Dissertations / Theses on the topic 'Anticonvulsants'
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1
Da, Costa Neil C. "The synthesis of potential anticonvulsants via 2-chloroamides." Thesis, University of Hertfordshire, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314617.
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Tan, Shiou Shiou. "Pharmacokinetic-pharmacodynamic modelling of anti-allodynic effects of gabapentin and oxycodone in a rodent model of persistent neuropathic pain /." [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19074.pdf.
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Eriksson, Ann-Sofie. "A pharmacokinetic and pharmacodynamic study of an antiepileptic drug (lamotrigine) in young patients with drug-resistant generalized epilepsy /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4205-6/.
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Shah, Vibhakar Jayantilal. "Synthesis of cannabidiol stereoisomers and analogs as potential anticonvulsant agents." Diss., The University of Arizona, 1988. http://hdl.handle.net/10150/184523.
Full textAbstract:
Anticonvulsant activity of cannabidiol (CBD) has been well documented in various laboratory animal species and also in man. As part of our continuing effort to study and to define the structure anticonvulsant relationship several analogs of CBD were synthesized wherein its structural units, namely, the terpene ring, aryl ring and/or side chain were systematically modified. These analogs include the: (1) unnatural (+)-Cannabidol (1b), (2) Delta-3-carenyl analog-(+)-carenadiol (45a), its diacetate (45b) and its 1",1"-dimethylheptyl side chain analog (45c), and (3) unnatural 7-acetoxycannabidiol (46b). (+)-Cannabidiol (1b) was synthesized in about 20-25% yield from olivetol (51) and two different p-menthadienols (67 and 70) as monoterpenoid synthons. (-)-p-Mentha-1,8-dien-3-ol (67) was prepared from (-)-limonene (65) by chromium trioxide-pyridine complex oxidation followed by cerium trichloride assisted sodium borohydride reduction of the obtained ketone (66a). (-)-p-Mentha-2,8-dien-1-ol (70) was synthesized from 1:1 mixture of cis- (69a) and trans-epoxide (68a) of limonene (65) in about 35% yield. The reaction involves phenylselenide anion mediated stereospecific trans-diaxial opening of the epoxide ring to give the required alcohol (70) along with its regioisomer (71) as the major product (79%). The delta-3-carenyl analog (+)-carenadiol (45a) was synthesized from car-4-en-3β-ol (80) and olivetol (51) in about 20% yield. Car-4-en-3β-ol (80) was prepared in about 90-95% yield from the corresponding 3β,4β-epoxy carane (77) by following the same methodology described for (70). The compounds were evaluated for anticonvulsant activity in seizure susceptible (AGS) rats and for neurotoxicity in the rotorod (ROT) test. A general lack of stereoselectivity for the anti-AGS and ROT neurotoxic effects was observed for CBD and its derivatives. Thus (-)-CBD (1a) was marginally more potent than (+)-CBD (1b). But the CBD analog derived from (+)-car-3-ene (72), i.e., (+)-carenadiol (45a), is of interest because of its high protective index (PI = 5.1) and is therefore comparable to(1b) (to which it is stereochemically related) in potency. The 1",1"-dimethylheptyl derivative ((+)-45b), could not separate anticonvulsant activity from neurotoxicity. (Abstract shortened with permission of author.)
5
Acheampong, Andrew Adu. "Quantitative structure-anticonvulsant activity studies of valproic acid analogues." Thesis, University of British Columbia, 1985. http://hdl.handle.net/2429/25552.
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Valproic acid (2-propylpentanoic acid) is an antiepileptic drug widely used for treatment of absence seizures. Valproic acid has a unique chemical structure which does not contain the imide structure found in most conventional antiepileptic drugs. An in vivo study of the antagonism of pentylenetetrazol-induced clonic seizures by alkyl-substituted carboxylic acids and tetrazoles was of interest owing to the known bioisosterism between the carboxylic and the tetrazolyl moiety. The main objective of this study was to investigate the role played by the lipophilicity, the electronic properties and the steric influence of compounds on their anticonvulsant potency.
Quantitative structure-activity relationships of the aliphatic and alicyclic substituted carboxylic acids and tetrazoles have been performed
using the Hansch linear free-energy relationships model. The study proceeded by synthesis of compounds using known procedures. The di-unsaturated derivatives of valproic acid, 2-[(E)-l'-propenyl]-(E)-2-pentenoic acid and 2-[(Z)-l'-propenyl]-(E)-2-pentenoic acid were prepared via a stereoselective synthetic route. The synthesized di-unsaturated acids were used in identification of the major diunsaturated metabolite of valproic acid as 2-[(E)-l'-propenyl]-(E)-2-pentenoic acid.
The anticonvulsant potency of test compounds was determined in mice (CD1 strain, 20-32g) by the standard subcutaneous pentylenetetrazole seizure threshold test. The pentylenetetrazole clonic seizure test was found to be more sensitive to structural effects than the pentylenetetrazole
mortality assay. The lipophilicity (octanol-water partition coefficient) of compounds was determined indirectly by reversed phase liquid chromatography employing an octadecylsilane column (Hypersil ODS) and mobile phase as 70% methanol : 30% phosphate buffer (pH 3.5). The electronic character of the compounds was monitored by the apparent acid ionization constant obtained from potentiometric titration in 10% raethanol-water system.
The ED₅₀ of 0.70 mmol/kg found for valproic acid was similar to literature values. 5-Heptyltetrazole was found to be the most potent compound in the series of analogues studied. The carboxylic plus tetrazole group gave a low correlation (r = 0.63) between the anticonvulsant
potency and a linear combination of lipophilicity and apparent ionization constant. However, in the series of active carboxylic acids, the anticonvulsant activity was noted to be significantly correlated with lipophilicity and apparent ionization constant (r = 0.91).
The usefulness of the electronic parameters, acid ionization constant
and dipole moment, were explored in an extensive set of alkyl-substituted anticonvulsant compounds with different polar moieties. Addition of the dipole moment term to the lipophilicity term led to significantly better correlations (r = 0.81) as compared to that with an added pKa term. The negative dependency of anticonvulsant activity on dipole moment supported previous findings in studies of 1,4-benzo-diazepines and phenyl-substituted anticonvulsant compounds.
There were some exceptions to the dependence of anticonvulsant activity on lipophilicity and dipole moment or pKa. N,N-dibutyl-succinamic acid showed convulsant properties at sublethal doses. The lack of activity of cyclohexylacetic acid and 5-cyclohexylmethyltetra-zole, in comparison to the active l-methylcyclohexanecarboxylic acid, has some pharmacological significance. It shows a certain degree of molecular specificity in the anticonvulsant action of valproic acid analogues. The cyclohexylmethyl conformation was suggested, from aproposed model, to be less effective in hydrophobic binding due to a steric effect at a stereoselective position on the hydrophobic site of the GABA receptor complex. Thus it can be concluded that while lipophilicity
governed access to sites of action, the dependence of activity on the polar character may explain the diverse structures of anticonvulsants
provided that the steric requirements of the hydrophobic binding site are met. Steric effects may lead to inactivity or even convulsant properties of alkyl-substituted compounds.Pharmaceutical Sciences, Faculty of
Graduate
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Mana, Michael Joseph. "Contingent and pharmacologic tolerance to the anticonvulsant effects of antiepileptic drugs." Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/31438.
Full textAbstract:
The development of tolerance to anticonvulsant drug effects
has traditionally been studied in terms of pharmacological
variables associated with the drug itself ; for example, the dose
or the schedule of administration. This type of tolerance is
referred to as pharmacologic drug tolerance. In contrast, we
have demonstrated that the development of tolerance to ethanol's
anticonvulsant effect is contingent upon the adminstration of
convulsive stimulation during periods of ethanol exposure; we
refer to this as contingent drug tolerance.
