproic acid, lamotrigine, and topiramate, but worse for phenytoin when compared with carbamazepine. PMID:27583857

  4. Large-Scale Phenotype-Based Antiepileptic Drug Screening in a Zebrafish Model of Dravet Syndrome1,2,3

    PubMed Central

    Dinday, Matthew T.

    2015-01-01

    Abstract Mutations in a voltage-gated sodium channel (SCN1A) result in Dravet Syndrome (DS), a catastrophic childhood epilepsy. Zebrafish with a mutation in scn1Lab recapitulate salient phenotypes associated with DS, including seizures, early fatality, and resistance to antiepileptic drugs. To discover new drug candidates for the treatment of DS, we screened a chemical library of ∼1000 compounds and identified 4 compounds that rescued the behavioral seizure component, including 1 compound (dimethadione) that suppressed associated electrographic seizure activity. Fenfluramine, but not huperzine A, also showed antiepileptic activity in our zebrafish assays. The effectiveness of compounds that block neuronal calcium current (dimethadione) or enhance serotonin signaling (fenfluramine) in our zebrafish model suggests that these may be important therapeutic targets in patients with DS. Over 150 compounds resulting in fatality were also identified. We conclude that the combination of behavioral and electrophysiological assays provide a convenient, sensitive, and rapid basis for phenotype-based drug screening in zebrafish mimicking a genetic form of epilepsy. PMID:26465006

  5. Multidrug resistance-associated protein 1 decreases the concentrations of antiepileptic drugs in cortical extracellular fluid in amygdale kindling rats

    PubMed Central

    Chen, Ying-hui; Wang, Cui-cui; Xiao, Xia; Wei, Li; Xu, Guoxiong

    2013-01-01

    Aim: To investigate whether multidrug resistance-associated protein 1 (MRP1) was responsible for drug resistence in refractory epilepsy in amygdale kindling rats. Methods: Rat amygdale kindling was used as a model of refractory epilepsy. The expression of MRP1 mRNA and protein in the brains was examined using RT-PCR and Western blot. MRP1-positive cells in the cortex and hippocampus were studied with immunohistochemical staining. The rats were intraperitoneally injected with phenytoin (50 mg/kg) or carbamazepine (20 mg/kg), and their concentrations in the cortical extracellular fluid were measured using microdialysis and HPLC. Probenecid, a MRP1 inhibitor (40 mmol/L, 50 μL) was administered through an inflow tube into the cortex 30 min before injection of the antiepileptic drugs. Results: The expression of MRP1 mRNA and protein was significantly up-regulated in the cortex and hippocampus in amygdale kindling rats compared with the control group. Furthermore, the number of MRP1-positive cells in the cortex and hippocampus was also significantly increased in amygdale kindling rats. Microdialysis studies showed that the concentrations of phenytoin and carbamazepine in the cortical extracellular fluid were significantly decreased in amygdale kindling rats. Pre-administration of probenecid could restore the concentrations back to their control levels. Conclusion: Up-regulation of MRP1 is responsible for the resistance of brain cells to antiepileptic drugs in the amygdale kindling rats. PMID:23474709

  6. Assessment of oral side effects of Antiepileptic drugs and traumatic oro-facial injuries encountered in Epileptic children

    PubMed Central

    Ghafoor, P A Fazal; Rafeeq, Mohammed; Dubey, Alok

    2014-01-01

    Background: Epilepsy is a chronic disorder with unpredictably recurring seizure. Uncontrolled attacks can put patients at risk of suffering oro-facial trauma. Antiepileptic drugs (AED) provide satisfactory control of seizures in most of the patients with epilepsy. However use of AED has been found to cause many side effects inclusive of side effects in the oral cavity also. Materials & Methods: This study was conducted on 150 epileptic children, who were on anti epileptic medication for one year. Results: Gingival over growth was seen as common side effect of the AED drugs. Lip and cheek biting were the most common soft tissue injury, while tooth fracture was the most common hard tissue dental injury. Conclusion: General physicians, physicians & dentists should be well aware of the potential side effects of AED. A Dentist should be well versed and trained to manage oro-facial injuries in the emergency department. How to cite the article: Ghafoor PA, Rafeeq M, Dubey A. Assessment of oral side effects of Antiepileptic drugs and traumaticoro-facial injuries encountered in Epileptic children. J Int Oral Health 2014;6(2):126-8. PMID:24876713

  7. Large-Scale Phenotype-Based Antiepileptic Drug Screening in a Zebrafish Model of Dravet Syndrome(1,2,3).

    PubMed

    Dinday, Matthew T; Baraban, Scott C

    2015-01-01

    Mutations in a voltage-gated sodium channel (SCN1A) result in Dravet Syndrome (DS), a catastrophic childhood epilepsy. Zebrafish with a mutation in scn1Lab recapitulate salient phenotypes associated with DS, including seizures, early fatality, and resistance to antiepileptic drugs. To discover new drug candidates for the treatment of DS, we screened a chemical library of ∼1000 compounds and identified 4 compounds that rescued the behavioral seizure component, including 1 compound (dimethadione) that suppressed associated electrographic seizure activity. Fenfluramine, but not huperzine A, also showed antiepileptic activity in our zebrafish assays. The effectiveness of compounds that block neuronal calcium current (dimethadione) or enhance serotonin signaling (fenfluramine) in our zebrafish model suggests that these may be important therapeutic targets in patients with DS. Over 150 compounds resulting in fatality were also identified. We conclude that the combination of behavioral and electrophysiological assays provide a convenient, sensitive, and rapid basis for phenotype-based drug screening in zebrafish mimicking a genetic form of epilepsy. PMID:26465006

  8. Impact of early life exposure to antiepileptic drugs on neurobehavioral outcomes based on laboratory animal and clinical research

    PubMed Central

    Bath, Kevin G.; Scharfman, Helen E.

    2014-01-01

    Epilepsy affects approximately 1% of children under the age of 15, making it a very common neurological disorder in the pediatric population (Russ et al., 2012 [1]). In addition, ∼0.4–0.8% of all pregnant women have some form of epilepsy (Hauser et al., 1996a,b; Borthen et al., 2009; Krishnamurthy, 2012 [2–5]). Despite the potential deleterious effects of antiepileptic drugs (AEDs) on the developing brain, their use is still required for seizure control in pregnant women (Krishnamurthy, 2012 [5]), and they represent the standard approach for treating children with epilepsy (Chu-Shore and Thiele, 2010; Quach et al., 2010; Verrotti et al., 2011 [6–8]). Even when AEDs are effective, there are potential side effects, including cognitive and affective changes or altered sleep and appetite. The consequences of AED exposure in development have been studied extensively (Canger et al., 1999; Modi et al., 2011a,b; Oguni, 2011 [9–12]). Despite intensive study, there is still debate about the long-term consequences of early life AED exposure. Here, we consider the evidence to date that AED exposure, either prenatally or in early postnatal life, has significant adverse effects on the developing brain and incorporate studies of laboratory animals as well as those of patients. We also note the areas of research where greater clarity seems critical in order to make significant advances. A greater understanding of the impact of AEDs on somatic, cognitive and behavioral development has substantial value because it has the potential to inform clinical practice and guide studies aimed at understanding the genetic and molecular bases of comorbid pathologies associated with common treatment regimens. Understanding these effects has the potential to lead to AEDs with fewer side effects. Such advances would expand treatment options, diminish the risk associated with AED exposure in susceptible populations, and improve the quality of life and health outcomes of children with

  9. Adverse reactions to new anticonvulsant drugs.

    PubMed

    Wong, I C; Lhatoo, S D

    2000-07-01

    A lack of systematic pharmacoepidemiological studies investigating adverse drug reactions (ADRs) to anticonvulsants makes it difficult to assess accurately the incidence of anticonvulsant-related ADRs. Most of the available information in this regard stems from clinical trial experience, case reports and postmarketing surveillance, sources that are not, by any means, structured to provide precise data on adverse event epidemiology. For various ethical, statistical and logistical reasons, the organisation of structured clinical trials that are likely to provide substantial data on ADRs is extremely difficult. This review concentrates on current literature concerning serious and life-threatening ADRs. As with the older anticonvulsants, the majority of ADRs to newer anticonvulsants are CNS-related, although there are several that are apparently unique to some of these new drugs. Gabapentin has been reported to cause aggravation of seizures, movement disorders and psychiatric disturbances. Felbamate should only be prescribed under close medical supervision because of aplastic anaemia and hepatotoxicity. Lamotrigine causes hypersensitivity reactions that range from simple morbilliform rashes to multi-organ failure. Psychiatric ADRs and deterioration of seizure control have also been reported with lamotrigine treatment. Oxcarbazepine has a safety profile similar to that of carbamazepine. Hyponatraemia associated with oxcarbazepine is also a problem; however, it is less likely to cause rash than carbamazepine. Nonconvulsive status epilepticus has been reported frequently with tiagabine, although there are insufficient data at present to identify risk factors for this ADR. Topiramate frequently causes cognitive ADRs and, in addition, also appears to cause word-finding difficulties, renal calculi and bodyweight loss. Vigabatrin has been reported to cause seizure aggravation, especially in myoclonic seizures. There have been rare reports of other neurological ADRs to

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

    PubMed

    Fukuoka, Noriyasu; Tsukamoto, Toyohisa; Uno, Junji; Kimura, Michio; Morita, Shushi

    2004-12-01

    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

  11. Learning Lessons from Adverse Drug Reactions in Children

    PubMed Central

    Sammons, Helen M.; Choonara, Imti

    2016-01-01

    Drug toxicity is, unfortunately, a significant problem in children both in the hospital and in the community. Drug toxicity in children is different to that seen in adults. At least one in 500 children will experience an adverse drug reaction each year. For children in hospital, the risk is far greater (one in ten). Additionally, different and sometimes unique adverse drug reactions are seen in the paediatric age groups. Some of the major cases of drug toxicity historically have occurred in neonates. It is important that we understand the mechanism of action of adverse drug reactions. Greater understanding alongside rational prescribing should hopefully reduce drug toxicity in children in the future. PMID:27417239

  12. Extraction of potential adverse drug events from medical case reports

    PubMed Central

    2012-01-01

    The sheer amount of information about potential adverse drug events published in medical case reports pose major challenges for drug safety experts to perform timely monitoring. Efficient strategies for identification and extraction of information about potential adverse drug events from free‐text resources are needed to support pharmacovigilance research and pharmaceutical decision making. Therefore, this work focusses on the adaptation of a machine learning‐based system for the identification and extraction of potential adverse drug event relations from MEDLINE case reports. It relies on a high quality corpus that was manually annotated using an ontology‐driven methodology. Qualitative evaluation of the system showed robust results. An experiment with large scale relation extraction from MEDLINE delivered under‐identified potential adverse drug events not reported in drug monographs. Overall, this approach provides a scalable auto‐assistance platform for drug safety professionals to automatically collect potential adverse drug events communicated as free‐text data. PMID:23256479

  13. Antiepileptics for aggression and associated impulsivity

    PubMed Central

    Huband, Nick; Ferriter, Michael; Nathan, Rajan; Jones, Hannah

    2014-01-01

    delinquent boys. Authors’ conclusions The authors consider that the body of evidence summarised in this review is insufficient to allow any firm conclusion to be drawn about the use of antiepileptic medication in the treatment of aggression and associated impulsivity. Four antiepileptics (valproate/ divalproex, carbamazepine, oxcarbazepine and phenytoin) were effective, compared to placebo, in reducing aggression in at least one study, although for three drugs (valproate, carbamazepine and phenytoin) at least one other study showed no statistically significant difference between treatment and control conditions. Side effects were more commonly noted for the intervention group although adverse effects were not well reported. Absence of information does not necessarily mean that the treatment is safe, nor that the potential gains from the medication necessarily balance the risk of an adverse event occurring. Further research is needed. PMID:20166067

  14. Intrapatient variation in antiepileptic drug plasma concentration after generic substitution vs stable brand-name drug regimens.

