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Sample records for antiepileptic compound valproic

  1. Current Research on Antiepileptic Compounds.

    PubMed

    Wei, Cheng-Xi; Bian, Ming; Gong, Guo-Hua

    2015-11-20

    Epilepsy affects about 1% of the world's population. Due to the fact all antiepileptic drugs (AEDs) have some undesirable side effects and about 30% of epileptic patients are not seizure-free with the existing AEDs, there is still an urgent need for the development of more effective and safer AEDs. Based on our research work on antiepileptic compounds and other references in recent years, this review covers the reported work on antiepileptic compounds which are classified according to their structures. This review summarized 244 significant anticonvulsant compounds which are classified by functional groups according to the animal model data, although there are some limitations in the data. This review highlights the properties of new compounds endowed with promising antiepileptic properties, which may be proven to be more effective and selective, and possibly free of unwanted side effects. The reviewed compounds represent an interesting possibility to overcome refractory seizures and to reduce the percentage of patients with a poor response to drug therapy.

  2. Efficacy of antiepileptic tetramethylcyclopropyl analogues of valproic acid amides in a rat model of neuropathic pain.

    PubMed

    Winkler, Ilan; Sobol, Eyal; Yagen, Boris; Steinman, Amir; Devor, Marshall; Bialer, Meir

    2005-12-01

    Antiepileptic drugs (AEDs) are widely utilized in the management of neuropathic pain. The AED valproic acid (VPA) holds out particular promise as it engages a variety of different anticonvulsant mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but potentially life-threatening side effects: teratogenicity and hepatotoxicity. We have synthesized several tetramethylcyclopropyl analogues of VPA amides that are non-teratogenic, and are likely to be non-hepatotoxic, and that exhibit good antiepileptic efficacy. In the present study we have assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation (SNL) model of neuropathic pain. TMCA (2,2,3,3-tetramethylcyclopropanecarboxylic acid, 100-250 mg/kg), TMCD (2,2,3,3-tetramethylcyclopropanecarboxamide, 40-150 mg/kg), MTMCD (N-methyl-TMCD, 20-100 mg/kg), and TMCU (2,2,3,3-tetramethylcyclopropanecarbonylurea, 40-240 mg/kg) all showed dose-related reversal of tactile allodynia, with ED(50) values of 181, 85, 41, and 171 mg/kg i.p., respectively. All were more potent than VPA (ED(50)=269 mg/kg). An antiallodynic effect was obtained for TMCD, MTMCD and TMCU at plasma concentrations as low as 23, 6 and 22 mg/L, respectively. MTMCD was found to be non-toxic, non-sedative and equipotent to gabapentin, currently the leading AED in neuropathic pain treatment. Tetramethylcyclopropyl analogues of VPA amides have potential to become a new series of drugs for neuropathic pain treatment.

  3. Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain

    PubMed Central

    Winkler, Ilan; Blotnik, Simcha; Shimshoni, Jakob; Yagen, Boris; Devor, Marshall; Bialer, Meir

    2005-01-01

    Antiepileptic drugs (AEDs) are often utilized in the treatment of neuropathic pain. The major AED valproic acid (VPA) is of particular interest as it is thought to engage a variety of different neural mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but life-threatening side effects: teratogenicity and hepatotoxicity. We synthesized VPA's corresponding amide: valpromide (VPD), two of VPAs isomers and their corresponding amides; valnoctic acid (VCA), valnoctamide (VCD), diisopropyl acetic acid (DIA), diisopropylacetamide (DID), and VPD's congener: N-methyl-VPD (MVPD). VCD, DID and VPD are nonteratogenic, potentially nonhepatotoxic, and exhibit better anticonvuslant potency than VPA. In this study, we assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation model of neuropathic pain (SNL, Chung model). VCA and MVPD were inactive. However, VPD (20–100 mg kg− 1), VCD (20–100 mg kg− 1) and DID (20–90 mg kg− 1) produced dose-related reversal of tactile allodynia with ED50 values of 61, 52 and 58 mgkg− 1, respectively. All the amides were more potent than VPA (ED50=269 mgkg− 1). The antiallodynic effect of VPA, VPD, VCD and DID was obtained at plasma concentrations of 125, 24, 18 and 7 mg l− 1, respectively, with a good pharmacokinetic–pharmacodynamic correlation and a minimal lag response. VCD and DID were found to have minimal motor and sedative side effects at analgesic doses, and were equipotent to GBP, currently the leading drug in neuropathic pain treatment. Consequently, VCD and DID have potential to become new drugs for the treatment of neuropathic pain. PMID:15997234

  4. Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain.

    PubMed

    Winkler, Ilan; Blotnik, Simcha; Shimshoni, Jakob; Yagen, Boris; Devor, Marshall; Bialer, Meir

    2005-09-01

    Antiepileptic drugs (AEDs) are often utilized in the treatment of neuropathic pain. The major AED valproic acid (VPA) is of particular interest as it is thought to engage a variety of different neural mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but life-threatening side effects: teratogenicity and hepatotoxicity. We synthesized VPA's corresponding amide: valpromide (VPD), two of VPAs isomers and their corresponding amides; valnoctic acid (VCA), valnoctamide (VCD), diisopropyl acetic acid (DIA), diisopropylacetamide (DID), and VPD's congener: N-methyl-VPD (MVPD). VCD, DID and VPD are nonteratogenic, potentially nonhepatotoxic, and exhibit better anticonvuslant potency than VPA. In this study, we assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation model of neuropathic pain (SNL, Chung model). VCA and MVPD were inactive. However, VPD (20-100 mg kg(- 1)), VCD (20-100 mg kg(- 1)) and DID (20-90 mg kg(- 1)) produced dose-related reversal of tactile allodynia with ED50 values of 61, 52 and 58 mgkg(- 1), respectively. All the amides were more potent than VPA (ED50=269 mgkg(- 1)). The antiallodynic effect of VPA, VPD, VCD and DID was obtained at plasma concentrations of 125, 24, 18 and 7 mg l(- 1), respectively, with a good pharmacokinetic-pharmacodynamic correlation and a minimal lag response. VCD and DID were found to have minimal motor and sedative side effects at analgesic doses, and were equipotent to GBP, currently the leading drug in neuropathic pain treatment. Consequently, VCD and DID have potential to become new drugs for the treatment of neuropathic pain.

  5. Tetramethylcyclopropyl analogue of a leading antiepileptic drug, valproic acid. Synthesis and evaluation of anticonvulsant activity of its amide derivatives.

    PubMed

    Sobol, Eyal; Bialer, Meir; Yagen, Boris

    2004-08-12

    Although valproic acid (VPA) is an extensively used antiepileptic drug for treatment of various kinds of epilepsies, it has been proven to possess two life-threatening side effects: hepatotoxicity and teratogenicity. Amide and urea derivatives of 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA) were prepared to discover lead compounds with clinical potential. In the amide and alkylamide series of TMCA derivatives, N-methoxy-2,2,3,3-tetramethylcyclopropanecarboxamide (21) was one of the most active compounds, having the subcutaneous metrazol test (scMet) ED50 values of 35 mg/kg in rats and 74 mg/kg in mice. In the maximal electroshock-induced seizure test (MES), this compound had ED50 values of 108 mg/kg in rats and 115 mg/kg in mice. Compound 21 was 18.5 and 4.5 times more potent than VPA in the corresponding rat tests. The most active compound in the series of urea derivatives was 2,2,3,3-tetramethylcyclopropanecarbonylurea (25), possessing MES ED50 values of 29 mg/kg in rats and 90 mg/kg in mice. In the scMet test this compound had ED50 values of 92 mg/kg in rats and 125 mg/kg in mice. The median toxic dose (TD50) in rats was 538 mg/kg, providing compound 25 with a wide safety margin and a protective index (TD50/ED50) of 18.5 in the MES test, which is about 12 times greater than that of VPA. Compounds 21 and 25 have the potential for development as novel potent and safe central nervous system active drugs with a broad spectrum of antiepileptic activity. Copyright 2004 American Chemical Society

  6. The antiepileptic and anticancer agent, valproic acid, induces P-glycoprotein in human tumour cell lines and in rat liver

    PubMed Central

    Eyal, S; Lamb, J G; Smith-Yockman, M; Yagen, B; Fibach, E; Altschuler, Y; White, H S; Bialer, M

    2006-01-01

    Background and purpose: The antiepileptic drug valproic acid, a histone deacetylase (HDAC) inhibitor, is currently being tested as an anticancer agent. However, HDAC inhibitors may interact with anticancer drugs through induction of P-glycoprotein (P-gp, MDR1) expression. In this study we assessed whether valproic acid induces P-gp function in tumour cells. We also investigated effects of valproic acid on the mRNA for P-gp and the cytochrome P450, CYP3A, in rat livers. >Experimental approach: Effects of valproic acid on P-gp were assessed in three tumour cell lines, SW620, KG1a and H4IIE. Accumulation of acetylated histone H3 in rats' livers treated for two or seven days with valproic acid was evaluated using a specific antibody. Hepatic expression of the P-gp genes, mdr1a, mdr1b and mdr2, was determined by real-time polymerase chain reaction. The effects of valproic acid on CYP3A were assessed by Northern blot analysis and CYP3A activity assays. Key results: Valproic acid (0.5–2.0 mM) induced P-gp expression and function up to 4-fold in vitro. The effect of a series of valproic acid derivatives on P-gp expression in SW620 and KG1a cells correlated with their HDAC inhibition potencies. Treatment of rats with 1 mmol kg−1 valproic acid for two and seven days increased hepatic histone acetylation (1.3- and 3.5-fold, respectively) and the expression of mdr1a and mdr2 (2.2–4.1-fold). Valpromide (0.5–2.0 mM) did not increase histone acetylation or P-gp expression in rat livers, but induced CYP3A expression. Conclusions: Valproic acid increased P-gp expression and function in human tumour cell lines and in rat liver. The clinical significance of this increase merits further investigation. PMID:16894351

  7. A postulated role of garlic organosulfur compounds in prevention of valproic acid hepatotoxicity.

    PubMed

    Sabayan, Behnam; Foroughinia, Farzaneh; Chohedry, Abdolhamid

    2007-01-01

    Valproic acid (2-propyl-pentanoic acid, VPA) is well established as a first-line and widely used antiepileptic agent. VPA is well tolerated in most patients and has an impressive safety profile. VPA induced hepatotoxicity is rare, but often there is fatal complication of this drug and it is more frequent in children under 2 years of age and in those taking multiple drugs. Several findings showed that oxidative stress induced by reactive oxygen species (ROS) over production and/or compromised antioxidant capacity play an important role in the development of hepatotoxicity in VPA treated patients. Reduced glutathione (GSH) and its related enzymes are important cellular defense against oxidative stress in which VPA induced oxidative stress impairs their function in hepatocytes. Consequently any mechanism which removes ROS or prevents hepatic GSH depletion or induce activation and production of GSH dependent enzymes may provide protection for hepatotoxicity in VPA-treated patient. As garlic organosulfur compounds enhance cellular antioxidant activity by free radical scavenging and augmentation of endogenous antioxidants via prevention of GSH depletion and alteration of GSH dependent enzymes activity and/or their gene expression, we propose the hypothesis that garlic organosulfur compounds can prevent valproic acid hepatotoxicity.

  8. Modulation of Antioxidant Enzymatic Activities by Certain Antiepileptic Drugs (Valproic Acid, Oxcarbazepine, and Topiramate): Evidence in Humans and Experimental Models

    PubMed Central

    Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Rivera-Espinosa, Liliana; Romero-Toledo, Arantxa; Sampieri, Aristides III; Ortega-Cuellar, Daniel; Montesinos-Correa, Hortencia; Floriano-Sánchez, Esaú; Carmona-Aparicio, Liliana

    2013-01-01

    It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA) receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity). This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS) activation and the generation of reactive oxygen species (ROS). Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs) exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA), oxcarbazepine (OXC), and topiramate (TPM) modulate oxidative stress. PMID:24454986

  9. Modulation of antioxidant enzymatic activities by certain antiepileptic drugs (valproic acid, oxcarbazepine, and topiramate): evidence in humans and experimental models.

    PubMed

    Cárdenas-Rodríguez, Noemí; Coballase-Urrutia, Elvia; Rivera-Espinosa, Liliana; Romero-Toledo, Arantxa; Sampieri, Aristides; Ortega-Cuellar, Daniel; Montesinos-Correa, Hortencia; Floriano-Sánchez, Esaú; Carmona-Aparicio, Liliana

    2013-01-01

    It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA) receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity). This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS) activation and the generation of reactive oxygen species (ROS). Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs) exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA), oxcarbazepine (OXC), and topiramate (TPM) modulate oxidative stress.

  10. Preclinical evaluation of 2,2,3,3-tetramethylcyclopropanecarbonyl-urea, a novel, second generation to valproic acid, antiepileptic drug.

    PubMed

    Sobol, Eyal; Yagen, Boris; Steve White, H; Wilcox, Karen S; Lamb, John G; Pappo, Orit; Wlodarczyk, Bogdan J; Finnell, Richard H; Bialer, Meir

    2006-09-01

    2,2,3,3-Tetramethylcyclopropanecarbonylurea (TMCU) is an amide derivative of a tetramethylcyclopropyl analogue of valproic acid (VPA), one of the leading antiepileptic drugs. Structural considerations used in the design of TMCU aimed to enhance the anticonvulsant potency of VPA and to prevent its two life-threatening side effects; i.e., teratogenicity and hepatotoxicity. The anticonvulsant activity of TMCU was evaluated in the MES, scMet, 6-Hz, scBic and scPic tests, and also in the hippocampal kindling model of partial seizures and lamotrigine-resistant amygdala kindling model of therapy-resistant seizures. Minimal motor impairment was determined using the rotorod test in mice and the positional sense test, muscle tone test, and gait and stance test in rats. The antinociceptive effect of TMCU was evaluated in the mouse formalin model of acute-tonic pain. The molecular mechanisms of action of TMCU were investigated in electrophysiological studies using the whole-cell patch-clamp technique. Teratogenicity studies were performed in a SWV/Fnn-mouse model of VPA-induced teratogenicity. TMCU hepatotoxicity was evaluated following 1-week intraperitoneal and oral administration of 50, 250 and 500 mg/kg doses to rats. In the hepatotoxicity study the blood levels of TMCU were evaluated at day 1 and day 7 of the treatment. TMCU mutagenicity was evaluated in the Ames test.

