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Sample records for broad-spectrum antiepileptic drug

  1. N-alkyl-[1,1'-biphenyl]-2-sulfonamide derivatives as novel broad spectrum anti-epileptic drugs with efficacy equivalent to that of sodium valproate.

    Science.gov (United States)

    Tanaka, Tomoyuki; Yajima, Nana; Kiyoshi, Tomoko; Miura, Yoshiki; Iwama, Seiji

    2017-09-01

    In order to develop phenyl sulfonamides as a novel class of anti-epileptic drugs (AED) for both general and partial seizure, we initiated in vivo screening of our chemical library in the mice MES and sc-PTZ models and found compounds 1 and 2 as lead compounds. Optimization of 1 and 2 led to the discovery of compound 21, which showed potent anticonvulsant effect in MES, scPTZ and rat amygdala kindling models. These findings indicate that compound 21 could be a useful new broad spectrum AED like sodium valproate and provide an opportunity to struggle current therapy-resistant epilepsy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Antiepileptic drugs and intrauterine death

    DEFF Research Database (Denmark)

    Tomson, Torbjörn; Battino, Dina; Bonizzoni, Erminio

    2015-01-01

    OBJECTIVE: To compare the risk of spontaneous abortions and stillbirth associated with maternal use of different antiepileptic drugs (AEDs). METHODS: The EURAP registry is an observational international cohort study primarily designed to determine the risk of major congenital malformations (MCMs...

  3. Intravenous Antiepileptic Drugs in Russia

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    P. N. Vlasov

    2014-01-01

    Full Text Available Launching four intravenous antiepileptic drugs: valproate (Depakene and Convulex, lacosamide (Vimpat, and levetiracetam (Keppra – into the Russian market has significantly broadened the possibilities of rendering care to patients in seizure emergency situations. The chemi- cal structure, mechanisms of action, indications/contraindications, clinical effectiveness and tolerability, advantages/disadvantages, and adverse events of using these drugs in urgent and elective neurology are discussed. 

  4. Rational Polytherapy with Antiepileptic Drugs

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    Jong Woo Lee

    2010-07-01

    Full Text Available Approximately 30–40% of patients do not achieve seizure control with a single antiepileptic drug (AED. With the advent of multiple AEDs in the past 15 years, rational polytherapy, the goal of finding combinations of AEDs that have favorable characteristics, has become of greater importance. We review the theoretical considerations based on AED mechanism of action, animal models, human studies in this field, and the challenges in finding such optimal combinations. Several case scenarios are presented, illustrating examples of rational polytherapy.

  5. Antiepileptic drugs in Rett Syndrome.

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    Pintaudi, Maria; Calevo, Maria Grazia; Vignoli, Aglaia; Baglietto, Maria Giuseppina; Hayek, Yussef; Traverso, Maria; Giacomini, Thea; Giordano, Lucio; Renieri, Alessandra; Russo, Silvia; Canevini, MariaPaola; Veneselli, Edvige

    2015-07-01

    We investigated drugs most often used to treat epilepsy in Rett Syndrome and their efficacy in a large cohort of Italian patients. This is a multi-centre retrospective study. Data of 165 Rett subjects were collected from the patients' files, and hospital charts. The efficacy of antiepileptic drugs (AEDs) was classified as follows: not effective; decrease in seizure frequency ≥50% for at least 6 months; seizure-free for at least 2 years. Phenotypic and genetic categorization of patients was performed and it was considered in AEDs efficacy evaluation. There were 130 epileptic patients.Sodium valproate (VPA) was the most commonly administered AED (44.3%) at seizure onset, followed by Carbamazepine (CBZ) (25.4%) and Phenobarbital (PB) (13%). Monotherapy was the first treatment option in most patients. VPA and CBZ proved to be equally effective in Rett patients who presented seizures within the typical age range (4-5 years), while Lamotrigine (LTG) was effective for patients in whom epilepsy started later. Overall, the frequency of side effects was low and the most often observed ones were restlessness and somnolence. Our study suggests that LTG, VPA and CBZ can be used as drugs of first choice in Rett Syndrome. The association of four drugs should be avoided since it did not result in any significant clinical improvement. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  6. Computer-aided identifications of thin-layer chromatographic patterns in broad-spectrum drug screening.

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    Siek, T J; Stradling, C W; McCain, M W; Mehary, T C

    1997-04-01

    We have developed a systematic thin-layer chromatographic (TLC) technique for detecting and identifying drugs and drug metabolites on 10-cm-long silica-gel plates with organic binder (fluorescent indicator); a computer program (SPOT CHEK) assists in matching the data from a particular chromatogram with those obtained for known drugs recovered from serum, urine, or other specimens. The plates are developed in a single mobile phase. Visualization and detection reagents used to characterize unknowns include fluorescamine, ferric chloride/perchloric acid/nitric acid, Dragendorff, Marquis, Mandelin, and iodinated Dragendorff solutions, 254 nm ultraviolet light, and vapor from chlorine or hydrochloric acid. Detection limits of 5-200 ng per sample spot were obtained for drugs in the database. The computer program database is based on nine reaction responses plus the plate zone locations for 243 drug substances but requires entry of only one TLC property to generate a matching list. We ran the program with an IBM-compatible 386/486 PC using an MS-DOS operating system (version 6.2).

  7. Assessment of drug candidates for broad-spectrum antiviral therapy targeting cellular pyrimidine biosynthesis.

    Science.gov (United States)

    Marschall, Manfred; Niemann, Ina; Kosulin, Karin; Bootz, Anna; Wagner, Sabrina; Dobner, Thomas; Herz, Thomas; Kramer, Bernd; Leban, Johann; Vitt, Daniel; Stamminger, Thomas; Hutterer, Corina; Strobl, Stefan

    2013-12-01

    Currently available antiviral drugs frequently induce side-effects or selection of drug-resistant viruses. We describe a novel antiviral principle based on targeting the cellular enzyme dihydroorotate dehydrogenase (DHODH). In silico drug design and biochemical evaluation identified Compound 1 (Cmp1) as a selective inhibitor of human DHODH in vitro (IC50 1.5±0.2nM). Crystallization data specified the mode of drug-target interaction. Importantly, Cmp1 displayed a very potent antiviral activity that could be reversed by co-application of uridine or other pyrimidine precursors, underlining the postulated DHODH-directed mode of activity. Human and animal cytomegaloviruses as well as adenoviruses showed strong sensitivity towards Cmp1 in cell culture-based infection systems with IC50 values in the low micromolar to nanomolar range. Particularly, broad inhibitory activity was demonstrated for various types of laboratory and clinically relevant adenoviruses. For replication of human cytomegalovirus in primary fibroblasts, antiviral mode of activity was attributed to the early stage of gene expression. A mouse in vivo model proved reduced replication of murine cytomegalovirus in various organs upon Cmp1 treatment. These findings suggested Cmp1 as drug candidate and validated DHODH as a promising cellular target for antiviral therapy. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. New antiepileptic drugs and preparations.

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    Yoon, Y; Jagoda, A

    2000-11-01

    Epilepsy affects 1.2% to 4.4% of the general population. Given the clinical profile of the newer antiepileptic agents, it is likely their usage will increase in the coming years, thus increasing the emergency physician's exposure to these medications and their side effects. Several of these side effects can have high morbidity, such as the aplastic anemia and hepatotoxicity caused by felbamate, and the Stevens-Johnson syndrome associated with lamotrigine. Overdoses of these medications also could increase, as will our knowledge of recognizing and managing them. The clinical spectrum of the newer medications is the treatment of partial seizures. None of the newer medications can be orally loaded nor are they available in an i.v. preparation. Serum drug levels are not available in most institutions and are not routinely measured in the ED. The new preparations of phenytoin, diazepam, and valporic acid add increased efficiency in drug administration, providing a new method for prehospital treatment of seizures and a more tolerable means of administration in the ED.

  9. Snake Venom PLA2, a Promising Target for Broad-Spectrum Antivenom Drug Development

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    Liao, Keren; Yang, Mengxue

    2017-01-01

    Snakebite envenomation is a neglected global health problem, causing substantial mortality, disability, and psychological morbidity, especially in rural tropical and subtropical zones. Antivenin is currently the only specific medicine for envenomation. However, it is restricted by cold storage, snakebite diagnosis, and high price. Snake venom phospholipase A2s (svPLA2s) are found in all kinds of venomous snake families (e.g., Viperidae, Elapidae, and Colubridae). Along with their catalytic activity, svPLA2s elicit a wide variety of pharmacological effects that play a pivotal role in envenomation damage. Hence, neutralization of the svPLA2s could weaken or inhibit toxic damage. Here we overviewed the latest knowledge on the distribution, pathophysiological effects, and inhibitors of svPLA2s to elucidate the potential for a novel, wide spectrum antivenom drug targeting svPLA2s. PMID:29318152

  10. Snake Venom PLA2, a Promising Target for Broad-Spectrum Antivenom Drug Development

    Directory of Open Access Journals (Sweden)

    Huixiang Xiao

    2017-01-01

    Full Text Available Snakebite envenomation is a neglected global health problem, causing substantial mortality, disability, and psychological morbidity, especially in rural tropical and subtropical zones. Antivenin is currently the only specific medicine for envenomation. However, it is restricted by cold storage, snakebite diagnosis, and high price. Snake venom phospholipase A2s (svPLA2s are found in all kinds of venomous snake families (e.g., Viperidae, Elapidae, and Colubridae. Along with their catalytic activity, svPLA2s elicit a wide variety of pharmacological effects that play a pivotal role in envenomation damage. Hence, neutralization of the svPLA2s could weaken or inhibit toxic damage. Here we overviewed the latest knowledge on the distribution, pathophysiological effects, and inhibitors of svPLA2s to elucidate the potential for a novel, wide spectrum antivenom drug targeting svPLA2s.

  11. Endocrine Disorders Induced by Antiepileptic Drugs

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    J Gordon Millichap

    2006-05-01

    Full Text Available Endocrine disturbances in adolescent women with epilepsy, and the effects of antiepileptic drugs (AEDs and hormonal contraception are discussed by a pediatric neurologist and epileptologist at the Children’s Hospital of Wisconsin, Milwaukee, WI.

  12. When antiepileptic drugs aggravate epilepsy.

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    Genton, P

    2000-03-01

    Paradoxically, an antiepileptic drug (AED) may aggravate epilepsy. The number of AEDs is steadily increasing, and the occurrence of paradoxical aggravation will probably become a frequent problem. The overall status of the patient treated for epilepsy can be altered due to maladjustment to the diagnosis of epilepsy, to unwanted side-effects, to overdosage and to the occurrence of tolerance. However, the main mechanism of aggravation is the occurrence of an inverse pharmacodynamic effect. The specific effect of the AED is such that it controls epilepsy in most cases and increases seizures in other cases. Idiopathic generalised epilepsies (IGE) are particularly prone to pharmacodynamic aggravation: typical absences are constantly increased by carbamazepine (CBZ), vigabatrin, tiagabine, gabapentin, while phenytoin (PHT) is less aggravating. Juvenile myoclonic epilepsy is often aggravated by CBZ, less constantly by PHT and other AEDs. Generalised tonic-clonic seizures found in IGEs may respond to AEDs that aggravate the other seizure types. In symptomatic generalised epilepsies, patients have often several seizure types that respond differently to AEDs: myoclonias are generally aggravated by the same drugs that aggravated IGEs; tonic seizures in the Lennox-Gastaut syndrome respond to CBZ, which may however aggravate atypical absences. In severe myoclonic epilepsy of infancy, there is a nearly constant aggravating effect of lamotrigine. In some patients with benign rolandic epilepsy, a clear aggravation may be produced by CBZ, with occurrence of negative myoclonias, atypical absences, drop attacks, and at the maximum evolution into a state of electrical status epilepticus during sleep. It is much more difficult to pinpoint specific pharmacological sensitivity in other focal epilepsies, but aggravation clearly occurs. When treating epilepsy, the clinician should act according to seizure type, or, better, to epilepsy type. Patients are usually aware of aggravation before

  13. Exoproteome and secretome derived broad spectrum novel drug and vaccine candidates in Vibrio cholerae targeted by Piper betel derived compounds.

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    Debmalya Barh

    Full Text Available Vibrio cholerae is the causal organism of the cholera epidemic, which is mostly prevalent in developing and underdeveloped countries. However, incidences of cholera in developed countries are also alarming. Because of the emergence of new drug-resistant strains, even though several generic drugs and vaccines have been developed over time, Vibrio infections remain a global health problem that appeals for the development of novel drugs and vaccines against the pathogen. Here, applying comparative proteomic and reverse vaccinology approaches to the exoproteome and secretome of the pathogen, we have identified three candidate targets (ompU, uppP and yajC for most of the pathogenic Vibrio strains. Two targets (uppP and yajC are novel to Vibrio, and two targets (uppP and ompU can be used to develop both drugs and vaccines (dual targets against broad spectrum Vibrio serotypes. Using our novel computational approach, we have identified three peptide vaccine candidates that have high potential to induce both B- and T-cell-mediated immune responses from our identified two dual targets. These two targets were modeled and subjected to virtual screening against natural compounds derived from Piper betel. Seven compounds were identified first time from Piper betel to be highly effective to render the function of these targets to identify them as emerging potential drugs against Vibrio. Our preliminary validation suggests that these identified peptide vaccines and betel compounds are highly effective against Vibrio cholerae. Currently we are exhaustively validating these targets, candidate peptide vaccines, and betel derived lead compounds against a number of Vibrio species.

  14. [Pharmacological basis for withdrawal of antiepileptic drugs].

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    Armijo, J A; Adín, J

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

  15. Evaluation of Carbohydrate-Derived Fulvic Acid (CHD-FA) as a Topical Broad-Spectrum Antimicrobial for Drug-Resistant Wound Infections

    Science.gov (United States)

    2016-10-01

    acid is a highly promising topical agent to enhance healing of wounds infected with drug-resistant pathogens” on the Journal of Trauma and Acute Care...Drug- Resistant Wound Infections PRINCIPAL INVESTIGATOR: David S. Perlin, Ph.D. CONTRACTING ORGANIZATION: Rutgers, The State University of New Jersey...of Carbohydrate-Derived Fulvic Acid (CHD-FA) as a Topical Broad- Spectrum Antimicrobial for Drug-Resistant Wound Infections 5b. GRANT NUMBER 5c

  16. Evaluation of Carbohydrate-Derived Fulvic Acid (CHD-FA) as a Topical Broad-Spectrum Antimicrobial for Drug-Resistant Wound Infections

    Science.gov (United States)

    2013-10-01

    Fulvic Acid (CHD-FA) as a Topical Broad-Spectrum Antimicrobial for Drug- Resistant Wound Infections. PRINCIPAL INVESTIGATOR: David S. Perlin...Spectrum Antimicrobial for Drug- Resistant Wound Infections. 5b. GRANT NUMBER W81XWH-12-2-0076 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) David S...Manchester, UK , and the Perlin Pfizer Reference Center for molecular characterization of echinocandin resistance in yeasts and molds and from the

  17. Interactions between hormonal contraception and antiepileptic drugs

    DEFF Research Database (Denmark)

    Reimers, Arne; Brodtkorb, Eylert; Sabers, Anne

    2015-01-01

    Antiepileptic drugs (AEDs) and hormonal contraceptives may affect each other's metabolism and clinical efficacy. Loss of seizure control and unplanned pregnancy may occur when these compounds are used concomitantly. Although a large number of available preparations yield a plethora of possible dr...

  18. Trends in Anti-Epileptic Drug Development

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    Lennart Gram

    1990-01-01

    Full Text Available Several avenues are being explored in the development of new anti-epileptic drugs (AEDs. For a number of years efforts have been directed towards compounds which may augment neuronal inhibition, and these efforts have resulted in the development of several valuable drugs. More recently, increased attention has been focused on the role which excitatory transmitters may play in epileptogenesis, and various substances which decrease excitation are currently being investigated at the preclinical level. Since considerable potential still resides in several of the drugs already on the market, resources have been spent on trying to modify/improve the chemical formula of some of these substances, and a number of new drugs has emerged as a result of this approach. The major accomplishments reviewed here in the development of new anti-epileptic drugs suggest that even more successful advances may be achieved in the near future.

  19. An "All-In-One" Pharmacophoric Architecture for the Discovery of Potential Broad-Spectrum Anti-Flavivirus Drugs.

    Science.gov (United States)

    Ncube, Nomagugu B; Ramharack, Pritika; Soliman, Mahmoud E S

    2018-01-18

    A precipitous increase in the number of flaviviral infections has been noted over the last 5 years. Despite these outbreaks, treatment protocols for infected individuals remain ambiguous. Numerous studies have identified NITD008 as a potent flavivirus inhibitor; however, clinical testing was dismissed due to undesirable toxic effects. The binding landscape of NITD008 in complex with five detrimental flaviviruses at the RNA-dependent RNA polymerase active sites was explored. An "all-in-one" pharmacophore model was created for the design of small molecules that may inhibit a broad spectrum of flaviviruses. This pharmacophore model approach serves as a robust cornerstone, thus assisting medicinal experts in the composition of multifunctional inhibitors that will eliminate cross-resistance and toxicity and enhance patient adherence.

  20. Managing antiepileptic drugs during pregnancy and lactation

    DEFF Research Database (Denmark)

    Sabers, Anne; Tomson, Torbjörn

    2009-01-01

    PURPOSE OF REVIEW: This review discusses data on the pharmacokinetics of antiepileptic drugs (AEDs) in pregnancy and lactation, and the clinical consequences thereof, thus providing a basis for a rational management of AEDs during pregnancy and lactation. RECENT FINDINGS: Studies have confirmed...... of AEDs in pregnancy and during lactation is important to enable optimal treatment. Gestation induced alterations in pharmacokinetics vary with the AED but also between patients and are difficult to predict. Therapeutic drug monitoring is, therefore, advisable during pregnancy and the use...... of the individual patient's optimal prepregnancy drug level is recommended as reference. Breastfeeding is in general safe but needs appropriate observation of the nursing infant....

  1. Broad-spectrum amino acid-sensing class C G-protein coupled receptors: molecular mechanisms, physiological significance and options for drug development.

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    Conigrave, Arthur D; Hampson, David R

    2010-09-01

    In this article, we consider the molecular mechanisms that underlie broad-spectrum amino acid sensing by a discrete subgroup of class C G-protein-coupled receptors that includes the calcium-sensing receptor, GPRC6A and heterodimers composed of two closely related receptor subunits, T1R(1) and T1R(3). We consider their physiological significance highlighting their diverse spectrum of cellular responses and the phenotypes of global and conditional knock-out mice. In addition, we consider strategies for the development of new drugs that target these receptors. 2010 Elsevier Inc. All rights reserved.

  2. Pharmacokinetic interactions between contraceptives and antiepileptic drugs

    DEFF Research Database (Denmark)

    Sabers, A.

    2008-01-01

    The occurrence of bi-directional drug interactions between antiepileptic drugs (AEDs) and combined oral contraceptives (M) pose potential risks of unintended pregnancy and as well as seizure deterioration. It is well established that several of the older AEDs (carbamazepine, phenytoin...... AEDs, which undergoes glucuronidation processes, such as valproate and oxcarbazepine, may be affected by OCs. The magnitude of the drug-drug interactions show in general wide inter-individual variability and the change in the elimination rate is often unpredictable and can be influenced by a number...... of co-variants such as co-medication of other drugs, as well as genetic and environmental factors. It is therefore recommended that change in OC use is assisted by AED monitoring whenever possible. (C) 2007 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved Udgivelsesdato: 2008/3...

  3. Cognitive and behavioral effects of antiepileptic drugs.

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    Voorhies, T M

    1988-01-01

    In managing epilepsy, drugs that offer the best seizure control to the patient should be used, but their influence on quality of life must also be considered. This must include any effects on mood and mental state, which should be minimal in order that these patients may achieve their full potential. Subtle behavioral and cognitive disadvantages may occur with anticonvulsant drug use. Behavioral changes with phenobarbital are both idiosyncratic and dose related. Carbamazepine and valproic acid can have adverse effects on mood and cognition, but do so less frequently than the other medications or combinations (Table 1). Cognitive dysfunction may relate to antiepileptic drug blood levels, but impairment of skills can occur in the nonintoxicated patient. Thus, office neurologic examinations are insufficient to detect these subtle mental impairments. Practical methods need to be developed to identify and monitor these problems so that in the future cognitive and behavioral dysfunction in epileptic patients can be minimized.

  4. Antiepileptic drug withdrawal in dogs with epilepsy

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    Felix Kaspar Gesell

    2015-08-01

    Full Text Available Epilepsy is one of the most common neurological disorders in dogs and is treated by chronic administration of antiepileptic drugs (AEDs. In humans 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, 4 of these dogs remained seizure free, 7 dogs suffered from seizure recurrence, of which only 3 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.

  5. Antiepileptic Drug Withdrawal in Dogs with Epilepsy.

    Science.gov (United States)

    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.

  6. Drug utilisation study in patients receiving antiepileptic drugs in Colombia.

    Science.gov (United States)

    Machado-Alba, J E; Calvo-Torres, L F; García-Betancur, S; Aguirre-Novoa, A; Bañol-Giraldo, A M

    2016-03-01

    This study examines the indications according to which antiepileptic drugs are prescribed and used in a population of patients enrolled in the Colombian national health system (SGSSS). Retrospective cross-sectional study. From the pool of individuals in 34 Colombian cities who used antiepileptic drugs between 18 July, 2013 and 31 August, 2014 during a period of no less than 12 months, we obtained a random sample stratified by city. Socio-demographic, pharmacological and comorbidity variables were analysed. Continuous and categorical variables were compared, and logistic regression models were used. Our patient total was 373 patients, with 197 women (52.1%) and a mean age of 41.9 ± 21.7 years; 65.4% of the patients were treated with monotherapy. The most frequently used drugs were valproic acid (53.1%) and carbamazepine (33.2%). Epilepsy was the most frequent indication (n=178; 47.7%); however, 52.3% of the patients were prescribed antiepileptics for different indications, especially neuropathic pain (26.8%), affective disorders (14.2%) and migraine prophylaxis (12.3%). A total of 81 patients with epilepsy (46.6%) displayed good seizure control while another 25 (14.4%) had drug-resistant epilepsy. In the multivariate analysis, medication adherence was associated with a lower risk of treatment failure in patients with epilepsy (OR: 0.27; 95%CI, 0.11-0.67). In Colombia, antiepileptic drugs are being used for indications other than those originally intended. Monotherapy is the most commonly used treatment approach, together with the use of classic antiepileptic drugs. Copyright © 2015 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  7. Biogenic nanoparticles bearing antibacterial activity and their synergistic effect with broad spectrum antibiotics: Emerging strategy to combat drug

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    Syed Baker

    2017-01-01

    Full Text Available The present study emphasizes on synthesis of bimetallic silver–gold nanoparticles from cell free supernatant of Pseudomonas veronii strain AS41G inhabiting Annona squamosa L. The synthesized nanoparticles were characterized using hyphenated techniques with UV–Visible spectra ascertained absorbance peak between 400 and 800 nm. Possible interaction of biomolecules in mediating and stabilization of nanoparticles was depicted with Fourier transform infrared spectroscopy (FTIR. X-ray diffraction (XRD displayed Bragg’s peak conferring the 100, 111, 200, and 220 facets of the face centered cubic symmetry of nanoparticles suggesting that these nanoparticles were crystalline in nature. Size and shape of the nanoparticles were determined using Transmission electron microscopy (TEM microgram with size ranging from 5 to 50 nm forming myriad shapes. Antibacterial activity of nanoparticles against significant human pathogens was conferred with well diffusion assay and its synergistic effect with standard antibiotics revealed 87.5% fold increased activity with antibiotic “bacitracin” against bacitracin resistant strains Bacillus subtilis, Escherichia coli and Klebsiella pneumoniae followed by kanamycin with 18.5%, gentamicin with 11.15%, streptomycin with 10%, erythromycin with 9.7% and chloramphenicol with 9.4%. Thus the study concludes with biogenic and ecofriendly route for synthesizing nanoparticles with antibacterial activity against drug resistant pathogens and attributes growing interest on endophytes as an emerging source for synthesis of nanoparticles.

  8. Levels of Antiepileptic Drugs and the Ketogenic Diet

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    J Gordon Millichap

    2006-08-01

    Full Text Available Introduction of the ketogenic diet did not change the plasma levels of antiepileptic drugs in an open study of 51 children (mean age 6.6 years with refractory epilepsy studied at Karolinska University Hospital, Stockholm, Sweden.

  9. Basic Mechanisms of Action of the Antiepileptic Drugs

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    Kuzmanova R.

    2017-10-01

    Full Text Available Available antiepileptic drugs interact with a variety of different molecular targets. The mechanism of action of most anticonvulsants is most often complex with a number of affected regions. The combination of mechanisms of action of drugs in particular proportions can possibly determine the showcase of its antiepileptic activity. The common factor between the different supposed mechanisms for a number of drugs includes the possibility for modulating the excitatory and inhibitory neurotransmission through effects upon the voltage-gated ion channels, synaptic plasticity, heterogeneous receptors, and metabolism of neurotransmitters. There are controversial data on the extent to which a specific action can be the reason for the wholesome anticonvulsive characteristics of various medications, as well as the relation with the presence of undesired drug effects. The complexity of the action of some antiepileptic drugs creates conditions for optimal choice during therapy. In many cases, the insufficient familiarity with individual genetic differences and the disease related receptor damages can hinder defining a particular drug action. Characterizing the mechanisms of action of the present antiepileptic medications would increase the understanding for the pathophysiological mechanisms of epileptic seizures, as well as the development of new therapeutic strategies. The development of novel antiepileptic drugs and the ongoing research regarding the mechanism of action of established antiepileptic drugs, are continuously increasing the level of complexity in the spectrum of molecular targets relevant for epilepsy therapy. The current state of knowledge as well as the limitations in our understanding should guide future research aiming for a more detailed elucidation of the impact of genetics and pathophysiological mechanisms on interindividual differences in expression and function of antiepileptic drug targets.

  10. Antiepileptic drug poisoning: Three-year experience

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    Yahya Kemal Günaydın

    2015-01-01

    Conclusion: First generation antiepileptics are more toxic than SGAEs. In patients with serum carbamazepine level, particularly those over 30 mg/L, serious disorders of consciousness, cardiovascular toxicity, and metabolic disorders may occur. In VPA intoxication, there is a positive correlation between the serum VPA levels and ammonia levels. On account of this finding, one should be more careful about hyperammonemic hepatic encephalopathy as the serum VPA level rises.

  11. Antiepileptic Drug Status in Adult Outpatients with Mental Retardation.

    Science.gov (United States)

    Singh, Baldev K.; Towle, Patricia O.

    1993-01-01

    Review of the charts of 100 patients with mental retardation and epilepsy revealed that 60 patients were taking 1 antiepileptic drug and 40 were taking 2 or 3 drugs. Most subjects had generalized tonic-clonic seizures, but individuals with profound retardation had relatively more mixed seizures. (Author/JDD)

  12. Hypoactive sexual desire disorder caused by antiepileptic drugs

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    M Singh

    2015-01-01

    Full Text Available 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.

  13. Antiepileptic Drug Nonadherence and Its Predictors among People with Epilepsy

    Directory of Open Access Journals (Sweden)

    Asmamaw Getnet

    2016-01-01

    Full Text Available Introduction. Antiepileptic drugs are effective in the treatment of epilepsy to the extent that about 70% of people with epilepsy can be seizure-free, but poor adherence to medication is major problem to sustained remission and functional restoration. The aim of this study was to assess the prevalence and associated factors of antiepileptic drug nonadherence. Methods. Cross-sectional study was conducted on 450 individuals who were selected by systematic random sampling method. Antiepileptic drug nonadherence was measured by Morisky Medication Adherence Scale (MMAS and logistic regression was used to look for significant associations. Result. The prevalence of AEDs nonadherence was 37.8%. Being on treatment for 6 years and above [AOR = 3.47, 95% CI: 1.88, 6.40], payment for AEDs [AOR = 2.76, 95% CI: 1.73, 4.42], lack of health information [AOR = 2.20, 95% CI: 1.41,3.43], poor social support [AOR = 1.88, 95%, CI: 1.01, 3.50], perceived stigma [AOR = 2.27, 95% CI: 1.45, 3.56], and experience side effect [AOR = 1.70, 95% CI: 1.06, 2.72] were significantly associated with antiepileptic drug nonadherence. Conclusion. More than one-third of people with epilepsy were not compliant with their AEDs. Giving health information about epilepsy and its management and consequent reduction in stigma will help for medication adherence.

  14. The Effects of Antiepileptic Drugs on Classroom Performance

    Science.gov (United States)

    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…

  15. Co-prescription of antiepileptic drugs and contraceptives

    NARCIS (Netherlands)

    Wang, H.; Bos, J.H.; de Jong-van den Berg, L.T.

    Background: Enzyme-inducing antiepileptic drugs (AEDs) reduce the efficacy of oral contraceptives. Little is known of contraceptive practice among reproductive-age women who receive AEDs. Study Design: We explored the use of contraceptive methods among Dutch women aged 15 to 49 years with

  16. Severe early onset osteopenia and osteoporosis caused by antiepileptic drugs.

    NARCIS (Netherlands)

    Beerhorst, K.; Huvers, F.C.; Renier, W.O.

    2005-01-01

    We describe two adult patients with epilepsy who received long-term antiepileptic drug therapy, a woman aged 39 years and a man aged 38 years, in whom severe osteopenia and osteoporosis, respectively, were diagnosed. Both had had epilepsy since childhood, both were seizure free and off medication

  17. Antiepileptic drugs and risk of suicide: a nationwide study

    DEFF Research Database (Denmark)

    Olesen, Jonas Bjerring; Hansen, Peter Riis; Erdal, Jesper

    2010-01-01

    Purpose Patients with epilepsy or psychiatric diseases have increased risk of suicide, but whether the risk is influenced by antiepileptic drug (AED) treatment is unclear. Studies have suggested that AEDs in general increase the risk of suicidal behaviour shortly after initiation. This study inve...

  18. Antiepileptic drugs in development pipeline: A recent update

    Directory of Open Access Journals (Sweden)

    Harjeet Kaur

    2016-09-01

    Full Text Available Epilepsy is the most common neurological disorder which significantly affects the quality of life and poses a health as well as economic burden on society. Epilepsy affects approximately 70 million people in the world. The present article reviews the scientific rationale, brief pathophysiology of epilepsy and newer antiepileptic drugs which are presently under clinical development. We have searched the investigational drugs using the key words ‘antiepileptic drugs,’ ‘epilepsy,’ ‘Phase I,’ ‘Phase II’ and ‘Phase III’ in American clinical trial registers (clinicaltrials.gov, the relevant published articles using National Library of Medicine's PubMed database, company websites and supplemented results with a manual search of cross-references and conference abstracts. This review provides a brief description about the antiepileptic drugs which are targeting different mechanisms and the clinical development status of these drugs. Besides the presence of old as well as new AEDs, still there is a need of new drugs or the modified version of old drugs in order to make affected people free of seizures. An optimistic approach should be used to translate the success of preclinical testing to clinical practice. There is an urgent need to improve animal models and to explore new targets with better understanding in order to develop the novel drugs with more efficacy and safety.

  19. Preventive Agents for Migraine: Focus on the Antiepileptic Drugs

    Directory of Open Access Journals (Sweden)

    R. Shahien

    2012-04-01

    Full Text Available Migraine is among the 10 most disabling disorders worldwide. It is characterized by episodes of moderate or severe headaches with various degree of disability, resulting in a considerable health burden upon the sufferers and their family. The objective of this article is to review the use of prophylaxis with antiepileptic drugs. Particular focus is given to their mechanism of action, metabolism, pharmacokinetics, safety profile, efficacy and to provide a summary of the most relevant clinical studies and patient preference.

  20. [Therapeutic drug monitoring of three antiepileptic drugs - Back on twenty years of experience].

    Science.gov (United States)

    Serragui, Samira; Zalagh, Fatima; Tanani, Driss Soussi; Ouammi, Lahcen; Moussa, Latifa Ait; Badrane, Narjis; Bencheikh, Rachida Soulaymani

    2016-01-01

    The therapeutic drug monitoring (TDM) of antiepileptic drugs is a tool widely used in the management of epilepsy. In Morocco, this monitoring is carried out by the Centre Anti Poison et Pharmacovigilance (CAPM) since April 1995. This is a retrospective study spanning 20 years. It concerns the therapeutic drug monitoring of Phenobarbital (PB) of carbamazepine (CBZ) and valproic acid (VPA). Therapeutic drug monitoring of the 3 antiepileptic drugs represent 58.85% of all applications received by the CAPM. The dosage of PB was ranked first followed by that of CBZ and finally by the VPA. Weak demand for therapeutic drug monitoring in Morocco could be explained by the low number of neurologists in addition to social factors. With its affordable price by patients, PB is the most prescribed antiepileptic drug in our country, which explains the high demand for its dosage. As for the therapeutic drug monitoring of the antiepileptic drug, they were mainly related to age, the occurrence of adverse effects, the association antiepileptic drugs or in the case of verification of patient compliance. Efforts are required for promoting the interests of therapeutic drug monitoring of antiepileptic drug in the management of epilepsy in Morocco.

  1. MRJP1-containing glycoproteins isolated from honey, a novel antibacterial drug candidate with broad spectrum activity against multi-drug resistant clinical isolates.

    Science.gov (United States)

    Brudzynski, Katrina; Sjaarda, Calvin; Lannigan, Robert

    2015-01-01

    The emergence of extended- spectrum β-lactamase (ESBL) is the underlying cause of growing antibiotic resistance among Gram-negative bacteria to β-lactam antibiotics. We recently reported the discovery of honey glycoproteins (glps) that exhibited a rapid, concentration-dependent antibacterial activity against both Gram-positive Bacillus subtilis and Gram-negative Escherichia coli that resembled action of cell wall-active β-lactam drugs. Glps showed sequence identity with the Major Royal Jelly Protein 1 (MRJP1) precursor that harbors three antimicrobial peptides: Jelleins 1, 2, and 4. Here, we used semi-quantitative radial diffusion assay and broth microdilution assay to evaluate susceptibility of a number of multi-drug resistant (MDR) clinical isolates to the MRJP1-contaning honey glycoproteins. The MDR bacterial strains comprised three methicillin-resistant Staphylococcus aureus (MRSA), four Pseudomonas aeruginosa, two Klebsiella pneumoniae, two vancomycin-resistant Enterococci (VRE), and five ESBL identified as one Proteus mirabilis, three E. coli, and one E. coli NDM. Their resistance to different classes of antibiotics was confirmed using automated system Vitek 2. MDR isolates differed in their susceptibility to glps with MIC90 values ranging from 4.8 μg/ml against B. subtilis to 14.4 μg/ml against ESBL K. pneumoniae, Klebsiella spp. ESBL and E. coli and up to 33 μg/ml against highly resistant strains of P. aeruginosa. Glps isolated from different honeys showed a similar ability to overcome bacterial resistance to β-lactams suggesting that (a) their mode of action is distinct from other classes of β-lactams and that (b) the common glps structure was the lead structure responsible for the activity. The results of the current study together with our previous evidence of a rapid bactericidal activity of glps demonstrate that glps possess suitable characteristics to be considered a novel antibacterial drug candidate.

  2. MRJP1-containing glycoproteins isolated from honey, a novel antibacterial drug candidate with broad spectrum activity against multi-drug resistant clinical isolates

    Directory of Open Access Journals (Sweden)

    Katrina eBrudzynski

    2015-07-01

    Full Text Available The emergence of extended- spectrum β-lactamase (ESBL is the underlying cause of growing antibiotic resistance among Gram-negative bacteria to β-lactam antibiotics. We recently reported the discovery of honey glycoproteins (glps that exhibited a rapid, concentration-dependent antibacterial activity against both Gram-positive Bacillus subtilis and Gram-negative Escherichia coli that resembled action of cell wall-active β-lactam drugs. Glps showed sequence identity with the Major Royal Jelly Protein 1 (MRJP1 precursor that harbors three antimicrobial peptides: Jelleins 1, 2 and 4. Here, we used semi-quantitative radial diffusion assay and broth microdilution assay to evaluate susceptibility of a number of multi-drug resistant (MDR clinical isolates to the MRJP1-contaning honey glycoproteins. The MDR bacterial strains comprised 3 MRSA, 4 Pseudomonas aeruginosa, 2 Klebsiella pneumoniae, 2 VRE and 5 Extended-spectrum beta-lactamase (ESBL identified as 1 Proteus mirabilis, 3 Escherichia coli and 1 Escherichia coli NDM. Their resistance to different classes of antibiotics was confirmed using automated system Vitek 2. MDR isolates differred in their susceptibility to glps with MIC90 values ranging from 4.8μg/ml against B. subtilis to 14.4μg/ml against ESBL K. pneumoniae, Klebsiella spp ESBL and E. coli and up to 33μg/ml against highly resistant strains of P. aeruginosa. Glps isolated from different honeys showed a similar ability to overcome bacterial resistance to β-lactams suggesting that (a their mode of action is distinct from other classes of β-lactams and that (b the common glps structure was the lead structure responsible for the activity. The results of the current study together with our previous evidence of a rapid bactericidal activity of glps demonstrate that glps possess suitable characteristics to be considered a novel antibacterial drug candidate.

  3. Pharmacokinetic aspects of the anti-epileptic drug substance vigabatrin

    DEFF Research Database (Denmark)

    Nøhr, Martha Kampp; Frølund, Sidsel; Holm, René

    2014-01-01

    are discussed in detail. Special focus is on the contribution of the proton-coupled amino acid transporter 1 (PAT1) for intestinal vigabatrin absorption. Furthermore, the review gives an overview of the pharmacokinetic parameters of vigabatrin across different species and drug-food and drug-drug interactions......Drug transporters in various tissues, such as intestine, kidney, liver and brain, are recognized as important mediators of absorption, distribution, metabolism and excretion of drug substances. This review gives a current status on the transporter(s) mediating the absorption, distribution......, metabolism and excretion properties of the anti-epileptic drug substance vigabatrin. For orally administered drugs, like vigabatrin, the absorption from the intestine is a prerequisite for the bioavailability. Therefore, transporter(s) involved in the intestinal absorption of vigabatrin in vitro and in vivo...

  4. Cognitive functions, epileptic syndromes and antiepileptic drugs

    Directory of Open Access Journals (Sweden)

    Paulo R. M. Bittencourt

    1992-03-01

    Full Text Available Cognitive function of patients on monotherapy specific for their epileptic syndrome has been studied infrequently. We evaluated 7 patients with symptomatic localised epilepsies (SEL on phenytoin aged 30±12 (mean±standard deviation years, 8 with idiopathic generalised epilepsies on sodium valproate aged 18±4 years, 16 with SEL on carbamazepine aged 28±11 years, and 35 healthy controls aged 27±11 years. All subjects were of normal intelligence, educated appropriately to age, and led productive lives in the community. Two of the patients on carbamazepine and one on valproate had less than five partial, absence or myoclonic seizures monthly, the remaining were controlled. Carbamazepine serum concentrations were 12±5 ug/ml, phenytoin were 23±7, and valproate were 62±23 (mean±sd. Tests included immediate recall and recognition for pictures, Stroop test, delayed recall and recognition of pictures. Patients on phenytoin and valproate performed significantly worse than controls on immediate recall, and patients on carbamazepine performed significantly worse than controls in Stroop test (p<0,01. The results indicate relatively minor effects of the epileptic syndromes and of phenytoin, carbamazepine and valproate on cognition of patients with controlled epilepsy leading productive lives in the community. We conclude that the cognitive deficit found in chronic epileptic patients on polytherapeutic drug regimen must be multifactorial, and that future studies need to control for all possible variables in order to achieve meaningul results.

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

    Science.gov (United States)

    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

  6. Antiepileptic drugs targeting sodium channels: subunit and neuron-type specific interactions

    NARCIS (Netherlands)

    Qiao, X.

    2013-01-01

    Certain antiepileptic drugs (e.g. carbamazepine and lamotrigine) block sodium channels in an use-dependent manner and this mechanism contributes to the anti-convulsant properties of these drugs. There are, however, subtle differences in sodium current blocking properties of the antiepileptic drugs

  7. Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity

    Energy Technology Data Exchange (ETDEWEB)

    Hargrove, Tatiana Y.; Garvey, Edward P.; Hoekstra, William J.; Yates, Christopher M.; Wawrzak, Zdzislaw; Rachakonda, Girish; Villalta, Fernando; Lepesheva, Galina I.

    2017-05-01

    ABSTRACT

    Within the past few decades, the incidence and complexity of human fungal infections have increased, and therefore, the need for safer and more efficient, broad-spectrum antifungal agents is high. In the study described here, we characterized the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14α-demethylase (CYP51B) from the filamentous fungusAspergillus fumigatus. VT-1598 displayed a high affinity of binding to the enzyme in solution (dissociation constant, 13 ± 1 nM) and in the reconstituted enzymatic reaction was revealed to have an inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/A. fumigatusCYP51 complex was determined and depicts the distinctive binding mode of the inhibitor in the enzyme active site, suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His374, the CYP51 residue that is highly conserved across fungal pathogens and fungus specific. Comparative structural analysis ofA. fumigatusCYP51/voriconazole andCandida albicansCYP51/VT-1161 complexes supports the role of H bonding in fungal CYP51/inhibitor complexes and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using twoA. fumigatusstrains (strains 32820 and 1022) displayed a direct

  8. Development of a Broad-Spectrum Antiviral Agent with Activity ...

    African Journals Online (AJOL)

    Development of a Broad-Spectrum Antiviral Agent with. Activity Against Herpesvirus Replication .... deviation. The data were analyzed by SPSS software, version 16. Significant differences (p <. 0.01) between groups were determined using unpaired Student's t-test. RESULTS. Cytotoxic and optimum drug concentrations.

  9. Interchangeability of generic anti-epileptic drugs: a quantitative analysis of topiramate and gabapentin.

    NARCIS (Netherlands)

    Maliepaard, M.; Banishki, N.; Gispen-de Wied, C.C.; Teerenstra, S.; Elferink, A.J.

    2011-01-01

    PURPOSE: The objective of this study was to determine whether the so-called "shift" or "drift" problem might occur when generic anti-epileptic drugs are interchanged, and thus to assess if generic anti-epileptic drugs are interchangeable and can be used in an efficacious and safe way on the basis of

  10. Teratogenic effects of antiepileptic drugs : Use of an international database on malformations and drug exposure (MADRE)

    NARCIS (Netherlands)

    Arpino, C; Brescianini, S; Robert, E; Castilla, EE; Cocchi, G; Cornel, MC; de Vigan, C; Lancaster, PAL; Merlob, P; Sumiyoshi, Y; Zampino, G; Renzi, C; Resano, A; Mastroiacovo, P

    2000-01-01

    Purpose: The study goal was to assess teratogenic effects of antiepileptic drugs (AEDs) through the use of a surveillance system (MADRE) of infants with malformations. Methods: Information on all malformed infants (1990-1996) with maternal first-trimester drug exposure was collected by the

  11. [Epicutaneous patch testing in delayed drug hypersensitivity reactions induced by antiepileptic drugs].

    Science.gov (United States)

    Ben Mahmoud, Lobna; Bahloul, Najla; Ghozzi, Hanen; Kammoun, Brahim; Hakim, Ahmed; Sahnoun, Zouheir; Kammoun, Sami; Zeghal, Khaled

    2017-10-01

    Antiepileptic drugs are widely used and are associated with numerous side effects including skin eruptions. Epicutaneous tests have been used with variable success in skin drug reactions. The purpose of this study was to evaluate the profitability of epicutaneous tests in delayed hypersensitivity reactions induced by antiepileptic drugs. We analyzed all cases of allergic skin reactions to antiepileptic drugs notified in regional pharmacovigilance center of Sfax (Tunisia) between June 1, 2014 and April 30, 2016. The imputation score, determined using the French imputation method, should be at least doubtful. Patch-tests were performed in accordance with the general Europen network on Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) guidelines. Patch-tests were read according to the generally accepted criteria of the International contact dermatitis research group (ICDRG). In our study, 20 patients were included, among which 23 events were observed. The drug involved in delayed hypersensitivity reactions was carbamazepine in 11 cases, phenobarbital in 10 cases and valproic acid in 4 cases. The clinical reactions caused by the drug were classified as maculopapular exanthema (11 cases), DRESS syndrome (6 cases), Stevens-Johnson syndrome (2 cases), fixed drug eruption (2 cases) and erythroderma (2 cases). Patch-tests were positive in 19 patients (95 %). Cross-reactivity between antiepileptic drugs was observed in 4 cases: between valproic acid and carbamazepine in 2 cases between valproic acid and phenobarbital in 1 case and between phenobarbital and carbamazepine in 1 case. In this study, patch testing was a safe and useful method in confirming the culprit drug in delayed hypersensitivity reactions induced by antiepileptic drugs. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  12. Evaluation of Carbohydrate-Derived Fulvic Acid (CHD-FA) as a Topical Broad-Spectrum Antimicrobial for Drug-Resistant Wound Infections

    Science.gov (United States)

    2015-10-01

    from day 3 in the 6-day study. The biofilm matrix formed on day 3 post-inoculation may be restricting the penetration of the drug. During the next...burn wound eschar and the biofilm matrix. Overall, we have made significant progress in the third year in demonstrating the value of CHD-FA to treat...wiped with betadine. Two symmetrical burn wounds were created on the dorsum of each rat using a heated 1 cm cylinder steel block for 10 seconds

  13. Prediction of antiepileptic drug treatment outcomes using machine learning.

    Science.gov (United States)

    Colic, Sinisa; Wither, Robert G; Lang, Min; Zhang, Liang; Eubanks, James H; Bardakjian, Berj L

    2017-02-01

    Antiepileptic drug (AED) treatments produce inconsistent outcomes, often necessitating patients to go through several drug trials until a successful treatment can be found. This study proposes the use of machine learning techniques to predict epilepsy treatment outcomes of commonly used AEDs. Machine learning algorithms were trained and evaluated using features obtained from intracranial electroencephalogram (iEEG) recordings of the epileptiform discharges observed in Mecp2-deficient mouse model of the Rett Syndrome. Previous work have linked the presence of cross-frequency coupling (I CFC) of the delta (2-5 Hz) rhythm with the fast ripple (400-600 Hz) rhythm in epileptiform discharges. Using the I CFC to label post-treatment outcomes we compared support vector machines (SVMs) and random forest (RF) machine learning classifiers for providing likelihood scores of successful treatment outcomes. (a) There was heterogeneity in AED treatment outcomes, (b) machine learning techniques could be used to rank the efficacy of AEDs by estimating likelihood scores for successful treatment outcome, (c) I CFC features yielded the most effective a priori identification of appropriate AED treatment, and (d) both classifiers performed comparably. Machine learning approaches yielded predictions of successful drug treatment outcomes which in turn could reduce the burdens of drug trials and lead to substantial improvements in patient quality of life.

  14. Evaluation of patch test in identification of causative agent in drug rashes due to antiepileptics

    Directory of Open Access Journals (Sweden)

    Vatve Maneesha

    2000-01-01

    Full Text Available Patch test was evaluated for the identification of causative agent in cutaneous eruptions due to antiepileptics. Patch tests were carried out in twenty patients and ten controls with carbamazepine, phenytoin sodium, phenobarbitone and sodium valproate. Sodium valproate was found tobe irritant in 1 and 5% concentration and further dilution is recommended for patch testing. Patch test was positive in 14 (70% patients and in 7 with suspected drug alone, and remaining 7 were positive with more than one antiepileptic drug. We recommended patch test for identification of causative drug in rashes due to antiepileptics.

  15. Modified Atkins diet may reduce serum concentrations of antiepileptic drugs.

    Science.gov (United States)

    Kverneland, M; Taubøll, E; Selmer, K K; Iversen, P O; Nakken, K O

    2015-03-01

    Modified Atkins diet is a treatment option for patients with pharmacoresistant epilepsy that is not suitable for surgery. In the last few years, we have tried dietary treatment added to antiepileptic drugs (AEDs) in adult patients with severe epilepsy. To examine a possible pharmacokinetic interaction between the modified Atkins diet and AEDs. In four patients, AED serum concentrations were measured before onset and after 4 and 12 weeks on the diet. The patients used combinations of two or three AEDs, including carbamazepine, clobazam, lamotrigine, nitrazepam, oxcarbazepine, valproate, zonisamide, and topiramate. The patients did not change the type or dose of their AEDs during the diet period. After 12 weeks on the diet, the average serum concentrations of the respective AEDs were reduced by 35% (range 6-46%) compared to prediet values. Modified Atkins diet used as add-on therapy to AEDs in four patients with drug resistant seizures caused a considerable decrease in AED serum concentrations. In individual patients, this could be of clinical relevance, and we recommend that AED serum concentrations should be closely monitored when offering this diet to adults with epilepsy. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Chronotolerance study of the antiepileptic drug valproic acid in mice

    Directory of Open Access Journals (Sweden)

    Ben-Cherif Wafa

    2012-05-01

    Full Text Available Abstract Background Valproic acid (VPA is an antiepileptic drug widely used for the treatment of absence seizures and generalized tonic-clonic seizures. The present work aims to study whether VPA-induced toxicity varies according to the dosing-time in the 24 hour-scale. Methods The influence of dosing-time on tolerance to VPA was investigated in 120 male Swiss mice synchronized under a light-dark cycle (12:12. The mean VPA lethal dose was first determined to be 850 ± 0.2 mg/kg, i.p.. Such a dose was administered by i.p. route to a total of 90 mice divided in six circadian stages [1, 5, 9, 13, 17 and 21 Hours After Light Onset (HALO] (15 mice/circadian time; 30 mice were used as control (5 mice / circadian time. Results The surviving treated mice exhibited a significant circadian variation in rectal temperature and body weight loss (p 2 = 42.1, p  Conclusions With regards to these data the optimal tolerance to VPA occurred when the drug was administered in the second half of the light-rest span of mice which is physiologically analogous to the second half of the night for human patients.

  17. Broad spectrum antiangiogenic treatment for ocular neovascular diseases.

    Directory of Open Access Journals (Sweden)

    Ofra Benny

    2010-09-01

    Full Text Available Pathological neovascularization is a hallmark of late stage neovascular (wet age-related macular degeneration (AMD and the leading cause of blindness in people over the age of 50 in the western world. The treatments focus on suppression of choroidal neovascularization (CNV, while current approved therapies are limited to inhibiting vascular endothelial growth factor (VEGF exclusively. However, this treatment does not address the underlying cause of AMD, and the loss of VEGF's neuroprotective can be a potential side effect. Therapy which targets the key processes in AMD, the pathological neovascularization, vessel leakage and inflammation could bring a major shift in the approach to disease treatment and prevention. In this study we have demonstrated the efficacy of such broad spectrum antiangiogenic therapy on mouse model of AMD.Lodamin, a polymeric formulation of TNP-470, is a potent broad-spectrum antiangiogenic drug. Lodamin significantly reduced key processes involved in AMD progression as demonstrated in mice and rats. Its suppressive effects on angiogenesis, vascular leakage and inflammation were studied in a wide array of assays including; a Matrigel, delayed-type hypersensitivity (DTH, Miles assay, laser-induced CNV and corneal micropocket assay. Lodamin significantly suppressed the secretion of various pro-inflammatory cytokines in the CNV lesion including monocyte chemotactic protein-1 (MCP-1/Ccl2. Importantly, Lodamin was found to regress established CNV lesions, unlike soluble fms-like tyrosine kinase-1 (sFlk-1. The drug was found to be safe in mice and have little toxicity as demonstrated by electroretinography (ERG assessing retinal and by histology.Lodamin, a polymer formulation of TNP-470, was identified as a first in its class, broad-spectrum antiangiogenic drug that can be administered orally or locally to treat corneal and retinal neovascularization. Several unique properties make Lodamin especially beneficial for ophthalmic

  18. Various pharmacogenetic aspects of antiepileptic drug therapy: a review.

    Science.gov (United States)

    Mann, Michael W; Pons, Gerard

    2007-01-01

    Pharmacogenetics concerns the influence of an individual's genetic background on the pharmacokinetics and pharmacodynamics of xenobiotics. Much of the pharmacogenetic data in the field of epilepsy deals with the pharmacokinetics of antiepileptic drugs (AEDs). In particular, two polymorphisms of cytochrome P450 2C9 are known to slow down the metabolism of phenytoin to a degree that increases the risk of the neurotoxic adverse effects of this drug among carriers of these polymorphisms. A significant number of patients with epilepsy do not respond to AEDs and such pharmacoresistance is a major, largely unsolved, problem that is likely to be multifactorial in nature. In this regard, genetic factors may influence transmembrane drug transporter proteins, thereby modifying the intracerebral penetration of AEDs. Monogenic idiopathic epilepsies are rare and frequently associated with ion channel mutations; however, to date, a consistent relationship between changes in channel properties and clinical phenotype has not been established nor has any association between genotype and response to specific treatment options. Polymorphisms of drug targets may represent another genetic facet in epilepsy: a recent study demonstrated for the first time a polymorphism of a drug target (the alpha-subunit of a voltage-gated sodium channel) associated in clinical practice with differing response to two classic AEDs. Adverse drug reactions and teratogenicity of AEDs remain a major concern. Whole-genome single nucleotide polymorphism profiling might in the future help to determine genetic predisposing factors for adverse drug reactions. Recently, in Han Chinese treated with carbamazepine and presenting with Stevens-Johnson syndrome, a strong association was found with HLA B*1502. If genetically targeted drug development becomes more affordable/cost efficient in the near future, the development of new drugs for relatively rare diseases could become economically viable for the pharmaceutical

  19. Polycystic ovary syndrome in patients on antiepileptic drugs

    Directory of Open Access Journals (Sweden)

    Lakshminarayanapuram G Viswanathan

    2016-01-01

    Full Text Available 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 naοve 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.

  20. Severe cutaneous adverse reactions to antiepileptic drugs in Asians.

    Science.gov (United States)

    Yang, C-Y; Dao, R-L; Lee, T-J; Lu, C-W; Yang, C-H; Hung, S-I; Chung, W-H

    2011-12-06

    Ethnicity has been shown to be a contributing risk factor regarding antiepileptic drug (AED)-induced severe cutaneous adverse drug reactions (SCARs). To increase the clinical and epidemiologic information in Asians, we investigated the characteristics, outcome, and tolerability toward alternative drugs for AED-induced SCARs. A total of 154 patients with AED-induced SCARs, including Stevens-Johnson syndrome (SJS), toxic epidermal necrosis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), were analyzed for demographic characteristics, causative AEDs, latent period, organ involvement, complications, and mortality. Tolerability toward alternative AEDs was followed for patients after AED-SCARs episodes. Carbamazepine (CBZ) and phenytoin (PHT) were the most common causative AEDs for SJS/TEN (67.8%) and DRESS (43.6%), respectively. No SCARs case was caused by nonaromatic AEDs, e.g., valproic acid (VPA) and topiramate (TPM). The liver was the most frequently involved internal organ in AED-DRESS, whereas ocular complications were more commonly seen in AED-SJS/TEN. The mortality of AED-SJS/TEN and -DRESS was 6.1% and 7.7%, respectively. By following alternative AED usage of patients after AED-SCARs episodes, we noted that most patients were tolerant of nonaromatic AEDs. One case of oxcarbazepine-SJS had cross-hypersensitivity to lamotrigine (LTG) and further developed into DRESS. CBZ, PHT, and LTG were the major causative AEDs for SCARs. The mortality of PHT-SCARs was higher than CBZ-SCARs due to complicated comorbidity in patients. Nonaromatic AEDs were safe alternatives for patients with aromatic AED-induced SCARs.

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Abd Arwa Y

    2010-12-01

    Full Text Available Abstract 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

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

    Science.gov (United States)

    Salih, Muhannad R M; Bahari, Mohd Baidi; Abd, Arwa Y

    2010-12-31

    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. 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. 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. 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 imperative in certain clinical situations

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

    Science.gov (United States)

    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

  5. Placental passage of antiepileptic drugs at delivery and neonatal outcomes.

    Science.gov (United States)

    Bank, Anna M; Stowe, Zachary N; Newport, D Jeffrey; Ritchie, James C; Pennell, Page B

    2017-05-01

    Children of women treated with antiepileptic drugs (AEDs) are at increased risk of adverse outcomes detectable in the neonatal period, which may be associated with the amount of AEDs in the fetal circulation. Placental passage of AEDs can be measured by calculating the ratio of umbilical cord to maternal AED concentrations collected at delivery. The aims of this study were to determine the umbilical cord concentrations and umbilical-to-maternal ratios for AEDs, and whether higher cord concentrations are associated with increased risk of neonatal complications. AED cord and maternal blood concentrations from 70 mother-newborn dyads and neonatal complications were recorded. Logistic regressions were performed to determine the association between AED concentrations and complications. Mean umbilical-to-maternal ratios for total concentrations ranged from 0.79 for carbamazepine to 1.20 for valproic acid, and mean umbilical-to-maternal ratios for free concentrations ranged from 0.86 for valproic acid to 1.42 for carbamazepine, indicating complete placental passage. Neither umbilical cord concentrations nor umbilical-to-maternal ratios were associated with adverse neonatal outcomes. Additional investigations are warranted to delineate the relationship between quantified fetal AED exposure and neonatal complications. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

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

    OpenAIRE

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

    2016-01-01

    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.

  7. Prevalence, type of epilepsy and use of antiepileptic drugs in primary care

    National Research Council Canada - National Science Library

    Fernández-Suárez, Elena; Villa-Estébanez, Rubén; Garcia-Martinez, Alberto; Fidalgo-González, José A; Zanabili Al-Sibbai, Ahmad A; Salas-Puig, Javier

    2015-01-01

    .... To identify patients with a diagnosis of epilepsy in a primary care center and determine the prevalence, demographic characteristics, type of epileptic syndrome and the use of antiepileptic drugs...

  8. Effect of Antiepileptic Drugs for Acute and Chronic Seizures in Children with Encephalitis.

    Directory of Open Access Journals (Sweden)

    Kuang-Lin Lin

    Full Text Available Encephalitis presents with seizures in the acute phase and increases the risk of late unprovoked seizures and epilepsy. This study aimed to evaluate the effect of antiepileptic drugs in pediatric patients with acute seizures due to encephalitis and epilepsy.Cases of acute pediatric encephalitis between January 2000 and December 2010 were reviewed. Clinical data, including onset at age, seizure type, seizure frequency, effects of antiepileptic drugs, and prognosis were analyzed.During the study period, 1038 patients (450 girls, 588 boys were enrolled. Among them, 44.6% (463 had seizures in the acute phase, 33% had status epilepticus, and 26% (251 developed postencephalitic epilepsy. At one year of follow-up, 205 of the 251 patients with postencephalitic epilepsy were receiving antiepileptic drugs while 18% were seizure free even after discontinuing the antiepileptic drugs. Among those with postencephalitic epilepsy, 67% had favorable outcomes and were using <2 anti-epileptic drugs while 15% had intractable seizures and were using ≥ 2 antiepileptic drugs. After benzodiazepines, intravenous phenobarbital was preferred over phenytoin as treatment of postencephalitic seizures in the acute phase. For refractory status epilepticus, high-dose topiramate combined with intravenous high-dose phenobarbital or high-dose lidocaine had less side effects.Children with encephalitis have a high rate of postencephalitic epilepsy. Phenobarbital and clonazepam are the most common drugs used, alone or in combination, for postencephalitic epilepsy.

  9. EEG Monitoring and Antiepileptic Drugs in Children with Severe TBI.

    Science.gov (United States)

    Ruzas, Christopher M; DeWitt, Peter E; Bennett, Kimberly S; Chapman, Kevin E; Harlaar, Nicole; Bennett, Tellen D

    2017-04-01

    Traumatic brain injury (TBI) causes substantial morbidity and mortality in US children. Post-traumatic seizures (PTS) occur in 11-42% of children with severe TBI and are associated with unfavorable outcome. Electroencephalographic (EEG) monitoring may be used to detect PTS and antiepileptic drugs (AEDs) may be used to treat PTS, but national rates of EEG and AED use are not known. The purpose of this study was to describe the frequency and timing of EEG and AED use in children hospitalized after severe TBI. Retrospective cohort study of 2165 children at 30 hospitals in a probabilistically linked dataset from the National Trauma Data Bank (NTDB) and the Pediatric Health Information Systems (PHIS) database, 2007-2010. We included children (age 24 h, and non-missing disposition. The primary outcomes were EEG and AED use. Overall, 31.8% of the cohort had EEG monitoring. Of those, 21.8% were monitored on the first hospital day. The median duration of EEG monitoring was 2.0 (IQR 1.0, 4.0) days. AEDs were prescribed to 52.0% of the cohort, of whom 61.8% received an AED on the first hospital day. The median duration of AED use was 8.0 (IQR 4.0, 17.0) days. EEG monitoring and AED use were more frequent in children with known risk factors for PTS. EEG monitoring and AED use were not related to hospital TBI volume. EEG use is relatively uncommon in children with severe TBI, but AEDs are frequently prescribed. EEG monitoring and AED use are more common in children with known risk factors for PTS.

  10. Broad spectrum antibiotic compounds and use thereof

    Energy Technology Data Exchange (ETDEWEB)

    Koglin, Alexander; Strieker, Matthias

    2016-07-05

    The discovery of a non-ribosomal peptide synthetase (NRPS) gene cluster in the genome of Clostridium thermocellum that produces a secondary metabolite that is assembled outside of the host membrane is described. Also described is the identification of homologous NRPS gene clusters from several additional microorganisms. The secondary metabolites produced by the NRPS gene clusters exhibit broad spectrum antibiotic activity. Thus, antibiotic compounds produced by the NRPS gene clusters, and analogs thereof, their use for inhibiting bacterial growth, and methods of making the antibiotic compounds are described.

  11. Neuropsychological effects of antiepileptic drugs (carbamazepine versus valproate) in adult males with epilepsy

    OpenAIRE

    Ghaydaa A Shehata; Abd El-aziz M Bateh; Sherifa A Hamed; et al

    2009-01-01

    Ghaydaa A Shehata,1 Abd El-aziz M Bateh,2 Sherifa A Hamed,1 Tarek A Rageh,1 Yaser B Elsorogy11Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University, Egypt; 2Department of Psychology, Faculty of Arts, Banha University, EgyptPurpose: To evaluate the effect of antiepileptic drugs (AEDs) on cognition and behavior in adult epileptic males controlled on treatment with conventional antiepileptic medications. Methods: Cognitive, mood, behavior and personality traits were asse...

  12. Current status of the New Antiepileptic drugs in chronic pain.

    Directory of Open Access Journals (Sweden)

    Harpreet Singh Sidhu

    2016-08-01

    Full Text Available 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

  13. Effect of Antiepileptic Drugs for Acute and Chronic Seizures in Children with Encephalitis

    Science.gov (United States)

    Lin, Kuang-Lin; Lin, Jainn-Jim; Hsia, Shao-Hsuan; Chou, Min-Liang; Hung, Po-Cheng; Wang, Huei-Shyong

    2015-01-01

    Background Encephalitis presents with seizures in the acute phase and increases the risk of late unprovoked seizures and epilepsy. This study aimed to evaluate the effect of antiepileptic drugs in pediatric patients with acute seizures due to encephalitis and epilepsy. Patients and Methods Cases of acute pediatric encephalitis between January 2000 and December 2010 were reviewed. Clinical data, including onset at age, seizure type, seizure frequency, effects of antiepileptic drugs, and prognosis were analyzed. Results During the study period, 1038 patients (450 girls, 588 boys) were enrolled. Among them, 44.6% (463) had seizures in the acute phase, 33% had status epilepticus, and 26% (251) developed postencephalitic epilepsy. At one year of follow-up, 205 of the 251 patients with postencephalitic epilepsy were receiving antiepileptic drugs while 18% were seizure free even after discontinuing the antiepileptic drugs. Among those with postencephalitic epilepsy, 67% had favorable outcomes and were using seizures and were using ≥ 2 antiepileptic drugs. After benzodiazepines, intravenous phenobarbital was preferred over phenytoin as treatment of postencephalitic seizures in the acute phase. For refractory status epilepticus, high-dose topiramate combined with intravenous high-dose phenobarbital or high-dose lidocaine had less side effects. Conclusions Children with encephalitis have a high rate of postencephalitic epilepsy. Phenobarbital and clonazepam are the most common drugs used, alone or in combination, for postencephalitic epilepsy. PMID:26444013

  14. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study

    OpenAIRE

    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

    2013-01-01

    Background: Many women of childbearing potential take antiepileptic drugs, but the cognitive effects of fetal exposure are uncertain. We aimed to assess effects of commonly used antiepileptic drugs on cognitive outcomes in children up to 6 years of age. Methods: In this prospective, observational, assessor-masked, multicentre study, we enrolled pregnant women with epilepsy on antiepileptic drug monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and Februa...

  15. Antiepileptic drugs for seizure control in people with neurocysticercosis.

    Science.gov (United States)

    Sharma, Monika; Singh, Tejinder; Mathew, Amrith

    2015-10-12

    Neurocysticercosis is the most common parasitic infection of the brain. Epilepsy is the commonest clinical presentation, though it may also present with headache, symptoms of raised intracranial tension, hydrocephalus and ocular symptoms depending upon the localisation of the parasitic cysts. Anthelmintic drugs, anti-oedema drugs, such as steroids and antiepileptic drugs (AEDs) form the mainstay of treatment. To assess the effects (benefits and harms) of AEDs for the primary and secondary prevention of seizures in people with neurocysticercosis. We searched the Cochrane Epilepsy Group Specialized Register (5 May 2015), The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library April 2015, Issue 4), MEDLINE (1946 to 5 May 2015), LILACS (Latin American and Caribbean Literature in Health Sciences, 5 May 2015), SCOPUS (1823 to 15 April 2014), ClinicalTrials.gov (7 May 2015), and the WHO International Clinical Trials Registry Platform ICTRP (7 May 2015). We also checked the references lists of identified studies, and contacted experts in the field and colleagues to search for additional studies and for information about ongoing studies. Randomised and quasi-randomised controlled trials.The studies may be single blind, double blind or unblinded. One review author screened all citations for eligibility.Two review authors independently extracted data and evaluated each study for risk of bias. We did not find any trials that investigated the role of AEDs in preventing seizures among people with neurocysticercosis, presenting with symptoms other than seizures.We did not find any trials that evaluated evaluating individual AEDs in people with neurocysticercosis.We found one trial, comparing two AEDs in people with solitary neurocysticercosis with seizures. However, we excluded this study from the review as it was of poor quality.We found four trials that compared the efficacy of short term versus longer term AED treatment for people with solitary

  16. Interactions between cannabidiol and commonly used antiepileptic drugs.

    Science.gov (United States)

    Gaston, Tyler E; Bebin, E Martina; Cutter, Gary R; Liu, Yuliang; Szaflarski, Jerzy P

    2017-09-01

    To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs. In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate. Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01). Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the

  17. The impact of different antiepileptic drugs on the sedation of children during magnetic resonance imaging

    Directory of Open Access Journals (Sweden)

    Isil Davarci

    2014-10-01

    Full Text Available Background and objectives:The induction and inhibition of cytochrome P450 isoenzymes by antiepileptic drugs lead to changes in the clearance of anesthetic drugs eliminated via hepatic metabolism. We investigated the duration of the sedation and additional anesthetic needs during magnetic resonance imaging in epileptic children receiving antiepileptic drugs that cause either enzyme induction or inhibition.Methods:In American Society of Anesthesiology I–II, 120 children aged 3–10 years were included. Group 1: children using antiepileptic drugs that cause cytochrome P450 enzyme induction; Group 2: those using antiepileptic drugs that cause inhibition; and Group 3: those that did not use antiepileptic drugs. Sedation was induced with the use of 0.05 mg kg−1 midazolam and 1 mg kg−1 propofol. An additional 0.05 mg kg−1 of midazolam and rescue propofol (0.5 mg kg−1 were administered and repeated to maintain sedation. The duration of sedation and the additional sedation needed were compared.Results:The duration of the initial dose was significantly shorter in Group I compared with groups II and III (p = 0.001, p = 0.003, respectively. It was significantly longer in Group II compared with groups I and III (p = 0.001, p = 0.029, respectively. The additional midazolam needed for adequate sedation was increased in Group I when compared with groups II and III (p = 0.010, p = 0.001, respectively. In addition, the rescue propofol dose was significantly higher only in Group I when compared with Group III (p = 0.002.Conclusion:In epileptic children, the response variability to the initial sedative agents during the magnetic resonance imaging procedure resulting from the inhibition or induction of the cytochrome P450 isoenzymes by the antiepileptic drugs mandated the titration of anesthetic agents.

  18. Cutaneous drug reactions to antiepileptic drugs and relation with HLA alleles in the Turkish population.

    Science.gov (United States)

    Büyüköztürk, S; Kekik, Ç; Gökyiğit, A Z; Tezer Filik, F I; Karakaya, G; Saygi, S; Dursun, A B; Kirbaş, S; Tüfekçi, A; Sin, A Z; Aydoğdu, I; Sorgun, M H; Aydin, N; Gelincik, A; Çolakoğlu, B; Çelik, G; Oğuz, F

    2018-01-01

    Background and objective. Many studies have shown associations between HLAB*15:02, HLA-A*31:01 and carbamazepine (CBZ)-induced delayed cutaneous hypersensitivity reactions. The aim of this study is to evaluate a possible association between delayed cutaneous reactions to antiepileptic drugs (AEDs) and certain HLA-A and HLA-B alleles in the Turkish population. Methods. The study consisted of 3 groups: Group I (reactive group) included the patients who had documented delayed cutaneous reactions to any antiepileptic drug. Group II (non-reactive group) included the patients who have been on antiepileptic treatment at least for three months without any adverse reactions. Group III consisted of healthy subjects. The HLA-A and B alleles were analyzed in all groups. Results. Forty patients (29 female) had experienced different hypersensitivity reactions due to AEDs: maculopapular exanthema (26 patients), Stevens-Johnson syndrome (6 patients), drug rash with eosinophilia and systemic symptoms (7 patients), toxic epidermal necrolysis (1 patient). Lamotrigine (11) and CBZ (10) were the most common culprit drugs involved in the reactions. The HLA-B*15:02 was not present in any of the study groups. However, HLA-B*35:02 was found in 4 patients from the reactive group, while it was not observed in non-reactive patients and was detected in only one healthy subject (p = 0.021). Conclusion. Although our preliminary results did not indicate a strong allele association with AED hypersensitivity, HLA-B*35:02 appears to be a candidate allele for MPE / DRESS / DIHSS induced by AED's in Turkish population. Further studies with a larger sample size may result in more comprehensive data about the genetic tendency for AED hypersensitivity in the Turkish population.

  19. Selection criteria for the clinical use of the newer antiepileptic drugs.

    NARCIS (Netherlands)

    Deckers, C.L.P.; Knoester, P.D.; Haan, G.J. de; Keyser, A.J.M.; Renier, W.O.; Hekster, Y.A.

    2003-01-01

    In recent years, several new antiepileptic drugs (AEDs) have been licensed: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide. These drugs have proven efficacy as add-on therapy in patients with difficult-to-treat partial epilepsy, as

  20. MAJOR PRINCIPLES OF EPILEPSY TREATMENT. ALGORITHM OF SELECTION OF ANTIEPILEPTIC DRUGS

    Directory of Open Access Journals (Sweden)

    K. Yu. Mukhin

    2014-01-01

    Full Text Available The authors reviewed general principles of epilepsy treatment in details as well as provided their proprietary algorithm of selection of antiepileptic drugs developed Svt. Luka's Institute of Child Neurology and Epilepsy. This algorithm is designed for general practitioners that deal with treatment of epilepsy. In the course of selection of the first antiepileptic drug, the doctor must take into consideration the age of the patient, assess their level of development, clinical manifestations of seizures, data of electroencephalography and magnetic resonance imaging. The data received allows determination of the type of seizures, supposing of the syndrome-related diagnosis, and selection of the most appropriate antiepileptic drug of first choice in each specific case. There are also recommendations for further examination of patients and monitoring of efficacy of therapy.

