Co-prescription of antiepileptic drugs and contraceptives

NARCIS (Netherlands)

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

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

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

Science.gov (United States)

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

2010-12-31

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

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

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 drug...... combinations, most of these drug interactions are predictable and, thus, avoidable. Unfortunately, there is a substantial lack of data regarding the newer AEDs. Detailed understanding of these issues is necessary for those who prescribe AEDs and/or hormonal contraception to women with epilepsy, as well...

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. Copyright © 2015. Published by Elsevier Ltd.

Levels of Antiepileptic Drugs and the Ketogenic Diet

Directory of Open Access Journals (Sweden)

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.

Broad spectrum antiangiogenic treatment for ocular neovascular diseases.

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Ofra Benny

2010-09-01

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

Managing antiepileptic drugs during pregnancy and lactation

DEFF Research Database (Denmark)

Sabers, Anne; Tomson, Torbjörn

2009-01-01

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

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

NARCIS (Netherlands)

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

2003-01-01

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

The Effects of Antiepileptic Drugs on Classroom Performance

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Titus, Jeffrey B.; Thio, Liu Lin

2009-01-01

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

Pharmacokinetic interactions between contraceptives and antiepileptic drugs

DEFF Research Database (Denmark)

Sabers, A.

2008-01-01

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

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 inve...

Antiepileptic Drug Behavioral Side Effects in Individuals with Mental Retardation and the Use of Behavioral Measurement Techniques.

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Kalachnik, John E.; And Others

1995-01-01

Behavioral psychology measurement methods helped assess antiepileptic drug behavioral side effects in five individuals with mental retardation who could not verbally communicate presence of side effects. When the suspected antiepileptic drug was altered, an 81% reduction of maladaptive behaviors occurred. The measurement methods enabled systematic…

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

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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.

The role side effects play in the choice of antiepileptic therapy in brain tumor-related epilepsy: a comparative study on traditional antiepileptic drugs versus oxcarbazepine

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Maschio, Marta; Dinapoli, Loredana; Vidiri, Antonello; Pace, Andrea; Fabi, Alessandra; Pompili, Alfredo; Carapella, Maria Carmine; Jandolo, Bruno

2009-01-01

Background Seizure control doesn't represent the only challenging goal in patients with brain tumor-related epilepsy. Side effects have often taken precedence for patients' quality of life. Methods We performed an observational retrospective study on patients with brain tumor-related epilepsy: 35 who had assumed oxcarbazepine monotherapy and 35 patients who had undergone treatment with traditional antiepileptic drugs. Primary variable of efficacy was the mean seizure frequency per month and safety variables were the drop-out for side effects and total incidence of side effects. We applied the Propensity Score technique to minimize selection bias. Results Our results showed a similar efficacy of oxcarbazepine and traditional antiepileptic drugs over time, but the difference in safety and tolerability between the two groups was significant: traditional AEDs caused more side effects, both serious and non serious. Conclusion This study highlights the importance of taking into consideration not only seizure control but also the appearance of side effects when choosing antiepileptic drugs in this patients population. PMID:19419544

The new generation of antiepileptic drugs: advantages and disadvantages.

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Perucca, E

1996-11-01

1. After a hiatus of over 20 years, several new antiepileptic drugs (vigabatrin, lamotrigine, gabapentin, oxcarbazepine, topiramate, felbamate, zonisamide and tiagabine) have reached or approached the registration phase. 2. Compared with older agents, many new drugs exhibit simpler pharmacokinetics. This is especially true for vigabatrin and gabapentin, which are renally eliminated and have a low interaction potential. 3. Unlike most of the older agents, vigabatrin, lamotrigine, gabapentin and tiagabine are devoid of significant enzyme inducing or inhibiting properties. Topiramate, oxcarbazepine and felbamate may induce the metabolism of steroid oral contraceptives. In addition, felbamate also acts as a metabolic inhibitor. 4. To date, the efficacy of new drugs has been evaluated extensively only under add-on conditions in patients with partial seizures (with or without secondary generalization) refractory to conventional treatment. However, there is evidence that lamotrigine, zonisamide, felbamate and, possibly, topiramate may also be effective in generalized epilepsies. 5. In placebo-controlled studies, typically between 15 and 40% of patients with difficult-to-treat partial epilepsy have shown an improvement (defined as a 50% or greater decrease in seizure frequency) after addition of a new drug. Only a small minority of these patients achieved complete seizure control. 6. Compared with older agents, some of the new drugs may have a better tolerability profile. Felbamate, however, has been associated with a high risk of aplastic anaemia and hepatotoxicity. 7. At present, the main use of the new agents is in patients refractory to first-line drugs such as carbamazepine or valproate, and further studies are required to characterize their activity spectrum as well as their potential value in monotherapy. In most patients, new drugs cannot be recommended for first-line use until evidence is obtained that potential advantages in tolerability or ease of use outweigh

Novel Hybrid Anticonvulsants Derived from Pyrrolidine-2,5-dione Scaffold with Broad Spectrum of Activity in the Preclinical Studies.

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Kaminski, Krzysztof

2017-01-01

The multifunctional ligands application is an emerging approach in drug delivery, mainly in the treatment of diseases with complex pathology, such as Alzheimer's, cancer, and epilepsy. Using this method many biomolecules with different properties are combined to form a single unit that can provide a complex broad spectrum activity. Thus, a new type of hybrid anticonvulsants based on the pyrrolidine-2,5-dione frame are detailed with the aim of acquiring more effective antiepileptic drugs (AED) that could suppress various human convulsions. These hybrid molecules attach to the chemical particles of clinically relevant AEDs such as ethosuximide, levetiracetam, and lacosamide. As a result of this hybridization process the compounds obtained were effective in three most important animal epilepsy models, namely the maximal electroshock seizure (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-Hertz (6 Hz) model in mice. These substances displayed wider spectrum of protection, more potent efficacy, and better safety profile than the aforementioned AEDs. Several compounds were also active in the formalin model of persistent pain in mice. The in vitro ligand binding studies have proved that the most conceivable molecular mechanism of anticonvulsant and antinociceptive action was the influence on the neuronal voltage-sensitive sodium and L-type calcium channels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

OpenAIRE

Kazmin, Aleksey; Wong, Renee C.; Sermer, Mathew; Koren, Gideon

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)?

Pharmacokinetic aspects of the anti-epileptic drug substance vigabatrin

DEFF Research Database (Denmark)

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

2014-01-01

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

Severe overdosage with the antiepileptic drug oxcarbazepine

Science.gov (United States)

van Opstal, J M; Janknegt, R; Cilissen, J; L’Ortije, W H V M; Nel, J E; De Heer, F

2004-01-01

Few published human data are available concerning the acute toxicity of the new antiepileptic drug oxcarbazepine of which the metabolite 10- monohydroxy derivate (MHD) is the pharmacologically effective compound. Two hours after a documented overdosage of more than 100 tablets oxcarbazepine, the serum level of the parent compound was 10-fold higher than the therapeutic dosage (31.6 mg l−1). However, the concentration of MHD, which peaked 7 h after intake, was only twofold higher (59.0 mg l−1). No life-threatening situations occurred and the patient fully recovered. The fact that oxcarbazepine is a prodrug and that the formation of the active MHD metabolite is a rate-limiting process may contribute to the relative low toxicity of the drug in overdose. PMID:15327594

The role side effects play in the choice of antiepileptic therapy in brain tumor-related epilepsy: a comparative study on traditional antiepileptic drugs versus oxcarbazepine

Directory of Open Access Journals (Sweden)

Carapella Maria Carmine

2009-05-01

Full Text Available Abstract Background Seizure control doesn't represent the only challenging goal in patients with brain tumor-related epilepsy. Side effects have often taken precedence for patients' quality of life. Methods We performed an observational retrospective study on patients with brain tumor-related epilepsy: 35 who had assumed oxcarbazepine monotherapy and 35 patients who had undergone treatment with traditional antiepileptic drugs. Primary variable of efficacy was the mean seizure frequency per month and safety variables were the drop-out for side effects and total incidence of side effects. We applied the Propensity Score technique to minimize selection bias. Results Our results showed a similar efficacy of oxcarbazepine and traditional antiepileptic drugs over time, but the difference in safety and tolerability between the two groups was significant: traditional AEDs caused more side effects, both serious and non serious. Conclusion This study highlights the importance of taking into consideration not only seizure control but also the appearance of side effects when choosing antiepileptic drugs in this patients population.

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 ...

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

Science.gov (United States)

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

2016-07-01

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

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

DEFF Research Database (Denmark)

Vestergaard, Martin; Paulander, Wilhelm; Marvig, Rasmus L.

2016-01-01

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...

[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.

Preclinical optimization of a broad-spectrum anti-bladder cancer tri-drug regimen via the Feedback System Control (FSC) platform

Science.gov (United States)

Liu, Qi; Zhang, Cheng; Ding, Xianting; Deng, Hui; Zhang, Daming; Cui, Wei; Xu, Hongwei; Wang, Yingwei; Xu, Wanhai; Lv, Lei; Zhang, Hongyu; He, Yinghua; Wu, Qiong; Szyf, Moshe; Ho, Chih-Ming; Zhu, Jingde

2015-06-01

Therapeutic outcomes of combination chemotherapy have not significantly advanced during the past decades. This has been attributed to the formidable challenges of optimizing drug combinations. Testing a matrix of all possible combinations of doses and agents in a single cell line is unfeasible due to the virtually infinite number of possibilities. We utilized the Feedback System Control (FSC) platform, a phenotype oriented approach to test 100 options among 15,625 possible combinations in four rounds of assaying to identify an optimal tri-drug combination in eight distinct chemoresistant bladder cancer cell lines. This combination killed between 82.86% and 99.52% of BCa cells, but only 47.47% of the immortalized benign bladder epithelial cells. Preclinical in vivo verification revealed its markedly enhanced anti-tumor efficacy as compared to its bi- or mono-drug components in cell line-derived tumor xenografts. The collective response of these pathways to component drugs was both cell type- and drug type specific. However, the entire spectrum of pathways triggered by the tri-drug regimen was similar in all four cancer cell lines, explaining its broad spectrum killing of BCa lines, which did not occur with its component drugs. Our findings here suggest that the FSC platform holdspromise for optimization of anti-cancer combination chemotherapy.

Neurodevelopmental Effects of Antiepileptic Drugs.

Science.gov (United States)

Kellogg, Marissa; Meador, Kimford J

2017-07-01

Increasing evidence suggests that exposure to certain antiepileptic drugs (AEDs) during critical periods of development may induce transient or long-lasting neurodevelopmental deficits across cognitive, motor and behavioral domains. The developing nervous system may endure prolonged chronic exposure to AEDs during pregnancy (in utero) or during childhood, which can lead to neurodevelopmental defects such as congenital neural tube defects, lower IQ, language deficits, autism and ADHD. To date, valproate is the most widely recognized AED to significantly negatively affect neurodevelopment, and demonstrates greater adverse effects than any other AEDs that have been assessed. Although some AEDs appear to have low risk (i.e., lamotrigine, levetiracetam), other AEDs have been implicated in a variety of studies detailed below, and many AEDs have not been adequately assessed. The purpose of this review article is to summarize our current understanding of the neurodevelopmental effects of AEDs.

Intelligence quotient improves after antiepileptic drug withdrawal following pediatric epilepsy surgery

NARCIS (Netherlands)

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

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

Brain Graph Topology Changes Associated with Anti-Epileptic Drug Use

Science.gov (United States)

Levin, Harvey S.; Chiang, Sharon

2015-01-01

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

DILI (drug induced liver injury in a 9-month-old infant: a rare case of phenobarbital-induced hepatotoxicity

Directory of Open Access Journals (Sweden)

Anna Paola Pinna

2013-04-01

Full Text Available Phenobarbital is one of the most commonly prescribed antiepileptic drugs in childhood, but it can rarely cause serious adverse effects, such as hepatotoxicity that includes a broad clinical spectrum (from isolate hypertransaminasemia to acute liver failure. We describe a case of DILI in a 9-month-old infant caused by chronic therapy with phenobarbital.

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

Preventive Agents for Migraine: Focus on the Antiepileptic Drugs

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R. Shahien

2012-04-01

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

The effect of antiepileptic drugs on cognitive functions

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A. S. Kotov

2013-01-01

Full Text Available Impaired cognitive function is a common problem in epileptic patients. The exact cause of cognitive impairment in case of epilepsy has not been explored fully, but there is no doubt that a role in this is played by three factors: the disease underlying epilepsy; epileptic seizures proper; and negative side effects of antiepileptic drugs. Their cognitive effects are one of the major problems affecting the tolerance of therapy. The review considers the effects of phenobarbital, phenytoin, carbamazepine, valproates, oxcarbazepine, topiramate, lamotrigine, and levetiracetam in terms of their action on the cognitive function of healthy volunteers and epileptic patients.

NMDA Receptor Signaling Is Important for Neural Tube Formation and for Preventing Antiepileptic Drug-Induced Neural Tube Defects.

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Sequerra, Eduardo B; Goyal, Raman; Castro, Patricio A; Levin, Jacqueline B; Borodinsky, Laura N

2018-05-16

Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that during Xenopus laevis neural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that NMDA receptors are important for the formation of the neural tube and that the loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation. SIGNIFICANCE STATEMENT Neural tube defects are one of the most common birth defects. Clinical investigations have determined that the use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that they are side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy. Copyright © 2018 the authors 0270-6474/18/384762-12$15.00/0.

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

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

2010-01-01

of transmembrane transport and enzymatic degradation. The development of tiagabine selectively inhibiting the GABA transporter GAT1 constitutes a proof of concept that the GABA transporters are interesting drug targets in the context of antiepileptic drugs. The review provides a detailed analysis of the role......,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) has been shown to possess a novel anticonvulsant profile in animal models of epilepsy, involving the ability to inhibit GABA transport mediated by GAT1 and BGT1 at the same time....

Safety Profile of the Newest Antiepileptic Drugs: A Curated Literature Review.

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Palleria, Caterina; Cozza, Giuseppe; Khengar, Rajeshree; Libri, Vincenzo; De Sarro, Giovambattista

2017-01-01

Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remain unsatisfactory. In addition, whilst several antiepileptic drugs (AEDs) have been approved and consequently marketed in recent years, little is known about their long-term safety and tolerability. Availability of the newest AEDs, characterized by improved pharmacokinetic profiles, has positively impacted the treatment approach for patients with partial seizures in clinical practice. However, the main cause of treatment failure is still poor patient compliance due to the occurrence of adverse drug reactions (ADRs) that lead to treatment withdrawal in about 25% of cases before achieving maximal efficacy, and is associated with increasing health care costs. In this Review, we conducted an online database search using Medline, PubMed, Embase, and the Cochrane Online Library to review the available studies highlighting the clinical relevance of side effects, pharmacological interactions, safety and tolerability of the newest AEDs: Brivaracetam (BRV), Cannabidiol (CBD), Eslicarbazepine acetate (ESL), Lacosamide (LCM), and Perampanel (PER). The principal benefit of the newest AEDs, in addition to reduced frequency and seizure severity, is the low number and severity of ADRs reported compared to more historic drugs. Early detection of ADRs could lead to an improvement in patients' quality of life, therefore it is important to monitor ADRs and to adequately perform post marketing surveillance in the clinical practice setting. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Assessing suicidal risk with antiepileptic drugs

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Marco Mula

2010-09-01

Full Text Available Marco Mula2, Gail S Bell1, Josemir W Sander1,31Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, and National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, United Kingdom; 2Department of Clinical and Experimental Medicine, Division of Neurology, Amedeo Avogadro University, University Hospital Maggiore della Carità, Novara, Italy; 3SEIN – Epilepsy Institute in the Netherlands Foundation, Heemstede, The NetherlandsAbstract: Recently, the US Food and Drug Administration issued an alert about an increased risk for suicidality during treatment with antiepileptic drugs (AEDs for different indications, including epilepsy. We discuss the issue of suicide in epilepsy with special attention to AEDs and the assessment of suicide in people with epilepsy. It has been suggested that early medical treatment with AEDs might potentially reduce suicide risk of people with epilepsy, but it is of great importance that the choice of drug is tailored to the mental state of the patient. The issue of suicidality in epilepsy is likely to represent an example of how the underdiagnosis of psychiatric symptoms, the lack of input from professionals (eg, psychologists, social workers, and psychiatrists, and the delay in an optimized AED therapy may worsen the prognosis of the condition with the occurrence of severe complications such as suicide.Keywords: epilepsy, suicide, adverse effect, depression

Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed

NARCIS (Netherlands)

Deckers, C.L.P.; Czuczwar, S.J.; Hekster, Y.A.; Keyser, A.J.M.; Kubova, H.; Meinardi, H.; Patsalos, P.N.; Renier, W.O.; Rijn, C.M. van

2000-01-01

Purpose: When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried so as to improve effectiveness, by improving either efficacy, or tolerability, or both. We have reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be

Enzyme induction in neonates after fetal exposure to antiepileptic drugs

International Nuclear Information System (INIS)

Rating, D.; Jaeger-Roman, E.; Nau, H.; Kuhnz, W.; Helge, H.

1983-01-01

The 13 C-AP breath test is shown to be a convenient, noninvasive method to monitor velocity and capacity of P450-dependent AP N-demethylation in infancy and childhood. According to 13 C-AP breath tests, neonates have a very low capacity to eliminate 13 CO 2 , which is only 15 to 21% of the activity in adults. During the first year of life AP N-demethylation increases to reach its maximum at about 2 years; afterwards a slight decrease occurs. In 25 neonates exposed prenatally to different antiepileptic drugs 13 C-AP breath test was efficiently used to prove that cytochrome AP N-demethylation was considerably stimulated. After primidone/phenobarbitone, especially in combination with phenytoin, 13 C elimination reaches and even surpasses the range for older children. Valproate exposure during fetal life is not consistently followed by a significant increase in AP N-demethylation. The enzyme induction demonstrated by 13 C-AP breath test was often accompanied by accelerated metabolic clearance and shortened half-life times of transplacentally acquired antiepileptic drugs. There was good agreement between 13 C-AP breath tests and pharmacokinetic data for primidone/phenobarbitone but not for phenytoin. In contrast, in the case of phenytoin exposure during pregnancy the pharmacokinetic parameters and the 13 C breath test data will transport very different informations about enzyme induction in these neonates

Chronic antiepileptic drug use and functional network efficiency : a functional magnetic resonance imaging study

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van Veenendaal, T.M.; IJff, D.M.; Aldenkamp, A.P.; Lazeron, R.H.C.; Hofman, P.A.M.; de Louw, A.J.A.; Backes, W.H.; Jansen, J.F.A.

2017-01-01

AIM: To increase our insight in the neuronal mechanisms underlying cognitive side-effects of antiepileptic drug (AED) treatment. METHODS: The relation between functional magnetic resonance-acquired brain network measures, AED use, and cognitive function was investigated. Three groups of patients

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

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

Drug Interactions between some antiepileptic and certain hypocholesterolaemic drugs in irradiated animals

International Nuclear Information System (INIS)

Shaaban, D.M.L.

2015-01-01

Drug Interactions between antiepileptic drug such as phenytoin and certain hypercholesterolaemia drug namely rosuvastatin were investigated on several biological parameters. Phenytoin (60 mg/kg i.p) and rosuvastatin (1.25 mg/kg i.p) were given either alone and in combination to normal and irradiated animals to investigate drug interactions between the test drugs. Anticonvulsant activity was evaluated using pentylenetetrazole in a dose (80 mg/kg i.p) in normal and irradiated mice. Brain neurotransmitters (glutamate and GABA) were investigated. Lipid profile (total cholesterol (TC), Triacylglycerol (TG), High density lipoprotein-cholesterol (HDL-C) and low density lipoprotein- cholesterol (LDL-C) were determined. Liver functions such as serum Aspartate amino transferase (AST) and serum alanine amino transferase (ALT) were also estimated. Oxidative stress bio markers namely serum malondialdehyde (MDA), serum nitric oxide (NO) and blood superoxide dismutase activity (SOD) were studied. Histopathological examinations of brain and liver tissues were performed. Administration of phenytoin concurrently with rosuvastatin is not recommended in patients receiving radiotherapy as dangerous side effects on liver functions and lipid profile may occur. The interactions between the two drugs in normal rats improve liver functions and lipid peroxidation. Apart from the action of the combination on total cholesterol, it improves lipid profile pattern. Rosuvastatin administration in combination with phenytoin may have additive anticonvulsant activity.

Antiepileptic drugs for chronic non-cancer pain in children and adolescents.

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Cooper, Tess E; Wiffen, Philip J; Heathcote, Lauren C; Clinch, Jacqui; Howard, Richard; Krane, Elliot; Lord, Susan M; Sethna, Navil; Schechter, Neil; Wood, Chantal

2017-08-05

Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as importantWe designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can occur in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) relating to genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and for other unknown reasons.Antiepileptic (anticonvulsant) drugs, which were originally developed to treat convulsions in people with epilepsy, have in recent years been used to provide pain relief in adults for many chronic painful conditions and are now recommended for the treatment of chronic pain in the WHO list of essential medicines. Known side effects of antiepileptic drugs range from sweating, headache, elevated temperature, nausea, and abdominal pain to more serious effects including mental or motor function impairment. To assess the analgesic efficacy and adverse events of antiepileptic drugs used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting. We searched the

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.

Successful Treatment of Antiepileptic Drug-Induced DRESS Syndrome with Pulse Methylprednisolone

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Celebi Kocaoglu

2013-01-01

Full Text Available Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome is a rare but potentially life-threatening syndrome characterized by skin rash, fever, lymph node enlargement, and involvement of internal organs. It is most commonly induced by aromatic anticonvulsants and antibiotics. Nonaromatic anticonvulsants are rarely encountered as the causes of DRESS syndrome. In the present report, three discrete cases with DRESS syndrome developing due to three antiepileptic drugs, including valproic acid (nonaromatic, carbamazepine (aromatic, and lamotrigine (aromatic, and their treatment modalities were aimed to be discussed in light of the literature. To the best of our knowledge, our cases are the first children to be treated with pulse methylprednisolone in the literature.

The challenges of treating epilepsy with 25 antiepileptic drugs.

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

2016-05-01

Nowadays a substantial armamentarium of antiepileptic drugs (AEDs) is available, including drugs with different mechanisms of action, pharmacokinetics, efficacy and tolerability; therefore the choice for the right treatment is often challenging. The specific characteristic of the drug, the epileptic syndrome, seizure types and the patient's features need to be taken into consideration driving the choice through available evidence-based studies, which are often lacking for older AEDs. Besides, study conditions in registered clinical trials (RCTs) are quite different from daily clinical practice, which is more complex and various. When dealing with first diagnosed epilepsy, monotherapy is widely accepted as the gold standard option. Likewise, alternative monotherapy should be considered when the first drug treatment fails. However, the association of different AEDs in polytherapy is a common practice. The choice of AEDs used in association is often based on clinical experience or anecdotal observations or small clinical studies. Polytherapy should be as "rational" as possible and consider the mechanism of action, the pharmacokinetic characteristics and the safety of each drug. When dealing with drug resistant patients, clinicians should never give up and consider the use of AEDs acting on new targets. An attempt to come back to a monotherapy or simpler therapeutic regimen should be pursued even in patients who were previously drug resistant. This review will focus on the strategies to treat epilepsy by choosing among 25 available drugs. Copyright © 2016 Elsevier Ltd. All rights reserved.

FT-Raman, FT-IR and UV-visible spectral investigations and ab initio computations of anti-epileptic drug: Vigabatrin

Science.gov (United States)

Edwin, Bismi; Joe, I. Hubert

2013-10-01

Vibrational analysis of anti-epileptic drug vigabatrin, a structural GABA analog was carried out using NIR FT-Raman and FTIR spectroscopic techniques. The equilibrium geometry, various bonding features and harmonic vibrational wavenumbers were studied using density functional theory method. The detailed interpretation of the vibrational spectra has been carried out with the aid of VEDA.4 program. Vibrational spectra, natural bond orbital analysis and optimized molecular structure show clear evidence for the effect of electron charge transfer on the activity of the molecule. Predicted electronic absorption spectrum from TD-DFT calculation has been compared with the UV-vis spectrum. The Mulliken population analysis on atomic charges and the HOMO-LUMO energy were also calculated. Good consistency is found between the calculated results and experimental data for the electronic absorption as well as IR and Raman spectra. The blue-shifting of the Csbnd C stretching wavenumber reveals that the vinyl group is actively involved in the conjugation path. The NBO analysis confirms the occurrence of intramolecular hyperconjugative interactions resulting in ICT causing stabilization of the system.

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

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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.

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

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Berry Juliandi

2015-12-01

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

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

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

2005-11-01

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

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

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D. V. Dmitrenko

2014-01-01

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

Challenges in the clinical development of new antiepileptic drugs.

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

2016-01-01

Despite the current availability in the market of over two dozen antiepileptic drugs (AEDs), about one third of people with epilepsy fail to achieve complete freedom from seizures with existing medications. Moreover, currently available AEDs have significant limitations in terms of safety, tolerability and propensity to cause or be a target for clinically important adverse drug interactions. A review of the evidence shows that there are many misperceptions about the viability of investing into new therapies for epilepsy. In fact, there are clear incentives to develop newer and more efficacious medications. Developing truly innovative drugs requires a shift in the paradigms for drug discovery, which is already taking place by building on greatly expanded knowledge about the mechanisms involved in epileptogenesis, seizure generation, seizure spread and development of co-morbidities. AED development can also benefit by a review of the methodology currently applied in clinical AED development, in order to address a number of ethical and scientific concerns. As discussed in this article, many processes of clinical drug development, from proof-of-concept-studies to ambitious programs aimed at demonstrating antiepileptogenesis and disease-modification, can be facilitated by a greater integration of preclinical and clinical science, and by application of knowledge acquired during decades of controlled epilepsy trials. Copyright © 2015 Elsevier Ltd. All rights reserved.

Newer anti-epileptic drugs, vitamin status and neuropathy: A cross-sectional analysis.

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Cahill, V; McCorry, D; Soryal, I; Rajabally, Y A

Whether new antiepileptic drugs (AEDs) may result in neuropathy is unknown but possible given their effects on vitamin metabolism. This analysis aimed to determine frequency and correlates of neuropathy in subjects treated with new AEDs in relation to drug used, length of exposure and serum vitamin B12 and folate levels. We performed a cross-sectional study of 52 consecutive epileptic subjects. Presence of neuropathy was determined using the Utah Early Neuropathy Score (UENS). Exposure to anti-epileptic drugs was quantified. Serum vitamin B12 and folate levels were measured. Commonly used AEDs were levetiracetam (28/52), carbamazepine (20/52), lamotrigine (20/52), sodium valproate (10/52) and zonisamide (10/52). Eight of 52 (15.4%) patients had neuropathy. There was no association with any particular AED. Neuropathy correlated with age (P=0.038) and total exposure to AEDs (P=0.032). UENS correlated with age (P=0.001), total AED exposure (P=0.001) and serum vitamin B12L (P=0.018). Independent association of neuropathy was found with total AED exposure (P=0.032), but not age. UENS was independently associated with total exposure to AEDs (Pvitamin B12L (P=0.002), but not age. Serum vitamin B12 and folate levels were highly inter-correlated (Pvitamin B12 and folate metabolism. Although further research from controlled studies is needed and despite the presence of other possible confounding factors, monitoring for neuropathy and vitamin B12 and folate levels merits consideration in patients on long-term treatment with new AEDs. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

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...... with a hip fracture during the period 1996-2004. Controls (n = 27,575) were frequency matched by age and gender. Information on use of AEDs, other drugs, and hospital contacts was available from local registers. Odds ratios (ORs) with 95% confidence intervals (CI) for hip fracture were estimated...

Algunas consideraciones en relación con los medicamentos antiepilépticos de nueva generación en los niños Some considerations in relation to the new generation antiepileptic drugs in children

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Desiderio Pozo Lauzán

2005-06-01

Full Text Available El objetivo de este trabajo es revisar las principales drogas antiepilépticas de segunda generación y su administración en los niños: vigabatrina, felbamato, lamotrigina, topiramato, tiagabina, oxcarbazepina, zonisamida, levetiracetam y stiripentol. Al inicio se recomendaron en pacientes adultos con epilepsias focales refractarias, sin embargo desde hace varios años, se ha demostrado su eficacia en diferentes tipos de crisis en los niños. La lamotrigina y el topiramato se consideran medicamentos de amplio espectro. Se enfatiza en el metabolismo, vías de eliminación, indicaciones, dosis en los niños, interacciones medicamentosas y efectos colaterales de los medicamentos antiepilépticos de segunda generación. Se mencionan algunos de los nuevos medicamentos que actualmente están en investigación como antiepilépticos y que constituyen una tercera generaciónThe objective of this paper is to review the main second generation antiepileptic drugs and their administration in children: vigatrine, felbamate, lamotrigine, topiramate, tiagabine, oxcarbazepine, zonisamide, leventiracetam and stiripentol. At the beginning, they were recommended in adult patients with focal refractory epilepsies; however, their efficacy in different types of seizures in children has been proved for some years. Lamotrigine and topiramate are considered drugs of wide spectrum. Emphasis is made on metabolism, routes of elimination, indications, doses in children, drug interactions and side effects of the second generation antiepileptic drugs. Some of the new drugs that are currently under study as antiepileptic and that constitute a third generation, are mentioned.

Potential Adverse Effects of Broad-Spectrum Antimicrobial Exposure in the Intensive Care Unit.

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Wiens, Jenna; Snyder, Graham M; Finlayson, Samuel; Mahoney, Monica V; Celi, Leo Anthony

2018-02-01

The potential adverse effects of empiric broad-spectrum antimicrobial use among patients with suspected but subsequently excluded infection have not been fully characterized. We sought novel methods to quantify the risk of adverse effects of broad-spectrum antimicrobial exposure among patients admitted to an intensive care unit (ICU). Among all adult patients admitted to ICUs at a single institution, we selected patients with negative blood cultures who also received ≥1 broad-spectrum antimicrobials. Broad-spectrum antimicrobials were categorized in ≥1 of 5 categories based on their spectrum of activity against potential pathogens. We performed, in serial, 5 cohort studies to measure the effect of each broad-spectrum category on patient outcomes. Exposed patients were defined as those receiving a specific category of broad-spectrum antimicrobial; nonexposed were all other patients in the cohort. The primary outcome was 30-day mortality. Secondary outcomes included length of hospital and ICU stay and nosocomial acquisition of antimicrobial-resistant bacteria (ARB) or Clostridium difficile within 30 days of admission. Among the study cohort of 1918 patients, 316 (16.5%) died within 30 days, 821 (42.8%) had either a length of hospital stay >7 days or an ICU length of stay >3 days, and 106 (5.5%) acquired either a nosocomial ARB or C. difficile . The short-term use of broad-spectrum antimicrobials in any of the defined broad-spectrum categories was not significantly associated with either primary or secondary outcomes. The prompt and brief empiric use of defined categories of broad-spectrum antimicrobials could not be associated with additional patient harm.

FT-Raman, FT-IR and UV-visible spectral investigations and ab initio computations of anti-epileptic drug: vigabatrin.

Science.gov (United States)

Edwin, Bismi; Joe, I Hubert

2013-10-01

Vibrational analysis of anti-epileptic drug vigabatrin, a structural GABA analog was carried out using NIR FT-Raman and FTIR spectroscopic techniques. The equilibrium geometry, various bonding features and harmonic vibrational wavenumbers were studied using density functional theory method. The detailed interpretation of the vibrational spectra has been carried out with the aid of VEDA.4 program. Vibrational spectra, natural bond orbital analysis and optimized molecular structure show clear evidence for the effect of electron charge transfer on the activity of the molecule. Predicted electronic absorption spectrum from TD-DFT calculation has been compared with the UV-vis spectrum. The Mulliken population analysis on atomic charges and the HOMO-LUMO energy were also calculated. Good consistency is found between the calculated results and experimental data for the electronic absorption as well as IR and Raman spectra. The blue-shifting of the C-C stretching wavenumber reveals that the vinyl group is actively involved in the conjugation path. The NBO analysis confirms the occurrence of intramolecular hyperconjugative interactions resulting in ICT causing stabilization of the system. Copyright © 2013 Elsevier B.V. All rights reserved.

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

Science.gov (United States)

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

2016-03-02

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

The Use of Antiepileptic Drugs (AEDs) for the Treatment of Pediatric Aggression and Mood Disorders

OpenAIRE

Munshi, Kaizad R.; Oken, Tanya; Guild, Danielle J.; Trivedi, Harsh K.; Wang, Betty C.; Ducharme, Peter; Gonzalez-Heydrich, Joseph

2010-01-01

Aggressive symptomatology presents across multiple psychiatric, developmental, neurological and behavioral disorders, complicating the diagnosis and treatment of the underlying pathology. Anti-Epileptic Drugs (AEDs) have become an appealing alternative in the treatment of aggression, mood lability and impulsivity in adult and pediatric populations, although few controlled trials have explored their efficacy in treating pediatric populations. This review of the literature synthesizes the avail...

Determination of Four Anti-epileptic Drugs in Plasma Using Ultra Performance Liquid Chromatography with Mass Detection Technique.

Science.gov (United States)

Hassib, Sonia T; Hashem, Hanaa M A; Mahrouse, Marianne A; Mostafa, Eman A

2018-04-10

Status epilepticus (SE) is considered the second most frequent neurologic emergency. Its therapeutic management is performed using sequential anti-epileptic drug regimens. Diazepam (DIA), midazolam (MID), phenytoin (PHT) and phenobarbital (PB) are four drugs of different classes used sequentially in the management of SE. A sensitive, selective, accurate and precise method was developed and validated for simultaneous determination of the four anti-epileptic drugs in human plasma. Their separation and quantification were achieved using ultra performance liquid chromatography (UPLC) with mass detection using carbamazepine as internal standard (IS). For the first three drugs and IS, UPLC-MS/MS with electrospray ionization working in multiple reaction monitoring mode was used at the following transitions: m/z 285→193 for DIA, m/z 326→291 for MID, m/z 253→182 for PHT and m/z 237→194, 237→192 for IS. For the fourth drug (PB), molecular ion peak of PB [M+H] + at m/z 233 was used for its quantitation. The method was linear over concentration ranges of 5-500 ng/ml for DIA and MID and 0.25-20 μg/ml for PHT and PB, respectively. Bio-analytical validation of the developed method was carried out according to European Medicines Agency guidelines. The developed method can be applied for routine drug analysis, therapeutic drug monitoring and bioequivalence studies. This article is protected by copyright. All rights reserved.

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, Jonas Bjerring; Abildstrøm, Steen Zabell; Erdal, Jesper

2011-01-01

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).......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)....

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

NARCIS (Netherlands)

Battino, D.; Bonizzoni, E.; Craig, J.; Lindhout, D.; Perucca, E.; Sabers, A.; Tomson, T.; Vajda, F.

2009-01-01

P>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

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

Directory of Open Access Journals (Sweden)

Sander Josemir W

2007-03-01

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

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

Energy Technology Data Exchange (ETDEWEB)

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

2017-05-01

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

Individualized prediction of seizure relapse and outcomes following antiepileptic drug withdrawal after pediatric epilepsy surgery.

Science.gov (United States)

Lamberink, Herm J; Boshuisen, Kim; Otte, Willem M; Geleijns, Karin; Braun, Kees P J

2018-03-01

The objective of this study was to create a clinically useful tool for individualized prediction of seizure outcomes following antiepileptic drug withdrawal after pediatric epilepsy surgery. We used data from the European retrospective TimeToStop study, which included 766 children from 15 centers, to perform a proportional hazard regression analysis. The 2 outcome measures were seizure recurrence and seizure freedom in the last year of follow-up. Prognostic factors were identified through systematic review of the literature. The strongest predictors for each outcome were selected through backward selection, after which nomograms were created. The final models included 3 to 5 factors per model. Discrimination in terms of adjusted concordance statistic was 0.68 (95% confidence interval [CI] 0.67-0.69) for predicting seizure recurrence and 0.73 (95% CI 0.72-0.75) for predicting eventual seizure freedom. An online prediction tool is provided on www.epilepsypredictiontools.info/ttswithdrawal. The presented models can improve counseling of patients and parents regarding postoperative antiepileptic drug policies, by estimating individualized risks of seizure recurrence and eventual outcome. Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.

Management of Antiepileptic Treatment After Epilepsy Surgery

DEFF Research Database (Denmark)

Rubboli, Guido; Sabers, Anne; Uldall, Peter

2017-01-01

BACKGROUND: Although epilepsy surgery is a recognized treatment option for drug-resistant epilepsies since several decades, the management of antiepileptic drugs (AEDs) after successful surgery still remains one of the most difficult and unsolved therapeutic challenges. Indeed, no systematic cont...

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

Antiepileptic drug poisoning: Three-year experience

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Yahya Kemal Günaydın

2015-01-01

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

Epileptic seizure, as the first symptom of hypoparathyroidism in children, does not require antiepileptic drugs

OpenAIRE

Liu, Meng-Jia; Li, Jiu-Wei; Shi, Xiu-Yu; Hu, Lin-Yan; Zou, Li-Ping

2016-01-01

Objective Patients with hypoparathyroidism exhibit metabolic disorders (hypocalcemia) and brain structural abnormalities (brain calcifications). Currently, studies have determined whether antiepileptic drug (AED) treatment is required for epileptic seizures in children with hypoparathyroidism. Method This study aims to evaluate the data of two medical centers in Beijing based on the diagnosis of epileptic seizures as the first symptom of hypoparathyroidism in children. Result A total of 42 pa...

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

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

Reverse engineering truncations of an antimicrobial peptide dimer to identify the origins of potency and broad spectrum of action.

Science.gov (United States)

Anantharaman, Aparna; Sahal, Dinkar

2010-08-26

Antimicrobial peptides hold promise against antibiotic resistant pathogens. Here, to find the physicochemical origins of potency and broad spectrum antimicrobial action, we report the structure-activity relationships of synthetic intermediates (peptides A-D) of a potent lysine branched dimeric antibacterial peptide DeltaFd. Our studies show that a tetracationic character in a weak helical fold (peptide C) elicits potent but narrow spectrum antimicrobial activity [Minimum inhibitory concentrations (MICs) E. coli 10 microM, S. aureus>100 microM]. In contrast, a hexacationic character in a strong, amphipathic helix (DeltaFd) confers potent and broad spectrum action [MICs E. coli 2.5 microM, S. aureus 5 microM]. While DeltaFd caused rapid and potent permeabilization of the E. coli membranes, the less helical intermediates (peptides A-D) showed slow and weak to no responses. Two seminal findings that may aid future drug design are (a) at identical helicity, increasing charge enhanced outer membrane permeabilization, and (b) at identical charge, increasing helicity stimulated rate of outer membrane permeabilization and kill kinetics besides enhancing potency leading to broad spectrum action.

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

Science.gov (United States)

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

2017-02-03

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

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

Science.gov (United States)

Haug, Jon B; Myhr, Randi; Reikvam, Asmund

2011-12-13

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. 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. 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-weeks interval. There is a need for caution in

Seizure Recurrence in Children after Stopping Antiepileptic Medication: 5-Year Follow-Up

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Inn-Chi Lee

2017-08-01

Conclusion: We found that a history of status epilepticus, symptomatic partial epilepsy, treatment duration before stopping antiepileptic drugs, and an abnormal EEG when the medication was stopped are important predictors of SR. The risk factors of SR after discontinuing antiepileptic drugs have been investigated in several studies. However, a history of status epilepticus as a predictive factor is rarely mentioned.

Risk Factors for Emergence of Resistance to Broad-Spectrum Cephalosporins among Enterobacter spp.

Science.gov (United States)

Kaye, Keith S.; Cosgrove, Sara; Harris, Anthony; Eliopoulos, George M.; Carmeli, Yehuda

2001-01-01

Among 477 patients with susceptible Enterobacter spp., 49 subsequently harbored third-generation cephalosporin-resistant Enterobacter spp. Broad-spectrum cephalosporins were independent risk factors for resistance (relative risk [OR] = 2.3, P = 0.01); quinolone therapy was protective (OR = 0.4, P = 0.03). There were trends toward decreased risk for resistance among patients receiving broad-spectrum cephalosporins and either aminoglycosides or imipenem. Of the patients receiving broad-spectrum cephalosporins, 19% developed resistance. PMID:11502540

The effect of depression and side effects of antiepileptic drugs on injuries in patients with epilepsy.

Science.gov (United States)

Gur-Ozmen, S; Mula, M; Agrawal, N; Cock, H R; Lozsadi, D; von Oertzen, T J

2017-09-01

People with epilepsy are at increased risk of accidents and injuries but, despite several studies on this subject, data regarding preventable causes are still contradictory. The aim of this study was to investigate the relationship between injuries, side effects of antiepileptic drugs (AEDs) and depression. Data from a consecutive sample of adult patients with epilepsy attending the outpatient clinics at St George's University Hospital in London were included. All patients were asked if they had had any injury since the last clinic appointment and completed the Liverpool Adverse Event Profile (LAEP) and Neurological Disorders Depression Inventory for Epilepsy. Among 407 patients (243 females, mean age 43.1 years), 71 (17.4%) reported injuries since the last appointment. A two-step cluster analysis revealed two clusters with the major cluster (53.5% of the injured group) showing a total score for LAEP ≥45, a positive Neurological Disorders Depression Inventory for Epilepsy screening and presence of AED polytherapy. A total score for LAEP ≥45 was the most important predictor. Antiepileptic drug treatment should be reviewed in patients reporting injuries in order to evaluate the potential contribution and burden of AED side effects. © 2017 EAN.

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

Science.gov (United States)

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

2015-05-01

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

Broad spectrum bioactive sunscreens.

Science.gov (United States)

Velasco, Maria Valéria Robles; Sarruf, Fernanda Daud; Salgado-Santos, Idalina Maria Nunes; Haroutiounian-Filho, Carlos Alberto; Kaneko, Telma Mary; Baby, André Rolim

2008-11-03

The development of sunscreens containing reduced concentration of chemical UV filters, even though, possessing broad spectrum effectiveness with the use of natural raw materials that improve and infer UV absorption is of great interest. Due to the structural similarities between polyphenolic compounds and organic UV filters, they might exert photoprotection activity. The objective of the present research work was to develop bioactive sunscreen delivery systems containing rutin, Passiflora incarnata L. and Plantago lanceolata extracts associated or not with organic and inorganic UV filters. UV transmission of the sunscreen delivery system films was performed by using diffuse transmittance measurements coupling to an integrating sphere. In vitro photoprotection efficacy was evaluated according to the following parameters: estimated sun protection factor (SPF); Boot's Star Rating category; UVA/UVB ratio; and critical wavelength (lambda(c)). Sunscreen delivery systems obtained SPF values ranging from 0.972+/-0.004 to 28.064+/-2.429 and bioactive compounds interacted with the UV filters positive and negatively. This behavior may be attributed to: the composition of the delivery system; the presence of inorganic UV filter and quantitative composition of the organic UV filters; and the phytochemical composition of the P. incarnata L. and P. lanceolata extracts. Among all associations of bioactive compounds and UV filters, we found that the broad spectrum sunscreen was accomplished when 1.68% (w/w) P. incarnata L. dry extract was in the presence of 7.0% (w/w) ethylhexyl methoxycinnamate, 2.0% (w/w) benzophenone-3 and 2.0% (w/w) TiO(2). It was demonstrated that this association generated estimated SPF of 20.072+/-0.906 and it has improved the protective defense against UVA radiation accompanying augmentation of the UVA/UVB ratio from 0.49 to 0.52 and lambda(c) from 364 to 368.6nm.

Role of cytochrome P450-mediated metabolism and involvement of reactive metabolite formations on antiepileptic drug-induced liver injuries.

Science.gov (United States)

Sasaki, Eita; Yokoi, Tsuyoshi

2018-01-01

Several drugs have been withdrawn from the market or restricted to avoid unexpected adverse outcomes. Drug-induced liver injury (DILI) is a serious issue for drug development. Among DILIs, idiosyncratic DILIs have been a serious problem in drug development and clinical uses. Idiosyncratic DILI is most often unrelated to pharmacological effects or the dosing amount of a drug. The number of drugs that cause idiosyncratic DILI continue to grow in part because no practical preclinical tests have emerged that can identify drug candidates with the potential for developing idiosyncratic DILIs. Nevertheless, the implications of drug metabolism-related factors and immune-related factors on idiosyncratic DILIs has not been fully clarified because this toxicity can not be reproduced in animals. Therefore, accumulated evidence for the mechanisms of the idiosyncratic toxicity has been limited to only in vitro studies. This review describes current knowledge of the effects of cytochrome P450 (CYP)-mediated metabolism and its detoxification abilities based on studies of idiosyncratic DILI animal models developed recently. This review also focused on antiepileptic drugs, phenytoin (diphenyl hydantoin, DPH) and carbamazepine (CBZ), which have rarely caused severe adverse reactions, such as fulminant hepatitis, and have been recognized as sources of idiosyncratic DILI. The studies of animal models of idiosyncratic DILIs have produced new knowledge of chronic administration, CYP inductions/inhibitions, glutathione contents, and immune-related factors for the initiation of idiosyncratic DILIs. Considering changes in the drug metabolic profile and detoxification abilities, idiosyncratic DILIs caused by antiepileptic drugs will lead to understanding the mechanisms of these DILIs.

Exoproteome and Secretome Derived Broad Spectrum Novel Drug and Vaccine Candidates in Vibrio cholerae Targeted by Piper betel Derived Compounds

Science.gov (United States)

Barh, Debmalya; Barve, Neha; Gupta, Krishnakant; Chandra, Sudha; Jain, Neha; Tiwari, Sandeep; Leon-Sicairos, Nidia; Canizalez-Roman, Adrian; Rodrigues dos Santos, Anderson; Hassan, Syed Shah; Almeida, Síntia; Thiago Jucá Ramos, Rommel; Augusto Carvalho de Abreu, Vinicius; Ribeiro Carneiro, Adriana; de Castro Soares, Siomar; Luiz de Paula Castro, Thiago; Miyoshi, Anderson; Silva, Artur; Kumar, Anil; Narayan Misra, Amarendra; Blum, Kenneth; Braverman, Eric R.; Azevedo, Vasco

2013-01-01

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. PMID:23382822

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

Directory of Open Access Journals (Sweden)

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.

Age-Related Inducibility of Carboxylesterases by the Antiepileptic Agent Phenobarbital and Implications in Drug Metabolism and Lipid Accumulation 1, 2

Science.gov (United States)

Xiao, Da; Chen, Yi-Tzai; Yang, Dongfang; Yan, Bingfang

2014-01-01

Carboxylesterases (CES) constitute a class of hydrolytic enzymes that play critical roles in drug metabolism and lipid mobilization. Previous studies with a large number of human liver samples have suggested that the inducibility of carboxylesterases is inversely related with age. To directly test this possibility, neonatal (10 days of age) and adult mice were treated with the antiepileptic agent phenobarbital. The expression and hydrolytic activity were determined on six major carboxylesterases including ces1d, the ortholog of human CES1. Without exception, all carboxylesterases tested were induced to a greater extent in neonatal than adult mice. The induction was detected at mRNA, protein and catalytic levels. Ces1d was greatly induced and found to rapidly hydrolyze the antiplatelet agent clopidogrel and support the accumulation of neutral lipids. Phenobarbital represents a large number of therapeutic agents that induce drug metabolizing enzymes and transporters in a species-conserved manner. The higher inducibility of carboxylesterases in the developmental age likely represents a general phenomenon cross species including human. Consequently, individuals in the developmental age may experience greater drug-drug interactions. The greater induction of ces1d also provides a molecular explanation to the clinical observation that children on antiepileptic drugs increase plasma lipids. PMID:22513142

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.

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

Science.gov (United States)

2011-01-01

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-weeks interval

Trends in Antiepileptic Drug Use in Children and Adolescents With Epilepsy.

Science.gov (United States)

Liu, Xinyue; Carney, Paul R; Bussing, Regina; Segal, Richard; Cottler, Linda B; Winterstein, Almut G

2017-09-01

We describe the trends in antiepileptic drug (AED) use in children and adolescents with epilepsy in the United States. We undertook a cross-sectional study based on Medicaid Analytic eXtract data set from 26 US states. Children and adolescents aged three to 18 years with at least one year continuous Medicaid fee-for-service coverage after the second outpatient or the first inpatient diagnosis of epilepsy in each calendar year during 1999 to 2009 were included in the study; therefore, 11 cohorts were established. A patient was defined as being exposed to a specific AED if he or she had at least one-day supply of the AED during the 1-year follow-up period. The annual prevalence of AEDs was reported, stratified by gender and age. The trends in AED use were evaluated through linear regression. The sample sizes of the 11 cohorts ranged between 17,304 and 22,672. The annual prevalence of valproic acid use declined from 42.4% in 1999 to 26.5% in 2009, and the prevalence of carbamazepine use declined from 37.1% to 10.2%. Meanwhile, the prevalence of levetiracetam use increased from 5.1% to about 32.0% in 2009, and the prevalence of oxcarbazepine use increased from 1.3% to 19.1%. Since 2008, levetiracetam (29.6%) has replaced valproic acid (27.8%) as the most commonly used AED in children and adolescents with epilepsy. The prevalence of diazepam use increased from 11.6% to 28.1%. Compared with first- and second-generation antiepileptic drugs, third-generation AEDs have fewer adverse side effects, resulting in increased patient treatment adherence. Equally important is the economic impact of these newer AEDs. This first-of-its-kind study underscores the need for large database studies that objectively assess the cost-effectiveness of third-generation AEDs versus first- and second-generation AEDs in the treatment of childhood epilepsy. Copyright © 2017 Elsevier Inc. All rights reserved.

Detection of broad ultraviolet Fe II lines in the spectrum of NGC 1068

International Nuclear Information System (INIS)

Snijders, M.A.J.; Netzer, Hagai; Boksenberg, A.

1986-01-01

Ultraviolet observations of the nucleus of NGC 1068, obtained by the IUE over a period of 5 yr, are combined to give a high signal-to-noise spectrum of this source. The ultraviolet stellar continuum, obtained by comparison with ground-based data, is subtracted to show the nuclear non-stellar component. The resulting spectrum shows clearly the presence of strong broad FeII emission bands similar to those observed in many broad-line objects. Broad profiles are also seen in other strong emission lines. These observations confirm the recent discovery of an optical Seyfert type 1 spectrum in NGC 1068. (author)

Broad Spectrum Sanitizing Wipes with Food Additives, Phase I

Data.gov (United States)

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

Simultaneous HPLC-F analysis of three recent antiepileptic drugs in human plasma.