    PubMed

    Contin, Manuela; Alberghini, Lucia; Candela, Carmina; Benini, Giulia; Riva, Roberto

    2016-05-01

    Generic substitution of antiepileptic drugs (AEDs) is still a matter of controversy and concern among clinicians and patients. We aimed to assess intrasubject variation in plasma concentrations of lamotrigine (LTG), levetiracetam (LEV) and topiramate (TPM) after generic substitution compared with a stable brand-name drug regimen in a population of patients with epilepsy. A retrospective analysis was performed on prospectively collected and stored data from our therapeutic drug monitoring (TDM) database for the years 2009-2014. The main outcome variable was the proportion of patients who, after switching from branded to generic formulations, showed a greater than ±20% change in AED plasma concentrations compared to the proportion of control patients showing a change in AED plasma concentrations of the same extent while receiving stable branded formulations over repeated TDM tests. Fifty patients on LTG, 27 on LEV and 16 on TPM showing at least one TDM test while receiving generic products fulfilled the inclusion/exclusion criteria for the analysis and were compared with 200 control patients for LTG, 120 for LEV and 80 for TPM. The proportion of patients showing an intrasubject change greater than ±20% in AED plasma concentrations was similar in the brand name vs generic group compared with the control one for LTG (22% vs 33%) and LEV (44% vs 38%), while it was higher in the control group for TPM (41% vs 6%, p<0.01). These are the first data in the literature about the within-patient variation in steady-state plasma concentrations of a series of stable treatments with brand-name AEDs in a real clinical setting. In conclusion, a significant interday variability in intrapatient LTG, LEV and TPM plasma concentrations can be observed even in patients stabilized with the same brand name product over time. This suggests that any change in plasma AED concentration and possible related clinical effects after generic substitution may be not necessarily related to the switch

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

    PubMed

    Fukuoka, Noriyasu; Tsukamoto, Toyohisa; Uno, Junji; Kimura, Michio; Morita, Shushi

    2003-12-01

    We conducted a study to clarify the most suitable transforming factor related to the daily zonisamide dose (D) providing a steady-state serum concentration (C(t)) and analyzed the influences of the concomitant use of antiepileptic drugs on C(t) quantitatively. Data obtained by routine therapeutic drug monitoring from a total of 175 epileptic patients treated with the multiple oral administrations of zonisamide (ZNS) as a powder/tablets, were used for the analysis. Employing the extracellular water volume (V(ECW)) as a transforming factor, led the level/dose (L/D) ratio (:C(t)/(D/V(ECW))) to be independent of the patient's age and sex for the administration of ZNS alone. C(t) was revealed to be dependent on only one variable regarding D/V(ECW) and expressed as C(t)=0.604x(D/V(ECW)). Phenytoin (PHT) significantly lowered (p<0.01) the L/D ratio to 0.76 of the value for ZNS alone. For a more detailed analysis, we defined the parameter R(i) (i=1, 2, em leader, 6) as an alteration ratio, representing the influence of each antiepileptic drug on the L/D ratio of ZNS alone. A model based on the assumption that each R(i) value was independent from one another and multiplicative, was adopted. The analysis clarified that phenobarbital, valproic acid, carbamazepine, and PHT significantly lowered (p<0.05) the L/D ratio of ZNS to 0.849, 0.865, 0.846, and 0.804, 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 R(i) and compared with the measured ones. The mean of prediction error was calculated as 22.9%. Our results appear valid and R(i) should be available for clinical use. PMID:14646181

  16. Drug interactions with the newer antiepileptic drugs (AEDs)--Part 2: pharmacokinetic and pharmacodynamic interactions between AEDs and drugs used to treat non-epilepsy disorders.

    PubMed

    Patsalos, Philip N

    2013-12-01

    Since antiepileptic drugs (AEDs) are prescribed to treat various non-epilepsy-related disorders in addition to the fact that patients with epilepsy may develop concurrent disorders that will need treatment, the propensity for AEDs to interact with non-AEDs is considerable and indeed can present a difficult clinical problem. The present review details the pharmacokinetic and pharmacodynamic interactions that have been reported to occur with the new AEDs (eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine (ezogabine), rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide) and drugs used to treat non-epilepsy disorders. Interaction study details are described, as necessary, so as to allow the reader to take a view as to the possible clinical significance of particular interactions. Pharmacokinetic interactions relate to hepatic enzyme induction or inhibition and involved a variety of drugs including psychoactive drugs, cardioactive drugs, oral contraceptives, antituberculous agents, analgesics and antineoplastic drugs. A total of 68 pharmacokinetic interactions have been described, with lamotrigine (n = 22), topiramate (n = 18) and oxcarbazepine (n = 7) being associated with most, whilst lacosamide, pregabalin, stiripentol and vigabatrin are associated with none. Overall, only three pharmacodynamic interactions have been described and occur with oxcarbazepine, perampanel and pregabalin. PMID:23794036

  17. Renal tubular dysfunction measured by N-acetyl-beta glucosaminidase/Creatinine activity index in children receiving antiepileptic drugs: a randomized controlled trial.

    PubMed

    Mazaheri, Mojgan; Samaie, Afshin; Semnani, Vahid

    2011-01-01

    To evaluate renal side-effects of anti-epileptic medication by valproate (VPA) and carbamazepine (CBZ), we performed a prospective study to assess renal tubular function by measuring N-acetyl-β glucosaminidase (NAG)/Cr activity index in epileptic children. The study was conducted on 112 children who were diagnosed with epilepsy (28 patients were observed before treatment with anti-epileptics, 28 children were administered VPA, 28 children were treated with CBZ, and 28 healthy children were selected age &sex matched for). An especial NAG assay kit was used for quantitative measuring of NAG in patient urine samples. The patients receiving VPA exhibited higher rate of NAG activity compared with the two groups which not receiving anti-epileptic drugs. Measurement of urinary NAG/Cr index in the children who received CBZ also, was significantly higher than those who were not administered anti-epileptic drugs. The measurement of NAG/Cr index in the VPA group was significantly higher than that in the CBZ group (NAG index: 2.75 versus 1.71). Children on anti-epileptic treatment with VPA or CBZ might demonstrate signs of renal tubular dysfunction, reflected by NAG/Cr activity index. This side effect can be potentially more occurred following VPA administration. PMID:21569539

  18. Renal tubular dysfunction measured by N-acetyl-beta glucosaminidase/Creatinine activity index in children receiving antiepileptic drugs: a randomized controlled trial

    PubMed Central

    2011-01-01

    To evaluate renal side-effects of anti-epileptic medication by valproate (VPA) and carbamazepine (CBZ), we performed a prospective study to assess renal tubular function by measuring N-acetyl-β glucosaminidase (NAG)/Cr activity index in epileptic children. The study was conducted on 112 children who were diagnosed with epilepsy (28 patients were observed before treatment with anti-epileptics, 28 children were administered VPA, 28 children were treated with CBZ, and 28 healthy children were selected age &sex matched for). An especial NAG assay kit was used for quantitative measuring of NAG in patient urine samples. The patients receiving VPA exhibited higher rate of NAG activity compared with the two groups which not receiving anti-epileptic drugs. Measurement of urinary NAG/Cr index in the children who received CBZ also, was significantly higher than those who were not administered anti-epileptic drugs. The measurement of NAG/Cr index in the VPA group was significantly higher than that in the CBZ group (NAG index: 2.75 versus 1.71). Children on anti-epileptic treatment with VPA or CBZ might demonstrate signs of renal tubular dysfunction, reflected by NAG/Cr activity index. This side effect can be potentially more occurred following VPA administration. PMID:21569539

  19. Predicting adverse drug events from personal health messages.

    PubMed

    Chee, Brant W; Berlin, Richard; Schatz, Bruce

    2011-01-01

    Adverse drug events (ADEs) remain a large problem in the United States, being the fourth leading cause of death, despite post market drug surveillance. Much post consumer drug surveillance relies on self-reported "spontaneous" patient data. Previous work has performed datamining over the FDA's Adverse Event Reporting System (AERS) and other spontaneous reporting systems to identify drug interactions and drugs correlated with high rates of serious adverse events. However, safety problems have resulted from the lack of post marketing surveillance information about drugs, with underreporting rates of up to 98% within such systems. We explore the use of online health forums as a source of data to identify drugs for further FDA scrutiny. In this work we aggregate individuals' opinions and review of drugs similar to crowd intelligence3. We use natural language processing to group drugs discussed in similar ways and are able to successfully identify drugs withdrawn from the market based on messages discussing them before their removal. PMID:22195073

  20. Nonlinear neural mapping analysis of the adverse effects of drugs.

    PubMed

    Domine, D; Guillon, C; Devillers, J; Lacroix, R; Lacroix, J; Doré, J C

    1998-01-01

    Numerous drugs have been identified as presenting adverse effects towards the driving of vehicles. A large set of these drugs was compiled and classified into ten categories. Nonlinear neural mapping (N2M) was used to derive a typology of these molecules and also to link their adverse effects to therapeutic categories and structural information. PMID:9517012

  1. The Secondary Effects of Antiepileptic Drugs (AEDs) in Children and Their Implications on Augmentative and Alternative Communication (AAC) Processes: A Best-Evidence Synthesis

    ERIC Educational Resources Information Center

    Srinivasan, Saranya

    2009-01-01

    This study uses a best-evidence synthesis method to investigate the secondary effects of various antiepileptic drugs (AEDs) and their implications on augmentative and alternative communication (AAC) processes. Epilepsy is a common serious neurological disorder, a concomitant condition in individuals with severe developmental and intellectual…

  2. Differences between Drug-Induced and Contrast Media-Induced Adverse Reactions Based on Spontaneously Reported Adverse Drug Reactions