The purpose of the first two experiments in the present
thesis was to extend the phenomenon of contingent tolerance to
the anticonvulsant effects of three clinically relevant
antiepileptic drugs: carbamazepine (CBZ), diazepam (DZP), and
sodium valproate (VPA). In Experiment 1, kindled rats that
received an injection of CBZ (70 mg/kg, IP), DZP (2 mg/kg, IP),
or VPA (250 mg/kg, IP) 1 hr before each of 10 bidaily (one every
48 hr) convulsive stimulations displayed a significant amount of
tolerance to the drugs' anticonvulsant effects on the tolerance
test trial ; in contrast, there was no evidence of tolerance in
the rats from the three vehicle control groups. In Experiment 2,
the development of tolerance to the anticonvulsant effects of
CBZ, DZP, and VPA, administered on a bidaily basis, was shown to
be contingent upon the administration of convulsive stimulation
during the periods of drug exposure. Kindled rats in the three
drug-before-stimulation groups rapidly developed tolerance to the
anticonvulsant effects of CBZ, DZP, and VPA; in contrast, there
was no evidence of tolerance i n the respective drug-afterstimulation
groups, despite the fact that they had the same drug
history.
The purpose of the final three experiments was to compare
contingent and pharmacologic tolerance to the anticonvulsant
effects of DZP. Experiment 3 replicated earlier demonstrations
of pharmacologic tolerance to DZP's anticonvulsant effect;
kindled rats that received chronic DZP (2 mg/kg, every 8 hr, for
10 days) developed tolerance to the drug's anticonvulsant effect
even though they did not receive convulsive stimulation during
the periods of drug exposure. In Experiment 4, the rate of
dissipation of pharmacologic and contingent tolerance to DZP's
anticonvulsant effect was compared. Pharmacologic tolerance
gradually dissipated over the 16-day retention interval ; in
contrast, there was no evidence of dissipation of contingent
tolerance after 16 days of drug withdrawal. These data suggest
that different physiological changes are responsible for
pharmacologic and contingent tolerance to DZP's anticonvulsant
effect. This conclusion was supported by the results of
Experiment 5, in which a single injection of the benzodiazepine
receptor antagonist RO 15-1788 24 hr prior to a tolerance-retention
test trial significantly reduced the expression of
pharmacologic tolerance, but not contingent tolerance, to DZP's
anticonvulsant effect.
The results of these five experiments make two general
points. First, concurrent convulsive stimulation can have an
important effect on the development of tolerance to the
anticonvulsant effects of antiepileptic drugs. And second, there
are significant differences in the physiological changes
responsible for the development and the dissipation of contingent
and pharmacologic tolerance to DZP's anticonvulsant effect.
Because traditional theories do not address these differences, a
new model of contingent and pharmacologic tolerance is presented.Arts, Faculty of
Psychology, Department of
[title page not included]
Graduate
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Dhillon, Arvinder. "Short-term, frequency-dependent changes in synaptic transmission in the rat entorhinal cortex in vitro." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308860.
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Barkley, Angela. "The design and synthesis of anticonvulsants based on natural toxins." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ31915.pdf.
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Kroetz, Deanna L. "Inhibition of human liver microsomal epoxide hydrolase /." Thesis, Connect to this title online; UW restricted, 1990. http://hdl.handle.net/1773/7958.
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White, David Charles. "Synthesis of 3-Aryl-2-(2-aryl-2-oxoethyl)pyrido[2,3-d]-4(3H)pyrimidones and 3-Aryl-2-(2-arylethenyl)pyrido[2,3-d]-4(3H)pyrimidones as Potential Antiepileptic Drugs." Thesis, Virginia Tech, 1997. http://hdl.handle.net/10919/46506.
Full textAbstract:
A series of 2-alkyl-3-arylpyrido[2,3-d]pyrimidones were synthesized for testing as
potential antiepileptic drugs. The goal was to achieve better neurological activity and/or
lower toxicity than displayed by a series of 2-alkyl-3-aryl-4(3H)-quinazolinones prepared
previously in our research group. From the pharmacological testing data of these target
compounds, we have found that the additional nitrogen at the C-8 position of the quinazolinone
framework increased the anticonvulsant activity. However, the neurological toxicity increased
as well. The anticonvulsant and neurotoxic activity seen in the variuos 2-alkyl side chains
and 3-aryl substituents incorporated into these new pyridopyrimidones was consistent with the
activity observed with the same substituents on the 4(3H)-quinazolinones. The 3-aryl group
consists of various ortho-substituted phenyl rings, while the 2-alkyl chain consists of a
2-(2-aryl-2-oxo)ethyl or 2-arylethenyl group.Master of Science
11
Lindberger, Martin. "Monitoring of antiepileptic drugs using microdialysis : methodological and clinical aspects /." Stockholm : [Karolinska institutets bibl.], 2002. http://diss.kib.ki.se/2002/91-7349-338-4/.
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Yip, Fung-ping. "Comparison of hormone profiles in Chinese adult epilepsy patients treated with Sodium Valproate or lamotrigine monotherapy a prospective randomised trial /." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B4175797X.
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Puthucode, Ramanan Narayan. "Design and synthesis of some aryloxyaryl semicarbazones and related compounds as novel anticonvulsants." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1996. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq24036.pdf.
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Öhman, Inger. "Newer antiepileptic drugs in women of child-bearing age : pharmacokinetic studies during pregnancy, breastfeeding, and contraception /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7357-046-X/.
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Yip, Fung-ping, and 葉鳳萍. "Comparison of hormone profiles in Chinese adult epilepsy patients treated with Sodium Valproate or lamotrigine monotherapy: a prospective randomised trial." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B4175797X.
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Levin, April Robyn. "Early Seizure Blockade: Preventing Long-Term Epileptic Activity in Wag/Rij Rats." Yale University, 2008. http://ymtdl.med.yale.edu/theses/available/etd-08152007-130206/.
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The purpose of this study was to determine how early seizure blockade with ethosuximide (ESX) would influence ion channel expression and long-term spike-wave discharge (SWD) activity in epileptic WAG/Rij rats. The goal was to elucidate the question Do seizures beget seizures? in a genetically prone model and if so, to attempt to interrupt this cycle by early intervention. In our first experiment, we used immunocytochemistry to determine the effect of ESX on cortical expression of ion channels in treated and untreated WAG/Rij rats and age-matched Wistar controls. This experiment revealed that treatment with ESX blocked the upregulation of Nav1.1 and Nav1.6 as well as the downregulation of HCN1 that is associated with epileptic activity in rats (p < .05). In a second experiment, WAG/Rij rats were divided into 3 groups: untreated (H2O), temporary early treatment (ESX 4 month), and continuous early treatment (ESX continuous), and SWD activity was measured by electroencephalogram (EEG) at various timepoints. This second experiment revealed that animals in the ESX 4 month group spent less percent time in SWD (0.242 ± .068 SEM) than animals in the H2O group (0.769 ± .060 SEM, p < .001), although they spent slightly more percent time in SWD than animals in the ESX continuous group (0.020 ± .065 SEM, p = .003). This effect was predominantly due to seizure number, and average seizure duration did not vary among the three groups. Additionally, power spectrum analysis revealed a significant correlation when the difference between power spectra for H2O and ESX 4 month rats was compared to the power spectrum of a seizure (Pearson correlation equals 0.955, 2-tailed significance < .000000001), suggesting quantitatively that seizures were reduced by temporary early treatment. This suggests that early prevention of SWD may reduce the burden of seizures later in life, and that possibilities for prevention of genetic absence epilepsy should be further investigated.
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Errington, Adam C., and n/a. "Electrophysiological studies on the mechanism of action of the novel antiepileptic drug lacosamide." University of Otago. Department of Pharmacology & Toxicology, 2007. http://adt.otago.ac.nz./public/adt-NZDU20080613.162038.
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Lacosamide (LCM) is a new antiepileptic drug with a previously unknown mode of action. Using electrophysiological recording techniques in a range of in vitro preparations I have determined a mechanism of action of the new drug.