Science.gov (United States)

Mercolini, Laura; Mandrioli, Roberto; Amore, Mario; Raggi, Maria Augusta

2010-09-21

An original high-performance liquid chromatographic method with fluorescence detection is presented for the simultaneous determination of the three antiepileptic drugs gabapentin, vigabatrin and topiramate in human plasma. After pre-column derivatisation with dansyl chloride, the analytes were separated on a Hydro-RP column with a mobile phase composed of phosphate buffer (55%) and acetonitrile (45%) and detected at lambda(em)=500 nm, exciting at 300 nm. An original pre-treatment procedure on biological samples, based on solid-phase extraction with MCX cartridges for gabapentin and vigabatrin, and with Plexa cartridges for topiramate, gave high extraction yields (>91%), satisfactory precision (RSDvigabatrin and in the 1.0-50.0 microg mL(-1) range for topiramate, with limits of detection (LODs) between 0.1 and 0.3 microg mL(-1). After validation, the method was successfully applied to some plasma samples from patients undergoing therapy with one or more of these drugs. Accuracy results were satisfactory (recovery >91%). Therefore, the method seems to be suitable for the therapeutic drug monitoring (TDM) of patients treated with gabapentin, vigabatrin and topiramate. Copyright 2010 Elsevier B.V. All rights reserved.

The Effect of Antiepileptic Drug of Lamotrigine, on the Function of Reproductive Hormones in Male Rats

Directory of Open Access Journals (Sweden)

R. Khezri Motlagh

2016-08-01

Full Text Available Introduction: Lamotrigine is one of the never anti-epileptic drug. In this study the effects of lamotrigine have been observed on serum concentration of LH (Luteinizing hormone, FSH (Follicle-stimulating hormone, testosterone ,body and testis weight in male rat. Methods: The animal used in this experiment were 40 adult male rat from wistar race which were divided in to 5 group of 8.consisting of control group which received nothings, Sham group which received 0.2 ml distilled water via oral. Experimental group which received 100, 200, 400 mg/kg lamotrigine via oral after 14th day body weight were measured in all group and then the blood sample was taken from heart and concentration of LH.FSH, testosterone was measured. In addition the testis were separated and testis weight were measured in all group. Results: The result show that concentration of LH in experimental group did not show significant difference in compared with control group but in experimental group received 400mg/kg of lamotrigine  show a significant decrease in concentration of FSH and testosterone in comparison with control group .In addition lamotrigine had effect and testis weight in middle and high dose was reduce. Conclusion: Lamotrigine, an antiepileptic drug, reduced reproductive activity by inhibiting of hypothalamic-pituitary-gonadal axis in adult male rats.

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...

The precipitation synthesis of broad-spectrum UV absorber nanoceria

International Nuclear Information System (INIS)

Nurhasanah, Iis; Sutanto, Heri; Puspaningrum, Nurul Wahyu

2013-01-01

In this paper the possibility of nanoceria as broad-spectrum UV absorber was evaluated. Nanoceria were synthesized by precipitation process from cerium nitrate solution and ammonium hydroxide as precipitant agent. Isopropanol was mixed with water as solvent to prevent hard agglomeration. The structure of resulting nanoceria was characterized by x-ray diffractometer (XRD). The transparency in the visible light and efficiency of protection in UV A region were studied using ultraviolet-visible (UV - Vis) spectrophotometer. The results show that nanoceria possess good tranparency in visible light and high UV light absorption. The critical absorption wavelenght of 368 nm was obtained which is desirable for excellent broad-spectrum protection absorbers. Moreover, analysis of photodegradation nanoceria to methylene blue solution shows poor photocatalytic activity. It indicates that nanoceria suitable for used as UV absorber in personal care products

Antiepileptic drug use and the occurrence of pressure ulcers among bedridden institutionalized elderly patients: a retrospective chart review.

Science.gov (United States)

Arinzon, Zeev; Zeilig, Gabriel; Berner, Yitshal N; Adunsky, Abraham

2005-09-01

Phenytoin (PH) is indicated primarily for the control of grand mal and psychomotor seizures. However, topical PH has been used for the treatment of various types of ulcers, including pressure ulcers. The aim of this study was to investigate the possibility of a relationship between the use of oral PH and the prevalence of pressure ulcers among bedridden institutionalized elderly patients. This retrospective chart review was conducted in a state-run urban geriatric medical center in Israel and involved long-term bedridden institutionalized patients who were receiving chronic antiepileptic medication during the 7-year period between January 1996 and December 2003. The prevalence of pressure ulcers in patients who received treatment with PH alone or in combination with other antiepileptic drugs was compared with that in patients who received antiepileptic agents other than PH. The study analyzed data from the medical charts of 153 patients, 72 of whom received PH alone or in combination with other antiepileptic drugs, and 81 of whom received antiepileptic agents other than PH. Patients' mean (SD) age was 78.5 (7.2) years; 106 (69.3%) were women. All patients were totally dependent with respect to activities of daily living (mean Katz score, 2.0 [2.0]) and had severe cognitive decline (mean Mini-Mental State Examination score, 3.5 [3.3]). Pressure ulcers occurred in 9.7% of PH recipients and 27.2% of non-PH recipients (P = 0.006; chi2 = 7.55). In PH recipients, 85.7% of pressure ulcers were of mild to moderate severity (stage I or II), compared with 59.1% of ulcers in non-PH recipients; the difference between groups was not statistically significant. Four (18.2%) non-PH recipients and no PH recipients had stage IV pressure ulcers. In the PH group, 71.4% of patients had a pressure ulcer in only 1 anatomic location, compared with 22.7% of the non-PH group (P = 0.023; chi2 = 5.13); 28.6% of PH recipients and 63.6% of non-PH recipients had pressure ulcers in 2 or 3

Brivaracetam: a novel antiepileptic drug for focal-onset seizures.

Science.gov (United States)

Stephen, Linda J; Brodie, Martin J

2018-01-01

Brivaracetam (BRV), the n -propyl analogue of levetiracetam (LEV), is the latest antiepileptic drug (AED) to be licensed in Europe and the USA for the adjunctive treatment of focal-onset seizures with or without secondary generalization in patients aged 16 years or older. Like LEV, BRV binds to synaptic vesicle protein 2A (SV2A), but BRV has more selective binding and a 15- to 30-fold higher binding affinity than LEV. BRV is more effective than LEV in slowing synaptic vesicle mobilization and the two AEDs may act at different binding sites or interact with different conformational states of the SV2A protein. In animal models, BRV provides protection against focal and secondary generalized seizures and has significant anticonvulsant effects in genetic models of epilepsy. The drug undergoes first-order pharmacokinetics with an elimination half-life of 7-8 h. Although BRV is metabolized extensively, the main circulating compound is unchanged BRV. Around 95% of metabolites undergo renal elimination. No dose reduction is required in renal impairment, but it is recommended that the daily dose is reduced by one-third in hepatic dysfunction that may prolong half-life. BRV has a low potential for drug interactions. The efficacy and tolerability of adjunctive BRV in adults with focal-onset seizures have been explored in six randomized, placebo-controlled studies. These showed significant efficacy outcomes for doses of 50-200 mg/day. The most common adverse events reported were headache, somnolence, dizziness, fatigue and nausea. Patients who develop psychiatric symptoms with LEV appear to be at risk of similar side effects with BRV, although preliminary data suggest that these issues are likely to be less frequent and perhaps less severe. As with all AEDs, a low starting dose and slow titration schedule help to minimize side effects and optimize seizure control and thereby quality of life.

The Risk of Specific Congenital Anomalies in Relation to Newer Antiepileptic Drugs

DEFF Research Database (Denmark)

de Jong, Josta; Garne, Ester; de Jong-van den Berg, Lolkje T.W.

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...... studies with pregnancies exposed to newer AEDs and detailed information on congenital anomalies. The congenital anomalies in the studies were classified according to the congenital anomaly subgroups of European Surveillance of Congenital Anomalies (EUROCAT). We compared the prevalence of specific...... and were not supported by other studies. No signals were found for the other newer AEDs, or the information was too limited to provide such a signal. CONCLUSION: In terms of associations between monotherapy with a newer AED in the first trimester of pregnancy and a specific congenital anomaly, the signals...

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

DEFF Research Database (Denmark)

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

2013-01-01

Objective Some anti-epileptic drugs (AED) have well-known teratogenic effects. The aim of the present study was to elucidate the effect of prenatal exposure to AED and the risk of enamel defects in the primary and permanent dentition. Methods A total of 38 exposed and 129 non-exposed children, 6......–10 years of age, were recruited from the Aarhus Birth Cohort and the Department of Neurology, Viborg Regional Hospital, Denmark. Medication during pregnancy was confirmed by the Danish Prescription Database. All children had their teeth examined and outcomes in terms of enamel opacities and enamel...... hypoplasia were recorded. Results Children prenatally exposed to AED have an increased prevalence of enamel hypoplasia (11% vs. 4%, odds ratio (OR) = 3.6 [95% confidence interval (CI): 0.9 to 15.4]), diffuse opacities (18% vs. 7%, OR = 3.0; [95% CI: 1.0 to 8.7, p3) white opacities (18...

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.

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

Directory of Open Access Journals (Sweden)

Ghaydaa A Shehata

2009-10-01

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

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

Science.gov (United States)

Hamed, Sherifa Ahmed

2017-09-01

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

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

DEFF Research Database (Denmark)

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

2012-01-01

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

An acardiac acephalic monster following in-utero anti-epileptic drug exposure.

Science.gov (United States)

Kutlay, B; Bayramoglu, S; Kutlar, A I; Yesildaglar, N

1996-04-01

Acardia, the absence of the heart, is one of the rarest medical anomalies. The exact mechanism which causes this anomaly is still unknown. The authors report the acardiac acephalic fetus of an epileptic mother who was on primidone therapy. The mother who received no antenatal care stopped taking primidone (her sole medication) in the third month of pregnancy with the fear of delivering a malformed baby and had three convulsions until delivery. This is the first reported case of acardia associated with anti-epileptic medication. The cause of the anomaly in this patient may be an unknown genetic defect, the maternal epileptic disorder, the convulsions, the anti-epileptic medication, or a combination of these factors.

Comparing Safety and Efficacy of "Third-Generation" Antiepileptic Drugs: Long-Term Extension and Post-marketing Treatment.

Science.gov (United States)

Kwok, Charlotte S; Johnson, Emily L; Krauss, Gregory L

2017-11-01

Four "third-generation" antiepileptic drugs (AEDs) were approved for adjunctive treatment of refractory focal onset seizures during the past 10 years. Long-term efficacy and safety of the drugs were demonstrated in large extension studies and in reports of subgroups of patients not studied in pivotal trials. Reviewing extension study and post-marketing outcome series for the four newer AEDs-lacosamide, perampanel, eslicarbazepine acetate and brivaracetam-can guide clinicians in treating and monitoring patients. AED extension studies evaluate treatment retention, drug tolerability, and drug safety during individualized treatment with flexible dosing and thus provide information not available in rigid pivotal trials. Patient retention in the studies ranged from 75 to 80% at 1 year and from 36 to 68% at 2-year treatment intervals. Safety findings were generally similar to those of pivotal trials, with no major safety risks identified and with several specific adverse drug effects, such as hyponatremia, reported. The third-generation AEDs, some through new mechanisms and others with improved tolerability compared to related AEDs, provide new options in efficacy and tolerability.

Broad- versus Narrow-Spectrum Oral Antibiotic Transition and Outcomes in Health Care-associated Pneumonia.

Science.gov (United States)

Buckel, Whitney R; Stenehjem, Edward; Sorensen, Jeff; Dean, Nathan; Webb, Brandon

2017-02-01

Guidelines recommend a switch from intravenous to oral antibiotics once patients who are hospitalized with pneumonia achieve clinical stability. However, little evidence guides the selection of an oral antibiotic for patients with health care-associated pneumonia, especially where no microbiological diagnosis is made. To compare outcomes between patients who were transitioned to broad- versus narrow-spectrum oral antibiotics after initially receiving broad-spectrum intravenous antibiotic coverage. We performed a secondary analysis of an existing database of adults with community-onset pneumonia admitted to seven Utah hospitals. We identified 220 inpatients with microbiology-negative health care-associated pneumonia from 2010 to 2012. After excluding inpatient deaths and treatment failures, 173 patients remained in which broad-spectrum intravenous antibiotics were transitioned to an oral regimen. We classified oral regimens as broad-spectrum (fluoroquinolone) versus narrow-spectrum (usually a β-lactam). We compared demographic and clinical characteristics between groups. Using a multivariable regression model, we adjusted outcomes by severity (electronically calculated CURB-65), comorbidity (Charlson Index), time to clinical stability, and length of intravenous therapy. Age, severity, comorbidity, length of intravenous therapy, and clinical response were similar between the two groups. Observed 30-day readmission (11.9 vs. 21.4%; P = 0.26) and 30-day all-cause mortality (2.3 vs. 5.3%; P = 0.68) were also similar between the narrow and broad oral antibiotic groups. In multivariable analysis, we found no statistically significant differences for adjusted odds of 30-day readmission (adjusted odds ratio, 0.56; 95% confidence interval, 0.06-5.2; P = 0.61) or 30-day all-cause mortality (adjusted odds ratio, 0.55; 95% confidence interval, 0.19-1.6; P = 0.26) between narrow and broad oral antibiotic groups. On the basis of analysis of a limited number of patients

Observing broad-absorption line quasars with Spectrum-Rontgen-Gamma

DEFF Research Database (Denmark)

Singh, K.P.; Schnopper, H.W.; Westergaard, Niels Jørgen Stenfeldt

1998-01-01

Broad-absorption line quasars are found to have extremely weak soft X-ray emission when compared with other optically selected quasars. In the only example of PHL 5200 for which a detailed X-ray spectrum has been obtained with ASCA, strong absorption in the source appears to be responsible...

Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism

Science.gov (United States)

Cagno, Valeria; Andreozzi, Patrizia; D'Alicarnasso, Marco; Jacob Silva, Paulo; Mueller, Marie; Galloux, Marie; Le Goffic, Ronan; Jones, Samuel T.; Vallino, Marta; Hodek, Jan; Weber, Jan; Sen, Soumyo; Janeček, Emma-Rose; Bekdemir, Ahmet; Sanavio, Barbara; Martinelli, Chiara; Donalisio, Manuela; Rameix Welti, Marie-Anne; Eleouet, Jean-Francois; Han, Yanxiao; Kaiser, Laurent; Vukovic, Lela; Tapparel, Caroline; Král, Petr; Krol, Silke; Lembo, David; Stellacci, Francesco

2018-02-01

Viral infections kill millions yearly. Available antiviral drugs are virus-specific and active against a limited panel of human pathogens. There are broad-spectrum substances that prevent the first step of virus-cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them. We designed antiviral nanoparticles with long and flexible linkers mimicking HSPG, allowing for effective viral association with a binding that we simulate to be strong and multivalent to the VAL repeating units, generating forces (~190 pN) that eventually lead to irreversible viral deformation. Virucidal assays, electron microscopy images, and molecular dynamics simulations support the proposed mechanism. These particles show no cytotoxicity, and in vitro nanomolar irreversible activity against herpes simplex virus (HSV), human papilloma virus, respiratory syncytial virus (RSV), dengue and lenti virus. They are active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV.

Broadly Applicable Nanowafer Drug Delivery System for Treating Eye Injuries

Science.gov (United States)

2015-09-01

Systems in Systemic , Dermal, Transdermal , and Ocular Drug Delivery . Crit. Rev. Ther. Drug 2008, 25, 545–584. 14. Choy, Y. B.; Park, J.-H.; McCarey, B...AWARD NUMBER: W81XWH-13-1-0146 TITLE: Broadly Applicable Nanowafer Drug Delivery System for Treating Eye Injuries PRINCIPAL INVESTIGATOR: Dr...Broadly Applicable Nanowafer Drug Delivery System for Treating Eye Injuries” 5b. GRANT NUMBER W81XWH-13-1-0146 5c. PROGRAM ELEMENT NUMBER 6

Alteration of the threshold stimulus for intraoperative brain mapping via use of antiepileptic medications

Directory of Open Access Journals (Sweden)

John W. Amburgy, MD

2015-03-01

Full Text Available Intraoperative seizures during awake craniotomy with cortical and subcortical mapping are a common occurrence. Patients are routinely treated preoperatively with anti-convulsive medications to reduce seizure occurrence. Historically these drugs have not been believed to significantly affect awake craniotomy procedures. We report a patient undergoing intraoperative mapping with differential response and seizure occurrence based upon antiepileptic drug usage. A 43 year old female presented with history of seizures, right sided hemiparesis, electrical sensations, and difficulty with language function. She was determined to have a mass lesion involving the left frontal and temporal lobes and subsequently elected to undergo resection by awake craniotomy with intraoperative mapping. A first attempt at lesion resection was performed after a missed dose of anti-convulsant medication (levetiracetam and was subsequently aborted because of repeated seizure activity. The threshold for seizure generation (1.75 mA was observed to be significantly lower than expected. Therapy was begun with both levetiracetam and phenytoin prior to a second attempted resection one week later. Thresholds for cortical motor response in the second operation were significantly higher than expected (> 9.0 mA, and no intraoperative seizure activity was observed. To our knowledge this is the first quantitative example of antiepileptic drugs affecting the current required for intraoperative mapping. This case highlights the potential for higher current requirements in patients preoperatively treated with high doses of antiepileptic drugs, as well as the importance of confirming adequate dosage of antiepileptic drugs in patients at an increased risk of seizure generation.

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

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Huixiang Xiao

2017-01-01

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

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

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Zeun, Ronald; Scalliet, Gabriel; Oostendorp, Michael

2013-04-01

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

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

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Halvorsen, Kjell H; Johannessen Landmark, Cecilie; Granas, Anne Gerd

2016-01-01

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

Metabolic and functional MR biomarkers of antiepileptic drug effectiveness: A review.

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van Veenendaal, Tamar M; IJff, Dominique M; Aldenkamp, Albert P; Hofman, Paul A M; Vlooswijk, Marielle C G; Rouhl, Rob P W; de Louw, Anton J; Backes, Walter H; Jansen, Jacobus F A

2015-12-01

As a large number of patients with epilepsy do not respond favorably to antiepileptic drugs (AEDs), a better understanding of treatment failure and the cause of adverse side effects is required. The working mechanisms of AEDs also alter neurotransmitter concentrations and brain activity, which can be measured using MR spectroscopy and functional MR imaging, respectively. This review presents an overview of clinical research of MR spectroscopy and functional MR imaging studies to the effects of AEDs on the brain. Despite the scarcity of studies associating MR findings to the effectiveness of AEDs, the current research shows clear potential regarding this matter. Several GABAergic AEDs have been shown to increase the GABA concentration, which was related to seizure reductions, while language problems due to topiramate have been associated with altered activation patterns measured with functional MR imaging. MR spectroscopy and functional MR imaging provide biomarkers that may predict individual treatment outcomes, and enable the assessment of mechanisms of treatment failure and cognitive side effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antiepileptic and Antidepressive Polypharmacy in Patients with Multiple Sclerosis

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Georg Anton Giæver Beiske

2015-01-01

Full Text Available Objective. Patients with multiple sclerosis (MS are often suffering from neuropathic pain. Antiepileptic drugs (AEDs and tricyclic antidepressants (TCAs are commonly used and are susceptible to be involved in drug interactions. The aim of this retrospective study was to investigate the prevalence of use of antiepileptic and antidepressive drugs in MS patients and to discuss the theoretical potential for interactions. Methods. Review of the medical records from all patients treated at a dedicated MS rehabilitation centre in Norway between 2009 and 2012. Results. In total 1090 patients attended a rehabilitation stay during the study period. Of these, 342 (31%; 249 females with mean age of 53 (±10 years and EDSS 4.8 (±1.7 used at least one AED (gabapentin 12.7%, pregabalin 7.7%, clonazepam 7.8%, and carbamazepine 2.6% or amitriptyline (9.7%. Polypharmacy was widespread (mean 5.4 drugs with 60% using additional CNS-active drugs with a propensity to be involved in interactions. Age, gender, and EDSS scores did not differ significantly between those using and not using AED/amitriptyline. Conclusion. One-third of MS patients attending a rehabilitation stay receive AED/amitriptyline treatment. The high prevalence of polypharmacy and use of CNS-active drugs calls for awareness of especially pharmacodynamic interactions and possible excessive adverse effects.

Broad-spectrum enhanced absorption of graphene-molybdenum disulfide photovoltaic cells in metal-mirror microcavity

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Jiang-Tao, Liu; Yun-Kai, Cao; Hong, Tong; Dai-Qiang, Wang; Zhen-Hua, Wu

2018-04-01

The optical absorption of graphene-molybdenum disulfide photovoltaic cells (GM-PVc) in wedge-shaped metal-mirror microcavities (w-MMCs) combined with a spectrum-splitting structure was studied. Results showed that the combination of spectrum-splitting structure and w-MMC can enable the light absorption of GM-PVcs to reach about 65% in the broad spectrum. The influence of processing errors on the absorption of GM-PVcs in w-MMCs was 3-14 times lower than that of GM-PVcs in wedge photonic crystal microcavities. The light absorption of GM-PVcs reached 60% in the broad spectrum, even with the processing errors. The proposed structure is easy to implement and may have potentially important applications in the development of ultra-thin and high-efficiency solar cells and optoelectronic devices.

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

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

2014-01-01

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

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

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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.

Discovery of dapivirine, a nonnucleoside HIV-1 reverse transcriptase inhibitor, as a broad-spectrum antiviral against both influenza A and B viruses.

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Hu, Yanmei; Zhang, Jiantao; Musharrafieh, Rami Ghassan; Ma, Chunlong; Hau, Raymond; Wang, Jun

2017-09-01

The emergence of multidrug-resistant influenza viruses poses a persistent threat to public health. The current prophylaxis and therapeutic interventions for influenza virus infection have limited efficacy due to the continuous antigenic drift and antigenic shift of influenza viruses. As part of our ongoing effort to develop the next generation of influenza antivirals with broad-spectrum antiviral activity and a high genetic barrier to drug resistance, in this study we report the discovery of dapivirine, an FDA-approved HIV nonnucleoside reverse transcriptase inhibitor, as a broad-spectrum antiviral against multiple strains of influenza A and B viruses with low micromolar efficacy. Mechanistic studies revealed that dapivirine inhibits the nuclear entry of viral ribonucleoproteins at the early stage of viral replication. As a result, viral RNA and protein synthesis were inhibited. Furthermore, dapivirine has a high in vitro genetic barrier to drug resistance, and its antiviral activity is synergistic with oseltamivir carboxylate. In summary, the in vitro antiviral results of dapivirine suggest it is a promising candidate for the development of the next generation of dual influenza and HIV antivirals. Copyright © 2017 Elsevier B.V. All rights reserved.

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

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Gambler Angela S

2009-06-01

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

Comparative evaluation of oral hygiene status and gingival enlargement among epileptic and healthy children as related to various antiepileptic drugs

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Neelam Hasmukhbhai Joshi

2017-01-01

Full Text Available Background: Epilepsy is a gathering of neurological disorders characterized by epileptic seizures. Epileptic children, who are on active treatment with antiepileptic drugs, have a well-recognized side effect of gingival enlargement. Therefore, all efforts should be made, particularly for the population who are diagnosed or affected by the systemic disease. This study was conducted with an aim to determine oral hygiene status and gingival enlargement among epileptic and healthy children as related to various antiepileptic drugs. Materials and Methods: The cross-sectional observational study was conducted in the department of pedodontics and attached general hospital. A sample size of 120 participants with 60 healthy and 60 epileptic children between age 2 and 14 years were included. Oral health status of participants was examined using oral hygiene simplified index and plaque index. Gingival enlargement was assessed using Miranda–Brunet index. For statistical analysis, one-way ANOVA test, independent t-test, and Pearson's Chi-square test were used. Results: From the total participants included in the study, 49% of participants had good oral hygiene from healthy group, and 28% participants had poor oral hygiene from the epileptic group. Sodium valproate was the most common drug used and was associated with increased gingival enlargement. Conclusion: Conclusion can be drawn that epileptic children under medication had poor oral hygiene and an increased risk for gingival enlargement as compared to their healthy counterparts. It must be stressed that the epileptic patients should be given dental care without conditions and provided with best possible care to restore esthetics and functions.

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

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

2016-01-01

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

Newer antiepileptic drugs in the treatment of status epilepticus: impact on prognosis.

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Jaques, Léonore; Rossetti, Andrea O

2012-05-01

Newer antiepileptic drugs (AEDs) are increasingly prescribed and seem to have a comparable efficacy as the classical AEDs; however, their impact on status epilepticus (SE) prognosis has received little attention. In our prospective SE database (2006-2010), we assessed the use of older versus newer AEDs (levetiracetam, pregabalin, topiramate, lacosamide) over time and its relationship to outcome (return to clinical baseline conditions, new handicap, or death). Newer AEDs were used more often toward the end of the study period (42% of episodes versus 30%). After adjustment for SE etiology, SE severity score, and number of compounds needed to terminate SE, newer AEDs were independently related to a reduced likelihood of return to baseline (p<0.001) but not to increased mortality. These findings seem in line with recent findings on refractory epilepsy. Also, in view of the higher price of the newer AEDs, well-designed, prospective assessments analyzing the impact of newer AEDs on efficacy and tolerability in patients with SE appear mandatory. Copyright © 2012 Elsevier Inc. All rights reserved.

Novel engineered cationic antimicrobial peptides display broad-spectrum activity against Francisella tularensis, Yersinia pestis and Burkholderia pseudomallei.

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Abdelbaqi, Suha; Deslouches, Berthony; Steckbeck, Jonathan; Montelaro, Ronald; Reed, Douglas S

2016-02-01

Broad-spectrum antimicrobials are needed to effectively treat patients infected in the event of a pandemic or intentional release of a pathogen prior to confirmation of the pathogen's identity. Engineered cationic antimicrobial peptides (eCAPs) display activity against a number of bacterial pathogens including multi-drug-resistant strains. Two lead eCAPs, WLBU2 and WR12, were compared with human cathelicidin (LL-37) against three highly pathogenic bacteria: Francisella tularensis, Yersinia pestis and Burkholderia pseudomallei. Both WLBU2 and WR12 demonstrated bactericidal activity greater than that of LL-37, particularly against F. tularensis and Y. pestis. Only WLBU2 had bactericidal activity against B. pseudomallei. WLBU2, WR12 and LL-37 were all able to inhibit the growth of the three bacteria in vitro. Because these bacteria can be facultative intracellular pathogens, preferentially infecting macrophages and dendritic cells, we evaluated the activity of WLBU2 against F. tularensis in an ex vivo infection model with J774 cells, a mouse macrophage cell line. In that model WLBU2 was able to achieve greater than 50% killing of F. tularensis at a concentration of 12.5 μM. These data show the therapeutic potential of eCAPs, particularly WLBU2, as a broad-spectrum antimicrobial for treating highly pathogenic bacterial infections.

Co-morbidity and clinically significant interactions between antiepileptic drugs and other drugs in elderly patients with newly diagnosed epilepsy.

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Bruun, Emmi; Virta, Lauri J; Kälviäinen, Reetta; Keränen, Tapani

2017-08-01

A study was conducted to investigate the frequency of potential pharmacokinetic drug-to-drug interactions in elderly patients with newly diagnosed epilepsy. We also investigated co-morbid conditions associated with epilepsy. From the register of Kuopio University Hospital (KUH) we identified community-dwelling patients aged 65 or above with newly diagnosed epilepsy and in whom use of the first individual antiepileptic drug (AED) began in 2000-2013 (n=529). Furthermore, register data of the Social Insurance Institution of Finland were used for assessing potential interactions in a nationwide cohort of elderly subjects with newly diagnosed epilepsy. We extracted all patients aged 65 or above who had received special reimbursement for the cost of AEDs prescribed on account of epilepsy in 2012 where their first AED was recorded in 2011-2012 as monotherapy (n=1081). Clinically relevant drug interactions (of class C or D) at the time of starting of the first AED, as assessed via the SFINX-PHARAO database, were analysed. Hypertension (67%), dyslipidemia (45%), and ischaemic stroke (32%) were the most common co-morbid conditions in the hospital cohort of patients. In these patients, excessive polypharmacy (more than 10 concomitant drugs) was identified in 27% of cases. Of the patients started on carbamazepine, 52 subjects (32%) had one class-C or class-D drug interaction and 51 (31%) had two or more C- or D-class interactions. Only 2% of the subjects started on valproate exhibited a class-C interaction. None of the subjects using oxcarbazepine displayed class-C or class-D interactions. Patients with 3-5 (OR 4.22; p=0.05) or over six (OR 8.86; p=0.003) other drugs were more likely to have C- or D-class interaction. The most common drugs with potential interactions with carbamazepine were dihydropyridine calcium-blockers, statins, warfarin, and psychotropic drugs. Elderly patients with newly diagnosed epilepsy are at high risk of clinically relevant pharmacokinetic

Association of Broad- vs Narrow-Spectrum Antibiotics With Treatment Failure, Adverse Events, and Quality of Life in Children With Acute Respiratory Tract Infections.

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Gerber, Jeffrey S; Ross, Rachael K; Bryan, Matthew; Localio, A Russell; Szymczak, Julia E; Wasserman, Richard; Barkman, Darlene; Odeniyi, Folasade; Conaboy, Kathryn; Bell, Louis; Zaoutis, Theoklis E; Fiks, Alexander G

2017-12-19

Acute respiratory tract infections account for the majority of antibiotic exposure in children, and broad-spectrum antibiotic prescribing for acute respiratory tract infections is increasing. It is not clear whether broad-spectrum treatment is associated with improved outcomes compared with narrow-spectrum treatment. To compare the effectiveness of broad-spectrum and narrow-spectrum antibiotic treatment for acute respiratory tract infections in children. A retrospective cohort study assessing clinical outcomes and a prospective cohort study assessing patient-centered outcomes of children between the ages of 6 months and 12 years diagnosed with an acute respiratory tract infection and prescribed an oral antibiotic between January 2015 and April 2016 in a network of 31 pediatric primary care practices in Pennsylvania and New Jersey. Stratified and propensity score-matched analyses to account for confounding by clinician and by patient-level characteristics, respectively, were implemented for both cohorts. Broad-spectrum antibiotics vs narrow-spectrum antibiotics. In the retrospective cohort, the primary outcomes were treatment failure and adverse events 14 days after diagnosis. In the prospective cohort, the primary outcomes were quality of life, other patient-centered outcomes, and patient-reported adverse events. Of 30 159 children in the retrospective cohort (19 179 with acute otitis media; 6746, group A streptococcal pharyngitis; and 4234, acute sinusitis), 4307 (14%) were prescribed broad-spectrum antibiotics including amoxicillin-clavulanate, cephalosporins, and macrolides. Broad-spectrum treatment was not associated with a lower rate of treatment failure (3.4% for broad-spectrum antibiotics vs 3.1% for narrow-spectrum antibiotics; risk difference for full matched analysis, 0.3% [95% CI, -0.4% to 0.9%]). Of 2472 children enrolled in the prospective cohort (1100 with acute otitis media; 705, group A streptococcal pharyngitis; and 667, acute sinusitis), 868

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

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

2009-01-01

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

Broad-Spectrum Inhibitors against 3C-Like Proteases of Feline Coronaviruses and Feline Caliciviruses

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Shivanna, Vinay; Narayanan, Sanjeev; Prior, Allan M.; Weerasekara, Sahani; Hua, Duy H.; Kankanamalage, Anushka C. Galasiti; Groutas, William C.; Chang, Kyeong-Ok

2015-01-01

ABSTRACT Feline infectious peritonitis and virulent, systemic calicivirus infection are caused by certain types of feline coronaviruses (FCoVs) and feline caliciviruses (FCVs), respectively, and are important infectious diseases with high fatality rates in members of the Felidae family. While FCoV and FCV belong to two distinct virus families, the Coronaviridae and the Caliciviridae, respectively, they share a dependence on viral 3C-like protease (3CLpro) for their replication. Since 3CLpro is functionally and structurally conserved among these viruses and essential for viral replication, 3CLpro is considered a potential target for the design of antiviral drugs with broad-spectrum activities against these distinct and highly important viral infections. However, small-molecule inhibitors against the 3CLpro enzymes of FCoV and FCV have not been previously identified. In this study, derivatives of peptidyl compounds targeting 3CLpro were synthesized and evaluated for their activities against FCoV and FCV. The structures of compounds that showed potent dual antiviral activities with a wide margin of safety were identified and are discussed. Furthermore, the in vivo efficacy of 3CLpro inhibitors was evaluated using a mouse model of coronavirus infection. Intraperitoneal administration of two 3CLpro inhibitors in mice infected with murine hepatitis virus A59, a hepatotropic coronavirus, resulted in significant reductions in virus titers and pathological lesions in the liver compared to the findings for the controls. These results suggest that the series of 3CLpro inhibitors described here may have the potential to be further developed as therapeutic agents against these important viruses in domestic and wild cats. This study provides important insights into the structure and function relationships of 3CLpro for the design of antiviral drugs with broader antiviral activities. IMPORTANCE Feline infectious peritonitis virus (FIPV) is the leading cause of death in young cats

Fracture risk associated with use of antiepileptic drugs.

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Vestergaard, Peter; Rejnmark, Lars; Mosekilde, Leif

2004-11-01

To assess fracture risk associated with different antiepileptic drugs (AEDs). An increased fracture risk has been reported in patients with epilepsy. Classical AEDs have been associated with decreased bone mineral density. The effects of newer AEDs are unknown. We undertook a population-based pharmacoepidemiologic case-control study with any fracture as outcome and use of AEDs as exposure variables (124,655 fracture cases and 373,962 controls). All AEDs were associated with an increased fracture risk in an unadjusted analysis. After adjustment for prior fracture, use (ever) of corticosteroids, comorbidity, social variables, and diagnosis of epilepsy, carbamazepine [CBZ; odds ratio (OR), 1.18; 95% confidence interval (CI), 1.10-1.26], [and oxcarbazepine (OXC; 1.14, 1.03-1.26)], clonazepam (CZP; 1.27, 1.15-1.41), phenobarbital (PB; 1.79, 1.64-1.95), and valproate (VPA; 1.15, 1.05-1.26) were statistically significantly associated with risk of any fracture. Ethosuximide (0.75, 0.37-1.52), lamotrigine (1.04, 0.91-1.19), phenytoin (1.20, 1.00-1.43), primidone (1.18, 0.95-1.48), tiagabine (0.75, 0.40-1.41), topiramate (1.39, 0.99-1.96), and vigabatrin (0.93, 0.70-1.22) were not statistically significantly associated with fracture risk after adjustment for confounders. The relative increase was modest and in the same range for the significant and nonsignificant results. CBZ, PB, OXC, and VPA displayed a dose-response relation. Fracture risk was more increased by liver-inducing AEDs (OR, 1.38; 95% CI, 1.31-1.45) than by noninducing AEDs (1.19; 95% CI, 1.11-1.27). A very limited increased fracture risk is present in users of CBZ, CZP, OXC, PB, and VPA. A limited significant increase cannot be excluded for the other AEDs because of the statistical power.

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

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Katrina eBrudzynski

2015-07-01

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

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

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Pili Ferrer-Argeles

2014-07-01

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

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

Science.gov (United States)

Kevin Ii, Dion A; Meujo, Damaris Af; Hamann, Mark T

2009-02-01

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. 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. 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.

Simultaneous determination of ten antiepileptic drugs in human plasma by liquid chromatography and tandem mass spectrometry with positive/negative ion-switching electrospray ionization and its application in therapeutic drug monitoring.

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Yin, Lei; Wang, Tingting; Shi, Meiyun; Zhang, Ying; Zhao, Xiaojun; Yang, Yan; Gu, Jingkai

2016-03-01

A simple, rapid, and high-throughput liquid chromatography with tandem mass spectrometry method for the simultaneous quantitation of ten antiepileptic drugs in human plasma has been developed and validated. The method required only 10 μL of plasma. After simple protein precipitation using acetonitrile, the analytes and internal standard diphenhydramine were separated on a Zorbax SB-C18 column (50 × 4.6 mm, 2.7 μm) using acetonitrile/water as the mobile phase at a flow rate of 0.9 mL/min. The total run time was 6 min for each sample. The validation results of specificity, matrix effects, recovery, linearity, precision, and accuracy were satisfactory. The lower limit of quantification was 0.04 μg/mL for carbamazepine, 0.02 μg/mL for lamotrigine, 0.01 μg/mL for oxcarbazepine, 0.4 μg/mL for 10-hydroxycarbazepine, 0.1 μg/mL for carbamazepine-10,11-epoxide, 0.15 μg/mL for levetiracetam, 0.06 μg/mL for phenytoin, 0.3 μg/mL for valproic acid, 0.03 μg/mL for topiramate, and 0.15 μg/mL for phenobarbital. The intraday precision and interday precision were less than 7.6%, with the accuracy ranging between -8.1 and 7.9%. The method was successfully applied to therapeutic drug monitoring of 1237 patients with epilepsy after administration of standard antiepileptic drugs. The method has been proved to meet the high-throughput requirements in therapeutic drug monitoring. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Classical neurotransmitters and neuropeptides involved in generalized epilepsy in a multi-neurotransmitter system: How to improve the antiepileptic effect?

Science.gov (United States)

Werner, Felix-Martin; Coveñas, Rafael

2017-06-01

Here, we describe in generalized epilepsies the alterations of classical neurotransmitters and neuropeptides acting at specific subreceptors. In order to consider a network context rather than one based on focal substrates and in order to make the interaction between neurotransmitters and neuropeptides and their specific subreceptors comprehensible, neural networks in the hippocampus, thalamus, and cerebral cortex are described. In this disease, a neurotransmitter imbalance between dopaminergic and serotonergic neurons and between presynaptic GABAergic neurons (hypoactivity) and glutaminergic neurons (hyperactivity) occurs. Consequently, combined GABA A agonists and NMDA antagonists could furthermore stabilize the neural networks in a multimodal pharmacotherapy. The antiepileptic effect and the mechanisms of action of conventional and recently developed antiepileptic drugs are reviewed. The GASH:Sal animal model can contribute to examine the efficacy of antiepileptic drugs. The issues of whether the interaction of classical neurotransmitters with other subreceptors (5-HT 7 , metabotropic 5 glutaminergic, A 2A adenosine, and alpha nicotinic 7 cholinergic receptors) or whether the administration of agonists/antagonists of neuropeptides might improve the therapeutic effect of antiepileptic drugs should be addressed. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic". Copyright © 2015 Elsevier Inc. All rights reserved.

Discovery of potent broad spectrum antivirals derived from marine actinobacteria.

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Avi Raveh

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

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

Science.gov (United States)

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

2017-05-01

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

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

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

2018-03-01

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

Fatigue during treatment with antiepileptic drugs: A levetiracetam-specific adverse event?

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Mula, Marco; von Oertzen, Tim J; Cock, Hannah R; Yogarajah, Mahinda; Lozsadi, Dora A; Agrawal, Niruj

2017-07-01

To examine the prevalence and clinical correlates of fatigue as an adverse event (AE) of antiepileptic drug (AED) treatment in patients with epilepsy. Data from 443 adult outpatients with epilepsy assessed with the Adverse Event Profile (AEP) and the Neurological Disorder Depression Inventory for Epilepsy (NDDIE) were analysed. Fatigue is reported by 36.6% of patients as always a problem during AED treatment. Fatigue is more likely to be reported by females (64.8% vs. 35.2%; Chi-Square=16.762; df=3; p=0.001) and during treatment with levetiracetam (42.3% vs. 33.2%; Chi-Square=11.462; df=3; p=0.009). The associations with the female gender and levetiracetam treatment were not mediated by depression, as identified with the NDDIE, and could not be simply explained by the large number of subjects on levetiracetam treatment, as analogous figures resulted from the analysis of a monotherapy subsample (41.7% vs. 30.3%; Chi-Square=11.547; df=3; p=0.009). One third of patients with epilepsy reports fatigue as a significant problem during AED treatment. Fatigue is more likely to be reported by females and seems to be specifically associated with LEV treatment. However, fatigue is not mediated by a negative effect of LEV on mood. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Science.gov (United States)

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

2017-09-01

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

Wavelength characteristics of chirped quantum dot superluminescent diodes for broad spectrum

Energy Technology Data Exchange (ETDEWEB)

Bae, Hyung-Chul; Park, Hong-Lee [Yonsei University, Seoul (Korea, Republic of); You, Young-Chae [Sungkyunkwan University, Suwon (Korea, Republic of); Han, Il-Ki [Korea Institute of Science and Technology, Seoul (Korea, Republic of)

2006-04-15

A chirped InAs quantum dot superluminescent diode both with and without a In{sub 0.15}Ga{sub 0.85}As cap layer was fabricated for a broad-band spectrum. This study shows that the cap layer reduces strain and operates as a carrier capturer and that carriers excited by lattice heating also affect the radiative recombination in the quantum dots (QDs) as well as the cap layer through the characteristic temperature (T{sub 0}). In addition, by surveying peaks of each QD layers, the characteristics of carriers in QDs, such as band-filling effect and the thermal effect, were analyzed, in QDs, and a more effective method for creating a wider spectrum is proposed.

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.

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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. Copyright © 2014 John Wiley & Sons, Ltd.

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...

Relationship between the Broad Autism Phenotype, Social Relationships and Mental Health for Mothers of Children with Autism Spectrum Disorder

Science.gov (United States)

Pruitt, Megan M.; Rhoden, Madeline; Ekas, Naomi V.

2018-01-01

This study aimed to examine the mechanisms responsible for the association between the broad autism phenotype and depressive symptoms in mothers of a child with autism spectrum disorder. A total of 98 mothers who had a child with autism spectrum disorder between the ages of 2 and 16 years completed assessments of maternal broad autism phenotype,…

The effects of exogenous catalase on broad-spectrum near-UV (300-400nm) treated Escherichia coli cells

International Nuclear Information System (INIS)

Sammartano, L.J.; Tuveson, R.W.

1984-01-01

Catalase incorporated into plating medium protects against inactivation and mutagenesis by broad-spectrum near-ultraviolet wavelength (300-400nm) (NUV) radiation in strains of Escherichia coli. Plating medium containing catalase does not provide protection against inactivation by wavelengths in the FUV region. Catalase added to the cell suspension during or added immediately after NUV exposure also protects against inactivation. The protection provided by catalase suggests a possible role for hydrogen peroxide in the processes of inactivation and mutagenesis by broad-spectrum NUV. (author)

The impact of the use of antiepileptic drugs on the growth of children

Science.gov (United States)

2013-01-01

Background This study investigated whether long-term treatment with antiepileptic drugs (AEDs) had negative effects on statural growth and serum calcium levels in children with epilepsy in Taiwan. Methods Children with epilepsy treated with one prescription of AEDs (monotherapy) for at least 1 year were selected. The AEDs included valproic acid (VPA; Deparkin) in 27 children (11 boys and 16 girls) aged 4-18 years, oxcarbazepine (Trileptal) in 30 children (15 boys and 15 girls) aged 5-18 years, topiramate (Topamax) in 19 children (10 boys and 9 girls) aged 6-18 years, and lamotrigine (Lamicta) in eight children (5 boys and 3 girls) aged 5-13 years. Patients with a history of febrile convulsions were selected as the controls. Results One year of VPA treatment significantly impaired the statural growth of pediatric patients with epilepsy (p effect of VPA on the proliferation of growth plate chondrocytes rather than alterations of serum calcium. Conclusions These results raise serious concerns about the growth of pediatric epilepsy patients who use AEDs, and potentially the need to closely monitor growth in children with epilepsy and adolescents under AED treatment, especially VPA. PMID:24354857

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

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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.

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

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

2017-02-01

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

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

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Krentz Hartmut B

2010-06-01

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

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.

A natural component from Euphorbia humifusa Willd displays novel, broad-spectrum anti-influenza activity by blocking nuclear export of viral ribonucleoprotein

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Chang, So Young; Park, Ji Hoon [Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400 (Korea, Republic of); Kim, Young Ho; Kang, Jong Seong [College of Pharmacy, Chungnam National University, Daejeon, 305-764 (Korea, Republic of); Min, Ji-Young, E-mail: jiyoung.min@ip-korea.org [Respiratory Viruses Research Laboratory, Discovery Biology Department, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400 (Korea, Republic of)

2016-03-04

The need to develop anti-influenza drugs with novel antiviral mechanisms is urgent because of the rapid rate of antigenic mutation and the emergence of drug-resistant viruses. We identified a novel anti-influenza molecule by screening 861 plant-derived natural components using a high-throughput image-based assay that measures inhibition of the influenza virus infection. 1,3,4,6-tetra-O-galloyl-β-D-glucopyranoside (TGBG) from Euphorbia humifusa Willd showed broad-spectrum anti-influenza activity against two seasonal influenza A strains, A/California/07/2009 (H1N1) and A/Perth/16/2009 (H3N2), and seasonal influenza B strain B/Florida/04/2006. We investigated the mode of action of TGBG using neuraminidase activity inhibition and time-of-addition assays, which evaluate the viral release and entry steps, respectively. We found that TGBG exhibits a novel antiviral mechanism that differs from the FDA-approved anti-influenza drugs oseltamivir which inhibits viral release, and amantadine which inhibits viral entry. Immunofluorescence assay demonstrated that TGBG significantly inhibits nuclear export of influenza nucleoproteins (NP) during the early stages of infection causing NP to accumulate in the nucleus. In addition, influenza-induced activation of the Akt signaling pathway was suppressed by TGBG in a dose-dependent manner. These data suggest that a putative mode of action of TGBG involves inhibition of viral ribonucleoprotein (vRNP) export from the nucleus to the cytoplasm consequently disrupting the assembly of progeny virions. In summary, TGBG has potential as novel anti-influenza therapeutic with a novel mechanism of action. - Highlights: • The plant-derived natural product TGBG has broad-spectrum antiviral activity against seasonal influenza A and B viruses. • TGBG has a novel anti-viral mechanism of action that from differs from the currently available anti-influenza drugs. • TGBG hinders nuclear export of the influenza virus ribonucleoprotein (v

A natural component from Euphorbia humifusa Willd displays novel, broad-spectrum anti-influenza activity by blocking nuclear export of viral ribonucleoprotein

International Nuclear Information System (INIS)

Chang, So Young; Park, Ji Hoon; Kim, Young Ho; Kang, Jong Seong; Min, Ji-Young

2016-01-01

The need to develop anti-influenza drugs with novel antiviral mechanisms is urgent because of the rapid rate of antigenic mutation and the emergence of drug-resistant viruses. We identified a novel anti-influenza molecule by screening 861 plant-derived natural components using a high-throughput image-based assay that measures inhibition of the influenza virus infection. 1,3,4,6-tetra-O-galloyl-β-D-glucopyranoside (TGBG) from Euphorbia humifusa Willd showed broad-spectrum anti-influenza activity against two seasonal influenza A strains, A/California/07/2009 (H1N1) and A/Perth/16/2009 (H3N2), and seasonal influenza B strain B/Florida/04/2006. We investigated the mode of action of TGBG using neuraminidase activity inhibition and time-of-addition assays, which evaluate the viral release and entry steps, respectively. We found that TGBG exhibits a novel antiviral mechanism that differs from the FDA-approved anti-influenza drugs oseltamivir which inhibits viral release, and amantadine which inhibits viral entry. Immunofluorescence assay demonstrated that TGBG significantly inhibits nuclear export of influenza nucleoproteins (NP) during the early stages of infection causing NP to accumulate in the nucleus. In addition, influenza-induced activation of the Akt signaling pathway was suppressed by TGBG in a dose-dependent manner. These data suggest that a putative mode of action of TGBG involves inhibition of viral ribonucleoprotein (vRNP) export from the nucleus to the cytoplasm consequently disrupting the assembly of progeny virions. In summary, TGBG has potential as novel anti-influenza therapeutic with a novel mechanism of action. - Highlights: • The plant-derived natural product TGBG has broad-spectrum antiviral activity against seasonal influenza A and B viruses. • TGBG has a novel anti-viral mechanism of action that from differs from the currently available anti-influenza drugs. • TGBG hinders nuclear export of the influenza virus ribonucleoprotein (v

Anticataleptic and antiepileptic activity of ethanolic extract of leaves of Mucuna pruriens: A study on role of dopaminergic system in epilepsy in albino rats.

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Champatisingh, D; Sahu, P K; Pal, A; Nanda, G S

2011-04-01

To assess the anticataleptic and antiepileptic activity of leaves of Mucuna pruriens in albino rats. Haloperidol-induced catalepsy (HIC), maximum electro-shock (MES) method, pilocarpine-induced Status epilepticus (PISE) and single-dose effect of M. pruriens were employed. M. pruriens (100 mg/kg) had significant anticataleptic and antiepileptic activity in HIC, MES, and PISE. M. pruriens extract has the potential to be an anticataleptic and antiepileptic drug. Dopamine and 5-HT may have a role in such activity.

Current status of the New Antiepileptic drugs in chronic pain.

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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

Antiepileptic drug utilization in Bangladesh: experience from Dhaka Medical College Hospital.

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Habib, Mansur; Khan, Sharif Uddin; Hoque, Azhahul; Mondal, Badrul Alam; Hasan, A T M Hasibul; Chowdhury, Rajib Nayan; Haque, Badrul; Rahman, Kazi Mohibur; Chowdhury, Ahmed Hossain; Ghose, Swapon Kumar; Mohammad, Quazi Deen

2013-11-18

Epilepsy is a common health problem which carries a huge medical social psychological and economic impact for a developing country. The aim of this hospital-based study was to get an insight into the effectiveness and tolerability of low cost antiepileptic drugs (AEDs) in Bangladeshi people with epilepsy. This retrospective chart review was done from hospital records in weekly Epilepsy outdoor clinic of Department of Neurology, Dhaka Medical College Hospital (DMCH) from October 1998 to February 2013. A total of 854 epilepsy patients met the eligibility criteria (had a complete record of two years of follow up data) from hospital database. A checklist was used to take demographics (age and gender), epilepsy treatment and adverse event related data. At least two years of follow up data were considered for analysis. Out of 854 patients selected, majority of the patients attending outdoor clinic were >11-30 years age group (55.2%) with a mean age of 20.3 ± 9 years and with a male (53%) predominance. Focal epilepsy were more common (53%), among whom secondary generalized epilepsy was the most frequent diagnosis (67%) followed by complex partial seizure (21%). Among those with Idiopathic Generalized Epilepsy (46%), generalized tonic clonic seizure was encountered in 74% and absence seizure was observed in 13%. The number of patients on monotherapy and dual AED therapy were 67% and 24% respectively and polytherapy (i.e. >3 AEDs) was used only in 9%. CBZ (67%) was the most frequently prescribed AED, followed by VPA (43%), PHB (17%), and PHT (8%). CBZ was prescribed in 37% patients as monotherapy followed by VPA in 21% and PHB in 8% patients. Newer generation drugs eg lemotrigine and topiramate were used only as add on therapy in combination with CBZ and VPA in only 2% patients. The treatment retention rates over the follow up period for the AEDs in monotherapy varied between 86 and 91% and were highest for CBZ, followed by VPA. Most of the combination regimens had a

The roles of variants in human multidrug resistance (MDR1 gene and their haplotypes on antiepileptic drugs response: a meta-analysis of 57 studies.

