Home About us Contact
|
Home About us Contact | ||
|
|
||
Anticonvulsants
Terms modified by Anticonvulsants Selected AbstractsPharmacodynamic and Pharmacokinetic Interaction Studies of Loreclezole with Felbamate, Lamotrigine, Topiramate, and Oxcarbazepine in the Mouse Maximal Electroshock Seizure ModelEPILEPSIA, Issue 3 2005Jarogniew J. Luszczki Summary:,Purpose: The study investigated the types of interactions between loreclezole (LCZ) and a variety of newly licensed antiepileptic drugs (AEDs) with different mechanisms of actions [felbamate (FBM), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC)] by isobolographic analysis. Methods: Anticonvulsant and adverse-effect profiles of combinations of LCZ with other AEDs at fixed ratios of 1:3, 1:1, and 3:1 were investigated in the maximal electroshock (MES)-induced seizures and the chimney test (as a measure of motor impairment) in mice so as to identify optimal combinations. Protective indices (PIs) and benefit indices (BIs) were calculated so that a ranking in relation to advantageous combinations could be established. Results: With isobolography, it was observed that the combination of LCZ and TPM, at the fixed ratios of 1:1 and 3:1, was supraadditive (synergistic; p < 0.05), whereas LCZ with TPM at the fixed ratio of 1:3 and LCZ combined with LTG, FBM, or OXC at the fixed ratios of 1:3, 1:1, and 3:1 were associated with additive interactions. Moreover, the isobolographic analysis in the chimney test revealed that only one combination tested (LCZ and TPM at the fixed ratio of 1:1) was subadditive (antagonistic; p < 0.05), whereas the remaining combinations of LCZ with LTG, FBM, or OXC (at the fixed ratios of 1:3, 1:1, and 3:1) barely displayed additivity. However, these combinations were associated with significant pharmacokinetic interactions, in that LCZ increased brain TPM (94%), OXC (21%), FBM (46%), and LTG (8%) concentrations. In addition, brain LCZ concentrations were decreased by TPM (26%), OXC (37%), LTG (42%), and FBM (19%). None of the examined combinations between LCZ and TPM, OXC, LTG, and FBM altered long-term memory in the step-through passive-avoidance task. Conclusions: LCZ plus TPM appears to be a particularly favorable combination, based on the MES test and the chimney test. LCZ and OXC also is a favorable combination. However, these conclusions are confounded by the fact that LCZ is associated with significant pharmacokinetic interactions. [source] Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models,ANNALS OF NEUROLOGY, Issue 4 2009Carl E. Stafstrom MD Objective Conventional anticonvulsants reduce neuronal excitability through effects on ion channels and synaptic function. Anticonvulsant mechanisms of the ketogenic diet remain incompletely understood. Because 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, or bicuculline, and in vivo against seizures evoked by 6Hz stimulation in mice, audiogenic stimulation in Fring's mice, and maximal electroshock and subcutaneous pentylenetetrazol (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 7.5mM [K+]o, 4-aminopyridine, and bicuculline, and electrographic seizures induced by high [K+]o in CA3 of hippocampus. 2DG reduced seizures evoked by 6Hz stimulation in mice (effective dose [ED]50 = 79.7mg/kg) and audiogenic stimulation in Fring's mice (ED50 = 206.4mg/kg). 2DG exerted chronic antiepileptic action by increasing afterdischarge thresholds in perforant path (but not olfactory bulb) kindling and caused a twofold 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. Ann Neurol 2009;65:435,448. [source] Anticonvulsant and Neurotoxicity Evaluation of Some Novel Kojic Acids and Allomaltol DerivativesARCHIV DER PHARMAZIE, Issue 3 2010Mutlu Dilsiz Aytemir Abstract A series of new 3-hydroxy-6-hydroxymethyl/methyl-2-substituted 4H -pyran-4-ones were synthesized and prepared by the reaction of kojic acid or allomaltol with piperidine derivatives and formaline as potential anticonvulsant compounds. The structure of the synthesized compounds was confirmed using the elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, and ESI-MS. Anticonvulsant activities were examined by maximal electroshock (MES) and subcutaneous Metrazol (scMet)-induced seizure tests. Neurotoxicity was determined by the rotorod toxicity test. All these tests were performed in accordance with the procedures of the Antiepileptic Drug Development (ADD) program. According to the activity studies and at all doses, 3-hydroxy-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-6-methyl-4H -pyran-4-one (compound 1), 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl]methyl}-3-hydroxy-6-methyl-4H -pyran-4-one (compound 6), 2-[(4-acetyl-4-phenylpiperidin-1-yl)methyl]-3-hydroxy-6-(hydroxymethyl)-4H -pyran-4-one (compound 11), and 2-{[4-(4-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl] methyl}-3-hydroxy-6-hydroxymethyl-4H -pyran-4-one (compound 12) were found to have anticonvulsant activity against MES-induced seizures at 4 h. Also, 2-{[4-(4-bromophenyl)-4-hydroxypiperidin-1-yl]methyl}-3-hydroxy-6-(hydroxymethyl)-4H -pyran-4-one (compound 8) was determined to be the most active compound against scMet-induced seizures at all doses at 0.5 and 4 h. In the rotorod neurotoxicity screening, all compounds showed no toxicity at all doses. [source] Synthesis and Evaluation on Anticonvulsant and Antidepressant Activities of 5-Alkoxy-tetrazolo[1,5- a]quinazolinesARCHIV DER PHARMAZIE, Issue 11 2009Huo-Jian Wang Abstract Several 5-alkoxy-tetrazolo[1,5- a]quinazoline derivatives have been synthesized by reacting 2,4-dichloroquinazoline with various phenols or aliphatic alcohol and then with sodium azide. The structures of these compounds have been confirmed by IR, MS, 1H-NMR, and elementary analysis. Anticonvulsant activities were evaluated using the maximal electroshock (MES) test. Most of the synthesized compounds displayed weak anticonvulsant activity at a dose of 300 mg/kg. Antidepressant activities were investigated by forced swimming test. Two compounds, namely 5-(hexyloxy)tetrazolo[1,5- a]quinazoline and 5-(4-methoxyphenoxy)tetrazolo[1,5- a]quinazoline, showed significant antidepressant activity, which decreased the immobility time by 62.2 and 51.7% at 100 mg/kg dose level. [source] ChemInform Abstract: Derivatives of