In a 4-aminopyridine model of tonic-clonic seizures in rat visual cortex in vitro, LCM stereoselectively reduced maximal frequency and duration of tonic activity with EC[50�s] of 71 and 41 [mu]M respectively. LCM (100 [mu]M) significantly reduced excitability in whole cell patch clamped neurons producing non-selective reduction in the incidence of excitatory/inhibitory postsynaptic currents (EPSCs; LCM: 46.1 � 15.5 %, P <0.01, n = 4, IPSCs; LCM: 24.9 � 9.6 %, P <0.01, n = 4) and block of spontaneous action potentials (EC₅₀ 61 [mu]M). The inhibitory effects of LCM did not result from changes in passive membrane properties (including resting membrane potential or input resistance) as assessed by application of voltage ramps between -70 to +20 mV. LCM did not mimic the effects of diazepam as an allosteric modulator of GABA[A] receptor currents, nor did it inhibit evoked excitatory currents mediated by AMPA or NMDA receptors. Unlike phenytoin (DPH), carbamazepine (CBZ) or lamotrigine (LTG) that blocked sustained action potential firing evoked by brief depolarising steps (750 ms) or ramps (-70 to 20 mV, 90 mV.sec⁻�), LCM could weakly reduce the frequency of action potentials evoked by brief depolarisation suggesting a potential interaction with VGSCs. In accordance with this, the effect of LCM upon neurotransmission was negated in the presence of tetrodotoxin (200 nM, TTX). The frequency of miniature EPSCs was not altered by the drug (100 [mu]M). These results discounted some crucial potential anticonvulsant targets for LCM but implied a potential interaction with electrogenic VGSCs.
When SRF duration was prolonged (10 s) LCM produced significant (P <0.01, n = 4-10, EC₅₀: 48 [mu]M) inhibition, but not within the first second of the burst EC₅₀: 640 [mu]M). Evoked TTX sensitive sodium currents in N1E-115 neuroblastoma cells were significantly reduced by LCM, CBZ, LTG and DPH when V[h]: -60 mV. Hyperpolarizing pulses (500 ms) to -100 mV could reverse block by CBZ, LTG and DPH but not LCM. The V₅₀ for steady state fast inactivation was more hyperpolarized by CBZ (-79.45 � 2.64 mV, n = 5, P < 0.001), LTG (-72.30 � 1.70 mV, n = 6, P <0.05) and DPH (-77.17 � 2.32 mV, n = 6, P <0.05) but not by LCM (-65.02 � 1.75 mV, n = 6, CONTROL: -65.84 � 0.86 mV). In contrast to CBZ, LCM did not slow recovery from fast inactivation or produce frequency dependent facilitation of block of a 3 s, 10 Hz pulse train. LCM (100 [mu]M) did produce a (V₅₀: CONTROL ~64 mV, LCM -57.47 � 4.53 mV, P <0.001, n = 4-8) hyperpolarizing shift in the voltage dependence of slow sodium channel inactivation and promoted channel entry into the slow inactivated state (P <0.001, n = 6) but did not alter the rate of recovery. I therefore conclude that LCM produces inhibition of epileptiform cellular activity, at least in part, via enhancement of voltage gated sodium channel slow inactivation and represents a molecule possessing a unique anticonvulsant mechanism of action.
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Shim, Stacey. "Alterations of the Monoaminergic Systems in the Rat Brain by Sustained Administration of Carisbamate and Lamotrigine." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23478.
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Carisbamate (CRS) and lamotrigine (LTG) are anticonvulsants which act mainly on neuronal voltage-gated sodium channels, that have been shown to have antidepressant-like effects in animal models of depression. In vivo electrophysiological recordings were carried out following 2 and 14 days of CRS or LTG administration. Overall firing activity in the dorsal raphe, locus coeruleus and ventral tegmental area were decreased with CRS. Similarly, a decrease in the dorsal raphe was also observed with LTG. Despite these presynaptic decreases in firing activity, both anticonvulsants exhibited significant enhancement of serotonergic transmission in the hippocampus as demonstrated by increased tonic activation of postsynaptic 5-HT1A receptors. This may be attributed to the observed desensitization of the terminal 5-HT1B autoreceptors. This study suggests that the enhanced serotonergic effect may be associated with an antiglutamatergic effect, and may contribute to the antidepressant-like effect of CRS in the forced swim test and the antidepressant properties of LTG.
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Charlton, Rachel. "The general practice research database as an alternative to registries for studying drug safety in pregnancy : anticonvulsants as a case study." Thesis, University of Bath, 2012. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.557803.
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Background: In recent years, there has been an increase in the use of automated healthcare databases for drug safety in pregnancy evaluation; their suitability for this purpose needs to be evaluated. Aim: To evaluate the utility of the United Kingdom’s General Practice Research Database (GPRD) to act as an alternative to pregnancy registries, using anticonvulsants as a case study. Methods: Pregnancies in women with epilepsy were identified and first trimester anticonvulsant exposure was determined. Major congenital malformations in the offspring were identified and verified. The risk of major congenital malformations following exposure to a range of anticonvulsants was calculated and compared to those reported by the UK Epilepsy and Pregnancy Register. The ability to identify a known teratogenic association using GPRD data was also assessed. An algorithm was created to identify and classify different types of pregnancy loss in an automated manner. Results: The risks of a pregnancy outcome with a major congenital malformation following first trimester anticonvulsant exposures, were found to be similar in the GPRD to those of the UK Register. The number of exposures to individual products in the GPRD was often small and therefore lacked statistical power. It was, however, possible to identify a known teratogenic association using data from the GPRD. Verification of the algorithm developed to classify pregnancy losses demonstrated that, although not perfect, it would be a beneficial tool when using the GPRD for drug safety in pregnancy research. Conclusion: It is unlikely a single data source or study design will be sufficient for monitoring all aspects of the safety of medicine use during pregnancy. The GPRD has the potential to make a valuable contribution to this field of research and could play an important role in complementing the work of other surveillance systems.
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Koller, Anthony. "The newer anticonvulsants in the treatment of generalised anxiety disorder: a systematic review and meta-analysis." Master's thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/23047.
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Generalised anxiety disorder (GAD) is a common, chronic and debilitating mental disorder impairing quality of life and functioning. The 1st line treatments for GAD include the selective serotonergic reuptake inhibitors (SSRIs) and the selective serotonergic noradrenergic reuptake inhibitors (SNRIs). However, they have rates of non-response ranging from 25 to 40%. There is justification to search for new and more efficacious GAD medication. It has hypothesised anticonvulsants possess anxiolytic properties based on animal studies and epilepsy trials. There is inconsistent evidence that anticonvulsants are efficacious in GAD. It was considered useful and timely to investigate this further. The newer anticonvulsants (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate and zonisamide) were investigated as they were considered to have a more benign side effect profile and fewer drug interactions than older anticonvulsants. This study is a systematic review and meta-analysis of the newer anticonvulsants in the treatment of GAD. The main objective was to use randomised controlled trial (RCT) data to estimate efficacy of the newer anticonvulsants in GAD. using A search strategy was designed and three separate searches conducted by the Cochrane Depression Anxiety and Neurosis Group of the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) and clinicaltrials.gov (the last search in May 2013). An updated, independent, search was conducted in May 2016 with no additional citations retrieved. 287 citations were retrieved and screened in total. Two independent raters assessed citations using the abstracts and selected trials that satisfied the inclusion criteria. 12 RCTs were included with eight using pregabalin and four using tiagabine. A single rater collated data from RCTs assisted by Covidence Systematic Review Software. All statistical analyses were performed using Review Manager. A random effects meta-analysis was performed expressing summary statistics as effect estimates with 95% confidence intervals (CI). There were 4001 participants in total with 2516 in the anticonvulsant group and 1485 in the placebo. Primary outcomes were reduction in symptom severity using the Hamilton Anxiety Rating Scale (HAM-A) and treatment response using the Clinical Global Impressions Scale-Improvement item (CGI-I). Secondary outcome was medication acceptability. Reduction of symptom severity on the HAM-A for: the anticonvulsant group (pregabalin and tiagabine combined) was significantly favourable with a mean difference (MD) of -2.10 ([-2.83, -1.36] 95% CI); pregabalin was significantly favourable (MD -2.86 [-3.52, -2.21] 95% CI) tiagabine was statistically insignificant (MD - 0.58 [-1.41, 0.25] 95% CI). The risk ratio (RR) of treatment response using the CGI-I (RR >1 favours the anticonvulsant) for: the anticonvulsant group was significantly favourable (RR 1.23 [1.12, 1.35] 95% CI); pregabalin was significantly favourable (RR 1.35 [1.21, 1.50] 95% CI) tiagabine was statistically insignificant (RR 1.09 [0.98, 1.22] 95% CI). The RR of treatment acceptability (RR >1 favoured placebo) for: the anticonvulsant group was significantly unfavourable (RR 1.49 [1.18, 1.88] 95% CI); pregabalin was statistically insignificant (RR 1.23 [0.92, 1.65] 95% CI) tiagabine was significantly unfavourable (RR 1.95 [1.29, 2.93] 95% CI). In conclusion, this systematic review of the newer anticonvulsants included only RCTs of pregabalin and tiagabine. The main finding was that pregabalin showed significant efficacy in reducing symptom severity and improving treatment response in GAD. Tiagabine failed to show significant efficacy in primary outcomes. Further work is needed to better clarify the place of the newer anticonvulsants in the treatment armamentarium of GAD.