  11. Valproic Acid: second generation.

    PubMed

    Bialer, Meir; Yagen, Boris

    2007-01-01

    The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become second-generation VPA drugs. Valproic acid is one of the four most widely prescribed antiepileptic drugs (AEDs) and is effective (and regularly approved) in migraine prophylaxis and in the treatment of bipolar disorders. Valproic acid is also currently undergoing clinical trials in cancer patients. Valproic acid is the least potent of the established AEDs and its use is limited by two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity. Because AEDs treat the symptoms (seizure) and not the cause of epilepsy, epileptic patients need to take AEDs for a long period of time. Consequently, there is a substantial need to develop better and safer AEDs. To become a successful second-generation VPA, the new drug should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than VPA, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with VPA including a low potential for drug interactions.

  12. Tetramethylcyclopropyl analogue of the leading antiepileptic drug, valproic acid: evaluation of the teratogenic effects of its amide derivatives in NMRI mice.

    PubMed

    Okada, Akinobu; Onishi, Yuko; Yagen, Boris; Shimshoni, Jakob Avi; Kaufmann, Dan; Bialer, Meir; Fujiwara, Michio

    2008-09-01

    Although valproic acid (VPA) is used extensively for treating various kinds of epilepsy, it causes hepatotoxicity and teratogenicity. In an attempt to develop a more potent and safer second generation to VPA drug, the amide derivatives of the tetramethylcyclopropyl VPA analogue, 2,2,3,3-tetramethylcyclopropanecarboxamide (TMCD), N-methyl-TMCD (MTMCD), 4-(2,2,3,3-tetramethylcyclopropanecarboxamide)-benzenesulfonamide (TMCD-benzenesulfonamide), and 5-(TMCD)-1,3,4-thiadiazole-2-sulfonamide (TMCD-thiadiazolesulfonamide) were synthesized and shown to have more potent anticonvulsant activity than VPA. Teratogenic effects of these CNS-active compounds were evaluated in Naval Medical Research Institute (NMRI) mice susceptible to VPA-induced teratogenicity by comparing them to those of VPA. Pregnant NMRI mice were given a single sc injection of either VPA or TMC-amide derivatives on gestation day 8.5, and then the live fetuses were examined to detect any external malformations on gestation day 18. After double-staining for bone and cartilage, their skeletons were examined. In contrast to VPA, which induced NTDs in a high number of fetuses at 2.4-4.8 mmol/kg, TMCD, TMCD-benzenesulfonamide, and TMCD-thiadiazolesulfonamide at 4.8 mmol/kg and MTMCD at 3.6 mmol/kg did not induce a significant number of NTDs. TMCD-thiadiazolesulfonamide exhibited a potential to induce limb defects in fetuses. Skeletal examination also revealed that fetuses exposed to all four of the tetramethylcyclopropanecarboxamide derivatives developed vertebral and rib abnormalities less frequently than those exposed to VPA. Our results established that TMCD, MTMCD, and TMCD-benzenesulfonamide are distinctly less teratogenic than VPA in NMRI mice. The CNS-active amides containing a tetramethylcyclopropanecarbonyl moiety demonstrated better anticonvulsant potency compared to VPA and a lack of teratogenicity, which makes these compounds good second-generation VPA antiepileptic drug candidates. (c) 2008 Wiley

  13. Valproic Acid Induces Antimicrobial Compound Production in Doratomyces microspores

    PubMed Central

    Zutz, Christoph; Bacher, Markus; Parich, Alexandra; Kluger, Bernhard; Gacek-Matthews, Agnieszka; Schuhmacher, Rainer; Wagner, Martin; Rychli, Kathrin; Strauss, Joseph

    2016-01-01

    One of the biggest challenges in public health is the rising number of antibiotic resistant pathogens and the lack of novel antibiotics. In recent years there is a rising focus on fungi as sources of antimicrobial compounds due to their ability to produce a large variety of bioactive compounds and the observation that virtually every fungus may still contain yet unknown so called “cryptic,” often silenced, compounds. These putative metabolites could include novel bioactive compounds. Considerable effort is spent on methods to induce production of these “cryptic” metabolites. One approach is the use of small molecule effectors, potentially influencing chromatin landscape in fungi. We observed that the supernatant of the fungus Doratomyces (D.) microsporus treated with valproic acid (VPA) displayed antimicrobial activity against Staphylococcus (S.) aureus and two methicillin resistant clinical S. aureus isolates. VPA treatment resulted in enhanced production of seven antimicrobial compounds: cyclo-(L-proline-L-methionine) (cPM), p-hydroxybenzaldehyde, cyclo-(phenylalanine-proline) (cFP), indole-3-carboxylic acid, phenylacetic acid (PAA) and indole-3-acetic acid. The production of the antimicrobial compound phenyllactic acid was exclusively detectable after VPA treatment. Furthermore three compounds, cPM, cFP, and PAA, were able to boost the antimicrobial activity of other antimicrobial compounds. cPM, for the first time isolated from fungi, and to a lesser extent PAA, are even able to decrease the minimal inhibitory concentration of ampicillin in MRSA strains. In conclusion we could show in this study that VPA treatment is a potent tool for induction of “cryptic” antimicrobial compound production in fungi, and that the induced compounds are not exclusively linked to the secondary metabolism. Furthermore this is the first discovery of the rare diketopiperazine cPM in fungi. Additionally we could demonstrate that cPM and PAA boost antibiotic activity

  14. The effects of antiepileptic drugs on the growth of glioblastoma cell lines.

    PubMed

    Lee, Ching-Yi; Lai, Hung-Yi; Chiu, Angela; Chan, She-Hung; Hsiao, Ling-Ping; Lee, Shih-Tseng

    2016-05-01

    To determine the effects of antiepileptic drug compounds on glioblastoma cellular growth, we exposed glioblastoma cell lines to select antiepileptic drugs. The effects of selected antiepileptic drugs on glioblastoma cells were measured by MTT assay. For compounds showing significant inhibition, cell cycle analysis was performed. Statistical analysis was performed using SPSS. The antiepileptic compounds selected for screening included carbamazepine, ethosuximide, gabapentin, lamotrigine, levetiracetam, magnesium sulfate, oxcarbazepine, phenytoin, primidone, tiagabine, topiramate, valproic acid, and vigabatrin. Dexamethasone and temozolomide were used as a negative and positive control respectively. Our results showed temozolomide and oxcarbazepine significantly inhibited glioblastoma cell growth and reached IC50 at therapeutic concentrations. The other antiepileptic drugs screened were unable to reach IC50 at therapeutic concentrations. The metabolites of oxcarbazepine were also unable to reach IC50. Dexamethasone, ethosuximide, levetiracetam, and vigabatrin showed some growth enhancement though they did not reach statistical significance. The growth enhancement effects of ethosuximide, levetiracetam, and vigabatrin found in the study may indicate that these compounds should not be used for prophylaxis or short term treatment of epilepsy in glioblastoma. While valproic acid and oxcarbazepine were effective, the required dose of valproic acid was far above that used for the treatment of epilepsy and the metabolites of oxcarbazepine failed to reach significant growth inhibition ruling out the use of oral oxcarbazepine or valproic acid as monotherapy in glioblastoma. The possibility of using these compounds as local treatment is a future area of study.

  15. Conserved valproic-acid-induced lipid droplet formation in Dictyostelium and human hepatocytes identifies structurally active compounds.

    PubMed

    Elphick, Lucy M; Pawolleck, Nadine; Guschina, Irina A; Chaieb, Leila; Eikel, Daniel; Nau, Heinz; Harwood, John L; Plant, Nick J; Williams, Robin S B

    2012-03-01

    Lipid droplet formation and subsequent steatosis (the abnormal retention of lipids within a cell) has been reported to contribute to hepatotoxicity and is an adverse effect of many pharmacological agents including the antiepileptic drug valproic acid (VPA). In this study, we have developed a simple model system (Dictyostelium discoideum) to investigate the effects of VPA and related compounds in lipid droplet formation. In mammalian hepatocytes, VPA increases lipid droplet accumulation over a 24-hour period, giving rise to liver cell damage, and we show a similar effect in Dictyostelium following 30 minutes of VPA treatment. Using (3)H-labelled polyunsaturated (arachidonic) or saturated (palmitic) fatty acids, we shown that VPA treatment of Dictyostelium gives rise to an increased accumulation of both types of fatty acids in phosphatidylcholine, phosphatidylethanolamine and non-polar lipids in this time period, with a similar trend observed in human hepatocytes (Huh7 cells) labelled with [(3)H]arachidonic acid. In addition, pharmacological inhibition of β-oxidation in Dictyostelium phenocopies fatty acid accumulation, in agreement with data reported in mammalian systems. Using Dictyostelium, we then screened a range of VPA-related compounds to identify those with high and low lipid-accumulation potential, and validated these activities for effects on lipid droplet formation by using human hepatocytes. Structure-activity relationships for these VPA-related compounds suggest that lipid accumulation is independent of VPA-catalysed teratogenicity and inositol depletion. These results suggest that Dictyostelium could provide both a novel model system for the analysis of lipid droplet formation in human hepatocytes and a rapid method for identifying VPA-related compounds that show liver toxicology.

  16. Conserved valproic-acid-induced lipid droplet formation in Dictyostelium and human hepatocytes identifies structurally active compounds

    PubMed Central

    Elphick, Lucy M.; Pawolleck, Nadine; Guschina, Irina A.; Chaieb, Leila; Eikel, Daniel; Nau, Heinz; Harwood, John L.; Plant, Nick J.; Williams, Robin S. B.

    2012-01-01

    SUMMARY Lipid droplet formation and subsequent steatosis (the abnormal retention of lipids within a cell) has been reported to contribute to hepatotoxicity and is an adverse effect of many pharmacological agents including the antiepileptic drug valproic acid (VPA). In this study, we have developed a simple model system (Dictyostelium discoideum) to investigate the effects of VPA and related compounds in lipid droplet formation. In mammalian hepatocytes, VPA increases lipid droplet accumulation over a 24-hour period, giving rise to liver cell damage, and we show a similar effect in Dictyostelium following 30 minutes of VPA treatment. Using 3H-labelled polyunsaturated (arachidonic) or saturated (palmitic) fatty acids, we shown that VPA treatment of Dictyostelium gives rise to an increased accumulation of both types of fatty acids in phosphatidylcholine, phosphatidylethanolamine and non-polar lipids in this time period, with a similar trend observed in human hepatocytes (Huh7 cells) labelled with [3H]arachidonic acid. In addition, pharmacological inhibition of β-oxidation in Dictyostelium phenocopies fatty acid accumulation, in agreement with data reported in mammalian systems. Using Dictyostelium, we then screened a range of VPA-related compounds to identify those with high and low lipid-accumulation potential, and validated these activities for effects on lipid droplet formation by using human hepatocytes. Structure-activity relationships for these VPA-related compounds suggest that lipid accumulation is independent of VPA-catalysed teratogenicity and inositol depletion. These results suggest that Dictyostelium could provide both a novel model system for the analysis of lipid droplet formation in human hepatocytes and a rapid method for identifying VPA-related compounds that show liver toxicology. PMID:22003123

  17. A pharmacodynamic evaluation of midazolam as an antiepileptic compound.

    PubMed Central

    Jawad, S; Oxley, J; Wilson, J; Richens, A

    1986-01-01

    Midazolam is a water soluble 1,4 benzodiazepine which is suitable for intramuscular administration. It is currently used for pre-medication and the induction of anaesthesia. Its antiepileptic properties have been evaluated by studying its effect on interictal spikes on the EEG of six adult epileptic patients. The results indicate that intramuscular midazolam 15 mg is more effective than intramuscular diazepam 10 mg in abolishing interictal spikes and as effective as intravenous diazepam 20 mg five minutes after administration. PMID:3760894

  18. Identifying an uptake mechanism for the antiepileptic and bipolar disorder treatment valproic acid using the simple biomedical model Dictyostelium

    PubMed Central

    Terbach, Nicole; Shah, Rishita; Kelemen, Rachel; Klein, Peter S.; Gordienko, Dmitri; Brown, Nigel A.; Wilkinson, Christopher J.; Williams, Robin S. B.

    2011-01-01

    Valproic acid (VPA) is the most highly prescribed epilepsy treatment worldwide and is also used to prevent bipolar disorder and migraine. Surprisingly, very little is known about its mechanisms of cellular uptake. Here, we employ a range of cellular, molecular and genetic approaches to characterize VPA uptake using a simple biomedical model, Dictyostelium discoideum. We show that VPA is taken up against an electrochemical gradient in a dose-dependent manner. Transport is protein-mediated, dependent on pH and the proton gradient and shows strong substrate structure specificity. Using a genetic screen, we identified a protein homologous to a mammalian solute carrier family 4 (SLC4) bicarbonate transporter that we show is involved in VPA uptake. Pharmacological and genetic ablation of this protein reduces the uptake of VPA and partially protects against VPA-dependent developmental effects, and extracellular bicarbonate competes for VPA uptake in Dictyostelium. We further show that this uptake mechanism is likely to be conserved in both zebrafish (Danio rerio) and Xenopus laevis model systems. These results implicate, for the first time, an uptake mechanism for VPA through SLC4-catalysed activity. PMID:21652627

  19. Concentrations of carbamazepine and carbamazepine-10,11-epoxide in maternal and umbilical cord blood at birth: Influence of co-administration of valproic acid or enzyme-inducing antiepileptic drugs.

    PubMed

    Kacirova, Ivana; Grundmann, Milan; Brozmanova, Hana

    2016-05-01

    Carbamazepine is one of the three most frequently prescribed antiepileptic drugs in pregnancy. However, data relating to both carbamazepine and carbamazepine-10,11-epoxide transplacental passage remain sparse. We have analysed in a cohort of 114 women carbamazepine and carbamazepine-10,11-epoxide levels in maternal and umbilical cord serum at birth during 25 years retrospectively. The carbamazepine maternal apparent oral clearance, ratio of the umbilical cord/maternal level and ratio of the carbamazepine-10,11-epoxide/carbamazepine ratio were estimated. The influence of co-medication with valproic acid or enzyme-inducing antiepileptic drugs was evaluated. The maternal carbamazepine levels varied from 0.6 to 11.8mg/L (carbamazepine-10,11-epoxide 0.1-2.5mg/L) and in umbilical cord between 0.1 and 10.5mg/L (carbamazepine-10,11-epoxide 0.1-2.2mg/L). The ratio the of umbilical cord/maternal level of carbamazepine ranged from 0.03 to 2.23 (median 0.80) and of carbamazepine-10,11-epoxide between 0.17 and 2.00 (median 0.83). Concomitant administration with enzyme inducers significantly increased the maternal apparent oral clearance by approximately 50% and co-administration with valproic acid approximately by 70%. Combination with valproic acid significantly increased the rate of carbamazepine-10,11-epoxide to the parent drug both in maternal serum (by approximately 80%) and in umbilical cord (by 100%). The data showed the wide interindividual variability of the ratio of the umbilical cord/maternal level of both carbamazepine and carbamazepine-10,11-epoxide. It is the first study showing the significant increase of the ratio of umbilical cord/maternal level of carbamazepine-10,11-epoxide and carbamazepine-10,11-epoxide/carbamazepine ratio not only in maternal serum but also in umbilical cord in addition of valproic acid. The present study demonstrates that a concomitant administration of enzyme-inducing antiepileptics and valproic acid increases the maternal apparent oral

  20. Lacosamide-induced valproic acid toxicity.

    PubMed

    Jones, Gina L; Popli, Gautam S; Silvia, Mary T

    2013-04-01

    Valproic acid is commonly used in the treatment of both focal and generalized epilepsies and is often well tolerated. There are many reported cases of hyperammonemic encephalopathy and other well-known side effects reported during use of valproic acid either alone or in combination with other antiepileptics. This case report demonstrates valproic acid toxicity in the presence of lacosamide, which has not previously been reported. Full recovery occurred after withdrawal of both valproic acid and lacosamide.