Benzimidazole Pharmacophore: Synthesis, Anticonvulsant, Antidiabetic and DNA Cleavage Studies.CHEMINFORM, Issue 33 2010Ramya V. Shingalapur Abstract A group of 1,3,4-oxadiazoles and 4-thiazolidinones containing a 2-mercapto-benzimidazole moiety is synthesized and screened for new lead structures. [source] Some Novel 2-Methyl-3-(1,,3,,4,-thiadiazoyl)-4-(3H)quinazolinones with Anticonvulsant and CNS Depressant Activity.CHEMINFORM, Issue 34 2007Pradeep Mishra Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Synthesis and Reactions of Some New Substituted Pyridine and Pyrimidine Derivatives as Analgesic Anticonvulsant and Antiparkinsonian Agents.CHEMINFORM, Issue 2 2006Abd El-Galil E. Amr Abstract For Abstract see ChemInform Abstract in Full Text. [source] Interaction between Anticonvulsants and Human Placental Carnitine TransporterEPILEPSIA, Issue 3 2004Shu-Pei Wu Summary: Purpose: To examine the inhibitory effect of anticonvulsants (AEDs) on carnitine transport by the human placental carnitine transporter. Methods: Uptake of radiolabeled carnitine by human placental brush-border membrane vesicles was measured in the absence and presence of tiagabine (TGB), vigabatrin (VGB), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), valproic acid (VPA), and phenytoin (PHT). The mechanism of the inhibitory action of TGB was determined. Results: Most of the AEDs inhibited placental carnitine transport. Kinetic analyses showed that TGB had the greatest inhibitory effect [50% inhibitory concentration (IC50, 190 ,M)], and the order of inhibitory potency was TGB > PHT > GBP > VPA > VGB, TPM > LTG. Further studies showed that TGB competitively inhibited carnitine uptake by the human placental carnitine transporter, suggesting that it may be a substrate for this carrier. Conclusions: Although the involvement of carnitine deficiency in fetal anticonvulsant syndrome requires further evaluation, potential interference with placental carnitine transport by several AEDs was demonstrated. Despite the higher inhibitory potency of TGB, given the therapeutic unbound concentrations, the results for VPA and PHT are probably more clinically significant. [source] Topiramate as an Adjunctive Treatment in Migraine ProphylaxisHEADACHE, Issue 10 2003Héctor R. Martínez MD Background.,Anticonvulsants now are commonly used for headache prevention. Topiramate, one of the newer anticonvulsants, recently has been demonstrated to be effective as monotherapy for migraine prophylaxis. Objective.,To assess the efficacy, safety, and tolerability of topiramate as adjunctive prophylactic therapy for migraine. Material and Methods.,A prospective trial involving patients with more than 3 migraine attacks per month was performed. Patients continued their usual prophylactic treatment. Baseline analgesic use and frequency and duration of migraine attacks were recorded. A 4-point visual analog scale evaluated severity. Laboratory tests, electrocardiogram, and computed tomography or magnetic resonance imaging were performed before study entry. After informed consent was obtained, patients were instructed to take 25 mg of topiramate per day, with 25- to 50-mg weekly increments to a maximum of 100 mg per day. Safety was assessed at the first month; tolerability and efficacy were assessed every week for the first month and then every month for 3 months. Effectiveness was assessed by comparing baseline and on-treatment migraine status, and data were analyzed by the Fisher exact test. Results.,Twenty-five women and 11 men (mean age, 44 years) were evaluated. Existing prophylactic treatment was either propranolol or flunarizine (or both) in 80% of the patients. At 3 months of therapy with topiramate, headache frequency decreased from 17 to 3 episodes per month, headache duration from 559 to 32 minutes, and intensity from 9 to 1 by visual analog scale (P < .001). Improvement in frequency and severity of migraine was observed in 83% of patients. Slight or no changes in headache were observed in 6 patients. Tolerability was good in 30 patients. The most common side effects were acroparesthesias, weight loss, sleepiness, and headache worsening. No adverse interaction with propranolol or flunarizine was observed. Conclusions.,These results suggest that topiramate is efficacious and safe as an adjunctive treatment in patients with migraine whose prior response to prophylactic management has been less than satisfactory. [source] Update on Anticonvulsants for the Treatment of Alcohol WithdrawalTHE AMERICAN JOURNAL ON ADDICTIONS, Issue 2001Robert Malcolm M.D. Some anticonvulsants have been shown to be as effective as some benzodiazepines for the treatment of alcohol withdrawal. Anticonvulsants may offer advantages over benzodiazepines in the outpatient treatment of alcohol withdrawal: they lack abuse potential, have minimal interactions with alcohol, and may be more effective in ameliorating psychiatric symptoms of alcohol withdrawal. Carbamazepine appears to be as effective as lorazepam and oxazepam in ameliorating the symptoms of alcohol withdrawal. In addition, a recent study indicates that carbamazepine may suppress post-withdrawal alcohol use. Divalproex may also reduce symptoms of alcohol withdrawal, based on several open-label studies. However, both carbamazepine and divalproex have limited usefulness in alcoholics with severe hepatic or hematologic complications. Newer anticonvulsants, such as gabapentin and vigabatrin, also appear to reduce alcohol withdrawal symptoms in preclinical and open-label clinical trials while lacking the toxicities of carbamazepine and divalproex. Controlled trials are underway exploring the efficacy and safety of newer anticonvulsants for the treatment of alcohol withdrawal. [source] Tiagabine in treatment refractory bipolar disorder: a clinical case seriesBIPOLAR DISORDERS, Issue 5 2002Trisha Suppes Objectives:, Anticonvulsants have provided major treatment advances for patients with bipolar disorder. Many of these drugs, including several with proven efficacy in bipolar mania or depression, enhance the activity of the ,-amino butyric acid (GABA) neurotransmitter system. A new anticonvulsant, tiagabine, has selective GABAergic activity and is approved for patients with partial epilepsy. Few reports of its potential effectiveness in bipolar