  1. Do antiepileptic drugs play a role in sudden unexpected death in epilepsy?

    Science.gov (United States)

    Walczak, Thaddeus

    2003-01-01

    Sudden unexpected death in epilepsy (SUDEP) accounts for approximately 2% of deaths in population-based cohorts of epilepsy, and up to 25% of deaths in cohorts of more severe epilepsy. When it occurs, SUDEP usually follows a generalised tonic-clonic seizure. Unresponsiveness, apnoea, and cardiac arrest occur in SUDEP, rather than the typical gradual recovery. The great majority of tonic-clonic seizures occur without difficulty and how the rare seizure associated with SUDEP differs from others is unknown.Three mechanisms have been proposed for SUDEP: cardiac arrhythmia, neurogenic pulmonary oedema, and postictal suppression of brainstem respiratory centres leading to central apnoea. Recent studies have found that the incidence of SUDEP increases with the severity of epilepsy in the population studied. The duration of epilepsy, number of tonic-clonic seizures, mental retardation, and simultaneous treatment with more than two antiepileptic drugs are independent risk factors for SUDEP. Some studies have reported that carbamazepine use, carbamazepine toxicity, and frequent, rapid changes in carbamazepine levels, may be associated with SUDEP. Other evidence indicates that carbamazepine could potentially increase the risk for SUDEP by causing arrhythmia or by altering cardiac autonomic function. However, this evidence is tenuous and most studies have not found an association between the use of carbamazepine or any other individual antiepileptic drug and SUDEP. There is little information regarding antiepileptic drugs other than phenytoin and carbamazepine. The incidence of SUDEP with gabapentin, tiagabine, and lamotrigine clinical development programmes is in the range found in other populations with refractory epilepsy. This suggests that these individual antiepileptic drugs are no more likely to cause SUDEP than antiepileptic drugs in general. Best current evidence indicates that the risk of SUDEP can be decreased by aggressive treatment of tonic-clonic seizures with as

  2. Clinical and economic outcomes of pharmacist-managed antiepileptic drug therapy.

    Science.gov (United States)

    Bond, C A; Raehl, Cynthia L

    2006-10-01

    This study explores the associations between pharmacist-managed antiepileptic drug therapy in hospitalized Medicare patients and diagnoses indicating the need for these drugs. It also explores the following major heath care outcomes: death rate, hospital length of stay (LOS), Medicare charges, drug charges, laboratory charges, complications, and adverse drug reactions. Data were drawn from the 1998 MedPAR and 1998 National Clinical Pharmacy Services databases. Pharmacist-managed antiepileptic drug therapy was evaluated in a study population of 9380 Medicare patients with diagnosed epilepsy or seizure disorders treated in 794 United States hospitals. This population was derived from the 38,311 hospitalized Medicare patients with epilepsy or seizure disorders (MedPAR). In hospitals without pharmacist-managed antiepileptic drug therapy, death rates were 120.61% higher, with 374 excess deaths (chi(2)=5.983, df=1, p=0.014, odds ratio [OR]=1.553, 95% confidence interval [CI] 1.102-2.189). Hospital LOS was 14.68% higher, with 8069 patient-days (Mann-Whitney U test [U]=3833132, p=0.0009); total Medicare charges were 11.19% higher, with 14,372,550 dollars in excess total charges (U=3644199, p=0.0003); per-patient drug charges were $115 +/- $92 higher (p=NS); laboratory charges were 32.24% higher, with 5,664,970 dollars in excess charges; and aspiration pneumonia rate was 54.61% higher (chi(2)=5.848, df=1, p=0.015, OR=1.233, 95% CI 1.081-1.901). Although the frequencies of other complications and adverse effects were higher, these differences were not statistically significant compared with hospitals with pharmacist-managed antiepileptic drug therapy. Clinical and economic outcomes were improved among hospitalized Medicare patients whose antiepileptic drug therapy was managed by pharmacists.

  3. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry

    DEFF Research Database (Denmark)

    Tomson, Torbjörn; Battino, Dina; Bonizzoni, Erminio

    2011-01-01

    Prenatal exposure to antiepileptic drugs is associated with a greater risk of major congenital malformations, but there is inadequate information on the comparative teratogenicity of individual antiepileptic drugs and the association with dose. We aimed to establish the risks of major congenital ...

  4. Morphological Pattern of Cutaneous Adverse Drug Reactions due to Antiepileptic Drugs in Eastern India

    Science.gov (United States)

    Singh, Punit Kumar; Kumar, Dharmendra; Kumar, Prashant

    2015-01-01

    Introduction: Cutaneous manifestations of adverse drug reactions are a common occurrence and need to be differentiated from other causes of similar manifestations. Antiepileptic drugs (AED) usually are responsible for severe cutaneous adverse drug reactions (CADR) like Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophillia and systemic symptoms (DRESS). There is paucity of published research regarding morphological pattern of CADR due to various antiepileptic drugs AED. Objective: To study the morphological patterns of CADR due to AED and common anticonvulsant drugs implicated particularly in severe CADR such as SJS/TEN and DRESS in a tertiary care teaching hospital in eastern India. Materials and Methods: A prospective, observational study was conducted over a period of 4 years from August 2009 to July 2013 after the approval of the Institutional Ethics Committee using self-reporting method for selection of cases. Settings: All patients with CADR after AED consumption for various conditions presenting to the Dermatology outpatient department (OPD) and Pediatric OPD and Indoor patients of a tertiary care teaching hospital located in Rohtas district of Bihar were included in this study. Results: During the study period, 64 cases of severe CADRs were included in this study. Out of 64 patients, 28 were male and 36 were female with mean age 36.1 years (range 6 years to 72 years). Most common AED implicated for CADR was Phenytoin. Maculopapular rash was the most common cutaneous manifestation of ADRs (42.85%). Serious CADR like TEN and SSJS were more likely in patients prescribed Phenytoin and Carbemazepine simultaneously. Conclusion: CADRs are a common occurrence and awareness about the same is essential for diagnosis and prevention. This study identified combined use of phenytoin and carbamezepine as a most important risk factor for serious CADR like SJS and TEN. PMID:25738068

  5. COST ANALYSIS OF LONG ESTABLISHED AND NEWER ORAL ANTIEPILEPTIC DRUGS AVAILABLE IN THE INDIAN MARKET

    Directory of Open Access Journals (Sweden)

    Phatak Abhishek M, Hotwani Jitendra H, Deshmukhkiran R, Panchal Sagar S, Naik Madhura S

    2015-10-01

    Full Text Available Background: Large number of pharmaceutical companies manufactures antiepileptic drugs in India. The price variations among the marketed drugs are wide. Aims: The present study was aimed to find the cost of different oral antiepileptic drugs available in Indian market as monotherapy, combination therapy and number of manufacturing companies for each, to evaluate difference in cost of different brands of same dosage of same active drug by calculating percentage variation of cost. Methods and Materials: Cost of a drug being manufactured by different companies, in the same strength and dosage forms was obtained from “Indian Drug Review” Vol. XXI, Issue No.4, 2014 and “Current Index of Medical Specialties” July-October 2014. The difference in the maximum and minimum price of the same drug manufactured by different pharmaceutical companies and percentage variation in price was calculated. Results: The percentage price variation noted of long-established drugs was – Phenytoin (50mg: 140%, Carbamazepine (100mg: 1033%, Phenobarbital (30mg : 730%, Valproic acid (300mg : 420%. Newer drugs –Levetiracetam (250mg: 75%, Lamotrigine (25mg: 66%, Topiramate (50mg: 108%, Zonisamide (100mg: 19%. Combination drugs – Phenobarbital + Phenytoin (30+100 mg: 354.55%. Conclusion: The percentage price variation of different brands of the same commonly used long-established oral antiepileptic drug manufactured in India is very wide. The formulation or brand of Antiepileptic drugs (AED’s should preferably not be changed since variations in bioavailability or different pharmacokinetic profiles may increase the potential for reduced effect or excessive side effects. Hence, manufacturing companies should aim to decrease the price variation while maintaining the therapeutic efficacy.

  6. Antiepileptic Drugs-induced Stevens?Johnson syndrome: A case Series

    OpenAIRE

    Trivedi, Bhavi S.; Darji, Nishita H.; Malhotra, Supriya D.; Patel, Pankaj R.

    2016-01-01

    Stevens?Johnson syndrome (SJS) is an acute life-threatening mucocutaneous reaction, characterized by extensive necrosis and detachment of the epidermis from the skin. The overall incidence of SJS is seen in five cases per million people per year. SJS is typically caused by drugs and is a kind of idiosyncratic reaction. Adverse drug reactions such an SJS have a remarkable effect on patient's safety issues. We encountered nine cases of antiepileptic drug (AED)-induced SJS, specifically with car...

  7. The Australian Register of Antiepileptic Drugs in Pregnancy : The first 1002 pregnancies

    NARCIS (Netherlands)

    Vajda, Frank J. E.; Hitchcock, Alison; Graham, Janet; O'Brien, Terence; Lander, Cecilie; Eadie, Mervyn

    2007-01-01

    Prospective studies are needed to assess the maternal and fetal hazards of antiepileptic drug (AED) therapy in pregnancy. To make the Australian Register of AEDs in Pregnancy better known to the Australian obstetric community by presenting results derived from it. Analysis of data collected by the

  8. Association of antiepileptic drug usage, trace elements and thyroid hormone status

    NARCIS (Netherlands)

    C. Zevenbergen (Chantal); T.I.M. Korevaar (Tim); Schuette, A. (Andrea); R.P. Peeters (Robin); M. Medici (Marco); T.J. Visser (Theo); L. Schomburg (Lutz); W.E. Visser (Wil Edward)

    2016-01-01

    textabstractBackground: Levels of thyroid hormone (TH) and trace elements (copper (Cu) and selenium (Se)) are important for development and function of the brain. Anti-epileptic drugs (AEDs) can influence serum TH and trace element levels. As the relationship between AEDs, THs, and trace elements

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

    Science.gov (United States)

    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…

  10. Cognitive Effects Of Anti-Epileptic Drugs In Nigerians With Epilepsy ...

    African Journals Online (AJOL)

    Background Epilepsy is particularly highly prevalent in developing African countries and has been associated with cognitive disturbances, but more importantly is the contribution of the anti-epileptic drugs (AEDs). Objective This study aimed at comparing the effects of AEDs on the cognitive functions of Nigerian epileptic ...

  11. Antiepileptic drug use in seven electronic health record databases in europe: A methodological comparison

    NARCIS (Netherlands)

    De Groot, Mark C.H.; Schuerch, Markus; De Vries, Frank; Hesse, Ulrik; Oliva, Belén; Alvarez, Consuelo Huerta; Gil, Miguel; Requena, Gema; Abajo, Francisco; Afonso, Ana; Souverein, Patrick C.; Alvarez, Yolanda; Slattery, Jim; Rottenkolber, Marietta; Schmiedl, Sven; Van Dijk, Liset; Schlienger, Raymond G.; Reynolds, Robert; Klungel, Olaf

    2013-01-01

    Background: The annual prevalence of antiepileptic drug (AED) prescribing reported in the literature differs considerably among European countries; this may be due to differences in type of data sources, time periods, population distributions, and methodology. Objectives: To assess the prevalence of

  12. Antiepileptic drug use in seven electronic health record databases in Europe: a methodological comparison.

    NARCIS (Netherlands)

    Groot, M.C.H. de; Schuerch, M.; Vries, F. de; Hesse, U.; Oliva, B.; Huerta Alvarez, C.; Gil, M.; Requena, G.; Abajo, F.; Afonso, A.; Souverein, P.C.; Alvarez, Y.; Slattery, J.; Rottenkolber, M.; Schmiedl, S.; Dijk, L. van; Schlienger, R.; Reynolds, R.; Klungel, O.

    2013-01-01

    Background: The annual prevalence of antiepileptic drug (AED) prescribing reported in the literature differs considerably among European countries; this may be due to differences in type of data sources, time periods, population distributions, and methodology. Objectives: To assess the prevalence of

  13. Exposure to antiepileptic drugs and the risk of hip fracture: a case-control study

    DEFF Research Database (Denmark)

    Tsiropoulos, Ioannis; Andersen, Morten; Nymark, Tine

    2008-01-01

    PURPOSE: To investigate whether the use of antiepileptic drugs (AEDs) increases the risk of hip fracture. METHODS: We performed a case-control study using data from the Funen County (population 2004: 475,000) hip fracture register. Cases (n = 7,557) were all patients admitted to county hospitals ...

  14. Adverse events with use of antiepileptic drugs: a prescription and event symmetry analysis

    DEFF Research Database (Denmark)

    Tsiropoulos, Ioannis; Andersen, Morten; Hallas, Jesper

    2009-01-01

    PURPOSE: To assess adverse events with use of antiepileptic drugs (AEDs) by the method of sequence symmetry analysis. METHODS: We used data from two population-based sources in Funen County, Denmark (population 2006: 479 000); prescription data from Odense University Pharmacoepidemiological Datab...

  15. Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs

    DEFF Research Database (Denmark)

    Madsen, Karsten K; White, H Steve; Schousboe, Arne

    2010-01-01

    Epileptic seizure activity is associated with an imbalance between excitatory and inhibitory synaptic activities. The latter is mediated by GABA, and several currently used antiepileptic drugs target entities of the GABAergic synapse such as the receptors or the inactivation mechanism consisting ...

  16. Intelligence quotient improves after antiepileptic drug withdrawal following pediatric epilepsy surgery

    NARCIS (Netherlands)

    Boshuisen, Kim|info:eu-repo/dai/nl/343391511; van Schooneveld, Monique M. J.|info:eu-repo/dai/nl/30481427X; Uiterwaal, Cuno S. P. M.|info:eu-repo/dai/nl/136603947; Cross, J. Helen; Harrison, Sue; Polster, Tilman; Daehn, Marion; Djimjadi, Sarina; Yalnizoglu, Dilek; Turanli, Guzide; Sassen, Robert; Hoppe, Christian; Kuczaty, Stefan; Barba, Carmen; Kahane, Philippe; Schubert-Bast, Susanne; Reuner, Gitta; Bast, Thomas; Strobl, Karl; Mayer, Hans; de Saint-Martin, Anne; Seegmuller, Caroline; Laurent, Agathe; Arzimanoglou, Alexis; Braun, Kees P. J.|info:eu-repo/dai/nl/207237239

    ObjectiveAntiepileptic drugs (AEDs) have cognitive side effects that, particularly in children, may affect intellectual functioning. With the TimeToStop (TTS) study, we showed that timing of AED withdrawal does not majorly influence long-term seizure outcomes. We now aimed to evaluate the effect of

  17. SPECTRUM OF NEURAL-TUBE DEFECTS IN 34 INFANTS PRENATALLY EXPOSED TO ANTIEPILEPTIC DRUGS

    NARCIS (Netherlands)

    LINDHOUT, D; OMTZIGT, JGC; CORNEL, MC

    We analyzed the spectrum of neural-tube defects associated with maternal exposure to antiepileptic drugs (AEDs) and the possible contribution of familial and genetic factors to epilepsy or neural-tube defects. No specific association with maternal family history of neural-tube defects or epilepsy

  18. Anti-epileptic drug changes and quality of life in the community

    NARCIS (Netherlands)

    Wassenaar, M.; Leijten, F.S.S.; Sander, J.W.; Uijl, S.G.; Egberts, A.C.G.

    2016-01-01

    Objective: Changes in anti-epileptic drug (AED) regimens may indicate unsatisfactory treatment results such as insufficient seizure control or adverse effects. This inference underlies epilepsy management and research, yet current studies often do not account for AED changes. We assessed AED change

  19. Development Enamel Defects in Children Prenatally Exposed to Anti-Epileptic Drugs

    DEFF Research Database (Denmark)

    Jacobsen, Pernille Endrup; Henriksen, Tine Brink; Haubek, Dorte

    2013-01-01

    Objective Some anti-epileptic drugs (AED) have well-known teratogenic effects. The aim of the present study was to elucidate the effect of prenatal exposure to AED and the risk of enamel defects in the primary and permanent dentition. Methods A total of 38 exposed and 129 non-exposed children, 6...

  20. The relationship between polycystic ovary syndrome and antiepileptic drugs: a review of the evidence.

    Science.gov (United States)

    Rasgon, Natalie

    2004-06-01

    Polycystic ovary syndrome (PCOS) is a serious endocrine disorder characterized by ovulatory dysfunction and hyperandrogenism that is thought to have a higher prevalence in women with epilepsy and perhaps bipolar disorder. Various theories have been offered to explain this higher prevalence of PCOS and other reproductive disorders in these patient populations, including the effects of the disease itself and of antiepileptic drugs, especially valproate, which may directly cause PCOS or indirectly lead to the disorder by causing weight gain that triggers insulin resistance, increased testosterone levels, and other reproductive abnormalities. A prospective, longitudinal study with larger cohorts in newly diagnosed women with epilepsy or bipolar disorder is needed to definitively characterize the relationship between antiepileptic drugs and PCOS. Until data from such a study are available, physicians need to be aware that there is a possibility of developing symptoms of PCOS in women of reproductive age who are treated with antiepileptic drugs. Despite this concern, the choice of antiepileptic drug for women with epilepsy or bipolar disorder should be based on the most effective agent for controlling neurologic symptoms.

  1. [Social aspects of epilepsy: marriage, pregnancy, driving, antiepileptic drug withdrawal and against social stigma].

    Science.gov (United States)

    Tsuji, Sadatoshi

    2004-11-01

    Persons with epilepsy need adequate advice and effective counselling about issues such as marriage, pregnancy, risks of inheriting epilepsy, driving, employment and antiepileptic drug withdrawal, because these persons are not receiving important information and education about their condition and possible adverse effects of treatment. Furthermore, women with epilepsy have increased rates of pregnancy complications and poor fetal outcomes including congenital malformations and developmental delay related to both their epilepsy and antiepileptic drugs. However, approximately 90% of all women with epilepsy undergo normal pregnancy and give birth to children free of birth defects. Pregnancy is generally safe in women with epilepsy. The study of long-term prognosis of childhood-onset epilepsy in Japan shows that the majority of these patients have lower levels of educational background as well as employment and marital status compared with the general population (Wakamoto H. et al). Of patients with epilepsy, 60% to 70% achieve control with antiepileptic medication. However, several antiepileptic drug withdrawal studies show variable rates of success, with relapse rates ranging from 12% to 63% (Britton J.W.). Driving is listed as major problem in persons with epilepsy. However, the patients with seizure-free more than two years have been able to get the driver's license since June, 2002. Social attitudes towards epilepsy cause more distress to the patient than the disease itself. We should realize that persons with epilepsy are normal or near-normal. To ameliorate the social stigma against epilepsy, continuous and repetitive educational efforts would be needed.

  2. [Antiepileptic drugs in the control of the impulses disorders].

    Science.gov (United States)

    Roncero, C; Rodríguez-Urrutia, A; Grau-López, L; Casas, M

    2009-01-01

    The disorders classified as control of the impulses; explosive intermittent disorder, pathological gambling, kleptomania, pyromania, pathological gambling, hair pullers, compulsive purchases, skin picking and onychophagia are a heterogeneous set of clinical entities, most of them with little prevalence. Nevertheless, they cause important personal and social dysfunctions and present great comorbidity with other psychiatric disorders. Antipsychotics, antidepressive agents, serotoninergic agonists, naltrexone, beta blockers antiandrogen, lithium and anticonvulsants have been used in their pharmacological treatment. Currently, interest is growing on the use of the antiepileptics because their possible usefulness has been described in these disorders. However, the neurobiological effects are only partially known in some cases. We have reviewed the literature regarding the treatment of these disorders with mood stabilizers, (lithium, carbamazepine, valproate, phenitoin, oxcarbacepin, topiramate, lamotrigin, leviteracetam) and have described those studies on which the current knowledge and evidence are based. The results must be considered as provisional and must be updated in the future, since they are mostly based on case reports, case series or opened clinical trials, their being little knowledge based on double blind clinical trials.

  3. Cannabidiol--antiepileptic drug comparisons and interactions in experimentally induced seizures in rats.

    Science.gov (United States)

    Consroe, P; Wolkin, A

    1977-04-01

    A comparison of the anticonvulsant and neurotoxic effects of cannabidiol (CBD), delta 9tetrahydrocannabinol, cannabinol and antiepileptic drugs (phenytoin, phenobarbital, carbamazepine, chlordiazepoxide, clonazepam, ethosuximide and trimethadione) was made in rats. Median effective potencies (ED 50 values) for maximal electroshock, audiogenic seizures and TD50 values for a rotor rod neurotoxicity test were calculated. Additionally, the interactive effects of CBD and the antiepileptic drugs against maximal electroshock and audiogenic seizures were studied. Each drug was given orally at peak effect time. CBD was an effective and relatively potent anticonvulsant in both maximal electroshock and audiogenic seizure tests. The anticonvulsant potency of phenytoin was significantly increased when combined with phenobarbital, CBD and phenobarbital plus CBD. Additionally, CBD reliably reduced the anticonvulsant potencies of chlordiazepoxide, clonazepam, trimethadione and ethosuximide. These data indicate that CBD is an effective anticonvulsant with a specificity more comparable to drugs clinically effective in major than minor seizures. Furthermore, it appears that CBD enhances the anticonvulsant effects of the former and reduces the effects of the latter types of antiepileptic drugs.

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

    Science.gov (United States)

    Callegari, Camilla; Ielmini, M; Bianchi, L; Lucano, M; Bertù, Lorenza; Vender, Simone

    2016-01-01

    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.

  5. Reduced Adult Hippocampal Neurogenesis and Cognitive Impairments following Prenatal Treatment of the Antiepileptic Drug Valproic Acid

    Directory of Open Access Journals (Sweden)

    Berry Juliandi

    2015-12-01

    Full Text Available Prenatal exposure to valproic acid (VPA, an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running.

  6. Breastfeeding in children of women taking antiepileptic drugs: Cognitive outcomes at age 6 years

    OpenAIRE

    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) therapymay 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 Prospec...

  7. Ilizarov treatment of humeral shaft nonunion in an antiepileptic drug patient with uncontrolled generalized tonic-clonic seizure activity

    Directory of Open Access Journals (Sweden)

    Koulouvaris Panayiotis

    2010-07-01

    Full Text Available Abstract Nonunion of the humeral shaft in patients with antiepileptic drug associated metabolic bone disorder constitute a challenging surgical problem difficult to treat due to seizure activity, osteoporosis, and poor stabilization options. We report a case of nonunion of the humeral shaft in an antiepileptic drug patient with uncontrolled generalized tonic-clonic seizure activity successfully treated with Ilizarov external fixator and a follow-up of 4 years.

  8. An evaluation of the impact of memory and mood on antiepileptic drug adherence.

    Science.gov (United States)

    McAuley, James W; Passen, Nina; Prusa, Christine; Dixon, Joanne; Cotterman-Hart, Sheri; Shneker, Bassel F

    2015-02-01

    Antiepileptic drugs are the mainstay of treatment for patients with epilepsy. Adherence to the prescribed regimen is a major factor in achieving a reduced seizure burden, which can decrease morbidity and mortality. Patients with epilepsy oftentimes complain about difficulty with memory. Because little is known about the relationship between memory and mood and adherence, the purpose of this project was to determine the impact of the confounding factors of memory and mood on antiepileptic drug adherence in patients with epilepsy. One hundred adult patients with epilepsy were recruited from the outpatient neurology clinic for this cross-sectional study. Patients who met the inclusion criteria completed measures of subjective memory (subset of 6 memory questions from the QOLIE-89) and objective memory (Hopkins Verbal Learning Test - Revised), subjective adherence (Morisky scale) and objective adherence (medication possession ratio), and mood (Neurological Disorders Depression Inventory for Epilepsy). Refill records from each patient's community pharmacy were used to objectively assess adherence. Medication possession ratios were calculated based on the antiepileptic drug refill records over the previous 6months. Patients were considered adherent if their MPR was >80%. Women made up the majority of the sample (n=59), and, on average, patients had been living with epilepsy for nearly 20years. Approximately 40% of the sample were on antiepileptic drug monotherapy; most patients (>70%) took their antiepileptic drugs twice daily, and the mean number of total medications was 4.25±2.98. Based on the objective measure of adherence, 35% of the patients were nonadherent. Patients self-reported better adherence than what was objectively measured. Only the retention metric of the objective memory measure differentiated adherent patients from nonadherent patients. Patients in the adherent group had significantly lower depression scores (indicating better mood) compared with those

  9. Broad Spectrum Sanitizing Wipes with Food Additives Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Microcide proposes to develop novel multipurpose non-toxic sanitizing wipes that are aqueous based, have shelf life of 3-5 years, have broad spectrum microbicidal...

  10. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Halling-Sørensen, Bent; Birkved, Franziska Maria A Kramer

    2008-01-01

    of 1.4-49.7 mM. Carbamazepine, gabapentin, primidone, topiramate and vigabatrin showed no inhibition. Additionally, binary drug combinations were tested to investigate if combination therapy could potentiate the aromatase inhibition. Additive inhibition was seen in combination experiments...... with valproate and phenobarbital. When adding carbamazepine to a range of valproate concentrations no additional inhibition was seen. The data for some of the AEDs show that side effects on steroid synthesis in humans due to inhibition of aromatase should be considered....

  11. Prenatal exposure to antiepileptic drugs and dental agenesis.

    Directory of Open Access Journals (Sweden)

    Pernille E Jacobsen

    Full Text Available 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.

  12. Effect of reduction of antiepileptic drugs in patients with drug-refractory epilepsy.

    Science.gov (United States)

    Dash, Deepa; Aggarwal, Vikas; Joshi, Rupa; Padma, Madakasira Vasantha; Tripathi, Manjari

    2015-04-01

    The present study was conducted with the aim of evaluating the effects of reducing the number of antiepileptic drugs (AEDs) administered to patients with drug-refractory epilepsy (DRE) during their admission and document any change in seizure frequency in subsequent follow up. A total of 962 patients with DRE who were admitted to the neurology wards waiting for connection to video EEG were recruited for this prospective study. After their admission to the neurology ward, modifications in the number and dosage of AEDs were done with a target of a maximum of three AEDs in every patient. Drug tapering was done using a standardized protocol. The primary outcome was the change in seizure frequency in the follow-up period of 6 months. Secondary outcome measures were the adverse event profile (AEP) and the quality of life (QOL). Of the 1134 patients screened, 962 patients gave consent to participate in the study. The mean number of AEDs received by each patient was 4.24. After the tapering following a standardized protocol each patient received a mean of 2.65 AEDs per patient. In 82.70% patients with DRE, there was either a reduction or no change in seizure frequency in the subsequent 6 months follow up. There was a significant reduction in the AEP score after the reduction in the number of AEDs (P = 0. 001). Our study proves that optimization of reduction of the number of AED's in patients with DRE leads to reduction or no change in seizure frequency with a significant decrease in adverse effects. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  13. A NEW ANTIEPILEPTIC DRUG — ZONEGRAN (ZONISAMIDE — IN THE TREATMENT OF EPILEPSY (A REVIEW

    Directory of Open Access Journals (Sweden)

    O. A. Pylaeva

    2012-01-01

    Full Text Available Despite the considerable advances of epileptology drug-resistant epilepsies consist about 30% among all forms of epilepsy. Authors represent the review of the literature devoted to efficacy and tolerability of zonisamide in the treatment of drug-resistant epilepsy. The current review of studies devoted to efficacy and safety of a new antiepileptic drug zonisamide in the treatment of epilepsy is proposed. The mechanism of action and pharmacokinetic of zonisamide are described; the questions of efficacy and tolerability in the treatment of drug-resistant focal epilepsies and other types of seizures and forms of epilepsy are considered. The possibilities of the use of the drug in the treatment of comorbid disorders are considered

  14. Partial epilepsies: Choice of antiepileptic drugs in adults in the outpatient setting

    Directory of Open Access Journals (Sweden)

    P. N. Vlasov

    2016-01-01

    Full Text Available The paper depicts the author's view on how a neurologist/epileptologist chooses an antiepileptic drug in his practice under present-day conditions. It considers possible clinical situations and therapeutic tactics in relation to the efficiency of performed therapy, as well as methods for switching to other antiepileptic drugs if the previous/first monotherapy is ineffective. The author gives main international and Russian guidelines in terms of the type of epileptic seizure/form of epilepsy/epilepsy syndrome. Despite its almost semicentennial history of effective clinical application, valproate is shown to be now a first-line choice drug for the therapy of undifferentiated, cryptogenic, and symptomatic partial epilepsies in patients of different age groups. The properties of valproate, such as efficacy against different types of seizures and forms of epilepsy, good tolerability, minimal aggravation risk, high monotherapy retention rates, various dosage forms, including the brand-name extendedrelease drug Depakine chrono or Depakine chronosphere and its intravenous formulation, favorable pharmacokinetic and pharmacodynamics profiles, make it indispensable at the present developmental stage of epileptology.

  15. Vancomycin and Five Broad-spectrum Antibiotic Utilization Evaluation in an Educational Medical Center in One Year

    OpenAIRE

    SiminDokht Shoaei; Aliasghar Bagherzadeh; Mehrdad Haghighi; Meinoosh Shabani

    2015-01-01

     Background: Antibiotics can be life saving if they are used correctly, and can have unwanted side effects specially resistance with incorrect use. Unfortunately in fear of no response, physicians use broad spectrum antibiotics meticulously. In this Drug Utilization Evaluation (DUE), improper use of Vancomycin and five broad-spectrum antibiotics are studied to find faults and solution for this problem. Methods:This descriptive cross-sectional study performed during the March of 2012 to March ...

  16. [Prevalence, type of epilepsy and use of antiepileptic drugs in primary care].

    Science.gov (United States)

    Fernández-Suárez, Elena; Villa-Estébanez, Rubén; Garcia-Martinez, Alberto; Fidalgo-González, José A; Zanabili Al-Sibbai, Ahmad A; Salas-Puig, Javier

    2015-06-16

    Epilepsy is a disease with great social and economic impact. The prevalence should be used as the most important basis for planning the secondary and tertiary prevention. To identify patients with a diagnosis of epilepsy in a primary care center and determine the prevalence, demographic characteristics, type of epileptic syndrome and the use of antiepileptic drugs. Retrospective cross-sectional descriptive study. Included 196 patients with a diagnosis of epilepsy belonging to a primary care center and review the medical history, studying socio-demographic variables and clinical-pharmacological. The prevalence of epilepsy: 8.4/1000 inhabitants. Mean age: 50.3 years. Sex: 52.6% men. 79.6% urban. Family history of epilepsy: 14.8%. Type of epilepsy: symptomatic focal stroke (14.3%), idiopathic generalized (13.8%), focal cryptogenic (8.7%), not classified (31.1%). Average age at the beginning of seizures: 31.6 years. Neurological and/or psychiatric comorbidity: 62.8%. Last follow-up: 18.9% without antiepileptic treatment, 56.6% monotherapy and 24.5% polytherapy. Seizure-free: 76.5%. Drugs most frequently prescribed: valproic acid, carbamazepine, phenytoin, lamotrigine, levetiracetam. 78.6% without side effects. Exitus: 4.1%. The prevalence of patients with epilepsy was 8.4/1000 inhabitants, most frequent etiology the symptomatic focal stroke. More than half of patients suffered neurological and/or psychiatric comorbidity. At the end of follow-up the great majority were seizure-free without adverse effects of the antiepileptic drug treatment.

  17. Antiepileptic Drugs-induced Stevens–Johnson syndrome: A case Series

    Science.gov (United States)

    Trivedi, Bhavi S.; Darji, Nishita H.; Malhotra, Supriya D.; Patel, Pankaj R.

    2016-01-01

    Stevens–Johnson syndrome (SJS) is an acute life-threatening mucocutaneous reaction, characterized by extensive necrosis and detachment of the epidermis from the skin. The overall incidence of SJS is seen in five cases per million people per year. SJS is typically caused by drugs and is a kind of idiosyncratic reaction. Adverse drug reactions such an SJS have a remarkable effect on patient's safety issues. We encountered nine cases of antiepileptic drug (AED)-induced SJS, specifically with carbamazepine, oxcarbazepine, and phenytoin. To manage the reaction, the clinician withdrew the drug in all 8 cases, and in 1 case, the patient was shifted to valproate and symptomatic treatment was provided. There is still a controversy whether or not all AEDs can cause SJS. Recent studies have investigated the role of genetic factors - HLAB*502 allele in the development of AED-induced SJS in patients of Asian ancestry. PMID:28104975

  18. Antiepileptic Drugs-induced Stevens-Johnson syndrome: A case Series.

    Science.gov (United States)

    Trivedi, Bhavi S; Darji, Nishita H; Malhotra, Supriya D; Patel, Pankaj R

    2016-12-01

    Stevens-Johnson syndrome (SJS) is an acute life-threatening mucocutaneous reaction, characterized by extensive necrosis and detachment of the epidermis from the skin. The overall incidence of SJS is seen in five cases per million people per year. SJS is typically caused by drugs and is a kind of idiosyncratic reaction. Adverse drug reactions such an SJS have a remarkable effect on patient's safety issues. We encountered nine cases of antiepileptic drug (AED)-induced SJS, specifically with carbamazepine, oxcarbazepine, and phenytoin. To manage the reaction, the clinician withdrew the drug in all 8 cases, and in 1 case, the patient was shifted to valproate and symptomatic treatment was provided. There is still a controversy whether or not all AEDs can cause SJS. Recent studies have investigated the role of genetic factors - HLAB*502 allele in the development of AED-induced SJS in patients of Asian ancestry.

  19. Mechanochemical preparation of hydantoins from amino esters: application to the synthesis of the antiepileptic drug phenytoin.

    Science.gov (United States)

    Konnert, Laure; Reneaud, Benjamin; de Figueiredo, Renata Marcia; Campagne, Jean-Marc; Lamaty, Frédéric; Martinez, Jean; Colacino, Evelina

    2014-11-07

    The eco-friendly preparation of 5- and 5,5-disubstituted hydantoins from various amino ester hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-step protocol consisted in the formation of ureido ester intermediates, followed by a base-catalyzed cyclization to hydantoins. This easy-handling mechanochemical methodology was applied to a large variety of α- and β-amino esters, in smooth conditions, leading to hydantoins in good yields and with no need of purification steps. As an example, the methodology was applied to the "green" synthesis of the antiepileptic drug Phenytoin, with no use of any harmful organic solvent.

  20. New antiepileptic drugs in the treatment of Lennox-Gastaut syndrome

    Directory of Open Access Journals (Sweden)

    Francesco CHIARELLI

    2009-12-01

    Full Text Available Lennox–Gastaut syndrome is a childhood epileptic encephalopathy characterised by polymorphic seizures and neuropsychological decline. The most characteristic seizures are tonic fits, atypical absences and atonic seizures, in that order. Treatment options for patients with LGS are limited because of the resistance of seizures to pharmacological treatment. Owing to the many seizure types, many drugs are used in combinations that are mostly guided by anecdotal evidence or personal experience. Opinions towards treatment are further complicated because an antiepileptic drug might be of some benefit for the control of one type of seizure while aggravating another type. Concomitantly, polytherapy increases the potential for adverse events. The ultimate goal of epilepsy treatment is to achieve seizure control in a safe manner. Seizure freedom appears to be unrealistic in some refractory epilepsies, especially LGS. In this Review, we discuss newer antiepileptic drugs (Felbamate, Lamotrigine, Levetiracetam, Topiramate, Rufinamide, Vigabatrin, Zonisamide in the treatment of Lennox-Gastaut syndrome. Investigation of the effects of newer medications might help to identify treatments that, when used in the early stages of the disorder, might have long-term beneficial effects on seizures and the associated comorbidities.

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

    Science.gov (United States)

    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 (reporting practices. © 2015 American Society for Clinical Pharmacology and Therapeutics.

  2. Discovery of potent broad spectrum antivirals derived from marine actinobacteria.

    Directory of Open Access Journals (Sweden)

    Avi Raveh

    Full Text Available Natural products provide a vast array of chemical structures to explore in the discovery of new medicines. Although secondary metabolites produced by microbes have been developed to treat a variety of diseases, including bacterial and fungal infections, to date there has been limited investigation of natural products with antiviral activity. In this report, we used a phenotypic cell-based replicon assay coupled with an iterative biochemical fractionation process to identify, purify, and characterize antiviral compounds produced by marine microbes. We isolated a compound from Streptomyces kaviengensis, a novel actinomycetes isolated from marine sediments obtained off the coast of New Ireland, Papua New Guinea, which we identified as antimycin A1a. This compound displays potent activity against western equine encephalitis virus in cultured cells with half-maximal inhibitory concentrations of less than 4 nM and a selectivity index of greater than 550. Our efforts also revealed that several antimycin A analogues display antiviral activity, and mechanism of action studies confirmed that these Streptomyces-derived secondary metabolites function by inhibiting the cellular mitochondrial electron transport chain, thereby suppressing de novo pyrimidine synthesis. Furthermore, we found that antimycin A functions as a broad spectrum agent with activity against a wide range of RNA viruses in cultured cells, including members of the Togaviridae, Flaviviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Finally, we demonstrate that antimycin A reduces central nervous system viral titers, improves clinical disease severity, and enhances survival in mice given a lethal challenge with western equine encephalitis virus. Our results provide conclusive validation for using natural product resources derived from marine microbes as source material for antiviral drug discovery, and they indicate that host mitochondrial electron transport is a viable

  3. Discovery of potent broad spectrum antivirals derived from marine actinobacteria.

    Science.gov (United States)

    Raveh, Avi; Delekta, Phillip C; Dobry, Craig J; Peng, Weiping; Schultz, Pamela J; Blakely, Pennelope K; Tai, Andrew W; Matainaho, Teatulohi; Irani, David N; Sherman, David H; Miller, David J

    2013-01-01

    Natural products provide a vast array of chemical structures to explore in the discovery of new medicines. Although secondary metabolites produced by microbes have been developed to treat a variety of diseases, including bacterial and fungal infections, to date there has been limited investigation of natural products with antiviral activity. In this report, we used a phenotypic cell-based replicon assay coupled with an iterative biochemical fractionation process to identify, purify, and characterize antiviral compounds produced by marine microbes. We isolated a compound from Streptomyces kaviengensis, a novel actinomycetes isolated from marine sediments obtained off the coast of New Ireland, Papua New Guinea, which we identified as antimycin A1a. This compound displays potent activity against western equine encephalitis virus in cultured cells with half-maximal inhibitory concentrations of less than 4 nM and a selectivity index of greater than 550. Our efforts also revealed that several antimycin A analogues display antiviral activity, and mechanism of action studies confirmed that these Streptomyces-derived secondary metabolites function by inhibiting the cellular mitochondrial electron transport chain, thereby suppressing de novo pyrimidine synthesis. Furthermore, we found that antimycin A functions as a broad spectrum agent with activity against a wide range of RNA viruses in cultured cells, including members of the Togaviridae, Flaviviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Finally, we demonstrate that antimycin A reduces central nervous system viral titers, improves clinical disease severity, and enhances survival in mice given a lethal challenge with western equine encephalitis virus. Our results provide conclusive validation for using natural product resources derived from marine microbes as source material for antiviral drug discovery, and they indicate that host mitochondrial electron transport is a viable target for the

  4. Epileptiform activity and cognitive deficits in SNAP-25(+/-) mice are normalized by antiepileptic drugs.

    Science.gov (United States)

    Corradini, Irene; Donzelli, Andrea; Antonucci, Flavia; Welzl, Hans; Loos, Maarten; Martucci, Roberta; De Astis, Silvia; Pattini, Linda; Inverardi, Francesca; Wolfer, David; Caleo, Matteo; Bozzi, Yuri; Verderio, Claudia; Frassoni, Carolina; Braida, Daniela; Clerici, Mario; Lipp, Hans-Peter; Sala, Mariaelvina; Matteoli, Michela

    2014-02-01

    Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs.

  5. Antiepileptic, behavioral, and antidepressant effects of adjuvant lamotrigine therapy in drug-resistant epilepsy

    Directory of Open Access Journals (Sweden)

    Martinović Žarko J.

    2004-01-01

    Full Text Available Aim. To evaluate the behavioral effects of lamotrigine as add-on therapy in treatment-resistant epilepsy. Methods. An open, prospective, long-term study of lamotrigine as adjuvant therapy was performed in 56 patients with drug-resistant epilepsy (female/male ratio 35/21, age range 16-51 years. All the patients kept seizure diaries, and electroencephalograms were recorded at baseline and during 24 months of the treatment. Quality of life questionnaire, Hamilton depression scale (HMD, Beck depression scale (BDI, and Hamilton anxiety scale (HMA were used before and during lamotrigine therapy. Comparative assessments were made in an age- and sex-matched control group treated with other antiepileptic drugs. Results. Overall, seizure control was improved in 55.3% of the patients, remained unchanged in 39.3%, and deteriorated in 5.4%. Improvement in some quality of life measures occurred in 50% of the patients. The HMD subscales and BDI scale showed significant improvement in lamotrigine treated patients compared to the control group (ANOVA, p < 0.01. Negative behavioral effects occurred in 10.7% of the patients. Conclusion. Lamotrigine demonstrated significant antiepileptic long-term efficacy, and its positive effects on the mood and quality of life, which surpassed the negative behavioral effects, and contributed highly to the favorable treatment outcome.

  6. Development of a Broad-Spectrum Antiviral Agent with Activity ...

    African Journals Online (AJOL)

    Purpose: To evaluate the broad-spectrum antiviral activity of peptide H9 (H9) in vitro in order to gain insight into its underlying molecular mechanisms. Method: Antiviral activity against Herpes simplex virus type 1 (HSV-1) was determined using thiazolyl blue (MTT) assay. Polymerase Chain Reaction (PCR) was employed to ...

  7. Experience-based teaching of therapeutics and clinical pharmacology of antiepileptic drugs. Sudden unexplained death in epilepsy: do antiepileptic drugs have a role?

    Science.gov (United States)

    Lathers, C M; Schraeder, P L

    1995-06-01

    The contents of this paper have been written to be used in a teaching program specifically designed for medical postgraduate education of resident physicians and fellows in training interested in the clinical pharmacology of antiepileptic drugs and their role in the treatment of epilepsy and/or in the prevention of sudden unexpected death associated with this disease. With some modifications, such as a specific lecture to provide an overview of the numerous concepts presented in the text, the article could be used when teaching fourth-year medical students. The format of the paper is a combination of didactic review and eight case reports in a self-learning format. A quiz for self-assessment is included at the end of the article (see Appendix). This material was covered in part in the 1992 Board Review Course for Clinical Pharmacology sponsored by the American College of Clinical Pharmacology. The format or setting of instruction for this material could include small learning groups composed of 10 to 15 students. When used in combination with other topics prepared in similar formats, this could become a take home course for those preparing to take the Boards in Clinical Pharmacology. Each instructor could select specific publications from the reference list for assigned readings depending upon the material emphasized by the instructor. The questions included at the end of the text could be used as either a closed or an open book quiz to assess student learning.

  8. Antiepileptic drugs patterns in elderly inpatients in a Brazilian tertiary center, Salvador, Brazil

    Directory of Open Access Journals (Sweden)

    Telma Rocha de Assis

    2014-11-01

    Full Text Available Epilepsy is very prevalent among elderly inpatients and treatment is far from ideal. Objective To analyze prescribing patterns of antiepileptic drugs (AEDs for hospitalized elderly with epilepsy, their relations with comorbidities and comedications. Method We assessed prescription regimen of elderly patients that were under AED use for treatment of epileptic seizures, during hospitalization. One hundred and nine patients were enrolled. AED regimen was categorized into two groups: Group 1 defined as appropriate (carbamazepine, oxcarbazepine, valproic acid, gabapentin, clobazan and lamotrigine and Group 2 as inappropriate (phenytoin and phenobarbital. Results We found 73.4% of patients used inappropriate AEDs (p<0.001. Monotherapy was prescribed for 71.6% of patients. The most common comorbidity was hypertension. Potentially proconvulsant drugs as comedications were used for nearly half of patients. Conclusion Inappropriate AED therapy was commonly prescribed regimen for elderly inpatients. Some recommendations are discussed for a better care of elderly inpatients with epilepsy.

  9. Synaptic and extrasynaptic GABA transporters as targets for anti-epileptic drugs

    DEFF Research Database (Denmark)

    Madsen, Karsten K; Clausen, Rasmus P; Larsson, Orla M

    2009-01-01

    Inhibition of the GABA transporter subtype GAT1 by the clinically available anti-epileptic drug tiagabine has proven to be an effective strategy for the treatment of some patients with partial seizures. In 2005, the investigational drug EF1502 was described as possessing activity at both GAT1...... and BGT-1. When combined with the GAT1 selective inhibitor tiagabine, EF1502 was found to possess a synergistic anti-convulsant action in the Frings audiogenic seizure-susceptible mouse model of reflex epilepsy. This effect was subsequently attributed to inhibition of BGT-1. In this study, the anti......-convulsant effect of the GAT2/3 inhibitor SNAP-5114 was assessed in the Frings audiogenic seizure-susceptible mouse alone, and in combination with tiagabine and EF1502. The results showed that SNAP-5114 produced a synergistic anti-convulsant effect in combination with EF1502 but not when used in combination...

  10. Use of an antiepileptic drug to control epileptic seizures associated with cranioplasty: A randomized controlled trial.

    Science.gov (United States)

    Chen, Fei; Duan, Yaqi; Li, Yongqin; Han, Wenjie; Shi, Weilei; Zhang, Weiwei; Huang, Yonghua

    2017-04-01

    Epilepsy is a common complication of cranioplasty. The present study was designed to explore the clinical effect of prophylactic anti-epilepsy drugs (AED) to control epileptic seizures associated with cranioplasty. and design: This trial was a prospective, randomized, open-label, single-centre, active controlled study designed to investigate the use of antiepileptic drug to control epileptic seizures associated with cranioplasty. We tested the necessity and methods of drug use. Three hundred twenty epilepsy patients who underwent cranioplasty were included in this study. The patients were randomly divided into the control group (160 cases) and the experimental group (160 cases). AED were administered to experimental group from 4 days before the surgery until 1 month after the surgery. The incidence of early and late epileptic seizures after cranioplasty was analyzed. The liver function, abnormal blood test 1 month after surgery were compared between these two groups. The incidence of seizures in the Control group was 28.6% (43 cases in 149 cases) while in the experimental group was only 5.9% (9 cases in 151 cases), which had statistical significance. The incidence of epileptic seizure was significantly higher in patients who received no AED treatment than in those who received AED treatment. Besides, the abnormal liver function and blood routine examination in both control and experimental group had no significant differences. The incidence of epilepsy associated with the cranioplasty is high and early use of anti-epileptic drugs can effectively reduce the occurrence of seizures. Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

  11. Antiepileptic drugs prescription utilization behavior and direct costs of treatment in a national hospital of India

    Directory of Open Access Journals (Sweden)

    Ahsan Haroon

    2012-01-01

    Full Text Available Background and Objectives: The present study evaluated the direct costs of active epilepsy and looked at the pattern of drug prescription and utilization in epileptic patients visiting the neuroscience centre of a national hospital of India. Materials and Methods: A total of 134 epileptic patients were studied over a period of 4 months. Patients demography, commonly prescribed antiepileptic drugs (AEDs, socioeconomic status, direct costs, response ratio (RR for newer drugs, and quality of life (QOLIE-10 was evaluated. Results and Discussion: We found a higher percentage of male patients (67.9% as compared with females. Most of the patients were in the age group 11-30 years and majority of them (39.6% belonged to lower middle group. A higher percentage (68.7 of drugs was prescribed as polytherapy. Higher monthly cost was observed for some of the newer AEDs including the lamotrigine, levetiracetam, and lacosamide as compared with older drugs. Among the newer drugs, clobazam had the lowest cost. RR was calculated for 12 patients out of which 8 had a RR < −0.50. The QOL domains, following conventional or newer drugs, were not much affected. Conclusion: The study indicates an increasing trend toward clinical usage of newer AEDs, increasing trend of poly-therapy with significant escalations in the cost of therapy.

  12. Impact of taking antiepileptic drugs at school in a group of children and adolescents.

    Science.gov (United States)

    Anderson, G D; Kim, H; Warner, M H

    2000-02-01

    The impact of epilepsy on the quality of life can be significant. Peer acceptance is important for the social adjustment of children. Even children with controlled seizures may appear different from their peers if they are required to leave the classroom to take antiepileptic drugs. The objective of this pilot study was to determine if there is a measurable effect on peer relationships in children having to leave the classroom or recess time to take antiepileptic medications in a school setting. Results of surveys mailed or distributed by a pharmacist were obtained from 47 children, aged 6 to 18 years. Children who reported poor seizure control were significantly more likely to have trouble making friends compared with those with seizures controlled (70% vs 27%, P = 0.02). Even though the majority reported good seizure control (7/8), the children who left the classroom to take medications reported that they had significantly more trouble making friends than those who did not leave the classroom (63% vs 21%, P = 0.03). Therefore, the effect of taking medication at school may be associated with a significant decrease in social and peer relationships, even in children with self-reported good seizure control. Copyright © 2000 Academic Press. All rights reserved.

  13. Strategies for improving adherence to antiepileptic drug treatment in people with epilepsy.

    Science.gov (United States)

    Al-Aqeel, Sinaa; Gershuni, Olga; Al-Sabhan, Jawza; Hiligsmann, Mickael

    2017-02-03

    Poor adherence to antiepileptic medication is associated with increased mortality, morbidity and healthcare costs. In this review, we focus on interventions designed and tested in randomised controlled trials and quasi-randomised controlled trials to assist people with adherence to antiepileptic medication. This is an updated version of the original Cochrane review published in the Cochrane Library, Issue 1, 2010. To determine the effectiveness of interventions aimed at improving adherence to antiepileptic medication in adults and children with epilepsy. For the latest update, on 4 February 2016 we searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid 1946 to 4 February 2016), CINAHL Plus (EBSCOhost 1937 to 4 February 2016), PsycINFO (EBSCOhost 1887 to 4 February 2016), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. We also searched the reference lists of relevant articles. Randomised and quasi-randomised controlled trials of adherence-enhancing interventions aimed at people with a clinical diagnosis of epilepsy (as defined in individual studies), of any age and treated with antiepileptic drugs in a primary care, outpatient or other community setting. All review authors independently assessed lists of potentially relevant citations and abstracts. At least two review authors independently extracted data and performed quality assessment of each study according to the Cochrane tool for assessing risk of bias. We graded the level of evidence for each outcome according to the GRADE working group scale.The studies differed widely according to the type of intervention and measures of adherence; therefore combining data was not appropriate. We included 12 studies reporting data on 1642 participants (intervention = 833, control = 809). Eight studies targeted adults with epilepsy, one study included participants

  14. Neuropsychological effects of antiepileptic drugs (carbamazepine versus valproate) in adult males with epilepsy.

    Science.gov (United States)

    Shehata, Ghaydaa A; Bateh, Abd El-aziz M; Hamed, Sherifa A; Rageh, Tarek A; Elsorogy, Yaser B

    2009-01-01

    To evaluate the effect of antiepileptic drugs (AEDs) on cognition and behavior in adult epileptic males controlled on treatment with conventional antiepileptic medications. Cognitive, mood, behavior and personality traits were assessed in 45 epileptic patients treated with carbamazepine and/or valproate and free of seizures for >/=1 year. Thirty-four newly diagnosed or untreated patients with epilepsy and 58 matched healthy subjects were also included for comparison. A battery of psychometric tests was utilized including Stanford-Binet (4th edition), Beck Inventory for Depression, Aggressive Scale and Eysenck Personality Questionnaire. Compared to matched control subjects, treated and untreated epileptic patients had poor performance in different cognitive and behavioral functions testing. Treated patients had worse scores in memory for digits forward and backward, total short-term memory, extroversion and psychosis. The duration of AEDs intake was correlated with memory of objects (r = -0.323; P = 0.030), bead memory (r = -0.314; P = 0.036) and total nonverbal short-term memory (r = -0.346; P = 0.020). Treated and untreated epileptic patients had poor performance of similar extent in behavioral functions testing (depression, aggression and neurosis). The dose of AEDs was correlated with testing scores for neurosis (r = 0.307; P = 0.040), verbal aggression (r = 0.483; P = 0.001) and nonverbal aggression (r = 0.526; P = 0.000), and duration of drug intake was correlated with scores for depression (r = 0.384; P = 0.009), psychosis (r = 0.586; P = 0.0001) and nonverbal aggression (r = 0.300; P = 0.045). This study provides support for the notion that AEDs can impair performance in cognition, mood and behavior. Duration of drug intake and the number of the utilized AEDs are the main confounding variables. This study did not provide clues on how to exclude the effect of epilepsy itself and psychosocial variables as additional important confounding variables.

  15. Importance of competing risks in the analysis of anti-epileptic drug failure

    Directory of Open Access Journals (Sweden)

    Sander Josemir W

    2007-03-01

    Full Text Available Abstract Background Retention time (time to treatment failure is a commonly used outcome in antiepileptic drug (AED studies. Methods Two datasets are used to demonstrate the issues in a competing risks analysis of AEDs. First, data collection and follow-up considerations are discussed with reference to information from 15 monotherapy trials. Recommendations for improved data collection and cumulative incidence analysis are then illustrated using the SANAD trial dataset. The results are compared to the more common approach using standard survival analysis methods. Results A non-significant difference in overall treatment failure time between gabapentin and topiramate (logrank test statistic = 0.01, 1 degree of freedom, p-value = 0.91 masked highly significant differences in opposite directions with gabapentin resulting in fewer withdrawals due to side effects (Gray's test statistic = 11.60, 1 degree of freedom, p = 0.0007 but more due to poor seizure control (Gray's test statistic = 14.47, 1 degree of freedom, p-value = 0.0001. The significant difference in overall treatment failure time between lamotrigine and carbamazepine (logrank test statistic = 5.6, 1 degree of freedom, p-value = 0.018 was due entirely to a significant benefit of lamotrigine in terms of side effects (Gray's test statistic = 10.27, 1 degree of freedom, p = 0.001. Conclusion Treatment failure time can be measured reliably but care is needed to collect sufficient information on reasons for drug withdrawal to allow a competing risks analysis. Important differences between the profiles of AEDs may be missed unless appropriate statistical methods are used to fully investigate treatment failure time. Cumulative incidence analysis allows comparison of the probability of failure between two AEDs and is likely to be a more powerful approach than logrank analysis for most comparisons of standard and new anti-epileptic drugs.

  16. Antiepileptic Drug Treatment in Community-Dwelling Older Patients with Epilepsy: A Retrospective Observational Study of Old- Versus New-Generation Antiepileptic Drugs.

    Science.gov (United States)

    Theitler, Jacques; Brik, Anna; Shaniv, Dotan; Berkovitch, Matitiahu; Gandelman-Marton, Revital

    2017-06-01

    The use of antiepileptic drugs (AEDs) in older patients with epilepsy is challenged by polypharmacy and decreased drug elimination. Newer AEDs have a lower potential for drug interactions and are reported to be better tolerated by the elderly than old-generation AEDs. The objective of this study was to evaluate AED use and the related adverse event rate in an outpatient cohort of older patients with epilepsy. We retrospectively reviewed the computerized database and medical records of all the patients aged ≥60 years who visited our epilepsy outpatient clinic (Assaf Harofeh Medical Center, Zerifin, Israel) during a 4-year period from February 2012 to February 2016. In this study, phenytoin, valproic acid, carbamazepine, phenobarbital, clobazam, and clonazepam were defined as old-generation AEDs. Gabapentin, levetiracetam, lamotrigine, topiramate, oxcarbazepine, lacosamide, and perampanel were defined as new-generation AEDs. The study group included 115 patients aged 60-90 years (mean 70.5 ± 7.8 years), 70 (61%) of whom were men. Co-morbidities were present in 98.3% of the patients, including neuropsychiatric illnesses in 21.2%. Present medical treatment included new-generation AEDs in 49 (44.5%) and both old- and new-generation AEDs in 20 (18.2%) patients. The most commonly used current AEDs were phenytoin, gabapentin, levetiracetam, and lamotrigine. Adverse reactions mainly included fatigue and CNS-related symptoms, and were more frequent among patients treated with new-generation AEDs than in those treated with old-generation AEDs or a combination of old- and new-generation AEDs; however, these reactions were mostly related to levetiracetam treatment. The likelihood of levetiracetam-related adverse events was increased by slow levetiracetam titration [defined as a weekly dose increase of ≤250 mg/day in this study; odds ratio (OR) 16.35, 95% confidence interval (CI) 2.94-90.98], and by low- (OR 5.68, 95% CI 1.40-22.95) and high (OR 4.24, 95% CI 1

  17. Antiepileptic drug therapy and recommendations for withdrawal in patients with seizures and epilepsy due to neurocysticercosis.

    Science.gov (United States)

    Bustos, Javier A; García, Héctor H; Del Brutto, Oscar H

    2016-09-01

    Neurocysticercosis (NCC) is a leading causes of secondary epilepsy worldwide. There is increasing evidence on the epileptogenic role of NCC, and the presence of edema, calcified scars, gliosis and hippocampal sclerosis support this phenomenon. We summarized principles of antiepileptic drug (AED) therapy as well as risk factors associated with seizure recurrence after AED withdrawal in patients with NCC. Expert commentary: First-line AED monotherapy is effective as a standard approach to control seizures in most NCC patients. Risks and benefits of AED withdrawal have not been systematically studied, and this decision must be individualized. However, a seizure-free period of at least two years seem prudent before attempting withdrawal. Risk factors for seizure recurrence after AED withdrawal include a history of status epilepticus, poor seizure control during treatment, neuroimaging evidence of perilesional gliosis, hippocampal sclerosis and calcified lesions, as well as persistence of paroxysmal activity in the EEG.

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

    Science.gov (United States)

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

    2016-08-01

    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.

  19. Monotherapy trials in antiepileptic drugs: are modified "presurgical studies" a way out of the dilemma?

    Science.gov (United States)

    Bien, C G; Elger, C E

    2001-04-01

    Monotherapy trials in epilepsy are confronted with a dilemma: either they are in conflict with ethical requirements, or they are scientifically not meaningful. Monotherapy trials, which are performed as controlled studies randomizing patients to ineffective (pseudo)placebo treatment, are incompatible with the Helsinki Declaration. On the other hand, equivalence or noninferiority studies using an active-control design do not permit valid conclusions on the efficacy of the test drug. Therefore, they do not fulfill scientific requirements for trials on new drugs. As an alternative approach, a monotherapy trial design for epilepsy patients undergoing presurgical evaluation was outlined. During presurgical evaluation, antiepileptic drugs are routinely tapered down for seizure recording. This situation is used for a placebo-controlled short-term monotherapy trial. Four trials according to this design have been completed so far. Recently, several points of concern have been raised against this design, especially for matters of ethics and external validity. In the present article, these objections are outlined and discussed. In the proposed modification the randomization and the titration of the test drug or control begins prior to the presurgical investigations. The advantages are: the test drug does not have to be titrated quickly, pure monotherapy conditions are achieved, and the subjects do not have to experience more seizures than are required for the presurgical evaluation.

  20. Influence of chemical structure on hypersensitivity reactions induced by antiepileptic drugs: the role of the aromatic ring.

    NARCIS (Netherlands)

    Handoko, K.B.; Puijenbroek, E.P. van; Bijl, A.H.; Hermens, W.A.; Rijkom, JE Zwart-van; Hekster, Y.A.; Egberts, T.C.G.

    2008-01-01

    OBJECTIVE: Antiepileptic drugs (AEDs) can cause various 'idiosyncratic' hypersensitivity reactions, i.e. the mechanism by which AEDs induce hypersensitivity is unknown. The aim of this study was to assess whether the presence of an aromatic ring as a commonality in chemical structures of AEDs can

  1. Influence of chemical structure on hypersensitivity reactions induced by antiepileptic drugs : the role of the aromatic ring

    NARCIS (Netherlands)

    Handoko, Kim B; van Puijenbroek, Eugène P; Bijl, Annemarie H; Hermens, Walter A J J; Zwart-van Rijkom, Jeannette E F; Hekster, Yechiel A; Egberts, Toine C G

    2008-01-01

    OBJECTIVE: Antiepileptic drugs (AEDs) can cause various 'idiosyncratic' hypersensitivity reactions, i.e. the mechanism by which AEDs induce hypersensitivity is unknown. The aim of this study was to assess whether the presence of an aromatic ring as a commonality in chemical structures of AEDs can

  2. Utilization of antiepileptic drugs during pregnancy: Comparative patterns in 38 countries based on data from the EURAP registry

    DEFF Research Database (Denmark)

    Battino, D.; Bonizzoni, E.; Craig, J.

    2009-01-01

    We assessed the utilization of antiepileptic drugs (AEDs), 1999-2005, in 4,798 prospective epilepsy pregnancies from 38 countries participating in EURAP, an international AED and pregnancy registry. Prominent differences in utilization patterns were observed across the various countries. Exposure...

  3. Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers.

    LENUS (Irish Health Repository)

    Campbell, E

    2014-09-01

    Antiepileptic drug (AED) exposure during pregnancy increases the risk of major congenital malformations (MCMs). The magnitude of this risk varies by AED exposure. Here we provide updated results from the UK Epilepsy and Pregnancy Register of the risk of MCMs after monotherapy exposure to valproate, carbamazepine and lamotrigine.

  4. Does brain slices from pentylenetetrazole-kindled mice provide a more predictive screening model for antiepileptic drugs?

    DEFF Research Database (Denmark)

    Hansen, Suzanne L.; Sterjev, Zoran; Werngreen, Marie

    2012-01-01

    The cortical wedge is a commonly applied model for in vitro screening of new antiepileptic drugs (AEDs) and has been extensively used in characterization of well-known AEDs. However, the predictive validity of this model as a screening model has been questioned as, e.g., carbamazepine has been re...

  5. Glucuronidation of antiepileptic drugs in women with epilepsy : on the role of age, steroid hormones and oral contraceptives

    NARCIS (Netherlands)

    Wegner, I.

    2013-01-01

    Epilepsy is a common neurological disorder with clinically important gender differences in both the expression and the impact of epilepsy. Understanding the complex interactions between sex hormones, epilepsy and antiepileptic drugs (AEDs) can greatly improve the care for women with epilepsy. This

  6. Transient Splenial Lesion of Corpus Callosum Associated with Antiepileptic Drug: Conventional and Diffusion-weighted Magnetic Resonance Images

    Energy Technology Data Exchange (ETDEWEB)

    Hakyemez, B.; Erdogan, C.; Yildirim, N.; Gokalp, G.; Parlak, M. [Uludag Univ. Medical School, Bursa (Turkey). Dept. of Radiology

    2005-11-01

    Transient focal lesions of splenium of corpus callosum can be seen as a component of many central nervous system diseases, including antiepileptic drug toxicity. The conventional magnetic resonance (MR) findings of the disease are characteristic and include ovoid lesions with high signal intensity at T2-weighted MRI. Limited information exists about the diffusion-weighted MRI characteristics of these lesions vanishing completely after a period of time. We examined the conventional, FLAIR, and diffusion-weighted MR images of a patient complaining of depressive mood and anxiety disorder after 1 year receiving antiepileptic medication.

  7. Interchangeability of generic anti-epileptic drugs: a quantitative analysis of topiramate and gabapentin.

    Science.gov (United States)

    Maliepaard, Marc; Banishki, Nikola; Gispen-de Wied, Christine C; Teerenstra, Steven; Elferink, André J

    2011-10-01

    The objective of this study was to determine whether the so-called "shift" or "drift" problem might occur when generic anti-epileptic drugs are interchanged, and thus to assess if generic anti-epileptic drugs are interchangeable and can be used in an efficacious and safe way on the basis of their bioequivalence to one and the same reference product. The bioequivalence of topiramate and gabapentin generics was evaluated. For proper interstudy comparison, individual exposure data (AUC and C(max)) for each bioequivalence study present in the registration dossier was normalized based on the absolute exposure data of one of two innovators. The exposure-normalized plasma concentration curves of the generic product arms between studies were compared, providing indirect evidence of bioequivalence of the different generics. Additionally, comparisons were made for generic-generic as well as innovator-innovator exchange based on absolute exposure data from individual bioequivalence studies. In almost all cases, estimated 90% confidence intervals of the AUC and C(max) ratios for generic-generic interchange were within the routine 80-125% criterion. When absolute, non-corrected exposure data were used for this interstudy comparison, in a number of cases 90% confidence intervals outside the 80-125% criterion were found upon interchanging generics from two studies. However, a similar pattern of 90% confidence intervals outside the 80-125% criterion was observed for the comparison of innovator arms, despite the fact that the innovator was identical in all studies. Our results strongly indicate that the so-called drifting problem upon generic-generic substitution does not result in important differences in exposure upon exchanging topiramate generics or gabapentin generics.

  8. Enzyme-inducing antiepileptic drugs and fractures in people with epilepsy: A systematic review.

    Science.gov (United States)

    Fraser, Lisa-Ann; Burneo, Jorge G; Fraser, J Alexander

    2015-10-01

    People with epilepsy (PWE) have an increased fracture risk, independent of seizures. Antiepileptic drugs are thought to increase this risk, particularly those that induce the hepatic cytochrome P450 enzyme system. We aimed to determine whether PWE treated with enzyme-inducing antiepileptic drugs (EIAEDs) have decreased bone mineral density (BMD), or increased fracture incidence, versus those treated with non-EIAEDs. We searched MedLine, EMBase, CENTRAL, and CINAHL prior to November 2014 for all studies comparing fracture risk, or BMD change, in PWE treated for ≥ 1 year with EIAEDs versus non-EIAEDs. Thirteen observational studies met eligibility criteria. These studies, representing 68,973 adult PWE, were significantly heterogeneous, making meta-analysis impossible. Study results were split, with 5 studies showing decreased BMD in EIAED users, 5 studies showing no effect of EIAED on BMD, 2 studies showing increased fracture incidence in EIAED users, and 1 study showing no difference in fracture risk. The largest study (n = 63,259), which was also the most methodologically rigorous, showed an increased hazard ratio of 9-22% for any fracture, and 49-53% for hip fracture, in EIAED users. The literature is divided regarding the bone effects of EIAEDs; however, current best evidence supports an increased fracture risk in PWE treated with an EIAED compared to those treated with non-EIAEDs. A single article dominated our review, and other large methodologically rigorous studies are needed to confirm or refute its results. Further small studies, with limited power to control for multiple potentially confounding variables, are not likely to help. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Antiepileptic drug prescribing patterns in Iraq and Afghanistan war veterans with epilepsy.

    Science.gov (United States)

    Rohde, Natalie N; Baca, Christine B; Van Cott, Anne C; Parko, Karen L; Amuan, Megan E; Pugh, Mary Jo

    2015-05-01

    We examined patterns of antiepileptic drug (AED) use in a cohort of Iraq/Afghanistan war veterans (IAVs) who were previously identified as having epilepsy. We hypothesized that clinicians would be more likely to prescribe newer AEDs and would select specific AEDs to treat seizures based on patient characteristics including gender and comorbidities. From the cohort of IAVs previously identified with epilepsy between fiscal years 2009 and 2010, we selected those who received AEDs from the Veterans Health Administration in FY2010. Regimens were classified as monotherapy or polytherapy, and specific AED use was examine overall and by gender. Multivariable logistic regression examined associations of age; gender; race/ethnicity; medical, psychiatric, and neurological comorbidities; and receipt of neurology specialty care associated with the six most commonly used AEDs. Among 256,284 IAVs, 2123 met inclusion criteria (mean age: 33years; 89% men). Seventy-two percent (n=1526) received monotherapy, most commonly valproate (N=425) and levetiracetam (n=347). Sixty-one percent of those on monotherapy received a newer AED (levetiracetam, topiramate, lamotrigine, zonisamide, oxcarbazepine). Although fewer women than men received valproate, nearly 90% (N=45) were of reproductive age (≤45years). Antiepileptic drug prescribing patterns were associated with posttraumatic stress disorder, bipolar disorder, cerebrovascular disease, dementia/cognitive impairment, headache, and receipt of neurological specialty care (all p<0.01). In this cohort of veterans with epilepsy, most received AED monotherapy and newer AEDs. Prescribing patterns were different for men and women. The patterns observed between AEDs and neurological/psychiatric comorbidities suggest that clinicians are practicing rational prescribing. Copyright © 2015. Published by Elsevier Inc.

  10. Comparative study of antiepileptic drug use during pregnancy over a period of 12 years in Spain. Efficacy of the newer antiepileptic drugs lamotrigine, levetiracetam, and oxcarbazepine.

    Science.gov (United States)

    Martinez Ferri, M; Peña Mayor, P; Perez López-Fraile, I; Escartin Siquier, A; Martin Moro, M; Forcadas Berdusan, M

    2016-07-21

    The prescription pattern of antiepileptic drugs (AEDs) during pregnancy is changing but to what extent this is occurring in Spain remains unknown. The efficacy of newer drugs for controlling seizures is a key issue and may have changed over the years as doctors gained familiarity with these drugs during pregnancy. To assess these 2 topics, we report the results from the Spanish EURAP register gathered over a 12-year period. After signing informed consent forms, patients were included in the register and evaluated at onset of pregnancy, at the end of the second and third trimesters, after delivery, and one year after delivery. For the purposes of this study, we analysed AEDs, type of epilepsy, seizure frequency per trimester and throughout pregnancy, percentage of seizure-free pregnancies, and frequency of congenital malformations. We then compared data from 2 periods (June 2001-October 2007) and (January 2008-May 2015) RESULTS: We compared 304 monotherapies from the older period to 127 from the more recent one. There was a clear increase in the use of levetiracetam (LEV) with declining use of carbamazepine (CBZ), phenytoin, and phenobarbital; a slight decline in use of valproate (VPA), and a slight increase in the use of lamotrigine (LTG) and oxcarbazepine (OXC). Epilepsy types treated with CBZ and VPA remained unchanged, whereas fewer cases of generalised epilepsy were treated with LTG in the new period. This trend was not associated with significant changes in seizure frequency, but rather linked to better control over de novo seizures in the third trimester. LEV was similar to CBZ and VPA with regard to levels of seizure control, and more effective than LTG. Generalised epilepsy accounted for 64% of the cases treated with LEV. The prescription pattern of AEDs during pregnancy has changed in Spain, with diminishing use of CBZ, phenytoin, and phenobarbital. Changes also reflect the type of epilepsy, since there is less use of LTG for generalised epilepsy. LEV

  11. Differential impact of contraceptive methods on seizures varies by antiepileptic drug category: Findings of the Epilepsy Birth Control Registry.

    Science.gov (United States)

    Herzog, Andrew G; Mandle, Hannah B; Cahill, Kaitlyn E; Fowler, Kristen M; Hauser, W Allen

    2016-07-01

    The aim of this study was to determine whether categories of contraception differ in their impact on seizures in women with epilepsy and whether the impact varies by antiepileptic drug category. Retrospective survey data came from 2712 contraceptive experiences reported by 1144 women with epilepsy. We compared risk ratios for reports of increase and decrease in seizure frequency on hormonal versus nonhormonal contraception, stratified by antiepileptic drug categories. More women with epilepsy reported a change in seizures on hormonal (28.2%) than on nonhormonal contraception (9.7%) (phormonal (18.7%) versus nonhormonal contraception (4.2%) was 4.47 (phormonal (9.5%) versus nonhormonal contraception (5.5%) was 1.71, phormonal contraception, the risk ratio for seizure increase was greater than for decrease (1.98, phormonal patch and progestin-only pills had greater risk ratios for seizure increase. Depomedroxyprogesterone was the only hormonal method with a greater risk ratio for seizure decrease than combined pills. Seizure increase was greater for hormonal than nonhormonal contraception for each antiepileptic drug category (phormonal contraception, relative to the non-enzyme-inducing antiepileptic drug category which had the lowest rate, each of the other categories had significantly greater risks for seizure increase, especially the enzyme-inhibiting (valproate) category (risk ratio=2.53, p=0.0002). The findings provide community-based, epidemiological survey evidence that contraceptive methods may differ in their impact on seizures and that this impact may vary by antiepileptic drug category. Copyright © 2016. Published by Elsevier Inc.

  12. Patients' perspectives on management and barriers of regular antiepileptic drug intake.

    Science.gov (United States)

    May, Theodor W; Berkenfeld, Ralf; Dennig, Dieter; Scheid, Brigitte; Hausfeld, Heiko; Walther, Sonja; Specht, Ulrich

    2018-02-01

    The aim of our study was to assess the management of drug intake and potential barriers to adherence reported by two different patient groups. The study was performed in cooperation with the Regional Chamber of Pharmacists of Rhineland-Palatinate and three neurologists in private practice specialized in epileptology. In total, 108 patients surveyed in 43 pharmacies (Group P) and 118 patients treated by the specialized neurologists (Group N) completed anonymously a questionnaire on intake of antiepileptic drugs (AEDs). The statistical evaluation was performed using nonparametric tests and logistic regression analyses. Group N more often used adherence aids, compared with Group P (68.6% vs. 46.3%, pproblems with the regular intake of their medication did not differ significantly between groups (Group N vs. P: 47.0% vs. 40.0%). If patients noticed that they missed a dose, 45.3% completely skipped the missed dose (Group N vs. P: 43.0% vs. 48.1%, n.s.). In a multivariate analysis, significant risk factors of problems with regular drug intake were ageproblems with adherence than patients surveyed in pharmacies. Since barriers for a regular intake are diverse, the use of a short questionnaire on management of drug intake may lead to an individually tailored counseling of patients to improve adherence. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Investigating the potential of the anti-epileptic drug imepitoin as a treatment for co-morbid anxiety in dogs with idiopathic epilepsy

    National Research Council Canada - National Science Library

    Rowena M A Packer; Luisa De Risio; Holger A Volk

    2017-01-01

    Background Behavioural changes associated with idiopathic epilepsy (IE) have been identified in dogs, with fear and anxiety-related problems seen in both drug-naive dogs and dogs treated with anti-epileptic drugs (AEDs...

  14. [Therapeutic potential of thyreoliberin (TRH) and its analogues as antiepileptic and neuroprotective drugs].

    Science.gov (United States)

    Jantas, Danuta

    2010-01-01

    Thyreoliberin (TRH, thyrotropin releasing hormone) is a hypothalamic tripeptide, whose regulatory role in the endocrine system is well recognized. TRH and its receptors are also widely distributed in the central nervous system (CNS), where they are involved in neurotransmission and neuromodulation, as well as in maintaining of homeostasis in the brain. This review article is a short presentation of the role of TRH in CNS function, with special emphasis on mechanisms of its action and future perspectives of potential use of TRH and its analogues in the treatment of epilepsy and some neurodegenerative diseases. A potential clinical utility of TRH as the CNS drug is limited by its short half-life, low bioavailability and some undesired effects (endocrine, peripheral). Thus, new analogues of TRH with better pharmacokinetic and pharmacodynamic parameters are intensively searched for. TRH shows a multidirectional influence on the CNS functions, i.e. it activates motoneurons, has analeptic, antidepressive and hyperthermic properties. Of special interest is antiepileptic activity of TRH, which suggests its potential use as an add-on drug in intractable epilepsy. An increasing body of preclinical evidences shows that TRH protects neuronal cells against a variety of damaging agents. Considering the lack of an efficient neuroprotective drug, the above facts suggest a potential utility of TRH and its analogues in the treatment of neurodegenerative disorders.

