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Sample records for broad-spectrum antiepileptic drug

  1. Rufinamide: a novel broad-spectrum antiepileptic drug.

    Science.gov (United States)

    Wheless, James W; Vazquez, Blanca

    2010-01-01

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

  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. Pharmacokinetic monitoring of antiepileptic drugs.

    Science.gov (United States)

    Aldaz, A; Ferriols, R; Aumente, D; Calvo, M V; Farre, M R; García, B; Marqués, R; Mas, P; Porta, B; Outeda, M; Soy, D

    2011-01-01

    Monitoring plasma levels of antiepileptic drugs for the treatment and prophylaxis of epilepsy is one of the strategies enabling clinical results to improve by reducing adverse affects and increasing effectiveness. The objective of this article is to review the basic aspects in the monitoring of antiepileptic drugs using a consensus document prepared and endorsed by the pharmacokinetics and pharmacogenetics working group (PK.gen) of the Sociedad Española de Farmacia Hospitalaria (Spanish Society of Hospital Pharmacists).

  4. Teratogenicity of Antiepileptic Drugs

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    Güveli, Betül Tekin; Rosti, Rasim Özgür; Güzeltaş, Alper; Tuna, Elif Bahar; Ataklı, Dilek; Sencer, Serra; Yekeler, Ensar; Kayserili, Hülya; Dirican, Ahmet; Bebek, Nerses; Baykan, Betül; Gökyiğit, Ayşen; Gürses, Candan

    2017-01-01

    Objective Antiepileptic drugs (AED) have chronic teratogenic effects, the most common of which are congenital heart disease, cleft lip/palate, urogenital and neural tube defects. The aim of our study is to examine teratogenic effects of AED and the correlation between these malformations and AED in single or multiple pregnancies. Methods This is a retrospective study of malformations in children born to mothers currently followed up by our outpatient clinics who used or discontinued AED during their pregnancy. Their children were then investigated using echocardiography, urinary ultrasound, cranial magnetic resonance image, and examined by geneticists and pediatric dentists. Results One hundred and seventeen children were included in the study. Ninety one of these children were exposed to AED during pregnancy. The most commonly used AED were valproic acid and carbamazepine in monotherapy. The percentage of major anomaly was 6.8% in all children. Dysmorphic features and dental anomalies were observed more in children exposed especially to valproic acid. There were 26 mothers with two and four mothers with three pregnancies from the same fathers. No correlation was found between the distribution of malformations in recurring pregnancies and AED usage. Conclusion Our study has the highest number of dysmorphism examined in literature, found in all the children exposed to valproic acid, which may account for the higher rate of facial dysmorphism and dental anomalies. On lower doses of valproic acid, major malformations are not seen, although the risk increases with polytherapy. Our data also indicate possible effects of genetic and environmental factors on malformations. PMID:28138106

  5. Antiepileptic drugs and bone metabolism.

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    Valsamis, Helen A; Arora, Surender K; Labban, Barbara; McFarlane, Samy I

    2006-09-06

    Anti-epileptic medications encompass a wide range of drugs including anticonvulsants, benzodiazepines, enzyme inducers or inhibitors, with a variety effects, including induction of cytochrome P450 and other enzyme, which may lead to catabolism of vitamin D and hypocalcemia and other effects that may significantly effect the risk for low bone mass and fractures. With the current estimates of 50 million people worldwide with epilepsy together with the rapid increase in utilization of these medications for other indications, bone disease associated with the use of anti-epileptic medications is emerging as a serious health threat for millions of people. Nevertheless, it usually goes unrecognized and untreated. In this review we discuss the pathophysiologic mechanisms of bone disease associated with anti-epileptic use, including effect of anti-epileptic agents on bone turnover and fracture risk, highlighting various strategies for prevention of bone loss and associated fractures a rapidly increasing vulnerable population.

  6. 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. 

  7. Antiepileptic drugs and pregnancy outcomes.

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    Wlodarczyk, Bogdan J; Palacios, Ana M; George, Timothy M; Finnell, Richard H

    2012-08-01

    The treatment of epilepsy in women of reproductive age remains a clinical challenge. While most women with epilepsy (WWE) require anticonvulsant drugs for adequate control of their seizures, the teratogenicity associated with some antiepileptic drugs (AEDs) is a risk that needs to be carefully addressed. Antiepileptic medications are also used to treat an ever broadening range of medical conditions such as bipolar disorder, migraine prophylaxis, cancer, and neuropathic pain. Despite the fact that the majority of pregnancies of WWE who are receiving pharmacological treatment are normal, studies have demonstrated that the risk of having a pregnancy complicated by a major congenital malformation is doubled when comparing the risk of untreated pregnancies. Furthermore, when AEDs are used in polytherapy regimens, the risk is tripled, especially when valproic acid (VPA) is included. However, it should be noted that the risks are specific for each anticonvulsant drug. Some investigations have suggested that the risk of teratogenicity is increased in a dose-dependent manner. More recent studies have reported that in utero exposure to AEDs can have detrimental effects on the cognitive functions and language skills in later stages of life. In fact, the FDA just issued a safety announcement on the impact of VPA on cognition (Safety Announcement 6-30-2011). The purpose of this document is to review the most commonly used compounds in the treatment of WWE, and to provide information on the latest experimental and human epidemiological studies of the effects of AEDs in the exposed embryos.

  8. Stiripentol. A novel antiepileptic drug.

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    Trojnar, Michał K; Wojtal, Katarzyna; Trojnar, Marcin P; Czuczwar, Stanisław J

    2005-01-01

    Epilepsy is one of the most widespread pathologies of human brain, affecting approximately 1% of world population. Despite the development of new methods of seizure control, chronic administration of antiepileptic drugs (AEDs) remains the treatment of choice. Nevertheless, pharmacotherapy is not always effective. In the case of single drug treatment, the number of non-responding patients is as high as 30%. Moreover, chronic medication with currently available AEDs may result in severe side-effects and undesired drug interactions. That is why in recent years intensive research has been carried out aiming at the development of new therapeutic strategies in epilepsy. The goal of this review is to assemble current literature data on stiripentol (STP), a novel anticonvulsant unrelated to any other AEDs. STP potentiates central gamma-aminobutyric acid (GABA) transmission and is characterized by nonlinear pharmacokinetics and inhibition of liver microsomal enzymes. STP has proved its anticonvulsant potency in different types of animal seizures, as well as in clinical trials. The drug seems a good candidate for adjunctive therapy in intractable epilepsy.

  9. Potential Broad Spectrum Inhibitors of the Coronavirus 3CLpro: A Virtual Screening and Structure-Based Drug Design Study.

    Science.gov (United States)

    Berry, Michael; Fielding, Burtram C; Gamieldien, Junaid

    2015-12-15

    Human coronaviruses represent a significant disease burden; however, there is currently no antiviral strategy to combat infection. The outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) less than 10 years later demonstrates the potential of coronaviruses to cross species boundaries and further highlights the importance of identifying novel lead compounds with broad spectrum activity. The coronavirus 3CL(pro) provides a highly validated drug target and as there is a high degree of sequence homology and conservation in main chain architecture the design of broad spectrum inhibitors is viable. The ZINC drugs-now library was screened in a consensus high-throughput pharmacophore modeling and molecular docking approach by Vina, Glide, GOLD and MM-GBSA. Molecular dynamics further confirmed results obtained from structure-based techniques. A highly defined hit-list of 19 compounds was identified by the structure-based drug design methodologies. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds is bioactive is excellent. Additionally, the compounds segregate into 15 significantly dissimilar (p < 0.05) clusters based on shape and features, which represent valuable scaffolds that can be used as a basis for future anti-coronaviral inhibitor discovery experiments. Importantly though, the enriched subset of 19 compounds identified from the larger library has to be validated experimentally.

  10. Broad-spectrum antiviral agents

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    Jun-Da eZhu

    2015-05-01

    Full Text Available Development of highly effective, broad-spectrum antiviral agents is the major objective shared by the fields of virology and pharmaceutics. Antiviral drug development has focused on targeting viral entry and replication, as well as modulating cellular defense system. High throughput screening of molecules, genetic engineering of peptides, and functional screening of agents have identified promising candidates for development of optimal broad-spectrum antiviral agents to intervene in viral infection and control viral epidemics. This review discusses current knowledge, prospective applications, opportunities, and challenges in the development of broad-spectrum antiviral agents.

  11. Antiepileptic drugs: newer targets and new drugs

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    Vihang S. Chawan

    2016-06-01

    Full Text Available Epilepsy is a common neurological disorder affecting 0.5-1% of the population in India. Majority of patients respond to currently available antiepileptic drugs (AEDs, but a small percentage of patients have shown poor and inadequate response to AEDs in addition to various side effects and drug interactions while on therapy. Thus there is a need to develop more effective AEDs in drug resistant epilepsy which have a better safety profile with minimal adverse effects. The United States food and drug administration (USFDA has approved eslicarbazepine acetate, ezogabine, perampanel and brivaracetam which have shown a promising future as better AEDs and drugs like ganaxolone, intranasal diazepam, ICA- 105665, valnoctamide, VX-765, naluzotan are in the pipeline. [Int J Basic Clin Pharmacol 2016; 5(3.000: 587-592

  12. 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.

  13. 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 t...

  14. 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...

  15. 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.

  16. Adverse motor effects induced by antiepileptic drugs.

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    Zaccara, G; Cincotta, M; Borgheresi, A; Balestrieri, F

    2004-09-01

    Cognitive effects of anti-epileptic drugs (AEDs) have been already extensively reported. In contrast, motor disturbances, frequently induced by these drugs, have not received similar attention. We review subjective and objective adverse motor effects of traditional and new AEDs. We discuss the methodological issues caused by the heterogeneous sources of information on drug adverse effects (controlled clinical studies, open studies, and case reports). We describe specific disturbances (vestibulocerebellar, dyskinesias, parkinsonism, tics, myoclonus, and tremor) as the effects of different AEDs on distinct motor circuitries. Finally, we summarize the role of sophisticated technical studies which provide a valuable insight into the specific or subtle effects of AEDs on the central nervous system.

  17. Psychotic disorders induced by antiepileptic drugs in people with epilepsy.

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    Chen, Ziyi; Lusicic, Ana; O'Brien, Terence J; Velakoulis, Dennis; Adams, Sophia J; Kwan, Patrick

    2016-10-01

    Antiepileptic drug treatment can induce psychosis in some patients. However, there are no agreed definitions or diagnostic criteria for antiepileptic drug-induced psychotic disorder in the classification systems of either epileptology or psychiatry. In this study we investigated the clinical spectrum of antiepileptic drug-induced psychotic disorder in patients with epilepsy. The medical records of all patients with epilepsy who were diagnosed by a neuropsychiatrist as having a psychotic disorder at the Royal Melbourne Hospital from January 1993 to June 2015 were reviewed. Data were extracted regarding epilepsy and its treatment, psychotic symptoms profile and outcome. The diagnosis of epilepsy was established in accordance to the classification system of the International League Against Epilepsy while that of psychotic disorder was made according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition and the proposal on neuropsychiatric disorders in epilepsy. Patients with antiepileptic drug-induced psychotic disorder were compared to those with psychotic disorders unrelated to antiepileptic drugs assessed over the same period (non-antiepileptic drug induced psychotic disorder group). Univariate comparisons were performed and variables with a value of P psychosis after valproate withdrawal, 76.9% in the antiepileptic drug induced psychotic disorder group were female and the percentage of temporal lobe involvement was higher in the antiepileptic drug induced psychotic disorder group (69.2% versus 38.1%, P psychosis had antiepileptic drug-induced psychotic disorder. In these patients, female gender, temporal lobe involvement and current use of levetiracetam were significantly associated with antiepileptic drug induced psychotic disorder compared to other types of psychosis, while carbamazepine had a negative association. Disorganized behaviours and thinking were predominant in antiepileptic drug-induced psychotic disorder. Patients with

  18. Effects of antiepileptic drugs in electrophysiological tests.

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    Rump, S; Kowalczyk, M

    1987-01-01

    Methods of the study of antiepileptic drugs activity by means of analysis of their effects on bioelectrical ictal phenomena in the animal brain are described. The paper deals especially with EEG signal processing methods. Application of various nonparametric models (e.g. interval-amplitude scatter plots, power spectra analysis) as well as parametric models (e.g. autoregressive model, segmentation analysis) is discussed. A discriminative approach to some of these methods (especially to autoregressive model) is also presented. Special attention is stressed on the value of these methods for the study of anticonvulsant drugs activity.

  19. 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 and phenoba......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...... and phenobarbital), are strong inducers of the hepatic cytochrome P450 (CYP) 3A4 enzyme system, and are associated with increased the risk of contraceptive failure. In addition, it is demonstrated that also some of the newer AEDs, oxcarbazepine and topiramate influence on the pharmacokinetics of OCs, which...... 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...

  20. Interactions between antiepileptic drugs and hormones.

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

    2015-05-01

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

  1. [New antiepileptic drugs: characteristics and clinical applications].

    Science.gov (United States)

    Ohtsuka, Yoko

    2014-05-01

    New antiepileptic drugs (AEDs) that have been used in many other countries for more than 10 years have only recently became available for use in Japan. Gabapentin, topiramate, lamotrigine and levetiracetam were licensed for use in Japan between 2006 and 2010. Stiripentol for Dravet syndrome and rufinamide for Lennox-Gastaut syndrome were also approved in 2012 and 2013 as orphan drugs. Clinical trials of other new AEDs such as oxcarbazepine, vigabatrin, lacosamide, and perampanel are in progress. In this review, the general characteristics of the new AEDs are discussed with regards to their effectiveness, tolerability, drug interaction, safety and mechanisms of action. The effectiveness, of the new AEDs compared with established AEDs is also discussed. Clinical applications of the new AEDs, focusing on gabapentin, topiramate, lamotrigine and levetiracetam are also discussed based on our domestic experience as well as overseas reports.

  2. Antiepileptic Drug Withdrawal in Dogs with Epilepsy.

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    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.

  3. Antiepileptic drug withdrawal in dogs with epilepsy

    Directory of Open Access Journals (Sweden)

    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.

  4. Perioperative substitution of anti-epileptic drugs.

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    Wichards, Wilma S W; Schobben, Alfred F A M; Leijten, Frans S S

    2013-11-01

    A common problem in brain and abdominal surgery is the perioperative substitution of antiepileptic drugs (AEDs) when patients are temporarily unable to take these drugs orally. We searched the literature for clinical trials with patients or healthy volunteers in whom non-oral formulations of AEDs as substitution were tested. Different search engines, handbooks, expert opinion and our own experience, were used. Pharmaceutical companies were approached for recommendations. This led to three categories of replacement: 1. commercial alternative (n = 10) for clonazepam, diazepam, lacosamide, levetiracetam, lorazepam, midazolam, nitrazepam, phenobarbital, phenytoin, and valproic acid; 2. alternatives that must be prepared (n = 6) for carbamazepine, clobazam, lamotrigine, oxcarbazepine, primidone, topiramate; 3. no alternative (n = 7) for ethosuccimide, felbamate, retigabine, stiripentol, tiagabine, vigabatrin, zonisamide. Thus, for a substantial number of AEDs, unofficial perioperative treatment strategies need to be followed for lack of alternatives to oral administration. There is little clinical research addressing the equivalence of oral and parenteral formulas. Perioperative substitution of AEDs is an underestimated problem, and may increase the risk of postoperative seizures.

  5. 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.

  6. Neurodevelopmental effects of fetal antiepileptic drug exposure.

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    Velez-Ruiz, Naymee J; Meador, Kimford J

    2015-03-01

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

  7. Antiepileptic drug regimens and major congenital abnormalities in the offspring.

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    Samrén, E B; van Duijn, C M; Christiaens, G C; Hofman, A; Lindhout, D

    1999-11-01

    To assess the risk of major congenital abnormalities associated with specific antiepileptic drug regimens, a large retrospective cohort study was performed. The study comprised 1,411 children born between 1972 and 1992 in four provinces in The Netherlands who were born to mothers with epilepsy and using antiepileptic drugs during the first trimester of pregnancy, and 2,000 nonepileptic matched controls. We found significantly increased risks of major congenital abnormalities for carbamazepine and valproate monotherapy, with evidence for a significant dose-response relationship for valproate. The risk of major congenital abnormalities was nonsignificantly increased for phenobarbital monotherapy when caffeine comedication was excluded, but a significant increase in risk was found when caffeine was included. Phenytoin monotherapy was not associated with an increased risk of major congenital abnormalities. Regarding polytherapy regimens, increased risks were found for several antiepileptic drug combinations. Clonazepam, in combination with other antiepileptic drugs, showed a significantly increased relative risk. Furthermore, there were significantly increased relative risks for the combination of carbamazepine and valproate and the combination of phenobarbital and caffeine with other antiepileptic drugs. This study shows that most antiepileptic drug regimens were associated with an increased risk of major congenital abnormalities in the offspring, in particular valproate (dose-response relationship) and carbamazepine monotherapy, benzodiazepines in polytherapy, and caffeine comedication in combinations with phenobarbital.

  8. Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites

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    Kevin, Dion A; Meujo, Damaris AF; Hamann, Mark T

    2016-01-01

    Background As multidrug-resistant (MDR) pathogens continue to emerge, there is a substantial amount of pressure to identify new drug candidates. Carboxyl polyethers, also referred to as polyether antibiotics, are a unique class of compounds with outstanding potency against a variety of critical infectious disease targets including protozoa, bacteria and viruses. The characteristics of these molecules that are of key interest are their selectivity and high potency against several MDR etiological agents. Objective Although many studies have been published about carboxyl polyether antibiotics, there are no recent reviews of this class of drugs. The purpose of this review is to provide the reader with an overview of the spectrum of activity of polyether antibiotics, their mechanism of action, toxicity and potential as drug candidates to combat drug-resistant infectious diseases. Conclusion Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic infections. Despite the long history of use of this class of drugs, very limited medicinal chemistry and drug optimization studies have been reported, thus leaving the door open to these opportunities in the future. Scifinder and PubMed were the main search engines used to locate articles relevant to the topic presented in the present review. Keywords used in our search were specific names of each of the 88 compounds presented in the review as well as more general terms such as polyethers, ionophores, carboxylic polyethers and polyether antibiotics. PMID:23480512

  9. Effects of fetal antiepileptic drug exposure

    Science.gov (United States)

    Baker, G.A.; Browning, N.; Cohen, M.J.; Bromley, R.L.; Clayton-Smith, J.; Kalayjian, L.A.; Kanner, A.; Liporace, J.D.; Pennell, P.B.; Privitera, M.; Loring, D.W.; Labiner, David; Moon, Jennifer; Sherman, Scott; Combs Cantrell, Deborah T.; Silver, Cheryl; Goyal, Monisha; Schoenberg, Mike R.; Pack, Alison; Palmese, Christina; Echo, Joyce; Meador, Kimford J.; Loring, David; Pennell, Page; Drane, Daniel; Moore, Eugene; Denham, Megan; Epstein, Charles; Gess, Jennifer; Helmers, Sandra; Henry, Thomas; Motamedi, Gholam; Flax, Erin; Bromfield, Edward; Boyer, Katrina; Dworetzky, Barbara; Cole, Andrew; Halperin, Lucila; Shavel-Jessop, Sara; Barkley, Gregory; Moir, Barbara; Harden, Cynthia; Tamny-Young, Tara; Lee, Gregory; Cohen, Morris; Penovich, Patricia; Minter, Donna; Moore, Layne; Murdock, Kathryn; Liporace, Joyce; Wilcox, Kathryn; Kanner, Andres; Nelson, Michael N.; Rosenfeld, William; Meyer, Michelle; Clayton-Smith, Jill; Mawer, George; Kini, Usha; Martin, Roy; Privitera, Michael; Bellman, Jennifer; Ficker, David; Baade, Lyle; Liow, Kore; Baker, Gus; Booth, Alison; Bromley, Rebecca; Casswell, Miranda; Barrie, Claire; Ramsay, Eugene; Arena, Patricia; Kalayjian, Laura; Heck, Christianne; Padilla, Sonia; Miller, John; Rosenbaum, Gail; Wilensky, Alan; Constantino, Tawnya; Smith, Julien; Adab, Naghme; Veling-Warnke, Gisela; Sam, Maria; O'Donovan, Cormac; Naylor, Cecile; Nobles, Shelli; Santos, Cesar; Holmes, Gregory L.; Druzin, Maurice; Morrell, Martha; Nelson, Lorene; Finnell, Richard; Yerby, Mark; Adeli, Khosrow; Wells, Peter; Browning, Nancy; Blalock, Temperance; Crawford, Todd; Hendrickson, Linda; Jolles, Bernadette; Kunchai, Meghan Kelly; Loblein, Hayley; Ogunsola, Yinka; Russell, Steve; Winestone, Jamie; Wolff, Mark; Zaia, Phyllis; Zajdowicz, Thad

    2012-01-01

    Objective: To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure. Methods: The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999–2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5). Results: Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102–109), lamotrigine 106 (102–109), phenytoin 105 (102–109), valproate 96 (91–100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills. Conclusions: Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed. PMID:22491865

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Antimicrobial interactions (synergy) of teicoplanin with two broad-spectrum drugs (cefotaxime, ofloxacin) tested against gram-positive isolates from Germany and the United States.

    Science.gov (United States)

    Jones, R N; Marshall, S A; Grimm, H

    1997-10-01

    Teicoplanin, a glycopeptide, has been widely used in some nations alone and in empiric therapy combinations to address infections caused by Gram-positive cocci. However, glycopeptide resistance and the increasing incidence of oxacillin-resistant staphylococci have compromised contemporary chemotherapy. In this study, teicoplanin was tested in combinations with ampicillin, cefotaxime with and without desacetylcefotaxime, and ofloxacin against 151 Gram-positive cocci to assess the potential for enhanced action. The strains included recent isolates from the United States and Germany having well-characterized resistance mechanisms (oxacillin-resistant staphylococci, vancomycin-resistant enterococci), each tested by NCCLS methods, checkerboard synergy tests, and kill-curves. Teicoplanin alone was active (MIC90s, 0.25-2 micrograms/mL) against all species except vanA enterococci. Drug interactions of teicoplanin with beta-lactams revealed synergy and partial synergy versus oxacillin-resistant Staphylococcus spp. (67-100%) and vancomycin-resistant enterococci (70-100%), many at clinically achievable drug concentrations. However, confirming kill-curve experiments showed static action and no significant bactericidal effect. Combinations of ofloxacin with teicoplanin or cefotaxime plus desacetylcefotaxime showed a dominant additive and indifferent interaction. Teicoplanin continues to be a viable alternative to vancomycin, especially in combination therapy with selected broad-spectrum cephalosporins or fluoroquinolones. Many emerging pathogens that test resistant to individual drugs appear to be inhibited by tested combinations, extending their potential clinical utility.

  12. Antiepileptic drug poisoning: Three-year experience

    Directory of Open Access Journals (Sweden)

    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.

  13. Functional roles of benzothiazole motif in antiepileptic drug research.

    Science.gov (United States)

    Amir, Mohammad; Hassan, Mohd Zaheen

    2013-12-01

    Benzothiazoles are promising candidates for the design of novel antiepileptic drugs. The endocyclic sulphur and nitrogen functions present in this heterocyclic nucleus have been shown to be critical for the anticonvulsant activity. The present review outlines the rational design and anticonvulsant potential of promising benzothiazole lead molecules. Particular focus has been placed on the structure activity relationship of different benzothiazole derivatives giving selected examples of molecules with significant activity being that these molecules may serve as prototypes for the development of more active antiepileptic drugs.

  14. 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

    is the enzyme system that converts androgens to estrogens and consequently an inhibition may induce a hormone imbalance. Twelve antiepileptic drugs, used in mono or polytherapy for the treatment of children, were tested for their ability to inhibit aromatase (CYP19) with commercially available microsomes from......Antiepileptic drugs and epilepsy are often associated with sexual disorder in women such as hyperandrogenism, menstrual disorders and ovarian cysts. In children, until puberty, a hormone imbalance may influence many aspects of development, e.g. growth and sexual maturation. The aromatase complex...

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

    OpenAIRE

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

    2012-01-01

    bjective  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  Ther...

  16. 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...

  17. Co-prescription of antiepileptic drugs and contraceptives

    NARCIS (Netherlands)

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

    2012-01-01

    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 prescripti

  18. 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.

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

    DEFF Research Database (Denmark)

    Olesen, J.B.; 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...

  20. Levetiracetam as an antiepileptic, neuroprotective, and hyperalgesic drug

    Directory of Open Access Journals (Sweden)

    J L Cortes-Altamirano

    2016-01-01

    Full Text Available The main purpose of this review was to expound upon the mechanism of action of Levetiracetam (LEV as an antiepileptic, neuroprotective, and hyperalgesic drug. LEV is a second-generation anti-epileptic drug (AED that is approved for clinical use as monotherapy and may also be used for adjunctive treatment of patients with seizures. Several researchers have recommended LEV as a treatment option in different diseases causing neuronal damage, and recently, LEV has been used as an antihyperalgesic drug. LEV exhibits favorable characteristics, including a low potential for interaction, a short elimination half-life, and has neither active metabolites nor major negative effects on cognition. This has generated many new research avenues for the utilization of this drug. However, the precise mechanism of action of LEV has not been fully elucidated. In this review, a search was conducted on PubMed, ProQuest, EBSCO, and the Science Citation index for studies evaluating the effects of LEV as an antiepileptic, neuroprotective, and hyperalgesic drug. A total of 32 studies related to the use of LEV suggested different mechanisms of action, such as binding to the synaptic vesicle glycoprotein 2A (SV2A protein, inhibition of Ca2+ N-type channels, and its presence as a neuromodulator. These studies concluded that the pharmacodynamics of LEV should be viewed as a single pathway, and should not be based on specific molecular targets that depend on the physiological or pathological conditions prevalent at that time.

  1. Neuropathological sequelae of developmental exposure to antiepileptic and anesthetic drugs

    Directory of Open Access Journals (Sweden)

    Chrysanthy eIkonomidou

    2012-08-01

    Full Text Available Glutamate (Glu and aminobutyric acid (GABA are major neurotransmitters in the mammalian brain which regulate brain development at molecular, cellular and systems level. Sedative, anesthetic and antiepileptic drugs interact with glutamate and GABA receptors to produce their desired effects. The question is posed whether such interference with glutamatergic and GABAergic neurotransmission may exert undesired, and perhaps even detrimental effects on human brain development. Preclinical research in rodents and non-human primates has provided extensive evidence that sedative, anesthetic and antiepileptic drugs can trigger suicide of neurons and oligodendroglia, suppress neurogenesis, and inhibit normal synapse development and sculpting. Behavioral correlates in rodents and non-human primates consist of long-lasting cognitive impairment. Retrospective clinical studies in humans exposed to anesthetics or antiepileptic drugs in utero, during infancy or early childhood have delivered conflicting but concerning results in terms of a correlation between drug exposure and impaired neurodevelopmental outcomes. Prospective studies are currently ongoing. This review provides a short overview of the current state of knowledge on this topic.

  2. Broad-spectrum antiviral therapeutics.

    Directory of Open Access Journals (Sweden)

    Todd H Rider

    Full Text Available Currently there are relatively few antiviral therapeutics, and most which do exist are highly pathogen-specific or have other disadvantages. We have developed a new broad-spectrum antiviral approach, dubbed Double-stranded RNA (dsRNA Activated Caspase Oligomerizer (DRACO that selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have created DRACOs and shown that they are nontoxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arenaviruses, Guama bunyavirus, and H1N1 influenza. We have also demonstrated that DRACOs can rescue mice challenged with H1N1 influenza. DRACOs have the potential to be effective therapeutics or prophylactics for numerous clinical and priority viruses, due to the broad-spectrum sensitivity of the dsRNA detection domain, the potent activity of the apoptosis induction domain, and the novel direct linkage between the two which viruses have never encountered.

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    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...... 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...

  4. 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

  5. Cost analysis of antiepileptic drugs available in India

    Directory of Open Access Journals (Sweden)

    Ajay Kumar Shukla

    2016-08-01

    Conclusions: The average percentage price variation of different brands of the same oral antiepileptic drugs in Indian market is very wide. Treatment of epilepsy has a long course with compliance being a key factor for successful treatment. Improved adherence to the treatment can be ensured by decreasing the cost of therapy, by changes in the government policies and regulations and creating awareness among treating physicians for switching to cost effective therapy. [Int J Basic Clin Pharmacol 2016; 5(4.000: 1636-1640

  6. Pharmacy and generic substitution of antiepileptic drugs: missing in action?

    Science.gov (United States)

    Welty, Timothy E

    2007-06-01

    Generic substitution of antiepileptic drugs is an issue that is gathering a lot of attention in the neurology community but is not receiving much attention within pharmacy. Several proposals have been drafted that restrict a pharmacist's decision-making in generic substitution. These proposals highlight concerns about the pharmacy community related to generic substitution. Careful consideration needs to be given to these issues by pharmacists and pharmacy professional organizations. Unless pharmacy as a profession takes strong positions in support of a pharmacist's ability to make decisions about pharmacotherapy and addresses many of the pharmacy-related problems of generic substitution, policies that negatively impact pharmacy will be established.

  7. Teratogenic Potential of Antiepileptic Drugs in the Zebrafish Model

    Directory of Open Access Journals (Sweden)

    Sung Hak Lee

    2013-01-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

  9. 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 w

  10. 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

  11. Neurological teratogenic effects of antiepileptic drugs during pregnancy

    Science.gov (United States)

    Nie, Qingmei; Su, Baohua; Wei, Jianping

    2016-01-01

    Epilepsy is one of the few neurologic disorders that requires a constant treatment during pregnancy. Epilepsy affects 0.3–0.8% of pregnant women. Prescription of antiepileptic drugs (AEDs) to pregnant women with epilepsy requires monitoring and maintaining a balance between limiting seizures and decreasing fetal exposure to the potential teratogenic effects. AEDs are also commonly used for psychiatric disorders, pain disorders, and migraines. The types of malformations that can result in fetuses exposed to AEDs include minor anomalies, major congenital malformations, intrauterine growth retardation, cognitive dysfunction, low IQ, microcephaly, and infant mortality. In the present review, we analyzed and summarized the current understanding of neurological development in fetuses that are exposed to various AEDs administered to pregnant epileptic women. PMID:27698740

  12. 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

    Objective. 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. Approach. 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. Main results. (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. Significance. 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.

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

    Science.gov (United States)

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

    2016-08-01

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

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

    Science.gov (United States)

    2014-10-01

    cutaneous wound model in rats with the drug resistant Gram negative bacteria Acinetobacter baumannii , Escherichia coli, Klebsiella pneumoniae and...wound model in rats with the drug resistant Gram negative bacteria Acinetobacter baumannii , Escherichia coli, Klebsiella pneumoniae and pathogenic mold...organisms respectively. Section 3. Establishing the wound infection in rats with Acinetobacter baumannii strain ATCC BAA-747 (specific aim 2). Q5

  15. 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

  16. 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.

  17. Polycystic ovary syndrome in patients on antiepileptic drugs

    Science.gov (United States)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Yu Liu

    2015-01-01

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

  19. Antiepileptic drugs in pregnancy and hemorrhagic disease of the newborn: An update

    OpenAIRE

    2010-01-01

    QUESTION What is the current evidence regarding the association between hemorrhagic disease of the newborn and maternal use of hepatic enzyme-inducing antiepileptic drugs (eg, carbamazepine, phenobarbitone, topiramate)?

  20. Influence of normal versus slow antiepileptic drugs withdrawal on seizure recurrence in patients with epilepsy

    Institute of Scientific and Technical Information of China (English)

    王凌玲

    2013-01-01

    Objective To explore the influence of normal and slow antiepileptic drugs(AEDs) withdrawal on recurrence of epilepsy. Methods Epileptic patients with seizure-free more than 2 years were recruited to the study. They were first divided into normal

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

    OpenAIRE

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

    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 progno...

  2. 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

    with regenerated skin . By day 10 the regenerated skin has normal activity with the presence of fur. Wound measurement in this model was not practical...in quarterly report Q9.01.2015. Therefore, the dermal pH value in the open wound of rat skin was measured in vivo using a pH micro- electrode over a...restricting the penetration of the drug. During the next quarter and throughout next year, we will perform studies with a modified application method

  3. Stiripentol: an example of antiepileptic drug development in childhood epilepsies.

    Science.gov (United States)

    Nabbout, Rima; Chiron, Catherine

    2012-09-01

    The efficacy of stiripentol (STP) in Dravet Syndrome (DS) was discovered first in an exploratory study in pediatric pharmacoresistant epilepsies. This efficacy signal, used as a proof of concept, led to - two independent multicenter randomized, double-blind, placebo-controlled trials in DS patients: STICLO-France and STICLO-Italy. In adjunction to valproate and clobazam, STP demonstrated marked efficacy and these trials became the basis for the registration of STP as an orphan drug for DS. Although STP had previously shown antiepileptic activity, since it inhibits cytochromes P450, the increased plasma levels of clobazam (CLB), norclobazam (NCLB), and NCLB/CLB ratio reported in STICLO studies brought into question the activity of STP per se. Recent pharmacological studies demonstrated that (i) STP is a direct allosteric modulator of the GABA receptors at a site distinct from benzodiazepines; (ii) STP and CLB/NCLB act independently at GABA(A) receptors; (iii) their combination increases the maximum response beyond that of either drug alone. All these effects are independent of considerations of changes in metabolism. Some responders in STICLO studies failed to display any increase of plasmatic concentrations of NCLB/CLB ratio as STP could not inhibit CYP2C19 because of its inhibition by progabide or due to an inactivating CYP polymorphism. The responder rate proved to be in the same range whether the NCLB/CLB ratio increased or not. These analyses confirmed that the effects of STP cannot result from a simple pharmacokinetic interaction. We propose that the success of STP should serve as a model for AED development in rare pediatric epileptic syndromes.

  4. [Antiepileptic drugs as mood stabilizers: what did we learn from the epileptology?].

    Science.gov (United States)

    Rajna, Péter

    2008-09-30

    Author summarizes the practical aspects of psychiatric application of mood stabilizing antiepileptic drugs. He observes how to transfer experiences taken from the "epileptologic" practice into the psychiatric care of bipolar patients. He shortly demonstrates the relevant information on the mechanisms of action, controversies and possible clinical effects influenced by the seizure inhibiting effect of the concerning molecules. By the opinion of the author the clinical importance of pharmacokinetic parameters are underestimated in the psychiatric practice. Therefore--as an original approach in the literature--he summarizes the detailed clinical indications of serum level measurements of antiepileptic drugs applied in psychiatry as mood stabilizers. The therapeutic experiences in epilepsy added a lot of practices for the most effective dosing, building, tapering and exchange of the mood stabilizer antiepileptics. Drug interactions (appear among the psychotropic drugs or with the commonly used medicines). As in any chronic therapies the main condition of patient's compliance is the lacking or very mild presence of the applied therapy. The paper discusses the most frequently occurring and drug-specific side effects in table forms. Using the term of "relative therapeutic potential" the need of balance between the efficacy (influenced by the choice and dosing) and the tolerance are pointed. Rules of application can change significantly in special populations like in pregnancy, obesity, chronic diseases or in chronic comorbid states and in case of polytherapy. As for the special therapeutic effects, the experiences are not completed even in group of antiepileptics: we have larger and more favorable knowledge on the traditional drugs (carbamazepine and valproate) and on lamotrigine (from the newer generation) but promising but not enough information exists on the newest antiepileptic molecules. Further targeted studies are needed for the identification and positioning of

  5. 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

  6. Historical Origin And Antiepileptic Drug Development [história Do Surgimento E Desenvolvimento Das Drogas Antiepilépticas

    OpenAIRE

    Guerreiro C.A.M.

    2006-01-01

    Introduction: New antiepileptic drugs are needed because many epileptic patients do not achieve complete control with current antiepileptic drugs. Methods: We reviewed the historical origin of antiepileptic drugs, the different phases of the medical treatment related to monotherapy or polytheraphy, and the experimental models applied to develop new medications nowadays. Results: Experimental models have been used for many years in order to detect some rational mechanisms of action. The result...

  7. Broad spectrum antiangiogenic treatment for ocular neovascular diseases.

    Directory of Open Access Journals (Sweden)

    Ofra Benny

    Full Text Available UNLABELLED: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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

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

    Science.gov (United States)

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

    2016-05-01

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

  9. 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.

  10. Rufinamide: a new antiepileptic drug treatment for Lennox-Gastaut syndrome.

    Science.gov (United States)

    Ferrie, Colin D

    2010-06-01

    Lennox-Gastaut syndrome is a relatively rare epilepsy syndrome that usually begins in early-mid childhood and is characterized by multiple seizure types, particularly generalized seizures, which are often resistant to antiepileptic drug medication. Rufinamide is a new antiepileptic drug approved as adjunctive therapy to treat seizures in Lennox-Gastaut syndrome in those 4 years of age and older. In this article, the putative mechanism of action is described, along with data relating to its pharmacokinetics and metabolism. Key findings from clinical trials are presented and discussed. Adverse effects are summarized and compared with those encountered with competitor antiepileptic drugs. Finally, the role of rufinamide in the holistic management of subjects with Lennox-Gastaut syndrome is considered.

  11. 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 ...

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. The Risk of Specific Congenital Anomalies in Relation to Newer Antiepileptic Drugs : A Literature Review

    NARCIS (Netherlands)

    de Jong, Josta; Garne, Ester; Jong-van den Berg, de Lolkje; Wang, Hao

    2016-01-01

    BACKGROUND: More information is needed about possible associations between the newer anti-epileptic drugs (AEDs) in the first trimester of pregnancy and specific congenital anomalies of the fetus. OBJECTIVES: We performed a literature review to find signals for potential associations between newer A

  17. 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 R

  18. 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 ...

  19. Four-year outcome after early withdrawal of antiepileptic drugs in childhood epilepsy

    NARCIS (Netherlands)

    Geerts, AT; Niermeijer, JMF; Arts, WFM; Brouwer, OF; Stroink, H; Peeters, EAJ; van Donselaar, CA

    2005-01-01

    Four-year follow-up of children with epilepsy included in a randomized trial of early withdrawal of antiepileptic drugs showed that 51% achieved a terminal remission of at least 2 years without medication and 21% with medication; 15% had seizures during the fourth year. Early medication withdrawal i

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

    NARCIS (Netherlands)

    LINDHOUT, D; OMTZIGT, JGC; CORNEL, MC

    1992-01-01

    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 wa

  1. Trends in the use of anti-epileptic drugs during pregnancy in the netherlands

    NARCIS (Netherlands)

    van Puijenbroek, Eugene; de Vries, Loes; Kant, Agnes

    2014-01-01

    Background: The use of anti-epileptic drugs (AEDs) during pregnancy is associated with an increased risk of birth defects. Since epilepsy itself is also associated with potential risks for mother and child, an optimal AED treatment is needed. Over the past years, the introduction of new AEDs and the

  2. Bone mineral density in adult patients treated with various antiepileptic drugs

    DEFF Research Database (Denmark)

    Beniczky, Simona Alexandra; Viken, Janina; Jensen, Lars Thorbjørn;

    2012-01-01

    There is considerable evidence suggesting, that older antiepileptic drugs (AEDs) and some of the newer ones decrease bone mineral density (BMD). However, there is only limited and conflicting data concerning the effect of levetiracetam on BMD. In this cross-sectional study we analysed data from 1...

  3. Changing Australian prescribing patterns for antiepileptic drugs in pregnancy and their possible consequences

    NARCIS (Netherlands)

    Vajda, F. J. E.; Lander, C. M.; Hitchcock, A.; Graham, J.; Solinas, C.; O'Brien, T.; Eadie, M. J.

    2007-01-01

    We report progress in the accumulation of data by the Australian Pregnancy Register over 64 months, confirming the rise in enrolment and the predominantly epileptic indication for taking antiepileptic drugs. Eighty percent of the enrolment was prospective. The focus of the current report is the obse

  4. [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.

  5. The role of reactive species in epileptogenesis and influence of antiepileptic drug therapy on oxidative stress.

    Science.gov (United States)

    Martinc, Boštjan; Grabnar, Iztok; Vovk, Tomaž

    2012-12-01

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

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

    Science.gov (United States)

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

    2016-05-01

    Using the mouse maximal electroshock test, the reference model of tonic-clonic seizures, the aim of the present study was to determine the type of interaction between mexiletine (a class IB antiarrhythmic drug) and classical antiepileptics: valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis of obtained data indicated antagonistic interactions between mexiletine and valproate (for fixed ratio combinations of 1:1 and 3:1). Additivity was observed between mexiletine and valproate applied in proportion of 1:3 as well as between mexiletine and remaining antiepileptics for the fixed ratios of 1:3, 1:1, and 3:1. Neither motor performance nor long-term memory were impaired by mexiletine or antiepileptic drugs regardless of whether they were administered singly or in combination. Mexiletine did not significantly affected brain concentrations of carbamazepine, phenobarbital or phenytoin. In contrast, the antiarrhythmic drug decreased by 23 % the brain level of valproate. This could be, at least partially, the reason of antagonistic interaction between the two drugs. In conclusion, the observed additivity suggests that mexiletine can be safely applied in epileptic patients treated with carbamazepine, phenytoin or phenobarbital. Because of undesirable pharmacodynamics and pharmacokinetic interactions with valproate, mexiletine should not be used in such combinations.

  7. 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, L; Vender, Simone

    2016-05-13

    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.

  8. Lacosamide: A novel antiepileptic and anti-nociceptive drug on the block

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    Sukhminder Jit Singh Bajwa

    2014-01-01

    Full Text Available With an increasing demand for newer anti-epileptic agents having a better pharmacological profile, many newer agents are being investigated. Lacosamide is a newer functional amino acid being developed as an adjunctive therapy for resistant partial-onset seizures owing to its activity of enhancing the slow inactivation of voltage-gated sodium channels thereby reducing pathologic hyperactivity in neurons. It has also being investigated for its role as anti-nociceptive in variety of pain scenarios specifically in diabetic neuropathic pain. It is well-absorbed orally, metabolized in liver and excreted by the kidneys. It has a favorable pharmacologic profile in having minimal drug interactions. The adverse effects include mild dizziness, behavioral changes and dose dependent prolongation of PR interval. This review is directed toward the development of lacosamide and its potential usefulness as an anti-epileptic and an anti-nociceptive drug.

  9. Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy

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    Junji Saruwatari

    2010-08-01

    Full Text Available Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmaco-dynamics of antiepileptic drugs (AEDs. However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450 (CYP 2C9 and/or CYP2C19 could affect not only the pharmacokinetics, but also the pharmacodynamics of phenytoin therapy. CYP2C19 deficient genotypes were associated with the higher serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the higher clinical efficacy of clobazam therapy than the other CYP2C19 genotypes. The defective alleles of CYP2C9 and/or CYP2C19 were also found to have clinically significant effects on the inter-individual variabilities in the population pharmacokinetics of phenobarbital, valproic acid and zonisamide. EPHX1 polymorphisms may be associated with the pharmacokinetics of carbamazepine and the risk of phenytoin-induced congenital malformations. Similarly, the UDP-glucuronosyltransferase 2B7 genotype may affect the pharmacokinetics of lamotrigine. Gluthatione S-transferase null genotypes are implicated in an increased risk of hepatotoxicity caused by carbamazepine and valproic acid. This article summarizes the state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies. Future directions for the dose-adjustment of AED are discussed.

  10. Broad spectrum anthelmintic potential of Cassia plants

    Institute of Scientific and Technical Information of China (English)

    Suman Kundu; Saptarshi Roy; Larisha Mawkhleing Lyndem

    2014-01-01

    Objective: To study the in vitro anthelmintic efficacy of Cassia alata (C. alata), Cassia(C. angustifolia) and Cassia occidentalis (C. occidentalis). angustifolia Methods: Crude ethanol extract from leaves of the three plants were prepared in rotary evaporator and different concentrations (10, 20 and 40 mg/mL) of leaf extracts were used for treatment on different representatives of helminthes (Heterakis gallinarum, Raillietina tetragona and Catatropis sp.) from domestic fowl (Gallus gallus domesticus). Loss of motility and death were monitored frequently.Results: C. alata showed early paralysis in all worms treated followed by C. angustifolia. C. occidentalis in combination with C. alata together caused early paralysis in all treated worms than the combination of C. alata with C. angustfolia. While Heterakis gallinarum in control survived for (81.33±2.07) h, treated worms lost their motility at (5.71±0.10) h, (6.60±0.86) h and (13.95±0.43) h with C. angustifolia, C. alata and C. occidentalis respectively at a concentration of 40 mg/mL which showed better efficacy than albendazole. Catatropis sp. survival period was (26.49±1.38) h in control, but with plant treatment, it lost its motility in just (0.57±0.08) h, (1.00±0.12) h and (1.47±0.40) h at 40 mg/mL concentration of C. alata, C. angustifolia and C. occidentalis respectively.Raillietina tetragona on the other hand became paralysed at (1.68±0.27) h, (2.95±0.29) h and (4.13±0.31) h with above concentrations treated with three plants respectively, however in control it survived up to (81.93±4.71) h.Conclusions:This present study indicated broad spectrum vermifugal activity of all plants tested.

  11. Clinical evaluation of clotrimazole. A broad-spectrum antifungal agent.

    Science.gov (United States)

    Spiekermann, P H; Young, M D

    1976-03-01

    The efficacy and safety of the broad-spectrum, topically applied antifungal agent clotrimazole were evaluated in two double-blind, multicentric trials. Ten investigators reported on a total of 1,361 cases in which a 1% solution or a 1% cream formulation was compared with its respective vehicle. Clotrimazole was therapeutically effective, as confirmed by mycological cure (negative microscopy and culture) and clinical improvement, in tinea pedis, tinea cruris, tinea corporis, pityriasis versicolor, and cutaneous candidasis. Furthermore, species identification established the efficacy of clotrimazole against Trichophyton rubrum, T mentagrophytes, Epidermophyton floccosum, Microsporum canis, Malassezia furfur (Pityrosporum orbiculare), and Candida albicans. Safety was demonstrated by the low incidence of possibly drug-related adverse experiences, namely, 19 (2.7%) of 699 patients who were treated with clotrimazole, of whom four (0.6%) discontinued treatment.

  12. Differences in antiepileptic drug efficacy in hippocampally kindled normal and microcephalic rats.

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    Majkowski, J; Danneberg, P; Knappen, F; Sersen, E A

    1986-10-29

    The difference in antiepileptic drug efficacy was investigated in two groups of animals: 5 normal and 4 microcephalic rats. The latter were produced by a single i.p. injection of 30 mg/kg methylazoxymethanol acetate in the mother on the 15th day of gestation. Hippocampal kindling was performed to a seizure criterion in all animals followed by testing of the antiepileptic drugs vs placebo. Besides carbamazepine (CBZ), two new anticonvulsants were tested: (E)-2-[(alpha-amino)phenylmethylene]-benzo-[b]-thiophene-3(2H)-one (AF-CX 921) and its metabolite (E)-2-[alpha-amino)phenylmethylene]-benzo-[b]-thiophene-3(2H)-one- 1- oxide (AF-CX 1325). Frequency of occurrence and duration of afterdischarges and seizures were statistically examined. The duration of early afterdischarges (AD1) tended to be shorter in microcephalic than in normal animals in control and placebo periods. In contrast, during treatment with the antiepileptic drugs, AD1 durations were longer in microcephalic than in normal animals. This suggests that the drugs inhibited AD1 to a lesser extent in the microcephalics. Two other characteristics of EEG epileptic activity, focal spiking (FS) and late afterdischarges (AD2) also varied in the two groups. Both were significantly lower in occurrence in the microcephalic rats independent of treatment. Three types of behavioral manifestations were also examined: convulsive seizures (CS), epileptic behavior (EB) and quiet states (Q). The two groups of animals responded differently to the drugs with respect to Q and CS. In the microcephalics, AFCX 1325 and AFCX 921 were superior to CBZ, which in turn, was superior to placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Tall gastrodis tuber combined with antiepileptic drugs repairs abnormal perfusion foci in focal epilepsy

    Institute of Scientific and Technical Information of China (English)

    Weimin Wang; Zhenyu Fan; Yongqin Zhang; Yuxia Yang; Yaqing Liu; Xiaoli Dang; Wenjun Song; Yinping Wu; Jiang Ye

    2013-01-01

    One hundred patients with focal epilepsy were recruited for the present study and their seizures controlled with antiepileptic drugs. The patients then orally received a capsule of tall gastrodis tuber powder, a traditional Chinese drug, and underwent single photon emission computed tomography, long-term electroencephalogram, and CT/MRI. Blood drug levels were monitored throughout the study. Before treatment with tall gastrodis tuber, 35 of the 100 cases had abnormal CT/MRI scans; 79 cases had abnormal single photon emission computed tomography images; 86 cases had abnormal electroencephalogram; and a total of 146 abnormal perfusion foci were observed across the 100 subjects. After treatment, the number of patients with normal single photon emission computed tomography images increased by 12; normal electroencephalogram was observed in an additional 27 cases and the number of patients with epileptiform discharge decreased by 29 (34% of 86); the total number of abnormal perfusion foci decreased by 52 (36%) and changes in abnormal foci were visible in 65 patients. These changes indicate that the administration of tall gastrodis tuber in combination with antiepileptic drugs repairs abnormal perfusion foci in patients with focal epilepsy. Our results demonstrate that traditional Chinese drugs can repair abnormal perfusion foci and, as such, are a promising new pathway in the treatment of focal epilepsy.

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

    Science.gov (United States)

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

    2015-03-01

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

  15. On the Operational Meaning of Broad-Spectrum Philosophy Methodology

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    Miao Yi

    2012-06-01

    Full Text Available This study analyze the Broad-spectrum Philosophy Methodology on the operational meaning, and discusses three relatively primary methods of Broad-spectrum Philosophy Methodologies. The methodology of Broad-spectrum philosophy cannot pursuit of accuracy of numerical sense, but it pursuits of the exact nature of the research questions, the accuracy of the sense of set theory and sums up the experience which we solve problems in real life and make it up to the generalized quantization and procedural level and thus the methodology of Broad-spectrum philosophy has a general guide and it is a broad operations research. We gets the results that along with deep exploration and development of Broad-spectrum Philosophy Methodology, its function as generalized operation research can be more powerful.

  16. Current understanding of the mechanism of action of the antiepileptic drug lacosamide.

    Science.gov (United States)

    Rogawski, Michael A; Tofighy, Azita; White, H Steve; Matagne, Alain; Wolff, Christian

    2015-02-01

    The antiepileptic drug lacosamide [(R)-2-acetamido-N-benzyl-3-methoxypropanamide], a chiral functionalized amino acid, was originally identified by virtue of activity in the mouse and rat maximal electroshock (MES) test. Attention was drawn to lacosamide because of its high oral potency and stereoselectivity. Lacosamide is also active in the 6 Hz seizure model but inactive against clonic seizures in rodents induced by subcutaneous pentylenetetrazol, bicuculline and picrotoxin. It is also ineffective in genetic models of absence epilepsy. At doses greater than those required to confer protection in the MES test, lacosamide inhibits behavioral and electrographic seizures in hippocampal kindled rats. It also effectively terminates seizures in the rat perforant path stimulation status epilepticus model when administered early after the onset of seizures. Lacosamide does not exhibit antiepileptogenic effects in kindling or post-status epilepticus models. The profile of lacosamide in animal seizure and epilepsy models is similar to that of sodium channel blocking antiepileptic drugs, such as phenytoin and carbamazepine. However, unlike these agents, lacosamide does not affect sustained repetitive firing (SRF) on a time scale of hundreds of milliseconds or affect fast inactivation of voltage-gated sodium channels; however, it terminates SRF on a time scale of seconds by an apparent effect on sodium channel slow inactivation. Lacosamide shifts the slow inactivation curve to more hyperpolarized potentials and enhances the maximal fraction of channels that are in the slow inactivated state. Currently, lacosamide is the only known antiepileptic drug in clinical practice that exerts its anticonvulsant activity predominantly by selectively enhancing slow sodium channel inactivation.

  17. Isobolographic analysis of interactions among losigamone analog AO-620 and two conventional antiepileptic drugs.

    Science.gov (United States)

    Borowicz, Kinga K; Jaszczyk, Bozena; Czuczwar, Stanisław J

    2005-01-01

    In the present study, we investigated pharmacodynamic interactions among AO-620, a losigamone analog, and two conventional antiepileptic drugs, valproate (VPA) and phenobarbital (PB). Experiments were conducted in the maximal electroshock test in mice. Isobolographic analysis of the obtained data revealed pure additive interactions between AO-620 and PB applied at three dose ratios of 1:1, 1:3 and 3:1. Antagonism was observed when AO-620 was co-administered with VPAat the ratio of 3:1, while additive interactions were seen in two remaining proportions (1:3 and 1:1). Surprisingly, the interaction pattern of AO-620 appeared quite different from that of losigamone.

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

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    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.

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

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    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.