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Hui Li

Full Text Available Previous studies reported the associations between the ATP-binding cassette sub-family B member 1 (ABCB1, also known as MDR1 polymorphisms and their haplotypes with risk of response to antiepileptic drugs in epilepsy, however, the results were inconclusive.The Pubmed, Embase, Web of Science, CNKI and Chinese Biomedicine databases were searched up to July 15, 2014. Pooled odds ratios (ORs and 95% confidence intervals (CIs were calculated using a fixed-effects or random-effects model based on heterogeneity tests. Meta-regression and Galbraith plot analysis were carried out to explore the possible heterogeneity.A total of 57 studies involving 12407 patients (6083 drug-resistant and 6324 drug-responsive patients with epilepsy were included in the pooled-analysis. For all three polymorphisms (C3435T, G2677T/A, and C1236T, we observed a wide spectrum of minor allele frequencies across different ethnicities. A significantly decreased risk of AEDs resistance was observed in Caucasian patients with T allele of C3435T variant, which was still significant after adjusted by multiple testing corrections (T vs C: OR=0.83, 95%CI=0.71-0.96, p=0.01. However, no significant association was observed between the other two variants and AEDs resistance. Of their haplotypes in ABCB1 gene (all studies were in Indians and Asians, no significant association was observed with AEDs resistance. Moreover, sensitivity and Cumulative analysis showed that the results of this meta-analysis were stable.In summary, this meta-analysis demonstrated that effect of C3435T variant on risk of AEDs resistance was ethnicity-dependent, which was significant in Caucasians. Additionally, further studies in different ethnic groups are warranted to clarify possible roles of haplotypes in ABCB1 gene in AEDs resistance, especially in Caucasians.

Use of antiepileptic drugs and risk of falls in old age: A systematic review.

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Haasum, Ylva; Johnell, Kristina

2017-12-01

The aim of this study is to systematically review the scientific literature to investigate if use of antiepileptic drugs (AEDs) is associated with falls and/or recurrent falls in old age. We searched the literature for relevant articles in PubMed and Embase published up until 3rd December 2015. Studies on people aged 60 years and over with an observational design assessing the risk of fall in people exposed to AEDs compared to people not exposed to AED were included. We found 744 studies by searching Medline and Embase and an additional 9 studies by reviewing relevant reference lists. Of these studies, 13 fulfilled our predefined criteria. The articles were of various study design, sizes and follow-up times, and presented the results in different ways. Also, confounder adjustment varied considerably between the studies. Ten studies presented results for the association between use of any AED and any fall/injurious fall. Of these studies, 6 presented adjusted estimates, of which all but one showed statistically significant associations between use of any AED and any fall/injurious fall. Six studies investigated the association between use of any AED and recurrent falls. Of these, only 3 studies presented adjusted effect estimates of which 2 reached statistical significance for the association between use of AEDs and recurrent falls in elderly people. Our results indicate an association between use of AEDs and risk of falls and recurrent falls in older people. This finding may be clinically important given that a substantial amount of older people use these drugs. However, further research is needed to increase the knowledge about the actual risk of falls when using these drugs in old age. Copyright © 2017 Elsevier B.V. All rights reserved.

Improving clinical drug development regulatory procedures for anticonvulsants

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Janković Slobodan

2015-01-01

Full Text Available Background: Clinical development of antiepileptic drugs is demanding due to complex character of the disorder and to diversity of its forms and etiologies. Objective: The aim of this review was to suggest improvements in regulatory procedures for clinical development of antiepileptic drugs. Methods: The following databases of scientific articles were searched: MEDLINE, SCOPUS and SCINDEKS. In total 558 publications were retrieved. The types of articles selected were reviews, reports on clinical trials and letters to the Editor. Results: There are several changes of regulatory documents necessary for improving process of clinical development of antiepileptic drugs: preference of parallel groups design for add-on trials should be explicit; the noninferiority design for monotherapy clinical trials should be acceptable; restrictive formulations when trials of antiepileptic drugs in children are in question should be avoided; requirements in regard to the efficacy measures should be harmonized among the regulatory bodies; proactive attitude towards discovery of adverse events; and precise requirements for clinical trials specifically designed to prove anti-epileptogenic effects should be made clear. Conclusion: Current regulatory documents are incomplete in many aspects; an international effort to improve and harmonize guidelines for clinical development of antiepileptic drugs is necessary for improvement of this process.

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

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

2017-12-15

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

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

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Jantima Roongruangchai

2017-05-01

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

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

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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.

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

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

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

The evaluation of 25-hydroxy vitamin D, calcium, phosphate and alkaline phosphatase levels in epileptic children under antiepileptic medication

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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

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

DEFF Research Database (Denmark)

Nielsen, Carsten Uhd

2014-01-01

Vigabatrin is an antiepileptic drug substance mainly used in pediatric treatment of infantile spasms. The main source of nutrition for infants is breast milk and/or infant formula. Our hypothesis was that infant formula may affect the intestinal absorption of vigabatrin. The aim was therefore...... to investigate the potential effect of coadministration of infant formula with vigabatrin on the oral absorption in vitro and in vivo. The effect of vigabatrin given with an infant formula on the oral uptake and transepithelial transport was investigated in vitro in Caco-2 cells. In vivo effects of infant...... formula and selected amino acids on the pharmacokinetic profile of vigabatrin was investigated after oral coadministration to male Sprague–Dawley rats using acetaminophen as a marker for gastric emptying. The presence of infant formula significantly reduced the uptake rate and permeability of vigabatrin...

Particle acceleration model for the broad-band baseline spectrum of the Crab nebula

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Fraschetti, F.; Pohl, M.

2017-11-01

We develop a simple one-zone model of the steady-state Crab nebula spectrum encompassing both the radio/soft X-ray and the GeV/multi-TeV observations. By solving the transport equation for GeV-TeV electrons injected at the wind termination shock as a log-parabola momentum distribution and evolved via energy losses, we determine analytically the resulting differential energy spectrum of photons. We find an impressive agreement with the observed spectrum of synchrotron emission, and the synchrotron self-Compton component reproduces the previously unexplained broad 200-GeV peak that matches the Fermi/Large Area Telescope (LAT) data beyond 1 GeV with the Major Atmospheric Gamma Imaging Cherenkov (MAGIC) data. We determine the parameters of the single log-parabola electron injection distribution, in contrast with multiple broken power-law electron spectra proposed in the literature. The resulting photon differential spectrum provides a natural interpretation of the deviation from power law customarily fitted with empirical multiple broken power laws. Our model can be applied to the radio-to-multi-TeV spectrum of a variety of astrophysical outflows, including pulsar wind nebulae and supernova remnants, as well as to interplanetary shocks.

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

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Shuk-Li Man

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

Narrowly versus Broadly Defined Autism Spectrum Disorders: Differences in Pre-and Perinatal Risk Factors

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Visser, Janne C.; Rommelse, Nanda; Vink, Lianne; Schrieken, Margo; Oosterling, Iris J.; Gaag, Rutger J.; Buitelaar, Jan K.

2014-01-01

This study examined the differential contribution of pre-and perinatal risks in narrowly versus broadly defined autism spectrum disorder (ASD) and across core symptom domains, IQ and co-morbid problems. Children with a DSM-IV diagnosis of autistic disorder (AD) (n = 121) or pervasive developmental disorder not otherwise specified (PDD-NOS)…

A Review of Traditional and Novel Treatments for Seizures in Autism Spectrum Disorder: Findings from a Systematic Review and Expert Panel

OpenAIRE

Frye, Richard E.; Rossignol, Daniel; Casanova, Manuel F.; Brown, Gregory L.; Martin, Victoria; Edelson, Stephen; Coben, Robert; Lewine, Jeffrey; Slattery, John C.; Lau, Chrystal; Hardy, Paul; Fatemi, S. Hossein; Folsom, Timothy D.; MacFabe, Derrick; Adams, James B.

2013-01-01

Despite the fact that seizures are commonly associated with autism spectrum disorder (ASD), the effectiveness of treatments for seizures has not been well studied in individuals with ASD. This manuscript reviews both traditional and novel treatments for seizures associated with ASD. Studies were selected by systematically searching major electronic databases and by a panel of experts that treat ASD individuals. Only a few anti-epileptic drugs (AEDs) have undergone carefully controlled trials ...

Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs.

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Devarbhavi, Harshad; Andrade, Raúl J

2014-05-01

Antimicrobial agents including antituberculosis (anti-TB) agents are the most common cause of idiosyncratic drug-induced liver injury (DILI) and drug-induced liver failure across the world. Better molecular and genetic biomarkers are acutely needed to help identify those at risk of liver injury particularly for those needing antituberculosis therapy. Some antibiotics such as amoxicillin-clavulanate and isoniazid consistently top the lists of agents in retrospective and prospective DILI databases. Central nervous system agents, particularly antiepileptics, account for the second most common class of agents implicated in DILI registries. Hepatotoxicity from older antiepileptics such as carbamazepine, phenytoin, and phenobarbital are often associated with hypersensitivity features, whereas newer antiepileptic drugs have a more favorable safety profile. Antidepressants and nonsteroidal anti-inflammatory drugs carry very low risk of significant liver injury, but their prolific use make them important causes of DILI. Early diagnosis and withdrawal of the offending agent remain the mainstays of minimizing hepatotoxicity. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Common allergies do not influence the prevalence of cutaneous hypersensitivity reactions to antiepileptic drugs.

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Bosak, Magdalena; Porębski, Grzegorz; Słowik, Agnieszka; Turaj, Wojciech

2017-09-01

The aim of the study was to establish whether the presence of common allergies increases the risk of drug-related hypersensitivity reactions among patients with epilepsy treated with antiepileptic drugs (AEDs). We studied 753 patients with epilepsy seen in tertiary outpatient epilepsy clinic. We obtained data related to epilepsy type, past and ongoing treatment with AEDs, occurrence of maculopapular exanthema or more serious cutaneous adverse reactions (Stevens-Johnson syndrome - SJS) and their characteristics. We noted an occurrence of allergic reactions unrelated to treatment with AED, including rash unrelated to AED, bronchial asthma, persistent or seasonal allergic rhinitis, atopic dermatitis, rash after specific food and other allergic reactions. There were 61 cases of AED-related cutaneous hypersensitivity reaction (including 3 cases of SJS) noted in association with 2319 exposures to AEDs (2.63%) among 55 out of 753 patients (7.3%). Cutaneous hypersensitivity reaction to AED was most commonly noted after lamotrigine (12.1%), carbamazepine (5.4%) and oxcarbazepine (4.1%). Prevalence of allergic reactions unrelated to AED was similar between patients with and without AED-related cutaneous hypersensitivity reaction (rash unrelated to AED: 16.4% vs. 10.2%; bronchial asthma: 1.8% vs. 0.1%; persistent allergic rhinitis: 7.3% vs. 10.2%; seasonal allergic rhinitis: 7.3% vs. 11.7%; atopic dermatitis: 0 vs. 0.7%; rash after specific food: 5.4% vs. 6.4%; other allergic reactions: 5.4% vs. 5.2%, respectively; P>0.1 for each difference). Presence of common allergies is not a significant risk factor for AED-related cutaneous hypersensitivity reaction among patients with epilepsy. Copyright © 2017 Elsevier B.V. All rights reserved.

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

OpenAIRE

Taylor, Jenny C; Martin, Hilary C; 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

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 e...

Broad spectrum microarray for fingerprint-based bacterial species identification

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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.

Screening of broad spectrum natural pesticides against conserved target arginine kinase in cotton pests by molecular modeling.

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Sakthivel, Seethalakshmi; Habeeb, S K M; Raman, Chandrasekar

2018-03-12

Cotton is an economically important crop and its production is challenged by the diversity of pests and related insecticide resistance. Identification of the conserved target across the cotton pest will help to design broad spectrum insecticide. In this study, we have identified conserved sequences by Expressed Sequence Tag profiling from three cotton pests namely Aphis gossypii, Helicoverpa armigera, and Spodoptera exigua. One target protein arginine kinase having a key role in insect physiology and energy metabolism was studied further using homology modeling, virtual screening, molecular docking, and molecular dynamics simulation to identify potential biopesticide compounds from the Zinc natural database. We have identified four compounds having excellent inhibitor potential against the identified broad spectrum target which are highly specific to invertebrates.

Comparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis.

Science.gov (United States)

Androsova, Ganna; Krause, Roland; Borghei, Mojgansadat; Wassenaar, Merel; Auce, Pauls; Avbersek, Andreja; Becker, Felicitas; Berghuis, Bianca; Campbell, Ellen; Coppola, Antonietta; Francis, Ben; Wolking, Stefan; Cavalleri, Gianpiero L; Craig, John; Delanty, Norman; Koeleman, Bobby P C; Kunz, Wolfram S; Lerche, Holger; Marson, Anthony G; Sander, Josemir W; Sills, Graeme J; Striano, Pasquale; Zara, Federico; Sisodiya, Sanjay M; Depondt, Chantal

2017-10-01

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. We report retention, efficacy, and tolerability in a cohort of patients with MTLE-HS. Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS. Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

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

VNS Therapy versus the latest antiepileptic drug.

Science.gov (United States)

Ben-Menachem, Elinor; French, Jacqueline A

2005-09-01

Pro AED: The central issue in medical decision-making is risk-benefit assessment. Surgery of any type is still considered to be a major undertaking. To warrant these risks, the patient has a right to expect that they have a greater chance of a good outcome with an invasive therapy than with a non-invasive one. The main question is when, if ever, this becomes the case when comparing implantation of a VNS Therapy System versus adding an antiepileptic drug (AED)? After the first drug? The second? After all AEDs have failed? To date, no randomized trial comparing the addition of an AED against vagus nerve stimulation (VNS Therapy) has been undertaken, although several are currently being contemplated. Without this information, it is more difficult to make a case for early implementation of VNS Therapy. Unfortunately, few data are available regarding the potential for patients to become seizure-free after implantation of a VNS Therapy System. Another issue is side effects. It is important to remember that VNS Therapy also produces adverse events, albeit very different in character than those associated with AEDs, to which physicians have become accustomed. These include cough, dyspnea, pharyngitis, voice alteration and sleep apnea. A less frequently discussed, potentially negative consequence of VNS Therapy relates to the ability to obtain imaging of the patient. Patients who have undergone VNS Therapy System implantation are not candidates for imaging of the chest, breast, or abdomen. A second issue is that imaging of the brain can only be performed with MRI scanners that meet certain requirements, and as MRI technology develops, scanners meeting these requirements may become harder to find. However, to summarize, VNS Therapy is an excellent and useful treatment choice. Fortunately, the choice between AEDs and VNS Therapy is not an "either/or" decision. Each has a role in the treatment of patients with epilepsy, and the advantages and disadvantages of each should be

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

Science.gov (United States)

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

2012-12-01

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

Retrospective evaluation of low long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5-related epilepsy.

Science.gov (United States)

Müller, A; Helbig, I; Jansen, C; Bast, T; Guerrini, R; Jähn, J; Muhle, H; Auvin, S; Korenke, G C; Philip, S; Keimer, R; Striano, P; Wolf, N I; Püst, B; Thiels, Ch; Fogarasi, A; Waltz, S; Kurlemann, G; Kovacevic-Preradovic, T; Ceulemans, B; Schmitt, B; Philippi, H; Tarquinio, D; Buerki, S; von Stülpnagel, C; Kluger, G

2016-01-01

Mutations in the CDKL5 gene cause an early-onset epileptic encephalopathy. To date, little is known about effective antiepileptic treatment in this disorder. Accordingly, the aim of this retrospective study was to explore the role of different antiepileptic drugs (AEDs) and the ketogenic diet (KD) in the treatment of this rare genetic disorder. We evaluated the efficacy in 39 patients with CDKL5 mutations at 3, 6 and 12 months after the introduction of each treatment. One patient was lost to follow-up after 6 and 12 months. The responder rate (>50% reduction in seizure frequency) to at least one AED or KD was 69% (27/39) after 3 months, 45% (17/38) after 6 months and 24% (9/38) after 12 months. The highest rate of seizure reduction after 3 months was reported for FBM (3/3), VGB (8/25), CLB (4/17), VPA (7/34), steroids (5/26), LTG (5/23) and ZNS (2/11). Twelve patients (31%) experienced a seizure aggravation to at least one AED. Most patients showed some but only initial response to various AEDs with different modes of actions. Considering both age-related and spontaneous fluctuation in seizure frequency and the unknown impact of many AEDs or KD on cognition, our data may help defining realistic treatment goals and avoiding overtreatment in patients with CDKL5 mutations. There is a strong need to develop new treatment strategies for patients with this rare mutation. Copyright © 2015. Published by Elsevier Ltd.

Broad spectrum antimicrobial activity of melimine covalently bound to contact lenses.

Science.gov (United States)

Dutta, Debarun; Cole, Nerida; Kumar, Naresh; Willcox, Mark D P

2013-01-07

To develop a stable antimicrobial contact lens, which is effective against the International Organization for Standardization (ISO) panel microorganisms, Acanthamoeba castellanii and drug resistant strains of Pseudomonas aeruginosa and Staphylococcus aureus. Melimine was covalently incorporated into etafilcon A lenses. The amount of peptide present on the lens surface was quantified using amino acid analysis. After coating, the heat stability (121°C), lens surface hydrophobicity (by captive bubble), and in vitro cytotoxicity to mouse L929 cells of the lenses were investigated. Antimicrobial activity against the micro-organisms was evaluated by viable plate count and fluorescence microscopy, measuring the proportion of cell death compared with control lenses with no melimine. The most effective concentration was determined to be 152 ± 44 μg lens(-1) melimine on the lens surface. After coating, lenses were relatively hydrophilic and were nontoxic to mammalian cells. The activity remained high after autoclaving (e.g., 3.1, 3.9, 1.2, and 1.0 log inhibition against P. aeruginosa, S. aureus, A. castellanii, and Fusarium solani, respectively). Fluorescence microscopy confirmed significantly reduced (P bacteria to melimine contact lenses. Viable count confirmed that lenses were active against all the bacteria and fungi from the ISO panel, Acanthamoeba and gave at least 2 log inhibition against all the multidrug resistant S. aureus and P. aeruginosa strains. Melimine may offer excellent potential for development as a broad spectrum antimicrobial coating for contact lenses, showing activity against all the bacterial and fungal ISO panel microorganisms, Acanthamoeba, and antibiotic resistant strains of P. aeruginosa and S. aureus.

Recent Advances in Antiepileptic Herbal Medicine.

Science.gov (United States)

Manchishi, Stephen M

2018-01-01

Epilepsy is one of the most common neurological disorders worldwide, with about 80 percent of cases thought to be in developing nations where it is mostly linked to superstition. The limited supply, high cost as well as low efficacy and adverse side effects of antiepileptic drugs (AEDs) is a matter of major concern. Herbal medicine has always been traditionally part of treatment of epilepsy. Herbal medicines are generally well tolerated, with fewer side effects. To highlight some herbal extracts that have been studied for their anticonvulsant activity in animal models, literature search from PubMed and Science Direct, was performed. The keywords for the search consisted of combinations of the following terms: Herbal antiepileptic and/or anticonvulsant, botanicals + epilepsy. Literature published in the last five years was considered. Eighteen (18) anticonvulsant herbal agents are reported and discussed. Experiments mostly consisted of phenotypic screens in rodents, with little diversity in screening methods. In most experiments, the tested extracts prolonged the time to onset of seizures and decreased their duration. Most experimenters implicate potentiation of GABAergic activity as the mode of action of the extracts, even though some experimenters did not fully characterise the bioactive chemical composition of their extracts. Potential herbal remedies have shown positive results in animal models. It remains unclear how many make it into clinical trials and eventually making part of the AED list. More rigorous research, applying strict research methodology with uniform herbal combinations, as well as clinical studies are urgently needed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Antiepileptic activity of total triterpenes isolated from Poria cocos is mediated by suppression of aspartic and glutamic acids in the brain.

Science.gov (United States)

Gao, Yanqiong; Yan, Hua; Jin, Ruirui; Lei, Peng

2016-11-01

Triterpenes from Poria cocos Wolf (Polyporaceae) have been used to treat various diseases in traditional Chinese medicine. However, the antiepileptic effects and mechanism are not fully understood. The objective of this study is to investigate the antiepileptic properties of total triterpenes (TTP) from the whole P. cocos. The ethanol extract TTP was identified by HPLC fingerprint analysis. Male ICR mice were gavaged (i.g.) with TTP (5, 20, 80 or 160 mg/kg) or reference drugs twice a day for 7 d. Antiepileptic activities of TTP were evaluated by maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced seizures in mice for 30 and 60 min, respectively. Locomotor activity and Rota-rod tests were performed for 60 min and 5 min, respectively. The levels of glutamic acid (Glu), aspartic acid (Asp), γ-aminobutyric acid (GABA) and glycine (Gly) in convulsive mice were estimated. The chronic epileptic model of Wistar rats was built to measure expressions of glutamate decarboxylase 65 (GAD65) and GABA A in rat brain after TTP treatment. The LC 50 of TTP (i.g.) was above 6 g/kg. TTP (5-160 mg/kg) protected mice against MES- and PTZ-induced convulsions at 65.0% and 62.5%, respectively, but have no effect on rota-rod treadmill; TTP (20-160 mg/kg) significantly reduced the locomotor activities, shortened the onset of pentobarbital sodium-induced sleep; TTP decreased Glu and Asp levels in convulsive mice, but increased the GAD65 and GABA A expressions in chronic epileptic rats at doses usage. TTP extracted from P. cocos possessed potential antiepileptic properties and is a candidate for further antiepileptic drug development.

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

Science.gov (United States)

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

2009-01-01

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

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

Science.gov (United States)

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

2017-06-28

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

The Use of Antiepileptic Drugs (AEDs for the Treatment of Pediatric Aggression and Mood Disorders

Directory of Open Access Journals (Sweden)

Joseph Gonzalez-Heydrich

2010-09-01

Full Text Available Aggressive symptomatology presents across multiple psychiatric, developmental, neurological and behavioral disorders, complicating the diagnosis and treatment of the underlying pathology. Anti-Epileptic Drugs (AEDs have become an appealing alternative in the treatment of aggression, mood lability and impulsivity in adult and pediatric populations, although few controlled trials have explored their efficacy in treating pediatric populations. This review of the literature synthesizes the available data on ten AEDs – valproate, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, topiramate, levetiracetam, zonisamide, gabapentin and tiagabine – in an attempt to assess evidence for the efficacy of AEDs in the treatment of aggression in pediatric populations. Our review revealed modest evidence that some of the AEDs produced improvement in pediatric aggression, but controlled trials in pediatric bipolar disorder have not been promising. Valproate is the best supported AED for aggression and should be considered as a first line of treatment. When monotherapy is insufficient, combining an AED with either lithium or an atypical anti-psychotic can result in better efficacy. Additionally, our review indicates that medications with predominately GABA-ergic mechanisms of action are not effective in treating aggression, and medications which decrease glutaminergic transmission tended to have more cognitive adverse effects. Agents with multiple mechanisms of action may be more effective.

The Use of Antiepileptic Drugs (AEDs) for the Treatment of Pediatric Aggression and Mood Disorders.

Science.gov (United States)

Munshi, Kaizad R; Oken, Tanya; Guild, Danielle J; Trivedi, Harsh K; Wang, Betty C; Ducharme, Peter; Gonzalez-Heydrich, Joseph

2010-09-10

Aggressive symptomatology presents across multiple psychiatric, developmental, neurological and behavioral disorders, complicating the diagnosis and treatment of the underlying pathology. Anti-Epileptic Drugs (AEDs) have become an appealing alternative in the treatment of aggression, mood lability and impulsivity in adult and pediatric populations, although few controlled trials have explored their efficacy in treating pediatric populations. This review of the literature synthesizes the available data on ten AEDs - valproate, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, topiramate, levetiracetam, zonisamide, gabapentin and tiagabine - in an attempt to assess evidence for the efficacy of AEDs in the treatment of aggression in pediatric populations. Our review revealed modest evidence that some of the AEDs produced improvement in pediatric aggression, but controlled trials in pediatric bipolar disorder have not been promising. Valproate is the best supported AED for aggression and should be considered as a first line of treatment. When monotherapy is insufficient, combining an AED with either lithium or an atypical anti-psychotic can result in better efficacy. Additionally, our review indicates that medications with predominately GABA-ergic mechanisms of action are not effective in treating aggression, and medications which decrease glutaminergic transmission tended to have more cognitive adverse effects. Agents with multiple mechanisms of action may be more effective.

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.

Designing clinical trials to assess antiepileptic drugs as monotherapy : difficulties and solutions.

Science.gov (United States)

Perucca, Emilio

2008-01-01

Designing monotherapy trials in epilepsy is fraught with many hurdles, including diagnostic and classification difficulties, sparse information regarding the natural history of the disorder, and ethical objections to the use of placebo or a suboptimal comparator in a condition where the consequences of therapeutic failure can be serious. These issues are further complicated by regulatory differences between the US and the EU.In the US, the FDA considers that evidence of efficacy requires demonstration of superiority to a comparator. Because available antiepileptic drugs possess relatively high efficacy, in most settings it is unrealistic to expect that a new treatment will be superior to a standard treatment used at optimized dosages. To circumvent this problem, trial designs have been developed whereby patients in the control group are assigned to receive a suboptimal comparator and are required to exit from the trial if seizure deterioration occurs. This allows demonstration of a between-group difference in efficacy endpoints, such as time to exit or time to first seizure. Although these trials have come under increasing criticism because of ethical concerns, extensive information is now available on the outcome of patients with chronic epilepsy randomized to suboptimal treatment in similarly designed conversion to monotherapy trials. This has allowed the construction of a dataset of historical controls against which response to a fully active treatment can be compared. A number of studies using this novel approach are now in progress.In the EU, in addition to requiring data on conversion to monotherapy in refractory patients, the European Medicines Agency stipulates that a monotherapy indication in newly diagnosed epilepsy can only be granted if a candidate drug has shown at least a similar benefit/risk balance compared with an acknowledged standard at its optimal use during an assessment period of no less than 1 year. This has led to the implementation of

The Elements of Antifungal Drug Discovery

DEFF Research Database (Denmark)

Kjellerup, Lasse

In this PhD thesis I will explore the development of antifungal drugs. Fungal infections are estimated to cause the death of 1.5 million patients each year. There is currently a need for new antifungal drugs as the existing drugs are hampered by lack of broad-spectrum antifungal activity, resista...

Time Course of the Changes in Novel Trioxane Antimalarial 99/411 Pharmacokinetics upon Antiepileptic Drugs Co-Administration in SD Rats

Directory of Open Access Journals (Sweden)

Yeshwant Singh

2014-01-01

Full Text Available Objective. The study aimed to evaluate the influences of coadministration of antiepileptic drugs (AEDs on an antimalarial candidate 99/411 pharmacokinetic (PK profile. Method. For this, single oral dose PK drug interaction studies were conducted between 99/411 and FDA approved AEDs, namely, Phenytoin (PHT, Carbamazepine (CBZ, and Gabapentin (GB in both male and female SD rats, to assess the coadministered and intersexual influences on 99/411 PK profile. Results. Studies revealed that there were no significant alterations in the PK profile of 99/411 upon PHT and CBZ coadministration in both male and female rats, while systemic exposure of 99/411 was significantly increased by about 80% in female rats upon GB coadministration. In terms of AUC, there was an increase from 2471 ± 586 to 4560 ± 1396 ng·h/mL. Overall, it was concluded that simultaneous administration of AEDs with 99/411 excludes the requirements for dose adjustment, additional therapeutic monitoring, contraindication to concomitant use, and/or other measures to mitigate risk, except for GB coadministration in females. These findings are further helpful to predict such interactions in humans, when potentially applied through proper allometric scaling to extrapolate the data.

A Broad-Spectrum Inhibitor of CRISPR-Cas9.

Science.gov (United States)

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

2017-09-07

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

Vinpocetine inhibits glutamate release induced by the convulsive agent 4-aminopyridine more potently than several antiepileptic drugs.

Science.gov (United States)

Sitges, M; Sanchez-Tafolla, B M; Chiu, L M; Aldana, B I; Guarneros, A

2011-10-01

4-Aminopyridine (4-AP) is a convulsing agent that in vivo preferentially releases Glu, the most important excitatory amino acid neurotransmitter in the brain. Here the ionic dependence of 4-AP-induced Glu release and the effects of several of the most common antiepileptic drugs (AEDs) and of the new potential AED, vinpocetine on 4-AP-induced Glu release were characterized in hippocampus isolated nerve endings pre-loaded with labelled Glu ([3H]Glu). 4-AP-induced [3H]Glu release was composed by a tetrodotoxin (TTX) sensitive and external Ca2+ dependent fraction and a TTX insensitive fraction that was sensitive to the excitatory amino acid transporter inhibitor, TBOA. The AEDs: carbamazepine, phenytoin, lamotrigine and oxcarbazepine at the highest dose tested only reduced [3H]Glu release to 4-AP between 50-60%, and topiramate was ineffective. Vinpocetine at a much lower concentration than the above AEDs, abolished [3H]Glu release to 4-AP. We conclude that the decrease in [3H]Glu release linked to the direct blockade of presynaptic Na+ channels, may importantly contribute to the anticonvulsant actions of all the drugs tested here (except topiramate); and that the significantly greater vinpocetine effect in magnitude and potency on [3H]Glu release when excitability is exacerbated like during seizures, may involve the increase additionally exerted by vinpocetine in some K+ channels permeability. Copyright © 2011 Elsevier B.V. All rights reserved.

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...

Clinical spectrum of seizures and efficacy of anticonvulsive treatment in children

International Nuclear Information System (INIS)

Mahmud, S.; Zman, S.Q.

2017-01-01

Objective: To study the clinical spectrum of seizures and efficacy of anticonvulsive treatment in children. Study Design: A descriptive study. Place and Duration of Study: Military Hospital (MH) Rawalpindi from October 2011 to March 2012. Material and Methods: One hundred children of either gender aged 1 month to 12 years presenting with seizures at Military Hospital Rawalpindi were evaluated and consented to participate in the study. All children with a febrile seizures were evaluated. The seizures were classified according to international league against epilepsy guidelines. Antiepileptic treatment regimen was evaluated in terms of number of drugs, correct dosage and efficacy in control of seizures. Results: It was observed that generalized seizures were (58 percent) followed by focal seizures (32 percent) in children. Valproic acid was prescribed in (51 percent) cases. Epilepsy was diagnosed in (56 percent) followed by cerebral palsy (20 percent), post meningoencephalitis sequalae (11 percent), intracranial hemorrhage (7 percent) and leukodystrophies (3 percnet) as underlying cause of seizures. Statistically significant association was seen between age groups and diagnosis (p value=0.001); age groups and types of seizures (p value=0.046); correct dosage of antiepileptics and control of seizures (p value=0.007); compliance to treatment and control of seizures (p value=0.007). Conclusion: Generalized seizures are the commonest form followed by focal seizures. Epilepsy was the common etiology of seizures in all age groups in children. Cerebral palsy was the second leading cause of seizures in children followed by post meningoencephalitis, stroke and leukodystrophies. Valproic acid was the most commonly prescribed antiepileptic. Normal delivery with delayed cry was the major risk factor for cerebral palsy. Prescription of appropriate antiepileptics according to diagnosis in optimum dosage and compliance to treatment affect control of seizures in children. (author)

Broad photoelectron spectrum and lowered electron affinity due to hydrogen in ZnOH: A joint experimental and theoretical study

Science.gov (United States)

Iordanov, I.; Gunaratne, K. D. D.; Harmon, C. L.; Sofo, J. O.; Castleman, A. W.

2012-06-01

We report a combined experimental and theoretical photoelectron spectroscopy study of ZnOH-. We find that the electron binding energy spectrum of ZnOH- reveals a broad and featureless peak between 1.4 and 2.4 eV in energy. The vertical detachment energy (VDE) of ZnOH- is determined to be 1.78 eV, which is lower than the 2.08 eV VDE of ZnO-. Our theoretical calculations match the VDE of ZnOH- accurately, but we find that the broadness of the peak cannot be explained by rotational or vibrational state excitation. The broadness of this peak is in strong contrast to the narrow and easily understood first peak of the ZnO spectrum, which features a well-resolved vibrational progression that can be readily explained by calculating the Franck-Condon transition factors. This study provides spectroscopic evidence of the effect of hydrogen on diatomic ZnO.

Choline and Geranate Deep Eutectic Solvent as a Broad-Spectrum Antiseptic Agent for Preventive and Therapeutic Applications.

Science.gov (United States)

Zakrewsky, Michael; Banerjee, Amrita; Apte, Sanjana; Kern, Theresa L; Jones, Mattie R; Sesto, Rico E Del; Koppisch, Andrew T; Fox, David T; Mitragotri, Samir

2016-06-01

Antiseptic agents are the primary arsenal to disinfect skin and prevent pathogens spreading within the host as well as into the surroundings; however the Food and Drug Administration published a report in 2015 requiring additional validation of nearly all current antiseptic agents before their continued use can be allowed. This vulnerable position calls for urgent identification of novel antiseptic agents. Recently, the ability of a deep eutectic, Choline And Geranate (CAGE), to treat biofilms of Pseudomonas aeruginosa and Salmonella enterica was demonstrated. Here it is reported that CAGE exhibits broad-spectrum antimicrobial activity against a number of drug-resistant bacteria, fungi, and viruses including clinical isolates of Mycobacterium tuberculosis, Staphylococcus aureus, and Candida albicans as well as laboratory strains of Herpes Simplex Virus. Studies in human keratinocytes and mice show that CAGE affords negligible local or systemic toxicity, and an ≈180-14 000-fold improved efficacy/toxicity ratio over currently used antiseptic agents. Further, CAGE penetrates deep into the dermis and treats pathogens located in deep skin layers as confirmed by the ability of CAGE in vivo to treat Propionibacterium acnes infection. In combination, the results clearly demonstrate CAGE holds promise as a transformative platform antiseptic agent for preventive as well as therapeutic applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A broad-spectrum sunscreen prevents cumulative damage from repeated exposure to sub-erythemal solar ultraviolet radiation representative of temperate latitudes.

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Seité, S; Christiaens, F; Bredoux, C; Compan, D; Zucchi, H; Lombard, D; Fourtanier, A; Young, A R

2010-02-01

We have previously shown the detrimental effects of 19 sub-erythemal exposures to daily ultraviolet radiation (DUVR, which mimics non-extreme exposure conditions), delivered over 4 weeks to volunteers. This source had UVA (320-400 nm) to UVB (290-320 nm) irradiance ratio of 25, instead of that close to 10 that is typically the case with solar-simulated radiation (SSR) that represents summer global sunlight with a clear sky and quasi-zenith solar irradiance. Here, we report on an extension of this previous study, in which we evaluated the photoprotection afforded by a broad-spectrum daily-care product with a low-sun protection factor (SPF 8, UVA-PF 7 and 3* rated UVA protection). We assessed cellular and molecular markers of photodamage that are relevant to skin cancer and photoageing. This study shows that biological effects of repeated exposure to DUVR can be prevented by a broad-spectrum daily-care product and that the level of protection afforded varies with the studied endpoint. Efficient daily UVR protection, as provided by a broad-spectrum daily-care product, is necessary to prevent the 'silent' sub-erythemal cumulative effects of UVR from inadvertent sun exposure.

Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases.

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Chuck, Chi-Pang; Chen, Chao; Ke, Zhihai; Wan, David Chi-Cheong; Chow, Hak-Fun; Wong, Kam-Bo

2013-01-01

Coronaviral infection is associated with up to 5% of respiratory tract diseases. The 3C-like protease (3CL(pro)) of coronaviruses is required for proteolytic processing of polyproteins and viral replication, and is a promising target for the development of drugs against coronaviral infection. We designed and synthesized four nitrile-based peptidomimetic inhibitors with different N-terminal protective groups and different peptide length, and examined their inhibitory effect on the in-vitro enzymatic activity of 3CL(pro) of severe-acute-respiratory-syndrome-coronavirus. The IC(50) values of the inhibitors were in the range of 4.6-49 μM, demonstrating that the nitrile warhead can effectively inactivate the 3CL(pro) autocleavage process. The best inhibitor, Cbz-AVLQ-CN with an N-terminal carbobenzyloxy group, was ~10x more potent than the other inhibitors tested. Crystal structures of the enzyme-inhibitor complexes showed that the nitrile warhead inhibits 3CL(pro) by forming a covalent bond with the catalytic Cys145 residue, while the AVLQ peptide forms a number of favourable interactions with the S1-S4 substrate-binding pockets. We have further showed that the peptidomimetic inhibitor, Cbz-AVLQ-CN, has broad-spectrum inhibition against 3CL(pro) from human coronavirus strains 229E, NL63, OC43, HKU1, and infectious bronchitis virus, with IC(50) values ranging from 1.3 to 3.7 μM, but no detectable inhibition against caspase-3. In summary, we have shown that the nitrile-based peptidomimetic inhibitors are effective against 3CL(pro), and they inhibit 3CL(pro) from a broad range of coronaviruses. Our results provide further insights into the future design of drugs that could serve as a first line defence against coronaviral infection. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Applying a perceptions and practicalities approach to understanding nonadherence to antiepileptic drugs.

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Chapman, Sarah C E; Horne, Rob; Eade, Rona; Balestrini, Simona; Rush, Jennifer; Sisodiya, Sanjay M

2015-09-01

Nonadherence to antiepileptic drugs (AEDs) is a common cause of poor seizure control. This study examines whether reported adherence to AEDs is related to variables identified in the National Institute for Health and Clinical Excellence (NICE) Medicines Adherence Guidelines as being important to adherence: perceptual factors (AED necessity beliefs and concerns), practical factors (limitations in capability and resources), and perceptions of involvement in treatment decisions. This was a cross-sectional study of people with epilepsy receiving AEDs. Participants completed an online survey hosted by the Epilepsy Society (n = 1,010), or as an audit during inpatient admission (n = 118). Validated questionnaires, adapted for epilepsy, assessed reported adherence to AEDs (Medication Adherence Report Scale [MARS]), perceptions of AEDs (Beliefs about Medicines Questionnaire [BMQ]), and patient perceptions of involvement in treatment decisions (Treatment Empowerment Scale [TES]). Low adherence was related to AED beliefs (doubts about necessity: t(577) = 3.90, p < 0.001; and concerns: t(995) = 3.45, p = 0.001), reported limitations in capability and resources (t(589) = 7.78, p < 0.001), and to perceptions of a lack of involvement in treatment decisions (t(623) = 4.48, p < 0.001). In multiple logistic regression analyses, these factors significantly (p < 0.001) increased variance in reported adherence, above that which could be explained by age and clinical variables (seizure frequency, type, epilepsy duration, number of AEDs prescribed). Variables identified in the NICE Medicines Adherence Guidelines as potentially important factors for adherence were found to be related to adherence to AEDs. These factors are potentially modifiable. Interventions to support optimal adherence to AEDs should be tailored to address doubts about AED necessity and concerns about harm, and to overcome practical difficulties, while engaging patients in treatment decisions. Wiley Periodicals, Inc. �

Uncertainties from a worldwide survey on antiepileptic drug withdrawal after seizure remission.

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Bartolini, Luca; Majidi, Shahram; Koubeissi, Mohamad Z

2018-04-01

We sought to determine differences in practice for discontinuation of antiepileptic drugs (AEDs) after seizure remission and stimulate the planning and conduction of withdrawal trials. We utilized a worldwide electronic survey that included questions about AED discontinuation for 3 paradigmatic cases in remission: (1) focal epilepsy of unknown etiology, (2) temporal lobe epilepsy after surgery, and (3) juvenile myoclonic epilepsy. We analyzed 466 complete questionnaires from 53 countries, including the United States. Statistical analysis included χ 2 and multivariate logistic regression. Case 1: responders in practice for <10 years were less likely to taper AEDs: odds ratio (OR) (95% confidence interval [CI]) 0.52 (0.32-0.85), p = 0.02. The likelihood of stopping AEDs was higher among doctors treating children: OR (95% CI): 11.41 (2.51-40.13), p = 0.002. Doctors treating children were also more likely to stop after 2 years or less of remission: OR (95% CI): 6.91 (2.62-19.31), p = 0.002, and the same was observed for US physicians: OR (95% CI): 1.61 (1.01-2.57), p = 0.0049. Case 2: responders treating children were more likely to taper after 1 year or less of postoperative remission, with the goal of discontinuing all medications: OR (95% CI): 1.91 (1.09-3.12), p = 0.015, and so were US-based responders: OR (95% CI): 1.73 (1.21-2.41), p = 0.003. Case 3: epileptologists were less likely to withdraw the medication: OR (95% CI): 0.56 (0.39-0.82), p = 0.003, and so were those in practice for 10 or more years: OR (95% CI): 0.54 (0.31-0.95), p = 0.025. We observed several differences in practice for AED withdrawal after seizure remission that highlight global uncertainty. Trials of AED discontinuation are needed to provide evidence-based guidance.

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

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

2012-06-01

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

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

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Ekta Arora

2016-01-01

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

Women with epilepsy in childbearing age: Pregnancy-related knowledge, information sources, and antiepileptic drugs.

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Friedrich, Latica; Sruk, Ana; Bielen, Ivan

2018-03-01

Pregnancy-related issues in epilepsy (PRIE) are essential for management of epilepsy in women. We conducted a study among women with epilepsy (WWE) aged 15-45years about their knowledge, sources, and needs for information regarding PRIE, which included their current antiepileptic drugs (AEDs) usage. Women with epilepsy, visitors of Croatian Association for Epilepsy webpage, were offered an online questionnaire, and 200 responses were analyzed. The mean number of correct answers about PRIE was 3.5 out of 5. Main predictors of knowledge on PRIE were a prior consultation with a neurologist and higher usage of books/brochures. A prior neurologist consultation on PRIE was stated by 45% of subjects. As the preferred future mode of being informed on PRIE, majority of women (61%) chooses their neurologist, 22% written materials distributed by a neurologist, and only 13% Internet. Levetiracetam was the most commonly used AED (34.5%). Valproate was used by 26%, and of those 59% stated no previous consultation on PRIE with their neurologist. In summary, we believe our study shows that knowledge of PRIE among WWE in their childbearing age is unsatisfactory, as are the neurologist consultation rates about PRIE. Our results demonstrate that, despite modern technologies, educational activities should be based on neurologist consultations and providing the patients with appropriate written materials. This is especially true for the relatively large proportion of women still taking valproate. Copyright © 2018 Elsevier Inc. All rights reserved.

Role of reflexology and antiepileptic drugs in managing intractable epilepsy--a randomized controlled trial.

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Dalal, Krishna; Devarajan, Elanchezhiyan; Pandey, Ravindra Mohan; Subbiah, Vivekanandan; Tripathi, Manjari

2013-01-01

This report is based on the results of a randomized parallel controlled trial conducted to determine the efficacy of reflexology therapy in managing intractable epilepsy. Subjects who failed epilepsy surgery or were not candidates for epilepsy surgery or were non-responders of antiepileptic drugs (AEDs) took part in this study. The trial was completed by 77 subjects randomly assigned to 2 arms: control (AEDs) and reflexology (AEDs + reflexology therapy). The hypothesis was that hand reflexology therapy could produce results similar to those of vagus nerve stimulation, and foot reflexology therapy could maintain homeostasis in the functional status of individual body parts. Reflexology therapy was applied by family members. The follow-up period was 1.5 years. Quality of life in epilepsy patients was assessed with the QOLIE-31 instrument. In the reflexology group, the median baseline seizure frequency decreased from 9.5 (range 2-120) to 2 (range 0-110) with statistical significance (p reflexology group were 41.05 ± 7 and 43.6 ± 8, respectively. Posttherapy data were 49.07 ± 6 and 65.4 ± 9, respectively (p reflexology method allowed detection of knee pain in 85% of the reflexology group patients (p reflexology group patients reported nausea/vomiting (n = 1), change in voice (n = 2), and hoarseness (n = 1). Reflexology therapy together with AEDs may help reducing seizure frequency and improving quality of life in individuals with epilepsy. Copyright © 2013 S. Karger AG, Basel.

Impact of broad-spectrum antimicrobial treatment on the ecology of intestinal flora.

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Yang, Jen-Jia; Wang, Jann-Tay; Cheng, Aristine; Chuang, Yu-Chung; Sheng, Wang-Huei

2017-06-28

Suppression of intestinal flora by broad-spectrum antimicrobial agents facilitated risk of colonization or infection with resistant pathogen. We aimed to investigate the changes in bowel carriage of target resistant microorganisms (TRO) among patients treated with three different classes of Pseudomonas-sparing broad-spectrum antimicrobial agents (ertapenem, moxifloxacin and flomoxef) with anaerobic coverage. Risk factors for developing colonization of TRO were also analyzed. We prospectively enrolled the adult hospitalized patients (>20 years old) who were indicated for at least 7-day course with either of ertapenem, moxifloxacin or flomoxef. Rectal swabs were performed for the patients who received at least 1-day course of study antibiotics during the treatment duration. The TROs included Pseudomonas aeruginosa, Enterobacteriaceae, and Acinetobacter baumannii. MacConkey agars with study antibiotics were used to isolate the TROs and evaluate the antimicrobial resistance. The mean age of our study population was 61.6 years, and 58.8% were males. The rates of rectal colonization for Pseudomonas aeruginosa was similar among the study medications (ertapenem 13.2%, flomoxef 20%, moxifloxacin 14.3%, p = 0.809). Compared with ertapenem, flomoxef (odds ratio [OR], 4.30; 95% confidence interval [95% CI], 1.28-14.48, p = 0.019) and moxifloxacin (OR, 6.95; 95% CI, 1.36-35.52, p = 0.019) had higher risk for colonization of ertapenem-resistant Escherichiacoli colonization. The patients who received treatment of ertapenem may have a lower risk of rectal colonization for ertapenem resistant Escherichia coli than those who received flomoxef or moxifloxacin. The rate of Pseudomonas colonization did not differ between the three study Pseudomonas-sparing agents. Copyright © 2017. Published by Elsevier B.V.

Changes in Cell Viability of Wounded Fibroblasts following Laser Irradiation in Broad-Spectrum or Infrared Light

International Nuclear Information System (INIS)

Hawkins, D.; Abrahamse, H.

2007-01-01

Objective. This study aimed to establish if broad-spectrum or infrared (IR) light in combination with laser therapy can assist phototherapy to improve the cell function of wounded cells. Background. The effect of laser light may be partly or completely reduced by broad-spectrum light. Methods. Wounded human skin fibroblasts were irradiated with 5 J/cm2 using a helium-neon laser, a diode laser, or an Nd:YAG laser in the dark, in the light, or in IR. Changes in cell viability were evaluated by cell morphology, ATP cell viability, LDH membrane integrity, and caspase 3/7 as an early marker of apoptosis. Results. Wounded cells exposed to 5 J/cm2 using 632.8 nm in the dark or 830 nm in the light or 1064 nm in the dark showed an increase in ATP viability, an increase in cytokine expression, and a decrease in LDH cytotoxicity indicating that the metabolic activity of the wounded cells was stimulated. Conclusion. Wounded cells irradiated in IR light showed an undesirable thermal effect that was proportional to the duration of exposure.

Development of a broad-spectrum antiviral with activity against Ebola virus.

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Aman, M Javad; Kinch, Michael S; Warfield, Kelly; Warren, Travis; Yunus, Abdul; Enterlein, Sven; Stavale, Eric; Wang, Peifang; Chang, Shaojing; Tang, Qingsong; Porter, Kevin; Goldblatt, Michael; Bavari, Sina

2009-09-01

We report herein the identification of a small molecule therapeutic, FGI-106, which displays potent and broad-spectrum inhibition of lethal viral hemorrhagic fevers pathogens, including Ebola, Rift Valley and Dengue Fever viruses, in cell-based assays. Using mouse models of Ebola virus, we further demonstrate that FGI-106 can protect animals from an otherwise lethal infection when used either in a prophylactic or therapeutic setting. A single treatment, administered 1 day after infection, is sufficient to protect animals from lethal Ebola virus challenge. Cell-based assays also identified inhibitory activity against divergent virus families, which supports a hypothesis that FGI-106 interferes with a common pathway utilized by different viruses. These findings suggest FGI-106 may provide an opportunity for targeting viral diseases.

Off-label use analysis of novel antiepileptic drugs in Sichuan area: a multicenter survey in pediatric patients

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CAI Qian-yun

2012-10-01

Full Text Available Objective To investigate current status and safety about off-label use of levetiracetam, topiramate, oxcarbazepine, lamotrigine among pediatric patients in Sichuan area, so as to provide baseline data for formulating guidelines of off-label drug use. Methods Medical records of pediatric epileptic patients receiving antiepileptic drugs (AEDs from July 2010 to November 2011 were collected at the following hospitals: West China Second University Hospital of Sichuan University, Chengdu Women's and Children's Central Hospital and Sichuan Provincial People's Hospital. The numbers of patients receiving AEDs and novel AEDs were calculated. Off-label drug use and the category of off-label drug use were judged according to the indications listed in drug instructions. The incidence of off-label drug use was calculated. The patients receiving novel AEDs were devided into on-label and off-label use groups; the clinical characteristics of these two groups were summarized and adverse reactions of two groups were compared by using χ2 test. Results During the study period, there were totally 854 patients receiving AEDs including 670 patients receiving novel AEDs. Among 670 patients 406 patients off-label use group received off-label use of novel AEDs, accounting for 47.54% (406/854 of the total patients receiving AEDs and 60.60% (406/670 of patients receiving novel AEDs. When compared with on-label use group, off-label use group had more younger patients, more patients with single-drug use and more patients with generalized epilepsy or epileptic syndrome. The rates of off-label using drug were levetiracetam 78.50% (157/200, topiramate 79.81% (253/317, oxcarbazepine 21.32% (42/197 and lamotrigine 33.33% (21/63. The off-label use of levetiracetam and topiramate occured in all three aspects: age, single-drug use and seizure type. The adverse reaction rates of off-label use were oxcarbazepine 16.67% (7/42, topiramate 14.81% (36/243, levetiracetam 10.60% (16

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

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

2015-08-01

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

Toxic epidermal necrolysis due to concomitant use of lamotrigine and valproic acid

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Sukhjot Kaur

2013-01-01

Full Text Available Anti-epileptic drugs can be associated with a wide spectrum of cutaneous adverse reactions ranging from simple maculopapular rashes to more severe and life threatening reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis. These rashes are well documented with older antiepileptic drugs like phenytoin, phenobarbitone and carbamazapine. Lamotrigine is a newer, unrelated antiepileptic drug that causes skin rashes in 3-10% of new users. Higher starting dose or rapid escalation, concurrent treatment with valproic acid, and a previous history of a rash with other antiepileptic drugs are well recognized risk factors for lamotrigine related serious rashes. We report two patients with toxic epidermal necrolysis, resulting from concomitant use of lamotrigine and valproic acid. It is emphasized that clinicians adhere to the recommended dosage guidelines and adopt a slow dose titration when initiating treatment with lamotrigine.