  15. Neuropsychological effects of antiepileptic drugs (carbamazepine versus valproate in adult males with epilepsy

    Directory of Open Access Journals (Sweden)

    Ghaydaa A Shehata

    2009-10-01

    Full Text Available Ghaydaa A Shehata,1 Abd El-aziz M Bateh,2 Sherifa A Hamed,1 Tarek A Rageh,1 Yaser B Elsorogy11Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University, Egypt; 2Department of Psychology, Faculty of Arts, Banha University, EgyptPurpose: To evaluate the effect of antiepileptic drugs (AEDs on cognition and behavior in adult epileptic males controlled on treatment with conventional antiepileptic medications. Methods: Cognitive, mood, behavior and personality traits were assessed in 45 epileptic patients treated with carbamazepine and/or valproate and free of seizures for ≥1 year. Thirty-four newly diagnosed or untreated patients with epilepsy and 58 matched healthy subjects were also included for comparison. A battery of psychometric tests was utilized including Stanford-Binet (4th edition, Beck Inventory for Depression, Aggressive Scale and Eysenck Personality Questionnaire.Results: Compared to matched control subjects, treated and untreated epileptic patients had poor performance in different cognitive and behavioral functions testing. Treated patients had worse scores in memory for digits forward and backward, total short-term memory, extroversion and psychosis. The duration of AEDs intake was correlated with memory of objects (r = -0.323; P = 0.030, bead memory (r = -0.314; P = 0.036 and total nonverbal short-term memory (r = -0.346; P = 0.020. Treated and untreated epileptic patients had poor performance of similar extent in behavioral functions testing (depression, aggression and neurosis. The dose of AEDs was correlated with testing scores for neurosis (r = 0.307; P = 0.040, verbal aggression (r = 0.483; P = 0.001 and nonverbal aggression (r = 0.526; P = 0.000, and duration of drug intake was correlated with scores for depression (r = 0.384; P = 0.009, psychosis (r = 0.586; P = 0.0001 and nonverbal aggression (r = 0.300; P = 0.045.Conclusions: This study provides support for the notion that AEDs can impair performance

  16. Broad spectrum antiviral activity of favipiravir (T-705: protection from highly lethal inhalational Rift Valley Fever.

    Directory of Open Access Journals (Sweden)

    Amy L Caroline

    2014-04-01

    Full Text Available BACKGROUND: Development of antiviral drugs that have broad-spectrum activity against a number of viral infections would be of significant benefit. Due to the evolution of resistance to currently licensed antiviral drugs, development of novel anti-influenza drugs is in progress, including Favipiravir (T-705, which is currently in human clinical trials. T-705 displays broad-spectrum in vitro activity against a number of viruses, including Rift Valley Fever virus (RVFV. RVF is an important neglected tropical disease that causes human, agricultural, and economic losses in endemic regions. RVF has the capacity to emerge in new locations and also presents a potential bioterrorism threat. In the current study, the in vivo efficacy of T-705 was evaluated in Wistar-Furth rats infected with the virulent ZH501 strain of RVFV by the aerosol route. METHODOLOGY/PRINCIPAL FINDINGS: Wistar-Furth rats are highly susceptible to a rapidly lethal disease after parenteral or inhalational exposure to the pathogenic ZH501 strain of RVFV. In the current study, two experiments were performed: a dose-determination study and a delayed-treatment study. In both experiments, all untreated control rats succumbed to disease. Out of 72 total rats infected with RVFV and treated with T-705, only 6 succumbed to disease. The remaining 66 rats (92% survived lethal infection with no significant weight loss or fever. The 6 treated rats that succumbed survived significantly longer before succumbing to encephalitic disease. CONCLUSIONS/SIGNIFICANCE: Currently, there are no licensed antiviral drugs for treating RVF. Here, T-705 showed remarkable efficacy in a highly lethal rat model of Rift Valley Fever, even when given up to 48 hours post-infection. This is the first study to show protection of rats infected with the pathogenic ZH501 strain of RVFV. Our data suggest that T-705 has potential to be a broad-spectrum antiviral drug.

  17. Antiepileptic Drug Removal by Continuous Renal Replacement Therapy: A Review of the Literature.

    Science.gov (United States)

    Mahmoud, Sherif Hanafy

    2017-01-01

    Continuous renal replacement therapy (CRRT) is used for managing acute kidney injury in critically ill patients. Removal of antiepileptic drugs (AEDs) by CRRT could be significant and may complicate patients' intensive care unit stay. The objective of the current review was to summarize the available evidence for AED removal by CRRT. An electronic literature search of PubMed (1946 to May 2016), Medline (1946 to May 2016), and Embase (1974 to May 2016) databases for studies discussing AED removal by CRRT was conducted. A total of 31 case reports discussing 32 patients were found. AEDs reported were levetiracetam (n = 3), valproic acid (n = 9), carbamazepine (n = 10), phenytoin (n = 3), phenobarbital (n = 4), lacosamide (n = 1), gabapentin (n = 1), and topiramate (n = 1). Two-thirds of the reports were about using CRRT in drug overdose and one-third was about AED removal by CRRT during therapy. Based on the current limited evidence and pharmacokinetic characteristics of AEDs, renally eliminated AEDs and/or AEDs with limited protein binding such as levetiracetam are more likely to be removed by CRRT than AEDs that are mainly metabolized and extensively protein bound such as carbamazepine. In conclusion, there is not enough evidence to provide robust dosing recommendations for AEDs in patients undergoing CRRT. Further studies are needed.

  18. The effect of antiepileptic drugs on the kidney function and structure.

    Science.gov (United States)

    Hamed, Sherifa Ahmed

    2017-09-01

    Long-term use of antiepileptic drugs (AEDs) is associated with number of somatic conditions. Data from experimental, cross-sectional and prospective studies have evidence for the deleterious effect of some AEDs on the kidney. Areas covered: This review summarized the current knowledge of the effect of AEDs on the kidney including evidence and mechanisms. Fanconi syndrome was reported with valproate (VPA) therapy in severely disabled children with epilepsy. Renal tubular acidosis and urolithiasis were reported with acetazolamide, topirmate and zonisamide, drugs with carbonic anhydrase inhibition properties. Increased levels of urinary N-acetyl-beta-D-glucosaminidase (NAG) to urinary creatinine (U-NAG/UCr), urinary excretion of α1-micrglobulin, β-galactosidase activity; and urinary malondialdehyde to creatinine (MDA/Cr), markers of renal glomerular and tubular injury, were reported with chronic use of some AEDs (VPA, carbamazepine and phenytoin). The mechanism(s) of kidney dysfunction/injury induced by AEDs is unknown. Experimental and clinical studies have shown that VPA induces oxidative stress, mitochondrial deficits, carnitine deficiency and inflammation and fibrosis in renal tissue in mice and in vitro studies. Expert commentary: It seems reasonable to monitor kidney function during treating patients with epilepsy at high risk of kidney injury (e.g. on combined therapy with more than one AED, severely disabled children, etc).

  19. Variations in pill appearance of antiepileptic drugs and the risk of nonadherence.

    Science.gov (United States)

    Kesselheim, Aaron S; Misono, Alexander S; Shrank, William H; Greene, Jeremy A; Doherty, Michael; Avorn, Jerry; Choudhry, Niteesh K

    2013-02-11

    Generic prescription drugs are bioequivalent to brand-name versions but may not have consistent color or shape, which can cause confusion and lead to interruptions in medication use. We sought to determine whether switching among different-appearing antiepileptic drugs (AEDs) is associated with increased rates of medication nonpersistence, which can have serious medical, financial, and social consequences. We designed a nested case-control study of commercially insured patients in the United States who initiated an AED. Cases were patients who became nonpersistent, defined as failure to fill a prescription within 5 days of the elapsed days supplied. Controls had no delay in refilling and were matched by sex, age, number of refills, and the presence of a seizure disorder diagnosis. We evaluated the 2 refills preceding nonpersistence and determined whether pill color and/or shape matched ("concordant") or did not match ("discordant"). We compared the odds of discordance among cases and controls using multivariate conditional logistic regression, adjusting for baseline characteristics, and drug type. We repeated our analysis among patients with a seizure diagnosis. The AEDs dispensed had 37 colors and 4 shapes. A total of 11,472 patients with nonpersistence were linked to 50,050 controls. Color discordance preceded 136 cases (1.20%) but only 480 controls (0.97%) (adjusted odds ratio [OR], 1.27 [95% CI, 1.04-1.55]). Shape discordance preceded 18 cases (0.16%) and 54 controls (0.11%) (OR, 1.47 [95% CI, 0.85-2.54]). Within the seizure disorder diagnosis subgroup, the risk of nonpersistence after changes in pill color was also significantly elevated (OR, 1.53 [95%, CI 1.07-2.18]). Changes in pill color significantly increase the odds of nonpersistence; this may have important clinical implications. Our study supports a reconsideration of current regulatory policy that permits wide variation in the appearance of bioequivalent drugs.

  20. Multivalent dendritic molecules as broad spectrum bacteria agglutination agents.

    Science.gov (United States)

    Xiao, Shuzhang; Abu-Esba, Lica; Turkyilmaz, Serhan; White, Alexander G; Smith, Bradley D

    2013-01-01

    This study reports the first set of synthetic molecules that act as broad spectrum agglutination agents and thus are complementary to the specific targeting of antibodies. The molecules have dendritic architecture and contain multiple copies of zinc(II)-dipicolylamine (ZnDPA) units that have selective affinity for the bacterial cell envelope. A series of molecular structures were evaluated, with the number of appended ZnDPA units ranging from four to thirty-two. Agglutination assays showed that the multivalent probes rapidly cross-linked ten different strains of bacteria, regardless of Gram-type and cell morphology. Fluorescence microscopy studies using probes with four ZnDPA units indicated a high selectivity for bacteria agglutination in the presence of mammalian cells and no measurable effect on the health of the cells. The high bacterial selectivity was confirmed by conducting in vivo optical imaging studies of a mouse leg infection model. The results suggest that multivalent ZnDPA molecular probes with dendritic structures have great promise as selective, broad spectrum bacterial agglutination agents for infection imaging and theranostic applications.

  1. Broad-spectrum antimicrobial polycarbonate hydrogels with fast degradability.

    Science.gov (United States)

    Pascual, Ana; Tan, Jeremy P K; Yuen, Alex; Chan, Julian M W; Coady, Daniel J; Mecerreyes, David; Hedrick, James L; Yang, Yi Yan; Sardon, Haritz

    2015-04-13

    In this study, a new family of broad-spectrum antimicrobial polycarbonate hydrogels has been successfully synthesized and characterized. Tertiary amine-containing eight-membered monofunctional and difunctional cyclic carbonates were synthesized, and chemically cross-linked polycarbonate hydrogels were obtained by copolymerizing these monomers with a poly(ethylene glycol)-based bifunctional initiator via organocatalyzed ring-opening polymerization using 1,8-diazabicyclo[5.4.0]undec-7-ene catalyst. The gels were quaternized using methyl iodide to confer antimicrobial properties. Stable hydrogels were obtained only when the bifunctional monomer concentration was equal to or higher than 12 mol %. In vitro antimicrobial studies revealed that all quaternized hydrogels exhibited broad-spectrum antimicrobial activity against Staphylococcus aureus (Gram-positive), Escherichia coli (Gram-negative), Pseudomonas aeruginosa (Gram-negative), and Candida albicans (fungus), while the antimicrobial activity of the nonquaternized hydrogels was negligible. Moreover, the gels showed fast degradation at room temperature (4-6 days), which makes them ideal candidates for wound healing and implantable biomaterials.

  2. The Teratogenic Effects of Antiepileptic Drug, Topiramate, on the Development of Chick Embryos

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    Jantima Roongruangchai

    2017-05-01

    Full Text Available Background: Anti-epileptic drugs are known to be the risk of teratogenicity. Topiramate (TPM is a new kind of such drug, for which no research has confirmed the incidence of producing congenital abnormalities. Objective: This study was conducted to study the teratogenic effects of TPM by using chick embryos as an animal model and the results can be compared to the human embryo of the same stage. Methods: Fertilized Leghorn hen eggs were injected in ovo with two concentrations of TPM, which were 10mg, and 20mg, in NSS at a volume of 0.1 ml into the yolk sac at 21 hrs of incubation and repeated injections at 72 hrs at a volume of 0.05 ml. The chick embryos on day 3, 6 and 11 of incubation were sacrificed and all living embryos were processed for total mount and serial section. Results: The mortality rate increased corresponding to the concentrations of TPM, and the embryonic stage. The total mount of day 3 showed major abnormalities of the eye and heart, such as microphthalmia and looser of heart looping. The serial section of day 3 showed opening of the anterior neuropore, ectopia viscerae and multiple malformations of the eye and heart. Day 6 chick embryos showed ectopia cordis and ectopia viscerae. Moreover, there were retardation and abnormalities of several organs such as eye, heart, liver, mesonephros and gonads. Day 11 chick embryos showed ectopia viscerae and several growth retardations, retardation of ossification of both limb bones and skull bones. Conclusion: This study showed that TPM might cause embryonic death, growth retardation and abnormalities of the eye, heart, an opening of the anterior neuropore and ectopia viscerae. This might indicate abnormalities to the baby born from mother with gestational epilepsy who was taking this drug continuously, and it might lead to spontaneous abortion or congenital anomalies of the fetus.

  3. Cross-National comparison of antiepileptic drug use: Catalonia, Denmark and Norway, 2007-2011

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    Pili Ferrer-Argeles

    2014-07-01

    Full Text Available Background: Antiepileptic drug  (AEDconsumption has increased in recent years mainly from those AEDs marketed since 1990. The purpose is to describe and compare AED consumption in Catalonia, Denmark and Norway.Methods: Population-based descriptive study set in the outpatient healthcare sector. Data were retrieved from the Norwegian Prescription Register, Danish Register of Medicinal Product Statistics and DATAMART® in Catalonia, for 2007-2011.We calculated defined daily doses/1000 inhabitants/day (DID, by age and gender. AEDs were defined according to the Anatomical Therapeutic Chemical classification (N03A. We reviewed the population covered by the databases, the drug data source and the definition of outpatient healthcare sector to compare the results across the three settings.Results: Total AED use steadily increased over the study period in the three settings. In 2011, consumption was highest in Catalonia (15.20 DID, followed by Denmark (15.06 DID and Norway (14.24 DID. The “other AEDs” (N03AX subgroup represented 60% of all AED use. The N03A pattern by gender did not differ across the three settings. Marked differences by age and gender appeared when studying lamotrigine, topiramate, gabapentin, pregabalin and levetiracetam.  Differences among the databases were mainly in the definition of outpatient healthcare setting.Conclusions: There was a rapid increase in “other AEDs” in all three settings. Although we did not have information on the indication for the use of AEDs, the drug data source, population coverage of the database and definition of the healthcare setting helped us interpret the results.

  4. Metabolic and hormonal disturbances in women with epilepsy on antiepileptic drug monotherapy.

    Science.gov (United States)

    Kim, Jee Young; Lee, Hyang Woon

    2007-07-01

    Women with epilepsy (WWE) tend to have hormonal and metabolic abnormalities, raising concerns about an increased risk of cardiovascular disorders. This study was performed to determine whether epilepsy itself and/or antiepileptic drug (AED) medication cause metabolic abnormalities. WWE in premenopausal state aged 18 to 45 years old, currently on AED monotherapy for more than six months, were recruited for this study. The subjects checked their oral temperature each morning, and tested serum levels for lipid profiles, insulin, glucose, and leptin. A HOMA-index was used as a marker for insulin resistance. Of the 54 total patients, 18 women were diagnosed with primary generalized epilepsy (PGE) and the other 36 were diagnosed with localization-related epilepsy (LRE). Among the subjects, 19 women were on carbamazepine (CBZ), 12 on valproate (VPA), 12 on lamotrigine (LTG), and 11 on topiramate (TPM). Body mass index increased and HDL-cholesterol decreased in patients on VPA monotherapy compared with CBZ, LTG, or TPM (p=0.046 and 0.002). Metabolic syndrome was more frequently associated with VPA-treated patients (41.7%) than CBZ (5.3%), LTG (0%), or TPM group (0%) (p=0.005). There were no differences in hormonal and metabolic indices between PGE and LRE groups. WWE on VPA monotherapy are more obese and more frequently suffer from metabolic syndrome. LTG or TPM may be safer when prescribed to the patients with high risk of cardiovascular disease.

  5. Impact of antiepileptic drugs on bone health: Need for monitoring, treatment, and prevention strategies

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    Ekta Arora

    2016-01-01

    Full Text Available Epilepsy is the most common neurological disorder affecting approximately 50 million people worldwide. In India, overall prevalence of epilepsy is reported to be 5.59/1000 population. Antiepileptic drugs (AEDs constitute the main-stay of treatment with a large number of AEDs available in the market. High incidence of adverse effects is a major limitation with AEDs. One of the major concerns is significant metabolic effects on the bone. However, little attention has been paid to this issue because most of the bone effects remain subclinical for a long time and may take years to manifest clinically. The main effects include hypocalcemia, hypophosphatemia, reduced serum levels of Vitamin D, increase in parathormone (PTH levels, and alterations in bone turnover markers. The CYP450 enzyme-inducing AEDs such as phenytoin, phenobarbital, carbamazepine, and primidone are the most common AEDs associated with bone disorders while the data regarding the effect of valproate and newer AEDs such as lamotrigine, gabapentin, vigabatrin, levetiracetam, and topiramate on bone metabolism and bone density are scanty and controversial. Deficiency of Vitamin D is commonly described as a cause for the bone loss in epileptic patients while others being decreased absorption of calcium, increased PTH levels, and inhibition of calcitonin secretion, etc. However, there are no formal practical guidelines for the management of bone disease among those taking AEDs. Evidence-based strategies regarding monitoring, prevention, and treatment of bone diseases in patients on AED therapy are needed.

  6. Chronic antiepileptic drug use and functional network efficiency: A functional magnetic resonance imaging study.

    Science.gov (United States)

    van Veenendaal, Tamar M; IJff, Dominique M; Aldenkamp, Albert P; Lazeron, Richard H C; Hofman, Paul A M; de Louw, Anton J A; Backes, Walter H; Jansen, Jacobus F A

    2017-06-28

    To increase our insight in the neuronal mechanisms underlying cognitive side-effects of antiepileptic drug (AED) treatment. The relation between functional magnetic resonance-acquired brain network measures, AED use, and cognitive function was investigated. Three groups of patients with epilepsy with a different risk profile for developing cognitive side effects were included: A "low risk" category (lamotrigine or levetiracetam, n = 16), an "intermediate risk" category (carbamazepine, oxcarbazepine, phenytoin, or valproate, n = 34) and a "high risk" category (topiramate, n = 5). Brain connectivity was assessed using resting state functional magnetic resonance imaging and graph theoretical network analysis. The Computerized Visual Searching Task was used to measure central information processing speed, a common cognitive side effect of AED treatment. Central information processing speed was lower in patients taking AEDs from the intermediate and high risk categories, compared with patients from the low risk category. The effect of risk category on global efficiency was significant (P 0.2). Also no significant associations between information processing speed and global efficiency or the clustering coefficient (linear regression analysis, P > 0.15) were observed. Only the four patients taking topiramate show aberrant network measures, suggesting that alterations in functional brain network organization may be only subtle and measureable in patients with more severe cognitive side effects.

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

    Science.gov (United States)

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

    2013-11-26

    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. 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. 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. 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.

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

    Science.gov (United States)

    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. Copyright © 2015. Published by Elsevier Ltd.

  9. Effects of Antiepileptic Drugs on the Carotid Artery Intima-Media Thickness in Epileptic Patients.

    Science.gov (United States)

    Lai, Qilun; Shen, Chunhong; Zheng, Yang; Zhang, Yinxi; Guo, Yi; Ding, Meiping

    2017-10-01

    It has been reported that taking antiepileptic drugs (AEDs) may increase the risk of atherosclerosis. We performed a meta-analysis to evaluate the carotid artery intima-media thickness (CA-IMT) as a surrogate factor for atherosclerosis in epileptic patients. We searched NCBI (PubMed), ISI Web of Knowledge, EMBASE, and the Cochrane Library databases for studies of the association between AEDs and CA-IMT in epileptic patients. A random-effects meta-analysis was used to pool results across studies. Fifteen studies involving 1,775 epileptic patients were included in the analysis. The overall CA-IMT was significantly larger among users of AEDs [mean difference (MD)=0.09 mm, 95% confidence interval (CI)=0.06-0.12 mm). When stratified by age, the MD was similar in adult patients (MD=0.09 mm, 95% CI=0.06-0.13 mm), but no significant difference was observed in children (MD=0.03 mm, 95% CI=0.00-0.07 mm). Regarding specific AEDs, monotherapy with carbamazepine (CBZ) or valproic acid (VPA) was associated with a larger CA-IMT, while phenytoin monotherapy was not and the result for lamotrigine was inconclusive. This study suggests that using AEDs is associated with the CA-IMT in patients with epilepsy, particularly for adult patients. In particular, CBZ and VPA may be related to a significant increase in CA-IMT.

  10. Antiepileptic drugs during pregnancy in primary care: a UK population based study.

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    Shuk-Li Man

    Full Text Available Antiepileptic drugs (AEDs are commonly prescribed for epilepsy and bipolar disorder but little is known about their use in pregnancy. We examined secular trends in AED prescribing in pregnancy and pregnancy as a determinant for stopping AED prescribing.We identified 174,055 pregnancies from The Health Improvement Network UK primary care database. Secular trends in AED prescribing during pregnancy were examined between 1994 and 2009. We used Cox's regression analyses to compare time to discontinuation of AED prescriptions between pregnant and non-pregnant women and to identify predictors of discontinuation of AEDs in pregnancy.Prescribing of carbamazepine and sodium valproate have declined since 1994 despite being the most commonly prescribed AEDs in pregnancy up to 2004. Prescribing of lamotrigine in pregnancy has steadily increased and has been the most popular AED prescribed in pregnancy since 2004. Pregnant women with epilepsy were twice as likely to stop receiving AEDs (Hazard Ratio (HR 2.00, 95% Confidence Interval (CI 1.62-2.47 when compared to non-pregnant women and for women with bipolar disorder this was even higher (HR 3.07, 95% CI 2.04-4.62. For pregnant women with epilepsy, those receiving AEDs less regularly before pregnancy were more likely to stop receiving AEDs in pregnancy.Lamotrigine has been increasingly prescribed in pregnancy over older AEDs namely carbamazepine and sodium valproate. Pregnancy is a strong determinant for the discontinuation of AED prescribing particularly for women with bipolar disorder.

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

    OpenAIRE

    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 epi...

  12. Studies on the effects of acetylcholine and antiepileptic drugs on /sup 32/P incorporation into phospholipids of rat brain synaptosomes

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    Aly, M.I.; Abdel-Latif, A.A.

    1982-02-01

    Studies were conducted on the effects of antiepileptic drugs on the acetylcholine-stimulated /sup 32/P labeling of phospholipids in rat brain synaptosomes. Of the four antiepileptic drugs investigated in the present study, namely phenytoin, carbamazepine, phenobarbital, and valproate, only phenytoin blocked the acetylcholine-stimulated /sup 32/P labeling of phosphatidylinositol and phosphatidic acid, and the acetylcholine-stimulated breakdown of polyphosphoinositides. Phenytoin alone, like atropine alone, had no effect on the /sup 32/P labeling of phospholipids nor on the specific radioactivity of (/sup 32/P)ATP. Omission of Na/sup +/ drastically reduced both the /sup 32/P labeling of synaptosomal phospholipids and the specific radioactivity of (/sup 32/P)ATP and furthermore it significantly decreased the phosphoinositide effect. It was concluded that certain antiepileptic drugs, such as phenytoin, could exert their pharmacological actions through their antimuscarinic effects. In addition the finding that phenytoin, which acts to regulate NA/sup +/ and Ca/sup 2 +/ permeability of neuronal membranes, also inhibited the phosphoinositide effects in synaptosomes, support the conclusions that Ca2+ and Na+ are probably involved in the molecular mechanism underlying this phenomenon in excitable tissues.

  13. Prevention of Fetal Congenital Malformations with Allowance for the Pharmacogenetic Features of the Metabolism of Antiepileptic Drugs and Hereditary Abnormalities in the Folate Cycle

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    D. V. Dmitrenko

    2014-01-01

    Full Text Available Fetal congenital malformations are among the most dangerous complications of pregnancy in women with epilepsy taking antiepileptic drugs. Valproic acid and phenobarbital have the greatest risk of teratogenic effects. Insights into the current mechanisms of teratogenic effect of antiepileptic drugs, pharmacogenetic features of the metabolism of valproates and hereditary abnormalities in the folate cycle enables prevention of fetal congenital malformations. 

  14. Lamotrigine, an antiepileptic drug, inhibits 5-HT3 receptor currents in NCB-20 neuroblastoma cells.

    Science.gov (United States)

    Kim, Ki Jung; Jeun, Seung Hyun; Sung, Ki-Wug

    2017-03-01

    Lamotrigine is an antiepileptic drug widely used to treat epileptic seizures. Using whole-cell voltage clamp recordings in combination with a fast drug application approach, we investigated the effects of lamotrigine on 5-hydroxytryptamine (5-HT)3 receptors in NCB-20 neuroblastoma cells. Co-application of lamotrigine (1~300 µM) resulted in a concentration-dependent reduction in peak amplitude of currents induced by 3 µM of 5-HT for an IC50 value of 28.2±3.6 µM with a Hill coefficient of 1.2±0.1. These peak amplitude decreases were accompanied by the rise slope reduction. In addition, 5-HT3-mediated currents evoked by 1 mM dopamine, a partial 5-HT3 receptor agonist, were inhibited by lamotrigine co-application. The EC50 of 5-HT for 5-HT3 receptor currents were shifted to the right by co-application of lamotrigine without a significant change of maximal effect. Currents activated by 5-HT and lamotrigine co-application in the presence of 1 min pretreatment of lamotrigine were similar to those activated by 5-HT and lamotrigine co-application alone. Moreover, subsequent application of lamotrigine in the presence of 5-HT and 5-hydroxyindole, known to attenuate 5-HT3 receptor desensitization, inhibited 5-HT3 receptor currents in a concentration-dependent manner. The deactivation of 5-HT3 receptor was delayed by washing with an external solution containing lamotrigine. Lamotrigine accelerated the desensitization process of 5-HT3 receptors. There was no voltage-dependency in the inhibitory effects of lamotrigine on the 5-HT3 receptor currents. These results indicate that lamotrigine inhibits 5-HT3-activated currents in a competitive manner by binding to the open state of the channels and blocking channel activation or accelerating receptor desensitization.

  15. [Consensus clinical practice guidelines of the Andalusian Epilepsy Society on prescribing generic antiepileptic drugs].

    Science.gov (United States)

    Cañadillas-Hidalgo, F M; Sánchez-Alvarez, J C; Serrano-Castro, P J; Mercadé-Cerdá, J M

    Pharmaceutical spending in Spain accounts for 1.2-1.4% of the gross domestic product and is increasing by 5-12% per year. One of the measures adopted by the government to cut this spending is the possible substitution of original prescribed drugs by generics. In the case of antiepileptic drugs (AED), which are characterised by a scant therapeutic margin, these steps have sparked a scientific debate about their repercussion on the control of epileptic patients. We propose to draw up a set of implicit evidence-based consensus practice guidelines concerning issues related with this topic. A selective search for quality scientific information on the subject was conducted on PubMed-Medline, Tripdatabase and the Biblioteca Cochrane Plus. The selected references were analysed and discussed by the authors, and the recommendations deriving from them were collected. A total of 21 primary documents and 16 practice guidelines, protocols or experts' recommendations were identified. Our recommendations were explicitly included at the end of the text. The Andalusian Epilepsy Society makes the following recommendations: 1) not replacing an innovative AED by its generic in a controlled patient; 2) beginning treatment with a generic AED in monotherapy or in association is acceptable; 3) not exchanging generic AED from different pharmaceutical companies; 4) explaining to the patient the rules governing the authorization of generics and the importance of avoiding exchanges between different generic AED; and 5) if there is some worsening of the clinical condition or side effects appear following the introduction of a generic, the causes must be investigated and communicated to the bodies responsible for pharmacovigilance.

  16. Clinical outcomes and immune benefits of anti-epileptic drug therapy in HIV/AIDS

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    Krentz Hartmut B

    2010-06-01

    Full Text Available Abstract Background Anti-epileptic drugs (AEDs are frequently prescribed to persons with HIV/AIDS receiving combination antiretroviral therapy (cART although the extent of AED use and their interactions with cART are uncertain. Herein, AED usage, associated toxicities and immune consequences were investigated. Methods HIV replication was analysed in proliferating human T cells during AED exposure. Patients receiving AEDs in a geographically-based HIV care program were assessed using clinical and laboratory variables in addition to assessing AED indication, type, and cumulative exposures. Results Valproate suppressed proliferation in vitro of both HIV-infected and uninfected T cells (p 0.05 but AED exposures did not affect HIV production in vitro. Among 1345 HIV/AIDS persons in active care between 2001 and 2007, 169 individuals were exposed to AEDs for the following indications: peripheral neuropathy/neuropathic pain (60%, seizure/epilepsy (24%, mood disorder (13% and movement disorder (2%. The most frequently prescribed AEDs were calcium channel blockers (gabapentin/pregabalin, followed by sodium channel blockers (phenytoin, carbamazepine, lamotrigine and valproate. In a nested cohort of 55 AED-treated patients receiving cART and aviremic, chronic exposure to sodium and calcium channel blocking AEDs was associated with increased CD4+ T cell levels (p 0.05 with no change in CD8+ T cell levels over 12 months from the beginning of AED therapy. Conclusions AEDs were prescribed for multiple indications without major adverse effects in this population but immune status in patients receiving sodium or calcium channel blocking drugs was improved.

  17. Persistence with antiepileptic drugs in epilepsy patients treated in neurological practices in Germany.

    Science.gov (United States)

    Jacob, Louis; Hamer, Hajo M; Kostev, Karel

    2017-08-01

    The goal of this study was to analyze the persistence with antiepileptic drugs (AED) and associated factors in patients followed in neurological practices in Germany. This study included patients aged 18years or over who received two initial diagnoses of epilepsy and a first prescription of AED between 2007 and 2015 in a neurological practice (index date). The main outcome measure was the rate of AED persistence within five years of the index date. Kaplan-Meier analyses were performed to study treatment persistence as a function of age. A Cox proportional hazards regression model was used to estimate the relationship between non-persistence and demographic/clinical variables. A total of 8192 patients followed in neurological practices were included. After five years of follow-up, 41.1% (≤40years), 45.2%, (41-60years) and 50.1% (>60years) of patients followed in neurological practices were persistent (log-rank p-value60years: OR=1.19, 95% CI: 1.09-1.31; 41-60years vs. >60years: OR=1.10, 95% CI: 1.01-1.19). Furthermore, patients receiving old AED (OR=1.16, 95% CI: 1.01-1.34) or gabapentin (OR=1.46, 95% CI: 1.16-1.83) and those diagnosed with depression (OR=1.12, 95% CI: 1.03-1.21) were at a higher risk of non-persistence, whereas those receiving levetiracetam (OR=0.69, 95% CI: 0.60-0.80) or lamotrigine (OR=0.88, 95% CI: 0.79-0.97) and those with dementia (OR=0.74, 95% CI: 0.65-0.83) were at a lower risk. The rate of epilepsy patients persistent with AED was low after five years of treatment. Age, gender, co-morbidities, and drug characteristics were associated with this persistence. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Efficacy and safety of Levetiracetam vs. other antiepileptic drugs in Hispanic patients with glioblastoma.

    Science.gov (United States)

    Cardona, Andrés F; Rojas, Leonardo; Wills, Beatriz; Bernal, Laura; Ruiz-Patiño, Alejandro; Arrieta, Oscar; Hakim, Enrique Jiménez; Hakim, Fernando; Mejía, Juan Armando; Useche, Nicolás; Bermúdez, Sonia; Carranza, Hernán; Vargas, Carlos; Otero, Jorge; Mayor, Luis Carlos; Ortíz, León Darío; Franco, Sandra; Ortíz, Carlos; Gil-Gil, Miguel; Balaña, Carmen; Zatarain-Barrón, Zyanya Lucia

    2018-01-01

    Epilepsy is a common symptom in patients with glioblastoma (GB). 213 patients with GB from RedLANO follow-up registry were included. All patients underwent surgery, if feasible, followed by chemoradiation based on temozolomide (Stupp platform). Information was recorded regarding demographics, seizure timing, anti-epileptic drugs (AEDs), dosage, time to next seizure, total seizures in 6 months, and main side effects of AEDs. The relationship between epilepsy treatment and overall survival (OS) was evaluated. Mean age was 53 years old and 56.8% were male. Seventy-eight patients (37%) were treated with levetiracetam (LEV), 27% were given another AED and 36% did not require any AED. Choice of AED was not associated with age (p = 0.67), performance status (p = 0.24) or anatomic tumor site (p = 0.34). Seizures and AED requirement were greater in those having primary GB (p = 0.04). After starting an AED, the mean time until next crisis was 9.9 days (SD ± 6.3), which was shorter in those receiving LEV (p = 0.03); mean number of seizures during the first 3 and 6 months were 2.9 and 4, respectively. Most patients treated with LEV (n = 46) required less than two medication adjustments compared to those treated with other AEDs (p = 0.02). Likewise, less patients exposed to LEV required a coadjuvant drug (p = 0.04). Additionally, patients receiving LEV had significantly less adverse effects compared to patients treated with another AED. OS was significantly higher in the group treated with LEV compared to other AEDs (25.5 vs. 17.9 months; p = 0.047). Patients treated with LEV had better seizure control and longer OS compared to other AEDs.

  19. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.

    Science.gov (United States)

    Nevitt, Sarah J; Sudell, Maria; Weston, Jennifer; Tudur Smith, Catrin; Marson, Anthony G

    2017-06-29

    Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices. To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus). We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016. We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types). This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary

  20. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.

    Science.gov (United States)

    Nevitt, Sarah J; Sudell, Maria; Weston, Jennifer; Tudur Smith, Catrin; Marson, Anthony G

    2017-12-15

    Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices. To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus). We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016. We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types). This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary

  1. Nitroimidazoles: Molecular Fireworks That Combat a Broad Spectrum of Infectious Diseases.

    Science.gov (United States)

    Ang, Chee Wei; Jarrad, Angie M; Cooper, Matthew A; Blaskovich, Mark A T

    2017-09-28

    Infectious diseases claim millions of lives every year, but with the advent of drug resistance, therapeutic options to treat infections are inadequate. There is now an urgent need to develop new and effective treatments. Nitroimidazoles are a class of antimicrobial drugs that have remarkable broad spectrum activity against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. While nitroimidazoles were discovered in the 1950s, there has been renewed interest in their therapeutic potential, particularly for the treatment of parasitic infections and tuberculosis. In this review, we summarize different classes of nitroimidazoles that have been described in the literature in the past five years, from approved drugs and clinical candidates to examples undergoing preclinical or early stage development. The relatively "nonspecific" mode of action and resistance mechanisms of nitromidazoles are discussed, and contemporary strategies to facilitate nitroimidazole drug development are highlighted.

  2. Nanomedicine for Infectious Disease Applications: Innovation towards Broad-Spectrum Treatment of Viral Infections.

    Science.gov (United States)

    Jackman, Joshua A; Lee, Jaywon; Cho, Nam-Joon

    2016-03-02

    Nanomedicine enables unique diagnostic and therapeutic capabilities to tackle problems in clinical medicine. As multifunctional agents with programmable properties, nanomedicines are poised to revolutionize treatment strategies. This promise is especially evident for infectious disease applications, for which the continual emergence, re-emergence, and evolution of pathogens has proven difficult to counter by conventional approaches. Herein, a conceptual framework is presented that envisions possible routes for the development of nanomedicines as superior broad-spectrum antiviral agents against enveloped viruses. With lipid membranes playing a critical role in the life cycle of medically important enveloped viruses including HIV, influenza, and Ebola, cellular and viral membrane interfaces are ideal elements to incorporate into broad-spectrum antiviral strategies. Examples are presented that demonstrate how nanomedicine strategies inspired by lipid membranes enable a wide range of targeting opportunities to gain control of critical stages in the virus life cycle through either direct or indirect approaches involving membrane interfaces. The capabilities can be realized by enabling new inhibitory functions or improving the function of existing drugs through nanotechnology-enabled solutions. With these exciting opportunities, due attention is also given to the clinical translation of nanomedicines for infectious disease applications, especially as pharmaceutical drug-discovery pipelines demand new routes of innovation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Mapping the availability, price, and affordability of antiepileptic drugs in 46 countries.

    Science.gov (United States)

    Cameron, Alexandra; Bansal, Amit; Dua, Tarun; Hill, Suzanne R; Moshe, Solomon L; Mantel-Teeuwisse, Aukje K; Saxena, Shekhar

    2012-06-01

    In low- and middle-income countries (LMICs), a large proportion of people with epilepsy do not receive treatment. An analysis of the availability, price, and affordability of antiepileptic drugs (AEDs) was conducted to evaluate whether these factors contribute to the treatment gap. Data for five AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, and diazepam) were obtained from facility-based surveys conducted in 46 countries using the World Health Organization/Health Action International (WHO/HAI) methodology. Outcome measures were percentage availability, ratios of local prices to international reference prices, and number of days' wages needed by the lowest-paid unskilled government worker to purchase treatment. Prices were adjusted for inflation/deflation and purchasing power parity. The average availability of generic AEDs in the public sector was availability of generic oral AEDs ranged from 42.2% for phenytoin to 69.6% for phenobarbital. Public sector patient prices for generic carbamazepine and phenytoin were 4.95 and 17.50 times higher than international reference prices, respectively, whereas private sector patient prices were 11.27 and 24.77 times higher, respectively. For both medicines, originator brand prices were about 30 times higher. The highest prices were observed in the lowest income countries. The lowest-paid government worker would need wages from 1-2.6 days' to purchase a month's supply of phenytoin, whereas carbamazepine would cost 2.7-16.2 days' wages. Despite its widespread use in LMICs, WHO/HAI survey data for phenobarbital was only available from a small number of countries. In LMICs, availability and affordability of AEDs are poor and may be acting as a barrier to accessing treatment for epilepsy. Ensuring a consistent supply of AEDs at an affordable price should be a priority. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

  4. Psychiatric and behavioral side effects of anti-epileptic drugs in adolescents and children with epilepsy.

    Science.gov (United States)

    Chen, B; Detyniecki, K; Choi, H; Hirsch, L; Katz, A; Legge, A; Wong, R; Jiang, A; Buchsbaum, R; Farooque, P

    2017-05-01

    The objective of the study was to compare the psychiatric and behavioral side effect (PBSE) profiles of both older and newer antiepileptic drugs (AEDs) in children and adolescent patients with epilepsy. We used logistic regression analysis to test the correlation between 83 non-AED/patient related potential predictor variables and the rate of PBSE. We then compared for each AED the rate of PBSEs and the rate of PBSEs that led to intolerability (IPBSE) while controlling for non-AED predictors of PBSEs. 922 patients (≤18 years old) were included in our study. PBSEs and IPBSEs occurred in 13.8% and 11.2% of patients, respectively. Overall, a history of psychiatric condition, absence seizures, intractable epilepsy, and frontal lobe epilepsy were significantly associated with increased PBSE rates. Levetiracetam (LEV) had the greatest PBSE rate (16.2%). This was significantly higher compared to other AEDs. LEV was also significantly associated with a high rate of IPBSEs (13.4%) and dose-decrease rates due to IPBSE (6.7%). Zonisamide (ZNS) was associated with significantly higher cessation rate due to IPBSE (9.1%) compared to other AEDs. Patients with a history of psychiatric condition, absence seizures, intractable epilepsy, or frontal lobe epilepsy are more likely to develop PBSE. PBSEs appear to occur more frequently in adolescent and children patients taking LEV compared to other AEDs. LEV-attributed PBSEs are more likely to be associated with intolerability and subsequent decrease in dose. The rate of ZNS-attributed IPBSEs is more likely to be associated with complete cessation of AED. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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

    2015-09-10

    It is unknown if prenatal exposure to antiepileptic drugs (AEDs) increases the risk of low Apgar score in offspring. Population-based study using health registers in Denmark. 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. 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. 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 Apgar score associated with certain AEDs. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  6. Response to first antiepileptic drug trial predicts health outcome in epilepsy.

    Science.gov (United States)

    Perucca, Piero; Hesdorffer, Dale C; Gilliam, Frank G

    2011-12-01

    Failure to respond to the initial antiepileptic drug (AED) is a predictor of increased risk of pharmacoresistant epilepsy. Whether response to the first AED also predicts adverse health outcomes is unknown. This longitudinal study compared rates of major adverse health outcomes (loss of driving privileges, unemployment, divorce/separation, injury, emergency room admission, hospitalization, and death) in 33 patients who failed the first AED (cases) and 30 patients who became seizure-free with the first AED (controls). Patient data were obtained by chart review and confirmed through a structured interview with each subject at 5-7 years after starting AED treatment. We also assessed between-group differences in quality of life, depression, and adverse AED effects by using standardized instruments completed by each subject at the end of follow-up. The number of major adverse health outcomes was similarly high during the first year of AED treatment [mean ± standard deviation (SD) 2.64 ± 0.99 for cases and 2.50 ± 1.14 for controls], but thereafter decreased to a greater extent in controls than in cases (p rates similar to those recorded in patients with persisting seizures. After 4 years, however, cases who achieved late seizure freedom tended to show a more favorable outcome. Patients with epilepsy failing the initial AED trial are at increased risk of experiencing adverse health outcomes, at least for the first 4 years after diagnosis. Incorporating these findings into clinical decision making may aid in reducing delays in surgical referrals for pharmacoresistant epilepsy. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

  7. Relation between sexual dysfunctions and epilepsy, type of epilepsy, type of antiepileptic drugs: a prospective study.

    Science.gov (United States)

    Pavone, Carlo; Giacalone, Ninfa; Vella, Marco; Urso, Lidia; Zummo, Leila; Fierro, Brigida

    2017-04-28

    The aim of this study was to evaluate the incidence of sexual dysfunctions in males with epilepsy, the type of epilepsy, the frequency of seizures, the type of antiepileptic drugs (AEDs), the serum hormonal profile and the presence of psychiatric comorbidity. Sixty-one patients focused on type of epilepsy, frequency of seizures, AEDs, hormonal profile and presence of mood disorders. We excluded all patients with severe neurologic and psychiatric impairment and patient who were not able to fill questionnaires. Mean age was 31.2 years (range 18-50 years); 31 patients (50.8%) had an idiopathic generalised epilepsy and 30 (49.2%) a focal epilepsy; among them, latter 18 (60%) had probably symptomatic type and 12 (40%) symptomatic type. Sexual functions were evaluated by "International Inventory of Erectile Function" questionnaire. Out of 61 enrolled patients, 22 (36.7%) showed sexual dysfunctions: erectile dysfunctions in 14 (23%), orgasmic dysfunctions in (11.5%) and sexual drive dysfunctions in 12 (19.7%). Out of 61 patients, 36 were subjected to blood measurement of sexual hormones and 21 (58.3%) showed hormonal modifications. Sexual dysfunction are present in 36.7% of enrolled males with epilepsy; there is any association between sexual dysfunctions and various AEDs in the treatment, except for carbamazepine (CBZ); there is not any association between sexual dysfunctions and frequency of seizures; hormonal changes are associated with sexual dysfunction in males with epilepsy treated with AEDs but not with the orgasmic dysfunction; there is not any association between hormonal changes and type of AEDs, except for CBZ; depression is associated with sexual dysfunctions.

  8. Antiepileptic drug-induced bone loss in young male patients who have seizures.

    Science.gov (United States)

    Andress, Dennis L; Ozuna, Judy; Tirschwell, David; Grande, Lucinda; Johnson, Meshell; Jacobson, Arnold F; Spain, William

    2002-05-01

    Long-term antiepileptic drug (AED) therapy is a known risk factor for bone loss and fractures. Vitamin D deficiency is frequently cited as a cause for bone loss in patients who have seizures. To determine whether men who have seizures, but who are otherwise healthy, suffer substantial bone loss in the hip while taking AEDs. We prospectively examined femoral neck bone mineral density (BMD) by dual-energy x-ray absorptiometry in 81 consecutive men, aged between 25 and 54 years old (mean age, 45 years), who were attending an outpatient seizure clinic. Low BMD values were analyzed for known risk factors for bone loss. Dual-energy x-ray absorptiometry scans were repeated in 54 patients, 12 to 29 months later (mean, 19 months), to assess the rate of change in BMD over time. Multivariate linear regression analysis revealed that age (P<.001) and time receiving AEDs (P<.003) were the 2 important risk factors associated with low femoral neck BMD. Neither vitamin D deficiency, hypogonadism, cigarette smoking, nor excess alcohol intake were associated with low BMD after correcting for age and time on AEDs. Longitudinal analysis of femoral neck BMD revealed that only those in the youngest age group (25-44 years) showed significant declines in femoral neck BMD (1.8% annualized loss; 95% confidence interval, -3.1 to -0.9; P<.003) while receiving AED therapy. There was no evidence that a specific type of AED was more causally related to bone loss in this group although most patients were taking phenytoin sodium or carbamazepine during the longitudinal assessment. Long-term AED therapy in young male patients who have seizures causes significant bone loss at the hip in the absence of vitamin D deficiency. Dual-energy x-ray absorptiometry scanning of the hip is useful in identifying patients who are particularly susceptible to rapid bone loss while taking AEDs.

  9. Anti-epileptic Drug (AED) Use in Subarachnoid Hemorrhage (SAH) and Intracranial Hemorrhage (ICH).

    Science.gov (United States)

    Feng, Rui; Mascitelli, Justin; Chartrain, Alexander G; Margetis, Konstantinos; Mocco, J

    2017-10-30

    Aneurysmal subarachnoid hemorrhage (aSAH) and spontaneous intracranial hemorrhage (ICH) are frequently associated with epileptic complications. The use of anti-epileptic drugs (AEDs) for seizure prophylaxis, however, is controversial. In patients with aSAH, nonconvulsive status epilepticus has been associated with poor outcome. Effect of other forms of less severe epileptiform activity on clinical outcome remains unclear. Evidence on efficacy of AEDs in reducing seizure incidence is also mixed. However, increasing number of studies suggest that AEDs may have significant adverse effects on outcome, especially with phenytoin. Similarly, in patients with ICH, the impact of seizures that do not progress to status epilepticus on clinical outcome is controversial, and whether prophylactic AED use has independent effects on outcome remains ambiguous. Currently, there are no large scale randomized control trials investigating the efficacy and safety of AED prophylaxis in patients with hemorrhagic stroke. There are also no trials comparing the efficacy and safety of the different AEDs. Survey based studies have found a wide range of prescribing patterns across treatment centers and clinicians for seizure prophylaxis in patients with hemorrhagic stroke. The lack of clear guidelines and recommendations also highlights the paucity of good quality evidence in this area. In conclusion, a well-designed randomized, double blinded, and appropriately powered trial is needed to evaluate the incidence as well as clinical outcomes in patients with aSAH and ICH who received AED prophylaxis versus controls. The results will be extremely valuable in providing evidence to establish management guidelines for patients with hemorrhagic stroke. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis.

    Science.gov (United States)

    Chuang, Yao-Chung; Chuang, Hung-Yi; Lin, Tsu-Kung; Chang, Chiung-Chih; Lu, Cheng-Hsien; Chang, Wen-Neng; Chen, Shang-Der; Tan, Teng-Yeow; Huang, Chi-Ren; Chan, Samuel H H

    2012-01-01

    Long-term therapy with antiepileptic drugs (AEDs) has been associated with metabolic consequences that lead to an increase in risk of atherosclerosis in patients with epilepsy. We compared the long-term effects of monotherapy using different categories of AEDs on markers of vascular risk and the atherosclerotic process. One hundred sixty adult patients who were receiving AED monotherapy, including two enzyme-inducers (carbamazepine, CBZ; and phenytoin, PHT), an enzyme-inhibitor (valproic acid, VPA), and a noninducer (lamotrigine, LTG) for more than 2 years, and 60 controls were enrolled in this study. All study participants received measurement of common carotid artery (CCA) intima media thickness (IMT) by B-mode ultrasonography to assess the extent of atherosclerosis. Other measurements included body mass index, and serum lipid profile or levels of total homocysteine (tHcy), folate, uric acid, fasting blood sugar, high sensitivity C-reactive protein (hs-CRP), or thiobarbituric acid reactive substances (TBARS). Long-term monotherapy with older-generation AEDs, including CBZ, PHT, and VPA, caused significantly increased CCA IMT in patients with epilepsy. After adjustment for the confounding effects of age and gender, the CCA IMT was found to be positively correlated with the duration of AED therapy. Patients with epilepsy who were taking enzyme-inducing AED monotherapy (CBZ, PHT) manifested disturbances of cholesterol, tHcy or folate metabolism, and elevation of the inflammation marker, hs-CRP. On the other hand, patients on enzyme-inhibiting AED monotherapy (VPA) exhibited an increase in the levels of uric acid and tHcy, and elevation of the oxidative marker, TBARS. However, no significant alterations in the markers of vascular risk or CCA IMT were observed in patients who received long-term LTG monotherapy. Patients with epilepsy who were receiving long-term monotherapy with CBZ, PHT, or VPA exhibited altered circulatory markers of vascular risk that may

  11. Patient emotions and perceptions of antiepileptic drug changes and titration during treatment for epilepsy.

    Science.gov (United States)

    Fishman, Jesse; Cohen, Greg; Josephson, Colin; Collier, Ann Marie; Bharatham, Srikanth; Zhang, Ying; Wild, Imane

    2017-04-01

    To investigate the impact of antiepileptic drug (AED) change and dose titration on the emotional well-being of patients with epilepsy. Members of an online epilepsy community were invited to voluntarily participate in an online survey. The cross-sectional anonymous survey consisted of 31 multiple choice questions balanced in terms of variety and positivity/negativity of emotions concerning participants' most recent AED change. To substantiate survey results, spontaneous comments from epilepsy-related online forums and social media websites that mentioned participants' experiences with AED medication changes (termed passive listening statements) were analyzed and categorized by theme. All 345 survey participants (270 [78.3%] female; 172 [49.9%] were 26-45years old) self-reported an epilepsy/seizure diagnosis and were currently taking seizure medication; 263 (76.2%) were taking ≥2 AEDs and 301 (87.2%) had ≥1 seizure in the previous 18months. All participants reported a medication change within the previous 12months (dose increased [153 participants (44.3%)], medication added [105 (30.4%)], dose decreased [49 (14.2%)], medication removed [38 (11.0%)]). Improving seizure control (247 [71.6%]) and adverse events (109 [31.6%]) were the most common reasons for medication change. Primary emotions most associated (≥10% of participants) with an AED regimen change were (before medication change; during/after medication change) hopefulness (50 [14.5%]; 43 [12.5%]), uncertainty (50 [14.5%]; 69 [20.0%]), and anxiety (35 [10.1%]; 45 [13.0%]), and were largely due to concerns whether the change would work (212/345 [61.4%]; 180/345 [52.2%]). In the text analysis segment aimed at validating the survey, 230 participants' passive listening statements about medication titration were analyzed; additional seizure activity during dose titration (93 [40.4%]), adverse events during titration (71 [30.9%]), higher medication dosages (33 [14.3%]), and drug costs (25 [10.9%]) were the

  12. Antiepileptic drugs prescribed in pregnancy and prevalence of major congenital malformations: comparative prevalence studies

    Directory of Open Access Journals (Sweden)

    Petersen I

    2017-02-01

    Full Text Available Irene Petersen,1,2 Shuk-Li Collings,1,3 Rachel L McCrea,1 Irwin Nazareth,1 David P Osborn,4 Phil J Cowen,5 Cormac J Sammon1 1Department of Primary Care and Population Health, University College London, London, UK; 2Department of Clinical Epidemiology, Aarhus University, Aarhus N, Denmark; 3OXON Epidemiology, London, UK; 4Division of Psychiatry, University College London, London, UK; 5University Department of Psychiatry, Warneford Hospital, Oxford, UK Objective: The aim of this study was to examine the prevalence of major congenital malformations associated with antiepileptic drug (AED treatment in pregnancy.Patients and methods: Using data from The Health Improvement Network, we identified women who have given live birth and their offspring. Four subgroups were selected based on the AED treatment in early pregnancy, valproate, carbamazepine, lamotrigine and women not receiving AED treatment. We compared the prevalence of major congenital malformations within children of these four groups and estimated prevalence ratios (PRs using Poisson regression adjusted for maternal age, sex of child, quintiles of Townsend deprivation score and indication for treatment.Results: In total, 240,071 women were included in the study. A total of 229 women were prescribed valproate in pregnancy, 357 were prescribed lamotrigine and 334 were prescribed carbamazepine and 239,151 women were not prescribed AEDs. Fifteen out of 229 (6.6% women prescribed valproate gave birth to a child with a major congenital malformation. The figures for lamotrigine, carbamazepine and women not prescribed AEDs were 2.7%, 3.3% and 2.2%, respectively. The prevalence of major congenital malformation was similar for women prescribed lamotrigine or carbamazepine compared to women with no AED treatment in pregnancy. For women prescribed valproate in polytherapy, the prevalence was fourfold higher. After adjustments, the effect of estimates attenuated, but the prevalence remained two- to

  13. A Broad-Spectrum Inhibitor of CRISPR-Cas9.

    Science.gov (United States)

    Harrington, Lucas B; Doxzen, Kevin W; Ma, Enbo; Liu, Jun-Jie; Knott, Gavin J; Edraki, Alireza; Garcia, Bianca; Amrani, Nadia; Chen, Janice S; Cofsky, Joshua C; Kranzusch, Philip J; Sontheimer, Erik J; Davidson, Alan R; Maxwell, Karen L; Doudna, Jennifer A

    2017-09-07

    CRISPR-Cas9 proteins function within bacterial immune systems to target and destroy invasive DNA and have been harnessed as a robust technology for genome editing. Small bacteriophage-encoded anti-CRISPR proteins (Acrs) can inactivate Cas9, providing an efficient off switch for Cas9-based applications. Here, we show that two Acrs, AcrIIC1 and AcrIIC3, inhibit Cas9 by distinct strategies. AcrIIC1 is a broad-spectrum Cas9 inhibitor that prevents DNA cutting by multiple divergent Cas9 orthologs through direct binding to the conserved HNH catalytic domain of Cas9. A crystal structure of an AcrIIC1-Cas9 HNH domain complex shows how AcrIIC1 traps Cas9 in a DNA-bound but catalytically inactive state. By contrast, AcrIIC3 blocks activity of a single Cas9 ortholog and induces Cas9 dimerization while preventing binding to the target DNA. These two orthogonal mechanisms allow for separate control of Cas9 target binding and cleavage and suggest applications to allow DNA binding while preventing DNA cutting by Cas9. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Broad spectrum microarray for fingerprint-based bacterial species identification

    Directory of Open Access Journals (Sweden)

    Frey Jürg E

    2010-02-01

    Full Text Available Abstract Background Microarrays are powerful tools for DNA-based molecular diagnostics and identification of pathogens. Most target a limited range of organisms and are based on only one or a very few genes for specific identification. Such microarrays are limited to organisms for which specific probes are available, and often have difficulty discriminating closely related taxa. We have developed an alternative broad-spectrum microarray that employs hybridisation fingerprints generated by high-density anonymous markers distributed over the entire genome for identification based on comparison to a reference database. Results A high-density microarray carrying 95,000 unique 13-mer probes was designed. Optimized methods were developed to deliver reproducible hybridisation patterns that enabled confident discrimination of bacteria at the species, subspecies, and strain levels. High correlation coefficients were achieved between replicates. A sub-selection of 12,071 probes, determined by ANOVA and class prediction analysis, enabled the discrimination of all samples in our panel. Mismatch probe hybridisation was observed but was found to have no effect on the discriminatory capacity of our system. Conclusions These results indicate the potential of our genome chip for reliable identification of a wide range of bacterial taxa at the subspecies level without laborious prior sequencing and probe design. With its high resolution capacity, our proof-of-principle chip demonstrates great potential as a tool for molecular diagnostics of broad taxonomic groups.

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

    Science.gov (United States)

    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. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  16. Intelligence quotient improves after antiepileptic drug withdrawal following pediatric epilepsy surgery.

    Science.gov (United States)

    Boshuisen, Kim; van Schooneveld, Monique M J; Uiterwaal, Cuno S P M; Cross, J Helen; Harrison, Sue; Polster, Tilman; Daehn, Marion; Djimjadi, Sarina; Yalnizoglu, Dilek; Turanli, Guzide; Sassen, Robert; Hoppe, Christian; Kuczaty, Stefan; Barba, Carmen; Kahane, Philippe; Schubert-Bast, Susanne; Reuner, Gitta; Bast, Thomas; Strobl, Karl; Mayer, Hans; de Saint-Martin, Anne; Seegmuller, Caroline; Laurent, Agathe; Arzimanoglou, Alexis; Braun, Kees P J

    2015-07-01

    Antiepileptic drugs (AEDs) have cognitive side effects that, particularly in children, may affect intellectual functioning. With the TimeToStop (TTS) study, we showed that timing of AED withdrawal does not majorly influence long-term seizure outcomes. We now aimed to evaluate the effect of AED withdrawal on postoperative intelligence quotient (IQ), and change in IQ (delta IQ) following pediatric epilepsy surgery. We collected IQ scores of children from the TTS cohort with both pre- and postoperative neuropsychological assessments (NPAs; n = 301) and analyzed whether reduction of AEDs prior to the latest NPA was related to postoperative IQ and delta IQ, using linear regression analyses. Factors previously identified as independently relating to (delta) IQ, and currently identified predictors of (delta) IQ, were considered possible confounders and used for adjustment. Additionally, we adjusted for a compound propensity score that contained previously identified determinants of timing of AED withdrawal. Mean interval to the latest NPA was 19.8 ± 18.9 months. Reduction of AEDs at the latest NPA significantly improved postoperative IQ and delta IQ (adjusted regression coefficient [RC] = 3.4, 95% confidence interval [CI] = 0.6-6.2, p = 0.018 and RC = 4.5, 95% CI = 1.7-7.4, p = 0.002), as did complete withdrawal (RC = 4.8, 95% CI = 1.4-8.3, p = 0.006 and RC = 5.1, 95% CI = 1.5-8.7, p = 0.006). AED reduction also predicted ≥ 10-point IQ increase (p = 0.019). The higher the number of AEDs reduced, the higher was the IQ (gain) after surgery (RC = 2.2, 95% CI = 0.6-3.7, p = 0.007 and RC = 2.6, 95% CI = 1.0-4.2, p = 0.001, IQ points per AED reduced). Start of AED withdrawal, number of AEDs reduced, and complete AED withdrawal were associated with improved postoperative IQ scores and gain in IQ, independent of other determinants of cognitive outcome. © 2015 American Neurological Association.

  17. Calcified neurocysticercosis lesions and antiepileptic drug-resistant epilepsy: a surgically remediable syndrome?

    Science.gov (United States)

    Rathore, Chaturbhuj; Thomas, Bejoy; Kesavadas, Chandrasekharan; Abraham, Mathew; Radhakrishnan, Kurupath

    2013-10-01

    In contrast to the well-recognized association between acute symptomatic seizures and neurocysticercosis, the association between antiepileptic drug (AED)-resistant epilepsy and calcified neurocysticercosis lesions (CNLs) is poorly understood. We studied the association between AED-resistant epilepsy and CNLs, including the feasibility and outcome of resective surgery. From the prospective database maintained at our epilepsy center, we reviewed the data of all patients with AED-resistant epilepsy who underwent presurgical evaluation from January 2001 to July 2010 and had CNL on imaging. We used clinical, neuroimaging, and interictal, ictal, and intracranial electroencephalography (EEG) findings to determine the association between CNL and epilepsy. Suitable candidates underwent resective surgery. Forty-five patients fulfilled the inclusion criteria. In 17 patients, CNL was proven to be the causative lesion for AED-resistant epilepsy (group 1); in 18 patients, CNL was associated with unilateral hippocampal sclerosis (HS; group 2); and in 10 patients, CNLs were considered as incidental lesions (group 3). In group 1 patients, CNLs were more common in frontal lobes (12/17), whereas in group 2 patients, CNLs were more commonly located in temporal lobes (11/18; p = 0.002). Group 2 patients were of a younger age at epilepsy onset than those in group 1 (8.9 ± 7.3 vs. 12.6 ± 6.8 years, p = 0.003). Perilesional gliosis was more common among patients in group 1 when compared to group 3 patients (12/17 vs. 1/10; p = 0.006). Fifteen patients underwent resective surgery. Among group 1 patients, four of five became seizure-free following lesionectomy alone. In group 2, four patients underwent anterior temporal lobectomy (ATL) alone, of whom one became seizure-free; five underwent ATL combined with removal of CNL (two of them after intracranial EEG and all of them became seizure-free, whereas one patient underwent lesionectomy alone and did not become seizure-free. In endemic

  18. Association between sociodemographic status and antiepileptic drug prescriptions in children with epilepsy.

    Science.gov (United States)

    Mattsson, Peter; Tomson, Torbjörn; Edebol Eeg-Olofsson, Karin; Brännström, Lars; Ringbäck Weitoft, Gunilla

    2012-12-01

    We investigated whether in Sweden sociodemographic differences are associated with access to expert health care and antiepileptic drug (AED) prescriptions in children with epilepsy. Data on epilepsy, prescription of AEDs, and sociodemographic variables were obtained from several national administrative registers. We linked individual data to examine whether access by pediatric epilepsy patients to neuropediatricians and the prescription of individual AEDs differed according to gender, age, parental education, place of residence, parental region of birth, and household income. We also assessed whether AEDs are prescribed differently to patients with epilepsy by neuropediatricians as compared to other physicians. Of 1,788,382 children aged 1-17 years in 2006, living in the country by the end of 2006, 9,935 had a diagnosis of epilepsy (0.56%). Patients with epilepsy on AED treatment (n = 3,631) comprised 0.24% of the total Swedish population aged 1-17 years. Out of 3631 patients with epilepsy on AED treatment, 2301 (63.4%) received prescriptions from a neuropediatrician. Children with epilepsy aged 1-5 years old--as opposed to older children and adolescents--and children with epilepsy residing in large cities--as opposed to children living in smaller cities and rural areas--were more likely to be treated by a neuropediatrician. Children living in large cities received oxcarbazepine to a greater extent than children living in rural areas. Levetiracetam was prescribed more extensively to children whose parents had higher incomes. Of the five most frequently used AEDs, three (lamotrigine, oxcarbazepine, and levetiracetam) were prescribed to a larger extent by a neuropediatrician rather than by other specialists, and one AED (carbamazepine) was prescribed to a lesser extent. The results of this nationwide cross-sectional study of children with epilepsy are important because they show that universal coverage for medical care does not eliminate inequalities of access to

  19. Antiepileptic Drug Titration and Related Health Care Resource Use and Costs.

    Science.gov (United States)

    Fishman, Jesse; Kalilani, Linda; Song, Yan; Swallow, Elyse; Wild, Imane

    2018-02-27

    Unexpected breakthrough seizures resulting from suboptimal antiepileptic drug (AED) dosing during the titration period, as well as adverse events resulting from rapid AED titration, may influence the titration schedule and significantly increase health care resource use (HRU) and health care costs. To assess the relationship between AEDs, HRU, and costs during AED titration and maintenance. Practicing neurologists were recruited from a nationwide panel to provide up to 3 patient records each for this retrospective medical chart review. Patients with epilepsy who were aged ≥ 18 years and had initiated an AED between January 1, 2014, and January 1, 2016, were followed for 6 months from AED initiation. Titration duration was the time from AED initiation to the beginning of treatment maintenance as determined by the physician. Outcomes were epilepsy-specific HRU (hospitalizations, emergency department visits, outpatient visits, physician referral, laboratory testing/diagnostic imaging, and phone calls) and related costs that occurred during the titration or maintenance treatment periods. Of 811 patients, 156, 128, 125, 120, 114, 107, and 61 initiated the following AEDs: levetiracetam, lamotrigine, lacosamide, valproate, topiramate, carbamazepine, and phenytoin, respectively. Most patients (619/803 [77.1%] with complete AED data) received monotherapy. Baseline characteristics were similar across AEDs (mean [SD] age, 36.6 [14.4] years; 59.0% male). Kaplan-Meier estimates of titration duration ranged from 3.3 weeks (phenytoin) to 8.1 weeks (lamotrigine). From titration to maintenance, the overall incidence of HRU per person-month decreased 54.5%-89.3% for each HRU measure except outpatient visits (24.6% decrease). Total epilepsy-related costs decreased from $80.48 to $42.77 per person-month, or 46.9% from titration to maintenance. AED titration periods had higher HRU rates and costs than AED maintenance, suggesting that use of AEDs with shorter titration requirements

  20. Prenatal exposure to antiepileptic drugs and use of primary healthcare during childhood: a population-based cohort study in Denmark

    DEFF Research Database (Denmark)

    Würtz, Anne Mette Lund; Rytter, Dorte; Vestergaard, Claus Høstrup

    2017-01-01

    OBJECTIVE: Prenatal exposure to antiepileptic drugs (AEDs) has been associated with adverse outcomes in the offspring such as congenital malformations and neuropsychiatric disorders. The objective of this study was to investigate whether prenatal exposure to AEDs is also associated with more...... of the child, maternal age, cohabitation status, income, education, substance abuse, depression, severe psychiatric disorders and use of antipsychotics, antidepressants and insulin. RESULTS: Children exposed prenatally to AEDs (n=4478) had 3% (95% CI 0 to 5%) more GP contacts during the study period than...

  1. Clinical characteristics and use of antiepileptic drugs among adolescents with uncomplicated epilepsy at a referral center in Novi Sad, Serbia.

    Science.gov (United States)

    Gebauer-Bukurov, Ksenija; Bozic, Ksenija; Sekulic, Slobodan

    2012-06-01

    The study aimed to investigate the type and etiology of epileptic seizures and the use of antiepileptic drugs for the treatment of various forms of epileptic seizures among adolescents with active but uncomplicated epilepsy at a tertiary referral center in Novi Sad, Serbia. The study design was cross sectional. Data were obtained from patients and medical records. A total of 103 adolescents (39 males and 64 females) with active but uncomplicated epilepsy were included. Patients with primary generalized seizures had significantly better control of epilepsy than those with partial seizures with or without secondary generalization. A total of 80 (77.7%) adolescents had no known underlying etiology based on initial diagnosis and evaluation. All adolescents were classified into known idiopathic syndromes (54.4%), non-classifiable cryptogenic etiology (23.3%), and secondary epilepsy attributed to MRI-identified lesions (22.3%). Eighty-eight percent of adolescents were taking monotherapy and 64.8% of these were taking valproate. New antiepileptic drugs (AEDs), topiramate and lamotrigine, the only drugs available free of charge at the Serbian market, were used in 19.4% of patients. A total of 57.3% adolescents were seizure-free, 24.2% had occasional seizures, and 18.5% had seizures despite AED treatment.

  2. The benefits of antiepileptic drug (AED) blood level monitoring to complement clinical management of people with epilepsy.

    Science.gov (United States)

    Stepanova, Daria; Beran, Roy G

    2015-01-01

    Some argue that there is no evidence to support the use of antiepileptic drug (AED) blood level monitoring when treating people with epilepsy (PWE). This paper identifies how AED monitoring can be invaluable in such treatment. SPECIFIC EXAMPLES: (i) Compliance: Antiepileptic drug blood levels often confirm noncompliance rather than adequate seizure control, confirming subtherapeutic levels in PWE attending hospitals due to seizures. Routine monitoring of AED levels may prevent breakthrough seizures by identifying noncompliance and instituting heightened compliance measures before experiencing breakthrough seizures without modifying dosages. For PWE attending hospitals due to seizures, loading with the AED shown to be subtherapeutic may be all that is required. (ii) Cluster seizures and status epilepticus: When using long-acting AEDs to complement benzodiazepines, blood level monitoring confirms that an adequate dosage was given and, if not, a further bolus can be administered with further monitoring. This is particularly useful when using rectal administration of AEDs. (iii) Polypharmacy: Polypharmacy provokes drug interactions in which case AED monitoring helps in differentiating adequate dosing, offending AED with toxicity and free level measuring benefits when total levels are unhelpful. (iv) Generic substitution: Generic AEDs can fluctuate considerably from a parent compound, and even a parent compound, sourced from an alternative supplier, may have altered bioavailability for which blood level monitoring is very useful. While therapeutic blood level monitoring is not a substitute for good clinical judgment, it offers a valuable adjunct to patient care. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. A Novel Scaffold for Developing Specific or Broad-Spectrum Chitinase Inhibitors.

    Science.gov (United States)

    Jiang, Xi; Kumar, Ashutosh; Liu, Tian; Zhang, Kam Y J; Yang, Qing

    2016-12-27

    Chitinases play important roles in pathogen invasion, arthropod molting, plant defense, and human inflammation. Inhibition of the activity of a typical chitinase by small molecules is of significance in drug development and biological research. On the basis of a recent reported crystal structure of OfChtI, the insect chitinase derived from the pest Ostrinia furnacalis, we computationally identified 17 compounds from a library of over 4 million chemicals by two rounds virtual screening. Among these, three compounds from one chemical class inhibited the activity of OfChtI with single-digit-micromolar IC50 values, and one compound from another chemical class exhibited a broad inhibitory activity not only toward OfChtI but also toward bacterial, fungal, and human chitinases. A new scaffold was discovered, and a structure-inhibitory activity relationship was proposed. This work may provide a novel starting point for the development of specific or broad-spectrum chitinase inhibitors.

  4. Utilization of antiepileptic drugs during pregnancy: Comparative patterns in 38 countries based on data from the EURAP registry

    DEFF Research Database (Denmark)

    Battino, D.; Bonizzoni, E.; Craig, J.

    2009-01-01

    We assessed the utilization of antiepileptic drugs (AEDs), 1999-2005, in 4,798 prospective epilepsy pregnancies from 38 countries participating in EURAP, an international AED and pregnancy registry. Prominent differences in utilization patterns were observed across the various countries. Exposure...... to second-generation AEDs ranged from 3.5% in India and 7.3% in Italy to 75% in Denmark. Even wider variation was recorded in exposure to individual AEDs. The utilization of second-generation AEDs increased over time (for lamotrigine, from 9.9% of all pregnancies before 2001 to 29.6% after 2003......). The differences in use of individual AEDs across countries probably reflect lack of evidence concerning the optimal treatment of epilepsy in women of childbearing age, as well as variation in country-specific traditions, medication costs, and drug promotion. Our observations underscore the need for comparative...

  5. A mastoparan-derived peptide has broad-spectrum antiviral activity against enveloped viruses.

    Science.gov (United States)

    Sample, Christopher J; Hudak, Kathryn E; Barefoot, Brice E; Koci, Matthew D; Wanyonyi, Moses S; Abraham, Soman; Staats, Herman F; Ramsburg, Elizabeth A

    2013-10-01

    Broad-spectrum antiviral drugs are urgently needed to treat individuals infected with new and re-emerging viruses, or with viruses that have developed resistance to antiviral therapies. Mammalian natural host defense peptides (mNHP) are short, usually cationic, peptides that have direct antimicrobial activity, and which in some instances activate cell-mediated antiviral immune responses. Although mNHP have potent activity in vitro, efficacy trials in vivo of exogenously provided mNHP have been largely disappointing, and no mNHP are currently licensed for human use. Mastoparan is an invertebrate host defense peptide that penetrates lipid bilayers, and we reasoned that a mastoparan analog might interact with the lipid component of virus membranes and thereby reduce infectivity of enveloped viruses. Our objective was to determine whether mastoparan-derived peptide MP7-NH2 could inactivate viruses of multiple types, and whether it could stimulate cell-mediated antiviral activity. We found that MP7-NH2 potently inactivated a range of enveloped viruses. Consistent with our proposed mechanism of action, MP7-NH2 was not efficacious against a non-enveloped virus. Pre-treatment of cells with MP7-NH2 did not reduce the amount of virus recovered after infection, which suggested that the primary mechanism of action in vitro was direct inactivation of virus by MP7-NH2. These results demonstrate for the first time that a mastoparan derivative has broad-spectrum antiviral activity in vitro and suggest that further investigation of the antiviral properties of mastoparan peptides in vivo is warranted. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Papel de la monoterapia con nuevos fármacos antiepilépticos en el tratamiento de la epilepsia infantil Role of monotherapy with new antiepileptic drugs in the treatment of childhood epilepsy

    Directory of Open Access Journals (Sweden)

    Ignacio Valencia

    2009-01-01

    Full Text Available En este trabajo se revisa la información actual sobre el uso de los nuevos fármacos antiepilépticos (FAEs en monoterapia en niños, resaltando nuestra experiencia personal. Específicamente, se incluyen los siguientes FAEs: lamotrigina (Lamictal®, topiramato (Topamax®, zonisamida (Zonegran®, levetiracetam (Keppra®, y oxcarbacepina (Trileptal®. Todos estos FAEs tienen un amplio espectro de acción en el tratamiento de crisis epilépticas parciales y generalizadas, excepto la oxcarbacepina, que es eficaz exclusivamente en crisis parciales. No está claro si la monoterapia con estos FAEs, en comparación con los FAEs clásicos (fenobarbital, fenitoína, carbamacepina, valproato sódico, proporciona una mayor eficacia y/o causa menos efectos secundarios y, si por lo tanto, mejora significativamente la calidad de vida de los niños con epilepsia. Se necesitan más estudios para poder contestar estas preguntas.In this paper we review the current information regarding the use of new antiepileptic drugs (AEDs used as monotherapy in children. We specifically include the following AEDs: lamotrigine (Lamictal®, topiramate (Topamax®, zonisamide (Zonegran®, levetiracetam (Keppra®, and oxcarbazepine (Trileptal®. All of these AEDs have a broad spectrum of action in the treatment of partial and generalized seizures, except Oxcarbazepine, which is effective only in partial seizures. It is unclear whether or not monotherapy with the new AEDs offers higher efficacy and/or lower side effects compared to classic AEDs (phenobarbital, phenytoin, carbamazepine, or valproate thereby significantly improving the quality of life in children with epilepsy. More studies are needed to answer these questions.

