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Diazepam
Selected AbstractsTetrazepam drug sensitivity , usefulness of the patch testCONTACT DERMATITIS, Issue 3 2002C. Pirker The muscle relaxant tetrazepam may cause severe cutaneous adverse effects. We report 4 cases of varying intensity: Stevens,Johnson syndrome, erythema,multiforme-like exanthema, maculopapular and maculo-urticarial exanthema. Patch testing with tetrazepam (10% in petrolatum) was strongly positive in the 2 patients with severe skin eruptions and weakly positive in the other 2. Oral rechallenge with tetrazepam was positive in 3 patients (1 not done). Diazepam, with a similar chemical structure to tetrazepam, was negative on patch testing and on oral challenge testing in 2 patients. Although the optimal patch test concentration of tetrazepam has still to be determined, it is a useful diagnostic tool to confirm sensitization, particularly in patients with severe bullous eruptions. [source] Determination of Diazepam, Temazepam and Oxazepam at the Lead Film Electrode by Adsorptive Cathodic Stripping VoltammetryELECTROANALYSIS, Issue 17-18 2010Katarzyna Tyszczuk Abstract The determination of psychoactive 1,4-benzodiazepine drugs is of relevant interest in clinical, biomedical areas. Therefore a highly sensitive and simple voltammetric method for the determination of temazepam, diazepam and oxazepam at an in situ plated lead film electrode was developed. The method was successfully applied to the determination of diazepam and temazepam in pharmaceutical formulations with minimum sample manipulation and oxazepam in human urine samples without any separation steps. The determinations of oxazepam in human urine samples were performed in a flow system. Therefore a previous extraction procedure was not necessary to separate the active compound before its determination. [source] Diazepam Terminates Brief but Not Prolonged Seizures in Young, Naïve RatsEPILEPSIA, Issue 8 2003Howard P. Goodkin Summary: Purpose: Ample evidence exists from both clinical and animal studies that the success of benzodiazepine intervention during status epilepticus (SE) in the mature nervous system is inversely related to seizure duration. This relationship has not been well studied in the developing nervous system. Methods: The objective of this study was to investigate the relation of age and success of diazepam (DZP) treatment in the lithium-pilocarpine model of secondarily generalized seizure in the rat by using naïve rats of three age groups, roughly corresponding to the human ages of infancy (P15), adolescence (P20), and adult (P60). Results: In all age groups, the dosage of DZP that stopped the seizures at 5 min was not effective in terminating seizures at 60 min. This decline in efficacy was present as early as 15 min after seizure onset. Conclusions: These findings demonstrate that the inverse relation between the success of benzodiazepine intervention and seizure duration is observed in young as well as in adult rats and provide further evidence that intervention for SE should commence early. [source] Antiepileptogenesis and Seizure Prevention Trials with Antiepileptic Drugs: Meta-Analysis of Controlled TrialsEPILEPSIA, Issue 4 2001Nancy R. Temkin Summary: ,Purpose: To synthesize evidence concerning the effect of antiepileptic drugs (AEDs) for seizure prevention and to contrast their effectiveness for provoked versus unprovoked seizures. Methods: Medline, Embase, and The Cochrane Clinical Trials Register were the primary sources of trials, but all trials found were included. Minimal requirements: seizure-prevention outcome given as fraction of cases; AED or control assigned by random or quasi-random mechanism. Single abstracter. Aggregate relative risk and heterogeneity evaluated using Mantel,Haenszel analyses; random effects model used if heterogeneity was significant. Results: Forty-seven trials evaluated seven drugs or combinations for preventing seizures associated with fever, alcohol, malaria, perinatal asphyxia, contrast media, tumors, craniotomy, and traumatic brain injury. Effective: Phenobarbital for recurrence of febrile seizures [relative risk (RR), 0.51; 95% confidence interval (CI), 0.32,0.82) and cerebral malaria (RR, 0.36; CI, 0.23,0.56). Diazepam for contrast media,associated seizures (RR, 0.10; CI, 0.01,0.79). Phenytoin for provoked seizures after craniotomy or traumatic brain injury (craniotomy: RR, 0.42; CI, 0.25,0.71; TBI: RR, 0.33; CI, 0.19,0.59). Carbamazepine for provoked seizures after traumatic brain injury (RR, 0.39; CI, 0.17,0.92). Lorazepam for alcohol-related seizures (RR, 0.12; CI, 0.04,0.40). More than 25% reduction ruled out valproate for unprovoked seizures after traumatic brain injury (RR, 1.28; CI, 0.76,2.16), and carbamazepine for unprovoked seizures after craniotomy (RR, 1.30; CI, 0.75,2.25). Conclusions: Effective or promising results predominate for provoked (acute, symptomatic) seizures. For unprovoked (epileptic) seizures, no drug has been shown to be effective, and some have had a clinically important effect ruled out. [source] Differential sensitivity to Zolpidem of IPSPs activated by morphologically identified CA1 interneurons in slices of rat hippocampusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2000Alex M. Thomson Abstract Hippocampal pyramidal cells express several ,-subunits, which determine the affinity of GABAA (,-aminobutyric acid) receptors for benzodiazepine site ligands. This study asked whether inhibitory postsynaptic potentials (IPSPs) elicited by specific interneuronal subclasses were differentially sensitive to the ,1-preferring agonist Zolpidem, i.e. whether different receptors mediate different inhibitory connections. Paired intracellular recordings in which the presynaptic cell was an interneuron and the postsynaptic cell a CA1 pyramid were performed in slices of adult rat hippocampus. Resultant IPSPs were challenged with Zolpidem, cells filled with biocytin and identified morphologically. IPSPs elicited by fast spiking (FS) basket cells (n = 9) were enhanced more than IPSPs elicited by regular spiking (RS) basket cells (n = 10). At