Definition of rational antiepileptic polypharmacy.

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Wilder, B J; Homan, R W

1996-01-01

Rational polypharmacy is in its earliest stages of development and will require substantial additional development to realize its full potential. Indeed, despite the powerful appeal of the concept, clinical proof is not yet available that RP is superior to monotherapy. Important questions need to be addressed: 1. Will RP control seizures more effectively than monotherapy? 2. What data are needed to develop RP for a specific patient? 3. Will RP be cost effective? 4. Can RP be developed which will treat or prevent epilepsy while controlling seizures? Possible approaches to these questions could include: 1. The development of a data base for prospective use to monitor patients being treated at Epilepsy Centers using RP principles. 2. Use the data obtained from the above to construct more specific studies to compare identified combination therapies with monotherapy. 3. Prospectively compare in a placebo controlled, blinded study, the effect of the combination of an anti-ictal medication and a laboratory proven antiepileptic drug for prevention of the development of epilepsy in an at risk population such as head trauma or stroke.

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.

Targeting N-Glycan Cryptic Sugar Moieties for Broad-Spectrum Virus Neutralization: Progress in Identifying Conserved Molecular Targets in Viruses of Distinct Phylogenetic Origins

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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.

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

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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; 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; Muralidhar, Vinayak; Muqbil, Irfana; 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; Shantha Kumara, H M C; 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

2015-12-01

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 be relatively inexpensive, it should help us

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

Science.gov (United States)

Emory, Hamlin; Wells, Christopher; Mizrahi, Neptune

2015-07-01

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

Isolation of a new broad spectrum antifungal polyene from Streptomyces sp. MTCC 5680.

Science.gov (United States)

Vartak, A; Mutalik, V; Parab, R R; Shanbhag, P; Bhave, S; Mishra, P D; Mahajan, G B

2014-06-01

A new polyene macrolide antibiotic PN00053 was isolated from the fermentation broth of Streptomyces sp. wild-type strain MTCC-5680. The producer strain was isolated from fertile mountain soil of Naldehra region, Himachal Pradesh, India. The compound PN00053 was purified through various steps of chromatographic techniques and bio-activity guided fractionation followed by its characterization using physiochemical properties, spectral data ((1) H-NMR, (13) C-NMR, HMBC, HSQC, and COSY) and MS analysis. PN00053 exhibited broad spectrum in vitro antifungal activity against strains of Aspergillus fumigatus (HMR), A. fumigatus ATCC 16424, Candida albicans (I.V.), C. albicans ATCC 14503, C. krusei GO6, C. glabrata HO4, Cryptococcus neoformans, Trichophyton sp. as well as fluconazole resistant strains C. krusei GO3 and C. glabrata HO5. It did not inhibit growth of gram positive and gram-negative bacteria, displaying its specificity against fungi. PN00053 is a novel polyene macrolide isolated from a wild strain of Streptomyces sp. PM0727240 (MTCC5680), an isolate from the mountainous rocky regions of Himachal Pradesh, India. The compound is a new derivative of the antibiotic Roflamycoin [32, 33-didehydroroflamycoin (DDHR)]. It displayed broad spectrum antifungal activity against yeast and filamentous fungi. However, it did not show any antibacterial activity. The in vitro study revealed that PN00053 has better potency as compared to clinical gold standard fluconazole. The development of pathogenic resistance against the polyenes has been seldom reported. Hence, we envisage PN00053 could be a potential antifungal lead. © 2014 The Society for Applied Microbiology.

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

Wild Coastline Birds as Reservoirs of Broad-Spectrum-β-Lactamase-Producing Enterobacteriaceae in Miami Beach, Florida

Science.gov (United States)

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

2012-01-01

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. PMID:22314536

Gamma-irradiated scrub typhus immunogens: broad-spectrum immunity with combinations of rickettsial strains

International Nuclear Information System (INIS)

Eisenberg, G.H. Jr.; Osterman, J.V.

1979-01-01

Scrub typhus immunogens were prepared from Rickettsia tsutsugamushi strains Karp, Kato, Gilliam, Kostival, and Buie by exposing frozen infected yolk sac suspensions to 300 krad of gamma radiation. Mouse protection tests showed that each of the irradiated immunogens protected C3H/HeDub mice against high challenge levels of Karp and Gilliam, but that none of these single-strain immunogens were capable of protecting against all five of the challenge strains. Broad-spectrum protection was achieved by using combinations of three strains of irradiated rickettsiae in a vaccination regimen of three injections at 5-day intervals

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.

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

International Nuclear Information System (INIS)

Benedictis, P. de; Minola, A.; Rota, E.; Aiello, R.; Zecchin, B.; Salomoni, A.; Foglierini, M.; Agatic, G.; Vanzetta, F.; Lavenir, R.; Lepelletier, A.; Bentley, E.; Weiss, R.; Cattoli, G.

2016-01-01

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

Endophytic Paraconiothyrium sp. from Zingiber officinale Rosc. Displays Broad-Spectrum Antimicrobial Activity by Production of Danthron.

Science.gov (United States)

Anisha, C; Sachidanandan, P; Radhakrishnan, E K

2018-03-01

The bioactivity spectrum of fungal endophytes isolated from Zingiber officinale was analyzed against clinical pathogens and against the phytopathogen Pythium myriotylum, which causes Pythium rot in ginger. One of the isolates GFM13 showed broad bioactivity against various pathogens tested including P. myriotylum. The spore suspension as well as the culture filtrate of the endophytic fungal isolate was found to effectively protect ginger rhizomes from Pythium rot. By molecular identification, the fungal endophyte was identified as Paraconiothyrium sp. The bioactive compound produced by the isolate was separated by bioactivity-guided fractionation and was identified by GC-MS as danthron, an anthraquinone derivative. PCR amplification showed the presence of non-reducing polyketide synthase gene (NR-PKS) in the endophyte GFM13, which is reported to be responsible for the synthesis of anthraquinones in fungi. This is the first report of danthron being produced as the biologically active component of Paraconiothyrium sp. Danthron is reported to have wide pharmaceutical and agronomic applications which include its use as a fungicide in agriculture. The broad-spectrum antimicrobial activity of danthron and the endophytic origin of Paraconiothyrium sp. offer immense applications of the study.

Opioids, antiepileptic and anticholinergic drugs and the risk of fractures in patients 65 years of age and older: a prospective population-based study.

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Nurminen, Janne; Puustinen, Juha; Piirtola, Maarit; Vahlberg, Tero; Lyles, Alan; Kivelä, Sirkka-Liisa

2013-05-01

in men, the concomitant use of two or more benzodiazepines or two or more antipsychotics is associated with an increased risk of fracture(s). Potential associations between the concomitant use of drugs with central nervous system effects and fracture risk have not been studied. the purpose was to describe the gender-specific risk of fractures in a population aged 65 years or over associated with the use of an opioid, antiepileptic or anticholinergic drug individually; or, their concomitant use with each other; or the concomitant use of one of these with a psychotropic drug. this study was part of a prospective, population-based study performed in Lieto, Finland. Information about fractures in 1,177 subjects (482 men and 695 women) was confirmed with radiology reports. at 3 years of follow-up, the concomitant use of an opioid with an antipsychotic was associated with an increased risk of fractures in men. During the 6-year follow-up, the concomitant use of an opioid with a benzodiazepine was also related to the risk of fractures for males. No significant associations were found for females. the concomitant use of an opioid with an antipsychotic, or with a benzodiazepine may increase the risk of fractures in men aged 65 years and older.

The secreted fructose 1,6-bisphosphate aldolase as a broad spectrum vaccine candidate against pathogenic bacteria in aquaculture.

Science.gov (United States)

Sun, Zhongyang; Shen, Binbing; Wu, Haizhen; Zhou, Xiangyu; Wang, Qiyao; Xiao, Jingfan; Zhang, Yuanxing

2015-10-01

The development of aquaculture has been hampered by different aquatic pathogens that can cause edwardsiellosis, vibriosis, or other diseases. Therefore, developing a broad spectrum vaccine against different fish diseases is necessary. In this study, fructose 1,6-bisphosphate aldolase (FBA), a conserved enzyme in the glycolytic pathway, was demonstrated to be located in the non-cytoplasmic components of five aquatic pathogenic bacteria and exhibited remarkable protection and cross-protection against these pathogens in turbot and zebrafish. Further analysis revealed that sera sampled from vaccinated turbot had a high level of specific antibody and bactericidal activity against these pathogens. Meanwhile, the increased expressions of immune response-related genes associated with antigen recognition and presentation indicated that the adaptive immune response was effectively aroused. Taken together, our results suggest that FBA can be utilized as a broad-spectrum vaccine against various pathogenic bacteria of aquaculture in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.

Aspectos farmacológicos relevantes de los antiepilépticos nuevos Relevant pharmacological aspects of the new antiepileptic drugs

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Alicia Zapata Martínez

2005-12-01

Full Text Available Dada la importancia de la epilepsia como enfermedad crónica no transmisible, se decidió realizar una revisión de los fármacos nuevos que en los últimos años han sido comercializados para su tratamiento en el mundo. Se enfatizó en la necesidad de establecer una correcta relación beneficio/riesgo/costo a partir del conocimiento de la eficacia, seguridad, conveniencia y costo de los fármacos empleados en el tratamiento de cualquier enfermedad, y por supuesto, de la epilepsia. Los nuevos medicamentos antiepilépticos todavía no han demostrado de forma convincente ser superiores a los ya conocidos, y de los cuales también se exponen sus principales características farmacológicas. Aunque en la mayoría de las ocasiones no son mejores, sí no hay dudas que son más caros e incrementan el precio de los tratamientos.Due to the importance of epilepsy as a non-communicable chronic disease, it was decided to make a review of the new drugs that in the last years have been commercialized for its treatement in the world. Emphasis was given to the need of establishing a correct benefit/risk/cost relation, starting from the knowledge of efficiency, safety, convenience and cost of the drugs used in the treatment of any disease and, of course, of epilepsy. The new antiepileptic drugs have not proved yet to be superior than the already known, whose main pharmacological characteristics are also exposed. Though in most of the ocassions they are not better, they are undoubtedly more expensive and increase the prices of the treatments.

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

Science.gov (United States)

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

2012-05-01

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

An aggregated perylene-based broad-spectrum, efficient and label-free quencher for multiplexed fluorescent bioassays.

Science.gov (United States)

Liu, Tao; Hu, Rong; Lv, Yi-Fan; Wu, Yuan; Liang, Hao; Huan, Shuang-Yan; Zhang, Xiao-Bing; Tan, Weihong; Yu, Ru-Qin

2014-08-15

Fluorescent sensing systems based on the quenching of fluorophores have found wide applications in bioassays. An efficient quencher will endow the sensing system a high sensitivity. The frequently used quenchers are based on organic molecules or nanomaterials, which usually need tedious synthesizing and modifying steps, and exhibit different quenching efficiencies to different fluorophores. In this work, we for the first time report that aggregated perylene derivative can serve as a broad-spectrum and label-free quencher that is able to efficiently quench a variety of fluorophores, such as green, red and far red dyes labeled on DNA. By choosing nucleases as model biomolecules, such a broad-spectrum quencher was then employed to construct a multiplexed bioassay platform through a label-free manner. Due to the high quenching efficiency of the aggregated perylene, the proposed platform could detect nuclease with high sensitivity, with a detection limit of 0.03U/mL for EcoRV, and 0.05U/mL for EcoRI. The perylene quencher does not affect the activity of nuclease, which makes it possible to design post-addition type bioassay platform. Moreover, the proposed platform allows simultaneous and multicolor analysis of nucleases in homogeneous solution, demonstrating its value of potential application in rapid screening of multiple bio-targets. Copyright © 2014 Elsevier B.V. All rights reserved.

Spectrum of microbial growth and antimicrobial usage in an ...

African Journals Online (AJOL)

Intensive-care units (ICUs) are a source of multidrug-resistant organisms, owing to the indiscriminate usage of broad-spectrum antimicrobial drugs. In such ... Staphylococcus aureus was the most common isolate from blood and central venous lines, and Pseudomonas aeruginosa from tracheal aspirates and wound swabs.

Parametric instability producing broad symmetrical structure in the spectrum of ionospheric heating-induced radiation

International Nuclear Information System (INIS)

Kuo, S.P.

1997-01-01

A four-wave interaction process in which an O-mode electromagnetic pump decays parametrically into a lower hybrid decay mode and two-electron Bernstein sidebands is analyzed. It is shown that the instability can be excited in a spatial region near the electron Bernstein/upper hybrid double resonance and in a narrow pump frequency range slightly below the third harmonic electron cyclotron resonance. The two electron Bernstein sidebands have about the same intensity and thus, produce Broad Symmetrical Structure (BSS) in the emission spectrum after being converted into electromagnetic radiation by scattering off background field-aligned density irregularities. The results also show that the size of the instability zone becomes very small as the pump frequency operates near a cyclotron harmonic higher than the third. Thus, the converted emission will be too weak to be detected. This explains why the BSS feature in the spectrum of stimulated electromagnetic emissions (SEEs) has only been observed in the third harmonic case. copyright 1997 American Institute of Physics

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

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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.

Ciprofloxacin prophylaxis delays initiation of broad-spectrum antibiotic therapy and reduces the overall use of antimicrobial agents during induction therapy for acute leukaemia: A single-centre study.

Science.gov (United States)

Hallböök, Helene; Lidström, Anna-Karin; Pauksens, Karlis

2016-01-01

Due to an outbreak of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae, the routine use of fluoroquinolone prophylaxis was questioned. As a result, this study was conducted with the aim to evaluate the impact of ciprofloxacin-prophylaxis on the use of broad-spectrum antibioctics and anti-mycotics. A cohort of 139 consecutive patients with acute leukaemia treated with remission-inducing induction chemotherapy between 2004-2012 at the Department of Haematology in Uppsala University Hospital was analysed. Fifty-three patients (38%) received broad-spectrum antibiotics at the initiation of chemotherapy and were not eligible for prophylaxis. Of the remaining patients, the initiation of broad-spectrum antibiotics was delayed by 3 days in those receiving ciprofloxacin prophylaxis (n = 47) compared with those receiving no prophylaxis (n = 39). The median duration of systemic antibiotic treatment was 6 days shorter in patients receiving ciprofloxacin prophylaxis (12 vs 18 days; p = 0.0005) and the cumulative (total) median days on systemic antibiotic treatment was shortened by 8 days (15 vs 23 days, p = 0.0008). Piperacillin/tazobactam (p = 0.02), carbapenems (p = 0.05) and empiric broad-spectrum antifungals (p antibiotic use in this study. These benefits must be evaluated vs the risks of development of resistant bacterial strains, making fluoroquinolone prophylaxis an open question for debate.

Modification of polydopamine-coated Fe3O4 nanoparticles with multi-walled carbon nanotubes for magnetic-μ-dispersive solid-phase extraction of antiepileptic drugs in biological matrices.

Science.gov (United States)

Zhang, Ruiqi; Wang, Siming; Yang, Ye; Deng, Yulan; Li, Di; Su, Ping; Yang, Yi

2018-06-01

In this study, multi-walled carbon nanotubes were coated on the surface of magnetic nanoparticles modified by polydopamine. The synthesized composite was characterized and applied to magnetic-μ-dispersive solid-phase extraction of oxcarbazepine (OXC), phenytoin (PHT), and carbamazepine (CBZ) from human plasma, urine, and cerebrospinal fluid samples prior to analysis by a high-performance liquid chromatography-photodiode array detector. The extraction parameters were investigated and the optimum condition was obtained when the variables were set to the following: sorbent type, Fe 3 O 4 @polyDA-MWCNTs (length Graphical abstract Magnetic multi-walled carbon nanotube core-shell composites were applied as magnetic-μ-dispersive solid-phase extraction adsorbents for determination of antiepileptic drugs in biological matrices.

Effect and Safety of Shihogyejitang for Drug Resistant Childhood Epilepsy

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Jinsoo Lee

2016-01-01

Full Text Available Objective. Herbal medicine has been widely used to treat drug resistant epilepsy. Shihogyejitang (SGT has been commonly used to treat epilepsy. We investigated the effect and safety of SGT in children with drug resistant epilepsy. Design. We reviewed medical records of 54 patients with epilepsy, who failed to respond to at least two antiepileptic drugs and have been treated with SGT between April 2006 and June 2014 at the Department of Pediatric Neurology, I-Tomato Hospital, Korea. Effect was measured by the response rate, seizure-free rate, and retention rate at six months. We also checked adverse events, change in antiepileptic drugs use, and the variables related to the outcome. Results. Intent-to-treat analysis showed that, after six months, 44.4% showed a >50% seizure reduction, 24.1% including seizure-free, respectively, and 53.7% remained on SGT. Two adverse events were reported, mild skin rash and fever. Focal seizure type presented significantly more positive responses when compared with other seizure types at six months (p=0.0284, Fisher’s exact test. Conclusion. SGT is an effective treatment with excellent tolerability for drug resistant epilepsy patients. Our data provide evidence that SGT may be used as alternative treatment option when antiepileptic drug does not work in epilepsy children.

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

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

International Nuclear Information System (INIS)

Reinhardt, P.; Cybulski, M.; Miller, S.M.; Ferrarotto, C.; Wilkins, R.; Deslauriers, Y.

2006-01-01

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 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-1α (IL-1α), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α). 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-1α levels increased with LOM concentration. The release of TNF-α and IL-6 followed the same pattern at lower concentrations of LOM but peaked at 15 μmol/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)

A Broad-Spectrum Integrative Design for Cancer Prevention and Therapy

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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

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

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

2014-02-01

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

Surprises from a Deep ASCA Spectrum of the Broad Absorption Line Quasar PHL 5200

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Mathur, Smita; Matt, G.; Green, P. J.; Elvis, M.; Singh, K. P.

2002-01-01

We present a deep (approx. 85 ks) ASCA observation of the prototype broad absorption line quasar (BALQSO) PHL 5200. This is the best X-ray spectrum of a BALQSO yet. We find the following: (1) The source is not intrinsically X-ray weak. (2) The line-of-sight absorption is very strong, with N(sub H) = 5 x 10(exp 23)/sq cm. (3) The absorber does not cover the source completely; the covering fraction is approx. 90%. This is consistent with the large optical polarization observed in this source, implying multiple lines of sight. The most surprising result of this observation is that (4) the spectrum of this BALQSO is not exactly similar to other radio-quiet quasars. The hard X-ray spectrum of PHL 5200 is steep, with the power-law spectral index alpha approx. 1.5. This is similar to the steepest hard X-ray slopes observed so far. At low redshifts, such steep slopes are observed in narrow-line Seyfert 1 (NLS1) galaxies, believed to be accreting at a high Eddington rate. This observation strengthens the analogy between BALQSOs and NLS1 galaxies and supports the hypothesis that BALQSOs represent an early evolutionary state of quasars. It is well accepted that the orientation to the line of sight determines the appearance of a quasar: age seems to play a significant role as well.

Drug-refractory aggression, self-injurious behavior, and severe tantrums in autism spectrum disorders: a chart review study.

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Adler, Benjamin A; Wink, Logan K; Early, Maureen; Shaffer, Rebecca; Minshawi, Noha; McDougle, Christopher J; Erickson, Craig A

2015-01-01

Aggression, self-injurious behavior, and severe tantrums are impairing symptoms frequently experienced by individuals with autism spectrum disorders. Despite US Food and Drug Administration approval of two atypical antipsychotics targeting these symptoms in youth with autistic disorder, they remain frequently drug refractory. We define drug-refractory aggression, self-injurious behavior, and severe tantrums in people with autism spectrum disorders as behavioral symptoms requiring medication adjustment despite previous trials of risperidone and aripiprazole or previous trials of three psychotropic drugs targeting the symptom cluster, one of which was risperidone or aripiprazole. We reviewed the medical records of individuals of all ages referred to our clinic for autism spectrum disorder diagnostic evaluation, as well as pharmacotherapy follow-up notes for all people meeting autism spectrum disorder criteria, for drug-refractory symptoms. Among 250 consecutively referred individuals, 135 met autism spectrum disorder and enrollment criteria, and 53 of these individuals met drug-refractory symptom criteria. Factors associated with drug-refractory symptoms included age 12 years or older (p diagnosis of autistic disorder (p = 0.0139), and presence of intellectual disability (p = 0.0273). This pilot report underscores the significance of drug-refractory aggression, self-injurious behavior, and severe tantrums; suggests the need for future study clarifying factors related to symptom development; and identifies the need for focused treatment study of this impairing symptom domain. © The Author(s) 2014.

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

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

2018-02-27

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

The broad spectrum revisited: evidence from plant remains.

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

2004-06-29

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 transition to farming in southwest Asia entailed a period during which foragers broadened their resource base to encompass a wide array of foods that were previously ignored in an attempt to overcome food shortages. Although these resources undoubtedly included plants, nearly all BSR hypothesis-inspired research has focused on animals because of a dearth of Upper Paleolithic archaeobotanical assemblages. Now, however, a collection of >90,000 plant remains, recently recovered from the Stone Age site Ohalo II (23,000 B.P.), Israel, offers insights into the plant foods of the late Upper Paleolithic. The staple foods of this assemblage were wild grasses, pushing back the dietary shift to grains some 10,000 years earlier than previously recognized. Besides the cereals (wild wheat and barley), small-grained grasses made up a large component of the assemblage, indicating that the BSR in the Levant was even broader than originally conceived, encompassing what would have been low-ranked plant foods. Over the next 15,000 years small-grained grasses were gradually replaced by the cereals and ultimately disappeared from the Levantine diet.

Spectrum of antimicrobial activity associated with ionic colloidal silver.

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Morrill, Kira; May, Kathleen; Leek, Daniel; Langland, Nicole; Jeane, La Deana; Ventura, Jose; Skubisz, Corey; Scherer, Sean; Lopez, Eric; Crocker, Ephraim; Peters, Rachel; Oertle, John; Nguyen, Krystine; Just, Scott; Orian, Michael; Humphrey, Meaghan; Payne, David; Jacobs, Bertram; Waters, Robert; Langland, Jeffrey

2013-03-01

Silver has historically and extensively been used as a broad-spectrum antimicrobial agent. However, the Food and Drug Administration currently does not recognize colloidal silver as a safe and effective antimicrobial agent. The goal of this study was to further evaluate the antimicrobial efficacy of colloidal silver. Several strains of bacteria, fungi, and viruses were grown under multicycle growth conditions in the presence or absence of ionic colloidal silver in order to assess the antimicrobial activity. For bacteria grown under aerobic or anaerobic conditions, significant growth inhibition was observed, although multiple treatments were typically required. For fungal cultures, the effects of ionic colloidal silver varied significantly between different genera. No viral growth inhibition was observed with any strains tested. The study data support ionic colloidal silver as a broad-spectrum antimicrobial agent against aerobic and anaerobic bacteria, while having a more limited and specific spectrum of activity against fungi.

Novel α-MSH peptide analogues with broad spectrum antimicrobial activity.

Directory of Open Access Journals (Sweden)

Paolo Grieco

Full Text Available Previous investigations indicate that α-melanocyte-stimulating hormone (α-MSH and certain synthetic analogues of it exert antimicrobial effects against bacteria and yeasts. However, these molecules have weak activity in standard microbiology conditions and this hampers a realistic clinical use. The aim in the present study was to identify novel peptides with broad-spectrum antimicrobial activity in growth medium. To this purpose, the Gly10 residue in the [DNal(2'-7, Phe-12]-MSH(6-13 sequence was replaced with conventional and unconventional amino acids with different degrees of conformational rigidity. Two derivatives in which Gly10 was replaced by the residues Aic and Cha, respectively, had substantial activity against Candida strains, including C. albicans, C. glabrata, and C. krusei and against gram-positive and gram-negative bacteria. Conformational analysis indicated that the helical structure along residues 8-13 is a key factor in antimicrobial activity. Synthetic analogues of α-MSH can be valuable agents to treat infections in humans. The structural preferences associated with antimicrobial activity identified in this research can help further development of synthetic melanocortins with enhanced biological activity.

Application of broad-spectrum resequencing microarray for genotyping rhabdoviruses.

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Dacheux, Laurent; Berthet, Nicolas; Dissard, Gabriel; Holmes, Edward C; Delmas, Olivier; Larrous, Florence; Guigon, Ghislaine; Dickinson, Philip; Faye, Ousmane; Sall, Amadou A; Old, Iain G; Kong, Katherine; Kennedy, Giulia C; Manuguerra, Jean-Claude; Cole, Stewart T; Caro, Valérie; Gessain, Antoine; Bourhy, Hervé

2010-09-01

The rapid and accurate identification of pathogens is critical in the control of infectious disease. To this end, we analyzed the capacity for viral detection and identification of a newly described high-density resequencing microarray (RMA), termed PathogenID, which was designed for multiple pathogen detection using database similarity searching. We focused on one of the largest and most diverse viral families described to date, the family Rhabdoviridae. We demonstrate that this approach has the potential to identify both known and related viruses for which precise sequence information is unavailable. In particular, we demonstrate that a strategy based on consensus sequence determination for analysis of RMA output data enabled successful detection of viruses exhibiting up to 26% nucleotide divergence with the closest sequence tiled on the array. Using clinical specimens obtained from rabid patients and animals, this method also shows a high species level concordance with standard reference assays, indicating that it is amenable for the development of diagnostic assays. Finally, 12 animal rhabdoviruses which were currently unclassified, unassigned, or assigned as tentative species within the family Rhabdoviridae were successfully detected. These new data allowed an unprecedented phylogenetic analysis of 106 rhabdoviruses and further suggest that the principles and methodology developed here may be used for the broad-spectrum surveillance and the broader-scale investigation of biodiversity in the viral world.

Application of Broad-Spectrum Resequencing Microarray for Genotyping Rhabdoviruses▿

Science.gov (United States)

Dacheux, Laurent; Berthet, Nicolas; Dissard, Gabriel; Holmes, Edward C.; Delmas, Olivier; Larrous, Florence; Guigon, Ghislaine; Dickinson, Philip; Faye, Ousmane; Sall, Amadou A.; Old, Iain G.; Kong, Katherine; Kennedy, Giulia C.; Manuguerra, Jean-Claude; Cole, Stewart T.; Caro, Valérie; Gessain, Antoine; Bourhy, Hervé

2010-01-01

The rapid and accurate identification of pathogens is critical in the control of infectious disease. To this end, we analyzed the capacity for viral detection and identification of a newly described high-density resequencing microarray (RMA), termed PathogenID, which was designed for multiple pathogen detection using database similarity searching. We focused on one of the largest and most diverse viral families described to date, the family Rhabdoviridae. We demonstrate that this approach has the potential to identify both known and related viruses for which precise sequence information is unavailable. In particular, we demonstrate that a strategy based on consensus sequence determination for analysis of RMA output data enabled successful detection of viruses exhibiting up to 26% nucleotide divergence with the closest sequence tiled on the array. Using clinical specimens obtained from rabid patients and animals, this method also shows a high species level concordance with standard reference assays, indicating that it is amenable for the development of diagnostic assays. Finally, 12 animal rhabdoviruses which were currently unclassified, unassigned, or assigned as tentative species within the family Rhabdoviridae were successfully detected. These new data allowed an unprecedented phylogenetic analysis of 106 rhabdoviruses and further suggest that the principles and methodology developed here may be used for the broad-spectrum surveillance and the broader-scale investigation of biodiversity in the viral world. PMID:20610710

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

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

2017-05-01

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

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

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

2017-04-01

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

Psychological Adjustment and Sibling Relationships in Siblings of Children with Autism Spectrum Disorders: Environmental Stressors and the Broad Autism Phenotype

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Petalas, Michael A.; Hastings, Richard P.; Nash, Susie; Hall, Louise M.; Joannidi, Helen; Dowey, Alan

2012-01-01

Research with siblings of children with Autism Spectrum Disorders (ASD) suggests that they may be at increased risk for behavioural and emotional problems and relatively poor sibling relationships. This study investigated a diathesis-stress model, whereby the presence of Broad Autism Phenotype features in the typically developing siblings might…

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.

Role of bronchoalveolar lavage in immunocompromised patients with pneumonia treated with a broad spectrum antibiotic and antifungal regimen

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Hohenadel, I; Kiworr, M; Genitsariotis, R; Zeidler, D; Lorenz, J

2001-01-01

BACKGROUND—In a retrospective study the value of bronchoalveolar lavage (BAL) in the diagnosis of pneumonia was investigated in 95 immunocompromised patients suffering from haematological disorders and receiving a regimen of broad spectrum antibiotics and antifungal agents (BSAR).
METHODS—With the exception of four afebrile patients, all had fever, raised C reactive protein (CRP) levels, and new infiltrates visible on chest radiography. All patients underwent BAL to identify the organism causing the pneumonia and surveillance cultures were performed regularly for pathogens at different sites. Following classification of the isolates, patients with positive cultures were subdivided into two groups, pathogenic or contaminated. We investigated whether relevant pathogens were cultured only from the BAL fluid and whether they were susceptible to BSAR.
RESULTS—Although 77 of the 95 patients were thrombocytopenic, bleeding during BAL occurred in only 15% of all patients. Ten days after the procedure the fever improved in 88% of patients, radiographic findings improved in 71%, and CRP levels improved in 75% of patients; 22% of patients died within 28 days. Pathologically relevant isolates were found in 65% of all patients. Respiratory pathogens were detected only in the BAL fluid of 29 of the 95 patients (35% Gram positive species, 40% Gram negative species, 11% Mycobacterium, 11% fungi, and 3% cytomegalovirus). In 16 of these 29 patients (55%) the pathogens cultured only from the BAL fluid were resistant to treatment. Pathogens detected only in the BAL fluid were not susceptible to a standard broad spectrum antibiotic and antifungal regimen including teicoplanin, ceftriaxon, tobramycin, and amphotericin B in 12 of the 29 patients (41%).
CONCLUSIONS—Our data suggest that 12 patients were treated with broad spectrum antimicrobial agents which were not directed at the appropriate organism on in vitro sensitivity tests without BAL. BAL is a relatively safe

Broad spectrum antibiotic enrofloxacin modulates contact sensitivity through gut microbiota in a murine model.

Science.gov (United States)

Strzępa, Anna; Majewska-Szczepanik, Monika; Lobo, Francis M; Wen, Li; Szczepanik, Marian

2017-07-01

Medical advances in the field of infection therapy have led to an increasing use of antibiotics, which, apart from eliminating pathogens, also partially eliminate naturally existing commensal bacteria. It has become increasingly clear that less exposure to microbiota early in life may contribute to the observed rise in "immune-mediated" diseases, including autoimmunity and allergy. We sought to test whether the change of gut microbiota with the broad spectrum antibiotic enrofloxacin will modulate contact sensitivity (CS) in mice. Natural gut microbiota were modified by oral treatment with enrofloxacin prior to sensitization with trinitrophenyl chloride followed by CS testing. Finally, adoptive cell transfers were performed to characterize the regulatory cells that are induced by microbiota modification. Oral treatment with enrofloxacin suppresses CS and production of anti-trinitrophenyl chloride IgG1 antibodies. Adoptive transfer experiments show that antibiotic administration favors induction of regulatory cells that suppress CS. Flow cytometry and adoptive transfer of purified cells show that antibiotic-induced suppression of CS is mediated by TCR αβ + CD4 + CD25 + FoxP3 + Treg, CD19 + B220 + CD5 + IL-10 + , IL-10 + Tr1, and IL-10 + TCR γδ + cells. Treatment with the antibiotic induces dysbiosis characterized by increased proportion of Clostridium coccoides (cluster XIVa), C coccoides-Eubacterium rectale (cluster XIVab), Bacteroidetes, and Bifidobacterium spp, but decreased segmented filamentous bacteria. Transfer of antibiotic-modified gut microbiota inhibits CS, but this response can be restored through oral transfer of control gut bacteria to antibiotic-treated animals. Oral treatment with a broad spectrum antibiotic modifies gut microbiota composition and promotes anti-inflammatory response, suggesting that manipulation of gut microbiota can be a powerful tool to modulate the course of CS. Copyright © 2017 American Academy of Allergy, Asthma & Immunology

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

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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

Plasmid-mediated AmpC-type beta-lactamase isolated from Klebsiella pneumoniae confers resistance to broad-spectrum beta-lactams, including moxalactam.

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Horii, T; Arakawa, Y; Ohta, M; Ichiyama, S; Wacharotayankun, R; Kato, N

1993-01-01

Klebsiella pneumoniae NU2936 was isolated from a patient and was found to produce a plasmid-encoded beta-lactamase (MOX-1) which conferred resistance to broad spectrum beta-lactams, including moxalactam, flomoxef, ceftizoxime, cefotaxime, and ceftazidime. Resistance could be transferred from K. pneumoniae NU2936 to Escherichia coli CSH2 by conjugation with a transfer frequency of 5 x 10(-7). The structural gene of MOX-1 (blaMOX-1) was cloned and expressed in E. coli HB101. The MIC of moxalactam for E. coli HB101 producing MOX-1 was > 512 micrograms/ml. The apparent molecular mass and pI of this enzyme were calculated to be 38 kDa and 8.9, respectively. Hg2+ and Cu2+ failed to block enzyme activity, and the presence of EDTA in the reaction buffer did not reduce the enzyme activity. However, clavulanate and cloxacillin, serine beta-lactamase inhibitors, inhibited the enzyme activity competitively (Kis = 5.60 and 0.35 microM, respectively). The kinetic study of MOX-1 suggested that it effectively hydrolyzed broad-spectrum beta-lactams. A hybridization study confirmed that blaMOX-1 is encoded on a large resident plasmid (pRMOX1; 180 kb) of strain NU2936. By deletion analysis, the functional region was localized within a 1.2-kb region of the plasmid. By amino acid sequencing, 18 of 33 amino acid residues at the N terminus of MOX-1 were found to be identical to those of Pseudomonas aeruginosa AmpC. These findings suggest that MOX-1 is a plasmid-mediated AmpC-type beta-lactamase that provides enteric bacteria resistance to broad-spectrum beta-lactams, including moxalactam. Images PMID:8517725

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

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Levine, Joseph; Toker, Lilach; Agam, Galila

2018-01-01

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

Drug: D05817 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D05817 Drug Seletracetam (USAN/INN) ... C10H14F2N2O2 D05817.gif ... Neuropsychiatric agent ... DG02038 ... Piracetam... antiepileptics Chemical group: DG02506 ... Piracetam derivative Treatment of epilepsy

Depressive and anxiety disorders in epilepsy: do they differ in their potential to worsen common antiepileptic drug-related adverse events?

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Kanner, Andres M; Barry, John J; Gilliam, Frank; Hermann, Bruce; Meador, Kimford J

2012-06-01

To compare the effect of anxiety disorders, major depressive episodes (MDEs), and subsyndromic depressive episodes (SSDEs) on antiepileptic drug (AED)-related adverse events (AEs) in persons with epilepsy (PWE). The study included 188 consecutive PWE from five U.S. outpatient epilepsy clinics, all of whom underwent structured interviews (SCID) to identify current and past mood disorders and other current Axis I psychiatric diagnoses according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria. A diagnosis of SSDE was made in patients with total Beck Depression Inventory-II (BDI-II) scores >12 or the Centers of Epidemiologic Studies-Depression (CES-D) > 16 (in the absence of any DSM diagnosis of mood disorder. The presence and severity of AEs was measured with the Adverse Event Profile (AEP). Compared to asymptomatic patients (n = 103), the AEP scores of patients with SSDE (n = 26), MDE only (n = 10), anxiety disorders only (n = 21), or mixed MDE/anxiety disorders (n = 28) were significantly higher, suggesting more severe AED-related AEs. Univariate analyses revealed that having persistent seizures in the last 6 months and taking antidepressants was associated with more severe AEs. Post hoc analyses, however, showed that these differences were accounted for by the presence of a depressive and/or anxiety disorders. Depressive and anxiety disorders worsen AED-related AEs even when presenting as a subsyndromic type. These data suggest that the presence of psychiatric comorbidities must be considered in their interpretation, both in clinical practice and AED drug trials. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

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

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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.

The investigation of copper-based impregnated activated carbons prepared from water-soluble materials for broad spectrum respirator applications

International Nuclear Information System (INIS)

Smith, J.W.H.; Westreich, P.; Abdellatif, H.; Filbee-Dexter, P.; Smith, A.J.; Wood, T.E.; Croll, L.M.; Reynolds, J.H.; Dahn, J.R.

2010-01-01

The preparation of impregnated activated carbons (IACs) from aqueous, copper-containing solutions for broad spectrum gas filtration applications is studied here. Several samples were studied to determine the effect that impregnant loading, impregnant distribution and impregnant recipe had on the overall performance. Dynamic flow testing was used to determine the gas filtration capacity of the IAC samples versus a variety of challenge gases. X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDX) were used to characterize the impregnant distribution on the carbon as a function of impregnant loading. Oven tests were performed to determine the thermal stability of the IAC samples exposed to elevated temperatures. The role impregnant distribution plays in gas filtration capacity and the overall performance of the IAC samples is discussed. The IAC samples prepared in this work were found to have gas filtration capacities as good as or better than broad spectrum respirator carbon samples prepared from the patent literature. IACs impregnated with an aqueous 2.4 M Cu(NO 3 ) 2 /0.04 M H 3 PO 4 .12MoO 3 /4 M HNO 3 solution that were heated to 200 deg. C under argon were found to have the best overall performance of the samples studied in this work.

Comparison between pathogen directed antibiotic treatment and empirical broad spectrum antibiotic treatment in patients with community acquired pneumonia: a prospective randomised study

NARCIS (Netherlands)

van der Eerden, M. M.; Vlaspolder, F.; de Graaff, C. S.; Groot, T.; Bronsveld, W.; Jansen, H. M.; Boersma, W. G.

2005-01-01

Background: There is much controversy about the ideal approach to the management of community acquired pneumonia ( CAP). Recommendations differ from a pathogen directed approach to an empirical strategy with broad spectrum antibiotics. Methods: In a prospective randomised open study performed

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

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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.

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

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

2016-01-01

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

White LEDs as broad spectrum light sources for spectrophotometry: demonstration in the visible spectrum range in a diode-array spectrophotometric detector.

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Piasecki, Tomasz; Breadmore, Michael C; Macka, Mirek

2010-11-01

Although traditional lamps, such as deuterium lamps, are suitable for bench-top instrumentation, their compatibility with the requirements of modern miniaturized instrumentation is limited. This study investigates the option of utilizing solid-state light source technology, namely white LEDs, as a broad band spectrum source for spectrophotometry. Several white light LEDs of both RGB and white phosphorus have been characterized in terms of their emission spectra and energy output and a white phosphorus Luxeon LED was then chosen for demonstration as a light source for visible-spectrum spectrophotometry conducted in CE. The Luxeon LED was fixed onto the base of a dismounted deuterium (D(2) ) lamp so that the light-emitting spot was geometrically positioned exactly where the light-emitting spot of the original D(2) lamp is placed. In this manner, the detector of a commercial CE instrument equipped with a DAD was not modified in any way. As the detector hardware and electronics remained the same, the change of the deuterium lamp for the Luxeon white LED allowed a direct comparison of their performances. Several anionic dyes as model analytes with absorption maxima between 450 and 600 nm were separated by CE in an electrolyte of 0.01 mol/L sodium tetraborate. The absorbance baseline noise as the key parameter was 5 × lower for the white LED lamp, showing clearly superior performance to the deuterium lamp in the available, i.e. visible part of the spectrum. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Effects of Fall-Risk-Increasing Drugs on Postural Control : A Literature Review

NARCIS (Netherlands)

de Groot, Maartje H.; van Campen, Jos P. C. M.; Moek, Marije A.; Tulner, Linda R.; Beijnen, Jos H.; Lamoth, Claudine J. C.

Meta-analyses showed that psychotropic drugs (antidepressants, neuroleptics, benzodiazepines, antiepileptic drugs) and some cardiac drugs (digoxin, type IA anti-arrhythmics, diuretics) are associated with increased fall risk. Because balance and gait disorders are the most consistent predictors of

Antiepileptic drug prescribing before, during and after pregnancy: a study in seven European regions.

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Charlton, Rachel; Garne, Ester; Wang, Hao; Klungsøyr, Kari; Jordan, Sue; Neville, Amanda; Pierini, Anna; Hansen, Anne; Engeland, Anders; Gini, Rosa; Thayer, Daniel; Bos, Jens; Puccini, Aurora; Nybo Andersen, Anne-Marie; Dolk, Helen; de Jong-van den Berg, Lolkje

2015-11-01

The aim of this study was to explore antiepileptic drug (AED) prescribing before, during and after pregnancy as recorded in seven population-based electronic healthcare databases. Databases in Denmark, Norway, the Netherlands, Italy (Emilia Romagna/Tuscany), Wales and the Clinical Practice Research Datalink, representing the rest of the UK, were accessed for the study. Women with a pregnancy starting and ending between 2004 and 2010, which ended in a delivery, were identified. AED prescriptions issued (UK) or dispensed (non-UK) at any time during pregnancy and the 6 months before 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. In total, 978 957 women with 1 248 713 deliveries were identified. In all regions, AED prescribing declined during pregnancy and was lowest during the third trimester, before returning to pre-pregnancy levels by 6 months following delivery. For all deliveries, the prevalence of AED prescribing during pregnancy was 51 per 10 000 pregnancies (CI95 49-52%) and was lowest in the Netherlands (43/10 000; CI95 33-54%) and highest in Wales (60/10 000; CI95 54-66%). In Denmark, Norway and the two UK databases lamotrigine was the most commonly prescribed AED; whereas in the Italian and Dutch databases, carbamazepine, valproate and phenobarbital were most frequently prescribed. Few women prescribed with AEDs in the 3 months before pregnancy were co-prescribed with high-dose folic acid: ranging from 1.0% (CI95 0.3-1.8%) in Emilia Romagna to 33.5% (CI95 28.7-38.4%) in Wales. 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

Mechanisms of Broad-Spectrum Antiemetic Efficacy of Cannabinoids against Chemotherapy-Induced Acute and Delayed Vomiting

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Nissar A. Darmani

2010-09-01

Full Text Available Chemotherapy-induced nausea and vomiting (CINV is a complex pathophysiological condition and consists of two phases. The conventional CINV neurotransmitter hypothesis suggests that the immediate phase is mainly due to release of serotonin (5-HT from the enterochromaffin cells in the gastrointestinal tract (GIT, while the delayed phase is a consequence of release of substance P (SP in the brainstem. However, more recent findings argue against this simplistic neurotransmitter and anatomical view of CINV. Revision of the hypothesis advocates a more complex, differential and overlapping involvement of several emetic neurotransmitters/modulators (e.g. dopamine, serotonin, substance P, prostaglandins and related arachidonic acid derived metabolites in both phases of emesis occurring concomitantly in the brainstem and in the GIT enteric nervous system (ENS [1]. No single antiemetic is currently available to completely prevent both phases of CINV. The standard antiemetic regimens include a 5-HT3 antagonist plus dexamethasone for the prevention of acute emetic phase, combined with an NK1 receptor antagonist (e.g. aprepitant for the delayed phase. Although NK1 antagonists behave in animals as broad-spectrum antiemetics against different emetogens including cisplatin-induced acute and delayed vomiting, by themselves they are not very effective against CINV in cancer patients. Cannabinoids such as D9-THC also behave as broad-spectrum antiemetics against diverse emetic stimuli as well as being effective against both phases of CINV in animals and patients. Potential side effects may limit the clinical utility of direct-acting cannabinoid agonists which could be avoided by the use of corresponding indirect-acting agonists. Cannabinoids (both phyto-derived and synthetic behave as agonist antiemetics via the activation of cannabinoid CB1 receptors in both the brainstem and the ENS emetic loci. An endocannabinoid antiemetic tone may exist since inverse CB1

Brain tumors in eloquent areas: A European multicenter survey of intraoperative mapping techniques, intraoperative seizures occurrence, and antiepileptic drug prophylaxis.

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Spena, Giannantonio; Schucht, Philippe; Seidel, Kathleen; Rutten, Geert-Jan; Freyschlag, Christian Franz; D'Agata, Federico; Costi, Emanule; Zappa, Francesca; Fontanella, Marco; Fontaine, Denys; Almairac, Fabien; Cavallo, Michele; De Bonis, Pasquale; Conesa, Gerardo; Foroglou, Nicholas; Gil-Robles, Santiago; Mandonnet, Emanuel; Martino, Juan; Picht, Thomas; Viegas, Catarina; Wager, Michel; Pallud, Johan

2017-04-01

Intraoperative mapping and monitoring techniques for eloquent area tumors are routinely used world wide. Very few data are available regarding mapping and monitoring methods and preferences, intraoperative seizures occurrence and perioperative antiepileptic drug management. A questionnaire was sent to 20 European centers with experience in intraoperative mapping or neurophysiological monitoring for the treatment of eloquent area tumors. Fifteen centers returned the completed questionnaires. Data was available on 2098 patients. 863 patients (41.1%) were operated on through awake surgery and intraoperative mapping, while 1235 patients (58.8%) received asleep surgery and intraoperative electrophysiological monitoring or mapping. There was great heterogeneity between centers with some totally AW oriented (up to 100%) and other almost totally ASL oriented (up to 92%) (31% SD). For awake surgery, 79.9% centers preferred an asleep-awake-asleep anesthesia protocol. Only 53.3% of the centers used ECoG or transcutaneous EEG. The incidence of intraoperative seizures varied significantly between centers, ranging from 2.5% to 54% (p mapping technique and the risk of intraoperative seizures. Moreover, history of preoperative seizures can significantly increase the risk of intraoperative seizures (p mapping and monitoring protocols and the management of peri- and intraoperative seizures. This data can help identify specific aspects that need to be investigated in prospective and controlled studies.

Antiepileptic popular ketogenic diet: emerging twists in an ancient story.

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Vamecq, Joseph; Vallée, Louis; Lesage, Florian; Gressens, Pierre; Stables, James P

2005-01-01

The antiepileptic activity associated with ketogenic diets (KD) have been known for some time. First reports date back to the Middle Ages and even Biblical times where KD was achieved by fasting (i.e. "water diet") [see Swink, T.D., Vining, E.P.G., Freeman, J.M., 1997. The ketogenic diet: 1997. Adv. Pediatr. 44, 297-329, and references therein]. In the early 20th century, changes in the design of the KD were introduced, shifting the so-called "water diet" to a high-fat diet. Initial clinical evaluations undertaken between the 1920s and 1940s were enthusiastic, but the popularity of the KD was retrograded upon clinical introduction of phenytoin and subsequently other antiepileptic drugs. Today, despite a pharmacological arsenal targeting cerebral receptors and specific events in seizure initiation and development, about 30-40% patients are still refractory to available medications. Thus, the KD has been re-introduced in recent years as an alternative therapy, averring to be efficacious against some instances of resistant or intractable epilepsy. Despite a long historical background and enlarged clinical use, identification of the underlying anticonvulsant mechanisms associated with this nonpharmacological approach is still in stagnation. The present review is an attempt to encourage current research orientation through well-based and directed proposals for putative emerging candidates mediating KD anticonvulsant mechanisms. The reader is provided with a special emphasis on ATP-sensitive and recently cloned two-pore (or tandem) domain potassium channels, as well as several emerging conceptual views and advances such as nuclear receptors, uncoupling proteins and gap junctions that the authors speculate may contribute to understanding the basic mechanisms linked to the KD.

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

Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4.

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Burastero, Samuele E; Frigerio, Barbara; Lopalco, Lucia; Sironi, Francesca; Breda, Daniela; Longhi, Renato; Scarlatti, Gabriella; Canevari, Silvana; Figini, Mariangela; Lusso, Paolo

2011-01-01

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.

Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4.

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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.

The influence of folate serum levels on depressive mood and mental processing in patients with epilepsy treated with enzyme-inducing anti-epileptic drugs.

Science.gov (United States)

Rösche, J; Uhlmann, C; Weber, R; Fröscher, W

2003-04-01

Folate deficiency is common in patients with epilepsy and also occurs in patients with depression or cognitive deficits. This study investigates whether low serum folate levels may contribute to depressive mood and difficulties in mental processing in patients with epilepsy treated with anti-epileptic drugs inducing the cytochrome P450. We analysed the serum folate levels, the score in the Self Rating Depression Scale (SDS) and the results of a bedside test in mental processing in 54 patients with epilepsy. There was a significant negative correlation between the serum folate levels and the score in SDS and significant positive correlations between the score in SDS and the time needed to process an interference task or a letter-reading task. Low serum folate levels may contribute to depressive mood and therefore to difficulties in mental processing. Further studies utilizing total plasma homocysteine as a sensitive measure of functional folate deficiency and more elaborate tests of mental processing are required to elucidate the impact of folate metabolism on depressive mood and cognitive function in patients with epilepsy.

Identification and preclinical testing of novel antiepileptic compounds.

Science.gov (United States)

Meldrum, B S

1997-01-01

Procedures for identifying novel antiepileptic drugs (AEDs) are changing and need to change more. Widespread reliance on two primary screens has led to the identification of novel compounds that resemble either phenytoin (suppressing high-frequency repetitive firing in cultured neurons and prolonging inactivation of voltage-dependent sodium channels identified by the maximal electroshock test) or benzodiazepines (potentiating the inhibitory effect of gamma-aminobutyric acid (GABA), identified by the threshold pentylenetetrazol test). Advances in molecular neurobiology have identified specific molecular targets (subunits of ion channels, neurotransmitter receptors, and transporters) and have made them available in a form permitting high-throughput screening. AEDs can be designed to interact with specific sites on the target molecules. Alternatively, the molecular screens can be used to identify active components in natural products, including folk remedies. Preclinical in vivo screens can be improved by using animals with genetic or acquired epilepsies that have similar modifications in the properties of the target molecules as do human epilepsy syndromes. Future work is likely to define molecular targets for AEDs that will block or reverse chronic epileptogenesis.