  1. The antiepileptic drug valproic acid and other medium-chain fatty acids acutely reduce phosphoinositide levels independently of inositol in Dictyostelium.

    PubMed

    Chang, Pishan; Orabi, Benoit; Deranieh, Rania M; Dham, Manik; Hoeller, Oliver; Shimshoni, Jakob A; Yagen, Boris; Bialer, Meir; Greenberg, Miriam L; Walker, Matthew C; Williams, Robin S B

    2012-01-01

    Valproic acid (VPA) is the most widely prescribed epilepsy treatment worldwide, but its mechanism of action remains unclear. Our previous work identified a previously unknown effect of VPA in reducing phosphoinositide production in the simple model Dictyostelium followed by the transfer of data to a mammalian synaptic release model. In our current study, we show that the reduction in phosphoinositide [PtdInsP (also known as PIP) and PtdInsP(2) (also known as PIP(2))] production caused by VPA is acute and dose dependent, and that this effect occurs independently of phosphatidylinositol 3-kinase (PI3K) activity, inositol recycling and inositol synthesis. In characterising the structural requirements for this effect, we also identify a family of medium-chain fatty acids that show increased efficacy compared with VPA. Within the group of active compounds is a little-studied group previously associated with seizure control, and analysis of two of these compounds (nonanoic acid and 4-methyloctanoic acid) shows around a threefold enhanced potency compared with VPA for protection in an in vitro acute rat seizure model. Together, our data show that VPA and a newly identified group of medium-chain fatty acids reduce phosphoinositide levels independently of inositol regulation, and suggest the reinvestigation of these compounds as treatments for epilepsy.

  2. Antiepileptic Drugs and Pregnancy Outcomes

    PubMed Central

    Wlodarczyk, Bogdan J.; Palacios, Ana M.; George, Timothy M.; Finnell, Richard H.

    2012-01-01

    The treatment of epilepsy in women of reproductive age remains a clinical challenge. While most women with epilepsy require anticonvulsant drugs for adequate control of their seizures, the teratogenicity associated with some antiepileptic drugs is a risk that needs to be carefully addressed. Antiepileptic medications are also used to treat an ever broadening range of medical conditions such as bipolar disorder, migraine prophylaxis, cancer and neuropathic pain. Despite the fact that the majority of pregnancies of women with epilepsy who are receiving pharmacological treatment are normal, studies have demonstrated that the risk of having a pregnancy complicated by a major congenital malformation is doubled when comparing the risk of untreated pregnancies. Furthermore, when antiepileptic drugs (AEDs) are used in polytherapy regimens, the risk is tripled, especially when valproic acid (VPA) is included. However, it should be noted that the risks are specific for each anticonvulsant drug. Some investigations have suggested that the risk of teratogenicity is increased in a dose-dependent manner. More recent studies have reported that in utero exposure to AEDs can have detrimental effects on the cognitive functions and language skills in later stages of life. In fact, the FDA just issued a safety announcement on the impact of VPA on cognition (Safety Announcement 6-30-2011). The purpose of this document is to review the most commonly used compounds in the treatment of women with epilepsy, and to provide information on the latest experimental and human epidemiological studies of the effects of antiepileptic drugs in the exposed embryos. PMID:22711424

  3. In silico inhibition of GABARAP activity using antiepileptic medicinal derived compounds

    PubMed Central

    Mathew, Shilu; Faheem, Muhammad; Al-Malki, Abdulrahman L; Kumosani, Taha A; Qadri, Ishtiaq

    2015-01-01

    Epilepsy is a neurological disorder affecting more than 50 million people worldwide. It can be controlled by antiepileptic drugs (AEDs) but more than 30% patients are still resistant to AEDs. To overcome this problem, researchers are trying to develop novel approaches to treat epilepsy including the use of herbal medicines. The γ-amino butyric acid type-A receptor associated protein (GABARAP) is ubiquitin-like modifier implicated in the intracellular trafficking of GABAAR. An in silico mutation was created at 116 amino acid position G116A, and an in silico study was carried out to identify the potential binding inhibitors (with antiepileptic properties) against the active sites of GABARAP. Five different plant derived compounds namely (a) Aconitine (b) Berberine (c) Montanine (d) Raubasine (e) Safranal were selected, and their quantitative structure-activity relationships (QSAR) have been conducted to search the inhibitory activity of the selected compounds. The results have shown maximum number of hydrogen bond (H-bond) interactions of Raubasine with highest interaction energy among all of the five compounds. So, Raubasine could be the best fit ligand of GABARAP but in vitro, and in vivo studies are necessary for further confirmation. PMID:26124559

  4. Adverse drug reactions induced by valproic acid.

    PubMed

    Nanau, Radu M; Neuman, Manuela G

    2013-10-01

    Valproic acid is a widely-used first-generation antiepileptic drug, prescribed predominantly in epilepsy and psychiatric disorders. VPA has good efficacy and pharmacoeconomic profiles, as well as a relatively favorable safety profile. However, adverse drug reactions have been reported in relation with valproic acid use, either as monotherapy or polytherapy with other antiepileptic drugs or antipsychotic drugs. This systematic review discusses valproic acid adverse drug reactions, in terms of hepatotoxicity, mitochondrial toxicity, hyperammonemic encephalopathy, hypersensitivity syndrome reactions, neurological toxicity, metabolic and endocrine adverse events, and teratogenicity. Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  5. Valproic Acid

    MedlinePlus

    Valproic acid is used alone or with other medications to treat certain types of seizures. Valproic acid is also used to treat mania (episodes of ... to relieve headaches that have already begun. Valproic acid is in a class of medications called anticonvulsants. ...

  6. Valproic acid, compared to other antiepileptic drugs, is associated with improved overall and progression-free survival in glioblastoma but worse outcome in grade II/III gliomas treated with temozolomide.

    PubMed

    Redjal, Navid; Reinshagen, Clemens; Le, Andrew; Walcott, Brian P; McDonnell, Erin; Dietrich, Jorg; Nahed, Brian V

    2016-05-01

    Valproic acid (VPA) is an anti-epileptic drug with properties of a histone deacetylase inhibitor (HDACi). HDACi play a key role in epigenetic regulation of gene expression and have been increasingly used as anticancer agents. Recent studies suggest that VPA is associated with improved survival in high-grade gliomas. However, effects on lower grade gliomas have not been examined. This study investigates whether use of VPA correlates with tumor grade, histological progression, progression-free and overall survival (OS) in grade II, III, and IV glioma patients. Data from 359 glioma patients (WHO II-IV) treated with temozolomide plus an antiepileptic drug (VPA or another antiepileptic drug) between January 1997 and June 2013 at the Massachusetts General Hospital was analyzed retrospectively. After confounder adjustment, VPA was associated with a 28 % decrease in hazard of death (p = 0.031) and a 28 % decrease in the hazard of progression or death (p = 0.015) in glioblastoma. Additionally, VPA dose correlated with reduced hazard of death by 7 % (p = 0.002) and reduced hazard of progression or death by 5 % (p < 0.001) with each 100 g increase in total dose. Conversely, in grade II and III gliomas VPA was associated with a 118 % increased risk of tumor progression or death (p = 0.014), and every additional 100 g of VPA raised the hazard of progression or death by 4 %, although not statistically significant (p = 0.064). Moreover, grade II and III glioma patients taking VPA had 2.17 times the risk of histological progression (p = 0.020), although this effect was no longer significant after confounder adjustment. In conclusion, VPA was associated with improved survival in glioblastoma in a dose-dependent manner. However, in grade II and III gliomas, VPA was linked to histological progression and decrease in progression-free survival. Prospective evaluation of VPA treatment for glioma patients is warranted to confirm these findings.

  7. Epidemiological study of epilepsy by monitoring prescriptions of antiepileptic drugs.

    PubMed

    Banfi, R; Borselli, G; Marinai, C; Borgheresi, A; Cavalieri, A

    1995-07-28

    The aim of this study is to evaluate a simple and effective method of acquiring epidemiological information about epilepsy. Data on antiepileptic drug prescriptions was collected, the utilization pattern being based on defined daily doses (DDDs). Antiepileptic drugs are epidemiological tracers of epilepsy due to their chronic and highly specific usage. Consequently, a prevalence rate for the whole population may be obtained by using DDDs. Data on antiepileptic drug prescriptions for a period of 6 months in 1992 and 6 months in 1993 indicate a utilization of approximately 7 DDDs of antiepileptic drugs per 1,000 inhabitants. The prevalence of epilepsy was estimated by correcting the exposure calculated in DDDs by a factor of 0.68. In our sample, the prevalence of the disease was 5.2 per 1,000 inhabitants in 1992 and 4.9 per 1,000 in 1993. Physician prescriptions were concentrated on four compounds, namely phenobarbital, carbamazepine, valproic acid and phenytoin, which together represented 90% of total antiepileptic drug prescriptions.

  8. Model steatogenic compounds (amiodarone, valproic acid, and tetracycline) alter lipid metabolism by different mechanisms in mouse liver slices.

    PubMed

    Szalowska, Ewa; van der Burg, Bart; Man, Hai-Yen; Hendriksen, Peter J M; Peijnenburg, Ad A C M

    2014-01-01

    Although drug induced steatosis represents a mild type of hepatotoxicity it can progress into more severe non-alcoholic steatohepatitis. Current models used for safety assessment in drug development and chemical risk assessment do not accurately predict steatosis in humans. Therefore, new models need to be developed to screen compounds for steatogenic properties. We have studied the usefulness of mouse precision-cut liver slices (PCLS) as an alternative to animal testing to gain more insight into the mechanisms involved in the steatogenesis. To this end, PCLS were incubated 24 h with the model steatogenic compounds: amiodarone (AMI), valproic acid (VA), and tetracycline (TET). Transcriptome analysis using DNA microarrays was used to identify genes and processes affected by these compounds. AMI and VA upregulated lipid metabolism, whereas processes associated with extracellular matrix remodelling and inflammation were downregulated. TET downregulated mitochondrial functions, lipid metabolism, and fibrosis. Furthermore, on the basis of the transcriptomics data it was hypothesized that all three compounds affect peroxisome proliferator activated-receptor (PPAR) signaling. Application of PPAR reporter assays classified AMI and VA as PPARγ and triple PPARα/(β/δ)/γ agonist, respectively, whereas TET had no effect on any of the PPARs. Some of the differentially expressed genes were considered as potential candidate biomarkers to identify PPAR agonists (i.e. AMI and VA) or compounds impairing mitochondrial functions (i.e. TET). Finally, comparison of our findings with publicly available transcriptomics data showed that a number of processes altered in the mouse PCLS was also affected in mouse livers and human primary hepatocytes exposed to known PPAR agonists. Thus mouse PCLS are a valuable model to identify early mechanisms of action of compounds altering lipid metabolism.

  9. Model Steatogenic Compounds (Amiodarone, Valproic Acid, and Tetracycline) Alter Lipid Metabolism by Different Mechanisms in Mouse Liver Slices

    PubMed Central

    Szalowska, Ewa; van der Burg, Bart; Man, Hai-Yen; Hendriksen, Peter J. M.; Peijnenburg, Ad A. C. M.

    2014-01-01

    Although drug induced steatosis represents a mild type of hepatotoxicity it can progress into more severe non-alcoholic steatohepatitis. Current models used for safety assessment in drug development and chemical risk assessment do not accurately predict steatosis in humans. Therefore, new models need to be developed to screen compounds for steatogenic properties. We have studied the usefulness of mouse precision-cut liver slices (PCLS) as an alternative to animal testing to gain more insight into the mechanisms involved in the steatogenesis. To this end, PCLS were incubated 24 h with the model steatogenic compounds: amiodarone (AMI), valproic acid (VA), and tetracycline (TET). Transcriptome analysis using DNA microarrays was used to identify genes and processes affected by these compounds. AMI and VA upregulated lipid metabolism, whereas processes associated with extracellular matrix remodelling and inflammation were downregulated. TET downregulated mitochondrial functions, lipid metabolism, and fibrosis. Furthermore, on the basis of the transcriptomics data it was hypothesized that all three compounds affect peroxisome proliferator activated-receptor (PPAR) signaling. Application of PPAR reporter assays classified AMI and VA as PPARγ and triple PPARα/(β/δ)/γ agonist, respectively, whereas TET had no effect on any of the PPARs. Some of the differentially expressed genes were considered as potential candidate biomarkers to identify PPAR agonists (i.e. AMI and VA) or compounds impairing mitochondrial functions (i.e. TET). Finally, comparison of our findings with publicly available transcriptomics data showed that a number of processes altered in the mouse PCLS was also affected in mouse livers and human primary hepatocytes exposed to known PPAR agonists. Thus mouse PCLS are a valuable model to identify early mechanisms of action of compounds altering lipid metabolism. PMID:24489787

  10. Teratogenicity of Antiepileptic Drugs

    PubMed Central

    Güveli, Betül Tekin; Rosti, Rasim Özgür; Güzeltaş, Alper; Tuna, Elif Bahar; Ataklı, Dilek; Sencer, Serra; Yekeler, Ensar; Kayserili, Hülya; Dirican, Ahmet; Bebek, Nerses; Baykan, Betül; Gökyiğit, Ayşen; Gürses, Candan

    2017-01-01

    Objective Antiepileptic drugs (AED) have chronic teratogenic effects, the most common of which are congenital heart disease, cleft lip/palate, urogenital and neural tube defects. The aim of our study is to examine teratogenic effects of AED and the correlation between these malformations and AED in single or multiple pregnancies. Methods This is a retrospective study of malformations in children born to mothers currently followed up by our outpatient clinics who used or discontinued AED during their pregnancy. Their children were then investigated using echocardiography, urinary ultrasound, cranial magnetic resonance image, and examined by geneticists and pediatric dentists. Results One hundred and seventeen children were included in the study. Ninety one of these children were exposed to AED during pregnancy. The most commonly used AED were valproic acid and carbamazepine in monotherapy. The percentage of major anomaly was 6.8% in all children. Dysmorphic features and dental anomalies were observed more in children exposed especially to valproic acid. There were 26 mothers with two and four mothers with three pregnancies from the same fathers. No correlation was found between the distribution of malformations in recurring pregnancies and AED usage. Conclusion Our study has the highest number of dysmorphism examined in literature, found in all the children exposed to valproic acid, which may account for the higher rate of facial dysmorphism and dental anomalies. On lower doses of valproic acid, major malformations are not seen, although the risk increases with polytherapy. Our data also indicate possible effects of genetic and environmental factors on malformations. PMID:28138106

  11. Evidence for a potential protective effect of carnitine-pantothenic acid co-treatment on valproic acid-induced hepatotoxicity.