  20. Effect of Antiepileptic drugs on plasma lipoprotein (a) and other lipid levels in childhood.

    Science.gov (United States)

    Aynaci, F M; Orhan, F; Orem, A; Yildirmis, S; Gedik, Y

    2001-05-01

    Antiepileptic drugs may alter plasma lipid status in epileptic patients. We conducted a study to assess the effect of phenobarbital, carbamazepine, and valproate on plasma levels of lipoprotein (a), total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein A, and apolipoprotein B in 22 epileptic children. The children were separated as group 1, seven children, mean age 1.6+/-0.2 years, treated with phenobarbital, 5 mg/kg/day, twice daily; group 2, seven children, mean age 9.8+/-1.2 years, treated with carbamazepine, 20 mg/kg/day, twice daily; and group 3, eight children, mean age 6.8+/-0.6 years, treated with valproate, 20 mg/kg/day, twice daily. Plasma lipoprotein (a) and other lipid levels were studied before (pretreatment) and at 3 and 6 months of treatment. Friedman two-way analysis of variance and Wilcoxon's signed-rank test were used for statistical analysis, and the results were expressed as the mean and standard error of the mean. The mean age of children in group 1 was significantly low, compared with groups 2 and, 3 (P < .001). The mean pretreatment lipid levels between the groups were not significant. The increase in lipoprotein (a) at 3 and 6 months and high-density lipoprotein cholesterol at 6 months was statistically significant in group 1 (P < .025). We suggest a careful monitoring of plasma levels of lipoprotein (a) and other lipids in epileptic children treated with antiepileptic drugs.

  1. Effect of antiepileptic drugs on plasma lipids, lipoprotein (a), and liver enzymes.

    Science.gov (United States)

    Sonmez, Fatma Mujgan; Demir, Ercan; Orem, Asim; Yildirmis, Sermet; Orhan, Fazil; Aslan, Adnan; Topbas, Murat

    2006-01-01

    We conducted a study to assess the effect of phenobarbital, carbamazepine, and valproate on serum lipid profiles and lipoprotein (a) in 64 children with epilepsy (aged between 1 and 15 years) admitted to the child neurology outpatient clinic between July 2000 and July 2002. The children were separated as group 1 (18 children), treated with phenobarbital, 5 mg/kg/day; group 2 (22 children), treated with carbamazepine, 10 to 15 mg/kg/day; and group 3 (24 children), treated with sodium valproate, 20 mg/kg/day. Plasma lipoprotein (a), total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein A and apolipoprotein B levels, and liver enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase were determined before the initiation of the treatment and at 3, 6, and 12 months of the treatment period. The mean age of children in group 1 was significantly low compared with those in groups 2 and 3 (P 30 mg/dL) were observed only in carbamazepine-treated patients at 6 and 12 months. The percentage of children with lipoprotein (a) levels over 30 mg/dL was 44%, 63%, and 33% in the phenobarbital-, carbamazepine-, and valproate-treated children, respectively. Antiepileptic drugs significantly increase the level of lipoprotein (a), which is a major risk factor for atherosclerosis, and also have variable effects on other lipid parameters. Lipoprotein (a) levels should be closely followed in patients receiving antiepileptic drugs. (J Child Neurol 2006;21:70-74).

  2. Interactions between two enantiomers of losigamone and conventional antiepileptic drugs in the mouse maximal electroshock model--an isobolographic analysis.

    Science.gov (United States)

    Borowicz, Kinga K; Jaszczyk, Bozena; Luszczki, Jarogniew J; Czuczwar, Stanislaw J

    2007-07-12

    The aim of this study was the isobolographic evaluation of interactions between two enantiomers of losigamone, AO-242 [(+)-5(R)-alpha(S)-5-(2-chlorophenylhydroxymethyl)-4-methoxy-2(5H)-furanone] and AO-294 [(-)-5(S)-alpha(R)-5-(2-chlorophenylhydroxymethyl)-4-methoxy-2(5H)-furanone], and valproate, carbamazepine, phenytoin, or phenobarbital in the maximal electroshock test in mice. Both enantiomers interacted additively with conventional antiepileptic drugs at all studied fixed dose ratios (1:3, 1:1, 3:1). Furthermore, AO-242, AO-294 and antiepileptics applied alone, as well as combinations of enantiomers and antiepileptics did not affect motor performance in the chimney test. Significant impairment of long-term memory (passive-avoidance task) was noted only in the case of valproate alone, given at the dose equal to its median effective dose (ED(50)) against maximal electroshock. All other antiepileptics and their combinations with AO-242 or AO-294 did not impair memory of mice. Enantiomers did not affect the brain concentrations of antiepileptic drugs, indicating a pharmacodynamic nature of the observed interactions. In conclusion, the present results suggest both AO-242 and AO-294 as promising candidate drugs in the add-on therapy of refractory epilepsy.

  3. Ceftobiprole: a new broad spectrum cephalosporin.

    Science.gov (United States)

    El Solh, Ali

    2009-07-01

    Ceftobiprole, formerly designated BAL9141/Ro 63-9141, is a pyrrolidinone-3-ylidene-methyl cephalosporin with demonstrated in vitro activity against MRSA, Enterococcus faecalis, Enterobacteriaceae and Pseudomonas aeruginosa. Ceftobiprole has a low potential for inducing chromosomal AmpC beta-lactamases but it is hydrolyzed by most extended spectrum beta-lactamases and metallo-beta-lactamases. Glomerular filtration is predominantly responsible for removal of the free drug from the systemic circulation. The efficacy of ceftobiprole in the treatment of complicated skin and ski-structure infections has been recently demonstrated in two Phase III randomized clinical trials involving 1600 patients. Two other Phase III clinical trials to assess ceftobiprole's efficacy in community-acquired pneumonia and nosocomial pneumonia have also concluded. While the drug met the noninferiority criteria for community-acquired pneumonia and nosocomial pneumonia involving non-ventilator associated pneumonia, ceftobiprole was less effective than the comparator in ventilator associated pneumonia subjects. Ceftobiprole was well tolerated with a safety profile consistent with the cephalosporin class of antibiotic. The most frequent drug-related adverse event was dysgeusia. Ceftobiprole is intended for use in the hospital for the treatment of infections that frequently involve beta-lactam-resistant Gram-negative and Gram-positive organisms.

  4. 5-Alkyloxytryptamines are membrane-targeting, broad-spectrum antibiotics.

    Science.gov (United States)

    Faulkner, Katherine C; Hurley, Katherine A; Weibel, Douglas B

    2016-11-15

    Antibiotic adjuvant therapy represents an exciting opportunity to enhance the activity of clinical antibiotics by co-dosing with a secondary small molecule. Successful adjuvants decrease the concentration of antibiotics used to defeat bacteria, increase activity (in some cases introducing activity against organisms that are drug resistant), and reduce the frequency at which drug-resistant bacteria emerge. We report that 5-alkyloxytryptamines are a new class of broad-spectrum antibacterial agents with exciting activity as antibiotic adjuvants. We synthesized 5-alkyloxytryptamine analogs and found that an alkyl chain length of 6-12 carbons and a primary ammonium group are necessary for the antibacterial activity of the compounds, and an alkyl chain length of 6-10 carbons increased the membrane permeability of Gram-positive and Gram-negative bacteria. Although several of the most potent analogs also have activity against the membranes of human embryonic kidney cells, we demonstrate that below the minimum inhibitory concentration (MIC)-where mammalian cell toxicity is low-these compounds may be successfully used as adjuvants for chloramphenicol, tetracycline, ciprofloxacin, and rifampicin against clinical strains of Salmonella typhimurium, Acinetobacter baumannii and Staphylococcus aureus, reducing MIC values by as much as several logs.

  5. Broad Spectrum Sanitizing Wipes with Food Additives Project

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    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...

  6. Antiepileptic drugs: are women aware of interactions with oral contraceptives and potential teratogenicity?

    Science.gov (United States)

    Pack, Alison M; Davis, Anne R; Kritzer, Jordana; Yoon, Ava; Camus, Adela

    2009-04-01

    Women with epilepsy (WWE)'s knowledge of the interaction between antiepileptic drugs (AEDs) and oral contraceptives (OCs) and the potential teratogenicity of AEDs has received limited study. We conducted a cross-sectional questionnaire study (English or Spanish) among young WWE (18-44 years) to assess demographic characteristics, current AED use, and knowledge of AED interactions with OCs and teratogenicity. We used the Food and Drug Administration's classification system to categorize each AED's teratogenic potential. Participants (n=148) had a mean age of 32 years (SD 8); 32% spoke Spanish and described themselves as Hispanic. Among women prescribed a cytochrome p450-inducing AED, 65% were unaware of decreased OC efficacy. Forty percent of those prescribed Category D AEDs were unaware of potential teratogenic effects. WWE have limited knowledge of the potential interaction between AEDs and OCs and the teratogenic effects of AEDs. Educational efforts should highlight the reproductive health effects of AEDs in WWE.

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

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    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.

  8. Fluoxetine enhances the anticonvulsant effects of conventional antiepileptic drugs in maximal electroshock seizures in mice.

    Science.gov (United States)

    Borowicz, Kinga K; Stepień, Karolina; Czuczwar, Stanisław J

    2006-01-01

    The present study was designed to investigate the effects of fluoxetine (FXT), a selective serotonin reuptake inhibitor, on the effect of antiepileptic drugs (AEDs) in the maximal electroshock seizure (MES) model in mice. FXT at the doses of 25, 20 and 15 mg/kg significantly increased the electroconvulsive threshold. The antidepressant applied at the lower doses (10, 5 and 2.5 mg/kg) did not influence the threshold. Moreover, FXT (at the highest subprotective dose of 10 mg/kg) increased the anticonvulsive potential of carbamazepine (CBZ), diphenylhydantoin (DPH), valproate (VPA) and phenobarbital (PB), producing a dose-related decrease in their ED50 values against MES. Nevertheless, pharmacokinetic events may be involved in the interaction between FXT and PB or CBZ, since the antidepressant raised the total brain concentration of the two antiepileptics. FXT in combination with AEDs did not influence the motor performance in the chimney test and long-term memory. In conclusion, the data suggest that FXT modulates seizure processes in the brain and may be advantageous in the treatment of epilepsy in depressed patients, improving the seizure control in epilepsy.

  9. Toxic Epidermal Necrolysis Associated with Antiepileptic Drugs and Cranial Radiation Therapy

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    Shereen Elazzazy

    2013-01-01

    Full Text Available Case reports on the development of toxic epidermal necrolysis (TEN associated with concurrent administration of phenytoin with cranial radiation therapy (Ahmed (2004, Criton et al. (1997, and Rzany et al. (1996, but reports about erythema multiforme, which can develop in patients treated with levetiracetam and cranial irradiation, are very limited. This paper presents evidence that TEN may be induced by concurrent use of radiation with both phenytoin and levetiracetam. Our case is a 42-year-old male patient, a case of gliosarcoma who developed purpuric dermatitis associated with phenytoin when combined with cranial radiation therapy; although phenytoin was discontinued and switched to levetiracetam, the patient had more severe symptoms of toxic epidermal necrolysis (TEN on levetiracetam; the patient improved with aggressive symptom management, discontinuation of antiepileptic drugs (AEDs, and holding radiotherapy. Although TEN is a rare toxicity, physicians should pay a special attention to the monitoring of brain tumor patients on antiepileptic prophylaxis during cranial irradiation; furthermore, patients should be counselled to notify their physicians if they develop any new or unusual symptoms.

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

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    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.

  11. Interactions between riluzole and conventional antiepileptic drugs -- a comparison of results obtained in the subthreshold method and isobolographic analysis.

    Science.gov (United States)

    Borowicz, K K; Rwiader, M; Drelewska, E; Czuczwar, S J

    2004-12-01

    The exact types of pharmacodynamic interactions between riluzole and conventional antiepileptic drugs were evaluated in two available ways, the subthreshold and isobolographic analysis. Maximal electroshock test in mice was used as an animal model for generalized tonic-clonic convulsions. In the first method, riluzole (1.25-2.5 mg/kg) significantly raised the electroconvulsive threshold in mice. The drug administered at its subprotective dose of 0.3125 mg/kg enhanced the antiseizure activity of carbamazepine and phenobarbital, while, when applied at the higher dose of 0.625 mg/kg, it potentiated also the action of valproate and diphenylhydantoin. Riluzole (0.625) alone and in combinations with antiepileptic drugs did not produced any motor or log-term memory deficit. Results obtained from isobolographic analysis determined pure additive interaction between riluzole and all used conventional antiepileptic drugs. Since riluzole did not change plasma concentrations of co-administered antiepileptics, pharmacokinetic interactions, at least in terms of their free plasma levels, do not seem probable. The results of the present study confirm significant antiseizure properties of riluzole in the model of generalized tonic-clonic epileptic attacks. Moreover, comparison of effects obtained from both methods evaluating drug interactions strongly indicates a crucial role of the isobolographic analysis in verification and supplementation data achieved from the subthreshold method.

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

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    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.

  13. Effects of Antiepileptic Drugs on Sexual Function and Reproductive Hormones of Male Epileptic Patients

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    Ali Sonbolestan

    2012-01-01

    Full Text Available Background: Diminished libido and sexual dysfunction are unusually common among male epileptic patients. The most important etiologic factor may be antiepileptic drugs (AEDs-induced androgen deficiency. We compared reproductive hormone levels among men with epilepsy taking various AEDs and normal controls. Methods: Subjects were 59 male epileptic patients who aged 24 ± 5 years. They had been receiving lamotrigine (LTG (n = 17, carbamazepine (CBZ (n = 18, and sodium valproate (VPA (n = 15 for at least 6 months. We also recruited 23 healthy controls. Testosterone, estradiol, dehydroepiandrosterone sulfate (DHEAS, sex hormone binding globulin (SHBG, androstenedione (AND, luteinizing hormone (LH, and follicle stimulating hormone (FSH levels and gonadal efficiency (testosterone/LH were compared between the four groups. The patients and the control group were examined and evaluated for male reproduction by urology and endocrinology services. Results: Subjects receiving CBZ, VPA, and LTG had significantly lower mean testosterone levels than the control group (P < 0.01. In addition, patients receiving LTG had significantly higher mean testosterone levels than CBZ and VPA groups (P < 0.01 and controls (P < 0.05. There were not any significant differences between the groups in mean estradiol levels. The mean and level in VPA was higher than CBZ, LTG, and control groups (P < 0.01. Men receiving CBZ had significantly lower DHEAS levels than the other groups (P < 0.01. Testosterone/LH ratio in the control group was more than other groups (P < 0.01. On the other hand, this value in LTG group was higher than CBZ and VPA groups (P < 0.01. However, CBZ and VPA groups were not significantly different in terms of testosterone/LH ratio. Conclusion: Although the mean levels of reproductive hormones were lower in the LTG group compared to the controls, among traditional antiepileptic drugs, LTG had fewer side effects on reproductive hormones. Therefore, it is a good

  14. 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 ex

  15. 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 ex

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

    DEFF Research Database (Denmark)

    Nøhr, Martha Kampp; Thale, Zia I; Brodin, Birger;

    2014-01-01

    Vigabatrin is an antiepileptic drug substance mainly used in pediatric treatment of infantile spasms. The main source of nutrition for infants is breast milk and/or infant formula. Our hypothesis was that infant formula may affect the intestinal absorption of vigabatrin. The aim was therefore to ...

  17. 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 t

  18. 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...

  19. 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.

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

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    Brahyan Galindo-Mendez

    2015-01-01

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

  1. 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

    2016-01-01

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

  2. 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.

  3. Lecture: profile of risks and benefits of new antiepileptic drugs in brain tumor-related epilepsy.

    Science.gov (United States)

    Maschio, Marta; Dinapoli, L

    2011-11-01

    In patients with brain tumor, seizures are the onset symptom in 20-40% of the patients, while a further 20-45% of the patients will present them during the course of the disease. These data are important when considering the choice of antiepileptic drugs for this particular patient population, because brain tumor-related epilepsy (BTRE) is often drug resistant, has a strong impact on the quality of life and weighs heavily on public health expenditures. In brain tumor patients, the presence of epilepsy is considered as the most important risk factor for long-term disability. For this reason, the problem of the proper administration of medications and their potential side effects is of great importance, because good seizure control can significantly improve the patient's psychological and relational sphere. In these patients, new generation drugs such as gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate, and zonisamide are preferred, because they have fewer drug interactions and cause fewer side effects. Among the recently marketed drugs, lacosamide has demonstrated promising results and should be considered as a possible treatment option. Therefore, it is necessary to develop a customized treatment plan for each patient with BTRE, whose goals are complete seizure control, minimal or no side effects, and elimination of cognitive impairment and/or psychosocial problems.

  4. Effect of clobazam as add-on antiepileptic drug in patients with epilepsy

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    Rupa Joshi

    2014-01-01

    Full Text Available Background & objectives: The use of clobazam in epilepsy has increased since its introduction in 1975. However, it has not been audited for its overall usefulness in Indian set up. The present study was aimed to evaluate usage pattern, retention rate, effectiveness and tolerability of clobazam during routine practice in an outpatient epilepsy clinic of a tertiary care hospital in New Delhi, India. Methods: This study was performed on the patients prescribed antiepileptic medication who had clobazam as last added drug in their treatment regimen during October 2010 - March 2012. These patients were followed up for two OPD visits. The primary points evaluated were retention rate, percentage of seizure-free patients and reasons for discontinuing clobazam. Results: o0 f the 417 consecutive patients, 132 (31.7% were on clobazam treatment for more than four years (median 6 yr, range 4-15 yr. No seizure for previous 12 months was considered as seizure free and was observed in 151 (36.2% patients. There was no improvement in seizure control in 32 (7.7% patients. A decrease in seizure severity without any change in seizure frequency was observed in 76 (18.2% patients. Clobazam was discontinued by 15 (3.6% patients due to complaints like drowsiness (13, fatigue/tiredness (8, headache (6, poor memory (6, irritable behaviour (5, abdominal pain (3 and dizziness (3. Interpretation & conclusions: Our results provide valuable information about the clinical use of clobazam as add-on antiepileptic drug therapy in the management of patients with epilepsy.

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

    Science.gov (United States)

    Afifi, Samar

    2015-01-01

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

  6. Antiepileptic Drug-Related Adverse Reactions and Factors Influencing These Reactions

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    Parvaneh KARIMZADEH

    2013-08-01

    Full Text Available How to Cite This Article: Karimzadeh P, Bakrani V. Antiepileptic Drug-Related Adverse Reactions And Factors Influencing These Reactions. Iran J Child Neurol. 2013 Summer; 7(3:23-27. ObjectiveAccording to the basic role of drug side effects in selection ofan appropriate drug, patient compliance and the quality of life inepileptic patients, and forasmuch as new dugs with unknown side effect have been produced and introduced, necessity of this research and similar studies is explained. This study was conducted to evaluate the incidence and clinical characteristics of anti epileptic drug (AED related adverse reactions in children treated with AEDs.Material & MethodsIn this descriptive study, children less than 14 years old with AEDside effects referred to the Children’s Medical Center and MofidChilderen’s Hospital (Tehran, Iran were evaluated during 2010-2012.The informations were: sex, age, incriminating drug, type of drug side effect, incubation period, history of drug usage, and patient and family allergy history. Exclusive criterions were age more than 14 years old and reactions due to reasons other than AEDs (Food, bite, non-AEDs, etc..ResultsA total of 70 patients with AED reaction were enrolled in thisstudy. They included 26 (37% females and 44 (63 % males. The maximum rate of incidence was seen at age less than 5 years old. All the patients had cutaneous eruptions that the most common cutaneous drug eruption was maculopapular rash. The incidence of systemic and laboratory adverse events was less than similar studies. The most common culprit was phenobarbital (70% and the least common was lamotrigine (1.4%.ConclusionIn this study, we found higher rates of drug rash in patients treated with aromatic AEDs and lower rates with non-aromatic AEDs. Various endogenous and environmental factors may influence the propensity to develop these reactions. Refrences1. Blume WT, Lu¨ders HO, Mizrahi E, et al. Glossary of descriptive terminology for

  7. Effects of Antiepileptic Drugs on Electroencephalographic Findings in Patients with Idiopathic Generalized Epilepsy

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    Ali Akbar ASADI-POOYA

    2011-09-01

    Full Text Available ObjectiveSeveral antiepileptic drugs (AEDs such as phenobarbital (Pb, carbamazepine (CBZ, and valproate (VPA may suppress interictal epileptiform activity. We investigated the effects of AEDs on electroencephalography (EEG data from patients with idiopathic generalized epilepsy (IGE.Materials & MethodsIn this cross-sectional study, all patients electroclinically diagnosed with IGE were recruited in the outpatient epilepsy clinic at Shiraz University of Medical Sciences from September 2008 through August 2010. A routine EEG was requested at the time of referral for all patients. Statistical analyses were performed using Chi square and Fisher’s exact test.ResultsThis study comprised of 336 patients. For about 20.8% (70 patients of them, the initial EEG appeared normal. The first EEG was normal in 14.2% of the patients who had newly diagnosed IGE (19 patients. Normal EEG was also detected for 27.6% of the patients who received VPA monotherapy (16 patients, 31% of the patients who received CBZ monotherapy (9 patients, 29.4% of the patients who received Pb monotherapy (5 patients, and 11.1% of the patients who received lamotrigine (LTG (1 patient.ConclusionThis study shows that compared to LTG, VPA suppresses generalized interictal epileptiform activity in patients with IGE more effectively. Theoretically, if a drug can frequently induce normalization of EEG, then it may be a better drug for treating IGEs.

  8. Characteristics of doripenem: a new broad-spectrum antibiotic

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    Francisco Alvarez-Lerma

    2009-05-01

    Full Text Available Francisco Alvarez-Lerma1, Santiago Grau2, Olivia Ferrández21Intensive Care Unit, 2Pharmacy Department, Hospital Del Mar, Barcelona, SpainAbstract: Doripenem (S-4661 is a new parenteral antibiotic from the carbapenem class; similarly to imipenem and meropenem, it has a broad-spectrum activity against Gram-positive, Gram-negative, and anaerobic bacteria. It is active against multiresistant Gram-negative bacilli such as extended-spectrum beta-lactamase-producing (ESBL Gram-negative Enterobacteriaceae and nonfermentative Gram-negative bacilli including some strains of Pseudomonas aeruginosa that are resistant to other carbapenems. Doripenem’s chemical structure is similar to that of meropenem (substitution of one sulfamoxil-aminomethyl chain for the dimethyl-carboxyl chain, and has one 1-beta-methyl chain which provides resistance to dehydropeptidase-I enzyme. The clinical trials conducted so far have focused on the treatment of severe infections such as complicated intra-abdominal infections, complicated urinary tract infections and pyelonephritis, nosocomial pneumonia, and ventilator-associated pneumonia. Given its activity profile and the results from the clinical trials, this antibiotic may be used for empirical treatment of multibacterial infections produced by potentially multiresistant Gram-negative bacilli. In 2007, the US Food and Drug Administration approved the use of doripenem for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. The European Medicines Agency has approved the use of doripenem for the same indications in addition to nosocomial pneumonia regardless of whether it is ventilator-associated or not.Keywords: doripenem, antimicrobial activity, clinical efficacy, pharmacokinetics, tolerability

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

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    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

  10. P-glycoprotein alters blood–brain barrier penetration of antiepileptic drugs in rats with medically intractable epilepsy

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    Ma A

    2013-12-01

    Full Text Available Aimei Ma,1,* Cuicui Wang,2,3,* Yinghui Chen,2,3 Weien Yuan4 1Department of Neurology, The People's Hospital of Shanxi Province, Taiyuan, 2Department of Neurology, Jinshan Hospital, Fudan University, 3Department of Neurology, Shanghai Medical College, Shanghai, 4School of Pharmacy, Shanghai JiaoTong University, Shanghai, People's Republic of China *These authors contributed equally to this work Abstract: P-glycoprotein is one of the earliest known multidrug transporters and plays an important role in resistance to chemotherapeutic drugs. In this study, we detected levels of P-glycoprotein and its mRNA expression in a rat brain model of medically intractable epilepsy established by amygdala kindling and drug selection. We investigated whether inhibition of P-glycoprotein affects the concentration of antiepileptic drugs in cortical extracellular fluid. We found that levels of P-glycoprotein and its mRNA expression were upregulated in epileptic cerebral tissue compared with cerebral tissue from normal rats. The concentrations of two antiepileptic drugs, carbamazepine and phenytoin, were very low in the cortical extracellular fluid of rats with medically intractable epilepsy, and were restored after blockade of P-glycoprotein by verapamil. These results show that increased P-glycoprotein levels alter the ability of carbamazepine and phenytoin to penetrate the blood–brain barrier and reduce the concentrations of these agents in extracellular cortical fluid. High P-glycoprotein levels may be involved in resistance to antiepileptic drugs in medically intractable epilepsy. Keywords: P-glycoprotein, medically intractable epilepsy, antiepileptic drugs, amygdala kindling, verapamil

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

    Science.gov (United States)

    Bialer, Meir; Midha, Kamal K

    2010-06-01

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

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

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    Jacobs K

    2016-04-01

    Full Text Available Karen Jacobs,1 Marlene Julyan,2 Martie S Lubbe,1 Johanita R Burger,1 Marike Cockeran1 1Medicine Usage in South Africa, Faculty of Health Sciences, 2Clinical Pharmacy, School of Pharmacy, North-West University (Potchefstroom Campus, Potchefstroom, South Africa Objective: To determine the adherence status to antiepileptic drugs (AEDs among epilepsy patients; to observe the association between adherence status and age, sex, active ingredient prescribed, treatment period, and number of comorbidities; and to determine the effect of nonadherence on direct medicine treatment cost of AEDs. Methods: A retrospective study analyzing medicine claims data obtained from a South African pharmaceutical benefit management company was performed. Patients of all ages (N=19,168, who received more than one prescription for an AED, were observed from 2008 to 2013. The modified medicine possession ratio (MPRm was used as proxy to determine the adherence status to AED treatment. The MPRm was considered acceptable (adherent if the calculated value was ≥80%, but ≤110%, whereas an MPRm of <80% (unacceptably low or >110% (unacceptably high was considered nonadherent. Direct medicine treatment cost was calculated by summing the medical scheme contribution and patient co-payment associated with each AED prescription. Results: Only 55% of AEDs prescribed to 19,168 patients during the study period had an acceptable MPRm. MPRm categories depended on the treatment period (P>0.0001; Cramer’s V=0.208 but were independent of sex (P<0.182; Cramer’s V=0.009. Age group (P<0.0001; Cramer’s V=0.067, active ingredient (P<0.0001; Cramer’s V=0.071, and number of comorbidities (P<0.0001; Cramer’s V=0.050 were statistically but not practically significantly associated with MPRm categories. AEDs with an unacceptably high MPRm contributed to 3.74% (US$736,376.23 of the total direct cost of all AEDs included in the study, whereas those with an unacceptably low MPRm amounted to US

  13. Effects of topiramate versus other antiepileptic drugs on the cognitive function of patients with epilepsy

    Institute of Scientific and Technical Information of China (English)

    Fei Xu; Qionghua Feng; Liang Yu; Jie Liu; Hongbin Sun

    2007-01-01

    BACKGROUND: Only very large dose of topiramate has neurotoxicity, indicating that topiramate has low neurotoxicity and high safety. The residual rate of topiramate is affected by many cognitive-related adverse effects. Patients who take topiramate often accompany with thought slowness, difficulty in finding words,dyscalculia, blunt reaction, attention decreasing, memory deterioration, etc.OBJECTIVE: To compare the effects of topiramate with traditional anti-epileptic drugs (including carbamazepine and Valproic acid (VPA) on cognitive function of patients with epilepsy.DESIGN: Observational experiment, self-control and intergroup comparison.SETTING: Sichuan Academy of Medical Science.PARTICIPANTS: Eighty-seven inpatients and outpatients with newly diagnosed epilepsy who received preliminary diagnosis and follow-up in the Department of Neurology, Sichuan People's Hospital between January 2004 and June 2006 were involved in this survey. They were diagnosed according to disease history and electroencephalogram (EEG). The onset type was diagnosed following the definition of epilepsy and epileptic syndrome in 1989 International Anti-epileptic League. The involved patients and their relatives were informed of detection and therapeutic regimen. The patients were assigned into two groups according to table of random digit: traditional antiepileptic drugs group (AEDs group, n =44) and topiramate (TPM) group (n =43).partial seizures or partial secondarily generalized seizures, and VPA for 23 patients with generalized seizures.The initial dose of carbamazepine was 300 mg/d, and that of VPA was 500 mg/d. Patients in the TPM group took TPM with the initial dose of 25 mg/d, increased by 25 mg/d each week to target dose 150 mg/d within 8 months after administration by using Wechsler Adult Intelligence Scale(WAIS) or Wechsler Intelligence Scale for Children (WISC, Chinese edition), (Higher scores indicated better cognitive function), Stroop color word interference, test of memory

  14. Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa.

    Science.gov (United States)

    Vestergaard, Martin; Paulander, Wilhelm; Marvig, Rasmus L; Clasen, Julie; Jochumsen, Nicholas; Molin, Søren; Jelsbak, Lars; Ingmer, Hanne; Folkesson, Anders

    2016-01-01

    Combination therapy with several antibiotics is one strategy that has been applied in order to limit the spread of antimicrobial resistance. We compared the de novo evolution of resistance during combination therapy with the β-lactam ceftazidime and the fluoroquinolone ciprofloxacin with the resistance evolved after single-drug exposure. Combination therapy selected for mutants that displayed broad-spectrum resistance, and a major resistance mechanism was mutational inactivation of the repressor gene mexR that regulates the multidrug efflux operon mexAB-oprM. Deregulation of this operon led to a broad-spectrum resistance phenotype that decreased susceptibility to the combination of drugs applied during selection as well as to unrelated antibiotic classes. Mutants isolated after single-drug exposure displayed narrow-spectrum resistance and carried mutations in the MexCD-OprJ efflux pump regulator gene nfxB conferring ciprofloxacin resistance, or in the gene encoding the non-essential penicillin-binding protein DacB conferring ceftazidime resistance. Reconstruction of resistance mutations by allelic replacement and in vitro fitness assays revealed that in contrast to single antibiotic use, combination therapy consistently selected for mutants with enhanced fitness expressing broad-spectrum resistance mechanisms.

  15. Association between antiepileptic drugs and hepatocellular carcinoma in patients with epilepsy: a population‐based case–control study

    OpenAIRE

    2016-01-01

    Abstract Background This study explored whether antiepileptic drugs (AEDs) use increases the risk of hepatocellular carcinoma (HCC). Methods We conducted a case–control study using data from the National Health Insurance system of Taiwan. The case group comprised 1,454 epilepsy patients with newly diagnosed HCC, and the control group comprised 1,448 epilepsy patients without HCC. Both groups had similar distributions of sex and age, and follow‐up duration. Possible associations with the AEDs ...

  16. Adult-onset temporal lobe epilepsy, cognitive decline, multi-antiepileptic drug hypersensitivity, and Hashimoto's encephalopathy: Two case studies ☆

    OpenAIRE

    Sadan, Ofer; Seyman, Estelle; Ash, Elissa L.; Kipervasser, Svetlana; Neufeld, Miri Y.

    2013-01-01

    Hashimoto's encephalopathy is defined by the coexistence of encephalopathy and antithyroid antibodies. We report two cases of adult-onset temporal lobe epilepsy with subacute cognitive decline, high titers of antithyroid antibodies, multi-antiepileptic drug hypersensitivity, and good response to immunomodulatory treatment. The relevance of multidrug hypersensitivity in the setting of adult-onset epilepsy and the importance of searching for autoimmune causes for epilepsy are discussed.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Lacosamide neurotoxicity associated with concomitant use of sodium channel-blocking antiepileptic drugs: a pharmacodynamic interaction?

    Science.gov (United States)

    Novy, Jan; Patsalos, Philip N; Sander, Josemir W; Sisodiya, Sanjay M

    2011-01-01

    Lacosamide is a new antiepileptic drug (AED) apparently devoid of major pharmacokinetic interactions. Data from a small postmarketing assessment suggest people who had lacosamide co-prescribed with a voltage-gated sodium channel (VGSC)-blocking AED seemed more likely to discontinue lacosamide because of tolerability problems. Among 39 people with refractory epilepsy who developed neurotoxicity (diplopia, dizziness, drowsiness) on lacosamide treatment given in combination with VGSC-blocking AEDs, we identified 7 (17.9%) without any changes in serum levels of other AEDs in whom the symptoms were ameliorated by dose reduction of the concomitant VGSC-blocking AED. Symptoms in these people seem to have arisen from a pharmacodynamic interaction between lacosamide and other VGSC-blocking AEDs. Slow-inactivated VGSCs targeted by lacosamide might be more sensitive to the effects of conventional VGSC-blocking AEDs. Advising people to reduce concomitantly the conventional VGSC-blocking AEDs during lacosamide uptitration in cases of neurotoxicity might improve the tolerability of combination treatment.

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

    Science.gov (United States)

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

    2016-03-01

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

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

    Directory of Open Access Journals (Sweden)

    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. 

  1. Role of P-glycoprotein in refractoriness of seizures to antiepileptic drugs in Lennox-Gastaut syndrome.

    Science.gov (United States)

    Kumar, Achal; Tripathi, Deepak; Paliwal, Vimal Kumar; Neyaz, Zafar; Agarwal, Vikas

    2015-02-01

    Mechanism of seizure refractoriness to antiepileptic drugs in children with Lennox-Gastaut syndrome is not known. Efflux of antiepileptic drugs due to increased expression/function of P-glycoprotein, a multidrug efflux transporter protein on the cell surface is a proposed mechanism. The authors studied the expression/function of P-glycoprotein on peripheral blood mononuclear cells of 29 children with Lennox-Gastaut syndrome, 23 children with other epilepsies, and 19 healthy children. The authors found a higher P-glycoprotein expression/function in Lennox-Gastaut syndrome, a higher percent positive cells as compared to children with other epilepsy (P P = 0.012), higher P-glycoprotein expression as compared to healthy controls (P = 0.003), a higher total P-glycoprotein expression (relative florescence intensity × percent positive cells) as compared to children with other epilepsies (P P P-glycoprotein function as compared to children with other epilepsies (P = 0.001) and healthy controls (P = 0.002). These findings may explain seizure refractoriness to anti-epileptic drugs in Lennox-Gastaut syndome.

  2. The broad spectrum revisited: Evidence from plant remains

    OpenAIRE

    Weiss, Ehud; Wetterstrom, Wilma; Nadel, Dani; Bar-Yosef, Ofer

    2004-01-01

    The beginning of agriculture is one of the most important developments in human history, with enormous consequences that paved the way for settled life and complex society. Much of the research on the origins of agriculture over the last 40 years has been guided by Flannery's [Flannery, K. V. (1969) in The Domestication and Exploitation of Plants and Animals, eds. Ucko, P. J. & Dimbleby, G. W. (Duckworth, London), pp. 73–100] “broad spectrum revolution” (BSR) hypothesis, which posits that the...

  3. 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.

  4. Comparative study of lacosamide and classical sodium channel blocking antiepileptic drugs on sodium channel slow inactivation.

    Science.gov (United States)

    Niespodziany, Isabelle; Leclère, Nathalie; Vandenplas, Catherine; Foerch, Patrik; Wolff, Christian

    2013-03-01

    Many antiepileptic drugs (AEDs) exert their therapeutic activity by modifying the inactivation properties of voltage-gated sodium (Na(v) ) channels. Lacosamide is unique among AEDs in that it selectively enhances the slow inactivation component. Although numerous studies have investigated the effects of AEDs on Na(v) channel inactivation, a direct comparison of results cannot be made because of varying experimental conditions. In this study, the effects of different AEDs on Na(v) channel steady-state slow inactivation were investigated under identical experimental conditions using whole-cell patch-clamp in N1E-115 mouse neuroblastoma cells. All drugs were tested at 100 μM, and results were compared with those from time-matched control groups. Lacosamide significantly shifted the voltage dependence of Na(v) current (I(Na) ) slow inactivation toward more hyperpolarized potentials (by -33 ± 7 mV), whereas the maximal fraction of slow inactivated channels and the curve slope did not differ significantly. Neither SPM6953 (lacosamide inactive enantiomer), nor carbamazepine, nor zonisamide affected the voltage dependence of I(Na) slow inactivation, the maximal fraction of slow inactivated channels, or the curve slope. Phenytoin significantly increased the maximal fraction of slow inactivated channels (by 28% ± 9%) in a voltage-independent manner but did not affect the curve slope. Lamotrigine slightly increased the fraction of inactivated currents (by 15% ± 4%) and widened the range of the slow inactivation voltage dependence. Lamotrigine and rufinamide induced weak, but significant, shifts of I(Na) slow inactivation toward more depolarized potentials. The effects of lacosamide on Na(v) channel slow inactivation corroborate previous observations that lacosamide has a unique mode of action among AEDs that act on Na(v) channels.

  5. Effects of antiepileptic drugs on associative LTP-like plasticity in human motor cortex.

    Science.gov (United States)

    Heidegger, Tonio; Krakow, Karsten; Ziemann, Ulf

    2010-10-01

    Antiepileptic drugs (AEDs) are used extensively in clinical practice but relatively little is known on their specific effects at the systems level of human cortex. Here we tested, using a double-blind randomized placebo-controlled crossover design in healthy subjects, the effects of a single therapeutic oral dose of seven AEDs with different modes of action (tiagabine, diazepam, gabapentin, lamotrigine, topiramate, levetiracetam and piracetam) on long-term potentiation (LTP)-like motor cortical plasticity induced by paired associative transcranial magnetic stimulation (PAS). PAS-induced LTP-like plasticity was assessed from the increase in motor evoked potential amplitude in a hand muscle contralateral to the stimulated motor cortex. Levetiracetam significantly reduced LTP-like plasticity when compared to the placebo condition. Tiagabine, diazepam, lamotrigine and piracetam resulted in nonsignificant trends towards reduction of LTP-like plasticity while gabapentin and topiramate had no effect. The particularly depressant effect of levetiracetam is probably explained by its unique mode of action through binding at the vesicle membrane protein SV2A. Enhancement of gamma-amino butyric acid-dependent cortical inhibition by tiagabine, diazepam and possibly levetiracetam, and blockage of voltage-gated sodium channels by lamotrigine, may also depress PAS-induced LTP-like plasticity but these mechanisms appear to be less relevant. Findings may inform about AED-related adverse effects on important LTP-dependent central nervous systems processes such as learning or memory formation. The particular depressant effect of levetiracetam on LTP-like plasticity may also relate to the unique properties of this drug to inhibit epileptogenesis, a potentially LTP-associated process.

  6. Do no harm - But first we need to know more: The case of adverse drug reactions with antiepileptic drugs

    Directory of Open Access Journals (Sweden)

    Gagandeep Singh

    2011-01-01

    Full Text Available An adverse drug reaction (ADR is defined by the World Health Organization as a noxious, unintended, and undesired drug effect, when used for therapeutic purposes in humans. ADRs to anti-epileptic drugs (AEDs significantly impact the quality of life of people with epilepsy and account for a little less than half of all recorded treatment failures with AEDs. Hence prevention and early recognition of ADRs constitute an important aspect of management of epilepsy. Recent developments have improved our ability to predict and hence potentially prevent the occurrence of some of the serious ADRs to AEDs. One example is the potential prediction of the risk of severe cutaneous hypersensitivity reactions including Stevens Johnson syndrome and toxic epidermal necrolysis by testing for expression of HLA BFNx011502 allele in people of Asian origin who are prescribed carbamazepine. The association between HLA BFNx011502 expression and carbamazepine skin reactions has been documented in India but the role of HLA testing in Indian populations needs to be clarified in larger studies across different ethnic groups within the country.

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

    Science.gov (United States)

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

    2016-02-01

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

  8. Antiepileptic drug teratogenesis: what are the risks for congenital malformations and adverse cognitive outcomes?

    Science.gov (United States)

    Harden, Cynthia L

    2008-01-01

    Antiepileptic drug (AED) exposure in utero has been associated with major congenital malformations (MCMs) and adverse cognitive outcomes in the offspring of women with epilepsy (WWE). However, determining the exact risk and the relative risks of AEDs for these outcomes has been challenging, and only in recent years has improved study designs enabled us to get a clearer picture of the risks. Still, there is a startling lack of information for many of the newer and widely used AEDs. At this point of time, studies clearly show that valproate (VPA) as a part of polytherapy or when used as a monotherapy is associated with an increased risk of MCMs, and that it poses about threefold the risk of carbamazepine (CBZ). It is unclear if any other AEDs studied pose an increased risk of MCM occurrence; in the best available large study the absolute rates of MCMs with other several other AEDs were not different from untreated WWE. The absolute risks have been reported as CBZ 2.2%, lamotrigine (LTG) 3.2%, phenytoin (PHT) 3.7%, untreated WWE 3.5%, with VPA as the outlier at 6.2%. In utero VPA exposure is also associated with a risk of lower verbal intelligence quotient (IQ) in children, at approximately 10 points lower than controls. CBZ appears to pose no risk to cognitive outcome, and there is some evidence that PHT and phenobarbital (PB) may be associated with risk of reduced cognitive outcome. Polytherapy is associated with greater risk than monotherapy for both MCMs and cognitive outcome. Although more information is needed and hopefully will be obtained from ongoing prospective studies, it is clear that WWE taking VPA and planning pregnancy should have a discussion with their physician about considering changing to another AED before pregnancy, if possible.

  9. Effects of antiepileptic drugs on the serum folate and vitamin B12 in various epileptic patients.

    Science.gov (United States)

    Huang, Hong-Li; Zhou, Hao; Wang, Nuan; Yu, Chun-Yu

    2016-10-01

    Epilepsy is a common neurodegenerative disease with an increasing morbidity. Clinical treatment of epilepsy includes symptomatic treatment, etiological treatment, surgery and prevention. The aim of the present study was to determine the effects of antiepileptic drugs (AEDs) on serum folate and vitamin B12 in various epileptic patients, and to examine the correlation between these effects and secondary cerebrovascular events. A total of 68 epileptic patients, diagnosed between May 2012 and May 2014, were included in the present study. The study included 8 cases of autonomic seizures, 10 cases of absence seizures, 13 cases of complex partial seizures, 28 cases of generalized tonic-clonic seizures, and 9 cases of simple partial seizures. The patients received appropriate AED treatment according to the characteristics of epileptic seizure and the treatment guidance. The differences in the serum levels of folate and vitamin B12 in these patients, and the differences in the secondary cerebrovascular events in these patients after 1 year follow-up were analyzed. The difference in the AEDs used by various epileptic patients was statistically significant (PB12 in these patients following treatment were significantly lower than those prior to treatment (PB12 in these groups following treatment were not statistically significant (P>0.05). The difference in the incidence of cerebrovascular events in these groups at follow up was not statistically significant (P>0.05). The multifactorial logistic regression analysis revealed that the serum levels of folate and vitamin B12 were the independent risk factors for epilepsy with secondary cerebrovascular events [folate: odds ratio (OR)=0.536, P=0.039; vitamin: OR=0.382, P=0.041]. In conclusion, various AEDs may decrease the serum levels of folate and vitamin B12 and affect the secondary cerebrovascular events in various epileptic patients. Thus, regular supplementation of folate and vitamin B12 may be an option.

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

    Science.gov (United States)

    Petersen, Irene; Collings, Shuk-Li; McCrea, Rachel L; Nazareth, Irwin; Osborn, David P; Cowen, Phil J; Sammon, Cormac J

    2017-01-01

    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 threefold higher in women prescribed valproate. Conclusion The results of our study suggest that lamotrigine and carbamazepine are safer treatment options than valproate in pregnancy and should be considered as alternative treatment options for women of childbearing potential and in pregnancy. PMID:28243149

  11. Low potency and limited efficacy of antiepileptic drugs in the mouse 6 Hz corneal kindling model.

    Science.gov (United States)

    Leclercq, K; Matagne, A; Kaminski, R M

    2014-05-01

    Corneal kindling is a useful alternative to electrically induced amygdala or hippocampal kindling, which requires advanced surgical and EEG techniques that may not be easily available in many laboratories. Therefore the first aim of this study was to evaluate whether repeated 6 Hz corneal stimulation in mice would lead to an increased and persistent seizure response as described for higher frequency (50/60 Hz) corneal kindling. Male NMRI mice stimulated twice daily (except weekends) for 3 s with 6 Hz electrical current at 44 mA displayed robust kindling development, i.e., a progressive increase in seizure severity. The majority of the animals (about 90%) developed a fully kindled state, defined as at least 10 consecutive stage 3-5 seizures within 5 weeks of corneal stimulation. Afterwards, the fully kindled state was maintained for at least 8 weeks with only two days of stimulations per week. Next, the protective efficacy of four mechanistically different antiepileptic drugs (AEDs; clonazepam, valproate, carbamazepine and levetiracetam) was assessed and compared between 6 Hz and 50 Hz fully kindled mice. All tested AEDs showed a relatively lower potency in the 6 Hz kindling model and a limited efficacy against partial seizures was observed with carbamazepine and levetiracetam. We can conclude that 6 Hz kindling may be more advantageous than the previously described 50/60 Hz corneal kindling models due to its robustness and persistence of the fully kindled state. Furthermore, the observed low potency and limited efficacy of AEDs in 6 Hz fully kindled mice suggest that this model could be a useful tool in the discovery of novel AEDs targeting treatment resistant epilepsy.

  12. 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.

  13. Pharmacological characterization of antiepileptic drugs and experimental analgesics on low magnesium-induced hyperexcitability in rat hippocampal slices.

    Science.gov (United States)

    Arias, Robert L; Bowlby, Mark R

    2005-06-21

    Perfusion of acute hippocampal slices with stimulatory buffers has long been known to induce rhythmic, large amplitude, synchronized spontaneous neuronal bursting in areas CA1 and CA3. The characteristics of this model of neuronal hyperexcitability were investigated in this study, particularly with respect to the activity of antiepileptic drugs and compounds representing novel mechanisms of analgesic action. Toward that end, low Mg(2+)/high K(+)-induced spontaneous activity was quantified by a virtual instrument designed for the digitization and analysis of bursting activity. Uninterrupted streams of extracellular field potentials were digitized and analyzed in 10-s sweeps, yielding four quantified parameters of neuronal hyperexcitability. Following characterization of the temporal stability of low Mg(2+)/high K(+)-induced hyperexcitability, compounds representing a diversity of functional mechanisms were tested for their effectiveness in reversing this activity. Of the four antiepileptic drugs tested in this model, only phenytoin proved ineffective, while valproate, gabapentin and carbamazepine varied in their potencies, with only the latter drug proving to be completely efficacious. In addition, three investigational compounds having analgesic potential were examined: ZD-7288, a blocker of HCN channels; EAA-090, an NMDA antagonist; and WAY-132983, a muscarinic agonist. Each of these compounds showed strong efficacy by completely blocking spontaneous bursting activity, along with potency greater than that of the antiepileptic drugs. These data indicate that pharmacological agents with varying mechanisms of action are able to block low Mg(2+)/high K(+)-induced hyperexcitability, and thus this model may represent a useful tool for identifying novel agents and mechanisms involved in epilepsy and neuropathic pain.

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. Influence of Ivabradine on the Anticonvulsant Action of Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice.

    Science.gov (United States)

    Sawicka, Katarzyna M; Wawryniuk, Agnieszka; Zwolak, Agnieszka; Daniluk, Jadwiga; Szpringer, Monika; Florek-Luszczki, Magdalena; Drop, Bartlomiej; Zolkowska, Dorota; Luszczki, Jarogniew J

    2017-04-01

    Although the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in neuronal excitability and synaptic transmission is still unclear, it is postulated that the HCN channels may be involved in seizure activity. The aim of this study was to assess the effects of ivabradine (an HCN channel inhibitor) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) against maximal electroshock-induced seizures in mice. Tonic seizures (maximal electroconvulsions) were evoked in adult male albino Swiss mice by an electric current (sine-wave, 25 mA, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles of the combinations of ivabradine with classical antiepileptic drugs were measured in mice along with total brain antiepileptic drug concentrations. Results indicate that ivabradine (10 mg/kg, i.p.) significantly enhanced the anticonvulsant activity of valproate and considerably reduced that of phenytoin in the mouse maximal electroshock-induced seizure model. Ivabradine (10 mg/kg) had no impact on the anticonvulsant potency of carbamazepine and phenobarbital in the maximal electroshock-induced seizure test in mice. Ivabradine (10 mg/kg) significantly diminished total brain concentration of phenytoin and had no effect on total brain valproate concentration in mice. In conclusion, the enhanced anticonvulsant action of valproate by ivabradine in the mouse maximal electroshock-induced seizure model was pharmacodynamic in nature. A special attention is required when combining ivabradine with phenytoin due to a pharmacokinetic interaction and reduction of the anticonvulsant action of phenytoin in mice. The combinations of ivabradine with carbamazepine and phenobarbital were neutral from a preclinical viewpoint.

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

    DEFF Research Database (Denmark)

    Nøhr, Martha Kampp; Hansen, Steen Honoré; Brodin, Birger;

    2014-01-01

    Vigabatrin is an anti-epileptic drug substance. The oral bioavailability of vigabatrin is high (60-70%), however, little is known about the mechanism(s) mediating the intestinal absorption. The aim of the present study was to identify which solute carrier(s) are involved in the absorption...... of the human proton-coupled amino acid transporter (hPAT1) to the apical solution. The present study indicates that the transepithelial A-B flux of vigabatrin is mainly mediated by hPAT1 in Caco-2 cells at dose-relevant concentrations....

  20. Isobolographic analysis of interactions between losigamone and conventional antiepileptic drugs in the mouse maximal electroshock model.

    Science.gov (United States)

    Borowicz, Kinga K; Kimber-Trojnar, Zaneta; Ratnaraj, Neville; Patsalos, Philip N; Luszczki, Jarogniew J; Czuczwar, Stanislaw J

    2007-01-15

    The aim of this study was the isobolographic evaluation of interactions between losigamone (LSG), valproate (VPA), carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PB) in the maximal electroshock (MES) test in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, and tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor coordination) and the passive avoidance task (long-term memory). Brain concentrations of antiepileptic drugs (AEDs) were measured by immunofluorescence or high-performance liquid chromatography. Isobolographic analysis indicated synergistic interactions between LSG and VPA. For example, in the proportion of 1:1 the theoretically calculated 50% effective dose for additivity (ED(50add)) was 138 mg/kg, while the experimentally derived ED(50) for the mixture (ED(50mix)) was 85.2 mg/kg. The difference was significant at p<0.001. LSG combined with CBZ or PHT showed additivity, whereas the combinations of LSG with PB were either additive, for the fixed ratios of 1:3 and 1:1, or antagonistic for the ratio of 3:1 (ED(50add)=18.4 mg/kg versus ED(50mix)=26.7 mg/kg, p<0.05). Impairment of long-term memory was noted only in the case of VPA given at its ED(50), however this AED did not affect motor performance. LSG, CBZ, PHT and PB (applied at their ED(50) values) and co-administration of LSG with conventional AEDs (including VPA) impaired neither motor performance nor long-term memory. LSG did not affect the brain concentration of VPA or PB, but significantly elevated the brain concentrations of CBZ and PHT. In contrast, VPA, CBZ and PHT significantly increased the brain concentration of LSG, indicating a pharmacokinetic contribution to the observed pharmacodynamic interactions. Although LSG exhibited some favorable pharmacodynamic interactions with various AEDs, these were complicated by pharmacokinetic interactions and emphasize the

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

    Institute of Scientific and Technical Information of China (English)

    Ying-hui CHEN; Cui-cui WANG; Xia XIAO; Li WEI; Guoxiong XU

    2013-01-01

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

  2. Broad spectrum moderators and advanced reflector filters using 208Pb

    DEFF Research Database (Denmark)

    Schönfeldt, Troels; Batkov, K.; Klinkby, Esben Bryndt

    2015-01-01

    thermalizing property of 208Pb to design a broad spectrum moderator, i.e. a moderator which emits thermal and cold neutrons from the same position. Using 208Pb as a reflector filter material is shown to be slightly less efficient than a conventional beryllium reflector filter. However, when surrounding...... the reflector filter by a cold moderator it is possible to regain the neutrons with wavelengths below the Bragg edge, which are suppressed in the beryllium reflector filter. In both the beryllium and lead case surrounding the reflector filter with a cold moderator increases the cold brightness significantly......Cold and thermal neutrons used in neutrons scattering experiments are produced in nuclear reactors and spallation sources. The neutrons are cooled to thermal or cold temperatures in thermal and cold moderators, respectively. The present study shows that it is possible to exploit the poor...

  3. 药物基因组学与抗癫(癎)药物治疗%Pharmacogenomics and antiepileptic drugs

    Institute of Scientific and Technical Information of China (English)

    吴晔

    2015-01-01

    药物基因组学是在整个基因组水平,通过探讨基因的DNA或RNA的变异与药物效应和不良反应之间的相关性,来研究基因的变异对于个体对药物反应的影响.药物基因组学研究的最终目的是实现个体化治疗.现就药物基因组学在抗癫(癎)药物治疗中的角色进行简述.%Pharmacogenomics is defined as the study of variation in DNA and RNA at the whole genome level,and its effects on drug response including effectiveness and adverse events.Pharmacogenomics is helpful for individualized drug therapy.The role of pharmacogenomics in antiepileptic drugs in therapy of epilepsy was briefly reviewed.

