Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new topamax research articles will be listed here shortly after becoming available to us.
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Use of second-generation antiepileptic drugs in the pediatric population.
Paediatr Drugs. 2008; 10(4): 217-54
Chung AM, Eiland LS
Epilepsy is common in the pediatric population. Nine second-generation antiepileptic drugs have been approved in the US for use in epilepsy over the past 15 years: felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, zonisamide, and pregabalin. Their use in pediatric patients is fairly widespread, despite most of these agents not having US FDA indications for use.Felbamate and gabapentin were the first two second-generation antiepileptic drugs to be approved in the US. Felbamate use has been limited because of the occurrence of hepatotoxicity and aplastic anemia. Although gabapentin is a fairly well tolerated antiepileptic drug, its use has also been limited as a result of inconsistent efficacy and concern about seizure exacerbation. Lamotrigine and topiramate are broad-spectrum antiepileptic drugs with efficacy in a wide variety of seizure types. Both agents have some tolerability concerns: rash with lamotrigine and neuropsychiatric events with topiramate. There are very little data on tiagabine use in children, but this agent appears to be effective and to have a good tolerability profile. Levetiracetam is a second-generation antiepileptic agent that is available intravenously. Considering its good efficacy, fast onset of action, and low incidence of serious adverse effects, its use in the acute setting could potentially increase. Oxcarbazepine and zonisamide have been relatively well studied in pediatric seizure patients, including use as monotherapy. Both agents have demonstrated good efficacy and tolerability for patients as young as 1 month old. Vigabatrin and rufinamide are currently not available in the US, but have been shown to have some success in other countries. Pregabalin is the newest antiepileptic agent, but lacks pediatric data currently.
Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides.
Bioorg Med Chem. 2008 Jun 10;
Yang B, Zhang H, Verkman AS
Inhibitors of brain glial water channel aquaporin-4 (AQP4) are of potential clinical utility, as they are predicted to modulate brain edema, neuroexcitation and glial scarring. Recently, Huber et al. (Bioorg. Med. Chem.2007, 17, 1270-1273; in press) reported that a series of arylsulfonamides, antiepileptics, and related small molecules strongly inhibited AQP4 water transport with IC(50)s down to 1muM. We retested the compounds with greatest reported potencies, including acetylsulfanilamide, acetazolamide, 6-ethoxy-benzothiazole-2-sulfonamide, topiramate, zonisamide, phenytoin, lamotrigine, and sumatriptan, in AQP4-transfected mammalian cells and primary cultures of brain glial cells, using several sensitive assays of osmotic water permeability. Contrary to the findings of Huber et al., in our studies we found no significant inhibition of AQP4 water permeability by any of the compounds at concentrations up to 100muM.
VEP indices of cortical lateral interactions in epilepsy treatment.
Vision Res. 2008 Jun 20;
Conte MM, Victor JD
We extend Spekreijse's strategy for analyzing lateral interactions in visual evoked potentials (VEPs) to clinical neurophysiologic testing of patients with epilepsy. Stimuli consisted of the radial windmill/dartboard pattern [Ratliff, F., & Zemon, V. (1982). Some new methods for the analysis of lateral interactions that influence the visual evoked potential. In: Bodis-Wollner (Ed.), Evoked potentials, Vol. 388. (pp. 113-124). New York: Annals of the New York Academy of Sciences.] and conventional checkerboards. The fundamental and 2nd-harmonic components of the steady-state responses were used to calculate indices reflecting facilitatory (FI) and suppressive (SI) cortical interactions. We carried out two studies. In the first, VEPs in 38 patients receiving antiepileptic drug (AED) therapy were compared to those of age-matched controls. For three AEDs (tiagabine, topiramate, and felbamate), addition of the drug did not change the FI and SI compared to baseline values or those of normal controls. However, the addition of gabapentin was associated with an increase of the FI, and this change was reversed when the medication was withdrawn. This suggested a medication-specific change in cortical lateral interactions. The second study focused on the effects of neurostimulation therapy. Eleven epilepsy patients receiving chronic vagus nerve stimulation (VNS) treatment were tested. By comparing VEPs recorded with the stimulator on (Stim-ON) and turned off (Stim-OFF) in the same session, we determined that VNS did not have a short-acting effect on lateral interactions. However, when compared with normal controls, the VNS patients had a significantly smaller SI (p
Estimating the effects of co-medications on plasma olanzapine concentrations by using a mixed model.