    PubMed

    Felker, Dana; Lynn, Alexandra; Wang, Sue; Johnson, Dale E

    2014-03-01

    Valproic acid is approved for treatment of seizures and manic episodes of bipolar disorder, and continues to be one of the most commonly prescribed antiepileptic drugs in the world. Hepatotoxicity is a rare but serious side effect resulting from its use, particularly in young patients. This adverse effect does not display normal dose-response curves and can be lethal in children. A review of the purported mechanisms of action suggest hepatotoxicity results from increased oxidative stress, caused by a reduction in beta-oxidation and an increase in activation of certain metabolizing enzymes. There is also evidence that both carnitine and pantothenic acid are involved in the regulation of valproic acid-induced hepatotoxic processes, and clinical evidence has shown that treatment with either compound shows protective effects against hepatotoxicity. These results suggest a potential increase in protective effects with cotreatment of carnitine and pantothenic acid.

  12. Valproic acid toxicity: overview and management.

    PubMed

    Sztajnkrycer, Matthew D

    2002-01-01

    Acute valproic acid intoxication is an increasing problem, accounting for more than 5000 calls to the American Association of Poison Control Centers in 2000. The purpose of this paper is to review the pharmacology and toxicology of valproic acid toxicity. Unlike earlier antiepileptic agents, valproic acid appears to function neither through sodium channel inhibition nor through direct gamma-aminobutyric acid agonism, but through an indirect increase in regional brain gamma-aminobutyric acid levels. Manifestations of acute valproic acid toxicity are myriad, and reflect both exaggerated therapeutic effect and impaired intermediary metabolism. Central nervous system depression is the most common finding noted in overdose, and may progress to coma and respiratory depression. Cerebral edema has also been observed. Although hepatotoxicity is rare in the acute overdose setting, pancreatitis and hyperammonemia have been reported. Metabolic and hematologic derangements have also been described. Management of acute valproic acid ingestion requires supportive care and close attention to the airway. The use of controversial adjunctive therapies, including extracorporeal drug elimination and L-carnitine supplementation, will be discussed.

  13. Valproic Acid and Pregnancy

    MedlinePlus

    ... live chat Live Help Fact Sheets Share Valproic Acid and Pregnancy Wednesday, 01 July 2015 In every ... This sheet talks about whether exposure to valproic acid may increase the risk for birth defects over ...

  14. Serum biotinidase activity in children treated with valproic acid and carbamazepine.

    PubMed

    Castro-Gago, Manuel; Gómez-Lado, Carmen; Eirís-Puñal, Jesús; Díaz-Mayo, Isabel; Castiñeiras-Ramos, Daisy E

    2010-01-01

    There is evidence that valproic acid causes a reduction of serum biotinidase enzyme activity. We determined the serum concentration of antiepileptic drugs, transaminases, gamma-glutamyl transferase, ammonia, and biotinidase enzyme activity in 57 children treated with valproic acid, in 17 children treated with carbamazepine, and in 75 age- and sex-matched healthy controls. There were no significant differences in the serum biotinidase enzyme activity between the patients treated with valproic acid, the patients treated with carbamazepine, and the control group. Hyperammonemia was detected in 8 patients treated with valproic acid. Hair loss was observed in 3 female patients treated with valproic acid, and the alopecia disappeared with the oral administration of biotin (10 mg/ d) in 3 months. These results suggest that the treatment with valproic acid does not alter the serum biotinidase enzyme activity.

  15. Irinotecan chemotherapy during valproic acid treatment: pharmacokinetic interaction and hepatotoxicity.

    PubMed

    de Jong, Floris A; van der Bol, Jessica M; Mathijssen, Ron H J; Loos, Walter J; Mathôt, Ron A A; Kitzen, Jos J E M; van den Bent, Martin J; Verweij, Jaap

    2007-09-01

    Because of its supposed inhibiting capacities of uridine-diphosphate glucuronosyltransferase 1A (UGT1A)-mediated glucuronidation in rats, the antiepileptic drug valproic acid has been investigated as modulator of irinotecan-induced delayed-type diarrhea in rats. Here, we report on the pharmacokinetic and pharmacodynamic effects of this combination in a cancer patient. A patient who used valproic acid was administered irinotecan (600 mg). To investigate dose-limiting hepatotoxicity encountered during the first course, which was clinically attributed to a supposed higher exposure to the active irinotecan metabolite SN-38, valproic acid was tapered off. Blood samples for pharmacokinetic purposes were drawn during a course with and a course without concomitant valproic acid. Plasma-levels of irinotecan, SN-38, and SN-38G were determined using HPLC-assays. When irinotecan was combined with valproic acid, the exposure to SN-38 was 41% lower. Additionally, reversible elevations of the liver enzyme tests were noted. In particular, seven days after irinotecan administration gammaGT and transaminase levels raised up to 5.3-11.3 times the ULN (CTCAE grade 3). Valproic acid-induced plasma protein binding displacement and/or metabolic modulation of enzymes and drug transporters involved in irinotecan disposition may explain the reduced exposure to SN-38 in the presence of valproic acid. Given the herewith-coupled potential undertreatment, patients should firstly switch to another antiepileptic drug not known to interfere with irinotecan treatment. Additionally, this particular combination should not be implemented in clinical studies without simultaneously adjusting the irinotecan dose, and the risk of (severe) hepatotoxicity should be considered when designing protocols studying valproic acid (as histone deacetylase-inhibitor) in combination with other (anticancer) drugs.

  16. New generation of valproic acid.

    PubMed

    Trojnar, Michał K; Wierzchowska-Cioch, Ewa; Krzyzanowski, Maciej; Jargiełło, Małgorzata; Czuczwar, Stanisław J

    2004-01-01

    Valproic acid (VPA) is one of four first-line antiepileptic drugs (AEDs) currently established in the long-term treatment of epilepsy. Despite VPA's wide spectrum of action, in some cases its use is limited due to specific pharmacokinetics and dangerous adverse effects. These include hepatotoxicity and teratogenecity. Such limitations account for intensive research that has been carried out in order to develop new analogues or derivatives of VPA. In our review, we focus on three out of a number of substances that have been lately under investigation: NPS 1776, valrocemide and DP-VPA. These potential AEDs present both good anticonvulsive and safety profiles and seem to be more potent than the original VPA. Clinical trials, which are now ongoing, will answer the question whether or not they could become second generation of VPA.

  17. Pharmacokinetics and Clinical Utility of Valproic Acid Administered via Continuous Infusion.

    PubMed

    Cook, Aaron M; Zafar, Muhammad S; Mathias, Sally; Stewart, Alejandra M; Albuja, Ana C; Bensalem-Owen, Meriem; Kapoor, Siddharth; Baumann, Robert J

    2016-01-01

    Valproic acid is a versatile antiepileptic drug that is often used in the acute care setting. Intravenous valproic acid lends itself well to a continuous infusion as it exhibits a relatively short half-life. We evaluated the pharmacokinetics and clinical efficacy of continuous infusion valproic acid in hospitalized patients with migraine and seizures. A retrospective cohort study was performed utilizing information from the medical records of patients receiving an intravenous continuous infusion of valproic acid. Patients were included if they were aged 1 month to 85 years and they received a continuous infusion of valproic acid. Therapeutic response, common adverse effects, and the pharmacokinetic profile of valproic acid were evaluated. Continuous infusion valproic acid led to a concentration within the desired range (50-100 μg/ml) in 83.4% of patients, a rate that was higher in pediatric patients. The clinical response rate was also higher in pediatric patients with seizures or migraines and appeared to be better when the concentration was >75 μg/ml. Analysis of safety parameters suggests similar safety considerations to valproic acid when administered via intermittent infusion. Continuous infusion valproic acid appears to be a safe, effective, and predictable manner by which to administer valproic acid to pediatric and adult patients admitted to the hospital.

  18. Antiepileptic drugs and breastfeeding

    PubMed Central

    2013-01-01

    Introduction This review provides a synopsis for clinicians on the use of antiepileptic drugs (AEDs) in the breastfeeding mother. Methods For each AED, we collected all retrievable data from Hale’s “Medications and Mother Milk” (2012), from the LactMed database (2013) of the National Library of Medicine, and from a MedLine Search of relevant studies in the past 10 years. Results Older AEDs, such as carbamazepine, valproic acid, phenytoin, phenobarbital, primidone are considered to have a good level of safety during lactation, due to the long term clinical experience and the consequent amount of available data from the scientific literature. On the contrary, fewer data are available on the use of new AEDs. Therefore, gabapentin, lamotrigine, oxcarbazepine, vigabatrin, tiagabine, pregabalin, leviracetam and topiramate are compatible with breastfeeding with a less documented safety profile. Ethosuximide, zonisamide and the continue use of clonazepam and diazepam are contraindicated during breastfeeding. Conclusions Although the current available advice on the use of AEDs during breastfeeding, given by different accredited sources, present some contradictions, most AEDs can be considered safe according to our review. PMID:23985170

  19. New CNS-active drugs which are second-generation valproic acid: can they lead to the development of a magic bullet?

    PubMed

    Isoherranen, Nina; Yagen, Boris; Bialer, Meir

    2003-04-01

    Valproic acid (VPA) is one of the four first line antiepileptic drugs (AEDs). VPA is also an effective drug in migraine prophylaxis and in treatment of bipolar disorders. The use of VPA is limited by its two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity, and it is the least potent of the established AEDs. Consequently, there is an incentive to develop a second-generation VPA. A successful, second-generation VPA would need to possess the following characteristics: broad-spectrum antiepileptic activity; better potency than VPA; and lack of teratogenicity and hepatotoxicity. These characteristics would give such a drug the potential to be utilized in epilepsy and other CNS disorders. Intensive research has been carried out in order to develop a second-generation VPA that would be more potent and safer than VPA. Amide derivatives of VPA have shown particular value as potential follow-up compounds and have better in-vivo performance than VPA. Several CNS-active valproylamides are more potent as antiepileptics than VPA, they possess broad-spectrum antiepileptic activity, and have been found to be nonteratogenic in animal models. The amide analogues of VPA that emerged from structure-pharmacokinetic-pharmacodynamic relationship studies as promising second-generation compounds are: N-methyl-tetramethylcyclopropane carboxamide, (2S,3S)-valnoctamide, (R)-propylisopropyl acetamide and valproyl glycinamide. At present there are three compounds in clinical trials in patients with epilepsy that can be regarded as second-generation VPA: valproyl glycinamide, 3-methylbutanamide or isovaleramide and SPD421 (DP-VPA). For any one of these second-generation valproic acids to become a successful follow-up compound to VPA, it has to fulfil the above criteria and also possess favorable pharmacokinetics.

  20. Antiepileptic Drugs with Mood Stabilizing Properties and Their Relation with Psychotropic Drug Use in Institutionalized Epilepsy Patients with Intellectual Disability

    ERIC Educational Resources Information Center

    Leunissen, C. L. F.; de la Parra, N. M.; Tan, I. Y.; Rentmeester, Th. W.; Vader, C. I.; Veendrick-Meekes, M. J. B. M.; Aldenkamp, A. P.

    2011-01-01

    A large number of patients with epilepsy and intellectual disability take medication, amongst which antiepileptic and psychotropic drugs, often simultaneously. Certain antiepileptic drugs have mood-stabilizing properties, e.g. carbamazepine, valproic acid and lamotrigine. The aim of this study was to investigate whether the use of these…

  1. Antiepileptic Drugs with Mood Stabilizing Properties and Their Relation with Psychotropic Drug Use in Institutionalized Epilepsy Patients with Intellectual Disability

    ERIC Educational Resources Information Center

    Leunissen, C. L. F.; de la Parra, N. M.; Tan, I. Y.; Rentmeester, Th. W.; Vader, C. I.; Veendrick-Meekes, M. J. B. M.; Aldenkamp, A. P.

    2011-01-01

    A large number of patients with epilepsy and intellectual disability take medication, amongst which antiepileptic and psychotropic drugs, often simultaneously. Certain antiepileptic drugs have mood-stabilizing properties, e.g. carbamazepine, valproic acid and lamotrigine. The aim of this study was to investigate whether the use of these…

  2. Endocrine effects of valproic acid therapy in girls with epilepsy: a prospective study.

    PubMed

    Goldberg-Stern, Hadassa; Yaacobi, Eyal; Phillip, Moshe; de Vries, Liat

    2014-11-01

    It is controversial whether the endocrine dysfunction in epilepsy patients is caused by the epilepsy itself, the antiepileptic therapy, or both. We prospectively evaluated the long-term impact of valproic acid monotherapy compared to other anti-epileptic drugs on anthropometric, metabolic, hormonal, and ultrasonographic parameters in girls with epilepsy. Fifty-seven female patients with epilepsy who had started therapy at mean age of 11.5 ± 3.3 years, 42 with valproic acid (mean dose 13.1 ± 7.0 mg/kg/day and 15 with other anti-epileptic agents were followed for a mean of 3.2 years (range 1.0-8.5 years) in our center. Clinical, hormonal and transabdominal pelvic ultrasound data were collected at 3 time points: before and 6-12 months after onset of anti-epileptic drug treatment; and at the last visit while patients were still taking anti-epileptic drugs. There were no significant between-group differences regarding changes in height, body mass index standard deviation score, levels of glucose and insulin, or lipid and endocrine profile from first to last visits. Mean thyroid-stimulating hormone level increased significantly between first and last visit only in the valproic acid group (p < 0.001), with no significant difference in free T4 level over time or between groups. The rate of clinical polycystic ovary syndrome for the valproic acid group (11%) was comparable to that reported in healthy controls (5-10%). Administration of valproic acid had no adverse effect on body weight, metabolic status or endocrine function over an average follow-up of 3.2 years. Valproic acid appears to be safe for use in girls with epilepsy. Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  3. Synthesis and evaluation of antiallodynic and anticonvulsant activity of novel amide and urea derivatives of valproic acid analogues.