disorder, however, have been published. We sought to evaluate the effectiveness of tiagabine added to ongoing medication regimens in patients with bipolar disorder inadequately responsive to or intolerant of usual treatments. Methods:, Seventeen treatment-refractory patients participating in the Stanley Foundation Bipolar Network (SFBN) long-term follow-up study were offered open treatment with add-on tiagabine after discussion of the risks, benefits, other treatment options and giving informed consent. Patients' clinical symptoms and somatic complaints were closely monitored with SFBN longitudinal and cross-sectional ratings. Four patients discontinued low-dose tiagabine prior to the second visit and were excluded from data analysis. Results:, Thirteen patients received a mean of 38 days of treatment at a mean dose of 8.7 mg/day of tiagabine. On the Clinical Global Impression Scale for Bipolar Disorder Overall category, three (23%) patients showed much or very much improvement and 10 (77%) patients showed no change or worsening. Three significant adverse events were noted, including two presumptive seizures. Conclusions:, Open add-on tiagabine for treatment-refractory patients with bipolar disorder demonstrated limited efficacy with the majority of patients showing no change or worsening of clinical symptoms. In addition, patients experienced serious side-effects attributed as likely due to the medication, which resolved without lasting consequence when tiagabine was discontinued. [source] ChemInform Abstract: Design of Semicarbazones and Their Bio-isosteric Analogues as Potential Anticonvulsants.CHEMINFORM, Issue 18 2001S. N. Pandeya Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Possible mechanisms for the anticonvulsant activity of fructose-1,6-diphosphateEPILEPSIA, Issue 2008Janet L. Stringer Summary Fructose-1,6-diphosphate (FDP), an intracellular metabolite of glucose, has anticonvulsant activity in several models of acute seizures in laboratory animals. The anticonvulsant effect of FDP is most likely due to a direct effect since intraperitoneal and oral administration results in significant increases in brain levels. A number of mechanisms have been proposed for this action of FDP. One possibility is that peripheral administration of FDP results in changes in brain metabolism that are anticonvulsant. Glucose can be metabolized through the glycolytic or pentose phosphate pathway. There is evidence that the pentose phosphate pathway is more active in the brain than in other tissues, and that, in the presence of elevated levels of FDP, the majority of glucose is metabolized by the pentose phosphate pathway. The pentose phosphate pathway generates NADPH, which is used to reduce glutathione. The reduced form of endogenous glutathione has been shown to have anticonvulsant activity. Taken together, the data suggest a hypothesis that exogenously administered FDP gets into the brain and astrocytes where it increases the flux of glucose through the pentose phosphate pathway, generating additional NADPH for the reduction of glutathione. [source] The Influence of Gonadal Hormones on Neuronal Excitability, Seizures, and Epilepsy in the FemaleEPILEPSIA, Issue 9 2006Helen E. Scharfman Summary:, It is clear from both clinical observations of women, and research in laboratory animals, that gonadal hormones exert a profound influence on neuronal excitability, seizures, and epilepsy. These studies have led to a focus on two of the primary ovarian steroid hormones, estrogen and progesterone, to clarify how gonadal hormones influence seizures in women with epilepsy. The prevailing view is that estrogen is proconvulsant, whereas progesterone is anticonvulsant. However, estrogen and progesterone may not be the only reproductive hormones to consider in evaluating excitability, seizures, or epilepsy in the female. It seems unlikely that estrogen and progesterone would exert single, uniform actions given our current understanding of their complex pharmacological and physiological relationships. Their modulatory effects are likely to depend on endocrine state, relative concentration, metabolism, and many other factors. Despite the challenges these issues raise to future research, some recent advances have helped clarify past confusion in the literature. In addition, testable hypotheses have developed for complex clinical problems such as "catamenial epilepsy." Clinical and animal research, designed with the relevant endocrinological and neurobiological issues in mind, will help advance this field in the future. [source] Causal Links between Brain Cytokines and Experimental Febrile Convulsions in the RatEPILEPSIA, Issue 12 2005James G. Heida Summary:,Purpose: Despite the prevalence of febrile convulsions (FCs), their pathophysiology has remained elusive. We tested the hypothesis that components of the immune response, particularly the proinflammatory cytokine interleukin-1, (IL-1,) and its naturally occurring antagonist interleukin-1 receptor antagonist (IL-1ra) may play a role in the genesis of FC. Methods: Postnatal day 14 rats were treated with lipopolysaccharide (LPS; 200 ,g/kg, i.p.) followed by a subconvulsant dose of kainic acid (1.75 mg/kg, i.p.). Brains were harvested at and 2 h after onset of FCs to measure brain levels of IL-1, and IL-1ra. Separate groups of animals were given intracerebroventricular (ICV) injections of IL-1,, or IL-1ra in an attempt to establish a causal relation between the IL-1,/IL-1ra system and FCs. Results: Animals with FCs showed increased IL-1, in the hypothalamus and hippocampus but not in the cortex compared with noFC animals that also received LPS and kainic acid. This increase was first detected in the hippocampus at onset of FCs. No detectable difference in IL-1ra was found in brain regions examined in either group. When animals were treated with IL-1, ICV, a dose-dependant increase was noted in the proportion of animals that experienced FCs, whereas increasing doses of IL-1ra, given to separate groups of animals, were anticonvulsant. Conclusions: Our results suggest that excessive amounts of IL-1, may influence the genesis of FCs. This may occur by overproduction of IL-1,, or by alteration in the IL-1,/IL-1ra ratio in the brain after an immune challenge. [source] Voltage-Dependent