  7. Unraveling novel broad-spectrum antibacterial targets in food and waterborne pathogens using comparative genomics and protein interaction network analysis.

    Science.gov (United States)

    Jadhav, Ankush; Shanmugham, Buvaneswari; Rajendiran, Anjana; Pan, Archana

    2014-10-01

    Food and waterborne diseases are a growing concern in terms of human morbidity and mortality worldwide, even in the 21st century, emphasizing the need for new therapeutic interventions for these diseases. The current study aims at prioritizing broad-spectrum antibacterial targets, present in multiple food and waterborne bacterial pathogens, through a comparative genomics strategy coupled with a protein interaction network analysis. The pathways unique and common to all the pathogens under study (viz., methane metabolism, d-alanine metabolism, peptidoglycan biosynthesis, bacterial secretion system, two-component system, C5-branched dibasic acid metabolism), identified by comparative metabolic pathway analysis, were considered for the analysis. The proteins/enzymes involved in these pathways were prioritized following host non-homology analysis, essentiality analysis, gut flora non-homology analysis and protein interaction network analysis. The analyses revealed a set of promising broad-spectrum antibacterial targets, present in multiple food and waterborne pathogens, which are essential for bacterial survival, non-homologous to host and gut flora, and functionally important in the metabolic network. The identified broad-spectrum candidates, namely, integral membrane protein/virulence factor (MviN), preprotein translocase subunits SecB and SecG, carbon storage regulator (CsrA), and nitrogen regulatory protein P-II 1 (GlnB), contributed by the peptidoglycan pathway, bacterial secretion systems and two-component systems, were also found to be present in a wide range of other disease-causing bacteria. Cytoplasmic proteins SecG, CsrA and GlnB were considered as drug targets, while membrane proteins MviN and SecB were classified as vaccine targets. The identified broad-spectrum targets can aid in the design and development of antibacterial agents not only against food and waterborne pathogens but also against other pathogens. Copyright © 2014 Elsevier B.V. All rights

  8. Modulation of Antioxidant Enzymatic Activities by Certain Antiepileptic Drugs (Valproic Acid, Oxcarbazepine, and Topiramate: Evidence in Humans and Experimental Models

    Directory of Open Access Journals (Sweden)

    Noemí Cárdenas-Rodríguez

    2013-01-01

    Full Text Available It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity. This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS activation and the generation of reactive oxygen species (ROS. Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA, oxcarbazepine (OXC, and topiramate (TPM modulate oxidative stress.

  9. USE OF THE NEW ANTIEPILEPTIC DRUG PERAMPANEL (FYCOMPA IN THE TREATMENT OF EPILEPSY: A REVIEW OF FOREIGN LITERATURE

    Directory of Open Access Journals (Sweden)

    O. A. Pylaeva

    2014-01-01

    Full Text Available Despite a considerable advance made in epileptology, resistant epilepsies are about 30% among all epilepsy types particularly in patients with focal seizures. In these cases, there is hope for the success of neurosurgical treatment and the synthesis of new antiepileptic drugs (AEDs. The authors provide a review of the literature dealing the new AED perampanel (Fycompa and consider its mechanism of action, pharmacokinetics, clinical and postmarketing trials of its efficacy, tolerability, and safety. Based on the data available in the literature, it may be concluded that parampanel is a promising highly effective and well tolerated AED to treat partial and secondary generalized seizures.

  10. Long-term neurological outcome of term-born children treated with two or more anti-epileptic drugs during the neonatal period

    NARCIS (Netherlands)

    van der Heide, Mariska J.; Roze, Elise; van der Veere, Christa N.; ter Horst, Hendrik J.; Brouwer, Oebele F.; Bos, Arend F.

    Background: Neonatal seizures may persist despite treatment with multiple anti-epileptic drugs (AEDs). Objective: To determine in term-born infants with seizures that required two or more AEDs, whether treatment efficacy and/or the underlying disorder were related to neurological outcome.

  11. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy.

    NARCIS (Netherlands)

    E.B. Samren (Bettina); C.M. van Duijn (Cornelia); S. Koch; V.K. Hiilesma; H. Klepel; A.H. Bardy; B. Mannegetta; A.W. Deichl; E. Gaily; M.L. Granstrom; H. Meinardi; D.E. Grobbee (Diederick); D. Lindhout (Dick); A. Hofman (Albert)

    1997-01-01

    textabstractPURPOSE: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy. METHODS: Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy

  12. Intestinal absorption of the antiepileptic drug substance vigabatrin in Göttingen mini-pigs is unaffected by co-administration of amino acids

    DEFF Research Database (Denmark)

    Nøhr, Martha Kampp; Holm, René; Thale, Zia Irene

    2014-01-01

    The anti-epileptic drug substance vigabatrin is used against infantile spasms. In vitro evidence suggests that vigabatrin is transported via the proton coupled amino acid transporter (PAT1). The aim of the present study was to investigate whether the intestinal absorption of vigabatrin in vivo wa...

  13. Cognitive consequences of early versus late antiepileptic drug withdrawal after pediatric epilepsy surgery, the TimeToStop (TTS) trial : study protocol for a randomized controlled trial

    NARCIS (Netherlands)

    Boshuisen, Kim|info:eu-repo/dai/nl/343391511; Lamberink, Herm J; van Schooneveld, Monique MJ|info:eu-repo/dai/nl/30481427X; Cross, J Helen; Arzimanoglou, Alexis; van der Tweel, Ingeborg|info:eu-repo/dai/nl/262684438; Geleijns, Karin|info:eu-repo/dai/nl/275854965; Uiterwaal, Cuno Spm|info:eu-repo/dai/nl/136603947; Braun, Kees PJ|info:eu-repo/dai/nl/207237239

    2015-01-01

    BACKGROUND: The goals of intentional curative pediatric epilepsy surgery are to achieve seizure-freedom and antiepileptic drug (AED) freedom. Retrospective cohort studies have indicated that early postoperative AED withdrawal unmasks incomplete surgical success and AED dependency sooner, but not at

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

    Science.gov (United States)

    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…

  15. An Australian nationwide survey on medicinal cannabis use for epilepsy: History of antiepileptic drug treatment predicts medicinal cannabis use.

    Science.gov (United States)

    Suraev, Anastasia S; Todd, Lisa; Bowen, Michael T; Allsop, David J; McGregor, Iain S; Ireland, Carol; Lintzeris, Nicholas

    2017-05-01

    Epilepsy Action Australia conducted an Australian nationwide online survey seeking opinions on and experiences with the use of cannabis-based products for the treatment of epilepsy. The survey was promoted via the Epilepsy Action Australia's main website, on their Facebook page, and by word of mouth. The survey consisted of 39 questions assessing demographics, clinical factors, including diagnosis and seizure types, and experiences with and opinions towards cannabis use in epilepsy. A total of 976 responses met the inclusion criteria. Results show that 15% of adults with epilepsy and 13% of parents/guardians of children with epilepsy were currently using, or had previously used, cannabis products to treat epilepsy. Of those with a history of cannabis product use, 90% of adults and 71% of parents reported success in reducing seizure frequency after commencing cannabis products. The main reasons for medicinal cannabis use were to manage treatment-resistant epilepsy and to obtain a more favorable side-effect profile compared to standard antiepileptic drugs. The number of past antiepileptic drugs tried was a significant predictor of medicinal cannabis use in both adults and children with epilepsy. Fifty-six percent of adults with epilepsy and 62% of parents/guardians of children with epilepsy expressed willingness to participate in clinical trials of cannabinoids. This survey provides insight into the use of cannabis products for epilepsy, in particular some of the likely factors influencing use, as well as novel insights into the experiences of and attitudes towards medicinal cannabis in people with epilepsy in the Australian community. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy". Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Fully validated method for rapid and simultaneous measurement of six antiepileptic drugs in serum and plasma using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry.

    Science.gov (United States)

    Kuhn, Joachim; Knabbe, Cornelius

    2013-06-15

    Therapeutic drug monitoring (TDM) may be very useful in the clinical management of antiepileptic drug therapy for multiple reasons, such as individual variability, metabolism, genetic factors or drug-drug or drug-food interactions. In addition, TDM is helpful to study the variation in pharmacokinetics that occurs between individuals. Here, we describe a rapid assay using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry to measure the antiepileptic drugs lacosamide, lamotrigine, levetiracetam, primidone, topiramate, and zonisamide. After the addition of internal standards (ISs) and protein precipitation of serum or plasma, 1 μl of sample was separated on a 2.1×50 mm reverse phase column (Waters, Acquity UPLC BEH Phenyl, 1.7 μm). Analytes were then ionized and detected by electrospray ionization mass spectrometry with multiple reaction monitoring. Runtime was 2.5 min per injection. Matrix effects were investigated by systematical ion suppression and in-source fragmentation experiments. The calibration curves of the 6 antiepileptic drugs were linear over the working range between 0.05 and 50 mg/L (r>0.99). The limit of detection (LOD) was measured in the assay. The intraassay and interassay coefficients of variation for all compounds were 1.0 mg/L). Mean recoveries were between 87.8 and 98.6% for all drugs. There were no significant ion suppressions detected at the elution times of the analytes. The mean differences between serum and heparinized plasma values were less than 6% for the 6 antiepileptic drugs. All drugs were stable in serum at -20°C, 4°C, and even at RT for at least 1 month. In summary, a specific and sensitive stable isotope dilution UPLC-MS/MS method was developed and validated for routine clinical monitoring of lacosamide, lamotrigine, levetiracetam, primidone, topiramate, and zonisamide. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. EFFECTIVE RELEASE OF A BROAD SPECTRUM ANTIBIOTIC FROM ELASTIN-LIKE POLYPEPTIDE-COLLAGEN COMPOSITE

    Science.gov (United States)

    Anderson, Tiffany R.; Marquart, Mary E.; Janorkar, Amol V.

    2014-01-01

    Preparation of hydrogels that possess an effective antibiotic release profile and better mechanical properties compared to the traditionally used collagen hydrogels has the potential to minimize post-surgical infections and support wound healing. Towards this goal, we prepared elastin-like polypeptide (ELP)-collagen composite hydrogels that displayed a significantly higher elastic modulus compared to the collagen hydrogels. We then characterized the release behavior of the collagen and ELP-collagen hydrogels loaded with varying dosages (1 – 5% w/w) of a commonly used broad spectrum antibiotic, doxycycline hyclate. Both collagen and ELP-collagen hydrogels showed a gradual time dependent doxycycline release over a period of 5 days. The ELP-collagen hydrogels, in general, showed a slower release of the doxycycline compared to the collagen hydrogels. The released doxycycline was found to be effective against four bacterial strains (Escherichia coli, Pseudomonas aeruginosa, Streptococcus sanguinis, and methicillin-resistant Staphylococcus aureus) in a dose dependent manner. Combined with their improved mechanical properties, the gradual and effective drug release from the biocompatible ELP-collagen hydrogels shown here may be beneficial for drug delivery and tissue engineering applications. PMID:24825292

  18. Predictive compound accumulation rules yield a broad-spectrum antibiotic

    Science.gov (United States)

    Richter, Michelle F.; Drown, Bryon S.; Riley, Andrew P.; Garcia, Alfredo; Shirai, Tomohiro; Svec, Riley L.; Hergenrother, Paul J.

    2017-05-01

    Most small molecules are unable to rapidly traverse the outer membrane of Gram-negative bacteria and accumulate inside these cells, making the discovery of much-needed drugs against these pathogens challenging. Current understanding of the physicochemical properties that dictate small-molecule accumulation in Gram-negative bacteria is largely based on retrospective analyses of antibacterial agents, which suggest that polarity and molecular weight are key factors. Here we assess the ability of over 180 diverse compounds to accumulate in Escherichia coli. Computational analysis of the results reveals major differences from the retrospective studies, namely that the small molecules that are most likely to accumulate contain an amine, are amphiphilic and rigid, and have low globularity. These guidelines were then applied to convert deoxynybomycin, a natural product that is active only against Gram-positive organisms, into an antibiotic with activity against a diverse panel of multi-drug-resistant Gram-negative pathogens. We anticipate that these findings will aid in the discovery and development of antibiotics against Gram-negative bacteria.

  19. A cost analysis of a broad-spectrum antibiotic therapy in the empirical treatment of health care-associated infections in cirrhotic patients

    Science.gov (United States)

    Lucidi, Cristina; Di Gregorio, Vincenza; Ceccarelli, Giancarlo; Venditti, Mario; Riggio, Oliviero; Merli, Manuela

    2017-01-01

    Background Early diagnosis and appropriate treatment of infections in cirrhosis are crucial. As new guidelines in this context, particularly for health care-associated (HCA) infections, would be needed, we performed a trial documenting whether an empirical broad-spectrum antibiotic therapy is more effective than the standard one for these infections. Because of the higher daily cost of broad-spectrum than standard antibiotics, we performed a cost analysis to compare: 1) total drug costs, 2) profitability of hospital admissions. Methods This retrospective observational analysis was performed on patients enrolled in the trial NCT01820026, in which consecutive cirrhotic patients with HCA infections were randomly assigned to a standard vs a broad-spectrum treatment. Antibiotic daily doses, days of treatment, length of hospital stay, and DRG (diagnosis-related group) were recorded from the clinical trial medical records. The profitability of hospitalizations was calculated considering DRG tariffs divided by length of hospital stay. Results We considered 84 patients (42 for each group). The standard therapy allowed to obtain a first-line treatment cost lower than in the broad-spectrum therapy. Anyway, the latter, being related to a lower failure rate (19% vs 57.1%), resulted in cost saving in terms of cumulative antibiotic costs (first- and second-line treatments). The mean cost saving per patient for the broad-spectrum arm was €44.18 (−37.6%), with a total cost saving of about €2,000. Compared to standard group, we observed a statistically significant reduction in hospital stay from 17.8 to 11.8 days (pprofitable daily cost than standard group (€345.61 vs €252.23; +37%). Conclusion Our study supports the idea that the use of a broad-spectrum empirical treatment for HCA infections in cirrhosis would be cost-saving and that hospitals need to be aware of the clinical and economic consequences of a wrong antibiotic treatment in this setting. PMID:28721080

  20. Do antiepileptic drugs increase the risk of suicidality in adult patients with epilepsy?: a critically appraised topic.

    Science.gov (United States)

    Ziemba, Kristine S; O'Carroll, Cumara B; Drazkowski, Joseph F; Wingerchuk, Dean M; Hoffman-Snyder, Charlene; Wellik, Kay E; Demaerschalk, Bart M

    2010-09-01

    The US Food and Drug Administration (FDA) released an alert in 2008 regarding an increased risk of suicidality in patients taking antiepileptic drugs (AEDs). The analysis that prompted this blanket warning has since been criticized for multiple flaws, and its relevance to patients with epilepsy is unclear. To critically assess current evidence regarding the risk of suicidality in adult patients with epilepsy taking commonly prescribed AEDs as monotherapy. The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of epilepsy. A structured literature search led to selection of one article providing the highest level of evidence currently available to answer our clinical question: a recent cohort study. The primary results of this study were based on comparisons of several AEDs to topiramate as a reference drug for any indication (including epilepsy), and identified gabapentin, lamotrigine, oxcarbazepine, tiagabine, and valproate as increasing risk of suicidality. A secondary analysis using carbamazepine as the reference drug failed to show statistically significant differences. A subgroup analysis of patients with epilepsy revealed an increased risk of suicidality in patients taking gabapentin as compared with those taking carbamazepine (relative risk, 13.92; 95% confidence interval, 1.82-106.38). Evidence of increased suicidality in patients taking AEDs for epilepsy is sparse. On the basis of this critical appraisal, gabapentin is one drug that may increase risk of suicide attempts and completions in these patients.

  1. THE PROBLEMS ASSOCIATED WITH SWITCHING BRAND-NAME ANTIEPILEPTIC DRUGS TO GENERICS: A FOCUS ON TOPAMAX: A REVIEW OF LITERATURE AND A CASE REPORT

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    K. Yu. Mukhin

    2016-01-01

    Full Text Available Despite the rather high efficiency of treatment for epilepsy (overall, 65–70 % of patients can achieve remission or show a considerable decrease in the frequency of seizures, there remains a challenge due to the need to use antiepileptic drugs long and regularly: therapy adherence, compliance, treatment tolerability, and impact of therapy on quality of patent’s life. One of the aspects of this problem is a very common tendency to switch brand-name antiepileptic drugs to their generics that are 1ess expensive, but also less predictably effective and tolerable. The authors review the literature on the interchangeability of brand-name and generic drugs and describe their case. 

  2. The Effect of High and Low Antiepileptic Drug Dosage on Simulated Driving Performance in Person's with Seizures: A Pilot Study

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    Alexander M. Crizzle

    2015-10-01

    Full Text Available Background: Prior studies examining driving performance have not examined the effects of antiepileptic drugs (AED’s or their dosages in persons with epilepsy. AED’s are the primary form of treatment to control seizures, but they are shown to affect cognition, attention, and vision, all which may impair driving. The purpose of this study was to describe the characteristics of high and low AED dosages on simulated driving performance in persons with seizures. Method: Patients (N = 11; mean age 42.1 ± 6.3; 55% female; 100% Caucasian were recruited from the Epilepsy Monitoring Unit and had their driving assessed on a simulator. Results: No differences emerged in total or specific types of driving errors between high and low AED dosages. However, high AED drug dosage was significantly associated with errors of lane maintenance (r = .67, p < .05 and gap acceptance (r = .66, p < .05. The findings suggest that higher AED dosages may adversely affect driving performance, irrespective of having a diagnosis of epilepsy, conversion disorder, or other medical conditions. Conclusion: Future studies with larger samples are required to examine whether AED dosage or seizure focus alone can impair driving performance in persons with and without seizures.

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

    Science.gov (United States)

    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. British Veterinary Association.

  4. Transient improvement after brief antiepileptic drug withdrawal in the epilepsy monitoring unit--possible relationship to AED tolerance.

    Science.gov (United States)

    Azar, Nabil J; Lagrange, Andre H; Wang, Lily; Song, Yanna; Abou-Khalil, Bassel W

    2010-05-01

    A drug holiday seems to produce seizure interval prolongation (SIP) after reinstitution of antiepileptic drugs (AEDs). This effect was demonstrated mainly with carbamazepine. We evaluated SIP with newer AEDs and tested the relationship of SIP to history of AED tolerance. We prospectively studied patients with refractory epilepsy admitted to the Vanderbilt epilepsy monitoring unit (EMU) over a period of 12 months. We included only patients on levetiracetam, lamotrigine, or oxcarbazepine who had their AEDs withdrawn on admission and reinstituted without change upon discharge. We defined SIP as the interval from EMU discharge to first seizure minus the interval between the last two seizures before EMU admission. A total of 43 patients completed the study; 15 were on monotherapy. SIP was greater than zero in this patient group (p a mean prolongation of 19.4 +/- 28.0 days. The average SIP was higher (p = 0.01) in patients on monotherapy (29.7 +/- 23.8 days) than patients on polytherapy (13.9 +/- 29.0 days). SIP tended to be greater in patients with a prior history of AED tolerance (25.7 +/- 36.8 days) compared to patient with no prior history of AED tolerance (14.0 +/- 16.3 days). SIP does occur after brief AED withdrawal. This effect is greater in patients on monotherapy and tends to be larger in patients with a history of AED tolerance. The SIP effect may be related to the phenomenon of tolerance, clinically seen as resistance to AED therapeutic effect.

  5. Oxabicyclooctane-Linked Novel Bacterial Topoisomerase Inhibitors as Broad Spectrum Antibacterial Agents

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Sheo B.; Kaelin, David E.; Wu, Jin; Miesel, Lynn; Tan, Christopher M.; Meinke, Peter T.; Olsen, David; Lagrutta, Armando; Bradley, Prudence; Lu, Jun; Patel, Sangita; Rickert, Keith W.; Smith, Robert F.; Soisson, Stephen; Wei, Changqing; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Fukuda, Yasumichi (Merck); (WuXi App Tec); (Kyorin)

    2014-05-08

    Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIs with reduced off-target activity (hERG IC50 > 18 μM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC50 = 1.02 μM) and topo IV (IC50 = 10.4 μM). AM8191 showed parenteral and oral efficacy (ED50) at less than 2.5 mg/kg doses in a S. aureus murine infection model. A cocrystal structure of AM8191 bound to S. aureus DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker.

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

    Science.gov (United States)

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

    2016-01-01

    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. 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 cancer over the period of January 2005 to May 2014. The upper limit of the 95% CI of adjusted sequence ratio (ASR) 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. 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 cancer, and hematological malignancies.

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

    Directory of Open Access Journals (Sweden)

    Kjell H. Halvorsen

    2016-01-01

    Full Text Available 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.

  8. Pharmacists' knowledge of issues in pharmacotherapy of epilepsy using antiepileptic drugs: A cross-sectional study in Palestinian pharmacy practice.

    Science.gov (United States)

    Shawahna, Ramzi; Atrash, Ahlam; Jebril, Aman; Khalaf, Areen; Shaheen, Eman; Tahboosh, Hala

    2017-02-01

    Antiepileptic drugs (AEDs) are mainstay in controlling epileptic seizures. As experts in medications, pharmacists should be able to ensure accuracy of dosing regimens, explain adverse effects, and screen for and alert people with epilepsy (PWE) and their physicians to possible drug-drug interactions (DDIs). The aim of this study was to evaluate pharmacists' knowledge of issues in pharmacotherapy of epilepsy using AEDs. This was a cross-sectional observational study conducted in the Palestinian pharmacy practice. A 10-item case-based questionnaire was used to determine actions taken by pharmacists in theoretical situations in pharmacotherapy of epilepsy. Demographic and practice details of the study participants were also collected. Scores were calculated as percentage of correct answers for each participant. The number of participants was 394. The majority (approximately 75%) identified themselves as community pharmacists. The median score was 33.4% with an IQR of 33.3. Pharmacists who received training on epilepsy and AEDs during their pharmacy degree program were 4.78-fold (95% C.I. of 1.82-12.60) more likely to score ≥50% in the test than those who did not receive training on epilepsy and AEDs. Despite gaps in knowledge, pharmacists tended to perform the necessary action in cases of adverse effects and aggravated seizures associated with AEDs. Pharmacists can play a crucial role in providing essential information on AEDs to patients and prescribers. There are many knowledge gaps that need to be filled. Specifically designed pedagogic and/or training interventions might be helpful in filling these gaps. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Comparison of antiepileptic drugs on cognitive function in newly diagnosed epileptic children: a psychometric and neurophysiological study.

    Science.gov (United States)

    Chen, Y J; Kang, W M; So, W C

    1996-01-01

    Using a randomized parallel group study design, we compared the cognit ive effects of carbamazepine (CBZ), phenobarbital (PB), and valproate (VPA) in children with epilepsy. Seventy-three children with newly diagnosed epilepsy were tested with the Wechsler Intelligence Scale for Children-Revised (WISC-R), Bender-Gestalt test, and auditory event-related potentials (P 300) before and 6 and 12 months after antiepileptic drug (AED) treatment. There were no significant differences in WISC-R IQs and Bender-Gestalt scores for children in any group at any of the three sessions. P 300 latencies were increased in the children receiving PB but not in children receiving CBZ and VPA. P 300 amplitudes were significantly reduced in treated children in all three groups, but amplitudes were not significantly different among the three groups. These findings suggest that PB may affect cognitive function of epileptic children and that the P 300 may be a sensitive additional procedure that can be used to assess the cognitive effect of AEDs.

  10. Severity of anxiety and depression are related to a higher perception of adverse effects of antiepileptic drugs.

    Science.gov (United States)

    Gómez-Arias, Bety; Crail-Meléndez, Daniel; López-Zapata, Rosario; Martínez-Juárez, Iris E

    2012-10-01

    After reviewing the negative effects of antiepileptic drugs (AEDs) on general health and quality of life, the Commission on Outcome Measurement from the International League Against Epilepsy (ILAE) recommended incorporating reliable and valid tools in clinical essays in order to achieve a more accurate assessment of the subjective adverse effects rate and disease severity when using AEDs. The aim of this study was to correlate the severity of adverse effects of AEDs, with the presence of anxiety and depression in patients with epilepsy. The Spanish version of the Liverpool Adverse Events Profile (LAEP) and the hospital anxiety and depression scale (HADS) were applied on 130 consecutive outpatients with epilepsy from the epilepsy clinic at the Mexico's National Institute of Neurology and Neurosurgery. A correlation analysis was carried out to determine if the presence of depression and anxiety was related to the adverse effects of AEDs. The relation between LAEP scores with other epidemiological variables was also assessed. Our study found a positive correlation between the LAEP and the HADS scores (p anxiety and depression in patients with epilepsy. Copyright © 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  11. Exploring differential prescribing between anti-epileptic drugs in epilepsy patients with a history of mood disorders.

    Science.gov (United States)

    Ishihara, Lianna; Webb, David J; Irizarry, Michael; Weil, John

    2010-03-01

    To explore differential prescribing of anti-epileptic drugs (AEDs) to patients with epilepsy by history of mood disorder. Epilepsy was defined as at least one diagnosis code and one AED prescription, and all patients must have been on the database 182 days before and after their first AED prescription. The Integrated HealthCare Information Services (IHCIS) insurance claims database included 44 557 patients with epilepsy between January 1997 and March 2007. The General Practice Research Database (GPRD) included 16 904 patients with epilepsy up to March 2007. Patients were categorized by their first use of specified AEDs. Mood disorders were defined as diagnosis codes for depression and bipolar disorder, or anti-depressant use. The unadjusted odds ratios and 95% confidence intervals for a history of mood disorder diagnosis ever or within the three months prior to AED use were calculated with carbamazepine and oxcarbazepine (CBZ) as the referent. In the US IHCIS, a history of mood disorders was significantly more common in new users of most AEDs compared to CBZ new users, indicating differential prescribing. Clonazepam and gabapentin were the most commonly prescribed AEDs in patients with epilepsy and a history of mood disorders.In the UK GPRD, there was less evidence of differential prescribing of AEDs, although gabapentin was prescribed most often to epilepsy patients with a history of mood disorders. Any observational studies of AEDs and suicidality would have to consider potential channeling bias by history of mood disorders, which is a major risk factor for suicide.

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

    Science.gov (United States)

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

    2015-11-24

    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.

  13. Quantitative EEG and Current Source Density Analysis of Combined Antiepileptic Drugs and Dopaminergic Agents in Genetic Epilepsy: Two Case Studies.

    Science.gov (United States)

    Emory, Hamlin; Wells, Christopher; Mizrahi, Neptune

    2015-07-01

    Two adolescent females with absence epilepsy were classified, one as attention deficit and the other as bipolar disorder. Physical and cognitive exams identified hypotension, bradycardia, and cognitive dysfunction. Their initial electroencephalograms (EEGs) were considered slightly slow, but within normal limits. Quantitative EEG (QEEG) data included relative theta excess and low alpha mean frequencies. A combined treatment of antiepileptic drugs with a catecholamine agonist/reuptake inhibitor was sequentially used. Both patients' physical and cognitive functions improved and they have remained seizure free. The clinical outcomes were correlated with statistically significant changes in QEEG measures toward normal Z-scores in both anterior and posterior regions. In addition, low resolution electromagnetic tomography (LORETA) Z-scored source correlation analyses of the initial and treated QEEG data showed normalized patterns, supporting a neuroanatomic resolution. This study presents preliminary evidence for a neurophysiologic approach to patients with absence epilepsy and comorbid disorders and may provide a method for further research. © EEG and Clinical Neuroscience Society (ECNS) 2014.

  14. Effects of antiepileptic drug monotherapy on one-carbon metabolism and DNA methylation in patients with epilepsy.

    Directory of Open Access Journals (Sweden)

    Guanzhong Ni

    Full Text Available The aim of this study was to compare the serum levels of one-carbon metabolism (OCM nutrients (e.g., folate, homocysteine and vitamin B12 and peripheral blood DNA methylation in epileptic patients under treatment with antiepileptic drugs (AEDs and in healthy controls.In this cross-sectional study, 60 patients with epilepsy who were receiving valproate (VPA (n = 30 or lamotrigine (LTG (n = 30 monotherapy were enrolled. Thirty age and sex matched healthy subjects served as the controls. Serum concentrations of OCM nutrients and peripheral blood DNA methylation status were measured.Compared to the control group, the VPA group had higher serum levels of homocysteine (p<0.05. No difference in homocysteine concentration was observed in the LTG group. Patients receiving VPA or LTG had significantly lower serum folate levels in comparison with controls (p<0.001. The level of methylation of long interspersed nucleotide element-1 (LINE-1 in peripheral blood was not significantly different between the AED monotherapy group and healthy controls. A difference in the methylation levels of methylenetetrahydrofolate reductase (MTHFR amplicon was observed between AED-treated patients with epilepsy and controls (p<0.01. A positive correlation between serum folate levels and peripheral blood MTHFR amplicon methylation status was also observed (r = 0.25, p = 0.023.Our findings suggest that the effects of AED monotherapy on OCM may induce specific regions of DNA hypomethylation.

  15. Broad-spectrum L-amino acid sensing by class 3 G-protein-coupled receptors.

    Science.gov (United States)

    Conigrave, Arthur D; Hampson, David R

    2006-12-01

    The sensing of nutrients is essential to the control of growth and metabolism. Although the sensing mechanisms responsible for the detection and coordination of metabolic responses to some nutrients, most notably glucose, are well understood, the molecular basis of amino acid sensing by cells and tissues is only now emerging. In this article, we consider evidence that some members of G-protein-coupled receptor class 3 are broad-spectrum amino acid sensors that couple changes in extracellular amino acid levels to the activation of intracellular signaling pathways. In particular, we consider both the molecular basis of specific and broad-spectrum amino acid sensing by different members of class 3 and the physiological significance of broad spectrum amino acid sensing by the extracellular calcium-sensing receptor, heterodimeric taste receptors and the recently "deorphanized" receptor GPRC6A and its goldfish homolog, the 5.24 chemoreceptor.

  16. Relationship between ABCB1 3435TT genotype and antiepileptic drugs resistance in Epilepsy: updated systematic review and meta-analysis.

    Science.gov (United States)

    Chouchi, Malek; Kaabachi, Wajih; Klaa, Hedia; Tizaoui, Kalthoum; Turki, Ilhem Ben-Youssef; Hila, Lamia

    2017-02-15

    Antiepileptic drugs (AEDs) are effective medications available for epilepsy. However, many patients do not respond to this treatment and become resistant. Genetic polymorphisms may be involved in the variation of AEDs response. Therefore, we conducted an updated systematic review and a meta-analysis to investigate the contribution of the genetic profile on epilepsy drug resistance. We proceeded to the selection of eligible studies related to the associations of polymorphisms with resistance to AEDs therapy in epilepsy, published from January 1980 until November 2016, using Pubmed and Cochrane Library databases. The association analysis was based on pooled odds ratios (ORs) and 95% confidence intervals (CIs). From 640 articles, we retained 13 articles to evaluate the relationship between ATP-binding cassette sub-family C member 1 (ABCB1) C3435T polymorphism and AEDs responsiveness in a total of 454 epileptic AEDs-resistant cases and 282 AEDs-responsive cases. We found a significant association with an OR of 1.877, 95% CI 1.213-2.905. Subanalysis by genotype model showed a more significant association between the recessive model of ABCB1 C3435T polymorphism (TT vs. CC) and the risk of AEDs resistance with an OR of 2.375, 95% CI 1.775-3.178 than in the dominant one (CC vs. TT) with an OR of 1.686, 95% CI 0.877-3.242. Our results indicate that ABCB1 C3435T polymorphism, especially TT genotype, plays an important role in refractory epilepsy. As genetic screening of this genotype may be useful to predict AEDs response before starting the treatment, further investigations should validate the association.

  17. Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs.

    Science.gov (United States)

    Boothe, Dawn Merton; Dewey, Curtis; Carpenter, David Mark

    2012-05-01

    To compare efficacy and safety of treatment with phenobarbital or bromide as the first-choice antiepileptic drug (AED) in dogs. Double-blinded, randomized, parallel, clinical trial. 46 AED-naïve dogs with naturally occurring epilepsy. Study inclusion was based on age, history, findings on physical and neurologic examinations, and clinicopathologic test results. For either phenobarbital treatment (21 dogs) or bromide treatment (25), a 7-day loading dose period was initiated along with a maintenance dose, which was adjusted on the basis of monthly monitoring. Efficacy and safety outcomes were compared between times (baseline and study end [generally 6 months]) and between drugs. Phenobarbital treatment resulted in eradication of seizures (17/20 [85%]) significantly more often than did bromide (12/23 [52%]); phenobarbital treatment also resulted in a greater percentage decrease in seizure duration (88 ± 34%), compared with bromide (49 ± 75%). Seizure activity worsened in 3 bromide-treated dogs only. In dogs with seizure eradication, mean ± SD serum phenobarbital concentration was 25 ± 6 μg/mL (phenobarbital dosage, 4.1 ± 1.1 mg/kg [1.9 ± 0.5 mg/lb], p.o., q 12 h) and mean serum bromide concentration was 1.8 ± 0.6 mg/mL (bromide dosage, 31 ± 11 mg/kg [14 ± 5 mg/lb], p.o., q 12 h). Ataxia, lethargy, and polydipsia were greater at 1 month for phenobarbital-treated dogs; vomiting was greater for bromide-treated dogs at 1 month and study end. Both phenobarbital and bromide were reasonable first-choice AEDs for dogs, but phenobarbital was more effective and better tolerated during the first 6 months of treatment.

  18. Suicide-related behaviors in older patients with new anti-epileptic drug use: data from the VA hospital system

    Directory of Open Access Journals (Sweden)

    Dersh Jeffrey J

    2010-01-01

    Full Text Available Abstract Background The U.S. Food and Drug Administration (FDA recently linked antiepileptic drug (AED exposure to suicide-related behaviors based on meta-analysis of randomized clinical trials. We examined the relationship between suicide-related behaviors and different AEDs in older veterans receiving new AED monotherapy from the Veterans Health Administration (VA, controlling for potential confounders. Methods VA and Medicare databases were used to identify veterans 66 years and older, who received a care from the VA between 1999 and 2004, and b an incident AED (monotherapy prescription. Previously validated ICD-9-CM codes were used to identify suicidal ideation or behavior (suicide-related behaviors cases, epilepsy, and other conditions previously associated with suicide-related behaviors. Each case was matched to controls based on prior history of suicide-related behaviors, year of AED prescription, and epilepsy status. Results The strongest predictor of suicide-related behaviors (N = 64; Controls N = 768 based on conditional logistic regression analysis was affective disorder (depression, anxiety, or post-traumatic stress disorder (PTSD; Odds Ratio 4.42, 95% CI 2.30 to 8.49 diagnosed before AED treatment. Increased suicide-related behaviors were not associated with individual AEDs, including the most commonly prescribed AED in the US - phenytoin. Conclusion Our extensive diagnostic and treatment data demonstrated that the strongest predictor of suicide-related behaviors for older patients newly treated with AED monotherapy was a previous diagnosis of affective disorder. Additional, research using a larger sample is needed to clearly determine the risk of suicide-related behaviors among less commonly used AEDs.

  19. Do antiepileptic drugs increase the risk of infectious diseases? A meta-analysis of placebo-controlled studies.

    Science.gov (United States)

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

    2017-09-01

    Experimental studies show that some antiepileptic drugs (AEDs) may modify natural immune defences, thus influencing the risk of developing infectious diseases. The aim of this meta-analysis was to explore whether AEDs as a class of drugs or singularly may increase risk of infectious diseases. A meta-analysis of all randomized, double-blind, placebo-controlled trials (RCTs) investigating any AED in any condition was performed. All terms that could be coded in the System Organ Classes (SOCs) of infections and infestations using the Medical Dictionary for Regulatory Activities were recorded. Additional subanalyses were performed also pooling together AEDs sharing similar mechanisms of action. Two hundreds and sixty-nine double-blind, placebo-controlled studies were identified and, among them, 127 RCTs with 16 AEDs (brivaracetam, gabapentin, lacosamide, levetiracetam, lamotrigine, oxcarbazepine, perampanel, pregabalin, phenytoin, remacemide, retigabine, rufinamide, tiagabine, topiramate, valproate, zonisamide) reported at least one of 19 symptoms or diseases that could be included in the Medical Dictionary for Regulatory Activities SOC term infections and infestations. These terms were singularly recorded and then pooled together in the SOC term infection and infestation. Topiramate was significantly associated with an increased risk of infection (risk difference = 0.04; 95% confidence interval = 0.01/0.06), while oxcarbazepine was significantly associated with a lower risk (-0.005; -0.09/-0.01). Risk difference of all studies with all AEDs showed a slight, but significantly increased risk of infection (0.01; 0.00/0.002). Levetiracetam and brivaracetam RCTs, when pooled together, were associated with a significantly increased risk of infection (0.03; 0.01/0.05). Some AEDs are associated with a mild increased risk of infection. © 2017 The British Pharmacological Society.

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

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    Bindu Menon

    2014-01-01

    Full Text Available 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.

  1. Recurrence rate of seizure following discontinuation of anti-epileptic drugs in patients with normal long term electroencephalography

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    V Abdul Gafoor

    2014-01-01

    Full Text Available Background: The usefulness of electroencephalography (EEG in predicting seizure recurrence after antiepileptic drugs (AED tapering is a controversial subject. There have been no studies which tested the additional yield of long-term over routine EEG recordings in predicting seizure recurrence after AED withdrawal. Objective: The primary objective of our study is to determine the recurrence rate of seizure following AED withdrawal in patients with focal epilepsy, unknown cause who had normal long-term electroencephalography (LTEEG and secondary objective is to analyze the variables that would predict seizure recurrence. Materials and Methods: This was a prospective observational study. A total of 91 patients were included. 62 patients who had normal routine and LTEEG entered the final phase of the study were followed-up regularly for 1 year or until seizure recurrence whichever was earlier. Results: A total number of 91 patients were enrolled for the first phase of the study. Of these, 13 (14.29% patients had an abnormal routine EEG. Of the remaining patients, another 16 (17.58% had abnormal LTEEG. The remaining 62 patients with normal routine and long-term EEG entered the final phase of the study. Of these, 17 patients (27.41% had seizure recurrence during the follow-up while 45 (72.58% remained seizure free until the end of the 1 year follow-up. The significant variables associated with a higher risk of seizure relapse were a positive past history of seizure recurrence on prior drug withdrawal (relative risk: 2.19, confidence interval: 1.01-4.74, P < 0.05 and the duration of epilepsy until seizure control was achieved (P < 0.009. Conclusions: The recurrence rate of seizure in patients with a normal LTEEG is 27.41%. A positive past history of seizure recurrence and a longer time to achieve seizure freedom with AED increased the risk of seizure recurrence.

  2. Anti-Epileptic Drug Combination Efficacy in an In Vitro Seizure Model - Phenytoin and Valproate, Lamotrigine and Valproate.

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    Kim Det Taing

    Full Text Available In this study, we investigated the relative efficacy of different classes of commonly used anti-epileptic drugs (AEDs with different mechanisms of action, individually and in combination, to suppress epileptiform discharges in an in vitro model. Extracellular field potential were recorded in 450 μm thick transverse hippocampal slices prepared from juvenile Wistar rats, in which "epileptiform discharges" (ED's were produced with a high-K+ (8.5 mM bicarbonate-buffered saline solution. Single and dual recordings in stratum pyramidale of CA1 and CA3 regions were performed with 3-5 MΩ glass microelectrodes. All drugs-lamotrigine (LTG, phenytoin (PHT and valproate (VPA-were applied to the slice by superfusion at a rate of 2 ml/min at 32°C. Effects upon frequency of ED's were assessed for LTG, PHT and VPA applied at different concentrations, in isolation and in combination. We demonstrated that high-K+ induced ED frequency was reversibly reduced by LTG, PHT and VPA, at concentrations corresponding to human therapeutic blood plasma concentrations. With a protocol using several applications of drugs to the same slice, PHT and VPA in combination displayed additivity of effect with 50μM PHT and 350μM VPA reducing SLD frequency by 44% and 24% individually (n = 19, and together reducing SLD frequency by 66% (n = 19. 20μM LTG reduced SLD frequency by 32% and 350μM VPA by 16% (n = 18. However, in combination there was a supra-linear suppression of ED's of 64% (n = 18. In another independent set of experiments, similar results of drug combination responses were also found. In conclusion, a combination of conventional AEDs with different mechanisms of action, PHT and VPA, displayed linear additivity of effect on epileptiform activity. More intriguingly, a combination of LTG and VPA considered particularly efficacious clinically showed a supra-additive suppression of ED's. This approach may be useful as an in vitro platform for assessing drug combination

  3. Characterization of broad-spectrum Mycobacterium abscessus class A β-lactamase.

    Science.gov (United States)

    Soroka, Daria; Dubée, Vincent; Soulier-Escrihuela, Olivia; Cuinet, Guillaume; Hugonnet, Jean-Emmanuel; Gutmann, Laurent; Mainardi, Jean-Luc; Arthur, Michel

    2014-03-01

    Imipenem and cefoxitin are used to treat Mycobacterium abscessus infections and have moderate activity against this fast-growing mycobacterium (MIC₅₀ of 16 and 32 mg/L, respectively). M. abscessus is highly resistant to most other β-lactams, although the underlying mechanisms have not been explored. Here, we characterized M. abscessus class A β-lactamase (Bla(Mab)) and investigated its role in β-lactam resistance. Hydrolysis kinetic parameters of purified Bla(Mab) were determined by spectrophotometry for various β-lactams and compared with those of related BlaC from Mycobacterium tuberculosis. MICs of β-lactams were determined for M. abscessus CIP104536 and for Escherichia coli producing Bla(Mab) and BlaC. Bla(Mab) had a broad hydrolysis spectrum, similar to that of BlaC, but with overall higher catalytic efficiencies, except for cefoxitin. As expected from its in vivo efficacy, cefoxitin was very slowly hydrolysed by Bla(Mab) (k(cat)/K(m) = 6.7 M(-1) s(-1)). Bla(Mab) hydrolysed imipenem more efficiently (k(cat)/K(m) = 3.0 × 10(4) M(-1) s(-1)), indicating that the in vivo activity of this drug might be improved by combination with a β-lactamase inhibitor. β-Lactamase inhibitors clavulanate, tazobactam and sulbactam did not inhibit Bla(Mab). This enzyme efficiently hydrolysed clavulanate, in contrast to BlaC, which is irreversibly acylated by this inhibitor. Bla(Mab) and BlaC were functional in E. coli and the resistance profiles mediated by these enzymes were in agreement with the kinetic parameters. M. abscessus produces a clavulanate-insensitive broad-spectrum β-lactamase that limits the in vivo efficacy of β-lactams.

  4. Discontinuation of antiepileptic drugs in seizure-free patients - when and how?

    Science.gov (United States)

    Lossius, Morten I; Alfstad, Kristin Å; Aaberg, Kari M; Nakken, Karl O

    2017-03-01

    In seizure-free patients with epilepsy, the question of whether, and if so when, it is acceptable to withdraw treatment may be difficult to answer. A thorough risk-benefit assessment should be undertaken with the patient and next of kin, during which the consequences of a relapse must be weighed against the disadvantages of continued administration of the drug. As a main rule, adult patients should have been seizure-free for at least two years before discontinuation is considered. In children with epilepsy with a known good prognosis, discontinuation may be considered even earlier.

  5. Central nervous system adverse effects of new antiepileptic drugs. A meta-analysis of placebo-controlled studies.

    Science.gov (United States)

    Zaccara, G; Gangemi, P F; Cincotta, M

    2008-07-01

    Systematic review and meta-analysis of the most frequent treatment-emergent central nervous system adverse events (CNS AEs) of new antiepileptic drugs (AEDs) from double-blind, add-on, placebo-controlled studies conducted in adult epileptic patients and identification of dose-adverse effect relationships. Trial reports found by searching Medline and journals. Outcome was the number of patients complaining of treatment-emergent CNS AEs. Sixteen predefined CNS AEs were considered. Risk differences (RDs) were calculated for individual studies and summary statistics estimated using the random effect model. Predefined CNS AEs in patients treated with active drug (broken down into dose levels) or placebo were extracted and the RDs (95% CI) for CNS AEs were calculated. Thirty-six suitable studies identified. No meta-analysis was possible for oxcarbazepine and tiagabine (only one study each included). For these drugs RDs were calculated from single studies. Gabapentin was significantly associated with somnolence 0.13 (0.06-0.2) and dizziness 0.11 (0.07-0.15); lamotrigine with dizziness 0.11 (0.05-0.17), ataxia 0.12 (0.01-0.24) and diplopia 0.12 (0.00-0.24); levetiracetam with somnolence 0.06 (0.01-0.11); pregabalin with somnolence 0.11 (0.07-0.15), dizziness 0.22 (0.16-0.28), ataxia 0.10 (0.06-0.14) and fatigue 0.04 (0.01-0.08); topiramate with somnolence 0.09 (0.04-0.14), dizziness 0.06 (0.00-0.11), cognitive impairment 0.14 (0.06-0.22) and fatigue 0.06 (0.01-0.12); zonisamide with somnolence 0.06 (0.02-0.11) and dizziness 0.06 (0.00-0.12). The dose-response relationship was analysed only for those CNS AEs significantly associated with the AED. No comparison between drugs was possible. One CNS AE was significantly more frequent for levetiracetam, two for zonisamide and gabapentin, three for lamotrigine and four for pregabalin and topiramate.

  6. A cost analysis of a broad-spectrum antibiotic therapy in the empirical treatment of health care-associated infections in cirrhotic patients.

    Science.gov (United States)

    Lucidi, Cristina; Di Gregorio, Vincenza; Ceccarelli, Giancarlo; Venditti, Mario; Riggio, Oliviero; Merli, Manuela

    2017-01-01

    Early diagnosis and appropriate treatment of infections in cirrhosis are crucial. As new guidelines in this context, particularly for health care-associated (HCA) infections, would be needed, we performed a trial documenting whether an empirical broad-spectrum antibiotic therapy is more effective than the standard one for these infections. Because of the higher daily cost of broad-spectrum than standard antibiotics, we performed a cost analysis to compare: 1) total drug costs, 2) profitability of hospital admissions. This retrospective observational analysis was performed on patients enrolled in the trial NCT01820026, in which consecutive cirrhotic patients with HCA infections were randomly assigned to a standard vs a broad-spectrum treatment. Antibiotic daily doses, days of treatment, length of hospital stay, and DRG (diagnosis-related group) were recorded from the clinical trial medical records. The profitability of hospitalizations was calculated considering DRG tariffs divided by length of hospital stay. We considered 84 patients (42 for each group). The standard therapy allowed to obtain a first-line treatment cost lower than in the broad-spectrum therapy. Anyway, the latter, being related to a lower failure rate (19% vs 57.1%), resulted in cost saving in terms of cumulative antibiotic costs (first- and second-line treatments). The mean cost saving per patient for the broad-spectrum arm was €44.18 (-37.6%), with a total cost saving of about €2,000. Compared to standard group, we observed a statistically significant reduction in hospital stay from 17.8 to 11.8 days (pempirical treatment for HCA infections in cirrhosis would be cost-saving and that hospitals need to be aware of the clinical and economic consequences of a wrong antibiotic treatment in this setting.

  7. The Influence of Solid Microneedles on the Transdermal Delivery of Selected Antiepileptic Drugs

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    Julia Nguyen

    2016-11-01

    Full Text Available The aim of this project was to examine the effect of microneedle rollers on the percutaneous penetration of tiagabine hydrochloride and carbamazepine across porcine skin in vitro. Liquid chromatography-mass spectrometric analysis was carried out using an Agilent 1200 Series HPLC system coupled to an Agilent G1969A TOF-MS system. Transdermal flux values of the drugs were determined from the steady-state portion of the cumulative amount versus time curves. Following twelve hours of microneedle roller application, there was a 6.74-fold increase in the percutaneous penetration of tiagabine hydrochloride (86.42 ± 25.66 µg/cm2/h compared to passive delivery (12.83 ± 6.30 µg/cm2/h. For carbamazepine in 20% ethanol, passive transdermal flux of 7.85 ± 0.60 µg/cm2/h was observed compared to 10.85 ± 0.11 µg/cm2/h after microneedle treatment. Carbamazepine reconstituted in 30% ethanol resulted in only a 1.19-fold increase in drug permeation across porcine skin (36.73 ± 1.83 µg/cm2/h versus 30.74 ± 1.32 µg/cm2/h. Differences in flux values of untreated and microneedle-treated porcine skin using solid microneedles for the transdermal delivery of tiagabine were statistically significant. Although there were 1.38- and 1.19-fold increases in transdermal flux values of carbamazepine when applied as 20% and 30% ethanol solutions across microneedle-treated porcine skin, respectively, the increases were not statistically significant.

  8. The Influence of Solid Microneedles on the Transdermal Delivery of Selected Antiepileptic Drugs.

    Science.gov (United States)

    Nguyen, Julia; Ita, Kevin B; Morra, Matthew J; Popova, Inna E

    2016-11-15

    The aim of this project was to examine the effect of microneedle rollers on the percutaneous penetration of tiagabine hydrochloride and carbamazepine across porcine skin in vitro. Liquid chromatography-mass spectrometric analysis was carried out using an Agilent 1200 Series HPLC system coupled to an Agilent G1969A TOF-MS system. Transdermal flux values of the drugs were determined from the steady-state portion of the cumulative amount versus time curves. Following twelve hours of microneedle roller application, there was a 6.74-fold increase in the percutaneous penetration of tiagabine hydrochloride (86.42 ± 25.66 µg/cm²/h) compared to passive delivery (12.83 ± 6.30 µg/cm²/h). For carbamazepine in 20% ethanol, passive transdermal flux of 7.85 ± 0.60 µg/cm²/h was observed compared to 10.85 ± 0.11 µg/cm²/h after microneedle treatment. Carbamazepine reconstituted in 30% ethanol resulted in only a 1.19-fold increase in drug permeation across porcine skin (36.73 ± 1.83 µg/cm²/h versus 30.74 ± 1.32 µg/cm²/h). Differences in flux values of untreated and microneedle-treated porcine skin using solid microneedles for the transdermal delivery of tiagabine were statistically significant. Although there were 1.38- and 1.19-fold increases in transdermal flux values of carbamazepine when applied as 20% and 30% ethanol solutions across microneedle-treated porcine skin, respectively, the increases were not statistically significant.

  9. Modified-Release Formulations of Second-Generation Antiepileptic Drugs: Pharmacokinetic and Clinical Aspects.

    Science.gov (United States)

    Anderson, Gail D; Saneto, Russell P

    2015-08-01

    Modified-release or extended-release (XR) formulations are used to decrease the frequency of dosing for drugs with rapid elimination, to improve convenience and adherence. Use of a modified-release formulation can decrease the peak to trough fluctuations in serum concentrations and theoretically improve the therapeutic benefit of the drug, by decreasing adverse events associated with the higher peak concentrations. Once-daily formulations of lamotrigine (Lamictal XR(®)), levetiracetam (Keppra XR(®)), oxcarbazepine (Oxtellar XR(®), Apydan(®) extent) and topiramate (Qudexy XR™, Trokendi XR™) are approved for the treatment of focal and/or generalized onset seizures. Other seizure medications have been approved for non-epileptic symptoms. Gabapentin XR (Gralise(®)) is approved for the treatment of post-herpetic neuralgias. Gabapentin enacarbil XR (Horizant(®)) is a prodrug of gabapentin and is indicated for treatment of post-herpetic neuralgia and restless leg syndrome, a novel indication. For all but Qudexy XR™, the tablets/capsules must be swallowed whole, without cutting, crushing or chewing, in order to maintain the XR properties of the formulation. Qudexy XR™ can be swallowed intact or the capsules can be opened and sprinkled onto soft food for those with swallowing difficulties, for example, children and the elderly. The bioavailability of Gralise(®) and Horizant(®) is significantly affected by food, specifically fat content, and should be taken with a meal to maximize absorption. Overall, the primary advantage of the newly released XR formulations is the once-daily dosing to improve convenience and adherence, with very limited data suggesting improved tolerability.

  10. A Potent, Broad-Spectrum Antiviral Agent that Targets Viral Membranes

    Directory of Open Access Journals (Sweden)

    Jason A. Wojcechowskyj

    2010-05-01

    Full Text Available Commentary on Wolf, M.C.; Freiberg, A.N.; Zhang, T.; Akyol-Ataman, Z.; Grock, A.; Hong, P.W.; Li, J.; Watson, N.F.; Fang, A.Q.; Aguilar, H.C.; et al. A broad-spectrum antiviral targeting entry of enveloped viruses. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 3157-3162.

  11. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

    DEFF Research Database (Denmark)

    Taylor, Jenny C; Martin, Hilary C; Lise, Stefano

    2015-01-01

    To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the numb...

  12. Dissemination and genetic support of broad-spectrum beta-lactam ...

    African Journals Online (AJOL)

    Dissemination and genetic support of broad-spectrum beta-lactam-resistant. Escherichia coli strain isolated from two Tunisian hospitals during 2004-2012. Khaoula Ayari1, Amel Bourouis1, Hela Chihi1, Sihem Mahrouki1, Thierry Naas2, Omrane Belhadj1. 1. Laboratory of Biochemistry and technobiology, Faculty of ...

  13. Novel water-based antiseptic lotion demonstrates rapid, broad-spectrum kill compared with alcohol antiseptic.

    Science.gov (United States)

    Czerwinski, Steven E; Cozean, Jesse; Cozean, Colette

    2014-01-01

    A novel alcohol-based antiseptic and a novel water-based antiseptic lotion, both with a synergistic combination of antimicrobial ingredients containing 0.2% benzethonium chloride, were evaluated using the standard time-kill method against 25 FDA-specified challenge microorganisms. The purpose of the testing was to determine whether a non-alcohol product could have equivalent rapid and broad-spectrum kill to a traditional alcohol sanitizer. Both the alcohol- and water-based products showed rapid and broad-spectrum antimicrobial activity. The average 15-s kill was 99.999% of the challenge organism for the alcohol-based antiseptic and 99.971% for the water-based antiseptic. The alcohol-based product demonstrated 100% of peak efficacy (60s) within the first 15s, whereas the water-based product showed 99.97%. The novel alcohol-based antiseptic reduced concentrations of 100% of organisms by 99.999%, whereas the water-based antiseptic lotion showed the same reduction for 96% of organisms. A novel water-based antiseptic product demonstrated equivalent rapid, broad-spectrum antimicrobial activity to an alcohol-based sanitizer and provided additional benefits of reduced irritation, persistent effect, and greater efficacy against common viruses. The combination of rapid, broad-spectrum immediate kill and persistent efficacy against pathogens may have significant clinical benefit in limiting the spread of disease. Copyright © 2014 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

  14. Effects of new antiepileptic drugs on circulatory markers for vascular risk in patients with newly diagnosed epilepsy.

    Science.gov (United States)

    Kim, Dong Wook; Lee, Seo-Young; Shon, Young-Min; Kim, Ji Hyun

    2013-10-01

    Although it is well documented that long-term therapy with older antiepileptic drugs (AEDs) leads to an increase in risk for atherosclerosis, there has been only limited information regarding the vascular risk in patients who are treated with new AEDs. We therefore conducted a prospective longitudinal study to assess the potential effects of new AEDs on the circulatory markers for vascular risk in patients with newly diagnosed epilepsy. We recruited adult patients with epilepsy who began to receive monotherapy with one of the new AEDs, including levetiracetam (LEV), oxcarbazepine (OXC), and topiramate (TPM). Circulatory markers of vascular risk were measured twice before and after 6 months of AED monotherapy. A total of 109 patients completed the study (LEV, n = 40; OXC, n = 40; TPM, n = 29). Six months of monotherapy resulted in significant increases in low-density lipoprotein cholesterol (LEV, from 90.2 to 98.5 mg/dl, 9.2% increase, p = 0.025; OXC, from 96.5 to 103.2 mg/dl, 7.0% increase, p = 0.049), homocysteine (LEV, from 7.9 to 10.4 μm, 31.6% increase, p = 0.001; OXC, from 8.7 to 11.5 μm, 32.2% increase, p cholesterol, triglyceride, high-density lipoprotein cholesterol, lipoprotein(a), and vitamin B12 in all three groups. Our findings suggest that treatment with some new AEDs might be associated with alterations in circulatory markers of vascular risk, which could contribute to the acceleration of atherosclerosis and increased risk of vascular diseases. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

  15. Antiepileptic drug use among women from the Taiwanese Registry of Epilepsy and Pregnancy: Obstetric complications and fetal malformation outcomes.

    Science.gov (United States)

    Yeh, Chang Ching; Lussier, Eric C; Sun, Yi-Ting; Lan, Tzuo-Yun; Yu, Hsiang-Yu; Chang, Tung-Yao

    2017-01-01

    To investigate antiepileptic drugs (AEDs) prescription and pregnancy outcomes in pregnancies with epilepsy in Taiwan between 2004 and 2015. We retrospectively reviewed data from the Taiwanese Registry of Epilepsy and Pregnancy (TREP). The TREP registry is a voluntary prospective cohort registry, which tracks pregnant women with epilepsy and AED prescription throughout pregnancy, delivery, and early childhood development. All TREP pregnancies (n = 318) that had completed questionnaires up until delivery or had had an unsuccessful pregnancy were analyzed. Over 94.7% of women had been prescribed AEDs during pregnancy, with 69.0% and 25.7% having received monotherapy, or polytherapy, respectively. Among live births, 12 (3.9%) reported malformation. Cesarean section rate was reported higher than usual (54.5%). In 2004, 73.3% of AEDs prescribed were 1st generation, with 1st generation prescription rates falling to only 8.3% of total prescribed in 2015. AED polytherapy also fell during the study period (40.0% to 20.0%). Cesarean sections were found to be higher for women over 35 years, who had generalized epilepsy, or had experienced an obstetric complication during pregnancy term. Binary logistic regression revealed that Cesarean section was associated with maternal complications (OR = 5.11, CI 95% = 1.11-23.51, p = 0.036), while malformations were associated with obstetric complication (OR = 20.46, CI 95% = 4.80-87.21, pObstetric complications were associated with Cesarean section. Fetal malformations were significantly associated with obstetric complications. AED risk factors were not significantly associated with either complications or malformations.

  16. Effects of antiepileptic drugs on reproductive endocrine function, sexual function and sperm parameters in Chinese Han men with epilepsy.

    Science.gov (United States)

    Xiaotian, Xu; Hengzhong, Zhang; Yao, Xu; Zhipan, Zhao; Daoliang, Xu; Yumei, Wu

    2013-11-01

    The effects of the antiepileptic drugs sodium valproate (VPA) and levetiracetam (LEV) on reproductive endocrine function, sexual function, and spermatozoa were explored, together with their possible etiological mechanisms, in Chinese Han men with epilepsy. Following VPA treatment (n=32), luteinizing hormone and follicle-stimulating hormone levels were significantly lower than in controls (n=30). The bioactive testosterone/luteinizing hormone ratio and the prolactin level were significantly elevated in the VPA treatment group. There were no significant differences in these hormones between the LEV treatment (n=20) and control groups. The rates of sperm morphologic abnormality (head, body, and tail) were significantly higher in the VPA treatment group than the control group but did not differ significantly between the LEV treatment and control groups. The sperm motility rate was significantly lower in the VPA treatment group (grade A sperm motility rate <25%, grade A+B sperm motility rate <50%) than in controls, as well as in the LEV treatment group (grade A sperm motility rate <25%). Patients in the VPA and LEV treatment groups had lower scores on questions 1, 2 and 3 of a simplified International Index of Erectile Function Scale than controls, but no significant difference on questions 4 or 5. The total International Index of Erectile Function Scale scores were significantly lower in the VPA and LEV treatment groups. We conclude that treatment with VPA adversely affects reproductive endocrine function, sperm parameters and sexual function to varying degrees in Chinese men with epilepsy. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  17. Timing of antiepileptic drug withdrawal in adult epilepsy patients after neocortical surgical resection: a critically appraised topic.

    Science.gov (United States)

    Ziemba, Kristine S; Wellik, Kay E; Hoffman-Snyder, Charlene; Noe, Katherine H; Demaerschalk, Bart M; Wingerchuk, Dean M

    2011-05-01

    The ideal efficacy outcome after surgery for medically refractory epilepsy is seizure freedom without need for antiepileptic drug (AED) therapy but the appropriate timing of AED withdrawal and other prognostic factors remain unclear. To critically evaluate current evidence regarding factors that influence the risk of seizure relapse after tapering AEDs in adult postepilepsy surgery patients. The objective was addressed through the development of a structured, critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of epilepsy. A structured literature search led to selection and appraisal of a retrospective cohort study. Of 147 patients who underwent AED tapering after epilepsy surgery, 61 (41.5%) ended up seizure-free off AEDs, 47 (32%) were seizure-free with AED continuation, and 39 (26.5%) continued to have seizures while on AEDs. Risk factors associated with seizure recurrence included: less time to AED reduction [11 y vs. ≤11 y; P=0.02; HR=1.75; 95% CI=1.09-2.81). Cortical location of the epileptic focus was not associated with taper success. In adults who have undergone neocortical resection surgery for medically refractory epilepsy, longer time from surgery to beginning AED taper (eg, greater than 9 months) is associated with a greater proportion of patients maintaining seizure freedom. Other risk factors associated with lower rate of seizure freedom after AED taper include longer duration of epilepsy, normal preoperative magnetic resonance imaging, and occurrence of postoperative seizures before initiation of AED withdrawal, but not cortical location of the epilepsy focus.

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

    Science.gov (United States)

    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 dogs in the imepitoin group, but not to the same extent as commonly seen in dogs with primary hypothyroidism. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Antiepileptic drug selection for people with HIV/AIDS: evidence-based guidelines from the ILAE and AAN.

    Science.gov (United States)

    Birbeck, Gretchen L; French, Jacqueline A; Perucca, Emilio; Simpson, David M; Fraimow, Henry; George, Jomy M; Okulicz, Jason F; Clifford, David B; Hachad, Houda; Levy, René H

    2012-01-01

    A joint panel of the American Academy of Neurology (AAN) and the International League Against Epilepsy (ILAE) convened to develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Key findings from this literature search included the following: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of approximately 50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of approximately 50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C). Wiley

  20. Prescription patterns of antiepileptic drugs in young women: development of a tool to distinguish between epilepsy and psychiatric disorders.

    Science.gov (United States)

    Naldi, Ilaria; Piccinni, Carlo; Mostacci, Barbara; Renzini, Jessica; Accetta, Gabriele; Bisulli, Francesca; Tappatà, Maria; Piazza, Antonella; Pagano, Paola; Bianchi, Stefano; D'Alessandro, Roberto; Tinuper, Paolo; Poluzzi, Elisabetta

    2016-07-01

    Antiepileptic drugs (AEDs) are also prescribed for therapeutic indications other than epilepsy (EPI), namely, psychiatric disorders (PSY). Our aim was to develop an algorithm able to distinguish between EPI and PSY among childbearing age women based on differences in AED exposure in these patient groups. Two groups of women (18-45 years) with EPI or PSY treated with AEDs in the first semester of 2010 or 2011 were extracted from paper or electronic medical charts of specialized centers. Through the prescription database of Bologna Local Health Authority (Italy), AEDs, treatment schedule and co-treatments were collected for each patient. A prescription-based hierarchical classification system was developed. The algorithm obtained was subsequently validated on internal and external data. Eighty-one EPI and 94 PSY subjects were recruited. AED monotherapy was the most common choice in both groups (69% EPI vs 79% PSY). Some AEDs were used only in EPI, others exclusively in PSY. Co-treatments with antipsychotics (6% vs 67%), lithium (0% vs 9%), and antidepressants (7% vs 70%) were fewer in EPI than in PSY. The hierarchical classification system identified antipsychotics, SSRIs (Selective Serotonin Reuptake Inhibitors), and number of AEDs as variables to discriminate EPI and PSY, with an overall error rate estimate of 9.7% (95%CI: 5.3% to 14.1%). Among the differences between EPI and PSY, prescription data alone allowed an algorithm to be developed to diagnose each childbearing age woman receiving AEDs. This approach will be useful to stratify patients for risk estimates of AED-treated patients based on administrative databases. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  1. Long-term outcomes of surgical treatment for epilepsy in adults with regard to seizures, antiepileptic drug treatment and employment.

    Science.gov (United States)

    Malmgren, Kristina; Edelvik, Anna

    2017-01-01

    There is Class I evidence for short-term efficacy of epilepsy surgery from two randomized controlled studies of temporal lobe resection. Long-term outcome studies are observational. The aim of this narrative review was to summarise long-term outcomes taking the study methodology into account. A PubMed search was conducted identifying articles on long-term outcomes of epilepsy surgery in adults with regard to seizures, antiepileptic drug treatment and employment. Definitions of seizure freedom were examined in order to identify the proportions of patients with sustained seizure freedom. The quality of the long-term studies was assessed. In a number of high-quality studies 40-50% of patients had been continuously free from seizures with impairment of consciousness 10 years after resective surgery, with a higher proportion seizure-free at each annual follow-up. The proportion of seizure-free adults in whom AEDs have been withdrawn varied widely across studies, from 19-63% after around 5 years of seizure freedom. Few long-term vocational outcome studies were identified and results were inconsistent. Some investigators found no postoperative changes, others found decreased employment for patients with continuing seizures, but no change or increased employment for seizure-free patients. Having employment at baseline and postoperative seizure freedom were the strongest predictors of employment after surgery. Long-term studies of outcomes after epilepsy surgery are by necessity observational. There is a need for more prospective longitudinal studies of both seizure and non-seizure outcomes, considering individual patient trajectories in order to obtain valid outcome data needed for counselling patients about epilepsy surgery. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  2. The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptic drugs.

    Science.gov (United States)

    Frey, Noel; Bodmer, Michael; Bircher, Andreas; Rüegg, Stephan; Jick, Susan S; Meier, Christoph R; Spoendlin, Julia

    2017-12-01

    Older antiepileptic drugs (AEDs) are known to cause Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). However, evidence for newer AED is sparse. We quantified risks of SJS/TEN in association with use of all AEDs in the United Kingdom. In a matched case-control study of 480 previously validated SJS/TEN cases (1995-2013) we used conditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs), and calculated absolute risks of SJS/TEN within separate cohorts of new users of 28 AEDs. We assessed causality between drugs and SJS/TEN in each exposed case, using an adapted version of the algorithm of drug causality for epidermal necrolysis (ALDEN) score. We observed a strong association between SJS/TEN and new use of carbamazepine (OR 92.57, 95% CI 19.89-∞), phenytoin (OR 49.96, 95% CI 10.13-∞), and lamotrigine (OR 26.90, 95% CI 4.88-∞), where causality, according to the ALDEN score, was very probable or probable for most exposed cases. Absolute risks for SJS/TEN were highest for phenytoin (45.86 cases/100,000 exposed), lamotrigine (44.17 cases/100,000 exposed), and carbamazepine (20.38 cases/100,000 exposed). Despite increased ORs for valproate (40,941 exposed), gabapentin (116,037 exposed), pregabalin (59,967 exposed), and clobazam (4,300 exposed), ALDEN suggested no causal association. There were no observed cases of SJS/TEN among new users of levetiracetam (n = 96,77), clonazepam (n = 18,075), or topiramate (n = 11,307). The results of our study are consistent with those of previous studies of SJS/TEN, which found increased risks of SJS/TEN in new use of carbamazepine, phenytoin, and lamotrigine. Despite frequent use, no ALDEN-score confirmed cases were observed in new users of valproate, gabapentin, pregabalin, levetiracetam, topiramate, or clonazepam. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  3. Clinical risk factors associated with anti-epileptic drug responsiveness in canine epilepsy.

    Directory of Open Access Journals (Sweden)

    Rowena M A Packer

    Full Text Available The nature and occurrence of remission, and conversely, pharmacoresistance following epilepsy treatment is still not fully understood in human or veterinary medicine. As such, predicting which patients will have good or poor treatment outcomes is imprecise, impeding patient management. In the present study, we use a naturally occurring animal model of pharmacoresistant epilepsy to investigate clinical risk factors associated with treatment outcome. Dogs with idiopathic epilepsy, for which no underlying cause was identified, were treated at a canine epilepsy clinic and monitored following discharge from a small animal referral hospital. Clinical data was gained via standardised owner questionnaires and longitudinal follow up data was gained via telephone interview with the dogs' owners. At follow up, 14% of treated dogs were in seizure-free remission. Dogs that did not achieve remission were more likely to be male, and to have previously experienced cluster seizures. Seizure frequency or the total number of seizures prior to treatment were not significant predictors of pharmacoresistance, demonstrating that seizure density, that is, the temporal pattern of seizure activity, is a more influential predictor of pharmacoresistance. These results are in line with clinical studies of human epilepsy, and experimental rodent models of epilepsy, that patients experiencing episodes of high seizure density (cluster seizures, not just a high seizure frequency pre-treatment, are at an increased risk of drug-refractoriness. These data provide further evidence that the dog could be a useful naturally occurring epilepsy model in the study of pharmacoresistant epilepsy.

  4. Clinical risk factors associated with anti-epileptic drug responsiveness in canine epilepsy.

    Science.gov (United States)

    Packer, Rowena M A; Shihab, Nadia K; Torres, Bruno B J; Volk, Holger A

    2014-01-01

    The nature and occurrence of remission, and conversely, pharmacoresistance following epilepsy treatment is still not fully understood in human or veterinary medicine. As such, predicting which patients will have good or poor treatment outcomes is imprecise, impeding patient management. In the present study, we use a naturally occurring animal model of pharmacoresistant epilepsy to investigate clinical risk factors associated with treatment outcome. Dogs with idiopathic epilepsy, for which no underlying cause was identified, were treated at a canine epilepsy clinic and monitored following discharge from a small animal referral hospital. Clinical data was gained via standardised owner questionnaires and longitudinal follow up data was gained via telephone interview with the dogs' owners. At follow up, 14% of treated dogs were in seizure-free remission. Dogs that did not achieve remission were more likely to be male, and to have previously experienced cluster seizures. Seizure frequency or the total number of seizures prior to treatment were not significant predictors of pharmacoresistance, demonstrating that seizure density, that is, the temporal pattern of seizure activity, is a more influential predictor of pharmacoresistance. These results are in line with clinical studies of human epilepsy, and experimental rodent models of epilepsy, that patients experiencing episodes of high seizure density (cluster seizures), not just a high seizure frequency pre-treatment, are at an increased risk of drug-refractoriness. These data provide further evidence that the dog could be a useful naturally occurring epilepsy model in the study of pharmacoresistant epilepsy.

  5. A Comparative Investigation of Neuropsychological Dysfunctions of Antiepileptic Drugs in Epileptic Patients

    Directory of Open Access Journals (Sweden)

    M. Mazdeh

    2014-07-01

    Full Text Available Introduction & Objective: Patients suffering from epilepsy can experience a wide range of neuropsychological disorders such as impaired memory, attention and information process-ing. The aim of the present study was to evaluate and compare the performance of neuropsy-chological epileptic patients according to their pharmacotherapy. Materials & Methods: In this retrospective causal- comparative study, 90 patients with idio-pathic grand mal epilepsy in three groups of 30 subjects taking drug valproate acid, car-bamazepine and combination lamotrigine (with carbamazepine or valproate were selected in Hamadan clinics in 2012. 30 cases of normal subjects with an age range of 15 to 55 years were included (control group. The four groups of subjects were matched in age and educa-tion and were evaluated according to continuous performance tests, Benton visual retention test, and Paced Auditory Serial Addition Test (PASAT. The data was analyzed by SPSS software and Manova, Scheffe, Tamhane tests. Results: The results show that the rate of PASAT in normal group was significantly higher than epilepsy group (P=0.01, but among the groups taking valproate acid, carbamazepine and combination lamotrigine (with carbamazepine or valproate no significant difference was observed in the level of depression. In PASAT and Benton visual retention tests the results were similar. In continuous performance test n the scale of incorrect response the results were reversed and with regard to the correct response, the previous results were confirmed. On omission reply scale, the group which used combination lamotrigine and the normal group showed similar results, thus they were separated from the group using carbamazepine and valproate. On reaction time scale, patients taking carbamazepine significantly (P=0.01 differed from patients taking amotrigine and valproate and from the normal group. Conclusion: There are significant differences between the AEDs as valporate

  6. Profilaxis con drogas antiepilépticas en enfermedades neurológicas Prophylactic treatment with antiepileptic drugs in neurological conditions

    Directory of Open Access Journals (Sweden)

    Luciano A. Sposato

    2011-02-01

    Full Text Available El uso profiláctico de drogas antiepilépticas en enfermedades neurológicas como el accidente cerebrovascular isquémico y hemorrágico, la hemorragia subaracnoidea, el traumatismo de cráneo y los tumores cerebrales ha sido motivo de controversia durante muchos años. Estas drogas son indicadas con el fin de disminuir el daño neurológico secundario a las crisis epilépticas. Sin embargo, la escasa evidencia científica disponible para avalar esta hipótesis, las potenciales interacciones farmacológicas, los efectos adversos y algunos informes sobre neurotoxicidad generan dudas en cuanto a esta conducta terapéutica. En esta revisión, analizamos la evidencia acerca del uso profiláctico de drogas epilépticas en las enfermedades neurológicas arriba mencionadas.Prophylactic use of antiepileptic drugs in neurological conditions such as ischemic and hemorrhagic stroke, subarachnoid hemorrhage, head injury, and brain tumors has been matter of debate for many years. These drugs are used for reducing secondary neurological damage caused by epileptic seizures. However, the evidence supporting this indication is scarce. Potential drug interactions, side effects, and even neurotoxicity related to these drugs have raised concern about this therapeutic approach. In this review, we examine the evidence on the prophylactic use of antiepileptic drugs in the neurological disorders above mentioned.