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Myllynen, P. (Päivi). "In search of models for hepatic and placental pharmacokinetics." Doctoral thesis, University of Oulu, 2003. http://urn.fi/urn:isbn:9514270231.
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Abstract
Several in vitro methods using both human and animal tissues have been developed to study hepatic metabolism and placental transfer. The pressure to minimize animal studies has increased during the past few decades due to the public opinion and ethical considerations. However, these methods need further evaluation of their predictive power when applied in vivo. The aim of this work was to produce new information of the metabolism and transplacental passage of several anticonvulsants as well as to evaluate the usefulness of the placental perfusion method and several in vitro methods for analyzing metabolism in the prediction of clinical pharmacokinetics.
Carbamazepine (CBZ) metabolism was studied using human and mouse liver microsomes, human hepatocytes, human liver slices and yeast cells expressing recombinant enzymes. All test systems predicted well the major metabolite carbamazepine-10,11-epoxide (CBZ-E). Also, minor metabolites were produced in slightly variable amounts in all systems except cells with recombinant enzymes. All human liver systems demonstrated that CYP3A4 is the principal CBZ metabolising enzyme. However, our results on CBZ-treated mice suggested that the metabolism of CBZ to CBZ-E is mainly mediated by CYP1A1 in C57/BL6 mice. Autoinduction of CBZ metabolism was seen in hepatocytes and in incubations using microsomes from CBZ-treated mice. Human liver and mouse liver microsomes metabolized oxcarbazepine (OCBZ) mainly to its active metabolite, 10-hydroxy-10,11-dihydro-carbamazepine (10-OH-CBZ). Also, 10,11-trans-dihydroxy-10,11-dihydro-carbamazepine (10,11-D) and an unknown metabolite were detected.
Placental transfer of lamotrigine (LTG) and diazepam (DZP) was considerable in the human placental perfusion system, indicating marked fetal exposure in vivo. The OCBZ, 10-OH-CBZ and 10,11-D analyzed from maternal venous and cord blood also suggested significant fetal exposure. The placental perfusion system predicts well the transplacental passage of LTG and OCBZ and its major metabolite. However, in vivo cord blood concentrations of DZP are higher than maternal concentrations. Placental perfusion studies did not predict this. Still, even with its limitations, the human placental perfusion method provides information that can be used to evaluate the risk factors associated with drug use during pregnancy because understanding of specific transport characteristics is a good basis for rational risk assessment.
In conclusion, all of the tested in vitro systems were useful in the prediction of at least some aspects of in vivo pharmacokinetics and metabolism, but validation and refinement are still essential, as is also the need to keep in mind the limitations characteristic of each in vitro method.
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Hurst, Susan I. "Roles of cytochromes P450 and microsomal epoxide hydrolase in drug-drug interactions involving valporic acid and its analogues /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/7940.
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Cunningham, Mark Oliver. "Patch clamp studies of the effects of anticonvulsants on glutamate and GABA release in the rat entorhinal cortex in vitro." Thesis, University of Bristol, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364923.
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Teär, Fahnehjelm Kristina. "Posterior ocular malformations in children : teratological aspects /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-470-4.
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Leroy, Brendan A. "Immunological characterization and localization of cell cycle regulatory proteins in preimplantation mouse embryos." Virtual Press, 1999. http://liblink.bsu.edu/uhtbin/catkey/1125138.
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The anticonvulsant drug, Dilantin, in many cases must be taken by epileptic mothers to control seizures during pregnancy, but unfortunately, it has been characterized as a human teratogen. It has also been demonstrated that many of the teratogenic effects of Dilantin occur during postimplantation, but some studies implicate a detrimental role for Dilantin during the preimplantation stages of development. Some of the postimplantation effects include congenital malformations and the potential'loss of the fetus. Our lab has proposed that in preimplantation mouse embryos the drug may be altering the timing of expression of cell cycle regulatory proteins and therefore, we have begun to examine the expression of these proteins. Thus, it was the goal of this study to characterize and localize various cell cycle proteins at specific time points in normal in vivo preimplantation mouse embryos, as this will provide important baseline information for studies on how anticonvulsant drugs may alter cell cycle regulation in embryos.Western blotting has confirmed the presence of cyclin BI in G1 of the first cell cycle. Both cyclin E and CDK2 were not detected in GI or G2/M of the first cell cycle or GI of the second cell cycle.From the immunogold TEM experiments, the density of cyclin B1 staining was observed to be the highest at G1 of the first cell cycle and declined at S and G2/M. Cyclin B 1 was detected in all regions of the embryo including the microvilli, cortical cytoplasm, interior cytoplasm, and was observed to be associated with vesicles and some filaments. The gold particles at GI, S, and G2/N4 of the first cell cycle and G1 of the second cell cycle appear to be associated with filamentous and membraneous structures and not free in the cytoplasmic spaces. Cyclin B 1 expression was more concentrated around vesicles at G1 of the first cell cycle and in general, was more concentrated around vesicles than in microvilli and cortical cytoplasm, interior cytoplasm, or around filaments at each cell cycle stage tested.Department of Biology
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Dandekar, Sushama A. "Studies of intramolecular SRN1 reactions of carbanions derived from 2-(o-halobenzyl)amides and 3-(o-halobenzyl)imides: application to the synthesis of succinimido[3,4-b]indane, a potential anticonvulsant." Diss., Virginia Tech, 1992. http://hdl.handle.net/10919/40096.
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Taveira, Ana Claudia de Almeida. "Atitude do psiquiatra brasileiro frente ao uso de lítio e outros estabilizadores do humor no transtorno bipolar." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5142/tde-28092007-143040/.
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Objetivo: Identificar os medicamentos preferidos no Brasil para tratar o transtorno bipolar e a opinião dos psiquiatras brasileiros sobre a litioterapia. Métodos: Um questionário de múltipla escolha com 14 itens foi desenvolvido para estudar estas questões. Foram enviados 10.059 questionários para psiquiatras brasileiros. Resultados: 820 psiquiatras (8,6%) responderam aos questionários. Lítio foi a medicação de primeira escolha em todas as fases do transtorno. Antipsicóticos foram a segunda escolha no tratamento da mania, superando os anticonvulsivantes. Antidepressivos foram a segunda medicação mais utilizada nos episódios depressivos. Mais de 80% de psiquiatras acreditam que o lítio é um medicamento seguro e de fácil manejo. Características epidemiólogicas como região de origem, alto nível educacional, grande experiência clínica e interesses acadêmicos podem ter influenciado tais resultados. Conclusão: Lítio é o medicamento de primeira linha no tratamento do transtorno bipolar no Brasil, a despeito do que ocorre em outros países. Apesar deste panorama favorável, algumas dificuldades podem ser identificadas como a falta de conhecimento sobre o lítio por profissionais da área de saúde mental e pacientes.Objective: Identify preferred drugs to treat bipolar disorder in Brazil and the impressions of Brazilian psychiatrits about lithium therapy. Methods: A 14 items multiple-choice questionnaire was developed to answer this issue. Questionnaires were posted to 10,059 Brazilian psychiatrists. Results: 820 psychiatrists (8.6%) have answered the questionnaires. Lithium was the preferred medication used in all phases of the disorder. Antipsychotics were second choice in treatment of mania, overcoming anticonvulsants. Antidepressants were the second more used medication for depressive episode. More than 80% of psychiatrists believe that lithium is a safe drug and there is no difficult to handle with. Epidemiological characteristics such region of origen, high degree, large clinical practice and academic interests may influenced those results. Conclusion: Lithium is the first line drug to treat bipolar disorder in Brazil, despite what occur in others countries. Although this favorable panel, some difficults can be identified as mental health professional and patients\' lack of information about lithium.