Block of N -Methyl- d -Aspartate Receptors by the Novel Anticonvulsant Dibenzylamine, a Bioactive Constituent of l -(+)-,-HydroxybutyrateEPILEPSIA, Issue 10 2003Sean D. Donevan Summary:,Purpose: Previously we demonstrated that l -(+)-,-hydroxybutyrate (L-BHB), acetoacetate (ACA), acetone, and dibenzylamine (DBA) were anticonvulsant in an audiogenic seizure,susceptible model, and that DBA was a bioactive contaminant identified in commercial lots of L-BHB. In the present study, we asked whether these effects could be mediated by ionotropic glutamate or ,-aminobutyric acidA (GABAA) receptors. Methods: We studied the effects of both stereoisomers of BHB (as well as the racemate), ACA, and DBA on N -methyl- d -aspartate (NMDA), ,-amino-3-hydroxy-5methyl-4-isoxazole-proprionic acid (AMPA), and GABAA receptors in cultured rodent neocortical neurons by using whole-cell voltage-clamp recording techniques. Results: Only L-BHB and DBA exerted a concentration- and voltage-dependent block of NMDA-evoked currents, whereas none of the tested substrates affected AMPA- or GABA-activated currents. The kinetics of whole-cell block by L-BHB and DBA were similar, providing additional evidence that DBA is responsible for the anticonvulsant activity of L-BHB. Conclusions: BHB and ACA do not exert direct actions on GABAA or ionotropic glutamate receptors in cultured neocortical neurons. In addition, we provide additional evidence that DBA is responsible for the anticonvulsant activity of L-BHB, and that this action may be mediated in part by voltage-dependent blockade of NMDA receptors. [source] Riluzole inhibits the persistent sodium current in mammalian CNS neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2000Andrea Urbani Abstract The effects of 0.1,100 ,m riluzole, a neuroprotective agent with anticonvulsant properties, were studied on neurons from rat brain cortex. Patch-clamp whole-cell recordings in voltage-clamp mode were performed on thin slices to examine the effects of the drug on a noninactivating (persistent) Na+ current (INa,p). INa,p was selected because it enhances neuronal excitability near firing threshold, which makes it a potential target for anticonvulsant drugs. When added to the external solution, riluzole dose-dependently inhibited INa,p up to a complete blocking of the current (EC50 2 ,m), showing a significant effect at therapeutic drug concentrations. A comparative dose-effect study was carried out in the same cells for the other main known action of riluzole, the inhibitory effect on the fast transient sodium current. This effect was confirmed in our experiments, but we found that it was achieved at levels much higher than putative therapeutic concentrations. Only the effect on INa,p, and not that on fast sodium current, can account for the reduction in neuronal excitability observed in cortical neurons following riluzole treatment at therapeutic concentrations, and this might represent a novel mechanism accounting for the anticonvulsant and neuroprotective properties of riluzole. [source] Effects of the paratemnus elongatus pseudoscorpion venom in the uptake and binding of the L -glutamate and GABA from rat cerebral cortexJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 1 2006Wagner Ferreira dos Santos Abstract L -Glu is the most important and widespread excitatory neurotransmitter of the vertebrates. Four types of receptors for L -glu have been described. This neurotransmitter modulates several neuronal processes, and its dysfunction causes chronic and acute diseases. L -Glu action is terminated by five distinct transporters. Antagonists for these receptors and modulators of these transporters have anticonvulsant and neuroprotective potentials, as observed with the acylpoliamines and peptides isolated from spiders, solitary and social wasp venoms. On the other hand, the major inhibitory neurotransmitter in mammalian nervous tissue is the GABA. Drugs that enhance GABA neurotransmission comprise effective approaches to protecting the brain against neuronal injury. Is this study, we demonstrate for the first time the inhibition of the [3H]L -glu binding to its specific sites in synaptosomal membranes from rat cerebral cortex, produced by 0.027 U of Paratemnus elongatus venom (EC50). The venom of P. elongatus changes Km and Vmax into the high affinity uptake of the L -glu and decreases Km and Vmax into the parameters of the GABA uptake from rat synaptosomes. This leads us to speculate on the possible presence of selective and specific compounds in this venom that act in L -glu and GABA dynamics, and therefore, that can serve as tools and new drug models for understanding these neurotransmissions. © 2006 Wiley Periodicals, Inc. J Biochem Mol Toxicol 20:27,34, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20113 [source] New derivatives of dibenzo[b,e][1,4]diazepin-1-ones by an efficient synthesis and spectroscopyJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 1 2007Eduardo Cortés Cortés An efficient synthesis of four steps to obtain twelve new derivatives of 3,3-dimethyl-2,3,4,5,10,11-hexahydro-8-[(o -; and p -methoxy)phenoxy]-11-[(o -; and p -R)phenyl]-1H -dibenzo[b,e][1,4]diazepin-1-ones IV, 1-12 with possible biological and pharmacological activity as anticonvulsant and schizophrenia treatment in the central nervous system (CNS). The final products were obtained by condensation and cyclization between 3-{4-[(o -; and p -methoxy)phenoxy]-1,2-phenylenediamine}-5,5-dimethyl-2-cyclohexenone with (o -; and p -R)benzaldehyde. The structure of all products was corroborated by spectroscopy of ir, 1H-nmr, 13C-nmr, with bidimensional experiments and MS in Low and high resolution with Collision-Induced Dissociation experiments (CID). [source] Maternal Mortality Associated with Eclampsia and Severe Preeclampsia of PregnancyJOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 5 2000Dr. H. Sawhney Abstract Objective: To analyse factors associated with maternal mortality in eclampsia and preeclampsia. Method: Retrospective analysis of 69 maternal deaths due to (eclampsia-61; severe preeclampsia-8) was carried out during a period of 17 years (1982,1998). Maternal condition on admission, associated complications and principal cause of death was analysed in each case. Results: Mean time interval