    PubMed

    Kaufmann, Dan; Bialer, Meir; Shimshoni, Jakob Avi; Devor, Marshall; Yagen, Boris

    2009-11-26

    Valproic acid (VPA, 1) is a major broad spectrum antiepileptic and central nervous system drug widely used to treat epilepsy, bipolar disorder, and migraine. VPA's clinical use is limited by two severe and life-threatening side effects, teratogenicity and hepatotoxicity. A number of VPA analogues and their amide, N-methylamide and urea derivatives, were synthesized and evaluated in animal models of neuropathic pain and epilepsy. Among these, two amide and two urea derivatives of 1 showed the highest potency as antineuropathic pain compounds, with ED(50) values of 49 and 51 mg/kg for the amides (19 and 20) and 49 and 74 mg/kg for the urea derivatives (29 and 33), respectively. 19, 20, and 29 were equipotent to gabapentin, a leading drug for the treatment of neuropathic pain. These data indicate strong potential for the above-mentioned novel compounds as candidates for future drug development for the treatment of neuropathic pain.

  4. Valproic acid inhibits TTX-resistant sodium currents in prefrontal cortex pyramidal neurons.

    PubMed

    Szulczyk, Bartlomiej; Nurowska, Ewa

    2017-09-16

    Valproic acid is frequently prescribed and used to treat epilepsy, bipolar disorder and other conditions. However, the mechanism of action of valproic acid has not been fully elucidated. The aim of this study was to assess the influence of valproic acid (200 μM) on TTX-resistant sodium currents in mPFC pyramidal neurons. Valproic acid inhibited the maximal amplitude and did not change the activation parameters of TTX-resistant sodium currents. Moreover, valproic acid (2 μM and 200 μM) shifted the TTX-resistant sodium channel inactivation curve towards hyperpolarisation. In the presence of valproic acid, TTX-resistant sodium currents recovered from inactivation more slowly. Valproic acid did not influence the use-dependent blockade of TTX-resistant sodium currents. This study suggests that a potential new mechanism of the antiepileptic action of valproic acid is, among others, inhibition of TTX-resistant sodium currents. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. The influence of valproic acid and carbamazepine treatment on serum biotin and zinc levels and on biotinidase activity.

    PubMed

    Castro-Gago, Manuel; Pérez-Gay, Laura; Gómez-Lado, Carmen; Castiñeiras-Ramos, Daisy E; Otero-Martínez, Santiago; Rodríguez-Segade, Santiago

    2011-12-01

    We determined the serum concentration of biotin, zinc, antiepileptic drugs, and biotinidase enzyme activity in 20 children treated with valproic acid, in 10 children treated with carbamazepine, and in 75 age- and sex-matched healthy controls. There were no significant differences in the serum levels of biotin, and biotinidase enzyme activity between the patients treated with valproic acid, the patients treated with carbamazepine, and the control group. Zinc serum levels were lower in the patients treated with valproic acid and with carbamazepine than in the control group, but within the normal range. Hair loss was observed in 3 patients treated with valproic acid, with normal serum levels of biotin, zinc, and biotinidase activity, and the alopecia disappeared with the oral administration of biotin (10 mg/d) in 3 months. These results suggest that the treatment with valproic acid does not alter the serum levels of biotin, zinc, and biotinidase enzyme activity.

  6. Valproic acid increases conservative homologous recombination frequency and reactive oxygen species formation: a potential mechanism for valproic acid-induced neural tube defects.

    PubMed

    Defoort, Ericka N; Kim, Perry M; Winn, Louise M

    2006-04-01

    Valproic acid, a commonly used antiepileptic agent, is associated with a 1 to 2% incidence of neural tube defects when taken during pregnancy; however, the molecular mechanism by which this occurs has not been elucidated. Previous research suggests that valproic acid exposure leads to an increase in reactive oxygen species (ROS). DNA damage due to ROS can result in DNA double-strand breaks, which can be repaired through homologous recombination (HR), a process that is not error-free and can result in detrimental genetic changes. Because the developing embryo requires tight regulation of gene expression to develop properly, we propose that the loss or dysfunction of genes involved in embryonic development through aberrant HR may ultimately cause neural tube defects. To determine whether valproic acid induces HR, Chinese hamster ovary 3-6 cells, containing a neomycin direct repeat recombination substrate, were exposed to valproic acid for 4 or 24 h. A significant increase in HR after exposure to valproic acid (5 and 10 mM) for 24 h was observed, which seems to occur through a conservative HR mechanism. We also demonstrated that exposure to valproic acid (5 and 10 mM) significantly increased intracellular ROS levels, which were attenuated by preincubation with polyethylene glycol-conjugated (PEG)-catalase. A significant change in the ratio of 8-hydroxy-2'-deoxyguanosine/2'-de-oxyguanosine, a measure of DNA oxidation, was not observed after valproic acid exposure; however, preincubation with PEG-catalase significantly blocked the increase in HR. These data demonstrate that valproic acid increases HR frequency and provides a possible mechanism for valproic acid-induced neural tube defects.

  7. No pharmacokinetic interaction between lacosamide and valproic acid in healthy volunteers.

    PubMed

    Cawello, Willi; Bonn, Rainer

    2012-11-01

    Two open-label, randomized, multiple-dose clinical studies evaluated the potential for pharmacokinetic interaction between the antiepileptic drugs lacosamide and valproic acid. The influence of lacosamide on valproic acid pharmacokinetics (trial A) and valproic acid on lacosamide pharmacokinetics (trial B) was investigated in 32 healthy male volunteers, 16 in each trial. Volunteers in trial A received valproic acid (300 mg bid) with randomization to either early or late addition of lacosamide (200 mg bid). Those in trial B received lacosamide (200 mg bid) with randomization to either early or late addition of valproic acid (300 mg bid). Area under the concentration-time curve during a 12-hour dosing interval at steady state (AUC(τ,ss)) and maximum steady-state plasma drug concentration (C(max,ss)) were measured for each drug alone and together and tested for equivalence. The point estimates (90% confidence intervals) for AUC(τ,ss) and C(max,ss) were 104% (99%-109%) and 101% (97%-107%), respectively, for valproic acid and 100% (98%-103%) and 101% (96%-107%), respectively, for lacosamide, which were within the generally accepted equivalence range of 80% to 125%. No changes in the rate or extent of absorption, terminal half-life, or time to maximum concentration were observed. These results suggest that lacosamide and valproic acid have no relevant pharmacokinetic drug-drug interaction.

  8. Evidence for a trigger function of valproic acid in xenobiotic-induced hepatotoxicity.

    PubMed

    Klee, S; Johanssen, S; Ungemach, F R

    2000-08-01

    The influence of the antiepileptic drug, valproic acid (2-n-propylpentanoic acid), on the hepatocellular capacity, to cope with an extrinsic oxidative stress was investigated. Freshly isolated rat hepatocytes exposed to therapeutic concentrations of valproic acid (0.25-1.0 mmol/l) were less resistant than controls, as evidenced by a significant cytotoxic response after challenge of the cells with a non-toxic dose of allyl alcohol (2-propen-1-ol). Valproic acid alone was not toxic to hepatocytes even at ten times higher concentrations (10 mmol/l), suggesting that cell damage was not a mere additive effect. Incubation with valproic acid plus allyl alcohol induced an irreversible depletion of hepatocellular glutathione, in contrast to allyl alcohol alone which induced a transient loss. Hepatocytes treated with valproic acid plus allyl alcohol were protected by N-acetylcysteine, a precursor of glutathione. These findings indicate that valproic acid affects hepatocellular defence mechanisms and suggest that a predisposition of hepatocytes to oxidative stress may play a role in the fatal hepatotoxicity of valproic acid in epileptic patients.

  9. Recent progress in anticonvulsant drug research: strategies for anticonvulsant drug development and applications of antiepileptic drugs for non-epileptic central nervous system disorders.

    PubMed

    Dalkara, Sevim; Karakurt, Arzu

    2012-01-01

    Major advances in antiepileptic drug therapy have taken place since 1950s. In the first period, several antiepileptic drugs (AEDs) such as phenobarbital, diphenylhydantoin, ethosuximide, carbamazepine, benzodiazepines and valproic acid were introduced to epilepsy treatment. After 1990 many new generation drugs (lamotrigine, topiramate, gabapentine, pregabaline, felbamate, lacosamide, levetiracetam etc.) have been developed. These novel AEDs have offered some advantages such as fewer side effects, fewer drug-drug interactions, and better pharmacokinetic properties. But pharmacoresistance and therapeutic failure in 20-25% of the patients remain the main reasons to continue efforts to find safer and more efficacious drugs and ultimate a treatment for this devastating disease. Several AEDs especially novel compounds have been found to be effective also in the treatment of several other neurologic and psychiatric disorders. Chemical diversity of the newer antiepileptic drugs as well as those currently in clinical development is another point that encourages medicinal chemists to study this subject. This review summarizes recent studies on the development of potential anticonvulsant compounds in different chemical structures, their structure-activity relationships and also therapeutic usages of AEDs other than epilepsy.

  10. Serum nitrite and nitrate levels in epileptic children using valproic acid or carbamazepine.

    PubMed

    Karabiber, Hamza; Yakinci, Cengiz; Durmaz, Yasar; Temel, Ismail; Mehmet, Nihayet

    2004-01-01

    In experimental epilepsy studies, nitric oxide was found to act as both proconvulsant and anticonvulsant. The objective of this study was to investigate the effects of valproic acid and carbamazepine on serum levels of nitrite and nitrate, which are the metabolites of nitric oxide. To achieve this goal, serum nitrite and nitrate levels were determined in active epileptic 34 children using valproic acid and 23 children using carbamazepine and in non-active epileptic 38 children (control group) not using any antiepileptic drug. In the valproic acid group serum nitrite and nitrate levels were 2.66 +/- 2.11 micromol/l and 69.35 +/- 23.20 micromol/l, 1.89 +/- 1.01 micromol/l and 49.39 +/- 10.61 micromol/l in the carbamazepine group, and 1.22 +/- 0.55 micromol/l, 29.53 +/- 10.05 micromol in the control group, respectively. Nitrite and nitrate levels were significantly high in both valproic acid and carbamazepine groups compared to the control group (P < 0.01). When valproic acid and carbamazepine groups were compared to each other, level of nitrate was found statistically higher in the valproic acid group in relation to the carbamazepine group (P < 0.01), however, there was no statistically significant difference in the levels of nitrite (P > 0.05). No relation could be found between serum drug levels and nitrite and nitrate levels. According to these results, it can be suggested that valproic acid and carbamazepine might have antiepileptic effects through nitric oxide.

  11. Potential new methods for antiepileptic drug delivery.

    PubMed

    Fisher, Robert S; Ho, Jet

    2002-01-01

    Use of novel drug delivery methods could enhance the efficacy and reduce the toxicity of antiepileptic drugs (AEDs). Slow-release oral forms of medication or depot drugs such as skin patches might improve compliance and therefore seizure control. In emergency situations, administration via rectal, nasal or buccal mucosa can deliver the drug more quickly than can oral administration. Slow-release oral forms and rectal forms of AEDs are already approved for use, nasal and buccal administration is currently off-label and skin patches for AEDs are an attractive but currently hypothetical option. Therapies under development may result in the delivery of AEDs directly to the regions of the brain involved in seizures. Experimental protocols are underway to allow continuous infusion of potent excitatory amino acid antagonists into the CSF. In experiments with animal models of epilepsy, AEDs have been delivered successfully to seizure foci in the brain by programmed infusion pumps, acting in response to computerised EEG seizure detection. Inactive prodrugs can be given systemically and activated at the site of the seizure focus by locally released compounds. One such drug under development is DP-VPA (or DP16), which is cleaved to valproic acid (sodium valproate) by phospholipases at the seizure focus. Liposomes and nanoparticles are engineered micro-reservoirs of a drug, with attached antibodies or receptor-specific binding agents designed to target the particles to a specific region of the body. Liposomes in theory could deliver a high concentration of an AED to a seizure focus. Penetration of the blood-brain barrier can be accomplished by linking large particles to iron transferrin or biological toxins that can cross the barrier. In the near future, it is likely that cell transplants that generate neurotransmitters and neuromodulators will accomplish renewable endogenous drug delivery. However, the survival and viability of transplanted cells have yet to be demonstrated

  12. Adiponectin and visfatin concentrations in children treated with valproic acid.

    PubMed

    Rauchenzauner, Markus; Haberlandt, Edda; Scholl-Bürgi, Sabine; Ernst, Barbara; Hoppichler, Fritz; Karall, Daniela; Ebenbichler, Christoph F; Rostasy, Kevin; Luef, Gerhard

    2008-02-01

    Chronic antiepileptic therapy with valproic acid (VPA) is associated with increased body weight and insulin resistance in adults and children. Attempts to determine the underlying pathophysiologic mechanisms have failed. Adipocytokines have recently been defined as a link between glucose and fat metabolism. We herein demonstrate that VPA-associated overweight is accompanied by lower adiponectin and higher leptin concentrations in children. The absence of any relationship with visfatin concentration does not suggest a role of this novel insulin-mimetic hormone in VPA-associated metabolic alterations. Therefore, adiponectin and leptin but not visfatin may be considered as potential regulators of glucose and fat metabolism during VPA-therapy.

  13. Molecular and Therapeutic Potential and Toxicity of Valproic Acid

    PubMed Central

    Chateauvieux, Sébastien; Morceau, Franck; Dicato, Mario; Diederich, Marc

    2010-01-01

    Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels. VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible. VPA is a widely used drug, particularly for children suffering from epilepsy. Due to the increasing number of clinical trials involving VPA, and interesting results obtained, this molecule will be implicated in an increasing number of therapies. However side effects of VPA are substantially described in the literature whereas they are poorly discussed in articles focusing on its therapeutic use. This paper aims to give an overview of the different clinical-trials involving VPA and its side effects encountered during treatment as well as its molecular properties. PMID:20798865

  14. Antiepileptic drugs during pregnancy: pharmacokinetics and transplacental transfer.

    PubMed

    De Santis, Marco; De Luca, Carmen; Mappa, Ilenia; Cesari, Elena; Quattrocchi, Tomasella; Spagnuolo, Terryann; Visconti, Daniela; Caruso, Alessandro

    2011-05-01

    Epilepsy represents the most common maternal neurological disorder requiring continuous treatment during pregnancy. Maintaining optimum seizure control is an important objective in pregnancy, and the majority of women with epilepsy will need to continue antiepileptic drugs (AEDs). AEDs are frequently used to treat several other conditions, such as headaches and mood disorders. They have been associated with an increased risk of congenital malformations, minor anomalies, congenital syndrome and development disorders. This risk seems to be higher among women using polypharmacy and valproic acid. Neural tube defects are associated with valproic acid and carbamazepine exposure. New AEDs seem to have a less teratogenic effect, but human experience is still limited. The purpose of this review is to provide an update on AED exposure in pregnancy, focusing on pharmacokinetics and transplacental transport.