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Persson, Håkan. "Autonomic cardiac control in patients with epilepsy : spectral analysis of heart rate variability /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-963-7/.
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Lopes, Luciano da Silva. "Estudo do efeito analgÃsico do topiramato em modelos de dor aguda e neuropatia diabÃtica." Universidade Federal do CearÃ, 2007. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=869.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel SuperiorNo presente estudo, o Topiramato (TP) foi avaliado em modelos de dor aguda e de dor neuropÃtica diabÃtica. Camundongos Swiss machos foram utilizados nos testes de nocicepÃÃo aguda (formalina, placa quente e capsaicina) e ratos Wistar machos no teste de dor neuropÃtica (filamentos de von Frey). No teste da formalina (2 %; 20 ÂL/i.pl.), foi quantificado o tempo que o animal lambia a pata que recebeu o estÃmulo durante 0-10 min (fase 01) e 20-40 min (fase 02). Os resultados mostraram uma reduÃÃo na segunda fase (***p<0,001) nas trÃs doses utilizadas do TP, enquanto que apenas a maior dose mostrou efeito na primeira fase do teste (***p<0,001). O efeito do TP (80 mg/Kg) foi revertido pela naloxona 2 mg/Kg na segunda fase do teste da formalina , mas nÃo pela glibenclamida 3mg/Kg, ciproeptadina 5 mg/Kg e ondansetrona 0,5 mg/Kg quando comparado com o controle em ambas as fases. No teste da placa quente (52Â) foi verificada a reaÃÃo do camundongo ao estÃmulo tÃrmico onde o animal responde tentando pular ou lamber uma de suas patas traseiras. Os animais foram submetidos a placa aos 00, 30, 60, 120 e 240 min apÃs os tratamentos e comparou-se os grupos que receberam TP nas diferentes doses ( 20, 40 e 80 mg/Kg) e o grupo controle. Nesse modelo, TP demonstrou atividade aos 90 e 120min (**p<0,01; ***p<0,001) apenas na maior dose utilizada (80 mg/Kg). Em outro protocolo, os animais receberam capsaicina (20 ÂL, 2 Âg/ i.pl), sendo quantificado o tempo durante 5 min que estes lamberam ou morderam a pata estimulada, com comparaÃÃo posterior entre os grupos NÃo se verificou efeito significativo de TP em todas as doses utilizadas quando comparado com o controle. Para avaliaÃÃo da aÃÃo antinociceptiva em dor neuropÃtica, os animais foram inicialmente induzidos a diabetes com estreptozotocina 40 mg/Kg i.p e apÃs trinta dias foram submetidos ao teste com filamentos de von. NÃo se verificou efeito significativo do TP nas doses utilizadas quando comparado com o controle. O TP nÃo alterou a freqÃÃncia de locomoÃÃo dos animais no teste do campo aberto e no teste do Rota rod e nÃo aumentou o nÃmero de quedas nem diminuiu o tempo de permanÃncia na barra giratÃria, sugerindo que o TP nÃo exerce sua atividade antinociceptiva por aÃÃo depressora ou relaxante muscular. Em conclusÃo, a partir desses resultados podemos sugerir que o TP apresenta efeito antinociceptivo frente a diferentes estÃmulos de dor aguda, mas nÃo na dor neuropÃtica diabÃtica. O efeito analgÃsico nos testes de dor aguda, provavelmente envolve sistema opiÃide, porÃm nÃo os canais de potÃssio sensÃveis ao ATP e sistema serotoninÃrgico
In the present study, Topiramate (TP) was evaluated in acute pain and diabetic neuropathic animal models. Male Swiss mice were used in the tests of acute nocicepcion (formalin, hot plat and capsaicin) e male Wistar rats in the neuropathic pain test (filaments of von Frey). In the formalin test (2%, 20 ÂL/i.pl), it was measured the time spent by the animal licking the left hind paw which received the stimulation during 0-10 min (phase 01) and 20-40 min (phase 02).The results showed a reduction of the second phase (*** p<0.001) in the three doses used of TP while only the biggest dose showed effect in the first stage of test (*** p< 0.001). The TP effect (80 mg/Kg) was reverted by naloxone 2 mg/kg in the second phase of the test of the formalin, but not for glibenclamide 3 mg/kg, cyproeptadine 5 mg/kg and ondansetron 0.5 mg/kg when compared to control in both phases. In the hot plate test (52Â) was analysed the reaction of the mouse to the thermal stimulation where the animal respond tryning to jump or to lick one of its brack legs. The animals had been submitted the plate to 00, 30, 60 and 120 min after the treatments and compared the groups that had received TP in the different doses (20,40 e 80 mg/kg). The results showed, TP demonstrated activity to 90 and 120 min (**p < 0.01; *** p < 0.001) only in the biggest dose used (80mg/kg). In another protocol, the animals received capsaicin (20 ÂL/2Âg/i.pl), but the results ere not significant. For evaluations of the antinociceceptive action in neuropathic pain, the animals had been initially induced diabetes with streptozotocine 40 mg/Kg i.p. and after thirty days had been submitted to the test with filaments of von Frey. No significant effect of TP was observed in all doses used when compared with the controls. TP did not modify the frequency of locomotion of the animals in the open field and presented no effect in the Rota rod test suggesting that the TP does not exert its analgesic effect by depressive actions or relaxant muscular activity. In conclusion, the results may suggest that TP presents antinociceptive effect front the different stimulations of acute pain, but not in diabetic neuropathic pain. The analgesic effect in acute pain, probably involves system opioid, and seems do not involve potassium canals or serotoninergic system
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Englund, Marita. "Effects of hypoxia and antiepileptic drugs on electrophysiological properties of CA1 neurons in hippocampus /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-237-8/.
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Medeiros, Palas Atenéia Dantas de. "Estudo clínico-laboratorial do uso de fenobarbital como anticonvulsivante entre pacientes do Hospital Universitário Alcides Carneiro (HUAC)." Universidade Estadual da Paraíba, 2014. http://tede.bc.uepb.edu.br/tede/jspui/handle/tede/2606.
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Introduction: This study characterized the profile of patients treated at the “Alcides Carneiro” University Hospital (HUAC), users of phenobarbital in order to support actions of therapeutic drug monitoring. Methods: Fifty patients were interviewed using a standardized questionnaire. Results: It was observed that 50% of patients have been using the drug for a long time (7.68 years on average). About 74% of respondents are under monotherapy and 59.5% of these have their seizures controlled. The patients under monotherapy have more chance of success in controlling seizures. The main anticonvulsant drug combination observed was phenobarbital with carbamazepine (66% of patients). Sedation and dizziness are among the main adverse effects, reported by 34% of patients. Monotherapy seems to be a protective factor only for adverse effect dizziness (OR=3.1). Conclusions: The analysis of these and other results presented in this paper may be useful in promoting rational use of anticonvulsants at the HUAC.
Este trabalho caracteriza o perfil clínico e epidemiológico dos pacientes atendidos no Hospital Universitário Alcides Carneiro (HUAC), que usam fenobarbital como anticonvulsivante, a fim de subsidiar ações de monitorização terapêutica. Entrevistou-se 50 pacientes, de 2011 a 2012, mediante um questionário padronizado. Observou-se que, 74% dos entrevistados estão sob monoterapia e 59,5% destes possuem suas crises controladas. Nos pacientes sob politerapia (26%) o índice de controle das crises é de 23,07%. É possível afirmar que pacientes sob monoterapia têm mais chance de sucesso no controle das crises convulsivas (Odds Ratio = 4,400). A principal associação anticonvulsivante observada foi do fenobarbital com a carbamazepina (66%). Entre os efeitos adversos relatados destacam-se a sedação e a tontura (34% dos pacientes). A monoterapia parece se constituir como fator de proteção apenas para o efeito adverso tontura (OR de 3,1). Esses resultados poderão ser úteis na promoção do uso racional de anticonvulsivantes no HUAC.