  4. Effect of magnesium oxide on the activity of standard anti-epileptic drugs against experimental seizures in rats

    Directory of Open Access Journals (Sweden)

    Dhande Priti

    2009-01-01

    Full Text Available Objectives : To study the effect of oral magnesium oxide supplementation alone and on the activity of standard anti-epileptic drugs in the animal models of maximal electroshock seizures (MES and chemically (pentylenetetrazole [PTZ]-induced seizures. Methods : Healthy male albino rats were given magnesium oxide (MgO supplementation orally in various doses (500, 750 and 1000 mg/kg /day for 4 weeks (day 1 to day 28. On day 0 and day 29, response to MES (180 mA for 0.2 s was tested 1 h after pre-administration of phenytoin or carbamazepine orally. Similarly, in the other groups, the response to PTZ 40 mg/kg i.p. was tested 1 h after pre-administration of oral sodium valproate. Results : Oral administration of MgO in a low dose (500 mg/kg for 4 weeks in healthy rats appears to exert protective effect against MES. High oral doses of MgO (750 and 1000 mg/kg appear to enhance the activity of phenytoin and carbamazepine in the MES model. MgO supplementation was seen to decrease the latency of PTZ-induced seizures. Conclusion : The dose of oral MgO appears to have an inverse relation with the protective effect in MES-induced seizure model. High doses of MgO supplementation given orally appear to enhance the activity of standard anti-epileptic drugs in the MES-induced seizure model.

  5. Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model.

    Science.gov (United States)

    Luszczki, Jarogniew J; Ratnaraj, Neville; Patsalos, Philip N; Czuczwar, Stanislaw J

    2006-05-01

    This study examined the interaction characteristics between loreclezole (LCZ) and various conventional antiepileptic drugs (phenytoin--PHT, carbamazepine--CBZ, valproate--VPA and phenobarbital--PB) in the mouse maximal electroshock (MES)-induced seizure model using isobolographic analysis. Drug-related adverse effects were ascertained by use of the chimney test (motor impairment) and the step-through passive avoidance task (learning and retrieval). It was observed that the combination of LCZ with VPA or PB, at the fixed ratio of 1:1, was supra-additive (synergistic) and the combination of LCZ with CBZ, at all fixed ratios tested (1:3, 1:1 and 3:1), was supra-additive against electroconvulsions. The remaining combinations evaluated, i.e., LCZ with PB or VPA at fixed ratios of 1:3 and 3:1, as well as all fixed-ratio combinations between LCZ and PHT, were additive in the MES test in mice. Pharmacokinetic characterization revealed that LCZ significantly increased both free plasma and brain concentrations of CBZ and PHT, but was without effect on PB. Moreover, a bi-directional pharmacokinetic interaction between LCZ and VPA was observed in that while LCZ increased free plasma, but not total brain VPA concentrations, VPA increased the total brain, but not free plasma LCZ concentrations. Adverse-effect testing revealed that for all antiepileptic drug combinations neither motor performance nor long-term memory was altered. Of the drug combinations investigated, only that of LCZ and PB at the fixed ratio of 1:1 was not associated with any pharmacokinetic interactions, and thus it may be concluded that the supra-additive (synergistic) isobolographic interaction was pharmacodynamic in nature. Furthermore, the fact that LCZ and PB have similar mechanisms of action would suggest that drugs with similar mechanisms of action may provide rational polytherapy regimens.

  6. 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.

  7. 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.

  8. 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 (Cock); 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

  9. 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.

    2012-01-01

    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. Design/met

  10. Interactions between non-barbiturate injectable anesthetics and conventional antiepileptic drugs in the maximal electroshock test in mice--an isobolographic analysis.

    Science.gov (United States)

    Borowicz, Kinga K; Łuszczki, Jarogniew; Czuczwar, Stanisław J

    2004-03-01

    The aim of this study was the isobolographic evaluation of interactions between three non-barbiturate intravenous anesthetics and conventional antiepileptic drugs in the maximal electroshock-induced seizures in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor performance) and passive avoidance task (long-term memory). Plasma levels of antiepileptic drugs were measured by immunofluorescence. Obtained results indicate that ketamine acts synergistically with valproate and carbamazepine. Also the combinations of propofol and valproate or phenobarbital led to synergistic interactions. An antagonism was found between etomidate and carbamazepine or phenobarbital. On the other hand, interactions between diphenylhydantoin and injectable anesthetics proved to be additive. The only exception was the combination of diphenylhydantoin and propofol (1:3). Pharmacokinetic phenomena do not seem to interfere with the observed interactions, since none of anesthetics influenced the free plasma concentrations of antiepileptic drugs. Referring to undesired effects, only propofol impaired long-term memory. Although propofol did not disturbed motor coordination, it enhanced motor impairment caused by carbamazepine and diphenylhydantoin. Results of the present study suggest that etomidate needs to be avoided in epileptic patients due to a possibility of negative interactions with some antiepileptic drugs and seizure precipitation.

  11. Zebrafish embryotoxicity test for developmental (neuro)toxicity: Demo case of an integrated screening approach system using anti-epileptic drugs

    NARCIS (Netherlands)

    Beker van Woudenberg, A.; Snel, C.; Rijkmans, E.; Groot, D. de; Bouma, M.; Hermsen, S.; Piersma, A.; Menke, A.; Wolterbeek, A.

    2014-01-01

    To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid

  12. Zebrafish embryotoxicity test for developmental (neuro)toxicity : Demo case of an integrated screening approach system using anti-epileptic drugs

    NARCIS (Netherlands)

    Beker van Woudenberg, Anna; Snel, Cor; Rijkmans, Eke; De Groot, Didima; Bouma, Marga; Hermsen, Sanne; Piersma, Aldert; Menke, Aswin; Wolterbeek, André

    2014-01-01

    To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid

  13. Pregnancy outcome in women exposed to antiepileptic drugs: teratogenic role of maternal epilepsy and its pharmacologic treatment.

    Science.gov (United States)

    Cassina, Matteo; Dilaghi, Arianna; Di Gianantonio, Elena; Cesari, Elena; De Santis, Marco; Mannaioni, Guido; Pistelli, Alessandra; Clementi, Maurizio

    2013-08-01

    Infants born to epileptic women treated with antiepileptic drugs (AEDs) have an increased risk of major congenital malformations (MCMs). In order to determine the role of maternal epilepsy we conducted a prospective cohort study on three cohorts of pregnant women: (i) 385 epileptic women treated with AEDs, (ii) 310 non-epileptic women treated with AEDs, (iii) 867 healthy women not exposed to AEDs (control group). The rate of MCMs in the epileptic group (7.7%) was not statistically higher than in the non-epileptic one (3.9%) (p=0.068). The rate in the first group was higher compared to the control group (p=0.001), while the rate in the second one was not (p=0.534). Our data confirm that AEDs therapy is the main cause of the increased risk of malformations in the offspring of epileptic women; however a teratogenic role of the maternal epilepsy itself cannot be excluded.

  14. 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.

  15. Modulation of antioxidant enzymatic activities by certain antiepileptic drugs (valproic acid, oxcarbazepine, and topiramate): evidence in humans and experimental models.

    Science.gov (United States)

    Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Rivera-Espinosa, Liliana; Romero-Toledo, Arantxa; Sampieri, Aristides; Ortega-Cuellar, Daniel; Montesinos-Correa, Hortencia; Floriano-Sánchez, Esaú; Carmona-Aparicio, Liliana

    2013-01-01

    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.

  16. 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.

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

    Science.gov (United States)

    Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Rivera-Espinosa, Liliana; Romero-Toledo, Arantxa; Sampieri, Aristides III; Ortega-Cuellar, Daniel; Montesinos-Correa, Hortencia; Floriano-Sánchez, Esaú; Carmona-Aparicio, Liliana

    2013-01-01

    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. PMID:24454986

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

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    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.

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

    Science.gov (United States)

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

    2016-09-02

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

  20. 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

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    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.

  1. Characterization of Disopyramide derivative ADD424042 as a non-cardiotoxic neuronal sodium channel blocker with broad-spectrum anticonvulsant activity in rodent seizure models.

    Science.gov (United States)

    Król, Marek; Ufnal, Marcin; Szulczyk, Bartłomiej; Podsadni, Piotr; Drapała, Adrian; Turło, Jadwiga; Dawidowski, Maciej

    2016-01-01

    It was reported that antiarrhythmic drugs (AADs) can be useful in controlling refractory seizures in humans or in enhancing the action of antiepileptic drugs (AEDs) in animal models. Disopyramide phosphate (DISO) is an AAD that blocks sodium channels in cardiac myocytes. We evaluated a DISO derivative, 2-(2-chlorophenyl)-2-(pyridin-2-yl)acetamide (ADD424042) for its anticonvulsant activity in a battery of rodent models of epileptic seizures. The compound displayed a broad spectrum of activity in the 'classical' models as well as in the models of pharmacoresistant seizures. Furthermore, ADD424042 showed good therapeutic indices between the anticonvulsant activity and the motor impairment. On the contrary, no anticonvulsant effects but severe lethality were observed in the primary anticonvulsant testing of the parent DISO. By performing the whole-cell voltage-clamp experiments in dispersed cortical neurons we demonstrated that ADD424042 decreased the maximal amplitude of voltage-gated sodium channels with an IC50 value in nM range. Moreover, the compound enhanced use-dependent block and decreased excitability in pyramidal neurons in the current-clamp experiments in cortical slices. Importantly, we found that ADD424042 possessed either no, or very small cardiotoxic effect. In contrast to DISO, ADD424042 did not produce any apparent changes in electrocardiogram (ECG) and arterial blood pressure recordings. ADD424042 had no effect on QT and corrected QT intervals, at a dose which was 15 times higher than ED50 for the anticonvulsant effect in the MES model. Taken together, these data suggest that ADD424042 has the potential to become a lead structure for novel broadly acting AEDs with wide margin of cardiac safety.

  2. Use of anti-epileptic drugs in a tertiary care hospital of Eastern India with emphasis on epilepsy due to neurocysticercosis

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    Amrita Sil

    2012-01-01

    Full Text Available Introduction: Epilepsy is a chronic disease and neurocysticercosis is an important cause of secondary seizures. Its therapy is modified by a number of parameters and thus the pattern of anti-epileptic drugs used varies in different clinical settings. It was our objective to evaluate clinico-demographic and treatment profile of epilepsy patients attending neurology outpatient department, efficacy and side-effect profile of anti-epileptic drugs with special emphasis on epilepsy resulting from neurocysticercosis. Materials and Methods: This was a cross-sectional descriptive study of epilepsy patients over four months in neurology outpatient department. Clinico-biological data were obtained by interrogating patients and from recorded data using standard case-report form. Results: 79 patients were studied with 54.43% having primary etiology, 40.51% having seizures secondary to neurocysticercosis. 81% had generalized tonic-clonic seizure, 17.7% partial and 1.3% myoclonic seizures. Phenytoin (86.08%, valproate (30.38%, clobazam (26.58% and carbamazepine (10.13% were used either alone or in combination, with no use of anthelmintics even in cases of neurocysticercosis. Control of seizure was obtained in 79.7% with significant decrease in seizure frequency from 2.92 to 0.51 (P < 0.0001. Weight loss, nausea, decreased appetite, increased sleep, drowsiness, tremors were found to be significantly associated (P < 0.05 with phenytoin use. Conclusion: Phenytoin is the primary antiepileptic in spite of its side effects; though addition of other anti-epileptic drugs (valproate, clobazam was required for better seizure control. Cases of neurocysticercosis respond to anti-epileptic drugs without addition of anthelmintics. Side effects observed were mostly neurological in nature.

  3. Formulation and evaluation of an anti-epileptic drug-loaded microemulsion for nose to brain delivery

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    Kawtikwar P

    2009-01-01

    Full Text Available The aim of the present study was to formulate an anti-epileptic drug-loaded microemulsion for nose-to-brain delivery. The oil system evaluated for the preparation of a stable microemulsion was iso-propyl myristate. A non-ionic surfactant like Tween 80 was used with polyethylene glycol 400 as a co-surfactant. A pseudoternary phase diagram for various proportions of S mix :oil was constructed by the water titration method. The effect of changing concentration of alcohol as a co-surfactant was also studied. The t-phase diagram shows that the water consumption capacity of the system was increased as the surfactant concentration was increased. It was also found that as the concentration of the alcohol was increased, the viscosity of the microemulsion decreased. After the identification of the microemulsion region, the composition of the microemulsion was fixed at oil 9-10%, S mix 35-40% and water 45-50%. The formulated microemulsion was evaluated for various parameters like pH, conductivity, zeta potential, viscosity and in vitro drug diffusion studies. All the evaluation parameters showed satisfactory results. Using this microemulsion, the solubility of valproic acid was increased from 1.29 to 36 mg/ml. Diffusion studies have shown a lag period of 45 min. Thirteen percent drug diffusion was achieved in 3 h. The prepared microemulsion was stable at 40°C and 75% relative humidity.

  4. 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. 

  5. Pharmacy sales data versus ward stock accounting for the surveillance of broad-spectrum antibiotic use in hospitals

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    Haug Jon B

    2011-12-01

    Full Text Available Abstract Background Antibiotic consumption in hospitals is commonly measured using the accumulated amount of drugs delivered from the pharmacy to ward held stocks. The reliability of this method, particularly the impact of the length of the registration periods, has not been evaluated and such evaluation was aim of the study. Methods During 26 weeks, we performed a weekly ward stock count of use of broad-spectrum antibiotics - that is second- and third-generation cephalosporins, carbapenems, and quinolones - in five hospital wards and compared the data with corresponding pharmacy sales figures during the same period. Defined daily doses (DDDs for antibiotics were used as measurement units (WHO ATC/DDD classification. Consumption figures obtained with the two methods for different registration intervals were compared by use of intraclass correlation analysis and Bland-Altman statistics. Results Broad-spectrum antibiotics accounted for a quarter to one-fifth of all systemic antibiotics (ATC group J01 used in the hospital and varied between wards, from 12.8 DDDs per 100 bed days in a urological ward to 24.5 DDDs in a pulmonary diseases ward. For the entire study period of 26 weeks, the pharmacy and ward defined daily doses figures for all broad-spectrum antibiotics differed only by 0.2%; however, for single wards deviations varied from -4.3% to 6.9%. The intraclass correlation coefficient, pharmacy versus ward data, increased from 0.78 to 0.94 for parenteral broad-spectrum antibiotics with increasing registration periods (1-4 weeks, whereas the corresponding figures for oral broad-spectrum antibiotics (ciprofloxacin were from 0.46 to 0.74. For all broad-spectrum antibiotics and for parenteral antibiotics, limits of agreement between the two methods showed, according to Bland-Altman statistics, a deviation of ± 5% or less from average mean DDDs at 3- and 4-weeks registration intervals. Corresponding deviation for oral antibiotics was ± 21% at a 4

  6. Protection from phenytoin-induced congenital malformations by coadministration of the antiepileptic drug stiripentol in a mouse model.

    Science.gov (United States)

    Finnell, R H; Kerr, B M; van Waes, M; Steward, R L; Levy, R H

    1994-01-01

    To test the hypothesis that the cytochrome P-450-inhibiting antiepileptic drug (AED) stiripentol (STP) can reduce the incidence of phenytoin (PHT) induced congenital malformations, we chronically administered the AEDs to three inbred mouse strains. The frequency of congenital defects in PHT-treated animals was dosage dependent, ranging from 7 to 55%. When STP was coadministered orally with PHT, there was a significant reduction in fetal defects in SWV and C57BL/6J mouse strains. A replication of the experiment was conducted with addition of a seventh group of mice that received the high dosage of PHT together with STP. In the replicate, all three strains demonstrated a significant reduction in fetal defects in fetuses exposed to PHT (60 mg/kg) and STP (200 mg/kg) as compared with PHT (60 mg/kg) monotherapy. These results strongly suggest that oxidative metabolites activated by cytochrome P-450 are the primary teratogenic molecules involved in PHT-induced teratogenesis and that clinical management of pregnant epileptic patients may be improved through heightened awareness of these drug interactions.

  7. 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.

  8. The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes.

    Science.gov (United States)

    Noyer, M; Gillard, M; Matagne, A; Hénichart, J P; Wülfert, E

    1995-11-14

    Levetiracetam ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide, ucb L059) is a novel potential antiepileptic agent presently in clinical development with unknown mechanism of action. The finding that its anticonvulsant activity is highly stereoselective (Gower et al., 1992) led us to investigate the presence of specific binding sites for [3H]levetiracetam in rat central nervous system (CNS). Binding assays, performed on crude membranes, revealed the existence of a reversible, saturable and stereoselective specific binding site. Results obtained in hippocampal membranes suggest that [3H]levetiracetam labels a single class of binding sites (nH = 0.92 +/- 0.06) with modest affinity (Kd = 780 +/- 115 nM) and with a high binding capacity (Bmax = 9.1 +/- 1.2 pmol/mg protein). Similar Kd and Bmax values were obtained in other brain regions (cortex, cerebellum and striatum). ucb L060, the (R) enantiomer of levetiracetam, displayed about 1000 times less affinity for these sites. The binding of [3H]levetiracetam is confined to the synaptic plasma membranes in the central nervous system since no specific binding was observed in a range of peripheral tissues including heart, kidneys, spleen, pancreas, adrenals, lungs and liver. The commonly used antiepileptic drugs carbamazepine, phenytoin, valproate, phenobarbital and clonazepam, as well as the convulsant agent t-butylbicyclophosphorothionate (TBPS), picrotoxin and bicuculline did not displace [3H]levetiracetam binding. However, ethosuximide (pKi = 3.5 +/- 0.1), pentobarbital (pKi = 3.8 +/- 0.1), pentylenetetrazole (pKi = 4.1 +/- 0.1) and bemegride (pKi = 5.0 +/- 0.1) competed with [3H]levetiracetam with pKi values comparable to active drug concentrations observed in vivo. Structurally related compounds, including piracetam and aniracetam, also displaced [3H]levetiracetam binding. (S) Stereoisomer homologues of levetiracetam demonstrated a rank order of affinity for [3H]levetiracetam binding in correlation with their

  9. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs.

    Science.gov (United States)

    Löscher, Wolfgang

    2011-06-01

    Animal models for seizures and epilepsy have played a fundamental role in advancing our understanding of basic mechanisms underlying ictogenesis and epileptogenesis and have been instrumental in the discovery and preclinical development of novel antiepileptic drugs (AEDs). However, there is growing concern that the efficacy of drug treatment of epilepsy has not substantially improved with the introduction of new AEDs, which, at least in part, may be due to the fact that the same simple screening models, i.e., the maximal electroshock seizure (MES) and s.c. pentylenetetrazole (PTZ) seizure tests, have been used as gatekeepers in AED discovery for >6 decades. It has been argued that these old models may identify only drugs that share characteristics with existing drugs, and are unlikely to have an effect on refractory epilepsies. Indeed, accumulating evidence with several novel AEDs, including levetiracetan, has shown that the MES and PTZ models do not identify all potential AEDs but instead may fail to discover compounds that have great potential efficacy but work through mechanisms not tested by these models. Awareness of the limitations of acute seizure models comes at a critical crossroad. Clearly, preclinical strategies of AED discovery and development need a conceptual shift that is moving away from using models that identify therapies for the symptomatic treatment of epilepsy to those that may be useful for identifying therapies that are more effective in the refractory population and that may ultimately lead to an effective cure in susceptible individuals by interfering with the processes underlying epilepsy. To realize this goal, the molecular mechanisms of the next generation of therapies must necessarily evolve to include targets that contribute to epileptogenesis and pharmacoresistance in relevant epilepsy models.

  10. Effect of acutely and chronically administered venlafaxine on the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock model.

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    Borowicz, Kinga K; Gołyska, Dorota; Luszczki, Jarogniew J; Czuczwar, Stanislaw J

    2011-11-16

    The influence of acute and chronic treatments with intraperitoneal venlafaxine, a selective serotonin/norepinephrine reuptake inhibitor, on the anticonvulsant activity of selected antiepileptic drugs was studied in the maximal electroshock test in mice. Venlafaxine (12.5 and 25mg/kg), given either acutely or chronically, significantly increased the electroconvulsive threshold. Moreover, both acute and chronic venlafaxine, applied at the highest subprotective dose of 6.25mg/kg, enhanced the anticonvulsant effect of valproate, without affecting the protective action of carbamazepine, phenobarbital and phenytoin. The antidepressant did not affect brain concentration of valproate, indicating that the interaction between the two drugs seems pharmacodynamic in nature. Despite the lack of effect on the antielectroshock action of the remaining antiepileptics, acute venlafaxine increased the brain concentration of phenobarbital, while chronic venlafaxine reduced the brain level of phenytoin. In terms of adverse effects, acute/chronic venlafaxine and antiepileptic drugs alone, as well as their combinations, did not produce significant motor or long-term memory deficits in mice. Summing up, it seems that venlafaxine may be considered as a safe drug for the clinical use in patients with epilepsy and depressive disorders.

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

    Science.gov (United States)

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

    2016-06-01

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

  12. Pharmacokinetics and pharmacodynamics of ceftobiprole, an anti-MRSA cephalosporin with broad-spectrum activity.

    Science.gov (United States)

    Murthy, Bindu; Schmitt-Hoffmann, Anne

    2008-01-01

    Ceftobiprole, a beta-lactam, is the first of a new generation of broad-spectrum cephalosporins in late-stage development with activity against methicillin-resistant Staphylococcus aureus (MRSA) in addition to broad-spectrum bactericidal activity against other Gram-positive and Gram-negative pathogens. The prodrug, ceftobiprole medocaril, is converted rapidly and almost completely to the active drug, ceftobiprole, upon infusion by type A esterases. In humans, ceftobiprole binds minimally (16%) to plasma proteins, and binding is independent of the drug and protein concentrations. Its steady-state volume of distribution (18.4 L) approximates the extracellular fluid volume in humans. Ceftobiprole undergoes minimal hepatic metabolism, and the primary metabolite is the beta-lactam ring-opened hydrolysis product (open-ring metabolite). Systemic exposure of the open-ring metabolite accounts for 4% of ceftobiprole exposure following single-dose administration; approximately 5% of the dose is excreted in the urine as the metabolite. Ceftobiprole does not significantly induce or inhibit relevant cytochrome P450 enzymes and is neither a substrate nor an inhibitor of P-glycoprotein. Ceftobiprole is rapidly eliminated, primarily unchanged, by renal excretion, with a terminal elimination half-life of 3 hours; the predominant mechanism responsible for elimination is glomerular filtration, with approximately 89% of the dose being excreted as the prodrug, active drug (ceftobiprole) and open-ring metabolite. The pharmacokinetics of ceftobiprole are linear following single and multiple infusions of 125-1000 mg. Steady-state drug concentrations are attained on the first day of dosing, with no appreciable accumulation when administered three times daily (every 8 hours) and twice daily (every 12 hours) in subjects with normal renal function. Low intersubject variability has been seen across studies. Ceftobiprole exposure is slightly higher (~15%) in females than in males; this difference

  13. Novel antiepileptic drug lacosamide exerts neuroprotective effects by decreasing glial activation in the hippocampus of a gerbil model of ischemic stroke

    OpenAIRE

    Ahn, Ji Yun; Yan, Bing Chun; Park, Joon Ha; Ahn, Ji Hyeon; LEE, DAE HWAN; Kim, In Hye; Cho, Jeong-Hwi; Chen, Bai Hui; Lee, Jae-Chul; Cho, Young Shin; SHIN, MYOUNG CHUL; Cho, Jun Hwi; Hong, Seongkweon; Won, Moo-Ho; Kim, Sung Koo

    2015-01-01

    Lacosamide, which is a novel antiepileptic drug, has been reported to exert various additional therapeutic effects. The present study investigated the neuroprotective effects of lacosamide against transient cerebral ischemia-induced neuronal cell damage in the hippocampal cornu ammonis (CA)-1 region of a gerbil model. Neuronal Nuclei immunohistochemistry demonstrated that pre- and post-surgical treatment (5 min ischemia) with 25 mg/kg lacosamide protected CA1 pyramidal neurons in the lacosami...

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

    Science.gov (United States)

    Hansen, Suzanne L; Sterjev, Zoran; Werngreen, Marie; Simonsen, Bodil J; Knudsen, Katrine E; Nielsen, Ane H; Pedersen, Mikael E; Badolo, Lassiana; Kristiansen, Uffe; Vestergaard, Henrik T

    2012-05-05

    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 reported to lack effect in this model. The neuroplastic changes induced in acute and chronic animal models of epilepsy are known to affect the pharmacological profile of AEDs in vivo. Hence, we investigated whether brain slices from pentylenetetrazole (PTZ)-kindled animals could provide a more predictive screening model for AEDs. To this end, we compared the in vitro and in vivo pharmacological profile of several selected AEDs (phenobarbital, phenytoin, tiagabine, fosphenytoin, valproate, and carbamazepine) along with citalopram using the PTZ-kindled model and brain slices from naïve, saline-injected and PTZ-kindled mice. Our data suggest that the use of slices from PTZ-kindled mice in the cortical wedge does not increase the predictive validity of the model as an in vitro screening model for AEDs. Traditionally, the incidence of certain seizure types is widely used as a measure to characterize drug action in animal models of epilepsy. In our study, the anticonvulsant effect of the AEDs was investigated in vivo using several observational parameters (i.e., incidence and duration of convulsions, latency to clonic convulsions, and severity of convulsions). We found that including the observational parameter "severity" offered important additional information about the drug profile that would otherwise be lost if only a single parameter as "incidence" was used.

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

    Science.gov (United States)

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

    2016-03-01

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

  16. Preclinical evaluation of 2,2,3,3-tetramethylcyclopropanecarbonyl-urea, a novel, second generation to valproic acid, antiepileptic drug.

    Science.gov (United States)

    Sobol, Eyal; Yagen, Boris; Steve White, H; Wilcox, Karen S; Lamb, John G; Pappo, Orit; Wlodarczyk, Bogdan J; Finnell, Richard H; Bialer, Meir

    2006-09-01

    2,2,3,3-Tetramethylcyclopropanecarbonylurea (TMCU) is an amide derivative of a tetramethylcyclopropyl analogue of valproic acid (VPA), one of the leading antiepileptic drugs. Structural considerations used in the design of TMCU aimed to enhance the anticonvulsant potency of VPA and to prevent its two life-threatening side effects; i.e., teratogenicity and hepatotoxicity. The anticonvulsant activity of TMCU was evaluated in the MES, scMet, 6-Hz, scBic and scPic tests, and also in the hippocampal kindling model of partial seizures and lamotrigine-resistant amygdala kindling model of therapy-resistant seizures. Minimal motor impairment was determined using the rotorod test in mice and the positional sense test, muscle tone test, and gait and stance test in rats. The antinociceptive effect of TMCU was evaluated in the mouse formalin model of acute-tonic pain. The molecular mechanisms of action of TMCU were investigated in electrophysiological studies using the whole-cell patch-clamp technique. Teratogenicity studies were performed in a SWV/Fnn-mouse model of VPA-induced teratogenicity. TMCU hepatotoxicity was evaluated following 1-week intraperitoneal and oral administration of 50, 250 and 500 mg/kg doses to rats. In the hepatotoxicity study the blood levels of TMCU were evaluated at day 1 and day 7 of the treatment. TMCU mutagenicity was evaluated in the Ames test.

  17. The effects of antiepileptic drugs on estrogen-induced electrographic spike-wave discharge.

    Science.gov (United States)

    Julien, R M; Fowler, G W; Danielson, M G

    1975-05-01

    In locally anesthetized, paralyzed cats with bilateral conjugated estrogen (CE)-induced foci in sensory motor cortex, electrographic activity was characterized by 2 to 3 Hz spike and slow wave discharge. Commonly used anti-petit mal drugs (esthosuximide, trimethadione, acetazolamide and diazepam) all reduced CE-induced spike wave activity while diphenylhydantoin converted such activity into 9 to 12 Hz polyspike bursts separated by periods of interictal silence. Correlation appears to exist, therefore, between the ability of the drug to reduce CE-induced spike wave activity and its clinical utility in petit mal epilepsy. In addition to the above compounds, five drugs of less proven utility were evaluated. Of these, two benzodiazepine derivatives (clonazepam and clorazepate) were found to exert a potent and prolonged depressant action on CE-induced activity. The relation of CE to clinical petit mal epilepsy and the potential usefulness of CE as a laboratory model for the evaluation of anti-petit mal drugs are discussed.

  18. Correlation of the "EMIT" antiepileptic drug assay with a gas liquid chromatographic method.

    Science.gov (United States)

    Legaz, M; Raisys, V A

    1976-02-01

    Many methodologies have been developed for determining anticonvulsant drug levels in human serum. Unfortunately, most procedures are either time consuming or subject to a variety of interferring substances. The "Enzyme Multiplied Immunoassay Technique" (EMIT) system has been evaluated for its speed, sensitivity, accuracy, and precision. When compared with a gas-liquid chromatographic procedure, the EMIT assay appeared to yield results which were statistically comparable for the drugs diphenylhydantoin, phenobarbital, and primidone. The EMIT assay also demonstrated no significant interference when challenged with extraordinarily high levels of potentially cross reacting drugs. Results obtained with the EMIT assay correlated well with GLC data and rank it as an attractive alternative to many of the existing procedures now being used.

  19. 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.

  20. An evaluation of factors affecting adherence to antiepileptic drugs in patients with epilepsy: a cross-sectional study

    Science.gov (United States)

    Gurumurthy, Ranjana; Chanda, Kulkarni; Sarma, GRK

    2017-01-01

    INTRODUCTION Adherence to antiepileptic drug (AED) therapy is important for controlling seizures in patients with epilepsy (PWE). It is vital to identify the factors influencing adherence to AED therapy using validated tools. This study aimed to evaluate the pattern and extent of AED adherence among PWE and to identify the factors that influence adherence. METHODS This was a cross-sectional study involving PWE who had a confirmed diagnosis. Treatment adherence was assessed using the four-item Morisky Medication Adherence Scale. Univariate analysis with chi-square test was used to observe the association between different variables and AED adherence. Binary logistic regression analysis was used to identify the predictors of adherence. RESULTS 451 PWE (mean age 27.3 ± 8.1 years) were enrolled in the study; 251 (55.7%) were male and 198 (43.9%) were from the lower socioeconomic class. 326 (72.3%) patients had high adherence to AED therapy, while 125 (27.7%) had low adherence. AED adherence was significantly associated with socioeconomic status (p = 0.043) and type of epilepsy (p = 0.033). However, no significant difference was observed between adherence and age, gender, marital status, epilepsy duration, number and type of AEDs, and occurrence of adverse drug reactions. Patients with focal epilepsy and those from the middle/lower-middle socioeconomic classes were less likely to be nonadherent. The primary reason for nonadherence was forgetfulness. CONCLUSION This study found that a majority of PWE have optimal rates of AED adherence and that forgetfulness is the primary reason for nonadherence among PWE. PMID:26805666

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

    Directory of Open Access Journals (Sweden)

    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. Acne keloidalis-like lesions on the scalp associated with antiepileptic drugs.

    Science.gov (United States)

    Grunwald, M H; Ben-Dor, D; Livni, E; Halevy, S

    1990-10-01

    A man developed acne keloidalis-like lesions in the scalp during treatment with diphenylhydantoin and carbamazepine for epilepsy. These drugs were suspected to play a role in the pathogenesis of this skin disease in an unusual location, based on clinical evidence and on the in vitro test, mast cell degranulation (MCD).

  3. Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent.

    Science.gov (United States)

    Miceli, Marisa H; Kauffman, Carol A

    2015-11-15

    Isavuconazole is a new extended-spectrum triazole with activity against yeasts, molds, and dimorphic fungi. It is approved for the treatment of invasive aspergillosis and mucormycosis. Advantages of this triazole include the availability of a water-soluble intravenous formulation, excellent bioavailability of the oral formulation, and predictable pharmacokinetics in adults. A randomized, double-blind comparison clinical trial for treatment of invasive aspergillosis found that the efficacy of isavuconazole was noninferior to that of voriconazole. An open-label trial that studied primary as well as salvage therapy of invasive mucormycosis showed efficacy with isavuconazole that was similar to that reported for amphotericin B and posaconazole. In patients in these studies, as well as in normal volunteers, isavuconazole was well tolerated, appeared to have few serious adverse effects, and had fewer drug-drug interactions than those noted with voriconazole. As clinical experience increases, the role of this new triazole in the treatment of invasive fungal infections will be better defined.

  4. Novel, broad-spectrum anticonvulsants containing a sulfamide group: pharmacological properties of (S)-N-[(6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112).

    Science.gov (United States)

    McComsey, David F; Smith-Swintosky, Virginia L; Parker, Michael H; Brenneman, Douglas E; Malatynska, Ewa; White, H Steve; Klein, Brian D; Wilcox, Karen S; Milewski, Michael E; Herb, Mark; Finley, Michael F A; Liu, Yi; Lubin, Mary Lou; Qin, Ning; Reitz, Allen B; Maryanoff, Bruce E

    2013-11-27

    Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such "neurostabilizers" have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4-9, 10a-i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures. Mechanistically, 4 inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels and was effective as a K(+) channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies.

  5. Status epilepticus induction has prolonged effects on the efficacy of antiepileptic drugs in the 6-Hz seizure model.

    Science.gov (United States)

    Leclercq, Karine; Kaminski, Rafal M

    2015-08-01

    Several factors may influence the efficacy of antiepileptic drugs (AEDs) in patients with epilepsy, and treatment resistance could be related to genetics, neuronal network alterations, and modification of drug transporters or targets. Consequently, preclinical models used for the identification of potential new, more efficacious AEDs should reflect at least a few of these factors. Previous studies indicate that induction of status epilepticus (SE) may alter drug efficacy and that this effect could be long-lasting. In this context, we wanted to assess the protective effects of mechanistically diverse AEDs in mice subjected to pilocarpine-induced SE in another seizure model. We first determined seizure thresholds in mice subjected to pilocarpine-induced SE in the 6-Hz model, 2 weeks and 8 weeks following SE. We then evaluated the protective effects of mechanistically diverse AEDs in post-SE and control animals. No major differences in 6-Hz seizure susceptibility were observed between control groups, while the seizure threshold of pilocarpine mice at 8 weeks after SE was higher than at 2 weeks and higher than in control groups. Treatment with AEDs revealed major differences in drug response depending on their mechanism of action. Diazepam produced a dose-dependent protection against 6-Hz seizures in control and pilocarpine mice, both at 2 weeks and 8 weeks after SE, but with a more pronounced increase in potency in post-SE animals at 2 weeks. Levetiracetam induced a potent and dose-dependent protection in pilocarpine mice, 2 weeks after SE, while its protective effects were observed only at much higher doses in control mice. Its potency decreased in post-SE mice at 8 weeks and was very limited (30% protection at the highest tested dose) in the control group. Carbamazepine induced a dose-dependent protection at 2 weeks in control mice but only limited effect (50% at the highest tested dose) in pilocarpine mice. Its efficacy deeply decreased in post-SE mice at 8 weeks

  6. Orientações ao pediatra sobre o manejo das drogas psicoativas e antiepilépticas Use of psychoactive and antiepileptic drugs: guidelines for pediatricians

    Directory of Open Access Journals (Sweden)

    Gibsi P. Rocha

    2004-04-01

    Full Text Available OBJETIVO: Revisar as indicações e o manejo clínico das drogas psicoativas e antiepilépticas na infância e adolescência. FONTES DE DADOS: Estudo baseado em revisão de literatura. Os autores organizam, de acordo com os quadros patológicos, uma rotina para o manejo dos psicofármacos e das drogas antiepilépticas na infância e na adolescência. SÍNTESE DOS DADOS: Indicação clínica, dosagem terapêutica e efeitos colaterais dos psicofármacos e drogas antiepilépticas são descritos. O uso de psicofármacos na infância e adolescência está se tornando mais freqüente, com a disponibilidade de novos medicamentos e com o crescimento do conhecimento sobre diagnóstico de transtornos emocionais nessa faixa etária. CONCLUSÕES: O manejo dos psicofármacos e drogas antiepilépticas na faixa etária pediátrica requer amplo conhecimento da farmacocinética dos mesmos, assim como de seus efeitos colaterais deletérios. A escolha do fármaco adequado é determinante no sucesso terapêutico.OBJECTIVE: To review the guidelines for the use of psychoactive and antiepileptic drugs in childhood and adolescence. SOURCES OF DATA: Literature review. SUMMARY OF THE FINDINGS: The clinical indications, dosage and side effects of psychoactive and antiepileptic drugs are presented. The use of psychoactive drugs is increasing due to the release of new drugs and to the better understanding of emotional disorders in children and adolescents. CONCLUSIONS: The use of antiepileptic and psychoactive drugs in childhood requires extensive knowledge concerning pharmacokinetics and deleterious side effects. An adequate choice of drugs is essential to ensure a successful treatment.

  7. Effect of topiramate and traditional antiepileptic drugs on pituitary-sexual gland axis in adult males with epilepsy

    Institute of Scientific and Technical Information of China (English)

    Fei Xu; Liang Yu; Jie Liu; Yongjie Luo; Hongbin Sun

    2007-01-01

    BACKGROUND: Some reports indicate that traditional antiepileptic drugs can cause a certain effect on reproductive endocrine system in epileptic patients. However, the effect of topiramate on reproductive endocrine system needs to be further studied.OBJECTIVE: To compare the effects of topiramate and traditional valproic acid and carbamazepine on pituitary-sexual gland axis in adult males with epilepsy.DESIGN: Self-contrast and randomly parallel controlled study.SETTING: Sichuan Academy of Medical Sciences (Department of Neurology, Sichuan Provincial People's Hospital).PARTICIPANTS: A total of 54 male epileptic patients aged from 18 to 75 years were selected from Department of Neurology, Sichuan Provincial People's Hospital from January 2004 to June 2006. All patients were diagnosed as epilepsy based on illness history and electroencephalogram (EEG), and types of epilepsy were classified based on the theory of epilepsy and epilepsy syndrome established by International Anti-epilepsy League in 1989 and 2001. The accepted patients and their relatives provided the confirmed consent.METHODS: ① The accepted patients were randomly divided into traditional treatment group [n =26,mean age of (34 ±14) years] and topiramate group [n =28, mean age of (28 ±17) years]. In addition, based on various kinds of drugs, patients in the traditional treatment group were divided into two subgroups,including carbamazepine group (n =14) and valproic acid group (n =12). Patients in both subgroups were respectively treated with carbamazepine (100 mg/table, Shanghai Sanwei Pharmaceutical Factory, batch number: 060705) and valproic acid (200 mg/table, Hunan Xiangzhong Pharmaceutical Co., Ltd., batch number: 061128). Patients in topiramate group were treated with topiramate (25 mg/table, Xi'an Yangsen Pharmaceutical Co., Ltd., batch number: 060215836). Administration: The beginning dosage of topiramate was 25 mg/d, and then increased 25 mg/d per week. The final dosage was 150 mg/d. In

  8. Effect of the new antiepileptic drug retigabine in a rodent model of mania

    DEFF Research Database (Denmark)

    Dencker, Ditte; Dias, Rebecca; Pedersen, Mette Lund;

    2008-01-01

    Bipolar spectrum disorders are severe chronic mood disorders that are characterized by episodes of mania or hypomania and depression. Because patients with manic symptoms often experience clinical benefit from treatment with anticonvulsant drugs, it was hypothesized that retigabine, a novel...... compound with anticonvulsant efficacy, may also possess antimanic activity. The amphetamine (AMPH)+chlordiazepoxide (CDP)-induced hyperactivity model has been proposed as a suitable model for studying antimanic-like activity of novel compounds in mice and rats. The aims of the present study in rats were...

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

    Science.gov (United States)

    Bath, Kevin G; Scharfman, Helen E

    2013-03-01

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

  10. Safety and efficacy of clobazam versus phenytoin-sodium in the antiepileptic drug treatment of solitary cysticercus granulomas

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    Kaushal Sandeep

    2006-01-01

    Full Text Available Background: It is now agreed that the prognosis of seizure disorder due to solitary cysticercus granuloma (SCG is generally good. However, the choice antiepileptic drugs (AEDs remain empirical, with no comparative trials of different AEDs being available. Aims: To determine the safety and efficacy (measured by the incidence of ′treatment failure′ of clobazam in comparison to standard treatment with phenytoin-sodium for prevention of seizures in persons with solitary cysticercus granulomas (SCGs. Settings and Design: This pilot study was conducted in a neurology department of a medical college hospital in the form of a prospective, randomized, open-labeled trial. Materials and Methods: Forty-eight patients with seizures due to SCG were randomized in an open-labeled trial to either, clobazam (1 mg/kg oral loading followed by 0.5 mg/kg/d (n=21 or phenytoin (15 mg/kg, oral loading in 3 divided doses over 24 h, followed by 5 mg/kg/d (n=27. They were followed over 6 months with the primary outcome measure being treatment failure (either discontinuation or modification of AEDs due to either adverse effects or breakthrough seizures. Results: Treatment failures were noted to be significantly less common ( P =0.03 in the clobazam-treated group (n=1; 4.7% than in phenytoin-treated group (n=9; 33.3%. These included one patient (4.7% in the clobazam-group who had breakthrough seizures and 3 (11.1% who had breakthrough seizures and 6 (22.2% in the phenytoin-treated group who had adverse effects requiring treatment discontinuation. Conclusions: Clobazam was well tolerated, safe and more effective than phenytoin in the AED treatment of patients with SCG.

  11. Low risk of development of substance dependence for barbiturates and clobazam prescribed as antiepileptic drugs: results from a questionnaire study.

    Science.gov (United States)

    Uhlmann, Carmen; Fröscher, Walter

    2009-01-01

    There is no systematical research about the topic of dependence on antiepileptic drugs (AED) for patients with epilepsy, despite the fact that barbiturates and benzodiazepines comprise a potential risk of dependence. We hypothesize that there is no psychological substance dependence for patients with epilepsy, possibly because of their outcome expectations. The aim of the study was to examine these patients in terms of substance dependence. One hundred inpatients at the Lake Constance Epilepsy Center were asked about their experiences with AED in terms of dependence in a structured interview. We registered general statements about dependence of AED, markers for substance dependence, and outcome expectations. About 50% of the patients reported withdrawal symptoms and the development of tolerance, but less than 10% noticed loss of control and craving. Withdrawal symptoms and development of tolerance were significantly lower in a group of patients without barbiturates or clobazam versus patients with barbiturates or/and clobazam. There was no significant difference between these two groups in psychological criteria of dependence, that is, loss of control and craving. Outcome expectations of AED were clearly related to the efficacy against seizures, and only to a small amount to psychotropic effects. The study demonstrates that physiological variables of dependence are present more in patients with epilepsy with a permanent intake of barbiturates or clobazam, but psychological variables of dependence are rarely present in epileptic patients, with or without an intake of barbiturates and clobazam. These results confirm our hypothesis that substance dependence is not a major problem in benzodiazepines and barbiturates in patients with epilepsy. Outcome expectations seem to be related mainly to the anticonvulsant and not the psychotropic effect. This might be the reason for the absence of dependence.

  12. 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.

    2016-01-01

    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. PMID:27854292

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Antipneumococcal activity of ceftobiprole, a novel broad-spectrum cephalosporin.

    Science.gov (United States)

    Kosowska, Klaudia; Hoellman, Dianne B; Lin, Gengrong; Clark, Catherine; Credito, Kim; McGhee, Pamela; Dewasse, Bonifacio; Bozdogan, Bülent; Shapiro, Stuart; Appelbaum, Peter C

    2005-05-01

    Ceftobiprole (previously known as BAL9141), an anti-methicillin-resistant Staphylococcus aureus cephalosporin, was very highly active against a panel of 299 drug-susceptible and -resistant pneumococci, with MIC(50) and MIC(90) values (microg/ml) of 0.016 and 0.016 (penicillin susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0 (penicillin resistant). Ceftobiprole, imipenem, and ertapenem had lower MICs against all pneumococcal strains than amoxicillin, cefepime, ceftriaxone, cefotaxime, cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally varied in parallel, whereas fluoroquinolone MICs did not correlate with penicillin or macrolide susceptibility or resistance. All strains were susceptible to linezolid, quinupristin-dalfopristin, daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that at 1x and 2x the MIC, ceftobiprole was bactericidal against 10/12 and 11/12 strains, respectively. Levofloxacin, moxifloxacin, vancomycin, and teicoplanin were each bactericidal against 10 to 12 strains at 2x the MIC. Azithromycin and clarithromycin were slowly bactericidal, and telithromycin was bactericidal against only 5/12 strains at 2x the MIC. Linezolid was mainly bacteriostatic, whereas quinupristin-dalfopristin and daptomycin showed marked killing at early time periods. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to yield mutants with high MICs towards this cephalosporin, and single-passage selection showed very low frequencies of spontaneous mutants with breakthrough MICs towards ceftobiprole.

  15. A High-Throughput Screen Identifies a New Natural Product with Broad-Spectrum Antibacterial Activity

    Science.gov (United States)

    Ymele-Leki, Patrick; Cao, Shugeng; Sharp, Jared; Lambert, Kathleen G.; McAdam, Alexander J.; Husson, Robert N.; Tamayo, Giselle; Clardy, Jon; Watnick, Paula I.

    2012-01-01

    Due to the inexorable invasion of our hospitals and communities by drug-resistant bacteria, there is a pressing need for novel antibacterial agents. Here we report the development of a sensitive and robust but low-tech and inexpensive high-throughput metabolic screen for novel antibiotics. This screen is based on a colorimetric assay of pH that identifies inhibitors of bacterial sugar fermentation. After validation of the method, we screened over 39,000 crude extracts derived from organisms that grow in the diverse ecosystems of Costa Rica and identified 49 with reproducible antibacterial effects. An extract from an endophytic fungus was further characterized, and this led to the discovery of three novel natural products. One of these, which we named mirandamycin, has broad-spectrum antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Vibrio cholerae, methicillin-resistant Staphylococcus aureus, and Mycobacterium tuberculosis. This demonstrates the power of simple high throughput screens for rapid identification of new antibacterial agents from environmental samples. PMID:22359585

  16. Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents.

    Science.gov (United States)

    Brai, Annalaura; Fazi, Roberta; Tintori, Cristina; Zamperini, Claudio; Bugli, Francesca; Sanguinetti, Maurizio; Stigliano, Egidio; Esté, José; Badia, Roger; Franco, Sandra; Martinez, Miguel A; Martinez, Javier P; Meyerhans, Andreas; Saladini, Francesco; Zazzi, Maurizio; Garbelli, Anna; Maga, Giovanni; Botta, Maurizio

    2016-05-10

    Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEAD-box polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target.

  17. 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.

  18. 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.

  19. 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

  20. The Brain Activity in Brodmann Area 17: A Potential Bio-Marker to Predict Patient Responses to Antiepileptic Drugs.

    Directory of Open Access Journals (Sweden)

    Yida Hu

    Full Text Available In this study, we aimed to predict newly diagnosed patient responses to antiepileptic drugs (AEDs using resting-state functional magnetic resonance imaging tools to explore changes in spontaneous brain activity. We recruited 21 newly diagnosed epileptic patients, 8 drug-resistant (DR patients, 11 well-healed (WH patients, and 13 healthy controls. After a 12-month follow-up, 11 newly diagnosed epileptic patients who showed a poor response to AEDs were placed into the seizures uncontrolled (SUC group, while 10 patients were enrolled in the seizure-controlled (SC group. By calculating the amplitude of fractional low-frequency fluctuations (fALFF of blood oxygen level-dependent signals to measure brain activity during rest, we found that the SUC patients showed increased activity in the bilateral occipital lobe, particularly in the cuneus and lingual gyrus compared with the SC group and healthy controls. Interestingly, DR patients also showed increased activity in the identical cuneus and lingual gyrus regions, which comprise Brodmann's area 17 (BA17, compared with the SUC patients; however, these abnormalities were not observed in SC and WH patients. The receiver operating characteristic (ROC curves indicated that the fALFF value of BA17 could differentiate SUC patients from SC patients and healthy controls with sufficient sensitivity and specificity prior to the administration of medication. Functional connectivity analysis was subsequently performed to evaluate the difference in connectivity between BA17 and other brain regions in the SUC, SC and control groups. Regions nearby the cuneus and lingual gyrus were found positive connectivity increased changes or positive connectivity changes with BA17 in the SUC patients, while remarkably negative connectivity increased changes or positive connectivity decreased changes were found in the SC patients. Additionally, default mode network (DMN regions showed negative connectivity increased changes or

  1. Effects of WIN 55,212-2 (a synthetic cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant activity of various novel antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice.

    Science.gov (United States)

    Florek-Luszczki, Magdalena; Wlaz, Aleksandra; Zagaja, Mirosław; Andres-Mach, Marta; Kondrat-Wrobel, Maria W; Luszczki, Jarogniew J

    2015-03-01

    The purpose of this study was to determine the influence of WIN 55,212-2 mesylate (WIN-a non-selective cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant activity of various second- and third-generation antiepileptic drugs (i.e., gabapentin, lacosamide, levetiracetam, oxcarbazepine, pregabalin and tiagabine) in the mouse 6 Hz-induced psychomotor seizure model. Psychomotor seizures were evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3s stimulus duration) delivered via ocular electrodes. Additionally, total brain antiepileptic drug concentrations were measured. Results indicate that WIN (5 mg/kg, administered i.p.) significantly potentiated the anticonvulsant action of gabapentin (P < 0.05) and levetiracetam (P < 0.01), but not that of lacosamide, oxcarbazepine, pregabalin or tiagabine in the mouse psychomotor seizure model. Moreover, WIN (2.5 mg/kg) had no significant effect on the anticonvulsant activity of all tested antiepileptic drugs in the 6 Hz test in mice. Measurement of total brain antiepileptic drug concentrations revealed that WIN (5 mg/kg) had no impact on gabapentin or levetiracetam total brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse 6Hz model. In conclusion, WIN in combination with gabapentin and levetiracetam exerts beneficial anticonvulsant pharmacodynamic interactions in the mouse psychomotor seizure model.

  2. 抗癫痫药基因多态性研究进展%Research on genetic polymorphism of antiepileptic drugs

    Institute of Scientific and Technical Information of China (English)

    高森

    2014-01-01

    Clinical agrees that drug's gene polymorphism has important meaning for individual differences of antiepileptic drugs, gene polymorphism leads individuals appear different pharmacological and toxicological effects. Pharmacogenetics is a genetics discipline, along with in-depth study of pharmacogenetics, personalized medicine has a new situation. This paper firstly analyzes the types and the effect of antiepileptic drugs, then discusse gene polymorphism on epilepsy medicine clinical research progress.%临床医学上一致认为药物的基因多态性对于抗癫痫药的个体差异有着重要的意义,基因多态性导致个体出现不同的药理和毒理作用。遗传药理学是一门遗传学学科,随着人们对遗传药理学的深入研究,个体化用药有了新的局面。本文首先分析了抗癫痫药的种类及其疗效,然后详细介绍了当前基因多态性对抗癫痫药疗效研究进展。

  3. (R)-[11C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance: evaluation in a rat epilepsy model.

    Science.gov (United States)

    Bogdanović, Renée Marie; Syvänen, Stina; Michler, Christina; Russmann, Vera; Eriksson, Jonas; Windhorst, Albert D; Lammertsma, Adriaan A; de Lange, Elisabeth C; Voskuyl, Rob A; Potschka, Heidrun

    2014-10-01

    Neuroinflammation has been suggested as a key determinant of the intrinsic severity of epilepsy. Glial cell activation and associated inflammatory signaling can influence seizure thresholds as well as the pharmacodynamics and pharmacokinetics of antiepileptic drugs. Based on these data, we hypothesized that molecular imaging of microglia activation might serve as a tool to predict drug refractoriness of epilepsy. Brain uptake of (R)-[11C]PK11195, a ligand of the translocator protein 18 kDa and molecular marker of microglia activation, was studied in a chronic model of temporal lobe epilepsy in rats with selection of phenobarbital responders and non-responders. In rats with drug-sensitive epilepsy, (R)-[11C]PK11195 brain uptake values were comparable to those in non-epileptic controls. Analysis in non-responders revealed enhanced brain uptake of up to 39% in different brain regions. The difference might be related to the fact that non-responders exhibited higher baseline seizure frequencies than responders indicating a more pronounced intrinsic disease severity. In hippocampal sections, ED1 immunostaining argued against a general difference in microglia activation between both groups. Our data suggest that TSPO PET imaging might serve as a biomarker for drug resistance in temporal lobe epilepsy. However, it needs to be considered that our findings indicate that the TSPO PET data might merely reflect seizure frequency. Future experimental and clinical studies should further evaluate the validity of TSPO PET data to predict the response to phenobarbital and other antiepileptic drugs in longitudinal studies with scanning before drug exposure and with a focus on the early phase following an epileptogenic brain insult.

  4. Isobolographic analysis of interactions between 1-methyl-1,2,3,4-tetrahydroisoquinoline and four conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model.

    Science.gov (United States)

    Luszczki, Jarogniew J; Antkiewicz-Michaluk, Lucyna; Czuczwar, Stanislaw J

    2009-01-14

    The anticonvulsant activity of 1-methyl-1,2,3,4-tetrahydroisoquinoline (MeTHIQ--an endogenous parkinsonism-preventing substance) administered alone and in combination with four conventional antiepileptic drugs (carbamazepine, phenytoin, phenobarbital and valproate) was determined in the mouse maximal electroshock-induced seizure model. The types of interactions of MeTHIQ with the antiepileptic drugs were characterized using isobolographic analysis. The isobolographic analysis revealed that the combination of MeTHIQ with phenobarbital at the fixed-ratios of 1:3, 1:1 and 3:1 exerted supra-additive (synergistic) interaction in the maximal electroshock-induced seizure test. In contrast, the combinations of MeTHIQ with carbamazepine, phenytoin and valproate exerted additive interaction for all three fixed-ratios (1:3, 1:1 and 3:1) tested in the maximal electroshock-induced seizure test. In conclusion, MeTHIQ produces a clear-cut anticonvulsant effect in the maximal electroshock-induced seizure test in mice. The supra-additive interaction of MeTHIQ with phenobarbital against maximal electroshock-induced seizures makes their combination of pivotal importance from a clinical viewpoint.