between hospitalization and maternal death was 49.56 + 62.01 hrs (1,240 hrs). Twenty (28.9%) women died undelivered. Twenty-three (37.7%) women were in grade IV coma and 52.4% of eclampsia patients had recurrent convulsions (> 10) prior to admission. Associated complications in form of hemorrhage, cerebrovascular accidents, acute renal failure, jaundice, aspiration pneumonia and pulmonary oedema were 30.4, 31.8, 34.8, 18.8, 17.8, and 5.8%, respectively. Maternal mortality in eclampsia was significantly low in time period B (4.1%) when magnesium sulphate was used as an anticonvulsant. Conclusions: Maternal condition on admission and associated complications are the major determinant of maternal outcome. Use of magnesium sulphate is associated with significant reduction of maternal mortality. [source] GABAA -Receptor , Subunit Knockout Mice Have Multiple Defects in Behavioral Responses to EthanolALCOHOLISM, Issue 12 2001Robert M. Mihalek Background: The ,-aminobutyric acid type A receptors (GABARs) are involved in mediating some of the behavioral effects of beverage alcohol (ethanol). However, the unique pharmacological and behavioral responses conferred by each of the various receptor subunits are not well understood. Methods: To address the role of the GABAR , subunit in mediating ethanol responses, gene knockout mice that lack this subunit were tested for a variety of ethanol-induced behavioral responses. Results: Our results indicate that, compared with controls, ,-deficient mice (,,/,) have (1) reduced ethanol consumption, (2) attenuated withdrawal from chronic ethanol exposure, and (3) reduced anticonvulsant (seizure-protective) effects of ethanol. These mice demonstrate a normal anxiolytic response to ethanol and a normal hypothermic response to ethanol, and they develop both chronic and acute tolerance. Conclusions: These results further establish the link between GABARs and specific behavioral responses to ethanol and begin to reveal the role of the , subunit in these responses. [source] Plasma profile and pharmacokinetics of dextromethorphan after intravenous and oral administration in healthy dogsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2004B. KuKanich Dextromethorphan is an N -methyl- d -aspartate (NMDA) noncompetitive antagonist which has been used as an antitussive, analgesic adjunct, probe drug, experimentally to attenuate acute opiate and ethanol withdrawal, and as an anticonvulsant. A metabolite of dextromethorphan, dextrorphan, has been shown to behave pharmacodynamically in a similar manner to dextromethorphan. The pharmacokinetics of dextromethorphan were examined in six healthy dogs following intravenous (2.2 mg/kg) and oral (5 mg/kg) administration in a randomized crossover design. Dextromethorphan behaved in a similar manner to other NMDA antagonists upon injection causing muscle rigidity, ataxia to recumbency, sedation, urination, and ptyalism which resolved within 90 min. One dog repeatedly vomited upon oral administration and was excluded from oral analysis. Mean ± SD values for half-life, apparent volume of distribution, and clearance after i.v. administration were 2.0 ±0.6 h, 5.1 ± 2.6 L/kg, and 33.8 ± 16.5 mL/min/kg. Oral bioavailability was 11% as calculated from naïve pooled data. Free dextrorphan was not detected in any plasma sample, however enzymatic treatment of plasma with glucuronidase released both dextromethorphan and dextrorphan indicating that conjugation is a metabolic route. The short half-life, rapid clearance, and poor bioavailability of dextromethorphan limit its potential use as a chronic orally administered therapeutic. [source] Evaluation of mutagenic and antimutagenic properties of some bioactive xanthone derivatives using Vibrio harveyi testLETTERS IN APPLIED MICROBIOLOGY, Issue 3 2010Abstract Aims:, Drug safety evaluation plays an important role in the early phase of drug development, especially in the preclinical identification of compounds' biological activity. The Vibrio harveyi assay was used to assess mutagenic and antimutagenic activity of some aminoalkanolic derivatives of xanthone (1,5), which were synthesized and evaluated for their anticonvulsant and hemodynamic activities. Methods and Results:, A novel V. harveyi assay was used to assess mutagenic and antimutagenic activity of derivatives of xanthone 1,5. Two V. harveyi strains were used: BB7 (natural isolate) and BB7M (BB7 derivative containing mucA and mucB genes on a plasmid pAB91273, products of these genes enhance error-prone DNA repair). According to the results obtained, the most beneficial mutagenic and antimutagenic profiles were observed for compounds 2 and 3. A modification of the chemical structure of compound 2 by the replacement of the hydroxy group by a chloride improved considerably the antimutagenic activity of the compound. Thus, antimutagenic potency reached a maximum with the presence of tertiary amine and chloride atom in the side chain. Conclusions:, Among the newly synthesized aminoalkanolic derivatives of xanthone with potential anticonvulsant properties, there are some compounds exhibiting in vitro antimutagenic activity. In addition, it appears that the V. harveyi assay can be applied for primary mutagenicity and antimutagenicity assessment of compounds. Significance and Impact of the Study:, The obtained preliminary mutagenicity and antimutagenicity results encourage further search in the group of amino derivatives of xanthone as the potential antiepileptic drugs also presenting some antimutagenic potential. Furthermore, V. harveyi test may be a useful tool for compounds safety evaluation. [source] Painful neuropathy alters the effect of gabapentin on sensory neuron excitability in ratsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2004A. Kanai Background:, Pain following peripheral nerve injury is associated with increased excitability of sensory neurons. Gabapentin (GBP), a novel anticonvulsant with an uncertain mechanism of action, is an effective treatment for neuropathic pain. We therefore investigated the effect of GBP on dorsal root ganglion (DRG) neurons from normal rats and those with painful peripheral nerve injury. Methods:, Dorsal root ganglions were excised from rats with neuropathic pain behaviour following chronic constriction injury (CCI) of