    PubMed Central

    Suh, JinUk; Yang, MyungSuk; Kang, WonKu; Kim, EunYoung

    2015-01-01

    Objective We analyzed differences between spontaneously reported drug-induced (not including contrast media) and contrast media-induced adverse reactions. Methods Adverse drug reactions reported by an in-hospital pharmacovigilance center (St. Mary’s teaching hospital, Daejeon, Korea) from 2010–2012 were classified as drug-induced or contrast media-induced. Clinical patterns, frequency, causality, severity, Schumock and Thornton’s preventability, and type A/B reactions were recorded. The trends among causality tools measuring drug and contrast-induced adverse reactions were analyzed. Results Of 1,335 reports, 636 drug-induced and contrast media-induced adverse reactions were identified. The prevalence of spontaneously reported adverse drug reaction-related admissions revealed a suspected adverse drug reaction-reporting rate of 20.9/100,000 (inpatient, 0.021%) and 3.9/100,000 (outpatients, 0.004%). The most common adverse drug reaction-associated drug classes included nervous system agents and anti-infectives. Dermatological and gastrointestinal adverse drug reactions were most frequently and similarly reported between drug and contrast media-induced adverse reactions. Compared to contrast media-induced adverse reactions, drug-induced adverse reactions were milder, more likely to be preventable (9.8% vs. 1.1%, p < 0.001), and more likely to be type A reactions (73.5% vs. 18.8%, p < 0.001). Females were over-represented among drug-induced adverse reactions (68.1%, p < 0.001) but not among contrast media-induced adverse reactions (56.6%, p = 0.066). Causality patterns differed between the two adverse reaction classes. The World Health Organization–Uppsala Monitoring Centre causality evaluation and Naranjo algorithm results significantly differed from those of the Korean algorithm version II (p < 0.001). Conclusions We found differences in sex, preventability, severity, and type A/B reactions between spontaneously reported drug and contrast media-induced adverse

  3. The Portland Neurotoxicity Scale: validation of a brief self-report measure of antiepileptic-drug-related neurotoxicity.

    PubMed

    Salinsky, Martin C; Storzbach, Daniel

    2005-03-01

    The Portland Neurotoxicity Scale (PNS) is a brief patient-based survey of neurotoxicity complaints commonly encountered with the use of antiepileptic drugs (AEDs). The authors present data on the validity of this scale, particularly when used in longitudinal studies. Participants included 55 healthy controls, 23 epilepsy patient controls, and 86 healthy volunteers who took various AEDs or placebos for 12 weeks as part of randomized, double-blind studies of AED effects on cognitive abilities. Test-retest reliability in the control groups averaged .80 (total score). Test-retest changes in the PNS were sensitive to AED usage in general (p < .001) and to each of the five AEDs tested but not to placebo. Test-retest changes in the PNS were strongly correlated with several scales of the Profile of Mood States but only weakly correlated with objective cognitive test measures. The PNS has satisfactory psychometric properties and is sensitive to AED usage in test-retest studies. PMID:15695749

  4. A Review for the Analysis of Antidepressant, Antiepileptic and Quinolone Type Drugs in Pharmaceuticals and Environmental Samples.

    PubMed

    Rani, Susheela; Malik, Ashok Kumar; Kaur, Ramandeep; Kaur, Ripneel

    2016-09-01

    The analysis of drugs in various biological fluids is an important criterion for the determination of the physiological performance of a drug. After sampling of the biological fluid, the next step in the analytical process is sample preparation. Sample preparation is essential for isolation of desired components from complex biological matrices and greatly influences their reliable and accurate determination. The complexity of biological fluids adds to the challenge of direct determination of the drug by chromatographic analysis, therefore demanding a sample preparation step that is often time consuming, tedious and frequently overlooked. However, direct online injection methods offer the advantage of reducing sample preparation steps and enabling effective pre-concentration and clean-up of biological fluids. These procedures can be automated and therefore reduce the requirements for handling potentially infectious biomaterial, improve reproducibility, and minimize sample manipulations and potential contamination. This review is focused on the discovery and development of high-performance liquid chromatography (HPLC) and gas chromatography (GC) with different detectors. The drugs covered in this review are antiepileptics, antidepressant (AD), and quinolones. The application of these methods for determination of these drugs in biological, environmental and pharmaceutical samples has also been discussed. PMID:26939618

  5. Comparative efficacy and tolerability of anti-epileptic drugs for refractory focal epilepsy: systematic review and network meta-analysis reveals the need for long term comparator trials

    PubMed Central

    Bodalia, Pritesh N; Grosso, Anthony M; Sofat, Reecha; MacAllister, Raymond J; Smeeth, Liam; Dhillon, Soraya; Casas, Juan-Pablo; Wonderling, David; Hingorani, Aroon D

    2013-01-01

    Aims To evaluate the comparative efficacy (50% reduction in seizure frequency) and tolerability (premature withdrawal due to adverse events) of anti-epileptic drugs (AEDs) for refractory epilepsy. Methods We searched Cochrane Central Register of Controlled Trials (Cochrane Library 2009, issue 2) including Epilepsy Group's specialized register, MEDLINE (1950 to March 2009), EMBASE (1980 to March 2009), and Current Contents Connect (1998 to March 2009) to conduct a systematic review of published studies, developed a treatment network and undertook a network meta-analysis. Results Forty-three eligible trials with 6346 patients and 12 interventions, including placebo, contributed to the analysis. Only three direct drug comparator trials were identified, the remaining 40 trials being placebo-controlled. Conventional random-effects meta-analysis indicated all drugs were superior in efficacy to placebo (overall odds ratio (OR] 3.78, 95% CI 3.14, 4.55) but did not permit firm distinction between drugs on the basis of the efficacy or tolerability. A Bayesian network meta-analysis prioritized oxcarbazepine, topiramate and pregabalin on the basis of short term efficacy. However, sodium valproate, levetiracetam, gabapentin and vigabatrin were prioritized on the basis of short-term efficacy and tolerability, with the caveat that vigabatrin is recognized as being associated with serious visual disturbance with chronic use. Conclusion Of the wide range of AEDs licensed for the treatment of refractory epilepsy, sodium valproate, levetiracetam and gabapentin demonstrated the best balance of efficacy and tolerability. Until regulators mandate greater use of active comparator trials with longer term follow-up, network meta-analysis provides the only available means to quantify these clinically important parameters. PMID:23351090

  6. Common Variants of KCNJ10 Are Associated with Susceptibility and Anti-Epileptic Drug Resistance in Chinese Genetic Generalized Epilepsies

    PubMed Central

    Guo, Yong; Yan, Kui Po; Qu, Qiang; Qu, Jian; Chen, Zi Gui; Song, Tao; Luo, Xiang-Ying; Sun, Zhong-Yi; Bi, Chang-Long; Liu, Jin-Fang

    2015-01-01

    To explore genetic mechanism of genetic generalized epilepsies (GGEs) is challenging because of their complex heritance pattern and genetic heterogeneity. KCNJ10 gene encodes Kir4.1 channels and plays a major role in modulating resting membrane potentials in excitable cells. It may cause GGEs if mutated. The purpose of this study was to investigate the possible association between KCNJ10 common variants and the susceptibility and drug resistance of GGEs in Chinese population. The allele-specific MALDI–TOF mass spectrometry method was used to assess 8 single nucleotide polymorphisms (SNPs) of KCNJ10 in 284 healthy controls and 483 Chinese GGEs patients including 279 anti-epileptic drug responsive patients and 204 drug resistant patients. We found the rs6690889 TC+TT genotypes were lower frequency in the GGEs group than that in the healthy controls (6.7% vs 9.5%, p = 0.01, OR = 0.50[0.29–0.86]). The frequency of rs1053074 G allele was lower in the childhood absence epilepsy (CAE) group than that in the healthy controls (28.4% vs 36.2%, p = 0.01, OR = 0.70[0.53–0.93]). The frequency of rs12729701 G allele and AG+GG genotypes was lower in the CAE group than that in the healthy controls (21.2% vs 28.4%, p = 0.01, OR = 0.74[0.59–0.94] and 36.3% vs 48.1%, p = 0.01, OR = 0.83[0.72–0.96], respectively). The frequency of rs12402969 C allele and the CC+CT genotypes were higher in the GGEs drug responsive patients than that in the drug resistant patients (9.3% vs 5.6%, OR = 1.73[1.06–2.85], p = 0.026 and 36.3% vs 48.1%, p = 0.01, OR = 0.83[0.72–0.96], respectively). This study identifies potential SNPs of KCNJ10 gene that may contribute to seizure susceptibility and anti-epileptic drug resistance. PMID:25874548

  7. Using Literature-Based Discovery to Explain Adverse Drug Effects.

    PubMed

    Hristovski, Dimitar; Kastrin, Andrej; Dinevski, Dejan; Burgun, Anita; Žiberna, Lovro; Rindflesch, Thomas C

    2016-08-01

    We report on our research in using literature-based discovery (LBD) to provide pharmacological and/or pharmacogenomic explanations for reported adverse drug effects. The goal of LBD is to generate novel and potentially useful hypotheses by analyzing the scientific literature and optionally some additional resources. Our assumption is that drugs have effects on some genes or proteins and that these genes or proteins are associated with the observed adverse effects. Therefore, by using LBD we try to find genes or proteins that link the drugs with the reported adverse effects. These genes or proteins can be used to provide insight into the processes causing the adverse effects. Initial results show that our method has the potential to assist in explaining reported adverse drug effects. PMID:27318993

  8. Promoting adverse drug reaction reporting: comparison of different approaches

    PubMed Central

    Ribeiro-Vaz, Inês; Santos, Cristina Costa; Cruz-Correia, Ricardo

    2016-01-01

    ABSTRACT OBJECTIVE To describe different approaches to promote adverse drug reaction reporting among health care professionals, determining their cost-effectiveness. METHODS We analyzed and compared several approaches taken by the Northern Pharmacovigilance Centre (Portugal) to promote adverse drug reaction reporting. Approaches were compared regarding the number and relevance of adverse drug reaction reports obtained and costs involved. Costs by report were estimated by adding the initial costs and the running costs of each intervention. These costs were divided by the number of reports obtained with each intervention, to assess its cost-effectiveness. RESULTS All the approaches seem to have increased the number of adverse drug reaction reports. We noted the biggest increase with protocols (321 reports, costing 1.96 € each), followed by first educational approach (265 reports, 20.31 €/report) and by the hyperlink approach (136 reports, 15.59 €/report). Regarding the severity of adverse drug reactions, protocols were the most efficient approach, costing 2.29 €/report, followed by hyperlinks (30.28 €/report, having no running costs). Concerning unexpected adverse drug reactions, the best result was obtained with protocols (5.12 €/report), followed by first educational approach (38.79 €/report). CONCLUSIONS We recommend implementing protocols in other pharmacovigilance centers. They seem to be the most efficient intervention, allowing receiving adverse drug reactions reports at lower costs. The increase applied not only to the total number of reports, but also to the severity, unexpectedness and high degree of causality attributed to the adverse drug reactions. Still, hyperlinks have the advantage of not involving running costs, showing the second best performance in cost per adverse drug reactions report. PMID:27143614

  9. Gene-to-gene interaction between sodium channel-related genes in determining the risk of antiepileptic drug resistance.