  5. The novel antiepileptic drug imepitoin compares favourably to other GABA-mimetic drugs in a seizure threshold model in mice and dogs.

    Science.gov (United States)

    Löscher, Wolfgang; Hoffmann, Katrin; Twele, Friederike; Potschka, Heidrun; Töllner, Kathrin

    2013-11-01

    Recently, the imidazolinone derivative imepitoin has been approved for treatment of canine epilepsy. Imepitoin acts as a low-affinity partial agonist at the benzodiazepine (BZD) site of the GABAA receptor and is the first compound with such mechanism that has been developed as an antiepileptic drug (AED). This mechanism offers several advantages compared to full agonists, including less severe adverse effects and a lack of tolerance and dependence liability, which has been demonstrated in rodents, dogs, and nonhuman primates. In clinical trials in epileptic dogs, imepitoin was shown to be an effective and safe AED. Recently, seizures in dogs have been proposed as a translational platform for human therapeutic trials on new epilepsy treatments. In the present study, we compared the anticonvulsant efficacy of imepitoin, phenobarbital and the high-affinity partial BZD agonist abecarnil in the timed i.v. pentylenetetrazole (PTZ) seizure threshold test in dogs and, for comparison, in mice. Furthermore, adverse effects of treatments were compared in both species. All drugs dose-dependently increased the PTZ threshold in both species, but anticonvulsant efficacy was higher in dogs than mice. At the doses selected for this study, imepitoin was slightly less potent than phenobarbital in increasing seizure threshold, but markedly more tolerable in both species. Effective doses of imepitoin in the PTZ seizure model were in the same range as those suppressing spontaneous recurrent seizures in epileptic dogs. The study demonstrates that low-affinity partial agonists at the benzodiazepine site of the GABAA receptor, such as imepitoin, offer advantages as a new category of AEDs.

  6. 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...

  7. 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.

  8. Draft Genome Sequence of the Broad-Spectrum Xenobiotic Degrader Achromobacter xylosoxidans ADAF13.

    Science.gov (United States)

    Iyer, Rupa; Damania, Ashish

    2016-04-14

    Achromobacter xylosoxidansADAF13, isolated from farmland soil, possesses a large number of putative degradation genes and pathways that break down a wide variety of aromatic hydrocarbons, pesticides, endocrine disruptors, and other high-impact xenobiotics. These properties make this strain an excellent candidate for further development as a broad-spectrum bioremediation agent.

  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.

  10. Broad-Spectrum Antibiotic Treatment and Subsequent Childhood Type 1 Diabetes: A Nationwide Danish Cohort Study

    Science.gov (United States)

    Bergholt, Thomas; Bouaziz, Olivier; Arpi, Magnus; Eriksson, Frank; Rasmussen, Steen; Keiding, Niels; Løkkegaard, Ellen C.

    2016-01-01

    Background Studies link antibiotic treatment and delivery by cesarean section with increased risk of chronic diseases through changes of the gut-microbiota. We aimed to evaluate the association of broad-spectrum antibiotic treatment during the first two years of life with subsequent onset 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 of life (HR 1.13; 95% CI 1.02 to 1.25), however, the rate was modified by mode of delivery. Broad-spectrum antibiotics were associated with an increased rate of type 1 diabetes in children delivered by either intrapartum cesarean section (HR 1.70; 95% CI 1.15 to 2.51) or prelabor cesarean section (HR 1.63; 95% CI 1.11 to 2.39), but not in vaginally delivered children. Number needed to harm was 433 and 562, respectively. The association with broad-spectrum antibiotics was not modified by parity, genetic predisposition or maternal redemption of antibiotics during pregnancy or lactation. Conclusions Redemption of broad-spectrum antibiotics during infancy is associated with an increased risk of childhood type 1 diabetes in children delivered by cesarean section. PMID:27560963

  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. 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.

  13. Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential.

    Science.gov (United States)

    Zasloff, Michael; Adams, A Paige; Beckerman, Bernard; Campbell, Ann; Han, Ziying; Luijten, Erik; Meza, Isaura; Julander, Justin; Mishra, Abhijit; Qu, Wei; Taylor, John M; Weaver, Scott C; Wong, Gerard C L

    2011-09-20

    Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacity of squalamine, a cationic amphipathic sterol, to neutralize the negative electrostatic surface charge of intracellular membranes in a way that renders the cell less effective in supporting viral replication. Because squalamine can be readily synthesized and has a known safety profile in man, we believe its potential as a broad-spectrum human antiviral agent should be explored.

  14. The Discussion about Truth Viewpoint and its Significance on the View of Broad-Spectrum Philosophy

    Directory of Open Access Journals (Sweden)

    Facheng Shang

    2012-11-01

    Full Text Available In this study, we have a discussion about truth viewpoint and its significance on the view of Broad-spectrum Philosophy, which inherit and develop the truth of Marxist philosophy Broad-spectrum. Philosophy provides a unique perspective; it introduces the concept of observocontrol mode, which regards the truth as an image in the equivalence class. By changing the observocontrol mode, it reveals “Multilobe” of the truth of the same objective. To answer the question on "how to test the truth", it constructs the procedures and criteria to knowledge the truth. These researches have an important revelation on the enrichment and development of the study of Marxism truth theory.

  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. Broad-spectrum antimicrobial epiphytic and endophytic fungi from marine organisms: isolation, bioassay and taxonomy.

    Science.gov (United States)

    Zhang, Yi; Mu, Jun; Feng, Yan; Kang, Yue; Zhang, Jia; Gu, Peng-Juan; Wang, Yu; Ma, Li-Fang; Zhu, Yan-Hua

    2009-04-17

    In the search for new marine derived antibiotics, 43 epi- and endophytic fungal strains were isolated from the surface or the inner tissue of different marine plants and invertebrates. Through preliminary and secondary screening, 10 of them were found to be able to produce broad-spectrum antimicrobial metabolites. By morphological and molecular biological methods, three active strains were characterized to be Penicillium glabrum, Fusarium oxysporum, and Alternaria alternata.

  17. Broad-Spectrum Antimicrobial Epiphytic and Endophytic Fungi from Marine Organisms: Isolation, Bioassay and Taxonomy

    Directory of Open Access Journals (Sweden)

    Yan-Hua Zhu

    2009-04-01

    Full Text Available In the search for new marine derived antibiotics, 43 epi- and endophytic fungal strains were isolated from the surface or the inner tissue of different marine plants and invertebrates. Through preliminary and secondary screening, 10 of them were found to be able to produce broad-spectrum antimicrobial metabolites. By morphological and molecular biological methods, three active strains were characterized to be Penicillium glabrum, Fusarium oxysporum, and Alternaria alternata.

  18. Broad-Spectrum Antimicrobial Epiphytic and Endophytic Fungi from Marine Organisms: Isolation, Bioassay and Taxonomy

    OpenAIRE

    2009-01-01

    In the search for new marine derived antibiotics, 43 epi- and endophytic fungal strains were isolated from the surface or the inner tissue of different marine plants and invertebrates. Through preliminary and secondary screening, 10 of them were found to be able to produce broad-spectrum antimicrobial metabolites. By morphological and molecular biological methods, three active strains were characterized to be Penicillium glabrum, Fusarium oxysporum, and Alternaria alternata.

  19. Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential

    OpenAIRE

    2011-01-01

    Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacit...

  20. 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.

  1. Broad spectrum moderators and advanced reflector filters using 208Pb

    OpenAIRE

    Schönfeldt, Troels; Batkov, K.; Klinkby, Esben Bryndt; Lauritzen, Bent; F.Mezei; Muhrer, G.; PITCHER, E; Takibayev, A.; Willendrup, Peter Kjær; Zanini, L.

    2015-01-01

    Cold and thermal neutrons used in neutrons scattering experiments are produced in nuclear reactors and spallation sources. The neutrons are cooled to thermal or cold temperatures in thermal and cold moderators, respectively. The present study shows that it is possible to exploit the poor thermalizing property of 208Pb to design a broad spectrum moderator, i.e. a moderator which emits thermal and cold neutrons from the same position. Using 208Pb as a reflector filter material is shown to be sl...

  2. Effects of epilepsy and selected antiepileptic drugs on risk of myocardial infarction, stroke, and death in patients with or without previous stroke: a nationwide cohort study

    DEFF Research Database (Denmark)

    Olesen, J. B.; Abildstrom, S. Z.; Erdal, Jesper;

    2011-01-01

    Purpose Patients with epilepsy have increased morbidity and mortality. We evaluated the risk of myocardial infarction (MI), stroke, and death associated with epilepsy and examined if this risk was modified by treatment with antiepileptic drugs (AEDs). Methods A cohort consisting of the Danish...... population was followed from January 1997 to December 2006. The risk of MI, stroke, cardiovascular death, and all-cause death associated with epilepsy was estimated by multivariable Cox proportional hazard models stratified for occurrence of previous stroke. AED use was determined at baseline, and risks...... associated with exposure to individual AEDs were examined in patients with epilepsy. Results In patients without previous stroke, AED-treated epilepsy was associated with an increased risk of MI (hazard ratio [HR], 1.09; 95%CI, 1.00-1.19), stroke (HR, 2.22; 95%CI, 2.09-2.36), cardiovascular death (HR, 1...

  3. 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.

  4. N-valproyl-L-phenylalanine as new potential antiepileptic drug: synthesis, characterization and in vitro studies on stability, toxicity and anticonvulsant efficacy.

    Science.gov (United States)

    De Caro, Viviana; Scaturro, Anna Lisa; Sutera, Flavia Maria; Avellone, Giuseppe; Schiera, Gabriella; Ferrantelli, Evelina; Carafa, Maria; Rizzo, Valerio; Carletti, Fabio; Sardo, Pierangelo; Giannola, Libero Italo

    2014-01-01

    Valproic acid (VPA) is considered first-line drug in treatment of generalized idiopathic seizures such as absence, generalized tonic-clonic and myoclonic seizures. Among major antiepileptic drugs, VPA is also considered effective in childhood epilepsies and infantile spasms. Due to its broad activity, VPA acts as a mood stabilizer in bipolar disorder and it is useful in migraine prophylaxis. Despite its long-standing usage, severe reactions to VPA, such as liver toxicity and teratogenicity, are reported. To circumvent side effects due to structural characteristics of VPA, we synthesized in good yield a new VPA-aminoacid conjugate, the N-valproyl-L-Phenylalanine, and characterized by FT-IR, MS, (13)C and (1)H- NMR analyses. The Log D(pH7.4) value (0.19) indicated that new molecule was potentially able to cross biological membranes. The resistance to chemical and enzymatic hydrolysis of N-valproyl-L-phenylalanine was also assessed. All trials suggested that the compound, at the pH conditions of the entire gastro-intestinal tract, remained unmodified. Furthermore, the new compound did not undergo enzymatic cleavage both in plasma and in cerebral medium up to 24 h. The toxicity assay on primary cultures of astrocytes indicated that the synthetized conjugate was less toxic than both free VPA and L-Phenylalanine. In this paper, the anticonvulsant activity of the new compound against epileptic burst discharges evoked in vitro in rat hippocampal slices was also evaluated. These preliminary results underline that N-valproyl-L-phenylalanine as new potential antiepileptic agent could represent a good candidate to further investigations.

  5. Ceftobiprole: a review of a broad-spectrum and anti-MRSA cephalosporin.

    Science.gov (United States)

    Zhanel, George G; Lam, Ashley; Schweizer, Frank; Thomson, Kristjan; Walkty, Andrew; Rubinstein, Ethan; Gin, Alfred S; Hoban, Daryl J; Noreddin, Ayman M; Karlowsky, James A

    2008-01-01

    Ceftobiprole, an investigational cephalosporin, is currently in phase III clinical development. Ceftobiprole is a broad-spectrum cephalosporin with demonstrated in vitro activity against Gram-positive cocci, including meticillin-resistant Staphylococcus aureus (MRSA) and meticillin-resistant S. epidermidis, penicillin-resistant S. pneumoniae, Enterococcus faecalis, Gram-negative bacilli including AmpC-producing Escherichia coli and Pseudomonas aeruginosa, but excluding extended-spectrum beta-lactamase-producing strains. Like cefotaxime, ceftriaxone, ceftazidime, and cefepime, ceftobiprole demonstrates limited activity against anaerobes such as Bacteroides fragilis and non-fragilis Bacteroides spp. In single-step and serial passage in vitro resistance development studies, ceftobiprole demonstrated a low propensity to select for resistant subpopulations. Ceftobiprole, like cefepime, is a weak inducer and a poor substrate for AmpC beta-lactamases.Ceftobiprole medocaril, the prodrug of ceftobiprole, is converted by plasma esterases to ceftobiprole in ceftobiprole observed at the end of a single 30-minute infusion were 35.5 mug/mL for a 500-mg dose and 59.6 mug/mL for a 750-mg dose. The volume of distribution of ceftobiprole is 0.26 L/kg ( approximately 18 L), protein binding is 16%, and its serum half-life is approximately 3.5 hours. Ceftobiprole is renally excreted ( approximately 70% in the active form) and systemic clearance correlates with creatinine clearance, meaning that dosage adjustment is required in patients with renal dysfunction. Ceftobiprole has a modest post-antibiotic effect (PAE) of approximately 0.5 hours for MRSA and a longer PAE of approximately 2 hours for penicillin-resistant pneumococci. Ceftobiprole, when administered intravenously at 500 mg once every 8 hours (2-hour infusion), has a >90% probability of achieving f T(>MIC) (free drug concentration exceeds the minimum inhibitory concentration [MIC]) for 40% and 60%, respectively, of the dosing

  6. The European patient with Dravet syndrome: results from a parent-reported survey on antiepileptic drug use in the European population with Dravet syndrome.

    Science.gov (United States)

    Aras, Luis Miguel; Isla, Julián; Mingorance-Le Meur, Ana

    2015-03-01

    Dravet syndrome is a rare form of epilepsy largely refractory to current antiepileptic medications. The only precedents of randomized placebo-controlled trials in Dravet syndrome are the two small trials that led to the approval of stiripentol. With the arrival of new clinical trials for Dravet syndrome, we sought to determine the characteristics of the patient population with Dravet syndrome in Europe today, which has possibly evolved subsequent to the approval of stiripentol and the ability to diagnose milder clinical cases via genetic testing. From May to June 2014, we conducted an online parent-reported survey to collect information about the demographics, disease-specific clinical characteristics, as well as current and past use of antiepileptic medications by European patients with Dravet syndrome. We present data from 274 patients with Dravet syndrome from 15 European countries. Most patients were between 4 and 8years of age, and 90% had known mutations in SCN1A. Their epilepsy was characterized by multiple seizure types, although only 45% had more than 4 tonic-clonic seizures per month on average. The most common drug combination was valproate, clobazam, and stiripentol, with 42% of the total population currently taking stiripentol. Over a third of patients with Dravet syndrome had taken sodium channel blockers in the past, and most had motor and behavioral comorbidities. Our study helps define the current typical European patient with Dravet syndrome. The results from this survey may have important implications for the design of future clinical trials that investigate new treatments for Dravet syndrome.

  7. Detection of 22 antiepileptic drugs by ultra-performance liquid chromatography coupled with tandem mass spectrometry applicable to routine therapeutic drug monitoring.

    Science.gov (United States)

    Shibata, Mai; Hashi, Sachiyo; Nakanishi, Haruka; Masuda, Satohiro; Katsura, Toshiya; Yano, Ikuko

    2012-12-01

    The purpose of this study was to develop an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method of 22 antiepileptics for routine therapeutic monitoring. The antiepileptics used in the analyses were carbamazepine, carbamazepine-10,11-epoxide, clobazam, N-desmethylclobazam, clonazepam, diazepam, N-desmethyldiazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, N-desmethylmesuximide, nitrazepam, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin and zonisamide. After protein precipitation of 50 μL plasma with methanol, the supernatant was diluted with water or was evaporated to dryness and reconstituted with mobile phase in the case of benzodiazepines. Separation was achieved on an Acquity UPLC BEH C₁₈ column with a gradient mobile phase of 10 mm ammonium acetate containing 0.1% formic acid and methanol at a flow rate of 0.4 mL/min. An Acquity TQD instrument in multiple reaction monitoring mode with ion mode switching was used for detection. All antiepileptics were detected and quantified within 10 min, with no endogenous interference. All the calibration curves showed good linearity in the therapeutic range (r²  < 0.99). The precision and accuracy values for intra- and inter-assays were within ±15% except for phenobarbital and tiagabine. A good correlation was observed between the concentration of clinical samples measured by the new method described here and the conventional methods. The values of carbamazepine and phenytoin by UPLC-MS/MS were lower than those detected by the immunoassays, which might be caused by the cross-reaction of antibodies with their metabolites. In conclusion, we developed a simple and selective UPLC-MS/MS method suitable for routine therapeutic monitoring of antiepileptics.

  8. Effects of levetiracetam, a novel antiepileptic drug, on convulsant activity in two genetic rat models of epilepsy.

    Science.gov (United States)

    Gower, A J; Hirsch, E; Boehrer, A; Noyer, M; Marescaux, C

    1995-11-01

    The anticonvulsant effects of levetiracetam were assessed in two genetic rat models. In the audiogenic-seizure prone rat, levetiracetam, 5.4 to 96 mg/kg i.p. dose-dependently inhibited both wild running and tonic-clonic convulsions. In the GAERS model of petit mal epilepsy, levetiracetam markedly suppressed spontaneous spike-and-wave discharge (SWD) but left the underlying EEG trace normal. The effects were already marked at 5.4 mg/kg and did not increase significantly up to 170 mg/kg although more animals were completely protected. Levetiracetam produced no observable effects on behaviour apart from slight reversible sedation at 170 mg/kg. In contrast, piracetam, a structural analogue of levetiracetam, significantly and consistently suppressed SWD in GAERS rats only at the high dose of 1000 mg/kg with some slight effects at lower doses. The effect of piracetam appeared to be due to increased sleeping rather than to a direct antiepileptic effect. The results with levetiracetam argue for a clinical application in both petit mal, absence epilepsy and in treating generalised tonic-clonic and partial seizures.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 4城市2011-2013年抗癫痫类药物使用情况的分析与比较%The Analysis and Comparison of Four Cities Antiepileptic Drug Use in 2011-2013

    Institute of Scientific and Technical Information of China (English)

    王佳庆; 王莉文; 赵志刚

    2014-01-01

    Objective:Analyzing the Antiepileptic drug use situation in four cities:Beijing, Shanghai, Guangzhou, Chengdu in 2011-2013. Methods:Antiepileptic drug use from four cities in 2011-2013 was analyzed by using Microsoft office access 2007 software. Results:There are more men than women in these four cities for antiepileptic drug use in 2011-2013;the age distribution is quite different;and there is small defined daily dose and frequency difference. Conclusion:DDD and DDDs in four cities are basically the same, and drug use is fairly standard.%目的:研究北京、上海、广州、成都四个城市2011-2013年抗癫痫类药物用药情况。方法:利用Microsoft Office Access 2007软件对2011-2013年四个城市抗癫痫类药物用药进行统计分析。结果:四个城市2011-2013年抗癫痫类用药患者男性高于女性,年龄分布有较大差异,限定日剂量及用药频度差异较小。结论:四个城市用药限定日剂量及用药频度基本一致,药物使用比较规范。

  15. Broad Spectrum Chemotherapy: A Novel Approach Using Beta-Galactosidase Activated Pro-Drugs

    Science.gov (United States)

    2007-03-01

    significantly faster than WT. We tried to synthesize a conjugate of 5FU with galactose, although parts of the synthesis were successful, inseparable...100ug 1000ug Re la tiv e vi ab le c el l ( % o f c on tro l) 5-Fu-G / PC3-WT 5-FU/ PC3-WT 5-FU-G/PC3-lacZ 5-FU/PC3-lacZ 13 5FU has a notoriously...narrow window of efficacy. High concentrations cause systemic toxicity. We tested whether lacZ/β-gal could be used to activate and release 5FU in

  16. A multicenter comparative study of cefepime versus broad-spectrum antibacterial therapy in moderate and severe bacterial infections

    Directory of Open Access Journals (Sweden)

    Badaró Roberto

    2002-01-01

    Full Text Available The safety and efficacy of cefepime empiric monotherapy compared with standard broad-spectrum combination therapy for hospitalized adult patients with moderate to severe community-acquired bacterial infections were evaluated. In an open-label, multicenter study, 317 patients with an Acute Physiology and Chronic Health Evaluation (APACHE II score ranging from >5 to =19 were enrolled with documented pneumonia (n=196, urinary tract infection (n=65, intra-abdominal infection (n=38, or sepsis (n=18. Patients were randomly assigned 1:1 to receive cefepime 1 to 2 g IV twice daily or three times a day or IV ampicillin, cephalothin, or ceftriaxone ± aminoglycoside therapy for 3 to 21 days. For both treatment groups, metronidazole, vancomycin, or macrolide therapy was added as deemed necessary. The primary efficacy variable was clinical response at the end of therapy. Two hundred ninety-six (93% patients met evaluation criteria and were included in the efficacy analysis. Diagnoses included the following: 180 pneumonias (90 cefepime, 90 comparator, 62 urinary tract infections (29 cefepime, 33 comparator, 37 intra-abdominal infections (19 cefepime, 18 comparator, and 17 sepses (8 cefepime, 9 comparator. At the end of therapy, overall clinical success rates were 131/146 (90% for patients treated with cefepime vs 125/150 (83% for those treated with comparator (95% confidence interval [CI]: - 2.6% to 16.3%. The clinical success rate for patients with community-acquired pneumonia, the most frequent infection, was 86% for both treatment groups. Among the patients clinically evaluated, 162 pathogens were isolated and identified before therapy. The most commonly isolated pathogens were Escherichia coli (n=49, Streptococcus pneumoniae (n=29, Haemophilus influenzae (n=14, and Staphylococcus aureus (n=11. Bacteriologic eradication/presumed eradication was 97% for cefepime vs 94% for comparator-treated patients. Drug-related adverse events were reported in 16% of

  17. Evaluating the efficacy of memantine on improving cognitive functions in epileptic patients receiving anti-epileptic drugs: A double-blind placebo-controlled clinical trial (Phase IIIb pilot study)

    OpenAIRE

    Priya Marimuthu; Sathyanarayanan Varadarajan; Muthuraj Krishnan; Sundar Shanmugam; Gireesh Kunjuraman; Jamuna Rani Ravinder; Balasubramanian Arumugam; Divya Alex; Porchelvan Swaminathan

    2016-01-01

    Objectives: People with epilepsy have greater cognitive and behavioral dysfunction than the general population. There is no specific treatment available for cognitive impairment of these patients. We aimed to evaluate the effects of memantine, an N-methyl-D-aspartate-type glutamate receptor noncompetitive antagonist, on improving cognition and memory functions in epileptic patients with cognitive and memory impairment, who received anti-epileptic drugs (AEDs). Methods: We did a randomized, do...

  18. Are adverse effects of antiepileptic drugs different in symptomatic partial and idiopathic generalized epilepsies? The Portuguese-Brazilian validation of the Liverpool Adverse Events Profile.

    Science.gov (United States)

    Martins, H H; Alonso, N B; Vidal-Dourado, M; Carbonel, T D; de Araújo Filho, G M; Caboclo, L O; Yacubian, E M; Guilhoto, L M

    2011-11-01

    We report the results of administration of the Portuguese-Brazilian translation of the Liverpool Adverse Events Profile (LAEP) to 100 patients (mean age=34.5, SD=12.12; 56 females), 61 with symptomatic partial epilepsy (SPE) and 39 with idiopathic generalized epilepsy (IGE) (ILAE, 1989) who were on a stable antiepileptic drug (AED) regimen and being treated in a Brazilian tertiary epilepsy center. Carbamazepine was the most commonly used AED (43.0%), followed by valproic acid (32.0%). Two or more AEDs were used by 69.0% of patients. The mean LAEP score (19 questions) was 37.6 (SD=13.35). The most common adverse effects were sleepiness (35.0%), memory problems (35.0%), and difficulty in concentrating (25.0%). Higher LAEP scores were associated with polytherapy with three or more AEDs (P=0.005), female gender (P0.001) and Hospital Anxiety and Depression Scale (Depression: r=0.637, P<0.001; Anxiety: r=0.621, P<0.001) dimensions. LAEP overall scores were similar in people with SPE and IGE and were not helpful in differentiating adverse effects in these two groups. Clinical variables that influenced global LAEP were seizure frequency (P=0.050) and generalized tonic-clonic seizures in the last month (P=0.031) in the IGE group, and polytherapy with three or more AEDs (P=0.003 and P=0.003) in both IGE and SPE groups.

  19. Effect of N-(m-bromoanilinomethyl-p-isopropoxyphenylsuccinimide on the anticonvulsant action of four classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

    Directory of Open Access Journals (Sweden)

    Luszczki Jarogniew J.

    2014-06-01

    Full Text Available The purpose of this study was to determine the effects of N-(m-bromoanilinomethyl- p-isopropoxyphenylsuccinimide (BAM-IPPS - a new succinimide derivative on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA] in the mouse maximal electroshock (MES-induced tonic seizure model. Tonic hind limb extension (seizure activity was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration delivered via ear-clip electrodes. BAM-IPPS administered (i.p. at a dose of 150 mg/kg significantly elevated the threshold for electroconvulsions in mice (P<0.05. Lower doses of BAM-IPPS (50 and 100 mg/kg had no significant impact on the threshold for electroconvulsions in mice. Moreover, BAM-IPPS (100 mg/kg did not significantly affect the anticonvulsant potency of CBZ, PB, PHT and VPA in the mouse MES model. BAM-IPPS elevated the threshold for electroconvulsions in mice in a dosedependent manner. However, BAM-IPPS (100 mg/kg did not affect the anticonvulsant action of various classical AEDs in the mouse MES model, making the combinations of BAM-IPPS with CBZ, PB, PHT and VPA neutral, from a preclinical point of view.

  20. Novel antiepileptic drug lacosamide exerts neuroprotective effects by decreasing glial activation in the hippocampus of a gerbil model of ischemic stroke.

    Science.gov (United States)

    Ahn, Ji Yun; Yan, Bing Chun; Park, Joon Ha; Ahn, Ji Hyeon; Lee, Dae Hwan; Kim, In Hye; Cho, Jeong-Hwi; Chen, Bai Hui; Lee, Jae-Chul; Cho, Young Shin; Shin, Myoung Chul; Cho, Jun Hwi; Hong, Seongkweon; Won, Moo-Ho; Kim, Sung Koo

    2015-12-01

    Lacosamide, which is a novel antiepileptic drug, has been reported to exert various additional therapeutic effects. The present study investigated the neuroprotective effects of lacosamide against transient cerebral ischemia-induced neuronal cell damage in the hippocampal cornu ammonis (CA)-1 region of a gerbil model. Neuronal Nuclei immunohistochemistry demonstrated that pre- and post-surgical treatment (5 min ischemia) with 25 mg/kg lacosamide protected CA1 pyramidal neurons in the lacosamide-treated-ischemia-operated group from ischemic injury 5 days post-ischemia, as compared with gerbils in the vehicle-treated-ischemia-operated group. Furthermore, treatment with 25 mg/kg lacosamide markedly attenuated the activation of astrocytes and microglia in the ischemic CA1 region at 5 days post-ischemia. The results of the present study suggested that pre- and post-surgical treatment of the gerbils with lacosamide was able to protect against transient cerebral ischemic injury-induced CA1 pyramidal neuronal cell death in the hippocampus. In addition, the neuroprotective effects of lacosamide may be associated with decreased activation of glial cells in the ischemic CA1 region.

  1. Zebrafish embryotoxicity test for developmental (neuro)toxicity: Demo case of an integrated screening approach system using anti-epileptic drugs.

    Science.gov (United States)

    Beker van Woudenberg, Anna; Snel, Cor; Rijkmans, Eke; de Groot, Didima; Bouma, Marga; Hermsen, Sanne; Piersma, Aldert; Menke, Aswin; Wolterbeek, André

    2014-11-01

    To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid (VPA), carbamazepine (CBZ), ethosuximide (ETH) and levetiracetam (LEV). For VPA, histopathology was the most sensitive parameter, showing effects already at 60μM. For CBZ, morphology and MA were the most sensitive parameters, showing effects at 180μM. For ETH, all endpoints showed similar sensitivity (6.6mM), whereas MA was the most sensitive parameter for LEV (40mM). Inclusion of kinetics did not alter the absolute ranking of the compounds, but the relative potency was changed considerably. Taking all together, this demo-case study showed that inclusion of multiple-endpoints in ZET may increase the sensitivity of the assay, contribute to the elucidation of the mode of toxic action and to a better definition of the applicability domain of ZET.

  2. Effects of antiepileptic drugs on mRNA levels of BDNF and NT-3 and cell neogenesis in the developing rat brain.

    Science.gov (United States)

    Shi, Xiu-Yu; Wang, Ji-Wen; Cui, Hong; Li, Bao-Min; Lei, Ge-Fei; Sun, Ruo-Peng

    2010-03-01

    Epilepsy is a common neurological disorder that occurs more frequently in childhood than in adulthood. Antiepileptic drugs (AEDs) which are used to treat seizures in pregnant women, infants, and young children may cause cognitive impairment or other uncertain injury. However, the exact mechanisms responsible for adverse effects of AEDs in the developing brain are still not clear. In the present study, we investigate the effects of AEDs on mRNA levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), cell neogenesis and mossy fiber sprouting (MFS) in the developing rat brain. Long-term treatment with Phenobarbital (40mg/kg), valproate (100mg/kg) and topiramate (40mg/kg) reduces BDNF and NT-3 mRNA expression in the developing brain, while lamotrigine reduces mRNA expression only at high dose level (80mg/kg). Cell neogenesis only increases in the rats treated with valproate and lamotrigine. And no differences are observed between the control group and the AEDs-treated groups in the Timm scores of the CA3 region and supragranular region. Our findings present some possible mechanisms to explain why different AEDs cause different cognitive impairment.

  3. Pharmacological and clinical evaluation of the antiepileptic drug clobazam%癫痫治疗新药氯巴占的药理与临床评价

    Institute of Scientific and Technical Information of China (English)

    高君伟; 孙搏; 李晓宇; 吴佳琪; 刘皋林

    2013-01-01

    氯巴占为1,5-苯二氮草类药物,具有抗癫痫作用,FDA于2011年10月21日批准其用于难治性癫痫——林-戈综合征(Lennox-Gastaut syndrome)的辅助治疗.本文通过Medline对氯巴占进行文献检索,并对其药理作用、药动学、药物相互作用、临床研究和安全性进行了综述.%Clobazam, a 1 ,5-benzodiazepine, possesses antiepileptic activity. It has been approved by the FDA for treatment of Lennox-Gastaut syndrome, one of the refractory epilepsies, in October 21th, 2011. Literature search was conducted by searching MEDLINE with the key words clobazam. The pharmacology, pharmacokinetics, drug interactions, clinical trials and side effects of clobazam were reviewed in this paper.

  4. A broad-spectrum, efficient and nontransgenic approach to control plant viruses by application of salicylic acid and jasmonic acid.

    Science.gov (United States)

    Shang, Jing; Xi, De-Hui; Xu, Fei; Wang, Shao-Dong; Cao, Sen; Xu, Mo-Yun; Zhao, Ping-Ping; Wang, Jian-Hui; Jia, Shu-Dan; Zhang, Zhong-Wei; Yuan, Shu; Lin, Hong-Hui

    2011-02-01

    Plant viruses cause many diseases that lead to significant economic losses. However, most of the approaches to control plant viruses, including transgenic processes or drugs are plant-species-limited or virus-species-limited, and not very effective. We introduce an application of jasmonic acid (JA) and salicylic acid (SA), a broad-spectrum, efficient and nontransgenic method, to improve plant resistance to RNA viruses. Applying 0.06 mM JA and then 0.1 mM SA 24 h later, enhanced resistance to Cucumber mosaic virus (CMV), Tobacco mosaic virus (TMV) and Turnip crinkle virus (TCV) in Arabidopsis, tobacco, tomato and hot pepper. The inhibition efficiency to virus replication usually achieved up to 80-90%. The putative molecular mechanism was investigated. Some possible factors affecting the synergism of JA and SA have been defined, including WRKY53, WRKY70, PDF1.2, MPK4, MPK2, MPK3, MPK5, MPK12, MPK14, MKK1, MKK2, and MKK6. All genes involving in the synergism of JA and SA were investigated. This approach is safe to human beings and environmentally friendly and shows potential as a strong tool for crop protection against plant viruses.

  5. 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.

  6. 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.

  7. Multilayer nanoparticle arrays for broad spectrum absorption enhancement in thin film solar cells

    CERN Document Server

    Krishnan, Aravind; Krishna, Siva Rama; Khan, Mohammed Zafar Ali

    2013-01-01

    In this paper, we present a theoretical study on the absorption efficiency enhancement of a thin film amorphous Silicon (a-Si) photovoltaic cell over a broad spectrum of wavelengths using multiple nanoparticle arrays. The light absorption efficiency is enhanced in the lower wavelengths by a nanoparticle array on the surface and in the higher wavelengths by another nanoparticle array embedded in the active region. The efficiency at intermediate wavelengths is enhanced by the constructive interference of plasmon coupled light. We optimize this design by tuning the radius of particles in both arrays, the period of the array and the distance between the two arrays. The optimization results in 61.44% increase in total quantum efficiency for a 500 nm thick a-Si substrate.

  8. Interfamily transfer of a plant pattern-recognition receptor confers broad-spectrum bacterial resistance.

    Science.gov (United States)

    Lacombe, Séverine; Rougon-Cardoso, Alejandra; Sherwood, Emma; Peeters, Nemo; Dahlbeck, Douglas; van Esse, H Peter; Smoker, Matthew; Rallapalli, Ghanasyam; Thomma, Bart P H J; Staskawicz, Brian; Jones, Jonathan D G; Zipfel, Cyril

    2010-04-01

    Plant diseases cause massive losses in agriculture. Increasing the natural defenses of plants may reduce the impact of phytopathogens on agricultural productivity. Pattern-recognition receptors (PRRs) detect microbes by recognizing conserved pathogen-associated molecular patterns (PAMPs). Although the overall importance of PAMP-triggered immunity for plant defense is established, it has not been used to confer disease resistance in crops. We report that activity of a PRR is retained after its transfer between two plant families. Expression of EFR (ref. 4), a PRR from the cruciferous plant Arabidopsis thaliana, confers responsiveness to bacterial elongation factor Tu in the solanaceous plants Nicotiana benthamiana and tomato (Solanum lycopersicum), making them more resistant to a range of phytopathogenic bacteria from different genera. Our results in controlled laboratory conditions suggest that heterologous expression of PAMP recognition systems could be used to engineer broad-spectrum disease resistance to important bacterial pathogens, potentially enabling more durable and sustainable resistance in the field.

  9. 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

    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......). Antihistamine use did not increase the patients' MUD but did suppress wheal formation and itch, and only immediate erythema sharply located in the irradiated areas occurred. The combination of sunscreen and antihistamine acted synergistically and increased the tolerance to UV radiation markedly (80-267 times...

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

    Science.gov (United States)

    Lise, Stefano; Broxholme, John; Cazier, Jean-Baptiste; Rimmer, Andy; Kanapin, Alexander; Lunter, Gerton; Fiddy, Simon; Allan, Chris; Aricescu, A. Radu; Attar, Moustafa; Babbs, Christian; Becq, Jennifer; Beeson, David; Bento, Celeste; Bignell, Patricia; Blair, Edward; Buckle, Veronica J; Bull, Katherine; Cais, Ondrej; Cario, Holger; Chapel, Helen; Copley, Richard R; Cornall, Richard; Craft, Jude; Dahan, Karin; Davenport, Emma E; Dendrou, Calliope; Devuyst, Olivier; Fenwick, Aimée L; Flint, Jonathan; Fugger, Lars; Gilbert, Rodney D; Goriely, Anne; Green, Angie; Greger, Ingo H.; Grocock, Russell; Gruszczyk, Anja V; Hastings, Robert; Hatton, Edouard; Higgs, Doug; Hill, Adrian; Holmes, Chris; Howard, Malcolm; Hughes, Linda; Humburg, Peter; Johnson, David; Karpe, Fredrik; Kingsbury, Zoya; Kini, Usha; Knight, Julian C; Krohn, Jonathan; Lamble, Sarah; Langman, Craig; Lonie, Lorne; Luck, Joshua; McCarthy, Davis; McGowan, Simon J; McMullin, Mary Frances; Miller, Kerry A; Murray, Lisa; Németh, Andrea H; Nesbit, M Andrew; Nutt, David; Ormondroyd, Elizabeth; Oturai, Annette Bang; Pagnamenta, Alistair; Patel, Smita Y; Percy, Melanie; Petousi, Nayia; Piazza, Paolo; Piret, Sian E; Polanco-Echeverry, Guadalupe; Popitsch, Niko; Powrie, Fiona; Pugh, Chris; Quek, Lynn; Robbins, Peter A; Robson, Kathryn; Russo, Alexandra; Sahgal, Natasha; van Schouwenburg, Pauline A; Schuh, Anna; Silverman, Earl; Simmons, Alison; Sørensen, Per Soelberg; Sweeney, Elizabeth; Taylor, John; Thakker, Rajesh V; Tomlinson, Ian; Trebes, Amy; Twigg, Stephen RF; Uhlig, Holm H; Vyas, Paresh; Vyse, Tim; Wall, Steven A; Watkins, Hugh; Whyte, Michael P; Witty, Lorna; Wright, Ben; Yau, Chris; Buck, David; Humphray, Sean; Ratcliffe, Peter J; Bell, John I; Wilkie, Andrew OM; Bentley, David; Donnelly, Peter; McVean, Gilean

    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 across a broad spectrum of disorders in whom prior screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritisation. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease causing variants in 21% of cases, rising to 34% (23/68) for Mendelian disorders and 57% (8/14) in trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, though only four were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis, but also highlight many outstanding challenges. PMID:25985138

  11. 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.

  12. The Arabidopsis NPR1 gene confers broad-spectrum disease resistance in strawberry.

    Science.gov (United States)

    Silva, Katchen Julliany P; Brunings, Asha; Peres, Natalia A; Mou, Zhonglin; Folta, Kevin M

    2015-08-01

    Although strawberry is an economically important fruit crop worldwide, production of strawberry is limited by its susceptibility to a wide range of pathogens and the lack of major commercial cultivars with high levels of resistance to multiple pathogens. The objective of this study is to ectopically express the Arabidopsis thaliana NPR1 gene (AtNPR1) in the diploid strawberry Fragaria vesca L. and to test transgenic plants for disease resistance. AtNPR1 is a key positive regulator of the long-lasting broad-spectrum resistance known as systemic acquired resistance (SAR) and has been shown to confer resistance to a number of pathogens when overexpressed in Arabidopsis or ectopically expressed in several crop species. We show that ectopic expression of AtNPR1 in strawberry increases resistance to anthracnose, powdery mildew, and angular leaf spot, which are caused by different fungal or bacterial pathogens. The increased resistance is related to the relative expression levels of AtNPR1 in the transgenic plants. In contrast to Arabidopsis plants overexpressing AtNPR1, which grow normally and do not constitutively express defense genes, the strawberry transgenic plants are shorter than non-transformed controls, and most of them fail to produce runners and fruits. Consistently, most of the transgenic lines constitutively express the defense gene FvPR5, suggesting that the SAR activation mechanisms in strawberry and Arabidopsis are different. Nevertheless, our results indicate that overexpression of AtNPR1 holds the potential for generation of broad-spectrum disease resistance in strawberry.

  13. 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

  14. 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)

  15. Fosinopril and zofenopril, two angiotensin-converting enzyme (ACE) inhibitors, potentiate the anticonvulsant activity of antiepileptic drugs against audiogenic seizures in DBA/2 mice.

    Science.gov (United States)

    Sarro, Giovambattista De; Paola, Eugenio Donato Di; Gratteri, Santo; Gareri, Pietro; Rispoli, Vincenzo; Siniscalchi, Antonio; Tripepi, Giovanni; Gallelli, Luca; Citraro, Rita; Russo, Emilio

    2012-03-01

    The renin-angiotensin system (RAS) exists in the brain and it may be involved in pathogenesis of neurological and psychiatric disorders including seizures. The aim of the present research was to evaluate the effects of some angiotensin-converting enzyme inhibitors (ACEi; captopril, enalapril, fosinopril and zofenopril), commonly used as antihypertensive agents, in the DBA/2 mice animal model of generalized tonic-clonic seizures. Furthermore, the co-administration of these compounds with some antiepileptic drugs (AEDs; carbamazepine, diazepam, felbamate, gabapentin, lamotrigine, phenobarbital, phenytoin, topiramate and valproate) was studied in order to identify possible positive interactions in the same model. All ACEi were able to decrease the severity of audiogenic seizures with the exception of enalapril up to the dose of 100mg/kg, the rank order of activity was as follows: fosinopril>zofenopril>captopril. The co-administration of ineffective doses of all ACE inhibitors with AEDs, generally increased the potency of the latter. Fosinopril was the most active in potentiating the activity of AEDs and the combination of ACEi with lamotrigine and valproate was the most favorable, whereas, the co-administrations with diazepam and phenobarbital seemed to be neutral. The increase in potency was generally associated with an enhancement of motor impairment, however, the therapeutic index of combined treatment of AEDs with ACEi was predominantly more favorable than control. ACEi administration did not influence plasma and brain concentrations of the AEDs studied excluding pharmacokinetic interactions and concluding that it is of pharmacodynamic nature. In conclusion, fosinopril, zofenopril, enalapril and captopril showed an additive anticonvulsant effect when co-administered with some AEDs, most notably carbamazepine, felbamate, lamotrigine, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations.

  16. Prescribing pattern of anti-epileptic drugs in an Italian setting of elderly outpatients: a population-based study during 2004–07

    Science.gov (United States)

    Oteri, Alessandro; Trifirò, Gianluca; Gagliostro, Maria Silvia; Tari, Daniele Ugo; Moretti, Salvatore; Bramanti, Placido; Spina, Edoardo; Caputi, Achille Patrizio; Arcoraci, Vincenzo

    2010-01-01

    AIMS The aims of the study were to assess the trend of older and newer anti-epileptic drugs (AEDs) in the elderly population and to analyze the effects of a health-policy intervention with regard to AED use in general practice in a setting in Southern Italy. METHODS Data were extracted from the ‘Caserta-1’ Local-Health-Unit Arianna database in the years 2004–07. Patients aged over 65 years, receiving at least one AED prescription and registered in the lists of 88 general practitioners, were selected. The use of older and newer AEDs was calculated as 1 year prevalence and incidence of use and defined daily dose (DDD) per 1000 inhabitants day−1. Sub-analyses by gender, age and indication of use were performed. RESULTS Most of AED users were treated because of neuropathic pain (64.8%). However, the main indication of use for older AEDs (57.8%) was epilepsy, whereas newer AEDs (79.5%) were used for neuropathic pain. Prevalence and incidence of newer AED use increased until 2006, followed by a reduction in 2007. Newer AEDs, particularly gabapentin and pregabalin, were used in the treatment of more patients than older AEDs. However phenobarbital, accounting for more than 50% of total AED volume, was the most prescribed medication during the entire study period. CONCLUSIONS An increasing use of AEDs has been observed during 2004–07, mostly due to the prescription of newer compounds for neuropathic pain. The fall in the use of newer AEDs during 2007 coincides with revised re-imbursement criteria for gabapentin and pregabalin. The large use of phenobarbital in the elderly should be considered in the light of a risk of adverse drug reactions. PMID:20840443

  17. 哺乳期女性抗癫痫药物的合理应用%The management of antiepileptic drugs in women during lactation

    Institute of Scientific and Technical Information of China (English)

    方敩; 禚志红; 田培超; 王怀立

    2016-01-01

    Epilepsy is one of the most common chronic diseases of the central nervous system,many epilepsy patients need lifelong medication.Epidemiological studies have shown that 3‰-5‰ neonates born by women suffering from epilepsy.Treatment become more challenging because not only the patients themselves but also the breastfed in fants should be taken into consideration.This paper reviewed how to choose lactation antiepileptic drug.In short,choosing drugs which transport less to milk and have less side effects to infants,using the lowest effective dose and avoiding combination if possible can ensure the safety of breastfeeding.%癫痫是最常见的慢性中枢神经系统疾病之一,许多癫痫患者需要终身服药.流行病学研究显示3‰~5‰婴儿的母亲患有癫痫,这些癫痫患者在哺乳期服用抗癫痫药物时,不但要考虑患者本人,还要考虑母乳喂养的婴儿.现对哺乳期女性如何选择抗癫痫药物进行了综述.总的来说,选择向母乳中转运少、不良反应小的药物,并尽量减少用药种类、应用最低有效剂量,可以保证母乳喂养的安全.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Be sure to read the fine print: the agency for healthcare research and quality comparative effectiveness report on antiepileptic drugs.

    Science.gov (United States)

    Welty, Timothy E; Faught, Edward; Schmidt, Dieter; McAuley, James W; Ryan, Melody

    2012-05-01

    For many questions related to the pharmacotherapy of epilepsy, there are few or no published data. This lack of data presents dilemmas to practitioners who must make informed, rational decisions about therapy on a daily basis and to policymakers dealing with drug formulary management and reimbursement. Reliance on randomized, clinical trial data is inefficient because of the extensive time and expense involved in conducting a study and the inability to answer every question encountered in practice. In addition, results from randomized, clinical studies are not fully applicable in the clinical setting because of short trial duration and the frequent use of surrogate controls that are rarely seen in routine practice.

  20. Be Sure to Read the Fine Print: The Agency for Healthcare Research and Quality Comparative Effectiveness Report on Antiepileptic Drugs

    Science.gov (United States)

    Welty, Timothy E.; Faught, Edward; Schmidt, Dieter; McAuley, James W.; Ryan, Melody

    2012-01-01

    For many questions related to the pharmacotherapy of epilepsy, there are few or no published data. This lack of data presents dilemmas to practitioners who must make informed, rational decisions about therapy on a daily basis and to policymakers dealing with drug formulary management and reimbursement. Reliance on randomized, clinical trial data is inefficient because of the extensive time and expense involved in conducting a study and the inability to answer every question encountered in practice. In addition, results from randomized, clinical studies are not fully applicable in the clinical setting because of short trial duration and the frequent use of surrogate controls that are rarely seen in routine practice. PMID:22690134

  1. Interaction of an antiepileptic drug, lamotrigine with human serum albumin (HSA): Application of spectroscopic techniques and molecular modeling methods.

    Science.gov (United States)

    Poureshghi, Fatemeh; Ghandforoushan, Parisa; Safarnejad, Azam; Soltani, Somaieh

    2017-01-01

    Lamotrigine (an epileptic drug) interaction with human serum albumin (HSA) was investigated by fluorescence, UV-Vis, FTIR, CD spectroscopic techniques, and molecular modeling methods. Binding constant (Kb) of 5.74×10(3) and number of binding site of 0.97 showed that there is a slight interaction between lamotrigine and HSA. Thermodynamic studies was constructed using the flourimetric titrations in three different temperatures and the resulted data used to calculate the parameters using Vant Hoff equation. Decreased Stern Volmer quenching constant by enhanced temperature revealed the static quenching mechanism. Negative standard enthalpy (ΔH) and standard entropy (ΔS) changes indicated that van der Waals interactions and hydrogen bonds were dominant forces which facilitate the binding of Lamotrigine to HSA, the results were confirmed by molecular docking studies which showed no hydrogen binding. The FRET studies showed that there is a possibility of energy transfer between Trp214 and lamotrigine. Also the binding of lamotrigine to HSA in the studied concentrations was not as much as many other drugs, but the secondary structure of the HSA was significantly changed following the interaction in a way that α-helix percentage was reduced from 67% to 57% after the addition of lamotrigine in the molar ratio of 4:1 to HSA. According to the docking studies, lamotrigine binds to IB site preferably.

  2. Isobolographic analysis of interactions between remacemide and conventional antiepileptic drugs in the mouse model of maximal electroshock.

    Science.gov (United States)

    Borowicz, Kinga K; Malek, Robert; Luszczki, Jarogniew J; Ratnaraj, Neville; Patsalos, Philip N; Czuczwar, Stanislaw J

    2007-08-01

    Using the mouse maximal electroshock-induced seizure model, indicative of tonic-clonic seizures in humans, the present study was aimed at characterizing the interaction between remacemide and valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis indicated additive interactions between remacemide and valproate, carbamazepine, and phenytoin (for all fixed ratios of tested drugs: 1:3, 1:1, and 3:1). Additivity was also observed between remacemide and phenobarbital applied in proportions of 1:1 and 3:1. In contrast, the combination of remacemide and phenobarbital at the fixed-ratio of 1:3 resulted in antagonism. Neither motor performance nor long-term memory was impaired by remacemide or by carbamazepine, phenobarbital, phenytoin, and valproate whether or not these drugs were administered singly or in combination. In combination with remacemide, brain concentrations of carbamazepine, phenobarbital, and phenytoin were increased by 71, 21, and 16%, respectively. Although brain valproate concentrations were unaffected by remacemide co-administration, brain concentrations of remacemide and its active metabolite, desglycinyl-remacemide, were increased by 68 and 162%, respectively. In contrast, phenobarbital co-administration was associated with decreases in brain remacemide (27%) and desglycinyl-remacemide (9%) concentrations, whereas only remacemide concentrations (increased by 131%) were affected by carbamazepine co-administration. In conclusion, significant and desirable pharmacodynamic interactions were observed between remacemide and valproate, carbamazepine, phenytoin, and phenobarbital. However, the concurrent pharmacokinetic interactions associated with remacemide complicate these observations and do not make remacemide a good candidate for adjunctive treatment of epilepsy.

  3. T-current related effects of antiepileptic drugs and a Ca2+ channel antagonist on thalamic relay and local circuit interneurons in a rat model of absence epilepsy.

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    Broicher, Tilman; Seidenbecher, Thomas; Meuth, Patrick; Munsch, Thomas; Meuth, Sven G; Kanyshkova, Tatyana; Pape, Hans-Christian; Budde, Thomas

    2007-09-01

    Channel blocking, anti-oscillatory, and anti-epileptic effects of clinically used anti-absence substances (ethosuximide, valproate) and the T-type Ca2+ current (IT) blocker mibefradil were tested by analyzing membrane currents in acutely isolated local circuit interneurons and thalamocortical relay (TC) neurons, slow intrathalamic oscillations in brain slices, and spike and wave discharges (SWDs) occurring in vivo in Wistar Albino Glaxo rats from Rijswijk (WAG/Rij). Substance effects in vitro were compared between WAG/Rij and a non-epileptic control strain, the ACI rats. Ethosuximide (ETX) and valproate were found to block IT in acutely isolated thalamic neurons. Block of IT by therapeutically relevant ETX concentrations (0.25-0.75 mM) was stronger in WAG/Rij, although the maximal effect at saturating concentrations (>or=10 mM) was stronger in ACI. Ethosuximide delayed the onset of the low threshold Ca2+ spike (LTS) of neurons recorded in slice preparations. Mibefradil (>or=2 microM) completely blocked IT and the LTS, dampened evoked thalamic oscillations, and attenuated SWDs in vivo. Computational modeling demonstrated that the complete effect of ETX can be replicated by a sole reduction of IT. However, the necessary degree of IT reduction was not induced by therapeutically relevant ETX concentrations. A combined reduction of IT, the persistent sodium current, and the Ca2+ activated K+ current resulted in an LTS alteration resembling the experimental observations. In summary, these results support the hypothesis of IT reduction as part of the mechanism of action of anti-absence drugs and demonstrate the ability of a specific IT antagonist to attenuate rhythmic burst firing and SWDs.

  4. Zebrafish larvae exposed to ginkgotoxin exhibit seizure-like behavior that is relieved by pyridoxal-5′-phosphate, GABA and anti-epileptic drugs

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    Gang-Hui Lee

    2012-11-01

    The etiology of epilepsy is a very complicated, multifactorial process that is not completely understood. Therefore, the availability of epilepsy animal models induced by different mechanisms is crucial in advancing our knowledge and developing new therapeutic regimens for this disorder. Considering the advantages of zebrafish, we have developed a seizure model in zebrafish larvae using ginkgotoxin, a neurotoxin naturally occurring in Ginkgo biloba and hypothesized to inhibit the formation of the neurotransmitter γ-aminobutyric acid (GABA. We found that a 2-hour exposure to ginkgotoxin induced a seizure-like behavior in zebrafish larvae. This seizure-like swimming pattern was alleviated by the addition of either pyridoxal-5′-phosphate (PLP or GABA and responded quickly to the anti-convulsing activity of gabapentin and phenytoin, two commonly prescribed anti-epileptic drugs (AEDs. Unexpectedly, the ginkgotoxin-induced PLP depletion in our experimental setting did not affect the homeostasis of folate-mediated one-carbon metabolism, another metabolic pathway playing a crucial role in neural function that also relies on the availability of PLP. This ginkgotoxin-induced seizure behavior was also relieved by primidone, which had been tested on a pentylenetetrazole-induced zebrafish seizure model but failed to rescue the seizure phenotype, highlighting the potential use and complementarity of this ginkgotoxin-induced seizure model for AED development. Structural and morphological characterization showed that a 2-hour ginkgotoxin exposure did not cause appreciable changes in larval morphology and tissues development. In conclusion, our data suggests that this ginkgotoxin-induced seizure in zebrafish larvae could serve as an in vivo model for epileptic seizure research and potential AED screening.