the sciatic nerve, and from normal rats. Intercellular recordings were made from myelinated sensory neuron somata using a microelectrode technique from DRGs bathed in artificial CSF with or without GBP (100 µM). Results:, Compared with normal neurons, injury decreased the refractory interval (RI) for repeat action potential (AP) generation increased the number of APs during sustained depolariza- tion, and shortened the after hyperpolarization following an AP. In normal neurons, GBP decreased the RI and increased the AP number during sustained depolarization. In an opposite fashion, the result of GBP application to injured neurons was a decreased number of APs during depolarization and no change in RI. In injured neurons only, GBP increased the time-to-peak for AP depolarization. Conclusions:, Nerve injury by CCI is associated with increased sensory neuron excitability, associated with a decreased AHP. In normal peripheral sensory neurons, GBP has pro-excitatory effects, whereas GBP decreases excitability in injured neurons, possibly on the basis of altered sodium channel function. [source] A double blind randomized placebo control trial of levetiracetam in tourette syndromeMOVEMENT DISORDERS, Issue 12 2007Constance L. Smith-Hicks MD Abstract The objective of this study was to investigate the effectiveness of levetiracetam for the treatment of tics in children with Tourette syndrome (TS). Levetiracetam, an atypical anticonvulsant, has been suggested in open-label protocols to be an effective tic-suppressing agent in individuals with TS. A double blind, randomized, placebo-controlled, cross-over trial was performed to investigate this medication in children with moderate to moderately-severe tics. Subjects received, in a randomized sequence, 4-weeks of levetiracetam (maximum dose 30 mg/kg/day) or placebo, with a 2-week intervening washout period between cycles. Primary outcome measures included two separate scales from the Yale Global Tic Severity Scale; the Total Tic score and the Total overall score. Measures were assessed at baseline, prior to randomization, on Day 28 (end of Phase 1), on Day 42 (baseline for second phase) and on Day 70 (end of Phase 2). Twenty-two subjects (21 boys and 1 girl) with TS, mean age 12.2 ± 2.3 years, range 8 to 16 years, participated. A mild reduction in tics occurred during both the levetiracetam and placebo treatment phases. There was no significant difference between treatments and no evidence of sequence or cross-over effects. In conclusion, Levetiracetam is not more beneficial than placebo in suppressing tics in children with TS. © 2007 Movement Disorder Society [source] Quantitative analysis of safranal in saffron extract and nanoparticle formulation by a validated high-performance thin-layer chromatographic method,PHYTOCHEMICAL ANALYSIS, Issue 3 2010Shadab Ahmad Pathan Abstract Introduction , Safranal is an effective anticonvulsant shown to act as an agonist at GABAA receptors. Nose to brain delivery via nanoparticle formulation might improve its brain delivery. A selective and sensitive analytical method is required for evaluation of safranal-based novel drug delivery systems. Objective , To develop and validate a high-performance thin-layer chromatographic (HPTLC) method for the quantitative analysis of safranal as bulk, in saffron extract and in developed safranal-loaded nanoparticle formulation. Methodology , Chromatographic separation was achieved on silica gel pre-coated TLC aluminium plates 60F-254, using n -hexane:ethyl acetate (9,:,1, v/v) as the mobile phase. Quantitative analysis was carried out by densitometry at a wavelength of 310,nm. The method was validated and applied to detect related impurities, to analyse safranal in saffron extract and to evaluate safranal-loaded nanoparticles. Results , Compact spots of safranal were observed at Rf value 0.51 ± 0.02. The method was linear (r = 0.9991) between 0.5 and 5.0,,g/spot. The intra- and inter-day precisions were 1.08,2.17 and 1. 86,3.47%, respectively. The limit of detection was 50,ng/spot and the limit of quantification was 150,ng/spot. The method proved to be accurate (recovery 97.4,102.0%) and was selective for safranal. Evaluation of safranal-loaded nanoparticle formulation demonstrated drug loading of 23.0%, encapsulation efficiency of 42.0% and sustained drug release following biphasic pattern. Conclusion , The present method is useful for the quantitative and qualitative analysis of safranal and safranal-loaded nanoparticle formulation. It provides significant advantages in terms of greater specificity and rapid analysis. Copyright © 2009 John Wiley & Sons, Ltd. [source] Anticonvulsant activities of nutmeg oil of Myristica fragransPHYTOTHERAPY RESEARCH, Issue 2 2009Abdul Wahab Abstract The purpose of this study was to investigate the anticonvulsant activity of the volatile oil of nutmeg, the dried seed kernel of Myristica fragrans Houtt, using well-established animal seizure models and to evaluate its potential for acute toxicity and acute neurotoxicity. The volatile oil of nutmeg (nutmeg oil) was tested for its effects in maximal electroshock, subcutaneous pentylenetetrazole, strychnine and bicuculline seizure tests. All the experiments were performed at the time of peak effect of nutmeg oil. Nutmeg oil showed a rapid onset of action and short duration of anticonvulsant effect. It was found to possess significant anticonvulsant activity against electroshock-induced hind limb tonic extension. It exhibited dose dependent anticonvulsant activity against pentylenetetrazole-induced tonic seizures. It delayed the onset of hind limb tonic extensor jerks induced by strychnine. It was anticonvulsant at lower doses, whereas weak proconvulsant at a higher dose against pentylenetetrazole and bicuculline induced clonic seizures. Nutmeg oil was found to possess wide therapeutic margin, as it did not induce motor impairment when tested up to 600 µL/kg in the inverted screen acute neurotoxicity test. Furthermore, the LD50 (2150 µL/kg) value was much higher than its anticonvulsant doses (50,300 µL/kg). The results indicate that nutmeg oil may be effective against grand mal and partial seizures, as it prevents seizure spread in a set of established animal models. Slight potentiation of clonic seizure activity limits its