    PubMed

    Jang, Sin-Young; Kim, Myeong-Kyu; Lee, Kee-Ra; Park, Man-Seok; Kim, Byeong-Chae; Cho, Ki-Hyun; Lee, Min-Cheol; Kim, Yo-Sik

    2009-02-01

    The pathogenesis of antiepileptic drug (AED) resistance is multifactorial. However, most candidate gene association studies typically assess the effects of candidate genes independently of each other, which is partly because of the limitations of the parametric-statistical methods for detecting the gene-to-gene interactions. A total of 200 patients with drug-resistant epilepsy and 200 patients with drug-responsive epilepsy were genotyped for 3 representative the single nucleotide polymorphisms (SNPs) of the voltage-gated sodium channel genes (SCN1A, SCN1B, and SCN2A) by polymerase chain reaction and direct sequencing analysis. Besides the typical parametric statistical method, a new statistical method (multifactor dimensionality reduction [MDR]) was used to determine whether gene-to-gene interactions increase the risk of AED resistance. None of the individual genotypes or alleles tested in the present study showed a significant association with AED resistance, regardless of their theoretical functional value. With the MDR method, of three possible 2-locus genotype combinations, the combination of SCN2A-PM with SCN1B-PM was the best model for predicting susceptibility to AED resistance, with a p value of 0.0547. MDR, as an analysis paradigm for investigating multi-locus effects in complex disorders, may be a useful statistical method for determining the role of gene-to-gene interactions in the pathogenesis of AED resistance. PMID:19270815

  10. Adverse drug reactions in veterinary patients associated with drug transporters.

    PubMed

    Mealey, Katrina L

    2013-09-01

    For many drugs used in veterinary practice, plasma and tissue concentrations are highly dependent on the activity of drug transporters. This article describes how functional changes in drug transporters, whether mediated by genetic variability or drug-drug interactions, affect drug disposition and, ultimately, drug safety and efficacy in veterinary patients. A greater understanding of species, breed, and individual (genetic) differences in drug transporter function, as well as drug-drug interactions involving drug transporters, will result in improved strategies for drug design and will enable veterinarians to incorporate individualized medicine in their practices. PMID:23890239

  11. Cadec: A corpus of adverse drug event annotations.

    PubMed

    Karimi, Sarvnaz; Metke-Jimenez, Alejandro; Kemp, Madonna; Wang, Chen

    2015-06-01

    CSIRO Adverse Drug Event Corpus (Cadec) is a new rich annotated corpus of medical forum posts on patient-reported Adverse Drug Events (ADEs). The corpus is sourced from posts on social media, and contains text that is largely written in colloquial language and often deviates from formal English grammar and punctuation rules. Annotations contain mentions of concepts such as drugs, adverse effects, symptoms, and diseases linked to their corresponding concepts in controlled vocabularies, i.e., SNOMED Clinical Terms and MedDRA. The quality of the annotations is ensured by annotation guidelines, multi-stage annotations, measuring inter-annotator agreement, and final review of the annotations by a clinical terminologist. This corpus is useful for studies in the area of information extraction, or more generally text mining, from social media to detect possible adverse drug reactions from direct patient reports. The corpus is publicly available at https://data.csiro.au.(1). PMID:25817970

  12. [Frequency of drug adverse reactions among hospitalized patients].

    PubMed

    González Martínez, L

    1995-01-01

    This article describes the frequency of adverse reactions to drugs in a sample of hospitalized patients in the internal medicine ward seen during a year's term. Of 61 medical charts, we found 8 patients with adverse reactions to drugs during their hospital stay and another 4 patients hospitalized due to adverse reactions to drugs. The majority of the adverse reactions were of moderate degree (75%) and were related to drugs of cardiovascular action (58%). The frequency of reactions in hospitalized patients (13%) is comparable with the results obtained from other hospitals. Yet, the real magnitude of the problem is probably greater since the source of information (hospital charts) the totality of the clinical manifestations are not registered. PMID:8581452

  13. [Adverse drug reaction - Definitions, risk factors and pharmacovigilance].

    PubMed

    Krähenbühl, Stephan

    2015-12-01

    Adverse drug reactions (ADR} are the downside of active pharmacotherapies and can only partially be avoided. Risk factors have been identified for certain ADR which should be taken into account for the choice and dosing of critical drugs. Medical staff have a legal obligation to report severe ADR and ADR caused by newly licensed drugs. Such reports are important for monitoring the safety of drugs that are on the market. PMID:26654809

  14. Genotoxicity assessment of the antiepileptic drug AMP397, an Ames-positive aromatic nitro compound.

    PubMed

    Suter, Willi; Hartmann, Andreas; Poetter, Franziska; Sagelsdorff, Peter; Hoffmann, Peter; Martus, Hans-Jörg

    2002-07-25

    AMP397 is a novel antiepileptic agent and the first competitive AMPA antagonist with high receptor affinity, good in vivo potency, and oral activity. AMP397 has a structural alert (aromatic nitro group) and was mutagenic in Salmonella typhimurium strains TA97a, TA98 and TA100 without S9, but negative in the nitroreductase-deficient strains TA98NR and TA100NR. The amino derivative of AMP397 was negative in wild-type strains TA98 and TA100. AMP397 was negative in a mouse lymphoma tk assay, which included a 24h treatment without S9. A weak micronucleus induction in vitro was found at the highest concentrations tested in V79 cells with S9. AMP397 was negative in the following in vivo studies, which included the maximum tolerated doses of 320mg/kg in mice and 2000mg/kg in rats: MutaMouse assay in colon and liver (5x320mg/kg) at three sampling times (3, 7 and 31 days after the last administration); DNA binding study in the liver of mice and rats after a single treatment with [14C]-AMP397; comet assay (1x2000mg/kg) in jejunum and liver of rats, sampling times 3 and 24h after administration; micronucleus test (2x320mg/kg) in the bone marrow of mice, sampling 24h after the second administration. Based on these results, it was concluded that AMP397 has no genotoxic potential in vivo. In particular, no genotoxic metabolite is formed in mammalian cells, and, if formed by intestinal bacteria, is unable to exert any genotoxic activity in the adjacent intestinal tissue. These data were considered to provide sufficient safety to initiate clinical development of the compound. PMID:12113769

  15. Kinetic and chemical assessment of the UV/H2O2 treatment of antiepileptic drug carbamazepine.

    PubMed

    Vogna, Davide; Marotta, Raffaele; Andreozzi, Roberto; Napolitano, Alessandra; d'Ischia, Marco

    2004-01-01

    The UV/H2O2-induced degradation of carbamazepine, a worldwide used antiepileptic drug, recently found as contaminant in many municipal sewage treatment plant (STP) effluents and other aquatic environments, is investigated. The oxidation treatment caused an effective removal of the drug. At complete abatement of the substrate after 4 min treatment, a 35% value of removed total organic carbon (TOC) was obtained. A kinetic constant of (2.05+/-0.14) x 10(9) lmol(-1)s(-1) was determined for OH radical attack to carbamazepine in the UV/H2O2 process. Preparative TLC of the reaction mixture led to the isolation of acridine-9-carboxaldehyde as a reaction intermediate. HPLC and GC/MS analysis indicated formation of small amounts of acridine, salicylic acid, catechol and anthranilic acid among the reaction products. Under the same reaction conditions, synthetically prepared 10,11-epoxycarbamazepine was easily degraded to acridine as main product, suggesting that this epoxide is a likely intermediate in the oxidative conversion of carbamazepine to acridine. Under sunlight irradiation, carbamazepine in water underwent slow degradation to afford likewise acridine as main product. In view of the mutagenic properties of acridine, these results would raise important issues concerning the possible environmental impact of carbamazepine release through domestic wastewaters and support the importance of prolonged oxidation treatments to ensure complete degradation of aromatic intermediates. PMID:14581052

  16. A Survey of Adverse Drug Reactions in Family Practice

    PubMed Central

    Reynolds, J. L.

    1984-01-01

    In this study, 232 Canadian family physicians recorded suspected adverse drug reactions (SADRs) in their practices for five months. Patients' age and sex, the drug(s) implicated, type of reaction and any disability were recorded on a card and sent to a central coordinating office each week. The number of SADRs in clinical practice seems to be small. An estimated 300,000 patients were involved in the study, and a total of 314 suspected adverse drug reactions in 314 patients were reported. A proposal is made for a surveillance system for new drugs. Family physicians would monitor all patients taking a drug or group of drugs and matched controls. The status of patients and controls would be recorded regularly and any SADRs reported to a central coordinating centre. PMID:21283495

  17. Effect of the Anti-depressant Sertraline, the Novel Anti-seizure Drug Vinpocetine and Several Conventional Antiepileptic Drugs on the Epileptiform EEG Activity Induced by 4-Aminopyridine.

    PubMed

    Sitges, Maria; Aldana, Blanca Irene; Reed, Ronald Charles

    2016-06-01

    Seizures are accompanied by an exacerbated activation of cerebral ion channels. 4-aminopyridine (4-AP) is a pro-convulsive agent which mechanism of action involves activation of Na(+) and Ca(2+) channels, and several antiepileptic drugs control seizures by reducing these channels permeability. The antidepressant, sertraline, and the anti-seizure drug vinpocetine are effective inhibitors of cerebral presynaptic Na(+) channels. Here the effectiveness of these compounds to prevent the epileptiform EEG activity induced by 4-AP was compared with the effectiveness of seven conventional antiepileptic drugs. For this purpose, EEG recordings before and at three intervals within the next 30 min following 4-AP (2.5 mg/kg, i.p.) were taken in anesthetized animals; and the EEG-highest peak amplitude values (HPAV) calculated. In control animals, the marked increase in the EEG-HPAV observed near 20 min following 4-AP reached its maximum at 30 min. Results show that this epileptiform EEG activity induced by 4-AP is prevented by sertraline and vinpocetine at a dose of 2.5 mg/kg, and by carbamazepine, phenytoin, lamotrigine and oxcarbazepine at a higher dose (25 mg/kg). In contrast, topiramate (25 mg/kg), valproate (100 mg/kg) and levetiracetam (100 mg/kg) failed to prevent the epileptiform EEG activity induced by 4-AP. It is concluded that 4-AP is a useful tool to elicit the mechanism of action of anti-seizure drugs at clinical meaningful doses. The particular efficacy of sertraline and vinpocetine to prevent seizures induced by 4-AP is explained by their high effectiveness to reduce brain presynaptic Na(+) and Ca(2+) channels permeability. PMID:26830290

  18. Prevalence of Different Combinations of Antiepileptic Drugs and CNS Drugs in Elderly Home Care Service and Nursing Home Patients in Norway

    PubMed Central

    Johannessen Landmark, Cecilie; Granas, Anne Gerd

    2016-01-01

    Introduction. Antiepileptic drugs (AEDs) are used to treat different conditions in elderly patients and are among the drug classes most susceptible to be involved in drug-drug interactions (DDI). The aim of the study was to describe and compare use of AEDs between home care service and nursing home patients, as these patients are not included in nationwide databases of drug utilization. In the combined population, we investigate DDI of AEDs with other central nervous system- (CNS-) active drugs and DDIs involving AEDs in general. Materials and Methods. Point-prevalence study of Norwegian patients in home care services and nursing homes in 2009. At the patient level, we screened for different DDIs involving AEDs. Results. In total, 882 patients (7.8%) of 11,254 patients used AEDs and number of users did not differ between home care services and nursing homes (8.2% versus 7.7%). In the combined population, we identified 436 potential DDIs in 45% of the patients. Conclusions. In a large population of elderly, home care service and nursing home patients do not differ with respect to exposure of AEDs but use more AEDs as compared to the general population of similar age. The risk of DDIs with AEDs and other CNS-active drugs should be taken into consideration and individual clinical evaluations are assessed in this population. PMID:27525114

  19. Anti-epileptic drugs and bone loss: Phenytoin reduces pro-collagen I and alters the electrophoretic mobility of osteonectin in cultured bone cells.