  5. Quantification of new antiepileptic drugs by liquid chromatography/electrospray ionization tandem mass spectrometry and its application to cellular uptake experiment using human placental choriocarcinoma BeWo cells.

    Science.gov (United States)

    Furugen, Ayako; Kobayashi, Masaki; Nishimura, Ayako; Takamura, Shigeo; Narumi, Katsuya; Yamada, Takehiro; Iseki, Ken

    2015-10-01

    A method for quantification of new antiepileptic drugs, including lamotrigine (LTG), levetiracetam (LEV), gabapentin (GBP), and topiramate (TPM), in cellular samples, using liquid chromatography/electrospray ionization tandem mass spectrometry was developed to better understand the membrane transport mechanisms of these drugs. Cell lysate was deproteinized by methanol containing LEV-d3 as an internal standard (IS). Chromatographic separation was performed on a C18 column using gradient elution with methanol-water-formic acid (10:90:0.1, v/v/v) and methanol-formic acid (100:0.1, v/v). Analytes were detected in positive ion electrospray mode with selected reaction monitoring (SRM). This method was applicable for a linear range of 5 to 500pmol for LTG; 5 to 1000pmol for LEV; 10 to 10,000pmol for GBP; and 5 to 5000pmol for TPM. The intra-day precision, inter-day precision, and accuracy data were assessed and found to be acceptable. This developed and validated method was then successfully applied to the investigation of uptake of the new antiepileptic drugs in placental choriocarcinoma BeWo cells. The intracellular concentration of these drugs in BeWo cells, accumulating over 30min at 37°C was in the order of GBP>LTG>LEV≈TPM. Furthermore, the uptake of GBP at 4°C was much lower than that at 37°C. The uptake of GBP was saturated at high concentrations. The kinetic parameters calculated for GBP uptake in BeWo cells were determined as Km of 105.4±6.4μM and Vmax at 8153±348pmol/mg protein/min. The novel method described here should enable investigators to elucidate the transport mechanisms of these antiepileptic drugs in BeWo cells.

  6. Determination of a selection of anti-epileptic drugs and two active metabolites in whole blood by reversed phase UPLC-MS/MS and some examples of application of the method in forensic toxicology cases.

    Science.gov (United States)

    Karinen, Ritva; Vindenes, Vigdis; Hasvold, Inger; Olsen, Kirsten Midtbøen; Christophersen, Asbjørg S; Øiestad, Elisabeth

    2015-07-01

    Quantitative determination of anti-epileptic drug concentrations is of great importance in forensic toxicology cases. Although the drugs are not usually abused, they are important post-mortem cases where the question of both lack of compliance and accidental or deliberate poisoning might be raised. In addition these drugs can be relevant for driving under the influence cases. A reversed phase ultra-performance liquid chromatography-tandem mass spectrometry method has been developed for the quantitative analysis of the anti-epileptic compounds carbamazepine, carbamazepine-10,11-epoxide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, 10-OH-carbazepine, phenobarbital, phenytoin, pregabalin, and topiramate in whole blood, using 0.1 mL sample volume with methaqualone as internal standard. Sample preparation was a simple protein precipitation with acetonitrile and methanol. The diluted supernatant was directly injected into the chromatographic system. Separation was performed on an Acquity UPLC® BEH Phenyl column with gradient elution and a mildly alkaline mobile phase. The mass spectrometric detection was performed in positive ion mode, except for phenobarbital, and multiple reaction monitoring was used for drug quantification. The limits of quantification for the different anti-epileptic drugs varied from 0.064 to 1.26 mg/L in blood, within-day and day-to-day relative standard deviations from 2.2 to 14.7% except for phenobarbital. Between-day variation for phenobarbital was 20.4% at the concentration level of 3.5 mg/L. The biases for all compounds were within ±17.5%. The recoveries ranged between 85 and 120%. The corrected matrix effects were 88-106% and 84-110% in ante-mortem and post-mortem whole blood samples, respectively.

  7. 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.

  8. Broad-spectrum resistance to Bacillus thuringiensis toxins by western corn rootworm (Diabrotica virgifera virgifera).

    Science.gov (United States)

    Jakka, Siva R K; Shrestha, Ram B; Gassmann, Aaron J

    2016-06-14

    The evolution of resistance and cross-resistance threaten the sustainability of genetically engineered crops that produce insecticidal toxins derived from the bacterium Bacillus thuringiensis (Bt). Western corn rootworm, Diabrotica virgifera virgifera LeConte, is a serious pest of maize and has been managed with Bt maize since 2003. We conducted laboratory bioassays with maize hybrids producing Bt toxins Cry3Bb1, mCry3A, eCry3.1Ab, and Cry34/35Ab1, which represent all commercialized Bt toxins for management of western corn rootworm. We tested populations from fields where severe injury to Cry3Bb1 maize was observed, and populations that had never been exposed to Bt maize. Consistent with past studies, bioassays indicated that field populations were resistant to Cry3Bb1 maize and mCry3A maize, and that cross-resistance was present between these two types of Bt maize. Additionally, bioassays revealed resistance to eCry3.1Ab maize and cross-resistance among Cry3Bb1, mCry3A and eCry3.1Ab. However, no resistance or cross-resistance was detected for Cry34/35Ab1 maize. This broad-spectrum resistance illustrates the potential for insect pests to develop resistance rapidly to multiple Bt toxins when structural similarities are present among toxins, and raises concerns about the long-term durability of Bt crops for management of some insect pests.

  9. 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.

  10. Arbidol: a broad-spectrum antiviral that inhibits acute and chronic HCV infection

    Directory of Open Access Journals (Sweden)

    Pécheur Eve-Isabelle

    2006-07-01

    Full Text Available Abstract Arbidol (ARB is an antiviral compound that was originally proven effective for treatment of influenza and several other respiratory viral infections. The broad spectrum of ARB anti-viral activity led us to evaluate its effect on hepatitis C virus (HCV infection and replication in cell culture. Long-term ARB treatment of Huh7 cells chronically replicating a genomic length genotype 1b replicon resulted in sustained reduction of viral RNA and protein expression, and eventually cured HCV infected cells. Pre-treatment of human hepatoma Huh7.5.1 cells with 15 μM ARB for 24 to 48 hours inhibited acute infection with JFH-1 virus by up to 1000-fold. The inhibitory effect of ARB on HCV was not due to generalized cytotoxicity, nor to augmentation of IFN antiviral signaling pathways, but involved impaired virus-mediated membrane fusion. ARB's affinity for membranes may inhibit several aspects of the HCV lifecycle that are membrane-dependent.

  11. Development of broad-spectrum antimicrobial latex paint surfaces employing active amphiphilic compounds.

    Science.gov (United States)

    Fulmer, Preston A; Wynne, James H

    2011-08-01

    With the increase in antibiotic-resistant microbes, the production of self-decontaminating surfaces has become an area of research that has seen a surge of interest in recent years. Such surfaces, when incorporated into commercial products such as children's toys, medical devices and hospital surfaces could reduce the number of infections caused by pathogenic microorganisms. A number of active components for self-decontaminating surfaces have been investigated, including common antibiotics, metal ions, quaternary ammonium salts (QAS), and antimicrobial peptides (AMP). A recent research focus has been development of a wide range of amphiphilic antimicrobial additives that when combined with modern low volatile organic compound (VOC), water-based paints leads to a surface concentration of the active compounds as the coating cures. Herein we report the development of antimicrobial coatings containing a variety of additives, both QAS and AMP that are active against a broad-spectrum of potentially pathogenic bacteria (1-7 log kill), as well as enveloped viruses (2-7 log kill) and fungi (1-2 log kill). Additionally, these additives were compatible with water-dispersed acrylate coatings (latex paint) which have a broad range of real world applicability, and remained active for multiple challenges and when exposed to various cleaning scenarios in which they might encounter in real world situations.

  12. Isolation and Characterization of a Broad Spectrum Bacteriocin from Bacillus amyloliquefaciens RX7.

    Science.gov (United States)

    Lim, Kong Boon; Balolong, Marilen P; Kim, Sang Hoon; Oh, Ju Kyoung; Lee, Ji Yoon; Kang, Dae-Kyung

    2016-01-01

    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.

  13. Stability-indicating liquid chromatographic method for quantification of new anti-epileptic drug lacosamide in bulk and pharmaceutical formulation

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    Chhalotiya Usmangani K.

    2012-01-01

    Full Text Available An isocratic stability indicating reversed-phase liquid chromatographic determination was developed for the quantitative determination of lacosamide in the pharmaceutical dosage form. A Hypersil C-18, 4.5μm column with mobile phase containing acetonitrile-water (20:80, v/v was used. The flow rate was 1.0 mL min-1 and effluents were monitored at 258 nm. The retention time of lacosamide was 8.9 min. The method was found to be linear in the concentration range of 5-100 μg/ml and the recovery was found to be in the range of 99.15 - 100.09 %. The limit of detection and limit of quantification were found to be 2 μg/ml and 5 μg/ml, respectively. Lacosamide stock solutions were subjected to acid and alkali hydrolysis, chemical oxidation and dry heat degradation. The drug was found to be stable to the dry heat and acidic condition attempted. The proposed method was validated and successfully applied to the estimation of lacosamide in tablet dosage forms.

  14. Subchronic treatment with antiepileptic drugs modifies pentylenetetrazol-induced seizures in mice: Its correlation with benzodiazepine receptor binding

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    Luisa Rocha

    2008-06-01

    Full Text Available Luisa RochaPharmacobiology Department, Center for Research and Advanced Studies, Calz, Tenorios, MéxicoAbstract: Experiments using male CD1 mice were carried out to investigate the effects of subchronic (daily administration for 8 days pretreatments with drugs enhancing GABAergic transmission (diazepam, 10 mg/kg, ip; gabapentin, 100 mg/kg, po; or vigabatrin, 500 mg/kg, po on pentylenetetrazol (PTZ-induced seizures, 24 h after the last injection. Subchronic administration of diazepam reduced latencies to clonus, tonic extension and death induced by PTZ. Subchronic vigabatrin produced enhanced latency to the first clonus but faster occurrence of tonic extension and death induced by PTZ. Subchronic gabapentin did not modify PTZ-induced seizures. Autoradiography experiments revealed reduced benzodiazepine receptor binding in several brain areas after subchronic treatment with diazepam or gabapentin, whereas subchronic vigabatrin did not induce significant receptor changes. The present results indicate differential effects induced by the subchronic administration of diazepam, vigabatrin, and gabapentin on the susceptibility to PTZ-induced seizures, benzodiazepine receptor binding, or both.Keywords: diazepam, gabapentin, vigabatrin, pentylenetetrazol, benzodiazepine receptors

  15. 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

    2016-03-01

    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

  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. 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

  18. Comparative Long-Term Effectiveness of a Monotherapy with Five Antiepileptic Drugs for Focal Epilepsy in Adult Patients: A Prospective Cohort Study.

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    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.

  19. The antiepileptic drug on pregnant women with epilepsy%育龄妇女抗癫痫药的合理使用

    Institute of Scientific and Technical Information of China (English)

    王宇卉

    2015-01-01

    育龄妇女的抗癫痫治疗对临床医生是一个挑战,必须考虑很多问题.癫痫女性(WWE)怀孕期间终止甚或改变抗癫痫药(AEDs)方案很危险,可能导致母亲和胎儿的损害或死亡;少数情况下,中断AEDs似乎合理,但多数在孕期需要继续使用AEDs.怀孕期间AEDs的代谢可能发生很大变化,对WWE后代的风险包括特定AED的不良反应风险以及癫痫发作本身的风险,很多AEDs有众所周知的致畸作用,还有产科并发症、新生儿预后不良、先天性畸形,甚至对孩子随后的认知功能有风险.必须告知其相关风险,适当地指导其治疗,孕前优化癫痫治疗、选择最有效的 AEDs以控制癫痫,尽可能用单药治疗且用最小有效量,避免多药治疗和丙戊酸,补充叶酸,最大限度地控制癫痫发作并降低风险.%The treatment of pregnant women with epilepsy (WWE) is a challenge to the clinician, and many questions must be considered. In women with proven epilepsy, it may be dangerous to stop or even change the antiepileptic drug (AED) regimen during pregnancy. Changes could lead to injury or death in both the mother and the fetus. In the rare cases when discontinuing an AED is plausible, but most WWE are consigned to continue their AEDs before, during and after pregnancy. The metabolism of AEDs may change drastically during pregnancy, the risks to the fetus must be delineated in terms of side effects from specific drugs as well as risks from the seizure disorder itself. Many AEDs have well known teratogenic effects, there are risks for obstetrical complications, poor neonatal outcomes, congenital malformations and even cognitive effects on the child later in life. These must be elucidated to the mother. Recommendations include but are not limited to preconception counseling, prescribing the most effective AED while minimizing risks, avoiding poly therapy and valproate if possible, and taking folate pre- and post-conception.

  20. Long-term Effectiveness of Antiepileptic Drug Monotherapy in Partial Epileptic Patients: A 7-year Study in an Epilepsy Center in China

    Institute of Scientific and Technical Information of China (English)

    Fei Zhu; Sen-Yang Lang; Xiang-Qing Wang; Xiao-Bing Shi; Yun-Feng Ma; Xu Zhang; Ya-Nan Chen

    2015-01-01

    Background: It is important to choose an appropriate antiepileptic drug (AED) to manage partial epilepsy.Traditional AEDs, such as carbamazepine (CBZ) and valproate (VPA), have been proven to have good therapeutic effects.However, in recent years, a variety of new AEDs have increasingly been used as first-line treatments for partial epilepsy.As the studies regarding the effectiveness of new drugs and comparisons between new AEDs and traditional AEDs are few, it is determined that these are areas in need of further research.Accordingly, this study investigated the long-term effectiveness of six AEDs used as monotherapy in patients with partial epilepsy.Methods: This is a retrospective, long-term observational study.Patients with partial epilepsy who received monotherapy with one of six AEDs, namely, CBZ, VPA, topiramate (TPM), oxcarbazepine (OXC), lamotrigine (LTG), or levetiracetam (LEV), were identified and followed up from May 2007 to October 2014, and time to first seizure after treatment, 12-month remission rate, retention rate, reasons for treatment discontinuation, and adverse effects were evaluated.Results: A total of 789 patients were enrolled.The median time of follow-up was 56.95 months.CBZ exhibited the best time to first seizure, with a median time to first seizure of 36.06 months (95% confidential interval: 30.64-44.07).CBZ exhibited the highest 12-month remission rate (85.55%), which was significantly higher than those of TPM (69.38%, P =0.006), LTG (70.79%, P =0.001), LEV (72.54%,P =0.005), and VPA (73.33%, P =0.002).CBZ, OXC, and LEV had the best retention rate, followed by LTG, TPM, and VPA.Overall,adverse effects occurred in 45.87% of patients, and the most common adverse effects were memory problems (8.09%), rashes (7.76%),abnormal hepatic function (6.24%), and drowsiness (6.24%).Conclusion: This study demonstrated that CBZ, OXC, and LEV are relatively effective in managing focal epilepsy as measured by time to first seizure

  1. Pharmacodynamic and/or pharmacokinetic characteristics of interactions between loreclezole and four conventional antiepileptic drugs in pentylenetetrazole-induced seizures in mice: an isobolographic analysis.

    Science.gov (United States)

    Luszczki, Jarogniew J; Ratnaraj, Neville; Patsalos, Philip N; Czuczwar, Stanislaw J

    2005-12-01

    Isobolographic analysis was used to characterize the interactions between loreclezole (LCZ) and clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)-induced seizures and in producing acute neurotoxic adverse effects in the chimney test in mice so as to identify optimum combinations. Moreover, protective indices (PIs) and benefit indices (BIs) were calculated so that a ranking in relation to advantageous combination could be established. Any pharmacokinetic contribution was ascertained by measurement of brain antiepileptic drug (AED) concentrations. All AED combinations comprising LCZ and CZP, ETS, PB, and VPA (at the fixed ratios of 1:3, 1:1, and 3:1) were additive in their seizure suppression. However, these interactions were complicated by changes in brain AED concentrations consequent to pharmacokinetic interactions. Thus, LCZ significantly increased total brain ETS concentrations (VPA, CZP, and PB concentrations were unaffected), and ETS decreased, and VPA increased, total brain LCZ concentrations. Only combinations of LCZ with CZP and PB were completely free of any pharmacokinetic interaction. Furthermore, in the chimney test, isobolographic analysis showed that the combination of LCZ and CZP, at the fixed ratio of 1:1, was supra-additive (synergistic, P<0.05), whereas LCZ and ETS at fixed ratios of 1:3 and 1:1 were subadditive (antagonistic, P<0.05). The remaining combinations of LCZ with CZP (1:3 and 3:1), ETS (3:1), PB (all fixed ratios of 1:3, 1:1, and 3:1), and VPA (at the fixed ratios of 1:3, 1:1, and 3:1) barely displayed additivity. In conclusion, BI, which is a measure of the margin of safety and tolerability of drugs in combination and comprises anticonvulsant and neurotoxic measures, was favorable for only one combination (LCZ and ETS at a fixed ratio of 1:3) with a value of 1.39. In contrast, LCZ and CZP constitute an unfavorable combination (BI=0.61-1.01). The combinations of LCZ

  2. Long-term Effectiveness of Antiepileptic Drug Monotherapy in Partial Epileptic Patients: A 7-year Study in an Epilepsy Center in China

    Directory of Open Access Journals (Sweden)

    Fei Zhu

    2015-01-01

    Full Text Available Background: It is important to choose an appropriate antiepileptic drug (AED to manage partial epilepsy. Traditional AEDs, such as carbamazepine (CBZ and valproate (VPA, have been proven to have good therapeutic effects. However, in recent years, a variety of new AEDs have increasingly been used as first-line treatments for partial epilepsy. As the studies regarding the effectiveness of new drugs and comparisons between new AEDs and traditional AEDs are few, it is determined that these are areas in need of further research. Accordingly, this study investigated the long-term effectiveness of six AEDs used as monotherapy in patients with partial epilepsy. Methods: This is a retrospective, long-term observational study. Patients with partial epilepsy who received monotherapy with one of six AEDs, namely, CBZ, VPA, topiramate (TPM, oxcarbazepine (OXC, lamotrigine (LTG, or levetiracetam (LEV, were identified and followed up from May 2007 to October 2014, and time to first seizure after treatment, 12-month remission rate, retention rate, reasons for treatment discontinuation, and adverse effects were evaluated. Results: A total of 789 patients were enrolled. The median time of follow-up was 56.95 months. CBZ exhibited the best time to first seizure, with a median time to first seizure of 36.06 months (95% confidential interval: 30.64-44.07. CBZ exhibited the highest 12-month remission rate (85.55%, which was significantly higher than those of TPM (69.38%, P = 0.006, LTG (70.79%, P = 0.001, LEV (72.54%, P = 0.005, and VPA (73.33%, P = 0.002. CBZ, OXC, and LEV had the best retention rate, followed by LTG, TPM, and VPA. Overall, adverse effects occurred in 45.87% of patients, and the most common adverse effects were memory problems (8.09%, rashes (7.76%, abnormal hepatic function (6.24%, and drowsiness (6.24%. Conclusion: This study demonstrated that CBZ, OXC, and LEV are relatively effective in managing focal epilepsy as measured by time to first

  3. 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 inclu

  4. Cell-penetrating peptide TP10 shows broad-spectrum activity against both Plasmodium falciparum and Trypanosoma brucei brucei.

    Science.gov (United States)

    Arrighi, Romanico B G; Ebikeme, Charles; Jiang, Yang; Ranford-Cartwright, Lisa; Barrett, Michael P; Langel, Ulo; Faye, Ingrid

    2008-09-01

    Malaria and trypanosomiasis are diseases which afflict millions and for which novel therapies are urgently required. We have tested two well-characterized cell-penetrating peptides (CPPs) for antiparasitic activity. One CPP, designated TP10, has broad-spectrum antiparasitic activity against Plasmodium falciparum, both blood and mosquito stages, and against blood-stage Trypanosoma brucei brucei.

  5. Wild coastline birds as reservoirs of broad-spectrum-β-lactamase-producing Enterobacteriaceae in Miami Beach, Florida.

    Science.gov (United States)

    Poirel, Laurent; Potron, Anaïs; De La Cuesta, Carolina; Cleary, Timothy; Nordmann, Patrice; Munoz-Price, L Silvia

    2012-05-01

    A high rate of broad-spectrum-β-lactamase-producing Escherichia coli isolates was identified from seagull and pelican feces collected in the Miami Beach, Florida, area. The most commonly identified resistance determinants were CMY-2 and CTX-M-15. Those wild birds might be therefore considered vehicles for wide dissemination of multidrug-resistant Enterobacteriaceae in the United States.

  6. 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...

  7. 肝药酶CYP3A4与抗癫(癎)药物的代谢研究进展%Progress on the metabolism of antiepileptic drugs by human hepatic CYP3A4 enzymes

    Institute of Scientific and Technical Information of China (English)

    张君梅

    2011-01-01

    癫(癎)是危害人类健康的常见神经系统疾病,临床常用抗癫(癎)药多通过细胞色素P450等肝药酶代谢.CYP3A4是P450酶系中最重要的代谢酶,参与40%~60%的药物代谢,与临床常用抗癫(癎)药的代谢也有非常紧密的关系.该文对CYP3A4的一般特性及其与抗癫(癎)药物的代谢研究进展作一概述.%Epilepsy is a common disease in nervous system.Most antiepileptic drugs are metabolized by liver enzymes.such as cytochrome P450 enzyme.CYP3A4 iS the most important enzyme in P450 family.involved in the metabolism of about 40%~60% of the drugs use for clinic.It also has a close relationship with the metabolism of antiepileptie drugs.This review summarizes the general characteristic of CYP3A4 and itsrelationship with the metabolism of antiepileptic drugs.

  8. Systems analysis of a RIG-I agonist inducing broad spectrum inhibition of virus infectivity.

    Directory of Open Access Journals (Sweden)

    Marie-Line Goulet

    Full Text Available The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5' triphosphate (5'ppp terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5'pppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, and induction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5'pppRNA, and not by IFNα-2b, that included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5'pppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5'pppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach provides transcriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5'pppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents.

  9. 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

  10. Isolation and Characterization of a Broad Spectrum Bacteriocin from Bacillus amyloliquefaciens RX7

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    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.

  11. Activities of ceftobiprole, a novel broad-spectrum cephalosporin, against Haemophilus influenzae and Moraxella catarrhalis.

    Science.gov (United States)

    Bogdanovich, Tatiana; Clark, Catherine; Ednie, Lois; Lin, Gengrong; Smith, Kathy; Shapiro, Stuart; Appelbaum, Peter C

    2006-06-01

    Ceftobiprole, a broad-spectrum pyrrolidinone-3-ylidenemethyl cephem currently in phase III clinical trials, had MICs between 0.008 microg/ml and 8.0 microg/ml for 321 clinical isolates of Haemophilus influenzae and between Ceftobiprole MIC(50) and MIC(90) values for H. influenzae were 0.06 microg/ml and 0.25 microg/ml for beta-lactamase-positive strains (n = 262), 0.03 microg/ml and 0.25 microg/ml for beta-lactamase-negative strains (n = 40), and 0.5 microg/ml and 2.0 microg/ml for beta-lactamase-negative ampicillin-resistant strains (n = 19), respectively. Ceftobiprole MIC(50) and MIC(90) values for beta-lactamase-positive M. catarrhalis strains (n = 40) were 0.12 microg/ml and 0.5 microg/ml, respectively, whereas the ceftobiprole MIC range for beta-lactamase-negative M. catarrhalis strains (n = 9) was ceftobiprole, whereas amoxicillin-clavulanate MICs usually were higher than those of ceftobiprole. Azithromycin and telithromycin had unimodal MIC distributions against H. influenzae, with MIC(90) values of azithromycin and telithromycin of 2 microg/ml and 4 microg/ml, respectively. Except for selected quinolone-nonsusceptible H. influenzae strains, moxifloxacin proved highly active, with MIC(90) values of 0.12 microg/ml. Time-kill analyses showed that ceftobiprole, ceftriaxone, cefpodoxime, amoxicillin-clavulanate, azithromycin, telithromycin, and moxifloxacin were bactericidal at 2x MIC by 24 h against all 10 H. influenzae strains surveyed. Only modest increases in MICs were found for H. influenzae or M. catarrhalis clones after 50 serial passages in the presence of subinhibitory concentrations of ceftobiprole, and single-passage selection showed that the selection frequency of H. influenzae or M. catarrhalis clones with elevated ceftobiprole MICs is quite low.

  12. 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.

  13. 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

  14. Congenital Anomalies in Children of Mothers Taking Antiepileptic Drugs with and without Periconceptional High Dose Folic Acid Use: A Population-Based Cohort Study.

    Directory of Open Access Journals (Sweden)

    Lu Ban

    Full Text Available Antenatal antiepileptic drug (AED use has been found to be associated with increased major congenital anomaly (CA risks. However whether such AED-associated risks were different according to periconceptional high dose (5mg daily folic acid supplementation is still unclear.We included 258,591 singleton live-born children of mothers aged 15-44 years in 1990-2013 from The Health Improvement Network, a large UK primary care database. We identified all major CAs according to the European Surveillance of Congenital Anomalies classification. Absolute risks and adjusted odds ratios (aOR were calculated comparing children of mothers prescribed AEDs to those without such prescriptions, stratified by folic acid prescriptions around the time of conception (one month before conception to two months post-conception.CA risk was 476/10,000 in children of mothers with first trimester AEDs compared with 269/10,000 in those without AEDs equating to an aOR of 1.82, 95% confidence interval 1.30-2.56. The highest system-specific risks were for heart anomalies (198/10,000 and 79/10,000 respectively, aOR 2.49,1.47-4.21. Sodium valproate and lamotrigine were both associated with increased risks of any CA (aOR 2.63,1.46-4.74 and aOR 2.01,1.12-3.59 respectively and system-specific risks. Stratification by folic acid supplementation did not show marked reductions in AED-associated risks (e.g. for CAs overall aOR 1.75, 1.01-3.03 in the high dose folic acid group and 1.94, 95%CI 1.21-3.13 in the low dose or no folic acid group; however, the majority of mothers taking AEDs only initiated high dose folic acid from the second month of pregnancy.Children of mothers with AEDs in the first trimester of pregnancy have a 2-fold increased risk of major CA compared to those unexposed. We found no evidence that prescribed high dose folic acid supplementation reduced such AED-associated risks. Although statistical power was limited, prescribing of folic acid too late for it to be

  15. 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

  16. 网格蛋白介导型内吞作用与广谱抗病毒药%Clathrin-mediated endocytosis and broad-spectrum antivirals

    Institute of Scientific and Technical Information of China (English)

    周丽; 杨晓虹; 徐利保; 肖军海

    2013-01-01

    Viral disease is a serious threat for human health. Alhough plenty of antiviral agents have been used in clinical treatment, many viruses are resistant to them via virus mutation. And novel harmful viruses emerge in endlessly. So research and development of new antiviral drugs, especially the agents that are of broad-spectrum antiviral activity is particularly important. Clathrin-mediated endocytosis is the most common pathway used by viruses and pathogens for entering host cells. The inhibitors of clathrin-me-diated endocytosis may block the entry of viruses and pathogens, thus prevent viral infection. For the inhibitors do not directly act on the virus itself, it is hard to induce virus mutations which produce drug resistance. Clathrin-mediated endocytosis is the potential target of broad-spectrum antiviral agents in recent years. This review focuses on the mechanism of virus entry through clathrin-mediated endocytosis, the recent advances of clathrin-mediated endocytosis inhibitors and their potential applications in broad-spectrum antiviral therapeutics field.%病毒性疾病对人类的健康造成了巨大的威胁,虽然有很多药物用于临床治疗,但由于病毒的易变异性,对现有的抗病毒药物极易产生耐药性,而新发病毒又层出不穷,因此研发新的抗病毒药物尤其是广谱且不易产生耐药的抗病毒药物对于病毒性疾病的治疗就显得尤为重要.网格蛋白介导型内吞是许多病毒和病原体进入宿主细胞的主要途径,抑制此途径可阻断病毒进入宿主细胞,从而抑制病毒感染,由于其功能和机制与病毒自身无关,不易产生耐药,是近年来广谱抗病毒药物的潜在作用靶标.本文结合国内外最新研究报道,简要综述了病毒依赖网格蛋白介导型内吞入胞的机制,网格蛋白介导型内吞抑制剂的研究现状,及其在广谱抗病毒药物研发中的潜在应用前景.

  17. 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.

  18. Proteasome Accessory Factor C (pafC) Is a novel gene Involved in Mycobacterium Intrinsic Resistance to broad-spectrum antibiotics--Fluoroquinolones.

    Science.gov (United States)

    Li, Qiming; Xie, Longxiang; Long, Quanxin; Mao, Jinxiao; Li, Hui; Zhou, Mingliang; Xie, Jianping

    2015-07-03

    Antibiotics resistance poses catastrophic threat to global public health. Novel insights into the underlying mechanisms of action will inspire better measures to control drug resistance. Fluoroquinolones are potent and widely prescribed broad-spectrum antibiotics. Bacterial protein degradation pathways represent novel druggable target for the development of new classes of antibiotics. Mycobacteria proteasome accessory factor C (pafC), a component of bacterial proteasome, is involved in fluoroquinolones resistance. PafC deletion mutants are hypersensitive to fluoroquinolones, including moxifloxacin, norfloxacin, ofloxacin, ciprofloxacin, but not to other antibiotics such as isoniazid, rifampicin, spectinomycin, chloramphenicol, capreomycin. This phenotype can be restored by complementation. The pafC mutant is hypersensitive to H2O2 exposure. The iron chelator (bipyridyl) and a hydroxyl radical scavenger (thiourea) can abolish the difference. The finding that pafC is a novel intrinsic selective resistance gene provided new evidence for the bacterial protein degradation pathway as druggable target for the development of new class of antibiotics.

  19. Broad-spectrum health improvements with one year of soccer training in inactive mildly hypertensive middle-aged women

    DEFF Research Database (Denmark)

    Krustrup, P; Skoradal, M-B; Randers, M B

    2017-01-01

    The study tested the hypothesis that long-term soccer training has positive impact on cardiovascular profile, body composition, bone health, and physical capacity in inactive, pre-menopausal women with mild hypertension. The study applied a randomized controlled design in which physically inactiv...... in broad-spectrum improvements in the health profile of untrained, pre-menopausal women with mild hypertension, including cardiovascular, metabolic, and musculo-skeletal benefits....

  20. NBS Proifling Identiifes Potential Novel Locus from Solanum demissum That Confers Broad-Spectrum Resistance to Phytophthora infestans

    Institute of Scientific and Technical Information of China (English)

    ZHANG Kun; XU Jian-fei; DUAN Shao-guang; PANG Wan-fu; BIAN Chun-song; LIU Jie; JIN Li-ping

    2014-01-01

    Potato late blight, caused by the oomycete pathogen Phytophthora infestans, is the most serious disease of potato worldwide. The adoption of varieties with resistance genes, especially broad-spectrum resistance genes, is the most efifcient approach to control late blight. Solanum demissum is a well-known wild potato species from which 11 race-speciifc resistance genes have been identiifed, however, no broad-spectrum resistance genes like RB have been reported in this species. Here, we report a novel reisistance locus from S. demissum that potentially confer broad-spectrum resistance to late blight. A small segregating population of S. demissum were assessed for resistance to aggressive P. infestans isolates (race 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11). This coupled with nucleotide binding site (NBS) proifling analyses, led to the identiifcation of three fragments that linked to the potential candidate resistance gene(s). Cloning and sequence analysis of these fragments suggested that the identiifed resistance gene locus is located in the region containing R2 resistance gene at chromosome 4. Based on the sequences of the cloned fragments, a co-segregating sequence characterized ampliifed region (SCAR) marker, RDSP, was developed. The newly identiifed marker RDSP will be useful for marker assisted breeding and further cloning of this potential resistance gene locus.

  1. Pharmacological and behavioral characteristics of interactions between vigabatrin and conventional antiepileptic drugs in pentylenetetrazole-induced seizures in mice: an isobolographic analysis.

    Science.gov (United States)

    Luszczki, Jarogniew J; Wojcik-Cwikla, Joanna; Andres, Marta M; Czuczwar, Stanislaw J

    2005-05-01

    To characterize the anticonvulsant effects and types of interactions exerted by mixtures of vigabatrin (VGB) and conventional antiepileptic drugs (valproate (VPA), ethosuximide (ESM), phenobarbital (PB), and clonazepam (CZP)) in pentylenetetrazole (PTZ)-induced seizures in mice, the isobolographic analysis for three fixed-ratio combinations of 1 : 3, 1 : 1, and 3 : 1 was used. The adverse-effect profile of the combinations tested, at the doses corresponding to their median effective doses (ED(50)) at the fixed-ratio of 1 : 1 against PTZ-induced seizures, was determined by the chimney (motor performance), step-through passive avoidance (long-term memory), pain threshold (pain sensitivity), and Y-maze (general explorative locomotor activity) tests in mice. Additionally, the observed isobolographic interactions were verified in terms of a pharmacokinetic interaction existence. VGB combined with PB or ESM exerted supra-additive (synergistic) interactions against the clonic phase of PTZ-induced seizures, which was associated with the increment of PB or ESM concentrations in the brains of examined animals. The remaining combinations tested (ie VGB+VPA and VGB+CZP) occurred additive in the PTZ test, which was associated with no significant changes in the brain concentrations of VPA and CZP. None of the examined combinations exerted motor impairment in the chimney test in mice. In the standard variant of passive avoidance task (current of 0.6 mA; 2 s of stimulus duration), the combinations of VGB+CZP and VGB+VPA significantly affected long-term memory in mice. Moreover, VGB in a dose-dependent manner lengthened the latency to the first pain reaction in the pain threshold test in mice. The modified variant of step-through passive avoidance task (current of 0.6 mA; stimulus duration based on the latency from the pain threshold test) revealed no significant changes in the long-term memory of animals for the combinations of VGB+VPA and VGB+CZP; so the observed effects in the

  2. Expansion of a recent class of broad-spectrum antifungal agents: the echinocandins

    Directory of Open Access Journals (Sweden)

    Roberto Manfredi

    2009-09-01

    Full Text Available The echinocandins show comparable efficacy in the treatment of candidemia and invasive candidiasis. Caspofungin and micafungin appear to be similarly efficacious in salvage therapy in aspergillosis; anidulafungin has excellent in vitro activity against Aspergillus species but as yet there are no sufficient clinical data for anidulafungin in this disease state. Each drug has minor advantages and disadvantages compared to the others of the same classe; however, there are large differences in the approved indications for the different drugs. The formulary selection process should consider the direct and indirect costs of the single agents; the characteristics of the patient population at risk for invasive mycosis, such as frequent use of interacting drugs and the burden of monitoring plasma drug levels of drugs; and the implications of using products for indications which have not been still approved (off-label indications.

  3. The safety of a loading dose of intravenous antiepileptic drugs%静脉应用负荷剂量抗癫痫药物的安全性

    Institute of Scientific and Technical Information of China (English)

    宿英英; 田飞; 陈卫碧; 高冉; 张运周; 张艳; 叶红; 高岱俭; 刘芳

    2013-01-01

    和骨髓抑制分别为3、2、5和1例.地西泮组不良反应发生率明显低于地西泮后续苯巴比妥组(P =0.033).上述不良反应经停药与对症治疗后均可消除. 结论 静脉给予负荷剂量地西泮或丙戊酸或苯巴比妥治疗成人GCSE均安全有效.用药过程中应密切监测患者的不良反应,特别是对地西泮与苯巴比妥联用的患者.一旦出现不良反应,应及时停药并予以对症治疗.%Objective To investigate the safety of a loading dose of Ⅳ antiepileptic drugs (AED)in the treatment of adult patients with generalized convulsive status epilepticus (GCSE).Methods A method for the analysis of pooled data was adopted.The results from the two prospective randomized controlled trials (RCTs) performed by Xuanwu Hospital from January 2007 to January 2010 and from June 2010 to May 2012 were collected.The clinical data were analyzed and compared among the patients in the diazepam group,the diazepam and subsequent valproate group,and the diazepam and subsequent phenobarbital group.A loading dose of Ⅳ diazepam (0.2 mg/kg,5 mg/min) was as first-line AED treatment for all patients in the 3 groups.Second-line AED treatment were as follows:in the diazepam group,a loading dose of Ⅳ diazepam (0.2 mg/kg,5mg/min) was given,then a maintenance dose of Ⅳ diazepam (4.0 mg/h,increase by 1.0 μg/kg every 3 minutes) was given via a pump.In the diazepam subsequent valproate group,a loading dose of Ⅳ diazepam [30 mg/kg,6 mg/(kg · min)] was given,then a maintenance dose of Ⅳ valproate 1-2 mg/(kg · h) was given via a pump.In the diazepam subsequent phenobarbital group,a loading dose of Ⅳ phenobarbital (20 mg/kg,50 mg/min) was given,then a maintenance dose of Ⅳ phenobarbital (100 mg/6 h,50 mg/min) was given.The second-line AED treatment should be continued until 24 hours after epileptic seizure stopped,then the dosage was gradually reduced.The patients should be closely monitored for reactions after drug administration.Results A total of

  4. Anticonvulsant activity, neural tube defect induction, mutagenicity and pharmacokinetics of a new potent antiepileptic drug, N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide.

    Science.gov (United States)

    Sobol, Eyal; Yagen, Boris; Lamb, John G; White, H Steve; Wlodarczyk, Bogdan J; Finnell, Richard H; Bialer, Meir

    2007-01-01

    N-methoxy-2,2,3,3-tetramethylcyclopropane carboxamide (OM-TMCD) is a methoxyamide derivative of a cyclopropyl analogue of valproic acid (VPA). The structural considerations used in the design of OM-TMCD were aimed to enhance OM-TMCD anticonvulsant potency (compared to VPA) and to prevent VPA's two life-threatening side effects, i.e., induction of neural tube defects (NTDs) and hepatotoxicity. Following i.p. administration to rats OM-TMCD demonstrated a broad spectrum of anticonvulsant activity and showed better potency than VPA in the maximal electroshock seizure and subcutaneous pentylenetetrazole tests as well as in the hippocampal kindling model. OM-TMCD was inactive in the mouse 6-Hz test at 100 mg/kg dose. Teratogenicity studies performed in a SWV/Fnn-mouse model for VPA-induced-exencephaly showed that on the equimolar basis OM-TMCD possesses the same fetal toxicity and ability to induce NTDs as VPA, but since OM-TMCD is a much more potent anticonvulsant its activity/exencephaly formation ratio appears to be much more beneficial than that of VPA. OM-TMCD was found to be non-mutagenic and non-pro-mutagenic in the Ames test. It showed a beneficial pharmacokinetic profile in rats, having a high oral bioavailability of 75% and satisfactory values of clearance and volume of distribution. These results support further studies to fully characterize the therapeutic potential of OM-TMCD.

  5. Pinellia ternata agglutinin expression in chloroplasts confers broad spectrum resistance against aphid, whitefly, Lepidopteran insects, bacterial and viral pathogens.

    Science.gov (United States)

    Jin, Shuangxia; Zhang, Xianlong; Daniell, Henry

    2012-04-01

    Broad spectrum protection against different insects and pathogens requires multigene engineering. However, such broad spectrum protection against biotic stress is provided by a single protein in some medicinal plants. Therefore, tobacco chloroplasts were transformed with the agglutinin gene from Pinellia ternata (pta), a widely cultivated Chinese medicinal herb. Pinellia ternata agglutinin (PTA) was expressed up to 9.2% of total soluble protein in mature leaves. Purified PTA showed similar hemagglutination activity as snowdrop lectin. Artificial diet with purified PTA from transplastomic plants showed marked and broad insecticidal activity. In planta bioassays conducted with T0 or T1 generation PTA lines showed that the growth of aphid Myzus persicae (Sulzer) was reduced by 89%-92% when compared with untransformed (UT) plants. Similarly, the larval survival and total population of whitefly (Bemisia tabaci) on transplastomic lines were reduced by 91%-93% when compared with UT plants. This is indeed the first report of lectin controlling whitefly infestation. When transplastomic PTA leaves were fed to corn earworm (Helicoverpa zea), tobacco budworm (Heliothis virescens) or the beet armyworm (spodoptera exigua), 100% mortality was observed against all these three insects. In planta bioassays revealed Erwinia population to be 10,000-fold higher in control than in PTA lines. Similar results were observed with tobacco mosaic virus (TMV) challenge. Therefore, broad spectrum resistance to homopteran (sap-sucking), Lepidopteran insects as well as anti-bacterial or anti-viral activity observed in PTA lines provides a new option to engineer protection against biotic stress by hyper-expression of an unique protein that is naturally present in a medicinal plant.

  6. Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway

    Science.gov (United States)

    Thangamani, Shankar; Maland, Matthew; Mohammad, Haroon; Pascuzzi, Pete E.; Avramova, Larisa; Koehler, Carla M.; Hazbun, Tony R.; Seleem, Mohamed N.

    2017-01-01

    Current antifungal therapies have limited effectiveness in treating invasive fungal infections. Furthermore, the development of new antifungal is currently unable to keep pace with the urgent demand for safe and effective new drugs. Auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, inhibits growth of a diverse array of clinical isolates of fungi and represents a new antifungal agent with a previously unexploited mechanism of action. In addition to auranofin's potent antifungal activity against planktonic fungi, this drug significantly reduces the metabolic activity of Candida cells encased in a biofilm. Unbiased chemogenomic profiling, using heterozygous S. cerevisiae deletion strains, combined with growth assays revealed three probable targets for auranofin's antifungal activity—mia40, acn9, and coa4. Mia40 is of particular interest given its essential role in oxidation of cysteine rich proteins imported into the mitochondria. Biochemical analysis confirmed auranofin targets the Mia40-Erv1 pathway as the drug inhibited Mia40 from interacting with its substrate, Cmc1, in a dose-dependent manner similar to the control, MB-7. Furthermore, yeast mitochondria overexpressing Erv1 were shown to exhibit resistance to auranofin as an increase in Cmc1 import was observed compared to wild-type yeast. Further in vivo antifungal activity of auranofin was examined in a Caenorhabditis elegans animal model of Cryptococcus neoformans infection. Auranofin significantly reduced the fungal load in infected C. elegans. Collectively, the present study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antifungal agent and may offer a safe, effective, and quick supplement to current approaches for treating fungal infections. PMID:28149831

  7. Congenital diaphragmatic hernia and microtia in a newborn with mycophenolate mofetil (MMF) exposure: phenocopy for Fryns syndrome or broad spectrum of teratogenic effects?

    Science.gov (United States)

    Parisi, Melissa A; Zayed, Hatem; Slavotinek, Anne M; Rutledge, Joe C

    2009-06-01

    A newborn female infant born to a woman on immunosuppressive medications including mycophenolate mofetil (MMF) for a renal graft secondary to lupus nephritis presented with congenital diaphragmatic hernia (CDH) and additional findings of microtia, esophageal atresia with tracheoesophageal fistula, cleft palate, congenital heart defect, digital anomalies, and dysmorphic facial features. Pulmonary hypoplasia resulted in death at day 2 of life. She was presumed to have Fryns syndrome based on diagnostic criteria established for this recessive disorder with prominent features including CDH, facial anomalies, and nail hypoplasia. In retrospect, this infant's findings are more likely the result of teratogenic exposure to MMF, as more recent data have emerged linking aural atresia, digital anomalies, and dysmorphic features to this drug. To date, this is the only human report of CDH in an infant with prenatal exposure to MMF, although the manufacturer's package insert alludes to animal studies with a broad spectrum of malformations, including CDH. Thus, a teratogenic exposure can mimic a known Mendelian genetic syndrome, and caution is urged in presuming a genetic etiology for infants with potential teratogenic exposure to relatively new drugs with limited published animal data.

  8. Synthesis of 2,3,6-trideoxy sugar triazole hybrids as potential new broad spectrum antimicrobial agents.

    Science.gov (United States)

    Sharma, Smriti; Saquib, Mohammad; Verma, Saroj; Mishra, Nripendra N; Shukla, Praveen K; Srivastava, Ranjana; Prabhakar, Yenamandra S; Shaw, Arun K

    2014-08-18

    Here, we describe a molecular hybridization inspired design and synthesis of novel 6-triazolyl 2,3,6-trideoxy sugars as promising new broad-spectrum antimicrobial agents using click chemistry in key step. These compounds showed MIC between 0.39 and 50 μg/mL against different native and resistant bacteria and fungi with no toxicity. Among them, compound 29 was the most active molecule with MIC 0.78 μg/mL against Staphylococcus aureus and Klebsiella pneumoniae and 3.12 μg/mL against methicillin- and vancomycin-resistant S. aureus. Compound 26 was the most potent anti-fungal candidate with MIC 0.39 μg/mL against Trichophyton mentagrophytes. Compound 46 was found to be promising with broad-spectrum activity against both bacterial and fungal strains. The bioinformatic studies involving bacteria's protein co-crystals prompted penicillin binding protein-2 as the most likely target of these compounds.

  9. Occurrence of bacteria producing broad-spectrum beta-lactamases and qnr genes in hospital and urban wastewater samples.

    Science.gov (United States)

    Röderová, Magdaléna; Sedláková, Miroslava Htoutou; Pudová, Vendula; Hricová, Kristýna; Silová, Romana; Imwensi, Peter Eghonghon Odion; Bardoň, Jan; Kolář, Milan

    2016-04-01

    The aims were to investigate the level of antibiotic-resistant bacteria in hospital and urban wastewater and to determine the similarity of isolates obtained from wastewater and hospitalized patients. Wastewater samples were collected in September 2013 and 2014. After identification using MALDI-TOF MS, beta-lactamase production was determined by relevant phenotypic tests. Genes responsible for the production of single beta-lactamase groups and Qnr proteins were established. The epidemiological relationship of the isolates from wastewater and hospitalized patients was determined by PFGE. A total of 51 isolates of enterobacteria were obtained. Overall, 45.1% of them produced broad-spectrum beta-lactamases. Genes encoding TEM, SHV, CTX-M, CIT, DHA and EBC types of enzymes and Qnr proteins were detected. No broad-spectrum beta-lactamase production was confirmed in the urban wastewater treatment plant. The most important finding was the detection of two identical isolates of K. pneumoniae in 2013, one from a patient's urinary catheter and the other from a wastewater sample.

  10. A novel Pro197Glu substitution in acetolactate synthase (ALS) confers broad-spectrum resistance across ALS inhibitors.

    Science.gov (United States)

    Liu, Weitang; Yuan, Guohui; Du, Long; Guo, Wenlei; Li, Lingxu; Bi, Yaling; Wang, Jinxin

    2015-01-01

    Water chickweed (Myosoton aquaticum L.), a competitive broadleaf weed, is widespread in wheat fields in China. Tribenuron and pyroxsulam failed to control water chickweed in the same field in Qiaotian Village in 2011 and 2012, respectively. An initial tribenuron resistance confirmation test identified a resistant population (AH02). ALS gene sequencing revealed a previously unreported substitution of Glu for Pro at amino acid position 197 in resistant individuals. A purified subpopulation (WRR04) that was individually homozygous for the Pro197Glu substitution was generated and characterized in terms of its response to different classes of ALS inhibitors. A whole-plant experiment showed that the WRR04 population exhibited broad-spectrum resistance to tribenuron (SU, 318-fold), pyrithiobac sodium (PTB, > 197-fold), pyroxsulam (TP, 81-fold), florasulam (TP, > 36-fold) and imazethapyr (IMI, 11-fold). An in vitro ALS assay confirmed that the ALS from WRR04 showed high resistance to all the tested ALS inhibitors. These results established that the Pro197Glu substitution endows broad-spectrum resistance across ALS inhibitors in water chickweed. In addition, molecular markers were developed to rapidly identify the Pro197Glu mutation.

  11. A multidisciplinary antimicrobial stewardship programme safely decreases the duration of broad-spectrum antibiotic prescription in Singaporean adult renal patients.

    Science.gov (United States)

    Cai, Yiying; Shek, Pui Ying; Teo, Isabelle; Tang, Sarah S L; Lee, Winnie; Liew, Yi Xin; Chlebicki, Piotr; Kwa, Andrea L

    2016-01-01

    Patients with chronic kidney disease have increased risk of infections. Thus, physicians may favour prolonged broad-spectrum antibiotic use. Studies focused on antimicrobial stewardship programmes (ASPs) in renal patients are currently lacking. Here we describe the role of a multidisciplinary ASP and the impact of ASP interventions in renal patients. A multidisciplinary ASP was initiated at a tertiary hospital in Singapore. Patients prescribed broad-spectrum parenteral antibiotics were identified daily and were subjected to prospective review with immediate concurrent feedback. ASP data from January 2010 to December 2011 were analysed for all renal patients. Outcome measures included the duration and appropriateness of antibiotics, intervention acceptance rates, cost savings and safety outcomes. A total of 2084 antibiotic courses were reviewed, of which 24% were inappropriate, with meropenem most commonly prescribed inappropriately (31.0%). The commonest reasons for inappropriate use were wrong choice (51.0%) and wrong duration (21.4%). In total, 634 recommendations were made, with high acceptance rates (73.3%). Recommendations to discontinue antibiotics (33.4%) and to optimise doses (17.2%) comprised the bulk of ASP work. A mean reduction of -1.28 days of antibiotic use was observed among patients with interventions accepted versus those rejected (Pantibiotic use without compromising safety in renal patients. Continued effort is needed to produce a long-term impact on antibiotic prescription and resistance.

  12. Development of a broad spectrum polymer-released antimicrobial coating for the prevention of resistant strain bacterial infections.

    Science.gov (United States)

    Sinclair, K D; Pham, T X; Farnsworth, R W; Williams, D L; Loc-Carrillo, C; Horne, L A; Ingebretsen, S H; Bloebaum, R D

    2012-10-01

    More than 400,000 primary hip and knee replacement surgeries are performed each year in the United States. From these procedures, approximately 0.5-3% will become infected and when considering revision surgeries, this rate has been found to increase significantly. Antibiotic-resistant bacterial infections are a growing problem in patient care. This in vitro research investigated the antimicrobial potential of the polymer released, broad spectrum, Cationic Steroidal Antimicrobial-13 (CSA-13) for challenges against 5 × 10(8) colony forming units (CFU) of methicillin-resistant Staphylococcus aureus (MRSA). It was hypothesized that a weight-to-weight (w/w) concentration of 18% CSA-13 in silicone would exhibit potent bactericidal potential when used as a controlled release device coating. When incorporated into a polymeric device coating, the 18% (w/w) broad-spectrum polymer released CSA-13 antimicrobial eliminated 5 × 10(8) CFU of MRSA within 8 h. In the future, these results will be utilized to develop a sheep model to assess CSA-13 for the prevention of perioperative device-related infections in vivo.

  13. Broad-spectrum acquired resistance in barley induced by the Pseudomonas pathosystem shares transcriptional components with Arabidopsis systemic acquired resistance.

    Science.gov (United States)

    Colebrook, E H; Creissen, G; McGrann, G R D; Dreos, R; Lamb, C; Boyd, L A

    2012-05-01

    Inducible resistance responses play a central role in the defense of plants against pathogen attack. Acquired resistance (AR) is induced alongside defense toward primary attack, providing broad-spectrum protection against subsequent pathogen challenge. The localization and molecular basis of AR in cereals is poorly understood, in contrast with the well-characterized systemic acquired resistance (SAR) response in Arabidopsis. Here, we use Pseudomonas syringae as a biological inducer of AR in barley, providing a clear frame of reference to the Arabidopsis-P. syringae pathosystem. Inoculation of barley leaf tissue with the nonadapted P. syringae pv. tomato avrRpm1 (PstavrRpm1) induced an active local defense response. Furthermore, inoculation of barley with PstavrRpm1 resulted in the induction of broad-spectrum AR at a distance from the local lesion, "adjacent" AR, effective against compatible isolates of P. syringae and Magnaporthe oryzae. Global transcriptional profiling of this adjacent AR revealed similarities with the transcriptional profile of SAR in Arabidopsis, as well as transcripts previously associated with chemically induced AR in cereals, suggesting that AR in barley and SAR in Arabidopsis may be mediated by analogous pathways.

  14. Design of a photostabilizer having built-in antioxidant functionality and its utility in obtaining broad-spectrum sunscreen formulations.