FS basket cell synapses the efficacy of Zolpidem was equivalent to that of Diazepam, while RS basket cell IPSPs are enhanced 50% less by Zolpidem than by Diazepam. Thus, while ,1 subunits may dominate at synapses supplied by FS basket cells, RS basket cell synapses also involve ,2/3 subunits. Two bistratified cell IPSPs tested with Zolpidem did not increase in amplitude, despite powerful enhancements of bistratified cell IPSPs by Diazepam, consistent with previous indications that these synapses utilize ,5-containing receptors. Enhancements of basket cell IPSPs by Zolpidem and Diazepam were bi- or triphasic with steep amplitude increases separated by plateaux, occurring 10,15, 25,30 and 45,55 min after adding the drug to the bath. The entire enhancement was, however, blocked by the antagonist Flumazenil (n = 7). Flumazenil, either alone (n = 3), or after Zolpidem, reduced IPSP amplitude to ,,90% of control, suggesting that ,4-containing receptors were not involved. [source] Does rat global transient cerebral ischemia serve as an appropriate model to study emotional disturbances?FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2004Guy Bernard Bantsiele Abstract We used two validated psychopharmacological methods, the forced swimming test (FST 20 min and 5 min) and the elevated plus-maze (EPM), to quantify depression-like and anxiety-like behavior induced by transient global cerebral ischemia in the rat. We also validated use of these methods for the study of antidepressant (imipramine) and anti-anxiety drugs (diazepam). Twelve days after surgery to provoke transient global ischemia, spontaneous motor activity was 40% higher in ischemic rats than in sham-operated controls. Duration of immobility during the FST 20 min and 5 min was 28 and 30% shorter, respectively, than in controls. Treatment with imipramine (3 × 30 mg/kg i.p.) induced a significantly shorter duration of immobility during the FST 5 min, but with no difference between ischemia and control rats. The EPM demonstrated that ischemia did not induce any change in the six behavior parameters measured. Diazepam (1.5 mg/kg i.p.) induced significant anxiolytic effects which were similar in ischemic and sham-operated animals. Both tests failed to demonstrate perturbed performance but conversely, these findings did disclose the sensitivity of ischemia-exposed rats to the action of imipramine and diazepam, demonstrating the usefulness of these tests as psychopharmocological tools for evaluating the effect of psychotropics in the ischemic rat. [source] Diazepam-induced prospective memory impairment and its relation to retrospective memory, attention, and arousalHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 2 2006Jill B. Rich Abstract The amnestic effects of benzodiazepines are well documented on a variety of memory tasks. However, prospective memory (PM), or remembering to execute an action at a future time, has not been studied previously. This study examined the effect of diazepam on word list recall, PM, sustained attention, and subjective ratings of arousal. Forty-eight healthy participants, aged 19,35, received an average of 0.19,mg/kg oral diazepam or placebo in a double-blind manner. Retrospective memory and PM were assessed by free recall of unrelated word lists and by instructing participants to request a hidden belonging at the end of the session, respectively. Sustained attention was measured by multiple trials of a digit cancellation task, and subjective arousal was assessed by self-ratings of drowsiness. Diazepam impaired performance on all measures, including PM. Reduced PM performance was associated with decreased subjective arousal in the diazepam group but was unrelated to sustained attention. This is the first report of the effects of benzodiazepines on prospective remembering, and further supports the view that the arousal/attentional system is composed of partially independent subsystems that have differential relationships to memory. Copyright © 2005 John Wiley & Sons, Ltd. [source] Development and validation of a liquid chromatographic/electrospray ionization mass spectrometric method for the quantitation of prazepam and its main metabolites in human plasmaJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 4 2005Paraskevi Valavani Abstract A method was developed and fully validated for the quantitation of prazepam and its major metabolites, oxazepam and nordiazepam, in human plasma. Sample pretreatment was achieved by solid-phase extraction using Oasis HLB cartridges. The extracts were analysed by high-performance liquid chromatography (HPLC) coupled with single-quadrupole mass spectrometry (MS) with an electrospray ionization interface. The MS system was operated in the selected ion monitoring mode. HPLC was performed isocratically on a reversed-phase XTerra MS C18 analytical column (150 × 3.0 mm i.d., particle size 5 µm). Diazepam was used as the internal standard for quantitation. The assay was linear over a concentration range of 5.0,1000 ng ml,1 for all compounds analyzed. The limit of quantitation was 5 ng ml,1 for all compounds. Quality control samples (5, 10, 300 and 1000 ng ml,1) in five replicates from three different runs of analysis demonstrated an intra-assay precision (CV) of ,9.1%, an inter-assay precision of ,6.0% and an overall accuracy (relative error) of <4.6%. The method can be used to quantify prazepam and its metabolites in human plasma covering a variety of pharmacokinetic or bioequivalence studies. Copyright © 2005 John Wiley & Sons, Ltd. [source] Antiglutamatergic Strategies for Ethanol Detoxification: Comparison With Placebo and DiazepamALCOHOLISM, Issue 4 2007Evgeny M. Krupitsky Background: Benzodiazepines are the standard pharmacotherapies for ethanol detoxification, but concerns about their abuse potential and negative effects upon the transition to alcohol abstinence drive the search for new treatments. Glutamatergic activation and glutamate receptor up-regulation contribute to ethanol dependence and withdrawal. This study compared 3 antiglutamatergic strategies for ethanol detoxification with placebo and to the benzodiazepine, diazepam: the glutamate release inhibitor, lamotrigine; the N -methyl- d -aspartate glutamate receptor antagonist, memantine; and the AMPA/kainite receptor inhibitor, topiramate. Methods: This placebo-controlled randomized single-blinded psychopharmacology trial studied male alcohol-dependent inpatients (n=127) with clinically significant alcohol withdrawal symptoms. Subjects were assigned to 1 of 5 treatments for 7 days: placebo, diazepam 10 mg TID, lamotrigine 25 mg QID, memantine 10 mg TID, or topiramate 25 mg QID. Additional diazepam was administered when the assigned medication failed to suppress withdrawal symptoms adequately. Results: All active medications significantly reduced observer-rated and self-rated withdrawal severity, dysphoric mood, and supplementary diazepam administration compared with placebo. The active medications did not differ from diazepam. Conclusions: This study provides the first systematic clinical evidence supporting the efficacy of a number of antiglutamatergic approaches for treating alcohol withdrawal symptoms. These data support the hypothesis that glutamatergic activation contributes to human alcohol withdrawal. Definitive studies of each of these medications are now needed to further evaluate their effectiveness in treating alcohol withdrawal. [source] Midazolam Versus Diazepam for the Treatment of Status Epilepticus in Children and Young Adults: A Meta-analysisACADEMIC EMERGENCY MEDICINE, Issue 6 2010Jason McMullan MD Abstract Background:, Rapid treatment of status epilepticus (SE) is associated with better outcomes. Diazepam and midazolam are commonly used, but the optimal agent and administration route is unclear. Objectives:, The objective was to determine by systematic review if nonintravenous (non-IV) midazolam is as effective as diazepam, by any route, in terminating SE seizures in children and adults. Time to seizure cessation and respiratory complications was examined. Methods:, We performed a search of PubMed, Web of Knowledge, Embase, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, American College of Physicians Journal Club, Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature, and International Pharmaceutical Abstracts for studies published January 1, 1950, through July 4, 2009. English language quasi-experimental or randomized controlled trials comparing midazolam and diazepam as first-line treatment for SE, and meeting the Consolidated Standards of Reporting Trials (CONSORT)-based quality measures, were eligible. Two reviewers independently screened studies for inclusion and extracted outcomes data. Administration routes were stratified as non-IV (buccal, intranasal, intramuscular, rectal) or IV. Fixed-effects models generated pooled statistics. Results:, Six studies with 774 subjects were included. For seizure cessation, midazolam, by any route, was superior to diazepam, by any route (relative risk [RR] = 1.52; 95% confidence interval [CI] = 1.27 to 1.82). Non-IV midazolam is as effective as IV diazepam (RR = 0.79; 95% CI = 0.19 to 3.36), and buccal midazolam is superior to rectal diazepam in achieving seizure control (RR = 1.54; 95% CI = 1.29 to 1.85). Midazolam was administered faster than diazepam (mean difference = 2.46 minutes; 95% CI = 1.52 to 3.39 minutes) and had similar times between drug administration and seizure cessation. Respiratory complications requiring intervention were similar, regardless of administration route (RR = 1.49; 95% CI = 0.25 to 8.72). Conclusions:, Non-IV midazolam, compared to non-IV or IV diazepam, is safe and effective in treating SE. Comparison to lorazepam, evaluation in adults, and prospective confirmation of safety and efficacy is needed. ACADEMIC EMERGENCY MEDICINE 2010; 17:575,582 © 2010 by the Society for Academic Emergency Medicine [source] Ziprasidone, Diazepam, or the Combination for Prevention of Cocaine Toxicity in a Mouse ModelACADEMIC EMERGENCY MEDICINE, Issue 8 2007Nathan R. Cleveland MD BackgroundAcute cocaine poisoning is a common problem in the United States. Sedation with benzodiazepines is the standard treatment, but animal studies have suggested that ziprasidone is also protective. ObjectivesTo assess whether the combination of these two medications would offer more protection than either treatment alone. MethodsThis was a randomized, blinded, placebo-controlled trial in CF-1 mice. The authors administered intraperitoneal injections of 2 mg/kg diazepam (group D), 4 mg/kg ziprasidone (group Z), the same dose of both drugs (group DZ), or saline 15 minutes before intraperitoneal administration of 105 mg/kg cocaine (an estimated lethal dose to 70%). The number of animals with seizures and apparent lethality over the following 30 minutes was recorded. ResultsAll treatments increased survival relative to placebo (relative risk: D = 2.6, Z = 2.3, DZ = 2.9) and decreased seizures (relative risk: D = 0.5, Z = 0.3, DZ = 0.02). ConclusionsThis study suggests that diazepam and ziprasidone have efficacy for preventing lethality from cocaine poisoning in an animal model but that the combination offers little addition to either therapy alone. However, the combination may be more effective for prevention of cocaine-induced seizures. [source] Brain uptake of diazepam and phenytoin in a genetic animal model of absence epilepsyCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2010Joseph A Nicolazzo Summary 1. Although many studies have assessed changes to brain uptake of anti-epileptic drugs (AEDs) in chemically and electrically induced seizure models, there are limited data available on changes to brain uptake of AEDs in spontaneous seizure animal models, such as genetic absence epilepsy. 2. In the present study, the brain uptake of diazepam and phenytoin was assessed in a genetic mouse model of absence seizures harbouring a human GABAA receptor ,2-subunit gene GABRG2 mutation (R43Q) and results were compared with those obtained during acute seizures induced by subcutaneous administration of pentylenetetrazole (PTZ; 90 mg/kg). Diazepam and phenytoin were administered intraperitoneally at doses of 2 and 30 mg/kg, respectively, and brain and plasma concentrations were determined 60 min after administration using liquid chromatography,mass spectrometry. 