Prog Neuropsychopharmacol Biol Psychiatry. 2008 May 7;
Botts S, Diaz FJ, Santoro V, Spina E, Muscatello MR, Cogollo M, Castro FE, de Leon J
The purpose of this study was to estimate the effect sizes of drug interactions on plasma olanzapine concentrations while adjusting for potentially confounding factors such as smoking. The estimation was performed by using a mixed model, data from a series of previously published studies of lamotrigine, oxcarbazepine, topiramate, and mirtazapine, and unpublished data from patients under clinical therapeutic drug monitoring (TDM). The total sample included 163 adult patients (age >/=18 years) who provided both steady-state plasma olanzapine concentrations and smoking information. They provided a total of 360 olanzapine concentrations (1 to 11 measures per patient). Smoking and concomitant carbamazepine or lamotrigine use were found to have significant effects on median plasma olanzapine concentrations. The effects of lamotrigine on plasma olanzapine concentrations were modified by smoking. After adjusting for olanzapine dose and carbamazepine intake, plasma olanzapine concentrations were 10% lower in non-smokers who were taking lamotrigine than in non-smokers who were not taking lamotrigine; olanzapine concentrations were 35% higher in smokers who were taking lamotrigine than in smokers who were not taking lamotrigine; olanzapine concentrations were 41% lower in smokers who were not taking lamotrigine than in non-smokers who were not taking lamotrigine; and olanzapine concentrations were 11% lower in smokers who were taking lamotrigine than in non-smokers who were taking lamotrigine. After adjusting for olanzapine dose and taking carbamazepine, the correction factor comparing smokers taking lamotrigine versus non-smokers who were not taking lamotrigine was 1.3. Gender, age, and concomitant use of mirtazapine, valproic acid, lamotrigine, topiramate, lorazepam, citalopram or oxcarbazepine did not have significant effects on olanzapine concentrations. The main limitation of this clinical design is the unavoidable substantial "noise" that characterizes (uncontrolled) clinical environments, which may make it difficult to detect the effects of some variables. Other limitations were the small sample size of some drug sub-samples and the lack of testing for plasma olanzapine metabolites.
Vigabatrin, lamotrigine, topiramate and serum carnitine levels.
Pediatr Neurol. 2008 Jul; 39(1): 18-21
Zelnik N, Isler N, Goez H, Shiffer M, David M, Shahar E
Clinical studies indicate a decrease in free and total carnitine in children treated with old-generation antiepileptic drugs (especially valproate). Here, we studied the effect of new-generation antiepileptic drugs on serum carnitine levels. Serum carnitine levels were measured in 91 children: 24 treated with vigabatrin, 28 treated with lamotrigine, and 21 treated with topiramate. These drugs were given as monotherapy (54 children) or polytherapy (19 children). Eighteen additional children treated with valproate served as control subjects. Reduced mean serum carnitine level was evident only in children treated with valproate, with mean free and total carnitine level of 26.9 +/- 8.6 mumol/L and 29.1 +/- 10.4 mumol/L, respectively. In contrast, the mean serum carnitine levels of children treated with vigabatrin, lamotrigine, or topiramate were similar and normal. In these children, the free carnitine levels were 38.5 +/- 7.8 mumol/L, 37.2 +/- 7.7 mug/mL, and 40.4 +/- 8.7 mumol/L, respectively, and total carnitine levels were 43.5 +/- 8.8 mumol/L, 44.4 +/- 9.2 mumol/L, and 45.5 +/- 9.8 mumol/L (+/-S.D.), respectively. Only 4 children (treated with valproate) exhibited considerably lower serum carnitine levels. None of these children had significant clinical adverse effects attributable to carnitine deficiency. In conclusion, these new-generation antiepileptic drugs probably do not cause carnitine deficiency. In contrast, valproate may induce carnitine deficiency, but most cases are asymptomatic.
Decrease in tobacco consumption after treatment with topiramate and aripiprazole: a case report.
J Med Case Reports. 2008; 2: 198
Arbaizar B, Gómez-Acebo I, Llorca J
ABSTRACT: INTRODUCTION: A large part of research into drug addiction focuses on mesolimbic dopamine circuitry; however, both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and/or kainate and dopamine D2 receptors can play a role in maintaining the established addiction. CASE PRESENTATION: We report the case of a 34-year-old man who compulsively smoked 80 to 100 cigarettes each day. After receiving treatment with topiramate and aripiprazole, his tobacco consumption was dramatically reduced. CONCLUSION: Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and/or kainate blocking agents and a dopamine D2 receptor partial agonist may be novel instruments for nicotine abuse disorders.