    Science.gov (United States)

    Chaudhuri, Ratan K; Lascu, Zoia; Puccetti, Germain; Deshpande, Anant A; Paknikar, Sashikumar K

    2006-01-01

    Di-2,2'-diethylhexyl-3,5-dimethoxy-4-hydroxy-benzylidenemalonate (INCI name diethylhexyl syringylidene malonate, DESM), the target photostabilizer, was synthesized in one step by condensation of 3,5-dimethoxy-4-hydroxy benzaldehyde (Syringaldehyde) with di-2,2'-diethylhexyl malonate. Photostability data in sunscreen formulations showed that DESM is photostable and improves the photostability of avobenzone significantly when compared to control (without a photostabilizer). Photostable broad-spectrum sunscreen formulations with high SPF (>30) have been achieved by combining avobenzone, DESM and UV-B sunscreens, such as homosalate, octisalate or other UV-B sunscreens. It seems that (a) triplet-state energy transfer from avobenzone to DESM and (b) scavenging of reactive species are responsible for the observed stabilization of avobenzone. In vitro study of the two formulations containing DESM clearly showed critical wavelength of well over 370 nm and can thus be categorized as broad-spectrum sunscreens. DESM does not have any contribution to in vivo SPF; instead it boosts SPF by about 5 units in high-SPF products. DESM was found to be an excellent singlet-oxygen quencher, thereby reducing photodegradation of avobenzone caused by singlet oxygen. In short, the multiplicity of effects and formulation benefits seen with DESM makes it an ideal choice as a unique antioxidant photostabilizer for a variety of cosmetic products targeting young and mature skin alike.

  15. Screening bioactives reveals nanchangmycin as a broad spectrum antiviral active against Zika virus

    Science.gov (United States)

    Rausch, Keiko; Hackett, Brent; Weinbren, Nathan; Reeder, Sophia; Sadovsky, Yoel; Hunter, Christopher; Schultz, David C.; Coyne, Carolyn; Cherry, Sara

    2017-01-01

    Zika virus is an emerging arthropod-borne flavivirus for which there are no vaccines or specific therapeutics. We screened a library of 2000 ‘bioactive’ compounds for their ability to block Zika virus infection in three distinct cell-types with two different strains of Zika virus. Using a microscopy-based assay, we validated 38 drugs that inhibited Zika virus infection, including FDA approved nucleoside analogs. Cells expressing high levels of the attachment factor AXL can be protected from infection with receptor tyrosine kinase inhibitors, while placental-derived cells that lack AXL expression are insensitive to this inhibition. Importantly, we identified nanchangmycin as a potent inhibitor of Zika virus entry across all cell types tested including physiologically relevant primary cells. Nanchanmycin was also active against other medically relevant viruses including West Nile, dengue, and chikungunya virus that use a similar route of entry. This study provides a resource of small molecules to study Zika virus pathogenesis. PMID:28099856

  16. Bilogical and toxicological properties of econazole, a broad-spectrum antimycotic.

    Science.gov (United States)

    Thienpont, D; Van Cutsem, J; Van Nueten, J M; Niemegeers, C J; Marsboom, R

    1975-02-01

    The spectrum of activity of 1-(2,4-dichloro-beta-[(p-chlorobenzoyl)oxy]phenethyl)imidazole-nitrate (econazole, R 14827) was tested in vitro on various pathogenic fungi and bacteria, and also in vivo in guinea-pigs and rats experimentally infected with dermatophytes and C. albicans. The in vitro activity spectrum is very broad: the dermatophytes, the yeasts, the dimorphic fungi, the aspergilli, the mycetoma causing agents and the Gram-positive bacteria being most sensitive. Guinea-pigs infected with T. mentagrophytes, M. canis or C. albicans and treated topically or orally with econazole, were cured. In each of these tests the activity of econazole was compared with that of different reference drugs. Vaginal candidiasis in rats was cured after oral administration of econazole. Toxicity and teratogenicity studies in different laboratory animals indicate that econazole is well tolerated.

  17. MK-801与抗癫痫药合用对大鼠杏仁核点燃的影响%Effect of combination of dizocilpine with general antiepileptic drugs on amygdala kindling models in rats

    Institute of Scientific and Technical Information of China (English)

    仲伟珍; 赵永娟; 高桂梅; 杨志宏; 岳旺

    2004-01-01

    目的在大鼠杏仁核点燃模型研究MK-801(地佐西平)及其联合用药的抗癫痫作用.方法建立大鼠杏仁核慢性电刺激点燃模型,测定不同剂量的MK-801对点燃模型各项指标的影响,探讨MK-801与其他抗癫痫药的协同作用,用氨基脲诱发的小鼠惊厥模型测定MK-801抗惊厥作用. 结果 MK-801(0.1~0.25 mg·kg-1)可剂量依赖性抑制杏仁核点燃,缩短后放电时程,降低Racine's分级;在对点燃均无明显影响的剂量下,MK-801(0.05 mg·kg-1)与抗癫痫药(苯巴比妥、丙戊酸及尼卡地平)合用可缩短后放电时程或降低Racine's分级.MK-801(0.1~0.25 mg·kg-1)显著降低小鼠氨基脲诱发的发作潜伏期、惊厥发生率和死亡率.结论 MK-801具有抑制大鼠杏仁核点燃的作用,增强苯巴比妥、丙戊酸及尼卡地平的抗癫痫活性,为临床的合并用药提供实验依据.%Aim To investigate the antiepileptic effect of dizocilpine (MK-801) on amygdala kindling models in rats and the effects of its combination with general antiepileptic drugs. Methods To establish amygdala kindling models in rats and observe the effect of dizocilpine on kindling models and its combination with general antiepileptic drugs (phenobarbital, valproate and nicardipine) at ineffective dose. The influence of dizocilpine on convulsions induced by semicarbazide (SCZ) in mice were also observed. Results Dizocilpine (0.1-0.25 mg·kg-1, ip) was shown to dose-dependently inhibit amygdala kindled seizure, shorten the after discharge duration (ADD) and reduce the Racine's stage (P<0.01). The combination of dizocilpine with phenobarbital, valproate, nicardipine at ineffective dose shortened ADD or reduced Racine's stages (P<0.01). Dizocilpine (0.1-0.25 mg·kg-1, ip) significantly prolonged the latency and reduced the rate of convulsions and death in mice. Conclusion Dizocilpine inhibits the seizure of the amygdala kindling and improve the antiepileptic activity of phenobarbital

  18. 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

  19. MICROBIAL TRANSFORMATION OF GALLOTANNINS TO GALLIC ACID, AN INTERMEDIATE PRODUCT OF TRIMETHOPRIM, A BROAD SPECTRUM ANTIBOITIC

    Directory of Open Access Journals (Sweden)

    C. AYYANNA

    2006-01-01

    Full Text Available A method for producing Gallic acid by microbiological hydrolysis of the tannins of tripods powder is described in the present work. Hydrolysis of gallotanins of the substrate to Gallic acid by aspergilus niger MTCC 282 was studied. A simple extraction procedure is used. Fungal mycelia pre-induced with 5 g/l gallotanin was used as inocolums. Optimal values for various physico-chemical parameters including substrate concentration, inocolum levels, pH, temperature, fermentation, inocolum age, agitatioin, gallotanin concentration nultritional source and metal ion were determined. The yield of Gallic acide with respect to gallotannins present in the substrate is estimated. Yield of Gallic acid are about 82% with respect to gallotannin concentration, which suggests that this method ix exploitable industrially for manufacturing Trimethoprim drug.Currnet total requirment of Gallic acid is around 8,000 tones per year all over the world. Conventionally Gallic acid is being produced by acid hydrolysis of tannin rich source. But this technology has serval disadvantages regarding cost, yield and purity of the product. This technology alos causes a lot of environmental pollution being a chemical process. The present technique of conversion of teri tannins to Gallic acid using fungal mycelia viz, aspergillus niger MTCC 282, being purely a bioconversion is free from pollution with more purity of product.

  20. 生酮饮食联合抗癫痫药物对难治性癫痫的疗效评价%Evaluation of curative effect of Ketogenic diet combined with antiepileptic drugs on refractory epilepsy

    Institute of Scientific and Technical Information of China (English)

    吴春风; 金波; 卢孝鹏; 梁超

    2016-01-01

    目的:评价生酮饮食( KD)联合抗癫痫药物对难治性癫痫的疗效。方法对77例难治性癫痫患者在原有药物不变的基础上添加KD治疗3个月。观察癫痫临床发作频率的改变,判断疗效。比较有效组和无效组患者的临床资料,分析影响KD疗效的因素。结果在KD治疗后,完全控制16例(20.8%),显著有效14例(18.2%),有效12例(15.6%),无效35例(45.5%);KD添加治疗的总有效率为54.5%,保留率为76.6%。 KD添加治疗无效组合用药物种类、智能障碍比例及睡眠障碍比例均明显高于有效组;而痉挛发作比例则明显低于有效组(均P<0.05)。结论 KD联合抗癫痫药物治疗难治性癫痫总体有效,尤其是痉挛发作类;对伴有智能障碍、睡眠障碍及合用药物种类偏多者疗效欠佳。%Objective To evaluate the curative effect of Ketogenic diet ( KD) combined with antiepileptic drugs on refractory epilepsy ( RE) .Methods Seventy-seven RE patients were treated with KD and antiepileptic drugs for 3 months.The changes of clinical epilepsy seizure frequency were observed, and judged the curative effect.The clinical data of patients with effective group and invalid group were compared, and the influence factors of curative effect were analyzed.Results After the KD therapy, there were 16 cases (20.8%) with complete control, 14 cases (18.2%) with significantly effective, 12 cases ( 15.6%) with effective, 35 cases ( 45.5%) with invalid; the effective rate was 54.5%and the retention rate was 76.6%.The number of combined drugs and the rates of mental retardation and sleep disorders in invalid group were significantly higher than effective group, but the rate of spasms was significantly lower than effective group ( all P<0.05 ) .Conclusions KD combined with antiepileptic drugs is effective for RE patients, especially for spasm type.The curative effect is not very good for patients

  1. 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

  2. Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation.

    Science.gov (United States)

    Lewin, Matthew; Samuel, Stephen; Merkel, Janie; Bickler, Philip

    2016-08-25

    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.

  3. Broad spectrum β-lactam resistance in faecal Escherichia coli isolated from severely malnourished and nourished children attending Mbagathi district hospital, Nairobi: A case-control study

    Directory of Open Access Journals (Sweden)

    Samuel Mwangi Njoroge

    2014-01-01

    Full Text Available Context: Severely malnourished children have increased risk of being put on antibiotics due to co-morbidities. Aim: The study′s objective was to characterize the Escherichia coli β-lactamase mediated resistance to the broad spectrum β-lactam antimicrobials among this population and compare them with nourished children as controls. Settings and Design: In this case-control, hospital-based setup, 109 E. coli isolates were obtained from each group, one isolate per subject. Materials and Methods: Stool or anal swabs were collected, enriched in buffered peptone water and cultured on MacConkey and eosin methylene blue agars. Biochemical test were used to identify E. coli. antibiograms to determine phenotypic resistance were determined using a panel of 14 drugs. Only the isolates showing synergy between ampicillin-calvulanic acid and one or more third generation cephalosporins were picked as extended spectrum β-lactamase (ESBL producers. Statistical Analysis: Differences in ESBL rates and susceptibility percentages between cases and controls were evaluated for significance using 2-tailed Fisher′s exact test. Results: Prevalence of ESBL phenotype was higher in severely malnourished children (39% as compared to the controls (7%. The plasmid-encoded AmpC′s (pAmpC-like phenotype was observed in 11% isolates. Conclusions: Isolation of ESBL-E. coli among severely malnourished children is high. Surveillance of ESBL producers, both in the community and hospital settings needs to be stepped up in Kenya.

  4. Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation

    Science.gov (United States)

    Lewin, Matthew; Samuel, Stephen; Merkel, Janie; Bickler, Philip

    2016-01-01

    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. PMID:27571102

  5. 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.

  6. 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.

  7. Mussel-inspired synthesis of polydopamine-functionalized graphene oxide hydrogel as broad-spectrum antimicrobial material

    Science.gov (United States)

    Wang, Xinpeng; Liu, Zhiming; Zhong, Huiqing; Guo, Zhouyi; Yuan, Xiaochan

    2014-09-01

    Recently, three-dimensional GO-based hydrogels have attracted great attention due to the unique advantages. It is generally know that bacteria are everywhere and many of them could cause the diseases and threaten human health. However, developing new antibacterial materials with high-efficiency, low cost, broad-spectrum, and easy recycling is still a great challenge. Herein, inspired by mussel, we synthesized benzalkonium bromide/polydopamine/reduced graphene oxide hydrogel (BKB/PDA/rGOG). The as-prepared three-dimensional hydrogels were characterized by scanning eletron microscope (SEM), Fourier transform infrared spectroscopy (FT-IR) and Raman spectroscopy. The resultant hydrogels exhibited strong antibacterial effects to both Gram-negative and Gram-positive bacteria due to the synergistic effect of graphene oxide and benzalkonium bromide. In addition, the resultant hydrogels could be removed easily from the resolution, which was undoubtedly good news for industry application.

  8. A Strategy for Generating a Broad-Spectrum Monoclonal Antibody and Soluble Single-Chain Variable Fragments against Plant Potyviruses.

    Science.gov (United States)

    Liu, Han-Lin; Lin, Wei-Fang; Hu, Wen-Chi; Lee, Yung-An; Chang, Ya-Chun

    2015-10-01

    Potyviruses are major pathogens that often cause mixed infection in calla lilies. To reduce the time and cost of virus indexing, a detection method for the simultaneous targeting of multiple potyviruses was developed by generating a broad-spectrum monoclonal antibody (MAb) for detecting the greatest possible number of potyviruses. The conserved 121-amino-acid core regions of the capsid proteins of Dasheen mosaic potyvirus (DsMV), Konjak mosaic potyvirus (KoMV), and Zantedeschia mild mosaic potyvirus (ZaMMV) were sequentially concatenated and expressed as a recombinant protein for immunization. After hybridoma cell fusion and selection, one stable cell line that secreted a group-specific antibody, named C4 MAb, was selected. In the reaction spectrum test, the C4 MAb detected at least 14 potyviruses by indirect enzyme-linked immunosorbent assay (I-ELISA) and Western blot analysis. Furthermore, the variable regions of the heavy (VH) and light (VL) chains of the C4 MAb were separately cloned and constructed as single-chain variable fragments (scFvs) for expression in Escherichia coli. Moreover, the pectate lyase E (PelE) signal peptide of Erwinia chrysanthemi S3-1 was added to promote the secretion of C4 scFvs into the medium. According to Western blot analysis and I-ELISA, the soluble C4 scFv (VL-VH) fragment showed a binding specificity similar to that of the C4 MAb. Our results demonstrate that a recombinant protein derived from fusion of the conserved regions of viral proteins has the potential to produce a broad-spectrum MAb against a large group of viruses and that the PelE signal peptide can improve the secretion of scFvs in E. coli.

  9. 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

  10. Estabilishment of antiepileptic drug resistant model and its P-gp expression in rats%抗癫(癎)药耐药性鼠模型的建立及其P-gp的表达

    Institute of Scientific and Technical Information of China (English)

    刘晓英; 伍国锋; 郝勇; 陈文珍; 洪震

    2011-01-01

    Objective;To establish the antiepileptic drug-resistan model and to observe the expression of P-glycoprotein(P-gp)in rats. Methods.- The epileptic rat model were first with lithium chloride-pi-locarpine to induce epilepsy in rats. Then the antiepileptic drug resistant model were screened out with phenytoin from established rat models. RT-PCR, Western Blot and immunohistochemical staining was carried out to present expression of P-gp in different loci of the rat brains. Results; It was identified by clinical scoring and EEG that the pbarmaoresistantKor refractory) epilepstic models were successfully established with this method. The P-gp expressions in the hipocampus, cerebellum and cortex were all higher in refractory epileptic rats than those in the normal and non-refractory rats. Conclusions: Lithium-pilocarpine and drug-screening can be used to produce the refractory epilepsy models. The expression of P-gp in refractory epilepsy model rats is heightened significantly.%目的:建立抗癫(癎)药(AED)耐药性大鼠模型,并观察其P-糖蛋白(P-gp)的表达.方法:首先应用氯化锂-匹罗卡品诱导癫(癎)鼠模型,然后在此基础上进一步用苯妥英钠药物筛选的方法获得AED的耐药性大鼠模型.通过RT-PCR、蛋白印迹法(Western Blot)和免疫组化等方法研究P-gp在该动物模型脑内不同部位的表达.结果:应用氯化锂-匹罗卡品诱导的癫(癎)鼠模型进行药物筛选的方法成功获得了AED耐药性癫(癎)动物模型,并经临床评分和脑电图证实.耐药性癫痫(癎)模型大鼠海马、小脑及大脑皮层的P-gp表达水平均显著高于非耐药性癫(癎)大鼠及正常对照大鼠.结论:对氯化锂-匹罗卡品诱导的鼠模型进行药物筛选的方法可建立AED耐药性癫(癎)动物模型;P-gp 在AED耐药性癫(癎)大鼠脑内表达水平显著升高.

  11. 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 epilepti

  12. Antimicrobial activity of selected Iranian medicinal plants against a broad spectrum of pathogenic and drug multiresistant micro-organisms.

    Science.gov (United States)

    Abedini, A; Roumy, V; Mahieux, S; Gohari, A; Farimani, M M; Rivière, C; Samaillie, J; Sahpaz, S; Bailleul, F; Neut, C; Hennebelle, T

    2014-10-01

    The antimicrobial activities of 44 methanolic extracts from different parts of Iranian indigenous plant species used in traditional medicines of Iran were tested against a panel of 35 pathogenic and multiresistant bacteria and 1 yeast. The antimicrobial efficacy was determined using Müller-Hinton agar in Petri dishes seeded by a multiple inoculator and minimal inhibition concentration (MIC) method. The 21 most active extracts (MIC micro-organisms) were submitted to a more refined measurement. The best antibacterial activity was obtained by 10 plants. Microdilution assays allowed to determinate the MIC and MBC of the 21 most active extracts. The lowest achieved MIC value was 78 μg ml(-1), with 4 extracts. This work confirms the antimicrobial activity of assayed plants and suggests further examination to identify the chemical structure of their antimicrobial compounds. Significance and impact of the study: This study describes the antimicrobial screening of Iranian plant extracts chosen according to traditional practice against 36 microbial strains, from reference culture collections or recent clinical isolates, and enables to select 4 candidates for further chemical characterization and biological assessment: Dorema ammoniacum, Ferula assa-foetida, Ferulago contracta (seeds) and Perovskia abrotanoides (aerial parts). This may be useful in the development of potential antimicrobial agents, from easily harvested and highly sustainable plant parts. Moreover, the weak extent of cross-resistance between plant extracts and antibiotics warrants further research and may promote a strategy based on less potent but time-trained products.

  13. 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

  14. 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.

  15. ICF syndrome mutations cause a broad spectrum of biochemical defects in DNMT3B-mediated de novo DNA methylation.

    Science.gov (United States)

    Moarefi, Amir H; Chédin, Frédéric

    2011-06-24

    The DNMT3B de novo DNA methyltransferase (DNMT) plays a major role in establishing DNA methylation patterns in early mammalian development, but its catalytic mechanism remains poorly characterized. Here, we provide a comprehensive biochemical analysis of human DNMT3B function through the characterization of a series of site-directed DNMT3B variants associated with immunodeficiency, centromere instability, and facial anomalies (ICF) syndrome. Our data reveal several novel and important aspects of DNMT3B function. First, DNMT3B, unlike DNMT3A, requires a DNA cofactor in order to stably bind to S-adenosyl-l-methionine (SAM), suggesting that it proceeds according to an ordered catalytic scheme. Second, ICF mutations cause a broad spectrum of biochemical defects in DNMT3B function, including defects in homo-oligomerization, SAM binding, SAM utilization, and DNA binding. Third, all tested ICF mutations, including the A766P and R840Q variants, result in altered catalytic properties without interfering with DNMT3L-mediated stimulation; this indicates that DNMT3L is not involved in the pathogenesis of ICF syndrome. Finally, our study reveals a novel level of coupling between substrate binding, oligomerization, and catalysis that is likely conserved within the DNMT3 family of enzymes.

  16. 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

    2015-01-01

    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.

  17. Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas.

    Science.gov (United States)

    Wood, Laura D; Noë, Michaël; Hackeng, Wenzel; Brosens, Lodewijk A A; Bhaijee, Feriyl; Debeljak, Marija; Yu, Jun; Suenaga, Masaya; Singhi, Aatur D; Zaheer, Atif; Boyce, Alison; Robinson, Cemre; Eshleman, James R; Goggins, Michael G; Hruban, Ralph H; Collins, Michael T; Lennon, Anne Marie; Montgomery, Elizabeth A

    2017-02-10

    McCune-Albright Syndrome (MAS) is a rare sporadic syndrome caused by post-zygotic mutations in the GNAS oncogene, leading to constitutional mosaicism for these alterations. Somatic activating GNAS mutations also commonly occur in several gastrointestinal and pancreatic neoplasms, but the spectrum of abnormalities in these organs in patients with MAS has yet to be systematically described. We report comprehensive characterization of the upper gastrointestinal tract in seven patients with MAS and identify several different types of polyps, including gastric heterotopia/metaplasia (7/7), gastric hyperplastic polyps (5/7), fundic gland polyps (2/7), and a hamartomatous polyp (1/7). In addition, one patient had an unusual adenomatous lesion at the gastroesophageal junction with high-grade dysplasia. In the pancreas, all patients had endoscopic ultrasound findings suggestive of intraductal papillary mucinous neoplasm (IPMN), but only two patients met the criteria for surgical intervention. Both of these patients had IPMNs at resection, one with low-grade dysplasia and one with high-grade dysplasia. GNAS mutations were identified in the majority of lesions analyzed, including both IPMNs and the adenomatous lesion from the gastroesophageal junction. These studies suggest that there is a broad spectrum of abnormalities in the gastrointestinal tract and pancreas in patients with MAS and that patients with MAS should be evaluated for gastrointestinal pathology, some of which may warrant clinical intervention due to advanced dysplasia.

  18. Expression and post-translational processing of a broad-spectrum organophosphorus-neurotoxin-degrading enzyme in insect tissue culture

    Energy Technology Data Exchange (ETDEWEB)

    Dave, K.I.; Phillips, L.; Luckow, V.A.; Wild, J.R.

    1994-12-31

    A recombinant baculovirus, Autographa californica nuclear polyhedrosis virus (AcNPV), has been utilized to express the opd (organophosphate-degrading) gene from Pseudomonas diminuta in insect tissue-culture cells (Sf9) of the fall armyworm (Spodoptera frugiperda). The broad-spectrum organophosphate hydrolase (EC 3.1.8.1) encoded by this gene is a member of a general class of enzymes (organophosphate (OP) anhyorolases) that include parathion hydrolases, di-isopropyl-fluorophosphatases (DFpases), somanases, and OP phosphotrlesterases. This particular enzyme possesses the ability to hydrolyse paraoxon (P-O bond), DFP, sarin (P-F bond), VX (P-S bond) and tabun (P-CN bond), as well as a number of other extensively used organophosphorus pesticides. The enzyme produced in infected Sf9 cells is post-translationally processed and resembles the mature form of the enzyme expressed in various bacterial cells as identified by immunoprecipitation on Western blots. N-terminal sequence analysis of enzyme expressed in insect cells revealed Gly-29 as the terminal residue, whereas expression in Escherichia coli removes this residue, exposing Ser-30 at the N-terminus. Conditions for optimal expression of the enzyme in this system are described. Furthermore, hydrolytic efficiency of some OPs with purified enzyme from this system is discussed in relation to the in situ activity of Pseudomonas diminuta MG cells.

  19. 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.

  20. 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

  1. 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.

  2. A highly sensitive, multiplex broad-spectrum PCR-DNA-enzyme immunoassay and reverse hybridization assay for rapid detection and identification of Chlamydia trachomatis serovars.

    NARCIS (Netherlands)

    Quint, K.D.; Doorn, L.J. van; Kleter, B.; Koning, M.N. de; Munckhof, H.A. van den; Morre, S.A.; Harmsel, B. ter; Weiderpass, E.; Harbers, G.; Melchers, W.J.G.; Quint, W.G.V.

    2007-01-01

    Chlamydia trachomatis (Ct) comprises distinct serogroups and serovars. The present study evaluates a novel Ct amplification, detection, and genotyping method (Ct-DT assay). The Ct-DT amplification step is a multiplex broad-spectrum PCR for the cryptic plasmid and the VD2-region of ompl. The Ct-DT de

  3. 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.

  4. Broad spectrum late blight resistance in potato differential set plants MaR8 and MaR9 is conferred by multiple stacked R genes

    NARCIS (Netherlands)

    Kim, H.I.; Lee, H.; Jo, K.R.; Mortazavian, S.M.M.; Huigen, D.J.; Evenhuis, A.; Kessel, G.J.T.; Visser, R.G.F.; Vossen, J.H.; Jacobsen, E.

    2012-01-01

    Phytophthora infestans is the causal agent of late blight in potato. The Mexican species Solanum demissum is well known as a good resistance source. Among the 11 R gene differentials, which were introgressed from S. demissum, especially R8 and R9 differentials showed broad spectrum resistance both u

  5. 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...

  6. 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,

  7. 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 phytopat

  8. 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.

  9. 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.

  10. A genetically modified broad-spectrum strain of Bacillus thuringiensis toxic against Holotrichia parallela, Anomala corpulenta and Holotrichia oblita.

    Science.gov (United States)

    Jia, Yanhua; Zhao, Can; Wang, Qinglei; Shu, Changlong; Feng, Xiaojie; Song, Fuping; Zhang, Jie

    2014-02-01

    Cry8Ea1 from Bacillus thuringiensis strain Bt185 has insecticidal activity against Holotrichia parallela. Cry8Ca2 from strain HBF-1 is effective against Anomala corpulenta. Cry8Ga1 from strain HBF-18 is toxic to H. oblita. Given the need to broaden the spectrum of B. thuringiensis, a broad-spectrum coleopteran active strain of B. thuringiensis, BIOT185, engineered to express multiple cry genes, including cry8Ea1, cry8Fa1 and cry8Ca2, was created by homologous recombination introducing the cry8Ca2 into the B. thuringiensis strain Bt185 by Liu et al. (Appl Microbiol Biotechnol 87:243-249, 2010). To further broaden the spectrum, an engineered B. thuringiensis strain BIOT1858G was constructed by introducing the recombinant plasmid pSTK-8G containing cry8Ga1 into the engineered B. thuringiensis strain BIOT185. PCR and Southern blotting demonstrated that the cry8Ga1 gene was transferred to the novel strain BIOT1858G. SDS-PAGE and RT-PCR confirmed the normal expression and transcription of the cry8Ga1 gene in addition to the cry8Ea1, cry8Fa1 and cry8Ca2 genes. Bioassays of BIOT1858G indicated that the recombinant strain broadened the spectrum against not only H. parallela susceptible to the Cry8E protein and A. corpulenta susceptible to the Cry8C protein but also H. oblita susceptible to the Cry8G protein. The pesticide could also decrease the cost of production and field labor.

  11. The CD8-derived chemokine XCL1/lymphotactin is a conformation-dependent, broad-spectrum inhibitor of HIV-1.

    Directory of Open Access Journals (Sweden)

    Christina Guzzo

    Full Text Available CD8+ T cells play a key role in the in vivo control of HIV-1 replication via their cytolytic activity as well as their ability to secrete non-lytic soluble suppressive factors. Although the chemokines that naturally bind CCR5 (CCL3/MIP-1α, CCL4/MIP- 1β, CCL5/RANTES are major components of the CD8-derived anti-HIV activity, evidence indicates the existence of additional, still undefined, CD8-derived HIV-suppressive factors. Here, we report the characterization of a novel anti-HIV chemokine, XCL1/lymphotactin, a member of the C-chemokine family that is produced primarily by activated CD8+ T cells and behaves as a metamorphic protein, interconverting between two structurally distinct conformations (classic and alternative. We found that XCL1 inhibits a broad spectrum of HIV-1 isolates, irrespective of their coreceptor-usage phenotype. Experiments with stabilized variants of XCL1 demonstrated that HIV-1 inhibition requires access to the alternative, all-β conformation, which interacts with proteoglycans but does not bind/activate the specific XCR1 receptor, while the classic XCL1 conformation is inactive. HIV-1 inhibition by XCL1 was shown to occur at an early stage of infection, via blockade of viral attachment and entry into host cells. Analogous to the recently described anti-HIV effect of the CXC chemokine CXCL4/PF4, XCL1-mediated inhibition is associated with direct interaction of the chemokine with the HIV-1 envelope. These results may open new perspectives for understanding the mechanisms of HIV-1 control and reveal new molecular targets for the design of effective therapeutic and preventive strategies against HIV-1.

  12. Reduced TiO2-Graphene Oxide Heterostructure As Broad Spectrum-Driven Efficient Water-Splitting Photocatalysts.

    Science.gov (United States)

    Li, Lihua; Yu, Lili; Lin, Zhaoyong; Yang, Guowei

    2016-04-06

    The reduced TiO2-graphene oxide heterostructure as an alternative broad spectrum-driven efficient water splitting photocatalyst has become a really interesting topic, however, its syntheses has many flaws, e.g., tedious experimental steps, time-consuming, small scale production, and requirement of various additives, for example, hydrazine hydrate is widely used as reductant to the reduction of graphene oxide, which is high toxicity and easy to cause the second pollution. For these issues, herein, we reported the synthesis of the reduced TiO2-graphene oxide heterostructure by a facile chemical reduction agent-free one-step laser ablation in liquid (LAL) method, which achieves extended optical response range from ultraviolet to visible and composites TiO(2-x) (reduced TiO2) nanoparticle and graphene oxide for promoting charge conducting. 30.64% Ti(3+) content in the reduced TiO2 nanoparticles induces the electronic reconstruction of TiO2, which results in 0.87 eV decrease of the band gap for the visible light absorption. TiO(2-x)-graphene oxide heterostructure achieved drastically increased photocatalytic H2 production rate, up to 23 times with respect to the blank experiment. Furthermore, a maximum H2 production rate was measured to be 16 mmol/h/g using Pt as a cocatalyst under the simulated sunlight irradiation (AM 1.5G, 135 mW/cm(2)), the quantum efficiencies were measured to be 5.15% for wavelength λ = 365 ± 10 nm and 1.84% for λ = 405 ± 10 nm, and overall solar energy conversion efficiency was measured to be 14.3%. These findings provided new insights into the broad applicability of this methodology for accessing fascinate photocatalysts.

  13. The Teratogenic Risk of the Antiepileptic Drugs on Fetus of the Pregnant Women with Epilepsy%抗癫(痫)药物对妊娠癫(痫)患者子代的致畸风险

    Institute of Scientific and Technical Information of China (English)

    赵瑞; 康晓刚; 景芸芸; 江文

    2012-01-01

    Aim: To assess the teratogenic risk of the antiepilcptic drugs on fetus of pregnant women with epilepsy. Methods: A prospective, registering, follow-up study was used to analyze the medication, epileptic attack, fetal health status and pregnancy outcome of early pregnant women with epilepsy. Results: 105 cases were studied. 79 cases (75.2%) took antiepileptic drugs. 26 cases (24.8%) didn' t take AEDs prior to pregnancy. 60 cases (75.9%) were exposed to anti-epileptic drug monotherapy during pregnancy, with one case (1.7%) of abortion. Of the patients exposed to AEDs monotherapy, there were 2 cases (3.3%) whose children had congenital malformations. Of the 19 cases (24.1%) exposed to AEDs polytherapy, there was no case whose child appearing congenital malformations. Of the cases that didn't take AEDs, there were 2 cases of abortion, There was no case whose child appearing congenital malformations. Conclusion: The majority of women suffering from epilepsy was treated with AEDs monotherapy rather than polytherapy during pregnancy. There were 2 cases with congenital malformations, whose mothers were exposed to AED monotherapy (1 case carbamazepine, 1 case lamotrigine). Though valproate was now still used in pregnant women with epilepsy despite of its teratogenicity, there was no case whose child appearing congenital malformations.%目的:旨在评估抗癫(痫)药物(AEDs)对妊娠癫(痫)患者子代出现先天畸形的风险.方法:对妊娠癫(痫)患者采用登记和随访研究,分析其孕期AEDs用药情况、癫(痫)发作、妊娠结局及子代出现畸形的风险.结果:入选105例妊娠癫(痫)患者.服用AEDs患者79/105例(75.2%),未服用AEDs患者26/105例(24.8%).单药治疗60/79例(75.9%),其中1/60例(1.7%)流产;患者子代中2/60例(3.3%)先天性畸形(1例服用卡马西平,出现先天性心脏动脉导管未闭;1例服用拉莫三嗪,出现无胚心).联合用药19/79例(24.1%),子代无先天畸

  14. Study of factors responsible for recurrence of seizures in controlled epileptics for more than 1 years after withdrawal of antiepileptic drugs.

    Directory of Open Access Journals (Sweden)

    Lamdhade S

    2002-07-01

    Full Text Available 531 epileptic patients, who had achieved remission mostly for 2 years or more were studied. The mean follow up period was 5 years. Recurrence was noted in 103 patients (19% after gradual withdrawal of AED, over a period of 3-4 months. 424 patients (81% did not have recurrence. The recurrence rate was influenced adversely by factors like adolescent age and later onset seizures, pre-treatment duration of symptoms more than 3 years, pre-treatment precipitating factors like emotional stress, lack of sleep and meals (however, number in each group is small, positive family history of epilepsy, focal neurodeficit, absence and myoclonic plus grandmal type of clinical seizures, paroxysmal generalized spike and wave discharges and generalized short polyspike and wave discharges in the pretreatment EEG, atrophic changes on CT brain scan (in small numbers, head trauma at birth or later and hereditary factors as etiology of epilepsy, and more than 30 number of seizures before achieving the remission. Factors like, sex, frequency of seizures, period of remission i.e. two years or more and number of drugs used to achieve remission, did not have any significant adverse effect. However, in the last parameter 95% remission was achieved by one or a combination of two drugs (72% and 23% respectively.

  15. Trends in the use of antiepileptic drugs (AEDs) among pregnant women in the U.S., 2001-2007: a Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) study

    Science.gov (United States)

    Bobo, William V.; Davis, Robert L.; Toh, Sengwee D.; Li, De-Kun; Andrade, Susan E.; Cheetham, T. Craig; Pawloski, Pamala; Dublin, Sascha; Pinheiro, Simone; Hammad, Tarek; Scott, Pamela E.; Epstein, Richard A.; Arbogast, Patrick G.; Morrow, James A.; Dudley, Judith A.; Lawrence, Jean M.; Avalos, Lyndsay A.; Cooper, William O.

    2012-01-01

    Background Little is known about the extent of antiepileptic drug (AED) use in pregnancy, particularly for newer agents. Our objective was to assess whether AED use has increased among pregnant women in the U.S., 2001-2007. Methods We analyzed data from the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) database, 1 January 2001 to 31 December 2007. We identified live-born deliveries among women, aged 15-45 years on delivery date, who were members of MEPREP health plans (N = 585,615 deliveries). Pregnancy exposure to AEDs, determined through outpatient pharmacy dispensing files. Older AEDs were available for clinical use before 1993; other agents were considered newer AEDs. Information on sociodemographic and medical/reproductive factors was obtained from linked birth certificate files. Maternal diagnoses were identified based on ICD-9 codes. Results Prevalence of AED use during pregnancy increased between 2001 (15.7 per 1,000 deliveries) and 2007 (21.9 per 1,000 deliveries), driven primarily by a five-fold increase in the use of newer AEDs. Thirteen percent of AED-exposed deliveries involved a combination of two or more AEDs. Psychiatric disorders were the most prevalent diagnoses, followed by epileptic and pain disorders, among AED users regardless of AED type, year of conception or gestational period. Conclusions AED use during pregnancy increased between 2001 and 2007, driven by a five-fold increase in the use of newer AEDs. Nearly one in eight AED-exposed deliveries involved the concomitant use of more than one AED. Additional investigations of the reproductive safety of newer AEDs may be needed. PMID:23061694

  16. Mechanistic and conformational studies on the interaction of a platinum(II) complex containing an antiepileptic drug, levetiracetam, with bovine serum albumin by optical spectroscopic techniques in aqueous solution.

    Science.gov (United States)

    Shahabadi, Nahid; Hadidi, Saba

    2015-02-01

    Fluorescence spectroscopy in combination with circular dichroism (CD) and ultraviolet-visible (UV-vis) absorption spectroscopy were employed to investigate the binding of a new platinum(II) complex containing an antiepileptic drug "Levetiracetam" to bovine serum albumin (BSA) under the physiological conditions. In the mechanism discussion, it was proved that the fluorescence quenching of BSA by Pt(II) complex is a result of the formation of Pt(II) complex-BSA complex. The thermodynamic parameters ΔG, ΔH, and ΔS at different temperatures (283, 298, and 310 K) were calculated, and the negative value for ΔH and ΔS indicate that the hydrogen bonds and van der Waals interactions play major roles in Pt(II) complex-BSA association. Binding studies concerning the number of binding sites (n~1) and apparent binding constant K b were performed by fluorescence quenching method. The site marker competitive experiments indicated that the binding of Pt(II) complex to BSA primarily took place in site II. Based on the Förster's theory, the average binding distance between Pt(II) complex and BSA was obtained (r = 5.29 nm). Furthermore, UV-vis, CD, and synchronous fluorescence spectrum were used to investigate the structural change of BSA molecules with addition of Pt(II) complex. These results indicate that the binding of Pt(II) complex to BSA causes apparent change in the secondary structure of BSA and do affect the microenvironment around the tryptophan residue.

  17. Newly isolated Paenibacillus tyrfis sp. nov., from Malaysian tropical peat swamp soil with broad spectrum antimicrobial activity

    Directory of Open Access Journals (Sweden)

    Yoong Kit eAw

    2016-03-01

    Full Text Available Emergence of antimicrobial resistance coupled with the slowdown in discovery of new antimicrobial compounds points to serious consequences in human health. Therefore, scientists are looking for new antimicrobial compounds from unique and understudied ecosystem such as tropical peat swamp forests. Over the course of isolating antimicrobial producing bacteria from North Selangor tropical peat swamp forest, Malaysia, a Gram variable, rod shaped, endospore forming, facultative anaerobic novel strain MSt1T that exerts potent and broad spectrum antimicrobial activity was isolated. Phylogenetic analysis using 16S rRNA gene sequences showed that strain MSt1T belonged to the genus Paenibacillus with the highest similarity with Paenibacillus elgii SD17T (99.5%. Whole genome comparison between strain MSt1T with its closely related species using average nucleotide identity (ANI revealed that similarity between strain MSt1T with Paenibacillus elgii B69 (93.45% and Paenibacillus ehimensis A2 (90.42% was below the recommended threshold of 95%. Further analysis using in silico pairwise DDH also showed that similarity between strain MSt1T with P. elgii B69 (55.4% and P. ehimensis A2 (43.7% was below the recommended threshold of 70%. Strain MSt1T contained meso-diaminopilemic acid in the cell wall and MK-7 as the major menaquinone. The major fatty acids of strain MSt1T were anteiso-C15:0 (48.2% and C16:0 (29.0% whereas the polar lipid profile consisted of phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, one unknown lipid, two unknown glycolipids and one unknown phospholipid. Total DNA G+C content of strain MSt1T was 51.5 mol%. Extract from strain MSt1T exerted strong antimicrobial activity against Escherichia coli ATCC 25922 (MIC = 1.5 µg/mL, MRSA ATCC 700699 (MIC = 25 µg/mL and Candida albicans IMR (MIC = 12.5 µg/mL. Partially purified active fraction exerted strong effect against Escherichia coli ATCC 25922 resulting in cell rupture

  18. Antimicrobial activity of cathelicidins BMAP28, SMAP28, SMAP29, and PMAP23 against Pasteurella multocida is more broad-spectrum than host species specific.

    Science.gov (United States)

    Brogden, Kim A; Nordholm, Gwen; Ackermann, Mark

    2007-01-17

    The antimicrobial activity of linear, cationic alpha-helical peptides from cattle (BMAP28), sheep (SMAP28 and SMAP29), and pigs (PMAP23) were assessed to determine if activity was selective for Pasteurella multocida from a particular animal species or broad-spectrum against all P. multocida tested. The antimicrobial activities of synthetic peptides were determined for P. multocida isolated from cattle (10 isolates), sheep (10 isolates), and pigs (10 isolates) in a broth microdilution assay. All thirty isolates of P. multocida were susceptible to BMAP28 (MICs and MBCs, 1.0-1.9 microM); SMAP28 and SMAP29 (MICs and MBCs, 0.2-0.7 microM); and PMAP23 (MICs and MBCs, 4.3 to > or = 6.8 microM). Overall, the results of this study suggest that synthesized cathelicidins from cattle, sheep, and pigs had broad-spectrum antimicrobial activity against all P. multocida.

  19. Rice RING protein OSBBI1 with E3 ligase activity confers broad-spectrum resistance against Magnaporthe oryzae by modifying the cell wall defence

    Institute of Scientific and Technical Information of China (English)

    Wei Li; Zuhua He; Sihui Zhong; Guojun Li; Qun Li; Bizeng Mao; Yiwen Deng; Huijuan Zhang; Longjun Zeng; Fengming Song

    2011-01-01

    Emerging evidence suggests that E3 ligases play critical roles in diverse biological processes, including innate immune responses in plants. However, the mechanism of the E3 ligase involvement in plant innate immunity is unclear.We report that a rice gene, OsBBI1, encoding a RING finger protein with E3 ligase activity, mediates broad-spectrum disease resistance. The expression of OSBBI1 was induced by rice blast fungus Magnaporthe oryzae, as well as chemical inducers, benzothiadiazole and salicylic acid. Biochemical analysis revealed that OsBBI1 protein possesses E3ubiquitin ligase activity in vitro. Genetic analysis revealed that the loss of OsBBI1 function in a Tos17-insertion line increased susceptibility, while the overexpression of OsBBI1 in transgenic plants conferred enhanced resistance to multiple races of M.oryzae. This indicates that OsBBI1 modulates broad-spectrum resistance against the blast fungus. The OsBBII-overexpressing plants showed higher levels of H,O, accumulation in cells and higher levels of phenolic compounds and cross-linking of proteins in cell walls at infection sites by M. Oryzae compared with wild-type(WT)plants. The cell walls were thicker in the OsBB11-overexpressing plants and thinner in the mutant plants than in the WT plants. Our results suggest that OsBBH modulates broad-spectrum resistance to blast fungus by modifying cell wall defence responses. The functional characterization of OsBBI1 provides insight into the E3 ligase-mediated innate immunity, and a practical tool for constructing broad-spectrum resistance against the most destructive disease in rice.

  20. 关于广谱哲学的交叉性学科特点%The Features of Interdiscipline of Broad-spectrum Philosophy

    Institute of Scientific and Technical Information of China (English)

    苏淼

    2016-01-01

    Broad-spectrum philosophy is a new type of philosophy, which inosculates Marxist philosophy, system science and modern mathematics as a whole, with a laterally interdisciplinary characteristic. It has the important theoretical significance to study laterally interdisciplinary mechanism, functions and characteristics of broad-spectrum philosophy, because it can help to understand the broad-spectrum philosophy and understand the nature of common lateral interdiscipline.%广谱哲学是融马克思主义哲学、系统科学和现代数学为一体的新型哲学门派,具有跨领域性、跨学科性的横断交叉学科的特点。研究广谱哲学横断交叉的机制、作用和特点,对于人们了解广谱哲学,了解一般的横断交叉学科的性质,具有重要的理论意义。

  1. CLINICAL USE OF ANTIEPILEPTIC DRUGS IN THE MANAGEMENT OF CHRONIC PAIN%抗癫痫药物治疗神经病理性疼痛的对照研究

    Institute of Scientific and Technical Information of China (English)

    赵序利; 许永广; 宋文阁; 傅志俭

    2012-01-01

    目的:回顾性分析卡马西平和加巴喷丁治疗原发性三叉神经痛、带状疱疹以及带状疱疹后遗神经痛的疗效、安全性和不良反应.方法:102位患者进入本研究,比较卡马西平或加巴喷丁治疗前后患者疼痛强度的改变和对睡眠影响的改善;依据药物分类,比较两种药物的副作用和不良反应.结果:卡马西平治疗原发性三叉神经痛起效较加巴喷丁快,二者长期疗效相当;加巴喷丁治疗带状疱疹和带状疱疹后神经痛的疗效优于卡马西平;疗效随治疗时间的延长而增加.卡马西平的副作用和不良反应事件发生率较加巴喷丁高.结论:抗癫痫药物卡马西平和加巴喷丁是治疗神经病理性疼痛的有效药物,可以改善患者的睡眠,但副作用和不良反应发生率高.%Objective: To evaluate the effects, safety and adverse effects of carbamazepine and gabapentin in the treatment of primary trigeminal neuralgia, herpes zoster neuralgia and postherpetic neuralgia. Methods: A total of 102 patients who suffered from primary trigeminal neuralgia, herpes zoster neuralgia and postherpetic neuralgia were assessed with changes in pain and sleep interference improvement after treatment with carbamazepine or gabapentin. The adverse events were evaluated and calculated between the carbamazepine and gabapentin. Results: Both carbamazepine and gabapentin had the same long term effects on trigeminal neuralgia, but carbamazepine got a rapid analgesia and sleep improvement effect than gabapentin. Gabapentin was more effective than carbamazepine in controlling pain and in improving sleep interference caused by herpes zoster and postherpetic neuralgia. The therapeutic effects was continually improved over time. Carbamazepine caused more adverse events than gabapentin. Conclusion: Antiepileptic drugs were effective in controlling neuropathic pain, and improved patient's sleep interference caused by pain. But they had a high risk in causing

  2. Effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline on the protective action of various antiepileptic drugs in the maximal electroshock-induced seizure model: a type II isobolographic analysis.

    Science.gov (United States)

    Andres-Mach, Marta; Zadrożniak, Anna; Haratym-Maj, Agnieszka; Florek-Luszczki, Magdalena; Raszewski, Grzegorz; Antkiewicz-Michaluk, Lucyna; Luszczki, Jarogniew J

    2013-12-01

    The aim of this study was to characterize the interaction between 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTHIQ-an endogenous parkinsonism-preventing substance) and various antiepileptic drugs [AEDs: clonazepam (CZP), ethosuximide (ETS), gabapentin (GBP), levetiracetam (LEV), tiagabine (TGB) and vigabatrin (VGB)] in the mouse maximal electroshock (MES)-induced seizure model. Results indicate that 1-MeTHIQ in combination with CZP (at the fixed ratios of 50:1 and 25:1), ETS (1:10) and GBP (1:1, 1:2, 1:5 and 1:10) exerted supra-additive (synergistic) interactions in the mouse MES model. In contrast, 1-MeTHIQ in combination with CZP (200:1 and 100:1), ETS (1:1, 1:2 and 1:5), LEV and VGB (1:1, 1:2, 1:5 and 1:10), and TGB (200:1, 100:1, 50:1 and 25:1) produced additive interaction in the mouse MES model. Total brain AED concentrations were unaffected by 1-MeTHIQ, and inversely, CZP, ETS and GBP had no impact on total brain concentrations of 1-MeTHIQ, indicating pharmacodynamic nature of synergistic interactions between 1-MeTHIQ and the tested AEDs in the mouse MES model. In conclusion, the supra-additive interactions of 1-MeTHIQ with CZP (at the fixed ratios of 50:1 and 25:1), ETS (1:10) and GBP (1:1, 1:2, 1:5 and 1:10) in the mouse MES model appear to be particularly favorable combinations from a clinical viewpoint. The additive combinations of 1-MeTHIQ with CZP (100:1, 50:1), ETS (1:1, 1:2 and 1:5), LEV and VGB (1:1, 1:2, 1:5, and 1:10), and TGB (200:1, 100:1, 50:1 and 25:1) seem to be neutral and worthy of consideration in further clinical practice.

  3. Drug: D07655 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07655 Drug Cefteram (INN); CFTM C16H17N9O5S2 479.0794 479.4935 D07655.gif Antibiotic, cephalosporin... Semisynthetic cephalosporin: broad spectrum cephalosporin penicillin binding proteins inhi

  4. Drug: D07583 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07583 Mixture, Drug Phenytoin - phenobarbital mixt; Aleviatin with phenobarbital (TN) Phenytoin...ystem and sensory organs 11 Agents affecting central nervous system 113 Antiepileptics 1139 Others D07583 Phenytoin...TEM N03 ANTIEPILEPTICS N03A ANTIEPILEPTICS N03AB Hydantoin derivatives N03AB52 Phenytoin..., combinations D07583 Phenytoin - phenobarbital mixt PubChem: 96024446 ...

  5. 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, p<0.001], and were close to significance with respect to control group A (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, p<0.001], and with LTG-cases [(A)OR:147.00, p=0.001;(B)OR:115.00, p<0.001;(C)OR:124.70, p<0.001]. We found the HLA-B*15:02 allele in a 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, p<0.001], and in the LTG-cases [(A),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

  6. 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.

  7. Rufinamide: a new anti-epileptic medication.

    Science.gov (United States)

    Hakimian, Shahin; Cheng-Hakimian, Andrea; Anderson, Gail D; Miller, John W

    2007-08-01

    Rufinamide (1-[2,6-difluorobenzyl]-1H-1,2,3-triazole-4-carboxamide) is a new anti-epileptic drug with a novel triazole derivative structure. The suspected mechanism of action is limitation of sodium-dependent action potentials, thought to result in a membrane stabilizing effect. Rufinamide is extensively metabolized in the liver by non-CYP450 enzymes with an elimination half-life of 8 - 12 h. Three randomized, placebo-controlled trials have shown that rufinamide is effective against partial seizures in adults. Efficacy in the Lennox-Gastaut syndrome, a severe, disabling childhood onset epilepsy syndrome, was shown in a single, randomized, placebo-controlled trial. It has recently been approved for treatment of Lennox-Gastaut syndrome in Europe. In the US it is under regulatory review. Most common adverse effects are somnolence, fatigue, dizziness, dipolopia, nausea and ataxia. Rufinamide has shown promise as adjunctive treatment for Lennox-Gastaut syndrome and may have some role in localization related epilepsies as well.

  8. Identification and Preclinical Evaluation of SC144, a Novel Pyrroloquinoxaline Derivative with Broad-Spectrum Anticancer Activity.

    Science.gov (United States)

    Grande, Fedora; Aiello, Francesca; Garofalo, Antonio; Neamati, Nouri

    2016-01-01

    Design and discovery of new classes of anticancer agents with unique mechanisms of action is an urgent medical need. During the past several years, a series of salicylhydrazide class of compounds were reported to possess remarkable potency in a large panel of cancer cell lines from different tumor origins. In particular, the optimized lead compound, SC144, was further investigated and selected as a valuable drug candidate endowed with favorable pharmacokinetic and antiproliferative properties in various in vitro and in vivo xenograft models. This lead compound is active in cells resistant to conventional chemotherapies, synergistic with several standard-of-care drugs, and possesses an unique mechanism acting through the inhibition of the gp130-STAT3-survivin axis. Because of this novel mechanism, clinical development of SC144 will provide new therapeutic options for diverse cancers.

  9. 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.

  10. 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.

  11. 3C和3CL蛋白酶及广谱抑制剂的研究进展%Broad spectrum inhibitors of 3C and 3CL proteases:research advances

    Institute of Scientific and Technical Information of China (English)

    张启燕; 张文会; 肖军海; 李松

    2016-01-01

    Picornaviruses(PV)and coronaviruses(CoV) are positive-stranded RNA viruses. Pathogens in the family can cause hand,foot and mouth disease,myocarditis, common cold ,severe respiratory and intestinal diseases. 3C and 3CL proteases, belonging to cysteine proteases,are required to process polyproteins into mature proteins for viral replication,which plays an impor⁃tant role in viral replication because substrate binding sites are highly conservative and have similar catalytic mechanism. 3C and 3CL proteases are different from protease in the human body ,which represents a promising anti-viral drug target. Using 3C and 3CL pro⁃teinase structural similarities,broad spectrum protease inhibitors have been found successfully. This review describes recent develop⁃ments of broad spectrum protease inhibitors targeting on 3C and 3CL proteases,and briefly illustrates the mechanism of the inhibitors, which may benefit to the development of virus therapy.%小RNA病毒和冠状病毒属于单正链RNA病毒,其家族中的病原体易导致手足口病、心肌炎、普通感冒以及严重的呼吸道和肠道疾病。3C和3CL蛋白酶都属于半胱氨酸蛋白酶,底物结合位点高度保守且具有相似的催化机制,是催化单正链RNA病毒前体蛋白裂解的关键蛋白酶,对病毒的复制有重要作用。人体中没有与其相似的蛋白酶,是目前广谱抗单正链RNA病毒研究的重要靶点。利用3C和3CL蛋白酶结构的相同点,成功发现了具有广谱作用的蛋白酶抑制剂。本文简要概述3C和3CL蛋白酶的结构、功能和广谱抑制剂的研究进展,并简要阐释抑制剂的作用机制,对该类酶的广谱抑制剂研究和相关病毒的治疗具有指导意义。

  12. 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.