Evaluation of antiepileptic activity of the methanol extract of Trachyspermum ammi (L.

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Rajput Muhammad Ali

2013-01-01

Full Text Available This study aims to investigate the effect of a methanol extract of Trachyspermum ammi (L. as an antiepileptic agent. Tests were conducted with a single- and multiple-dosing schedule of Trachyspermum ammi (L., using a strychnine-induced seizure model for epilepsy. Twenty-one animals were divided into three groups; control (vehicle, standard (diazepam and test (Trachyspermum ammi (L. extract. Trachyspermum ammi (L. demonstrated antiepileptic effects, since there was a highly significant delay in the onset of convulsions as compared to the control, whereas the percentage of animals that survived or ignored seizure was also greater compared to the control. However, the duration of convulsions was significantly increased with both Trachyspermum ammi (L. and diazepam as compared to the control. The methanol extract of Trachyspermum ammi (L. showed antiepileptic activity, which may be due to the presence of thymol.

The investigation of copper-based impregnated activated carbons prepared from water-soluble materials for broad spectrum respirator applications

Energy Technology Data Exchange (ETDEWEB)

Smith, J.W.H.; Westreich, P.; Abdellatif, H.; Filbee-Dexter, P.; Smith, A.J. [Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Nova Scotia, B3H 3J5 (Canada); Wood, T.E. [3M Company, St. Paul, MN, 55144 (United States); Croll, L.M.; Reynolds, J.H. [3M Canada Company, Brockville, Ontario, K6V 5V8 (Canada); Dahn, J.R., E-mail: jeff.dahn@dal.ca [Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Nova Scotia, B3H 3J5 (Canada); Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, B3H 4J3 (Canada)

2010-08-15

The preparation of impregnated activated carbons (IACs) from aqueous, copper-containing solutions for broad spectrum gas filtration applications is studied here. Several samples were studied to determine the effect that impregnant loading, impregnant distribution and impregnant recipe had on the overall performance. Dynamic flow testing was used to determine the gas filtration capacity of the IAC samples versus a variety of challenge gases. X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDX) were used to characterize the impregnant distribution on the carbon as a function of impregnant loading. Oven tests were performed to determine the thermal stability of the IAC samples exposed to elevated temperatures. The role impregnant distribution plays in gas filtration capacity and the overall performance of the IAC samples is discussed. The IAC samples prepared in this work were found to have gas filtration capacities as good as or better than broad spectrum respirator carbon samples prepared from the patent literature. IACs impregnated with an aqueous 2.4 M Cu(NO{sub 3}){sub 2}/0.04 M H{sub 3}PO{sub 4}.12MoO{sub 3}/4 M HNO{sub 3} solution that were heated to 200 deg. C under argon were found to have the best overall performance of the samples studied in this work.

Psychomotor developmental effects of prenatal exposure to psychotropic drugs: a study in EFEMERIS database.

Science.gov (United States)

Hurault-Delarue, Caroline; Damase-Michel, Christine; Finotto, Laurent; Guitard, Claudine; Vayssière, Christophe; Montastruc, Jean-Louis; Montastruc, François; Lacroix, Isabelle

2016-10-01

Little is known about neurodevelopment of children exposed to psychotropic drugs during pregnancy. The purpose of this study was to evaluate the effects of prenatal exposure to psychotropic drugs on psychomotor development in children. This observational study used the EFEMERIS database. The database records the drugs prescribed and delivered during pregnancy and the resulting outcomes. Neurodevelopment at nine and 24 months of children born to women exposed to psychotropic drugs (anxiolytics, antidepressants, neuroleptics and anti-epileptics) during the second and/or third trimesters of pregnancy was compared to children who were not exposed to these drugs. Psychomotor development of 493 children (1.5%) exposed to psychotropic drugs during pregnancy was compared to 32 303 unexposed children. Exposure to psychotropic drugs during pregnancy was associated with an increased risk of abnormal motor development at 9 months (OR = 1.3 [1.1-2.2]) and abnormal motor and mental development at 24 months (OR = 4.8 [2.1-11.0] and OR = 2.3 [1.05-4.9]). Increased risk was observed in children born to women exposed to anti-epileptic drugs, neuroleptics or antidepressants during pregnancy. This study found a higher rate of deviation from the normal developmental milestones in children born to women exposed to psychotropic drugs during pregnancy and more particularly antidepressants, neuroleptics and anti-epileptics. © 2016 Société Française de Pharmacologie et de Thérapeutique.

Weak turbulence and broad-spectrum excitation in a nonmagnetized electron beam via second-harmonic generation

International Nuclear Information System (INIS)

Bogdanov, A.T.

1990-01-01

The nonlinear evolution of an initially monoenergetic [ν-bar(t = 0) = (0,0,u)] electron beam propagating in a nonmagnetized dielectric medium of permittivity ε > 1, with initial velocity u ≥ c/√ε (where c is the vacuum speed of light) is investigated. The specific instability of the beam under such conditions is the cause of the generation of a broad spectrum of transverse electromagnetic waves coupled to the simultaneous excitation of the second harmonic of the beam's oscillations, both at the expense of the beam's initial kinetic energy. The system of self-consistent nonlinear equations, describing the particle-field dynamics, is treated in the spirit of the weak-turbulence approach. The integrals of the resulting nonlinear system of equations for the amplitudes of the fields of the electron density are used to evaluate the spectral distribution of the amplitudes in the saturation phase, and hence the efficiency of the transformation of the beam's energy into electromagnetic radiation as a function of the width of the spectrum of the initially present electromagnetic fluctuations. A substantial increase in this efficiency is observed in comparison with the single-mode case. (author)

Repurposing drugs for the treatment and control of helminth infections

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Gordana Panic

2014-12-01

Full Text Available Helminth infections are responsible for a considerable public health burden, yet the current drug armamentarium is small. Given the high cost of drug discovery and development, the high failure rates and the long duration to develop novel treatments, drug repurposing circumvents these obstacles by finding new uses for compounds other than those they were initially intended to treat. In the present review, we summarize in vivo and clinical trial findings testing clinical candidates and marketed drugs against schistosomes, food-borne trematodes, soil-transmitted helminths, Strongyloides stercoralis, the major human filariases lymphatic filariasis and onchocerciasis, taeniasis, neurocysticercosis and echinococcosis. While expanding the applications of broad-spectrum or veterinary anthelmintics continues to fuel alternative treatment options, antimalarials, antibiotics, antiprotozoals and anticancer agents appear to be producing fruitful results as well. The trematodes and nematodes continue to be most investigated, while cestodal drug discovery will need to be accelerated. The most clinically advanced drug candidates include the artemisinins and mefloquine against schistosomiasis, tribendimidine against liver flukes, oxantel pamoate against trichuriasis, and doxycycline against filariasis. Preclinical studies indicate a handful of promising future candidates, and are beginning to elucidate the broad-spectrum activity of some currently used anthelmintics. Challenges and opportunities are further discussed.

Computational approaches for discovery of common immunomodulators in fungal infections: towards broad-spectrum immunotherapeutic interventions.

Science.gov (United States)

Kidane, Yared H; Lawrence, Christopher; Murali, T M

2013-10-07

newly generated or expanded data sets for further elucidation of additional drug targets. Moreover, identified immunomodulators may be used to generate experimentally testable hypotheses that could help in the discovery of broad-spectrum immunotherapeutic interventions. All of our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/~murali/supplements/2013-kidane-bmc.

Self-ordered pointing and visual conditional associative learning tasks in drug-free schizophrenia spectrum disorder patients

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Galluzzo Alessandro

2008-01-01

Full Text Available Abstract Background There is evidence of a link between schizophrenia and a deficit of working memory, but this has been derived from tasks not specifically developed to probe working memory per se. Our aim was to investigate whether working memory deficits may be detected across different paradigms using the self-ordered pointing task (SOPT and the visual conditional associative learning task (VCALT in patients with schizophrenia spectrum disorders and healthy controls. The current literature suggests deficits in schizophrenia spectrum disorder patients versus healthy controls but these studies frequently involved small samples, broad diagnostic criteria, inclusion of patients on antipsychotic medications, and were not controlled for symptom domains, severity of the disorder, etc. To overcome some of these limitations, we investigated the self-monitoring and conditional associative learning abilities of a numerically representative sample of healthy controls and a group of non-deteriorated, drug-free patients hospitalized for a schizophrenia spectrum disorder with florid, mainly positive psychotic symptoms. Methods Eighty-five patients with a schizophrenia spectrum disorder (DSM-IV-TR diagnosis of schizophrenia (n = 71 or schizophreniform disorder (n = 14 and 80 healthy controls entered the study. The clinical picture was dominated by positive symptoms. The healthy control group had a negative personal and family history of schizophrenia or mood disorder and satisfied all the inclusion and exclusion criteria other than variables related to schizophrenia spectrum disorders. Results Compared to controls, patients had worse performances on SOPT, VCALT and higher SOPT/VCALT ratios, not affected by demographic or clinical variables. ROC curves showed that SOPT, VCALT, and SOPT/VCALT ratio had good accuracy in discriminating patients from controls. The SOPT and VCALT scores were inter-correlated in controls but not in patients. Conclusion The

Patients' perspectives on antiepileptic medication: relationships between beliefs about medicines and adherence among patients with epilepsy in UK primary care.

OpenAIRE

Chapman, S. C.; Horne, R.; Chater, A.; Hukins, D.; Smithson, W. H.

2014-01-01

BACKGROUND: Nonadherence to antiepileptic drugs (AEDs) can result in suboptimal outcomes for patients. AIM: This study aimed to assess the utility of a theory-based approach to understanding patient perspectives on AEDs and adherence. METHOD: Patients with epilepsy, identified by a GP case note review, were mailed validated questionnaires assessing their perceptions of AEDs and their adherence to them. RESULTS: Most (84.9%) of the 398 AED-treated respondents accepted the necessity of AEDs, bu...

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

2015-01-01

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. PMID:26209665

Exploiting the potential of intranet for managing drug spectrum a web base publication in a Tertiary Care Hospital in Mumbai

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Yashashri Chandrakant Shetty

2015-01-01

Full Text Available Objective: The study surveyed the availability of the intranet in campus and also the knowledge related to drug spectrum an intranet publication. Materials and Methods: Institutional ethics committee permission was obtained. Verbal consent was taken from the faculty and resident doctors of departments where all the facilities were available. Universal sampling method was used for recruitment. Pre-validated questionnaires were given to approximately 100 faculty and 500 resident doctors in the year 2012-2013. The questionnaire contained 15 items. Content analysis was done. The study questionnaire focused on a survey to obtain participants feedback on the use of the intranet and to evaluate the use of intranet as a source of knowledge. It also dealt on the relevance of the drug spectrum in the context of their subject. The responses were taken after giving the participants sufficient time. Data was entered into an Excel 2003 spread sheet and analyzed by using descriptive statistics. Results: The total number of respondents who participated in our study was 134 including faculty and residents from various departments. A total of 117 (89.66% respondents stated that their departments have access to the internet. Departments having access to intranet was 103 (76.29%. 67 (49.62% respondents have accessed. 67 (49.62% did not have the time to visit intranet site whereas 67 (49.62% have not accessed intranet. 89 (65.92% respondents were not aware of the drug spectrum. 101 (74.81% respondents felt that drug spectrum is a useful activity on intranet. 45 (33.33% knew about the intranet periodical drug spectrum, but most of the respondents (33.33% explained the meaning of the word drug spectrum according to their understanding, but never knew about the online intranet journal drug spectrum. Conclusion: The study found that the intranet is available in the campus, but it is not being utilized. The awareness and knowledge regarding drug spectrum is lacking, but

Autistic spectrum disorder, epilepsy, and vagus nerve stimulation.

Science.gov (United States)

Hull, Mariam Mettry; Madhavan, Deepak; Zaroff, Charles M

2015-08-01

In individuals with a comorbid autistic spectrum disorder and medically refractory epilepsy, vagus nerve stimulation may offer the potential of seizure control and a positive behavioral side effect profile. We aimed to examine the behavioral side effect profile using longitudinal and quantitative data and review the potential mechanisms behind behavioral changes. We present a case report of a 10-year-old boy with autistic spectrum disorder and epilepsy, who underwent vagus nerve stimulation subsequent to unsuccessful treatment with antiepileptic medication. Following vagus nerve stimulation implantation, initial, if temporary, improvement was observed in seizure control. Modest improvements were also observed in behavior and development, improvements which were observed independent of seizure control. Vagus nerve stimulation in autistic spectrum disorder is associated with modest behavioral improvement, with unidentified etiology, although several candidates for this improvement are evident.

Effects of derivatization reagents consisting of n-alkyl chloroformate/n-alcohol combinations in LC-ESI-MS/MS analysis of zwitterionic antiepileptic drugs.

Science.gov (United States)

Kostić, Nađa; Dotsikas, Yannis; Malenović, Anđelija; Medenica, Mirjana

2013-11-15

In the current study, three antiepileptic drugs with zwitterionic properties, namely vigabatrin, pregabalin and gabapentin, were chosen as model analytes to undergo derivatization by applying various n-alkyl chloroformate/n-alcohol combinations, followed by LC-ESI-MS/MS analysis. The employment of 16 combinations per drug using methyl, ethyl, propyl or butyl chloroformate coupled with methanol, ethanol, propanol or butanol, greatly affected a series of parameters of the derivatives, such as retention time on C8 column, signal expressed via areas, limit of detection values, as well as the yields of the main and side reactions. Practically, even slight modification of n-alkyl group of either chloroformate or alcohol resulted in significant changes in the chromatographic and mass spectrometric behavior of the novel derivative. It was clearly demonstrated that all the estimated parameters were highly correlated with the length of n-alkyl groups of the involved chloroformate and alcohol. The most significant influence was monitored in peak area values, indicating that the length of the n-alkyl chain plays an important role in electrospray ionization efficiency. For this parameter, increasing the n-alkyl chain from methyl to butyl led to increment up to 2089%, 508.7% and 1075% for area values of derivatized vigabatrin, pregabalin and gabapentin, respectively. These changes affected also the corresponding values of limits of detection, with the estimated improvements up to 1553%, 397.7% and 875.0% for the aforementioned derivatized drugs, respectively. Besides the obvious utilization of these conclusions in the development of bioanalytical methods for these analytes with the current protocol, this study offers valuable data which can be useful in more general approaches, giving insights into the effects of this derivatization reaction and its performances. Copyright © 2013 Elsevier B.V. All rights reserved.

Are "social drugs" (tobacco, coffee and chocolate) related to the bipolar spectrum?

Science.gov (United States)

Maremmani, Icro; Perugi, Giulio; Rovai, Luca; Maremmani, Angelo Giovanni Icro; Pacini, Matteo; Canonico, Pier Luigi; Carbonato, Paolo; Mencacci, Claudio; Muscettola, Giovanni; Pani, Luca; Torta, Riccardo; Vampini, Claudio; Akiskal, Hagop S

2011-09-01

Across all ages and cultures, mankind has always used substances in order to induce pleasurable sensations or desirable psychophysical states. These substances, notably caffeine, tobacco, alcohol and chocolate, can be labeled 'social drugs'. We analyzed the social drug habits of 562 patients suffering from mood disorders, according to DSM-IV-R criteria (major depressive episode, recurrent depression, bipolar type I and II disorders and depression not otherwise specified). The sample was also divided into bipolar and non-bipolar according to Hypomania Check-list 32 (HCL-32), which proposes a broader concept of hypomania and soft bipolarity, comprising the spectrum of bipolar disorders proper, along with other, "softer" expressions of bipolarity intermediate between bipolar disorder and normality. Using HCL-32 criteria, but DSM-IV-R criteria, a link was confirmed between bipolar spectrum and substance use including social drugs such as tobacco and coffee. Observational correlational study. This study is in support of earlier theoretical formulations within the framework of the Pisa-San Diego collaboration. Copyright © 2011 Elsevier B.V. All rights reserved.

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

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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

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,

Drug use in first pregnancy and lactation

DEFF Research Database (Denmark)

Olesen, Charlotte; Steffensen, Flemming Hald; Nielsen, Gunnar Lauge

1999-01-01

pregnancy 44.2% of the women received prescriptions for at least one drug. Users received 2.6 prescriptions on average during pregnancy: 5% of the users redeemed 24.2% of all prescriptions. The proportion of women who redeemed prescriptions for more than three different drugs was 2.7%. The majority.......7%). CONCLUSION: A high proportion of the women received drugs during pregnancy. The pattern of drug use within the Anatomical Therapeutical Chemical (ATC) groups changed, i.e. the amount of broad spectrum antibiotics decreased and the proportion of prescriptions for local use increased. A small proportion...... of women redeemed prescriptions for more than three different drugs during pregnancy....

Antiepileptic drug behavioral side effects and baseline hyperactivity in children and adolescents with new onset epilepsy.

Science.gov (United States)

Guilfoyle, Shanna M; Follansbee-Junger, Katherine; Smith, Aimee W; Combs, Angela; Ollier, Shannon; Hater, Brooke; Modi, Avani C

2018-01-01

To examine baseline psychological functioning and antiepileptic drug (AED) behavioral side effects in new onset epilepsy and determine, by age, whether baseline psychological functioning predicts AED behavioral side effects 1 month following AED initiation. A retrospective chart review was conducted between July 2011 and December 2014 that included youths with new onset epilepsy. As part of routine interdisciplinary care, caregivers completed the Behavior Assessment System for Children, 2nd Edition: Parent Rating Scale to report on baseline psychological functioning at the diagnostic visit and the Pediatric Epilepsy Side Effects Questionnaire to identify AED behavioral side effects at the 1-month follow-up clinic visit following AED initiation. Children (age = 2-11 years) and adolescents (age = 12-18 years) were examined separately. A total of 380 youths with new onset epilepsy (M age  = 8.9 ± 4.3 years; 83.4% Caucasian; 34.8% focal epilepsy, 41.1% generalized epilepsy, 23.7% unclassified epilepsy) were included. Seventy percent of youths had at-risk or clinically elevated baseline psychological symptoms. Children had significantly greater AED behavioral side effects (M = 25.08 ± 26.36) compared to adolescents (M = 12.36 ± 17.73), regardless of AED. Valproic acid demonstrated significantly greater behavioral side effects compared to all other AEDs, with the exception of levetiracetam. Higher hyperactivity/impulsivity at baseline significantly predicted higher AED behavioral side effects 1 month after AED initiation in both age groups. Younger children seem to be more prone to experience behavioral side effects, and these are likely to be higher if youths with epilepsy have baseline hyperactivity/impulsivity. Baseline psychological screening, specifically hyperactivity, can be used as a precision medicine tool for AED selection. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

The antiepileptic Materia Medica of Pediacus Dioscorides.

Science.gov (United States)

Eadie, M J

2004-09-01

Since it was written about the middle of the 1st Century AD, and up to comparatively recent times, the great Herbal, or Materia Medica, of Dioscorides provided medicine with its chief source of information about what were then considered therapeutic substances. The work contained data on various materials of botanical, biological and mineral origin which were claimed to provide benefit to sufferers from epilepsy, though often with no clear underlying rationale for their use. Some of these materials continued to be used as antiepileptic remedies over many centuries till they were finally recognised to be without useful effect in the disorder. The longest survivor amongst the Dioscoridean antiepileptic remedies was a rather esoteric one, viz. two stones taken from the belly of a young swallow during the rising phase of the moon and also whilst the swallow's parent birds were absent from the nest. The stones, or one of them, were worn against the skin of the seizure sufferer. The use of the swallow stones for epilepsy was recommended as late as in the writings of Thomas Willis (1675).

Recognition of emotional facial expressions and broad autism phenotype in parents of children diagnosed with autistic spectrum disorder.

Science.gov (United States)

Kadak, Muhammed Tayyib; Demirel, Omer Faruk; Yavuz, Mesut; Demir, Türkay

2014-07-01

Research findings debate about features of broad autism phenotype. In this study, we tested whether parents of children with autism have problems recognizing emotional facial expression and the contribution of such an impairment to the broad phenotype of autism. Seventy-two parents of children with autistic spectrum disorder and 38 parents of control group participated in the study. Broad autism features was measured with Autism Quotient (AQ). Recognition of Emotional Face Expression Test was assessed with the Emotion Recognition Test, consisting a set of photographs from Ekman & Friesen's. In a two-tailed analysis of variance of AQ, there was a significant difference for social skills (F(1, 106)=6.095; p<.05). Analyses of variance revealed significant difference in the recognition of happy, surprised and neutral expressions (F(1, 106)=4.068, p=.046; F(1, 106)=4.068, p=.046; F(1, 106)=6.064, p=.016). According to our findings, social impairment could be considered a characteristic feature of BAP. ASD parents had difficulty recognizing neutral expressions, suggesting that ASD parents may have impaired recognition of ambiguous expressions as do autistic children. Copyright © 2014 Elsevier Inc. All rights reserved.

Phosphatase Inhibitors Function as Novel, Broad Spectrum Botulinum Neurotoxin Antagonists in Mouse and Human Embryonic Stem Cell-Derived Motor Neuron-Based Assays.

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Erkan Kiris

Full Text Available There is an urgent need to develop novel treatments to counter Botulinum neurotoxin (BoNT poisoning. Currently, the majority of BoNT drug development efforts focus on directly inhibiting the proteolytic components of BoNT, i.e. light chains (LC. Although this is a rational approach, previous research has shown that LCs are extremely difficult drug targets and that inhibiting multi-serotype BoNTs with a single LC inhibitor may not be feasible. An alternative approach would target neuronal pathways involved in intoxication/recovery, rather than the LC itself. Phosphorylation-related mechanisms have been implicated in the intoxication pathway(s of BoNTs. However, the effects of phosphatase inhibitors upon BoNT activity in the physiological target of BoNTs, i.e. motor neurons, have not been investigated. In this study, a small library of phosphatase inhibitors was screened for BoNT antagonism in the context of mouse embryonic stem cell-derived motor neurons (ES-MNs. Four inhibitors were found to function as BoNT/A antagonists. Subsequently, we confirmed that these inhibitors protect against BoNT/A in a dose-dependent manner in human ES-MNs. Additionally, these compounds provide protection when administered in post-intoxication scenario. Importantly, the inhibitors were also effective against BoNT serotypes B and E. To the best of our knowledge, this is the first study showing phosphatase inhibitors as broad-spectrum BoNT antagonists.

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

Directory of Open Access Journals (Sweden)

Zahid Raja

Full Text Available Antimicrobial peptides (AMPs are promising drugs to kill resistant pathogens. In contrast to bacteria, protozoan parasites, such as Leishmania, were little studied. Therefore, the antiparasitic mechanism of AMPs is still unclear. In this study, we sought to get further insight into this mechanism by focusing our attention on temporin-SHa (SHa, a small broad-spectrum AMP previously shown to be active against Leishmania infantum. To improve activity, we designed analogs of SHa and compared the antibacterial and antiparasitic mechanisms. [K3]SHa emerged as a highly potent compound active against a wide range of bacteria, yeasts/fungi, and trypanosomatids (Leishmania and Trypanosoma, with leishmanicidal intramacrophagic activity and efficiency toward antibiotic-resistant strains of S. aureus and antimony-resistant L. infantum. Multipassage resistance selection demonstrated that temporins-SH, particularly [K3]SHa, are not prone to induce resistance in Escherichia coli. Analysis of the mode of action revealed that bacterial and parasite killing occur through a similar membranolytic mechanism involving rapid membrane permeabilization and depolarization. This was confirmed by high-resolution imaging (atomic force microscopy and field emission gun-scanning electron microscopy. Multiple combined techniques (nuclear magnetic resonance, surface plasmon resonance, differential scanning calorimetry allowed us to detail peptide-membrane interactions. [K3]SHa was shown to interact selectively with anionic model membranes with a 4-fold higher affinity (KD = 3 x 10-8 M than SHa. The amphipathic α-helical peptide inserts in-plane in the hydrophobic lipid bilayer and disrupts the acyl chain packing via a detergent-like effect. Interestingly, cellular events, such as mitochondrial membrane depolarization or DNA fragmentation, were observed in L. infantum promastigotes after exposure to SHa and [K3]SHa at concentrations above IC50. Our results indicate that these

Possible drug-drug interaction between pregabalin and clozapine in patients with schizophrenia

DEFF Research Database (Denmark)

Schjerning, O; Lykkegaard, S; Damkier, P

2015-01-01

INTRODUCTION: Pregabalin is an antiepileptic drug with anti-anxiety properties and is approved for treatment of generalized anxiety disorder. Anxiety is common in patients with schizophrenia and pregabalin has been suggested as an off-label add-on treatment. METHODS: Pregabalin was added...... patient was less clear. DISCUSSION: This short report discusses the possible mechanism of a pregabalin-clozapine interaction....

An RNAi-mediated screen identifies novel targets for next-generation antiepileptic drugs based on increased expression of the homeostatic regulator pumilio.

Science.gov (United States)

Lin, Wei-Hsiang; He, Miaomiao; Fan, Yuen Ngan; Baines, Richard A

2018-05-02

Despite availability of a diverse range of anti-epileptic drugs (AEDs), only about two-thirds of epilepsy patients respond well to drug treatment. Thus, novel targets are required to catalyse the design of next-generation AEDs. Manipulation of neuron firing-rate homoeostasis, through enhancing Pumilio (Pum) activity, has been shown to be potently anticonvulsant in Drosophila. In this study, we performed a genome-wide RNAi screen in S2R + cells, using a luciferase-based dPum activity reporter and identified 1166 genes involved in dPum regulation. Of these genes, we focused on 699 genes that, on knock-down, potentiate dPum activity/expression. Of this subgroup, 101 genes are activity-dependent based on comparison with genes previously identified as activity-dependent by RNA-sequencing. Functional cluster analysis shows these genes are enriched in pathways involved in DNA damage, regulation of cell cycle and proteasomal protein catabolism. To test for anticonvulsant activity, we utilised an RNA-interference approach in vivo. RNAi-mediated knockdown showed that 57/101 genes (61%) are sufficient to significantly reduce seizure duration in the characterized seizure mutant, para bss . We further show that chemical inhibitors of protein products of some of the genes targeted are similarly anticonvulsant. Finally, to establish whether the anticonvulsant activity of identified compounds results from increased dpum transcription, we performed a luciferase-based assay to monitor dpum promoter activity. Third instar larvae exposed to sodium fluoride, gemcitabine, metformin, bestatin, WP1066 or valproic acid all showed increased dpum promoter activity. Thus, this study validates Pum as a favourable target for AED design and, moreover, identifies a number of lead compounds capable of increasing the expression of this homeostatic regulator.

Broad Energy Range Neutron Spectroscopy using a Liquid Scintillator and a Proportional Counter: Application to a Neutron Spectrum Similar to that from an Improvised Nuclear Device.

Science.gov (United States)

Xu, Yanping; Randers-Pehrson, Gerhard; Marino, Stephen A; Garty, Guy; Harken, Andrew; Brenner, David J

2015-09-11

A novel neutron irradiation facility at the Radiological Research Accelerator Facility (RARAF) has been developed to mimic the neutron radiation from an Improvised Nuclear Device (IND) at relevant distances (e.g. 1.5 km) from the epicenter. The neutron spectrum of this IND-like neutron irradiator was designed according to estimations of the Hiroshima neutron spectrum at 1.5 km. It is significantly different from a standard reactor fission spectrum, because the spectrum changes as the neutrons are transported through air, and it is dominated by neutron energies from 100 keV up to 9 MeV. To verify such wide energy range neutron spectrum, detailed here is the development of a combined spectroscopy system. Both a liquid scintillator detector and a gas proportional counter were used for the recoil spectra measurements, with the individual response functions estimated from a series of Monte Carlo simulations. These normalized individual response functions were formed into a single response matrix for the unfolding process. Several accelerator-based quasi-monoenergetic neutron source spectra were measured and unfolded to test this spectroscopy system. These reference neutrons were produced from two reactions: T(p,n) 3 He and D(d,n) 3 He, generating neutron energies in the range between 0.2 and 8 MeV. The unfolded quasi-monoenergetic neutron spectra indicated that the detection system can provide good neutron spectroscopy results in this energy range. A broad-energy neutron spectrum from the 9 Be(d,n) reaction using a 5 MeV deuteron beam, measured at 60 degrees to the incident beam was measured and unfolded with the evaluated response matrix. The unfolded broad neutron spectrum is comparable with published time-of-flight results. Finally, the pair of detectors were used to measure the neutron spectrum generated at the RARAF IND-like neutron facility and a comparison is made to the neutron spectrum of Hiroshima.

Quality of antiepileptic drugs in sub-Saharan Africa: A study in Gabon, Kenya, and Madagascar.

Science.gov (United States)

Jost, Jeremy; Ratsimbazafy, Voa; Nguyen, Thu Trang; Nguyen, Thuy Linh; Dufat, Hanh; Dugay, Annabelle; Ba, Alassane; Sivadier, Guilhem; Mafilaza, Yattussia; Jousse, Cyril; Traïkia, Mounir; Leremboure, Martin; Auditeau, Emilie; Raharivelo, Adeline; Ngoungou, Edgard; Kariuki, Symon M; Newton, Charles R; Preux, Pierre-Marie

2018-06-12

Epilepsy is a major public health issue in low- and middle-income countries, where the availability and accessibility of quality treatment remain important issues, the severity of which may be aggravated by poor quality antiepileptic drugs (AEDs). The primary objective of this study was to measure the quality of AEDs in rural and urban areas in 3 African countries. This cross-sectional study was carried out in Gabon, Kenya, and Madagascar. Both official and unofficial supply chains in urban and rural areas were investigated. Samples of oral AEDs were collected in areas where a patient could buy or obtain them. Pharmacological analytical procedures and Medicine Quality Assessment Reporting Guidelines were used to assess quality. In total, 102 batches, representing 3782 units of AEDs, were sampled. Overall, 32.3% of the tablets were of poor quality, but no significant difference was observed across sites: 26.5% in Gabon, 37.0% in Kenya, and 34.1% in Madagascar (P = .7). The highest proportions of substandard medications were found in the carbamazepine (38.7%; 95% confidence interval [CI] 21.8-57.8) and phenytoin (83.3%; 95% CI 35.8-99.5) batches, which were mainly flawed by their failure to dissolve. Sodium valproate was the AED with the poorest quality (32.1%; 95% CI 15.8-42.3). The phenobarbital (94.1%; 95% CI 80.3-99.2) and diazepam (100.0%) batches were of better quality. The prevalence of substandard quality medications increased in samples supplied by public facilities (odds ratio [OR] 9.9; 95% CI 1.2-84.1; P < .04) and manufacturers located in China (OR 119.8; 95% CI 8.7-1651.9; P < .001). The prevalence of AEDs of bad quality increased when they were stored improperly (OR 5.4; 95% CI 1.2-24.1; P < .03). No counterfeiting was observed. However, inadequate AED storage conditions are likely to lead to ineffective and possibly dangerous AEDs, even when good-quality AEDs are initially imported. Wiley Periodicals, Inc. © 2018 International League Against

Data-driven analysis of biomedical literature suggests broad-spectrum benefits of culinary herbs and spices

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Mukherjee, Jagriti

2018-01-01

Spices and herbs are key dietary ingredients used across cultures worldwide. Beyond their use as flavoring and coloring agents, the popularity of these aromatic plant products in culinary preparations has been attributed to their antimicrobial properties. Last few decades have witnessed an exponential growth of biomedical literature investigating the impact of spices and herbs on health, presenting an opportunity to mine for patterns from empirical evidence. Systematic investigation of empirical evidence to enumerate the health consequences of culinary herbs and spices can provide valuable insights into their therapeutic utility. We implemented a text mining protocol to assess the health impact of spices by assimilating, both, their positive and negative effects. We conclude that spices show broad-spectrum benevolence across a range of disease categories in contrast to negative effects that are comparatively narrow-spectrum. We also implement a strategy for disease-specific culinary recommendations of spices based on their therapeutic tradeoff against adverse effects. Further by integrating spice-phytochemical-disease associations, we identify bioactive spice phytochemicals potentially involved in their therapeutic effects. Our study provides a systems perspective on health effects of culinary spices and herbs with applications for dietary recommendations as well as identification of phytochemicals potentially involved in underlying molecular mechanisms. PMID:29813110

Data-driven analysis of biomedical literature suggests broad-spectrum benefits of culinary herbs and spices.

Science.gov (United States)

Rakhi, N K; Tuwani, Rudraksh; Mukherjee, Jagriti; Bagler, Ganesh

2018-01-01

Spices and herbs are key dietary ingredients used across cultures worldwide. Beyond their use as flavoring and coloring agents, the popularity of these aromatic plant products in culinary preparations has been attributed to their antimicrobial properties. Last few decades have witnessed an exponential growth of biomedical literature investigating the impact of spices and herbs on health, presenting an opportunity to mine for patterns from empirical evidence. Systematic investigation of empirical evidence to enumerate the health consequences of culinary herbs and spices can provide valuable insights into their therapeutic utility. We implemented a text mining protocol to assess the health impact of spices by assimilating, both, their positive and negative effects. We conclude that spices show broad-spectrum benevolence across a range of disease categories in contrast to negative effects that are comparatively narrow-spectrum. We also implement a strategy for disease-specific culinary recommendations of spices based on their therapeutic tradeoff against adverse effects. Further by integrating spice-phytochemical-disease associations, we identify bioactive spice phytochemicals potentially involved in their therapeutic effects. Our study provides a systems perspective on health effects of culinary spices and herbs with applications for dietary recommendations as well as identification of phytochemicals potentially involved in underlying molecular mechanisms.

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

Effect of healthcare associated infections and broad spectrum antibiotic use in newborn period on development of asthma, allergic rhinitis and atopic dermatitis in early childhood

Directory of Open Access Journals (Sweden)

Hacer Yapicioglu Yildizdas

2017-03-01

Full Text Available Purpose: The iam of this study was to investigate the effect of healthcare associated infections (HAIs and broad spectrum antibiotic use in newborn period on asthma, allergic rhinitis and atopic dermatitis. Material and Methods: Seventy three children treated for HAIs in newborn period in Neonatal Intesive Care Unitin a 6 years period, and their 41 siblings who were healthy in newborn period were included in the study. Parents answered a detailed questionnaire, children were examined and complete blood count, serum total Ig E and specific Ig E levels were studied. Results: Ventilator associated pneumonia was observed in 32 (45.2%, blood stream infection in 28 (38.4% and clinic sepsis in 12 (16.4% of 73 children with HAIs. Asthma was significantly higher in HAIs group compared to sibling group (32.9% vs. 4.9, whereas there was no significant difference in allergic rhinitis (4.1% vs.2.4% and atopic dermatitis (6.8% vs. 0% among groups. When non-allergic 85 subjects and allergic 29 children compared, children who had been hospitalised and treated with broad-spectrum antibiotics in newborn period were almost 11.5 times as likely to have an allergic disease. Conclusion: Asthma was significantly higher in HAI group, and allergic disease risk seems to increase in children treated with broad-spectrum antibiotics for HAIs in newborn period. [Cukurova Med J 2017; 42(1.000: 132-139

Brivaracetam: a rational drug discovery success story

Science.gov (United States)

Rogawski, M A

2008-01-01

Levetiracetam, the α-ethyl analogue of the nootropic piracetam, is a widely used antiepileptic drug (AED) that provides protection against partial seizures and is also effective in the treatment of primary generalized seizure syndromes including juvenile myoclonic epilepsy. Levetiracetam was discovered in 1992 through screening in audiogenic seizure susceptible mice and, 3 years later, was reported to exhibit saturable, stereospecific binding in brain to a ∼90 kDa protein, later identified as the ubiquitous synaptic vesicle glycoprotein SV2A. A large-scale screening effort to optimize binding affinity identified the 4-n-propyl analogue, brivaracetam, as having greater potency and a broadened spectrum of activity in animal seizure models. Recent phase II clinical trials demonstrating that brivaracetam is efficacious and well tolerated in the treatment of partial onset seizures have validated the strategy of the discovery programme. Brivaracetam is among the first clinically effective AEDs to be discovered by optimization of pharmacodynamic activity at a molecular target. PMID:18552880

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.

New insights into broad spectrum communities of the Early Holocene Near East: The birds of Hallan Çemi

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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

Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy.

Science.gov (United States)

López-García, Miguel A; Feria-Romero, Iris A; Serrano, Héctor; Rayo-Mares, Darío; Fagiolino, Pietro; Vázquez, Marta; Escamilla-Núñez, Consuelo; Grijalva, Israel; Escalante-Santiago, David; Orozco-Suarez, Sandra

2017-06-01

Identified the polymorphisms of CYP2D6, CYP2C9, CYP2C19 and CYP3A4, within a rigorously selected population of pediatric patients with drug-resistant epilepsy. The genomic DNA of 23 drug-resistant epilepsy patients and 7 patients with good responses were analyzed. Ten exons in these four genes were genotyped, and the drug concentrations in saliva and plasma were determined. The relevant SNPs with pharmacogenomics relations were CYP2D6*2 (rs16947) decreased your activity and CYP2D6*4 (rs1065852), CYP2C19*2 (rs4244285) and CYP3A4*1B (rs2740574) by association with poor metabolizer. The strongest risk factors were found in the AA genotype and allele of SNP rs3892097 from the CYP2D6 gene, followed by the alleles A and T of SNPs rs2740574 and rs2687116, respectively from CYP3A4. The most important concomitance was between homozygous genotype AA of rs3892097 and genotype AA of rs2740574 with 78.3% in drug-resistant epilepsy patients as compared to 14.3% in control patients. The results demonstrated the important role of the CYP 3A4*1B allelic variant as risk factor for developing drug resistance and CYP2D6, CYP2C19 SNPs and haplotypes may affect the response to antiepileptic drugs. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

Neurological adverse events of new generation sodium blocker antiepileptic drugs. Meta-analysis of randomized, double-blinded studies with eslicarbazepine acetate, lacosamide and oxcarbazepine.

Science.gov (United States)

Zaccara, Gaetano; Giovannelli, Fabio; Maratea, Dario; Fadda, Valeria; Verrotti, Alberto

2013-09-01

Analysis of overall tolerability and neurological adverse effects (AEs) of eslicarbazepine acetate (ESL), lacosamide (LCM) and oxcarbazepine (OXC) from double-blind, placebo-controlled trials. Indirect comparisons of patients withdrawing because of AEs, and the incidence of some vestibulocerebellar AEs between these three antiepileptic dugs (AEDs). We searched MEDLINE for all randomized, double-blind, placebo-controlled trials investigating therapeutic effects of fixed oral doses of ESL, LCM and OXC in patients with drug resistant epilepsy. Withdrawal rate due to AEs, percentages of patients with serious AEs, and the proportion of patients experiencing any neurological AE, nausea and vomiting were assessed for their association with the experimental drug. Analyses were performed between recommended daily doses of each AED according to the approved summary of product characteristics (SPC). Risk differences were used to evaluate the association of any AE [99% confidence intervals (CIs)] or study withdrawals because of AEs (95% CIs) with the experimental drug. Indirect comparisons between withdrawal rate and AEs dizziness, coordination abnormal/ataxia and diplopia were estimated according to network meta-analysis (Net-MA). Eight randomized, placebo-controlled, double-blind trials (4 with ESL, 3 with LCM, and 1 with OXC) were included in our analysis. At high doses (OXC 1200mg, ESL 1200mg and LCM 400mg) there was an increased risk of AE-related study withdrawals compared to placebo for all drugs. Several AEs were associated with the experimental drug. Both number and frequency of AEs were dose-related. At high recommended doses, patients treated with OXC withdrew from the experimental treatment significantly more frequently than patients treated with ESL and LCM. Furthermore, the AEs coordination abnormal/ataxia and diplopia were significantly more frequently observed in patients treated with OXC compared to patients treated with LCM and ESL. The overall tolerability

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

Science.gov (United States)

2016-10-01

the newly formulated CHD-FA-Zn. Our initial results demonstrated that CHD-FA-Zn reduced microbial burdens of susceptible and drug- resistant planktonic...wound-associated drug resistant bacteria and fungi. Rat models of wound infection (open, and burn model) will be established with healthy animals ...Establish MIC90s for CHD-FA with clinical isolates of major drug resistant pathogens Assess CHD-FA in animal models of wound infection for major

Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy.

Science.gov (United States)

Chen, Baibing; Choi, Hyunmi; Hirsch, Lawrence J; Katz, Austen; Legge, Alexander; Buchsbaum, Richard; Detyniecki, Kamil

2017-11-01

Psychiatric and behavioral side effects (PBSEs) are common, undesirable effects associated with antiepileptic drug (AED) use. The objective of the study was to compare the PBSE profiles of older and newer AEDs in a large specialty practice-based sample of patients diagnosed with epilepsy. As part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 4085 adult patients (age: 18 years) newly started on an AED regimen. Psychiatric and behavioral side effects were determined by patient or physician report in the medical record, which included depressive mood, psychosis, anxiety, suicidal thoughts, irritability, aggression, and tantrum. Significant non-AED predictors of PBSE rate were first determined from 83 variables using logistic regression. Predictors were then controlled for in the comparison analysis of the rate of PBSEs and intolerable PBSEs (PBSEs that led to dosage reduction or discontinuation) between 18 AEDs. Psychiatric and behavioral side effects occurred in 17.2% of patients and led to intolerability in 13.8% of patients. History of psychiatric condition(s), secondary generalized seizures, absence seizures, and intractable epilepsy were associated with increased incidence of PBSE. Levetiracetam (LEV) had the greatest PBSE rate (22.1%). This was statistically significant when compared with the aggregate of the other AEDs (P<0.001, OR=6.87). Levetiracetam was also significantly (P<0.001) associated with higher intolerability rate (17.7%), dose decreased rate (9.4%), and complete cessation rate (8.3%), when compared with the aggregate of the other AEDs. Zonisamide (ZNS) was also significantly associated with a higher rate of PBSE (9.7%) and IPBSE (7.9%, all P<0.001). On the other hand, carbamazepine (CBZ), clobazam (CLB), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), phenytoin (PHT), and valproate (VPA) were significantly associated with a decreased PBSE

An Update on Drug-induced Liver Injury.

Science.gov (United States)

Devarbhavi, Harshad

2012-09-01

Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. No age is exempt although adults and the elderly are at increased risk. DILI spans the entire spectrum ranging from asymptomatic elevation in transaminases to severe disease such as acute hepatitis leading to acute liver failure. The liver specific Roussel Uclaf Causality Assessment Method is the most validated and extensively used for determining the likelihood that an implicated drug caused DILI. Asymptomatic elevation in liver tests must be differentiated from adaptation. Drugs producing DILI have a signature pattern although no single pattern is characteristic. Antimicrobial and central nervous system agents including antiepileptic drugs are the leading causes of DILI worldwide. In the absence of a diagnostic test or a biomarker, the diagnosis rests on the evidence of absence of competing causes such as acute viral hepatitis, autoimmune hepatitis and others. Recent studies show that antituberculosis drugs given for active or latent disease are still a major cause of drug-induced liver injury in India and the West respectively. Presence of jaundice signifies a severe disease and entails a worse outcome. The pathogenesis is unclear and is due to a mix of host, drug metabolite and environmental factors. Research has evolved from incriminating candidate genes to genome wide analysis studies. Immediate cessation of the drug is key to prevent or minimize progressive damage. Treatment is largely supportive. N-acetylcysteine is the antidote for paracetamol toxicity. Carnitine has been tried in valproate injury whereas steroids and ursodeoxycholic acid may be used in DILI associated with hypersensitivity or cholestatic features respectively. This article provides an overview of the epidemiology, the patterns of

Behavioral effects of antiepileptic drugs in rats: Are the effects on mood and behavior detectable in open-field test?

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Zimcikova, Eva; Simko, Julius; Karesova, Iva; Kremlacek, Jan; Malakova, Jana

2017-11-01

Behavioral side effects of antiepileptic drugs (AEDs) are common including both positive and negative effects on mood, anxiety, depression, and psychosis. We aimed to evaluate behavioral patterns in rats after administration of lamotrigine, levetiracetam, phenytoin, topiramate, carbamazepine, gabapentin, pregabalin, and zonisamide. The open-field test was performed and locomotion, rearing, grooming, central latency and defecation were recorded over a 5min interval for each rat (8 rats in each group receiving AED and 16 controls). Kruskal-Wallis nonparametric test or ANOVA were used to assess differences among the groups. The experimental groups did not differ in latency to enter the center compartment, neither in the decline of locomotor activity in the 1st and the 5th minute of the observation, nor in number of rears. Significant differences among groups were observed in the total number of lines crossed, grooming, as well in the number of fecal pellets. Locomotor activity was significantly increased in lamotrigine, if compared with gabapentin and pregabalin (ANOVA; p <0.05). Rats exposed to topiramate displayed a significantly increased number of grooming (when compared to pregabalin: p<0.01). Defecation (the number of fecal pellets) significantly increased in the gabapentin and carbamazepine group. There are significant differences between AEDs in terms of their behavioral profile. It is of great importance to evaluate these effects in clinical practice to bring more clear insight into these positive or negative side effects of AEDs. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

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.

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 ...

Signaling to P-glycoprotein-A new therapeutic target to treat drug-resistant epilepsy?

NARCIS (Netherlands)

Hartz, A.M.; Notenboom, S.; Bauer, B.

2009-01-01

Epilepsy affects more than 60 million people worldwide. While most patients can be treated with antiepileptic drugs, up to 40% of patients respond poorly to pharmacotherapy. This drug resistance is not well understood and presents a major clinical problem. In this short review we provide background

Detection of a Mixed Infection in a Culture-Negative Brain Abscess by Broad-Spectrum Bacterial 16S rRNA Gene PCR ▿ †

Science.gov (United States)

Keller, Peter M.; Rampini, Silvana K.; Bloemberg, Guido V.

2010-01-01

We describe the identification of two bacterial pathogens from a culture-negative brain abscess by the use of broad-spectrum 16S rRNA gene PCR. Simultaneous detection of Fusobacterium nucleatum and Porphyromonas endodontalis was possible due to a 24-bp length difference of their partially amplified 16S rRNA genes, which allowed separation by high-resolution polyacrylamide gel electrophoresis. PMID:20392909

The broad-spectrum antiviral compound ST-669 restricts chlamydial inclusion development and bacterial growth and localizes to host cell lipid droplets within treated cells.

Science.gov (United States)

Sandoz, Kelsi M; Valiant, William G; Eriksen, Steven G; Hruby, Dennis E; Allen, Robert D; Rockey, Daniel D

2014-07-01

Novel broad-spectrum antimicrobials are a critical component of a strategy for combating antibiotic-resistant pathogens. In this study, we explored the activity of the broad-spectrum antiviral compound ST-669 for activity against different intracellular bacteria and began a characterization of its mechanism of antimicrobial action. ST-669 inhibits the growth of three different species of chlamydia and the intracellular bacterium Coxiella burnetii in Vero and HeLa cells but not in McCoy (murine) cells. The antichlamydial and anti-C. burnetii activity spectrum was consistent with those observed for tested viruses, suggesting a common mechanism of action. Cycloheximide treatment in the presence of ST-669 abrogated the inhibitory effect, demonstrating that eukaryotic protein synthesis is required for tested activity. Immunofluorescence microscopy demonstrated that different chlamydiae grow atypically in the presence of ST-669, in a manner that suggests the compound affects inclusion formation and organization. Microscopic analysis of cells treated with a fluorescent derivative of ST-669 demonstrated that the compound localized to host cell lipid droplets but not to other organelles or the host cytosol. These results demonstrate that ST-669 affects intracellular growth in a host-cell-dependent manner and interrupts proper development of chlamydial inclusions, possibly through a lipid droplet-dependent process. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

XA23 is an executor R protein and confers broad-spectrum disease resistance in rice.

Science.gov (United States)

Wang, Chunlian; Zhang, Xiaoping; Fan, Yinglun; Gao, Ying; Zhu, Qinlong; Zheng, Chongke; Qin, Tengfei; Li, Yanqiang; Che, Jinying; Zhang, Mingwei; Yang, Bing; Liu, Yaoguang; Zhao, Kaijun

2014-11-09

The majority of plant disease resistance (R) genes encode proteins that share common structural features. However, the transcription activator-like effector (TALE) associated executor type R genes show no considerable sequence homology to any known R genes. We adopted a map-based cloning approach and TALE-based technology to isolate and characterize Xa23, a new executor R gene derived from the wild rice (Oryza rufipogon) that confers an extremely broad spectrum of resistance to bacterial blight caused by Xanthomonas oryzae pv. oryzae (Xoo). Xa23 encodes a 113-amino acid protein that shares 50% identity to the known executor R protein XA10. The predicted transmembrane helices in XA23 also overlap with those of XA10. Unlike Xa10, however, Xa23 transcription is specifically activated by AvrXa23, a TALE present in all examined Xoo field isolates. Moreover, the susceptible xa23 allele has an identical open reading frame of Xa23, but differs in promoter region by lacking the TALE binding-element (EBE) for AvrXa23. XA23 can trigger strong hypersensitive response in rice, tobacco and tomato. Our results provide the first evidence that plant genomes have an executor R gene family in which members execute their function and spectrum of disease resistance by recognizing the cognate TALEs in pathogen. © The Author 2014. Published by the Molecular Plant Shanghai Editorial Office in association with Oxford University Press on behalf of CSPB and IPPE, SIBS, CAS.

Effects of Various Antiepileptics Used to Alleviate Neuropathic Pain on Compound Action Potential in Frog Sciatic Nerves: Comparison with Those of Local Anesthetics

Directory of Open Access Journals (Sweden)

Yuhei Uemura

2014-01-01

Full Text Available Antiepileptics used for treating neuropathic pain have various actions including voltage-gated Na+ and Ca2+ channels, glutamate-receptor inhibition, and GABAA-receptor activation, while local anesthetics are also used to alleviate the pain. It has not been fully examined yet how nerve conduction inhibitions by local anesthetics differ in extent from those by antiepileptics. Fast-conducting compound action potentials (CAPs were recorded from frog sciatic nerve fibers by using the air-gap method. Antiepileptics (lamotrigine and carbamazepine concentration dependently reduced the peak amplitude of the CAP (IC50=0.44 and 0.50 mM, resp.. Carbamazepine analog oxcarbazepine exhibited an inhibition smaller than that of carbamazepine. Antiepileptic phenytoin (0.1 mM reduced CAP amplitude by 15%. On the other hand, other antiepileptics (gabapentin, sodium valproate, and topiramate at 10 mM had no effect on CAPs. The CAPs were inhibited by local anesthetic levobupivacaine (IC50=0.23 mM. These results indicate that there is a difference in the extent of nerve conduction inhibition among antiepileptics and that some antiepileptics inhibit nerve conduction with an efficacy similar to that of levobupivacaine or to those of other local anesthetics (lidocaine, ropivacaine, and cocaine as reported previously. This may serve to know a contribution of nerve conduction inhibition in the antinociception by antiepileptics.