3. Although the brain uptake of phenytoin was significantly reduced following PTZ administration, no changes were observed in phenytoin disposition in the genetic absence epilepsy model. Similarly, the brain uptake of diazepam was significantly enhanced following PTZ administration, but it was not affected in absence epilepsy. 4. The cerebrovascular plasma volume (assessed by administration of the non-absorbable marker [14C]-inulin) was not significantly different in saline-treated compared with PTZ-treated mice and in wild-type compared with mutant R43Q mice. 5. These results demonstrate that although the brain uptake of AEDs may be altered in acute seizure models, similar changes to brain uptake may not be observed in the non-convulsive genetic absence epileptic model. [source] ,Respiratory depression in children receiving diazepam for acute seizures: a prospective study'DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 6 2000Robert L Kriel MD No abstract is available for this article. [source] Accidental and deliberate overdose among opiate addicts in methadone maintenance treatment: are deliberate overdoses systematically different?DRUG AND ALCOHOL REVIEW, Issue 2 2000Dr. DAVID BEST Abstract The frequency of accidental or deliberate overdose was investigated among 200 opiate addicts in methadone substitution treatment in clinics in Edinburgh and south London. One hundred and three of the participants reported a mean of 3.4 overdoses, with 71 (69%) reporting that their most recent overdose was accidental, 27 (26%) deliberate,the remainder were uncertain. Those whose last overdose was deliberate were more likely to have been prescribed diazepam at that time and were more depressed at the time of interview. Differentiation by self-reported reason for overdose suggests that treatment providers should distinguish between accidental and deliberate overdose in developing overdose prevention strategies. [source] Use of non-prescribed methadone and other illicit drugs during methadone maintenance treatmentDRUG AND ALCOHOL REVIEW, Issue 1 2000Dr. DAVID BEST Abstract Patterns of illicit and non-prescribed drug use among a cohort of 100 patients in methadone maintenance treatment were tracked over a 6-month period. While there were no statistically significant changes in alcohol or heroin use, there were significant increases in the frequency of crack cocaine and cannabis use. Use of non-prescribed methadone had also increased. Twenty-one percent reported non-prescribed methadone use at follow-up who had not done so at the first interview, with increases also in the mean quantities used. Non-prescribed methadone use at the second interview was strongly associated with the amounts of both methadone and diazepam prescribed at each of the data collecting points. [source] Preclinical abuse potential assessment of the anticonvulsant zonisamideDRUG DEVELOPMENT RESEARCH, Issue 2 2001Jenny L. Wiley Abstract Zonisamide (Zonegran®) is a broad-spectrum antiepileptic agent that shares some pharmacological properties with other anticonvulsants, including phenytoin, carbamazepine, and valproic acid, but is differentiated from these agents by the ability to significantly block T-type calcium channels. Zonisamide interacts with the ,-amino-butyric acid (GABA) receptor in an allosteric manner, and thus does not modulate GABA receptor effects. However, given the potential of drugs within the latter class for drug abuse in humans, an evaluation of zonisamide for abuse potential is an important component of its potential side-effect profile. In the present study, zonisamide was tested in animal models of the subjective and reinforcing effects of central nervous system (CNS) depressant drugs, e.g., diazepam discrimination in rats and intravenous self-administration in rhesus monkeys, respectively. In addition, zonisamide was evaluated for physical dependence liability in a chronic infusion model using rats. Zonisamide did not substitute for diazepam in rats trained to discriminate 2.5-mg/kg diazepam from vehicle nor was it self-administered by rhesus monkeys experienced in methohexital-reinforced responding. Continuous infusion of zonisamide (400 or 600 mg/kg/day) did not prevent the loss of body weight associated with discontinued pentobarbital infusion. These doses of zonisamide did produce some incomplete attenuation of observable signs of pentobarbital withdrawal, likely due to direct sedative or depressant effects of these high doses. These results suggest that zonisamide would not produce diazepam-like intoxication in humans nor would it likely be subject to abuse when made more widely available. Further, when administered chronically, zonisamide would not be expected to produce physical dependence of the CNS depressant type. Taken together, these results support the prediction that zonisamide would have low abuse liability. Drug Dev. Res. 54:66,74, 2001. © 2001 Wiley-Liss, Inc. [source] Determination of Diazepam, Temazepam and Oxazepam at the Lead Film Electrode by Adsorptive Cathodic Stripping VoltammetryELECTROANALYSIS, Issue 17-18 2010Katarzyna Tyszczuk Abstract The determination of psychoactive 1,4-benzodiazepine drugs is of relevant interest in clinical, biomedical areas. Therefore a highly sensitive and simple voltammetric method for the determination of temazepam, diazepam and oxazepam at an in situ plated lead film electrode was developed. The method was successfully applied to the determination of diazepam and temazepam in pharmaceutical formulations with minimum sample manipulation and oxazepam in human urine samples without any separation steps. The determinations of oxazepam in human urine samples were performed in a flow system. Therefore a previous extraction procedure was not necessary to separate the active compound before its determination. [source] Antiepileptic drugs combined with high-frequency electrical stimulation in the ventral hippocampus modify pilocarpine-induced status epilepticus in ratsEPILEPSIA, Issue 3 2010Manola Cuellar-Herrera