    PubMed

    Wilson, Emma L; Garton, Mark; Fuller, Heidi R

    2016-05-01

    Phenytoin is an antiepileptic drug used in the management of partial and tonic-clonic seizures. In previous studies we have shown that valproate, another antiepileptic drug, reduced the amount of two key bone proteins, pro-collagen I and osteonectin (SPARC, BM-40), in both skin fibroblasts and cultured osteoblast-like cells. Here we show that phenytoin also reduces pro-collagen I production in osteoblast-like cells, but does not appear to cause a decrease in osteonectin message or protein production. Instead, a 24h exposure to a clinically relevant concentration of phenytoin resulted in a dose-dependent change in electrophoretic mobility of osteonectin, which was suggestive of a change in post-translational modification status. The perturbation of these important bone proteins could be one of the mechanisms to explain the bone loss that has been reported following long-term treatment with phenytoin. PMID:26999801

  20. Systematic Analysis of Adverse Event Reports for Sex Differences in Adverse Drug Events

    PubMed Central

    Yu, Yue; Chen, Jun; Li, Dingcheng; Wang, Liwei; Wang, Wei; Liu, Hongfang

    2016-01-01

    Increasing evidence has shown that sex differences exist in Adverse Drug Events (ADEs). Identifying those sex differences in ADEs could reduce the experience of ADEs for patients and could be conducive to the development of personalized medicine. In this study, we analyzed a normalized US Food and Drug Administration Adverse Event Reporting System (FAERS). Chi-squared test was conducted to discover which treatment regimens or drugs had sex differences in adverse events. Moreover, reporting odds ratio (ROR) and P value were calculated to quantify the signals of sex differences for specific drug-event combinations. Logistic regression was applied to remove the confounding effect from the baseline sex difference of the events. We detected among 668 drugs of the most frequent 20 treatment regimens in the United States, 307 drugs have sex differences in ADEs. In addition, we identified 736 unique drug-event combinations with significant sex differences. After removing the confounding effect from the baseline sex difference of the events, there are 266 combinations remained. Drug labels or previous studies verified some of them while others warrant further investigation. PMID:27102014

  1. Predicting Adverse Drug Events from Personal Health Messages

    PubMed Central

    Chee, Brant W.; Berlin, Richard; Schatz, Bruce

    2011-01-01

    Adverse drug events (ADEs) remain a large problem in the United States, being the fourth leading cause of death, despite post market drug surveillance. Much post consumer drug surveillance relies on self-reported “spontaneous” patient data. Previous work has performed datamining over the FDA’s Adverse Event Reporting System (AERS) and other spontaneous reporting systems to identify drug interactions and drugs correlated with high rates of serious adverse events. However, safety problems have resulted from the lack of post marketing surveillance information about drugs, with underreporting rates of up to 98% within such systems1,2. We explore the use of online health forums as a source of data to identify drugs for further FDA scrutiny. In this work we aggregate individuals’ opinions and review of drugs similar to crowd intelligence3. We use natural language processing to group drugs discussed in similar ways and are able to successfully identify drugs withdrawn from the market based on messages discussing them before their removal. PMID:22195073

  2. Adverse Outcome Pathways and Drug-Induced Liver Injury Testing.

    PubMed

    Vinken, Mathieu

    2015-07-20

    Drug-induced liver injury is a prominent reason for premarketing and postmarketing drug withdrawal and can be manifested in a number of ways, such as cholestasis, steatosis, and fibrosis. The mechanisms driving these toxicological processes have been well characterized and have been emdedded in adverse outcome pathway frameworks in recent years. This review evaluates these constructs and simultaneously illustrates their use in the preclinical testing of drug-induced liver injury. PMID:26119269

  3. Adverse outcome pathways and drug-induced liver injury testing

    PubMed Central

    Vinken, Mathieu

    2015-01-01

    Drug-induced liver injury is a prominent reason for premarketing and postmarketing drug withdrawal and can be manifested in a number of ways, such as cholestasis, steatosis and fibrosis. The mechanisms driving these toxicological processes have been well characterized and have been emdedded in adverse outcome pathway frameworks in recent years. This paper reviews these constructs and simultaneously illustrates their use in the preclinical testing of drug-induced liver injury. PMID:26119269

  4. Efficacy of Anti-Epileptic Drugs in the Treatment of Tumor and Its Associated Epilepsy: An in vitro Perspective

    PubMed Central

    Kaur, Taranjeet; Manchanda, Shaffi; Saini, Vedangana; Lakhman, Sukhwinder S.; Kaur, Gurcharan

    2016-01-01

    The change in the therapeutic targets from neuron to glia has proved beneficial in the treatment of many psychiatric disorders. The anti-epileptic drugs (AEDs) have been widely prescribed for the treatment of partial and complete seizures, bipolar disorder among others. The current study was carried out to explore the efficacy of some conventional and novel AEDs for the treatment of tumor-associated epilepsy which develops in 29-49% of the patients diagnosed with brain tumors. We used C6 glioma cell line as model system to study the effect of selected AEDs, viz., gabapentin (GBP), valproic acid (VPA) and topiramate (TPM). Morphometry, cell cycle analysis, apoptosis, expression of different protein markers, viz., GFAP, HSP70 and nuclear factor-κB (NFκB) were studied in AED-treated cultures. The study was further extended to rat hypothalamic primary explant cultures, and cell migration and expression of plasticity markers - neural cell adhesion molecule (NCAM) and polysialylation of NCAM (PSA-NCAM) - were studied in the explants. TPM was observed to show more pronounced increase in apoptosis of glioblastoma cells accompanied by significant downregulation in the expression of HSP70 and NFκB. TPM-treated explants also showed highest process ramification and cellular migration accompanied by intense expression of the plasticity markers as compared to those treated with GBP and VPA. Among the 3 AEDs tested, TPM was observed to show more promising effects on cytoprotection and plasticity of C6 glioma cells. PMID:27536020

  5. Efficacy of Anti-Epileptic Drugs in the Treatment of Tumor and Its Associated Epilepsy: An in vitro Perspective.

    PubMed

    Kaur, Taranjeet; Manchanda, Shaffi; Saini, Vedangana; Lakhman, Sukhwinder S; Kaur, Gurcharan

    2016-03-01

    The change in the therapeutic targets from neuron to glia has proved beneficial in the treatment of many psychiatric disorders. The anti-epileptic drugs (AEDs) have been widely prescribed for the treatment of partial and complete seizures, bipolar disorder among others. The current study was carried out to explore the efficacy of some conventional and novel AEDs for the treatment of tumor-associated epilepsy which develops in 29-49% of the patients diagnosed with brain tumors. We used C6 glioma cell line as model system to study the effect of selected AEDs, viz., gabapentin (GBP), valproic acid (VPA) and topiramate (TPM). Morphometry, cell cycle analysis, apoptosis, expression of different protein markers, viz., GFAP, HSP70 and nuclear factor-κB (NFκB) were studied in AED-treated cultures. The study was further extended to rat hypothalamic primary explant cultures, and cell migration and expression of plasticity markers - neural cell adhesion molecule (NCAM) and polysialylation of NCAM (PSA-NCAM) - were studied in the explants. TPM was observed to show more pronounced increase in apoptosis of glioblastoma cells accompanied by significant downregulation in the expression of HSP70 and NFκB. TPM-treated explants also showed highest process ramification and cellular migration accompanied by intense expression of the plasticity markers as compared to those treated with GBP and VPA. Among the 3 AEDs tested, TPM was observed to show more promising effects on cytoprotection and plasticity of C6 glioma cells. PMID:27536020

  6. The effect of epilepsy and antiepileptic drugs on sexual, reproductive and gonadal health of adults with epilepsy.

    PubMed

    Hamed, Sherifa A

    2016-06-01

    Epilepsy is a common chronic medical illness. Hyposexuality is the most frequent abnormality in men and women with epilepsy. In men with epilepsy, hypoandrogenimia, hypogonadism and sperm abnormalities are common. Testicular atrophy was also infrequently reported. In women with epilepsy, hyperandrogenism, polycystic ovaries (PCOs) and PCO syndrome are frequent. Decreased serum free testosterone, dehydroepiandrosterone levels, free androgen index and free testosterone/leutinizing hormone (LH) ratio and increased sex hormone binding globulin, estradiol, prolactin, LH, follicle stimulating hormone (FSH) levels and LH/FSH ratio are common with epilepsy. Disturbance of central and/or peripheral control of hypothalamic-pituitary-gonadal axis and alteration of central neurotrasmitters (GABA, glutamate and serotonin) by epileptic discharges or antiepileptic drugs (AEDs), direct gonadal toxicity by AEDs and pcyshicatric/psychosocial factors are all incriminated in sexual, reproductive and gonadal abnormalities associated with epilepsy. Patients may benefit from multidisplinary evaluation, tight seizure control, change the AED, androgen therapy, genital vasodilators, L-carnitine supplementation and psychotherapy. PMID:26934627

  7. Intrinsic excitability measures track antiepileptic drug action and uncover increasing/decreasing excitability over the wake/sleep cycle

    PubMed Central

    Meisel, Christian; Schulze-Bonhage, Andreas; Freestone, Dean; Cook, Mark James; Achermann, Peter; Plenz, Dietmar