Complete Genome Sequence of Bacillus velezensis YJ11-1-4, a Strain with Broad-Spectrum Antimicrobial Activity, Isolated from Traditional Korean Fermented Soybean Paste.

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Lee, Hyo Jung; Chun, Byung-Hee; Jeon, Hye Hee; Kim, Yeon Bee; Lee, Se Hee

2017-11-30

Bacillus velezensis YJ11-1-4 is a strain that exhibits broad-spectrum antimicrobial activity against various pathogens. It was isolated from doenjang, a traditional Korean fermented soybean paste. The genome comprises a single circular chromosome of 4,006,637 bp with 46.42% G+C content without plasmids. Copyright © 2017 Lee et al.

New Treatments for Drug-Resistant Epilepsy that Target Presynaptic Transmitter Release

Science.gov (United States)

2015-07-01

may become a key piece in the arsenal of antiepileptic drugs in mesial temporal lobe epilepsy . Thereby, screening for a presynaptic action site may be...neuronal damage, mesial temporal lobe epilepsy (MTLE) in ~30% of patients, and resistance to available anticonvulsant drugs. Therefore, it is of... temporal lobe epilepsy (MTLE) (months 1-12). Working hypothesis: Drugs acting on presynaptic Ca 2+ channels, autoreceptors, and SV2a will be more

Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

DEFF Research Database (Denmark)

Mills, Philippa B; Footitt, Emma J; Mills, Kevin A

2010-01-01

to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive...

Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate.

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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.

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

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

1987-07-01

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

Genetic analysis of a novel broad-spectrum powdery mildew resistance gene from the wheat-Agropyron cristatum introgression line Pubing 74.

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Lu, Yuqing; Yao, Miaomiao; Zhang, Jinpeng; Song, Liqiang; Liu, Weihua; Yang, Xinming; Li, Xiuquan; Li, Lihui

2016-09-01

A novel broad-spectrum powdery mildew resistance gene PmPB74 was identified in wheat- Agropyron cristatum introgression line Pubing 74. Development of wheat cultivars with broad-spectrum, durable resistance to powdery mildew has been restricted by lack of superior genetic resources. In this study, a wheat-A. cristatum introgression line Pubing 74, originally selected from a wide cross between the common wheat cultivar Fukuhokomugi (Fukuho) and Agropyron cristatum (L.) Gaertn (2n = 4x = 28; genome PPPP), displayed resistance to powdery mildew at both the seedling and adult stages. The putative alien chromosomal fragment in Pubing 74 was below the detection limit of genomic in situ hybridization (GISH), but evidence for other non-GISH-detectable introgressions was provided by the presence of three STS markers specific to A. cristatum. Genetic analysis indicated that Pubing 74 carried a single dominant gene for powdery mildew resistance, temporarily designated PmPB74. Molecular mapping showed that PmPB74 was located on wheat chromosome arm 5DS, and flanked by markers Xcfd81 and HRM02 at genetic distances of 2.5 and 1.7 cM, respectively. Compared with other lines with powdery mildew resistance gene(s) on wheat chromosome arm 5DS, Pubing 74 was resistant to all 28 Blumeria graminis f. sp tritici (Bgt) isolates from different wheat-producing regions of northern China. Allelism tests indicated that PmPB74 was not allelic to PmPB3558 or Pm2. Our work showed that PmPB74 is a novel gene with broad resistance to powdery mildew, and hence will be helpful in broadening the genetic basis of powdery mildew resistance in wheat.

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

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Pan Kyeom Kim

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

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

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

2017-01-01

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

Drug-Refractory Aggression, Self-Injurious Behavior, and Severe Tantrums in Autism Spectrum Disorders: A Chart Review Study

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Adler, Benjamin A.; Wink, Logan K.; Early, Maureen; Shaffer, Rebecca; Minshawi, Noha; McDougle, Christopher J.; Erickson, Craig A.

2015-01-01

Aggression, self-injurious behavior, and severe tantrums are impairing symptoms frequently experienced by individuals with autism spectrum disorders. Despite US Food and Drug Administration approval of two atypical antipsychotics targeting these symptoms in youth with autistic disorder, they remain frequently drug refractory. We define…

Use of peri-operative anti-epileptic drugs in patients with newly diagnosed high grade malignant glioma: a single center experience.

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Lwu, Shelly; Hamilton, Mark G; Forsyth, Peter A; Cairncross, J Gregory; Parney, Ian F

2010-02-01

An American Academy of Neurology practice parameter recommends that long-term prophylactic anti-epileptic drugs (AED) should not be routine in patients with newly diagnosed brain tumors. However, prospective multi-center North American data shows that most newly diagnosed glioma patients receive prophylactic AED. We examined our own peri-operative AED practice patterns in newly-diagnosed patients with malignant glioma to determine if we deviate from published guidelines. A retrospective chart review was performed in adult patients with newly diagnosed malignant gliomas undergoing surgery in southern Alberta between January 2003 and December 2005. Demographic information, AED use, seizure incidence, adverse effects, tumor size, and tumor location were recorded. Of 164 eligible patients, 54 (33%) presented with seizures and all received AED. Prophylactic AED were given to 44 patients (27%). Peri-operative seizures (within 1 week) occurred in two patients without (3%) and no patients with seizure prophylaxis. Adverse AED reactions and adverse effects attributable to seizures were both rare. Prophylactic AED were continued >1 week post-op in 30 patients (18%). Patients receiving prophylactic AED were more likely to have had tumors involving the temporal lobe than those who did not (50 vs. 20%; P < 0.01). Patients receiving peri-operative AED prophylaxis were common, had a trend to reduced peri-operative seizures, and had few adverse effects. However, most of these patients were maintained on prophylactic AED continued beyond the first peri-operative week, contradicting published guidelines. Increased awareness of practice guidelines may help modify AED prescription patterns in malignant glioma patients.

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

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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

Papel de los fármacos antiepilépticos genéricos en el tratamiento de la epilepsia infantil Role of generic antiepileptic drugs in the treatment of childhood epilepsy

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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

The Probiotic Compound VSL#3 Modulates Mucosal, Peripheral, and Systemic Immunity Following Murine Broad-Spectrum Antibiotic Treatment

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Ira Ekmekciu

2017-05-01

Full Text Available There is compelling evidence linking the commensal intestinal microbiota with host health and, in turn, antibiotic induced perturbations of microbiota composition with distinct pathologies. Despite the attractiveness of probiotic therapy as a tool to beneficially alter the intestinal microbiota, its immunological effects are still incompletely understood. The aim of the present study was to assess the efficacy of the probiotic formulation VSL#3 consisting of eight distinct bacterial species (including Streptococcus thermophilus, Bifidobacterium breve, B. longum, B. infantis, Lactobacillus acidophilus, L. plantarum, L. paracasei, and L. delbrueckii subsp. Bulgaricus in reversing immunological effects of microbiota depletion as compared to reassociation with a complex murine microbiota. To address this, conventional mice were subjected to broad-spectrum antibiotic therapy for 8 weeks and perorally reassociated with either VSL#3 bacteria or a complex murine microbiota. VSL#3 recolonization resulted in restored CD4+ and CD8+ cell numbers in the small and large intestinal lamina propria as well as in B220+ cell numbers in the former, whereas probiotic intervention was not sufficient to reverse the antibiotic induced changes of respective cell populations in the spleen. However, VSL#3 application was as efficient as complex microbiota reassociation to attenuate the frequencies of regulatory T cells, activated dendritic cells and memory/effector T cells in the small intestine, colon, mesenteric lymph nodes, and spleen. Whereas broad-spectrum antibiotic treatment resulted in decreased production of cytokines such as IFN-γ, IL-17, IL-22, and IL-10 by CD4+ cells in respective immunological compartments, VSL#3 recolonization was sufficient to completely recover the expression of the anti-inflammatory cytokine IL-10 without affecting pro-inflammatory mediators. In summary, the probiotic compound VSL#3 has an extensive impact on mucosal, peripheral, and

Drug taper during long-term video-EEG monitoring

DEFF Research Database (Denmark)

Guld, A. T.; Sabers, A.; Kjaer, T. W.

2017-01-01

Objectives: Anti-epileptic drugs (AED) are often tapered to reduce the time needed to record a sufficient number of seizure during long-term video-EEG monitoring (LTM). Fast AED reduction is considered less safe, but few studies have examined this. Our goal is to examine whether the rate of AED r...

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

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

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

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

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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

New avenue in the treatment of temporal lobe epilepsy by classical anti-epileptics: A hypothetical establishment of executioner Caspase 3 inactivation by molecular modeling

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M Vijey Aanandhi

2015-01-01

Full Text Available Patients with temporal lobe epilepsy (TLE are prescribed first-line antiepileptic drugs and surgery to the management of this disorder. Unfortunately, the surgical treatment has been shown to be beneficial for the selected patients but fails to provide a seizure-free outcome in 20-30% of TLE patients. In our present study, we investigate the possibilities of marketed antiepileptic drugs in a different manner to improve the present situation in TLE. Molecular docking simulation study and various open source computational tools were used to perform the study. AutoDock 4.2 MGL tools, Pymol visualize tools, Patch dock server, and Swarm Dock servers (protein-protein docking were used to perform the molecular modeling. FTsite and computed atlas of surface topography of protein open source server were used to understand the pocket and ligand binding information respectively. Toxtree application was used to determine the toxicity profile of the drug by Cramers rule. The obtained molecular docking models (Caspase 3, Procaspase 8, and Fas-associated death domain [FADD] with selected compounds (Clonazepam, Clobazepam, and Retigabine showed promising trio blocking event of FADD, Caspase 3, and Procaspase 8 (−6.66 kcal, −8.1 kcal, 6.46 kcal by Clonazepam respectively. Protein-protein interaction study (Swarm Dock, Patch Dock server indicated promising results that helped to establish our hypothesis. Toxtree showed a quantitative structure toxicity relationship report that helps to clarify the toxicity of the selected compounds. Clonazepam showed a trio inhibition property that may lead to develop a new era of the new generation benzodiazepine prototype drugs in the future. Filtered compounds will further process for higher in vitro, in vivo models for better understanding of the mechanism.

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

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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

Mortality rates and causes of death in children with epilepsy prescribed antiepileptic drugs: a retrospective cohort study using the UK General Practice Research Database.

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Ackers, Ruth; Besag, Frank M C; Hughes, Elaine; Squier, Waney; Murray, Macey L; Wong, Ian C K

2011-05-01

Patients with epilepsy, including children, have an increased risk of mortality compared with the general population. Antiepileptic drugs (AEDs) were the most frequent class of drugs reported in a study looking at fatal suspected adverse drug reactions in children in the UK. The objective of the study was to identify cases and causes of death in a paediatric patient cohort prescribed AEDs with an associated epilepsy diagnosis. This was a retrospective cohort study supplemented with general practitioner-completed questionnaires, post-mortem reports and death certificates. The setting was UK primary care practices contributing to the General Practice Research Database. Participants were children and adolescents aged 0-18 years prescribed AEDs between 1993 and 2005. Causality assessment was undertaken by a consensus panel comprising paediatric specialists in neuropathology, neurology, neuropsychiatry, paediatric epilepsy, pharmacoepidemiology and pharmacy to determine crude mortality rate (CMR) and standardized mortality ratios (SMRs), and the likelihood of an association between AED(s) and the event of death. There were 6190 subjects in the cohort (contributing 26,890 person-years of data), of whom 151 died. Median age at death was 8.0 years. CMR was 56.2 per 10,000 person-years and the SMR was 22.4 (95% CI 18.9, 26.2). The majority of deceased subjects had severe underlying disorders. Death was attributable to epilepsy in 18 subjects; in 9 the cause of death was sudden unexpected death in epilepsy (SUDEP) [3.3 per 10 000 person-years (95% CI 1.5, 6.4)]. AEDs were probably (n = 2) or possibly (n = 3) associated causally with death in five subjects. Two status epilepticus deaths were associated causally with AED withdrawal. Children prescribed AEDs have an increased risk of mortality relative to the general population. Most of the deaths were in children with serious underlying disorders. A small number of SUDEP cases were identified. AEDs are not a major

Direct Determination of a Small-Molecule Drug, Valproic Acid, by an Electrically-Detected Microcantilever Biosensor for Personalized Diagnostics

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Long-Sun Huang

2015-01-01

Full Text Available Direct, small-molecule determination of the antiepileptic drug, valproic acid, was investigated by a label-free, nanomechanical biosensor. Valproic acid has long been used as an antiepileptic medication, which is administered through therapeutic drug monitoring and has a narrow therapeutic dosage range of 50–100 μg·mL−1 in blood or serum. Unlike labeled and clinically-used measurement techniques, the label-free, electrical detection microcantilever biosensor can be miniaturized and simplified for use in portable or hand-held point-of-care platforms or personal diagnostic tools. A micromachined microcantilever sensor was packaged into the micro-channel of a fluidic system. The measurement of the antiepileptic drug, valproic acid, in phosphate-buffered saline and serum used a single free-standing, piezoresistive microcantilever biosensor in a thermally-controlled system. The measured surface stresses showed a profile over a concentration range of 50–500 μg·mL−1, which covered the clinically therapeutic range of 50–100 μg·mL−1. The estimated limit of detection (LOD was calculated to be 45 μg·mL−1, and the binding affinity between the drug and the antibody was measured at around 90 ± 21 μg·mL−1. Lastly, the results of the proposed device showed a similar profile in valproic acid drug detection with those of the clinically-used fluorescence polarization immunoassay.

Steps toward broad-spectrum therapeutics: discovering virulence-associated genes present in diverse human pathogens

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de Rochefort Anna

2009-10-01

Full Text Available Abstract Background New and improved antimicrobial countermeasures are urgently needed to counteract increased resistance to existing antimicrobial treatments and to combat currently untreatable or new emerging infectious diseases. We demonstrate that computational comparative genomics, together with experimental screening, can identify potential generic (i.e., conserved across multiple pathogen species and novel virulence-associated genes that may serve as targets for broad-spectrum countermeasures. Results Using phylogenetic profiles of protein clusters from completed microbial genome sequences, we identified seventeen protein candidates that are common to diverse human pathogens and absent or uncommon in non-pathogens. Mutants of 13 of these candidates were successfully generated in Yersinia pseudotuberculosis and the potential role of the proteins in virulence was assayed in an animal model. Six candidate proteins are suggested to be involved in the virulence of Y. pseudotuberculosis, none of which have previously been implicated in the virulence of Y. pseudotuberculosis and three have no record of involvement in the virulence of any bacteria. Conclusion This work demonstrates a strategy for the identification of potential virulence factors that are conserved across a number of human pathogenic bacterial species, confirming the usefulness of this tool.

Comparative effectiveness of generic versus brand-name antiepileptic medications.

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Gagne, Joshua J; Kesselheim, Aaron S; Choudhry, Niteesh K; Polinski, Jennifer M; Hutchins, David; Matlin, Olga S; Brennan, Troyen A; Avorn, Jerry; Shrank, William H

2015-11-01

The objective of this study was to compare treatment persistence and rates of seizure-related events in patients who initiate antiepileptic drug (AED) therapy with a generic versus a brand-name product. We used linked electronic medical and pharmacy claims data to identify Medicare beneficiaries who initiated one of five AEDs (clonazepam, gabapentin, oxcarbazepine, phenytoin, zonisamide). We matched initiators of generic versus brand-name versions of these drugs using a propensity score that accounted for demographic, clinical, and health service utilization variables. We used a Cox proportional hazards model to compare rates of seizure-related emergency room (ER) visit or hospitalization (primary outcome) and ER visit for bone fracture or head injury (secondary outcome) between the matched generic and brand-name initiators. We also compared treatment persistence, measured as time to first 14-day treatment gap, between generic and brand-name initiators. We identified 19,760 AED initiators who met study eligibility criteria; 18,306 (93%) initiated a generic AED. In the matched cohort, we observed 47 seizure-related hospitalizations and ER visits among brand-name initiators and 31 events among generic initiators, corresponding to a hazard ratio of 0.53 (95% confidence interval, 0.30 to 0.96). Similar results were observed for the secondary clinical endpoint and across sensitivity analyses. Mean time to first treatment gap was 124.2 days (standard deviation [sd], 125.8) for brand-name initiators and 137.9 (sd, 148.6) for generic initiators. Patients who initiated generic AEDs had fewer adverse seizure-related clinical outcomes and longer continuous treatment periods before experiencing a gap than those who initiated brand-name versions. Copyright © 2015 Elsevier Inc. All rights reserved.

THE ANXIETY SPECTRUM AND THE REFLEX PHYSIOLOGY OF DEFENSE: FROM CIRCUMSCRIBED FEAR TO BROAD DISTRESS

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McTeague, Lisa M.; Lang, Peter J.

2013-01-01

Guided by the diagnostic nosology, anxiety patients are expected to show defensive hyperarousal during affective challenge, irrespective of the principal phenotype. In the current study, patients representing the whole spectrum of anxiety disorders (i.e., specific phobia, social phobia, panic disorder with or without agoraphobia, obsessive-compulsive disorder, generalized anxiety disorder (GAD), posttraumatic stress disorder(PTSD)), and healthy community control participants, completed an imagery-based fear elicitation paradigm paralleling conventional intervention techniques. Participants imagined threatening and neutral narratives as physiological responses were recorded. Clear evidence emerged for exaggerated reactivity to clinically relevant imagery—most pronounced in startle reflex responding. However, defensive propensity varied across principal anxiety disorders. Disorders characterized by focal fear and impairment (e.g., specific phobia) showed robust fear potentiation. Conversely, for disorders of long-enduring, pervasive apprehension and avoidance with broad anxiety and depression comorbidity (e.g., PTSD secondary to cumulative trauma, GAD), startle responses were paradoxically diminished to all aversive contents. Patients whose expressed symptom profiles were intermediate between focal fearfulness and broad anxious-misery in both severity and chronicity exhibited a still heightened but more generalized physiological propensity to respond defensively. Importantly, this defensive physiological gradient—the inverse of self-reported distress—was evident not only between but also within disorders. These results highlight that fear circuitry could be dysregulated in chronic, pervasive anxiety, and preliminary functional neuroimaging findings suggest that deficient amygdala recruitment could underlie attenuated reflex responding. In summary, adaptive defensive engagement during imagery may be compromised by long-term dysphoria and stress—a phenomenon

Efficient full-spectrum utilization, reception and conversion of solar energy by broad-band nanospiral antenna.

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Zhao, Huaqiao; Gao, Huotao; Cao, Ting; Li, Boya

2018-01-22

In this work, the collection of solar energy by a broad-band nanospiral antenna is investigated in order to solve the low efficiency of the solar rectenna based on conventional nanoantennas. The antenna impedance, radiation, polarization and effective area are all considered in the efficiency calculation using the finite integral technique. The wavelength range investigated is 300-3000 nm, which corresponds to more than 98% of the solar radiation energy. It's found that the nanospiral has stronger field enhancement in the gap than a nanodipole counterpart. And a maximum harvesting efficiency about 80% is possible in principle for the nanospiral coupled to a rectifier resistance of 200 Ω, while about 10% for the nanodipole under the same conditions. Moreover, the nanospiral could be coupled to a rectifier diode of high resistance more easily than the nanodipole. These results indicate that the efficient full-spectrum utilization, reception and conversion of solar energy can be achieved by the nanospiral antenna, which is expected to promote the solar rectenna to be a promising technology in the clean, renewable energy application.

Spectral properties of a broad-area diode laser with off-axis external-cavity feedback

DEFF Research Database (Denmark)

Chi, Mingjun; Petersen, Paul Michael

2013-01-01

Spectral properties, both the optical spectrum and the intensity noise spectrum, of a broad-area diode laser with off-axis external-cavity feedback are presented. We show that the optical spectrum of the diode laser system is shifted to longer wavelengths due to the external-cavity feedback....... The intensity noise spectrum of the diode laser shows that the intensity noise is increased strongly by the external-cavity feedback. External-cavity modes are excited in the external cavity even in the off-axis configuration. The peak spacing of the intensity noise spectrum shows that single roundtrip external......-cavity modes are excited. We believe that the four-wave mixing process in the broad-area diode laser is responsible for the establishment of the external-cavity mode....

INVESTIGATING THE COMPLEX X-RAY SPECTRUM OF A BROAD-LINE 2MASS RED QUASAR: XMM-NEWTON OBSERVATION OF FTM 0830+3759

International Nuclear Information System (INIS)

Piconcelli, Enrico; Nicastro, Fabrizio; Fiore, Fabrizio; Vignali, Cristian; Bianchi, Stefano; Miniutti, Giovanni

2010-01-01

We report results from a 50 ks XMM-Newton observation of the dust-reddened broad-line quasar FTM 0830+3759 (z = 0.413) selected from the Faint Images of the Radio Sky at Twenty cm/Two Micron All Sky Survey red quasar survey. For this active galactic nucleus (AGN), a very short 9 ks Chandra exposure had suggested a feature-rich X-ray spectrum and Hubble Space Telescope images revealed a very disturbed host galaxy morphology. Contrary to classical, optically selected quasars, the X-ray properties of red (i.e., with J - K s > 1.7 and R - K s > 4.0) broad-line quasars are still quite unexplored, although there is a growing consensus that, due to moderate obscuration, these objects can offer a unique view of spectral components typically swamped by the AGN light in normal, blue quasars. The XMM-Newton observation discussed here has definitely confirmed the complexity of the X-ray spectrum revealing the presence of a cold (or mildly ionized) absorber with N H ∼ 10 22 cm -2 along the line of sight to the nucleus and a Compton reflection component accompanied by an intense Fe Kα emission line in this quasar with a L 2-10 k eV ∼ 5 x 10 44 erg s -1 . A soft-excess component is also required by the data. The match between the column density derived by our spectral analysis and that expected on the basis of reddening due to the dust suggests the possibility that both absorptions occur in the same medium. FTM 0830+3759 is characterized by an extinction/absorption-corrected X-ray-to-optical flux ratio α ox = -2.3, which is steeper than expected on the basis of its UV luminosity. These findings indicate that the X-ray properties of FTM 0830+3759 differ from those typically observed for optically selected broad-line quasars with comparable hard X-ray luminosity.

Intratumor heterogeneity alters most effective drugs in designed combinations.

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Zhao, Boyang; Hemann, Michael T; Lauffenburger, Douglas A

2014-07-22

The substantial spatial and temporal heterogeneity observed in patient tumors poses considerable challenges for the design of effective drug combinations with predictable outcomes. Currently, the implications of tissue heterogeneity and sampling bias during diagnosis are unclear for selection and subsequent performance of potential combination therapies. Here, we apply a multiobjective computational optimization approach integrated with empirical information on efficacy and toxicity for individual drugs with respect to a spectrum of genetic perturbations, enabling derivation of optimal drug combinations for heterogeneous tumors comprising distributions of subpopulations possessing these perturbations. Analysis across probabilistic samplings from the spectrum of various possible distributions reveals that the most beneficial (considering both efficacy and toxicity) set of drugs changes as the complexity of genetic heterogeneity increases. Importantly, a significant likelihood arises that a drug selected as the most beneficial single agent with respect to the predominant subpopulation in fact does not reside within the most broadly useful drug combinations for heterogeneous tumors. The underlying explanation appears to be that heterogeneity essentially homogenizes the benefit of drug combinations, reducing the special advantage of a particular drug on a specific subpopulation. Thus, this study underscores the importance of considering heterogeneity in choosing drug combinations and offers a principled approach toward designing the most likely beneficial set, even if the subpopulation distribution is not precisely known.

Modified lysozymes as novel broad spectrum natural antimicrobial agents in foods.

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Aminlari, Ladan; Hashemi, Marjan Mohammadi; Aminlari, Mahmoud

2014-06-01

In recent years much attention and interest have been directed toward application of natural antimicrobial agents in foods. Some naturally occurring proteins such as lactoperoxidase, lactoferrin, and lysozyme have received considerable attention and are being considered as potential antimicrobial agents in foods. Lysozyme kills bacteria by hydrolyzing the peptidoglycan layer of the cell wall of certain bacterial species, hence its application as a natural antimicrobial agent has been suggested. However, limitations in the action of lysozyme against only Gram-positive bacteria have prompted scientists to extend the antimicrobial effects of lysozyme by several types of chemical modifications. During the last 2 decades extensive research has been directed toward modification of lysozyme in order to improve its antimicrobial properties. This review will report on the latest information available on lysozyme modifications and examine the applicability of the modified lysozymes in controlling growth of Gram-positive and Gram-negative bacteria in foods. The results of modifications of lysozyme using its conjugation with different small molecule, polysaccharides, as well as modifications using proteolytic enzymes will be reviewed. These types of modifications have not only increased the functional properties of lysozyme (such as solubility and heat stability) but also extended the antimicrobial activity of lysozyme. Many examples will be given to show that modification can decrease the count of Gram-negative bacteria in bacterial culture and in foods by as much as 5 log CFU/mL and in some cases essentially eliminated Escherichia coli. In conclusion this review demonstrates that modified lysozymes are excellent natural food preservatives, which can be used in food industry. The subject described in this review article can lead to the development of methods to produce new broad-spectrum natural antimicrobial agents, based on modification of chicken egg white lysozyme, which

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

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

2017-08-01

Children with cerebral palsy (CP) are vulnerable to developing vitamin D deficiency. There is little information on the prevalence and severity of vitamin D deficiency in these patients. To study vitamin D status in children with CP with special reference to their intake of anti-epileptic drugs (AED) and ambulatory status. The relative effects of AED use and ambulatory status on the vitamin D status of 120 children with CP aged 2-10 years were examined in this observational study. The patients were classified into four groups (30 in each) on the basis of AED use and ambulatory status: ambulatory (CPA), ambulatory receiving AED (CPAD), non-ambulatory (CPNA) and non-ambulatory receiving AED (CPNAD). A control group of 30 age-matched healthy children was also included. Parameters assessed included dietary calcium intake, sun exposure, serum total and ionised calcium (tCa, iCa), inorganic phosphate (iP), alkaline phosphatase (ALP), parathormone (PTH), 25 hydroxy vitamin D [25(OH)D] levels and a wrist radiograph to detect rickets. Vitamin D status was defined on the basis of serum 25(OH)D levels as normal (>50 nmol/L), mild deficiency (25-50 nmol/L), moderate deficiency (12.5-25 nmol/L), severe deficiency (D levels in patients with CP were 35.6 (26.75-64) nmol/L compared with 60 (37-69.25) nmol/L in controls (p = 0.04). Sixty per cent of children with CP and 36.7% of controls were vitamin D-deficient [25(OH)D D-deficient with median (IQR) 25(OH)D levels of 33.5 (12.5-45.25) nmol/L. Also, 53.3% of them had raised ALP and 17.2% raised PTH levels. Children with CP are highly vulnerable to vitamin D deficiency. In these patients, AED use and lack of sun exposure contribute towards poor vitamin D status, the effect being more pronounced when they co-exist.

Biogenic synthesis of Zinc oxide nanostructures from Nigella sativa seed: Prospective role as food packaging material inhibiting broad-spectrum quorum sensing and biofilm.

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Al-Shabib, Nasser A; Husain, Fohad Mabood; Ahmed, Faheem; Khan, Rais Ahmad; Ahmad, Iqbal; Alsharaeh, Edreese; Khan, Mohd Shahnawaz; Hussain, Afzal; Rehman, Md Tabish; Yusuf, Mohammad; Hassan, Iftekhar; Khan, Javed Masood; Ashraf, Ghulam Md; Alsalme, Ali Mohammed; Al-Ajmi, Mohamed F; Tarasov, Vadim V; Aliev, Gjumrakch

2016-12-05

Bacterial spoilage of food products is regulated by density dependent communication system called quorum sensing (QS). QS control biofilm formation in numerous food pathogens and Biofilms formed on food surfaces act as carriers of bacterial contamination leading to spoilage of food and health hazards. Agents inhibiting or interfering with bacterial QS and biofilm are gaining importance as a novel class of next-generation food preservatives/packaging material. In the present study, Zinc nanostructures were synthesised using Nigella sativa seed extract (NS-ZnNPs). Synthesized nanostructures were characterized hexagonal wurtzite structure of size ~24 nm by UV-visible, XRD, FTIR and TEM. NS-ZnNPs demonstrated broad-spectrum QS inhibition in C. violaceum and P. aeruginosa biosensor strains. Synthesized nanostructures inhibited QS regulated functions of C. violaceum CVO26 (violacein) and elastase, protease, pyocyanin and alginate production in PAO1 significantly. NS-ZnNPs at sub-inhibitory concentrations inhibited the biofilm formation of four-food pathogens viz. C. violaceum 12472, PAO1, L. monocytogenes, E. coli. Moreover, NS-ZnNPs was found effective in inhibiting pre-formed mature biofilms of the four pathogens. Therefore, the broad-spectrum inhibition of QS and biofilm by biogenic Zinc oxide nanoparticles and it is envisaged that these nontoxic bioactive nanostructures can be used as food packaging material and/or as food preservative.

Broad-spectrum antiviral properties of andrographolide.

Science.gov (United States)

Gupta, Swati; Mishra, K P; Ganju, Lilly

2017-03-01

Andrographolide, a diterpenoid, is known for its anti-inflammatory effects. It can be isolated from various plants of the genus Andrographis, commonly known as 'creat'. This purified compound has been tested for its anti-inflammatory effects in various stressful conditions, such as ischemia, pyrogenesis, arthritis, hepatic or neural toxicity, carcinoma, and oxidative stress, Apart from its anti-inflammatory effects, andrographolide also exhibits immunomodulatory effects by effectively enhancing cytotoxic T cells, natural killer (NK) cells, phagocytosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). All these properties of andrographolide form the foundation for the use of this miraculous compound to restrain virus replication and virus-induced pathogenesis. The present article covers antiviral properties of andrographolide in variety of viral infections, with the hope of developing of a new highly potent antiviral drug with multiple effects.

Comparative effectiveness of eight antiepileptic drugs in adults with focal refractory epilepsy: the influence of age, gender, and the sequence in which drugs were introduced onto the market.

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Mäkinen, Jussi; Peltola, Jukka; Raitanen, Jani; Alapirtti, Tiina; Rainesalo, Sirpa

2017-07-01

The first objective was to determine the long-term retention rate of eight antiepileptic drugs (AEDs) commonly used as adjunctive therapy in adults with focal refractory epilepsy. Second, we assessed the effects of age and gender on retention rates. Third, we examined if the retention rate could be influenced by the sequence in which the AEDs had entered the market. Patients with focal refractory epilepsy treated with any of the eight AEDs in Tampere University Hospital were identified retrospectively (N = 507). Retention rates were evaluated with the Kaplan-Meier method. Follow-up started at the first date of treatment and each individual was followed a maximum of 36 months. We calculated the following 3-year retention rates: lacosamide 77.1% (N = 137), lamotrigine 68.3% (N = 177), levetiracetam 66.7% (N = 319), clobazam 65.6% (N = 130), topiramate 61.6% (N = 178), zonisamide 60.4% (N = 103), pregabalin 54.6% (N = 127), and gabapentin 40.2% (N = 66). Lacosamide, levetiracetam, and clobazam were the most effective AEDs in the elderly. The retention rate for pregabalin was higher in males (65%) than females (51%) whereas females had higher retention rates for both topiramate (72 vs. 58%) and zonisamide (67 vs. 57%). The retention rate was influenced by the sequence in which these AEDs entered the market. We provide important information about practical aspects of these eight AEDs, revealing that there are differences in their effectiveness as adjunctive treatment for focal refractory epilepsy. Most importantly, the retention rate appears to be influenced by the sequence in which these AEDs were introduced onto the market.

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

Energy Technology Data Exchange (ETDEWEB)

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

2008-01-01

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

A systematic screen of FDA-approved drugs for inhibitors of biological threat agents.

Directory of Open Access Journals (Sweden)

Peter B Madrid

Full Text Available BACKGROUND: The rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. METHODOLOGY/PRINCIPAL FINDINGS: A large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. CONCLUSIONS/SIGNIFICANCE: The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses.

A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents

Science.gov (United States)

Madrid, Peter B.; Chopra, Sidharth; Manger, Ian D.; Gilfillan, Lynne; Keepers, Tiffany R.; Shurtleff, Amy C.; Green, Carol E.; Iyer, Lalitha V.; Dilks, Holli Hutcheson; Davey, Robert A.; Kolokoltsov, Andrey A.; Carrion, Ricardo; Patterson, Jean L.; Bavari, Sina; Panchal, Rekha G.; Warren, Travis K.; Wells, Jay B.; Moos, Walter H.; Burke, RaeLyn L.; Tanga, Mary J.

2013-01-01

Background The rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. Methodology/Principal Findings A large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. Conclusions/Significance The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses. PMID:23577127

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.

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

Science.gov (United States)

Zhu, Pan; He, Ru-Qian; Bao, Yi-Xin; Zheng, Rong-Yuan; Xu, Hui-Qin

2015-01-01

Objective To evaluate and compare long-term effectiveness of five antiepileptic drugs (AEDs) for monotherapy of adult patients with focal epilepsy in routine clinical practice. Methods 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. Results 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]). Conclusion 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. PMID:26147937

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

Directory of Open Access Journals (Sweden)

Qing-Yi Zeng

Full Text Available To evaluate and compare long-term effectiveness of five antiepileptic drugs (AEDs for monotherapy of adult patients with focal epilepsy in routine clinical practice.Adult patients with focal epilepsy, who were prescribed with carbamazepine (CBZ, valproate (VPA, lamotrigine (LTG, topiramate (TPM, or oxcarbazepine (OXC as monotherapy, during the period from January 2004 to June 2012 registered in Wenzhou Epilepsy Follow Up Registry Database (WEFURD, were included in the study. Prospective long-term follow-up was conducted until June 2013. The endpoints were time to treatment failure, time to seizure remission, and time to first seizure.This study included 654 patients: CBZ (n=125, VPA (n=151, LTG (n=135, TPM (n=76, and OXC (n=167. The retention rates of CBZ, VPA, LTG, TPM, and OXC at the third year were 36.1%, 32.4%, 57.6%, 37.9%, and 41.8%, respectively. For time to treatment failure, LTG was significantly better than CBZ and VPA (LTG vs. CBZ, hazard ratio, [HR] 0.80 [95% confidence interval: 0.67-0.96], LTG vs. VPA, 0.53 [0.37-0.74]; TPM was worse than LTG (TPM vs. LTG, 1.77 [1.15-2.74], and OXC was better than VPA (0.86 [0.78-0.96]. After initial target doses, the seizure remission rates of CBZ, VPA, LTG, TPM, and OXC were 63.0%, 77.0%, 83.6%, 67.9%, and 75.3%, respectively. LTG was significantly better than CBZ (1.44 [1.15-1.82] and OXC (LTG vs. OXC, 0.76 [0.63-0.93]; OXC was less effective than LTG in preventing the first seizure (1.20 [1.02-1.40].LTG was the best, OXC was better than VPA only, while VPA was the worst. The others were equivalent for comparisons between five AEDs regarding the long-term treatment outcomes of monotherapy for adult patients with focal epilepsy in a clinical practice. For selecting AEDs for these patients among the first-line drugs, LTG is an appropriate first choice; others are reservation in the first-line but VPA is not.

Pharmacogenetic evaluation of ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase polymorphisms in teratogenicity of anti-epileptic drugs in women with epilepsy

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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.

Brand name to generic substitution of antiepileptic drugs does not lead to seizure-related hospitalization: a population-based case-crossover study.

Science.gov (United States)

Polard, Elisabeth; Nowak, Emmanuel; Happe, André; Biraben, Arnaud; Oger, Emmanuel

2015-11-01

There is still controversy on brand-to-generic (B-G) antiepileptic drugs (AEDs) substitution. To assess association between B-G AED substitution and seizure-related hospitalization, we designed a case crossover using the French National Health Insurance Database. We identified a cohort of adult patients who filled a prescription in 2009-2011 for AEDs with at least one brand name and one generic form. The outcome date was defined as the date of hospitalization, coded G40.x or G41.x, with a G40/G41 hospitalization-free period of at least 1 year. Patients with a medical history of cancer and women who gave birth in 2009-2011 were excluded. We required individuals to have regular dispensations of AEDs within the year preceding the outcome date. Free patients were defined as patients who had only brand name dispensations before the control period. Eight thousand three hundred seventy nine patients (mean age ± standard deviation, 52.7 ± 18.8 years; sex ratio male/female, 1.27) were analyzed. Discordant pairs were 491 with B-G substitution in the control period only and 478 with B-G substitution in the case period only; odds ratio (95% confidence interval) 0.97 (0.86-1.10). No statistically significant interaction was detected among the four prespecified subgroup analyses (gender, age strata, free or non-free, and strict AED monotherapy or not). Controlling for non-seizure-related hospitalizations made no material difference. Sensitivity analyses yielded similar results. Brand-to-generic AED substitution was not associated with an elevated risk of seizure-related hospitalization. Copyright © 2015 John Wiley & Sons, Ltd.

Antilisterial activity of a broad-spectrum bacteriocin, enterocin LR/6 from Enterococcus faecium LR/6.

Science.gov (United States)

Kumar, Manoj; Srivastava, Sheela

2010-10-01

Enterocin LR/6, a purified bacteriocin, exhibited broad inhibitory spectrum both against related as well as some food-borne pathogens such as Listeria monocytogenes, Yersinia enterocolitica, Aeromonas sp., Shigella sp., and Bacillus licheniformis. In this investigation, we have focused on L. monocytogenes as the target organism, as it is not only an important pathogen but can also survive over a wide range of environmental conditions such as refrigeration temperature, low pH, and high-salt concentration. This allows the pathogen to overcome many food preservation and safety barriers and poses a potential risk to human health. The enterocin LR/6 showed a bactericidal action against L. monocytogenes and completely inhibited the growth on agar plates, supplemented with 200 AU/ml of enterocin LR/6. The effectiveness of enterocin LR/6 in completely killing a population of acid-adapted (pH 5.2, 2 h) L. monocytogenes exposed to different temperatures (4-37 degrees C), pH (2.5-8.0), and osmotic (up to 30% NaCl) stress is reported here. This paper focuses on the key issue of killing of the acid-adapted L. monocytogenes cells under adverse environmental conditions.

Development of Purification Protocol Specific for Bacteriocin 105B

Science.gov (United States)

2017-02-09

Bacillus anthracis. As the current application of broad-spectrum antimicrobials promotes the development of multi- drug resistant microorganisms...SPECTRUM TARGETED ANTIMICROBIALS ASSAYS PURIFICATION BACILLUS ANTHRACIS DRUG- RESISTANT MICROORGANISMS...through the purification procedure. The wide-spread use of broad-spectrum antimicrobial agents has led to the development of drug resistant

Broad spectrum reactivity versus subtype specificity-trade-offs in serodiagnosis of influenza A virus infections by competitive ELISA.

Science.gov (United States)

Postel, A; Ziller, M; Rudolf, M; Letzel, T; Ehricht, Ralf; Pourquier, P; Dauber, M; Grund, C; Beer, Martin; Harder, T C

2011-04-01

Avian influenza viruses (AIVs) of the H5 and H7 subtypes can cause substantial economic losses in the poultry industry and are a potential threat to public health. Serosurveillance of poultry populations is an important monitoring tool and can also be used for control of vaccination campaigns. The purpose of this study was to develop broadly reactive, yet subtype-specific competitive ELISAs (cELISAs) for the specific detection of antibodies to the notifiable AIV subtypes H5 and H7 as an alternative to the gold standard haemagglutination inhibition assay (HI). Broadly reacting monoclonal competitor antibodies (mAbs) and genetically engineered subtype H5 or H7 haemagglutinin antigen, expressed and in vivo biotinylated in insect cells, were used to develop the cELISAs. Sera from galliform species and water fowl (n=793) were used to evaluate the performance characteristics of the cELISAs. For the H5 specific cELISA, 98.1% test sensitivity and 91.5% test specificity (97.7% and 90.2% for galliforms; 98.9% and 92.6% for waterfowl), and for the H7 cELISA 97.3% sensitivity and 91.8% specificity (95.3% and 98.9% for galliforms; 100% and 82.7% for waterfowl) were reached when compared to HI. The use of competitor mAbs with broad spectrum reactivity within an AIV haemagglutinin subtype allowed for homogenous detection with high sensitivity of subtype-specific antibodies induced by antigenically widely distinct isolates including antigenic drift variants. However, a trade-off regarding sensitivity versus nonspecific detection of interfering antibodies induced by phylo- and antigenically closely related subtypes, e.g., H5 versus H2 and H7 versus H15, must be considered. The observed intersubtype antibody cross-reactivity remains a disturbance variable in AIV subtype-specific serodiagnosis which negatively affects specificity. Copyright © 2011 Elsevier B.V. All rights reserved.

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.

Use of artificial intelligence in the design of small peptide antibiotics effective against a broad spectrum of highly antibiotic-resistant superbugs.

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Cherkasov, Artem; Hilpert, Kai; Jenssen, Håvard; Fjell, Christopher D; Waldbrook, Matt; Mullaly, Sarah C; Volkmer, Rudolf; Hancock, Robert E W

2009-01-16

Increased multiple antibiotic resistance in the face of declining antibiotic discovery is one of society's most pressing health issues. Antimicrobial peptides represent a promising new class of antibiotics. Here we ask whether it is possible to make small broad spectrum peptides employing minimal assumptions, by capitalizing on accumulating chemical biology information. Using peptide array technology, two large random 9-amino-acid peptide libraries were iteratively created using the amino acid composition of the most active peptides. The resultant data was used together with Artificial Neural Networks, a powerful machine learning technique, to create quantitative in silico models of antibiotic activity. On the basis of random testing, these models proved remarkably effective in predicting the activity of 100,000 virtual peptides. The best peptides, representing the top quartile of predicted activities, were effective against a broad array of multidrug-resistant "Superbugs" with activities that were equal to or better than four highly used conventional antibiotics, more effective than the most advanced clinical candidate antimicrobial peptide, and protective against Staphylococcus aureus infections in animal models.

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

Directory of Open Access Journals (Sweden)

Kong Boon Lim

2016-01-01

Full Text Available We isolated a Bacillus strain, RX7, with inhibitory activity against Listeria monocytogenes from soil and identified it as Bacillus amyloliquefaciens based on 16S rRNA gene sequencing. The inhibitory activity was stable over a wide range of pH and was fully retained after 30 min at 80°C, after which it decreased gradually at higher temperatures. The activity was sensitive to the proteolytic action of α-chymotrypsin, proteinase-K, and trypsin, indicating its proteinaceous nature. This bacteriocin was active against a broad spectrum of bacteria and the fungus Candida albicans. Direct detection of antimicrobial activity on a sodium dodecyl sulfate-polyacrylamide gel suggested an apparent molecular mass of approximately 5 kDa. Ammonium sulfate precipitation and anion-exchange and gel permeation chromatography integrated with reverse phase-high-performance liquid chromatography were used for bacteriocin purification. Automated N-terminal Edman degradation of the purified RX7 bacteriocin recognized the first 15 amino acids as NH2-X-Ala-Trp-Tyr-Asp-Ile-Arg-Lys-Leu-Gly-Asn-Lys-Gly-Ala, where the letter X in the sequence indicates an unknown or nonstandard amino acid. Based on BLAST similarity search and multiple alignment analysis, the obtained partial sequence showed high homology with the two-peptide lantibiotic haloduracin (HalA1 from Bacillus halodurans, although at least two amino acids differed between the sequences. A time-kill study demonstrated a bactericidal mode of action of RX7 bacteriocin.

In vitro and in vivo antibacterial activities of E1077, a novel parenteral cephalosporin with a broad antibacterial spectrum.

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Hata, K; Otsuki, M; Nishino, T

1992-01-01

E1077 is a new injectable cephalosporin with a broad spectrum of antibacterial activity against gram-positive and gram-negative bacteria, including staphylococci and Pseudomonas aeruginosa. The in vitro activities of E1077 against clinical isolates of methicillin-susceptible Staphylococcus aureus (MIC of E1077 for 90% of the strains tested [MIC90], 0.78 microgram/ml) and methicillin-resistant S. aureus (MIC90, 50 micrograms/ml) were similar to those of cefpirome and flomoxef. Against Enterococcus faecalis (MIC90, 6.25 micrograms/ml), E1077 was the most active of the drugs tested and four times more active than cefpirome. The MIC90S of E1077 for streptococci, Haemophilus influenzae, and Neisseria gonorrhoeae ranged from 0.05 to 0.78 microgram/ml; E1077 was similar in activity to cefpirome. E1077 inhibited 90% of most species of the family Enterobacteriaceae at concentrations of less than or equal to 1.56 micrograms/ml, with the exception of Serratia marcescens and Proteus vulgaris (12.5 micrograms/ml). The activity of E1077 against P. aeruginosa (MIC90, 6.25 micrograms/ml) was comparable to that of ceftazidime. In vivo activity was evaluated with systemic infections in mice. E1077 showed a protective effect against systemic infections by gram-positive or gram-negative bacteria, as reflected by its in vitro activity. The protective effects of E1077 were higher than those of cefpirome against S. aureus and P. aeruginosa infections and similar to those of cefpirome against other bacterial infections. Morphological studies using differential interference and phase-contrast microscopy showed that low concentrations of E1077 caused swelling of S. aureus and spheroplast and bulge formation in P. aeruginosa. In general, the antibacterial profile of E1077 is similar to that of cefpirome. Images PMID:1416879

PG 1700 + 518 - a low-redshift, broad absorption line QSO

International Nuclear Information System (INIS)

Pettini, M.; Boksenberg, A.

1985-01-01

The first high-resolution optical spectra and lower resolution UV spectra of PG 1700 + 518, the only known broad-absorption-line (BAL) QSO at low emission redshift (0.288) are presented. The optical data were obtained with the Isaac Newton Telescope on the island of La Palma and the UV data with the International Ultraviolet Explorer satellite. The outstanding feature of the optical spectrum is a strong, broad Mg II absorption trough, detached from the Mg II emission line and indicative of ejection velocities of between 7000 and 18,000 km/s. Also detected were narrow (FWHM = 350 km/s) Mg II absorption lines at absolute z = 0.2698, which are probably related to the mass ejection phenomenon. It is concluded that the emission-line spectrum is similar to that of other low-redshift QSOs although there are some obvious differences from typical BAL QSOs, most notably in the unusually low level of ionization of both emission-line and broad absorption line gas. 21 references

Dissemination and genetic support of broad-spectrum beta-lactam-resistant Escherichia coli strain isolated from two Tunisian hospitals during 2004-2012.

Science.gov (United States)

Ayari, Khaoula; Bourouis, Amel; Chihi, Hela; Mahrouki, Sihem; Naas, Thierry; Belhadj, Omrane

2017-06-01

The dissemination of extended-spectrum β-lactamase (ESBL)-producing bacteria presented a great concern worldwide. Gram-negative organisms such as Escherichia coli and Klebsiella pneumoniae are the most frequently isolated pathogens responsible for nosocomial infections. The aim of this study was to investigate and to follow the emergence of resistance and the characterization of Extended-Spectrum Beta-Lactamases (ESBL) among broad-spectrum beta-lactam- Escherichia coli clinical isolates recovered from the military hospital and Habib Thameur hospital in Tunisia. A total of 113 E.coli isolates obtained during the period 2004 through 2012 showed a significant degree of multi-resistance. Among these strains, the double-disk synergy test confirmed the ESBL phenotype in 46 isolates. These included 32(70%) strains from Hospital A and 14(30%) from Hospital B. The ESBL was identified as CTX-M-15. The ESBL resistance was transferred by a 60 kb plasmid CTXM-15-producing isolates were unrelated according to the PFGE analysis and characterization of the regions surrounding the blaCTX-M-15 showed the ISEcp1 elements located in the upstream region of the bla gene and 20 of them truncated by IS26. ESBL producing E. coli strains are a serious threat in the community in Tunisia and we should take into consideration any possible spread of such epidemiological resistance.

Feasibility study of silica sol as the carrier of a hydrophobic drug in aqueous solution using enrofloxacin as the model

International Nuclear Information System (INIS)

Song Meirong; Song Junling; Ning Aimin; Cui Baoan; Cui Shumin; Zhou Yaobing; An Wankai; Dong Xuesong; Zhang Gege

2010-01-01

The aim of this study was to determine the feasibility of using silica sol to carry a hydrophobic drug in aqueous solution. Enrofloxacin, which was selected as the model drug because it is a broad-spectrum antibiotic drug with poor solubility in water, was adsorbed onto silica sol in aqueous solution during cooling from 60 deg. C to room temperature. The drug-loaded silica sol was characterized by transmission electron microscopy, Fourier transform infrared spectrum, thermal gravimetric analysis and ultraviolet-visible light spectroscopy. The results showed that enrofloxacin was adsorbed by silica sol without degradation at a loading of 15.23 wt.%. In contrast to the rapid release from pure enrofloxacin, the drug-loaded silica sol showed a slower release over a longer time. Kinetics analysis suggested the drug release from silica sol was mainly a diffusion-controlled process. Therefore, silica sol can be used to carry a hydrophobic drug in aqueous solution for controlled drug delivery.

Drug utilization profile in adult patients with refractory epilepsy at a tertiary referral center

Directory of Open Access Journals (Sweden)

Priscila de Freitas-Lima

2013-11-01

Full Text Available Objective To evaluate the utilization profile of antiepileptic drugs in a population of adult patients with refractory epilepsy attending a tertiary center. Method Descriptive analyses of data were obtained from the medical records of 112 patients. Other clinical and demographic characteristics were also registered. Results Polytherapies with ≥3 antiepileptic drugs were prescribed to 60.7% of patients. Of the old agents, carbamazepine and clobazam were the most commonly prescribed (72.3% and 58.9% of the patients, respectively. Among the new agents, lamotrigine was the most commonly prescribed (36.6% of the patients. At least one old agent was identified in 103 out of the 104 polytherapies, while at least one new agent was prescribed to 70.5% of the population. The most prevalent combination was carbamazepine + clobazam + lamotrigine. The mean AED load found was 3.3 (range 0.4–7.7. Conclusion The pattern of use of individual drugs, although consistent with current treatment guidelines, is strongly influenced by the public health system.