Summary Purpose:, To evaluate the effects of high-frequency electrical stimulation (HFS) in both ventral hippocampi, alone and combined with a subeffective dose of antiepileptic drugs, during the status epilepticus (SE) induced by lithium-pilocarpine (LP). Methods:, Male Wistar rats, stereotactically implanted in both ventral hippocampi, were injected with pilocarpine (30 mg/kg, i.p.) 24 h after lithium (3 mEq/kg) administration. One minute following pilocarpine injection, HFS (pulses of 60 ,s width at 130 Hz at subthreshold intensities and applied during 3 h) was applied alone or combined with subeffective doses of antiepileptic drugs. Results:, HFS alone reduced the incidence of severe generalized seizures. This effect was not evident when HFS was combined with phenytoin (33.3 mg/kg, i.p.). HFS combined with diazepam (0.41 mg/kg, i.p.) or phenobarbital (10 mg/kg, i.p.) reduced the incidence of severe generalized seizures and mortality rate, and augmented the latency to first forelimb clonus, generalized seizure, and status epilepticus (SE). When combined with gabapentin (46 mg/kg, i.p.), HFS reduced the incidence of severe generalized seizures, enhanced latency to SE, and decreased mortality rate. Discussion:, Subeffective doses of antiepileptic drugs that increase the ,-aminobutyric acid (GABA)ergic neurotransmission may represent a therapeutic tool to augment the HFS-induced anticonvulsant effects. [source] Blood,brain barrier damage and brain penetration of antiepileptic drugs: Role of serum proteins and brain edemaEPILEPSIA, Issue 4 2009Nicola Marchi Summary Purpose:, Increased blood,brain barrier (BBB) permeability is radiologically detectable in regions affected by drug-resistant epileptogenic lesions. Brain penetration of antiepileptic drugs (AEDs) may be affected by BBB damage. We studied the effects of BBB damage on brain distribution of hydrophilic [deoxy-glucose (DOG) and sucrose] and lipophilic (phenytoin and diazepam) molecules. We tested the hypothesis that lipophilic and hydrophilic drug distribution is differentially affected by BBB damage. Methods:, In vivo BBB disruption (BBBD) was performed in rats by intracarotid injection of hyperosmotic mannitol. Drugs (H3-sucrose, 3H-deoxy-glucose, 14C-phenytoin, and C14-diazepam) or unlabeled phenytoin was measured and correlated to brain water content and protein extravasation. In vitro hippocampal slices were exposed to different osmolarities; drug penetration and water content were assessed by analytic and densitometric methods, respectively. Results:, BBBD resulted in extravasation of serum protein and radiolabeled drugs, but was associated with no significant change in brain water. Large shifts in water content in brain slices in vitro caused a small effect on drug penetration. In both cases, total drug permeability increase was greater for lipophilic than hydrophilic compounds. BBBD reduced the amount of free phenytoin in the brain. Discussion:, After BBBD, drug binding to protein is the main controller of total brain drug accumulation. Osmotic BBBD increased serum protein extravasation and reduced free phenytoin brain levels. These results underlie the importance of brain environment and BBB integrity in determining drug distribution to the brain. If confirmed in drug-resistant models, these mechanisms could contribute to drug brain distribution in refractory epilepsies. [source] Characterization of the Tetanus Toxin Model of Refractory Focal Neocortical Epilepsy in the RatEPILEPSIA, Issue 2 2005Karen E. Nilsen Summary:,Purpose: To characterize in detail a model of focal neocortical epilepsy. Methods: Chronic focal epilepsy was induced by injecting 25,50 ng of tetanus toxin or vehicle alone (controls) into the motor neocortex of rats. EEG activity was recorded from electrodes implanted at the injection site, along with facial muscle electromyographic (EMG) activity and behavioral monitoring intermittently for up to 5 months in some animals. Drug responsiveness was assessed by using the antiepileptic drugs (AEDs) diazepam (DZP) and phenytoin (PHT) delivered systemically, while 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), a competitive antagonist at AMPA receptors, was administered directly to the brain to investigate the potential benefits of focal drug delivery. Results: Tetanus toxin induced mild behavioral seizures that persisted indefinitely in all animals. EEG spiking activity, occurring up to 80% of the time, correlated with clinical seizures consisting of interrupted behavioral activity, rhythmic bilateral facial twitching, and periods of abrupt motor arrest. Seizures were refractory to systemic administration of DZP and PHT. However, focal delivery of NBQX to the seizure site reversibly reduced EEG and behavioral seizure activity without detectable side effects. Conclusions: This study provides a long-term detailed characterisation of the tetanus toxin model. Spontaneous, almost continuous, well-tolerated seizures occur and persist, resembling those seen in neocortical epilepsy, including cortical myoclonus and epilepsia partialis continua. The seizures appear to be similarly resistant to conventional AEDs. The consistency, frequency, and clinical similarity of the seizures to refractory epilepsy in humans make this an ideal model for investigation of both mechanisms of seizure activity and new therapeutic approaches. [source] Diazepam Terminates Brief but Not Prolonged Seizures in Young, Naïve RatsEPILEPSIA, Issue 8 2003Howard P. Goodkin Summary: Purpose: Ample evidence exists from both clinical and animal studies that the success of benzodiazepine intervention during status epilepticus (SE) in the mature nervous system is inversely related to seizure duration. This relationship has not been well studied in the developing nervous system. Methods: The objective of this study was to investigate the relation of age and success of diazepam (DZP) treatment in the lithium-pilocarpine model of secondarily generalized seizure in the rat by using naïve rats of three age groups, roughly corresponding to the human ages of infancy (P15), adolescence (P20), and adult (P60). Results: In all age groups, the dosage of DZP that stopped the seizures at 5 min was not effective in terminating seizures at 60 min. This decline in efficacy was present as early as 15 min after seizure onset. Conclusions: These findings demonstrate that the inverse relation between the success of benzodiazepine intervention and seizure duration is observed in young as well as in adult rats and provide further evidence that intervention for SE should commence early. [source] Enhanced Anticonvulsant Activity of Neuroactive Steroids in a Rat Model of Catamenial EpilepsyEPILEPSIA, Issue 3 2001Doodipala S. Reddy Summary: ,Purpose: Perimenstrual catamenial epilepsy may in part be due to withdrawal of the endogenous progesterone-derived neurosteroid allopregnanolone that potentiates ,-aminobutyric acidA (GABAA) receptor,mediated inhibition. Here we sought to determine whether the anticonvulsant potencies of neuroactive steroids, benzodiazepines, phenobarbital (PB), and valproate (VPA) are altered during the heightened seizure susceptibility accompanying neurosteroid withdrawal in a rat model of perimenstrual catamenial epilepsy. Methods: Test drugs were evaluated for their ability to alter the convulsant activity of pentylenetetrazol (PTZ) in young adult female rats, in pseudopregnant rats with prolonged exposure to high levels of progesterone (and its neurosteroid metabolites), and in pseudopregnant rats 24 h after acute withdrawal of neurosteroids by treatment with the 5,-reductase inhibitor finasteride. Test drugs were administered at doses equivalent to twice their ED50 values for protection against PTZ-induced clonic seizures in naive young adult female rats. Results: The anticonvulsant activity of allopregnanolone (5 mg/kg, s.c.), pregnanolone (5 mg/kg, s.c.), allotetrahydrodeoxycorticosterone (15 mg/kg, s.c.), and tetrahydrodeoxycorticosterone (10 mg/kg, s.c.) were enhanced by 34,127% after neurosteroid withdrawal. The anticonvulsant activity of PB (65 mg/kg, i.p.) was also enhanced by 24% in neurosteroid-withdrawn animals. In contrast, the anticonvulsant activity of diazepam (4 mg/kg, i.p.), bretazenil (0.106 mg/kg, i.p.), and VPA (560 mg/kg, i.p.) were reduced or unchanged in neurosteroid-withdrawn animals. Conclusions: The anticonvulsant activity of neuroactive steroids is potentiated after neurosteroid withdrawal, supporting the use of such agents in the treatment of perimenstrual catamenial epilepsy. [source] Febrile Seizures: Treatment and PrognosisEPILEPSIA, Issue 1 2000Finn Ursin Knudsen Summary: Recent epidemiologic data indicate that the vast majority of children with febrile seizures have a normal long-term outcome. A precise knowledge of the short- and long-term outcome with or without treatment, and short- and long-term side effects is an important prerequisite for assessing the various treatment strategies. We focus on the impact of short-term or prophylactic treatment on the short- and long-term outcome of various types of febrile seizures. There is universal agreement that daily prophylaxis with antiepileptic agents should never be used routinely in simple febrile seizures, but only in highly selected cases, if at all. Intermittent diazepam (DZP) prophylaxis at times of fever may or may not reduce the recurrence rate, but it does not appear to improve the long-term outcome as compared with short-term seizure control. The treatment may be used to reduce the recurrence rate for a small arbitrarily defined group with multiple simple febrile seizures, complex febrile seizures, especially focal, prolonged or both, febrile status, and when parental anxiety is severe. However, there is no evidence that treatment of simple febrile seizures can prevent the rare cases of later epilepsy, and many children with complex febrile seizures have a benign long-term outcome, even without treatment. Many prefer a "wait and see" policy. An attractive alternative is to treat new febrile seizures with rectal DZP in solution at seizure onset, given by the parents at home to prevent febrile status. Newer, less well documented short-term strategies include nasal, oral, or rectal administration of other benzodiazepines. Short-term seizure control of febrile status and careful parental counseling are the two most important targets of treatment. [source] Drug/substance reversal effects of a novel tri-substituted benzoflavone moiety (BZF) isolated from Passiflora incarnata Linn.,a brief perspectiveADDICTION BIOLOGY, Issue 4 2003Kamaldeep Dhawan The present work is a mini-review of the author's original work on the plant Passiflora incarnata Linn., which is used in several parts of the world as a traditional medicine for the management of anxiety, insomnia, epilepsy and morphine addiction. A tri-substituted benzoflavone moiety (BZF) has been isolated from the bioactive methanol extract of this plant, which has been proposed in the author's earlier work to be responsible for the biological activities of this plant. The BZF moiety has exhibited significantly encouraging results in the reversal of tolerance and dependence of several addiction-prone psychotropic drugs, including morphine, nicotine, ethanol, diazepam and delta-9-tetrahydrocannabinol, during earlier pharmacological studies conducted by the author. In addition to this, the BZF moiety has exhibited aphrodisiac, libido-enhancing and virility-enhancing properties in 2-year-old male rats. When administered concomitantly with nicotine, ethanol and delta-9-tetrahydrocannabinol for 30 days in male rats, the BZF also prevented the drug-induced decline in sexuality in male rats. Because the BZF moiety isolated from P. incarnata is a tri-substituted derivative of alpha-naphthoflavone (7,8-benzoflavone), a well-known aromatase-enzyme inhibitor, the mode of action of BZF has been postulated to be a neurosteroidal mechanism vide in which the BZF moiety prevents the metabolic degradation of testosterone and upregulates blood-testosterone levels in the body. As several flavonoids (e.g. chrysin, apigenin) and other phytoconstituents also possess aromatase-inhibiting properties, and the IC 50 value of such