use for the treatment of myoclonic and absence seizures. Copyright © 2008 John Wiley & Sons, Ltd. [source] Anxiolytic and antiemetic activity of Zingiber officinalePHYTOTHERAPY RESEARCH, Issue 7 2002S. L. Vishwakarma Abstract The benzene fraction (BF) of a petroleum ether extract of dried rhizomes of ginger, which contained anticonvulsant principle(s), was screened for anxiolytic and antiemetic activity. Motor coordination was not affected by BF per se, but diazepam-induced motor incoordination was potentiated. Animals treated with BF showed decreased occupancy in the closed arm of the elevated plus maze suggesting the presence of anxiolytic principles in the BF. BF also blocked lithium sulphate-induced conditioned place aversion indicating antiemetic activity. These findings suggest that the fraction (BF) possesses anticonvulsant, anxiolytic and antiemetic activity. Copyright © 2002 John Wiley & Sons, Ltd. [source] Latest news and product developmentsPRESCRIBER, Issue 22 2007Article first published online: 28 DEC 200 Glitazones: benefits outweigh the risks Following a review of the safety of rosiglitazone and pioglitazone, the European Medicines Agency (EMEA) has concluded that their benefits outweigh their risks in the approved indications. The review was prompted by reports of an increased risk of fractures in women and, in patients taking rosiglitazone, ischaemic heart disease. The EMEA concluded that prescribing information for rosiglitazone should now include a warning that, in patients with ischaemic heart disease, it should only be used after careful evaluation of each patient's individual risk, and the combination of rosiglitazone and insulin should only be used in exceptional cases and under close supervision. No change was considered necessary to the prescribing information for pioglitazone. Modern dressings no better? A systematic review has found only weak evidence that modern dressings are better than saline gauze or paraffin gauze for healing acute and chronic wounds (Arch Dermatol 2007;143: 1297-304). The analysis, which included 99 studies, found that only hydrocolloids were demonstrably better than older dressings for healing chronic wounds, and alginates were superior to other modern dressings for debriding necrotic wounds. There was no evidence that modern dressings offered superior overall performance to the older alternatives. Hospital inflation twice primary care level The cost of drugs prescribed in secondary care but dispensed in the community increased by 6.4 per cent in 2006 - twice the rate of inflation in primary care - according to the latest statistics on hospital prescribing in England. The increase follows a reduction in costs in 2005 after the introduction of the new PPRS scheme. Data from The Information Centre (www.ic.nhs.uk) show that hospital medicines make up about 24 per cent of the NHS drugs budget. Secondary care has a consistently better record than primary care in prescribing lower-cost alternatives within therapeutic categories, eg simvastatin and pravastatin among the statins, omeprazole and lansoprazole among PPIs, and ACE inhibitors among drugs acting on the renin angiotensin system. The most expensive drug prescribed by hospital specialists and dispensed in the community is interferon beta. MHRA limits the use of fibrates The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that fibrates should now be reserved for the treatment of isolated severe hypertriglyceridaemia. They should be considered for hypercholesterolaemia only when a statin or other treatment is contraindicated or not tolerated. In the latest Drug Safety Update, the MHRA says there is insufficient evidence of long-term benefits from fibrates, and first-line use is no longer justified because the evidence for the benefits of statins is robust. The MHRA also warns that some breastfeeding infants have increased susceptibility to the adverse effects of codeine taken by their mother, and that St John's wort may affect the hepatic metabolism of any anticonvulsant. Annual zoledronic acid infusion cuts mortality after hip fracture Once-yearly infusion of zoledronic acid (Aclasta) after hip fracture reduces deaths over a two-year period by 28 per cent compared with placebo, US investigators say (N Engl J Med 2007;357:1799-809). The HORIZON Recurrent Fracture Trial randomised 2127 men and women (mean age 75) within 90 days of surgery for hip fracture to zoledronic acid 5mg yearly or placebo. Mortality over 1.9 years of follow-up was 9.6 per cent with zoledronic acid and 13.3 per cent with placebo. Zoledronic acid also significantly reduced the rate of any new clinical fractures (by 35 per cent) and new clinical vertebral fractures(by 45 per cent),but the lower rate of hip fracture (2.0 vs 3.5 per cent with placebo) was not statistically significant. Rivastigmine patch for mild to moderate AD Rivastigmine (Exelon) is now available as a transdermal patch for the treatment of mild to moderate Alzheimer's disease. Applied once daily, the patch delivers 9.5mg per 24 hours and, says manufacturer Novartis, is associated with a lower incidence of nausea and vomiting than a comparable oral dose. The patch is available in two strengths: 4.6mg per 24hr is equivalent to oral doses of 3 or 6mg per day, and the 9.5mg per 24hr patch is equivalent to 9 or 12mg per day orally. The recommended dose of the patch is 9.5mg per day; both strengths cost £83.84 for 30 patches. Women more aspirin resistant than men? The cardioprotective effect of low-dose aspirin may be lower in women than men, say Canadian investigators (BMC Medicine 2007;5:29 doi: 10.1186/1741-70155-29). Their meta-analysis of 23 randomised trials involving a total of 113 494 participants found that aspirin significantly reduced the risk of nonfatal but not fatal myocardial infarction (MI). About one-quarter of the variation in its effects on nonfatal MI was accounted for by the sex mix of the trial population. Separating the results by sex showed the reduction in risk with aspirin use was statistically significant in men (relative risk, RR, 0.62) but not in women (RR 0.87). Look after physical health of mentally ill GPs and other primary care workers should take more responsibility for the physical health of their mentally ill patients, say advocacy groups. Mind