    2015-01-01

    Pathological changes in excitability of cortical tissue commonly underlie the initiation and spread of seizure activity in patients suffering from epilepsy. Accordingly, monitoring excitability and controlling its degree using antiepileptic drugs (AEDs) is of prime importance for clinical care and treatment. To date, adequate measures of excitability and action of AEDs have been difficult to identify. Recent insights into ongoing cortical activity have identified global levels of phase synchronization as measures that characterize normal levels of excitability and quantify any deviation therefrom. Here, we explore the usefulness of these intrinsic measures to quantify cortical excitability in humans. First, we observe a correlation of such markers with stimulation-evoked responses suggesting them to be viable excitability measures based on ongoing activity. Second, we report a significant covariation with the level of AED load and a wake-dependent modulation. Our results indicate that excitability in epileptic networks is effectively reduced by AEDs and suggest the proposed markers as useful candidates to quantify excitability in routine clinical conditions overcoming the limitations of electrical or magnetic stimulation. The wake-dependent time course of these metrics suggests a homeostatic role of sleep, to rebalance cortical excitability. PMID:26554021

  8. Adverse drug reactions and safety considerations of NSAIDs: clinical analysis.

    PubMed

    Bahadur, Shiv; Keshri, Lav; Pathak, Kamla

    2011-11-01

    NSAIDs are the most frequently used drugs for treatment, in Europe and the United States, accounting for approximately 5% of all prescriptions. Moreover, the use of NSAIDs is increasing because these constitute the first-line drug therapy for a wide range of rheumatic conditions. This increase is in part the result of the increasing population of elderly patients, who constitute the group of patients with greatest demand for these agents. There are many types of NSAIDs that vary in potency, action and potential side effects. Thus various efforts have been made to determine the safety considerations including adverse drug effects, duration of drug therapy, drug interactions, precautions and other drugs applied to reduce side effects. Researchers have introduced some novel techniques to diagnose NSAIDs related adverse effects on the gastrointestinal mucosa. The researchers dealing with the development of drug delivery system for these drugs should aim at designing a therapeutically efficacious dosage form with reduced side/adverse effects. Thus an effort has been made in this review to deal with the safety parameters of various NSAIDs with a special emphasis on preclinical and clinical safety analysis and various attempts to minimize the side effects by structural modification or by drug delivery system. PMID:22424538

  9. The antiepileptic drug lamotrigine is a substrate of mouse and human breast cancer resistance protein (ABCG2).

    PubMed

    Römermann, Kerstin; Helmer, Renate; Löscher, Wolfgang

    2015-06-01

    Resistance to antiepileptic drugs (AEDs) is the major problem in the treatment of epilepsy. One hypothesis to explain AED resistance suggests that seizure-induced overexpression of efflux transporters at the blood-brain barrier (BBB) restricts AEDs to reach their brain targets. Various studies examined whether AEDs are substrates of P-glycoprotein (Pgp; MDR1; ABCB1), whereas information about the potential role of breast cancer resistance protein (BCRP; ABCG2) is scanty. We used a highly sensitive in vitro assay (concentration equilibrium transport assay; CETA) with MDCKII cells transduced with murine Bcrp1 or human BCRP to evaluate whether AEDs are substrates of this major efflux transporter. Six of 7 AEDs examined, namely phenytoin, phenobarbital, carbamazepine, levetiracetam, topiramate, and valproate, were not transported by Bcrp at therapeutic concentrations, whereas lamotrigine exhibited a marked asymmetric, Bcrp-mediated transport in the CETA, which could be almost completely inhibited with the Bcrp inhibitor Ko143. Significant but less marked transport of lamotrigine was determined in MDCK cells transfected with human BCRP. Lamotrigine is also a substrate of human Pgp, so that this drug is the first AED that has been identified as a dual substrate of the two major human efflux transporters at the BBB. Previous in vivo studies have demonstrated a synergistic or cooperative role of Pgp and Bcrp in the efflux of dual substrates at the BBB, so that transport of lamotrigine by Pgp and BCRP may be an important mechanism of pharmacoresistance in epilepsy patients in whom both transporters are overexpressed. PMID:25645391

  10. Low plasma antioxidant status in patients with epilepsy and the role of antiepileptic drugs on oxidative stress

    PubMed Central

    Menon, Bindu; Ramalingam, Krishnan; Kumar, Rajendiran Vinoth

    2014-01-01

    Background: Oxidative stress has been implicated in various disorders including epilepsy. We studied the antioxidant status in patients with epilepsy and aimed at determining whether there was any difference in the antioxidant levels between patients and controls, patients who are not on antiepileptic drugs (AEDs), and on treatment, between individual AEDs and patients on monotherapy and polytherapy. Materials and Methods: Antioxidant levels like catalase, glutathione peroxidase (GPx), vitamin E, glutathione (GSH), thiol group (SH), uric acid, and total antioxidant capacity (TAC) were compared between 100 patients with epilepsy and equal number of controls. Twenty-five patients who were not on AEDs were compared with patients on AEDs and the control group. Patients were divided into monotherapy and polytherapy group and antioxidant status was compared between the two groups and between individual drugs. Results: Catalase, SH, vitamin E, and TAC were significantly low in patients with epilepsy than those in the control group (P < 0.001). GSH and uric acid did not show any difference; GPx in patients was significantly higher than those in the control group There were no differences in the antioxidant levels between the treated and the untreated groups; however, it was lower in untreated patients than controls (P < 0.001), suggesting that AEDs do not modify the oxidative stress. Patients on Valproate (VPA) showed higher catalase and GPx levels. Catalase was higher in the monotherapy than polytherapy group (P < 0.04). Conclusion: Our study found significantly low levels of antioxidant in patients as compared to controls. AED did not influence the antioxidant status suggesting that seizures induce oxidative stress. PMID:25506160

  11. Predicting adverse drug events using pharmacological network models.

    PubMed

    Cami, Aurel; Arnold, Alana; Manzi, Shannon; Reis, Ben

    2011-12-21

    Early and accurate identification of adverse drug events (ADEs) is critically important for public health. We have developed a novel approach for predicting ADEs, called predictive pharmacosafety networks (PPNs). PPNs integrate the network structure formed by known drug-ADE relationships with information on specific drugs and adverse events to predict likely unknown ADEs. Rather than waiting for sufficient post-market evidence to accumulate for a given ADE, this predictive approach relies on leveraging existing, contextual drug safety information, thereby having the potential to identify certain ADEs earlier. We constructed a network representation of drug-ADE associations for 809 drugs and 852 ADEs on the basis of a snapshot of a widely used drug safety database from 2005 and supplemented these data with additional pharmacological information. We trained a logistic regression model to predict unknown drug-ADE associations that were not listed in the 2005 snapshot. We evaluated the model's performance by comparing these predictions with the new drug-ADE associations that appeared in a 2010 snapshot of the same drug safety database. The proposed model achieved an AUROC (area under the receiver operating characteristic curve) statistic of 0.87, with a sensitivity of 0.42 given a specificity of 0.95. These findings suggest that predictive network methods can be useful for predicting unknown ADEs. PMID:22190238

  12. Completeness of adverse drug reactions reports of the Saudi adverse event reporting system

    PubMed Central

    Alshammari, Thamir M.; Al-Kathiri, Wa’ad H.; Louet, Hervé Le; Aljadhey, Hisham S.

    2015-01-01

    Objectives: To assess completeness of reports in the Saudi Adverse Event Reporting System (SAERS), which is a part of the Saudi Food and Drug Authority pharmacovigilance system for monitoring the safety of medications. Methods: A cross-sectional study was conducted in Riyadh, Saudi Arabia using the reports that were received between December 2009 and June 2012 in the SAERS. The completeness was assessed by reviewing the components of the adverse drug reactions (ADRs) form, and how many fields were completed. Descriptive statistics are reported. Result: There were 14,783 reports during the study period. Eighty percent of these reports were spontaneous reports. Information related to the drug (99%) and adverse events (98%) of the reports were completed. While the patient’s demographic data were completed only in 38% of all reports, the least completed item in the ADRs form was the reporter information (15%). The most reported drug class was tumor necrosis factor inhibitors (7%), whereas events involving the respiratory organ system were the most frequently reported (4.5%). Conclusion: Although the SAERS is considered new, it has a high number of reports. More efforts are needed to improve the completeness of the SAERS to be a good source to assess the signals between events and suspected drugs, especially when there is a high number of reports. PMID:26108586

  13. Pharmacogenetic markers of severe cutaneous adverse drug reactions.

    PubMed

    Borroni, R G

    2014-04-01

    Different responses, in terms both of efficacy and toxicity, are commonly observed for any drug administered to apparently homogeneous groups of patients. It is estimated that adverse drug reactions (ADRs) cause 3-6% of all hospitalizations, accounting for 5% to 9% of hospital admission costs. The skin is often involved in ADRs and although most cutaneous ADRs have a favorable course, they may present as severe adverse cutaneous drug reactions (SCARs), such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (also referred to as drug-induced hypersensitivity syndrome), and acute generalized exanthematous pustulosis. SCARs are associated with significant mortality and require prompt diagnosis and adequate treatment. Pharmacogenetics studies individual variants in the DNA sequence associated with drug efficacy and toxicity, allowing prescription of a drug to patients expected to benefit from it, and excluding from treatment those who are at risk of developing ADRs. Pharmacogenetics already achieved several important results in the prevention of SCARs, and pharmacogenetic testing is now recommended by regulatory agencies before administration of abacavir and carbamazepine, leading to reduced incidence of SCARs. In this review, the pharmacogenetic associations of SCARs that have been validated in independent, case-control association studies will be presented. By familiarizing with principles of pharmacogenetics, dermatologists should be able to correlate specific cutaneous ADR phenotypes to the underlying genotype, thus contributing to better drug safety and facilitating drug discovery, development and approval. PMID:24819643

  14. A Clinical Evaluation of Gingival Overgrowth in Children on Antiepileptic Drug Therapy

    PubMed Central

    Chopra, Saroj; Thomas, Abi M; Pandian, Jeyraj

    2016-01-01

    Introduction Gingival overgrowth, a well-known side effect of chronic phenytoin therapy has also been known to be caused by other anti epileptic drugs (AED’s). Various factors like plaque, gingival inflammation, and periodontal health have been postulated to effect gingival overgrowth. Aim To identify the AED having an effect on gingival overgrowth and to study the factors affecting it. Materials and Methods Three groups of 30 children each on monotherapy of phenytoin, sodium valproate, and carbamazepine were longitudinally followed for six months. Their oral and epileptic health status was assessed and were monitored for change in plaque levels, gingival inflammation, probing depth and the status of gingival overgrowth at baseline, at the end of 3 months and finally at the end of 6 months. The data was recorded and statistically analysed. Results Phenytoin caused gingival overgrowth in a significant number of children (53.6%) within 3 months. Sodium valproate also led to gingival overgrowth, but not upto statistically significant levels. Patients on carbamazepine did not show any signs of gingival overgrowth. Gingival overgrowth is seen more on buccal side, in the anterior segment and in the lower arch. No correlation could be found between, either plaque level, or gingival inflammation with gingival overgrowth. Probing depth could be positively correlated with gingival overgrowth. Conclusion Phenytoin is the drug, which can be chiefly implicated for causing gingival overgrowth. Sodium valproate carries the potential for gingival overgrowth, although only up to clinically insignificant levels in 6 months. Carbamazepine can be considered a safe drug in children in relation to gingival overgrowth. PMID:26894172