  15. Levetiracetam compared with valproic acid for the prevention of postoperative seizures after supratentorial tumor surgery: a retrospective chart review.

    PubMed

    Lee, Young Jin; Kim, Tackeun; Bae, So Hyun; Kim, Young-Hoon; Han, Jung Ho; Yun, Chang-Ho; Kim, Chae-Yong

    2013-09-01

    Antiepileptic drugs are commonly given for perioperative prophylaxis after brain tumor surgery, and there has been growing interest in levetiracetam, a second-generation antiepileptic drug. This retrospective study compared the seizure outcomes, side effects and durability of levetiracetam with valproic acid after a craniotomy for supratentorial brain tumors. Between 2009 and 2012, 282 consecutive patients with a supratentorial brain tumor underwent a craniotomy at Seoul National University Bundang Hospital. Of these patients, 51 (18.1%) and 231 (81.9%) were pre-operatively administered levetiracetam and valproic acid, respectively. The postoperative seizure outcomes (within 1 month after surgery) and the long-term side effects of both drugs were evaluated. Of the 51 patients in the levetiracetam group, 4 (7.8%) experienced postoperative seizures after brain tumor surgery, and 15 (6.5%) of the 231 patients in the valproic acid group experienced postoperative seizures (p = 0.728). The long-term complication rate of the valproic acid group (26.8%; 62/231) was significantly higher than that of the levetiracetam group (9.8%; 5/51) [p = 0.010]. In the valproic acid group, 10 hepatotoxicities, 20 hyperammonemias and 10 hematologic abnormalities (6 thrombocytopenias, 3 pancytopenias, and 1 leucopenia) occurred. Moreover, 89 patients (38.5%) in the valproic acid group changed or added other anticonvulsants because of side effects or uncontrolled seizures, whereas only 9 patients (17.6%) in the levetiracetam group changed or added other anticonvulsants (p = 0.005). The postoperative seizure control rates of levetiracetam and valproic acid were not statistically significantly different; however, levetiracetam may be superior to valproic acid in terms of its safety and durability after supratentorial tumor surgery.

  16. The pharmacogenomics of valproic acid.

    PubMed

    Zhu, Miao-Miao; Li, Hui-Lan; Shi, Li-Hong; Chen, Xiao-Ping; Luo, Jia; Zhang, Zan-Ling

    2017-09-07

    Valproic acid is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder. Adverse effects of valproic acid are rare, but hepatotoxicity is severe in particular in those younger than 2 years old and polytherapy. During valproic acid treatment, it is difficult for prescribers to predict its individual response. Recent advances in the field of pharmacogenomics have indicated variants of candidate genes that affect valproic acid efficacy and safety. In this review, a large number of candidate genes that influence valproic acid pharmacokinetics and pharmacodynamics are discussed, including metabolic enzymes, drug transporters, neurotransmitters and drug targets. Furthermore, pharmacogenomics is an important tool not only in further understanding of interindividual variability but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization.Journal of Human Genetics advance online publication, 7 September 2017; doi:10.1038/jhg.2017.91.

  17. Standard antiepileptic drugs fail to block epileptiform activity in rat organotypic hippocampal slice cultures

    PubMed Central

    Albus, K; Wahab, A; Heinemann, U

    2008-01-01

    Background and purpose: Earlier studies had demonstrated that tonic–clonic seizure-like events (SLEs) resembling electrographic correlates of limbic seizures in animals and humans can be induced in organotypic hippocampal slice cultures (OHSCs). We have explored OHSCs for their suitability to serve as in vitro models of limbic seizures for studying seizure mechanisms and screening new antiepileptic compounds. Experimental approach: OHSCs were cultivated according to the interface method. Neuronal activity and extracellular potassium concentration were recorded under submerged conditions. SLEs were induced by lowering magnesium concentration or by applying the potassium channel blocker 4-aminopyridine. The effects of standard antiepileptic drugs (AEDs), carbamazepine, phenytoin, valproic acid, clonazepam, diazepam and phenobarbital sodium on SLEs were analysed. Key results: In more than 93% of OHSCs, AEDs did not prevent the induction of SLEs or stop ongoing seizure activity even when toxic concentrations were applied. This pharmacoresistance was independent of the method of seizure provocation, postnatal age at explantation (P2–P10) and cultivation time in vitro (2 months). SLEs were reversibly blocked by glutamate antagonists or the GABAA-agonist muscimol. Conclusions and implications: We present a simple to establish in vitro model of tonic–clonic SLEs that is a priori pharmacoresistant and thus has an advantage over animal models of pharmacoresistant seizures in which responders and non-responders can be sorted out only after an experiment. OHSCs could be suitable for exploring mechanisms of pharmacoresistant seizures and be used for the identification of new anticonvulsive compounds eventually effective in drug refractory epilepsy. PMID:18414393

  18. Quantitative determination of valproic acid in postmortem blood samples--evidence of strong matrix dependency and instability.

    PubMed

    Kiencke, Verena; Andresen-Streichert, Hilke; Müller, Alexander; Iwersen-Bergmann, Stefanie

    2013-11-01

    Most of the daily work of forensic toxicologists deals with fatal cases resulting from overdoses of licit and illicit drugs. However, another reason for fatalities in patients suffering from epilepsy can be undetectable or subtherapeutic levels of antiepileptic drugs. Some studies have shown a correlation between "sudden unexpected death in epilepsy" (SUDEP) and the ineffective treatment of epilepsy. Low levels of antiepileptic drugs may be a risk factor for SUDEP. The death of a psychiatric patient also suffering from epilepsy inspired the investigation. Subsequent to the death of the patient, the doctor was accused of providing inadequate therapy for epilepsy. The patient was to be treated with valproic acid. We developed and validated a simple method of determining valproic acid levels by gas chromatography-mass spectrometry for serum, but a transfer of the method from serum to postmortem whole blood failed. The method had to be modified and revalidated for postmortem whole blood specimens. A stability study of valproic acid in postmortem blood was conducted, showing a decline of valproic acid levels by 85 % after storage at room temperature for 28 days. During the storage time, the blood samples showed changes in consistency. Depending on the stage of decomposition, it is necessary to perform a determination by standard addition with an equilibration time of 4 h before extraction to achieve reliable results. For a proper interpretation of quantitative results, it is necessary to keep the postmortem decline of valproic acid concentrations in mind.

  19. Prescription of antiepileptics and the risk of road traffic crash.

    PubMed

    Orriols, Ludivine; Foubert-Samier, Alexandra; Gadegbeku, Blandine; Delorme, Bernard; Tricotel, Aurore; Philip, Pierre; Moore, Nicholas; Lagarde, Emmanuel

    2013-03-01

    Studies assessing the impact of epilepsy and its medication on the risk of road traffic crashes have shown inconsistent results. The aim in this study was to assess this risk using French databases. Data from three French national databases were extracted and matched: the national health care insurance database, police reports, and the national police database of injurious crashes. Only antiepileptics prescribed predominantly in epilepsy were studied (phenobarbital, phenytoin, ethosuximide, valproic acid, vigabatrin, tiagabin, levitiracetam, zonisamide, and lacosamide). A case-control analysis comparing responsible and non-responsible drivers and a case-crossover analysis were performed. Drivers (72 685) involved in an injurious crash in France between July 2005 and May 2008, were included. Drivers exposed to prescribed antiepileptic medicines (n = 251) had an increased risk of being responsible for a crash (OR 1.74 [1.29-2.34]). The association was also significant for the most severe epileptic patients (n = 99; OR = 2.20 [1.31-3.69]). Case-crossover analysis found no association between crash risk and treatment prescription. Patients with prescription of antiepileptic drugs should be cautioned about their potential risk of road traffic crash. This risk is however more likely to be related to seizures than to the effect of antiepileptic medicines.

  20. [Use of antiepileptic drugs for the preventive treatment of migraine].

    PubMed

    Hamada, Junichi

    2009-10-01

    Migraine and epilepsy share several common characteristic clinical features, and epilepsy is a comorbid disorder of migraine. Clinical studies have shown that some antiepileptic drugs are effective for the preventive treatment of migraine. The rationale for the use of these antiepileptic drugs in migraine prophylaxis is the hypothesis that migraine and epilepsy have several common pathophysiological mechanisms. It has been suggested that in these 2 pathological conditions, an imbalance exists between excitatory glutamate-mediated transmission and inhibitory GABA-mediated transmission in cerebral tissues, mainly in specific brain areas. Moreover, it has been postulated that abnormal activation of some kinds of voltage-gated ionic channels has been postulated to have a key role in both migraine and epilepsy, especially when caused by a genetic abnormality. It has been found that cortical spreading depression is involved in the pathophysiological mechanism of epilepsy, in addition to the generation of migraine aura. Preventive antiepileptic drugs can be chosen for treatment after considering clinical efficacy- scientific evidence, side effects, and patients' specific personal conditions. Recently, scientific evidence was found to demonstrate efficacy of valproic acid and topiramate in the preventive treatment of migraine. These drugs can reduce the incidence of migraine attacks in the large clinical studies. Other new antiepileptic drugs can be tried in future clinical study.

  1. Resistance to valproic acid as predictor of treatment resistance in genetic generalized epilepsies.

    PubMed

    Gesche, Joanna; Khanevski, Marina; Solberg, Carl; Beier, Christoph Patrick

    2017-04-01

    This study aimed at defining clinical predictors of drug resistance in adults with genetic generalized epilepsy (GGE) who were treated with a broad spectrum of antiepileptic drugs. Of a cohort of 137 unselected adult GGE patients with long-term follow up, clinical and demographic data, putative prognostic factors (e.g., psychiatric comorbidities, electroencephalography [EEG]), treatment response, and data indicative of social status were collected. Fifty-eight patients had seizures within the past year. Thirty-three patients met the definition of "drug-resistant epilepsy" according to the International League Against Epilepsy (ILAE) definition. Psychiatric comorbidities, age at first diagnosis, and absences were associated with worse seizure control, whereas focal changes in EEG remained without prognostic impact. Resistance to valproic acid was the most important prognostic factor for refractory seizures. Resistance to valproic acid had a specificity of 100% to identify patients with drug resistance and correlated strongly with bad social outcome and seizure burden. Conversely, 21.2% of all patients with refractory seizures according to the ILAE definition later became seizure free (mainly with valproic acid). Our data suggest that "drug resistant GGE" must not be declared unless patients were adequately treated with valproic acid, and advocate resistance to valproic acid as a new clinical biomarker for drug-resistant GGE. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  2. Established antiepileptic drugs.

    PubMed

    Brodie, M J; Dichter, M A

    1997-06-01

    Despite the recent entry into the market-place of a range of new pharmacological treatments for epilepsy, most patients still receive the standard antiepileptic drugs. This review considers the clinical place and practical use of these agents. Detailed consideration is given to carbamazepine, phenytoin, sodium valproate, phenobarbital and ethosuximide, with lesser emphasis on primidone, clobazam and clonazepam. Individualization of therapy, polypharmacy, refractory epilepsy, therapeutic drug monitoring, pregnancy, withdrawing treatment, epilepsy prophylaxis and referral to an epilepsy centre are also discussed. The paper concludes with a statement of 12 basic rules in prescribing established antiepileptic drugs.

  3. Drug utilisation study in patients receiving antiepileptic drugs in Colombia.

    PubMed

    Machado-Alba, J E; Calvo-Torres, L F; García-Betancur, S; Aguirre-Novoa, A; Bañol-Giraldo, A M

    2016-03-01

    This study examines the indications according to which antiepileptic drugs are prescribed and used in a population of patients enrolled in the Colombian national health system (SGSSS). Retrospective cross-sectional study. From the pool of individuals in 34 Colombian cities who used antiepileptic drugs between 18 July, 2013 and 31 August, 2014 during a period of no less than 12 months, we obtained a random sample stratified by city. Socio-demographic, pharmacological and comorbidity variables were analysed. Continuous and categorical variables were compared, and logistic regression models were used. Our patient total was 373 patients, with 197 women (52.1%) and a mean age of 41.9 ± 21.7 years; 65.4% of the patients were treated with monotherapy. The most frequently used drugs were valproic acid (53.1%) and carbamazepine (33.2%). Epilepsy was the most frequent indication (n=178; 47.7%); however, 52.3% of the patients were prescribed antiepileptics for different indications, especially neuropathic pain (26.8%), affective disorders (14.2%) and migraine prophylaxis (12.3%). A total of 81 patients with epilepsy (46.6%) displayed good seizure control while another 25 (14.4%) had drug-resistant epilepsy. In the multivariate analysis, medication adherence was associated with a lower risk of treatment failure in patients with epilepsy (OR: 0.27; 95%CI, 0.11-0.67). In Colombia, antiepileptic drugs are being used for indications other than those originally intended. Monotherapy is the most commonly used treatment approach, together with the use of classic antiepileptic drugs. Copyright © 2015 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  4. HPLC thermodynamic study of new potential antiepileptic compounds on cholesterol column using isocratic elution with methanol/water and acetonitrile/water eluent systems.

    PubMed

    Flieger, Jolanta; Trębacz, Hanna; Pizoń, Magdalena; Kowalska, Anna; Szczęsna, Agnieszka; Plech, Tomasz

    2017-09-04

    Basic thermodynamic functions responsible for retention of new 1,2,4-triazole derivatives exhibiting varied antiepileptic activity on cholesterol-based stationary phase were determined. Evaluation of the Gibbs energy change, the change in enthalpy and the change in entropy was based on the van 't Hoff relationship representing ln k vs. 1/T. A detailed discussion of the van 't Hoff equation, exploring the influence of the phase ratio on deviations from linearity in a Van 't Hoff plot is presented. We show chromatographic evidence to the question of how a varied mobile phase composition may cause different thermodynamic phase ratios. The analysis of data from a differential scanning calorimetry excluded any phase transitions of either the individual solutes or cholesterol stationary phase suspended in the mobile phase components within the studied temperature range. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  5. Valproic acid inhibits excess dopamine release in response to a fear-conditioned stimulus in the basolateral complex of the amygdala of methamphetamine-sensitized rats.