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Fischer, Wolfgang, Heike Franke, Ute Krügel, Heiko Müller, Klaus Dinkel, Brian Lord, Michael A. Letavic, David C. Henshall, and Tobias Engel. "Critical evaluation of P2X7 receptor antagonists in selected seizure models." Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-206115.
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The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567) and a natural compound derivative (tanshinone IIA sulfonate) in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ) seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders.
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Rodrigues, Marcelo Cairrão Araujo. "Análise neuroetológica e estudo da atividade pró-convulsivante e anticonvulsivante in vivo da peçonha bruta da aranha Parawixia bistriata em ratos: injeção central e periférica." Universidade de São Paulo, 1999. http://www.teses.usp.br/teses/disponiveis/59/59134/tde-13022003-091530/.
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Durante a evolução, alguns animais desenvolveram toxinas que são capazes tanto de paralisar quanto de matar suas presas, através de ação seletiva sobre receptores ou canais iônicos. As acilpoliaminas, por exemplo, são componentes não-proteicos antagonistas dos receptores glutamatérgicos acoplados a canais iönicos, que mostraram-se anticonvulsivantes em diversos modelos animais. Apesar do estudo das alterações comportamentais em animais após a injeção de substâncias químicas (etofarmacologia) ter auxiliado a estudar o mecanismo de ação destas substâncias no SNC, não há relatos sobre os efeitos comportamentais da injeção i.c.v. e i.v. da peçonha da aranha Parawixia bistriata. Descobriu-se recentemente na peçonha bruta da aranha Parawixa bistriata uma ação potencialmente anticonvulsivante in vitro: ela potencia a neurotransmissão gabaérgica e desloca receptores glutamatérgicos de seus sítios específicos em sinaptosomas do cérebro de rato (FONTANA, 1997). O objetivo do presente trabalho é estudar as alterações comportamentais causadas pela injeção central e periférica da peçonha bruta de P. bistriata através de uma metodologia quantificativa (método neuroetológico), e verificar se esta peçonha possui ação anticonvulsivante in vivo em um modelo químico de indução de crises agudas - o pentilenotetrazol (PTZ, 80 mg/kg, i.p.). Os resultados mostram que a injeção i.c.v. da peçonha bruta origina nos ratos dois quadros comportamentais, identificados como crises convulsivas, denominados de crises graves e leves. Nas crises graves, observou-se, entre outros, mioclonias semelhantes às crises convulsivas límbicas descritas por Racine (1972). As crises leves são caracterizadas por tremores generalizados, e sacudidelas de corpo (wet dog shakes). A injeção da peçonha i.v. não origina crises nos animais mas, no entanto, causa um intenso aumento nas interações estatísticas das seqüências comportamentais, que lembram em muito as atividades de deslocamento. Tanto nas crises graves, leves, e na injeção i.v., a neuroetologia permitiu a visualização das interações entre as mioclonias convulsivas límbicas e os outros comportamentos, dados não fornecidos pelas escalas de medição de intensidade das crises límbicas. Buscando indícios da presença de componentes anticonvulsivantes não-proteicos (como acilpoliaminas), injetou-se i.c.v. a peçonha de P. bistriata fervida (numa dose que não causa crises nem alteração motora per se), seguida da injeção i.p. de PTZ. Verificou-se que este tratamento abole as crises clônicas e tônicas induzidas por PTZ. Conclui-se que a peçonha bruta de P. bistriata provavelmente possui componentes pró-convulsivantes com possível ação sobre o sistema límbico. Esta peçonha pode conter, também, componentes anticonvulsivantes não-proteicos, possivelmente acilpoliaminas.Spider venoms have hight affinity and specificity for neuronal receptors, transporters and ion channels, therefore been important tools to characterize mammal and insect nervous system. However, behavioural alterations in mammals caused by injections of spider venoms have not been studied in detail. In this work we describe the rat behavioural alteration caused by central injection of the crude venom of the spider Parawixia bistriata, using a neuroethological methodology. There were seen two types of seizures, named mild and severe. Neuroethological flowcharts showed that in mild seizures, there was a strong statistical correlation (c2) between tremor followed by laying or by laying left, which indicates that the venom, perhaps, is difficulting central coordination of movements. In severe seizures, this effect is enworsed, with the animal falling.This type of seizure are similar to those described by Racine (1972). Since the crude venom of P. bistriata showed a potencial anticonvulsant activity in vitro, we tested if it would indeed inhibit clonic and tonic convulsions induced by pentilenetetrazole (PTZ; 80 mg/kg, i.p.). Boiled crude venom of P. bistriata was i.c.v. injected, and 20 minutes later, animals (n=10) received PTZ. A control group (n=10) received only PTZ. The results were: central injection of the venom abolished clonic and tonic convulsions induced by PTZ, in 60% of the animals. In conclusion, the crude spider venom of P. bistriata, centrally injected, causes central loss of movement coordination, and elicits limbic seizures similar to those described by Racine (1972), but, when boiled and injected in lower doses, it blocks clonic and tonic convulsions induced by PTZ (80 mg/kg).
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Wallin, Johan. "Experimental nerve injury-induced pain : mechanisms and modulation/." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-849-1/.
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Campos, Marília Silveira de Almeida. "Comparação da eficácia e tolerabilidade dos fármacos antiepilépticos : revisão sistemática com meta-análises." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2017. http://hdl.handle.net/10183/158714.
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OBJETIVO: Comparar a eficácia e a tolerabilidade dos fármacos antiepiléticos (FAE) no tratamento em monoterapia de pacientes com epilepsia focal ou generalizada. MÉTODOS: Uma revisão sistemática foi realizada por meio da busca nas bases de dados eletrônicas Pubmed, Scopus, Web of Science e Cochrane Register of Controlled Trials. Foram incluídos os ensaios clínicos controlados com pacientes com epilepsia, em tratamento com FAE, via oral, em monoterapia, e que avaliaram o número de pacientes que atingiram a remissão das crises epilépticas, que interromperam o tratamento devido à ineficácia terapêutica ou à ocorrência de reações adversas (RAM) intoleráveis. Meta-análises de comparação de múltiplos tratamentos foram realizadas por meio do modelo bayesiano de efeitos randômicos que permitiu o cálculo do Odds Ratio meta-analítico para os FAE estudados. Também foi realizado um ranqueamento da probabilidade de cada FAE ser a melhor opção em eficácia e tolerabilidade. RESULTADOS E CONCLUSÕES: A busca identificou 18874 publicações, no entanto apenas 71 estudos foram selecionados, compreendendo 17555 pacientes com epilepsia. Vinte e nove estudos apresentaram os desfechos de eficácia no tratamento de crises focais, 19 em crises generalizadas e 58 apresentaram dados de tolerabilidade. Nesses estudos, 15 FAE foram avaliados. No tratamento das crises focais, os FAE de nova geração levetiracetam (LEV), lamotrigina (LTG), oxcarbazepina, sultiame e topiramato (TPM) demonstraram possuir eficácia equivalente à carbamazepina (CBZ), clobazam e valproato (VPA). No entanto, a CBZ apresentou o pior perfil de tolerabilidade devido à grande probabilidade do paciente abandonar o tratamento devido à RAM intoleráveis. Quanto ao tratamento das crises generalizadas, a LTG, LEV e TPM são tão eficazes quanto o VPA para o tratamento de crises generalizadas tônico-clônicas, tônicas e clônicas. O VPA e a etosuximida constituem as melhores opções para o tratamento de crises de ausências, enquanto que a LTG mostrou-se menos eficaz. Para o tratamento de crises mioclônicas e espasmos infantis mais ensaios clínicos randomizados são necessários para fornecer boas evidências que possam guiar a decisão clínica dos profissionais de saúde. Dentre os FAE com perfil de eficácia adequado, a LTG destacou-se pela menor probabilidade de manifestar RAM intoleráveis.OBJECTIVE: To compare the efficacy and tolerability of the antiepileptic drugs (AED) in monotherapy of patients with focal or generalized epilepsy. METHODS: A systematic review was in the Medline/Pubmed, Scopus, Web of Science and Cochrane Register of Controlled Trials databases. We included randomized clinical trials of patients with epilepsy treated with oral monotherapy AED, which evaluated number of patients becoming seizure free at the maintenance treatment period; number of patients which withdrawals from the study because of therapeutic inefficacy and number of patients which withdrawals from the study because of intolerable adverse reaction. Network meta-analyses were performed using Bayesian random effects model. We also carried out a ranking of the probability of each AED be the best option in the efficacy and tolerability outcomes. Sensitivity analyses were conducted in order to check the robustness of the results. RESULTS AND CONCLUSIONS: The research identified 18,874 publications, but only 71 studies were selected, comprising 17555 patients with epilepsy.Twenty-nine trials showed the efficacy outcomes in the treatment of focal seizures, 19 in generalized seizures and 58 showed tolerability data. In the treatment of focal seizures, levetiracetam (LEV), lamotrigine (LTG), oxcarbazepine, sultiame and topiramate (TPM) have demonstrated equivalent efficacy to carbamazepine (CBZ), clobazam and valproate (VPA). LTG, LEV and TPM are as effective as the VPA for the treatment of generalized tonic-clonic, tonic and clonic seizures. VPA and ethosuximide are the best options for the treatment of absence seizures, whereas LTG was less effective. For the treatment of myoclonic seizures and infantile spasms, more randomized clinical trials are needed to provide good evidence to guide the clinical decision of health professionals. Among the AED with adequate efficacy profile, LTG stands out as the AED with the best tolerability profile, suggesting it may be the best option for the treatment of patients with epilepsy.