  7. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs.

    Science.gov (United States)

    Sake, John-Kenneth; Hebert, David; Isojärvi, Jouko; Doty, Pamela; De Backer, Marc; Davies, Kendra; Eggert-Formella, Andrea; Zackheim, James

    2010-12-01

    Lacosamide, a new antiepileptic drug (AED) with a different pharmacological action that enhances sodium channel slow inactivation, is approved for the adjunctive treatment of partial-onset seizures in adults. Previous analyses of pooled phase II/III trials have demonstrated that lacosamide provides additional efficacy when added to a broad range of AEDs. To further evaluate the efficacy and safety of lacosamide by grouping patients based upon the sodium channel-blocking properties of their concomitant AEDs. Post hoc exploratory analyses were performed on pooled data in which patients were grouped based upon inclusion or non-inclusion of at least one 'traditional' sodium channel-blocking AED (defined as carbamazepine, lamotrigine, oxcarbazepine and phenytoin derivatives) as part of their concomitant AED regimen. Data pooled from previously conducted phase II/III clinical trials of lacosamide. Adult patients with partial-onset seizures with or without secondary generalization (N = 1308). Four- to six-week Titration Phase followed by 12-week maintenance treatment with adjunctive lacosamide (Vimpat®) [200, 400 or 600 mg/day] or placebo. Efficacy variables included change in seizure frequency per 28 days and the proportion of patients experiencing a ≥50% reduction in seizure frequency (50% responder rate) from Baseline to the Maintenance Phase. The proportion of patients experiencing a ≥75% reduction in seizure frequency from Baseline to the Maintenance Phase (75% responder rate) was also assessed. Safety parameters assessed were treatment-emergent adverse events (TEAEs) and discontinuation due to TEAEs. Additional safety assessments were changes in ECG and laboratory parameters as well as vital signs (including bodyweight). Of 1308 patients in the pooled phase II/III population, the majority (82%) were using at least one 'traditional' sodium channel-blocking concomitant AED. In this subgroup of patients, adjunctive lacosamide showed significant reductions in

  8. ACEA (a highly selective cannabinoid CB1 receptor agonist) stimulates hippocampal neurogenesis in mice treated with antiepileptic drugs.

    Science.gov (United States)

    Andres-Mach, Marta; Haratym-Maj, Agnieszka; Zagaja, Miroslaw; Rola, Radoslaw; Maj, Maciej; Chrościńska-Krawczyk, Magdalena; Luszczki, Jarogniew J

    2015-10-22

    Hippocampal neurogenesis plays a very important role in learning and memory functions. In a search for best neurological drugs that protect neuronal cells and stimulate neurogenesis with no side effects, cannabinoids proved to be a strong group of substances having many beneficial properties. The aim of this study was to evaluate the impact of ACEA (arachidonyl-2'-chloroethylamide--a highly selective cannabinoid CB1 receptor agonist) combined with a classical antiepileptic drug sodium valproate (VPA) on neural precursor cells' proliferation and differentiation in the mouse brain. All experiments were performed on adolescent CB57/BL male mice injected i.p. with VPA (10mg/kg), ACEA (10mg/kg) and PMSF (30 mg/kg) (phenylmethylsulfonyl fluoride--a substance protecting ACEA against degradation by the fatty-acid amidohydrolase) for 10 days. Next an acute response of proliferating neural precursor cells to ACEA and VPA administration was evaluated with Ki-67 staining (Time point 1). Next, in order to determine whether acute changes translated into long-term alterations in neurogenesis, proliferating cells were labeled with 5-bromo-2deoxyuridine (BrdU) followed by confocal microscopy used to determine the percentage of BrdU-labeled cells that showed mature cell phenotypes (Time point 2). Results indicate that ACEA with PMSF significantly increase the total number of Ki-67-positive cells when compared to the control group. Moreover, ACEA in combination with VPA increased the number of Ki-67-positive cells, whereas VPA administered alone had no impact on proliferating cells' population. Accordingly, neurogenesis study results indicate that the combination of ACEA+PMSF administered alone and in combination with VPA considerably increases the total number of BrdU-positive cells in comparison to the control group while ACEA+PMSF alone and in combination with VPA increased total numbers of BrdU-positive cells, newly born neurons and astrocytes as compared to VPA group but not to

  9. Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: A post-hoc study.

    Science.gov (United States)

    Asadi-Pooya, Ali A; Sperling, Michael R; Chung, Steve; Klein, Pavel; Diaz, Anyzeila; Elmoufti, Sami; Schiemann, Jimmy; Whitesides, John

    2017-03-01

    Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) for adjunctive treatment of focal (partial-onset) seizures in adults with epilepsy. This post-hoc analysis was conducted to explore the efficacy of adjunctive BRV in patients with prior levetiracetam (LEV) exposure and whether changes in efficacy were related to the similar mechanism of action of these two drugs. Data were pooled from three Phase III studies (NCT00490035; NCT00464269; NCT01261325) of adults with focal seizures taking 1-2 AEDs who received placebo or BRV 50-200mg/day without titration over a 12-week treatment period. Patients taking concomitant LEV at enrollment were excluded from this analysis. Patients were categorized by their status of prior exposure to LEV, carbamazepine (CBZ), topiramate (TPM), or lamotrigine (LTG), to investigate any consistent trend towards reduced response in AED-exposed subgroups compared to AED-naïve subgroups, regardless of the mechanism of action. Study completion rates, percent reduction from baseline in focal seizure frequency over placebo, ≥50% responder rates, and tolerability were evaluated for each subgroup. A total of 1160 patients were investigated. Study completion rates were similar in the AED-exposed subgroups and AED-naïve subgroups. In subgroups with (531 patients) or without (629 patients) prior LEV exposure, ≥50% responder rates for each dose of BRV compared with placebo were generally higher among the LEV-naïve subgroups than the previously LEV-exposed subgroups. LEV-exposed subgroups receiving BRV doses ≥50mg/day showed greater ≥50% responder rates than those receiving placebo. Similar results were observed for CBZ, TPM, and LTG. Previous treatment failure with commonly prescribed AEDs (LEV, CBZ, TPM, or LTG) is associated with a reduced response to BRV irrespective of the mechanism of action. Hence, this post-hoc analysis indicates that previous treatment failure with LEV

  10. Comparison of brand versus generic antiepileptic drug adverse event reporting rates in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).

    Science.gov (United States)

    Rahman, Md Motiur; Alatawi, Yasser; Cheng, Ning; Qian, Jingjing; Plotkina, Annya V; Peissig, Peggy L; Berg, Richard L; Page, David; Hansen, Richard A

    2017-09-01

    Despite the cost saving role of generic anti-epileptic drugs (AEDs), debate exists as to whether generic substitution of branded AEDs may lead to therapeutic failure and increased toxicity. This study compared adverse event (AE) reporting rates for brand vs. authorized generic (AG) vs. generic AEDs. Since AGs are pharmaceutically identical to brand but perceived as generics, the generic vs. AG comparison minimized potential bias against generics. Events reported to the U.S. Food and Drug Administration Adverse Event Reporting System between January 2004 to March 2015 with lamotrigine, carbamazepine, and oxcarbazepine listed as primary or secondary suspect were classified as brand, generic, or AG based on the manufacturer. Disproportionality analyses using the reporting odds ratio (ROR) assessed the relative rate of reporting of labeled AEs compared to reporting these events with all other drugs. The Breslow-Day statistic compared RORs across brand, AG, and other generics using a Bonferroni-corrected Pevents with lamotrigine, 13,950 events with carbamazepine, and 5077 events with oxcarbazepine were reported, with generics accounting for 27%, 41%, and 32% of reports, respectively. Although RORs for the majority of known AEs were different between brand and generics for all three drugs of interest (Breslow-Day Preports of suicide or suicidal ideation compared with the respective AGs based on a multiple comparison-adjusted Preporting rates were observed for the AG and generic comparisons for most outcomes and drugs, suggesting that brands and generics have similar reporting rates after accounting for generic perception biases. Disproportional suicide reporting was observed for generics compared with AGs and brand, although this finding needs further study. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Vancomycin and Five Broad-spectrum Antibiotic Utilization Evaluation in an Educational Medical Center in One Year

    Directory of Open Access Journals (Sweden)

    SiminDokht Shoaei

    2015-10-01

    Full Text Available  Background: Antibiotics can be life saving if they are used correctly, and can have unwanted side effects specially resistance with incorrect use. Unfortunately in fear of no response, physicians use broad spectrum antibiotics meticulously. In this Drug Utilization Evaluation (DUE, improper use of Vancomycin and five broad-spectrum antibiotics are studied to find faults and solution for this problem. Methods:This descriptive cross-sectional study performed during the March of 2012 to March of 2013.DUE of Imipenem, Meropenem, Piperacillin-Tazobactam, Cefepime, Ciprofloxacin and Vancomycin was done in 6 wards of Imam Hossein Hospital in Tehran. Demographic, clinical, laboratory, imaging and treatment data were looked for in medical records of 686 patients. Evaluation was done by three infectious disease specialist based on reference text book of Mandell’s Principles and Practice of Infectious Diseases 2010 and IDSA Guidelines. Results:This study showed 38.5% of prescriptions were correct and the remained 61.5% were incorrect with different faults predominantly incorrect overuse in 51.1%.Ciprofloxacin was the most common incorrect used drug in 74.8% cases and Piperacillin-Tazobactam with 48.7% cases had the least common incorrect use. There was no fault in prescription of antibiotics observing age and sex (pregnancy, breast feeding factors. Conclusions:Our results reveal a significant high level of the inappropriate use of Antibiotics mostly as overuse and empirically without culture results. It is needed to establish continuing medical education (CME courses and a locally conformable guideline of antibiotic use based on antibiogram results.

  12. Malformation risk of antiepileptic drug exposure during pregnancy in women with epilepsy: Results from a pregnancy registry in South India.

    Science.gov (United States)

    Thomas, Sanjeev V; Jose, Manna; Divakaran, Srividya; Sankara Sarma, Prabhakaran

    2017-02-01

    Kerala Registry of Epilepsy and Pregnancy had been prospectively evaluating the reproductive issues of women with epilepsy since April 1998. This analysis aimed to estimate the relative risk of major congenital malformations (MCM) to the registrants. All pregnancies with known outcome in this register until December 2013 were included. Malformation status was evaluated by antenatal ultrasonography, physical examination at birth, echocardiography, and abdomen ultrasonography at 3 months of age and a final review at 1 year of age. There were 1,688 fetuses (singlets 1,643, twins 21, and triplet 1) resulting in 1,622 live births. All were born to women of Asian origin living in South India. The MCM rate for all live births was 6.84% (95% confidence interval [CI] 5.71-8.18) and for all pregnancy outcomes including fetal loss was 7.11% (95% CI 5.98-8.44). The MCM rates (mean with 95% CI) for exposed group were 6.4% (5.03-8.03) for monotherapy and 9.9% (7.37-13.13) for polytherapy; internal control group (women with epilepsy [WWE] not on antiepileptic drugs [AEDs] in first trimester) 5.6% (3.34-9.11), external control group (women without epilepsy or AED exposure in first trimester) 3.45% (1.94-6.07). Valproate monotherapy group had a dose-dependent relative risk for MCM of 2.6 (95% CI 1.30-5.20) compared to the external control group. The preliminary data on MCM rate for the nine total clobazam monotherapy (22.2%; 95% CI 6.2-54.7) signals increased risk that needs further validation on larger sample size. There was no association between MCM rate and maternal socioeconomic status, epilepsy syndrome, or use of folic acid in first trimester. This dataset from South India confirms the increased risk of MCM with exposure to AEDs, particularly polytherapy. A dose-dependent increased risk was observed with valproate. The increased risk associated with clobazam monotherapy is an important signal that needs to be confirmed in a larger sample. Wiley Periodicals, Inc. © 2017

  13. Broad-spectrum antibiotic activity of the arylomycin natural products is masked by natural target mutations.

    Science.gov (United States)

    Smith, Peter A; Roberts, Tucker C; Romesberg, Floyd E

    2010-11-24

    Novel classes of broad-spectrum antibiotics are needed to treat multidrug-resistant pathogens. The arylomycin class of natural products inhibits a promising antimicrobial target, type I signal peptidase (SPase), but upon initial characterization appeared to lack whole-cell activity against most pathogens. Here, we show that Staphylococcus epidermidis, which is sensitive to the arylomycins, evolves resistance via mutations in SPase and that analogous mutations are responsible for the natural resistance of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We identify diverse bacteria lacking these mutations and demonstrate that most are sensitive to the arylomycins. The results illustrate that the arylomycins have a broad-spectrum of activity and are viable candidates for development into therapeutics. The results also raise the possibility that naturally occurring resistance may have masked other natural product scaffolds that might be developed into therapeutics. Copyright © 2010 Elsevier Ltd. All rights reserved.

  14. Broad Spectrum Antibiotic Activity of the Arylomycin Natural Products is Masked by Natural Target Mutations

    Science.gov (United States)

    Smith, Peter A.; Roberts, Tucker C.; Romesberg, Floyd E.

    2010-01-01

    Summary Novel classes of broad-spectrum antibiotics are needed to treat multidrug resistant pathogens. The arylomycin class of natural products inhibits a promising antimicrobial target, type I signal peptidase (SPase), but upon initial characterization appeared to lack whole cell activity against most pathogens. Here, we show that Staphylococcus epidermidis, which is sensitive to the arylomycins, evolves resistance via mutations in SPase and that analogous mutations are responsible for the natural resistance of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We identify diverse bacteria lacking these mutations and demonstrate that most are sensitive to the arylomycins. The results illustrate that the arylomycins have a broad-spectrum of activity and are viable candidates for development into therapeutics. The results also raise the possibility that naturally occurring resistance may have masked other natural product scaffolds that might be developed into therapeutics. PMID:21095572

  15. Broad-Spectrum Antibiotic Treatment and Subsequent Childhood Type 1 Diabetes

    DEFF Research Database (Denmark)

    Clausen, Tine D; Bergholt, Thomas; Bouaziz, Olivier

    2016-01-01

    of childhood type 1 diabetes and the potential effect-modification by mode of delivery. MATERIALS AND METHODS: A Danish nationwide cohort study including all singletons born during 1997-2010. End of follow-up by December 2012. Four national registers provided information on antibiotic redemptions, outcome...... and confounders. Redemptions of antibiotic prescriptions during the first two years of life was classified into narrow-spectrum or broad-spectrum antibiotics. Children were followed from age two to fourteen, both inclusive. The risk of type 1 diabetes with onset before the age of 15 years was assessed by Cox...... regression. A total of 858,201 singletons contributed 5,906,069 person-years, during which 1,503 children developed type 1 diabetes. RESULTS: Redemption of broad-spectrum antibiotics during the first two years of life was associated with an increased rate of type 1 diabetes during the following 13 years...

  16. Synthesis and Broad-Spectrum Antiviral Activity of Some Novel Benzo-Heterocyclic Amine Compounds

    Directory of Open Access Journals (Sweden)

    Da-Jun Zhang

    2014-01-01

    Full Text Available A series of novel unsaturated five-membered benzo-heterocyclic amine derivatives were synthesized and assayed to determine their in vitro broad-spectrum antiviral activities. The biological results showed that most of our synthesized compounds exhibited potent broad-spectrum antiviral activity. Notably, compounds 3f (IC50 = 3.21–5.06 μM and 3g (IC50 = 0.71–34.87 μM showed potent activity towards both RNA viruses (influenza A, HCV and Cox B3 virus and a DNA virus (HBV at low micromolar concentrations. An SAR study showed that electron-withdrawing substituents located on the aromatic or heteroaromatic ring favored antiviral activity towards RNA viruses.

  17. Artificial TALE as a Convenient Protein Platform for Engineering Broad-Spectrum Resistance to Begomoviruses

    Directory of Open Access Journals (Sweden)

    Xiaofei Cheng

    2015-08-01

    Full Text Available Transcription activator–like effectors (TALEs are a class of sequence-specific DNA-binding proteins that utilize a simple and predictable modality to recognize target DNA. This unique characteristic allows for the rapid assembly of artificial TALEs, with high DNA binding specificity, to any target DNA sequences for the creation of customizable sequence-specific nucleases used in genome engineering. Here, we report the use of an artificial TALE protein as a convenient platform for designing broad-spectrum resistance to begomoviruses, one of the most destructive plant virus groups, which cause tremendous losses worldwide. We showed that artificial TALEs, which were assembled based on conserved sequence motifs within begomovirus genomes, could confer partial resistance in transgenic Nicotiana benthamiana to all three begomoviruses tested. Furthermore, the resistance was maintained even in the presence of their betasatellite. These results shed new light on the development of broad-spectrum resistance against DNA viruses, such as begomoviruses.

  18. Broad-spectrum transgenic resistance against distinct tospovirus species at the genus level.

    Science.gov (United States)

    Peng, Jui-Chu; Chen, Tsung-Chi; Raja, Joseph A J; Yang, Ching-Fu; Chien, Wan-Chu; Lin, Chen-Hsuan; Liu, Fang-Lin; Wu, Hui-Wen; Yeh, Shyi-Dong

    2014-01-01

    Thrips-borne tospoviruses cause severe damage to crops worldwide. In this investigation, tobacco lines transgenic for individual WLm constructs containing the conserved motifs of the L RNA-encoded RNA-dependent RNA polymerase (L) gene of Watermelon silver mottle virus (WSMoV) were generated by Agrobacterium-mediated transformation. The WLm constructs included: (i) translatable WLm in a sense orientation; (ii) untranslatable WLmt with two stop codons; (iii) untranslatable WLmts with stop codons and a frame-shift; (iv) untranslatable antisense WLmA; and (v) WLmhp with an untranslatable inverted repeat of WLm containing the tospoviral S RNA 3'-terminal consensus sequence (5'-ATTGCTCT-3') and an NcoI site as a linker to generate a double-stranded hairpin transcript. A total of 46.7-70.0% transgenic tobacco lines derived from individual constructs showed resistance to the homologous WSMoV; 35.7-100% plants of these different WSMoV-resistant lines exhibited broad-spectrum resistance against four other serologically unrelated tospoviruses Tomato spotted wilt virus, Groundnut yellow spot virus, Impatiens necrotic spot virus and Groundnut chlorotic fan-spot virus. The selected transgenic tobacco lines also exhibited broad-spectrum resistance against five additional tospoviruses from WSMoV and Iris yellow spot virus clades, but not against RNA viruses from other genera. Northern analyses indicated that the broad-spectrum resistance is mediated by RNA silencing. To validate the L conserved region resistance in vegetable crops, the constructs were also used to generate transgenic tomato lines, which also showed effective resistance against WSMoV and other tospoviruses. Thus, our approach of using the conserved motifs of tospoviral L gene as a transgene generates broad-spectrum resistance against tospoviruses at the genus level.

  19. Broad-spectrum transgenic resistance against distinct tospovirus species at the genus level.

    Directory of Open Access Journals (Sweden)

    Jui-Chu Peng

    Full Text Available Thrips-borne tospoviruses cause severe damage to crops worldwide. In this investigation, tobacco lines transgenic for individual WLm constructs containing the conserved motifs of the L RNA-encoded RNA-dependent RNA polymerase (L gene of Watermelon silver mottle virus (WSMoV were generated by Agrobacterium-mediated transformation. The WLm constructs included: (i translatable WLm in a sense orientation; (ii untranslatable WLmt with two stop codons; (iii untranslatable WLmts with stop codons and a frame-shift; (iv untranslatable antisense WLmA; and (v WLmhp with an untranslatable inverted repeat of WLm containing the tospoviral S RNA 3'-terminal consensus sequence (5'-ATTGCTCT-3' and an NcoI site as a linker to generate a double-stranded hairpin transcript. A total of 46.7-70.0% transgenic tobacco lines derived from individual constructs showed resistance to the homologous WSMoV; 35.7-100% plants of these different WSMoV-resistant lines exhibited broad-spectrum resistance against four other serologically unrelated tospoviruses Tomato spotted wilt virus, Groundnut yellow spot virus, Impatiens necrotic spot virus and Groundnut chlorotic fan-spot virus. The selected transgenic tobacco lines also exhibited broad-spectrum resistance against five additional tospoviruses from WSMoV and Iris yellow spot virus clades, but not against RNA viruses from other genera. Northern analyses indicated that the broad-spectrum resistance is mediated by RNA silencing. To validate the L conserved region resistance in vegetable crops, the constructs were also used to generate transgenic tomato lines, which also showed effective resistance against WSMoV and other tospoviruses. Thus, our approach of using the conserved motifs of tospoviral L gene as a transgene generates broad-spectrum resistance against tospoviruses at the genus level.

  20. A Novel Surfactant Nanoemulsion with Broad Spectrum Sporicidal Activity against Bacillus Species

    Science.gov (United States)

    1999-12-01

    1939 A Novel Surfactant Nanoemulsion with Broad-Spectrum Sporicidal Activity against Bacillus Species Tarek Hamouda,1 Michael M. Hayes,1,a Zhengyi... nanoemulsions , BCTP and BCTP 401, have been developed. These emulsions are composed of detergents and oils in 80% water. BCTP diluted up to 1 : 1000...was reduced 3-fold. These nanoemulsion formulas are stable, easily dispersed, nonirritant, and nontoxic compared with other available sporicidal

  1. A comparison of effects of broad-spectrum antibiotics and biosurfactants on established bacterial biofilms.

    Science.gov (United States)

    Quinn, Gerry A; Maloy, Aaron P; Banat, Malik M; Banat, Ibrahim M

    2013-11-01

    Current antibiofilm solutions based on planktonic bacterial physiology have limited efficacy in clinical and occasionally environmental settings. This has prompted a search for suitable alternatives to conventional therapies. This study compares the inhibitory properties of two biological surfactants (rhamnolipids and a plant-derived surfactant) against a selection of broad-spectrum antibiotics (ampicillin, chloramphenicol and kanamycin). Testing was carried out on a range of bacterial physiologies from planktonic and mixed bacterial biofilms. Rhamnolipids (Rhs) have been extensively characterised for their role in the development of biofilms and inhibition of planktonic bacteria. However, there are limited direct comparisons with antimicrobial substances on established biofilms comprising single or mixed bacterial strains. Baseline measurements of inhibitory activity using planktonic bacterial assays established that broad-spectrum antibiotics were 500 times more effective at inhibiting bacterial growth than either Rhs or plant surfactants. Conversely, Rhs and plant biosurfactants reduced biofilm biomass of established single bacterial biofilms by 74-88 and 74-98 %, respectively. Only kanamycin showed activity against biofilms of Bacillus subtilis and Staphylococcus aureus. Broad-spectrum antibiotics were also ineffective against a complex biofilm of marine bacteria; however, Rhs and plant biosurfactants reduced biofilm biomass by 69 and 42 %, respectively. These data suggest that Rhs and plant-derived surfactants may have an important role in the inhibition of complex biofilms.

  2. Current state of the union of epilepsy care in the United States: Antiepileptic drugs - An introduction to the Connectors Project.

    Science.gov (United States)

    Sirven, Joseph I; Shafer, Patricia O; Kalilani, Linda; Wild, Imane; Fishman, Jesse; Owens, Steve

    2018-02-01

    How antiepileptic drugs (AEDs) are used in the United States (US) is one proxy public health indicator for the current state of epilepsy management. The use of phenytoin, other older AEDs, and newer AEDs may act as an indicator for the quality of epilepsy practice in addition to the current American Academy of Neurology quality measures. Data on AED used by states and populations can help identify which public health interventions are necessary to improve the status of epilepsy care. The Connectors Project, a collaboration between the Epilepsy Foundation and UCB Pharma, is a multiyear project designed to improve epilepsy awareness and management in underserved communities. The objective of the first phase of the Connectors Project was to assess geographic variation in epilepsy care and identify locations in need of improved epilepsy care by initially evaluating AED use in the US. A retrospective cross-sectional administrative claim analysis was conducted using the QuintilesIMS™ database which included US longitudinal retail prescription and office medical claims data. Patients with a confirmed epilepsy diagnosis who were prescribed AEDs were identified. Patients with an AED prescription over a 3-year period from January 2013 to December 2015 were included if they had an epilepsy diagnosis in the 2-year period before their first AED prescription in the reporting period. The percentages of patients initially prescribed phenytoin, other older AEDs (carbamazepine and valproate), and newer AEDs (eslicarbazepine, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, topiramate) were calculated and stratified by US state and Washington, DC. Patients were considered newly treated if they had an epilepsy diagnosis code and had not received an epilepsy drug in the 1-year period preceding the first AED prescription in the reporting period. Data are reported using the moving annual total ending December 2015. Approximately 2.5 million US patients with epilepsy

  3. Effect of impaired ambulation and anti-epileptic drug intake on vitamin D status of children with cerebral palsy.

    Science.gov (United States)

    Seth, Anju; Aneja, Satinder; Singh, Ritu; Majumdar, Ritu; Sharma, Neera; Gopinath, Muthuselvan

    2017-08-01

    Children with cerebral palsy (CP) are vulnerable to developing vitamin D deficiency. There is little information on the prevalence and severity of vitamin D deficiency in these patients. To study vitamin D status in children with CP with special reference to their intake of anti-epileptic drugs (AED) and ambulatory status. The relative effects of AED use and ambulatory status on the vitamin D status of 120 children with CP aged 2-10 years were examined in this observational study. The patients were classified into four groups (30 in each) on the basis of AED use and ambulatory status: ambulatory (CPA), ambulatory receiving AED (CPAD), non-ambulatory (CPNA) and non-ambulatory receiving AED (CPNAD). A control group of 30 age-matched healthy children was also included. Parameters assessed included dietary calcium intake, sun exposure, serum total and ionised calcium (tCa, iCa), inorganic phosphate (iP), alkaline phosphatase (ALP), parathormone (PTH), 25 hydroxy vitamin D [25(OH)D] levels and a wrist radiograph to detect rickets. Vitamin D status was defined on the basis of serum 25(OH)D levels as normal (>50 nmol/L), mild deficiency (25-50 nmol/L), moderate deficiency (12.5-25 nmol/L), severe deficiency (<12.5 nmol/L). Median (IQR) serum 25 (OH)D levels in patients with CP were 35.6 (26.75-64) nmol/L compared with 60 (37-69.25) nmol/L in controls (p = 0.04). Sixty per cent of children with CP and 36.7% of controls were vitamin D-deficient [25(OH)D < 50 nmol/L]. Children with CP had a significantly lower dietary calcium intake and sun exposure than controls (p < 0.0001 each). Serum tCa and iCa levels were significantly lower (p = 0.01 and p < 0.001, respectively) and PTH and ALP levels significantly higher (p = 0.04 and p = 0.001, respectively) in children with CP than in controls. Patients in the CPNAD group were the worst affected, 83.3% of them being vitamin D-deficient with median (IQR) 25(OH)D levels of 33.5 (12.5-45.25) nmol/L. Also, 53.3% of

  4. The reasons for the epilepsy treatment gap in Kilifi, Kenya: using formative research to identify interventions to improve adherence to antiepileptic drugs.

    Science.gov (United States)

    Carter, Julie A; Molyneux, Catherine S; Mbuba, Caroline K; Jenkins, Jo; Newton, Charles R J C; Hartley, Sally D

    2012-12-01

    Many people with epilepsy (PWE) in resource-poor countries do not receive appropriate treatment, a phenomenon referred to as the epilepsy treatment gap (ETG). We conducted a qualitative study to explore the reasons for this gap and to identify possible interventions in Kilifi, Kenya. Focus group discussions (FGDs) were carried out of PWE and their caregivers. Individual interviews were conducted of PWE, their caregivers, traditional healers, community health workers and leaders, nurses and doctors. In addition, a series of workshops was conducted, and four factors contributing to the ETG were identified: 1) lack of knowledge about the causes, treatment and prognosis of epilepsy; 2) inaccessibility to antiepileptic drugs; 3) misconceptions about epilepsy derived from superstitions about its origin; 4) and dissatisfaction with the communication skills of health providers. These data indicated possible interventions: 1) education and support for PWE and their caregivers; 2) communication skills training for health providers; 3) and improved drug provision. Copyright © 2012 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    AlQuliti, Khalid; Ratrout, Basem; AlZaki, Alaa

    2014-09-01

    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. 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. 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.

  6. Hexagonal 2H-MoSe2 broad spectrum active photocatalyst for Cr(VI) reduction

    OpenAIRE

    Haipeng Chu; Xinjuan Liu; Baibai Liu; Guang Zhu; Wenyan Lei; Huigang Du; Junying Liu; Jianwei Li; Can Li; Changqing Sun

    2016-01-01

    To make full use of the solar energy, exploring broad spectrum active photocatalysts has become one of the core issues for photocatalysis. Here we report a novel hexagonal 2H-MoSe2 photocatalyst with ultraviolet (UV)-visible-near infrared (NIR) light response for the first time. The results indicate that the MoSe2 displays excellent photo-absorption and photocatalytic activity in the reduction of Cr(VI) under UV and visible even NIR light irradiation. MoSe2 synthesized at pH value of 2 achiev...

  7. Cost-effectiveness analysis for the use of serum antiepileptic drug level monitoring in children diagnosed with structural-metabolic epilepsy.

    Science.gov (United States)

    Salih, Muhannad R M; Bahari, Mohd Baidi; Shafie, Asrul Akmal; Hassali, Mohamed Azmi Ahmad; Al-Lela, Omer Qutaiba B; Abd, Arwa Y; Ganesan, Vigneswari M

    2013-03-01

    Treatment with antiepileptic drugs is commonly guided by serum level monitoring. Such monitoring requires expensive laboratory equipment and products. However, well-conducted studies on the cost-effectiveness of therapeutic drug monitoring for antiepileptic drugs are lacking particularly in patients with structural-metabolic epilepsy. The study aims to assess the cost-effectiveness of serum level monitoring services in the management of children with structural-metabolic epilepsy during the first year of diagnosis. A retrospective cost-effectiveness analysis was conducted from the provider perspective. It included patients attended a paediatric neurology clinic. The effectiveness measures used in this analysis were the number of patients that achieved ≥50% reduction in seizure frequency, and the number of patients with 3-month seizure free. Medical records of the patients were reviewed for the required information. Medical chart/billing data obtained from the hospital were collected to estimate the resources used (One Malaysian Ringgit MYR is equivalent to 0.31 USD). The recruited children were followed for one year following their first visit. The average cost effectiveness ratio for the monitored patients (MYR 2735 per patient that achieved a ≥50% reduction in seizure frequency) was lower than that for non-monitored patients (MYR 2921 per patients that achieved a ≥50% reduction in seizure frequency), with incremental cost-effectiveness ratio of MYR 2357 per one additional patient that achieved a ≥50% reduction in seizure frequency. The average cost effectiveness ratios for monitored and non-monitored group were MYR 8279 and MYR 6433 per patient with a 3-month seizure-free period, respectively, with incremental cost-effectiveness ratio of MYR 29,666 per one additional patient with a 3-month seizure-free period. In terms of the effectiveness measures used, serum level monitoring of antiepileptic drugs was found to be cost-effective. However, the incremental

  8. Risks and benefits of new antiepileptic agents in children

    National Research Council Canada - National Science Library

    Aicardi, J

    2000-01-01

    New antiepileptic drugs (AED) have generally a good pharmacokinetic profile. Their mode of action remains imperfectly known. Gabapentin (GBP), oxcarbazepine (OCBZ), topiramate (TPM), vigabatrin (VGB) and tiagabine (TGB...

  9. Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs.

    Science.gov (United States)

    Herrera, José A; Ward, Christopher S; Pitcher, Meagan R; Percy, Alan K; Skinner, Steven; Kaufmann, Walter E; Glaze, Daniel G; Wehrens, Xander H T; Neul, Jeffrey L

    2015-04-01

    One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with β-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a β-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na(+) channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na(+) channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na(+) channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na(+) channel blocker antiepileptic therapies. Thus, Na(+) channel blockers should be considered for the clinical management of LQT in individuals with RTT. © 2015. Published by The Company of Biologists Ltd.

  10. Tricyclic GyrB/ParE (TriBE inhibitors: a new class of broad-spectrum dual-targeting antibacterial agents.

    Directory of Open Access Journals (Sweden)

    Leslie W Tari

    Full Text Available Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB and topoisomerase IV (ParE have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD, we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.

  11. Tricyclic GyrB/ParE (TriBE) inhibitors: a new class of broad-spectrum dual-targeting antibacterial agents.

    Science.gov (United States)

    Tari, Leslie W; Li, Xiaoming; Trzoss, Michael; Bensen, Daniel C; Chen, Zhiyong; Lam, Thanh; Zhang, Junhu; Lee, Suk Joong; Hough, Grayson; Phillipson, Doug; Akers-Rodriguez, Suzanne; Cunningham, Mark L; Kwan, Bryan P; Nelson, Kirk J; Castellano, Amanda; Locke, Jeff B; Brown-Driver, Vickie; Murphy, Timothy M; Ong, Voon S; Pillar, Chris M; Shinabarger, Dean L; Nix, Jay; Lightstone, Felice C; Wong, Sergio E; Nguyen, Toan B; Shaw, Karen J; Finn, John

    2013-01-01

    Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.

  12. Hexagonal 2H-MoSe2 broad spectrum active photocatalyst for Cr(VI) reduction

    Science.gov (United States)

    Chu, Haipeng; Liu, Xinjuan; Liu, Baibai; Zhu, Guang; Lei, Wenyan; Du, Huigang; Liu, Junying; Li, Jianwei; Li, Can; Sun, Changqing

    2016-10-01

    To make full use of the solar energy, exploring broad spectrum active photocatalysts has become one of the core issues for photocatalysis. Here we report a novel hexagonal 2H-MoSe2 photocatalyst with ultraviolet (UV)-visible-near infrared (NIR) light response for the first time. The results indicate that the MoSe2 displays excellent photo-absorption and photocatalytic activity in the reduction of Cr(VI) under UV and visible even NIR light irradiation. MoSe2 synthesized at pH value of 2 achieves the highest Cr(VI) reduction rates of 99%, 91% and 100% under UV, visible and NIR light irradiation, respectively, which should be attributed to its comparatively higher light absorption, efficient charge separation and transfer as well as relatively large number of surface active sites. The excellent broad spectrum active photocatalytic activity makes the MoSe2 to be a promising photocatalyst for the effective utilization of solar energy.

  13. Identification and Structural Characterization of Naturally-Occurring Broad-Spectrum Cyclic Antibiotics Isolated from Paenibacillus

    Science.gov (United States)

    Knolhoff, Ann M.; Zheng, Jie; McFarland, Melinda A.; Luo, Yan; Callahan, John H.; Brown, Eric W.; Croley, Timothy R.

    2015-08-01

    The rise of antimicrobial resistance necessitates the discovery and/or production of novel antibiotics. Isolated strains of Paenibacillus alvei were previously shown to exhibit antimicrobial activity against a number of pathogens, such as E. coli, Salmonella, and methicillin-resistant Staphylococcus aureus (MRSA). The responsible antimicrobial compounds were isolated from these Paenibacillus strains and a combination of low and high resolution mass spectrometry with multiple-stage tandem mass spectrometry was used for identification. A group of closely related cyclic lipopeptides was identified, differing primarily by fatty acid chain length and one of two possible amino acid substitutions. Variation in the fatty acid length resulted in mass differences of 14 Da and yielded groups of related MSn spectra. Despite the inherent complexity of MS/MS spectra of cyclic compounds, straightforward analysis of these spectra was accomplished by determining differences in complementary product ion series between compounds that differ in molecular weight by 14 Da. The primary peptide sequence assignment was confirmed through genome mining; the combination of these analytical tools represents a workflow that can be used for the identification of complex antibiotics. The compounds also share amino acid sequence similarity to a previously identified broad-spectrum antibiotic isolated from Paenibacillus. The presence of such a wide distribution of related compounds produced by the same organism represents a novel class of broad-spectrum antibiotic compounds.

  14. Towards establishing broad-spectrum disease resistance in plants: silicon leads the way.

    Science.gov (United States)

    Van Bockhaven, Jonas; De Vleesschauwer, David; Höfte, Monica

    2013-03-01

    Plants are constantly threatened by a wide array of microbial pathogens. Pathogen invasion can lead to vast yield losses and the demand for sustainable plant-protection strategies has never been greater. Chemical plant activators and selected strains of rhizobacteria can increase resistance against specific types of pathogens but these treatments are often ineffective or even cause susceptibility against others. Silicon application is one of the scarce examples of a treatment that effectively induces broad-spectrum disease resistance. The prophylactic effect of silicon is considered to be the result of both passive and active defences. Although the phenomenon has been known for decades, very little is known about the molecular basis of silicon-afforded disease control. By combining knowledge on how silicon interacts with cell metabolism in diatoms and plants, this review describes silicon-induced regulatory mechanisms that might account for broad-spectrum plant disease resistance. Priming of plant immune responses, alterations in phytohormone homeostasis, regulation of iron homeostasis, silicon-driven photorespiration and interaction with defence signalling components all are potential mechanisms involved in regulating silicon-triggered resistance responses. Further elucidating how silicon exerts its beneficial properties may create new avenues for developing plants that are better able to withstand multiple attackers.

  15. Biological activity of sedaxane---a novel broad-spectrum fungicide for seed treatment.

    Science.gov (United States)

    Zeun, Ronald; Scalliet, Gabriel; Oostendorp, Michael

    2013-04-01

    Sedaxane is a new broad-spectrum seed treatment fungicide developed by Syngenta Crop Protection for control of seed- and soil-borne diseases in a broad range of crops. Its physicochemical properties and activity spectrum have been optimised for use as a seed treatment providing both local and systemic protection of the seed and roots of target crops. Sedaxane inhibits respiration by binding to the succinate dehydrogenase complex in the fungal mitochondrium. Its activity spectrum covers seed-borne fungi such as Ustilago nuda, Tilletia caries, Monographella nivalis and Pyrenophora graminea, as well as the soil-borne fungi Rhizoctonia solani, R. cerealis and Typhula incarnata. Under greenhouse conditions, sedaxane showed high levels and consistent protection against U. nuda, P. graminea and Rhizoctonia spp. Under field conditions, efficacy against Rhizoctonia spp. resulted in increased yield compared with the untreated check. Efficacy against snow mould has been shown under very high disease pressure conditions. The combination of sedaxane plus fludioxonil against snow mould can provide resistance management for sustainable use. The broad spectrum and high level of activity in combination with excellent crop tolerance allow the use of sedaxane as a seed treatment in a wide variety of crops. It is a potential tool for precautionary resistance management when combined with other fungicides, especially against pathogens showing a potential for resistance development, such as M. nivalis. © 2012 Society of Chemical Industry.

  16. Brevibacillus laterosporus, a Pathogen of Invertebrates and a Broad-Spectrum Antimicrobial Species

    Directory of Open Access Journals (Sweden)

    Luca Ruiu

    2013-09-01

    Full Text Available Brevibacillus laterosporus, a bacterium characterized by the production of a unique canoe-shaped lamellar body attached to one side of the spore, is a natural inhabitant of water, soil and insects. Its biopesticidal potential has been reported against insects in different orders including Coleoptera, Lepidoptera, Diptera and against nematodes and mollusks. In addition to its pathogenicity against invertebrates, different B. laterosporus strains show a broad-spectrum antimicrobial activity including activity against phytopathogenic bacteria and fungi. A wide variety of molecules, including proteins and antibiotics, have been associated with the observed pathogenicity and mode of action. Before being considered as a biological control agent against plant pathogens, the antifungal and antibacterial properties of certain B. laterosporus strains have found medical interest, associated with the production of antibiotics with therapeutic effects. The recent whole genome sequencing of this species revealed its potential to produce polyketides, nonribosomal peptides, and toxins. Another field of growing interest is the use of this bacterium for bioremediation of contaminated sites by exploiting its biodegradation properties. The aim of the present review is to gather and discuss all recent findings on this emerging entomopathogen, giving a wider picture of its complex and broad-spectrum biocontrol activity.

  17. Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non-protein-bound concentrations.

    Science.gov (United States)

    Patsalos, Philip N; Zugman, Miguel; Lake, Charlotte; James, Anthony; Ratnaraj, Neville; Sander, Josemir W

    2017-07-01

    Given that only the free non-protein-bound concentration of an antiepileptic drug (AED) crosses the blood-brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newer AEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25 AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine-epoxide and N-desmethyl clobazam), using standardized methodology and under set conditions. The protein binding of the various AEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non-protein-bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000 g for 15 min, and at 25°C. Free and total AED concentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques. Gabapentin and pregabalin are non-protein-bound, whereas highly bound AEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as the N-desmethyl-clobazam (89%) metabolite. The minimally bound drugs (<22%) include ethosuximide (21.8%), lacosamide (14.0%), levetiracetam (3.4%), topiramate, (19.5%) and vigabatrin (17.1%). Ten of the 25 AEDs exhibit moderate protein binding (mean range 27.7-74.8%). These data provide a comprehensive comparison of serum protein binding of all available AEDs including the metabolites, carbamazepine-epoxide and N-desmethyl-clobazam. Knowledge of the free fraction of these AEDs can be used to optimize epilepsy treatment. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  18. Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent

    National Research Council Canada - National Science Library

    Zahid Raja; Sonia André; Feten Abbassi; Vincent Humblot; Olivier Lequin; Tahar Bouceba; Isabelle Correia; Sandra Casale; Thierry Foulon; Denis Sereno; Bruno Oury; Ali Ladram

    2017-01-01

    ...), a small broad-spectrum AMP previously shown to be active against Leishmania infantum. To improve activity, we designed analogs of SHa and compared the antibacterial and antiparasitic mechanisms. [K3...

  19. Trends in broad-spectrum antibiotic prescribing for children with acute otitis media in the United States, 1998?2004

    OpenAIRE

    Coco, Andrew S; Horst, Michael A; Gambler, Angela S

    2009-01-01

    Abstract Background Overuse of broad-spectrum antibiotics is associated with antibiotic resistance. Acute otitis media (AOM) is responsible for a large proportion of antibiotics prescribed for US children. Rates of broad-spectrum antibiotic prescribing for AOM are unknown. Methods Analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, 1998 to 2004 (N = 6,878). Setting is office-based physicians, hospital outpatient departments, and emerge...

  20. Phenobarbital or potassium bromide as an add-on antiepileptic drug for the management of canine idiopathic epilepsy refractory to imepitoin.

    Science.gov (United States)

    Royaux, E; Van Ham, L; Broeckx, B J G; Van Soens, I; Gielen, I; Deforce, D; Bhatti, S F M

    2017-02-01

    Imepitoin has recently been approved in Europe for the management of dogs with idiopathic epilepsy. Currently, there is no evidence-based information available on the efficacy of antiepileptic drugs used as additions to the therapeutic regimen in dogs with idiopathic epilepsy that are not well controlled with imepitoin. The goal of this study was to evaluate the efficacy of phenobarbital or potassium bromide (KBr) as add-on antiepileptic drugs for controlling dogs refractory to a maximum dose of imepitoin (30 mg/kg twice daily). The study was performed as a prospective, randomised, controlled clinical trial. The efficacy of phenobarbital and KBr was evaluated by comparing monthly seizure frequency (MSF), monthly seizure day frequency (MSDF), the presence of cluster seizures during a retrospective 2-month period with a prospective follow-up of 6 months, and the overall responder rate. Twenty-seven dogs were included in the study, 14 dogs in the phenobarbital group and 13 dogs in the KBr group. Both median MSF and MSDF decreased in the phenobarbital group (both P = 0.001) and in the KBr group (P = 0.004 and P = 0.003, respectively). Overall, the number of dogs with cluster seizures decreased (P = 0.0005). The responder rate was 79% vs. 69% in the phenobarbital and KBr groups, respectively. We conclude that phenobarbital or KBr add-on treatment decreases median MSF and MSDF in epileptic dogs refractory to a maximum dose of imepitoin. Combination therapy was generally well tolerated and resulted in an improvement in seizure management in the majority of the dogs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. [Adult patients treated for focal epilepsy with antiepileptic drugs (AEDs) in combination in France: description according to the 2009 ILAE definition of AED resistance (ESPERA study)].

    Science.gov (United States)

    Vespignani, H; de Zélicourt, M; Laurendeau, C; Fagnani, F; Levy-Bachelot, L; Murat, C; Kahane, P; de Toffol, B

    2014-02-01

    To describe the adult population treated with antiepileptic drugs (AEDs) in combination for focal epilepsy according to the definition of AED resistance proposed by the International League Against Epilepsy (ILAE) in 2009 and to evaluate its implementation in current practice. ESPERA was a multicenter, observational, cross-sectional study with a clinical data collection covering the past 12 months conducted by neurologists. Classifications according to AED responsiveness established by investigators for each enrolled patient were revised by two experts. Seventy-one neurologists enrolled 405 patients. Their mean age was 42.7 years (sex-ratioM/F 0.98). According to the investigators, 60% of epilepsies were drug-resistant, 37% drug-responsive and 3% had an undefined drug-responsiveness. After revision of experts, 71% of epilepsies were classified as drug resistant, 22% as responsive and 7% as undefined. Among the participating neurologists, 76% have made at least one error in classifying their patients according to the 2009 ILAE definition of AED resistance. Because of epilepsy, 24% of patients (age≤65) were inactive and 42% could not drive (respectively 29 and 49% of patients with AED resistant epilepsy). Half of patients had at least one other chronic condition. Number of prescribed drugs in combination and health care resource utilisation were significantly higher in patients with drug-resistant epilepsies than in patients with drug responsive epilepsies. ESPERA study shows that the use of new definition of drug-resistance in everyday practice seems difficult without any additional training and that the social and professional disability is frequent in adults with focal epilepsies treated with polytherapy. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  2. Rational design of broad spectrum antibacterial activity based on a clinically relevant enoyl-acyl carrier protein (ACP) reductase inhibitor.

    Science.gov (United States)

    Schiebel, Johannes; Chang, Andrew; Shah, Sonam; Lu, Yang; Liu, Li; Pan, Pan; Hirschbeck, Maria W; Tareilus, Mona; Eltschkner, Sandra; Yu, Weixuan; Cummings, Jason E; Knudson, Susan E; Bommineni, Gopal R; Walker, Stephen G; Slayden, Richard A; Sotriffer, Christoph A; Tonge, Peter J; Kisker, Caroline

    2014-06-06

    Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549, a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-acyl carrier protein reductase (FabI), has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus infections, which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors, including CG400549. Based on these structures, we rationalize the 65-fold reduced affinity of CG400549 toward Escherichia coli versus S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo.

    Science.gov (United States)

    Fournel, Marielle; Bonfils, Claire; Hou, Yu; Yan, Pu Theresa; Trachy-Bourget, Marie-Claude; Kalita, Ann; Liu, Jianhong; Lu, Ai-Hua; Zhou, Nancy Z; Robert, Marie-France; Gillespie, Jeffrey; Wang, James J; Ste-Croix, Hélène; Rahil, Jubrail; Lefebvre, Sylvain; Moradei, Oscar; Delorme, Daniel; Macleod, A Robert; Besterman, Jeffrey M; Li, Zuomei

    2008-04-01

    Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.

  4. A novel alkaloid from marine-derived actinomycete Streptomyces xinghaiensis with broad-spectrum antibacterial and cytotoxic activities.

    Directory of Open Access Journals (Sweden)

    Wence Jiao

    Full Text Available Due to the increasing emergence of drug-resistant bacteria and tumor cell lines, novel antibiotics with antibacterial and cytotoxic activities are urgently needed. Marine actinobacteria are rich sources of novel antibiotics, and here we report the discovery of a novel alkaloid, xinghaiamine A, from a marine-derived actinomycete Streptomyces xinghaiensis NRRL B24674(T. Xinghaiamine A was purified from the fermentation broth, and its structure was elucidated based on extensive spectroscopic analysis, including 1D and 2D NMR spectrum as well as mass spectrometry. Xinghaiamine A was identified to be a novel alkaloid with highly symmetric structure on the basis of sulfoxide functional group, and sulfoxide containing compound has so far never been reported in microorganisms. Biological assays revealed that xinghaiamine A exhibited broad-spectrum antibacterial activities to both Gram-negative persistent hospital pathogens (e.g. Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli and Gram-positive ones, which include Staphylococcus aureus and Bacillus subtilis. In addition, xinghaiamine A also exhibited potent cytotoxic activity to human cancer cell lines of MCF-7 and U-937 with the IC50 of 0.6 and 0.5 µM, respectively.

  5. Synthesis and Properties of Benzo[a]phenoxazinium Chalcogen Analogues as Novel Broad-Spectrum Antimicrobial Photosensitizers

    Science.gov (United States)

    Foley, James W.; Song, Xiangzhi; Demidova, Tatiana N.; Jilal, Fatima; Hamblin, Michael R.

    2011-01-01

    The goal of this investigation was to develop improved photosensitizers for use as antimicrobial drugs in photodynamic therapy of localized infections. Replacement of the oxygen atom in 5-(ethylamino)-9-diethylaminobenzo[a]phenoxazinium chloride (1) with sulfur and selenium afforded thiazinium and selenazinium analogues 2 and 3, respectively. All three dyes are water soluble, lipophilic, and red light absorbers. The relative photodynamic activities of the chalcogen series were evaluated against a panel of prototypical pathogenic microorganisms: the Gram-positive Enterococcus faecalis, the Gram-negative Escherichia coli, and the fungus Candida albicans. Selenium dye 3 was highly effective as a broad-spectrum antimicrobial photosensitizer with fluences of 4–32 J/cm2 killing 2–5 more logs of all cell types than sulfur dye 2, which was slightly more effective than oxygen analogue 1. These data, taken with the findings of uptake and retention studies, suggest that the superior activity of selenium derivative 3 can be attributed to its much higher triplet quantum yield. PMID:16913718

  6. Synergistic effect of broad-spectrum Sunscreens and antihistamines in the control of idiopathic solar urticaria

    DEFF Research Database (Denmark)

    Faurschou, A.; Wulf, Hans Chr.

    2008-01-01

    . Observations: Three patients with idiopathic solar urticaria underwent phototesting with UV-B and UV-A radiation. The minimal urticarial dose (MUD) was determined 15 minutes after irradiation. The patients were subsequently tested with 5 times the MUD, and the reaction was graded every minute for 15 minutes......Background: It can be difficult to provide patients with idiopathic solar urticaria adequate protection from sunlight. In a nonrandomized controlled trial, we used a standardized phototest procedure to determine the effects of using sunscreen and antihistamine to control idiopathic solar urticaria....... The patients were then treated with a high-protection, broad-spectrum sunscreen and a nonsedative antihistamine alone and in combination and underwent similar phototesting. The use of sunscreen allowed the patients to tolerate much higher doses of UV radiation (32-38 times the MUD on untreated skin...

  7. Analysis of mobile health applications for a broad spectrum of consumers: a user experience approach.

    Science.gov (United States)

    García-Gómez, Juan M; de la Torre-Díez, Isabel; Vicente, Javier; Robles, Montserrat; López-Coronado, Miguel; Rodrigues, Joel J

    2014-03-01

    Mobile health (m-health) apps can bring health prevention and promotion to the general population. The main purpose of this article is to analyze different m-health apps for a broad spectrum of consumers by means of three different experiences. This goal was defined following the strategic documents generated by the main prospective observatories of Information and Communications Technology for health. After a general exploration of the app markets, we analyze the entries of three specific themes focused in this article: type 2 diabetes, obesity, and breast-feeding. The user experiences reported in this study mostly cover the segments of (1) chronically monitored consumers through a Web mobile app for predicting type 2 diabetes (Diab_Alert app), (2) information seekers through a mobile app for maternity (Lactation app) and partially (3) the motivated healthy consumers through a mobile app for a dietetic monitoring and assessment (SapoFit app). These apps were developed by the authors of this work.

  8. Immune Responses to Broad-Spectrum Antibiotic Treatment and Fecal Microbiota Transplantation in Mice.

    Science.gov (United States)

    Ekmekciu, Ira; von Klitzing, Eliane; Fiebiger, Ulrike; Escher, Ulrike; Neumann, Christian; Bacher, Petra; Scheffold, Alexander; Kühl, Anja A; Bereswill, Stefan; Heimesaat, Markus M

    2017-01-01

    Compelling evidence demonstrates the pivotal role of the commensal intestinal microbiota in host physiology and the detrimental effects of its perturbations following antibiotic treatment. Aim of this study was to investigate the impact of antibiotics induced depletion and subsequent restoration of the intestinal microbiota composition on the murine mucosal and systemic immunity. To address this, conventional C57BL/6j mice were subjected to broad-spectrum antibiotic treatment for 8 weeks. Restoration of the intestinal microbiota by peroral fecal microbiota transplantation (FMT) led to reestablishment of small intestinal CD4 + , CD8 + , and B220 + as well as of colonic CD4 + cell numbers as early as 7 days post-FMT. However, at d28 following FMT, colonic CD4 + and B220 + cell numbers were comparable to those in secondary abiotic (ABx) mice. Remarkably, CD8 + cell numbers were reduced in the colon upon antibiotic treatment, and FMT was not sufficient to restore this immune cell subset. Furthermore, absence of gut microbial stimuli resulted in decreased percentages of memory/effector T cells, regulatory T cells, and activated dendritic cells in the small intestine, colon, mesenteric lymph nodes (MLN), and spleen. Concurrent antibiotic treatment caused decreased cytokine production (IFN-γ, IL-17, IL-22, and IL-10) of CD4 + cells in respective compartments. These effects were, however, completely restored upon FMT. In summary, broad-spectrum antibiotic treatment resulted in profound local (i.e., small and large intestinal), peripheral (i.e., MLN), and systemic (i.e., splenic) changes in the immune cell repertoire that could, at least in part, be restored upon FMT. Further studies need to unravel the distinct molecular mechanisms underlying microbiota-driven changes in immune homeostasis subsequently providing novel therapeutic or even preventive approaches in human immunopathologies.

  9. Surveillance of broad-spectrum antibiotic prescription in Singaporean hospitals: a 5-year longitudinal study.

    Directory of Open Access Journals (Sweden)

    Yi-Xin Liew

    Full Text Available BACKGROUND: Inappropriate prescription of antibiotics may contribute towards higher levels antimicrobial resistance. A key intervention for improving appropriate antibiotic prescription is surveillance of prescription. This paper presents the results of a longitudinal surveillance of broad-spectrum antibiotic prescription in 5 public-sector hospitals in Singapore from 2006 to 2010. METHODOLOGY/PRINCIPAL FINDINGS: Quarterly antibiotic prescription data were obtained and converted to defined daily doses (DDDs per 1,000 inpatient-days. The presence of significant trends in antibiotic prescription over time for both individual and combined hospitals was tested by regression analysis and corrected for autocorrelation between time-points. Excluding fluoroquinolones, there was a significant increase in prescription of all monitored antibiotics from an average of 233.12 defined daily doses (DDD/1,000 inpatient-days in 2006 to 254.38 DDD/1,000 inpatient-days in 2010 (Coefficient = 1.13, 95%CI: 0.16-2.09, p = 0.025. Increasing utilization of carbapenems, piperacillin/tazobactam, and Gram-positive agents were seen in the majority of the hospitals, while cephalosporins were less prescribed over time. The combined expenditure for 5 hospitals increased from USD9.9 million in 2006 to USD16.7 million in 2010. CONCLUSIONS/SIGNIFICANCE: The rate of prescription of broad-spectrum antibiotics in Singaporean hospitals is much higher compared to those of European hospitals. This may be due to high rates of antimicrobial resistance. The increase in expenditure on monitored antibiotics over the past 5 years outstripped the actual increase in DDD/1,000 inpatient-days of antibiotics prescribed. Longitudinal surveillance of antibiotic prescription on a hospital and countrywide level is important for detecting trends for formulating interventions or policies. Further research is needed to understand the causes for the various prescription trends and to act on these where

  10. Broad-Spectrum Inhibition of the CC-Chemokine Class Improves Wound Healing and Wound Angiogenesis.

    Science.gov (United States)

    Ridiandries, Anisyah; Bursill, Christina; Tan, Joanne

    2017-01-13

    Angiogenesis is involved in the inflammation and proliferation stages of wound healing, to bring inflammatory cells to the wound and provide a microvascular network to maintain new tissue formation. An excess of inflammation, however, leads to prolonged wound healing and scar formation, often resulting in unfavourable outcomes such as amputation. CC-chemokines play key roles in the promotion of inflammation and inflammatory-driven angiogenesis. Therefore, inhibition of the CC-chemokine class may improve wound healing. We aimed to determine if the broad-spectrum CC-chemokine inhibitor "35K" could accelerate wound healing in vivo in mice. In a murine wound healing model, 35K protein or phosphate buffered saline (PBS, control) were added topically daily to wounds. Cohorts of mice were assessed in the early stages (four days post-wounding) and in the later stages of wound repair (10 and 21 days post-wounding). Topical application of the 35K protein inhibited CC-chemokine expression (CCL5, CCL2) in wounds and caused enhanced blood flow recovery and wound closure in early-mid stage wounds. In addition, 35K promoted neovascularisation in the early stages of wound repair. Furthermore, 35K treated wounds had significantly lower expression of the p65 subunit of NF-κB, a key inflammatory transcription factor, and augmented wound expression of the pro-angiogenic and pro-repair cytokine TGF-β. These findings show that broad-spectrum CC-chemokine inhibition may be beneficial for the promotion of wound healing.

  11. Broad-spectrum sunscreens prevent the secretion of proinflammatory cytokines in human keratinocytes exposed to ultraviolet A and phototoxic lomefloxacin

    Energy Technology Data Exchange (ETDEWEB)

    Reinhardt, P.; Cybulski, M. [Lasers and Electro-Optics Div., Consumer and Clinical Radiation Protection Bureau, Product Safety Program, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario (Canada)], E-mail: pascale_reinhardt@hc-sc.gc.ca; Miller, S.M.; Ferrarotto, C.; Wilkins, R. [Radiobiology Div., Consumer and Clinical Radiation Protection Bureau, Product Safety Program, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario (Canada); Deslauriers, Y. [Lasers and Electro-Optics Div., Consumer and Clinical Radiation Protection Bureau, Product Safety Program, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario (Canada)

    2006-02-15

    The combination of phototoxic drugs and ultraviolet (UV) radiation can trigger the release of proinflammatory cytokines. The present study measured the ability of sunscreens to prevent cytokine secretion in human keratinocytes following cotreatment of these cells with a known photoreactive drug and UVA. Keratinocytes were treated for 1 h with increasing concentrations of lomefloxacin (LOM) or norfloxacin (NOR), exposed to 15 J/cm{sup 2} UVA, and incubated for 24 h. NOR, owing to the absence of a fluorine atom in position 8, was non-phototoxic and used as a negative control. Cell viability and the release of 3 cytokines were assessed, namely interleukin-1{alpha} (IL-1{alpha}), interleukin-6 (IL-6), and tumour necrosis factor-{alpha} (TNF-{alpha}). The measurement of these cytokines may be a useful tool for detecting photoreactive compounds. To measure their ability to prevent cytokine secretion, various sunscreens were inserted between the UVA source and the cells. Treatment with NOR, NOR plus UVA, or LOM had no effect on the cells. LOM plus UVA, however, had an effect on cell viability and on cytokine secretion. IL-1{alpha} levels increased with LOM concentration. The release of TNF-{alpha} and IL-6 followed the same pattern at lower concentrations of LOM but peaked at 15 {mu}mol/L and decreased at higher concentrations. Sunscreens protected the cells from the effects of LOM plus UVA, as cell viability and levels of cytokines remained the same as in the control cells. In conclusion, the application of broad-spectrum sunscreen by individuals exposed to UVA radiation may prevent phototoxic reactions initiated by drugs such as LOM. (author)

  12. Trends in broad-spectrum antibiotic prescribing for children with acute otitis media in the United States, 1998–2004

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    Gambler Angela S

    2009-06-01

    Full Text Available Abstract Background Overuse of broad-spectrum antibiotics is associated with antibiotic resistance. Acute otitis media (AOM is responsible for a large proportion of antibiotics prescribed for US children. Rates of broad-spectrum antibiotic prescribing for AOM are unknown. Methods Analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, 1998 to 2004 (N = 6,878. Setting is office-based physicians, hospital outpatient departments, and emergency departments. Patients are children aged 12 years and younger prescribed antibiotics for acute otitis media. Main outcome measure is percentage of broad-spectrum antibiotics, defined as amoxicillin/clavulanate, macrolides, cephalosporins and quinolones. Results Broad-spectrum prescribing for acute otitis media increased from 34% of visits in 1998 to 45% of visits in 2004 (P Conclusion Prescribing of broad-spectrum antibiotics for acute otitis media has steadily increased from 1998 to 2004. Associations with non-clinical factors suggest potential for improvement in prescribing practice.

  13. Teratogenicity and fetotoxicity of the antiepileptics

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    Nikolić Predrag

    2011-01-01

    Full Text Available Pregnant women with epilepsy have more problems in maintenance of pregnancy and are under higher risk of spontaneous abort ion or occurrence of congenital fetal malformations. Use of antiepileptic drugs during pregnancy is also related to higher risk of congenital fetal malformations. The aim of our study was to determine teratogenicity and fetotoxicity of antiepileptics by performing systematic review of relevant papers. Systematic review was performed using PUBMED and Cochrane Database of Systematic Reviews. Original and review papers that relate to teratogenic effects of antiepileptic drugs were included in the analysis. Fourteen studies were found, out of which there were 7 original papers and 7 review papers. The lowest number of participants in a study was 54 and the highest 3607. Studies followed participants from 5 to 9 years. Antiepileptic drugs were used as monotherapy in 2 studies, while other studies examined both mono- and polytherapy. Doses administered varied from 600 mg (carbamazepine, 100-200 mg (lamotrigine and 600-1000 mg (valproate, depending on kind of administration (mono or polytherapy. Among all examined antiepileptic drugs, valproate has shown the highest relation to occurrence of any degree of mental retardation or congenital malformation. Risk of congenital malformations was correlated with administration of higher drug doses and the use of polytherapy. Carbamazepine was shown to be the safest drug to use during pregnancy. Literature data do not confirm teratogenic effects of antiepileptic drugs with certainty. There are not enough studies that compare drug effects in different stages of pregnancy. Limit of presented studies is also lack of information about the degree of epilepsy and eventual comorbidity.

  14. Controlled delivery of a new broad spectrum antibacterial agent against colitis: In vitro and in vivo performance.

    Science.gov (United States)

    Nieto-Bobadilla, M S; Siepmann, F; Djouina, M; Dubuquoy, L; Tesse, N; Willart, J-F; Dubreuil, L; Siepmann, J; Neut, C

    2015-10-01

    Coated pellets and mini-tablets were prepared containing a new broad spectrum antibacterial agent: CIN-102, a well-defined, synergistic blend of trans-cinnamaldehyde, trans-2-methoxycinnamaldehyde, cinnamyl acetate, linalool, β-caryophyllene, cineol and benzyl benzoate. The aim was to provide a new treatment method for colitis, especially for Inflammatory Bowel Disease (IBD) patients. Since the simple oral gavage of CIN-102 was not able to reduce the pathogenic bacteria involved in colitis (rat model), the drug was incorporated into multiparticulates. The idea was to minimize undesired drug release in the upper gastrointestinal tract and to control CIN-102 release in the colon, in order to optimize the resulting antibiotic concentration at the site of action. A particular challenge was the fact that CIN-102 is a volatile hydrophobic liquid. Pellet cores were prepared by extrusion-spheronization and coated with polymer blends, which are sensitive to colonic bacterial enzymes. Mini-tablets were prepared by direct compression. The release of the main compound of CIN-102 (cinnamaldehyde, 86.7% w/w) was monitored in vitro. Optimized coated pellets and mini-tablets were also tested in vivo: in seven-week-old, male mice suffering from dextran sodium sulfate induced colitis. Importantly, both types of multiparticulates were able: (i) to significantly reduce the number of luminal and mucosal enterobacteria in the mice (the levels of which are increased in the disease state), and (ii) to improve the clinical course of the intestinal inflammation (decrease in the percentages of mice with bloody stools and diarrhea). Thus, the proposed coated pellets and matrix mini-tablets allowing for controlled CIN-102 release show a promising potential for new treatment methods of colitis. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Investigating the potential of the anti-epileptic drug imepitoin as a treatment for co-morbid anxiety in dogs with idiopathic epilepsy.

    Science.gov (United States)

    Packer, Rowena M A; De Risio, Luisa; Volk, Holger A

    2017-04-07

    Behavioural changes associated with idiopathic epilepsy (IE) have been identified in dogs, with fear and anxiety-related problems seen in both drug-naïve dogs and dogs treated with anti-epileptic drugs (AEDs). Treating anxiety-related behaviour in dogs with IE may be challenging, as seizures are a contraindication for many conventional anxiolytic drugs. In addition, many dogs with IE are already treated with AEDs to reduce their seizure frequency, which may have negative effects if used in polytherapy. Imepitoin is low-affinity partial agonist at the benzodiazepine (BDZ) site of the GABA A receptor, and has been demonstrated to have both anticonvulsant and anxiolytic effects in laboratory rodents. Imepitoin has been developed for the treatment of IE in dogs, with demonstrated anticonvulsant effects and high tolerability and safety. To date, imepitoin's potential to reduce anxiety in dogs with IE has not been investigated. An online survey was conducted to investigate the effect of imepitoin on fear and anxiety-related behaviours in dogs with IE. Eighty-five valid responses were received from owners of dogs with IE currently treated with imepitoin. Anxiety-related behaviour was quantified before and during imepitoin treatment using a validated questionnaire tool (C-BARQ). No differences were observed in the five fear/anxiety-related measures between the two time periods (before vs. during treatment) for dog directed fear, stranger directed fear, non-social fear, pain sensitivity and separation related behaviour. A median 45% reduction in seizure frequency/month was observed following imepitoin treatment; however, imepitoin did not appear effective in reducing seizure frequency in a minority of cases. Polyphagia was the most common chronic side effect, and more side effects were reported in polytherapy cases. Imepitoin does not appear to improve anxiety-related behaviour in dogs with IE treated with this medication for its anti-epileptic effects. Investigating the

  16. The effects of ABCC2 G1249A polymorphism on the risk of resistance to antiepileptic drugs: a meta-analysis of the literature.

    Science.gov (United States)

    Chen, Pin; Yan, Qing; Xu, Haitao; Lu, Ailin; Zhao, Peng

    2014-02-01

    The G1249A variant of the multidrug resistance-associated protein 2 (ABCC2) gene may be associated with the development of antiepileptic drug (AED) resistance. Although numerous studies have investigated the association between the G1249A variant and the risk of drug resistance in epilepsy, the results of these studies have been inconclusive. To assess the role of G1249A polymorphism in drug resistance in epilepsy, a meta-analysis was performed. We systematically reviewed relevant studies retrieved by the PubMed and Embase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated based on the date extracted from the studies to evaluate the strength of association. We also analyzed the heterogeneity and sensitivity of each report and the publication bias of the studies. A total of 6 published studies, involving 2213 patients (1100 patients with drug-resistant epilepsy and 1113 controls with drug-responsive epilepsy) were reviewed in the present meta-analysis. The overall results indicated that the variant genotypes were associated with a significantly decreased risk of AED resistance (AA vs. GG: OR=0.372, 95% CI=0.182-0.762; recessive model: OR=0.399, 95% CI=0.200-0.795) (fixed-effects model). A stratified analysis by ethnicity showed similar findings for Caucasians in an additive model (A vs. G: OR=0.700, 95% CI=0.494-0.992). The meta-analysis suggests that the ABCC2 G1249A polymorphism is significantly associated with a decreased risk of AED resistance. However, further functional investigations are warranted to validate the association.

  17. Modulation of Cytokine Production by Drugs with Antiepileptic or Mood Stabilizer Properties in Anti-CD3- and Anti-CD40-Stimulated Blood In Vitro

    Directory of Open Access Journals (Sweden)

    Hubertus Himmerich

    2014-01-01

    Full Text Available Increased cytokine production possibly due to oxidative stress has repeatedly been shown to play a pivotal role in the pathophysiology of epilepsy and bipolar disorder. Recent in vitro and animal studies of valproic acid (VPA report antioxidative and anti-inflammatory properties, and suppression of interleukin (IL-6 and tumor necrosis factor (TNF-α. We tested the effect of drugs with antiepileptic or mood stabilizer properties, namely, primidone (PRM, carbamazepine (CBZ, levetiracetam (LEV, lamotrigine (LTG, VPA, oxcarbazepine (OXC, topiramate (TPM, phenobarbital (PB, and lithium on the production of the following cytokines in vitro: interleukin (IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22, and TNF-α. We performed a whole blood assay with stimulated blood of 14 healthy female subjects. Anti-human CD3 monoclonal antibody OKT3, combined with 5C3 antibody against CD40, was used as stimulant. We found a significant reduction of IL-1 and IL-2 levels with all tested drugs other than lithium in the CD3/5C3-stimulated blood; VPA led to a decrease in IL-1β, IL-2, IL-4, IL-6, IL-17, and TNF-α production, which substantiates and adds knowledge to current hypotheses on VPA’s anti-inflammatory properties.

  18. Modafinil and its metabolites enhance the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model.

    Science.gov (United States)

    Zolkowska, Dorota; Andres-Mach, Marta; Prisinzano, Thomas E; Baumann, Michael H; Luszczki, Jarogniew J

    2015-07-01

    Seizures occur when the excitability of brain circuits is not sufficiently restrained by inhibitory mechanisms. Although modafinil is reported to reduce GABA-activated currents and extracellular GABA levels in the brain, the drug exerts anticonvulsant effects in animal studies. The aim of this study was to determine the effects of modafinil and its metabolites (sulfone and carboxylic acid) on the anticonvulsant action of four classical antiepileptic drugs (AEDs)-carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA). Anticonvulsant activity was assessed with the maximal electroshock seizure threshold (MEST) test and MES test in mice. Brain concentrations of AEDs were measured to ascertain any pharmacokinetic contribution to the observed anticonvulsant effects. Intraperitoneal injection of 75 mg kg(-1) of modafinil or its metabolites significantly elevated the threshold for electroconvulsions in mice, whereas 50 mg kg(-1) of each compound enhanced the anticonvulsant activity of CBZ, PHT, and VPA, but not that of PB. A 25-mg kg(-1) dose of modafinil or its sulfone metabolite enhanced anticonvulsant activity of VPA. Modafinil and its metabolites (50 mg kg(-1)) did not alter total brain concentrations of PB and VPA but did elevate CBZ and PHT. Enhancement of anticonvulsant actions of VPA by modafinil in the mouse MES model is a pharmacodynamic effect. Collectively, our data suggest that modafinil may be a safe and beneficial adjunct to the therapeutic effects of AEDs in human patients.

  19. Development and characterization of novel chimeric monoclonal antibodies for broad spectrum neutralization of rabies virus.

    Directory of Open Access Journals (Sweden)

    Pan Kyeom Kim

    Full Text Available Current post-exposure prophylaxis for rabies virus infection has several limitations in terms of supply, cost, safety, and efficacy. Attempts to replace human or equine rabies immune globulins (HRIG or ERIG have been made by several companies and institutes. We developed potent monoclonal antibodies to neutralize a broad spectrum of rabies viruses by screening hybridomas received from the U.S. Centers for Disease Control and Prevention (CDC. Two kinds of chimeric human antibodies (chimeric #7 and #17 were constructed by cloning the variable regions from selected hybridomas and the constant region of a human antibody. Two antibodies were bound to antigenic site III and I/IV, respectively, and were able to neutralize 51 field isolates of rabies virus that were isolated at different times and places such as Asia, Africa, North America, South America, and Australia. These two antibodies neutralize rabies viruses with high efficacy in an in vivo test using Syrian hamster and mouse models and show low risk for adverse immunogenicity.