phytomoieties is the main factor determining their biochemical efficacy, by altering their chemical structures to attain a desirable IC 50 value new insights in medical therapeutics can be attained, keeping in view the menace of drug abuse worldwide. [source] How are we doing with the treatment of essential tremor (ET)?EUROPEAN JOURNAL OF NEUROLOGY, Issue 6 2010Persistence of patients with ET on medication: data from 528 patients in three settings Background:, The pharmacological treatment of essential tremor (ET) is not optimal. There are only two first-line medications and troublesome side effects are common. It is not uncommon for patients to simply stop taking medication. Yet, no published data substantiate or quantify this anecdotal impression. Objectives:, To determine, amongst patients with ET who were prescribed medication for tremor, what proportion are still taking medication and what proportion have stopped? Methods:, Five hundred and twenty-eight patients with ET from three distinct study settings (clinical, brain donors, population) were interviewed. Results:, A clear pattern that emerged across settings was that the proportion of patients with ET who had stopped medication was sizable and consistently similar (nearly one-third): 31.4% (clinical), 24.3% (brain donors), 30.0% (population), 29.8% (overall). A similarly high proportion of cases with severe tremor had stopped their medication: 31.9% (clinical), 36.4% (brain donors). For the four most commonly used medications (propranolol, primidone, diazepam, topiramate), one-half or more of the treated patients had stopped the medication; amongst the less commonly used medications, the proportion who stopped was even higher. Conclusions:, Nearly one of every three patients with ET who had been prescribed medication for tremor had discontinued pharmacotherapy. Even more revealing was that a similar proportion of cases with severe tremor had stopped medication. These data make tangibly evident that there is a sizable population of patients with ET who are untreated and disabled, and underscore the inadequacy of current pharmacotherapeutic options for this common neurological disease. [source] EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task forceEUROPEAN JOURNAL OF NEUROLOGY, Issue 8 2005G. Bråthen Despite being a considerable problem in neurological practice and responsible for one-third of seizure-related admissions, there is little consensus as to the optimal investigation and management of alcohol-related seizures. The final literature search was undertaken in September 2004. Consensus recommendations are given graded according to the EFNS guidance regulations. To support the history taking, use of a structured questionnaire is recommended. When the drinking history is inconclusive, elevated values of carbohydrate-deficient transferrin and/or gammaglutamyl transferase can support a clinical suspicion. A first epileptic seizure should prompt neuroimaging (CT or MRI). Before starting any carbohydrate containing fluids or food, patients presenting with suspected alcohol overuse should be given prophylactic thiamine parenterally. After an alcohol withdrawal seizure (AWS), the patient should be observed in hospital for at least 24 h and the severity of withdrawal symptoms needs to be followed. For patients with no history of withdrawal seizures and mild to moderate withdrawal symptoms, routine seizure preventive treatment is not necessary. Generally, benzodiazepines are efficacious and safe for primary and secondary seizure prevention; diazepam or, if available, lorazepam, is recommended. The efficacy of other drugs is insufficiently documented. Concerning long-term recommendations for non-alcohol dependant patients with partial epilepsy and controlled seizures, small amounts of alcohol may be safe. Alcohol-related seizures require particular attention both in the diagnostic work-up and treatment. Benzodiazepines should be chosen for the treatment and prevention of recurrent AWS. [source] Impaired fear conditioning but enhanced seizure sensitivity in rats given repeated experience of withdrawal from alcoholEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2001D. N. Stephens Abstract Repeated experience of withdrawal from chronic alcohol treatment increases sensitivity to seizures. It has been argued by analogy that negative affective consequences of withdrawal also sensitize, but repeated experience of withdrawal from another sedative-hypnotic drug, diazepam, results in amelioration of withdrawal anxiety and aversiveness. We tested whether giving rats repeated experience of withdrawal from alcohol altered their ability to acquire a conditioned emotional response (CER). Male Hooded Lister rats were fed a nutritionally complete liquid diet as their only food source. Different groups received control diet, or diet containing 7% ethanol. Rats receiving ethanol diet were fed for either 24 days (Single withdrawal, SWD), or 30 days, with two periods of 3 days, starting at day 11, and 21, in which they received control diet (Repeated withdrawal, RWD). All rats were fed lab chow at the end of their liquid diet feeding period. Starting 12 days after the final withdrawal, groups of Control, SWD and RWD rats were given pentylenetetrazole (PTZ; 30 mg/kg, i.p.) three times a week, and scored for seizures. The occurrence of two successive Stage 5 seizures was taken as the criterion for full PTZ kindling. Other groups of control, SWD and RWD rats were trained to operate levers to obtain food, and were then exposed, in a fully counterbalanced design, to light and tone stimuli which predicted unavoidable footshock (CS+), or which had no consequences (CS,). Rats consumed approximately 17.5 g/kg/day of ethanol, resulting in blood alcohol levels of approximately 100 mg/dL. Repeated administration of PTZ resulted in increasing seizure scores. RWD rats achieved kindling criterion faster than either Control or SWD rats. No differences were seen in the groups in flinch threshold to footshock (0.3 mA). At a shock intensity of 0.35 mA, Control, but not RWD or SWD rats showed significant suppression to the