    PubMed

    Miyagi, Junko; Oshibuchi, Hidehiro; Kasai, Akiko; Inada, Ken; Ishigooka, Jun

    2014-05-05

    Valproic acid, an established antiepileptic and antimanic drug, has recently emerged as a promising emotion-stabilizing agent for patients with psychosis. Although dopamine transmission in the amygdala plays a key role in emotional processing, there has been no direct evidence about how valproic acid acts on the dopaminergic system in the brain during emotional processing. In the present study, we tested the effect of valproic acid on a trait marker of vulnerability to emotional stress in psychosis, which is excess dopamine release in response to a fear-conditioned stimulus (CS) in the basolateral complex of the amygdala of methamphetamine-sensitized rats. Extracellular dopamine was collected from the amygdala of freely moving methamphetamine-sensitized rats by in vivo microdialysis and was measured using high-performance liquid chromatography. During microdialysis, valproic acid was intraperitoneally injected followed by CS exposure. Valproic acid treatment decreased baseline levels of dopamine and also attenuated the excess dopamine release in response to the CS in the amygdala of methamphetamine-sensitized rats. The results prove that valproic acid inhibits spontaneous dopamine release and also attenuates excess dopaminergic signaling in response to emotional stress in the amygdala. These findings suggest that the mechanisms of the emotion-stabilizing effect of valproic acid in psychosis involve modulation of dopaminergic transmission in emotional processing.

  6. [Therapeutic drug monitoring of three antiepileptic drugs - Back on twenty years of experience].

    PubMed

    Serragui, Samira; Zalagh, Fatima; Tanani, Driss Soussi; Ouammi, Lahcen; Moussa, Latifa Ait; Badrane, Narjis; Bencheikh, Rachida Soulaymani

    2016-01-01

    The therapeutic drug monitoring (TDM) of antiepileptic drugs is a tool widely used in the management of epilepsy. In Morocco, this monitoring is carried out by the Centre Anti Poison et Pharmacovigilance (CAPM) since April 1995. This is a retrospective study spanning 20 years. It concerns the therapeutic drug monitoring of Phenobarbital (PB) of carbamazepine (CBZ) and valproic acid (VPA). Therapeutic drug monitoring of the 3 antiepileptic drugs represent 58.85% of all applications received by the CAPM. The dosage of PB was ranked first followed by that of CBZ and finally by the VPA. Weak demand for therapeutic drug monitoring in Morocco could be explained by the low number of neurologists in addition to social factors. With its affordable price by patients, PB is the most prescribed antiepileptic drug in our country, which explains the high demand for its dosage. As for the therapeutic drug monitoring of the antiepileptic drug, they were mainly related to age, the occurrence of adverse effects, the association antiepileptic drugs or in the case of verification of patient compliance. Efforts are required for promoting the interests of therapeutic drug monitoring of antiepileptic drug in the management of epilepsy in Morocco.

  7. Antiepileptic drugs and apoptosis in the developing brain.

    PubMed

    Bittigau, Petra; Sifringer, Marco; Ikonomidou, Chrysanthy

    2003-05-01

    Epilepsy is the most common neurologic disorder in young humans. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects by unknown mechanisms. We tested whether common AEDs cause neurodegeneration in the developing rat brain. Rats aged 3-30 days received phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, or valproic acid. Histologic examination of the brains revealed that these drugs cause widespread and dose-dependent apoptotic neurodegeneration in the developing rat brain during the brain growth spurt period. Apoptotic neurodegeneration was triggered at plasma drug levels relevant for seizure control in humans. Antiepileptic drugs lead to reduced expression of neurotrophins and decreased concentrations of the active forms of ERK1/2, RAF, and AKT. beta-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorated AEDs-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with pre- or postnatal exposure of humans to antiepileptic therapy.

  8. Pharmacokinetic and pharmacodynamic interactions between antiepileptics and antidepressants.

    PubMed

    Italiano, Domenico; Spina, Edoardo; de Leon, Jose

    2014-11-01

    Antiepileptic-antidepressant combinations are frequently used by clinicians; their pharmacokinetic (PK) and pharmacodynamic (PD) drug interactions (DIs) have not been well studied but are frequently likely to be clinically relevant. This article provides a comprehensive review of PK DIs between antiepileptics and antidepressants. In the absence of PD DI studies, PD information on pharmacological mechanisms and studies on efficacy and safety of individual drugs are reviewed. The clinical relevance of the inductive properties of carbamazepine, phenytoin, phenobarbital and primidone and the inhibitory properties of valproic acid and some antidepressants are well understood; correction factors are provided if appropriate DI studies have been completed. More PK studies are needed for: i) antiepileptics with potent inductive effects for all recently approved antidepressants; ii) high doses of mild CYP3A4 inducers, such as clobazam, eslicarbazepine, oxcarbazepine, rufinamide and topiramate for reboxetine and vilazodone; iii) valproate as a possible inhibitor, mild inducer or both a mild inducer and competitive inhibitor of some antidepressants; and iv) inhibitory effects of long-term fluoxetine use on clobazam, lacosamide, phenobarbital, primidone, carbamazepine, felbamate, tiagabine and zonisamide. Possible synergistic or additive beneficial PD DIs in generalized anxiety disorder, chronic pain, migraine prophylaxis, weight control and menopausal symptoms need study.

  9. Potent anticonvulsant urea derivatives of constitutional isomers of valproic acid.

    PubMed

    Shimshoni, Jakob Avi; Bialer, Meir; Wlodarczyk, Bogdan; Finnell, Richard H; Yagen, Boris

    2007-12-13

    Valproic acid (VPA) is a major antiepileptic drug (AED); however, its use is limited by two life-threatening side effects: teratogenicity and hepatotoxicity. Several constitutional isomers of VPA and their amide and urea derivatives were synthesized and evaluated in three different anticonvulsant animal models and a mouse model for AED-induced teratogenicity. The urea derivatives of three VPA constitutional isomers propylisopropylacetylurea, diisopropylacetylurea, and 2-ethyl-3-methyl-pentanoylurea displayed a broad spectrum of anticonvulsant activity in rats with a clear superiority over their corresponding amides and acids. Enanatiomers of propylisopropylacetylurea and propylisopropylacetamide revealed enantioselective anticonvulsant activity, whereas only enantiomers of propylisopropylacetylurea displayed enantioselective teratogenicity. These potent urea derivatives caused neural tube defects, but only at doses markedly exceeding their effective dose, whereas VPA showed no separation between its anticonvulsant activity and teratogenicity. The broad spectrum of anticonvulsant activity of the urea derivatives coupled with their wide safety margin make them potential candidates to become new, potent AEDs.

  10. Clinically relevant drug interactions with antiepileptic drugs

    PubMed Central

    Perucca, Emilio

    2006-01-01

    Some patients with difficult-to-treat epilepsy benefit from combination therapy with two or more antiepileptic drugs (AEDs). Additionally, virtually all epilepsy patients will receive, at some time in their lives, other medications for the management of associated conditions. In these situations, clinically important drug interactions may occur. Carbamazepine, phenytoin, phenobarbital and primidone induce many cytochrome P450 (CYP) and glucuronyl transferase (GT) enzymes, and can reduce drastically the serum concentration of associated drugs which are substrates of the same enzymes. Examples of agents whose serum levels are decreased markedly by enzyme-inducing AEDs, include lamotrigine, tiagabine, several steroidal drugs, cyclosporin A, oral anticoagulants and many cardiovascular, antineoplastic and psychotropic drugs. Valproic acid is not enzyme inducer, but it may cause clinically relevant drug interactions by inhibiting the metabolism of selected substrates, most notably phenobarbital and lamotrigine. Compared with older generation agents, most of the recently developed AEDs are less likely to induce or inhibit the activity of CYP or GT enzymes. However, they may be a target for metabolically mediated drug interactions, and oxcarbazepine, lamotrigine, felbamate and, at high dosages, topiramate may stimulate the metabolism of oral contraceptive steroids. Levetiracetam, gabapentin and pregabalin have not been reported to cause or be a target for clinically relevant pharmacokinetic drug interactions. Pharmacodynamic interactions involving AEDs have not been well characterized, but their understanding is important for a more rational approach to combination therapy. In particular, neurotoxic effects appear to be more likely with coprescription of AEDs sharing the same primary mechanism of action. PMID:16487217

  11. The embryonic stem cell test as tool to assess structure-dependent teratogenicity: the case of valproic acid.

    PubMed

    Riebeling, Christian; Pirow, Ralph; Becker, Klaus; Buesen, Roland; Eikel, Daniel; Kaltenhäuser, Johanna; Meyer, Frauke; Nau, Heinz; Slawik, Birgitta; Visan, Anke; Volland, Jutta; Spielmann, Horst; Luch, Andreas; Seiler, Andrea

    2011-04-01

    Teratogenicity can be predicted in vitro using the embryonic stem cell test (EST). The EST, which is based on the morphometric measurement of cardiomyocyte differentiation and cytotoxicity parameters, represents a scientifically validated method for the detection and classification of chemicals according to their teratogenic potency. Furthermore, an abbreviated protocol applying flow cytometry of intracellular marker proteins to determine differentiation into the cardiomyocyte lineage is available. Although valproic acid (VPA) is in worldwide clinical use as antiepileptic drug, it exhibits two severe side effects, i.e., teratogenicity and hepatotoxicity. These limitations have led to extensive research into derivatives of VPA. Here we chose VPA as model compound to test the applicability domain and to further evaluate the reliability of the EST. To this end, we study six closely related congeners of VPA and demonstrate that both the standard and the molecular flow cytometry-based EST are well suited to indicate differences in the teratogenic potency among VPA analogs that differ only in chirality or side chain length. Our data show that identical results can be obtained by using the standard EST or a shortened protocol based on flow cytometry of intracellular marker proteins. Both in vitro protocols enable to reliably determine differentiation of murine stem cells toward the cardiomyocyte lineage and to assess its chemical-mediated inhibition.

  12. The Embryonic Stem Cell Test as Tool to Assess Structure-Dependent Teratogenicity: The Case of Valproic Acid

    PubMed Central

    Riebeling, Christian; Pirow, Ralph; Becker, Klaus; Buesen, Roland; Eikel, Daniel; Kaltenhäuser, Johanna; Meyer, Frauke; Nau, Heinz; Slawik, Birgitta; Visan, Anke; Volland, Jutta; Spielmann, Horst; Luch, Andreas; Seiler, Andrea

    2011-01-01

    Teratogenicity can be predicted in vitro using the embryonic stem cell test (EST). The EST, which is based on the morphometric measurement of cardiomyocyte differentiation and cytotoxicity parameters, represents a scientifically validated method for the detection and classification of chemicals according to their teratogenic potency. Furthermore, an abbreviated protocol applying flow cytometry of intracellular marker proteins to determine differentiation into the cardiomyocyte lineage is available. Although valproic acid (VPA) is in worldwide clinical use as antiepileptic drug, it exhibits two severe side effects, i.e., teratogenicity and hepatotoxicity. These limitations have led to extensive research into derivatives of VPA. Here we chose VPA as model compound to test the applicability domain and to further evaluate the reliability of the EST. To this end, we study six closely related congeners of VPA and demonstrate that both the standard and the molecular flow cytometry-based EST are well suited to indicate differences in the teratogenic potency among VPA analogs that differ only in chirality or side chain length. Our data show that identical results can be obtained by using the standard EST or a shortened protocol based on flow cytometry of intracellular marker proteins. Both in vitro protocols enable to reliably determine differentiation of murine stem cells toward the cardiomyocyte lineage and to assess its chemical-mediated inhibition. PMID:21227905

  13. Teratogenic potential of antiepileptic drugs in the zebrafish model.

    PubMed

    Lee, Sung Hak; Kang, Jung Won; Lin, Tao; Lee, Jae Eun; Jin, Dong Il

    2013-01-01

    The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs) arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ), ethosuximide (ETX), valproic acid (VPN), lamotrigine (LMT), lacosamide (LCM), levetiracetam (LVT), and topiramate (TPM)) in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf)) to termination of hatching (72 hpf) which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI) of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data.

  14. Teratogenic Potential of Antiepileptic Drugs in the Zebrafish Model

    PubMed Central

    Lee, Sung Hak; Kang, Jung Won; Lin, Tao; Lee, Jae Eun; Jin, Dong Il

    2013-01-01

    The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs) arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ), ethosuximide (ETX), valproic acid (VPN), lamotrigine (LMT), lacosamide (LCM), levetiracetam (LVT), and topiramate (TPM)) in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf)) to termination of hatching (72 hpf) which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI) of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data. PMID:24324971

  15. Pharmacokinetics of antiepileptic drugs.

    PubMed

    Tokola, R A; Neuvonen, P J

    1983-01-01

    The rational use of antiepileptic drugs requires the consideration of their pharmacokinetics, which may be influenced by the physiological and pathological factors. Pharmacokinetic interactions between antiepileptic drugs may lead to considerable fluctuation in plasma drug concentration, and monotherapy is often preferable. The absorption of phenytoin depends on pharmaceutical formulation. Phenytoin is highly bound to plasma proteins, thus the changes in the unbound fraction are of clinical significance. The saturation kinetics of its metabolism and drug interactions have further consequences. Carbamazepine is well absorbed and largely metabolized. Due to the autoinduction its half-life shortens in chronic administration. Valproate is highly, but variably bound to plasma proteins. It is eliminated mainly by metabolism. Due to the long half-life of phenobarbital its plasma concentrations change slowly, and time to the steady-state may be up to 30 days, if no loading dose is given. Primidone is partly metabolized to phenobarbital, and at steady-state plasma concentration of phenobarbital often exceeds that of primidone. Diazepam, clonazepam and nitrazepam are largely bound to plasma proteins and extensively metabolized with the half-lives of 20 to 60 hours.

  16. Methods of assessment of antiepileptic drugs.

    PubMed Central

    Milligan, N; Richens, A

    1981-01-01

    Epilepsy is a symptom with protean manifestations and as such it is a difficult disease in which to carry out a therapeutic trial. The methods available to research workers for the assessment of new antiepileptic drugs are hampered by the fact that epilepsy is a fluctuant condition. Although it is a chronic disorder open to study using cross-over trials and within-patient comparisons, accurate assessment cannot be easily made at any one point in time. Research workers are therefore automatically placed at a time factor disadvantage and this is especially so for those searching for quick methods of evaluating new compounds. The need for a quick and reliable method of assessing a new antiepileptic drug has long been appreciated. This article will discuss the methods currently available and we will begin by considering the most commonly used method of assessment with particular reference to some of the problems involved in conducting a controlled clinical trial in epilepsy. PMID:7272157

  17. [The clinical course of a three year-old girl after overdose of valproic acid].