  20. Development of broad-spectrum human monoclonal antibodies for rabies post-exposure prophylaxis.

    Science.gov (United States)

    De Benedictis, Paola; Minola, Andrea; Rota Nodari, Elena; Aiello, Roberta; Zecchin, Barbara; Salomoni, Angela; Foglierini, Mathilde; Agatic, Gloria; Vanzetta, Fabrizia; Lavenir, Rachel; Lepelletier, Anthony; Bentley, Emma; Weiss, Robin; Cattoli, Giovanni; Capua, Ilaria; Sallusto, Federica; Wright, Edward; Lanzavecchia, Antonio; Bourhy, Hervé; Corti, Davide

    2016-04-01

    Currently available rabies post-exposure prophylaxis (PEP) for use in humans includes equine or human rabies immunoglobulins (RIG). The replacement of RIG with an equally or more potent and safer product is strongly encouraged due to the high costs and limited availability of existing RIG. In this study, we identified two broadly neutralizing human monoclonal antibodies that represent a valid and affordable alternative to RIG in rabies PEP. Memory B cells from four selected vaccinated donors were immortalized and monoclonal antibodies were tested for neutralizing activity and epitope specificity. Two antibodies, identified as RVC20 and RVC58 (binding to antigenic site I and III, respectively), were selected for their potency and broad-spectrum reactivity. In vitro, RVC20 and RVC58 were able to neutralize all 35 rabies virus (RABV) and 25 non-RABV lyssaviruses. They showed higher potency and breath compared to antibodies under clinical development (namely CR57, CR4098, and RAB1) and commercially available human RIG. In vivo, the RVC20-RVC58 cocktail protected Syrian hamsters from a lethal RABV challenge and did not affect the endogenous hamster post-vaccination antibody response. © 2016 Humabs BioMed SA Published under the terms of the CC BY 4.0 license.

  1. Development and characterization of novel chimeric monoclonal antibodies for broad spectrum neutralization of rabies virus.

    Science.gov (United States)

    Kim, Pan Kyeom; Keum, Sun Ju; Osinubi, Modupe O V; Franka, Richard; Shin, Ji Young; Park, Sang Tae; Kim, Man Su; Park, Mi Jung; Lee, Soo Young; Carson, William; Greenberg, Lauren; Yu, Pengcheng; Tao, Xiaoyan; Lihua, Wang; Tang, Qing; Liang, Guodong; Shampur, Madhusdana; Rupprecht, Charles E; Chang, Shin Jae

    2017-01-01

    Current post-exposure prophylaxis for rabies virus infection has several limitations in terms of supply, cost, safety, and efficacy. Attempts to replace human or equine rabies immune globulins (HRIG or ERIG) have been made by several companies and institutes. We developed potent monoclonal antibodies to neutralize a broad spectrum of rabies viruses by screening hybridomas received from the U.S. Centers for Disease Control and Prevention (CDC). Two kinds of chimeric human antibodies (chimeric #7 and #17) were constructed by cloning the variable regions from selected hybridomas and the constant region of a human antibody. Two antibodies were bound to antigenic site III and I/IV, respectively, and were able to neutralize 51 field isolates of rabies virus that were isolated at different times and places such as Asia, Africa, North America, South America, and Australia. These two antibodies neutralize rabies viruses with high efficacy in an in vivo test using Syrian hamster and mouse models and show low risk for adverse immunogenicity.

  2. Investigation of aryl isonitrile compounds with potent, broad-spectrum antifungal activity.

    Science.gov (United States)

    Mohammad, Haroon; Kyei-Baffour, Kwaku; Younis, Waleed; Davis, Dexter C; Eldesouky, Hassan; Seleem, Mohamed N; Dai, Mingji

    2017-06-01

    Invasive fungal infections present a formidable global public health challenge due to the limited number of approved antifungal agents and the emergence of resistance to the frontline treatment options, such as fluconazole. Three fungal pathogens of significant concern are Candida, Cryptococcus, and Aspergillus given their propensity to cause opportunistic infections in immunocompromised individuals. New antifungal agents composed of unique chemical scaffolds are needed to address this public health challenge. The present study examines the structure-activity relationship of a set of aryl isonitrile compounds that possess broad-spectrum antifungal activity primarily against species of Candida and Cryptococcus. The most potent derivatives are capable of inhibiting growth of these key pathogens at concentrations as low as 0.5µM. Remarkably, the most active compounds exhibit an excellent safety profile and are non-toxic to mammalian cells even at concentrations up to 256µM. The present study lays the foundation for further investigation of aryl isonitrile compounds as a new class of antifungal agents. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Innovative cationic fullerenes as broad-spectrum light-activated antimicrobials.

    Science.gov (United States)

    Huang, Liyi; Terakawa, Mitsuhiro; Zhiyentayev, Timur; Huang, Ying-Ying; Sawayama, Yohei; Jahnke, Ashlee; Tegos, George P; Wharton, Tim; Hamblin, Michael R

    2010-06-01

    Photodynamic inactivation is a rapidly developing antimicrobial technology that combines a nontoxic photoactivatable dye or photosensitizer in combination with harmless visible light of the correct wavelength to excite the dye to its reactive-triplet state that will then generate reactive oxygen species that are highly toxic to cells. Buckminsterfullerenes are closed-cage molecules entirely composed of sp2-hybridized carbon atoms, and although their main absorption is in the UV, they also absorb visible light and have a long-lived triplet state. When C(60) fullerene is derivatized with cationic functional groups it forms molecules that are more water-soluble and can mediate photodynamic therapy efficiently upon illumination; moreover, cationic fullerenes can selectively bind to microbial cells. In this report we describe the synthesis and characterization of several new cationic fullerenes. Their relative effectiveness as broad-spectrum antimicrobial photosensitizers against gram-positive and gram-negative bacteria, and a fungal yeast was determined by quantitative structure-function relationships. Photodynamic inactivation (PDI) is a rapidly developing antimicrobial technology in which a non-toxic photoactivatable dye or photosensitizer is excited with harmless visible light to its reactive state, where it will generate highly toxic reactive oxygen species. Buckminsterfullerenes derivatized with cationic functional groups form molecules that are water-soluble and mediate PDI efficiently. These fullerenes can also selectively bind to microbial cells. Several new cationic fullerenes are presented in this paper, and their efficacy against Gram-positive, Gram-negative bacteria, and a fungal yeast is also demonstrated.

  4. Broad-spectrum identification and discrimination between biothreat agents and near-neighbor species

    Science.gov (United States)

    Malanoski, Anthony P.; Leski, Tomasz A.; Cheng, Luke; Wang, Zheng; Stenger, David A.; Lin, Baochuan

    2009-05-01

    A comprehensive resequencing microarray "Tropical and Emerging Infections (TessArray RPM-TEI 1.0 array)" has been developed to identify and distinguish between biothreat organisms of interest and genetically close related species. This array has undergone validation using an innovative approach where synthetic DNA fragments are used for organisms that it is not safe to work with outside a biosafety 3 facilities. The approach was confirmed from testing a subset of target organisms, such as Ebola viruses and Lassa viruses, at USAMRIID. Most potential biothreat organisms are actually endemic in some part of the world. Proper surveillance of biothreat agents will require some form of monitoring the evolution of the indigenous organisms under their natural environment, so when changes in the organisms occur, the diagnostic assays for these organisms can be reviewed to assure they still provide detection. Using the resequencing microarray (RPM) for detection in locations such as the Africa can support indigenous monitoring as it provides sequence information. An ongoing collaboration with Njala University aims to establish a broad-spectrum pathogen surveillance capability in the Republic of Sierra Leone, West Africa using RPM technology combined with a Geographic Information System. This has the potential to improve the public health efforts in an infected area as well as provide monitoring of the changes occurring to a biothreat organism, i.e. Lassa viruses, in its natural location.

  5. Broad spectrum pro-quorum-sensing molecules as inhibitors of virulence in vibrios.

    Directory of Open Access Journals (Sweden)

    Wai-Leung Ng

    Full Text Available Quorum sensing (QS is a bacterial cell-cell communication process that relies on the production and detection of extracellular signal molecules called autoinducers. QS allows bacteria to perform collective activities. Vibrio cholerae, a pathogen that causes an acute disease, uses QS to repress virulence factor production and biofilm formation. Thus, molecules that activate QS in V. cholerae have the potential to control pathogenicity in this globally important bacterium. Using a whole-cell high-throughput screen, we identified eleven molecules that activate V. cholerae QS: eight molecules are receptor agonists and three molecules are antagonists of LuxO, the central NtrC-type response regulator that controls the global V. cholerae QS cascade. The LuxO inhibitors act by an uncompetitive mechanism by binding to the pre-formed LuxO-ATP complex to inhibit ATP hydrolysis. Genetic analyses suggest that the inhibitors bind in close proximity to the Walker B motif. The inhibitors display broad-spectrum capability in activation of QS in Vibrio species that employ LuxO. To the best of our knowledge, these are the first molecules identified that inhibit the ATPase activity of a NtrC-type response regulator. Our discovery supports the idea that exploiting pro-QS molecules is a promising strategy for the development of novel anti-infectives.

  6. Novel cationic fullerenes as broad-spectrum light-activated antimicrobials

    Science.gov (United States)

    Huang, Liyi; Terakawa, Mitsuhiro; Zhiyentayev, Timur; Huang, Ying-Ying; Sawayama, Yohei; Jahnke, Ashlee; Tegos, George P; Wharton, Tim; Hamblin, Michael R

    2009-01-01

    Photodynamic inactivation (PDI) is a rapidly developing antimicrobial technology which combines a non-toxic photoactivatable dye or photosensitizer (PS) in combination with harmless visible light of the correct wavelength to excite the dye to its reactive triplet state that will then generate reactive oxygen species (ROS) that are highly toxic to cells. Buckminsterfullerenes are closed-cage molecules entirely composed of sp2 hybridized carbon atoms and although their main absorption is in the UV, they also absorb visible light and have a long-lived triplet state. When C60 fullerene is derivatized with cationic functional groups it forms molecules that are more water-soluble and can mediate PDT efficiently upon illumination, and moreover cationic fullerenes can selectively bind to microbial cells. In this report we describe the synthesis and characterization of several new cationic fullerenes. Their relative effectiveness as broad-spectrum antimicrobial photosensitizers against Gram-positive, Gram-negative bacteria, and a fungal yeast was determined by quantitative structure function relationships. PMID:19914400

  7. Tempered mlo broad-spectrum resistance to barley powdery mildew in an Ethiopian landrace.

    Science.gov (United States)

    Ge, Xintian; Deng, Weiwei; Lee, Zheng Zhou; Lopez-Ruiz, Francisco J; Schweizer, Patrick; Ellwood, Simon R

    2016-07-12

    Recessive mutations in the Mlo gene confer broad spectrum resistance in barley (Hordeum vulgare) to powdery mildew (Blumeria graminis f. sp. hordei), a widespread and damaging disease. However, all alleles discovered to date also display deleterious pleiotropic effects, including the naturally occurring mlo-11 mutant which is widely deployed in Europe. Recessive resistance was discovered in Eth295, an Ethiopian landrace, which was developmentally controlled and quantitative without spontaneous cell wall appositions or extensive necrosis and loss of photosynthetic tissue. This resistance is determined by two copies of the mlo-11 repeat units, that occur upstream to the wild-type Mlo gene, compared to 11-12 in commonly grown cultivars and was designated mlo-11 (cnv2). mlo-11 repeat unit copy number-dependent DNA methylation corresponded with cytological and macroscopic phenotypic differences between copy number variants. Sequence data indicated mlo-11 (cnv2) formed via recombination between progenitor mlo-11 repeat units and the 3' end of an adjacent stowaway MITE containing region. mlo-11 (cnv2) is the only example of a moderated mlo variant discovered to date and may have arisen by natural selection against the deleterious effects of the progenitor mlo-11 repeat unit configuration.

  8. Development of Broad-Spectrum Halomethyl Ketone Inhibitors Against Coronavirus Main Protease 3CL(pro)

    Energy Technology Data Exchange (ETDEWEB)

    Bacha,U.; Barilla, J.; Gabelli, S.; Kiso, Y.; Amzel, L.; Freire, E.

    2008-01-01

    Coronaviruses comprise a large group of RNA viruses with diverse host specificity. The emergence of highly pathogenic strains like the SARS coronavirus (SARS-CoV), and the discovery of two new coronaviruses, NL-63 and HKU1, corroborates the high rate of mutation and recombination that have enabled them to cross species barriers and infect novel hosts. For that reason, the development of broad-spectrum antivirals that are effective against several members of this family is highly desirable. This goal can be accomplished by designing inhibitors against a target, such as the main protease 3CLpro (Mpro), which is highly conserved among all coronaviruses. Here 3CLpro derived from the SARS-CoV was used as the primary target to identify a new class of inhibitors containing a halomethyl ketone warhead. The compounds are highly potent against SARS 3CLpro with Ki's as low as 300 nm. The crystal structure of the complex of one of the compounds with 3CLpro indicates that this inhibitor forms a thioether linkage between the halomethyl carbon of the warhead and the catalytic Cys 145. Furthermore, Structure Activity Relationship (SAR) studies of these compounds have led to the identification of a pharmacophore that accurately defines the essential molecular features required for the high affinity.

  9. Dissecting disease entities out of the broad spectrum of bipolar-disorders.

    Science.gov (United States)

    Levine, Joseph; Toker, Lilach; Agam, Galila

    2017-11-01

    The etiopathology of bipolar disorders is yet unraveled and new avenues should be pursued. One such avenue may be based on the assumption that the bipolar broad spectrum includes, among others, an array of rare medical disease entities. Towards this aim we propose a dissecting approach based on a search for rare medical diseases with known etiopathology which also exhibit bipolar disorders symptomatology. We further suggest that the etiopathologic mechanisms underlying such rare medical diseases may also underlie a rare variant of bipolar disorder. Such an assumption may be further reinforced if both the rare medical disease and its bipolar clinical phenotype demonstrate a] a similar mode of inheritance (i.e, autosomal dominant); b] brain involvement; and c] data implicating that the etiopathological mechanisms underlying the rare diseases affect biological processes reported to be associated with bipolar disorders and their treatment. We exemplify our suggested approach by a rare case of autosomal dominant leucodystrophy, a disease entity exhibiting nuclear lamin B1 pathology also presenting bipolar symptomatology. Copyright © 2017. Published by Elsevier B.V.

  10. Broad spectrum pro-quorum-sensing molecules as inhibitors of virulence in vibrios.

    Science.gov (United States)

    Ng, Wai-Leung; Perez, Lark; Cong, Jianping; Semmelhack, Martin F; Bassler, Bonnie L

    2012-01-01

    Quorum sensing (QS) is a bacterial cell-cell communication process that relies on the production and detection of extracellular signal molecules called autoinducers. QS allows bacteria to perform collective activities. Vibrio cholerae, a pathogen that causes an acute disease, uses QS to repress virulence factor production and biofilm formation. Thus, molecules that activate QS in V. cholerae have the potential to control pathogenicity in this globally important bacterium. Using a whole-cell high-throughput screen, we identified eleven molecules that activate V. cholerae QS: eight molecules are receptor agonists and three molecules are antagonists of LuxO, the central NtrC-type response regulator that controls the global V. cholerae QS cascade. The LuxO inhibitors act by an uncompetitive mechanism by binding to the pre-formed LuxO-ATP complex to inhibit ATP hydrolysis. Genetic analyses suggest that the inhibitors bind in close proximity to the Walker B motif. The inhibitors display broad-spectrum capability in activation of QS in Vibrio species that employ LuxO. To the best of our knowledge, these are the first molecules identified that inhibit the ATPase activity of a NtrC-type response regulator. Our discovery supports the idea that exploiting pro-QS molecules is a promising strategy for the development of novel anti-infectives.

  11. Ceftiofur sodium, a broad-spectrum cephalosporin: evaluation in vitro and in vivo in mice.

    Science.gov (United States)

    Yancey, R J; Kinney, M L; Roberts, B J; Goodenough, K R; Hamel, J C; Ford, C W

    1987-07-01

    Ceftiofur sodium, a broad-spectrum beta-lactamase-resistant cephalosporin, was evaluated in vitro and in vivo in mice. Ceftiofur is the sodium salt of (6R, 7R)-7[( 2-amino-4-thiazolyl)-Z- (methoxyimino)acetyl]amino)-3-[( (2-furanylcarbonyl)thio]methyl)-8-oxo-5- thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate. Minimal inhibitory concentration values were obtained with 264 strains representing 9 genera and 17 species of bacterial pathogens from cattle, swine, sheep, horses, poultry, dogs, cats, and human beings. Ceftiofur was more active than was ampicillin against all strains tested including beta-lactamase-producing organisms. In mice with systemic infections, ceftiofur was more active than or equivalent to ampicillin, cephalothin, cefamandole, cloxacillin, cefoperazone, or pirlimycin. These protection tests included infections with Escherichia coli, Haemophilus pleuropneumoniae, H somnus, Pasteurella haemolytica, P multocida, Salmonella typhimurium, or Staphylococcus aureus. In infant mice with E coli-induced lethal diarrhea and in mice with S aureus and E coli-induced mastitis, ceftiofur was comparable or more active than was ampicillin.

  12. SAFETY AND TOLERABILITY OF ANTIEPILEPTIC DRUGS AT WOMEN WITH EPILEPSY (DATA OF SVT. LUKA’S INSTITUTE OF CHILD NEUROLOGY AND EPILEPSY

    Directory of Open Access Journals (Sweden)

    K. Yu. Мukhin

    2015-01-01

    Full Text Available Women with epilepsy are referred to the special risk group due to the development of side effects of antiepileptic drugs (АED. Women’s neuroendocrinal disorders can be caused by the disease itself-epilepsy, as well as by the undertaken therapy. We have carried out a retrospective research in order to assess the safety and the tolerance of different AED at young girls and women of reproductive age. Was analyzed the data base of patients of Svt. Luka’s Institute of Child Neurology and Epilepsy, comprising all patients, who have been monitored in the period between 2000 and 2014 inclusive at the age between 15–40 years (n = 301. The research included patients, with different diagnosed forms of focal or generalized epilepsy, who were taking AED both during mono and polytherapy. Were analyzed all cases of neuroendocrinal, especially reproductive disorders, including the considerable gain of weight, menstrual disorder, sterility at AED background. Also was analyzed the result of all registered pregnancies at women with epilepsy (at the background of the antiepileptic therapy, as well as without treatment during pregnancy. The retrospective data analysis has revealed 51 сase (17 % in the group under review of expressed neuroendocrinal, reproductive and cosmetic side effects (including the menstrual disorder: dysmenorrhea, opsomenorrhea, amenorrhea, anovulatory cycles, sterility, unfavorable pregnancy outcomes, as well as cosmetic endocrinal side effects: obesity, hirsutism, hair loss. Most patients have got such combined side effects. Our research results show, that in most cases the pregnancy at women with epilepsy ends by birth of a healthy child, the pregnancy outcome depends on many factors, it also differs according to applied AED. Valproic acid drugs show the highest teratogenic risk. Also at the back ground of the therapy with valproic acid have been registered most cases of neuroendocrinal reproductive diseases at women

  13. Association of polymorphisms of CYP2C9, CYP2C19, and ABCB1, and activity of P-glycoprotein with response to anti-epileptic drugs

    Directory of Open Access Journals (Sweden)

    S R Taur

    2014-01-01

    Full Text Available Background and Objective: Epilepsy, the most common neurological disorder, has treatment failure rate of 20 to 25%. Inter-individual variability in drug response can be attributed to genetic polymorphism in genes encoding different drug metabolizing enzymes, drug transporters (P-gp, and enzymes involved in sodium channel biosynthesis. The present study attempted to evaluate association of polymorphisms of CYP2C9, CYP2C19, and ABCB1, and P-gp activity with treatment response in patients with epilepsy. Materials and Methods: Patients with epilepsy on phenytoin and/or phenobarbital and/or carbamazepine were categorized into responders and non-responders as per the International League Against Epilepsy. Plasma drug concentration was estimated by high-performance liquid chromatography. P-gp activity was measured by flow cytometry using rhodamine efflux. The polymerase chain reaction (PCR-RFLP was used to study polymorphisms of ABCB1 (C3435T, CYP2C9 (416 C > T, and 1061 A > T, and CYP2C19 (681 G > A and 636 G > A. Results: Of total 117 patients enrolled in this study, genotype data was available for 115 patients. P-gp activity was higher in non-responders (n = 68 compared to responders (n = 47 (P T and 1061 A > T in CYP2C9 or 681 G > A and 636 G > A in CYP2C19 was observed with response phenotype in genotypic analysis. Significant genotypic (odds ratio, OR = 4.5; 95% CI, 1.04 to 20.99 and allelic association (OR = 1.73; 95% CI, 1.02 to 2.95 was observed with ABCB1 C3435T and response phenotype. Conclusions: The response to antiepileptics seems to be modulated by C3435T in ABCB1 or P-gp activity. At present, role of other genetic factors in treatment responsiveness in epilepsy appears limited, warranting analysis in a larger cohort.

  14. Application of chitosan microparticles for treatment of metritis and in vivo evaluation of broad spectrum antimicrobial activity in cow uteri.

    Science.gov (United States)

    Jeon, Soo Jin; Ma, Zhengxin; Kang, Minyoung; Galvão, Klibs N; Jeong, Kwangcheol Casey

    2016-12-01

    Uterine disease such as metritis is associated with multiple bacterial infections in the uteri after parturition. However, treatment of metritis is challenging due to considerably high antibiotic treatment failure rate with unknown reason. Recently, chitosan microparticles (CM) have been developed to exert broad spectrum antimicrobial activity against bacterial pathogens, including multi-drug resistant bacteria, without raising CM resistant mutants. In this study, we tested, using metagenomics analysis, if CM maintain strong antimicrobial activity against pathogenic bacteria such as Fusobacteriaceae and Bacteroidaceae in cow uteri and evaluated CM's potency as an alternative antimicrobial agent to cure metritis in cows. Here, we report that efficacy of CM treatment for metritis was comparable to the antibiotic ceftiofur, and CM greatly altered uterine microflora of sick animals to healthy uterine microflora. Among uterine bacteria, CM significantly decreased Fusobacterium necrophorum, which is known pathogenic bacteria within the uterus. Taken together, we observed the broad spectrum antimicrobial activity of CM in vivo with an animal model, and further evaluated treatment efficacy in cows with metritis, providing insights into promising use of CM as an alternative antimicrobial agent for controlling uterine disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor.

    Directory of Open Access Journals (Sweden)

    Yunjeong Kim

    2016-03-01

    Full Text Available Coronaviruses infect animals and humans causing a wide range of diseases. The diversity of coronaviruses in many mammalian species is contributed by relatively high mutation and recombination rates during replication. This dynamic nature of coronaviruses may facilitate cross-species transmission and shifts in tissue or cell tropism in a host, resulting in substantial change in virulence. Feline enteric coronavirus (FECV causes inapparent or mild enteritis in cats, but a highly fatal disease, called feline infectious peritonitis (FIP, can arise through mutation of FECV to FIP virus (FIPV. The pathogenesis of FIP is intimately associated with immune responses and involves depletion of T cells, features shared by some other coronaviruses like Severe Acute Respiratory Syndrome Coronavirus. The increasing risks of highly virulent coronavirus infections in humans or animals call for effective antiviral drugs, but no such measures are yet available. Previously, we have reported the inhibitors that target 3C-like protease (3CLpro with broad-spectrum activity against important human and animal coronaviruses. Here, we evaluated the therapeutic efficacy of our 3CLpro inhibitor in laboratory cats with FIP. Experimental FIP is 100% fatal once certain clinical and laboratory signs become apparent. We found that antiviral treatment led to full recovery of cats when treatment was started at a stage of disease that would be otherwise fatal if left untreated. Antiviral treatment was associated with a rapid improvement in fever, ascites, lymphopenia and gross signs of illness and cats returned to normal health within 20 days or less of treatment. Significant reduction in viral titers was also observed in cats. These results indicate that continuous virus replication is required for progression of immune-mediated inflammatory disease of FIP. These findings may provide important insights into devising therapeutic strategies and selection of antiviral compounds for

  16. Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor

    Science.gov (United States)

    Kim, Yunjeong; Liu, Hongwei; Galasiti Kankanamalage, Anushka C.; Weerasekara, Sahani; Hua, Duy H.; Groutas, William C.; Chang, Kyeong-Ok; Pedersen, Niels C.

    2016-01-01

    Coronaviruses infect animals and humans causing a wide range of diseases. The diversity of coronaviruses in many mammalian species is contributed by relatively high mutation and recombination rates during replication. This dynamic nature of coronaviruses may facilitate cross-species transmission and shifts in tissue or cell tropism in a host, resulting in substantial change in virulence. Feline enteric coronavirus (FECV) causes inapparent or mild enteritis in cats, but a highly fatal disease, called feline infectious peritonitis (FIP), can arise through mutation of FECV to FIP virus (FIPV). The pathogenesis of FIP is intimately associated with immune responses and involves depletion of T cells, features shared by some other coronaviruses like Severe Acute Respiratory Syndrome Coronavirus. The increasing risks of highly virulent coronavirus infections in humans or animals call for effective antiviral drugs, but no such measures are yet available. Previously, we have reported the inhibitors that target 3C-like protease (3CLpro) with broad-spectrum activity against important human and animal coronaviruses. Here, we evaluated the therapeutic efficacy of our 3CLpro inhibitor in laboratory cats with FIP. Experimental FIP is 100% fatal once certain clinical and laboratory signs become apparent. We found that antiviral treatment led to full recovery of cats when treatment was started at a stage of disease that would be otherwise fatal if left untreated. Antiviral treatment was associated with a rapid improvement in fever, ascites, lymphopenia and gross signs of illness and cats returned to normal health within 20 days or less of treatment. Significant reduction in viral titers was also observed in cats. These results indicate that continuous virus replication is required for progression of immune-mediated inflammatory disease of FIP. These findings may provide important insights into devising therapeutic strategies and selection of antiviral compounds for further

  17. Several new diverse anticonvulsant agents discovered in a virtual screening campaign aimed at novel antiepileptic drugs to treat refractory epilepsy.

    Science.gov (United States)

    Di Ianni, Mauricio E; Enrique, Andrea V; Palestro, Pablo H; Gavernet, Luciana; Talevi, Alan; Bruno-Blanch, Luis E

    2012-12-21

    A virtual screening campaign was conducted in order to discover new anticonvulsant drug candidates for the treatment of refractory epilepsy. To this purpose, a topological discriminant function to identify antiMES drugs and a sequential filtering methodology to discriminate P-glycoprotein substrates and nonsubstrates were jointly applied to ZINC 5 and DrugBank databases. The virtual filters combine an ensemble of 2D classifiers and docking simulations. In the light of the results, 10 structurally diverse compounds were acquired and tested in animal models of seizure and the rotorod test. All 10 candidates showed some level of protection against MES test.

  18. Successful five-item triage for the broad spectrum of mental disorders in pregnancy - A validation study

    NARCIS (Netherlands)

    C. Quispel (Chantal); T.A.J. Schneider (Tom); W.J.G. Hoogendijk (Witte); G.J. Bonsel (Gouke); M.P. Lambregtse-van den Berg (Mijke)

    2015-01-01

    textabstractBackground: Mental disorders are prevalent during pregnancy, affecting 10% of women worldwide. To improve triage of a broad spectrum of mental disorders, we investigated the decision impact validity of: 1) a short set of currently used psychiatric triage items, 2) this set with the

  19. Competitive Interaction Between Phytophthora Infestans Effectors Leads to Increased Aggressiveness on Plants Containing Broad-spectrum Late Blight Resistance

    Science.gov (United States)

    The resistance (R) gene RB confers broad-spectrum resistance to potato late blight and belongs. The RB protein recognizes the presence of members of the Phytophthora infestans effector family IPI-O to elicit resistance. Most isolates of the pathogen contain IPI-O variants that are recognized by R...

  20. The broad-spectrum cation channel blocker pinokalant (LOE 908 MS) reduces brain infarct volume in rats

    DEFF Research Database (Denmark)

    Christensen, Thomas; Wienrich, Marion; Ensinger, Helmut A

    2005-01-01

    Activation of cation channels conducting Ca2+, Na+ and K+ is involved in the pathogenesis of infarction in experimental focal cerebral ischaemia. Pinokalant (LOE 908 MS) is a novel broad-spectrum inhibitor of several subtypes of such channels and has previously been shown to improve the metabolic...

  1. Aspectos farmacológicos relevantes de los antiepilépticos nuevos Relevant pharmacological aspects of the new antiepileptic drugs

    Directory of Open Access Journals (Sweden)

    Alicia Zapata Martínez

    2005-12-01

    Full Text Available Dada la importancia de la epilepsia como enfermedad crónica no transmisible, se decidió realizar una revisión de los fármacos nuevos que en los últimos años han sido comercializados para su tratamiento en el mundo. Se enfatizó en la necesidad de establecer una correcta relación beneficio/riesgo/costo a partir del conocimiento de la eficacia, seguridad, conveniencia y costo de los fármacos empleados en el tratamiento de cualquier enfermedad, y por supuesto, de la epilepsia. Los nuevos medicamentos antiepilépticos todavía no han demostrado de forma convincente ser superiores a los ya conocidos, y de los cuales también se exponen sus principales características farmacológicas. Aunque en la mayoría de las ocasiones no son mejores, sí no hay dudas que son más caros e incrementan el precio de los tratamientos.Due to the importance of epilepsy as a non-communicable chronic disease, it was decided to make a review of the new drugs that in the last years have been commercialized for its treatement in the world. Emphasis was given to the need of establishing a correct benefit/risk/cost relation, starting from the knowledge of efficiency, safety, convenience and cost of the drugs used in the treatment of any disease and, of course, of epilepsy. The new antiepileptic drugs have not proved yet to be superior than the already known, whose main pharmacological characteristics are also exposed. Though in most of the ocassions they are not better, they are undoubtedly more expensive and increase the prices of the treatments.

  2. What do the suffixes--XR, ER, Chrono, Chronosphere--really mean as it pertains to modified-release antiepileptic drugs?

    Science.gov (United States)

    Reed, R C; Meinhold, J; Dutta, S; Liu, W; Qiu, Y

    2010-08-01

    Epilepsy is a disease requiring chronic therapy with antiepileptic drugs (AEDs). Many conventional AEDs currently available have either too rapid an absorption or elimination, requiring the patient to take multiple doses per day, which may adversely impact adherence or cause peak-related side-effects. Consequently, some AEDs with immediate-release characteristics have been modified to prolong absorption and/or reduce peak serum concentration, enabling dosage regimen simplification. Modified-release (MR) AED formulations have been labelled with various suffixes or names ('XR, ER, -Chrono, -Chronosphere'), but such labelling may not adequately distinguish those MR AEDs with the most prolonged absorption or unique formulation characteristics. Such suffixes lack precise definition. We identified the formulation characteristics of currently available MR AEDs, attempting to distinguish them by suffix designation. Nine MR AED formulations, representing six different AEDs, were characterized, utilizing information from FDA-approved inserts (2001 +) and published literature. The formulation characteristics of commercially available MR AEDs are quite variable and do not appear to correlate with their brand name suffix. When all MR AEDs are compared, suffix designations do not provide distinguishable information about formulation characteristics. Clarification of MR AED suffix terminology may be warranted.

  3. Seizure clusters and adverse events during pre-surgical video-EEG monitoring with a slow anti-epileptic drug (AED) taper.

    Science.gov (United States)

    Di Gennaro, Giancarlo; Picardi, Angelo; Sparano, Antonio; Mascia, Addolorata; Meldolesi, Giulio N; Grammaldo, Liliana G; Esposito, Vincenzo; Quarato, Pier P

    2012-03-01

    To evaluate the efficiency and safety of pre-surgical video-EEG monitoring with a slow anti-epileptic drug (AED) taper and a rescue benzodiazepine protocol. Fifty-four consecutive patients with refractory focal epilepsy who underwent pre-surgical video-electroencephalography (EEG) monitoring during the year 2010 were included in the study. Time to first seizure, duration of monitoring, incidence of 4-h and 24-h seizure clustering, secondarily generalised tonic-clonic seizures (sGTCS), status epilepticus, falls and cardiac asystole were evaluated. A total of 190 seizures were recorded. Six (11%) patients had 4-h clusters and 21 (39%) patients had 24-h clusters. While 15 sGTCS were recorded in 14 patients (26%), status epilepticus did not occur and no seizure was complicated with cardiac asystole. Epileptic falls with no significant injuries occurred in three patients. The mean time to first seizure was 3.3days and the time to conclude video-EEG monitoring averaged 6days. Seizure clustering was common during pre-surgical video-EEG monitoring, although serious adverse events were rare with a slow AED tapering and a rescue benzodiazepine protocol. Slow AED taper pre-surgical video-EEG monitoring is fairly safe when performed in a highly specialised and supervised hospital setting. Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  4. Pyrodiversity and the anthropocene: the role of fire in the broad spectrum revolution.

    Science.gov (United States)

    Bird, Douglas W; Bliege Bird, Rebecca; Codding, Brian F

    2016-05-06

    The Anthropocene colloquially refers to a global regime of human-caused environmental modification of earth systems associated with profound changes in patterns of human mobility, as well as settlement and resource use compared with prior eras. Some have argued that the processes generating the Anthropocene are mainly associated with population growth and technological innovation, and thus began only in the late Holocene under conditions of dense sedentism and industrial agriculture.(1) However, it now seems clear that the roots of the Anthropocene lie in complex processes of intensification that significantly predate transitions to agriculture.(2,3) What intensification is remains less clear. For some it is increasing economic productivity that increases carrying capacity, the drivers of which may be too diverse and too local to generalize.(4,5) For others using Boserup's ideas about agrarian intensification, increasing density in hunter-gatherer populations can produce declines in subsistence efficiency that increase incentives for investing labor to boost yield per unit area, which then elevates Malthusian limits on carrying capacity.(6-8) As Morgan(9) demonstrates in a comprehensive review, the legacy of such Boserupian intensification is alive, well, and controversial in hunter-gatherer archeology. This is a result of its potential for illuminating processes involved in transformations of forager socio-political and economic systems, including those dominated by harvesting more immediate-return resources and high residential mobility as well as those characterized by more delayed-return material economies with reduced residential mobility, a broader spectrum of resources, degrees of storage, and greater social stratification. Here we detail hypotheses about the processes involved in such transitions and explore the way that anthropogenic disturbance of ecosystems, especially the use of landscape fire, could be fundamentally entangled with many broad-spectrum

  5. Extensive sequence variation in rice blast resistance gene Pi54 makes it broad spectrum in nature

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    Shallu eThakur

    2015-05-01

    Full Text Available Rice blast resistant gene, Pi54 cloned from rice line, Tetep, is effective against diverse isolates of Magnaporthe oryzae. In this study, we prospected the allelic variants of the dominant blast resistance gene from a set of 92 rice lines to determine the nucleotide diversity, pattern of its molecular evolution, phylogenetic relationships and evolutionary dynamics, and to develop allele specific markers. High quality sequences were generated for homologs of Pi54 gene. Using comparative sequence analysis, InDels of variable sizes in all the alleles were observed. Profiling of the selected sites of SNP (Single Nucleotide Polymorphism and amino acids (N sites ≥ 10 exhibited constant frequency distribution of mutational and substitutional sites between the resistance and susceptible rice lines, respectively. A total of 50 new haplotypes based on the nucleotide polymorphism was also identified. A unique haplotype (H_3 was found to be linked to all the resistant alleles isolated from indica rice lines. Unique leucine zipper and tyrosine sulfation sites were identified in the predicted Pi54 proteins. Selection signals were observed in entire coding sequence of resistance alleles, as compared to LRR domains for susceptible alleles. This is a maiden report of extensive variability of Pi54 alleles in different landraces and cultivated varieties, possibly, attributing broad-spectrum resistance to Magnaporthe oryzae. The sequence variation in two consensus region: 163 bp and 144 bp were used for the development of allele specific DNA markers. Validated markers can be used for the selection and identification of better allele(s and their introgression in commercial rice cultivars employing marker assisted selection.

  6. Overexpression of NPR1 in Brassica juncea Confers Broad Spectrum Resistance to Fungal Pathogens

    Directory of Open Access Journals (Sweden)

    Sajad Ali

    2017-10-01

    Full Text Available Brassica juncea (Indian mustard is a commercially important oil seed crop, which is highly affected by many biotic stresses. Among them, Alternaria leaf blight and powdery mildew are the most devastating diseases leading to huge yield losses in B. juncea around the world. In this regard, genetic engineering is a promising tool that may possibly allow us to enhance the B. juncea disease resistance against these pathogens. NPR1 (non-expressor of pathogen-related gene 1 is a bonafide receptor of salicylic acid (SA which modulates multiple immune responses in plants especially activation of induced and systemic acquired resistance (SAR. Here, we report the isolation and characterization of new NPR1 homolog (BjNPR1 from B. juncea. The phylogenetic tree constructed based on the deduced sequence of BjNPR1 with homologs from other species revealed that BjNPR1 grouped together with other known NPR1 proteins of Cruciferae family, and was nearest to B. napus. Furthermore, expression analysis showed that BjNPR1 was upregulated after SA treatment and fungal infection but not by jasmonic acid or abscisic acid. To understand the defensive role of this gene, we generated B. juncea transgenic lines overexpressing BjNPR1, and further confirmed by PCR and Southern blotting. The transgenic lines showed no phenotypic abnormalities, and constitutive expression of BjNPR1 activates defense signaling pathways by priming the expression of antifungal PR genes. Moreover, BjNPR1 transgenic lines showed enhanced resistance to Alternaria brassicae and Erysiphe cruciferarum as there was delay in symptoms and reduced disease severity than non-transgenic plants. In addition, the rate of disease spreading to uninfected or distal parts was also delayed in transgenic plants thus suggesting the activation of SAR. Altogether, the present study suggests that BjNPR1 is involved in broad spectrum of disease resistance against fungal pathogens.

  7. Expression of mouse beta defensin 2 in Escherichia coli and its broad-spectrum antimicrobial activity

    Directory of Open Access Journals (Sweden)

    Tianxiang Gong

    2011-09-01

    Full Text Available Mature mouse beta defensin 2 (mBD2 is a small cationic peptide with antimicrobial activity. Here we established a prokaryotic expression vector containing the cDNA of mature mBD2 fused with thioredoxin (TrxA, pET32a-mBD2. The vector was transformed into Escherichia Coli (E. coli Rosseta-gami (2 for expression fusion protein. Under the optimization of fermentation parameters: induce with 0.6 mM isopropylthiogalactoside (IPTG at 34ºC in 2×YT medium and harvest at 6 h postinduction, fusion protein TrxA-mBD2 was high expressed in the soluble fraction (>95%. After cleaved fusion protein by enterokinase, soluble mature mBD2 was achieved 6 mg/L with a volumetric productivity. Purified recombinant mBD2 demonstrated clear broad-spectrum antimicrobial activity for fungi, bacteria and virus. The MIC of antibacterial activity of against Staphylococcus aureus was 50 µg/ml. The MIC of against Candida albicans (C. albicans and Cryptococcus neoformans (C. neoformans was 12.5µg/ml and 25µg/ml, respectively. Also, the antimicrobial activity of mBD2 was effected by NaCl concentration. Additionally, mBD2 showed antiviral activity against influenza A virus (IAV, the protective rate for Madin-Darby canine kidney cells (MDCK was 93.86% at the mBD2 concentration of 100 µg/ml. These works might provide a foundation for the following research on the mBD2 as therapeutic agent for medical microbes.

  8. Isolation and Characterization of a Broad Spectrum Bacteriocin from Bacillus amyloliquefaciens RX7

    Directory of Open Access Journals (Sweden)

    Kong Boon Lim

    2016-01-01

    Full Text Available We isolated a Bacillus strain, RX7, with inhibitory activity against Listeria monocytogenes from soil and identified it as Bacillus amyloliquefaciens based on 16S rRNA gene sequencing. The inhibitory activity was stable over a wide range of pH and was fully retained after 30 min at 80°C, after which it decreased gradually at higher temperatures. The activity was sensitive to the proteolytic action of α-chymotrypsin, proteinase-K, and trypsin, indicating its proteinaceous nature. This bacteriocin was active against a broad spectrum of bacteria and the fungus Candida albicans. Direct detection of antimicrobial activity on a sodium dodecyl sulfate-polyacrylamide gel suggested an apparent molecular mass of approximately 5 kDa. Ammonium sulfate precipitation and anion-exchange and gel permeation chromatography integrated with reverse phase-high-performance liquid chromatography were used for bacteriocin purification. Automated N-terminal Edman degradation of the purified RX7 bacteriocin recognized the first 15 amino acids as NH2-X-Ala-Trp-Tyr-Asp-Ile-Arg-Lys-Leu-Gly-Asn-Lys-Gly-Ala, where the letter X in the sequence indicates an unknown or nonstandard amino acid. Based on BLAST similarity search and multiple alignment analysis, the obtained partial sequence showed high homology with the two-peptide lantibiotic haloduracin (HalA1 from Bacillus halodurans, although at least two amino acids differed between the sequences. A time-kill study demonstrated a bactericidal mode of action of RX7 bacteriocin.

  9. Mur-LH, the Broad-Spectrum Endolysin of Lactobacillus helveticus Temperate Bacteriophage φ-0303

    Science.gov (United States)

    Deutsch, Stéphanie-Marie; Guezenec, Stéphane; Piot, Michel; Foster, Simon; Lortal, Sylvie

    2004-01-01

    φ-0303 is a temperate bacteriophage isolated from Lactobacillus helveticus CNRZ 303 strain after mitomycin C induction. In this work, the gene coding for a lytic protein of this bacteriophage was cloned using a library of φ-0303 in Escherichia coli DH5α. The lytic activity was detected by its expression, using whole cells of the sensitive strain L. helveticus CNRZ 892 as the substrate. The lysin gene was within a 4.1-kb DNA fragment of φ-0303 containing six open reading frames (ORFs) and two truncated ORFs. No sequence homology with holin genes was found within the cloned fragment. An integrase-encoding gene was also present in the fragment, but it was transcribed in a direction opposite that of the lysin gene. The lysin-encoding lys gene was verified by PCR amplification from the total phage DNA and subcloned. The lys gene is a 1,122-bp sequence encoding a protein of 373 amino acids (Mur-LH), whose product had a deduced molecular mass of 40,207 Da. Comparisons with sequences in sequence databases showed homology with numerous endolysins of other bacteriophages. Mur-LH was expressed in E. coli BL21, and by renaturing sodium dodecyl sulfate-polyacrylamide gel electrophoresis with L. helveticus CNRZ 892 as the substrate, the recombinant protein showed an apparent molecular mass of 40 kDa. The N-terminal sequence of the protein confirmed the start codon. Hydrolysis of cell walls of L. helveticus CNRZ 303 by the endolysin and biochemical analysis of the residues produced demonstrated that Mur-LH has N-acetylmuramidase activity. Last, the endolysin exhibited a broad spectrum of lytic activity, as it was active on different species, mainly thermophilic lactobacilli but also lactococci, pediococci, Bacillus subtilis, Brevibacterium linens, and Enterococcus faecium. PMID:14711630

  10. Overexpression of NPR1 in Brassica juncea Confers Broad Spectrum Resistance to Fungal Pathogens

    Science.gov (United States)

    Ali, Sajad; Mir, Zahoor A.; Tyagi, Anshika; Mehari, Hailay; Meena, Rajendra P.; Bhat, Javaid A.; Yadav, Prashant; Papalou, Pradeep; Rawat, Sandhya; Grover, Anita

    2017-01-01

    Brassica juncea (Indian mustard) is a commercially important oil seed crop, which is highly affected by many biotic stresses. Among them, Alternaria leaf blight and powdery mildew are the most devastating diseases leading to huge yield losses in B. juncea around the world. In this regard, genetic engineering is a promising tool that may possibly allow us to enhance the B. juncea disease resistance against these pathogens. NPR1 (non-expressor of pathogen-related gene 1) is a bonafide receptor of salicylic acid (SA) which modulates multiple immune responses in plants especially activation of induced and systemic acquired resistance (SAR). Here, we report the isolation and characterization of new NPR1 homolog (BjNPR1) from B. juncea. The phylogenetic tree constructed based on the deduced sequence of BjNPR1 with homologs from other species revealed that BjNPR1 grouped together with other known NPR1 proteins of Cruciferae family, and was nearest to B. napus. Furthermore, expression analysis showed that BjNPR1 was upregulated after SA treatment and fungal infection but not by jasmonic acid or abscisic acid. To understand the defensive role of this gene, we generated B. juncea transgenic lines overexpressing BjNPR1, and further confirmed by PCR and Southern blotting. The transgenic lines showed no phenotypic abnormalities, and constitutive expression of BjNPR1 activates defense signaling pathways by priming the expression of antifungal PR genes. Moreover, BjNPR1 transgenic lines showed enhanced resistance to Alternaria brassicae and Erysiphe cruciferarum as there was delay in symptoms and reduced disease severity than non-transgenic plants. In addition, the rate of disease spreading to uninfected or distal parts was also delayed in transgenic plants thus suggesting the activation of SAR. Altogether, the present study suggests that BjNPR1 is involved in broad spectrum of disease resistance against fungal pathogens. PMID:29046679

  11. A Broad-Spectrum Integrative Design for Cancer Prevention and Therapy

    Science.gov (United States)

    Block, Keith I.; Gyllenhaal, Charlotte; Lowe, Leroy; Amedei, Amedeo; Amin, A.R.M. Ruhul; Amin, Amr; Aquilano, Katia; Arbiser, Jack; Arreola, Alexandra; Arzumanyan, Alla; Ashraf, S. Salman; Azmi, Asfar S.; Benencia, Fabian; Bhakta, Dipita; Bilsland, Alan; Bishayee, Anupam; Blain, Stacy W.; Block, Penny B.; Boosani, Chandra S.; Carey, Thomas E.; Carnero, Amancio; Carotenuto, Marianeve; Casey, Stephanie C.; Chakrabarti, Mrinmay; Chaturvedi, Rupesh; Chen, Georgia Zhuo; Chen, Helen; Chen, Sophie; Chen, Yi Charlie; Choi, Beom K.; Ciriolo, Maria Rosa; Coley, Helen M.; Collins, Andrew R.; Connell, Marisa; Crawford, Sarah; Curran, Colleen S.; Dabrosin, Charlotta; Damia, Giovanna; Dasgupta, Santanu; DeBerardinis, Ralph J.; Decker, William K.; Dhawan, Punita; Diehl, Anna Mae E.; Dong, Jin-Tang; Dou, Q. Ping; Drew, Janice E.; Elkord, Eyad; El-Rayes, Bassel; Feitelson, Mark A.; Felsher, Dean W.; Ferguson, Lynnette R; Fimognari, Carmela; Firestone, Gary L.; Frezza, Christian; Fujii, Hiromasa; Fuster, Mark M.; Generali, Daniele; Georgakilas, Alexandros G.; Gieseler, Frank; Gilbertson, Michael; Green, Michelle F.; Grue, Brendan; Guha, Gunjan; Halicka, Dorota; Helferich, William G.; Heneberg, Petr; Hentosh, Patricia; Hirschey, Matthew D.; Hofseth, Lorne J.; Holcombe, Randall F.; Honoki, Kanya; Hsu, Hsue-Yin; Huang, Gloria S.; Jensen, Lasse D.; Jiang, Wen G.; Jones, Lee W.; Karpowicz, Phillip A.; Keith, W Nicol; Kerkar, Sid P.; Khan, Gazala N.; Khatami, Mahin; Ko, Young H.; Kucuk, Omer; Kulathinal, Rob J.; Kumar, Nagi B.; Kumara, H.M.C. Shantha; Kwon, Byoung S.; Le, Anne; Lea, Michael A.; Lee, Ho-Young; Lichtor, Terry; Lin, Liang-Tzung; Locasale, Jason W.; Lokeshwar, Bal L.; Longo, Valter D.; Lyssiotis, Costas A.; MacKenzie, Karen L.; Malhotra, Meenakshi; Marino, Maria; Martinez-Chantar, Maria L.; Matheu, Ander; Maxwell, Christopher; McDonnell, Eoin; Meeker, Alan K.; Mehrmohamadi, Mahya; Mehta, Kapil; Michelotti, Gregory A.; Mohammad, Ramzi M.; Mohammed, Sulma I.; Morre, D. James; Muqbil, Irfana; Muralidhar, Vinayak; Murphy, Michael P.; Nagaraju, Ganji Purnachandra; Nahta, Rita; Niccolai, Elena; Nowsheen, Somaira; Panis, Carolina; Pantano, Francesco; Parslow, Virginia R.; Pawelec, Graham; Pedersen, Peter L.; Poore, Brad; Poudyal, Deepak; Prakash, Satya; Prince, Mark; Raffaghello, Lizzia; Rathmell, Jeffrey C.; Rathmell, W. Kimryn; Ray, Swapan K.; Reichrath, Jörg; Rezazadeh, Sarallah; Ribatti, Domenico; Ricciardiello, Luigi; Robey, R. Brooks; Rodier, Francis; Rupasinghe, H.P. Vasantha; Russo, Gian Luigi; Ryan, Elizabeth P.; Samadi, Abbas K.; Sanchez-Garcia, Isidro; Sanders, Andrew J.; Santini, Daniele; Sarkar, Malancha; Sasada, Tetsuro; Saxena, Neeraj K.; Shackelford, Rodney E; Sharma, Dipali; Shin, Dong M.; Sidransky, David; Siegelin, Markus David; Signori, Emanuela; Singh, Neetu; Sivanand, Sharanya; Sliva, Daniel; Smythe, Carl; Spagnuolo, Carmela; Stafforini, Diana M.; Stagg, John; Subbarayan, Pochi R.; Sundin, Tabetha; Talib, Wamidh H.; Thompson, Sarah K.; Tran, Phuoc T.; Ungefroren, Hendrik; Vander Heiden, Matthew G.; Venkateswaran, Vasundara; Vinay, Dass S.; Vlachostergios, Panagiotis J.; Wang, Zongwei; Wellen, Kathryn E.; Whelan, Richard L.; Yang, Eddy S.; Yang, Huanjie; Yang, Xujuan; Yaswen, Paul; Yedjou, Clement; Yin, Xin; Zhu, Jiyue; Zollo, Massimo

    2016-01-01

    Targeted therapies and the consequent adoption of “personalized” oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity “broad-spectrum” therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested; many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to help us address disease relapse, which is a

  12. Antiepileptic drug use and epileptic seizures in nursing home residents in the Province of Pavia, Italy: A reappraisal 12 years after a first survey.

    Science.gov (United States)

    Galimberti, Carlo Andrea; Tartara, Elena; Dispenza, Sabrina; Marchese, Daniele; Bonizzoni, Erminio; Perucca, Emilio

    2016-01-01

    To assess the prevalence of epileptic seizures, and antiepileptic drug (AED) use among nursing home elderly residents; to evaluate demographics, seizure characteristics, and seizure-related comorbidities associated with institutionalization; and to compare findings with a previous survey conducted 12 years earlier. Data on demographics, age at institutionalization, diagnoses, functional and cognitive status (Barthel Index and Mini Mental State Examination) and drug treatment were obtained by review of medical records of all individuals aged ≥ 60 years at 21 nursing homes. Data from individuals with a diagnosis of epileptic seizures and AED users were compared with non-seizure, non-AED individuals. Among the 2163 individuals surveyed (79% females, age at observation 84.9 ± 7.8 years, mean ± SD), 278 (12.8%, vs 4.3% in the previous survey) received chronic AED treatment, including 174 who did not have a diagnosis of seizures. Of the 116 residents with a diagnosis of seizures (5.4%, vs 2.9% in the previous study), 104 were on AED treatment and were younger and had lower cognitive abilities, and a higher number of comorbidities and co-medications compared with non-AED-users. The most commonly prescribed AEDs in seizure individuals were phenobarbital (43.3%, vs 70% in the previous survey) and levetiracetam (27.9%, not available at the time of previous survey). At multivariate analysis, a diagnosis of seizures was found to be associated with younger age at the time of the survey, a history of neurological (cerebrovascular events, meningiomas) and non-neurological conditions (psoriasis and chronic bronchitis), and a lower MMSE score. The prevalence of seizures and AED use was higher than in our previous survey and more aligned with data from other countries. Seizures, AED use and co-morbidities were associated with earlier institutionalization. There were indicators of treatment being suboptimal in many cases. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Neurological adverse events of new generation sodium blocker antiepileptic drugs. Meta-analysis of randomized, double-blinded studies with eslicarbazepine acetate, lacosamide and oxcarbazepine.

    Science.gov (United States)

    Zaccara, Gaetano; Giovannelli, Fabio; Maratea, Dario; Fadda, Valeria; Verrotti, Alberto

    2013-09-01

    Analysis of overall tolerability and neurological adverse effects (AEs) of eslicarbazepine acetate (ESL), lacosamide (LCM) and oxcarbazepine (OXC) from double-blind, placebo-controlled trials. Indirect comparisons of patients withdrawing because of AEs, and the incidence of some vestibulocerebellar AEs between these three antiepileptic dugs (AEDs). We searched MEDLINE for all randomized, double-blind, placebo-controlled trials investigating therapeutic effects of fixed oral doses of ESL, LCM and OXC in patients with drug resistant epilepsy. Withdrawal rate due to AEs, percentages of patients with serious AEs, and the proportion of patients experiencing any neurological AE, nausea and vomiting were assessed for their association with the experimental drug. Analyses were performed between recommended daily doses of each AED according to the approved summary of product characteristics (SPC). Risk differences were used to evaluate the association of any AE [99% confidence intervals (CIs)] or study withdrawals because of AEs (95% CIs) with the experimental drug. Indirect comparisons between withdrawal rate and AEs dizziness, coordination abnormal/ataxia and diplopia were estimated according to network meta-analysis (Net-MA). Eight randomized, placebo-controlled, double-blind trials (4 with ESL, 3 with LCM, and 1 with OXC) were included in our analysis. At high doses (OXC 1200mg, ESL 1200mg and LCM 400mg) there was an increased risk of AE-related study withdrawals compared to placebo for all drugs. Several AEs were associated with the experimental drug. Both number and frequency of AEs were dose-related. At high recommended doses, patients treated with OXC withdrew from the experimental treatment significantly more frequently than patients treated with ESL and LCM. Furthermore, the AEs coordination abnormal/ataxia and diplopia were significantly more frequently observed in patients treated with OXC compared to patients treated with LCM and ESL. The overall tolerability

  14. Insight into the mechanism of action of temporin-SHa, a new broad-spectrum antiparasitic and antibacterial agent.

    Directory of Open Access Journals (Sweden)

    Zahid Raja

    Full Text Available Antimicrobial peptides (AMPs are promising drugs to kill resistant pathogens. In contrast to bacteria, protozoan parasites, such as Leishmania, were little studied. Therefore, the antiparasitic mechanism of AMPs is still unclear. In this study, we sought to get further insight into this mechanism by focusing our attention on temporin-SHa (SHa, a small broad-spectrum AMP previously shown to be active against Leishmania infantum. To improve activity, we designed analogs of SHa and compared the antibacterial and antiparasitic mechanisms. [K3]SHa emerged as a highly potent compound active against a wide range of bacteria, yeasts/fungi, and trypanosomatids (Leishmania and Trypanosoma, with leishmanicidal intramacrophagic activity and efficiency toward antibiotic-resistant strains of S. aureus and antimony-resistant L. infantum. Multipassage resistance selection demonstrated that temporins-SH, particularly [K3]SHa, are not prone to induce resistance in Escherichia coli. Analysis of the mode of action revealed that bacterial and parasite killing occur through a similar membranolytic mechanism involving rapid membrane permeabilization and depolarization. This was confirmed by high-resolution imaging (atomic force microscopy and field emission gun-scanning electron microscopy. Multiple combined techniques (nuclear magnetic resonance, surface plasmon resonance, differential scanning calorimetry allowed us to detail peptide-membrane interactions. [K3]SHa was shown to interact selectively with anionic model membranes with a 4-fold higher affinity (KD = 3 x 10-8 M than SHa. The amphipathic α-helical peptide inserts in-plane in the hydrophobic lipid bilayer and disrupts the acyl chain packing via a detergent-like effect. Interestingly, cellular events, such as mitochondrial membrane depolarization or DNA fragmentation, were observed in L. infantum promastigotes after exposure to SHa and [K3]SHa at concentrations above IC50. Our results indicate that these

  15. A mechanistic paradigm for broad-spectrum antivirals that target virus-cell fusion.

    Directory of Open Access Journals (Sweden)

    Frederic Vigant

    .01 delayed the time to death in a murine lethal challenge model of Rift Valley Fever Virus (RVFV. The viral membrane may be a viable target for broad-spectrum antivirals that target virus-cell fusion.

  16. Integrated DNA walking system to characterize a broad spectrum of GMOs in food/feed matrices.

    Science.gov (United States)

    Fraiture, Marie-Alice; Herman, Philippe; Lefèvre, Loic; Taverniers, Isabel; De Loose, Marc; Deforce, Dieter; Roosens, Nancy H

    2015-08-14

    In order to provide a system fully integrated with qPCR screening, usually used in GMO routine analysis, as well as being able to detect, characterize and identify a broad spectrum of GMOs in food/feed matrices, two bidirectional DNA walking methods targeting p35S or tNOS, the most common transgenic elements found in GM crops, were developed. These newly developed DNA walking methods are completing the previously implemented DNA walking method targeting the t35S pCAMBIA element. Food/feed matrices containing transgenic crops (Bt rice or MON863 maize) were analysed using the integrated DNA walking system. First, the newly developed DNA walking methods, anchored on the sequences used for the p35S or tNOS qPCR screening, were tested on Bt rice that contains these two transgenic elements. Second, the methods were assessed on a maize sample containing a low amount of the GM MON863 event, representing a more complex matrix in terms of genome size and sensitivity. Finally, to illustrate its applicability in GMO routine analysis by enforcement laboratories, the entire workflow of the integrated strategy, including qPCR screening to detect the potential presence of GMOs and the subsequent DNA walking methods to characterize and identify the detected GMOs, was applied on a GeMMA Scheme Proficiency Test matrix. Via the characterization of the transgene flanking region between the transgenic cassette and the plant genome as well as of a part of the transgenic cassette, the presence of GMOs was properly confirmed or infirmed in all tested samples. Due to their simple procedure and their short time-frame to get results, the developed DNA walking methods proposed here can be easily implemented in GMO routine analysis by the enforcement laboratories. In providing crucial information about the transgene flanking regions and/or the transgenic cassettes, this DNA walking strategy is a key molecular tool to prove the presence of GMOs in any given food/feed matrix.

  17. Anti-Epileptic Drugs Delay Age-Related Loss of Spiral Ganglion Neurons via T-type Calcium Channel

    Science.gov (United States)

    Lei, Debin; Gao, Xia; Perez, Philip; Ohlemiller, Kevin K; Chen, Chien-Chang; Campbell, Kevin P.; Hood, Aizhen Yang; Bao, Jianxin

    2011-01-01

    Loss of spiral ganglion neurons is a major cause of age-related hearing loss (presbycusis). Despite being the third most prevalent condition afflicting elderly persons, there are no known medications to prevent presbycusis. Because calcium signaling has long been implicated in age-related neuronal death, we investigated T-type calcium channels. This family is comprised of three members (Cav3.1, Cav3.2, and Cav3.3), based on their respective main pore-forming alpha subunits: α1G, α1H, and α1I. In the present study, we report a significant delay of age-related loss of cochlear function and preservation of spiral ganglion neurons in α1H null and heterozygous mice, clearly demonstrating an important role for Cav3.2 in age-related neuronal loss. Furthermore, we show that anticonvulsant drugs from a family of T-type calcium channel blockers can significantly preserve spiral ganglion neurons during aging. To our knowledge, this is the first report of drugs capable of diminishing age-related loss of spiral ganglion neurons. PMID:21640179

  18. Seizure freedom is not adversely affected by early discontinuation of concomitant anti-epileptic drugs in the EULEV cohort of levetiracetam users.

    Science.gov (United States)

    Droz-Perroteau, Cécile; Marchal, Cécile; Dureau-Pournin, Caroline; Lassalle, Régis; Jové, Jérémy; Robinson, Philip; Lavernhe, Gilles; Vespignani, Hervé; Moore, Nicholas; Fourrier-Réglat, Annie

    2012-11-01

    Fear of discontinuing concomitant anti-epileptic drugs (AEDs) may lead to potentially unnecessary and perhaps unsafe polypharmacy. The effect of withdrawing concomitant AEDs on epilepsy control was therefore studied in long-term users of levetiracetam. The EULEV cohort followed patients initiating levetiracetam in France in 2005 or 2006 for one year. In those maintaining levetiracetam throughout the study period, the association of a reduction in the number of concomitant AEDs during the first six months with seizure-freedom during the last six months of follow-up was investigated using logistic regression. Of the 356 patients continuing levetiracetam for at least 1 year, 140 (39.3%) were seizure-free during the last six months of follow-up. Partial symptomatic or generalised idiopathic epilepsy were associated with greater seizure-freedom than partial cryptogenic disease. Factors associated with seizures were: longer disease duration, initial incapacity, increased number of seizures in the six months preceding levetiracetam initiation, and number of consultations for epilepsy in the six months preceding levetiracetam initiation. There was a trend for the association between the early reduction in the number of concomitant AEDs and seizure-free status later during follow-up, which however did not reach statistical significance in the final propensity score-adjusted multivariate model (OR = 1.8, 95%CI [0.8;4.0]). Taking into account the various risk factors for seizures, the early reduction of concomitant AEDs was not associated with worse seizure rates during follow-up in real-life users of levetiracetam. Copyright © 2012 John Wiley & Sons, Ltd.

  19. Broad-spectrum enhanced absorption of graphene-molybdenum disulfide photovoltaic cells in Metal-Mirror Microcavity.

    Science.gov (United States)

    Liu, Jiang Tao; Cao, Yunkai; Tong, Hong; Wang, Dahai; Wu, Zhenhua

    2018-01-29

    We investigate theoretically the optical absorption of graphene-molybdenum disulfide photovoltaic cells (GM-PVc) in wedge-shaped metal-mirror microcavities (w-MMCs) combined with spectrum-splitting structure. Results show that the combination of spectrum-splitting structure and w-MMC can enable the light absorption of GM-PVc to reach about 65% in the broad spectrum. The influence of processing errors on the absorption of GM-PVc in w-MMCs is effectively suppressed, i.e., 3 ~14 times lower than that of GM-PVc in common wedge photonic crystal microcavities. The light absorption of GM-PVc reaches 60% in broad spectrum even with the processing errors. This proposal of GM-PVc structure is easy to implement and has potentially important applications in the development of ultra-thin and high-efficiency solar cells and optoelectronic devices. © 2018 IOP Publishing Ltd.

  20. Repurposing the anti-epileptic drug sodium valproate as an adjuvant treatment for diffuse intrinsic pontine glioma.

    Science.gov (United States)

    Killick-Cole, Clare L; Singleton, William G B; Bienemann, Alison S; Asby, Daniel J; Wyatt, Marcella J; Boulter, Lisa J; Barua, Neil U; Gill, Steven S

    2017-01-01

    Targeting epigenetic changes in diffuse intrinsic pontine glioma (DIPG) may provide a novel treatment option for patients. This report demonstrates that sodium valproate, a histone deacetylase inhibitor (HDACi), can increase the cytotoxicity of carboplatin in an additive and synergistic manner in DIPG cells in vitro. Sodium valproate causes a dose-dependent decrease in DIPG cell viability in three independent ex vivo cell lines. Furthermore, sodium valproate caused an increase in acetylation of histone H3. Changes in cell viability were consistent with an induction of apoptosis in DIPG cells in vitro, determined by flow cytometric analysis of Annexin V staining and assessment of apoptotic markers by western blotting. Subsequently, immunofluorescent staining of neuronal and glial markers was used to determine toxicity in normal rat hippocampal cells. Pre-treatment of cells with sodium valproate enhanced the cytotoxic effects of carboplatin, in three DIPG cell lines tested. These results demonstrate that sodium valproate causes increased histone H3 acetylation indicative of HDAC inhibition, which is inversely correlated with a reduction in cell viability. Cell viability is reduced through an induction of apoptosis in DIPG cells. Sodium valproate potentiates carboplatin cytotoxicity and prompts further work to define the mechanism responsible for the synergy between these two drugs and determine in vivo efficacy. These findings support the use of sodium valproate as an adjuvant treatment for DIPG.

  1. Genetic engineering of the Xa10 promoter for broad-spectrum and durable resistance to Xanthomonas oryzae pv. oryzae.

    Science.gov (United States)

    Zeng, Xuan; Tian, Dongsheng; Gu, Keyu; Zhou, Zhiyun; Yang, Xiaobei; Luo, Yanchang; White, Frank F; Yin, Zhongchao

    2015-09-01

    Many pathovars of plant pathogenic bacteria Xanthomonas species inject transcription activator-like (TAL) effectors into plant host cells to promote disease susceptibility or trigger disease resistance. The rice TAL effector-dependent disease resistance gene Xa10 confers narrow-spectrum race-specific resistance to Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial blight disease in rice. To generate broad-spectrum and durable resistance to Xoo, we developed a modified Xa10 gene, designated as Xa10(E5) . Xa10(E5) has an EBE-amended promoter containing 5 tandemly arranged EBEs each responding specifically to a corresponding virulent or avirulent TAL effector and a stable transgenic rice line containing Xa10(E5) was generated in the cultivar Nipponbare. The Xa10(E5) gene was specifically induced by Xoo strains that harbour the corresponding TAL effectors and conferred TAL effector-dependent resistance to the pathogens at all developmental stages of rice. Further disease evaluation demonstrated that the Xa10(E5) gene in either Nipponbare or 9311 genetic backgrounds provided broad-spectrum disease resistance to 27 of the 28 Xoo strains collected from 11 countries. The development of Xa10(E5) and transgenic rice lines provides new genetic materials for molecular breeding of rice for broad-spectrum and durable disease resistance to bacterial blight. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

  2. Algunas consideraciones en relación con los medicamentos antiepilépticos de nueva generación en los niños Some considerations in relation to the new generation antiepileptic drugs in children

    Directory of Open Access Journals (Sweden)

    Desiderio Pozo Lauzán

    2005-06-01

    Full Text Available El objetivo de este trabajo es revisar las principales drogas antiepilépticas de segunda generación y su administración en los niños: vigabatrina, felbamato, lamotrigina, topiramato, tiagabina, oxcarbazepina, zonisamida, levetiracetam y stiripentol. Al inicio se recomendaron en pacientes adultos con epilepsias focales refractarias, sin embargo desde hace varios años, se ha demostrado su eficacia en diferentes tipos de crisis en los niños. La lamotrigina y el topiramato se consideran medicamentos de amplio espectro. Se enfatiza en el metabolismo, vías de eliminación, indicaciones, dosis en los niños, interacciones medicamentosas y efectos colaterales de los medicamentos antiepilépticos de segunda generación. Se mencionan algunos de los nuevos medicamentos que actualmente están en investigación como antiepilépticos y que constituyen una tercera generaciónThe objective of this paper is to review the main second generation antiepileptic drugs and their administration in children: vigatrine, felbamate, lamotrigine, topiramate, tiagabine, oxcarbazepine, zonisamide, leventiracetam and stiripentol. At the beginning, they were recommended in adult patients with focal refractory epilepsies; however, their efficacy in different types of seizures in children has been proved for some years. Lamotrigine and topiramate are considered drugs of wide spectrum. Emphasis is made on metabolism, routes of elimination, indications, doses in children, drug interactions and side effects of the second generation antiepileptic drugs. Some of the new drugs that are currently under study as antiepileptic and that constitute a third generation, are mentioned.

  3. Comparative Long-Term Effectiveness of a Monotherapy with Five Antiepileptic Drugs for Focal Epilepsy in Adult Patients: A Prospective Cohort Study.

    Directory of Open Access Journals (Sweden)

    Qing-Yi Zeng

    Full Text Available To evaluate and compare long-term effectiveness of five antiepileptic drugs (AEDs for monotherapy of adult patients with focal epilepsy in routine clinical practice.Adult patients with focal epilepsy, who were prescribed with carbamazepine (CBZ, valproate (VPA, lamotrigine (LTG, topiramate (TPM, or oxcarbazepine (OXC as monotherapy, during the period from January 2004 to June 2012 registered in Wenzhou Epilepsy Follow Up Registry Database (WEFURD, were included in the study. Prospective long-term follow-up was conducted until June 2013. The endpoints were time to treatment failure, time to seizure remission, and time to first seizure.This study included 654 patients: CBZ (n=125, VPA (n=151, LTG (n=135, TPM (n=76, and OXC (n=167. The retention rates of CBZ, VPA, LTG, TPM, and OXC at the third year were 36.1%, 32.4%, 57.6%, 37.9%, and 41.8%, respectively. For time to treatment failure, LTG was significantly better than CBZ and VPA (LTG vs. CBZ, hazard ratio, [HR] 0.80 [95% confidence interval: 0.67-0.96], LTG vs. VPA, 0.53 [0.37-0.74]; TPM was worse than LTG (TPM vs. LTG, 1.77 [1.15-2.74], and OXC was better than VPA (0.86 [0.78-0.96]. After initial target doses, the seizure remission rates of CBZ, VPA, LTG, TPM, and OXC were 63.0%, 77.0%, 83.6%, 67.9%, and 75.3%, respectively. LTG was significantly better than CBZ (1.44 [1.15-1.82] and OXC (LTG vs. OXC, 0.76 [0.63-0.93]; OXC was less effective than LTG in preventing the first seizure (1.20 [1.02-1.40].LTG was the best, OXC was better than VPA only, while VPA was the worst. The others were equivalent for comparisons between five AEDs regarding the long-term treatment outcomes of monotherapy for adult patients with focal epilepsy in a clinical practice. For selecting AEDs for these patients among the first-line drugs, LTG is an appropriate first choice; others are reservation in the first-line but VPA is not.

  4. Cognitive consequences of early versus late antiepileptic drug withdrawal after pediatric epilepsy surgery, the TimeToStop (TTS) trial: study protocol for a randomized controlled trial.

    Science.gov (United States)

    Boshuisen, Kim; Lamberink, Herm J; van Schooneveld, Monique Mj; Cross, J Helen; Arzimanoglou, Alexis; van der Tweel, Ingeborg; Geleijns, Karin; Uiterwaal, Cuno Spm; Braun, Kees Pj

    2015-10-26

    The goals of intentional curative pediatric epilepsy surgery are to achieve seizure-freedom and antiepileptic drug (AED) freedom. Retrospective cohort studies have indicated that early postoperative AED withdrawal unmasks incomplete surgical success and AED dependency sooner, but not at the cost of long-term seizure outcome. Moreover, AED withdrawal seemed to improve cognitive outcome. A randomized trial is needed to confirm these findings. We hypothesized that early AED withdrawal in children is not only safe, but also beneficial with respect to cognitive functioning. This is a multi-center pragmatic randomized clinical trial to investigate whether early AED withdrawal improves cognitive function, in terms of attention, executive function and intelligence, quality of life and behavior, and to confirm safety in terms of eventual seizure freedom, seizure recurrences and "seizure and AED freedom." Patients will be randomly allocated in parallel groups (1:1) to either early or late AED withdrawal. Randomization will be concealed and stratified for preoperative IQ and medical center. In the early withdrawal arm reduction of AEDs will start 4 months after surgery, while in the late withdrawal arm reduction starts 12 months after surgery, with intended complete cessation of drugs after 12 and 20 months respectively. Cognitive outcome measurements will be performed preoperatively, and at 1 and 2 years following surgery, and consist of assessment of attention and executive functioning using the EpiTrack Junior test and intelligence expressed as IQ (Wechsler Intelligence Scales). Seizure outcomes will be assessed at 24 months after surgery, and at 20 months following start of AED reduction. We aim to randomize 180 patients who underwent anticipated curative epilepsy surgery below 16 years of age, were able to perform the EpiTrack Junior test preoperatively, and have no predictors of poor postoperative seizure prognosis (multifocal magnetic resonance imaging (MRI

  5. Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepileptic drugs in seizure-free patients: a systematic review and individual participant data meta-analysis.

    Science.gov (United States)

    Lamberink, Herm J; Otte, Willem M; Geerts, Ada T; Pavlovic, Milen; Ramos-Lizana, Julio; Marson, Anthony G; Overweg, Jan; Sauma, Letícia; Specchio, Luigi M; Tennison, Michael; Cardoso, Tania M O; Shinnar, Shlomo; Schmidt, Dieter; Geleijns, Karin; Braun, Kees P J

    2017-07-01

    People with epilepsy who became seizure-free while taking antiepileptic drugs might consider discontinuing their medication, with the possibility of increased quality of life because of the elimination of adverse events. The risk with this action, however, is seizure recurrence. The objectives of our study were to identify predictors of seizure recurrence and long-term seizure outcomes and to produce nomograms for estimation of individualised outcomes. We did a systematic review and meta-analysis, and identified eligible articles and candidate predictors, using PubMed and Embase databases with a last update on Nov 6, 2014. Eligible articles had to report on cohorts of patients with epilepsy who were seizure-free and had started withdrawal of antiepileptic drugs; articles also had to contain information regarding seizure recurrences during and after withdrawal. We excluded surgical cohorts, reports with fewer than 30 patients, and reports on acute symptomatic seizures because these topics were beyond the scope of our objective. Risk of bias was assessed using the Quality in Prognosis Studies system. Data analysis was based on individual participant data. Survival curves and proportional hazards were computed. The strongest predictors were selected with backward selection. Models were converted to nomograms and a web-based tool to determine individual risks. We identified 45 studies with 7082 patients; ten studies (22%) with 1769 patients (25%) were included in the meta-analysis. Median follow-up was 5·3 years (IQR 3·0-10·0, maximum 23 years). Prospective and retrospective studies and randomised controlled trials were included, covering non-selected and selected populations of both children and adults. Relapse occurred in 812 (46%) of 1769 patients; 136 (9%) of 1455 for whom data were available had seizures in their last year of follow-up, suggesting enduring seizure control was not regained by this timepoint. Independent predictors of seizure recurrence were

  6. What does the U.S. Medicare administrative claims database tell us about initial antiepileptic drug treatment for older adults with new-onset epilepsy?