CS+ CS, presentation did not affect response rates. The three groups differed in their response to pairing the CS+ with increasing shock levels, the Controls remaining more sensitive to the CS+. SWD rats showed significant suppression of lever pressing during CS+ presentations only at 0.45 and 0.5 mA, and RWD rats only at 0.5 mA. Giving rats repeated experience of withdrawal from chronic ethanol results in increased sensitivity to PTZ kindling, but reduces their ability to acquire a CER. Withdrawal kindling of sensitivity to anxiogenic events does not seem to occur under circumstances which give rise to kindling of seizure sensitivity. [source] Previous experience of withdrawal from chronic diazepam ameliorates the aversiveness of precipitated withdrawal and reduces withdrawal-induced c-fos expression in nucleus accumbensEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2000Sarah J. Dunworth Abstract Flumazenil (20 mg/kg, i.p.)-precipitated withdrawal from chronic treatment with diazepam (DZP, 15 mg/kg, s.c. in sesame oil for 21 days) resulted in a decreased seizure threshold to the convulsant, pentylenetetrazole (PTZ), infused into the tail vein; withdrawal from 21-day chronic diazepam treatment, interspersed with two periods of drug withdrawal, resulted in a greater decrease in convulsant threshold. A separate experiment showed that consumption of a sucrose solution immediately prior to precipitated withdrawal resulted in a decreased subsequent consumption of the sucrose solution; no such evidence of a conditioned taste aversion (CTA) was seen in mice given prior experience of withdrawal. Thus, prior experience of withdrawal enhanced the effects of a subsequent precipitated withdrawal in increasing seizure sensitivity, but weakened the ability of this withdrawal to serve as an aversive unconditioned stimulus (US). The weakening of the aversive properties of precipitated withdrawal may reflect habituation to the withdrawal stimulus, and was accompanied by a loss of the ability of withdrawal to induce c-fos expression in the shell of the nucleus accumbens, an area sensitive to both novel, and stressful, as well as rewarding stimuli. [source] Benzodiazepines prescription in Dakar: a study about prescribing habits and knowledge in general practitioners, neurologists and psychiatristsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2006Amadou Moctar Dièye Abstract Benzodiazepines are relatively well-tolerated medicines but can induce serious problems of addiction and that is why their use is regulated. However, in developing countries like Senegal, these products are used without clear indications on their prescription, their dispensation or their use. This work focuses on the prescription of these medicines with a view to make recommendations for their rational use. Benzodiazepine prescription was studied with psychiatrists or neurologists and generalists in 2003. Specialist doctors work in two Dakar university hospitals and generalists in the 11 health centres in Dakar. We did a survey by direct interview with 29 of 35 specialists and 23 of 25 generalists. All doctors were interviewed in their office. The questionnaire focused on benzodiazepine indications, their pharmacological properties, benzodiazepines prescribed in first intention against a given disease and the level of training in benzodiazepines by doctors. Comparisons between specialists and generalists were made by chi-square test. Benzodiazepines were essentially used for anxiety, insomnia and epilepsy. With these diseases, the most benzodiazepines prescribed are prazepam against anxiety and insomnia and diazepam against epilepsy. About 10% of doctors do not know that there is a limitation for the period of benzodiazepine use. The principal reasons of drugs choice are knowledge of the drugs, habit and low side effects of drugs. All generalists (100%) said that their training on benzodiazepines is poor vs. 62.1% of specialists, and doctors suggest seminars, journals adhesions and conferences to complete their training in this field. There are not many differences between specialists and generalists except the fact that specialists prefer prazepam in first intention in the insomnia treatment where generalists choose bromazepam. In addition, our survey showed that specialists' training in benzodiazepines is better than that of generalists. Overall, benzodiazepine prescription poses problems particularly in training, and national authorities must take urgent measures for rational use of these drugs. [source] Does rat global transient cerebral ischemia serve as an appropriate model to study emotional disturbances?FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2004Guy Bernard Bantsiele Abstract We used two validated psychopharmacological methods, the forced swimming test (FST 20 min and 5 min) and the elevated plus-maze (EPM), to quantify depression-like and anxiety-like behavior induced by transient global cerebral ischemia in the rat. We also validated use of these methods for the study of antidepressant (imipramine) and anti-anxiety drugs (diazepam). Twelve days after surgery to provoke transient global ischemia, spontaneous motor activity was 40% higher in ischemic rats than in sham-operated controls. Duration of immobility during the FST 20 min and 5 min was 28 and 30% shorter, respectively, than in controls. Treatment with imipramine (3 × 30 mg/kg i.p.) induced a significantly shorter duration of immobility during the FST 5 min, but with no difference between ischemia and control rats. The EPM demonstrated that ischemia did not induce any change in the six behavior parameters measured. Diazepam (1.5 mg/kg i.p.) induced significant anxiolytic effects which were similar in ischemic and sham-operated animals. Both tests failed to demonstrate perturbed performance but conversely, these findings did disclose the sensitivity of ischemia-exposed rats to the action of imipramine and diazepam, demonstrating the usefulness of these tests as psychopharmocological tools for evaluating the effect of psychotropics in the ischemic rat. [source] | ||||||||||||||||||||||||||||||||||||||||