ANTICONVULSANT AND ANTIEPILEPTIC ACTIONS OF 2-DEOXY-DGLUCOSE IN EPILEPSY MODELS

Science.gov (United States)

Stafstrom, Carl E.; Ockuly, Jeffrey C.; Murphree, Lauren; Valley, Matthew T.; Roopra, Avtar; Sutula, Thomas P.

2009-01-01

Objective Conventional anticonvulsants reduce neuronal excitability through effects on ion channels and synaptic function. Anticonvulsant mechanisms of the ketogenic diet remain incompletely understood. Since carbohydrates are restricted in patients on the ketogenic diet, we evaluated the effects of limiting carbohydrate availability by reducing glycolysis using the glycolytic inhibitor 2-deoxy-D-glucose (2DG) in experimental models of seizures and epilepsy. Methods Acute anticonvulsant actions of 2DG were assessed in vitro in rat hippocampal slices perfused with 7.5mM [K+]o, 4-aminopyridine (4-AP), or bicuculline and in vivo against seizures evoked by 6 Hz stimulation in mice, audiogenic stimulation in Fring’s mice, and maximal electroshock and subcutaneous Metrazol in rats. Chronic antiepileptic effects of 2DG were evaluated in rats kindled from olfactory bulb or perforant path. Results 2DG (10mM) reduced interictal epileptiform bursts induced by high [K+]o, 4-AP and bicuculline, and electrographic seizures induced by high [K+]o in CA3 of hippocampus. 2DG reduced seizures evoked by 6 Hz stimulation in mice (ED50 = 79.7 mg/kg) and audiogenic stimulation in Fring’s mice (ED50 = 206.4 mg/kg). 2DG exerted chronic antiepileptic action by increasing afterdischarge thresholds in perforant path (but not olfactory bulb) kindling and caused a 2-fold slowing in progression of kindled seizures at both stimulation sites. 2DG did not protect against maximal electroshock or Metrazol seizures. Interpretation The glycolytic inhibitor 2DG exerts acute anticonvulsant and chronic antiepileptic actions and has a novel pattern of effectiveness in preclinical screening models. These results identify metabolic regulation as a potential therapeutic target for seizure suppression and modification of epileptogenesis. PMID:19399874

Molecular detection of TEM broad spectrum β-lactamase in clinical ...

African Journals Online (AJOL)

Resistance to β-lactam antibiotics, along with clinical isolates, frequently results to production of β- lactamase enzymes. In recent years, the production of extended spectrum β-lactamases (ESBLs) among clinical isolates, especially Escherichia coli has greatly increased. On the other hand, β lactamase genes have several ...

Structural Exploration of Quinazolin-4(3H)-ones as Anticonvulsants: Rational Design, Synthesis, Pharmacological Evaluation, and Molecular Docking Studies.

Science.gov (United States)

Ugale, Vinod G; Bari, Sanjay B

2016-11-01

Anticonvulsants effective against multiple seizures are of wide interest as antiepileptic drugs, especially if active against pharmaco-resistant seizures. Herein, we synthesized 16 different, rationally designed 2-((6,7-dimethoxy-4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-N-(substituted phenyl)acetamides and screened for anticonvulsant activities through in vivo experiments. Compound 4d emerged as prototype with excellent anti-seizure action in mice against electroshock, chemically induced and pharmaco-resistant 6-Hz seizure models with no symptoms of neurotoxicity and hepatotoxicity (ED 50  = 23.5 mg/kg, MES, mice, i.p.; ED 50  = 32.6 mg/kg, scPTZ, mice, i.p.; ED 50  = 45.2 mg/kg, 6-Hz, mice, i.p.; TD 50  = 325.9 mg/kg, mice, i.p.). In addition, investigation of compound 4l in mice for its pharmacological profile proved it as safer anticonvulsant, devoid of the side effects such as motor dysfunction and hepatotoxicity of classical antiepileptic drugs (ED 50  = 26.1 mg/kg, MES, mice, i.p.; ED 50  = 79.4 mg/kg, scPTZ, mice, i.p.; TD 50  = 361.2 mg/kg, mice, i.p.). We also predicted physiochemical and pharmacokinetic properties of structurally optimized quinazolin-4(3H)-ones by a computational protocol. A combination of in vivo anticonvulsant profile, ex vivo toxicity, and in silico studies suggested that the synthesized compounds may be useful as broad-spectrum anti-seizure drug candidates with favorable pharmacokinetic parameters. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Exacerbation of Acetaminophen Hepatotoxicity by the Anthelmentic Drug Fenbendazole

OpenAIRE

Gardner, Carol R.; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

2011-01-01

Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8–12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administra...

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. Copyright © 2011 Elsevier Inc. All rights reserved.

The Unusual Moessbauer Spectrum of Beryl

International Nuclear Information System (INIS)

Viana, R. R.; Costa, G. M. da; Grave, E. de; Evangelista, H. J.; Stern, W. B.

2001-01-01

The Moessbauer spectra of several aquamarine samples have been obtained in the temperature range of 4.2-500 K. A common feature observed in all room-temperature spectra is the presence of an asymmetric Fe 2+ doublet (ΔE Q ∼2.7 mm/s, δ∼1.1 mm/s), with a very broad low-velocity peak. This asymmetry is not caused by preferred orientation since the spectrum collected under the magic angle did not show any difference in the line intensities, nor is it caused by the superposition of a Fe 3+ doublet. At 4.2 K the spectrum of a deep-blue beryl could be well fitted with three symmetrical doublets, with the major Fe 2+ doublet accounting for 87% of the total spectral area. At 14 K the symmetry remains, but at 30 K the low-velocity peak is again broad. Surprisingly, the spectrum at 500 K also shows a broad, but symmetrical doublet, with a clear splitting of the lines indicating the presence of at least two Fe 2+ components. The room-temperature spectrum obtained after the 500 K run shows the same features as before the heating. A meaningful fit for the room-temperature spectrum, as well as an explanation for the temperature dependence of the Moessbauer spectra, are discussed

Transgenic Brassica rapa plants over-expressing eIF(iso)4E variants show broad-spectrum Turnip mosaic virus (TuMV) resistance.

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Kim, Jinhee; Kang, Won-Hee; Hwang, Jeena; Yang, Hee-Bum; Dosun, Kim; Oh, Chang-Sik; Kang, Byoung-Cheorl

2014-08-01

The protein-protein interaction between VPg (viral protein genome-linked) of potyviruses and eIF4E (eukaryotic initiation factor 4E) or eIF(iso)4E of their host plants is a critical step in determining viral virulence. In this study, we evaluated the approach of engineering broad-spectrum resistance in Chinese cabbage (Brassica rapa) to Turnip mosaic virus (TuMV), which is one of the most important potyviruses, by a systematic knowledge-based approach to interrupt the interaction between TuMV VPg and B. rapa eIF(iso)4E. The seven amino acids in the cap-binding pocket of eIF(iso)4E were selected on the basis of other previous results and comparison of protein models of cap-binding pockets, and mutated. Yeast two-hybrid assay and co-immunoprecipitation analysis demonstrated that W95L, K150L and W95L/K150E amino acid mutations of B. rapa eIF(iso)4E interrupted its interaction with TuMV VPg. All eIF(iso)4E mutants were able to complement an eIF4E-knockout yeast strain, indicating that the mutated eIF(iso)4E proteins retained their function as a translational initiation factor. To determine whether these mutations could confer resistance, eIF(iso)4E W95L, W95L/K150E and eIF(iso)4E wild-type were over-expressed in a susceptible Chinese cabbage cultivar. Evaluation of the TuMV resistance of T1 and T2 transformants demonstrated that the over-expression of the eIF(iso)4E mutant forms can confer resistance to multiple TuMV strains. These data demonstrate the utility of knowledge-based approaches for the engineering of broad-spectrum resistance in Chinese cabbage. © 2014 BSPP AND JOHN WILEY & SONS LTD.

Broad phenotypic spectrum in familial adenomatous polyposis; from early onset and severe phenotypes to late onset of attenuated polyposis with the first manifestation at age 72

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Johannsson Oskar

2008-11-01

Full Text Available Abstract Background Familial adenomatous polyposis (FAP is typically characterized by multiple colonic polyps and frequent extracolonic features. Whereas the number of colonic polyps has been linked to the APC gene mutation, possible genotype-phenotype correlations largely remain to be defined for the extracolonic manifestations. Methods Full genomic sequencing combined with multiplex ligation-dependent probe amplification was used to identify APC gene mutations, which were correlated to the clinical presentations. Results 10 novel APC gene mutations were identified in 11 families. A broad spectrum of extracolonic manifestations was identified in most of these individuals. Two sisters with an insertion in codon 528 (c.1582_1583insGC both showed severe phenotypes with classical polyposis, upper gastrointestinal polyps and thyroid cancer. A woman with a 3'APC mutation (c.5030_5031insAA developed colon cancer at age 72 as the first manifestation of attenuated FAP. Conclusion With an increasing number of FAP families diagnosed, a broad and variable tumor spectrum and a high frequency of extracolonic manifestations are gradually recognized. We report novel APC mutations and present two FAP cases that suggest familial aggregation of thyroid cancer and demonstrate the need to consider attenuated FAP also among elderly patients with colon cancer.

[Molecular characterization of resistance mechanisms: methicillin resistance Staphylococcus aureus, extended spectrum β-lactamases and carbapenemases].

Science.gov (United States)

Oteo, Jesús; Belén Aracil, María

2015-07-01

Multi-drug resistance in bacterial pathogens increases morbidity and mortality in infected patients and it is a threat to public health concern by their high capacity to spread. For both reasons, the rapid detection of multi-drug resistant bacteria is critical. Standard microbiological procedures require 48-72 h to provide the antimicrobial susceptibility results, thus there is emerging interest in the development of rapid detection techniques. In recent years, the use of selective and differential culture-based methods has widely spread. However, the capacity for detecting antibiotic resistance genes and their low turnaround times has made molecular methods a reference for diagnosis of multidrug resistance. This review focusses on the molecular methods for detecting some mechanisms of antibiotic resistance with a high clinical and epidemiological impact: a) Enzymatic resistance to broad spectrum β-lactam antibiotics in Enterobacteriaceae, mainly extended spectrum β-lactamases (ESBL) and carbapenemases; and b) methicillin resistance in Staphylococcus aureus. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

PfMDR2 and PfMDR5 are dispensable for Plasmodium falciparum asexual parasite multiplication but change in vitro susceptibility to anti-malarial drugs

NARCIS (Netherlands)

Velden, M. van der; Rijpma, S.R.; Russel, F.G.M.; Sauerwein, R.W.; Koenderink, J.B.

2015-01-01

BACKGROUND: Membrane-associated ATP binding cassette (ABC) transport proteins hydrolyze ATP in order to translocate a broad spectrum of substrates, from single ions to macromolecules across membranes. In humans, members from this transport family have been linked to drug resistance phenotypes, e.g.,

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

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Krustrup, P; Skoradal, M-B; Randers, M B; Weihe, P; Uth, J; Mortensen, J; Mohr, M

2017-12-01

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 inactive middle-aged women were separated into a soccer training group (n=19; SOC) and a control group (n=12; CON). SOC performed 128±29 (±SD) one-h small-sided soccer training sessions over one year. Blood pressure, body composition, blood lipid profile, and fitness level were determined pre- and post-intervention. Over one year, mean arterial pressure decreased more in SOC than in CON (-5±7 vs +4±5 mmHg; Pendurance level 1 (122±105 vs 2±21%) and 20-m sprint performance (6±6 vs -1±2%) increased more (Ptraining resulted in broad-spectrum improvements in the health profile of untrained, pre-menopausal women with mild hypertension, including cardiovascular, metabolic, and musculo-skeletal benefits. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Your brain on drugs: imaging of drug-related changes in the central nervous system.

Science.gov (United States)

Tamrazi, Benita; Almast, Jeevak

2012-01-01

Drug abuse is a substantial problem in society today and is associated with significant morbidity and mortality. Various drugs are associated with serious complications affecting the brain, and it is critical to recognize the imaging findings of these complications to provide prompt medical management. The central nervous system (CNS) is a target organ for drugs of abuse as well as specific prescribed medications. Drugs of abuse affecting the CNS include cocaine, heroin, alcohol, amphetamines, toluene, and cannabis. Prescribed medications or medical therapies that can affect the CNS include immunosuppressants, antiepileptics, nitrous oxide, and total parenteral nutrition. The CNS complications of these drugs include neurovascular complications, encephalopathy, atrophy, infection, changes in the corpus callosum, and other miscellaneous changes. Imaging abnormalities indicative of these complications can be appreciated at both magnetic resonance (MR) imaging and computed tomography (CT). It is critical for radiologists to recognize complications related to drugs of abuse as well as iatrogenic effects of various medications. Therefore, diagnostic imaging modalities such as MR imaging and CT can play a pivotal role in the recognition and timely management of drug-related complications in the CNS.

The use of inexpensive broad spectrum lower toxicity therapeutics in chronic lymphocytic leukemia.

Science.gov (United States)

Marjanovic, Goran

2017-01-01

The use of new and highly efficient targeted therapies for chronic lymphocytic leukemia (CLL) is costly and out of reach for many health care systems. On the other hand, in recent years, few inexpensive, broad-spectrum low-toxicity therapeutics have proven to be effective both in the preclinical and clinical settings. In early-stage CLL, the use of 2000 mg of epigallocatechin-3-gallate (EGCG) from the green tea extract twice a day was able to reduce the absolute leukocyte count. Supplementation of >2000 IU/day of Vitamin D in early low-risk CLL patients is able to delay disease progression and postpone the moment of initiation of the first treatment. The doses of both vitamin D and EGCG were shown to be safe in older patients. Vitamin D, EGCG and Curcumin, either as monotherapy or in combination, have additive and synergistic effects with conventional chemotherapy. Further observations have identified the improvement of response to rituximab-fludarabine-cyclophosphamide (R-FC) therapy with concomitant administration of statin and aspirin combination in relapsed/refractory CLL. Finally, high dose dexamethasone with 40mg/m 2 /day for 4 days, every 28 days, either alone or with monoclonal antibody, might be used as a salvage therapy or for debulking before transplantation in refractory/resistant cases. Dexamethasone therapy is followed by transient response and high rate of infections, but fluid retention and other toxicities are lower compared to high dose methylprednisolone schedules. The low cost therapeutics discussed in this review could not be a substitute for the more effective targeted therapies, but their use in every day practice might postpone the need for early implementation of new and costly medications.

Etiologic features and utilization of antiepileptic drugs in people with chronic epilepsy in China: Report from the Epilepsy Cohort of Huashan Hospital (ECoH).

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Ge, Yan; Yu, Peimin; Ding, Ding; Wang, Ping; Shi, Yunbo; Zhao, Ting; Tang, Xinghua; Hong, Zhen

2015-10-01

Chronic epilepsy is estimated to affect more than 2 million people in China. However, data of its clinical characteristics was rarely reported in China. In the present study, we summarized the etiologic features and utilization patterns of antiepileptic drugs (AEDs) in people with chronic epilepsy in a tertiary medical center in China. We prospectively recruited people with chronic epilepsy treated at the Epilepsy Outpatient Clinic of Huashan Hospital during October 2009 to August 2013. Demographic data, clinical characteristics, AED treatment, epilepsy-associated risk factors and medical history, and results of supplementary examinations of each participant were collected retrospectively via an interviewer-administered questionnaire and confirmed by the medical records. Among 554 people with chronic epilepsy, 58.0% of them were male, 66.8% had focal seizure, and 29.2% had symptomatic cause. Developmental anomalies of cerebral structure (16.7%) and cerebral trauma (16.7%) shared the leading cause of symptomatic epilepsy among children with epilepsy. While cerebral trauma (29.1%) and cerebrovascular disorder (36.4%) were the most common causes in groups of adults and elderly. Fifty percent of participants were taking AED monotherapy. Proportions of people with idiopathic, cryptogenic and symptomatic epilepsy treated by multitherapy were 35%, 46% and 45.6%, respectively. Valproic acid (VPA) was the most frequently utilized AED as monotherapy (32.7%) and within multitherapy (62.5%). This hospital-based study reported that etiologic features were diverse in different age groups of people with chronic epilepsy. VPA was widely utilized to treat chronic epilepsy in mainland China. Copyright © 2015 Elsevier B.V. All rights reserved.

Extreme Variability in a Broad Absorption Line Quasar

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Stern, Daniel; Jun, Hyunsung D. [Jet Propulsion Laboratory, California Institute of Technology, 4800 Oak Grove Drive, Mail Stop 169-221, Pasadena, CA 91109 (United States); Graham, Matthew J.; Djorgovski, S. G.; Donalek, Ciro; Drake, Andrew J.; Mahabal, Ashish A.; Steidel, Charles C. [California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125 (United States); Arav, Nahum; Chamberlain, Carter [Department of Physics, Virginia Tech, Blacksburg, VA 24061 (United States); Barth, Aaron J. [Department of Physics and Astronomy, 4129 Frederick Reines Hall, University of California, Irvine, CA 92697 (United States); Glikman, Eilat, E-mail: daniel.k.stern@jpl.nasa.gov [Department of Physics, Middlebury College, Middlebury, VT 05753 (United States)

2017-04-20

CRTS J084133.15+200525.8 is an optically bright quasar at z = 2.345 that has shown extreme spectral variability over the past decade. Photometrically, the source had a visual magnitude of V ∼ 17.3 between 2002 and 2008. Then, over the following five years, the source slowly brightened by approximately one magnitude, to V ∼ 16.2. Only ∼1 in 10,000 quasars show such extreme variability, as quantified by the extreme parameters derived for this quasar assuming a damped random walk model. A combination of archival and newly acquired spectra reveal the source to be an iron low-ionization broad absorption line quasar with extreme changes in its absorption spectrum. Some absorption features completely disappear over the 9 years of optical spectra, while other features remain essentially unchanged. We report the first definitive redshift for this source, based on the detection of broad H α in a Keck/MOSFIRE spectrum. Absorption systems separated by several 1000 km s{sup −1} in velocity show coordinated weakening in the depths of their troughs as the continuum flux increases. We interpret the broad absorption line variability to be due to changes in photoionization, rather than due to motion of material along our line of sight. This source highlights one sort of rare transition object that astronomy will now be finding through dedicated time-domain surveys.

Possible roles for frequent salivary antiepileptic drug monitoring in the management of epilepsy.

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Herkes, G K; Eadie, M J

1990-07-01

Salivary levels of phenytoin, phenobarbitone, carbamazepine and carbamazepine-epoxide correlate with the simultaneous plasma water levels of these substances, after correcting for the effects of pH differences between saliva and plasma in the case of phenobarbitone. Saliva is easy and painless to collect, and salivary levels of the drugs are conveniently measured. Frequent (often daily) monitoring of pre-dose morning anticonvulsant drug concentrations in saliva over periods of weeks or months in 3 groups of epileptic subjects showed that (i) in some but not all poorly controlled epileptic patients seizures tended to occur on days when salivary anticonvulsant levels were lower than on non-seizure days, (ii) in such subjects it was possible to estimate an anticipated optimal drug concentration and dose to minimize seizure activity from the plot of seizure frequency against drug concentrations, (iii) in women with 'catamenial' epilepsy, salivary anticonvulsant levels were lower on perimenstrual days than at mid-cycle in half of the subjects studied, and (iv) in pregnant epileptic women the time course of the change in drug levels relative to dose could be followed more closely throughout pregnancy and the post-natal period than was practicable when using blood level measurements. Frequent measurement of salivary anticonvulsant concentrations appears a promising and inexpensive adjunct to the investigation and management of certain problem areas in epilepsy.

Inhibition of human aromatase complex (CYP19) by antiepileptic drugs

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

2008-01-01

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

Homeostasis or channelopathy? Acquired cell type-specific ion channel changes in temporal lobe epilepsy and their antiepileptic potential

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Wolfart, Jakob; Laker, Debora

2015-01-01

Neurons continuously adapt the expression and functionality of their ion channels. For example, exposed to chronic excitotoxicity, neurons homeostatically downscale their intrinsic excitability. In contrast, the “acquired channelopathy” hypothesis suggests that proepileptic channel characteristics develop during epilepsy. We review cell type-specific channel alterations under different epileptic conditions and discuss the potential of channels that undergo homeostatic adaptations, as targets for antiepileptic drugs (AEDs). Most of the relevant studies have been performed on temporal lobe epilepsy (TLE), a widespread AED-refractory, focal epilepsy. The TLE patients, who undergo epilepsy surgery, frequently display hippocampal sclerosis (HS), which is associated with degeneration of cornu ammonis subfield 1 pyramidal cells (CA1 PCs). Although the resected human tissue offers insights, controlled data largely stem from animal models simulating different aspects of TLE and other epilepsies. Most of the cell type-specific information is available for CA1 PCs and dentate gyrus granule cells (DG GCs). Between these two cell types, a dichotomy can be observed: while DG GCs acquire properties decreasing the intrinsic excitability (in TLE models and patients with HS), CA1 PCs develop channel characteristics increasing intrinsic excitability (in TLE models without HS only). However, thorough examination of data on these and other cell types reveals the coexistence of protective and permissive intrinsic plasticity within neurons. These mechanisms appear differentially regulated, depending on the cell type and seizure condition. Interestingly, the same channel molecules that are upregulated in DG GCs during HS-related TLE, appear as promising targets for future AEDs and gene therapies. Hence, GCs provide an example of homeostatic ion channel adaptation which can serve as a primer when designing novel anti-epileptic strategies. PMID:26124723

The Investigation of Insulin Resistance in Two Groups of Epileptic Patients Treated with Sodium Valproate and Carbamazepine

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Mohammad Reza Najafi

2017-01-01

Full Text Available Background: Valproic acid (VPA is a widely used broad-spectrum antiepileptic drug for therapy of generalized and focal epilepsies. Cross-sectional studies have suggested that valproate treatment may be associated with hyperinsulinemia. We decided to investigate hyperinsulinemia as a health-threatening side effect of VPA in Iranian epileptic patients. Materials and Methods: Body mass index (BMI, lipid profile, fasting serum insulin, fasting blood glucose (FBS, and homeostatic model assessment-insulin resistance (HOMA-IR were measured in 30 VPA-treated epileptic patients and 30 controls (CBZ-treated. The Chi-square test, t-test, and Pearson correlation test were used. Results: BMI was higher in VPA group than in control group (25.7 ± 3.5 > 21.7 ± 4.1 (0.000 0.05. Conclusion: Despite the majority of previous studies that are against VPA and according to our study, VPA could be prescribed safely and it may not cause IR and its complications.

Extended spectrum β-lactamase producing Escherichia coli and Klebsiella pneumoniae: critical tools for antibiotic resistance pattern.

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Padmini, Nagarajan; Ajilda, Antony Alex Kennedy; Sivakumar, Natesan; Selvakumar, Gopal

2017-06-01

Drug resistance is a phenomenon where by an organism becomes fully or partially resistant to drugs or antibiotics being used against it. Antibiotic resistance poses an exacting intimidation for people with underlying medical immune conditions or weakened immune systems. Infections caused by the enzyme extended spectrum β-lactamase (ESBL) producing multi drug resistance (MDR) Enterobacteriaceae especially Escherichia coli and Klebsiella pneumoniae are resistant to a broad range of beta lactams, including third generation cephalosporins. Among all the pathogens, these two MDR E. coli and K. pneumoniae have emerged as one of the world's greatest health threats in past two decades. The nosocomial infections caused by these ESBL producing MDR E. coli and K. pneumoniae complicated the therapy and limit treatment options. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Prevalence of psychoactive drug consumption in an obese population].

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Cerdá Esteve, Maria A; Barral Tafalla, Diego; Gudelis, Mindaugas; Goday, Albert; Farre Albaladejo, Magi; Cano, Juan F

2010-04-01

To establish the prevalence of psychoactive drug consumption in an obese population. We collected data from the clinical records of obese patients attending the Endocrinology and Nutrition Department and Psychiatry Department of Hospital del Mar between June 2005 and May 2006 (n=259). We recorded anthropometric, epidemiological and toxicological data. We also investigated the prevalence of concomitant diseases in this population. Psychoactive drugs were consumed by 37% of obese patients, mainly antidepressants (27%), anxiolytics, sedatives and hypnotics, and anticonvulsants. Moreover, 15% of all patients received combination treatment with two or more psychoactive drugs, mostly the association of an antidepressant and an antiepileptic drug. The prevalence of psychoactive drug consumption in our sample was higher than prevalence data observed in the general population, with antidepressant consumption being three-fold higher. Copyright 2009 SEEN. Published by Elsevier Espana. All rights reserved.

An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity

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Chun-Bing Chen

2018-01-01

Full Text Available Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS/drug-induced hypersensitivity syndrome (DIHS, or Stevens–Johnson syndrome (SJS/toxic epidermal necrolysis (TEN. Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs. The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.

An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity

Science.gov (United States)

Abe, Riichiro; Pan, Ren-You; Wang, Chuang-Wei

2018-01-01

Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity. PMID:29651444

Prenatal exposure to antiepileptic drugs and dental agenesis.

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Pernille E Jacobsen

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

The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part II: Pharmacological issues and further understanding.

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de Leon, Jose

2015-01-01

The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. Part II of this comprehensive review on antiepileptic drug (AED) inducers provides clinicians with further educational material about the complexity of interpreting AED drug-drug interactions. The basic pharmacology of induction is reviewed including the cytochrome P450 (CYP) isoenzymes, the Uridine Diphosphate Glucuronosyltransferases (UGTs), and P-glycoprotein (P-gp). CYP2B6 and CYP3A4 are very sensitive to induction. CYP1A2 is moderately sensitive while CYP2C9 and CYP2C19 are only mildly sensitive. CYP2D6 cannot be induced by medications. Induction of UGT and P-gp are poorly understood. The induction of metabolic enzymes such as CYPs and UGTs, and transporters such as P-gp, implies that the amount of these proteins increases when they are induced; this is almost always explained by increasing synthesis mediated by the so-called nuclear receptors (constitutive androstane, estrogen, glucocorticoid receptors and pregnaneX receptors). Although parti provides correction factors for AEDs, extrapolation from an average to an individual patient may be influenced by administration route, absence of metabolic enzyme for genetic reasons, and presence of inhibitors or other inducers. AED pharmacodynamic DDIs may also be important. Six patients with extreme sensitivity to AED inductive effects are described. Copyright © 2014 SEP y SEPB. Published by Elsevier España. All rights reserved.

Drug hypersensitivity syndrome

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Rashmi Kumari

2011-01-01

Full Text Available Drug hypersensitivity syndrome (DHS is an adverse drug reaction commonly associated with the aromatic antiepileptic drugs (AEDs, viz., phenytoin (PHT, carbamazepine (CBZ, phenobarbital (PB, lamotrigine, primidone, etc. It can also be caused by other drugs, such as sulfonamides, dapsone, minocycline, gold derivatives, cyclosporine, captopril, diltiazem, terbinafine, azathioprine and allopurinol. Diagnosis of DHS may be difficult because of the variety of clinical and laboratory abnormalities and manifestations and because the syndrome may mimic infectious, neoplastic or collagen vascular disorders. The risk for developing hypersensitivity within 60 days of the first or second prescription in new users of PHT or CBZ was estimated to be 2.3-4.5 per 10,000 and 1-4.1 per 10,000, respectively. The syndrome is defined by the fever, skin rash, lymphadenopathy and internal organ involvement within the first 2-8 weeks after initiation of therapy. Internal manifestations include, among others, agranulocytosis, hepatitis, nephritis and myositis. Insufficient detoxification may lead to cell death or contribute to the formation of antigen that triggers an immune reaction. Cross-reactivity among PHT, CBZ and PB is as high as 70%-80%. Management mainly includes immediate withdrawal of the culprit drug, symptomatic treatment and systemic steroids or immunoglobulins.

Broad phenotypic spectrum in familial adenomatous polyposis; from early onset and severe phenotypes to late onset of attenuated polyposis with the first manifestation at age 72

DEFF Research Database (Denmark)

Nilbert, Mef; Kristoffersson, Ulf; Ericsson, Mats

2008-01-01

ABSTRACT: Background Familial adenomatous polyposis (FAP) is typically characterized by multiple colonic polyps and frequent extracolonic features. Whereas the number of colonic polyps has been linked to the APC gene mutation, possible genotype-phenotype correlations largely remain to be defined...... cancer at age 72 as the first manifestation of attenuated FAP. Conclusion With an increasing number of FAP families diagnosed, a broad and variable tumor spectrum and a high frequency of extracolonic manifestations are gradually recognized. We report novel APC mutations and present two FAP cases...

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

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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.

Evolução sócio-profissional de 140 pacientes epilépticos submetidos a tratamento medicamentoso The socio-professional evolution of 140 epileptic patients submitted to antiepileptic drug therapy

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Luís Marques-Assis

1968-09-01

Full Text Available É estudada a evolução sócio-profissional de 140 doentes epilépticos, submetidos apenas a tratamento medicamentoso. Foram empregadas drogas de fácil aquisição em nosso meio (barbitúricos, hidantoinatos, primidona e trimetadiona, utilizadas isolada ou combinadamente. No estudo foram consideradas basicamente as atividades escolares, domésticas e profissionais. A evolução sócio-profissional foi estudada em relação às manifestações clínicas, ao tempo de doença, à freqüência das crises e ao padrão eletrencefalográfico. Os resultados, expressos em índices percentuais, permitiram ao autor concluir que na maioria dos pacientes epilépticos, convenientemente tratados do ponto de vista clínico, os problemas sociais e profissionais podem ser corrigidos ou evitados, independentemente de outras medidas especializadas que possam ser postas em prática.The socio-professional evolution of 140 epileptic patients submitted to antiepileptic drug therapy is studied. Only barbiturates, hydantoin, primidone and trimethadione were administered to the patients, isolated or in association. The school, house keeper and professional activities were considered in the investigation. The socio-professional follow-up was investigated regarding to clinic manifestations, time of disease, frequency of seizures and electroencephalographic pattern. The results, analysed in percentage, led the author to the conclusion that in most epileptic patients, adequately controlled with drugs, the social and the professional problems can be avoided.

From Asperger's Autistischen Psychopathen to DSM-5 Autism Spectrum Disorder and Beyond: A Subthreshold Autism Spectrum Model.

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Dell'Osso, Liliana; Luche, Riccardo Dalle; Gesi, Camilla; Moroni, Ilenia; Carmassi, Claudia; Maj, Mario

2016-01-01

Growing interest has recently been devoted to partial forms of autism, lying at the diagnostic boundaries of those conditions previously diagnosed as Asperger's Disorder. This latter includes an important retrieval of the European classical psychopathological concepts of adult autism to which Hans Asperger referred in his work. Based on the review of Asperger's Autistische Psychopathie , from first descriptions through the DSM-IV Asperger's Disorder and up to the recent DSM-5 Autism Spectrum Disorder, the paper aims to propose a Subthreshold Autism Spectrum Model that encompasses not only threshold-level manifestations but also mild/atypical symptoms, gender-specific features, behavioral manifestations and personality traits associated with Autism Spectrum Disorder. This model includes, but is not limited to, the so-called broad autism phenotype spanning across the general population that does not fully meet Autism Spectrum Disorder criteria. From this perspective, we propose a subthreshold autism as a unique psychological/behavioral model for research that could help to understand the neurodevelopmental trajectories leading from autistic traits to a broad range of mental disorders.

Prognostic analysis of patients with epilepsy according to time of relapse after withdrawal of antiepileptic drugs following four seizure-free years.

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Park, Soochul; Lee, Dong Hyun; Kim, Seung Woo; Roh, Yun Ho

2017-01-01

We performed a retrospective, prognostic analysis of a cohort of patients with epilepsy according to time of relapse after four seizure-free years. Planned withdrawal of antiepileptic drugs (AEDs) and at least 3 years of follow-up after AED discontinuation were performed. The following two groups were assessed: (1) an early relapse (ER) group of patients who experienced recurrence during AED withdrawal and (2) a late relapse (LR) group of patients who experienced recurrence after completion of the AED discontinuation process. After dichotomization, the relapse rate, prognostic factors, and their impacts for each group were compared with those of a group of patients who continued to be seizure-free after AED withdrawal (SF group) using multiple logistic regression analysis. The AED intake mode was also analyzed. Two hundred seventeen (64.6%) of the 336 total patients experienced relapse. One hundred thirty-nine patients (41.4%) and 78 patients (23.2%) were included in the LR and ER groups, respectively. Symptom duration >120 months showed the strongest negative prognostic impact as demonstrated by the 4.7-fold higher risk of recurrence in the ER group compared with the SF group. Additional factors with a negative prognostic impact included an age at epilepsy onset of ≤20 years and the presence of localization-related epilepsy. No reliable predictor between the SF and LR groups was revealed. After exclusion of the SF group, post hoc analysis according to age at epilepsy onset and symptom duration showed that the above-mentioned negative prognostic factors significantly affected the relapse patterns of the LR and ER groups. The results suggest that longer symptom duration, which could be associated with intrinsic reactivation of epilepsy, is the strongest negative prognostic factor for relapse. Relapse after AED withdrawal in prolonged follow-up of seizure-free patients is one aspect of the natural history of epilepsy. © 2016 The Authors. Epilepsia published by

Prophylactic drug management for febrile seizures in children

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Martin Offringa

Full Text Available BACKGROUND Febrile seizures occurring in a child older than one month during an episode of fever affect 2% to 4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. OBJECTIVE To evaluate the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures. METHODS Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL (The Cochrane Library 2011. Issue 3; MEDLINE (1966 to May 2011; EMBASE (1966 to May 2011; Database of Abstracts of Reviews of Effectiveness (DARE (May 2011. No language restrictions were imposed. We also contacted researchers in the field to identify continuing or unpublished studies. Selection criteria: Trials using randomized or quasi-randomized patient allocation that compared the use of antiepileptic or antipyretic agents with each other, placebo or no treatment. Data collection and analysis: Two review authors (RN and MO independently applied pre-defined criteria to select trials for inclusion and extracted the pre-defined relevant data, recording methods for randomization, blinding and exclusions. Outcomes assessed were seizure recurrence at 6, 12, 18, 24, 36 months and at age 5 to 6 years in the intervention and non-intervention groups, and adverse medication effects. The presence of publication bias was assessed using funnel plots. MAIN RESULTS Thirty-six articles describing 26 randomized trials with 2740 randomized participants were included. Thirteen interventions of continuous or intermittent prophylaxis and their control treatments were analyzed. Methodological quality was moderate to poor in most studies. We could not do a meta-analysis for 8 of the 13 comparisons due to insufficient numbers of trials. No significant benefit for valproate, pyridoxine

[Diagnosis and management of de novo epilepsy].

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Louise, Tyvaert

2018-03-01

The diagnosis of de novo epilepsy is complex. An accurate diagnostic approach has to be followed based on specific key steps. Epileptic seizure or non-epileptic malaise: risk of diagnosis error around 20%. Facing a first unprovoked seizure, the practitioner has to know the risk factors specifically linked to an increase risk of seizure recurrence. In presence of these factors, an antiepileptic drug would be indicated. The first antiepileptic drug has to be highly selected according to the epilepsy type and causes but also to the patient characteristics (sex, age, comorbidities, associated drugs, profession, and way of life…) An exhaustive patient Education needs to support the first antiepileptic drug prescription: (sleep and nutritional advices, benefit of observance, antiepileptic drugs features and side effects, follow-up, prognosis…) A regular follow-up is essential to control the observance, tolerability and efficacy of the antiepileptic drug, and to control also the good acceptance of the disease. A systematic research of common comorbidities may be also performed. Electroencephalogram and antiepileptic drugs levels are unnecessary in the classical follow up of known epileptic patients (except specific cases). Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Divergence Palsy due to Divalproex and Oxcarbazepine.

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Bouffard, Marc Albert; Caplan, Louis R; Torun, Nurhan

This case series is the first to describe divergence palsy as an adverse effect of antiepileptic drug use. Diplopia is a common adverse effect of antiepileptic drugs, but no explanatory motility deficit has ever been reported. We present 2 patients, 1 on oxcarbazepine and 1 on divalproex, each with a normal examination result between spells and divergency palsy when symptomatic. Discontinuation of the antiepileptic medication led to resolution of the episodes in both cases. Rechallenge with the offending agent after washout in one patient resulted in recurrence of diplopia and divergence palsy, both resolving after subsequent withdrawal of the antiepileptic. Antiepileptic drugs may cause divergence palsy.

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

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Kadam, Rameshwar U.; Wilson, Ian A.

2016-12-21

The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers. This cavity is distal to the conserved epitope targeted by broadly neutralizing stem antibodies and is ~16 Å from the fusion peptide. Arbidol primarily makes hydrophobic interactions with the binding site but also induces some conformational rearrangements to form a network of inter- and intraprotomer salt bridges. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome. This unique binding mode compared with the small-molecule inhibitors of other class I fusion proteins enhances our understanding of how small molecules can function as fusion inhibitors and guides the development of broad-spectrum therapeutics against influenza virus.

CURRENT APPROACHES TO THERAPY OF RETT’S SYNDROME (A REVIEW OF LITERATURE

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N. Yu. Borovikova

2015-01-01

Full Text Available Antiepileptic therapy is one of the most urgent problems in the treatment of Rett’s syndrome. By taking into account a common concurrence of generalized and focal seizures with diffuse epileptiform activity on the electroencephalogram (EEG in Rett’s syndrome, there are effective broad-spectrum antiepileptic drugs (AEDs: valproates, topiramate, levetiracetam, lamotrigine. Carbamazepine is effective for focal seizures and in the absence of diffuse EEG changes. For atypical absences, ethosuximide may be added to valproates, topiramate, or levetiracetam. Reflex seizures show a high resistance; their frequency is occasionally reduced by AEDs in combination with neuroleptics. Sleep hygiene, as well as medication (clonidine, zolpidem, trazodone, melatonin, risperidone are recommended to correct various sleep disorders. Dopamine agonists, as well as L-carnitine are used for the drug correction of movement disorders in Rett’s syndrome. Therapeutic exercises are one of the most optimal ways to correct movement disorders. Orthopedic correction, including surgery, is indicated for skeletal deformities. Vitamin D used for long periods of time is beneficial, by considering its deficiency and osteoporosis at a fracture risk in Rett’s syndrome patients who receive AEDs particularly long. A special high-fat diet and a fractional diet in small portions are used in the therapy of cachexia and growth retardation due to oral dysfunction and malnutrition. A cardiological follow-up is needed in abnormalities, such as prolonged Q interval, tachyarrhythmia, and cardiac structural anomalies. Systematic learning to maintain communication and motor skills are of importance. In this case a special role is played by music therapy that exerts a calming effect on patients and partially compensates for loss of contact with the environment.

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

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

2017-02-01

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

Divide and conquer: processive transport enables multidrug transporters to tackle challenging drugs

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Nir Fluman

2014-09-01

Full Text Available Multidrug transporters are membrane proteins that catalyze efflux of antibiotics and other toxic compounds from cells, thereby conferring drug resistance on various organisms. Unlike most solute transporters that transport a single type of compound or similar analogues, multidrug transporters are extremely promiscuous. They transport a broad spectrum of dissimilar drugs and represent a serious obstacle to antimicrobial or anticancer chemotherapy. Many challenging aspects of multidrug transporters, which are unique, have been studied in detail, including their ability to interact with chemically unrelated drugs, and how they utilize energy to drive efflux of compounds that are not only structurally but electrically different. A new and surprising dimension of the promiscuous nature of multidrug transporters has been described recently: they can move long molecules through the membrane in a processive manner.

Computer-aided drug discovery [v1; ref status: indexed, http://f1000r.es/5ij

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Jürgen Bajorath

2015-08-01

Full Text Available Computational approaches are an integral part of interdisciplinary drug discovery research. Understanding the science behind computational tools, their opportunities, and limitations is essential to make a true impact on drug discovery at different levels. If applied in a scientifically meaningful way, computational methods improve the ability to identify and evaluate potential drug molecules, but there remain weaknesses in the methods that preclude naïve applications. Herein, current trends in computer-aided drug discovery are reviewed, and selected computational areas are discussed. Approaches are highlighted that aid in the identification and optimization of new drug candidates. Emphasis is put on the presentation and discussion of computational concepts and methods, rather than case studies or application examples. As such, this contribution aims to provide an overview of the current methodological spectrum of computational drug discovery for a broad audience.

Transgenic cotton coexpressing Vip3A and Cry1Ac has a broad insecticidal spectrum against lepidopteran pests.

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Chen, Wen-Bo; Lu, Guo-Qing; Cheng, Hong-Mei; Liu, Chen-Xi; Xiao, Yu-Tao; Xu, Chao; Shen, Zhi-Cheng; Wu, Kong-Ming

2017-10-01

Although farmers in China have grown transgenic Bt-Cry1Ac cotton to resist the major pest Helicoverpa armigera since 1997 with great success, many secondary lepidopteran pests that are tolerant to Cry1Ac are now reported to cause considerable economic damage. Vip3AcAa, a chimeric protein with the N-terminal part of Vip3Ac and the C-terminal part of Vip3Aa, has a broad insecticidal spectrum against lepidopteran pests and has no cross resistance to Cry1Ac. In the present study, we tested insecticidal activities of Vip3AcAa against Spodoptera litura, Spodoptera exigua, and Agrotis ipsilon, which are relatively tolerant to Cry1Ac proteins. The bioassay results showed that insecticidal activities of Vip3AcAa against these three pests are superior to Cry1Ac, and after an activation pretreatment, Vip3AcAa retained insecticidal activity against S. litura, S. exigua and A. ipsilon that was similar to the unprocessed protein. The putative receptor for this chimeric protein in the brush border membrane vesicle (BBMV) in the three pests was also identified using biotinylated Vip3AcAa toxin. To broaden Bt cotton activity against a wider spectrum of pests, we introduced the vip3AcAa and cry1Ac genes into cotton. Larval mortality rates for S. litura, A. ipsilon and S. exigua that had fed on this new cotton increased significantly compared with larvae fed on non-Bt cotton and Bt-Cry1Ac cotton in a laboratory experiment. These results suggested that the Vip3AcAa protein is an excellent option for a "pyramid" strategy for integrated pest management in China. Copyright © 2017 Elsevier Inc. All rights reserved.

The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part I: A summary of the current state for clinicians.

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de Leon, Jose

2015-01-01

The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. This is part i of a comprehensive review on antiepileptic drug (AED) inducers using both mechanistic pharmacological and evidence-based medicine to provide practical recommendations to neurologists and psychiatrists concerning how to control for them. Carbamazepine, phenobarbital and phenytoin, are clinically relevant AED inducers; correction factors were calculated for studied induced drugs. These correction factors are rough simplifications for orienting clinicians, since there is great variability in the population regarding inductive effects. As new information is published, the correction factors may need to be modified. Some of the correction factors are so high that the drugs (e.g., bupropion, quetiapine or lurasidone) should not co-prescribed with potent inducers. Clobazam, eslicarbazepine, felbamate, lamotrigine, oxcarbazepine, rufinamide, topiramate, vigabatrin and valproic acid are grouped as mild inducers which may (i)be inducers only in high doses; (ii)frequently combine with inhibitory properties; and (iii)take months to reach maximum effects or de-induction, definitively longer than the potent inducers. Potent inducers, definitively, and mild inducers, possibly, have relevant effects in the endogenous metabolism of (i)sexual hormones, (ii) vitamin D, (iii)thyroid hormones, (iv)lipid metabolism, and (v)folic acid. Copyright © 2014 SEP y SEPB. Published by Elsevier España. All rights reserved.

Clinical spectrum of psychogenic non epileptic seizures in children; an observational study.

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Madaan, Priyanka; Gulati, Sheffali; Chakrabarty, Biswaroop; Sapra, Savita; Sagar, Rajesh; Mohammad, Akbar; Pandey, R M; Tripathi, Manjari

2018-07-01

The current study was designed to analyze the clinical spectrum of Psychogenic non-epileptic seizures (PNES) in children. Children aged 6-16years with clinically suspected PNES, confirmed by short-term VEEG (STVEEG{video electroencephalogram}) and induction were classified as per Seneviratne classification. Stressors, associated co morbidities, Verbal IQ (Intelligence Quotient) and behavioral abnormalities were assessed using HTP(House tree person) test, DSM IV (Diagnostic and statistical manual of mental disorders) TR criteria, MISIC (Malin intelligence scale for Indian children) and CBCL (Child behaviour checklist). Eighty children with PNES {45 boys; mean age: 10.5 (±1.6) years} were enrolled. Median delay in diagnosis was 5 months {IQR(interquartile range)- 0.5 to 48 months}) and 45% patients were already on AEDs (antiepileptic drugs). Commonest semiology was dialeptic (42.5%), followed by mixed (28.8%), motor (15%) and nonepileptic aura (13.8%). Family stressors were the commonest followed by school related issues. The most common psychiatric comorbidity was adjustment disorder. Somatic complaints were observed in 50% children. Dialeptic PNES is commonest in children. In resource constrained settings, STVEEG along with induction is a reliable method to diagnose PNES. A comprehensive assessment protocol (including assessment of stressors) is needed for holistic management of pediatric PNES. Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Clarithromycine-Induced Ventricular Tachycardia in a Geriatric Patient Using Multiple Drugs

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Gulsah Karaoren

2016-07-01

Full Text Available Long QT syndrome is a cardiac repolarization disorder, which can be either idiopathic or congenital, and cause sudden cardiac death. The iatrogenic form is generally associated with drugs or electrolyte imbalance. Although prolonged QT interval is frequently seen due to antiarrhythmic agents, it can also be seen with antibiotics or anti-epileptics. Adverse drug interaction can manifest in several clinicopathological forms in elder individuals. In such cases, potential adverse effects of drugs used should be taken into consideration before prescribing additional drugs. Here, we present a case of clarithromycine-induced ventricular arrhythmia accompanied by QT prolongation on the third day of therapy, and the subsequent therapeutic approach, in a 91-year-old man. The patient was taking multiple drugs due to comorbid conditions and was prescribed clarithromycine therapy in the intensive care unit.

[Neonatal risks of drugs exposure at the end of pregnancy].

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Autret-Leca, Elisabeth; Cissoko, Hawaré; Jonville-Béra, Annie Pierre

2011-01-01

Foetal drugs exposure consequences depend according to the drug involved and to the length of the exposure which in the sum of length of treatment and of drug elimination (5 half life). Decisions are based upon risk evaluation and are a compromise between a risk banalisation and an excess of carefully. We described risks management for drugs used for a disease due to the pregnancy (glucocorticoïdes, antibiotics) then for drugs used for a chronic disease often preceding the pregnancy (non steroidal anti-inflammatory, serotonin recapture inhibitors, benzodiazepines, antiepileptics, conversion enzyme inhibitors/renine angiotensine antagonists, betabloquants). We also present the elements to take in account for the best drug choice at the end of pregnancy and/or for an adapted advice if the drug has been already taken: the drug itself (pharmacological effects, kinetics in neonate, toxicity marker, risk detection tool), drug amount possibly received by the neonate and literature data about neonatal manifestations due to the drug. © 2011 Société Française de Pharmacologie et de Thérapeutique.

Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior.

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Tielbeek, Jorim J; Johansson, Ada; Polderman, Tinca J C; Rautiainen, Marja-Riitta; Jansen, Philip; Taylor, Michelle; Tong, Xiaoran; Lu, Qing; Burt, Alexandra S; Tiemeier, Henning; Viding, Essi; Plomin, Robert; Martin, Nicholas G; Heath, Andrew C; Madden, Pamela A F; Montgomery, Grant; Beaver, Kevin M; Waldman, Irwin; Gelernter, Joel; Kranzler, Henry R; Farrer, Lindsay A; Perry, John R B; Munafò, Marcus; LoParo, Devon; Paunio, Tiina; Tiihonen, Jari; Mous, Sabine E; Pappa, Irene; de Leeuw, Christiaan; Watanabe, Kyoko; Hammerschlag, Anke R; Salvatore, Jessica E; Aliev, Fazil; Bigdeli, Tim B; Dick, Danielle; Faraone, Stephen V; Popma, Arne; Medland, Sarah E; Posthuma, Danielle

2017-12-01

Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation

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

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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.

Overexpression of NPR1 in Brassica juncea Confers Broad Spectrum Resistance to Fungal Pathogens

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Sajad Ali

2017-10-01

Full Text Available Brassica juncea (Indian mustard is a commercially important oil seed crop, which is highly affected by many biotic stresses. Among them, Alternaria leaf blight and powdery mildew are the most devastating diseases leading to huge yield losses in B. juncea around the world. In this regard, genetic engineering is a promising tool that may possibly allow us to enhance the B. juncea disease resistance against these pathogens. NPR1 (non-expressor of pathogen-related gene 1 is a bonafide receptor of salicylic acid (SA which modulates multiple immune responses in plants especially activation of induced and systemic acquired resistance (SAR. Here, we report the isolation and characterization of new NPR1 homolog (BjNPR1 from B. juncea. The phylogenetic tree constructed based on the deduced sequence of BjNPR1 with homologs from other species revealed that BjNPR1 grouped together with other known NPR1 proteins of Cruciferae family, and was nearest to B. napus. Furthermore, expression analysis showed that BjNPR1 was upregulated after SA treatment and fungal infection but not by jasmonic acid or abscisic acid. To understand the defensive role of this gene, we generated B. juncea transgenic lines overexpressing BjNPR1, and further confirmed by PCR and Southern blotting. The transgenic lines showed no phenotypic abnormalities, and constitutive expression of BjNPR1 activates defense signaling pathways by priming the expression of antifungal PR genes. Moreover, BjNPR1 transgenic lines showed enhanced resistance to Alternaria brassicae and Erysiphe cruciferarum as there was delay in symptoms and reduced disease severity than non-transgenic plants. In addition, the rate of disease spreading to uninfected or distal parts was also delayed in transgenic plants thus suggesting the activation of SAR. Altogether, the present study suggests that BjNPR1 is involved in broad spectrum of disease resistance against fungal pathogens.

Broad-band near-field ground motion simulations in 3-dimensional scattering media

KAUST Repository

Imperatori, W.; Mai, Paul Martin

2012-01-01

examine scattering phenomena, related to the loss of radiation pattern and the directivity breakdown. We first simulate broad-band ground motions for a point-source characterized by a classic ω2 spectrum model. Fault finiteness is then introduced by means

Rufinamide, an antiepileptic drug, improves cognition and increases neurogenesis in the aged gerbil hippocampal dentate gyrus via increasing expressions of IGF-1, IGF-1R and p-CREB.