  15. Signal Detection of Adverse Drug Reaction of Amoxicillin Using the Korea Adverse Event Reporting System Database.

    PubMed

    Soukavong, Mick; Kim, Jungmee; Park, Kyounghoon; Yang, Bo Ram; Lee, Joongyub; Jin, Xue Mei; Park, Byung Joo

    2016-09-01

    We conducted pharmacovigilance data mining for a β-lactam antibiotics, amoxicillin, and compare the adverse events (AEs) with the drug labels of 9 countries including Korea, USA, UK, Japan, Germany, Swiss, Italy, France, and Laos. We used the Korea Adverse Event Reporting System (KAERS) database, a nationwide database of AE reports, between December 1988 and June 2014. Frequentist and Bayesian methods were used to calculate disproportionality distribution of drug-AE pairs. The AE which was detected by all the three indices of proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) was defined as a signal. The KAERS database contained a total of 807,582 AE reports, among which 1,722 reports were attributed to amoxicillin. Among the 192,510 antibiotics-AE pairs, the number of amoxicillin-AE pairs was 2,913. Among 241 AEs, 52 adverse events were detected as amoxicillin signals. Comparing the drug labels of 9 countries, 12 adverse events including ineffective medicine, bronchitis, rhinitis, sinusitis, dry mouth, gastroesophageal reflux, hypercholesterolemia, gastric carcinoma, abnormal crying, induration, pulmonary carcinoma, and influenza-like symptoms were not listed on any of the labels of nine countries. In conclusion, we detected 12 new signals of amoxicillin which were not listed on the labels of 9 countries. Therefore, it should be followed by signal evaluation including causal association, clinical significance, and preventability. PMID:27510377

  16. Signal Detection of Adverse Drug Reaction of Amoxicillin Using the Korea Adverse Event Reporting System Database

    PubMed Central

    2016-01-01

    We conducted pharmacovigilance data mining for a β-lactam antibiotics, amoxicillin, and compare the adverse events (AEs) with the drug labels of 9 countries including Korea, USA, UK, Japan, Germany, Swiss, Italy, France, and Laos. We used the Korea Adverse Event Reporting System (KAERS) database, a nationwide database of AE reports, between December 1988 and June 2014. Frequentist and Bayesian methods were used to calculate disproportionality distribution of drug-AE pairs. The AE which was detected by all the three indices of proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) was defined as a signal. The KAERS database contained a total of 807,582 AE reports, among which 1,722 reports were attributed to amoxicillin. Among the 192,510 antibiotics-AE pairs, the number of amoxicillin-AE pairs was 2,913. Among 241 AEs, 52 adverse events were detected as amoxicillin signals. Comparing the drug labels of 9 countries, 12 adverse events including ineffective medicine, bronchitis, rhinitis, sinusitis, dry mouth, gastroesophageal reflux, hypercholesterolemia, gastric carcinoma, abnormal crying, induration, pulmonary carcinoma, and influenza-like symptoms were not listed on any of the labels of nine countries. In conclusion, we detected 12 new signals of amoxicillin which were not listed on the labels of 9 countries. Therefore, it should be followed by signal evaluation including causal association, clinical significance, and preventability. PMID:27510377

  17. Intestinal absorption of the antiepileptic drug substance vigabatrin is altered by infant formula in vitro and in vivo.

    PubMed Central

    Nøhr, Martha Kampp; Thale, Zia I; Brodin, Birger; Hansen, Steen H; Holm, René; Nielsen, Carsten Uhd

    2014-01-01

    Vigabatrin is an antiepileptic drug substance mainly used in pediatric treatment of infantile spasms. The main source of nutrition for infants is breast milk and/or infant formula. Our hypothesis was that infant formula may affect the intestinal absorption of vigabatrin. The aim was therefore to investigate the potential effect of coadministration of infant formula with vigabatrin on the oral absorption in vitro and in vivo. The effect of vigabatrin given with an infant formula on the oral uptake and transepithelial transport was investigated in vitro in Caco-2 cells. In vivo effects of infant formula and selected amino acids on the pharmacokinetic profile of vigabatrin was investigated after oral coadministration to male Sprague–Dawley rats using acetaminophen as a marker for gastric emptying. The presence of infant formula significantly reduced the uptake rate and permeability of vigabatrin in Caco-2 cells. Oral coadministration of vigabatrin and infant formula significantly reduced Cmax and prolonged tmax of vigabatrin absorption. Ligands for the proton-coupled amino acid transporter PAT1, sarcosine, and proline/l-tryptophan had similar effects on the pharmacokinetic profile of vigabatrin. The infant formula decreased the rate of gastric emptying. Here we provide experimental evidence for an in vivo role of PAT1 in the intestinal absorption of vigabatrin. The effect of infant formula on the oral absorption of vigabatrin was found to be due to delayed gastric emptying, however, it seems reasonable that infant formula may also directly affect the intestinal absorption rate of vigabatrin possibly via PAT1. PMID:25505585

  18. The absorptive flux of the anti-epileptic drug substance vigabatrin is carrier-mediated across Caco-2 cell monolayers.

    PubMed

    Nøhr, Martha Kampp; Hansen, Steen Honoré; Brodin, Birger; Holm, René; Nielsen, Carsten Uhd

    2014-01-23

    Vigabatrin is an anti-epileptic drug substance. The oral bioavailability of vigabatrin is high (60-70%), however, little is known about the mechanism(s) mediating the intestinal absorption. The aim of the present study was to identify which solute carrier(s) are involved in the absorption of vigabatrin in Caco-2 cells, a cell culture model of the small intestinal epithelium. The uptake and transepithelial flux of vigabatrin was measured using an LC-MS method for quantification. Transepithelial transport of vigabatrin was shown to be proton-dependent and polarized in the apical-to-basolateral (A-B) direction. The A-B flux of vigabatrin had a saturable component and a passive component, indicating the presence of a carrier system in parallel with a passive permeability. The Michaelis constant, Km, of the transepithelial A-B flux of vigabatrin was estimated to be 32.8±7.4 mM (n=3-5), whereas the Km of the apical uptake was found to be 12.7±3.7 mM (n=3). The carrier-mediated transepithelial A-B flux of vigabatrin accounted for 80-95% (50.0-1.0mM) of the total A-B flux. The transepithelial A-B flux (as well as apical uptake) of vigabatrin was significantly decreased upon addition of substrates or inhibitors of the human proton-coupled amino acid transporter (hPAT1) to the apical solution. The present study indicates that the transepithelial A-B flux of vigabatrin is mainly mediated by hPAT1 in Caco-2 cells at dose-relevant concentrations. PMID:24008184

  19. The effect of imepitoin, a recently developed antiepileptic drug, on thyroid parameters and fat metabolism in healthy Beagle dogs.

    PubMed

    Bossens, K; Daminet, S; Duchateau, L; Rick, M; Van Ham, L; Bhatti, S

    2016-07-01

    Since early 2013, imepitoin has been used in most European countries for the management of recurrent single generalised epileptic seizures in dogs with idiopathic epilepsy. It has been reported that imepitoin is as effective as phenobarbital (PB) in controlling seizures in dogs with newly diagnosed idiopathic epilepsy and it has a clinically superior safety profile. As the use of imepitoin gains popularity, its effect on serum thyroid parameters warrants further investigation since long-term PB administration influences thyroid parameters in dogs, which could lead to misinterpretation of laboratory results and incorrect diagnosis of thyroidal illness. A prospective study was conducted to compare the effect of orally administered PB and imepitoin on serum concentrations of total thyroxine (TT4), triiodothyronine, free thyroxine, thyroglobulin autoantibodies, thyroid-stimulating hormone, cholesterol and triglycerides in healthy Beagle dogs. These parameters were determined prior to and at 6, 12 and 18 weeks after antiepileptic drug administration. The starting dose of PB (5 mg/kg PO twice daily; range, 4.4-6.0 mg/kg) was monitored and adjusted to obtain optimal therapeutic serum concentrations (30-35 g/mL). Imepitoin was administered at 30 mg/kg PO twice daily (range, 29.2-35.7 mg/kg). Imepitoin administration did not affect any of the thyroid parameters over an 18-week period. In contrast, serum TT4 concentrations decreased significantly over time in dogs receiving PB (P <0.05). Serum cholesterol concentrations increased significantly over time in dogs in the imepitoin group, but not to the same extent as commonly seen in dogs with primary hypothyroidism. PMID:27240915

  20. Associations between Fracture Incidence and Use of Depot Medroxyprogesterone Acetate and Anti-Epileptic Drugs in Women with Developmental Disabilities

    PubMed Central

    Lentz, Martha J.; Cain, Kevin C.

    2007-01-01

    Purpose To evaluate any association between incidence of osteoporotic fractures and use of depot medroxyprogesterone acetate (DMPA) and/or anti-epileptic drugs (AEDs) among women and girls with developmental disabilities. Methods Cross-sectional population–based observational study of all non-institutionalized females with developmental disabilities age thirteen and older who received fee-for-service Medicaid in Washington State during 2002 (N=6773), using administrative data. Main Findings In a sample of 6,773 females, 140 women (2%) had an osteoporotic fracture during 2002. Among 340 users of DMPA, 13 (3.8%) had an osteoporotic fracture with an odds ratio of 2.4 (CI 95%, 1.3–4.4) for fracture compared to non-users. Among 1909 users of AEDs, 60 (3.1%) had an osteoporotic fracture with an odds ratio of 1.9 (CI 95%, 1.3–2.6) for fracture compared to non-users. We controlled for age and race (as Caucasian or non-Caucasian). Conclusions Use of either AEDs or DMPA by women with developmental disabilities is associated with significantly increased incidence of fracture. Women and girls who have developmental disabilities may be poor candidates for DMPA use due to increased risk of fractures. Further research is indicated (1) to determine the specific risks profile of DMPA for this population, (2) to explore alternative means of managing significant menstrual problems and contraceptive needs in this population and (3) to screen current and previous users of DMPA and chronic users of AEDs for osteoporosis risk, regardless of age. PMID:17188217

  1. [Photodegradation of chlorpromazine, a drug-related adverse event].

    PubMed

    Chabi, Yossounon; Brahim, Kheira; Da Costa, Maryline; Caffin, Anne-Gaëlle; Camus, Gisèle; Paillet, Michel; Bohand, Xavier

    2016-04-01

    The photodegradation of an active substance during treatment is a rare drug-related adverse event which can sometimes have serious consequences. Health professionals must be aware of the specific storage and administration instructions with regard to chlorpromazine and ensure that they are respected. PMID:27085925

  2. A time-indexed reference standard of adverse drug reactions

    PubMed Central

    Harpaz, Rave; Odgers, David; Gaskin, Greg; DuMouchel, William; Winnenburg, Rainer; Bodenreider, Olivier; Ripple, Anna; Szarfman, Ana; Sorbello, Alfred; Horvitz, Eric; White, Ryen W.; Shah, Nigam H.