    Science.gov (United States)

    Martin, Roy C; Faught, Edward; Szaflarski, Jerzy P; Richman, Joshua; Funkhouser, Ellen; Piper, Kendra; Juarez, Lucia; Dai, Chen; Pisu, Maria

    2017-04-01

    Disparities in epilepsy treatment are not uncommon; therefore, we examined population-based estimates of initial antiepileptic drugs (AEDs) in new-onset epilepsy among racial/ethnic minority groups of older US Medicare beneficiaries. We conducted retrospective analyses of 2008-2010 Medicare administrative claims for a 5% random sample of beneficiaries augmented for minority representation. New-onset epilepsy cases in 2009 had ≥1 International Classification of Diseases, Ninth Revision (ICD-9) 345.x or ≥2 ICD-9 780.3x, and ≥1 AED, AND no seizure/epilepsy claim codes or AEDs in preceding 365 days. We examined AED use and concordance with Quality Indicators of Epilepsy Treatment (QUIET) 6 (monotherapy as initial treatment = ≥30 day first prescription with no other concomitant AEDs), and prompt AED treatment (first AED within 30 days of diagnosis). Logistic regression examined likelihood of prompt treatment by demographic (race/ethnicity, gender, age), clinical (number of comorbid conditions, neurology care, index event occurring in the emergency room (ER)), and economic (Part D coverage phase, eligibility for Part D Low Income Subsidy [LIS], and ZIP code level poverty) factors. Over 1 year of follow-up, 79.6% of 3,706 new epilepsy cases had one AED only (77.89% of whites vs. 89% of American Indian/Alaska Native [AI/AN]). Levetiracetam was the most commonly prescribed AED (45.5%: from 24.6% AI/AN to 55.0% whites). The second most common was phenytoin (30.6%: from 18.8% Asians to 43.1% AI/AN). QUIET 6 concordance was 94.7% (93.9% for whites to 97.3% of AI/AN). Only 50% received prompt AED therapy (49.6% whites to 53.9% AI/AN). Race/ethnicity was not significantly associated with AED patterns, monotherapy use, or prompt treatment. Monotherapy is common across all racial/ethnic groups of older adults with new-onset epilepsy, older AEDs are commonly prescribed, and treatment is frequently delayed. Further studies on reasons for treatment delays are warranted

  7. Prognostic analysis of patients with epilepsy according to time of relapse after withdrawal of antiepileptic drugs following four seizure-free years.

    Science.gov (United States)

    Park, Soochul; Lee, Dong Hyun; Kim, Seung Woo; Roh, Yun Ho

    2017-01-01

    We performed a retrospective, prognostic analysis of a cohort of patients with epilepsy according to time of relapse after four seizure-free years. Planned withdrawal of antiepileptic drugs (AEDs) and at least 3 years of follow-up after AED discontinuation were performed. The following two groups were assessed: (1) an early relapse (ER) group of patients who experienced recurrence during AED withdrawal and (2) a late relapse (LR) group of patients who experienced recurrence after completion of the AED discontinuation process. After dichotomization, the relapse rate, prognostic factors, and their impacts for each group were compared with those of a group of patients who continued to be seizure-free after AED withdrawal (SF group) using multiple logistic regression analysis. The AED intake mode was also analyzed. Two hundred seventeen (64.6%) of the 336 total patients experienced relapse. One hundred thirty-nine patients (41.4%) and 78 patients (23.2%) were included in the LR and ER groups, respectively. Symptom duration >120 months showed the strongest negative prognostic impact as demonstrated by the 4.7-fold higher risk of recurrence in the ER group compared with the SF group. Additional factors with a negative prognostic impact included an age at epilepsy onset of ≤20 years and the presence of localization-related epilepsy. No reliable predictor between the SF and LR groups was revealed. After exclusion of the SF group, post hoc analysis according to age at epilepsy onset and symptom duration showed that the above-mentioned negative prognostic factors significantly affected the relapse patterns of the LR and ER groups. The results suggest that longer symptom duration, which could be associated with intrinsic reactivation of epilepsy, is the strongest negative prognostic factor for relapse. Relapse after AED withdrawal in prolonged follow-up of seizure-free patients is one aspect of the natural history of epilepsy. © 2016 The Authors. Epilepsia published by

  8. Modification in body weight associated with antiepileptic drugs Alteração de peso corpóreo associado às drogas antiepilépticas

    Directory of Open Access Journals (Sweden)

    Camilla N. De Gaspari

    2010-04-01

    Full Text Available Antiepileptic drugs (AED may cause body weight changes. OBJECTIVE: To evaluate the dietary habits and body weight associated with AED in epileptic patients. METHOD: Sixty-six patients were subjected to two interviews, and had their weight and body mass index calculated and compared at both times, interval between six to eight months. RESULTS: It was observed that 59.1% showed weight gain. The patients who had no weight gain had a greater proportion of individuals who engaged in some form of physical activity. However, of the 45 patients who maintained their initial dietary and medication pattern, 75.6% recorded a weight gain. Weight gain was seen in 66.7% of patients on carbamazepine (n=18, 60% on valproate (n=5, 50% on carbamazepine+clobazam treatment (n=14, and 58.3% of patients on other(s polytherapy (n=12. CONCLUSION: The patient should be alerted to possible weight gain, and should be advised about dieting and participating in regular physical activity.Drogas antiepilépticas (DAE podem causar alteração do peso corpóreo. OBJETIVO: Avaliar o hábito alimentar e do peso corpóreo associado às DAE em pacientes epilépticos. MÉTODO: Sessenta e seis pacientes foram submetidos a duas entrevistas, e tiveram peso e índice de massa corpórea (IMC calculados e comparados nos dois momentos, com intervalo de 6 a 8 meses. RESULTADOS: Apresentaram aumento de peso 59,1% dos pacientes. Porém, os pacientes que não tiveram ganho de peso apresentaram maior proporção de indivíduos desenvolvendo alguma atividade física. Enquanto que dentre os 45 que mantiveram o padrão alimentar e medicação inicial 75,6% registraram ganho de peso. Observou-se ganho de peso em 66,7% dos pacientes com carbamazepina (n=18; 60% com valproato (n=5; 50% com carbamazepina e clobazam (n=14; 58,3% dos pacientes com politerapia (n=12. CONCLUSÃO: Deve-se alertar o paciente sobre o ganho de peso, orientar quanto à dieta alimentar e, principalmente, incentivar atividade f

  9. A natural component from Euphorbia humifusa Willd displays novel, broad-spectrum anti-influenza activity by blocking nuclear export of viral ribonucleoprotein

    Energy Technology Data Exchange (ETDEWEB)

    Chang, So Young; Park, Ji Hoon [Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400 (Korea, Republic of); Kim, Young Ho; Kang, Jong Seong [College of Pharmacy, Chungnam National University, Daejeon, 305-764 (Korea, Republic of); Min, Ji-Young, E-mail: jiyoung.min@ip-korea.org [Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400 (Korea, Republic of)

    2016-03-04

    The need to develop anti-influenza drugs with novel antiviral mechanisms is urgent because of the rapid rate of antigenic mutation and the emergence of drug-resistant viruses. We identified a novel anti-influenza molecule by screening 861 plant-derived natural components using a high-throughput image-based assay that measures inhibition of the influenza virus infection. 1,3,4,6-tetra-O-galloyl-β-D-glucopyranoside (TGBG) from Euphorbia humifusa Willd showed broad-spectrum anti-influenza activity against two seasonal influenza A strains, A/California/07/2009 (H1N1) and A/Perth/16/2009 (H3N2), and seasonal influenza B strain B/Florida/04/2006. We investigated the mode of action of TGBG using neuraminidase activity inhibition and time-of-addition assays, which evaluate the viral release and entry steps, respectively. We found that TGBG exhibits a novel antiviral mechanism that differs from the FDA-approved anti-influenza drugs oseltamivir which inhibits viral release, and amantadine which inhibits viral entry. Immunofluorescence assay demonstrated that TGBG significantly inhibits nuclear export of influenza nucleoproteins (NP) during the early stages of infection causing NP to accumulate in the nucleus. In addition, influenza-induced activation of the Akt signaling pathway was suppressed by TGBG in a dose-dependent manner. These data suggest that a putative mode of action of TGBG involves inhibition of viral ribonucleoprotein (vRNP) export from the nucleus to the cytoplasm consequently disrupting the assembly of progeny virions. In summary, TGBG has potential as novel anti-influenza therapeutic with a novel mechanism of action. - Highlights: • The plant-derived natural product TGBG has broad-spectrum antiviral activity against seasonal influenza A and B viruses. • TGBG has a novel anti-viral mechanism of action that from differs from the currently available anti-influenza drugs. • TGBG hinders nuclear export of the influenza virus ribonucleoprotein (v

  10. Isolation and Characterization of Broad Spectrum Coaggregating Bacteria from Different Water Systems for Potential Use in Bioaugmentation

    Science.gov (United States)

    Wang, Haichao; Chen, Mei; Li, Mengying

    2014-01-01

    The bridging bacteria with broad-spectrum coaggregation ability play an important role during multispecies-biofilm development. In this study, through a visual and semi-quantitative assay, twenty-two bacterial strains with aggregation ability were obtained from 8 different water environments, and these strains were assigned to 7 genera according to their 16S rDNA and they were Aeromonas, Bacillus, Comamonas, Exiguobacterium, Pseudomonas, Shewanella and Comamonas. Furthermore, all possible 231 pairwise combinations among these 22 strains were explored for coaggregation ability by spectrophotometric assay. Among all these strains, it was found that Bacillus cereus G5 and Bacillus megaterium T1 coaggregated with themajority of assayed other strains, 90.5% (19 of 21 strains) and 76.2% respectively (17 of 21 strains) at a higher coaggregation rates (A.I. greater than 50%), indicating they have a broad-spectrum coaggregation property. The images of coaggregates also confirmed the coexistence of G5 and T1 with their partner strains. Biofilm biomass development of G5 cocultured with each of its partner strains were further evaluateded. The results showed that 15 of 21 strains, when paired with G5, developed greater biofilm biomass than the monocultures. Furthermore, the images from both fluorescence microscopy and scanning electron microscopy (SEM) demonstrated that G5 and A3-GFP (a 3,5-dinitrobenzoic acid-degrading strain, staining with gfp),could develop a typical spatial structure of dual-species biofilm when cocultured. These results suggested that bridging-bacteria with a broad spectrum coaggregating ability, such as G5,could mediate the integration of exogenous degrading bacteria into biofilms and contribute to the bioaugmentation treatment. PMID:24736645

  11. Isolation and characterization of broad spectrum coaggregating bacteria from different water systems for potential use in bioaugmentation.

    Directory of Open Access Journals (Sweden)

    Zhongqin Cheng

    Full Text Available The bridging bacteria with broad-spectrum coaggregation ability play an important role during multispecies-biofilm development. In this study, through a visual and semi-quantitative assay, twenty-two bacterial strains with aggregation ability were obtained from 8 different water environments, and these strains were assigned to 7 genera according to their 16S rDNA and they were Aeromonas, Bacillus, Comamonas, Exiguobacterium, Pseudomonas, Shewanella and Comamonas. Furthermore, all possible 231 pairwise combinations among these 22 strains were explored for coaggregation ability by spectrophotometric assay. Among all these strains, it was found that Bacillus cereus G5 and Bacillus megaterium T1 coaggregated with themajority of assayed other strains, 90.5% (19 of 21 strains and 76.2% respectively (17 of 21 strains at a higher coaggregation rates (A.I. greater than 50%, indicating they have a broad-spectrum coaggregation property. The images of coaggregates also confirmed the coexistence of G5 and T1 with their partner strains. Biofilm biomass development of G5 cocultured with each of its partner strains were further evaluateded. The results showed that 15 of 21 strains, when paired with G5, developed greater biofilm biomass than the monocultures. Furthermore, the images from both fluorescence microscopy and scanning electron microscopy (SEM demonstrated that G5 and A3-GFP (a 3,5-dinitrobenzoic acid-degrading strain, staining with gfp,could develop a typical spatial structure of dual-species biofilm when cocultured. These results suggested that bridging-bacteria with a broad spectrum coaggregating ability, such as G5,could mediate the integration of exogenous degrading bacteria into biofilms and contribute to the bioaugmentation treatment.

  12. The Lipid-Associated 3D Structure of SPA, a Broad-Spectrum Neuropeptide Antagonist with Anticancer Properties

    OpenAIRE

    Keire, David A; Kumar, Mohanraja; Hu, Weidong; Sinnett-Smith, James; Rozengurt, Enrique

    2006-01-01

    [D-Arg1, D-Trp5,7,9, Leu11] substance P (SPA) belongs to a family of peptides including antagonist G and SpD that act as broad-spectrum neuropeptide antagonists at several peripheral receptors. The lipid-induced structure of these peptides may be important for the receptor interactions of these analogs. Thus we describe the tertiary structure of SPA in the presence of sodium dodecylsulfate micelles at pH 5.0, and 25°C as determined from two-dimensional 1H-NMR data recorded at 500 MHz. The res...

  13. Antiepileptics for aggression and associated impulsivity

    Science.gov (United States)

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

    2014-01-01

    Background Aggression is a major public health issue and is integral to several mental health disorders. Antiepileptic drugs may reduce aggression by acting on the central nervous system to reduce neuronal hyper-excitability associated with aggression. Objectives To evaluate the efficacy of antiepileptic drugs in reducing aggression and associated impulsivity. Search methods We searched CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, metaRegister of Controlled Trials (mRCT) and ClinicalTrials.gov to April 2009. We also searched Cochrane Schizophrenia Group’s register of trials on aggression, National Research Record and handsearched for studies. Selection criteria Prospective, placebo-controlled trials of antiepileptic drugs taken regularly by individuals with recurrent aggression to reduce the frequency or intensity of aggressive outbursts. Data collection and analysis Three authors independently selected studies and two authors independently extracted data. We calculated standardised mean differences (SMDs), with odds ratios (ORs) for dichotomous data. Main results Fourteen studies with data from 672 participants met the inclusion criteria. Five different antiepileptic drugs were examined. Sodium valproate/divalproex was superior to placebo for outpatient men with recurrent impulsive aggression, for impulsively aggressive adults with cluster B personality disorders, and for youths with conduct disorder, but not for children and adolescents with pervasive developmental disorder. Carbamazepine was superior to placebo in reducing acts of self-directed aggression in women with borderline personality disorder, but not in children with conduct disorder. Oxcarbazepine was superior to placebo for verbal aggression and aggression against objects in adult outpatients. Phenytoin was superior to placebo on the frequency of aggressive acts in male prisoners and in outpatient men including those with personality disorder, but not on the frequency of ‘behavioral incidents’ in

  14. Fish liver oil and propolis as protective natural products against the effect of the anti-epileptic drug valproate on immunological markers of bone formation in rats.

    Science.gov (United States)

    Elwakkad, Amany S E; El Elshamy, Karima A I; Sibaii, H

    2008-07-01

    Epilepsy is a major public health problem affecting nearly 50 million people world wide. Treatment with anti-epileptic drugs (AEDs) is generally chronic if not life long and may be associated with significant metabolic effects including decreased bone mass and increased fractures. The aim of this work was to investigate the protective role of fish liver oil and propolis against the effect of the drug valproate that is widely used for treatment of epilepsy. Group of 40 rats was divided into four groups each contain 10 rats. The first group (group I) is healthy normal rats, as control. Epilepsy was conducted in the rest of the rats. The epileptic rats were divided into three subgroups: group II was epileptic group, supplemented orally with valproate. The third group was epileptic group which supplemented orally with valproate in concomitant with fish liver oil, the last group; group IV was epileptic group which supplemented orally with valproate in concomitant with propolis. In the present study oral administration of valproate to the epileptic rats by a dose of 400mg/kg/daily for six months (group II) resulted in a significant increase of bone alkaline phosphatase, osteocalcin and N-telepeptide of type 1 collagen (NTX) relative to the control group. There were increase of receptor activator of NF kappa B ligand (RANKL), tumor necrosis factor - alpha (TNF-alpha) and decrease of osteoprotegrin (OPG) compared to normal control. Administration of fish liver oil orally in a dose of 0.4mg/kg daily in concomitant with valproate 400mg/kg daily for six months (group III), result in reduction of N-telepeptide of type 1 collagen (NTX) in comparison to group II and with no significant increase than the control (group I). There were high significant increase of bone alkaline phosphatase and osteocalcin compared to control group I. There was high significant increase of bone alkaline phosphatase than group II and increase in osteocalcin, and decrease in N-telepeptide of type 1

  15. Cytotoxic 2-phenyacrylnitriles, the importance of the cyanide moiety and discovery of potent broad spectrum cytotoxic agents.

    Science.gov (United States)

    Tarleton, Mark; Gilbert, Jayne; Sakoff, Jennette A; McCluskey, Adam

    2012-11-01

    We previously reported the discovery of a simple conjugated cyano pharmacophore which had led to the development of (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylonitrile, as a selective inhibitor of oestrogen receptor positive (ER+ve) human breast cancer cell line, MCF-7. Further exploration though modification of the acrylonitrile and aromatic substituents has highlighted key structural components necessary for broad spectrum cytotoxicity. The acrylic acid derivates (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylic acid and (Z)-2-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid (9) were inactive; confirming the importance of the cyanide moiety. The most potent 2-phenylacrylonitriles synthesized were (Z)-2-(3,4-dichlorophenyl)-3-(1H-indol-3-yl)acrylonitrile and (Z)-2-(3,4-dichlorophenyl)-3-(1H-indol-5-yl)acrylonitrile (20) with an average GI(50) values of 1.4 and 0.53 μM respectively. Five additional (Z)-2-(3,4-dichlorophenyl)-3-(indolyl)acrylonitriles also displayed average GI(50) values of ≤8.4 μM. In the case of indole, this represents a 32-fold increase in broad spectrum cytotoxicity relative to the lead. Crown Copyright © 2012. Published by Elsevier Masson SAS. All rights reserved.

  16. The investigation of copper-based impregnated activated carbons prepared from water-soluble materials for broad spectrum respirator applications.

    Science.gov (United States)

    Smith, J W H; Westreich, P; Abdellatif, H; Filbee-Dexter, P; Smith, A J; Wood, T E; Croll, L M; Reynolds, J H; Dahn, J R

    2010-08-15

    The preparation of impregnated activated carbons (IACs) from aqueous, copper-containing solutions for broad spectrum gas filtration applications is studied here. Several samples were studied to determine the effect that impregnant loading, impregnant distribution and impregnant recipe had on the overall performance. Dynamic flow testing was used to determine the gas filtration capacity of the IAC samples versus a variety of challenge gases. X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDX) were used to characterize the impregnant distribution on the carbon as a function of impregnant loading. Oven tests were performed to determine the thermal stability of the IAC samples exposed to elevated temperatures. The role impregnant distribution plays in gas filtration capacity and the overall performance of the IAC samples is discussed. The IAC samples prepared in this work were found to have gas filtration capacities as good as or better than broad spectrum respirator carbon samples prepared from the patent literature. IACs impregnated with an aqueous 2.4 M Cu(NO(3))(2)/0.04 M H(3)PO(4).12MoO(3)/4M HNO(3) solution that were heated to 200 degrees C under argon were found to have the best overall performance of the samples studied in this work. Copyright 2010 Elsevier B.V. All rights reserved.

  17. Synthesis and antibacterial evaluation of novel cationic chalcone derivatives possessing broad spectrum antibacterial activity.

    Science.gov (United States)

    Chu, Wen-Chao; Bai, Peng-Yan; Yang, Zhao-Qing; Cui, De-Yun; Hua, Yong-Gang; Yang, Yi; Yang, Qian-Qian; Zhang, En; Qin, Shangshang

    2018-01-01

    There is an urgent need to identify new antibiotics with novel mechanisms that combat antibiotic resistant bacteria. Herein, a series of chalcone derivatives that mimic the essential properties of cationic antimicrobial peptides were designed and synthesized. Antibacterial activities against drug-sensitive bacteria, including Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Salmonella enterica, as well as clinical multiple drug resistant isolates of methicillin-resistant S. aureus (MRSA), KPC-2-producing and NDM-1-producing Carbapenem-resistant Enterobacteriaceae were evaluated. Representative compounds 5a (MIC: 1 μg/mL against S. aureus, 0.5 μg/mL against MRSA) and 5g (MIC: 0.5 μg/mL against S. aureus, 0.25 μg/mL against MRSA) showed good bactericidal activity against both Gram-positive and Gram-negative bacteria, including the drug-resistant species MRSA, KPC and NDM. These membrane-active antibacterial compounds were demonstrated to reduce the viable cell counts in bacterial biofilms effectively and do not induce the development of resistance in bacteria. Additionally, these representative molecules exhibited negligible toxicity toward mammalian cells at a suitable concentration. The combined results indicate that this series of cationic chalcone derivatives have potential therapeutic effects against bacterial infections. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. Comparison between pathogen directed antibiotic treatment and empirical broad spectrum antibiotic treatment in patients with community acquired pneumonia: a prospective randomised study

    NARCIS (Netherlands)

    van der Eerden, M. M.; Vlaspolder, F.; de Graaff, C. S.; Groot, T.; Bronsveld, W.; Jansen, H. M.; Boersma, W. G.

    2005-01-01

    Background: There is much controversy about the ideal approach to the management of community acquired pneumonia ( CAP). Recommendations differ from a pathogen directed approach to an empirical strategy with broad spectrum antibiotics. Methods: In a prospective randomised open study performed

  19. Synthesis, Biological Evaluation and Modeling Studies of New Pyrido[3,4-b]indole Derivatives as Broad-Spectrum Potent Anticancer Agents.

    Science.gov (United States)

    Patil, Shivaputra A; Addo, James K; Deokar, Hemantkumar; Sun, Shan; Wang, Jin; Li, Wei; Suttle, D Parker; Wang, Wei; Zhang, Ruiwen; Buolamwini, John K

    2017-03-01

    There is an urgent need drugs against particularly difficult to treat solid tumors such as pancreatic, triple negative breast, lung, colon, metastatic prostate cancers and melanoma. Thus, the objective of this study was to synthesize compounds based computational modeling that indicated the pyrido[3,4- b ]indole class bind to MDM2, a new cancer target for which there are still no drug on the market. Compounds were synthesized by established methods and tested for antiproliferative activity against a broad range of human cancer cell lines, comprising HCT116 colon, HPAC, MIA PaCa-2 and Panc-1 pancreatic, MCF-7 and MDA-MB-468 breast, A375 and WM164 melanoma, A549 lung, and LNCaP, DU145 and PC3 prostate cancer lines. Computational docking was also undertaken. The novel pyrido[3,4- b ]indoles synthesized exhibited a clear SAR with regards to antiproliferative activity, with potent broad-spectrum anticancer activity with IC 50 s down to 80, 130, 130 and 200 nM for breast, colon, melanoma and pancreatic cancer cells, respectively. 1-Naphthyl at C1 combined with methoxy at C6 provided the best antiproliferative activity. Thus, compound 11 (1-naphthyl-6-methoxy-9 H -pyrido[3,4-b]indole) showed the highest potency. A mechanistic feature of the compounds as a group is a strongly selective G2/M cell cycle phase arrest. Docking at on MDM2 suggested a hydrogen bond interaction between the 6-methoxy Tyr106, hydrophobic interaction with Val93, pi-pi stacking interactions with Tyr100 and His96 and hydrophobic interactions with Leu54 and Ile99. An N9-methyl group disrupted binding interactions, such as H-bond interactions involving the N9 hydrogen. We have identified a novel series of pyrido[3,4- b ]indoles with potent broad spectrum anticancer activity towards the most aggressive and difficult to treat cancers including metastatic pancreatic cancer, non-small cell lung cancer, triple negative breast cancers, and BRAF V600E mutant melanoma, as well as metastatic colon and prostate

  20. Broad spectrum anti-microbial compounds producing bacteria from coast of Qingdao bays.

    Science.gov (United States)

    Khan, Muhammad Naseem; Li, Meng; Mirani, Zulfiqar Ali; Wang, Jingxue; Lin, Hong; Buzdar, Muhammad Aslam

    2015-03-01

    Anti-microbial resistance burden and hazard associated with chemical treatment of infections demanded for new anti-microbial natural products. Marine associated microorganisms are the enormous source of bioactive compounds. In this study we have isolated 272 marine bacteria among them 136 (50%) were antagonistic to at least one of the four pathogenic strains Listeria monocytogenes, Vibrio cholerae, E. coli and S. aureus. Only two strains exhibited antibacterial activity against all four test strains, which were identified by 16S rDNA sequencing as Bacillus sp. DK1-SA11 and Vibrio sp. DK6-SH8. Marine isolate DK1-SA11 has potential to resist boiling temperature and pH 2-12. Furthermore cell free extract (CFE) inhibited all test organisms including superbug MRSA and pathogenic yeast Candida albicans. Marine isolate Bacillus sp. DK1-SA11 could be a potential combatant for the battle of drugs and bugs.

  1. Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses.

    Science.gov (United States)

    Mounce, Bryan C; Cesaro, Teresa; Moratorio, Gonzalo; Hooikaas, Peter Jan; Yakovleva, Anna; Werneke, Scott W; Smith, Everett Clinton; Poirier, Enzo Z; Simon-Loriere, Etienne; Prot, Matthieu; Tamietti, Carole; Vitry, Sandrine; Volle, Romain; Khou, Cécile; Frenkiel, Marie-Pascale; Sakuntabhai, Anavaj; Delpeyroux, Francis; Pardigon, Nathalie; Flamand, Marie; Barba-Spaeth, Giovanna; Lafon, Monique; Denison, Mark R; Albert, Matthew L; Vignuzzi, Marco

    2016-11-01

    RNA viruses present an extraordinary threat to human health, given their sudden and unpredictable appearance, the potential for rapid spread among the human population, and their ability to evolve resistance to antiviral therapies. The recent emergence of chikungunya virus, Zika virus, and Ebola virus highlights the struggles to contain outbreaks. A significant hurdle is the availability of antivirals to treat the infected or protect at-risk populations. While several compounds show promise in vitro and in vivo, these outbreaks underscore the need to accelerate drug discovery. The replication of several viruses has been described to rely on host polyamines, small and abundant positively charged molecules found in the cell. Here, we describe the antiviral effects of two molecules that alter polyamine levels: difluoromethylornithine (DFMO; also called eflornithine), which is a suicide inhibitor of ornithine decarboxylase 1 (ODC1), and diethylnorspermine (DENSpm), an activator of spermidine/spermine N(1)-acetyltransferase (SAT1). We show that reducing polyamine levels has a negative effect on diverse RNA viruses, including several viruses involved in recent outbreaks, in vitro and in vivo These findings highlight the importance of the polyamine biosynthetic pathway to viral replication, as well as its potential as a target in the development of further antivirals or currently available molecules, such as DFMO. RNA viruses present a significant hazard to human health, and combatting these viruses requires the exploration of new avenues for targeting viral replication. Polyamines, small positively charged molecules within the cell, have been demonstrated to facilitate infection for a few different viruses. Our study demonstrates that diverse RNA viruses rely on the polyamine pathway for replication and highlights polyamine biosynthesis as a promising drug target. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  2. Inhibition of an Aquatic Rhabdovirus Demonstrates Promise of a Broad-Spectrum Antiviral for Use in Aquaculture.

    Science.gov (United States)

    Balmer, Bethany F; Powers, Rachel L; Zhang, Ting-Hu; Lee, Jihye; Vigant, Frederic; Lee, Benhur; Jung, Michael E; Purcell, Maureen K; Snekvik, Kevin; Aguilar, Hector C

    2017-02-15

    Many enveloped viruses cause devastating disease in aquaculture, resulting in significant economic impact. LJ001 is a broad-spectrum antiviral compound that inhibits enveloped virus infections by specifically targeting phospholipids in the lipid bilayer via the production of singlet oxygen (1O2). This stabilizes positive curvature and decreases membrane fluidity, which inhibits virus-cell membrane fusion during viral entry. Based on data from previous mammalian studies and the requirement of light for the activation of LJ001, we hypothesized that LJ001 may be useful as a preventative and/or therapeutic agent for infections by enveloped viruses in aquaculture. Here, we report that LJ001 was more stable with a prolonged inhibitory half-life at relevant aquaculture temperatures (15°C), than in mammalian studies at 37°C. When LJ001 was preincubated with our model virus, infectious hematopoietic necrosis virus (IHNV), infectivity was significantly inhibited in vitro (using the epithelioma papulosum cyprini [EPC] fish cell line) and in vivo (using rainbow trout fry) in a dose-dependent and time-dependent manner. While horizontal transmission of IHNV in a static cohabitation challenge model was reduced by LJ001, transmission was not completely blocked at established antiviral doses. Therefore, LJ001 may be best suited as a therapeutic for aquaculture settings that include viral infections with lower virus-shedding rates than IHNV or where higher viral titers are required to initiate infection of naive fish. Importantly, our data also suggest that LJ001-inactivated IHNV elicited an innate immune response in the rainbow trout host, making LJ001 potentially useful for future vaccination approaches. Viral diseases in aquaculture are challenging because there are few preventative measures and/or treatments. Broad-spectrum antivirals are highly sought after and studied because they target common components of viruses. In our studies, we used LJ001, a broad-spectrum antiviral

  3. Broad-spectrum anti-biofilm peptide that targets a cellular stress response.

    Directory of Open Access Journals (Sweden)

    César de la Fuente-Núñez

    2014-05-01

    Full Text Available Bacteria form multicellular communities known as biofilms that cause two thirds of all infections and demonstrate a 10 to 1000 fold increase in adaptive resistance to conventional antibiotics. Currently, there are no approved drugs that specifically target bacterial biofilms. Here we identified a potent anti-biofilm peptide 1018 that worked by blocking (pppGpp, an important signal in biofilm development. At concentrations that did not affect planktonic growth, peptide treatment completely prevented biofilm formation and led to the eradication of mature biofilms in representative strains of both Gram-negative and Gram-positive bacterial pathogens including Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, methicillin resistant Staphylococcus aureus, Salmonella Typhimurium and Burkholderia cenocepacia. Low levels of the peptide led to biofilm dispersal, while higher doses triggered biofilm cell death. We hypothesized that the peptide acted to inhibit a common stress response in target species, and that the stringent response, mediating (pppGpp synthesis through the enzymes RelA and SpoT, was targeted. Consistent with this, increasing (pppGpp synthesis by addition of serine hydroxamate or over-expression of relA led to reduced susceptibility to the peptide. Furthermore, relA and spoT mutations blocking production of (pppGpp replicated the effects of the peptide, leading to a reduction of biofilm formation in the four tested target species. Also, eliminating (pppGpp expression after two days of biofilm growth by removal of arabinose from a strain expressing relA behind an arabinose-inducible promoter, reciprocated the effect of peptide added at the same time, leading to loss of biofilm. NMR and chromatography studies showed that the peptide acted on cells to cause degradation of (pppGpp within 30 minutes, and in vitro directly interacted with ppGpp. We thus propose that 1018 targets (pppGpp and marks it for

  4. A Broad-Spectrum Antimicrobial Activity of Bacillus subtilis RLID 12.1

    Directory of Open Access Journals (Sweden)

    Ramya Ramachandran

    2014-01-01

    Full Text Available In the present study, an attempt was made to biochemically characterize the antimicrobial substance from the soil isolate designated as RLID 12.1 and explore its potential applications in biocontrol of drug-resistant pathogens. The antimicrobial potential of the wild-type isolate belonging to the genus Bacillus was determined by the cut-well agar assay. The production of antimicrobial compound was recorded maximum at late exponential growth phase. The ultrafiltered concentrate was insensitive to organic solvents, metal salts, surfactants, and proteolytic and nonproteolytic enzymes. The concentrate was highly heat stable and active over a wide range of pH values. Partial purification, zymogram analysis, and TLC were performed to determine the preliminary biochemical nature. The molecular weight of the antimicrobial peptide was determined to be less than 2.5 kDa in 15% SDS-PAGE and in zymogram analysis against Streptococcus pyogenes. The N-terminal amino acid sequence by Edman degradation was partially determined to be T-P-P-Q-S-X-L-X-X-G, which shows very insignificant identity to other antimicrobial peptides from bacteria. The minimum inhibitory concentrations of dialysed and partially purified ion exchange fractions were determined against some selected gram-positive and gram-negative bacteria and some pathogenic yeasts. The presence of three important antimicrobial peptide biosynthesis genes ituc, fend, and bmyb was determined by PCR.

  5. Seizure Recurrence in Children after Stopping Antiepileptic Medication: 5-Year Follow-Up

    Directory of Open Access Journals (Sweden)

    Inn-Chi Lee

    2017-08-01

    Conclusion: We found that a history of status epilepticus, symptomatic partial epilepsy, treatment duration before stopping antiepileptic drugs, and an abnormal EEG when the medication was stopped are important predictors of SR. The risk factors of SR after discontinuing antiepileptic drugs have been investigated in several studies. However, a history of status epilepticus as a predictive factor is rarely mentioned.

  6. [Effect of a computer application on appropriate use and control of broad spectrum antibiotics].

    Science.gov (United States)

    Raveh-Brawer, David; Wiener-Well, Yonit; Lachish, Tamar; Ben-Chetrit, Eli; Megged, Orly; Bar-Meir, Maskit; Dahan, Maymone; Shraber, Tzipora; Bukatman, Estelle; Yinnon, Amos M

    2015-03-01

    Antibiotics are among the greatest contributions of modern medicine. However, since the onset of the antibiotic age, resistance has emerged, threatening the future usability of these drugs. The complexity of antibiotic prescribing and associated expense has led to the development of infectious disease (ID) expert stewardship programs. To describe an in-house created computer application, in use since 2005 with which all restricted antimicrobials are ordered and approved by ID physicians before being supplied by the pharmacy. In the nine years since the application was adopted by the entire hospital, 173,436 prescriptions for restricted antibiotics have been ordered through the application, of which 52% were for male patients, 8% for children ≤ 20 years, 31% for adults 21-70 years old and 61% for patients > 70. All prescriptions were reviewed by ID physicians; their response included approval (mean 87%, range 82-92%), rejection (7%, 3-12%), or change (6%, 4-18%). The latter two decisions always involved written and/or oral interaction with the prescribing physicians. The result analysis showed that: by clinical diagnoses, the approval rate ranged from 82% (for central line associated infection) to 94% (for tuberculosis); by class of antimicrobial, the approval rate ranged from 71% (IV ciprofloxacin) to 95% (IV amoxicillin-calvulanate). Overall hospital expenditure on antimicrobials, corrected by 100 admissions and 100 admission days, did not change significantly. During the nine years of its use, the described computer program has significantly contributed to physician awareness of appropriate antibiotic use, provided tools to assist physicians in their choice of antimicrobial treatment, allowed ID supervision with unprecedented scope and depth and has significantly contributed to cost control.

  7. Preclinical Evaluation of Novel Triphenylphosphonium Salts with Broad-Spectrum Activity

    Science.gov (United States)

    Millard, Melissa; Pathania, Divya; Shabaik, Yumna; Taheri, Laleh; Deng, Jinxia; Neamati, Nouri

    2010-01-01

    Background Recently, there has been a surge of interest in developing compounds selectively targeting mitochondria for the treatment of neoplasms. The critical role of mitochondria in cellular metabolism and respiration supports this therapeutic rationale. Dysfunction in the processes of energy production and metabolism contributes to attenuation of response to pro-apoptotic stimuli and increased ROS production both of which are implicated in the initiation and progression of most human cancers. Methodology/Principal Findings A high-throughput MTT-based screen of over 10,000 drug-like small molecules for anti-proliferative activity identified the phosphonium salts TP187, 197 and 421 as having IC50 concentrations in the submicromolar range. TP treatment induced cell cycle arrest independent of p53 status, as determined by analysis of DNA content in propidium iodide stained cells. In a mouse model of human breast cancer, TP-treated mice showed significantly decreased tumor growth compared to vehicle or paclitaxel treated mice. No toxicities or organ damage were observed following TP treatment. Immunohistochemical staining of tissue sections from TP187-treated tumors demonstrated a decrease in cellular proliferation and increased caspase-3 cleavage. The fluorescent properties of analog TP421 were exploited to assess subcellular uptake of TP compounds, demonstrating mitochondrial localization. Following mitochondrial uptake cells exhibited decreased oxygen consumption and concomittant increase in mitochondrial superoxide production. Proteomics analysis of results from a 600 target antibody microarray demonstrated that TP compounds significantly affected signaling pathways relevant to growth and proliferation. Conclusions/Significance Through our continued interest in designing compounds targeting cancer-cell metabolism, the Warburg effect, and mitochondria we recently discovered a series of novel, small-molecule compounds containing a triphenylphosphine moiety that

  8. Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity.

    Directory of Open Access Journals (Sweden)

    Melissa Millard

    Full Text Available BACKGROUND: Recently, there has been a surge of interest in developing compounds selectively targeting mitochondria for the treatment of neoplasms. The critical role of mitochondria in cellular metabolism and respiration supports this therapeutic rationale. Dysfunction in the processes of energy production and metabolism contributes to attenuation of response to pro-apoptotic stimuli and increased ROS production both of which are implicated in the initiation and progression of most human cancers. METHODOLOGY/PRINCIPAL FINDINGS: A high-throughput MTT-based screen of over 10,000 drug-like small molecules for anti-proliferative activity identified the phosphonium salts TP187, 197 and 421 as having IC₅₀ concentrations in the submicromolar range. TP treatment induced cell cycle arrest independent of p53 status, as determined by analysis of DNA content in propidium iodide stained cells. In a mouse model of human breast cancer, TP-treated mice showed significantly decreased tumor growth compared to vehicle or paclitaxel treated mice. No toxicities or organ damage were observed following TP treatment. Immunohistochemical staining of tissue sections from TP187-treated tumors demonstrated a decrease in cellular proliferation and increased caspase-3 cleavage. The fluorescent properties of analog TP421 were exploited to assess subcellular uptake of TP compounds, demonstrating mitochondrial localization. Following mitochondrial uptake cells exhibited decreased oxygen consumption and concomittant increase in mitochondrial superoxide production. Proteomics analysis of results from a 600 target antibody microarray demonstrated that TP compounds significantly affected signaling pathways relevant to growth and proliferation. CONCLUSIONS/SIGNIFICANCE: Through our continued interest in designing compounds targeting cancer-cell metabolism, the Warburg effect, and mitochondria we recently discovered a series of novel, small-molecule compounds containing a

  9. Tenascin-C is an innate broad-spectrum, HIV-1-neutralizing protein in breast milk.

    Science.gov (United States)

    Fouda, Genevieve G; Jaeger, Frederick H; Amos, Joshua D; Ho, Carrie; Kunz, Erika L; Anasti, Kara; Stamper, Lisa W; Liebl, Brooke E; Barbas, Kimberly H; Ohashi, Tomoo; Moseley, Martin Arthur; Liao, Hua-Xin; Erickson, Harold P; Alam, S Munir; Permar, Sallie R

    2013-11-05

    Achieving an AIDS-free generation will require elimination of postnatal transmission of HIV-1 while maintaining the nutritional and immunologic benefits of breastfeeding for infants in developing regions. Maternal/infant antiretroviral prophylaxis can reduce postnatal HIV-1 transmission, yet toxicities and the development of drug-resistant viral strains may limit the effectiveness of this strategy. Interestingly, in the absence of antiretroviral prophylaxis, greater than 90% of infants exposed to HIV-1 via breastfeeding remain uninfected, despite daily mucosal exposure to the virus for up to 2 y. Moreover, milk of uninfected women inherently neutralizes HIV-1 and prevents virus transmission in animal models, yet the factor(s) responsible for this anti-HIV activity is not well-defined. In this report, we identify a primary HIV-1-neutralizing protein in breast milk, Tenascin-C (TNC). TNC is an extracellular matrix protein important in fetal development and wound healing, yet its antimicrobial properties have not previously been established. Purified TNC captured and neutralized multiclade chronic and transmitted/founder HIV-1 variants, and depletion of TNC abolished the HIV-1-neutralizing activity of milk. TNC bound the HIV-1 Envelope protein at a site that is induced upon engagement of its primary receptor, CD4, and is blocked by V3 loop- (19B and F39F) and chemokine coreceptor binding site-directed (17B) monoclonal antibodies. Our results demonstrate the ability of an innate mucosal host protein found in milk to neutralize HIV-1 via binding to the chemokine coreceptor site, potentially explaining why the majority of HIV-1-exposed breastfed infants are protected against mucosal HIV-1 transmission.

  10. Varespladib (LY315920 Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation

    Directory of Open Access Journals (Sweden)

    Matthew Lewin

    2016-08-01

    Full Text Available Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2 activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2 inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.

  11. Toxicity modulation, resistance enzyme evasion, and A-site X-ray structure of broad-spectrum antibacterial neomycin analogs.

    Science.gov (United States)

    Maianti, Juan Pablo; Kanazawa, Hiroki; Dozzo, Paola; Matias, Rowena D; Feeney, Lee Ann; Armstrong, Eliana S; Hildebrandt, Darin J; Kane, Timothy R; Gliedt, Micah J; Goldblum, Adam A; Linsell, Martin S; Aggen, James B; Kondo, Jiro; Hanessian, Stephen

    2014-09-19

    Aminoglycoside antibiotics are pseudosaccharides decorated with ammonium groups that are critical for their potent broad-spectrum antibacterial activity. Despite over three decades of speculation whether or not modulation of pKa is a viable strategy to curtail aminoglycoside kidney toxicity, there is a lack of methods to systematically probe amine-RNA interactions and resultant cytotoxicity trends. This study reports the first series of potent aminoglycoside antibiotics harboring fluorinated N1-hydroxyaminobutyryl acyl (HABA) appendages for which fluorine-RNA contacts are revealed through an X-ray cocrystal structure within the RNA A-site. Cytotoxicity in kidney-derived cells was significantly reduced for the derivative featuring our novel β,β-difluoro-HABA group, which masks one net charge by lowering the pKa without compromising antibacterial potency. This novel side-chain assists in evasion of aminoglycoside-modifying enzymes, and it can be easily transferred to impart these properties onto any number of novel analogs.

  12. Technetium-99m Tricarbonyl Labeled a Broad-spectrum Quinolone as a Specific Imaging Agent in Infection Diseases.

    Science.gov (United States)

    Khoramrouz, Seyed Javad; Erfani, Mostafa; Athari Allaf, Mitra

    2017-01-01

    Nuclear medicine imaging has been used to localize infection sites, and efforts have been continued to develop modified infection specific radiopharmaceuticals. In this study gemifloxacin as a broad-spectrum quinolone has been labeled with [(99m)Tc (CO)3 (H2O)3](+) core in order to evaluate its feasibility as an infection imaging agent for in-vivo use. The stability of radioconjugate was checked in human serum at 37 °C and biodistribution was studied in mice. Labeling yield of > 95% was obtained corresponding to a specific activity of 0.14 GBq/μmol. The radioconjugate showed good stability in human serum. Our main achievement was the high accumulation in the infected muscle in mice (T/NT = 2.93 ± 0.3 at 1 h post injection), which may diagnostically be beneficial for differentiate sites of infection from sites of inflammation.

  13. Broad Spectrum Anti-Quorum Sensing Activity of Tannin-Rich Crude Extracts of Indian Medicinal Plants.

    Science.gov (United States)

    Shukla, Varsha; Bhathena, Zarine

    2016-01-01

    Quorum sensing (QS) mechanisms have been demonstrated to have significance in expression of pathogenicity in infectious bacteria. In Gram negative bacteria the autoinducer molecules that mediate QS are acyl homoserine lactones (AHL) and in Gram positive bacteria they are peptides called autoinducing peptides (AIP). A screening of tannin-rich medicinal plants was attempted to identify extracts that could interrupt the QS mechanisms in both Gram positive and Gram negative bacteria over a wide range of concentrations and therefore potentially be potent agents that could act as broad spectrum QS inhibitors. Six out of the twelve Indian medicinal plant extracts that were analyzed exhibited anti-QS activity in Chromobacterium violaceum 12472 and in S. aureus strain with agr:blaZ fusion over a broad range of subinhibitory concentrations, indicating that the extracts contain high concentration of molecules that can interfere with the QS mechanisms mediated by AHL as well as AIP.

  14. The Probiotic Compound VSL#3 Modulates Mucosal, Peripheral, and Systemic Immunity Following Murine Broad-Spectrum Antibiotic Treatment

    Directory of Open Access Journals (Sweden)

    Ira Ekmekciu

    2017-05-01

    Full Text Available There is compelling evidence linking the commensal intestinal microbiota with host health and, in turn, antibiotic induced perturbations of microbiota composition with distinct pathologies. Despite the attractiveness of probiotic therapy as a tool to beneficially alter the intestinal microbiota, its immunological effects are still incompletely understood. The aim of the present study was to assess the efficacy of the probiotic formulation VSL#3 consisting of eight distinct bacterial species (including Streptococcus thermophilus, Bifidobacterium breve, B. longum, B. infantis, Lactobacillus acidophilus, L. plantarum, L. paracasei, and L. delbrueckii subsp. Bulgaricus in reversing immunological effects of microbiota depletion as compared to reassociation with a complex murine microbiota. To address this, conventional mice were subjected to broad-spectrum antibiotic therapy for 8 weeks and perorally reassociated with either VSL#3 bacteria or a complex murine microbiota. VSL#3 recolonization resulted in restored CD4+ and CD8+ cell numbers in the small and large intestinal lamina propria as well as in B220+ cell numbers in the former, whereas probiotic intervention was not sufficient to reverse the antibiotic induced changes of respective cell populations in the spleen. However, VSL#3 application was as efficient as complex microbiota reassociation to attenuate the frequencies of regulatory T cells, activated dendritic cells and memory/effector T cells in the small intestine, colon, mesenteric lymph nodes, and spleen. Whereas broad-spectrum antibiotic treatment resulted in decreased production of cytokines such as IFN-γ, IL-17, IL-22, and IL-10 by CD4+ cells in respective immunological compartments, VSL#3 recolonization was sufficient to completely recover the expression of the anti-inflammatory cytokine IL-10 without affecting pro-inflammatory mediators. In summary, the probiotic compound VSL#3 has an extensive impact on mucosal, peripheral, and

  15. Mechanisms of Broad-Spectrum Antiemetic Efficacy of Cannabinoids against Chemotherapy-Induced Acute and Delayed Vomiting

    Directory of Open Access Journals (Sweden)

    Nissar A. Darmani

    2010-09-01

    Full Text Available Chemotherapy-induced nausea and vomiting (CINV is a complex pathophysiological condition and consists of two phases. The conventional CINV neurotransmitter hypothesis suggests that the immediate phase is mainly due to release of serotonin (5-HT from the enterochromaffin cells in the gastrointestinal tract (GIT, while the delayed phase is a consequence of release of substance P (SP in the brainstem. However, more recent findings argue against this simplistic neurotransmitter and anatomical view of CINV. Revision of the hypothesis advocates a more complex, differential and overlapping involvement of several emetic neurotransmitters/modulators (e.g. dopamine, serotonin, substance P, prostaglandins and related arachidonic acid derived metabolites in both phases of emesis occurring concomitantly in the brainstem and in the GIT enteric nervous system (ENS [1]. No single antiemetic is currently available to completely prevent both phases of CINV. The standard antiemetic regimens include a 5-HT3 antagonist plus dexamethasone for the prevention of acute emetic phase, combined with an NK1 receptor antagonist (e.g. aprepitant for the delayed phase. Although NK1 antagonists behave in animals as broad-spectrum antiemetics against different emetogens including cisplatin-induced acute and delayed vomiting, by themselves they are not very effective against CINV in cancer patients. Cannabinoids such as D9-THC also behave as broad-spectrum antiemetics against diverse emetic stimuli as well as being effective against both phases of CINV in animals and patients. Potential side effects may limit the clinical utility of direct-acting cannabinoid agonists which could be avoided by the use of corresponding indirect-acting agonists. Cannabinoids (both phyto-derived and synthetic behave as agonist antiemetics via the activation of cannabinoid CB1 receptors in both the brainstem and the ENS emetic loci. An endocannabinoid antiemetic tone may exist since inverse CB1

  16. Evaluation of the effectiveness of a broad-spectrum sunscreen in the prevention of chloasma in pregnant women.

    Science.gov (United States)

    Lakhdar, H; Zouhair, K; Khadir, K; Essari, A; Richard, A; Seité, S; Rougier, A

    2007-07-01

    Chloasma, or melasma, is a pigmentary disorder that can affect between 50% and 70% of pregnant women. During pregnancy, chloasma does not require any particular treatment beside the use of an effective sunscreen and avoiding the use of any photosensitizing products or inappropriate skin care routine. However, there exist very few studies related to the benefits of sunscreens to prevent this dermatosis. The aim of this study was to assess the role of a broad-spectrum sunscreen in the prevention and treatment of chloasma in pregnant women. We tested the effectiveness and tolerance of a sunscreen composition (SPF 50+, UVA-PF 28) during a 12-month clinical trial on 200 parturients. The 'excellent' tolerance of the sunscreen under evaluation was confirmed. Out of 185 patients who completed the study, only five new cases of chloasma were noted, an occurrence of 2.7%, which is much lower than the 53% previously observed in an usual condition study (same investigators, same geographical area and same time frame). In addition, the clinical effectiveness of the evaluated sunscreen was judged 'excellent' by the majority of parturients and by the research dermatologists during all the consultations. It is also worth noting that at 6 months, a clinical improvement was observed in 8 out of 12 volunteers who were affected by a pre-existing chloasma observed during their inclusion visit. Colorimetric measurements showed that, at the end of their pregnancy, the parturients' skin was, on average, significantly lightened (increase of parameter L* in 38% cases) and less pigmented (reduction of parameter b* in 50% cases); thus, resulting in a significantly lighter skin colour (increase of ITA degrees in 69% cases) compared to their inclusion visit. This study clearly demonstrates the effectiveness of the well-tolerated broad-spectrum sunscreen evaluated, in the prevention of the development of chloasma in pregnant women.

  17. Management of antiepileptic treatment after epilepsy surgery - practices and problems

    DEFF Research Database (Denmark)

    Rubboli, Guido; Sabers, Anne; Uldall, Peter

    2018-01-01

    BACKGROUND: Although epilepsy surgery is a recognized treatment option for drug-resistant epilepsies since several decades, the management of antiepileptic drugs (AEDs) after successful surgery still remains one of the most difficult and unsolved therapeutic challenges. Indeed, no systematic cont...

  18. Bioaugmentation of strain Methylobacterium sp. C1 towards p-nitrophenol removal with broad spectrum coaggregating bacteria in sequencing batch biofilm reactors.

    Science.gov (United States)

    Yue, Wenlong; Chen, Mei; Cheng, Zhongqin; Xie, Liqun; Li, Mengying

    2018-02-15

    This work was conducted in order to evaluate an instance of bioaugmentation, namely, the addition of a novel p-nitrophenol (PNP)-degrading bacterium Methylobacterium sp. C1 coaggregated with two other broad-spectrum coaggregating strains (Bacillus megaterium T1 and Bacillus cereus G5) within sequence batch biofilm reactors (SBBRs). Results showed that biofilms consisting of C1 and coaggregating bacteria were resistant to shock loads and were more efficient at PNP removal. High-throughput sequencing data revealed that biofilms formed in the presence of the coaggregating bacteria demonstrated greater microbial diversity. These results suggest that broad-spectrum coaggregating bacteria may be capable of mediating the immobilization of exogenous degrading bacteria into biofilms, rendering them more resistant to toxic compounds and environmental stresses. This represents the first attempt to assess the bioaugmentation of PNP-contaminated wastewater treatment through the utilization of broad-spectrum coaggregating bacteria. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. New insights into broad spectrum communities of the Early Holocene Near East: The birds of Hallan Çemi

    Science.gov (United States)

    Zeder, Melinda A.; Spitzer, Megan D.

    2016-11-01

    The Early Holocene in Near East was a pivotal transitional period that witnessed dramatic changes in climate and environment, human settlement, major changes in subsistence strategies focusing on a broad range of different plant and animal resources, and a radical restructuring of social relations. The remarkable corpus of avifauna from the Early Holocene site of Hallan Çemi in southeastern Turkey sheds new light on key issues about this dynamic period that has been termed the ;Broad Spectrum Revolution;. The avifauna from this important site demonstrate how Hallan Çemi occupants took advantage of the site's strategic location at the junction of multiple environmental zones by extracting a diverse range of seasonally available resources from both near-by and more distant eco-zones to cobble together a stable subsistence economy capable of supporting this small community throughout the year. They give testimony to the impacts of resource utilization over time, especially on species unable to rebound from sustained human hunting. At the same time, they show how Hallan Çemi residents mitigated these impacts by replacing depleted resources with alternative, more resilient ones that could be more sustainably harvested. They open a window onto the growing investment in feasting and ritual activity that helped bind this community together. In so doing they provide a means of empirically evaluating the efficacy of contrasting explanatory frameworks for the Broad Spectrum Revolution that gave rise to the subsequent domestication of plant and animals in the Near East. Contrary to frameworks that cast these developments as responses to resource depression, lessons learned from the Hallan Çemi avifauna lend support to frameworks that emphasize the human capacity to strategically target, capitalize, and improve upon circumscribed resource rich environments in a way that permits more permanent occupation of these niches. And they underscore the degree to which social and

  20. Eggplant Resistance to the Ralstonia solanacearum Species Complex Involves Both Broad-Spectrum and Strain-Specific Quantitative Trait Loci

    Directory of Open Access Journals (Sweden)

    Sylvia Salgon

    2017-05-01

    Full Text Available Bacterial wilt (BW is a major disease of solanaceous crops caused by the Ralstonia solanacearum species complex (RSSC. Strains are grouped into five phylotypes (I, IIA, IIB, III, and IV. Varietal resistance is the most sustainable strategy for managing BW. Nevertheless, breeding to improve cultivar resistance has been limited by the pathogen’s extensive genetic diversity. Identifying the genetic bases of specific and non-specific resistance is a prerequisite to breed improvement. A major gene (ERs1 was previously mapped in eggplant (Solanum melongena L. using an intraspecific population of recombinant inbred lines derived from the cross of susceptible MM738 (S × resistant AG91-25 (R. ERs1 was originally found to control three strains from phylotype I, while being totally ineffective against a virulent strain from the same phylotype. We tested this population against four additional RSSC strains, representing phylotypes I, IIA, IIB, and III in order to clarify the action spectrum of ERs1. We recorded wilting symptoms and bacterial stem colonization under controlled artificial inoculation. We constructed a high-density genetic map of the population using single nucleotide polymorphisms (SNPs developed from genotyping-by-sequencing and added 168 molecular markers [amplified fragment length polymorphisms (AFLPs, simple sequence repeats (SSRs, and sequence-related amplified polymorphisms (SRAPs] developed previously. The new linkage map based on a total of 1,035 markers was anchored on eggplant, tomato, and potato genomes. Quantitative trait locus (QTL mapping for resistance against a total of eight RSSC strains resulted in the detection of one major phylotype-specific QTL and two broad-spectrum QTLs. The major QTL, which specifically controls three phylotype I strains, was located at the bottom of chromosome 9 and corresponded to the previously identified major gene ERs1. Five candidate R-genes were underlying this QTL, with different alleles

  1. The broad-spectrum metalloproteinase inhibitor BB-94 inhibits growth, HER3 and Erk activation in fulvestrant-resistant breast cancer cell lines

    DEFF Research Database (Denmark)

    Kirkegaard, Tove; Yde, Christina Westmose; Kveiborg, Marie

    2014-01-01

    cells. This was prevented by treatment of resistant cells with the metalloproteinase inhibitor TAPI-2. Only the broad-spectrum metalloproteinase inhibitor BB-94, and not the more selective inhibitors GM6001 or TAPI-2, which inhibited shedding of the HER ligands produced by the fulvestrant...... of ligands. Only the broad-spectrum metalloproteinase inhibitor BB-94 could abrogate HER3 and Erk activation in the resistant cells, which stresses the complexity of the resistance mechanisms and the requirement of targeting signaling from HER receptors by multiple strategies....

  2. Sedaxane, Isopyrazam and Solatenol™: Novel Broad-spectrum Fungicides Inhibiting Succinate Dehydrogenase (SDH) - Synthesis Challenges and Biological Aspects.

    Science.gov (United States)

    Walter, Harald; Tobler, Hans; Gribkov, Denis; Corsi, Camilla

    2015-08-19

    Sedaxane (SDX) 1, isopyrazam (IZM) 2 and Solatenol™ (STL) 3 are broad-spectrum pyrazole carboxamides, which originate from novel chemical classes of fungicides. Their mode of action (MoA) is inhibition of succinate dehydrogenase (SDH), which was recognized for a long time to deliver only compounds with a narrow biological spectrum. This view changed with the market introduction of BASF's boscalid in 2003. All major agro-companies subsequently worked in parallel on this MoA successfully and recently introduced new compounds to the market. Syngenta entered the SDHI area in 1998 and was able to introduce three complementary compounds to the market between 2010 and 2012. In this short review some synthesis challenges and biological effects of SDX 1, IZM 2 and STL 3 will be covered. New cost-efficient synthesis strategies for the preparation of o-biscyclopropyl-aniline, new benzonorbornene intermediates and the key pyrazole carboxylic acid intermediate which is essential for all three Syngenta SDHIs, will be in the focus of this review.

  3. Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry.

    Science.gov (United States)

    Lin, Liang-Tzung; Chen, Ting-Ying; Lin, Song-Chow; Chung, Chueh-Yao; Lin, Ta-Chen; Wang, Guey-Horng; Anderson, Robert; Lin, Chun-Ching; Richardson, Christopher D

    2013-08-07

    We previously identified two hydrolyzable tannins, chebulagic acid (CHLA) and punicalagin (PUG) that blocked herpes simplex virus type 1 (HSV-1) entry and spread. These compounds inhibited viral glycoprotein interactions with cell surface glycosaminoglycans (GAGs). Based on this property, we evaluated their antiviral efficacy against several different viruses known to employ GAGs for host cell entry. Extensive analysis of the tannins' mechanism of action was performed on a panel of viruses during the attachment and entry steps of infection. Virus-specific binding assays and the analysis of viral spread during treatment with these compounds were also conducted. CHLA and PUG were effective in abrogating infection by human cytomegalovirus (HCMV), hepatitis C virus (HCV), dengue virus (DENV), measles virus (MV), and respiratory syncytial virus (RSV), at μM concentrations and in dose-dependent manners without significant cytotoxicity. Moreover, the natural compounds inhibited viral attachment, penetration, and spread, to different degrees for each virus. Specifically, the tannins blocked all these steps of infection for HCMV, HCV, and MV, but had little effect on the post-fusion spread of DENV and RSV, which could suggest intriguing differences in the roles of GAG-interactions for these viruses. CHLA and PUG may be of value as broad-spectrum antivirals for limiting emerging/recurring viruses known to engage host cell GAGs for entry. Further studies testing the efficacy of these tannins in vivo against certain viruses are justified.

  4. From Broad-Spectrum Biocides to Quorum Sensing Disruptors and Mussel Repellents: Antifouling Profile of Alkyl Triphenylphosphonium Salts

    Science.gov (United States)

    Martín-Rodríguez, Alberto J.; Babarro, Jose M. F.; Lahoz, Fernando; Sansón, Marta; Martín, Víctor S.; Norte, Manuel; Fernández, José J.

    2015-01-01

    ‘Onium’ compounds, including ammonium and phosphonium salts, have been employed as antiseptics and disinfectants. These cationic biocides have been incorporated into multiple materials, principally to avoid bacterial attachment. In this work, we selected 20 alkyl-triphenylphosphonium salts, differing mainly in the length and functionalization of their alkyl chains, in fulfilment of two main objectives: 1) to provide a comprehensive evaluation of the antifouling profile of these molecules with relevant marine fouling organisms; and 2) to shed new light on their potential applications, beyond their classic use as broad-spectrum biocides. In this regard, we demonstrate for the first time that these compounds are also able to act as non-toxic quorum sensing disruptors in two different bacterial models (Chromobacterium violaceum and Vibrio harveyi) as well as repellents in the mussel Mytilus galloprovincialis. In addition, their inhibitory activity on a fouling-relevant enzymatic model (tyrosinase) is characterized. An analysis of the structure-activity relationships of these compounds for antifouling purposes is provided, which may result useful in the design of targeted antifouling solutions with these molecules. Altogether, the findings reported herein provide a different perspective on the biological activities of phosphonium compounds that is particularly focused on, but, as the reader will realize, is not limited to their use as antifouling agents. PMID:25897858

  5. From broad-spectrum biocides to quorum sensing disruptors and mussel repellents: antifouling profile of alkyl triphenylphosphonium salts.

    Directory of Open Access Journals (Sweden)

    Alberto J Martín-Rodríguez

    Full Text Available 'Onium' compounds, including ammonium and phosphonium salts, have been employed as antiseptics and disinfectants. These cationic biocides have been incorporated into multiple materials, principally to avoid bacterial attachment. In this work, we selected 20 alkyl-triphenylphosphonium salts, differing mainly in the length and functionalization of their alkyl chains, in fulfilment of two main objectives: 1 to provide a comprehensive evaluation of the antifouling profile of these molecules with relevant marine fouling organisms; and 2 to shed new light on their potential applications, beyond their classic use as broad-spectrum biocides. In this regard, we demonstrate for the first time that these compounds are also able to act as non-toxic quorum sensing disruptors in two different bacterial models (Chromobacterium violaceum and Vibrio harveyi as well as repellents in the mussel Mytilus galloprovincialis. In addition, their inhibitory activity on a fouling-relevant enzymatic model (tyrosinase is characterized. An analysis of the structure-activity relationships of these compounds for antifouling purposes is provided, which may result useful in the design of targeted antifouling solutions with these molecules. Altogether, the findings reported herein provide a different perspective on the biological activities of phosphonium compounds that is particularly focused on, but, as the reader will realize, is not limited to their use as antifouling agents.

  6. Chitosan hydrogels embedding hyper-crosslinked polymer particles as reusable broad-spectrum adsorbents for dye removal.

    Science.gov (United States)

    Salzano de Luna, Martina; Castaldo, Rachele; Altobelli, Rosaria; Gioiella, Lucia; Filippone, Giovanni; Gentile, Gennaro; Ambrogi, Veronica

    2017-12-01

    The removal of dye and toxic ionic pollutants from water is an extremely important issue that requires systematic and efficient adsorbent preparation strategies. To address this challenge, we developed composite chitosan (CS)-based hydrogels containing hyper-crosslinked polymer (HCP) particles to be used as broad-spectrum adsorbents. The goal is to efficiently combine the dye adsorption ability of chitosan and the capacity of the porous particles of trapping pollutant molecules. The HCP particles are well distributed and firmly embedded into the chitosan matrix and the composite hydrogels exhibit improved mechanical properties. Adsorption experiments reveal a synergistic effect between CS and HCP particles, and the samples are able to remove both anionic and cationic dyes (indigo carmine, rhodamine 6G and sunset yellow) from water. The maximum dye uptake is higher than that of comparable biosorbents. Moreover, the mechanical properties of the composite hydrogels are enhanced respect to pure CS, and the samples can be regenerated and reused keeping their adsorption ability unaltered over successive cycles of adsorption, desorption, and washing. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset.

    Science.gov (United States)

    Safronetz, David; Rosenke, Kyle; Westover, Jonna B; Martellaro, Cynthia; Okumura, Atsushi; Furuta, Yousuke; Geisbert, Joan; Saturday, Greg; Komeno, Takashi; Geisbert, Thomas W; Feldmann, Heinz; Gowen, Brian B

    2015-10-12

    With up to 500,000 infections annually, Lassa virus (LASV), the cause of Lassa fever, is one of the most prevalent etiological agents of viral hemorrhagic fever (VHF) in humans. LASV is endemic in several West African countries with sporadic cases and prolonged outbreaks observed most commonly in Sierra Leone, Liberia, Guinea and Nigeria. Additionally several cases of Lassa fever have been imported into North America, Europe and Asia making LASV a global threat to public health. Despite this, currently no approved therapeutic or vaccine exists to treat or prevent LASV infections. Here, using a passaged strain of LASV that is uniformly lethal in Hartley guinea pigs, we demonstrate that favipiravir, a broad-spectrum antiviral agent and leading treatment option for influenza, has potent activity against LASV infection. In this model, once daily treatment with favipiravir significantly reduced viral titers in tissue samples and reduced mortality rates when compared with animals receiving vehicle-only or ribavirin, the current standard of care for Lassa fever. Favipiravir remained highly effective against lethal LASV infection when treatments were initiated nine days post-infection, a time when animals were demonstrating advanced signs of disease. These results support the further preclinical evaluation of favipiravir for Lassa fever and other VHFs.

  8. Endophytic Paraconiothyrium sp. from Zingiber officinale Rosc. Displays Broad-Spectrum Antimicrobial Activity by Production of Danthron.

    Science.gov (United States)

    Anisha, C; Sachidanandan, P; Radhakrishnan, E K

    2017-11-03

    The bioactivity spectrum of fungal endophytes isolated from Zingiber officinale was analyzed against clinical pathogens and against the phytopathogen Pythium myriotylum, which causes Pythium rot in ginger. One of the isolates GFM13 showed broad bioactivity against various pathogens tested including P. myriotylum. The spore suspension as well as the culture filtrate of the endophytic fungal isolate was found to effectively protect ginger rhizomes from Pythium rot. By molecular identification, the fungal endophyte was identified as Paraconiothyrium sp. The bioactive compound produced by the isolate was separated by bioactivity-guided fractionation and was identified by GC-MS as danthron, an anthraquinone derivative. PCR amplification showed the presence of non-reducing polyketide synthase gene (NR-PKS) in the endophyte GFM13, which is reported to be responsible for the synthesis of anthraquinones in fungi. This is the first report of danthron being produced as the biologically active component of Paraconiothyrium sp. Danthron is reported to have wide pharmaceutical and agronomic applications which include its use as a fungicide in agriculture. The broad-spectrum antimicrobial activity of danthron and the endophytic origin of Paraconiothyrium sp. offer immense applications of the study.

  9. From broad-spectrum biocides to quorum sensing disruptors and mussel repellents: antifouling profile of alkyl triphenylphosphonium salts.

    Science.gov (United States)

    Martín-Rodríguez, Alberto J; Babarro, Jose M F; Lahoz, Fernando; Sansón, Marta; Martín, Víctor S; Norte, Manuel; Fernández, José J

    2015-01-01

    'Onium' compounds, including ammonium and phosphonium salts, have been employed as antiseptics and disinfectants. These cationic biocides have been incorporated into multiple materials, principally to avoid bacterial attachment. In this work, we selected 20 alkyl-triphenylphosphonium salts, differing mainly in the length and functionalization of their alkyl chains, in fulfilment of two main objectives: 1) to provide a comprehensive evaluation of the antifouling profile of these molecules with relevant marine fouling organisms; and 2) to shed new light on their potential applications, beyond their classic use as broad-spectrum biocides. In this regard, we demonstrate for the first time that these compounds are also able to act as non-toxic quorum sensing disruptors in two different bacterial models (Chromobacterium violaceum and Vibrio harveyi) as well as repellents in the mussel Mytilus galloprovincialis. In addition, their inhibitory activity on a fouling-relevant enzymatic model (tyrosinase) is characterized. An analysis of the structure-activity relationships of these compounds for antifouling purposes is provided, which may result useful in the design of targeted antifouling solutions with these molecules. Altogether, the findings reported herein provide a different perspective on the biological activities of phosphonium compounds that is particularly focused on, but, as the reader will realize, is not limited to their use as antifouling agents.

  10. Structure activity relationship of pyridoxazinone substituted RHS analogs of oxabicyclooctane-linked 1,5-naphthyridinyl novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-6).

    Science.gov (United States)

    Singh, Sheo B; Kaelin, David E; Wu, Jin; Miesel, Lynn; Tan, Christopher M; Meinke, Peter T; Olsen, David B; Lagrutta, Armando; Wei, Changqing; Liao, Yonggang; Peng, Xuanjia; Wang, Xiu; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Yajima, Masanobu; Shibue, Taku; Shibata, Takeshi; Ohata, Kohei; Nishimura, Akinori; Fukuda, Yasumichi

    2015-09-01

    Oxabicyclooctane linked 1,5-naphthyridinyl-pyridoxazinones are novel broad-spectrum bacterial topoisomerase inhibitors (NBTIs) targeting bacterial DNA gyrase and topoisomerase IV at a site different than quinolones. Due to lack of cross-resistance to known antibiotics they present excellent opportunity to combat drug-resistant bacteria. A structure activity relationship of the pyridoxazinone moiety is described in this Letter. Chemical synthesis and activities of NBTIs with substitutions at C-3, C-4 and C-7 of the pyridoxazinone moiety with halogens, alkyl groups and methoxy group has been described. In addition, substitutions of the linker NH proton and its transformation into amide analogs of AM-8085 and AM-8191 have been reported. Fluoro, chloro, and methyl groups at C-3 of the pyridoxazinone moiety retained the potency and spectrum. In addition, a C-3 fluoro analog showed 4-fold better oral efficacy (ED50 3.9 mg/kg) as compared to the parent AM-8085 in a murine bacteremia model of infection of Staphylococcus aureus. Even modest polarity (e.g., methoxy) is not tolerated at C-3 of the pyridoxazinone unit. The basicity and NH group of the linker is important for the activity when CH2 is at the linker position-8. However, amides (with linker position-8 ketone) with a position-7 NH or N-methyl group retained potency and spectrum suggesting that neither basicity nor hydrogen-donor properties of the linker amide NH is essential for the activity. This would suggest likely an altered binding mode of the linker position-7,8 amide containing compounds. The amides showed highly improved hERG (functional IC50 >30 μM) profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. In vitro and clinical evaluation of SIG1273: a cosmetic functional ingredient with a broad spectrum of anti-aging and antioxidant activities.

    Science.gov (United States)

    Fernández, José R; Rouzard, Karl; Voronkov, Michael; Huber, Kristen L; Webb, Corey; Stock, Jeffry B; Stock, Maxwell; Gordon, Joel S; Pérez, Eduardo

    2016-06-01

    Isoprenylcysteine (IPC) small molecules were identified as a new class of anti-inflammatory compounds over 20 years ago. Since then, they have been developed as novel cosmetic functional ingredients (CFI) and topical drug candidates. SIG1273 is a second generation CFI that has previously been shown to provide a broad spectrum of benefits for the skin through its anti-inflammatory and antimicrobial properties. To determine whether SIG1273 possesses anti-aging properties in vitro and evaluate the tolerability and activity of SIG1273 when applied topically to human subjects. To model photoaging in vitro, human dermal fibroblasts (HDFs) were exposed in culture to UVA to induce collagenase (MMP-1) production. An in vitro wound-healing model was based on the activation of HDF migration into cell-free tissue culture surface. Hydrogen peroxide-induced oxidative stress was performed using HDFs to measure intracellular ROS activity. Radical scavenging capacity was determined using a colorimetric antioxidant assay kit (ABTS method). Lastly, a 4-week, 29-subject study was performed in which SIG1273 was applied topically as a cream to assess its tolerance and activity in reducing the appearance of aging. In vitro studies demonstrate SIG1273 inhibits UVA-induced MMP-1 production, hydrogen peroxide-induced oxidative stress and promotes wound healing. Moreover, SIG1273 was shown to be a radical scavenging antioxidant. Clinical assessment of SIG1273 cream (0.25%) showed it was well tolerated with significant improvement in the appearance of fine lines, coarse wrinkles, radiance/luminosity, pore size, texture/smoothness, hydration and increased firmness. SIG1273 represents a novel CFI with antioxidant, anti-aging, and anti-inflammatory properties that when applied topically is well tolerated and provides benefits to individuals with aging skin. © 2016 Wiley Periodicals, Inc.

  12. Durable broad-spectrum powdery mildew resistance in pea er1 plants is conferred by natural loss-of-function mutations in PsMLO1

    NARCIS (Netherlands)

    Humphry, M.; Reinstädler, A.; Ivanov, S.; Bisseling, T.; Panstruga, R.

    2011-01-01

    Loss-of-function alleles of plant-specific MLO (Mildew Resistance Locus O) genes confer broad-spectrum powdery mildew resistance in monocot (barley) and dicot (Arabidopsis thaliana, tomato) plants. Recessively inherited powdery mildew resistance in pea (Pisum sativum) er1 plants is, in many aspects,

  13. Naturally occurring broad-spectrum powdery mildw resistance in a central American tomato accession is caused by loss of Mlo function

    NARCIS (Netherlands)

    Bai, Y.; Pavan, S.N.C.; Zheng, Z.; Zappel, N.F.; Reinstadler, A.; Lotti, C.; Giovanni, de C.; Ricciardi, L.; Lindhout, P.; Visser, R.G.F.; Theres, K.; Panstruga, R.