and Body: Preventing and Improving Physical Health Problems in Patients With Schizophrenia points out that the mental health needs of patients with schizophrenia are met in secondary care, but their physical health needs should be met in primary care. In particular, the metabolic effects of antipsychotics may lead to obesity, diabetes and cardiovascular disease, and weight gain in particular is a frequent reason for nonadherence to treatment. The Mind and Body Manifesto was developed by SANE, The Mental Health Nurses Association, The National Obesity Forum and The Disability Rights Commission and sponsored by Bristol-Myers Squibb Pharmaceuticals Limited and Otsuka Pharmaceuticals (UK) Ltd. Copies are available from elizabeth.green@ ogilvyhealthworld.com. Health eCard costs Some costs quoted in our article on the Health eCard (The Health eCard: the way ahead for medical records?,5 October issue, pages 28-9) have been revised: the card and initial download will cost patients £39.50, and GPs will be entitled to charge patients £10 per annum for subsequent downloads. NICE appraisals of cytokine inhibitors in RA NICE has endorsed the use of the anti-TNF agents adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade), normally in conjunction with methotrexate, for the treatment of active RA when methotrexate and another DMARD have failed (also see New from NICE below). NICE has provisionally concluded, subject to consultation, that abatacept (Orencia) should not be recommended for the treatment of RA. Boots and BMJ launch health advice site www.askbootshealth.com is a new website providing information about health and medicines for the public produced by Boots using information provided by the BMJ Publishing Group. The website covers many of the topics already available from NHSDirect, with perhaps more information about available treatments. Diabetes care shows small improvement The third National Diabetes Audit in England and Wales has found that more people with diabetes were achieving the targets set by NICE for cholesterol levels, glycaemic control and blood pressure in 2005/06 - but younger patients were doing less well. Overall, the HbA1C target of ,7.5 per cent was achieved in 60 per cent of people with diabetes compared with 58 per cent in 2004/05. However, HbA1C was >9.5 per cent in 30 per cent of children and young people, of whom 9 per cent experienced at least one episode of ketoacidosis. More topics for NICE New topics referred to NICE include clinical guidelines on ovarian cancer, coeliac disease and stable angina, public health guidance on preventing cardiovascular disease, and technology appraisals on insulin detemir (Levemir) for type 1 diabetes, several treatments for cancer and hepatic and haematological disorders, and biological therapies for juvenile arthritis. New from NICE NICE appraisal on anti-TNFs for RA Since NICE published its first appraisal of agents acting against tumour necrosis factor-alpha (anti-TNFs) for the treatment of RA in 2002, the product licences for etanercept (Enbrel) and infliximab (Remicade) have changed and a new agent, adalimumab (Humira), has been introduced. The anti-TNFs act in different ways. Infliximab is a chimeric monoclonal antibody that binds to TNF-alpha, neutralising its activity. Etanercept, a recombinant human TNF-alpha receptor fusion protein, and adalimumab, a human-sequence antibody, both bind to TNF-alpha and block its interaction with cell surface receptors. Adalimumab also modulates some biological responses induced or regulated by TNF-alpha. These agents are recommended for adults with severe active RA (defined as a disease activity score - DAS28 - greater than 5.1) who have already tried two disease-modifying drugs, including methotrexate (if not contraindicated). Prior treatment should have been of at least six months' duration, including two months at the standard dose (unless limited by toxicity). Anti-TNFs should normally be prescribed with methotrexate; when this is not appropriate, etanercept and adalimumab may be prescribed as monotherapy. Treatment with an anti-TNF should be continued beyond six months only if there is an adequate response (defined as an improvement in DAS28 of at least 1.2). Data from the British Rheumatology Society Biologics register show that, after six months, 67 per cent of patients met NICE criteria for an adequate response; this declined to 55 per cent at 18 months. The basic annual cost of treatment is £9295 for adalimumab 40mg on alternate weeks or etanercept 25mg twice weekly; infliximab costs £3777 for a loading dose, then £7553-£8812 depending on dose. Assuming no progression of disability, the incremental costs per QALY (compared with sequential DMARDs) were £30 200 for adalimumab, £24 600 for etanercept and £39 400 for infliximab. There are no direct comparative trials of the anti-TNFs, and their clinical trial findings are not directly comparable. Unless other factors determine treatment choice, NICE therefore recommends the least expensive. If the first anti-TNF is withdrawn within six months due to an adverse event, a second may be tried. [source] Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models,ANNALS OF NEUROLOGY, Issue 4 2009Carl E. Stafstrom MD Objective Conventional anticonvulsants reduce neuronal excitability through effects on ion channels and synaptic function. Anticonvulsant mechanisms of the ketogenic diet remain incompletely understood. Because 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, or bicuculline, and in vivo against seizures evoked by 6Hz stimulation in mice, audiogenic stimulation in Fring's mice, and maximal electroshock and subcutaneous pentylenetetrazol (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 7.5mM [K+]o, 4-aminopyridine, and bicuculline, and electrographic seizures induced by high [K+]o in CA3 of hippocampus. 2DG reduced seizures evoked by 6Hz stimulation in mice (effective dose [ED]50 = 79.7mg/kg) and audiogenic stimulation in Fring's mice (ED50 = 206.4mg/kg). 2DG exerted chronic antiepileptic action by increasing afterdischarge thresholds in perforant path (but not olfactory bulb) kindling and caused a twofold 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. Ann Neurol 2009;65:435,448. [source] | |||||||||||||||||||||||||||||||||||||