    2013-01-01

    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. PMID:24145401

  13. Development of FGI-106 as a broad-spectrum therapeutic with activity against members of the family Bunyaviridae

    Directory of Open Access Journals (Sweden)

    Darci R Smith

    2010-02-01

    Full Text Available Darci R Smith1, Monica Ogg1, Aura Garrison1, Abdul Yunus2, Anna Honko1, Josh Johnson1, Gene Olinger1, Lisa E Hensley1, Michael S Kinch1United States Army Medical Research Institute of Infectious Diseases (USAMRII D, Fort Detrick, MD, USA; 2Functional Genetics, Inc., Gaithersburg, MD, USAAbstract: The family Bunyaviridae is a diverse group of negative-strand RNA viruses that infect a wide range of arthropod vectors and animal hosts. Based on the continuing need for new therapeutics to treat bunyavirus infections, we evaluated the potential efficacy of FGI-106, a small-molecular compound that previously demonstrated activity against different RNA viruses. FGI-106 displayed substantial antiviral activity in cell-based assays of different bunyavirus family members, including Asian and South American hantaviruses (Hantaan virus and Andes virus, Crimean-Congo hemorrhagic fever virus, La Crosse virus, and Rift Valley fever virus. The pharmacokinetic profile of FGI-106 revealed sufficient exposure of the drug to critical target organs (lung, liver, kidney, and spleen, which are frequently the sites of bunyavirus replication. Consistent with these findings, FGI-106 treatment delivered via intraperitoneal injection prior to virus exposure was sufficient to delay the onset of Rift Valley fever virus infection in mouse-based models and to enhance survival in the face of an otherwise lethal infection. Altogether, these results suggest a potential opportunity for the use of FGI-106 to treat infections by members of the family Bunyaviridae.Keywords: Rift Valley fever virus, bunyavirus, hantavirus, antiviral, therapeutic

  14. Structure activity relationship of C-2 ether substituted 1,5-naphthyridine analogs of oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents (Part-5).

    Science.gov (United States)

    Singh, Sheo B; Kaelin, David E; Meinke, Peter T; Wu, Jin; Miesel, Lynn; Tan, Christopher M; Olsen, David B; Lagrutta, Armando; Fukuda, Hideyuki; Kishii, Ryuta; Takei, Masaya; Takeuchi, Tomoko; Takano, Hisashi; Ohata, Kohei; Kurasaki, Haruaki; Nishimura, Akinori; Shibata, Takeshi; Fukuda, Yasumichi

    2015-09-01

    Oxabicyclooctane linked novel bacterial topoisomerase inhibitors (NBTIs) are new class of recently reported broad-spectrum antibacterial agents. They target bacterial DNA gyrase and topoisomerase IV and bind to a site different than quinolones. They show no cross-resistance to known antibiotics and provide opportunity to combat drug-resistant bacteria. A structure activity relationship of the C-2 substituted ether analogs of 1,5-naphthyridine oxabicyclooctane-linked NBTIs are described. Synthesis and antibacterial activities of a total of 63 analogs have been summarized representing alkyl, cyclo alkyl, fluoro alkyl, hydroxy alkyl, amino alkyl, and carboxyl alkyl ethers. All compounds were tested against three key strains each of Gram-positive and Gram-negative bacteria as well as for hERG binding activities. Many key compounds were also tested for the functional hERG activity. Six compounds were evaluated for efficacy in a murine bacteremia model of Staphylococcus aureus infection. Significant tolerance for the ether substitution (including polar groups such as amino and carboxyl) at C-2 was observed for S. aureus activity however the same was not true for Enterococcus faecium and Gram-negative strains. Reduced clogD generally showed reduced hERG activity and improved in vivo efficacy but was generally associated with decreased overall potency. One of the best compounds was hydroxy propyl ether (16), which mainly retained the potency, spectrum and in vivo efficacy of AM8085 associated with the decreased hERG activity and improved physical property.

  15. Antiepileptic teratogen valproic acid (VPA) modulates organisation and dynamics of the actin cytoskeleton

    DEFF Research Database (Denmark)

    Walmod, P S; Skladchikova, G; Kawa, A;

    1999-01-01

    The antiepileptic drug valproic acid (VPA) and teratogenic VPA analogues have been demonstrated to inhibit cell motility and affect cell morphology. We here show that disruption of microtubules or of microfilaments by exposure to nocodazole or cytochalasin D had different effects on morphology of...

  16. Antiepileptic Medications in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

    Science.gov (United States)

    Hirota, Tomoya; Veenstra-VanderWeele, Jeremy; Hollander, Eric; Kishi, Taro

    2014-01-01

    Electroencephalogram-recorded epileptiform activity is common in children with autism spectrum disorder (ASD), even without clinical seizures. A systematic literature search identified 7 randomized, placebo-controlled trials of antiepileptic drugs (AEDs) in ASD (total n = 171), including three of valproate, and one each of lamotrigine,…

  17. Anti-epileptic drug intake adherence: the value of the blood drug level measurement and the clinical approach Aderência à ingestão de medicamentos antiepilépticos: o valor da avaliação dos níveis sanguíneos e a abordagem clínica

    Directory of Open Access Journals (Sweden)

    MARLEIDE DA MOTA GOMES

    1998-12-01

    Full Text Available It was evaluated the patient antiepileptic drug (AED intake adherence in a pilot cross-sectional study carried out at a neurologic out-patient clinic of a university hospital. Ninety-three AED blood concentration (phenobarbital, phenytoin, carbamazepine were analyzed from 24 patients. The variability of the AED blood level was measured (in the steady state period by means of the variation coefficient and compared with the self-reported antiepileptic medication non-adherence, AED blood level according to the range (therapeutic or not, and the seizure control. It was not observed any strong correlation between the higher value of variability and the other three parameters of no adherence. The highest correlation was with the blood drug level (therapeutic or not. The evaluation of blood drug measurement alone, except in cases of extreme low adherence and variability of drug intake, is not enough for the recognition of incorrect drug intake, but the clinical markers and the self-reported adherence have to be also considered for this sort of evaluation.Avaliou-se a aderência à ingesta de drogas antiepilépticas (DAE em estudo piloto transversal conduzido em ambulatório de hospital neurológico universitário. Noventa e três amostras sanguíneas com concentraç��o de DAE (fenobarbital, fenitoína, carbamazepina foram analisadas de 24 pacientes. A variabilidade dos níveis sanguíneos das DAE (em estado estável - steady state period, analizada por meio do coeficiente de variação foi comparada com a auto-referida não aderência à ingesta da DAE, níveis sanguíneos das DAE de acordo com a faixa (terapêutica ou não e o controle das crises epilépticas. Não foi observada correlação forte entre o maior valor da variabilidade e os outros três parâmetros de aderência, apesar da maior correlação com o nível sanguíneo (terapêutico ou não. A avaliação do nível sérico isolado, exceto em caso de extrema baixa aderência e

  18. Novel, broad-spectrum anticonvulsants containing a sulfamide group: advancement of N-((benzo[b]thien-3-yl)methyl)sulfamide (JNJ-26990990) into human clinical studies.

    Science.gov (United States)

    Parker, Michael H; Smith-Swintosky, Virginia L; McComsey, David F; Huang, Yifang; Brenneman, Douglas; Klein, Brian; Malatynska, Ewa; White, H Steve; Milewski, Michael E; Herb, Mark; Finley, Michael F A; Liu, Yi; Lubin, Mary Lou; Qin, Ning; Iannucci, Robert; Leclercq, Laurent; Cuyckens, Filip; Reitz, Allen B; Maryanoff, Bruce E

    2009-12-10

    In seeking broad-spectrum anticonvulsants to treat epilepsy and other neurological disorders, we synthesized and tested a group of sulfamide derivatives (4a-k, 5), which led to the clinical development of 4a (JNJ-26990990). This compound exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures, with very weak inhibition of human carbonic anhydrase-II (IC(50) = 110 microM). The pharmacological profile for 4a supports its potential in the treatment of multiple forms of epilepsy, including pharmacoresistant variants. Mechanistically, 4a inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels but was not effective as a K(+) channel opener. The pharmacokinetics and metabolic properties of 4a are discussed.

  19. 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.

  20. Bio-Inspired Wide-Angle Broad-Spectrum Cylindrical Lens Based on Reflections from Micro-Mirror Array on a Cylindrical Elastomeric Membrane

    Directory of Open Access Journals (Sweden)

    Chi-Chieh Huang

    2014-06-01

    Full Text Available We present a wide-angle, broad-spectrum cylindrical lens based on reflections from an array of three-dimensional, high-aspect-ratio micro-mirrors fabricated on a cylindrical elastomeric substrate, functionally inspired by natural reflecting superposition compound eyes. Our device can perform one-dimensional focusing and beam-shaping comparable to conventional refraction-based cylindrical lenses, while avoiding chromatic aberration. The focal length of our cylindrical lens is 1.035 mm, suitable for micro-optical systems. Moreover, it demonstrates a wide field of view of 152° without distortion, as well as modest spherical aberrations. Our work could be applied to diverse applications including laser diode collimation, barcode scanning, holography, digital projection display, microlens arrays, and optical microscopy.

  1. CaLecRK-S.5, a pepper L-type lectin receptor kinase gene, confers broad-spectrum resistance by activating priming

    Science.gov (United States)

    Woo, Joo Yong; Jeong, Kwang Ju; Kim, Young Jin; Paek, Kyung-Hee

    2016-01-01

    In Arabidopsis, several L-type lectin receptor kinases (LecRKs) have been identified as putative immune receptors. However, to date, there have been few analyses of LecRKs in crop plants. Virus-induced gene silencing of CaLecRK-S.5 verified the role of CaLecRK-S.5 in broad-spectrum resistance. Compared with control plants, CaLecRK-S.5-silenced plants showed reduced hypersensitive response, reactive oxygen species burst, secondary metabolite production, mitogen-activated protein kinase activation, and defense-related gene expression in response to Tobacco mosaic virus pathotype P0 (TMV-P0) infection. Suppression of CaLecRK-S.5 expression significantly enhanced the susceptibility to Pepper mild mottle virus pathotype P1,2,3, Xanthomonas campestris pv. vesicatoria, Phytophthora capsici, as well as TMV-P0. Additionally, β-aminobutyric acid treatment and a systemic acquired resistance assay revealed that CaLecRK-S.5 is involved in priming of plant immunity. Pre-treatment with β-aminobutyric acid before viral infection restored the reduced disease resistance phenotypes shown in CaLecRK-S.5-silenced plants. Systemic acquired resistance was also abolished in CaLecRK-S.5-silenced plants. Finally, RNA sequencing analysis indicated that CaLecRK-S.5 positively regulates plant immunity at the transcriptional level. Altogether, these results suggest that CaLecRK-S.5-mediated broad-spectrum resistance is associated with the regulation of priming. PMID:27647723

  2. CaLecRK-S.5, a pepper L-type lectin receptor kinase gene, confers broad-spectrum resistance by activating priming.

    Science.gov (United States)

    Woo, Joo Yong; Jeong, Kwang Ju; Kim, Young Jin; Paek, Kyung-Hee

    2016-10-01

    In Arabidopsis, several L-type lectin receptor kinases (LecRKs) have been identified as putative immune receptors. However, to date, there have been few analyses of LecRKs in crop plants. Virus-induced gene silencing of CaLecRK-S.5 verified the role of CaLecRK-S.5 in broad-spectrum resistance. Compared with control plants, CaLecRK-S.5-silenced plants showed reduced hypersensitive response, reactive oxygen species burst, secondary metabolite production, mitogen-activated protein kinase activation, and defense-related gene expression in response to Tobacco mosaic virus pathotype P0 (TMV-P0) infection. Suppression of CaLecRK-S.5 expression significantly enhanced the susceptibility to Pepper mild mottle virus pathotype P1,2,3, Xanthomonas campestris pv. vesicatoria, Phytophthora capsici, as well as TMV-P0 Additionally, β-aminobutyric acid treatment and a systemic acquired resistance assay revealed that CaLecRK-S.5 is involved in priming of plant immunity. Pre-treatment with β-aminobutyric acid before viral infection restored the reduced disease resistance phenotypes shown in CaLecRK-S.5-silenced plants. Systemic acquired resistance was also abolished in CaLecRK-S.5-silenced plants. Finally, RNA sequencing analysis indicated that CaLecRK-S.5 positively regulates plant immunity at the transcriptional level. Altogether, these results suggest that CaLecRK-S.5-mediated broad-spectrum resistance is associated with the regulation of priming.

  3. Prevalence of broad-spectrum cephalosporin-resistant Escherichia coli isolates in food samples in Tunisia, and characterization of integrons and antimicrobial resistance mechanisms implicated.

    Science.gov (United States)

    Ben Slama, Karim; Jouini, Ahlem; Ben Sallem, Rym; Somalo, Sergio; Sáenz, Yolanda; Estepa, Vanesa; Boudabous, Abdellatif; Torres, Carmen

    2010-02-28

    The presence of broad-spectrum-cephalosporin-resistant Escherichia coli isolates and the implicated mechanisms of resistance were investigated in 79 food samples of animal origin obtained in different supermarkets and local butcheries in Tunisia. Ten of these samples (12.6%) harbored extended-spectrum beta-lactamase (ESBL) producing E. coli isolates and 13 ESBL-positive isolates were recovered (one or two/sample), which exhibited nine different Pulsed-Field-Gel-Electrophoresis (PFGE) patterns. ESBLs detected were the following: CTX-M-1 (10 strains), CTX-M-1+TEM-1b (2 strains) and CTX-M-1+TEM-20 (1 strain). The orf477 sequence was identified downstream of bla(CTX-M-1) gene in all 13 strains and ISEcp1 upstream in 9 strains. All ESBL-positive strains were included into phylogenetic group A or B1 (4 and 9 strains, respectively). Three of the 79 food samples (3.8%) contained broad-spectrum-cephalosporin-resistant and ESBL-negative E. coli isolates with AmpC phenotype. One isolate per sample was studied, and they showed unrelated PFGE patterns. The CMY-2 type beta-lactamase was identified in one of these 3 strains and specific point mutations in the promoter/attenuator region of ampC gene (at positions -42, -18, -1 and +58) were detected in the remaining two strains. Twelve ESBL-positive and one ESBL-negative E. coli strains contained class 1 integrons with the following gene cassette arrangements: dfrA1+aadA (6 strains) and dfrA17+aadA5 (7 strains). E. coli strains from food samples could represent a reservoir of ESBL-encoding genes and integrons that could be transmitted to humans through the food chain.

  4. 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.

  5. Drug: D07299 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07299 Drug Lacosamide (USAN/INN); Erlosamide; Vimpat (TN) C13H18N2O3 250.1317 250....ide D07299 Lacosamide (USAN/INN) USP drug classification... [BR:br08302] Anticonvulsants Sodium Channel Agents Lacosamide D07299 Lacosamide (USAN/INN) CAS: 175481-36-4... (ATC) classification [BR:br08303] N NERVOUS SYSTEM N03 ANTIEPILEPTICS N03A ANTIEPILEPTICS N03AX Other antiepileptics N03AX18 Lacosam

  6. 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

  7. 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

  8. 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

  9. Overexpression of MoSM1, encoding for an immunity-inducing protein from Magnaporthe oryzae, in rice confers broad-spectrum resistance against fungal and bacterial diseases

    Science.gov (United States)

    Hong, Yongbo; Yang, Yayun; Zhang, Huijuan; Huang, Lei; Li, Dayong; Song, Fengming

    2017-01-01

    Potential of MoSM1, encoding for a cerato-platanin protein from Magnaporthe oryzae, in improvement of rice disease resistance was examined. Transient expression of MoSM1 in rice leaves initiated hypersensitive response and upregulated expression of defense genes. When transiently expressed in tobacco leaves, MoSM1 targeted to plasma membrane. The MoSM1-overexpressing (MoSM1-OE) transgenic rice lines showed an improved resistance, as revealed by the reduced disease severity and decreased in planta pathogen growth, against 2 strains belonging to two different races of M. oryzae, causing blast disease, and against 2 strains of Xanthomonas oryzae pv. oryzae, causing bacterial leaf blight disease. However, no alteration in resistance to sheath blight disease was observed in MoSM1-OE lines. The MoSM1-OE plants contained elevated levels of salicylic acid (SA) and jasmonic acid (JA) and constitutively activated the expression of SA and JA signaling-related regulatory and defense genes. Furthermore, the MoSM1-OE plants had no effect on drought and salt stress tolerance and on grain yield. We conclude that MoSM1 confers a broad-spectrum resistance against different pathogens through modulating SA- and JA-mediated signaling pathways without any penalty on abiotic stress tolerance and grain yield, providing a promising potential for application of MoSM1 in improvement of disease resistance in crops. PMID:28106116

  10. Transplastomic Nicotiana benthamiana plants expressing multiple defence genes encoding protease inhibitors and chitinase display broad-spectrum resistance against insects, pathogens and abiotic stresses.

    Science.gov (United States)

    Chen, Peng-Jen; Senthilkumar, Rajendran; Jane, Wann-Neng; He, Yong; Tian, Zhihong; Yeh, Kai-Wun

    2014-05-01

    Plastid engineering provides several advantages for the next generation of transgenic technology, including the convenient use of transgene stacking and the generation of high expression levels of foreign proteins. With the goal of generating transplastomic plants with multiresistance against both phytopathogens and insects, a construct containing a monocistronic patterned gene stack was transformed into Nicotiana benthamiana plastids harbouring sweet potato sporamin, taro cystatin and chitinase from Paecilomyces javanicus. Transplastomic lines were screened and characterized by Southern/Northern/Western blot analysis for the confirmation of transgene integration and respective expression level. Immunogold localization analyses confirmed the high level of accumulation proteins that were specifically expressed in leaf and root plastids. Subsequent functional bioassays confirmed that the gene stacks conferred a high level of resistance against both insects and phytopathogens. Specifically, larva of Spodoptera litura and Spodoptera exigua either died or exhibited growth retardation after ingesting transplastomic plant leaves. In addition, the inhibitory effects on both leaf spot diseases caused by Alternaria alternata and soft rot disease caused by Pectobacterium carotovorum subsp. carotovorum were markedly observed. Moreover, tolerance to abiotic stresses such as salt/osmotic stress was highly enhanced. The results confirmed that the simultaneous expression of sporamin, cystatin and chitinase conferred a broad spectrum of resistance. Conversely, the expression of single transgenes was not capable of conferring such resistance. To the best of our knowledge, this is the first study to demonstrate an efficacious stacked combination of plastid-expressed defence genes which resulted in an engineered tolerance to various abiotic and biotic stresses.

  11. Tallow amphopolycarboxyglycinate-stabilized silver nanoparticles: new frontiers in development of plant protection products with a broad spectrum of action against phytopathogens

    Science.gov (United States)

    Krutyakov, Yurii A.; Kudrinskiy, Alexey A.; Zherebin, Pavel M.; Yapryntsev, Alexey D.; Pobedinskaya, Marina A.; Elansky, Sergey N.; Denisov, Albert N.; Mikhaylov, Dmitry M.; Lisichkin, Georgii V.

    2016-07-01

    Sustainable agriculture calls for minimal use of agrochemicals in order to protect the environment. It has caused an increase in the rate of nanoparticles use, in particular silver nanoparticles (AgNPs) due to their safety for mammals, unique biological activity and a broad spectrum of action against fungal and bacterial pathogens. Until now the use of AgNPs dispersions in the agricultural sector has been essentially limited due to many factors decreased their stability (mixing with other pesticides, presence of electrolytes). We present a versatile synthesis of polyampholyte surfactant (tallow amphopolycarboxyglycinate) stabilized AgNPs. We took a close look at unique aggregation behavior (via dynamic light scattering and UV-vis spectroscopy) and biocidal activity of obtained silver colloids. AgNPs are characterized by exclusively high aggregative stability in the presence of coagulating agents NaNO3 and NaSO4 (up to 1 M), during drying/redispergation, and frost/defrost cycles. The dispersion of AgNPs shows high biocidal activity (EC50 is ten times lower than commercial species ones) with respect to Phytophthora infestans and phytopathogenic fungi. This points to the possibility of successful application of silver preparations within agriculture with the goal of partial reduction of the use of toxic and expensive synthetic antibiotics and pesticides.

  12. Activity of broad-spectrum and reduced-risk insecticides on various life stages of cranberry fruitworm (Lepidoptera: Pyralidae) in highbush blueberry.

    Science.gov (United States)

    Wise, John C; Jenkins, Paul E; Poppen, Ryan Vander; Isaacs, Rufus

    2010-10-01

    Laboratory and semifield bioassays were conducted to determine the life-stage activity of insecticides for controlling cranberry fruitworm, Acrobasis vaccinii Riley (Lepidoptera: Pyralidae), a key lepidopteran pest of highbush blueberry, Vaccinium corymbosum L. The organophosphates azinphosmethyl and phosmet, the pyrethroid esfenvalerate, and the carbamate methomyl were lethal to all life stages. The neonicotinoids thiacloprid and acetamiprid demonstrated strong larvicidal and ovicidal activity but were somewhat weaker adulticides than the conventional broad-spectrum compounds. Bacillus thuringiensis, indoxacarb, and emamectin benzoate were shown to control A. vacinii primarily through their larvicidal activity. Spinosad was toxic to all life stages, including eggs laid on top of residues and those that were treated topically, but larvicidal activity was short lived. The growth regulators pyriproxyfen and novaluron had strong ovicidal activity when eggs were laid on top of residues but had limited larvicidal activity. Tebufenozide was not directly toxic to eggs, but demonstrated larvicidal activity, and ovilarvicidal activity when topically applied to eggs. Azinphosmethyl, phosmet, indoxacarb, thiacloprid, and acetamiprid were all toxic to the egg parasitoid Trichogramma minutum Riley. In contrast pyriproxyfen, emamectin benzoate, methomyl, novaluron, and spinosad did not negatively affect the survival of T. minutum within Acrobasis vacinii eggs. These results help inform the ongoing development of integrated strategies for insect management in blueberry.

  13. Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis.

    Science.gov (United States)

    Hata, Katsura; Horii, Takaaki; Miyazaki, Mamiko; Watanabe, Nao-Aki; Okubo, Miyuki; Sonoda, Jiro; Nakamoto, Kazutaka; Tanaka, Keigo; Shirotori, Syuji; Murai, Norio; Inoue, Satoshi; Matsukura, Masayuki; Abe, Shinya; Yoshimatsu, Kentaro; Asada, Makoto

    2011-10-01

    E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action-inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (P candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (P candidiasis caused by azole-resistant Candida albicans or Candida tropicalis. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (P candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated.

  14. 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.

  15. GhMPK7, a novel multiple stress-responsive cotton group C MAPK gene, has a role in broad spectrum disease resistance and plant development.

    Science.gov (United States)

    Shi, Jing; An, Hai-Long; Zhang, Liang; Gao, Zheng; Guo, Xing-Qi

    2010-09-01

    Mitogen-activated protein kinase (MAPK) cascades play a pivotal role in environmental responses and developmental processes in plants. Previous researches mainly focus on the MAPKs in groups A and B, and little is known on group C. In this study, we isolated and characterized GhMPK7, which is a novel gene from cotton belonging to the group C MAPK. RNA blot analysis indicated that GhMPK7 transcript was induced by pathogen infection and multiple defense-related signal molecules. Transgenic Nicotina benthamiana overexpressing GhMPK7 displayed significant resistance to fungus Colletotrichum nicotianae and virus PVY, and the transcript levels of SA pathway genes were more rapidly and strongly induced. Furthermore, the transgenic N. benthamiana showed reduced ROS-mediated injuries by upregulating expression of oxidative stress-related genes. Interestingly, the transgenic plants germinated earlier and grew faster in comparison to wild-type plants. beta-glucuronidase activity driven by the GhMPK7 promoter was detected in the apical meristem at the vegetative stage, and it was enhanced by treatments with signal molecules and phytohormones. These results suggest that GhMPK7 might play an important role in SA-regulated broad-spectrum resistance to pathogen infection, and that it is also involved in regulation of plant growth and development.

  16. A novel broad-spectrum cephalosporin ceftobiprole%新型广谱头孢菌素类抗菌药物头孢吡普

    Institute of Scientific and Technical Information of China (English)

    熊礼玲; 游莉; 刘家健; 李栋宏

    2011-01-01

    Antimicrobial resistance has become a significant problem over the past decade with marked increases in the incidence of MRSA, intermediate- and high level resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant enterococci. Ceftobiprole was the first of a new class of broad-spectrum cephalosporin antibiotics that had potent antibacterial activity towards methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus (VRSA). This review detailed its mechanism of action, synthesis methods, antibacterial activities in vivo, pharmacokinetic profie and clinical trials.%随着耐甲氧西林金葡萄球菌、耐药金黄色葡萄球菌、耐青霉素肺炎链球菌和耐万古霉素肠球菌显著增加,细菌耐药性成为近年来一个重大难题.Ceftobiprole是第一个对耐甲氧西林金葡萄球菌(MRSA)和万古霉素耐药金黄色葡葡球菌(VRSA)有效的广谱头孢菌素类抗生素.现对其作用机制、合成路线、体外抗菌活性、药动学特性、临床试验等方面作一综述.

  17. Inheritance studies of apple scab resistance and identification of Rvi14, a new major gene that acts together with other broad-spectrum QTL.

    Science.gov (United States)

    Soufflet-Freslon, V; Gianfranceschi, L; Patocchi, A; Durel, C-E

    2008-08-01

    Scab, caused by the fungal pathogen Venturia inaequalis, is the most common disease of cultivated apple (Malus xdomestica). The fungal races 6 and 7 have now overcome the major resistance gene Vf, which is widely used in apple breeding programmes. New breeding strategies to achieve durable resistance are thus necessary. The aim of this study was to determine the genetic basis of quantitative resistance of the apple cultivar 'Dülmener Rosenapfel', known to be scab resistant under different environmental conditions. An F1 progeny derived from the cross between the susceptible cultivar 'Gala' and 'Dülmener Rosenapfel' was tested in a greenhouse with a multi-isolate inoculum of V. inaequalis. Rvi14, a new major gene that conditions a chlorotic-type reaction, was mapped on linkage group (LG) 6 in a genomic region not known to be involved in disease resistance. A further three quantitative trait loci (QTL) for resistance were identified. One co-localized with Rvi14 on LG6, whereas the remaining two were detected on LG11 and LG17, in genomic regions already reported to carry broad-spectrum QTL in other genetic backgrounds. Since a selective genotyping approach was used to detect QTL, an expectation-maximization (EM) computation was used to estimate the corrected QTL contributions to phenotypic variation and was validated by entire progeny genotyping.

  18. The effect of heating temperature and nitric acid treatments on the performance of Cu- and Zn-based broad spectrum respirator carbons.

    Science.gov (United States)

    Smith, J W H; Romero, J V; Dahn, T R; Dunphy, K; Sullivan, B; Mallay, M; Croll, L M; Reynolds, J H; Andress, C; Dahn, J R

    2011-12-01

    Impregnated activated carbons (IACs) that are used in broad spectrum gas mask applications have historically contained copper and/or zinc impregnants. The addition of an oxidizing agent, such as nitric acid (HNO(3)) can be useful in distributing the metallic impregnants uniformly on the activated carbon substrate. In this work, we study IACs prepared from copper nitrate (Cu(NO(3))(2)) and zinc nitrate (Zn(NO(3))(2)) precursors as a function of HNO(3) content present in the impregnating solution and as a function of heating temperature. The gas adsorption capacity of the IACs was determined by dynamic flow testing using sulfur dioxide (SO(2)), ammonia (NH(3)), hydrogen cyanide (HCN) and cyclohexane (C(6)H(12)) challenge gases under dry and humid conditions. The thermal decomposition and distribution of the impregnant on the activated carbon substrate is studied using X-ray diffraction (XRD), scanning electron microscopy (SEM) and thermal analysis techniques. Relationships between gas adsorption capacity, impregnant distribution and the species of surface impregnants are discussed.

  19. Nuclear Magnetic Resonance Solution Structures of Lacticin Q and Aureocin A53 Reveal a Structural Motif Conserved among Leaderless Bacteriocins with Broad-Spectrum Activity.

    Science.gov (United States)

    Acedo, Jeella Z; van Belkum, Marco J; Lohans, Christopher T; Towle, Kaitlyn M; Miskolzie, Mark; Vederas, John C

    2016-02-02

    Lacticin Q (LnqQ) and aureocin A53 (AucA) are leaderless bacteriocins from Lactococcus lactis QU5 and Staphylococcus aureus A53, respectively. These bacteriocins are characterized by the absence of an N-terminal leader sequence and are active against a broad range of Gram-positive bacteria. LnqQ and AucA consist of 53 and 51 amino acids, respectively, and have 47% identical sequences. In this study, their three-dimensional structures were elucidated using solution nuclear magnetic resonance and were shown to consist of four α-helices that assume a very similar compact, globular overall fold (root-mean-square deviation of 1.7 Å) with a highly cationic surface and a hydrophobic core. The structures of LnqQ and AucA resemble the shorter two-component leaderless bacteriocins, enterocins 7A and 7B, despite having low levels of sequence identity. Homology modeling revealed that the observed structural motif may be shared among leaderless bacteriocins with broad-spectrum activity against Gram-positive organisms. The elucidated structures of LnqQ and AucA also exhibit some resemblance to circular bacteriocins. Despite their similar overall fold, inhibition studies showed that LnqQ and AucA have different antimicrobial potency against the Gram-positive strains tested, suggesting that sequence disparities play a crucial role in their mechanisms of action.

  20. RNA-dependent RNA polymerase (NIb) of the potyviruses is an avirulence factor for the broad-spectrum resistance gene Pvr4 in Capsicum annuum cv. CM334.

    Science.gov (United States)

    Kim, Saet-Byul; Lee, Hye-Young; Seo, Seungyeon; Lee, Joo Hyun; Choi, Doil

    2015-01-01

    Potyviruses are one of the most destructive viral pathogens of Solanaceae plants. In Capsicum annuum landrace CM334, a broad-spectrum gene, Pvr4 is known to be involved in resistance against multiple potyviruses, including Pepper mottle virus (PepMoV), Pepper severe mosaic virus (PepSMV), and Potato virus Y (PVY). However, a potyvirus avirulence factor against Pvr4 has not been identified. To identify the avirulence factor corresponding to Pvr4 in potyviruses, we performed Agrobacterium-mediated transient expressions of potyvirus protein coding regions in potyvirus-resistant (Pvr4) and -susceptible (pvr4) pepper plants. Hypersensitive response (HR) was observed only when a RNA-dependent RNA polymerase (NIb) of PepMoV, PepSMV, or PVY was expressed in Pvr4-bearing pepper leaves in a genotype-specific manner. In contrast, HR was not observed when the NIb of Tobacco etch virus (TEV), a virulent potyvirus, was expressed in Pvr4-bearing pepper leaves. Our results clearly demonstrate that NIbs of PepMoV, PepSMV, and PVY serve as avirulence factors for Pvr4 in pepper plants.

  1. Characterization and Genetic Analysis of a Novel Rice Spotted-leaf Mutant HM47 with Broad-spectrum Resistance to Xanthomonas oryzae pv.oryzae(F)

    Institute of Scientific and Technical Information of China (English)

    Bao-Hua Feng; Yang Yang; Yong-Feng Shi; Hai-Chao Shen; Hui-Mei Wang; Qi-Na Huang; Xia Xu

    2013-01-01

    A stable inherited rice spotted-leaf mutant HM47 derived from an EMS-induced IR64 mutant bank was identified.The mutant expressed hypersensitive response (HR)-like symptoms throughout its whole life from the first leaf to the flag leaf,without pathogen invasion.Initiation of the lesions was induced by light under natural summer field conditions.Expression of pathogenesis-related genes including PAL,PO-C1,POX22.3 and PBZ1 was enhanced significantly in association with cell death and accumulation of H2O2 at and around the site of lesions in the mutant in contrast to that in the wild-type (WT).Disease reaction to Xanthomonas oryzae pv.oryzae from the Philippines and China showed that HM47 is a broad-spectrum disease-resistant mutant with enhanced resistance to multiple races of bacterial blight pathogens tested.An F2 progeny test showed that bacterial blight resistance to race HB-17 was cosegregated with the expression of lesions.Genetic analysis indicated that the spotted-leaf trait was controlled by a single recessive gene,tentatively named splHM47,flanked by two insertion/deletion markers in a region of approximately 74 kb on the long arm of chromosome 4.Ten open reading frames are predicted,and all of them are expressed proteins.Isolation and validation of the putative genes are currently underway.

  2. Practical Synthesis of Cidofovir A Broad-Spectrum Antiviral Drug%广谱抗病毒药物西多福韦的合成

    Institute of Scientific and Technical Information of China (English)

    蒋兴凯; 何小羊; 郭焕芳; 刘琨; 马建洲; 谢蓝

    2009-01-01

    目的 优化西多福韦的合成工艺.方法 利用三苯甲基保护的(R)-缩水甘油经碳酸铯催化与胞嘧啶缩合,二甲基乙缩醛保护氨基后,在NaH作用下引入甲基磷酸二乙酯,再脱去不同的保护基得到西多福韦.结果 西多福韦结构经光谱确定;纯度>99.5%,总收率为23%.结论 该合成路线短,条件温和,纯化方便,试剂成本低,适合规模化合成制备.

  3. 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

    0.5 0.5 Aspergillus flavus 12 0.5 0.5 0.5 0.5 Aspergillus terreus 5 0.125 0.125 0.5 0.5 Aspergillus niger 10 0.5 0.5 0.5 0.5 Candida albicans...with saline administered via subcutaneous injection. The analgesic buprenorphine (0.05mg/kg) was administered twice daily for two days to minimize pain

  4. Third generation cephalosporin resistant Enterobacteriaceae and multidrug resistant gram-negative bacteria causing bacteremia in febrile neutropenia adult cancer patients in Lebanon, broad spectrum antibiotics use as a major risk factor, and correlation with poor prognosis

    Directory of Open Access Journals (Sweden)

    Rima eMoghnieh

    2015-02-01

    Full Text Available Bacteremia remains a major cause of life-threatening complications in patients receiving anticancer chemotherapy. The spectrum and susceptibility profiles of causative microorganisms differ with time and place. Data from Lebanon are scarce. We aim at evaluating the epidemiology of bacteremia in cancer patients in a university hospital in Lebanon, emphasizing antibiotic resistance and risk factors of multi-drug resistant organism (MDRO-associated bacteremia.This is a retrospective study of 75 episodes of bacteremia occurring in febrile neutropenic patients admitted to the hematology-oncology unit at Makassed General Hospital, Lebanon, from October 2009-January 2012.It corresponds to epidemiological data on bacteremia episodes in febrile neutropenic cancer patients including antimicrobial resistance and identification of risk factors associated with third generation cephalosporin resistance (3GCR and MDRO-associated bacteremia. Out of 75 bacteremias, 42.7% were gram-positive (GP, and 57.3% were gram-negative (GN. GP bacteremias were mostly due to methicillin-resistant coagulase negative staphylococci (28% of total bacteremias and 66% of GP bacteremias. Among the GN bacteremias, Escherichia coli (22.7% of total, 39.5% of GN organisms and Klebsiellapneumoniae(13.3% of total, 23.3% of GN organisms were the most important causative agents. GN bacteremia due to 3GC sensitive (3GCS bacteria represented 28% of total bacteremias, while 29% were due to 3GCR bacteria and 9% were due to carbapenem-resistant organisms. There was a significant correlation between bacteremia with MDRO and subsequent intubation, sepsis and mortality. Among potential risk factors, only broad spectrum antibiotic intake >4 days before bacteremia was found to be statistically significant for acquisition of 3GCR bacteria. Using carbapenems or piperacillin/ tazobactam>4 days before bacteremia was significantly associated with the emergence of MDRO (p value<0.05.

  5. Induction of a peptide with activity against a broad spectrum of pathogens in the Aedes aegypti salivary gland, following Infection with Dengue Virus.

    Directory of Open Access Journals (Sweden)

    Natthanej Luplertlop

    Full Text Available The ultimate stage of the transmission of Dengue Virus (DENV to man is strongly dependent on crosstalk between the virus and the immune system of its vector Aedes aegypti (Ae. aegypti. Infection of the mosquito's salivary glands by DENV is the final step prior to viral transmission. Therefore, in the present study, we have determined the modulatory effects of DENV infection on the immune response in this organ by carrying out a functional genomic analysis of uninfected salivary glands and salivary glands of female Ae. aegypti mosquitoes infected with DENV. We have shown that DENV infection of salivary glands strongly up-regulates the expression of genes that encode proteins involved in the vector's innate immune response, including the immune deficiency (IMD and Toll signalling pathways, and that it induces the expression of the gene encoding a putative anti-bacterial, cecropin-like, peptide (AAEL000598. Both the chemically synthesized non-cleaved, signal peptide-containing gene product of AAEL000598, and the cleaved, mature form, were found to exert, in addition to antibacterial activity, anti-DENV and anti-Chikungunya viral activity. However, in contrast to the mature form, the immature cecropin peptide was far more effective against Chikungunya virus (CHIKV and, furthermore, had strong anti-parasite activity as shown by its ability to kill Leishmania spp. Results from circular dichroism analysis showed that the immature form more readily adopts a helical conformation which would help it to cause membrane permeabilization, thus permitting its transfer across hydrophobic cell surfaces, which may explain the difference in the anti-pathogenic activity between the two forms. The present study underscores not only the importance of DENV-induced cecropin in the innate immune response of Ae. aegypti, but also emphasizes the broad-spectrum anti-pathogenic activity of the immature, signal peptide-containing form of this peptide.

  6. WRR4, a broad-spectrum TIR-NB-LRR gene from Arabidopsis thaliana that confers white rust resistance in transgenic oilseed Brassica crops.

    Science.gov (United States)

    Borhan, Mohammad Hossein; Holub, Eric B; Kindrachuk, Colin; Omidi, Mansour; Bozorgmanesh-Frad, Ghazaleh; Rimmer, S Roger

    2010-03-01

    White blister rust caused by Albugo candida (Pers.) Kuntze is a common and often devastating disease of oilseed and vegetable brassica crops worldwide. Physiological races of the parasite have been described, including races 2, 7 and 9 from Brassica juncea, B. rapa and B. oleracea, respectively, and race 4 from Capsella bursa-pastoris (the type host). A gene named WRR4 has been characterized recently from polygenic resistance in the wild brassica relative Arabidopsis thaliana (accession Columbia) that confers broad-spectrum white rust resistance (WRR) to all four of the above Al. candida races. This gene encodes a TIR-NB-LRR (Toll-like/interleukin-1 receptor-nucleotide binding-leucine-rich repeat) protein which, as with other known functional members in this subclass of intracellular receptor-like proteins, requires the expression of the lipase-like defence regulator, enhanced disease susceptibility 1 (EDS1). Thus, we used RNA interference-mediated suppression of EDS1 in a white rust-resistant breeding line of B. napus (transformed with a construct designed from the A. thaliana EDS1 gene) to determine whether defence signalling via EDS1 is functionally intact in this oilseed brassica. The eds1-suppressed lines were fully susceptible following inoculation with either race 2 or 7 isolates of Al. candida. We then transformed white rust-susceptible cultivars of B. juncea (susceptible to race 2) and B. napus (susceptible to race 7) with the WRR4 gene from A. thaliana. The WRR4-transformed lines were resistant to the corresponding Al. candida race for each host species. The combined data indicate that WRR4 could potentially provide a novel source of white rust resistance in oilseed and vegetable brassica crops.

  7. Natural herbicide resistance (HR) to broad-spectrum herbicide, glyphosate among traditional and inbred-cultivated rice (Oryza sativa L.) varieties in Sri Lanka.

    Science.gov (United States)

    Weerakoon, S R; Somaratne, S; Wijeratne, R G D; Ekanyaka, E M S I

    2013-08-15

    Weeds along with insect pests and plant diseases are sources of biotic stress in crop systems. Weeds are responsible for serious problems in rice worldwide affecting growth and causing a considerable reduction in quality and quantity in yield. High concentrations of pre-emergent-broad-spectrum systemic herbicide, Glyphosate is prevalently applied to control rice weeds which intern causes severe damages to cultivated rice varieties, susceptible to Glyphosate. However, there may be rice varieties with natural Herbicide Resistance (HR) which are so far, has not been evaluated. In this study Six traditional and eighteen developed-cultivated rice varieties (Bg, Bw, At and Ld series developed by Rice Research Development Institute, Sri Lanka) were used to screen their natural HR. RCBD with five replicates and three blocks in each treatment-combination was used as the experimental design. As observations, time taken-to seed germination, time taken to flowering; plant height and number of leaves at 12-weeks after sawing, leaf-length, breadth, panicle-length, number of seeds/panicle of resistant plants and controls were recorded. Plants with > or = 40% resistance were considered as resistant to Glyphosate. Ten inbred-cultivated rice varieties (Bg250, Bg94-1, Bg304, Bg359, Bg406, Bg379-2, Bg366, Bg300, Bw364, At362) and three traditional rice varieties ("Kalu Heenati", "Sudu Heenati", "Pachchaperumal") were naturally resistant to 0.25 g L(-1) Glyphosate concentration and when increased the concentration (0.5 g L(-1)) resistance was reduced. This study showed the usefulness of modern statistical method, classification and regression tree analysis (CART) in exploring and visualizing the patterns reflected by a large number of rice varieties (larger experimental database) on herbicide resistance in future.

  8. A broad spectrum, one-step reverse-transcription PCR amplification of the neuraminidase gene from multiple subtypes of influenza A virus

    Directory of Open Access Journals (Sweden)

    Chen Wenbin

    2008-07-01

    Full Text Available Abstract Background The emergence of high pathogenicity strains of Influenza A virus in a variety of human and animal hosts, with wide geographic distribution, has highlighted the importance of rapid identification and subtyping of the virus for outbreak management and treatment. Type A virus can be classified into subtypes according to the viral envelope glycoproteins, hemagglutinin and neuraminidase. Here we review the existing specificity and amplification of published primers to subtype neuraminidase genes and describe a new broad spectrum primer pair that can detect all 9 neuraminidase subtypes. Results Bioinformatic analysis of 3,337 full-length influenza A neuraminidase segments in the NCBI database revealed semi-conserved regions not previously targeted by primers. Two degenerate primers with M13 tags, NA8F-M13 and NA10R-M13 were designed from these regions and used to generate a 253 bp cDNA product. One-step RT-PCR testing was successful in 31/32 (97% cases using a touchdown protocol with RNA from over 32 different cultured influenza A virus strains representing the 9 neuraminidase subtypes. Frozen blinded clinical nasopharyngeal aspirates were also assayed and were mostly of subtype N2. The region amplified was direct sequenced and then used in database searches to confirm the identity of the template RNA. The RT-PCR fragment generated includes one of the mutation sites related to oseltamivir resistance, H274Y. Conclusion Our one-step RT-PCR assay followed by sequencing is a rapid, accurate, and specific method for detection and subtyping of different neuraminidase subtypes from a range of host species and from different geographical locations.

  9. Icariside II, a Broad-Spectrum Anti-cancer Agent, Reverses Beta-Amyloid-Induced Cognitive Impairment through Reducing Inflammation and Apoptosis in Rats

    Science.gov (United States)

    Deng, Yuanyuan; Long, Long; Wang, Keke; Zhou, Jiayin; Zeng, Lingrong; He, Lianzi; Gong, Qihai

    2017-01-01

    Beta-amyloid (Aβ) deposition, associated neuronal apoptosis and neuroinflammation are considered as the important factors which lead to cognitive deficits in Alzheimer’s disease (AD). Icariside II (ICS II), an active flavonoid compound derived from Epimedium brevicornum Maxim, has been extensively used to treat erectile dysfunction, osteoporosis and dementia in traditional Chinese medicine. Recently, ICS II attracts great interest due to its broad-spectrum anti-cancer property. ICS II shows an anti-inflammatory potential both in cancer treatment and cerebral ischemia-reperfusion. It is not yet clear whether the anti-inflammatory effect of ICS II could delay progression of AD. Therefore, the current study aimed to investigate the effects of ICS II on the behavioral deficits, Aβ levels, neuroinflammatory responses and apoptosis in Aβ25-35-treated rats. We found that bilateral hippocampal injection of Aβ25-35 induced cognitive impairment, neuronal damage, along with increase of Aβ, inflammation and apoptosis in hippocampus of rats. However, treatment with ICS II 20 mg/kg could improve the cognitive deficits, ameliorate neuronal death, and reduce the levels of Aβ in the hippocampus. Furthermore, ICS II could suppress microglial and astrocytic activation, inhibit expression of IL-1β, TNF-α, COX-2, and iNOS mRNA and protein, and attenuate the Aβ induced Bax/Bcl-2 ratio elevation and caspase-3 activation. In conclusion, these results showed that ICS II could reverse Aβ-induced cognitive deficits, possibly via the inhibition of neuroinflammation and apoptosis, which suggested a potential protective effect of ICS II on AD. PMID:28210222

  10. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models.

    Science.gov (United States)

    Zhao, Genshi; Li, Wei-Ying; Chen, Daohong; Henry, James R; Li, Hong-Yu; Chen, Zhaogen; Zia-Ebrahimi, Mohammad; Bloem, Laura; Zhai, Yan; Huss, Karen; Peng, Sheng-Bin; McCann, Denis J

    2011-11-01

    The fibroblast growth factor receptors (FGFR) are tyrosine kinases that are present in many types of endothelial and tumor cells and play an important role in tumor cell growth, survival, and migration as well as in maintaining tumor angiogenesis. Overexpression of FGFRs or aberrant regulation of their activities has been implicated in many forms of human malignancies. Therefore, targeting FGFRs represents an attractive strategy for development of cancer treatment options by simultaneously inhibiting tumor cell growth, survival, and migration as well as tumor angiogenesis. Here, we describe a potent, selective, small-molecule FGFR inhibitor, (R)-(E)-2-(4-(2-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3yl)vinyl)-1H-pyrazol-1-yl)ethanol, designated as LY2874455. This molecule is active against all 4 FGFRs, with a similar potency in biochemical assays. It exhibits a potent activity against FGF/FGFR-mediated signaling in several cancer cell lines and shows an excellent broad spectrum of antitumor activity in several tumor xenograft models representing the major FGF/FGFR relevant tumor histologies including lung, gastric, and bladder cancers and multiple myeloma, and with a well-defined pharmacokinetic/pharmacodynamic relationship. LY2874455 also exhibits a 6- to 9-fold in vitro and in vivo selectivity on inhibition of FGF- over VEGF-mediated target signaling in mice. Furthermore, LY2874455 did not show VEGF receptor 2-mediated toxicities such as hypertension at efficacious doses. Currently, this molecule is being evaluated for its potential use in the clinic.

  11. Linear biocompatible glyco-polyamidoamines as dual action mode virus infection inhibitors with potential as broad-spectrum microbicides for sexually transmitted diseases

    Science.gov (United States)

    Mauro, Nicolò; Ferruti, Paolo; Ranucci, Elisabetta; Manfredi, Amedea; Berzi, Angela; Clerici, Mario; Cagno, Valeria; Lembo, David; Palmioli, Alessandro; Sattin, Sara

    2016-09-01

    The initial steps of viral infections are mediated by interactions between viral proteins and cellular receptors. Blocking the latter with high-affinity ligands may inhibit infection. DC-SIGN, a C-type lectin receptor expressed by immature dendritic cells and macrophages, mediates human immunodeficiency virus (HIV) infection by recognizing mannose clusters on the HIV-1 gp120 envelope glycoprotein. Mannosylated glycodendrimers act as HIV entry inhibitors thanks to their ability to block this receptor. Previously, an amphoteric, but prevailingly cationic polyamidoamine named AGMA1 proved effective as infection inhibitor for several heparan sulfate proteoglycan-dependent viruses, such as human papilloma virus HPV-16 and herpes simplex virus HSV-2. An amphoteric, but prevailingly anionic PAA named ISA23 proved inactive. It was speculated that the substitution of mannosylated units for a limited percentage of AGMA1 repeating units, while imparting anti-HIV activity, would preserve the fundamentals of its HPV-16 and HSV-2 infection inhibitory activity. In this work, four biocompatible linear PAAs carrying different amounts of mannosyl-triazolyl pendants, Man-ISA7, Man-ISA14, Man-AGMA6.5 and Man-AGMA14.5, were prepared by reaction of 2-(azidoethyl)-α-D-mannopyranoside and differently propargyl-substituted AGMA1 and ISA23. All mannosylated PAAs inhibited HIV infection. Both Man-AGMA6.5 and Man-AGMA14.5 maintained the HPV-16 and HSV-2 activity of the parent polymer, proving broad-spectrum, dual action mode virus infection inhibitors.

  12. ABCB1基因位点(C3435T)多态性与癫痫耐药关联性的Meta分析%Meta analysis of relationship between polymorphism of gene site (C3435T) of ABCB1 and antiepileptic drug resistant

    Institute of Scientific and Technical Information of China (English)

    彭锐; 张洪; 张英; 魏丹芸

    2015-01-01

    目的:探讨ABCB1的基因位点(C3435T)多态性与癫痫耐药关联性。方法计算机检索Pubmed、Science direct、Wiley online library、Web of Science、中国知网、万方数据库和维普中文科技期刊数据库,纳入抗癫痫药耐药与抗癫痫药敏感的随机对照试验,同时查阅检索结果中所附相似文献及参考文献,检索文献均为建库至2014年6月15日。由两名评价员单独进行文献筛选及资料提取,采用RevMan 5.0软件进行Meta分析及其他统计学分析。结果共纳入文献10篇,癫痫患者中耐药815例,敏感976例。Meta分析结果显示,C3435T位点多态性在等位基因模型、显性模型、隐性模型、共显性模型(CC/TT组)下整体效应差异有统计学意义(P0.05);而印度地区ABCB1 C3435T位点基因多态性与癫痫耐药在等位基因模型和隐性基因模型下整体效应差异有统计学意义(P0.05). In the allele gene model, OR=0.70, 95%CI (0.54, 0.93);recessive gene model, OR=0.72, 95%CI (0.49, 1.07). Conclusion ABCB1 C3435T loci polymor-phism dose not relate to the antiepileptic drug resistant among Chinese; but ABCB1 C3435T loci polymorphism relates to the antiepileptic drug resistant among Indian.

  13. Enantioselective Synthesis of Antiepileptic Agent, (−-Levetiracetam, through Evans Asymmetric Strategy

    Directory of Open Access Journals (Sweden)

    K. Chandra Babu

    2013-01-01

    Full Text Available A practical and efficient enantioselective synthesis of antiepileptic drug, (−-Levetiracetam, has been described in five steps (33.0% overall yield and high optical purity (99.0% ee, using Evans asymmetric strategy for α-alkylation of carbonyl functionality as the key step. The simplicity of the experimental procedures and high stereochemical outcome make this method synthetically attractive for preparing the target compound on multigram scales.

  14. Enantioselective Synthesis of Antiepileptic Agent, (−)-Levetiracetam, through Evans Asymmetric Strategy

    OpenAIRE

    Chandra Babu, K.; Buchi Reddy, R.; Mukkanti, K.; Suresh, K.; Madhusudhan, G.; Satish Nigam

    2013-01-01

    A practical and efficient enantioselective synthesis of antiepileptic drug, (−)-Levetiracetam, has been described in five steps (33.0% overall yield) and high optical purity (99.0% ee), using Evans asymmetric strategy for α-alkylation of carbonyl functionality as the key step. The simplicity of the experimental procedures and high stereochemical outcome make this method synthetically attractive for preparing the target compound on multigram scales.

  15. Environmental fate of herbicides trifluralin, metazachlor, metamitron and sulcotrione compared with that of glyphosate, a substitute broad spectrum herbicide for different glyphosate-resistant crops.

    Science.gov (United States)

    Mamy, Laure; Barriuso, Enrique; Gabrielle, Benoît

    2005-09-01

    The introduction of crops resistant to the broad spectrum herbicide glyphosate, N-(phosphonomethyl)glycine, may constitute an answer to increased contamination of the environment by herbicides, since it should reduce the total amount of herbicide needed and the number of active ingredients. However, there are few published data comparing the fate of glyphosate in the environment, particularly in soil, with that of substitute herbicides. The objective of this study is to compare the fate of glyphosate in three soils with that of four herbicides frequently used on crops that might be glyphosate resistant: trifluralin, alpha,alpha,alpha-trifluoro-2,6-dinitro-N,N-dipropyl-p-toluidine, and metazachlor, 2-chloro-N-(pyrazol-1-ylmethyl)acet-2',6'-xylidide for oilseed rape, metamitron, 4-amino-4,5-dihydro-3-methyl-6-phenyl-1,2,4-triazin-5-one for sugarbeet and sulcotrione, 2-(2-chloro-4-mesylbenzoyl)cyclohexane-1,3-dione for maize. The distribution of herbicides between the volatilized, mineralized, extractable and non-extractable fractions was studied, along with the formation of their metabolites in laboratory experiments using 14C-labelled herbicides, over a period of 140 days. The main dissipation pathways were mineralization for glyphosate and sulcotrione, volatilization for trifluralin and non-extractable residues formation for metazachlor and metamitron. The five herbicides had low persistence. Glyphosate had the shortest half-life, which varied with soil type, whereas trifluralin had the longest. The half-lives of metazachlor and sulcotrione were comparable, whereas that of metamitron was highly variable. Glyphosate, metazachlor and sulcotrione were degraded into persistent metabolites. Low amounts of trifluralin and metamitron metabolites were observed. At 140 days after herbicide applications, the amounts of glyphosate and its metabolite residues in soils were the lowest in two soils, but not in the third soil, a loamy sand with low pH. The environmental advantage

  16. Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N-Docosahexaenoyl 2′, 2′-Difluorodeoxycytidine with Potent and Broad-Spectrum Antitumor Activity

    Directory of Open Access Journals (Sweden)

    Youssef W. Naguib

    2016-01-01

    Full Text Available In this study, a new compound, 4-(N-docosahexaenoyl 2′, 2′-difluorodeoxycytidine (DHA-dFdC, was synthesized and characterized. Its antitumor activity was evaluated in cell culture and in mouse models of pancreatic cancer. DHA-dFdC is a poorly soluble, pale yellow waxy solid, with a molecular mass of 573.3 Da and a melting point of about 96°C. The activation energy for the degradation of DHA-dFdC in an aqueous Tween 80–based solution is 12.86 kcal/mol, whereas its stability is significantly higher in the presence of vitamin E. NCI-60 DTP Human Tumor Cell Line Screening revealed that DHA-dFdC has potent and broad-spectrum antitumor activity, especially in leukemia, renal, and central nervous system cancer cell lines. In human and murine pancreatic cancer cell lines, the IC50 value of DHA-dFdC was up to 105-fold lower than that of dFdC. The elimination of DHA-dFdC in mouse plasma appeared to follow a biexponential model, with a terminal phase t1/2 of about 58 minutes. DHA-dFdC significantly extended the survival of genetically engineered mice that spontaneously develop pancreatic ductal adenocarcinoma. In nude mice with subcutaneously implanted human Panc-1 pancreatic tumors, the antitumor activity of DHA-dFdC was significantly stronger than the molar equivalent of dFdC alone, DHA alone, or the physical mixture of them (1:1, molar ratio. DHA-dFdC also significantly inhibited the growth of Panc-1 tumors orthotopically implanted in the pancreas of nude mice, whereas the molar equivalent dose of dFdC alone did not show any significant activity. DHA-dFdC is a promising compound for the potential treatment of cancers in organs such as the pancreas.