    2008-01-01

    The resistant cherry tomato (Solanum lycopersicum var. cerasiforme) line LC-95, derived from an accession collected in Ecuador, harbors a natural allele (ol-2) that confers broad-spectrum and recessively inherited resistance to powdery mildew (Oidium neolycopersici). As both the genetic and

  14. Comparison of nitroethane, 2-nitro-1-propanol, lauric acid, Lauricidin and the Hawaiian marine algae, Chaetoceros, for potential broad-spectrum control of anaerobically grown lactic acid bacteria

    Science.gov (United States)

    The gastrointestinal tract of bovines often contains bacteria that contribute to disorders of the rumen and may also contain foodborne or opportunistic human pathogens as well as bacteria capable of causing mastitis in cows. Thus, there is a need to develop broad-spectrum therapies that are effecti...

  15. Draft Genome Sequence of Streptomyces sp. Strain Wb2n-11, a Desert Isolate with Broad-Spectrum Antagonism against Soilborne Phytopathogens

    Energy Technology Data Exchange (ETDEWEB)

    Köberl, Martina; White, Richard A.; Erschen, Sabine; El-Arabi, Tarek F.; Jansson, Janet K.; Berg, Gabriele

    2015-08-06

    Streptomyces sp. strain Wb2n-11, isolated from native desert soil, exhibited broad-spectrum antagonism against plant pathogenic fungi, bacteria and nematodes. The 8.2 Mb draft genome reveals genes putatively responsible for its promising biocontrol activity and genes which enable the soil bacterium to directly interact beneficially with plants.

  16. Characterization of the UVA protection provided by avobenzone, zinc oxide, and titanium dioxide in broad-spectrum sunscreen products.

    Science.gov (United States)

    Beasley, Donathan G; Meyer, Thomas A

    2010-12-01

    Solar UV radiation (UVR) is composed of UVB (290-320 nm) and UVA (320-400 nm) wavelengths. Only two sunscreen active ingredients approved in the US, avobenzone (butylmethoxydibenzoylmethane) and zinc oxide (ZnO), provide true broad-spectrum protection against UVA wavelengths >360 nm. Although effective against shorter UVR wavelengths sunscreen film during UVR exposure, avobenzone needs to be formulated into sunscreen products using sound formulation strategies. To characterize the efficacy of avobenzone, ZnO, and TiO(2) in terms of their abilities to provide broad UVA protection and to demonstrate the effectiveness of the different formulation strategies used today to maintain the efficacy of avobenzone even during prolonged exposures to UVR. UVA efficacy was assessed by measuring absorbance profiles in vitro using Vitro Skin® (IMS Inc., Orange, CT, USA) as an inert substrate and by determining UVA protection factors (PFA) on human skin. The impact of avobenzone loss on sun protection factor (SPF) and PFA values was evaluated by serially reducing avobenzone concentrations in an otherwise photostable product. The photostabilizing influence of specific formulation ingredients was monitored by measuring the extent to which they prevented UVR-induced degradation of avobenzone, whereas photostability of commercial sunscreen products was quantified by measuring the percentage change in absorbance within the UVB and UVA spectral regions following irradiation of thin product films on inert substrates. Model formulations containing 3% avobenzone or 5% ZnO provided superior attenuation of UVA wavelengths >360 nm compared with formulas containing 5% TiO(2). Additionally, sunscreen products of similar SPF containing avobenzone or ZnO exhibited significantly higher PFA values than those containing TiO(2). The addition of photostabilized avobenzone or ZnO increased PFA values nearly 3-fold, whereas the addition of TiO(2) increased PFA values only modestly. Judicious

  17. Broad-spectrum antiviral activity including human immunodeficiency and hepatitis C viruses mediated by a novel retinoid thiosemicarbazone derivative.

    Science.gov (United States)

    Kesel, Andreas J

    2011-05-01

    Aromatic aldehyde-derived thiosemicarbazones 4-6, the S-substituted modified thiosemicarbazones 7/8, and a vitamin A-derived (retinoid) thiosemicarbazone derivative 12 were investigated as inhibitors of human hepatitis C virus (HCV) subgenomic RNA replicon Huh7 ET (luc-ubi-neo/ET) replication. Compounds 4-6 and 12 were found to be potent suppressors of HCV RNA replicon replication. The trifluoromethoxy-substituted thiosemicarbazone 6 and the retinoid thiosemicarbazone derivative 12 were even superior in selectivity to the included reference agent recombinant human alpha-interferon-2b, showing potencies in the nanomolar range of concentration. In addition, compounds 5, 6, 8 and 12 were tested as inhibitors of cytopathic effect (CPE) induced by human varicella-zoster virus (VZV) and/or human cytomegalovirus (HCMV). Compounds 4-6, 8 and 12 were additionally examined as inhibitors of CPE induced by cowpox virus and vaccinia virus. Thiosemicarbazone 4 was inhibitory on cowpox and vaccinia virus replication comparable in potency and selectivity to the reference agent cidofovir. Retinoid thiosemicarbazone derivative 12 was active as micromolar inhibitor of VZV, HCMV, and, in addition, human immunodeficiency virus type 1 (HIV-1) replication. These results indicate that thiosemicarbazone derivatives are appropriate lead structures to be evaluated in targeted antiviral therapies for hepatitis C (STAT-C), and that the vitamin A-related thiosemicarbazone derivative 12 emerges as a broad-spectrum antiviral agent, co-suppressing the multiplication of important RNA and DNA viruses. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  18. Broad spectrum infrared thermal desorption of wipe-based explosive and narcotic samples for trace mass spectrometric detection.

    Science.gov (United States)

    Forbes, Thomas P; Staymates, Matthew; Sisco, Edward

    2017-08-07

    Wipe collected analytes were thermally desorbed using broad spectrum near infrared heating for mass spectrometric detection. Employing a twin tube filament-based infrared emitter, rapid and efficiently powered thermal desorption and detection of nanogram levels of explosives and narcotics was demonstrated. The infrared thermal desorption (IRTD) platform developed here used multi-mode heating (direct radiation and secondary conduction from substrate and subsequent convection from air) and a temperature ramp to efficiently desorb analytes with vapor pressures across eight orders of magnitude. The wipe substrate experienced heating rates up to (85 ± 2) °C s(-1) with a time constant of (3.9 ± 0.2) s for 100% power emission. The detection of trace analytes was also demonstrated from complex mixtures, including plastic-bonded explosives and exogenous narcotics, explosives, and metabolites from collected artificial latent fingerprints. Manipulation of the emission power and duration directly controlled the heating rate and maximum temperature, enabling differential thermal desorption and a level of upstream separation for enhanced specificity. Transitioning from 100% power and 5 s emission duration to 25% power and 30 s emission enabled an order of magnitude increase in the temporal separation (single seconds to tens of seconds) of the desorption of volatile and semi-volatile species within a collected fingerprint. This mode of operation reduced local gas-phase concentrations, reducing matrix effects experienced with high concentration mixtures. IRTD provides a unique platform for the desorption of trace analytes from wipe collections, an area of importance to the security sector, transportation agencies, and customs and border protection.

  19. Inhibition of an aquatic rhabdovirus demonstrates promise of a broad-spectrum antiviral for use in aquaculture

    Science.gov (United States)

    Balmer, Bethany F.; Powers, Rachel L.; Zhang, Ting-Hu; Lee, Jihye; Vigant, Frederic; Lee, Benhur; Jung, Michael E.; Purcell, Maureen K.; Snekvik, Kevin; Aguilar, Hector C.

    2017-01-01

    Many enveloped viruses cause devastating disease in aquaculture, resulting in significant economic impact. LJ001 is a broad-spectrum antiviral compound that inhibits enveloped virus infections by specifically targeting phospholipids in the lipid bilayer via the production of singlet oxygen (1O2). This stabilizes positive curvature and decreases membrane fluidity, which inhibits virus-cell membrane fusion during viral entry. Based on data from previous mammalian studies and the requirement of light for the activation of LJ001, we hypothesized that LJ001 may be useful as a preventative and/or therapeutic agent for infections by enveloped viruses in aquaculture. Here, we report that LJ001 was more stable with a prolonged inhibitory half-life at relevant aquaculture temperatures (15°C), than in mammalian studies at 37°C. When LJ001 was preincubated with our model virus, infectious hematopoietic necrosis virus (IHNV), infectivity was significantly inhibited in vitro (using the epithelioma papulosum cyprini [EPC] fish cell line) and in vivo (using rainbow trout fry) in a dose-dependent and time-dependent manner. While horizontal transmission of IHNV in a static cohabitation challenge model was reduced by LJ001, transmission was not completely blocked at established antiviral doses. Therefore, LJ001 may be best suited as a therapeutic for aquaculture settings that include viral infections with lower virus-shedding rates than IHNV or where higher viral titers are required to initiate infection of naive fish. Importantly, our data also suggest that LJ001-inactivated IHNV elicited an innate immune response in the rainbow trout host, making LJ001 potentially useful for future vaccination approaches.

  20. GLD-2/RNP-8 cytoplasmic poly(A) polymerase is a broad-spectrum regulator of the oogenesis program

    Science.gov (United States)

    Wilson, Tracy L.; Kimble, Judith

    2010-01-01

    Regulated polyadenylation is a broadly conserved mechanism that controls key events during oogenesis. Pivotal to that mechanism is GLD-2, a catalytic subunit of cytoplasmic poly(A) polymerase (PAP). Caenorhabditis elegans GLD-2 forms an active PAP with multiple RNA-binding partners to regulate diverse aspects of germline and early embryonic development. One GLD-2 partner, RNP-8, was previously shown to influence oocyte fate specification. Here we use a genomic approach to identify transcripts selectively associated with both GLD-2 and RNP-8. Among the 335 GLD-2/RNP-8 potential targets, most were annotated as germline mRNAs and many as maternal mRNAs. These targets include gld-2 and rnp-8 themselves, suggesting autoregulation. Removal of either GLD-2 or RNP-8 resulted in shortened poly(A) tails and lowered abundance of four target mRNAs (oma-2, egg-1, pup-2, and tra-2); GLD-2 depletion also lowered the abundance of most GLD-2/RNP-8 putative target mRNAs when assayed on microarrays. Therefore, GLD-2/RNP-8 appears to polyadenylate and stabilize its target mRNAs. We also provide evidence that rnp-8 influences oocyte development; rnp-8 null mutants have more germ cell corpses and fewer oocytes than normal. Furthermore, RNP-8 appears to work synergistically with another GLD-2–binding partner, GLD-3, to ensure normal oogenesis. We propose that the GLD-2/RNP-8 enzyme is a broad-spectrum regulator of the oogenesis program that acts within an RNA regulatory network to specify and produce fully functional oocytes. PMID:20855596

  1. Baulamycins A and B, broad-spectrum antibiotics identified as inhibitors of siderophore biosynthesis in Staphylococcus aureus and Bacillus anthracis.

    Science.gov (United States)

    Tripathi, Ashootosh; Schofield, Michael M; Chlipala, George E; Schultz, Pamela J; Yim, Isaiah; Newmister, Sean A; Nusca, Tyler D; Scaglione, Jamie B; Hanna, Philip C; Tamayo-Castillo, Giselle; Sherman, David H

    2014-01-29

    Siderophores are high-affinity iron chelators produced by microorganisms and frequently contribute to the virulence of human pathogens. Targeted inhibition of the biosynthesis of siderophores staphyloferrin B of Staphylococcus aureus and petrobactin of Bacillus anthracis hold considerable potential as a single or combined treatment for methicillin-resistant S. aureus (MRSA) and anthrax infection, respectively. The biosynthetic pathways for both siderophores involve a nonribosomal peptide synthetase independent siderophore (NIS) synthetase, including SbnE in staphyloferrin B and AsbA in petrobactin. In this study, we developed a biochemical assay specific for NIS synthetases to screen for inhibitors of SbnE and AsbA against a library of marine microbial-derived natural product extracts (NPEs). Analysis of the NPE derived from Streptomyces tempisquensis led to the isolation of the novel antibiotics baulamycins A (BmcA, 6) and B (BmcB, 7). BmcA and BmcB displayed in vitro activity with IC50 values of 4.8 μM and 19 μM against SbnE and 180 μM and 200 μM against AsbA, respectively. Kinetic analysis showed that the compounds function as reversible competitive enzyme inhibitors. Liquid culture studies with S. aureus , B. anthracis , E. coli , and several other bacterial pathogens demonstrated the capacity of these natural products to penetrate bacterial barriers and inhibit growth of both Gram-positive and Gram-negative species. These studies provide proof-of-concept that natural product inhibitors targeting siderophore virulence factors can provide access to novel broad-spectrum antibiotics, which may serve as important leads for the development of potent anti-infective agents.

  2. Identification and growth optimization of a Marine Bacillus DK1-SA11 having potential of producing broad spectrum antimicrobial compounds.

    Science.gov (United States)

    Khan, Muhammad Naseem; Lin, Hong; Li, Meng; Wang, Jingxue; Mirani, Zulfiqar Ali; Khan, Seema Ismat; Buzdar, Muhammad Aslam; Ali, Imran; Jamil, Khalid

    2017-05-01

    Control of harmful bacteria in food, aquaculture, pharmaceuticals, agriculture, hospitals and recreation water pools are of great global concern. Marine bacteria are an enormous source of bio-controlling agents. The aim of this study was to identify and optimize the growth conditions including effect of different biotic and abiotic factors on antimicrobial activity of strain DK1-SA11 isolated from Qingdao Bay of China Yellow Sea. Microscopic characterization, API® 20E and 50 CHB kit base carbohydrates utilization, 16S rDNA and DNA gyrB gene sequencing studies identified the bacterium as Bacillus subtilis subsp. spizizenii DK1-SA11. Antimicrobial spectrum of cell free supernatant (CFS) has shown antimicrobial activities against all test strains including methicillin-resistant Staphylococcus aureus, E. coli O157:H7, Candida albicans, Klebsiella pneumoniae, Listeria monocytogenes, Vibrio parahaemolyticus, E. coli, Pseudomonas fluorescens, Salmonella typhimurium and Vibrio cholerae. Among all the media tested, Marine Broth 2216 was found to be the best medium for bacterial growth and production of antibacterial compounds. The other optimum conditions for growth were pH:7 and incubation temperature: 25°C with tested, D-mannose increases the antibacterial activity by 33.3% while D-arabitol decreases it by 44.4%. Crude CFS showed activity even after three months of storage below -20°C and boiling for 10 min, whereas it loses 100% of its antimicrobial activity after enzymatic treatments of lipase, trypsin and papain. The production of antimicrobial compounds and broad spectrum of antimicrobial activity against all tested pathogens suggested that the strain DK1-SA11 can be used as a source for probiotics, synbiotics and antibiotics.

  3. Competition between Phytophthora infestans effectors leads to increased aggressiveness on plants containing broad-spectrum late blight resistance.

    Directory of Open Access Journals (Sweden)

    Dennis A Halterman

    Full Text Available BACKGROUND: The destructive plant disease potato late blight is caused by the oomycete pathogen Phytophthora infestans (Mont. de Bary. This disease has remained particularly problematic despite intensive breeding efforts to integrate resistance into cultivated potato, largely because of the pathogen's ability to quickly evolve to overcome major resistance genes. The RB gene, identified in the wild potato species S. bulbocastanum, encodes a protein that confers broad-spectrum resistance to most P. infestans isolates through its recognition of highly conserved members of the corresponding pathogen effector family IPI-O. IpiO is a multigene family of effectors and while the majority of IPI-O proteins are recognized by RB to elicit host resistance, some variants exist that are able to elude detection (e.g. IPI-O4. METHODS AND FINDINGS: In the present study, analysis of ipiO variants among 40 different P. infestans isolates collected from Guatemala, Thailand, and the United States revealed a high degree of complexity within this gene family. Isolate aggressiveness was correlated with increased ipiO diversity and especially the presence of the ipiO4 variant. Furthermore, isolates expressing IPI-O4 overcame RB-mediated resistance in transgenic potato plants even when the resistance-eliciting IPI-O1 variant was present. In support of this finding, we observed that expression of IPI-O4 via Agrobacterium blocked recognition of IPI-O1, leading to inactivation of RB-mediated programmed cell death in Nicotiana benthamiana. CONCLUSIONS: In this study we definitively demonstrate and provide the first evidence that P. infestans can defeat an R protein through inhibition of recognition of the corresponding effector protein.

  4. Papel de los fármacos antiepilépticos genéricos en el tratamiento de la epilepsia infantil Role of generic antiepileptic drugs in the treatment of childhood epilepsy

    Directory of Open Access Journals (Sweden)

    Jaime Campos-Castelló

    2009-01-01

    Full Text Available La aparición de fármacos genéricos en el mercado, en sustitución de marcas registradas®, y las adecuadas regulaciones de las autoridades sanitarias en los distintos países ha condicionado hasta la actualidad una polémica sobre el riesgo costo/beneficio de tal sustitución en el paciente afecto de epilepsia. El binomio costo/beneficio debe dar por demostrado de manera clara que el paciente puede beneficiarse de tal sustitución sin correr riesgo alguno significativo. Por ello se valoran los distintos aportes en la literatura médica al respecto, que analizan estos riesgos y beneficios y en especial el hecho esencial de la bioequivalencia de ambas formulaciones, en especial en las situaciones de aquellos fármacos antiepilépticos de margen o índice terapéutico estrecho que hagan inviable la equivalencia de la biodisponibilidad del fármaco, la ausencia de repercusión clínica real en el paciente así como la evidencia que existe un beneficio económico claro al valorar el citado binomio riesgo/beneficio. La revisión efectuada señala la clara existencia de desventajas potenciales del cambio de un fármaco antiepiléptico (FAE original de marca a un genérico como: distinta biodisponibilidad, bioequivalencia no demostrada, riesgo de reaparición de crisis en pacientes controlados y variabilidad de la respuesta de los FAE en el paciente epiléptico, imposible de predecir. Por ello se aconseja valorar la importancia de un fracaso terapéutico tras un cambio a genérico, en especial en casos de margen terapéutico estrecho, la biodisponibilidad permisible con valoración de la variabilidad individual del paciente, situación médico-legal de tal cambio y la realidad de los ahorros y costos potenciales derivados.The use of generic instead of trade mark antiepileptic drugs raises the question of cost/benefit risks. The efficacy and side effects of the generic AED should be similar to the trade mark drugs. Otherwise, the substitution is not

  5. Drug: D00536 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00536 Drug Felbamate (USAN/INN); Felbatol (TN) C11H14N2O4 238.0954 238.2399 D00536.gif Antiepileptic...8303] N NERVOUS SYSTEM N03 ANTIEPILEPTICS N03A ANTIEPILEPTICS N03AX Other antiepileptic

  6. Switching to generic anti-epileptic medicines : A regulatory perspective

    NARCIS (Netherlands)

    Maliepaard, Marc; Hekster, Yechiel A.; Kappelle, Arnoud; Van Puijenbroek, Eugène P.; Elferink, André J.; Welink, Jan; Gispen-de Wied, Christine C.; Lekkerkerker, Frits J.F.

    2010-01-01

    Introduction: Currently, there is a lot of discussion about whether generic substitution of anti-epileptic drugs (AEDs) with the same active moiety but from different manufacturers can take place safely. Many AEDs are considered to have a narrow therapeutic index, and the consequences of an

  7. New antiepileptic therapies.

    Science.gov (United States)

    Ozuna, J

    1997-04-01

    This is an exciting time for AED development. Four new AEDs have been approved for use in the last 3 years and several more are being evaluated. New formulations of traditional therapies, such as Tegretol XR, and IV and IM fosphenytoin offer alternatives for the management of acute and chronic seizure disorders (see "Clip & Save" and "What's News"). With these new treatments options, providers will be challenged to choose the most appropriate drug or drug combination for their patients based on seizure type, AED mechanisms of action, pharmacokinetic properties, adverse effects, and drug interactions.

  8. Pharmacogenetic evaluation of ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase polymorphisms in teratogenicity of anti-epileptic drugs in women with epilepsy

    Directory of Open Access Journals (Sweden)

    Manna Jose

    2014-01-01

    Full Text Available Aim: Pregnancy in women with epilepsy (WWE who are on anti-epileptic drugs (AEDs has two- to three-fold increased risk of fetal malformations. AEDs are mostly metabolized by Cyp2C9, Cyp2C19 and Cyp3A4 and transported by ABCB1. Patients on AED therapy can have folate deficiency. We hypothesize that the polymorphisms in ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase (MTHFR might result in differential expression resulting in differential drug transport, drug metabolism and folate metabolism, which in turn may contribute to the teratogenic impact of AEDs. Materials and Methods: The ABCB1, Cyp2C9, Cyp2C19 and MTHFR polymorphisms were genotyped for their role in teratogenic potential and the nature of teratogenecity in response to AED treatment in WWE. The allelic, genotypic associations were tested in 266 WWE comprising of 143 WWE who had given birth to babies with WWE-malformation (WWE-M and 123 WWE who had normal offsprings (WWE-N. Results: In WWE-M, CC genotype of Ex07 + 139C/T was overrepresented (P = 0.0032 whereas the poor metabolizer allele FNx012 and FNx012 FNx012 genotype of CYP2C219 was significantly higher in comparison to WWE-N group (P = 0.007 and P = 0.005, respectively. All these observations were independent of the nature of malformation (cardiac vs. non cardiac malformations. Conclusion: Our study indicates the possibility that ABCB1 and Cyp2C19 may play a pivotal role in the AED induced teratogenesis, which is independent of nature of malformation. This is one of the first reports indicating the pharmacogenetic role of Cyp2C19 and ABCB1 in teratogenesis of AED in pregnant WWE.

  9. Co-administration of the broad-spectrum antiviral, brincidofovir (CMX001), with smallpox vaccine does not compromise vaccine protection in mice challenged with ectromelia virus.

    Science.gov (United States)

    Parker, Scott; Crump, Ryan; Foster, Scott; Hartzler, Hollyce; Hembrador, Ed; Lanier, E Randall; Painter, George; Schriewer, Jill; Trost, Lawrence C; Buller, R Mark

    2014-11-01

    Natural orthopoxvirus outbreaks such as vaccinia, cowpox, cattlepox and buffalopox continue to cause morbidity in the human population. Monkeypox virus remains a significant agent of morbidity and mortality in Africa. Furthermore, monkeypox virus's broad host-range and expanding environs make it of particular concern as an emerging human pathogen. Monkeypox virus and variola virus (the etiological agent of smallpox) are both potential agents of bioterrorism. The first line response to orthopoxvirus disease is through vaccination with first-generation and second-generation vaccines, such as Dryvax and ACAM2000. Although these vaccines provide excellent protection, their widespread use is impeded by the high level of adverse events associated with vaccination using live, attenuated virus. It is possible that vaccines could be used in combination with antiviral drugs to reduce the incidence and severity of vaccine-associated adverse events, or as a preventive in individuals with uncertain exposure status or contraindication to vaccination. We have used the intranasal mousepox (ectromelia) model to evaluate the efficacy of vaccination with Dryvax or ACAM2000 in conjunction with treatment using the broad spectrum antiviral, brincidofovir (BCV, CMX001). We found that co-treatment with BCV reduced the severity of vaccination-associated lesion development. Although the immune response to vaccination was quantifiably attenuated, vaccination combined with BCV treatment did not alter the development of full protective immunity, even when administered two days following ectromelia challenge. Studies with a non-replicating vaccine, ACAM3000 (MVA), confirmed that BCV's mechanism of attenuating the immune response following vaccination with live virus was, as expected, by limiting viral replication and not through inhibition of the immune system. These studies suggest that, in the setting of post-exposure prophylaxis, co-administration of BCV with vaccination should be considered

  10. Identification of a broad-spectrum antiviral small molecule against severe acute respiratory syndrome coronavirus and Ebola, Hendra, and Nipah viruses by using a novel high-throughput screening assay.

    Science.gov (United States)

    Elshabrawy, Hatem A; Fan, Jilao; Haddad, Christine S; Ratia, Kiira; Broder, Christopher C; Caffrey, Michael; Prabhakar, Bellur S

    2014-04-01

    Severe acute respiratory syndrome coronavirus (SARS-CoV) and Ebola, Hendra, and Nipah viruses are members of different viral families and are known causative agents of fatal viral diseases. These viruses depend on cathepsin L for entry into their target cells. The viral glycoproteins need to be primed by protease cleavage, rendering them active for fusion with the host cell membrane. In this study, we developed a novel high-throughput screening assay based on peptides, derived from the glycoproteins of the aforementioned viruses, which contain the cathepsin L cleavage site. We screened a library of 5,000 small molecules and discovered a small molecule that can inhibit the cathepsin L cleavage of all viral peptides with minimal inhibition of cleavage of a host protein-derived peptide (pro-neuropeptide Y). The small molecule inhibited the entry of all pseudotyped viruses in vitro and the cleavage of SARS-CoV spike glycoprotein in an in vitro cleavage assay. In addition, the Hendra and Nipah virus fusion glycoproteins were not cleaved in the presence of the small molecule in a cell-based cleavage assay. Furthermore, we demonstrate that the small molecule is a mixed inhibitor of cathepsin L. Our broad-spectrum antiviral small molecule appears to be an ideal candidate for future optimization and development into a potent antiviral against SARS-CoV and Ebola, Hendra, and Nipah viruses. We developed a novel high-throughput screening assay to identify small molecules that can prevent cathepsin L cleavage of viral glycoproteins derived from SARS-CoV and Ebola, Hendra, and Nipah viruses that are required for their entry into the host cell. We identified a novel broad-spectrum small molecule that could block cathepsin L-mediated cleavage and thus inhibit the entry of pseudotypes bearing the glycoprotein derived from SARS-CoV or Ebola, Hendra, or Nipah virus. The small molecule can be further optimized and developed into a potent broad-spectrum antiviral drug.

  11. Effect of healthcare associated infections and broad spectrum antibiotic use in newborn period on development of asthma, allergic rhinitis and atopic dermatitis in early childhood

    Directory of Open Access Journals (Sweden)

    Hacer Yapicioglu Yildizdas

    2017-03-01

    Full Text Available Purpose: The iam of this study was to investigate the effect of healthcare associated infections (HAIs and broad spectrum antibiotic use in newborn period on asthma, allergic rhinitis and atopic dermatitis. Material and Methods: Seventy three children treated for HAIs in newborn period in Neonatal Intesive Care Unitin a 6 years period, and their 41 siblings who were healthy in newborn period were included in the study. Parents answered a detailed questionnaire, children were examined and complete blood count, serum total Ig E and specific Ig E levels were studied. Results: Ventilator associated pneumonia was observed in 32 (45.2%, blood stream infection in 28 (38.4% and clinic sepsis in 12 (16.4% of 73 children with HAIs. Asthma was significantly higher in HAIs group compared to sibling group (32.9% vs. 4.9, whereas there was no significant difference in allergic rhinitis (4.1% vs.2.4% and atopic dermatitis (6.8% vs. 0% among groups. When non-allergic 85 subjects and allergic 29 children compared, children who had been hospitalised and treated with broad-spectrum antibiotics in newborn period were almost 11.5 times as likely to have an allergic disease. Conclusion: Asthma was significantly higher in HAI group, and allergic disease risk seems to increase in children treated with broad-spectrum antibiotics for HAIs in newborn period. [Cukurova Med J 2017; 42(1.000: 132-139

  12. Evolução sócio-profissional de 140 pacientes epilépticos submetidos a tratamento medicamentoso The socio-professional evolution of 140 epileptic patients submitted to antiepileptic drug therapy

    Directory of Open Access Journals (Sweden)

    Luís Marques-Assis

    1968-09-01

    Full Text Available É estudada a evolução sócio-profissional de 140 doentes epilépticos, submetidos apenas a tratamento medicamentoso. Foram empregadas drogas de fácil aquisição em nosso meio (barbitúricos, hidantoinatos, primidona e trimetadiona, utilizadas isolada ou combinadamente. No estudo foram consideradas basicamente as atividades escolares, domésticas e profissionais. A evolução sócio-profissional foi estudada em relação às manifestações clínicas, ao tempo de doença, à freqüência das crises e ao padrão eletrencefalográfico. Os resultados, expressos em índices percentuais, permitiram ao autor concluir que na maioria dos pacientes epilépticos, convenientemente tratados do ponto de vista clínico, os problemas sociais e profissionais podem ser corrigidos ou evitados, independentemente de outras medidas especializadas que possam ser postas em prática.The socio-professional evolution of 140 epileptic patients submitted to antiepileptic drug therapy is studied. Only barbiturates, hydantoin, primidone and trimethadione were administered to the patients, isolated or in association. The school, house keeper and professional activities were considered in the investigation. The socio-professional follow-up was investigated regarding to clinic manifestations, time of disease, frequency of seizures and electroencephalographic pattern. The results, analysed in percentage, led the author to the conclusion that in most epileptic patients, adequately controlled with drugs, the social and the professional problems can be avoided.

  13. New mixed ligand zinc(II) complexes based on the antiepileptic drug sodium valproate and bioactive nitrogen-donor ligands. Synthesis, structure and biological properties.

    Science.gov (United States)

    Darawsheh, Mohanad; Abu Ali, Hijazi; Abuhijleh, A Latif; Rappocciolo, Emilia; Akkawi, Mutaz; Jaber, Suhair; Maloul, Salam; Hussein, Yasmeen

    2014-07-23

    Starting from the precursor [Zinc Valproate complex] (1), new mixed ligand zinc(II) complexes of valproic acid and nitrogen-based ligands, formulating as, [Zn(valp)22,9-dmphen] (2), [Zn2(valp)4(quin)2] (3), [Zn(valp)2(2-ampy)2] (4), and [Zn(valp)2(2-ampic)2] (5) (valp = valproate, 2,9-dmphen = 2,9-dimethyl-1,10-phenanthroline, quin = quinoline, 2-ampy = 2-aminopyridine, 2-ampic = 2-amino-6-picoline) were synthesized and characterized using IR, (1)H NMR, (13)C{(1)H} NMR and UV-Vis spectrometry. The crystal structures of complexes 2, 3 and 4 were determined using single-crystal X-ray diffraction. The complexes were also evaluated for their anti-bacterial activity using in-vitro agar diffusion method against three Gram-positive (Micrococcus luteus, Staphylococcus aureus, and Bacillus subtilis) and three Gram-negative (Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis) species. Complex 2 showed considerable activity against all tested microorganisms and the effect of complexation on the anti-bacterial activity of the parent ligand of 2 was also investigated. The anti-bacterial activity of 2,9-dmphen against Gram-negative bacteria was enhanced upon complexation with zinc valproate. On the other hand, complexes 1 and 3 showed weak inhibition activity against the tested species and complexes 4 and 5 didn't show any activity at all. Two methods were used for testing the inhibition of ferriprotoporphyrinIX bio-mineralization: a semi-quantitative micro-assay and a previously self-developed quantitative in-vitro method. Both were used to study the efficiency of these complexes in inhibiting the formation of the Malaria pigment which considered being the target of many known anti-malarial drugs such as Chloroquine and Amodiaquine. Results showed that the efficiency of complex 2 in preventing the formation of β-Hematin was 80%. The efficiency of Amodiaquine as a standard drug was reported to give 91%. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  14. Targeting N-Glycan Cryptic Sugar Moieties for Broad-Spectrum Virus Neutralization: Progress in Identifying Conserved Molecular Targets in Viruses of Distinct Phylogenetic Origins

    Directory of Open Access Journals (Sweden)

    Denong Wang

    2015-03-01

    Full Text Available Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA, for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV, and human cytomegalovirus (HCMV. In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn. These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation.

  15. Synthesis, characterization, antibacterial and antiepileptic studies of some novel thiazolidinone derivatives

    Directory of Open Access Journals (Sweden)

    Jaya Dwivedi

    2016-09-01

    Full Text Available In the quest of finding new drug leads with potential antibacterial and antiepileptic activities, synthesis of thiazolidinone derivatives 6(a–c is reported which are obtained from 5-(4-chlorobenzylidine-3-[4-(7-chloroquinoline-4-ylamino]propyl-2-imino-thiazolidin-4-one derivatives by applying appropriate synthetic route. These compounds 6(a–c were evaluated for antibacterial and antiepileptic activities. Compound 6a having good lipophilicity is found to be most active.

  16. Recent Advances in Antiepileptic Herbal Medicine.

    Science.gov (United States)

    Manchishi, Stephen M

    2018-01-01

    Epilepsy is one of the most common neurological disorders worldwide, with about 80 percent of cases thought to be in developing nations where it is mostly linked to superstition. The limited supply, high cost as well as low efficacy and adverse side effects of antiepileptic drugs (AEDs) is a matter of major concern. Herbal medicine has always been traditionally part of treatment of epilepsy. Herbal medicines are generally well tolerated, with fewer side effects. To highlight some herbal extracts that have been studied for their anticonvulsant activity in animal models, literature search from PubMed and Science Direct, was performed. The keywords for the search consisted of combinations of the following terms: Herbal antiepileptic and/or anticonvulsant, botanicals + epilepsy. Literature published in the last five years was considered. Eighteen (18) anticonvulsant herbal agents are reported and discussed. Experiments mostly consisted of phenotypic screens in rodents, with little diversity in screening methods. In most experiments, the tested extracts prolonged the time to onset of seizures and decreased their duration. Most experimenters implicate potentiation of GABAergic activity as the mode of action of the extracts, even though some experimenters did not fully characterise the bioactive chemical composition of their extracts. Potential herbal remedies have shown positive results in animal models. It remains unclear how many make it into clinical trials and eventually making part of the AED list. More rigorous research, applying strict research methodology with uniform herbal combinations, as well as clinical studies are urgently needed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. In vitro evaluation of broad-spectrum beta-lactams tested in medical centers in Korea: role of fourth-generation cephalosporins. The Korean Antimicrobial Resistance Study Group.

    Science.gov (United States)

    Lewis, M T; Biedenbach, D J; Jones, R N

    1999-12-01

    Levels of resistance to the "third-generation" cephalosporins among isolates of clinical bacteria in Korea have been increasing at a rapid rate. This study evaluated the activity of cefepime, a "fourth-generation" cephalosporin, and six other broad-spectrum beta-lactam antimicrobials (cefpirome, ceftazidime, ceftriaxone, imipenem, piperacillin/tazobactam 4 micrograms/mL fixed concentration[, oxacillin) against 404 isolates of clinical bacteria from Korea. Susceptibility profiles of each isolate were established using the Etest (AB BIODISK, Solna, Sweden) method of susceptibility testing. Only the carbapenem imipenem was > 90% effective in inhibiting each of the species tested (Escherichia coli, Klebsiella, spp., Citrobacter spp., Enterobacter spp., indole-positive Proteae, Serratia spp., Acinetobacter spp., Pseudomonas aeruginosa, and oxacillin-susceptible staphylococci). Imipenem was followed by cefepime > cefpirome > piperacillin/tazobactam > ceftazidime > ceftriaxone in overall rank order of usable spectrum against the isolates tested. Extended spectrum beta-lactamase producing phenotypes were much more prevalent among the Klebsiella spp. (48.8%) than the E. coli (5.0%) isolates. Cefepime was much more active than cefpirome, 95.1% susceptible as compared with 70.7% susceptible, against the 41 isolates of Klebsiella spp. The results of this study corroborates findings from earlier studies with levels of resistance to the broad-spectrum beta-lactams in Korea continuing to rise indicating the need for intervention strategies.

  18. Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4.

    Directory of Open Access Journals (Sweden)

    Samuele E Burastero

    Full Text Available To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1.

  19. The broad-spectrum antiviral compound ST-669 restricts chlamydial inclusion development and bacterial growth and localizes to host cell lipid droplets within treated cells.

    Science.gov (United States)

    Sandoz, Kelsi M; Valiant, William G; Eriksen, Steven G; Hruby, Dennis E; Allen, Robert D; Rockey, Daniel D

    2014-07-01

    Novel broad-spectrum antimicrobials are a critical component of a strategy for combating antibiotic-resistant pathogens. In this study, we explored the activity of the broad-spectrum antiviral compound ST-669 for activity against different intracellular bacteria and began a characterization of its mechanism of antimicrobial action. ST-669 inhibits the growth of three different species of chlamydia and the intracellular bacterium Coxiella burnetii in Vero and HeLa cells but not in McCoy (murine) cells. The antichlamydial and anti-C. burnetii activity spectrum was consistent with those observed for tested viruses, suggesting a common mechanism of action. Cycloheximide treatment in the presence of ST-669 abrogated the inhibitory effect, demonstrating that eukaryotic protein synthesis is required for tested activity. Immunofluorescence microscopy demonstrated that different chlamydiae grow atypically in the presence of ST-669, in a manner that suggests the compound affects inclusion formation and organization. Microscopic analysis of cells treated with a fluorescent derivative of ST-669 demonstrated that the compound localized to host cell lipid droplets but not to other organelles or the host cytosol. These results demonstrate that ST-669 affects intracellular growth in a host-cell-dependent manner and interrupts proper development of chlamydial inclusions, possibly through a lipid droplet-dependent process. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  20. Biogenic synthesis of Zinc oxide nanostructures from Nigella sativa seed: Prospective role as food packaging material inhibiting broad-spectrum quorum sensing and biofilm.

    Science.gov (United States)

    Al-Shabib, Nasser A; Husain, Fohad Mabood; Ahmed, Faheem; Khan, Rais Ahmad; Ahmad, Iqbal; Alsharaeh, Edreese; Khan, Mohd Shahnawaz; Hussain, Afzal; Rehman, Md Tabish; Yusuf, Mohammad; Hassan, Iftekhar; Khan, Javed Masood; Ashraf, Ghulam Md; Alsalme, Ali Mohammed; Al-Ajmi, Mohamed F; Tarasov, Vadim V; Aliev, Gjumrakch

    2016-12-05

    Bacterial spoilage of food products is regulated by density dependent communication system called quorum sensing (QS). QS control biofilm formation in numerous food pathogens and Biofilms formed on food surfaces act as carriers of bacterial contamination leading to spoilage of food and health hazards. Agents inhibiting or interfering with bacterial QS and biofilm are gaining importance as a novel class of next-generation food preservatives/packaging material. In the present study, Zinc nanostructures were synthesised using Nigella sativa seed extract (NS-ZnNPs). Synthesized nanostructures were characterized hexagonal wurtzite structure of size ~24 nm by UV-visible, XRD, FTIR and TEM. NS-ZnNPs demonstrated broad-spectrum QS inhibition in C. violaceum and P. aeruginosa biosensor strains. Synthesized nanostructures inhibited QS regulated functions of C. violaceum CVO26 (violacein) and elastase, protease, pyocyanin and alginate production in PAO1 significantly. NS-ZnNPs at sub-inhibitory concentrations inhibited the biofilm formation of four-food pathogens viz. C. violaceum 12472, PAO1, L. monocytogenes, E. coli. Moreover, NS-ZnNPs was found effective in inhibiting pre-formed mature biofilms of the four pathogens. Therefore, the broad-spectrum inhibition of QS and biofilm by biogenic Zinc oxide nanoparticles and it is envisaged that these nontoxic bioactive nanostructures can be used as food packaging material and/or as food preservative.

  1. A broad-spectrum sunscreen prevents UVA radiation-induced gene expression in reconstructed skin in vitro and in human skin in vivo.

    Science.gov (United States)

    Marionnet, Claire; Grether-Beck, Susanne; Seité, Sophie; Marini, Alessandra; Jaenicke, Thomas; Lejeune, François; Bastien, Philippe; Rougier, André; Bernerd, Françoise; Krutmann, Jean

    2011-06-01

    The efficacy of sunscreens to protect against ultraviolet (UV) A radiation is usually assessed by measuring erythema formation and pigmentation. The biological relevance of these endpoints for UVA-induced skin damage, however, is not known. We therefore carried out two complementary studies to determine UVA protection provided by a broad-spectrum sunscreen product at a molecular level by studying UVA radiation-induced gene expression. One study was performed on human reconstructed skin in vitro with a semi-global gene expression analysis of 227 genes in fibroblasts and 244 in keratinocytes. The second one was conducted in vivo in human volunteers and focused on genes involved in oxidative stress response and photo-ageing (haeme oxygenase-1, superoxide dismutase-2, glutathione peroxidase, catalase, matrix metalloproteinase-1). In-vitro UVA radiation induced modulation of genes involved in extracellular matrix homeostasis, oxidative stress, heat shock responses, cell growth, inflammation and epidermal differentiation. Sunscreen pre-application abrogated or significantly reduced these effects, as underlined by unsupervised clustering analysis. The in vivo study confirmed that the sunscreen prevented UVA radiation-induced transcriptional expression of the five studied genes. These findings indicate the high efficacy of a broad-spectrum sunscreen in protecting human skin against UVA-induced gene responses and suggest that this approach is a biologically relevant complement to existing methods. © 2011 John Wiley & Sons A/S.

  2. Membrane Active Small Molecules Show Selective Broad Spectrum Antibacterial Activity with No Detectable Resistance and Eradicate Biofilms.

    Science.gov (United States)

    Hoque, Jiaul; Konai, Mohini M; Gonuguntla, Spandhana; Manjunath, Goutham B; Samaddar, Sandip; Yarlagadda, Venkateswarlu; Haldar, Jayanta

    2015-07-23

    Treating bacterial biofilms with conventional antibiotics is limited due to ineffectiveness of the drugs and higher propensity to develop bacterial resistance. Development of new classes of antibacterial therapeutics with alternative mechanisms of action has become imperative. Herein, we report the design, synthesis, and biological evaluations of novel membrane-active small molecules featuring two positive charges, four nonpeptidic amide groups, and variable hydrophobic/hydrophilic (amphiphilic) character. The biocides synthesized via a facile methodology not only displayed good antibacterial activity against wild-type bacteria but also showed high activity against various drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and β-lactam-resistant Klebsiella pneumoniae. Further, these biocides not only inhibited the formation of biofilms but also disrupted the established S. aureus and E. coli biofilms. The membrane-active biocides hindered the propensity to develop bacterial resistance. Moreover, the biocides showed negligible toxicity against mammalian cells and thus bear potential to be used as therapeutic agents.

  3. Prescription of emergency antiepileptic medication after a first childhood seizure: analysis of routine administrative data.

    Science.gov (United States)

    Chin, Richard Fm; Ajetunmobi, Omotomilola; Weir, Christopher J; Wood, Rachael

    2015-06-01

    UK guidelines do not recommend prescribing emergency antiepileptic drugs after first simple febrile seizures or for single afebrile seizures. Non-adherence to the guidelines could result in substantial health service cost. Scottish national hospital discharge records were used to identify children aged one month to 4 years admitted for a first febrile seizures or single afebrile seizures between April 2009 and March 2012. Prescriptions for antiepileptic drugs within 12 months of index admission were identified on the national community prescribing database by matching unique patient identifiers. There were 1,978 and 663 children admitted for febrile seizures and single afebrile seizures, respectively. One percent of children admitted with febrile seizures and 1.7% with single afebrile seizures had a subsequent community prescription record for emergency antiepileptic drugs within 12 months of index admission. Total cost of emergency antiepileptic drugs following febrile seizures and single afebrile seizures for the study period was just over £900. Health care providers and policy makers can be reassured that emergency antiepileptic drugs are not being inappropriately overprescribed for febrile seizures and single afebrile seizures.

  4. Dissection of broad-spectrum resistance of the Thai rice variety Jao Hom Nin conferred by two resistance genes against rice blast.

    Science.gov (United States)

    Chaipanya, Chaivarakun; Telebanco-Yanoria, Mary Jeanie; Quime, Berlaine; Longya, Apinya; Korinsak, Siripar; Korinsak, Siriporn; Toojinda, Theerayut; Vanavichit, Apichart; Jantasuriyarat, Chatchawan; Zhou, Bo

    2017-12-01

    Rice (Oryza sativa) is one of the most important food crops in the world. Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is one of the most destructive rice diseases worldwide. To effectively cope with this problem, the use of rice blast resistance varieties through innovative breeding programs is the best strategy to date. The Thai rice variety Jao Hom Nin (JHN) showed broad-spectrum resistance against Thai rice blast isolates. Two QTLs for blast resistance in JHN were reported on chromosome 1 (QTL1) and 11 (QTL11). Monogenic lines of QTL1 (QTL1-C) and QTL11 (QTL11-C) in the CO39 genetic background were generated. Cluster analysis based on the disease reaction pattern of QTL1-C and QTL11-C, together with IRBLs, showed that those two monogenic lines were clustered with IRBLsh-S (Pish) and IRBL7-M (Pi7), respectively. Moreover, sequence analysis revealed that Pish and Pi7 were embedded within the QTL1 and QTL11 delimited genomic intervals, respectively. This study thus concluded that QTL1 and QTL11 could encode alleles of Pish and Pi7, designated as Pish-J and Pi7-J, respectively. To validate this hypothesis, the genomic regions of Pish-J and Pi7-J were cloned and sequenced. Protein sequence comparison revealed that Pish-J and Pi7-J were identical to Pish and Pi7, respectively. The holistic disease spectrum of JHN was found to be exactly attributed to the additive ones of both QTL1-C and QTL11-C. JHN showed broad spectrum resistance against Thai and Philippine rice blast isolates. As this study demonstrated, the combination of two resistance genes, Pish-J and Pi7-J, in JHN, with each controlling broad-spectrum resistance to rice blast disease, explains the high level of resistance. Thus, the combination of Pish and Pi7 can provide a practical scheme for breeding durable resistance in rice against rice blast disease.

  5. Benzophenone C-glucosides and gallotannins from mango tree stem bark with broad-spectrum anti-viral activity.

    Science.gov (United States)

    Abdel-Mageed, Wael M; Bayoumi, Soad A H; Chen, Caixia; Vavricka, Christopher J; Li, Li; Malik, Ajamaluddin; Dai, Huanqin; Song, Fuhang; Wang, Luoqiang; Zhang, Jingyu; Gao, George F; Lv, Yali; Liu, Lihong; Liu, Xueting; Sayed, Hanaa M; Zhang, Lixin

    2014-04-01

    The high mutation rate of RNA viruses has resulted in limitation of vaccine effectiveness and increased emergence of drug-resistant viruses. New effective antivirals are therefore needed to control of the highly mutative RNA viruses. The n-butanol fraction of the stem bark of Mangifera indica exhibited inhibitory activity against influenza neuraminidase (NA) and coxsackie virus 3C protease. Bioassay guided phytochemical study of M. indica stem bark afforded two new compounds including one benzophenone C-glycoside (4) and one xanthone dimer (7), together with eleven known compounds. The structures of these isolated compounds were elucidated on the basis of spectroscopic evidences and correlated with known compounds. Anti-influenza and anti-coxsackie virus activities were evaluated by determining the inhibition of anti-influenza neuraminidase (NA) from pandemic A/RI/5+/1957 H2N2 influenza A virus and inhibition of coxsackie B3 virus 3C protease, respectively. The highest anti-influenza activity was observed for compounds 8 and 9 with IC50 values of 11.9 and 9.2μM, respectively. Compounds 8 and 9 were even more potent against coxsackie B3 virus 3C protease, with IC50 values of 1.1 and 2.0μM, respectively. Compounds 8 and 9 showed weak cytotoxic effect against human hepatocellular carcinoma and human epithelial carcinoma cell lines through MTT assay. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Significant HLA class I type associations with aromatic antiepileptic drug (AED)-induced SJS/TEN are different from those found for the same AED-induced DRESS in the Spanish population.

    Science.gov (United States)

    Ramírez, Elena; Bellón, Teresa; Tong, Hoi Y; Borobia, Alberto M; de Abajo, Francisco J; Lerma, Victoria; Moreno Hidalgo, Miguel A; Castañer, José L; Cabañas, Rosario; Fiandor, Ana; González-Ramos, Jessica; Herranz, Pedro; Cachafeiro, Lucía; González-Herrada, Carlos; González, Olga; Aramburu, José A; Laosa, Olga; Hernández, Rafael; Carcas, Antonio J; Frías, Jesús

    2017-01-01

    Aromatic antiepileptic drugs (AEDs) are among the drugs most frequently involved in severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). This study investigated the associations between the genetic polymorphisms of HLA class-I and AED-induced SCARs in the Spanish population. HLA class-I genotypes were determined in AED (phenytoin[PHT],lamotrigine[LTG],carbamazepine[CBZ],phenobarbital[PB])-induced SJS/TEN (n=15) or DRESS (n=12) cases included in the Spanish SCAR registry, PIELenRed. There were 3 control groups: (A)tolerant to a single AED, (B)tolerant to any AED, and (C)Spanish population controls. For SJS/TEN, concomitant HLA-A*02:01/Cw15:02 alleles were significantly associated with PHT-cases compared to control groups B and C [(B)odds ratio(OR):14.75, p=0.009;(C)OR:27.50, pA (p=0.060). The genotype frequency of the HLA-B*38:01 was significantly associated with PHT-LTG-cases compared with the 3 groups of controls [(A)OR:12.86, p=0.012;(B)OR:13.81; p=0.002;(C)OR:14.35, pA)OR:147.00, p=0.001;(B)OR:115.00, pa Spanish Romani patient with a CBZ-case. The HLA-A*11:01 was significantly associated with CBZ-cases [(A)OR:63.89, p=0.002;(B)OR:36.33, p=0.005;(C)OR:28.29, p=0.007]. For DRESS, the HLA-A*24:02 genotype frequency was statistically significant in the PHT-LTG-cases [(A)OR:22.56, p=0.003;(B)OR:23.50. p=0.001; (C)OR:33.25, pA),OR:49.00, p=0.015;(B)OR:27.77, p=0.005; (C)OR:34.53, p=0.002]. HLA-A*31:01 was significantly associated with the CBZ-cases [(A)OR:22.00, p=0.047;(B)OR:29.50, p=0.033;(C)OR:35.14, p=0.006]. In conclusion, we identified several significant genetic risk factors for the first time in the Spanish Caucasian population: HLA-A*02:01/Cw*15:02 combination as a risk factor for PHT-induced SJS/TEN, HLA-B*38:01 for LTG- and PHT- induced SJS/TEN, HLA-A*11:01 for CBZ-induced SJS/TEN, and HLA-A*24:02 for LTG- and PHT- induced

  7. Broad-spectrum in vitro antibacterial activities of clay minerals against antibiotic-susceptible and antibiotic-resistant bacterial pathogens

    Science.gov (United States)

    HAYDEL, SHELLEY E.; REMENIH, CHRISTINE M.; WILLIAMS, LYNDA B.

    2008-01-01

    SYNOPSIS Objectives The capacity to properly address the worldwide incidence of infectious diseases lies in the ability to detect, prevent, and effectively treat these infections. Therefore, identifying and analyzing inhibitory agents are worthwhile endeavors in an era when few new classes of effective antimicrobials have been developed. The use of geological nanomaterials to heal skin infections has been evident since the earliest recorded history, and specific clay minerals may prove valuable in the treatment of bacterial diseases, including infections for which there are no effective antibiotics, such as Buruli ulcer and multi-drug resistant infections. Methods We have subjected two iron-rich clay minerals, which have previously been used to treat Buruli ulcer patients, to broth culture testing of antibiotic-susceptible and -resistant pathogenic bacteria to assess the feasibility of using clay minerals as therapeutic agents. Results One specific mineral, CsAg02, demonstrated bactericidal activity against pathogenic Escherichia coli, extended-spectrum β-lactamase (ESBL) E. coli, S. enterica serovar Typhimurium, Pseudomonas aeruginosa, and Mycobacterium marinum and a combined bacteriostatic/bactericidal effect against Staphylococcus aureus, penicillin-resistant S. aureus (PRSA), methicillin-resistant S. aureus (MRSA), and Mycobacterium smegmatis, while another mineral with similar structure and bulk crystal chemistry, CsAr02, had no effect on or enhanced bacterial growth. The <0.2 μm fraction of CsAg02 and CsAg02 heated to 200°C or 550°C retained bactericidal activity, while cation-exchanged CsAg02 and CsAg02 heated to 900°C no longer killed E. coli. Conclusions Our results indicate that specific mineral products have intrinsic, heat-stable antibacterial properties, which could provide an inexpensive treatment against numerous human bacterial infections. PMID:18070832

  8. Facile synthesis of Fe3O4 nanoparticles decorated on 3D graphene aerogels as broad-spectrum sorbents for water treatment

    Science.gov (United States)

    Li, Yong; Zhang, Ruofang; Tian, Xike; Yang, Chao; Zhou, Zhaoxin

    2016-04-01

    In order to develop efficient and environment benign sorbents for water purification, the macroscopic multifunctional magnetite-reduced graphene oxides aerogels (M-RGOs) with strong interconnected networks were prepared via a one pot solvothermal method of graphene oxide sheets adsorbing iron ions and in situ simultaneous deposition of Fe3O4 nanoparticles in ethylene glycol or triethylene glycol solvents. Such M-RGOs exhibited excellent sorption capacity to different contaminants, including oils, organic solvents, arsenite ions, as well as dyes. In addition, it was demonstrated that the M-RGOs could be used as column packing materials to manufacture column for water purification by filtration. The method proposed was proved to be versatile to induce synergistic assembly of RGO sheets with other functional metal oxides nanoparticles and as a kind of broad-spectrum sorbents for removing different types of contaminants in water purification, simultaneously.

  9. Characterization of the novel broad-spectrum kinase inhibitor CTx-0294885 as an affinity reagent for mass spectrometry-based kinome profiling.

    Science.gov (United States)

    Zhang, Luxi; Holmes, Ian P; Hochgräfe, Falko; Walker, Scott R; Ali, Naveid A; Humphrey, Emily S; Wu, Jianmin; de Silva, Melanie; Kersten, Wilhelmus J A; Connor, Theresa; Falk, Hendrik; Allan, Lynda; Street, Ian P; Bentley, John D; Pilling, Patricia A; Monahan, Brendon J; Peat, Thomas S; Daly, Roger J

    2013-07-05

    Kinase enrichment utilizing broad-spectrum kinase inhibitors enables the identification of large proportions of the expressed kinome by mass spectrometry. However, the existing inhibitors are still inadequate in covering the entire kinome. Here, we identified a novel bisanilino pyrimidine, CTx-0294885, exhibiting inhibitory activity against a broad range of kinases in vitro, and further developed it into a Sepharose-supported kinase capture reagent. Use of a quantitative proteomics approach confirmed the selectivity of CTx-0294885-bound beads for kinase enrichment. Large-scale CTx-0294885-based affinity purification followed by LC-MS/MS led to the identification of 235 protein kinases from MDA-MB-231 cells, including all members of the AKT family that had not been previously detected by other broad-spectrum kinase inhibitors. Addition of CTx-0294885 to a mixture of three kinase inhibitors commonly used for kinase-enrichment increased the number of kinase identifications to 261, representing the largest kinome coverage from a single cell line reported to date. Coupling phosphopeptide enrichment with affinity purification using the four inhibitors enabled the identification of 799 high-confidence phosphosites on 183 kinases, ∼10% of which were localized to the activation loop, and included previously unreported phosphosites on BMP2K, MELK, HIPK2, and PRKDC. Therefore, CTx-0294885 represents a powerful new reagent for analysis of kinome signaling networks that may facilitate development of targeted therapeutic strategies. Proteomics data have been deposited to the ProteomeXchange Consortium ( http://proteomecentral.proteomexchange.org ) via the PRIDE partner repository with the data set identifier PXD000239.

  10. Multiple copies of eukaryotic translation initiation factors in Brassica rapa facilitate redundancy, enabling diversification through variation in splicing and broad-spectrum virus resistance.

    Science.gov (United States)

    Nellist, Charlotte F; Qian, Wei; Jenner, Carol E; Moore, Jonathan D; Zhang, Shujiang; Wang, Xiaowu; Briggs, William H; Barker, Guy C; Sun, Rifei; Walsh, John A

    2014-01-01

    Recessive strain-specific resistance to a number of plant viruses in the Potyvirus genus has been found to be based on mutations in the eukaryotic translation initiation factor 4E (eIF4E) and its isoform, eIF(iso)4E. We identified three copies of eIF(iso)4E in a number of Brassica rapa lines. Here we report broad-spectrum resistance to the potyvirus Turnip mosaic virus (TuMV) due to a natural mechanism based on the mis-splicing of the eIF(iso)4E allele in some TuMV-resistant B. rapa var. pekinensis lines. Of the splice variants, the most common results in a stop codon in intron 1 and a much truncated, non-functional protein. The existence of multiple copies has enabled redundancy in the host plant's translational machinery, resulting in diversification and emergence of the resistance. Deployment of the resistance is complicated by the presence of multiple copies of the gene. Our data suggest that in the B. rapa subspecies trilocularis, TuMV appears to be able to use copies of eIF(iso)4E at two loci. Transformation of different copies of eIF(iso)4E from a resistant B. rapa line into an eIF(iso)4E knockout line of Arabidopsis thaliana proved misleading because it showed that, when expressed ectopically, TuMV could use multiple copies which was not the case in the resistant B. rapa line. The inability of TuMV to access multiple copies of eIF(iso)4E in B. rapa and the broad spectrum of the resistance suggest it may be durable. © 2013 The Authors The Plant Journal © 2013 John Wiley & Sons Ltd.

  11. Drug: D09569 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 03] N NERVOUS SYSTEM N03 ANTIEPILEPTICS N03A ANTIEPILEPTICS N03AX Other antiepileptic...leptic, adjunctive therapy for partial onset seizures Same as: C13826 ATC code: N03...D09569 Drug Ezogabine (USAN); Retigabine (INN); Potiga (TN) C16H18FN3O2 303.1383 303.3314 D09569.gif Antiepi

  12. Hypnotic and antiepileptic effects of cannabidiol.

    Science.gov (United States)

    Carlini, E A; Cunha, J M

    1981-01-01

    Clinical trials with cannabidiol (CBD) in healthy volunteers, isomniacs, and epileptic patients conducted in the authors' laboratory from 1972 up to the present are reviewed. Acute doses of cannabidiol ranging from 10 to 600 mg and chronic administration of 10 mg for 20 days or 3 mg/kg/day for 30 days did not induce psychologic or physical symptoms suggestive of psychotropic or toxic effects; however, several volunteers complained of somnolence. Complementary laboratory tests (EKG, blood pressure, and blood and urine analysis) revealed no sign of toxicity. Doses of 40, 80, and 160 mg cannabidiol were compared to placebo and 5 mg nitrazepam in 15 insomniac volunteers. Subjects receiving 160 mg cannabidiol reported having slept significantly more than those receiving placebo; the volunteers also reported significantly less dream recall; with the three doses of cannabidiol than with placebo. Fifteen patients suffering from secondary generalized epilepsy refractory to known antiepileptic drugs received either 200 to 300 mg cannabidiol daily or placebo for as long as 4.5 months. Seven out of the eight epileptics receiving cannabidiol had improvement of their disease state, whereas only one placebo patient improved.

  13. Fungal Root Microbiome from Healthy and Brittle Leaf Diseased Date Palm Trees (Phoenix dactylifera L.) Reveals a Hidden Untapped Arsenal of Antibacterial and Broad Spectrum Antifungal Secondary Metabolites.

    Science.gov (United States)

    Mefteh, Fedia B; Daoud, Amal; Chenari Bouket, Ali; Alenezi, Faizah N; Luptakova, Lenka; Rateb, Mostafa E; Kadri, Adel; Gharsallah, Neji; Belbahri, Lassaad

    2017-01-01

    In this study, we aimed to explore and compare the composition, metabolic diversity and antimicrobial potential of endophytic fungi colonizing internal tissues of healthy and brittle leaf diseased (BLD) date palm trees (Phoenix dactylifera L.) widely cultivated in arid zones of Tunisia. A total of 52 endophytic fungi were isolated from healthy and BLD roots of date palm trees, identified based on internal transcribed spacer-rDNA sequence analysis and shown to represent 13 species belonging to five genera. About 36.8% of isolates were shared between healthy and diseased root fungal microbiomes, whereas 18.4 and 44.7% of isolates were specific to healthy and BLD root fungal microbiomes, respectively. All isolates were able to produce at least two of the screened enzymes including amylase, cellulase, chitinase, pectinase, protease, laccase and lipase. A preliminary screening of the isolates using disk diffusion method for antibacterial activity against four Gram-positive and three Gram-negative bacteria and antifungal activities against three phytopathogenic fungi indicated that healthy and BLD root fungal microbiomes displayed interesting bioactivities against examined bacteria and broad spectrum bioactivity against fungal pathogens. Some of these endophytic fungi (17 isolates) were fermented and their extracts were evaluated for antimicrobial potential against bacterial and fungal isolates. Results revealed that fungal extracts exhibited antibacterial activities and were responsible for approximately half of antifungal activities against living fungi. These results suggest a strong link between fungal bioactivities and their secondary metabolite arsenal. EtOAc extracts of Geotrichum candidum and Thielaviopsis punctulata originating from BLD microbiome gave best results against Micrococcus luteus and Bacillus subtilis with minimum inhibitory concentration (MIC, 0.78 mg/mL) and minimum bactericidal concentration (6.25 mg/mL). G. candidum gave the best result against

  14. Fungal Root Microbiome from Healthy and Brittle Leaf Diseased Date Palm Trees (Phoenix dactylifera L.) Reveals a Hidden Untapped Arsenal of Antibacterial and Broad Spectrum Antifungal Secondary Metabolites

    Science.gov (United States)

    Mefteh, Fedia B.; Daoud, Amal; Chenari Bouket, Ali; Alenezi, Faizah N.; Luptakova, Lenka; Rateb, Mostafa E.; Kadri, Adel; Gharsallah, Neji; Belbahri, Lassaad

    2017-01-01

    In this study, we aimed to explore and compare the composition, metabolic diversity and antimicrobial potential of endophytic fungi colonizing internal tissues of healthy and brittle leaf diseased (BLD) date palm trees (Phoenix dactylifera L.) widely cultivated in arid zones of Tunisia. A total of 52 endophytic fungi were isolated from healthy and BLD roots of date palm trees, identified based on internal transcribed spacer-rDNA sequence analysis and shown to represent 13 species belonging to five genera. About 36.8% of isolates were shared between healthy and diseased root fungal microbiomes, whereas 18.4 and 44.7% of isolates were specific to healthy and BLD root fungal microbiomes, respectively. All isolates were able to produce at least two of the screened enzymes including amylase, cellulase, chitinase, pectinase, protease, laccase and lipase. A preliminary screening of the isolates using disk diffusion method for antibacterial activity against four Gram-positive and three Gram-negative bacteria and antifungal activities against three phytopathogenic fungi indicated that healthy and BLD root fungal microbiomes displayed interesting bioactivities against examined bacteria and broad spectrum bioactivity against fungal pathogens. Some of these endophytic fungi (17 isolates) were fermented and their extracts were evaluated for antimicrobial potential against bacterial and fungal isolates. Results revealed that fungal extracts exhibited antibacterial activities and were responsible for approximately half of antifungal activities against living fungi. These results suggest a strong link between fungal bioactivities and their secondary metabolite arsenal. EtOAc extracts of Geotrichum candidum and Thielaviopsis punctulata originating from BLD microbiome gave best results against Micrococcus luteus and Bacillus subtilis with minimum inhibitory concentration (MIC, 0.78 mg/mL) and minimum bactericidal concentration (6.25 mg/mL). G. candidum gave the best result against

  15. In Vitro Activity of a Novel Broad-Spectrum Antifungal, E1210, Tested against Aspergillus spp. Determined by CLSI and EUCAST Broth Microdilution Methods ▿

    Science.gov (United States)

    Pfaller, Michael A.; Duncanson, Frederick; Messer, Shawn A.; Moet, Gary J.; Jones, Ronald N.; Castanheira, Mariana

    2011-01-01

    E1210 is a first-in-class broad-spectrum antifungal that suppresses hyphal growth by inhibiting fungal glycophosphatidylinositol (GPI) biosynthesis. In the present study, we extend these findings by examining the activity of E1210 and comparator antifungal agents against Aspergillus spp. by using the methods of the Clinical and Laboratory Standards Institute (CLSI) and the European Committee for Antimicrobial Susceptibility Testing (EUCAST) to test wild-type (WT) as well as amphotericin B (AMB)-resistant (-R) and azole-R strains (as determined by CLSI methods). Seventy-eight clinical isolates of Aspergillus were tested including 20 isolates of Aspergillus flavus species complex (SC), 22 of A. fumigatus SC, 13 of A. niger SC, and 23 of A. terreus SC. The collection included 15 AMB-R (MIC, ≥2 μg/ml) isolates of A. terreus SC and 10 itraconazole-R (MIC, ≥4 μg/ml) isolates of A. fumigatus SC (7 isolates), A. niger SC (2 isolates), and A. terreus SC (1 isolate). Comparator antifungal agents included anidulafungin, caspofungin, amphotericin B, itraconazole, posaconzole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparators. The essential agreement (EA; ±2 log2 dilution steps) was 100% for all comparisons with the exception of posaconazole versus A. terreus SC (EA = 91.3%). The minimum effective concentration (MEC)/MIC90 values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, and voriconazole, respectively, were as follows for each species: for A. flavus SC, 0.03, ≤0.008, 0.12, 1, 1, and 1; for A. fumigatus SC, 0.06, 0.015, 0.12, >8, 1, and 4; for A. niger SC, 0.015, 0.03, 0.12, 4, 1, and 2; and for A. terreus SC, 0.06, 0.015, 0.12, 1, 0.5, and 1. E1210 was very active against AMB-R strains of A. terreus SC (MEC range, 0.015 to 0.06 μg/ml) and itraconazole-R strains of A. fumigatus SC (MEC range, 0.03 to 0.12 μg/ml), A. niger SC (MEC, 0.008 μg/ml), and A. terreus SC (MEC, 0.015

  16. In vitro activity of a novel broad-spectrum antifungal, E1210, tested against Aspergillus spp. determined by CLSI and EUCAST broth microdilution methods.

    Science.gov (United States)

    Pfaller, Michael A; Duncanson, Frederick; Messer, Shawn A; Moet, Gary J; Jones, Ronald N; Castanheira, Mariana

    2011-11-01

    E1210 is a first-in-class broad-spectrum antifungal that suppresses hyphal growth by inhibiting fungal glycophosphatidylinositol (GPI) biosynthesis. In the present study, we extend these findings by examining the activity of E1210 and comparator antifungal agents against Aspergillus spp. by using the methods of the Clinical and Laboratory Standards Institute (CLSI) and the European Committee for Antimicrobial Susceptibility Testing (EUCAST) to test wild-type (WT) as well as amphotericin B (AMB)-resistant (-R) and azole-R strains (as determined by CLSI methods). Seventy-eight clinical isolates of Aspergillus were tested including 20 isolates of Aspergillus flavus species complex (SC), 22 of A. fumigatus SC, 13 of A. niger SC, and 23 of A. terreus SC. The collection included 15 AMB-R (MIC, ≥ 2 μg/ml) isolates of A. terreus SC and 10 itraconazole-R (MIC, ≥ 4 μg/ml) isolates of A. fumigatus SC (7 isolates), A. niger SC (2 isolates), and A. terreus SC (1 isolate). Comparator antifungal agents included anidulafungin, caspofungin, amphotericin B, itraconazole, posaconzole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparators. The essential agreement (EA; ± 2 log(2) dilution steps) was 100% for all comparisons with the exception of posaconazole versus A. terreus SC (EA = 91.3%). The minimum effective concentration (MEC)/MIC(90) values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, and voriconazole, respectively, were as follows for each species: for A. flavus SC, 0.03, ≤ 0.008, 0.12, 1, 1, and 1; for A. fumigatus SC, 0.06, 0.015, 0.12, >8, 1, and 4; for A. niger SC, 0.015, 0.03, 0.12, 4, 1, and 2; and for A. terreus SC, 0.06, 0.015, 0.12, 1, 0.5, and 1. E1210 was very active against AMB-R strains of A. terreus SC (MEC range, 0.015 to 0.06 μg/ml) and itraconazole-R strains of A. fumigatus SC (MEC range, 0.03 to 0.12 μg/ml), A. niger SC (MEC, 0.008 μg/ml), and A. terreus SC (MEC, 0.015

  17. Transgenic Brassica rapa plants over-expressing eIF(iso)4E variants show broad-spectrum Turnip mosaic virus (TuMV) resistance.

    Science.gov (United States)

    Kim, Jinhee; Kang, Won-Hee; Hwang, Jeena; Yang, Hee-Bum; Dosun, Kim; Oh, Chang-Sik; Kang, Byoung-Cheorl

    2014-08-01

    The protein-protein interaction between VPg (viral protein genome-linked) of potyviruses and eIF4E (eukaryotic initiation factor 4E) or eIF(iso)4E of their host plants is a critical step in determining viral virulence. In this study, we evaluated the approach of engineering broad-spectrum resistance in Chinese cabbage (Brassica rapa) to Turnip mosaic virus (TuMV), which is one of the most important potyviruses, by a systematic knowledge-based approach to interrupt the interaction between TuMV VPg and B. rapa eIF(iso)4E. The seven amino acids in the cap-binding pocket of eIF(iso)4E were selected on the basis of other previous results and comparison of protein models of cap-binding pockets, and mutated. Yeast two-hybrid assay and co-immunoprecipitation analysis demonstrated that W95L, K150L and W95L/K150E amino acid mutations of B. rapa eIF(iso)4E interrupted its interaction with TuMV VPg. All eIF(iso)4E mutants were able to complement an eIF4E-knockout yeast strain, indicating that the mutated eIF(iso)4E proteins retained their function as a translational initiation factor. To determine whether these mutations could confer resistance, eIF(iso)4E W95L, W95L/K150E and eIF(iso)4E wild-type were over-expressed in a susceptible Chinese cabbage cultivar. Evaluation of the TuMV resistance of T1 and T2 transformants demonstrated that the over-expression of the eIF(iso)4E mutant forms can confer resistance to multiple TuMV strains. These data demonstrate the utility of knowledge-based approaches for the engineering of broad-spectrum resistance in Chinese cabbage. © 2014 BSPP AND JOHN WILEY & SONS LTD.

  18. Dissemination and genetic support of broad-spectrum beta-lactam-resistant Escherichia coli strain isolated from two Tunisian hospitals during 2004-2012.

    Science.gov (United States)

    Ayari, Khaoula; Bourouis, Amel; Chihi, Hela; Mahrouki, Sihem; Naas, Thierry; Belhadj, Omrane

    2017-06-01

    The dissemination of extended-spectrum β-lactamase (ESBL)-producing bacteria presented a great concern worldwide. Gram-negative organisms such as Escherichia coli and Klebsiella pneumoniae are the most frequently isolated pathogens responsible for nosocomial infections. The aim of this study was to investigate and to follow the emergence of resistance and the characterization of Extended-Spectrum Beta-Lactamases (ESBL) among broad-spectrum beta-lactam-Escherichia coli clinical isolates recovered from the military hospital and Habib Thameur hospital in Tunisia. A total of 113 E.coli isolates obtained during the period 2004 through 2012 showed a significant degree of multi-resistance. Among these strains, the double-disk synergy test confirmed the ESBL phenotype in 46 isolates. These included 32(70%) strains from Hospital A and 14(30%) from Hospital B. The ESBL was identified as CTX-M-15. The ESBL resistance was transferred by a 60 kb plasmid CTXM-15-producing isolates were unrelated according to the PFGE analysis and characterization of the regions surrounding the blaCTX-M-15 showed the ISEcp1 elements located in the upstream region of the bla gene and 20 of them truncated by IS26. ESBL producing E. coli strains are a serious threat in the community in Tunisia and we should take into consideration any possible spread of such epidemiological resistance.

  19. Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate.

    Science.gov (United States)

    Kim, Chae; Haldiman, Tracy; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Sy, Man-Sun; Cohen, Mark; Safar, Jiri G

    2011-09-01

    The origin, range, and structure of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD), are largely unknown. To investigate the molecular mechanism responsible for the broad phenotypic variability of sCJD, we analyzed the conformational characteristics of protease-sensitive and protease-resistant fractions of the pathogenic prion protein (PrP(Sc)) using novel conformational methods derived from a conformation-dependent immunoassay (CDI). In 46 brains of patients homozygous for polymorphisms in the PRNP gene and exhibiting either Type 1 or Type 2 western blot pattern of the PrP(Sc), we identified an extensive array of PrP(Sc) structures that differ in protease sensitivity, display of critical domains, and conformational stability. Surprisingly, in sCJD cases homozygous for methionine or valine at codon 129 of the PRNP gene, the concentration and stability of protease-sensitive conformers of PrP(Sc) correlated with progression rate of the disease. These data indicate that sCJD brains exhibit a wide spectrum of PrP(Sc) structural states, and accordingly argue for a broad spectrum of prion strains coding for different phenotypes. The link between disease duration, levels, and stability of protease-sensitive conformers of PrP(Sc) suggests that these conformers play an important role in the pathogenesis of sCJD.

  20. Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate.

    Directory of Open Access Journals (Sweden)

    Chae Kim

    2011-09-01

    Full Text Available The origin, range, and structure of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD, are largely unknown. To investigate the molecular mechanism responsible for the broad phenotypic variability of sCJD, we analyzed the conformational characteristics of protease-sensitive and protease-resistant fractions of the pathogenic prion protein (PrP(Sc using novel conformational methods derived from a conformation-dependent immunoassay (CDI. In 46 brains of patients homozygous for polymorphisms in the PRNP gene and exhibiting either Type 1 or Type 2 western blot pattern of the PrP(Sc, we identified an extensive array of PrP(Sc structures that differ in protease sensitivity, display of critical domains, and conformational stability. Surprisingly, in sCJD cases homozygous for methionine or valine at codon 129 of the PRNP gene, the concentration and stability of protease-sensitive conformers of PrP(Sc correlated with progression rate of the disease. These data indicate that sCJD brains exhibit a wide spectrum of PrP(Sc structural states, and accordingly argue for a broad spectrum of prion strains coding for different phenotypes. The link between disease duration, levels, and stability of protease-sensitive conformers of PrP(Sc suggests that these conformers play an important role in the pathogenesis of sCJD.