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Dakin, Kelly Andrea. "Design and synthesis of anticonvulsant drugs based on endogenous anticonvulsant and antiepileptogenic factors." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq22453.pdf.
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Danielsson, Christian. "Role of the hERG-channel in arrhythmia and teratogenicity studies in animal models and the human embryonic heart /." Stockholm, 2010. http://diss.kib.ki.se/2010/978-91-7409-831-0/.
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Barcelos, Caroline Coutinho de 1982. "Efeitos neuromusculares do atracurio e do rocuronio em ratos pre-tratados com carbamazepina e fenobarbital : estudo in vitro e in vivo." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310321.
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Orientadores: Lea Rodrigues Simioni, Yoko Oshima FrancoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Atracúrio (ATC) e rocurônio (ROC) são bloqueadores neuromusculares de ação intermediária. Neste estudo, seus efeitos neuromusculares foram investigados in vitro e in vivo em ratos pré-tratados, via gavagem (7d), com os anticonvulsivantes (AC) carbamazepina (CBZ, 40 mg/kg) e fenobarbital (FB, 20 mg/kg) e sacrificados no 8º dia, sob anestesia com uretana. Os resultados foram comparados com a condição-controle (ratos não tratados com AC). A exposição crônica a AC pode determinar a indução de enzimas microssomais responsáveis pela metabolização (oxidação) de fármacos. Para o controle desse fenômeno farmacológico foram determinadas as concentrações enzimáticas de citocromo P450 e b5 redutase, em microssomos hepáticos de ratos tratados com AC, e comparados aos controles. As preparações in vitro e in vivo foram montadas de acordo com as técnicas de Bulbring e de Leeuwin e Wolters, respectivamente. As concentrações utilizadas dos bloqueadores nas preparações in vitro e in vivo foram, respectivamente, 20 µg/mL e 0,5 mg/kg para atracúrio (ATC); 4 µg/mL e 0,6 mg/kg para rocurônio (ROC). Cada protocolo teve um n=5 e as respostas foram observadas por 60 min. Os resultados tanto in vitro quanto in vivo mostraram que o pré-tratamento com a carbamazepina reduziu a resposta contrátil em cerca de 30%. Sob sua vigência, não houve alteração do bloqueio produzido pelo atracúrio e pelo rocurônio, possivelmente porque o tempo de tratamento com a carbamazepina não foi suficiente para causar indução enzimática. Em relação ao fenobarbital, os resultados in vitro e in vivo mostraram nenhuma alteração significativa sob a resposta contrátil. Sob sua vigência, diminuiu a sensibilidade do ATC em produzir o bloqueio neuromuscular in vitro. Contudo, in vivo potencializou o bloqueio neuromuscular de ambos os bloqueadores estudados. Essas alterações observadas em ambos os modelos experimentais podem ser devidas à indução ocorrida com o fenobarbital, conforme comprovado pela concentração de citocromo P450 (0,69 nmol/mg proteína) e b5 redutase (0,62 nmol/mg proteína)
Abstract: Atracurium (ATC) and rocuronium (ROC) are neuromuscular blockers of intermediate action. In this study, the neuromuscular effects had been investigated in vitro and in vivo in treated rats, by gavage (7d), with the anticonvulsantes (AC) carbamazepine (CBZ, 40 mg/kg) and phenobarbital (FB, 20 mg/kg) and sacrificed on the eight day, under anesthesia with urethane. The results had been compared with the control-condition (rats not treated AC). The chronic exposition the AC can determine the induction of microsomes enzyme for the responsible metabolization (oxidation) of drugs. For the control of this pharmacologic phenomenon the enzymatic concentrations of P450 and b5 cytochromes had been determined, in livers microsomes of rats treated with AC, and compared with the controls. The preparations in vitro and in vivo had been followed the Bulbring and Leeuwin and Wolters techniques, respectively. The in vitro and in vivo concentrations were 20 µg/ml and 0.5 mg/kg, respectively, for atracurium (ATC); and 4 µg/ml and 0.6 mg/kg for rocuronium (ROC). Each protocol presented n=5 and the answers were calculated during 60 minutes. The in vitro and in vivo results showed that treatment with carbamazepine reduced the extent of muscle response in about 30%. Under its validity, did not alter the extent of the muscle response block produced by atracurium and rocuronium possibly because the period of time of carbamazepine treatment was not enough to cause enzymatic induction. Regarding phenobarbital, the in vitro and in vivo results did not alter significant the extent of the muscle response block produced. Under its validity, reduced the ATC sensitivity the block neuromuscular in vitro produced. However, in vivo increased the neuromuscular block of both the blockers studied. These alterations observed in both the experimental models can have occured induction with the phenobarbital, as proven P450 (0,69 nmol/mg protein) and b5 (0,62 nmol/mg protein) of cytochrome concentration
Mestrado
Mestre em Farmacologia
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Riechelmann, Rachel Simões Pimenta [UNIFESP]. "Risco de interações medicamentosas em pacientes com câncer e recebendo cuidados de suporte exclusivo." Universidade Federal de São Paulo (UNIFESP), 2009. http://repositorio.unifesp.br/handle/11600/10066.
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Publico-020c.pdf: 2073396 bytes, checksum: 04ba8e01c6f7b4dd2421e5babffdd4b9 (MD5)Um número desconhecido de pacientes com câncer experimenta reações e interações de drogas graves, podendo resultar em hospitalização e até em morte. Particularmente, pacientes portadores de neoplasia maligna comumente recebem um grande número de medicamentos, além de receberem drogas com alto risco de efeitos adversos. Desta forma, dois estudos foram realizados como base para esta tese: uma revisão sistemática e em estudo retrospectivo. A revisão sistemática da literatura avaliou os estudos publicados sobre a epidemiologia de interações medicamentosas em pacientes com câncer. A busca identificou 8 estudos: 7 artigos publicados no PubMed e um resumo publicado nos proceedings do congresso da sociedade americana de oncologia (ASCO). A maioria dos estudos era retrospectiva e avaliou potenciais interações medicamentosas, com apenas dois estudos publicados sobre reais interações medicamentosas. Aparentemente, um terço dos pacientes oncológico ambulatoriais recebe combinações de drogas com risco de interação. Os principais fatores de risco para interações medicamentosas são: idade avançada, número crescente de medicações, presença de lesões cerebrais (primárias ou secundárias) e pacientes que recebem drogas consideradas de risco como anticonvulsivantes, varfarina e anti-inflamatórios hormonais e não-hormonais. O segundo estudo desta tese avaliou a prevalência de potenciais interações medicamentosas entre pacientes com câncer terminal. Desta forma, nós revisamos retrospectivamente os prontuários de todos os pacientes com câncer que foram atendidos no ambulatório de Cuidados Paliativos, do Hospital Princess Margaret, Toronto, Canadá, num período de 8 meses. As listas de medicações foram rastreadas para interações pelo programa eletrônico Drug Interaction Facts, que classifica as interações por nível de gravidade (maior, moderada e menor) e evidência científica (1 a 5, onde 1 = maior nível de evidência). Dentre os 372 pacientes avaliados, 250 interações medicamentosas potenciais foram identificadas em 115 pacientes (31%, 95% Intervalo de Confiança 26 - 36%), predominantemente envolvendo varfarina e fenitoína. A maioria das potenciais interações foi classificada como de gravidade moderada (59%) e 41,5% possuíam níveis de evidência 1-3. Na análise multivariada, idade crescente (p<0,001), pelo menos uma comorbidade (p=0,001), tipo de câncer (tumores cerebrais, p<0,001) e número crescente de medicamentos utilizados (p<0,001) foram associados a risco de interações medicamentosas. Portanto, concluiu-se que potenciais interações medicamentosas são comuns entre pacientes oncológicos que estejam recebendo cuidados de suporte exclusivos, sendo que a maioria envolve varfarina e/ou anticonvulsivantes. Fatores de risco incluem idade avançada, pacientes com múltiplas comorbidades, tumores cerebrais e aqueles que utilizam muitas medicações.