  17. Effects of a broad-spectrum caspase inhibitor, Z-VAD(OMe)-FMK, on viral hemorrhagic septicemia virus (VHSV) infection-mediated apoptosis and viral replication.

    Science.gov (United States)

    Kim, Min Sun; Lee, Ji Ae; Kim, Ki Hong

    2016-04-01

    In the development of inactivated or attenuated viral vaccines for cultured fish, viral titers harvested from the cultured cells would be the most important factor for the determination of vaccine's cost effectiveness. In this study, we hypothesized that the lengthening of cell survival time by the inhibition of apoptosis can lead to an increase of the final titer of viral hemorrhagic septicemia virus (VHSV). To test the hypothesis, we investigated the effects of a broad-spectrum caspase inhibitor, Z-VAD(OMe)-FMK, on VHSV infection-mediated apoptosis in Epithelioma papulosum cyprini (EPC) cells and on the VHSV titers. VHSV infection induced the DNA laddering in EPC cells, and the progression of DNA fragmentation was in proportion to the CPE extension. The progression of DNA fragmentation in EPC cells infected with VHSV was clearly inhibited by exposure to Z-VAD(OMe)-FMK, and the inhibition was intensified according to the increase of the inhibitor concentration. These results confirmed the previous reports that the death of host cells by VHSV infection is through apoptosis. Cells infected with a recombinant VHSV, rVHSV-ΔNV-eGFP, that was generated from our previous study by replacement of the NV gene ORF with the enhanced green fluorescent protein (eGFP) gene ORF, showed earlier and more distinct DNA fragmentations compared to the cells infected with wild-type VHSV, suggesting the inhibitory role of the NV protein in VHSV-mediated apoptosis that was previously reported. The final viral titers in the supernatant isolated from Z-VAD(OMe)-FMK treated cells after showing an extensive CPE were significantly higher than the viral titers from cells infected with virus alone, indicating that the delay of apoptosis by Z-VAD(OMe)-FMK extended the survival time of EPC cells, which lengthen the time for VHSV replication in the cells. In conclusion, Z-VAD(OMe)-FMK-mediated inhibition of apoptosis significantly increased the final titers of both wild-type VHSV and r

  18. Antiepileptic Potential of Matrine via Regulation the Levels of Gamma-Aminobutyric Acid and Glutamic Acid in the Brain

    Directory of Open Access Journals (Sweden)

    Jun Xiang

    2013-12-01

    Full Text Available Our present study aimed to determine the antiepileptic activity of matrine, and explore the possible molecular mechanism. To evaluate the antiepileptic activity of matrine, seizures in mice induced by PTZ and MES were established, then the pentobarbital sodium-induced anaesthetizing time and locomotor activity tests in mice were also carried out. For the molecular mechanism investigations, contents of aspartic acid (Asp, gamma-aminobutyric acid (GABA, glutamic acid (Glu, glycine (Gly in seizures mice were determined; then, the chronic seizures rats induced by PTZ were prepared, and western blotting was used to determine the expressions of GAD 65, GABAA and GABAB in the brains. In the results, matrine showed significant antiepileptic effects on seizures mice induced by MES and PTZ. Moreover, the pentobarbital sodium-induced anaesthetizing time and locomotor activity tests were also demonstrated that matrine had obvious antiepileptic effects. Additionally, our results revealed that after treatment with matrine, contents of GABA can be elevated, and the contents of Glu were obviously decreased. Furthermore, western blotting revealed that the mechanism regarding the antiepileptic effect of may be related to the up-regulations of GAD 65 and GABAA in the brain. Collectively, we suggested that matrine can be developed as an effective antiseptic drug.

  19. Antiepileptic potential of matrine via regulation the levels of gamma-aminobutyric acid and glutamic acid in the brain.

    Science.gov (United States)

    Xiang, Jun; Jiang, Yugang

    2013-12-05

    Our present study aimed to determine the antiepileptic activity of matrine, and explore the possible molecular mechanism. To evaluate the antiepileptic activity of matrine, seizures in mice induced by PTZ and MES were established, then the pentobarbital sodium-induced anaesthetizing time and locomotor activity tests in mice were also carried out. For the molecular mechanism investigations, contents of aspartic acid (Asp), gamma-aminobutyric acid (GABA), glutamic acid (Glu), glycine (Gly) in seizures mice were determined; then, the chronic seizures rats induced by PTZ were prepared, and western blotting was used to determine the expressions of GAD 65, GABAA and GABAB in the brains. In the results, matrine showed significant antiepileptic effects on seizures mice induced by MES and PTZ. Moreover, the pentobarbital sodium-induced anaesthetizing time and locomotor activity tests were also demonstrated that matrine had obvious antiepileptic effects. Additionally, our results revealed that after treatment with matrine, contents of GABA can be elevated, and the contents of Glu were obviously decreased. Furthermore, western blotting revealed that the mechanism regarding the antiepileptic effect of may be related to the up-regulations of GAD 65 and GABAA in the brain. Collectively, we suggested that matrine can be developed as an effective antiseptic drug.

  20. Drug: D03844 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D03844 Mixture, Drug Phenytoin - phenobarbital - caffeine and sodium benzoate; Hydantol F (TN) Phenytoin...3 Antiepileptics 1139 Others D03844 Phenytoin - phenobarbital - caffeine and sodium benzoate Anatomical Ther...PTICS N03A ANTIEPILEPTICS N03AB Hydantoin derivatives N03AB52 Phenytoin, combinations D03844 Phenytoin - phenobarbital - caffeine and sodium benzoate PubChem: 17397930 ...

  1. Comparative Study on the Effects of Three Kinds of Antiepileptic Drugs on EEG Background of Patients with Epilepsy%三种抗癫痫药对癫痫患者脑电图的背景影响比较研究

    Institute of Scientific and Technical Information of China (English)

    高俊淑; 李娜; 陈景红; 高永谦; 李哲; 杨春清

    2011-01-01

    Objective: To study an compare the effect of three kinds of antiepileptic drugs (phenytoin, sodium valproate, carba-mazepine) on patients with Epilepsy EEG background. Methods: hi our hospital from March 2009 to February 2011, 60 cases of epilepsy patients were randomized to phenytoin (PHT), carbamazepine (CBZ) and valproate (SVP) group with 20 cases in each group. Dynamic observation was performed in all groups of patients to detect the changes of epileptiform discharges frequency and EEG background during treatment period. Results: EEG epileptiform discharges inhibition rate of SVP was most obvious, and EEG background activity effects were stronger in CBZ than other two groups. Conclusions: The order of the three kinds of drugs in suppressing epileptic wave discharge is SVP > PHT > CBZ, and SVP group was significantly better than the other two groups.%目的:研究对比三种抗癫痫药(苯妥因钠、丙戊酸钠、卡马西平)对癫痫患者脑电图的背景影响.方法:选取我院于2009年3月至2011年2月收治的60例癫痫患者,随机分为苯妥因钠(PHT)、卡马西平(CBZ)和丙戊酸钠(SVP)组各20例,动态观察各组患者于治疗期间痫样波放电的频度和EEG背景的变化.结果:EEG痫样波放电的抑制率以SVP最为明显,而CBZ在EEG背景活动影响方面均比其他两组显著.结论:三种药物对癫痫波放电的抑制顺序是SVP> PHT> CBZ,SVP组明显优于其他两组.

  2. Correlation comparative analysis on the high performance liquid chromatography and fluorescence polarization immunoassay in the determination of serum concentrations of antiepileptic drugs%高效液相色谱法与荧光偏振免疫法在抗癫痫药血清浓度测定中的相关性比较分析

    Institute of Scientific and Technical Information of China (English)

    章佳佳

    2013-01-01

    Objective To explore the correlation of two methods of high performance liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA) in the determination of serum concentrations of antiepileptic drugs. Methods The serum of 103 patients with epilepsy treated by phenytoin(PT), phenobarbital(PB) and carbamazepine(CBZ) in our hospital were collected, and the serum concentrations were determined by respectively using HPLC and FPIA and dong linear regression analysis. Results The linear regression equation was YPT=-1.421+1.141X (r=0.963), YPB= -0.128+0.956X (r=0.949), YCBZ=0.183+0.954X (r=0.944), and the value obtained by the two methods showed the linear correlation; The paired t-test showed that the difference was not statistically significant between the both (P > 0.05). Conclusion The serum concentrations of antiepileptic drugs determined by the two methods of HPLC and FPIA is relevant. The determination of serum concentrations of CBZ, PT, PB by using HPLC and FPIA have their pros and cons, the monitoring methods are reasonably chosen by combining with the number of drugs and subjects.%目的:探究HPLC与FPIA两种方法在抗癫痫药血清浓度测定中的相关性。方法采集本院收治的经苯妥英钠(PT)、苯巴比妥(PB)、卡马西平(CBZ)治疗的103例癫痫患者血清,分别采用高效液相色谱法、荧光偏振免疫法测定其血药浓度并进行线性回归分析。结果所得的线性回归方程为YPT=-1.421+1.141X(r=0.963);YPB=-0.128+0.956X(r=0.949);YCBZ=0.183+0.954X(r=0.944),且两种方法测得的值呈线性相关;经配对t检验后,两者差异有统计学意义(P>0.05)。结论高效液相色谱法与荧光偏振免疫法两种方法测定抗癫痫药血清浓度具有相关性。采用HPLC法和FPIA法进行CBZ、PT、PB的血清浓度测定各有利弊,须结合检测药物种类数目、受检人数等合理选择监测方式。

  3. Compulsive gambling possibly associated with antiepileptic medication

    Directory of Open Access Journals (Sweden)

    Susanne Storrier

    2014-01-01

    Full Text Available Compulsive gambling is recognized with Parkinson's disease treatment with dopamine agonists but has not been reported with antiepileptic medications (AEMs in epilepsy. This is the first report regarding possible compulsive gambling, provoked by AEMs in a patient with idiopathic generalized epilepsy, who presented with nonconvulsive status epilepticus, having previously not achieved seizure control with carbamazepine, valproate, (VPA, topiramate, gabapentin (GPT, lamotrigine (LTG, and clobazam. Levetiracetam (LEV was added to VPA and GPT, which the patient was already taking and LTG subsequently retrialed. Following the reintroduction of LTG, she lost $4000–5000, which she concealed. With better seizure control, VPA and GPT were withdrawn, leaving her on LEV and LTG. With increased LTG dosage, she lost $50,000, prompting discovery of her gambling.

  4. Correlation analysis between epilepsy and anti-epileptic drugs and bone mineral density of patients with epilepsy%癫痫病及抗癫痫药物对癫痫患者骨密度影响的相关性分析

    Institute of Scientific and Technical Information of China (English)

    郭华爱; 毓青; 王凤楼; 杨卫东; 陈英; 陈旨娟; 杨二娟

    2013-01-01

    Objective: To investigate the effects of epilepsy and anti-epileptic drugs(AEDs) on bone mineral density(BMD) of patients with epilepsy. Methods: 160 cases aged between 20 and 60 years old were selected as subjects. All of them had the disease for more than nine months and had been taking AEDs for more than six months. All were free of other diseases and none was taking any medication that might interfere with bone metabolism other than AEDs. BMDs at the right heel were measured with the ultrasonic BMD instrument. Detailed clinical information of each patient were obtained by the researcher. All of the related risk factors in the data were stratified according to certain degree. Fifty normal controls were involved. Then single factor chi-square test and multivariate logistic regression analysis were analyzed. Results: There was statistically significant difference between epileptics and normal group in BMD (P0.05). Multivariate logistic regression analysis identified GTCS,polytherapy and the duration of anticonvulsant therapy were as the related and independent risk factors(OR value, 1.105, 5.710, 5.820, respectively; P<0.05). Conclusion: The results indicate that both epilepsy and anti-epileptic drugs can lead to the change of BMD of patients with epilepsy, and GTCS, polytherapy and the duration of anticonvulsant therapy are important risk factors of low BMD. It can be used as valuable reference to prevent bone mass loss and fractures of epileptic patients effectively.%目的:研究癫痫病本身及抗癫痫药物(AEDs)与癫痫患者骨密度(BMD)异常的相关性.方法:采用超声法对160例年龄在20~60岁、病程≥9个月、AEDs治疗时间≥6个月的癫痫患者进行BMD检测,收集相关的临床资料并设置正常对照组50例.根据癫痫的病程、发作类型、服用AEDs的数量及种类、治疗时间分组,分析各组临床指标与骨量异常的相关性.结果:癫痫患者组BMD异常率与正常对照组比较有显著差

  5. Effect on Intelligence in Children with Epilepsy and Adaptabli ty Analysis and Antiepileptic Drug Treatm ent%癫痫儿童智能和适应能力分析及抗癫痫药物治疗的影响

    Institute of Scientific and Technical Information of China (English)

    黄彦思; 林云宾; 冯婉萍; 曾丽韫; 朱国辉; 张美胡

    2015-01-01

    目的:分析癫痫儿童与正常儿童智能和适应能力差别,观察抗癫痫药物治疗前后对智能和适应能力的影响。方法:选择2013年1月至2013年12月我院50例9~16岁癫痫患儿,随机分为两组,分别给予奥卡西平( OXC)和卡马西平( CBZ)治疗,于治疗前和治疗12个月后测试智能和适应能力,并选择同期性别、年龄、父母文化程度与之相匹配的健康检查正常儿童50例设为正常组,采用相同的方法测试智能和适应能力。结果:癫痫组和正常组WISC-R评分中语言IQ、操作IQ及总IQ评分差异无显著性( P>0.05);单项评分中,算术、常识、理解、图片排列、类同、拼图评分差异无显著性( P>0.05);但癫痫儿童背数、译码、填缺评分明显低于正常组(P<0.05)。癫痫组患儿P300潜伏期异常率为28.0%,高于正常组,SLPS正常率为70.0%,低于正常组( P<0.05)。服用抗癫痫药物12个月,CBZ组患儿背数评分较治疗前略有降低,两组语言IQ、操作IQ、总IQ评分及各单项评分较治疗前均略有上升,差异均无显著性( P>0.05);治疗前后两组患儿适应能力比较差异无显著性( P>0.05)。结论:智力正常的癫痫患儿伴有不同程度的适应能力和智能低下,常规抗癫痫药物及新型抗癫痫药物均对智能和适应能力无明显影响,癫痫患儿一旦确诊及时治疗避免疾病造成更严重的智能损害。%Objective:To analyze the difference of intelligence of epileptic children and normal children and the ability to adapt, observe the intelligence and ability to adapt to the effect before and after treatment with antiepileptic drugs.Method: 50 cases of 9~16 years old children with epilepsy in our hospital from January 2013 to December 2013, were randomly divided into two groups, respectively given oxcarbazepine ( OXC) and C Masi Bing ( CBZ) treatment

  6. ucb L059, a novel anti-convulsant drug: pharmacological profile in animals.

    Science.gov (United States)

    Gower, A J; Noyer, M; Verloes, R; Gobert, J; Wülfert, E

    1992-11-10

    The anticonvulsant activity of ucb L059 ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide) was evaluated in a range of animal models. ucb L059 was active after oral and intraperitoneal administration in both rats and mice, with a unique profile of action incorporating features in common with several different types of antiepileptic drugs. The compound was active, with ED50 values generally within the range of 5.0-30.0 mg/kg, in inhibiting audiogenic seizures, electrically induced convulsions and convulsions induced chemically by pentylenetetrazole (PTZ), bicuculline, picrotoxin and N-methyl-D-aspartate (NMDA). ucb L059 retarded the development of PTZ-induced kindling in mice and reduced PTZ-induced EEG spike wave discharge in rats. The R enantiomer, ucb L060, had low intrinsic anticonvulsant activity, showing the stereospecificity of action of the molecule although the actual mechanism of action remains unknown. Neurotoxicity, evaluated with an Irwin-type observation test, the rotarod test and open-field exploration, was minimal, with only mild sedation being observed, even at doses 50-100 times higher than the anticonvulsant doses; at pharmacologically active doses, the animals appeared calm but slightly more active. ucb L059 thus presents as an orally active, safe, broad-spectrum anticonvulsant agent, with potential antiepileptogenic and anti-absence actions.

  7. Antiepileptic Effects of Lacosamide Loaded Polymers Implanted Subdurally in GAERS

    Directory of Open Access Journals (Sweden)

    Sebastien H. Bauquier

    2016-01-01

    Full Text Available The current experiment investigated the ability of coaxial electrospun poly(D,L-lactide-co-glycolide (PLGA biodegradable polymer implants loaded with the antiepileptic drugs (AED lacosamide to reduce seizures following implantation above the motor cortex in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS. In this prospective, randomized, masked experiments, GAERS underwent surgery for implantation of skull electrodes (n=6, skull electrodes and blank polymers (n=6, or skull electrodes and lacosamide loaded polymers (n=6. Thirty-minute electroencephalogram (EEG recordings were started at day 7 after surgery and continued for eight weeks. The number of SWDs and mean duration of one SWD were compared week-by-week between the three groups. There was no difference in the number of SWDs between any of the groups. However, the mean duration of one SWD was significantly lower in the lacosamide polymer group for up to 7 weeks when compared to the control group (0.004

  8. Experimental Assessment of the Efficacy of Five Veterinary Broad-Spectrum Anthelmintics to Control the Intestinal Capillariasis in Zebrafish (Danio rerio).

    Science.gov (United States)

    Samaee, Seyed-Mohammadreza

    2015-06-01

    Zebrafish in research facilities are frequently infected with capillarids. Since the health status (as a nonprotocol source of variation) of zebrafish can affect the validity of experiments, it is important to develop therapies for common zebrafish diseases. Regarding the likelihood of (1) the development of drug resistance and (2) the loss of the efficacy of a drug for laboratory zebrafish, the availability of alternatives for treatment is of direct importance. The efficacy of five dewormers from the same or different therapeutic groups was assessed in the current study. The exposure to each drug was repeated in triplicate (i.e., 3×100 fish in each treatment). The (1) elimination of parasite eggs, larvae, or adults from fresh fecal droppings (as the first main criterion) and (2) dissection of one-third of treated fish (i.e., 100 fish per drug) and examination of their gut contents (as the second major criterion) were considered to verify the efficacy of the drugs to eradicate the infection. Mebendazole (meb), praziquantel (pra; after the first round of treatment, i.e., six-fold administration, twice a day, for 3 days), fenbendazole (fen; after the second round of treatment), and ivermectin (ive; just after two administrations: twice during a day, i.e., a successful treatment with the smallest therapeutic effort) eradicated the infection, while albendazol (alb) was ineffective, although alb in a combined therapy with fen was successful. No age-, sex-, or disease severity-dependent responses to drugs were observed. The meb, pra, and ive were eliminating parasite eggs effectively in contrast with fen (that just was effective on adults). The drugs produced no observable side effects in zebrafish.

  9. Drug: D07647 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 655 D07647.gif Antibiotic, cephalosporin Same as: C06885 ATC code: J01DD01 Semisynthetic cephalosporin: broad spectrum cephalosporin...TAM ANTIBACTERIALS J01DD Third-generation cephalosporins J01DD01 Cefotaxime D07647 Cefotaxime (INN) USP drug

  10. Drug: D07646 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07646 Drug Cefoselis (INN); CFSL C19H22N8O6S2 522.1104 522.558 D07646.gif Antibiotic, cephalosporin... Same as: C11210 Semisynthetic cephalosporin: broad spectrum cephalosporin penicillin bindi

  11. Broad-spectrum Antibiotic Plus Metronidazole May Not Prevent the Deterioration of Necrotizing Enterocolitis From Stage II to III in Full-term and Near-term Infants: A Propensity Score-matched Cohort Study.

    Science.gov (United States)

    Luo, Li-Juan; Li, Xin; Yang, Kai-Di; Lu, Jiang-Yi; Li, Lu-Quan

    2015-10-01

    Necrotizing enterocolitis (NEC) is the most common and frequently dangerous neonatal gastrointestinal disease. Studies have shown broad-spectrum antibiotics plus anaerobic antimicrobial therapy did not prevent the deterioration of NEC among very low birth preterm infants. However, few studies about this therapy which focused on full-term and near-term infant with NEC has been reported. The aim of this study was to evaluate the effect of broad-spectrum antibiotic plus metronidazole in preventing the deterioration of NEC from stage II to III in full-term and near-term infants.A retrospective cohort study based on the propensity score (PS) 1:1 matching was performed among the full-term and near-term infants with NEC (Bell stage ≥II). All infants who received broad-spectrum antibiotics were divided into 2 groups: group with metronidazole treatment (metronidazole was used ≥4 days continuously, 15 mg/kg/day) and group without metronidazole treatment. The depraved rates of stage II NEC between the 2 groups were compared. Meanwhile, the risk factors associated with the deterioration of stage II NEC were analyzed by case-control study in the PS-matched cases.A total of 229 infants met the inclusion criteria. Before PS-matching, we found the deterioration of NEC rate in the group with metronidazole treatment was higher than that in the group without metronidazole treatment (18.1% [28/155] vs 8.1% [6/74]; P = 0.048). After PS-matching, 73 pairs were matched, and the depraved rate of NEC in the group with metronidazole treatment was not lower than that in the group without metronidazole treatment (15.1% vs 8.2%; P = 0.2). Binary logistic regression analysis showed that sepsis after NEC (odds ratio [OR] 3.748, 95% confidence interval [CI] 1.171-11.998, P = 0.03), the need to use transfusion of blood products after diagnosis of NEC (OR 8.003, 95% CI 2.365-27.087, P = 0.00), and the need of longer time for nasogastric suction were risk factors for stage II NEC progressing to

  12. 颅脑损伤后预防应用抗癫痫药物疗效Meta分析%Effect of antiepileptic drugs on prevention of epilepsy after craniocerebral injury: a Meta-analysis

    Institute of Scientific and Technical Information of China (English)

    张策; 李廷昱; 范青; 尹健; 李桂茹; 吕慧怡; 张宁; 范广俊; 郝堂娜; 罗晓燕

    2011-01-01

    目的 探讨颅脑损伤后应用抗癫痫药(AEDs)预防创伤后癫痫的疗效.方法 广泛检索PubMed、Ovid、Springer、维普、CNKI等数据库,对相关文献进行严格评价,最终纳入的21篇文献通过Meta分析,研究预防应用AEDs对创伤后早期、晚期癫痫是否有作用,研究颅脑损伤类型(外伤、颅脑手术)对预防用药效果的影响及预防用药后患者死亡率等情况.结果 在对预防用药是否有意义评价中,差异有统计学意义(OR=0.66,Z=4.310,P=0.000),故支持给药;在对早期癫痫预防用药效果评价中,差异有统计学意义(OR=0.48,Z=3.980,P=0.000),苯妥英钠组(OR=0.53)比卡马西平组(OR=0.40)对早期癫痫的预防效果更优;在对晚期癫痫预防用药效果评价中,差异没有统计学意义(OR=1.05,Z=0.310,P=0.760);在对不同类型颅脑损伤预防用药效果评价中,都具有应用意义(脑外伤OR=0.48,颅脑手术OR=0.69);在预防用药对死亡率影响比较分析中,对患者的死亡率都没有影响(OR=0.82,Z=0.920,P=0.360).结论 在已研究的药物范围内,颅脑损伤后预防性应用AEDs可使癫痫发病率明显降低;苯妥英钠对早期癫痫的预防效果较好;各类AEDs对晚期癫痫的预防效果差异无统计学意义;在外伤后癫痫和颅脑手术后癫痫患者中预防应用AEDs效果无明显差异;预防应用AEDs后对患者死亡率没有明显影响.%Objective To determine the efficacy ofantiepileptic drugs (AEDs) on prevention of epilepsy after craniocerebral injury. Methods Related articles searched from the databases such as PubMed, Ovid, Springer, VP and CNKI were collected and strictly evaluated; 21 articles were finally selected. Whether pretreatment with AEDs played its role in epilepsy appeared in the early/late stages was discussed with Meta-analysis; the influences of different craniocerebral injury types (resulting from trauma or surgery) on the efficacy of anti-epilepsy prophylaxis, and the mortality rate of

  13. Drug: D08964 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08964 Drug Perampanel (USAN); Fycompa (TN) C23H15N3O 349.1215 349.3847 D08964.gif ...ATC) classification [BR:br08303] N NERVOUS SYSTEM N03 ANTIEPILEPTICS N03A ANTIEPILEPTICS N03AX Other antiepileptics N03AX22 Perampane...l D08964 Perampanel (USAN) USP drug classification [BR:br08302] Anticonvulsants Glu...tamate Reducing Agents Perampanel D08964 Perampanel (USAN) Target-based classific...PA receptor [HSA:2890 2891 2892 2893] [KO:K05197 K05198 K05199 K05200] Perampanel [ATC:N03AX22] D08964 Perampanel

  14. Drug: D02103 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02103 Drug Phenytoin sodium for injection (JP16); Phenytoin sodium (USP); Aleviati...egory: 1132 ATC code: N03AB02 Hydantoins There is a strong association between the risk of developing SJS/TEN with Phenytoin... central nervous system 113 Antiepileptics 1132 Hydantoins D02103 Phenytoin sodiu...303] N NERVOUS SYSTEM N03 ANTIEPILEPTICS N03A ANTIEPILEPTICS N03AB Hydantoin derivatives N03AB02 Phenytoin D02103 Phenytoin... sodium for injection (JP16); Phenytoin sodium (USP) USP drug clas

  15. Drug: D05775 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D05775 Drug Rufinamide (JAN/USAN/INN); Banzel (TN) C10H8F2N4O 238.0666 238.1935 D05...03 ANTIEPILEPTICS N03A ANTIEPILEPTICS N03AF Carboxamide derivatives N03AF03 Rufinamide D05775 Rufinamide (JAN/USAN/INN) USP dru... Therapeutic category of drugs in Japan [BR:br08301] 1 Agents affecting nervous system and sensory organs 11... Agents affecting central nervous system 113 Antiepileptics 1139 Others D05775 Ru...g classification [BR:br08302] Anticonvulsants Sodium Channel Agents Ru

  16. Drug: D02716 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02716 Drug Pregabalin (JAN/USAN/INN); Lyrica (TN) C8H17NO2 159.1259 159.2261 D0271...6.gif Anticonvulsant Therapeutic category: 1190 ATC code: N03AX16 GABA [CPD:C00334] analog Pregabalin binds ...C) classification [BR:br08303] N NERVOUS SYSTEM N03 ANTIEPILEPTICS N03A ANTIEPILEPTICS N03AX Other antiepileptics N03AX16 Pregabalin... D02716 Pregabalin (JAN/USAN/INN) USP drug classification [BR:br08302] Anticonvulsan...ts Calcium Channel Modifying Agents Pregabalin D02716 Pregabalin (JAN/USAN/INN) C

  17. Adult epileptic patients’ perception of social support during rational antiepileptic therapy

    Directory of Open Access Journals (Sweden)

    P. N. Vlasov

    2012-01-01

    Full Text Available The problem of stigmatization of a patient with epilepsy is frequently essential in restricting the capacities of his social performance. Society is often unready to recognize an epileptic patient as its equal member. The authors consider the main sources of social support (SS to patients with epilepsy: the patient’s family takes first place; friends and other important persons also play a major role. The perception of SS has been found to be related to the number of used antiepileptic drugs and the hemispheric lateralization of a leading epileptic focus.

  18. Essential Oils and Non-volatile Compounds Derived from Chamaecyparis obtusa: Broad Spectrum Antimicrobial Activity against Infectious Bacteria and MDR(multidrug resistant) Strains.

    Science.gov (United States)

    Bae, Min-Suk; Park, Dae-Hun; Choi, Chul-Yung; Kim, Gye-Yeop; Yoo, Jin-Cheol; Cho, Seung-Sik

    2016-05-01

    The aim of this study was to evaluate the antibacterial activity of essential oil from Chamaecyparis obtusa against general infectious microbes and drug resistant strains of clinical origin. The results indicate that both essential oil and non-volatile residue have broad inhibitory activity against test strains. Essential oil and non-volatile residues showed antimicrobial activity not only against general infectious bacteria, but also against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) strains.

  19. Galleria mellonella: an in vivo model for accessing the efficacy of colistin in combination with broad spectrum antibiotics against biofilm forming Acinetobacter baumannii infections

    OpenAIRE

    Gillett, Alice Rose

    2015-01-01

    The emergence of opportunistic nosocomial bacteria Acinetobacter baumannii, which causes infections in critically ill patients with compromised immune systems, is one of the most clinically challenging pathogens to treat effectively. Most nosocomial pathogens grow as monoculture or poly-species biofilms in infections and the biofilm mode of existence for A. baumannii may almost certainly contribute to its increased multi-drug resistant (MDR), although resistance can also be attributed to m...

  20. Broad spectrum analgesic efficacy of IBNtxA is mediated by exon 11-associated splice variants of the mu-opioid receptor gene

    Science.gov (United States)

    Wieskopf, Jeffrey S.; Pan, Ying-Xian; Marcovitz, Jaclyn; Tuttle, Alexander H.; Majumdar, Susruta; Pidakala, John

    2014-01-01

    Mu-opioids remain vastly important for the treatment of pain, and would represent ideal analgesics if their analgesic effects could be separated from their many side effects. A recently synthesized compound, iodobenzoylnaltrexamide (IBNtxA), acting at 6-transmembrane (6-TM) splice variants of the mu-opioid receptor gene, was shown to have potent analgesic actions against acute, thermal pain accompanied by a vastly improved side-effect profile compared to 7-TM-acting drugs such as morphine. Whether such analgesia can be seen in longer-lasting and non-thermal algesiometric assays is not known. The current study demonstrates potent and efficacious IBNtxA inhibition of a wide variety of assays, including inflammatory and neuropathic hypersensitivity and spontaneous pain. We further demonstrate the dependence of such analgesia on 6-TM mu-opioid receptor variants using isobolographic analysis and the testing of Oprm1 (the mu-opioid receptor gene) exon 11 null mutant mice. Finally, the effect of nerve damage (spared nerve injury) and inflammatory injury (complete Freund’s adjuvant) on expression of mu-opioid receptor variant genes in pain-relevant central nervous system loci was examined, revealing a downregulation of the mMOR-1D splice variant in the dorsal root ganglion after spared nerve injury. These findings are supportive of the potential value of 6-TM-acting drugs as novel analgesics. PMID:25093831

  1. Effects of valproate derivatives I. Antiepileptic efficacy of amides, structural analogs and esters.

    Science.gov (United States)

    Redecker, C; Altrup, U; Hoppe, D; Düsing, R; Speckmann, E J

    2000-01-04

    Derivatives of the antiepileptic drug valproate (VPA, 2-propylpentanoic acid) have been synthesized and tested in order to improve the intracellular availability of VPA. The buccal ganglia of Helix pomatia were used as a test nervous system and antiepileptic efficacies were reconfirmed using rat cortex in vivo. Epileptiform activities consisted of typical paroxysmal depolarization shifts (PDS) which appeared in the identified neuron B3 with application of pentylenetetrazol. Epileptiform activities were found to be accelerated, unaffected or blocked. (i) The Amide-derivatives 2-propylpentanamide and N,N-dipropyl-2-propylpentanamide, and short chain ester derivatives 1-O-(2-propylpentanoyl)-2,3-propandiol, 2,2-di(hydroxymethyl)-1-O-(2-propylpentanoyl)-1,3-propanediol and 2,2-di(hydroxymethyl)-1,3-di-O-(2-propylpentanoyl)-1,3-propanediol accelerated epileptiform activities. Membrane potential often shifted to a permanent depolarization which corresponded to the PDS-inactivation level. (ii) The structural analogs 1-cycloheptene-1-carboxylic acid and cyclooctanecarboxylic acid accelerated epileptiform activities only slightly or were without effects. (iii) The small VPA-ester, 2-propylpentanoic acid ethyl ester, decreased the epileptiform activities in a way that is comparable to the effects of VPA well known from previous studies. It thus could be thought as a VPA-pro-drug. (iv) The mannitol-esters 1-O-(2-propylpentanoyl)-D-mannitol and 3,4;5,6-Di-O-isopropylidene-1-O-(2-propylpentanoyl)-D-mannitol blocked the PDS in a way which is different from the known effects of VPA. These substances are interpreted not to exert their effects after being metabolized to VPA and thus they are thought to be new antiepileptic substances.

  2. Effect of antiepileptic drug (valproic acid on children growth

    Directory of Open Access Journals (Sweden)

    Hussein Metwally Abdel Maksoud

    2016-06-01

    Conclusion: Childhood and adolescence are crucial periods in which to attain peak bone mass, and it is a crucial period for growth in general; and most patients with epilepsy are diagnosed and treated in this period, therefore, AEDs, and especially VPA, should be used with caution in pediatric patients with epilepsy.

  3. Antiepileptic drug prescribing before, during and after pregnancy

    DEFF Research Database (Denmark)

    Charlton, Rachel; Garne, Ester; Wang, Hao;

    2015-01-01

    and after pregnancy were identified in each of the databases. AED prescribing patterns were analysed, and the choice of AEDs and co-prescribing of folic acid were evaluated. Results In total, 978 957 women with 1 248 713 deliveries were identified. In all regions, AED prescribing declined during pregnancy...... co-prescribed with high-dose folic acid: ranging from 1.0% (CI950.3–1.8%) in Emilia Romagna to 33.5% (CI9528.7–38.4%) in Wales. Conclusion The country's differences in prescribing patterns may suggest different use, knowledge or interpretation of the scientific evidence base. The low co......-prescribing of folic acid indicates that more needs to be done to better inform clinicians and women of childbearing age taking AEDs about the need to offer and receive complete preconception care....

  4. [Combined treatment with antiepileptic drugs. Andalusian Epilepsy Guide 2015].

    Science.gov (United States)

    Sánchez-Álvarez, Juan C; Ramos-Lizana, Julio; Machado-Casas, Irene S; Serrano-Castro, Pedro J; Martínez-Antón, Jacinto L; Ruiz-Giménez, Jesús

    2015-04-16

    Objetivo. Elaborar unas recomendaciones basadas en evidencias cientificas y en consenso de los autores y revisores, que aborden las cuestiones basicas acerca de la combinacion de farmacos antiepilepticos. Desarrollo. Un comite de 11 expertos pertenecientes a la Sociedad Andaluza de Epilepsia (SAdE), constituido por siete neurologos, tres neuropediatras y un neurologo-neurofisiologo, todos con especial competencia en epilepsia, promovieron la realizacion de una revision bibliografica exhaustiva entre 55 expertos en epilepsia pertenecientes a la SAdE, en busca de evidencias disponibles relacionadas con temas diagnosticos o terapeuticos en epilepsia. La guia se estructuro en 35 capitulos. Uno de los capitulos abordo la combinacion de farmacos antiepilepticos en el tratamiento de la epilepsia. Basandose en 77 citas bibliograficas y en la opinion consensuada de autores y revisores, se confecciono una serie de recomendaciones de facil aplicacion. Conclusiones. La combinacion de farmacos antiepilepticos en los pacientes con epilepsia cuyas crisis no estan controladas con un solo farmaco puede conseguir en numerosas ocasiones que entren en remision. Existe una serie de factores relacionados con el tipo de epilepsia y caracteristicas del paciente y con los farmacos antiepilepticos que se van a utilizar en combinacion que pueden favorecer el exito terapeutico. Se debe evitar en lo posible el sobretratamiento con la combinacion de farmacos antiepilepticos. Los resultados de esta revision proveen unas recomendaciones sobre el tratamiento combinado con farmacos antiepilepticos, basadas en evidencias cientificas y en el consenso de los autores, utiles, sencillas y aplicables en los diferentes niveles asistenciales.

  5. PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.

    Directory of Open Access Journals (Sweden)

    Monica Puligheddu

    Full Text Available Nicotinic acetylcholine receptors (nAChRs are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-α (PPARα, nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing β2 subunits. On these bases, we tested whether PPARα agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ∼100% of mice. A single dose of the synthetic PPARα agonist WY14643 (WY, 80 mg/kg, i.p. or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2% for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARα antagonist MK886 (3 mg/kg, i.p.. Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARα agonists abolished nicotine-induced sIPSC increases. PPARα within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role.

  6. [Epilepsy and cognition: the role of antiepileptic drugs].

    Science.gov (United States)

    García-Peñas, Juan José; Fournier-Del Castillo, M Concepción; Domínguez-Carral, Jana

    2014-02-24

    Introduccion. Multiples y muy diversos factores se relacionan con la alteracion cognitiva en la epilepsia, incluyendo el efecto adverso directo de los farmacos antiepilepticos (FAE). El uso de los FAE requiere de un riguroso equilibrio entre riesgo y beneficio para conseguir asi el mejor control de las crisis con el menor numero de efectos adversos neurocognitivos. Objetivo. Analizar los efectos adversos cognitivos generales y especificos de los FAE de primera, segunda y tercera generacion. Desarrollo. Todos los FAE disponibles pueden producir efectos adversos cognitivos, que son mas frecuentes en politerapia, con dosis totales altas y niveles sericos elevados. Las alteraciones mas comunes son el descenso de la capacidad de reaccion y de la velocidad de procesamiento con afectacion concomitante de la memoria, la atencion y el lenguaje. Sin embargo, hay gran controversia sobre la existencia o no de perfiles cognitivos especificos para cada uno de los distintos FAE y se dispone de una informacion contradictoria al respecto por la inadecuada metodologia de los estudios comparativos. Conclusiones. Los efectos adversos cognitivos de los FAE son frecuentes y pueden afectar negativamente la tolerabilidad, el cumplimiento y el mantenimiento a largo plazo del tratamiento antiepileptico. Se debe considerar el potencial efecto adverso cognitivo de los distintos FAE a la hora de elegir un tratamiento y es importante reconocer e identificar precozmente estos efectos adversos y saber como pueden afectar a los pacientes.

  7. A novel method to depurate β-lactam antibiotic residues by administration of a broad-spectrum β-lactamase enzyme in fish tissues

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    Young-Sik Choe

    2016-12-01

    Full Text Available Abstract As a novel strategy to remove β-lactam antibiotic residues from fish tissues, utilization of β-lactamase, enzyme that normally degrades β-lactam structure-containing drugs, was explored. The enzyme (TEM-52 selectively degraded β-lactam antibiotics but was completely inactive against tetracycline-, quinolone-, macrolide-, or aminoglycoside-structured antibacterials. After simultaneous administration of the enzyme with cefazolin (a β-lactam antibiotic to the carp, significantly lowered tissue cefazolin levels were observed. It was confirmed that the enzyme successfully reached the general circulation after intraperitoneal administration, as the carp serum obtained after enzyme injection could also degrade cefazolin ex vivo. These results suggest that antibiotics-degrading enzymes can be good candidates for antibiotic residue depuration.

  8. Prenatal antiepileptic exposure associates with neonatal DNA methylation differences.

    Science.gov (United States)

    Smith, Alicia K; Conneely, Karen N; Newport, D Jeffrey; Kilaru, Varun; Schroeder, James W; Pennell, Page B; Knight, Bettina T; Cubells, Joseph C; Stowe, Zachary N; Brennan, Patricia A

    2012-05-01

    Antiepileptic drugs (AEDs) are used to treat a variety of neuropsychiatric illnesses commonly encountered in women during their reproductive years, including epilepsy and bipolar disorder. Despite their widespread use, the impact of prenatal exposure on fetal development remains obscure. To evaluate whether AEDs taken by pregnant mothers influence DNA methylation patterns in their neonates, DNA was extracted from the umbilical cord blood of 201 neonates whose mothers were treated for neuropsychiatric illness during pregnancy and interrogated across 27,578 CpG sites using the Illumina HumanMethylation27 BeadChip. The association of each methylation value with the cumulative duration of prenatal AED exposure was examined using a linear mixed model. The average methylation level across all CpG sites was calculated for each subject, and this global methylation measure was evaluated similarly. Neonates with a longer duration of AED exposure in pregnancy showed a decrease in average global methylation (p = 0.0045). Further, DNA methylation of CpG sites in 14 genes significantly decreased with the duration of prenatal AED exposure even after adjusting for multiple comparisons (FDR < 0.05). For a small subset (n = 19) of these neonates, a second tissue, placenta, was available in addition to cord blood. Methylation of 3 of these 14 CpG sites was also significantly decreased in placental tissue. These novel data suggest decreased DNA methylation in neonates of mothers who took AEDs during pregnancy. The long-term stability and potential impact of these changes warrant further attention, and caution may be warranted before prescribing AEDs to pregnant women.

  9. Intranasal delivery of antiepileptic medications for treatment of seizures.

    Science.gov (United States)

    Wermeling, Daniel P

    2009-04-01

    Acute isolated seizure, repetitive or recurrent seizures, and status epilepticus are all deemed medical emergencies. Mortality and worse neurologic outcome are directly associated with the duration of seizure activity. A number of recent reviews have described consensus statements regarding the pharmacologic treatment protocols for seizures when patients are in pre-hospital, institutional, and home-bound settings. Benzodiazepines, such as lorazepam, diazepam, midazolam, and clonazepam are considered to be medications of first choice. The rapidity by which a medication can be delivered to the systemic circulation and then to the brain plays a significant role in reducing the time needed to treat seizures and reduce opportunity for damage to the CNS. Speed of delivery, particularly outside of the hospital, is enhanced when transmucosal routes of delivery are used in place of an intravenous injection. Intranasal transmucosal delivery of benzodiazepines is useful in reducing time to drug administration and cessation of seizures in the pre-hospital setting, when actively seizing patients arrive in the emergency room, and at home where caregivers treat their dependents. This review summarizes factors to consider when choosing a benzodiazepine for intranasal administration, including formulation and device considerations, pharmacology and pharmacokinetic/pharmacodynamic profiles. A review of the most relevant clinical studies in epilepsy patients will provide context for the relative success of this technique with a number of benzodiazepines and relatively less sophisticated nasal preparations. Neuropeptides delivered intranasally, crossing the blood-brain barrier via the olfactory system, may increase the availability of medications for treatment of epilepsy. Consequently, there remains a significant unmet medical need to serve the pharamcotherapeutic requirements of epilepsy patients through commercial development and marketing of intranasal antiepileptic products.

  10. The Effectiveness of Mood Stabilizers and Antiepileptic Medication for the Management of Behaviour Problems in Adults with Intellectual Disability: A Systematic Review

    Science.gov (United States)

    Deb, S.; Chaplin, R.; Sohanpal, S.; Unwin, G.; Soni, R.; Lenotre, L.

    2008-01-01

    Background: Psychotropic medications are used to manage behaviour problems in adults with intellectual disability (ID). One group of psychotropic medication are mood stabilizers such as lithium and some antiepileptic drugs. Method: A comprehensive systematic review was performed to determine the evidence base for the effectiveness of mood…

  11. Epilepsy, anti-epileptic medication use and risk of cancer

    DEFF Research Database (Denmark)

    Kaae, Jeanette; Carstensen, Lisbeth; Wohlfahrt, Jan

    2014-01-01

    Whether the powerful medications used to treat epilepsy increase the risk of cancer has been debated for decades, but until now no study could disentangle the contributions of anti-epileptic medications and epilepsy itself to cancer risk. Using a cohort comprising all Danish residents ≥ 16 years...... old at some point during the period 1996-2010 (>56 million person-years of follow-up) and information from national health registers, we examined associations between anti-epileptic medication use and cancer rates in persons with and without epilepsy, and between epilepsy and cancer rates in treated...... and untreated individuals. Associations were expressed as incidence rate ratios (IRRs) estimated using Poisson regression. Among persons without epilepsy, use of anti-epileptic medication increased the rates of most cancers little or not at all, although we observed moderately increased rates of liver, mouth...

  12. Bone mineral density and serum levels of 25 OH vitamin D in chronic users of antiepileptic drugs Densidade mineral óssea e níveis séricos de 25 OH vitamina D em usuários crônicos de drogas antiepilépticas

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    Carolina A.M. Kulak

    2004-12-01

    Full Text Available The aim of this cross sectional study was to evaluate bone mineral density (BMD and serum levels of 25-hydroxy vitamin D (25OHD in a group of patients taking antiepileptic drugs (AED for a seizure disorder. Between May-2001 and January-2003, we evaluated 58 patients (40 women/18 men, 34.4±6 years old living in Curitiba or in its metropolitan area, on antiepileptic therapy for 2 to 38 years (10 on monotherapy /48 on multiple drugs regime. The group was matched by age, gender, and bone mass index to 29 healthy subjects (20 women/ 9 men; 34.2±5.9 years old. Medical history and physical exam were performed on all subjects with particular information sought about fractures and risks factors for osteoporosis. Blood samples were collected for total serum calcium, albumin, phosphorus, creatinine, total alkaline phosphatase, and liver function tests. BMD of the lumbar spine, femur and forearm was determined by dual energy X-ray absorptiometry (DXA, Hologic QDR 1000. Between February and April-2003, other blood samples were collected to measure 25OHD, intact paratohormone (PTH and calcium. Unemployment and smoking history were more frequent among patients than among controls (pO objetivo deste estudo transversal foi avaliar a densidade mineral óssea (DMO e os níveis de 25hidroxi vitamina D (25OHD em um grupo de pacientes com epilepsia e usuários crônicos de drogas antiepilépticas (DAE. Entre maio-2001 e janeiro-2003 avaliamos 58 pacientes (40 mulheres/18 homens residentes em Curitiba ou região metropolitana da cidade, com média de idade 34,4±6 anos e tempo de tratamento entre 2 e 38 anos (10 em monoterapia/48 em politerapia. O grupo de pacientes foi emparelhado por idade, sexo e índice de massa corpórea com 29 indivíduos aparentemente sadios (20 mulheres/9 homens; 34,2±5,9 anos. Pacientes e controles foram submetidos a anamnese e exame clínico, com ênfase na história de fraturas e fatores de risco para osteoporose. Nas visitas foram

  13. Repair of abnormal perfusion foci in idiopathic epilepsy patients under long-term antiepileptic treatment

    Institute of Scientific and Technical Information of China (English)

    Weimin Wang; Siyu Zhao; Yaqing Liu

    2011-01-01

    Epileptic seizure control and the disappearance of epileptiform discharge are not indicative of the absence of abnormal perfusion foci.Perfusion abnormalities are a major cause of epileptic discharge, and the existence of abnormal perfusion foci implies possible relapse.Very little is known about perfusion abnormality repair in epilepsy.The present study selected 43 cases of idiopathic epilepsy under antiepileptic drug control for an average of 24 months.Comparisons between interictal single-photon emission CT (SPECT)images and long-term electroencephalogram (EEG) pre- and post-treatment showed that cases of normal SPECT increased by 48% (12/25) following treatment, with a total number of 15 reduced foci (36%, 15/41).Perfusion foci, i.e., region of interest, were altered following treatment.These changes included:normal to abnormal in 3 cases (7%, 3/43; 2 hyperperfusion and 1 hypoperfusion); abnormal to normal in 14 cases (32%, 14/43; 10 pre-treatment hypoperfusion and 4 hyperperfusion); abnormal to abnormal in 7 cases (16%, 7/43; hyperperfusion to hypoperfusion in 5 cases, hypoperfusion to hyperperfusion in 2 cases).Long-term EEG revealed in an increase in the number of normal cases by 20 (40%, 20/39), and there were 25 fewer cases with epileptiform discharges (66%, 25/38).These findings demonstrate that long-term control of anti-epileptic drugs partially repaired cerebral perfusion abnormalities and reduced epileptiform discharges in idiopathic epilepsy.

  14. Use of antiepileptic or benzodiazepine medication and suicidal ideation--The Northern Finland Birth Cohort 1966.

    Science.gov (United States)

    Rissanen, I; Jääskeläinen, E; Isohanni, M; Koponen, H; Ansakorpi, H; Miettunen, J

    2015-05-01

    Both antiepileptic drugs (AEDs) and benzodiazepines (BZDs) have previously been associated with an increased risk of suicidality. Our aim was to study the association between the use of conventional AEDs and BZDs and suicidal ideation in a large population-based cohort. Information on the medications used in the Northern Finland Birth Cohort 1966 was collected from the subjects at the age of 31 years, using a postal questionnaire (N=8211). The presence of suicidal ideation and other symptoms of depression and anxiety was assessed via the Hopkins Symptom Checklist - 25 questionnaire. The associations between medications and suicidal ideation were studied in different diagnostic groups and adjusted for symptoms of depression and anxiety. No difference was observed in suicidal ideation between AED users (n=54) and nonusers (n=8157). Subjects using BZDs (n=147) had greater suicidal ideation compared with nonusers (n=8064). Antiepileptic drug and benzodiazepine users more often exhibited other depression and anxiety symptoms. After adjustment for these symptoms, both AED and BZD users had less suicidal ideation compared with nonusers. In conclusion, in this population-based cohort, neither the use of AEDs nor that of BZDs was found to be associated with increased suicidal ideation when the symptoms of depression and anxiety were taken into account.

  15. The evaluation of 25-hydroxy vitamin D, calcium, phosphate and alkaline phosphatase levels in epileptic children under antiepileptic medication

    Directory of Open Access Journals (Sweden)

    Keyhani doost Z

    2011-01-01

    Full Text Available "n 800x600 Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 st1":*{behavior:url(#ieooui } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman","serif";} Background: Epilepsy is a common disease in the pediatric neurology. There are frequent anti-epileptic drugs which are used in management of epilepsy. Anti-epileptic drugs may have some complications on bone and vitamin-D metabolism. In this study we aimed to evaluate vitamin-D metabolism in epileptic children."n"nMethods: The study was a prospective and cross sectional one. A total 89 epileptic children who were taking anti-epileptic drugs for longer than six months with no underlying disorder in Imam Khomeini and Bahrami Hospitals in Tehran, Iran were enrolled in our study"n"nResults: Forty nine boys and 40 girls were enrolled in this study; mean age of the patients was 7.8±2.1 years. Mean duration of anti-epileptic drug therapy was 2.3 years (SD=0.4, 70 of patients were under monotherapy and 19 were under polytherapy. None of the patients had signs of rickets. Serum calcium and phosphor levels were within normal ranges. Serum alkaline phosphates levels were increased more than two times in 43%. 42% had vitamin-D deficiency (25-OH Vit D<10 ng/ml and another 33% had vitamin-D insufficiency (10<25-oh Vit D<20 ng/ml. 29 patients (32% were taking prophylactic supplemental Vit D (200-400 IU/day. There was significant difference between patients taking supplemental vitamin-D as prophylaxis and patients who did not (p=0.04. There was no significant difference in vitamin-D levels between patients according to age, gender or different drugs."n"nConclusion: Periodic

  16. Role of piracetam on cognitive function in epilepsy and with antiepileptics in rats

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    Siddharth R. Chaudhari

    2013-10-01

    Full Text Available Background: To study extent of cognitive impairment by epilepsy & antiepileptic treatment and evaluate the role of piracetam on it. Methods: 48 animals were divided into 6 groups: I-Control, II- Topiramate, III-Topiramate+Piracetam, IV-Valproate, V-Valproate+Piracetam, VI-Piracetam. Baseline cognitive functions were measured using Cook’s pole climbing apparatus (CPCA and Elevated plus maze (EPM. In CPCA, on completion of training, number of avoidances (NOA out of 10 trials were noted while in EPM, transfer latency (TL was measured. Kindling was induced by 30mg/kg Pentylenetetrazol (PTZ, i.p. to all groups (except Group I on alternate days till seizures developed. Groups were treated with respective drugs orally for 21 days and cognitive functions measured again. Results: Significant decrease in NOA & increase in TL was observed after PTZ kindling. Topiramate further significantly impaired NOA and TL whereas Valproate significantly reduced NOA in CPCA but increase in TL was not significant. Treatment with Piracetam significantly increased Topiramate, Valproate and PTZ kindling induced decrease in NOA as also significantly reduced Topiramate and PTZ kindling induced increase in TL. Conclusion: Seizures are associated with cognitive impairment. Cognitive impairment caused by Sodium valproate differs from Topiramate. Piracetam, a known nootropic can be used in alleviating cognitive impairment associated with epilepsy & chronic antiepileptic therapy. [Int J Basic Clin Pharmacol 2013; 2(5.000: 634-639