Cogn Behav Neurol. 2008 Jun; 21(2): 104-6
Cruz M, Marinho V, Fontenelle LF, Engelhardt E, Laks J
Frontotemporal dementia (FTD) is an insidious presenile neurodegenerative disorder presenting with personality changes, compulsive behaviors, psychosis, apathetic, aberrant, and elated mood and behavior. No psychopharmacologic strategy has proven to be efficacious in the treatment of FTD yet. This is a case report of FTD in a 53-year-old male engineer whose alcohol abuse, but not other compulsive behaviors, responded to topiramate. Alcohol exerts reinforcing effects on cortico-mesolimbic dopamine pathways through the disinhibition of the inhibitory effects of gamma-amino-butyric acid-A neurons in the ventral tegmental area. Topiramate is a sulfamate-substituted fructopyranose derivative that may antagonize the reinforcing effects associated with the abuse liability of alcohol by modulation of cortico-mesolimbic dopamine function. On the basis of the mechanism of action of topiramate, we discuss the possible specificity of action of topiramate to control abusive drinking, but not to treat other clinical symptoms of FTD.
Arch Intern Med. 2008 Jun 9; 168(11): 1188-99
Johnson BA, Rosenthal N, Capece JA, Wiegand F, Mao L, Beyers K, McKay A, Ait-Daoud N, Addolorato G, Anton RF, Ciraulo DA, Kranzler HR, Mann K, O'Malley SS, Swift RM, ,
BACKGROUND: Topiramate can improve drinking outcomes via a hypothesized mechanism of facilitating gamma-aminobutyric acid function and inhibiting glutaminergic pathways in the corticomesolimbic system. We sought to determine whether topiramate's antidrinking effects are bolstered by improvements in physical and psychosocial well-being. METHODS: In a 17-site, 14-week, double-blind, randomized controlled trial, we compared the effects of topiramate (up to 300 mg/d) vs placebo on physical health, obsessional thoughts and compulsions about using alcohol, and psychosocial well-being among 371 alcohol-dependent subjects who received weekly adherence enhancement therapy. RESULTS: Topiramate was more efficacious than placebo in reducing body mass index (calculated as weight in kilograms divided by height in meters squared) (mean difference, 1.08; 95% confidence interval [CI], 0.81-1.34; P < .001), all liver enzyme levels (P < .01 for all comparisons), plasma cholesterol level (mean difference, 13.30 mg/dL; 95% CI, 5.09-21.44 mg/dL; P = .002), and systolic (mean difference, 9.70 mm Hg; 95% CI, 6.81-12.60 mm Hg; P < .001) and diastolic (mean difference, 6.74 mm Hg; 95% CI, 4.57-8.90 mm Hg; P < .001) blood pressure to about prehypertension levels-effects that might lower the risk of fatty liver degeneration and cirrhosis as well as cardiovascular disease. Topiramate compared with placebo significantly (P < .05 for all comparisons) decreased obsessional thoughts and compulsions about using alcohol, increased subjects' psychosocial well-being, and improved some aspects of quality of life, thereby diminishing the risk of relapse and longer-term negative outcomes. Paresthesia, taste perversion, anorexia, and difficulty with concentration were reported more frequently for topiramate than for placebo. CONCLUSION: Topiramate appears to be generally effective at improving the drinking outcomes and physical and psychosocial well-being of alcoholic subjects.
Common pathophysiologic mechanisms in migraine and epilepsy.
Arch Neurol. 2008 Jun; 65(6): 709-14
Rogawski MA
Migraine and epilepsy are comorbid episodic disorders that have common pathophysiologic mechanisms. Migraine attacks, like epileptic seizures, may be triggered by excessive neocortical cellular excitability; in migraine, however, the hyperexcitability is believed to transition to cortical spreading depression rather than to the hypersynchronous activity that characterizes seizures. Some forms of epilepsy and migraine are known to be channelopathies. Mutations in the same genes can cause either migraine or epilepsy or, in some cases, both. Given the likely commonalities in the underlying cellular and molecular mechanisms, it is not surprising that some antiepileptic drugs, including valproate, topiramate, and gabapentin, are effective antimigraine agents. Ionotropic glutamate receptors play roles in both migraine and epilepsy, with NMDA receptors that are critical to cortical spreading depression of particular importance in migraine. Greater understanding of the shared mechanisms of epilepsy and migraine can provide a basis for the development of improved treatment approaches that may be applicable to both conditions.
Topiramate-induced psychosis in two members of the one family: a case report.
J Med Case Reports. 2008; 2: 195
José RJ, Cairns A, Babbs C
ABSTRACT: INTRODUCTION: The use of topiramate has increased in recent years. It is now used by various specialties to treat a wide range of medical conditions. A small number of case reports describe psychosis as an adverse event of topiramate but most are in patients being treated for epilepsy and none describe a family history of this side effect. CASE PRESENTATION: We present a case report of topiramate-induced psychosis in a patient with familial essential tremor, whose sister also developed this same adverse effect. CONCLUSION: Physicians need to be aware of psychosis as a rare but debilitating side effect of this drug. Several predictors have been identified and a careful history, including family history, needs to be obtained prior to initiation of therapy to stratify the risk.