Background: Drug-drug interactions (DDIs) comprise an important problem in medical oncology practice. We systematically reviewed the frequency of DDIs in oncology. Methods: We searched PubMed for eligible articles and online databases abstracts of major oncology meetings. Results: Eight studies reported on the frequency of DDIs: six evaluated the frequency of potential DDIs while 2 studies reported on real DDIs, i.e. interactions that had clinical consequences. Studies of potential DDIs found that approximately one third of patients are exposed to dangerous drug doublets, with the most common ones involving warfarin and anticonvulsants. One study of real DDIs found that 2% of hospitalized cancer patients had a DDI as the cause of admission. Conclusion: Drug interactions comprise an important issue in oncology, with approximately one third of ambulatory cancer patients being at risk of DDIs. Data are limited on the clinical consequences of drug interactions among cancer patients.
TEDE
BV UNIFESP: Teses e dissertações
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McGuire, G. M. "Interactions of anticonvulsant drugs with haem biosynthesis." Thesis, University of Glasgow, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381489.
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Gilbert, Trevor H. "Anticonvulsant and behavioural toxic properties of conventional anticonvulsant drugs in the guinea pig kindling model of human partial epilepsy." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ64807.pdf.
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Jin, Albert Yongwon. "Biologically driven molecular modeling for anticonvulsant drug design." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0007/NQ42948.pdf.
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Jackson, Michael F. "Frequency-dependent actions of GABA enhancing anticonvulsant drugs." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0022/NQ50191.pdf.
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Hasan, Mohamed Yousif. "A pharmacological study on gaba modifying anticonvulsant agents." Thesis, Cardiff University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336178.
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Martin, Duncan J. "Mechanism of action of the anticonvulsant drug gabapentin." Thesis, University of Aberdeen, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395181.
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In this study, the whole-cell patch clamp technique and Fura-2 calcium (Ca2+) imaging techniques were employed to investigate the involvement of voltage activated calcium currents (VACCs) in the mechanism of action of the anticonvulsant drug gabapentin. Molecular biology studies were also carried out to assess which VACC subunits were required for drug sensitivity in particular cell cultures. Also investigated were the effects, if any, of gabapentin at GABA receptors and on cells of the F11 line. Voltage activated calcium currents were activated in cultured DRG neurones until a consistent current magnitude was achieved. Effects of gabapentin could then be measured by activation of subsequent currents in the presence of drug. The effects of various other compounds were also tested in this way, e.g. the effects of the related drug pregabalin, effects of the inhibitory neurotransmitter GABA, the effects of the GABAB antagonist saclofen and the effect of treating the cells with pertussis toxin. Gabapentin inhibited voltage activated calcium currents. This inhibition was voltage dependent but frequency independent. Gabapentin did not act at GABAA or GABAB receptors. Gabapentin effects were PTx sensitive suggesting a G-protein mechanism was involved. An experimental protocol for calcium fluorescence imaging was designed. This protocol allowed comparison of gabapentin and other drug effects against control responses, and is a protocol that could be used as an assay system to test the properties of compounds related to gabapentin. Gabapentin and pregabalin ((S)-isobutylgaba) both reduced the magnitude of evoked Ca2+ transients in both cultured DRG neurones and in F11 cells. The R-stereoisomer of pregabalin, PD-C, was shown to increase the magnitude of these transients. Both this increase and the decrease associated with gabapentin were PTx sensitive. These results indicate that gabapentin attenuates calcium currents at VACCs. The gabapentin binding site has been shown to be the α2δ subunit and it was observed that the activity of gabapentin is dependent on a G-protein linked mechanism and on the presence of modulatory VACC β subunits.
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Chessum, Nicola E. A. "The development of new GABA-based anticonvulsant agents." Thesis, University of York, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273822.
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Dhariwal, Mohammad Ali Husnain. "A study of anticonvulsant action of sodium valporate." Thesis, De Montfort University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303243.
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Salvat, Éric. "Traitements précoces et tardifs des douleurs neuropathiques et β2-agonistes : études thérapeutiques précliniques et cliniques." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ104/document.
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Les douleurs neuropathiques sont secondaires à une maladie ou à une lésion affectant le système nerveux somatosensoriel et sont mal soulagées par les antalgiques usuels. Dans notre travail préclinique, nous avons étudié l’effet de différentes molécules, dont des antidépresseurs et antiépileptiques recommandés dans le traitement des douleurs neuropathiques. Dans un modèle murin de neuropathie traumatique, nous avons étudié l’influence de la période de traitement, précoce ou tardif, sur l’allodynie mécanique. Un traitement précoce par gabapentine ou par carbamazépine permet d’observer un effet préventif sur la chronicisation de l’allodynie. Dans un modèle murin de neuropathie diabétique, nous avons caractérisé l’action anti-allodynique d’un traitement par nortriptyline et par terbutaline. En clinique, nous avons réalisé un travail d’enquête rétrospective sur des patients opérés par thoracotomie. L’analyse des résultats montre une diminution significative du risque de présenter des douleurs chroniques avec des caractéristiques neuropathiques chez les patients traités par β2-agonistes au long coursNeuropathic pain is caused by a lesion or disease of the somatosensory nervous system and is badly relieved by usual antalgics. In our preclinical work, we studied the effect of various molecules, in particular antidepressant and anticonvulsant drugs wich are recommended in the treatment of neuropathic pain. In a murine model of traumatic neuropathy, we studied the influence of the period of treatment, early or late, on the mechanical allodynia. An early treatment with gabapentin or carbamazepine leads to a preventive effect on sustained allodynia. In a murine model of diabetic neuropathy, we characterized the antiallodynic action of nortriptyline and terbutaline. In our clinical work, we realized a retrospective survey on patients operated by thoracotomy. The analysis of the results show a significant decrease of the risk to suffer from chronic pain with neuropathic characteristics in patients treated with long-term β2- agonists
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Hadid, Rebecca D. "Pre-clinical investigation of cannabidivarin in an animal model of temporal lobe epilepsy." Thesis, University of Reading, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.629084.
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Iyamu, Osaro. "Evaluation of the anticonvulsant activity of Elytropappus rhinocerotis (L.f) Less." University of the Western Cape, 2016. http://hdl.handle.net/11394/5872.
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Magister Pharmaceuticae - MpharmM.Pharm thesis, Discipline of Pharmacology, School of Pharmacy, University of the Western Cape. Epilepsy is a worldwide neurological disorder which is also prevalent in South Africa. Herbal medicines, besides orthodox medicines, have been used from time immemorial for the treatment of epilepsy even though, generally, there is want of scientific evidence to substantiate their effectiveness. People with epilepsy have used different types of plants and herbs now known as herbal therapies over thousands of years although no clinical benefit is implied by this term. Moreover, the use of traditional medicine to treat CNS disorders such as epilepsy in South Africa still lacks a lot of scientific data although a study that was conducted in the Western Cape Province of South Africa revealed that the people in the Bredasdorp community use Elytropappus rhinocerotis to treat convulsions.