    2014-01-01

    Undetected adverse drug reactions (ADRs) pose a major burden on the health system. Data mining methodologies designed to identify signals of novel ADRs are of deep importance for drug safety surveillance. The development and evaluation of these methodologies requires proper reference benchmarks. While progress has recently been made in developing such benchmarks, our understanding of the performance characteristics of the data mining methodologies is limited because existing benchmarks do not support prospective performance evaluations. We address this shortcoming by providing a reference standard to support prospective performance evaluations. The reference standard was systematically curated from drug labeling revisions, such as new warnings, which were issued and communicated by the US Food and Drug Administration in 2013. The reference standard includes 62 positive test cases and 75 negative controls, and covers 44 drugs and 38 events. We provide usage guidance and empirical support for the reference standard by applying it to analyze two data sources commonly mined for drug safety surveillance. PMID:25632348

  3. Mining for adverse drug events with formal concept analysis.

    PubMed

    Estacio-Moreno, Alexander; Toussaint, Yannick; Bousquet, Cédric

    2008-01-01

    The pharmacovigilance databases consist of several case reports involving drugs and adverse events (AEs). Some methods are applied consistently to highlight all signals, i.e. all statistically significant associations between a drug and an AE. These methods are appropriate for verification of more complex relationships involving one or several drug(s) and AE(s) (e.g; syndromes or interactions) but do not address the identification of them. We propose a method for the extraction of these relationships based on Formal Concept Analysis (FCA) associated with disproportionality measures. This method identifies all sets of drugs and AEs which are potential signals, syndromes or interactions. Compared to a previous experience of disproportionality analysis without FCA, the addition of FCA was more efficient for identifying false positives related to concomitant drugs. PMID:18487830

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

    PubMed Central

    Kim, Ji Young; Lee, Joongyub; Ko, Young-Jin; Shin, Ju-Young; Jung, Sun-Young; Choi, Nam-Kyong; Park, Byung-Joo

    2013-01-01

    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

  5. [ Preventing adverse drug events using clinical decision support systems].

    PubMed

    Salili, Ali Reza; Hammann, Felix; Taegtmeyer, Anne B

    2015-12-01

    Adverse drug events pose a great risk to patients, are an everyday clinical problem and can have potential/ega/ consequences. Computerized physician order entry or computerized provider order entry (CPOE} in combination with clinical decision support systems {CDSS) are popular and aim to reduce prescribing errors as well as identifying potentially harmful drug drug interactions. The quantifiable benejit these systems bring to patients, has however, yet to be definitively proven. This article focusses on the current standpoint of CPOE-/CDSS, their risks and benefits, the potential for improvement and their perspectives for the future. PMID:26654813

  6. Improvement of physicochemical properties of an antiepileptic drug by salt engineering.

    PubMed

    Rahman, Ziyaur; Zidan, Ahmed S; Samy, Raghu; Sayeed, Vilayat A; Khan, Mansoor A

    2012-09-01

    The focus of the present investigation was to evaluate the feasibility of using cyclamic salt of lamotrigine in order to improve its solubility and intrinsic dissolution rate (IDR). The salt was prepared by solution crystallization method and characterized chemically by fourier transform infrared spectroscopy (FTIR), proton ((1)H) and carbon ((13)C) nuclear magnetic resonance (liquid and solid, NMR) spectroscopy, physically by powder X-ray diffraction (PXRD), thermally by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), physicochemically for solubility, IDR, solution and solid-state stability, and polymorphism by solution recrystallization and slurry conversion studies. The FTIR, NMR, PXRD, DSC, and TGA spectra and thermograms indicated the salt formation. The salt formation increased lamotrigine solubility by 19-fold and IDR by 4.9-fold in water. The solution and solid-state stability were similar to parent molecule and were resistant to polymorphic transformation. In conclusion, cyclamic salt of lamotrigine provides another potential avenue for the pharmaceutical development of lamotrigine with improved physicochemical properties especially for pediatric population. It is also possible that appropriate dosage forms can be formulated with much lower drug amount and better safety profile than existing products. PMID:22588676

  7. Bioactivation and bioinactivation of drugs and drug metabolites: Relevance to adverse drug reactions.

    PubMed

    Park, B K; Pirmohamed, M; Tingle, M D; Madden, S; Kitteringham, N R

    1994-08-01

    Adverse drug reactions that cannot be predicted from the pharmacological properties of the drug and which are not easily reproduced in laboratory animals are a major complication of drug therapy. It is necessary to investigate the mechanisms of such reactions in order to (1) define structural features within a given drug molecule which are responsible for causing toxicity and (2) to identify those individuals who are particularly sensitive to a given drug reaction. In theory, drug toxicity may arise by direct toxicity, genotoxicity or immune-mediated toxicity caused by either parent drug or chemical. In this respect chemically reactive metabolites are of particular importance and the balance between bioactivation and bioinactivation pathways of drug metabolism will be a critical factor in both the type and extent of toxicity. We have therefore developed in vitro techniques that incorporate human cells for the detection and characterization of stable, chemically reactive and cytotoxic metabolites. In such experiments bioactivation (by CYP1A, CYP2D6, CYP3A, etc.) can be investigated by use of a liver bank, while lymphocytes provide accessible human cells, which can be obtained from both patients and volunteers, genotyped and/or phenotyped for particular drug-metabolizing enzymes (eg. glutathione transferase mu). The relevance of in vitro experiments to drug toxicity observed in humans will be illustrated by reference to studies with anticonvulsants and antimalarials. PMID:20692973

  8. Pharmacology, Toxicology, and Adverse Effects of Synthetic Cannabinoid Drugs.

    PubMed

    Gurney, S M R; Scott, K S; Kacinko, S L; Presley, B C; Logan, B K

    2014-01-01

    Synthetic cannabinoid drugs have become an established part of the recreational drug landscape in the United States and internationally. These drugs are manufactured in clandestine laboratories internationally and distributed in the United States in smoking mixtures, use of which produces effects very similar to use of marijuana. The adverse-effect profile of the drugs has not been studied in humans and infrequently in animal models, so much of the information about their toxicity comes from emergency department and treatment reports and forensic case studies. This review considers the discovery and characterization of the endocannabinoid system, approaches to receptor-binding studies of various synthetic cannabinoids from the first wave of naphthoylindoles (e.g., JWH-018) to the emerging adamantoylindole drugs (e.g., AKB-48), and their analogs, to evaluate the potential activity of drugs in this class. Currently employed approaches to assessing functional activity of the drugs using in vitro and in vivo models is also described, and comparisons made to the effects of THC. The physiological effects of activation of the endocannabinoid system in humans are reviewed, and the physiological effects of cannabinoid use are described. Case reports of adverse events including emergency department admissions, mental health admissions, and clinical and forensic case reports are presented in detail and discussed to summarize the current state of knowledge of adverse effects, both clinical and forensic in humans, including effects on driving ability, and tissue injury and death. The greatest weight is accorded to those reports that include toxicological confirmation of use. Finally, we discuss the current status of attempts to schedule and control the distribution of synthetic cannabinoids and the relevance of receptor binding and functional activity in this context. There is growing toxicological and pharmacological evidence of impairment, psychosis, tissue injury, and

  9. Effectiveness of adverse effects search filters: drugs versus medical devices

    PubMed Central

    Farrah, Kelly; Mierzwinski-Urban, Monika; Cimon, Karen

    2016-01-01

    Objective The study tested the performance of adverse effects search filters when searching for safety information on medical devices, procedures, and diagnostic tests in MEDLINE and Embase. Methods The sensitivity of 3 filters was determined using a sample of 631 references from 131 rapid reviews related to the safety of health technologies. The references were divided into 2 sets by type of intervention: drugs and nondrug health technologies. Keyword and indexing analysis were performed on references from the nondrug testing set that 1 or more of the filters did not retrieve. Results For all 3 filters, sensitivity was lower for nondrug health technologies (ranging from 53%–87%) than for drugs (88%–93%) in both databases. When tested on the nondrug health technologies set, sensitivity was lower in Embase (ranging from 53%–81%) than in MEDLINE (67%–87%) for all filters. Of the nondrug records that 1 or more of the filters missed, 39% of the missed MEDLINE records and 18% of the missed Embase records did not contain any indexing terms related to adverse events. Analyzing the titles and abstracts of nondrug records that were missed by any 1 filter, the most commonly used keywords related to adverse effects were: risk, complications, mortality, contamination, hemorrhage, and failure. Conclusions In this study, adverse effects filters were less effective at finding information about the safety of medical devices, procedures, and tests compared to information about the safety of drugs. PMID:27366123

  10. Identification of phototransformation products of the antiepileptic drug gabapentin: Biodegradability and initial assessment of toxicity.

    PubMed

    Herrmann, Manuel; Menz, Jakob; Olsson, Oliver; Kümmerer, Klaus

    2015-11-15

    The anticonvulsant drug Gabapentin (GAB) is used for the treatment of various diseases (e.g. epilepsy, bipolar disorder, neuropathic pain) and is being consumed in high amounts. As GAB is not metabolized and shows a weak elimination in sewage treatment plants (STPs), it has been detected in surface water and even in raw potable water. Moreover, the confirmed teratogenic effects of GAB indicate the need for further investigations regarding options for the elimination of GAB in the water cycle. Little is known about the behavior of GAB during treatment with UV light, which is normally used for the disinfection of potable water and discussed for advanced wastewater treatment. In this study, GAB was exposed to polychromatic UV irradiation at different initial concentrations in aqueous solution. Afterwards the structures of the resulting phototransformation products (PTPs) were identified and elucidated by means of high-resolution mass spectrometry. GAB and photolytic mixtures were submitted to the Closed Bottle Test (CBT; OECD 301 D) to assess biodegradability. Furthermore, the toxicity of GAB and its photolytic mixtures was initially addressed on screening level using a modified luminescent bacteria test (LBT) and the umu-test (ISO/FDIS 13829). Environmentally realistic concentrations of GAB were disclosed by predicting STP influent concentrations (24.3 and 23.2 μg L(-1)). GAB with initial concentration of 100 mg L(-1) was eliminated by 80% after 128 min of direct UV irradiation, but just 9% of non-purgeable organic carbon (NPOC) was removed indicating the formation of dead-end transformation products (TPs). Structures of different PTPs were elucidated and several identical PTPs could also be identified at lower initial treatment concentrations (20 mg L(-1), 5 mg L(-1), 1 mg L(-1) and 0.1 mg L(-1)). GAB was classified as not readily biodegradable. Moreover, photo treatment did not result in better biodegradable PTPs. With increasing UV treatment duration, photolytic