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Chen, Bai Hui; Ahn, Ji Hyeon; Park, Joon Ha; Song, Minah; Kim, Hyunjung; Lee, Tae-Kyeong; Lee, Jae Chul; Kim, Young-Myeong; Hwang, In Koo; Kim, Dae Won; Lee, Choong-Hyun; Yan, Bing Chun; Kang, Il Jun; Won, Moo-Ho

2018-04-25

Rufinamide is a novel antiepileptic drug and commonly used in the treatment of Lennox-Gastaut syndrome. In the present study, we investigated effects of rufinamide on cognitive function using passive avoidance test and neurogenesis in the hippocampal dentate gyrus using Ki-67 (a marker for cell proliferation), doublecortin (DCX, a marker for neuroblast) and BrdU/NeuN (markers for newly generated mature neurons) immunohistochemistry in aged gerbils. Aged gerbils (24-month old) were treated with 1 mg/kg and 3 mg/kg rufinamide for 4 weeks. Treatment with 3 mg/kg rufinamide, not 1 mg/kg rufinamide, significantly improved cognitive function and increased neurogenesis, showing that proliferating cells (Ki-67-immunoreactive cells), differentiating neuroblasts (DCX-immunoreactive neuroblasts) and mature neurons (BrdU/NeuN-immunoreactive cells) in the aged dentate gyrus compared with those in the control group. When we examined its mechanisms, rufinamide significantly increased immunoreactivities of insulin-like growth factor-1 (IGF-1), its receptor (IGF-1R), and phosphorylated cAMP response element binding protein (p-CREB). However, rufinamide did not show any increase in immunoreactivities of brain-derived neurotrophic factor and its receptor. Therefore, our results indicate that rufinamide can improve cognitive function and increase neurogenesis in the hippocampus of the aged gerbil via increasing expressions of IGF-1, IGF-1R and p-CREB. Copyright © 2018 Elsevier B.V. All rights reserved.

The sun protection factor (SPF) inadequately defines broad spectrum photoprotection: demonstration using skin reconstructed in vitro exposed to UVA, UVBor UV-solar simulated radiation.

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Bernerd, Françoise; Vioux, Corinne; Lejeune, François; Asselineau, Daniel

2003-01-01

Wavelength specific biological damage has been previously identified in human skin reconstructed in vitro. Sunburn cell and pyrimidine dimers were found after UVB exposure, and alterations of dermal fibroblasts after UVA exposure. These damages permitted us to discriminate UVB and UVA single absorbers. The present study shows that these biological effects can be obtained simultaneously by a combined UVB + UVA exposure using ultraviolet solar simulated light (UV-SSR), which represents a relevant UV source. In addition, the protection afforded by two broad spectrum sunscreen complex formulations was assessed after topical application. These two formulations displayed the same sun protection factor but different UVA protection factors determined by the persistent pigment darkening (PPD) method. Dose response experiments of UVA or UV-SSR showed that the preparation with the highest PF-UVA provided a better protection with regard to dermal damage compared to the other formulation. Using an original UVB source to obtain the UVB portion of SSR spectrum, the preparations provided the same protection. This study strikingly illustrates the fact that the photoprotection afforded by two sunscreen formulations having similar SPF values is not equal with regard to dermal damage related to photoaging.

Registries Help Moms Measure Medication Risks

Science.gov (United States)

... in the case of the North American Antiepileptic Drug Pregnancy Registry, which studies the effects of drugs for ... is taking. For example, the North American Antiepileptic Drug Pregnancy Registry website lists more than 30 medications being ...

Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens.

Science.gov (United States)

Fleeman, Renee; LaVoi, Travis M; Santos, Radleigh G; Morales, Angela; Nefzi, Adel; Welmaker, Gregory S; Medina-Franco, José L; Giulianotti, Marc A; Houghten, Richard A; Shaw, Lindsey N

2015-04-23

Mixture based synthetic combinatorial libraries offer a tremendous enhancement for the rate of drug discovery, allowing the activity of millions of compounds to be assessed through the testing of exponentially fewer samples. In this study, we used a scaffold-ranking library to screen 37 different libraries for antibacterial activity against the ESKAPE pathogens. Each library contained between 10000 and 750000 structural analogues for a total of >6 million compounds. From this, we identified a bis-cyclic guanidine library that displayed strong antibacterial activity. A positional scanning library for these compounds was developed and used to identify the most effective functional groups at each variant position. Individual compounds were synthesized that were broadly active against all ESKAPE organisms at concentrations development of resistance, and displayed almost no toxicity when tested against human lung cells and erythrocytes. Using a murine model of peritonitis, we also demonstrate that these agents are highly efficacious in vivo.

[Spectrum and drug sensitivity of pathogenic bacteria in children with nephrotic syndrome complicated by urinary tract infection: an analysis of 97 cases].

Science.gov (United States)

Song, Shao-Na; Zhang, Bi-Li; Wang, Wen-Hong; Zhang, Xuan

2012-09-01

To investigate the spectrum and drug sensitivity of pathogenic bacteria in children with nephrotic syndrome (NS) complicated by urinary tract infection (UTI). A retrospective analysis was performed on the spectrum and drug sensitivity of pathogenic bacteria in 97 children with NS complicated by UTI, who hospitalized from January to December, 2011. The incidence of UTI in children with NS was 36.5%. It was significantly more common in children with recurrent NS than in those with primary NS (44.0% vs 31.9%; Ppathogenic bacteria (50.5%), including Enterococcus faecium (29.4%) and Enterococcus faecalis (21.1%), followed by Gram-negative bacteria, such as Escherichia coli (15.6%) and Klebsiella pneumoniae (14.7%). Enterococcus was highly sensitive to nitrofurantoin, vacomycin and linezolid, but was highly resistant to tetracycline and moxifloxacin. More multi-resistant strains were detected in Enterococcus faecium than in Enterococcus faecalis (72% vs 17%; Pbacteria, 25% produced extended spectrum β-lactamases (ESBLs). ESBLs-producing bacteria had 100% sensitivity to imipenem, amikacin and piperacillin/tazobactam but were highly resistant to ampicillin, cefazolin and ceftriaxone. Children with recurrent NS are more susceptible to UTI than those with primary NS. Enterococcus is becoming major pathogenic bacteria for UTI in children with NS and has relatively high drug resistance, and most strains of Enterococcus faecium are multi-resistant.

The Sensitivity of the Crayfish Reward System to Mammalian Drugs of Abuse.

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Shipley, Adam T; Imeh-Nathaniel, Adebobola; Orfanakos, Vasiliki B; Wormack, Leah N; Huber, Robert; Nathaniel, Thomas I

2017-01-01

The idea that addiction occurs when the brain is not able to differentiate whether specific reward circuits were triggered by adaptive natural rewards or falsely activated by addictive drugs exist in several models of drug addiction. The suitability of crayfish ( Orconectes rusticus ) for drug addiction research arises from developmental variation of growth, life span, reproduction, behavior and some quantitative traits, especially among isogenic mates reared in the same environment. This broad spectrum of traits makes it easier to analyze the effect of mammalian drugs of abuse in shaping behavioral phenotype. Moreover, the broad behavioral repertoire allows the investigation of self-reinforcing circuitries involving appetitive and exploratory motor behavior, while the step-wise alteration of the phenotype by metamorphosis allows accurate longitudinal analysis of different behavioral states. This paper reviews a series of recent experimental findings that evidence the suitability of crayfish as an invertebrate model system for the study of drug addiction. Results from these studies reveal that unconditioned exposure to mammalian drugs of abuse produces a variety of stereotyped behaviors. Moreover, if presented in the context of novelty, drugs directly stimulate exploration and appetitive motor patterns along with molecular processes for drug conditioned reward. Findings from these studies indicate the existence of drug sensitive circuitry in crayfish that facilitates exploratory behavior and appetitive motor patterns via increased incentive salience of environmental stimuli or by increasing exploratory motor patterns. This work demonstrates the potential of crayfish as a model system for research into the neural mechanisms of addiction, by contributing an evolutionary, comparative context to our understanding of natural reward as an important life-sustaining process.

The Sensitivity of the Crayfish Reward System to Mammalian Drugs of Abuse

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Adam T. Shipley

2017-12-01

Full Text Available The idea that addiction occurs when the brain is not able to differentiate whether specific reward circuits were triggered by adaptive natural rewards or falsely activated by addictive drugs exist in several models of drug addiction. The suitability of crayfish (Orconectes rusticus for drug addiction research arises from developmental variation of growth, life span, reproduction, behavior and some quantitative traits, especially among isogenic mates reared in the same environment. This broad spectrum of traits makes it easier to analyze the effect of mammalian drugs of abuse in shaping behavioral phenotype. Moreover, the broad behavioral repertoire allows the investigation of self-reinforcing circuitries involving appetitive and exploratory motor behavior, while the step-wise alteration of the phenotype by metamorphosis allows accurate longitudinal analysis of different behavioral states. This paper reviews a series of recent experimental findings that evidence the suitability of crayfish as an invertebrate model system for the study of drug addiction. Results from these studies reveal that unconditioned exposure to mammalian drugs of abuse produces a variety of stereotyped behaviors. Moreover, if presented in the context of novelty, drugs directly stimulate exploration and appetitive motor patterns along with molecular processes for drug conditioned reward. Findings from these studies indicate the existence of drug sensitive circuitry in crayfish that facilitates exploratory behavior and appetitive motor patterns via increased incentive salience of environmental stimuli or by increasing exploratory motor patterns. This work demonstrates the potential of crayfish as a model system for research into the neural mechanisms of addiction, by contributing an evolutionary, comparative context to our understanding of natural reward as an important life-sustaining process.

A universal aptameric biosensor: Multiplexed detection of small analytes via aggregated perylene-based broad-spectrum quencher.

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Hu, Rong; Zhang, Xi; Xu, Qiang; Lu, Dan-Qing; Yang, Yun-Hui; Xu, Quan-Qing; Ruan, Qiong; Mo, Liu-Ting; Zhang, Xiao-Bing

2017-06-15

A universal aptameric system based on the taking advantage of double-stranded DNA/perylene diimide (dsDNA/PDI) as the signal probe was developed for multiplexed detection of small molecules. Aptamers are single-stranded DNA or RNA oligonucleotides which are selected in vitro by a process known as systematic evolution of ligands by exponential enrichment. In this work, we synthesized a new kind of PDI and reported this aggregated PDI could quench the double-stranded DNA (dsDNA)-labeled fluorophores with a high quenching efficiency. The quenching efficiencies on the fluorescence of FAM, TAMRA and Cy5 could reach to 98.3%±0.9%, 97.2%±0.6% and 98.1%±1.1%, respectively. This broad-spectrum quencher was then adopted to construct a multicolor biosensor via a label-free approach. A structure-switching-triggered enzymatic recycling amplification was employed for signal amplification. High quenching efficiency combined with autocatalytic target recycling amplification afforded the biosensor with high sensitivity towards small analytes. For other targets, changing the corresponding aptamer can achieve the goal. The quencher did not interfere with the catalytic activity of nuclease. The biosensor could be manipulated with similar sensitivity no matter in pre-addition or post-addition manner. Moreover, simultaneous and multiplexed analysis of several small molecules in homogeneous solution was achieved, demonstrating its potential application in the rapid screening of multiple biotargets. Copyright © 2017 Elsevier B.V. All rights reserved.

Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry

Science.gov (United States)

2013-01-01

Background We previously identified two hydrolyzable tannins, chebulagic acid (CHLA) and punicalagin (PUG) that blocked herpes simplex virus type 1 (HSV-1) entry and spread. These compounds inhibited viral glycoprotein interactions with cell surface glycosaminoglycans (GAGs). Based on this property, we evaluated their antiviral efficacy against several different viruses known to employ GAGs for host cell entry. Results Extensive analysis of the tannins’ mechanism of action was performed on a panel of viruses during the attachment and entry steps of infection. Virus-specific binding assays and the analysis of viral spread during treatment with these compounds were also conducted. CHLA and PUG were effective in abrogating infection by human cytomegalovirus (HCMV), hepatitis C virus (HCV), dengue virus (DENV), measles virus (MV), and respiratory syncytial virus (RSV), at μM concentrations and in dose-dependent manners without significant cytotoxicity. Moreover, the natural compounds inhibited viral attachment, penetration, and spread, to different degrees for each virus. Specifically, the tannins blocked all these steps of infection for HCMV, HCV, and MV, but had little effect on the post-fusion spread of DENV and RSV, which could suggest intriguing differences in the roles of GAG-interactions for these viruses. Conclusions CHLA and PUG may be of value as broad-spectrum antivirals for limiting emerging/recurring viruses known to engage host cell GAGs for entry. Further studies testing the efficacy of these tannins in vivo against certain viruses are justified. PMID:23924316

Broad-spectrum detection of H5 subtype influenza A viruses with a new fluorescent immunochromatography system.

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Akira Sakurai

Full Text Available Immunochromatography (IC is an antigen-detection assay that plays an important role in the rapid diagnosis of influenza virus because the protocol is short time and easy to use. Despite the usability of IC, the sensitivity is approximately 10(3 pfu per reaction. In addition, antigen-antibody interaction-based method cannot be used for the detection of influenza viruses with major antigenic change. In this study, we established the use of fluorescent immunochromatography (FLIC to detect a broad spectrum of H5 subtype influenza A viruses. This method has improved sensitivity 10-100 fold higher than traditional IC because of the use of fluorescent conjugated beads. Our Type-E FLIC kit detected all of the H5 subtype influenza viruses that were examined, as well as recombinant hemagglutinin (HA proteins (rHAs belonging to the Eurasian H5 subtype viruses and the Type-N diagnosed North American H5 subtype influenza A viruses. Thus, this kit has the improved potential to detect H5 subtype influenza viruses of different clades with both Type-E and Type-N FLIC kits. Compared with PCR-based diagnosis, FLIC has a strong advantage in usability, because the sample preparation required for FLIC is only mix-and-drop without any additional steps such as RNA extraction. Our results can provide new strategies against the spread and transmission of HPAI H5N1 viruses in birds and mammals including humans.

Marker-assisted introgression of broad-spectrum blast resistance genes into the cultivated MR219 rice variety.

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Miah, Gous; Rafii, Mohd Y; Ismail, Mohd R; Puteh, Adam B; Rahim, Harun A; Latif, Mohammad A

2017-07-01

The rice cultivar MR219 is famous for its better yield and long and fine grain quality; however, it is susceptible to blast disease. The main objective of this study was to introgress blast resistance genes into MR219 through marker-assisted selection (MAS). The rice cultivar MR219 was used as the recurrent parent, and Pongsu Seribu 1 was used as the donor. Marker-assisted foreground selection was performed using RM6836 and RM8225 to identify plants possessing blast resistance genes. Seventy microsatellite markers were used to estimate recurrent parent genome (RPG) recovery. Our analysis led to the development of 13 improved blast resistant lines with Piz, Pi2 and Pi9 broad-spectrum blast resistance genes and an MR219 genetic background. The RPG recovery of the selected improved lines was up to 97.70% with an average value of 95.98%. Selected improved lines showed a resistance response against the most virulent blast pathogen pathotype, P7.2. The selected improved lines did not express any negative effect on agronomic traits in comparison with MR219. The research findings of this study will be a conducive approach for the application of different molecular techniques that may result in accelerating the development of new disease-resistant rice varieties, which in turn will match rising demand and food security worldwide. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Czech Teratology Information Service: comparison of treatments by psychotropic and antiepileptic drugs.

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Manáková, Eva; Hubicková-Heringová, Lucie; Jelínek, Richard

2006-12-01

Care, treatment and follow-up in psychiatric and epileptic pregnant women were compared with women inquiring Czech Teratology Information Service (CZTIS) due to other exposure to drugs during pregnancy. Data were collected by CZTIS, member of European Network of Teratology Information Services from 1996. Exposed groups were compared with pregnant women exposed to drugs which were not classified as major teratogens or hyperthermia. Groups do not vary in age, reproductive history and other parameters. We observed higher frequency of miscarriage and voluntary termination of pregnancy in the group of psychiatric patients. The number of malformation in prospective follow-up cases was lower than in control group. Chronic diseases as epilepsy or psychiatric disorders have to be treated during pregnancy. Women should obtain accurate information about possible risk before pregnancy. Co-operation is needed in these cases. Physicians should keep in mind that appropriate information is to be given to the patient according to her disease, education and comprehension of the problem. If there is any doubt they should organize help for their patients.

Seizure characteristics and the use of anti-epileptic drugs in children and young people with brain tumours and epileptic seizures: Analysis of regional paediatric cancer service population.

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Pilotto, Chiara; Liu, Jo-Fen; Walker, David A; Whitehouse, William P

2018-03-21

Epileptic seizures complicate the management of childhood brain tumours. There are no published standards for clinical practice concerning risk factors, treatment selection or strategies to withdraw treatment with antiepileptic drugs (AED). we undertook a case note review of 120 patients with newly diagnosed brain tumours, referred to a regional paediatric cancer service. data was available on 117/120 (98%) children seizures. A cortical tumour location was associated with the highest risk of seizures (OR: 7.1; CI 95% 2.9-17.3). At a median follow up of 24 months (IQR 25°-75° : 15-48), 22/35 (63%) with seizures, had a single seizure episode, 15/35 (43%) were seizure free (SF) on AEDs, 13/35 (37%) were SF off AEDs, and 7/35 (20%) experienced continuing epileptic seizures. Overall 34/35 (97%) were treated with AEDs after a seizure, of whom 12/35 (35%) withdrew from AED medication, and although 4/35 (12%) had seizure relapse, all were after further acute events. The median duration of AED before withdrawal was 11 months (IQR 25°-75° 5-14 months), and the median follow up after withdrawal was 15 months (IQR 25°-75° 5-34 months). Seizures affect about 1/3rd of children and young people presenting with and being treated for brain tumours particularly when the tumour is in the cerebral cortex. The low risk of recurrent seizures after AED treatment justifies consideration of early withdrawal of AED after seizure control. Copyright © 2018. Published by Elsevier Ltd.

CNS Depressant and Antiepileptic Activities of the Methanol Extract of the Leaves of Ipomoea Aquatica Forsk

Directory of Open Access Journals (Sweden)

Dhanasekaran Sivaraman

2010-01-01

Full Text Available The central nervous system (CNS depressant and antiepileptic activities of the methanol extract of the leaves of Ipomoea aquatica Forsk (IAF were investigated on various animal models including pentobarbitone sleeping time and hole-board exploratory behavior for sedation tests and strychnine, picrotoxin and pentylenetetrazole-induced convulsions in mice. IAF (200 and 400 mg/kg, p.o., like chlorpromazine HCl (1 mg/kg, i.m., produced a dose-dependent prolongation of pentobarbitone sleeping time and suppression of exploratory behavior. IAF (200 and 400 mg/kg produced dose-dependent and significant increases in onset to clonic and tonic convulsions and at 400 mg/kg, showed complete protection against seizures induced by strychnine and picrotoxin but not with pentylenetetrazole. Acute oral toxicity test, up to 14 days, did not produce any visible signs of toxicity. These results suggest that potentially antiepileptic compounds are present in leaf extract of IAF that deserve the study of their identity and mechanism of action.

Autism spectrum disorders and drug addiction: Common pathways, common molecules, distinct disorders?

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Patrick E. Rothwell

2016-02-01

Full Text Available Autism spectrum disorders (ASDs and drug addiction do not share substantial comorbidity or obvious similarities in etiology or symptomatology. It is thus surprising that a number of recent studies implicate overlapping neural circuits and molecular signaling pathways in both disorders. The purpose of this review is to highlight this emerging intersection and consider implications for understanding the pathophysiology of these seemingly distinct disorders. One area of overlap involves neural circuits and neuromodulatory systems in the striatum and basal ganglia, which play an established role in addiction and reward but are increasingly implicated in clinical and preclinical studies of ASDs. A second area of overlap relates to molecules like Fragile X mental retardation protein (FMRP and methyl CpG-binding protein-2 (MECP2, which are best known for their contribution to the pathogenesis of syndromic ASDs, but have recently been shown to regulate behavioral and neurobiological responses to addictive drug exposure. These shared pathways and molecules point to common dimensions of behavioral dysfunction, including the repetition of behavioral patterns and aberrant reward processing. The synthesis of knowledge gained through parallel investigations of ASDs and addiction may inspire the design of new therapeutic interventions to correct common elements of striatal dysfunction.

Autism Spectrum Disorders and Drug Addiction: Common Pathways, Common Molecules, Distinct Disorders?

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Rothwell, Patrick E

2016-01-01

Autism spectrum disorders (ASDs) and drug addiction do not share substantial comorbidity or obvious similarities in etiology or symptomatology. It is thus surprising that a number of recent studies implicate overlapping neural circuits and molecular signaling pathways in both disorders. The purpose of this review is to highlight this emerging intersection and consider implications for understanding the pathophysiology of these seemingly distinct disorders. One area of overlap involves neural circuits and neuromodulatory systems in the striatum and basal ganglia, which play an established role in addiction and reward but are increasingly implicated in clinical and preclinical studies of ASDs. A second area of overlap relates to molecules like Fragile X mental retardation protein (FMRP) and methyl CpG-binding protein-2 (MECP2), which are best known for their contribution to the pathogenesis of syndromic ASDs, but have recently been shown to regulate behavioral and neurobiological responses to addictive drug exposure. These shared pathways and molecules point to common dimensions of behavioral dysfunction, including the repetition of behavioral patterns and aberrant reward processing. The synthesis of knowledge gained through parallel investigations of ASDs and addiction may inspire the design of new therapeutic interventions to correct common elements of striatal dysfunction.

Effects of adjunctive eslicarbazepine acetate on serum lipids in patients with partial-onset seizures: Impact of concomitant statins and enzyme-inducing antiepileptic drugs.

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Mintzer, Scott; Wechsler, Robert T; Rogin, Joanne B; Gidal, Barry E; Schwab, Matthias; Ben-Menachem, Elinor; Carreño, Mar; da Silva, Patrício Soares; Moreira, Joana; Li, Yan; Blum, David; Grinnell, Todd

2018-03-01

To evaluate the effects of eslicarbazepine acetate (ESL) on lipid metabolism and to determine whether reduced statin exposure during ESL therapy has clinical consequences. We conducted a post-hoc analysis of pooled data for serum lipids (laboratory values) from three phase III, multicenter, randomized, double-blind, placebo-controlled trials of adjunctive ESL therapy (400, 800, or 1200 mg once daily) in patients with treatment-refractory partial-onset seizures. Changes from baseline in serum lipid levels were analyzed according to use of statins and/or enzyme-inducing antiepileptic drugs (EIAEDs) during the baseline period. In total, 426 and 1021 placebo- and ESL-treated patients, respectively, were included in the analysis. With regard to the changes from baseline in serum concentrations, there were statistically significant differences between the placebo and ESL 1200 mg QD groups, for both total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), but the effect sizes were small (+4.1 mg/dL and +1.8 mg/dL, respectively). A small but significant difference in low-density lipoprotein cholesterol (LDL-C; -5.0 mg/dL) was observed between the ESL 400 mg QD group and the placebo group. In patients not taking a concomitant EIAED, there were no changes with ESL 400 mg QD, but modest and statistically significant increases in cholesterol fractions (TC, LDL-C and HDL-C) with ESL 800 mg QD (ESL 1200 mg QD (ESL had no consistent effect on lipids in patients taking a concomitant EIAED. In patients taking statins during baseline, there were no clinically relevant changes in serum lipids during use of ESL, although the subgroups were small. These results suggest that ESL does not appear to have clinically significant effects on serum lipids, nor does the pharmacokinetic interaction between ESL and statins have an impact on serum lipid concentrations. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Oldest human occupation of Wallacea at Laili Cave, Timor-Leste, shows broad-spectrum foraging responses to late Pleistocene environments

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Hawkins, Stuart; O'Connor, Sue; Maloney, Tim Ryan; Litster, Mirani; Kealy, Shimona; Fenner, Jack N.; Aplin, Ken; Boulanger, Clara; Brockwell, Sally; Willan, Richard; Piotto, Elena; Louys, Julien

2017-09-01

The Wallacea Archipelago provides an extraordinary laboratory for the study of human colonisation and adaptation, yet few detailed archaeological studies have been conducted in the region that span the earliest phase of human settlement. Laili Cave, in northern Timor-Leste, preserves the oldest human occupation in this insular region with a cultural sequence spanning 11,200 to 44,600 cal BP. Small-bodied vertebrates and invertebrates were recovered to the lowest excavated levels, associated with highly concentrated stone artefacts. We report on human behavioural adaptations within the context of Pleistocene environments and changing landscapes using zooarchaeological, stone artefact, bathymetric, and experimental isotopic analyses. Results indicate that Pleistocene humans used the abundant local chert liberally and engaged in mobile broad-spectrum exploitation of invertebrates and fishes from marine, estuarine, and freshwater environments within close proximity of Laili Cave. The faunal assemblage indicates heterogeneous but relatively stable environments during the late Pleistocene. Variability in subsistence strategies over time appears to be a response to changing landscapes and concomitant local resources. This record contrasts with marine specialisations evident from other sites in Timor-Leste and within the broader Wallacean region.

Molecular Docking Study, Green Synthesis and Pharmacological Evaluation of 1,3,4-thiadiazole Derivatives as Potential Antiepileptic Agents

Czech Academy of Sciences Publication Activity Database

Sahoo, B. M.; Dinda, S. C.; Kumar, B. V. V. R.; Panda, J. R.; Brahmkshatriya, Pathik

2013-01-01

Roč. 13, č. 14 (2013), s. 2076-2081 ISSN 1389-5575 Institutional support: RVO:61388963 Keywords : antiepileptic activity * docking study * epilepsy * green synthesis * neurotoxicity * thiadiazole Subject RIV: CC - Organic Chemistry Impact factor: 3.186, year: 2013

Stent-Graft Placement with Early Debridement and Antibiotic Treatment for Femoral Pseudoaneurysms in Intravenous Drug Addicts

International Nuclear Information System (INIS)

Fu, Qining; Meng, Xiyun; Li, Fenghe; Wang, Xuehu; Cheng, Jun; Huang, Wen; Ren, Wei; Zhao, Yu

2015-01-01

PurposeExplore the application of endovascular covered stent-graft (SG) placement in femoral pseudoaneurysms in intravenous drug addicts.Materials and MethodsWe evaluated a consecutive series of pseudoaneurysm in intravenous drug addicts treated with SGs from August 2010 to December 2013.Results15 patients with 16 arterial pseudoaneurysms were enrolled in this study. All were males with a mean age of 36.9 years. Hemorrhage was the most common reason (93.8 %) for seeking medical care, and 3 of these patients were in hemorrhagic shock at admission. All patients received broad-spectrum antibiotics, and debridement and drainage were implemented after SG placement. 7 of the 13 cases which had microbiologic results showed mixed infections, while gram-negative bacteria were the major pathogens. Except for 2 patients, who were lost to follow-up, two new pseudoaneurysms formed due to delayed debridement, and one stent thrombosis occurred, none of the remaining cases had SG infection or developed claudication.ConclusionsSG placement controls massive hemorrhage rapidly, gives enough time for subsequent treatment for pseudoaneurysms due to intravenous drug abuse, and reduces the incidence of postoperative claudication. With appropriate broad-spectrum antibiotics and early debridement, the incidence of SG infection is relatively low. It is an effective alternative especially as temporary bridge measure for critical patients. However, the high cost, uncertain long-term prospects, high demand for medical adherence, and the risk of using the conduits for re-puncture call for a cautious selection of patients. More evidence is required for the application of this treatment

Stent-Graft Placement with Early Debridement and Antibiotic Treatment for Femoral Pseudoaneurysms in Intravenous Drug Addicts

Energy Technology Data Exchange (ETDEWEB)

Fu, Qining, E-mail: cqmufqn@163.com; Meng, Xiyun, E-mail: 383274177@qq.com; Li, Fenghe, E-mail: lfh-cqmu@gmail.com; Wang, Xuehu, E-mail: 184037696@qq.co; Cheng, Jun, E-mail: cqdcj@163.com; Huang, Wen, E-mail: dhuangwen@hotmail.com; Ren, Wei, E-mail: renwei9771@yahoo.com.cn; Zhao, Yu, E-mail: zhaoyu-cqmu@126.com [The First Affiliated Hospital of Chongqing Medical University, Department of Vascular Surgery (China)

2015-06-15

PurposeExplore the application of endovascular covered stent-graft (SG) placement in femoral pseudoaneurysms in intravenous drug addicts.Materials and MethodsWe evaluated a consecutive series of pseudoaneurysm in intravenous drug addicts treated with SGs from August 2010 to December 2013.Results15 patients with 16 arterial pseudoaneurysms were enrolled in this study. All were males with a mean age of 36.9 years. Hemorrhage was the most common reason (93.8 %) for seeking medical care, and 3 of these patients were in hemorrhagic shock at admission. All patients received broad-spectrum antibiotics, and debridement and drainage were implemented after SG placement. 7 of the 13 cases which had microbiologic results showed mixed infections, while gram-negative bacteria were the major pathogens. Except for 2 patients, who were lost to follow-up, two new pseudoaneurysms formed due to delayed debridement, and one stent thrombosis occurred, none of the remaining cases had SG infection or developed claudication.ConclusionsSG placement controls massive hemorrhage rapidly, gives enough time for subsequent treatment for pseudoaneurysms due to intravenous drug abuse, and reduces the incidence of postoperative claudication. With appropriate broad-spectrum antibiotics and early debridement, the incidence of SG infection is relatively low. It is an effective alternative especially as temporary bridge measure for critical patients. However, the high cost, uncertain long-term prospects, high demand for medical adherence, and the risk of using the conduits for re-puncture call for a cautious selection of patients. More evidence is required for the application of this treatment.

Fighting Fire with Fire: Surgical Options for Patients with Drug-Resistant Epilepsy.

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Bayer, Alina D; Blum, Andrew S; Asaad, Wael F; Roth, Julie; Toms, Steven A; Deck, Gina M

2018-03-01

While antiepileptic drugs (AEDs) provide adequate seizure control for most patients with epilepsy, ~30% continue to have seizures despite treatment with two or more AEDs.1 In addition to direct harm from seizures, poor epilepsy control correlates with higher mortality, morbidity, 2, 3 and cost to the healthcare system.4 In the subset of patients with persistent seizures despite medical management, surgical intervention and neuromodulation may be more effective. Primary care physicians and general neurologists should be aware of non-AED treatment options that are standard of care for drug- resistant epilepsy (DRE). [Full article available at http://rimed.org/rimedicaljournal-2018-03.asp].

Development of an enantioseparation method for novel psychoactive drugs by HPLC using a Lux® Cellulose-2 column in polar organic phase mode.

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Taschwer, Magdalena; Grascher, Jörg; Schmid, Martin G

2017-01-01

Since the last decade, the hype of the recreational use of novel psychoactive drugs is still on its top in entire Europe. Every year, new derivatives enter the drug market and enlarge the broad spectrum of misused drugs. Many of these compounds contain a stereogenic centre and therefore two enantiomers exist. It is obvious that the pharmacological potency of the isomers differ as it is already known from various pharmaceutical ingredients. Therefore, the development of analytical methods for the chiral separation of new psychoactive substances is of great medical and forensic interest. The aim of this study was to establish an enantioseparation method, which is applicable at equal conditions for different drug compound classes including cathinones, amphetamines, benzofurans, thiophenes, phenidine and phenidate derivatives. A commercially available Lux ® Cellulose-2 column consisting of cellulose tris(3-chloro-4-methylphenylcarbamate) coated on silica gel was found to be appropriate for the chiral separation of the mentioned drug classes. Experiments were performed under isocratic conditions in polar organic phase mode using UV-detection. With a mobile phase consisting of acetonitrile:isopropanol:diethylamine:formic acid (100%) (95:5:0.1:0.1) 40 out of 43 psychoactive compounds were successfully baseline or partially separated. 3-Fluoroamphetamine, 4-fluoroamphetamine and 1-(benzofuran-6-yl)-N-ethylpropan-2-amine were not chirally separated. The established method enabled enantioseparation of a broad spectrum of different psychoactive compounds under equal conditions. Forty of forty-three compounds were separated in their enantiomers, thus this method has a wide applicability for the enantioseparation of novel psychoactive drugs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

On the origin of gamma rays in Fermi blazars: beyond the broad line region.

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Costamante, L.; Cutini, S.; Tosti, G.; Antolini, E.; Tramacere, A.

2018-05-01

The gamma-ray emission in broad-line blazars is generally explained as inverse Compton (IC) radiation of relativistic electrons in the jet scattering optical-UV photons from the Broad Line Region (BLR), the so-called BLR External Compton scenario. We test this scenario on the Fermi gamma-ray spectra of 106 broad-line blazars detected with the highest significance or largest BLR, by looking for cut-off signatures at high energies compatible with γ-γ interactions with BLR photons. We do not find evidence for the expected BLR absorption. For 2/3 of the sources, we can exclude any significant absorption (τmax 5). We conclude that for 9 out of 10 objects, the jet does not interact with BLR photons. Gamma-rays seem either produced outside the BLR most of the time, or the BLR is ˜100 × larger than given by reverberation mapping. This means that i) External Compton on BLR photons is disfavoured as the main gamma-ray mechanism, vs IC on IR photons from the torus or synchrotron self-Compton; ii) the Fermi gamma-ray spectrum is mostly intrinsic, determined by the interaction of the particle distribution with the seed-photons spectrum; iii) without suppression by the BLR, broad-line blazars can become copious emitters above 100 GeV, as demonstrated by 3C 454.3. We expect the CTA sky to be much richer of broad-line blazars than previously thought.

Levetiracetam is associated with decrease in subclinical epileptiform discharges and improved cognitive functions in pediatric patients with autism spectrum disorder.

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Wang, Minjian; Jiang, Li; Tang, Xiaoju

2017-01-01

Subclinical epileptiform discharges (SEDs) are common in pediatric patients with autism spectrum disorder (ASD), but the effect of antiepileptic drugs on SEDs in ASD remains inconclusive. This physician-blinded, prospective, randomized controlled trial investigated an association between the anticonvulsant drug levetiracetam and SEDs in children with ASD. A total of 70 children with ASD (4-6 years) and SEDs identified by electroencephalogram were randomly divided into two equal groups to receive either levetiracetam and educational training (treatment group) or educational training only (control). At baseline and after 6 months treatment, the following scales were used to assess each individual's behavioral and cognitive functions: the Chinese version of the Psychoeducational Profile - third edition (PEP-3), Childhood Autism Rating Scale (CARS), and Autism Behavior Checklist (ABC). A 24-hour electroencephalogram was recorded on admission (baseline) and at follow-up. The degree of satisfaction of each patient was also evaluated. Relative to baseline, at the 6-month follow-up, the PEP-3, CARS, and ABC scores were significantly improved in both the treatment and control groups. At the 6-month follow-up, the PEP-3 scores of the treatment group were significantly higher than those of the control, whereas the CARS and ABC scores were significantly lower, and the rate of electroencephalographic normalization was significantly higher in the treatment group. Levetiracetam appears to be effective for controlling SEDs in pediatric patients with ASD and was also associated with improved behavioral and cognitive functions.

X-ray Emitting GHz-Peaked Spectrum Galaxies: Testing a Dynamical-Radiative Model with Broad-Band Spectra

International Nuclear Information System (INIS)

Ostorero, L.; Moderski, R.; Stawarz, L.; Diaferio, A.; Kowalska, I.; Cheung, C.C.; Kataoka, J.; Begelman, M.C.; Wagner, S.J.

2010-01-01

In a dynamical-radiative model we recently developed to describe the physics of compact, GHz-Peaked-Spectrum (GPS) sources, the relativistic jets propagate across the inner, kpc-sized region of the host galaxy, while the electron population of the expanding lobes evolves and emits synchrotron and inverse-Compton (IC) radiation. Interstellar-medium gas clouds engulfed by the expanding lobes, and photoionized by the active nucleus, are responsible for the radio spectral turnover through free-free absorption (FFA) of the synchrotron photons. The model provides a description of the evolution of the GPS spectral energy distribution (SED) with the source expansion, predicting significant and complex high-energy emission, from the X-ray to the γ-ray frequency domain. Here, we test this model with the broad-band SEDs of a sample of eleven X-ray emitting GPS galaxies with Compact-Symmetric-Object (CSO) morphology, and show that: (i) the shape of the radio continuum at frequencies lower than the spectral turnover is indeed well accounted for by the FFA mechanism; (ii) the observed X-ray spectra can be interpreted as non-thermal radiation produced via IC scattering of the local radiation fields off the lobe particles, providing a viable alternative to the thermal, accretion-disk dominated scenario. We also show that the relation between the hydrogen column densities derived from the X-ray (N H ) and radio (N HI ) data of the sources is suggestive of a positive correlation, which, if confirmed by future observations, would provide further support to our scenario of high-energy emitting lobes.

A P25/(NH4)xWO3 hybrid photocatalyst with broad spectrum photocatalytic properties under UV, visible, and near-infrared irradiation.

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Yang, Linfen; Liu, Bin; Liu, Tongyao; Ma, Xinlong; Li, Hao; Yin, Shu; Sato, Tsugio; Wang, Yuhua

2017-04-03

In this study, a series of hybrid nanostructured photocatalysts P25/(NH 4 ) x WO 3 nanocomposites with the average crystallite size of P25 and (NH 4 ) x WO 3 of the sample was calculated to be about 30 nm and 130 nm, were successfully synthesized via a simple one-step hydrothermal method. The as-obtained samples was characterized by transmission electron microscopy (TEM), which implies that the P25/(NH 4 ) x WO 3 nanocomposites are fabricated with favourable nanosizd interfacial. The XPS results confirmed that the obtained sample consists of mixed chemical valences of W 5+ and W 6+ , the low-valance W 5+ sites could be the origin of NIR absorption. As revealed by optical absorption results, P25/(NH 4 ) x WO 3 nanocomposites possess high optical absorption in the whole solar spectrum of 200-2500 nm. Benefiting from this unique photo-absorption property and the synergistic effect of P25 and (NH 4 ) x WO 3 , broad spectrum response photocatalytic activities covering UV, visible and near infrared regions on degradation of Rhodamine B have been realized by P25/(NH 4 ) x WO 3 nanocomposites. Meanwhile, the stability of photocatalysts was examined by the XRD and XPS of the photocatalysts after the reaction. The results show that P25/(NH 4 ) x WO 3 photocatalysts has a brilliant application prospect in the energy utilization to solve deteriorating environmental issues.

Runs 800, 813, 842 and physics runs from 18.1.77 to 21.5.77, Development of a new set-up for working line measurements including a Fast Fourier Transform Spectrum Analyser and using weak beam excitiation with broad-band noise

CERN Document Server

Borer, J

1977-01-01

Runs 800, 813, 842 and physics runs from 18.1.77 to 21.5.77, Development of a new set-up for working line measurements including a Fast Fourier Transform Spectrum Analyser and using weak beam excitiation with broad-band noise

Characteristics of a broad lytic spectrum endolysin from phage BtCS33 of Bacillus thuringiensis

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Yuan Yihui

2012-12-01

Full Text Available Abstract Background Endolysins produced by bacteriophages lyse bacteria, and are thus considered a novel type of antimicrobial agent. Several endolysins from Bacillus phages or prophages have previously been characterized and used to target Bacillus strains that cause disease in animals and humans. B. thuringiensis phage BtCS33 is a Siphoviridae family phage and its genome has been sequenced and analyzed. In the BtCS33 genome, orf18 was found to encode an endolysin protein (PlyBt33. Results Bioinformatic analyses showed that endolysin PlyBt33 was composed of two functional domains, the N-terminal catalytic domain and the C-terminal cell wall binding domain. In this study, the entire endolysin PlyBt33, and both the N- and C-termini,were expressed in Escherichia coli and then purified. The lytic activities of PlyBt33 and its N-terminus were tested on bacteria. Both regions exhibited lytic activity, although PlyBt33 showed a higher lytic activity than the N-terminus. PlyBt33 exhibited activity against all Bacillus strains tested from five different species, but was not active against Gram-negative bacteria. Optimal conditions for PlyBt33 reactivity were pH 9.0 and 50°C. PlyBt33 showed high thermostability, with 40% of initial activity remaining following 1 h of treatment at 60°C. The C-terminus of PlyBt33 bound to B. thuringiensis strain HD-73 and Bacillus subtilis strain 168. This cell wall binding domain might be novel, as its amino acid sequence showed little similarity to previously reported endolysins. Conclusions PlyBt33 showed potential as a novel antimicrobial agent at a relatively high temperature and had a broad lytic spectrum within the Bacillus genus. The C-terminus of PlyBt33 might be a novel kind of cell wall binding domain.

High performance in silico virtual drug screening on many-core processors

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Price, James; Sessions, Richard B; Ibarra, Amaurys A

2015-01-01

Drug screening is an important part of the drug development pipeline for the pharmaceutical industry. Traditional, lab-based methods are increasingly being augmented with computational methods, ranging from simple molecular similarity searches through more complex pharmacophore matching to more computationally intensive approaches, such as molecular docking. The latter simulates the binding of drug molecules to their targets, typically protein molecules. In this work, we describe BUDE, the Bristol University Docking Engine, which has been ported to the OpenCL industry standard parallel programming language in order to exploit the performance of modern many-core processors. Our highly optimized OpenCL implementation of BUDE sustains 1.43 TFLOP/s on a single Nvidia GTX 680 GPU, or 46% of peak performance. BUDE also exploits OpenCL to deliver effective performance portability across a broad spectrum of different computer architectures from different vendors, including GPUs from Nvidia and AMD, Intel’s Xeon Phi and multi-core CPUs with SIMD instruction sets. PMID:25972727

High performance in silico virtual drug screening on many-core processors.

Science.gov (United States)

McIntosh-Smith, Simon; Price, James; Sessions, Richard B; Ibarra, Amaurys A

2015-05-01

Drug screening is an important part of the drug development pipeline for the pharmaceutical industry. Traditional, lab-based methods are increasingly being augmented with computational methods, ranging from simple molecular similarity searches through more complex pharmacophore matching to more computationally intensive approaches, such as molecular docking. The latter simulates the binding of drug molecules to their targets, typically protein molecules. In this work, we describe BUDE, the Bristol University Docking Engine, which has been ported to the OpenCL industry standard parallel programming language in order to exploit the performance of modern many-core processors. Our highly optimized OpenCL implementation of BUDE sustains 1.43 TFLOP/s on a single Nvidia GTX 680 GPU, or 46% of peak performance. BUDE also exploits OpenCL to deliver effective performance portability across a broad spectrum of different computer architectures from different vendors, including GPUs from Nvidia and AMD, Intel's Xeon Phi and multi-core CPUs with SIMD instruction sets.

Model Atmosphere Spectrum Fit to the Soft X-Ray Outburst Spectrum of SS Cyg

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V. F. Suleimanov

2015-02-01

Full Text Available The X-ray spectrum of SS Cyg in outburst has a very soft component that can be interpreted as the fast-rotating optically thick boundary layer on the white dwarf surface. This component was carefully investigated by Mauche (2004 using the Chandra LETG spectrum of this object in outburst. The spectrum shows broad ( ≈5 °A spectral features that have been interpreted as a large number of absorption lines on a blackbody continuum with a temperature of ≈250 kK. Because the spectrum resembles the photospheric spectra of super-soft X-ray sources, we tried to fit it with high gravity hot LTE stellar model atmospheres with solar chemical composition, specially computed for this purpose. We obtained a reasonably good fit to the 60–125 °A spectrum with the following parameters: Teff = 190 kK, log g = 6.2, and NH = 8 · 1019 cm−2, although at shorter wavelengths the observed spectrum has a much higher flux. The reasons for this are discussed. The hypothesis of a fast rotating boundary layer is supported by the derived low surface gravity.

What’s in the pipeline? Drugs in development for autism spectrum disorder

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Sung M

2014-02-01

Full Text Available Min Sung,1 Chee Hon Chin,1 Choon Guan Lim,1 Hwee Sen Alvin Liew,1 Chau Sian Lim,2 Espérance Kashala,1 Shih-Jen Weng1 1Department of Child and Adolescent Psychiatry, Institute of Mental Health, Singapore; 2Department of Psychological Medicine, Khoo Teck Puat Hospital, Singapore Abstract: Autism Spectrum Disorder (ASD is a complex neurodevelopmental disorder with both core symptoms and associated symptoms (eg, irritability, aggression, and comorbidities that affect both the individual and the family/systems around them. There have been recent advances in the understanding of the underlying pathophysiology of ASD pertaining to genetics, epigenetics, neurological, hormonal, and environmental factors that contribute to the difficulties found in individuals with ASD. With this improved understanding, there has been a shift in the application of psychopharmacology in ASD and its related disorders. A literature review was conducted to examine research published in the last 5 years between different classes of psychotropic medications and ASD. The broad scope of the existing literature for the use of conventional medications is summarized and novel medications are discussed. Keywords: pharmacology, treatment, autism, Asperger’s syndrome, medication

Hybrid protein-synthetic polymer nanoparticles for drug delivery.

Science.gov (United States)

Koseva, Neli S; Rydz, Joanna; Stoyanova, Ekaterina V; Mitova, Violeta A

2015-01-01

Among the most common nanoparticulate systems, the polymeric nanocarriers have a number of key benefits, which give a great choice of delivery platforms. Nevertheless, polymeric nanoparticles possess some limitations that include use of toxic solvents in the production process, polymer degradation, drug leakage outside the diseased tissue, and polymer cytotoxicity. The combination of polymers of biological and synthetic origin is an appealing modern strategy for the production of novel nanocarriers with unprecedented properties. Proteins' interface can play an important role in determining bioactivity and toxicity and gives perspective for future development of the polymer-based nanoparticles. The design of hybrid constructs composed of synthetic polymer and biological molecules such as proteins can be considered as a straightforward tool to integrate a broad spectrum of properties and biofunctions into a single device. This review discusses hybrid protein-synthetic polymer nanoparticles with different structures and levels in complexity and functionality, in view of their applications as drug delivery systems. © 2015 Elsevier Inc. All rights reserved.

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

DEFF Research Database (Denmark)

Tsiropoulos, Ioannis; Andersen, Morten; Hallas, Jesper

2009-01-01

Database (OPED) for the period of 1 August 1990-31 December 2006, and diagnoses from the County Hospital register for the period of 1994-2006 to perform sequence symmetry analysis. The method assesses the distribution of disease entities and prescription of other drugs (ODs), before and after initiation...

Gross hepatic changes in developing albino rats exposed to valproic acid

International Nuclear Information System (INIS)

Khan, M.; Khattak, S.T.; Elahi, M.

2011-01-01

Background: Valproid Acid (VPA) is a broad spectrum antiepileptic drug. Its use during pregnancy has been associated with congenital anomalies and hepatotoxicity. This study was designed to assess the effects of VPA on the gross structure of liver in developing albino rats exposed to the drug during various trimesters of pregnancy. Methods: In this experimental study 40 pregnant rats were divided into 4 equal groups A, B, C and D. Group A received VPA in a dose of 500 mg/Kg/day intraperitonealy (I/P) on days 3, 4 and 5 of gestation. Group B received the drug in a dose of 500 mg/Kg/day I/P on days 8, 9 and 10 of gestation. Group C received VPA in a dose of 500 mg/Kg/day I/P on days 16, 17 and 18 of gestation. Group D received no treatment and was kept as a control group. On day 21, the rats were euthanised by cervical dislocation. The liver of the foetuses were dissected out for the assessment of their gross structure. Results: Foetal liver of the experimental groups showed significant decrease in weight as well as relative tissue weight index (RTWI) as compared to the control group, although the gross appearance of the foetal liver was normal in all the groups. Conclusion: The use of VPA during various trimesters of pregnancy produces hepatotoxicity in the developing rats. So, the use of this drug during pregnancy should be carefully decided. (author)

Detection of electron beam irradiated crude drugs by electron spin resonance (ESR)

International Nuclear Information System (INIS)

Yamaoki, Rumi; Kimura, Shojiro; Aoki, Kenji; Nishimoto, Susumu

2007-01-01

Perillae Herba, Sennae Folium, Cinnamomi Cortex, Phellodendri Cortex, Ginseng Radix, Glycyrrhizae Radix, Paeoniae Radix, and Zingiberis Rhizoma were irradiated with electron beam (5 MeV) and organic radicals were detected by ESR measurement, before and after irradiation (10 kGy). A single line spectrum was detected at around g=2.005 in non-irradiated crude drugs, and radical concentrations were high in the leaf varieties of crude drugs. After irradiation, the signal intensity around g=2.005 increased, and a new subsignal was detected as a 3 mT shoulder of this signal. Broad, asymmetrically divided signals were also detected in irradiated root varieties of crude drugs. The free radical localized on the organic components of irradiated crude drugs tended to decrease with the water content. After irradiation, signal intensity reduced and reached a steady state after about 1 to 2 months. However, specificity of the ESR signal shape appearing after irradiation continued to be detectable for 6 months in leaf varieties and for a year in bark and root varieties of crude drugs. Consequently, it was concluded that ESR could be applied as an initial screening procedure to detect irradiated crude drugs. (author)

The treatment of autism with low-dose phenytoin: a case report.

Science.gov (United States)

Bird, Philip D

2015-01-16

The drug treatment of autism spectrum disorders is often poorly tolerated and has traditionally targeted associated conditions (such as inattention or irritability) that frequently coexist, with limited benefit for the core social deficits. Here, I describe the novel use of a low dose of the anti-epileptic phenytoin to enhance social functioning in a patient with an autism spectrum disorder. I present the case of a 19-year-old Caucasian man with autism spectrum disorder treated with stimulant medication since early childhood. He experienced long-standing difficulties in establishing and maintaining relationships and reading social cues, and was socially isolated. Within 10 minutes of a single sublingual low dose of phenytoin there was an immediate observable improvement in his eye contact and integration of both verbal and non-verbal communication. This enhanced social functioning associated with his adherence to the low-dose phenytoin therapy was maintained for over 18 months of follow-up. These clinical observations were supported by ratings using the Autism-Spectrum Quotient and the Depression, Anxiety and Stress Scales, recorded pre-treatment and after seven months on 5mg phenytoin. This case report provides the first potential evidence that a low dose of phenytoin, a widely used and well tolerated anti-epileptic medication, may be capable of modifying the core social cognitive deficits associated with autism spectrum disorders. While acknowledging this is a single case study, the lack of availability of safe and effective treatments to address the important core deficits associated with autism spectrum disorders makes this case noteworthy.

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.

An application in cheddar cheese manufacture for a strain of Lactococcus lactis producing a novel broad-spectrum bacteriocin, lacticin 3147.

Science.gov (United States)

Ryan, M P; Rea, M C; Hill, C; Ross, R P