    PubMed

    Blicher, Thalia Marie; Vestergaard, Esben Thyssen; Dalhoff, Kim Peder

    2012-04-23

    Valproic acid (VA) is an antiepileptic drug, and frequently prescribed in pediatrics. VA overdose results in central nervous system depression, insufficient respiration, tachycardia, hypotension, hepatotoxicity, and electrolyte derangement. We describe the clinical course of a three year-old girl after accidental intake of 6,000 mg VA. Treatment included activated charcoal. Clinical observation included measurements of blood pressure, cardiac telemetry, and measurements of serum VA and metabolic parameters every 4-6 hrs. The girl was discharged successfully after 72 hrs with her usual dose of VA.

  18. Placental passage of antiepileptic drugs at delivery and neonatal outcomes.

    PubMed

    Bank, Anna M; Stowe, Zachary N; Newport, D Jeffrey; Ritchie, James C; Pennell, Page B

    2017-05-01

    Children of women treated with antiepileptic drugs (AEDs) are at increased risk of adverse outcomes detectable in the neonatal period, which may be associated with the amount of AEDs in the fetal circulation. Placental passage of AEDs can be measured by calculating the ratio of umbilical cord to maternal AED concentrations collected at delivery. The aims of this study were to determine the umbilical cord concentrations and umbilical-to-maternal ratios for AEDs, and whether higher cord concentrations are associated with increased risk of neonatal complications. AED cord and maternal blood concentrations from 70 mother-newborn dyads and neonatal complications were recorded. Logistic regressions were performed to determine the association between AED concentrations and complications. Mean umbilical-to-maternal ratios for total concentrations ranged from 0.79 for carbamazepine to 1.20 for valproic acid, and mean umbilical-to-maternal ratios for free concentrations ranged from 0.86 for valproic acid to 1.42 for carbamazepine, indicating complete placental passage. Neither umbilical cord concentrations nor umbilical-to-maternal ratios were associated with adverse neonatal outcomes. Additional investigations are warranted to delineate the relationship between quantified fetal AED exposure and neonatal complications. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  19. Effects of antiepileptic drugs on antioxidant and oxidant molecular pathways: focus on trace elements.

    PubMed

    Nazıroğlu, Mustafa; Yürekli, Vedat Ali

    2013-07-01

    Current reports on trace elements, oxidative stress, and the effect of antiepileptic drugs are poor and controversial. We aimed to review effects of most common used antiepileptics on antioxidant, trace element, calcium ion (Ca(2+)) influx, and oxidant systems in human and experimental animal models. Observations of lower blood or tissue antioxidant levels in epileptic patients and animals compared to controls in recent publications may commonly support the proposed crucial role of antioxidants in the pathogenesis of epilepsy. Effects of old and new antiepileptics on reactive oxygen species (ROS) production in epilepsy are controversial. The old antiepileptic drugs like valproic acid, phenytoin, and carbamazepine induced ROS overproduction, while new epileptic drugs (e.g., topiramate and zonisamide) induced scavenger effects on over production of ROS in human and animals. Antioxidant trace element levels such as selenium, copper, and zinc were generally low in the blood of epileptic patients, indicating trace element deficiencies in the pathogenesis of epilepsy. Recent papers indicate that selenium with/without topiramate administration in human and animals decreased seizure levels, although antioxidant values were increased. Recent studies also reported that sustained depolarization of mitochondrial membranes, enhanced ROS production and Ca(2+) influx may be modulated by topiramate. In conclusion, there is a large number of recent studies about the role of antioxidants or neuroprotectants in clinical and experimental models of epilepsy. New antiepileptic drugs are more prone to restore antioxidant redox systems in brain and neurons.

  20. Oral valproic acid for epilepsy--long-term experience in therapy and side effects.

    PubMed

    Gerstner, Thorsten; Bell, Nellie; König, Stephan

    2008-02-01

    Valproic acid (VPA) is considered to be a drug of first choice and one of the most frequently-prescribed antiepileptic drugs worldwide for the therapy of generalized and focal epilepsies, including special epileptic. It is a broad-spectrum antiepileptic drug and is usually well tolerated. Rarely, serious complications may occur in some patients, including hemorrhagic pancreatitis, coagulopathies, bone marrow suppression, VPA-induced hepatotoxicity and encephalopathy, but there is still a lack of knowledge about the incidence and occurrence of these special side effects. Additionally, the consequences for VPA therapy and indication are more or less unclear. By literature review and own data this review addresses some of the challenges of VPA therapy and its side effects, which are not unique to epilepsy in childhood.

  1. Pharmacogenetics of adverse reactions to antiepileptic drugs.

    PubMed

    Fricke-Galindo, I; Jung-Cook, H; LLerena, A; López-López, M

    2015-05-11

    Adverse drug reactions (ADRs) are a major public health concern and a leading cause of morbidity and mortality in the world. In the case of antiepileptic drugs (AEDs), ADRs constitute a barrier to successful treatment since they decrease treatment adherence and impact patients' quality of life of patients. Pharmacogenetics aims to identify genetic polymorphisms associated with drug safety. This article presents a review of genes coding for drug metabolising enzymes and drug transporters, and HLA system genes that have been linked to AED-induced ADRs. To date, several genetic variations associated with drug safety have been reported: CYP2C9*2 and *3 alleles, which code for enzymes with decreased activity, have been linked to phenytoin (PHT)-induced neurotoxicity; GSTM1 null alleles with hepatotoxicity induced by carbamazepine (CBZ) and valproic acid (VPA); EPHX1 polymorphisms with teratogenesis; ABCC2 genetic variations with CBZ- and VPA-induced neurological ADRs; and HLA alleles (e.g. HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) with cutaneous ADRs. Published findings show that there are ADRs with a pharmacogenetic basis and a high interethnic variability, which indicates a need for future studies in different populations to gather more useful results for larger number of patients. The search for biomarkers that would allow predicting ADRs to AEDs could improve pharmacotherapy for epilepsy. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  2. Standard dose valproic acid does not cause additional cognitive impact in a rodent model of intractable epilepsy.

    PubMed

    Jellett, Adam P; Jenks, Kyle; Lucas, Marcella; Scott, Rod C

    2015-02-01

    Children with epilepsy face significant cognitive and behavioral impairments. These impairments are due to a poorly characterized interaction between the underlying etiology, the effect of seizures and the effect of medication. The large variation in these factors make understanding the main drivers of cognitive impairment in humans extremely difficult. Therefore, we investigated the cognitive effect of seizures and the antiepileptic drug valproic acid in a rodent model of cortical dysplasia. Rats were divided into seizure-receiving and non-receiving groups. Rats experienced frequent early life seizures using the flurothyl inhalation method: 50 seizures between postnatal day 5 and 15 and then one seizure a day following that. Rats were further divided into drug-treated and vehicle treated groups. Valproic acid treated animals were treated from 5 days preceding behavioral testing in the Morris water maze at a clinically relevant concentration. We show here that the main driver of cognitive impairments are the brain malformations, and that persistent seizures in animals with brain malformations and valproic acid caused no additional impact. These findings suggest that neither an appropriate dose of a standard antiepileptic drug or intractable seizures worsen cognition associated with a malformation of cortical development and that alternative treatment strategies to improve cognition are required. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Valproic acid and fatalities in children: a review of individual case safety reports in VigiBase.

    PubMed

    Star, Kristina; Edwards, I Ralph; Choonara, Imti

    2014-01-01

    Valproic acid is an effective first line drug for the treatment of epilepsy. Hepatotoxicity is a rare and potentially fatal adverse reaction for this medicine. Firstly to characterise valproic acid reports on children with fatal outcome and secondly to determine reporting over time of hepatotoxicity with fatal outcome. Individual case safety reports (ICSRs) for children ≤ 17 years with valproic acid and fatal outcome were retrieved from the WHO Global ICSR database, VigiBase, in June 2013. Reports were classified into hepatotoxic reactions or other reactions. Shrinkage observed-to-expected ratios were used to explore the relative reporting trend over time and for patient age. The frequency of polytherapy, i.e. reports with more than one antiepileptic medicine, was investigated. There have been 268 ICSRs with valproic acid and fatal outcome in children, reported from 25 countries since 1977. A total of 156 fatalities were reported with hepatotoxicity, which has been continuously and disproportionally reported over time. There were 31 fatalities with pancreatitis. Other frequently reported events were coma/encephalopathy, seizures, respiratory disorders and coagulopathy. Hepatotoxicity was disproportionally and most commonly reported in children aged 6 years and under (104/156 reports) but affected children of all ages. Polytherapy was significantly more frequently reported for valproic acid with fatal outcome (58%) compared with non-fatal outcome (34%). Hepatotoxicity remains a considerable problem. The risk appears to be greatest in young children (6 years and below) but can occur at any age. Polytherapy is commonly reported and seems to be a risk factor for hepatotoxicity, pancreatitis and other serious adverse drug reactions with valproic acid.

  4. Valproic Acid and Fatalities in Children: A Review of Individual Case Safety Reports in VigiBase

    PubMed Central

    Star, Kristina; Edwards, I. Ralph; Choonara, Imti

    2014-01-01

    Introduction Valproic acid is an effective first line drug for the treatment of epilepsy. Hepatotoxicity is a rare and potentially fatal adverse reaction for this medicine. Objective Firstly to characterise valproic acid reports on children with fatal outcome and secondly to determine reporting over time of hepatotoxicity with fatal outcome. Methods Individual case safety reports (ICSRs) for children ≤17 years with valproic acid and fatal outcome were retrieved from the WHO Global ICSR database, VigiBase, in June 2013. Reports were classified into hepatotoxic reactions or other reactions. Shrinkage observed-to-expected ratios were used to explore the relative reporting trend over time and for patient age. The frequency of polytherapy, i.e. reports with more than one antiepileptic medicine, was investigated. Results There have been 268 ICSRs with valproic acid and fatal outcome in children, reported from 25 countries since 1977. A total of 156 fatalities were reported with hepatotoxicity, which has been continuously and disproportionally reported over time. There were 31 fatalities with pancreatitis. Other frequently reported events were coma/encephalopathy, seizures, respiratory disorders and coagulopathy. Hepatotoxicity was disproportionally and most commonly reported in children aged 6 years and under (104/156 reports) but affected children of all ages. Polytherapy was significantly more frequently reported for valproic acid with fatal outcome (58%) compared with non-fatal outcome (34%). Conclusion Hepatotoxicity remains a considerable problem. The risk appears to be greatest in young children (6 years and below) but can occur at any age. Polytherapy is commonly reported and seems to be a risk factor for hepatotoxicity, pancreatitis and other serious adverse drug reactions with valproic acid. PMID:25302991

  5. [Specific antiepileptic therapy in childhood].

    PubMed

    Kelemen, A; Bozić, K; Zikić, M; Gebauer, K; Filipović, D

    1999-01-01

    This paper deals with basic rational antiepileptic therapeutic procedures in children with special consideration of numerous specificities which occur in childhood: difficulties in establishing correct syndrome diagnosis, predominantly after the first or first few seizures which makes it difficult to decide about appropriate syndrome-specific therapy in regard to efficacy, mechanism of action and range of antiepileptic action; difficulties in assessment of subjective factors (their adverse effects and recognition of seizures with subjective symptoms), children's vulnerability in regard to drug toxicity; age-specific pharmacokinetics of these drugs. The number of available antiepileptics today is great due to new drugs, but carbamazepine (CBZ) and valproate (VAL) are still basic antiepileptics, although carbamazepine's action is reduced to partial epilepsies. The paper describes range of action of available antiepileptics in regard to classification of epileptic seizures and most frequent epileptic syndromes. Adverse effects of antiepileptic agents depend on the age, so examples of age-dependent adverse effects are given considering conventional and new antiepileptics. It is well known that optimal control of seizures depends not only on correct choice of drug, but also on appropriate dosage; it is necessary to be informed about age-dependent characteristics of clinical pharmacokinetics: resorption, metabolism, elimination and half-life of antiepileptics. Although 70-80% of children may be well treated with monotherapy, 15% of children require combination of 2 or more drugs causing drug interactions in resorption, distribution, metabolism and elimination. Examples of antiepileptic interactions as well as interactions of other drugs and antiepileptics are given. The paper also deals with special importance of the psychosocial aspects of epilepsy. These children are often unaccepted by others, mostly because others are afraid of their disease, which contributes to

  6. Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis

    SciTech Connect

    Van Beneden, Katrien; Geers, Caroline; Pauwels, Marina; Mannaerts, Inge; Wissing, Karl M.; Van den Branden, Christiane; Grunsven, Leo A. van

    2013-09-01

    Histone deacetylase (HDAC) inhibitors are promising new compounds for the therapy of fibrotic diseases. In this study we compared the effect of two HDAC inhibitors, trichostatin A and valproic acid, in an experimental model of kidney fibrosis. In mice, doxorubicin (adriamycin) can cause nephropathy characterized by chronic proteinuria, glomerular damage and interstitial inflammation and fibrosis, as seen in human focal segmental glomerulosclerosis. Two treatment regimens were applied, treatment was either started prior to the doxorubicin insult or delayed until a significant degree of proteinuria and fibrosis was present. Pre-treatment of trichostatin A significantly hampered glomerulosclerosis and tubulointerstitial fibrosis, as did the pre-treatment with valproic acid. In contrast, the development of proteinuria was only completely inhibited in the pre-treated valproic acid group, and not in the pre-treated trichostatin A animals. In the postponed treatment with valproic acid, a complete resolution of established doxorubicin-induced proteinuria was achieved within three days, whereas trichostatin A could not correct proteinuria in such a treatment regimen. However, both postponed regimens have comparable efficacy in maintaining the kidney fibrosis to the level reached at the start of the treatments. Moreover, not only the process of fibrosis, but also renal inflammation was attenuated by both HDAC inhibitors. Our data confirm a role for HDACs in renal fibrogenesis and point towards a therapeutic potential for HDAC inhibitors. The effect on renal disease progression and manifestation can however be different for individual HDAC inhibitors. - Highlights: • Valproic acid is a potent antiproteinuric drug, whereas trichostatin A is not. • Trichostatin A and valproic acid reduce kidney fibrosis in doxorubicin nephropathy. • Both valproic acid and trichostatin A attenuate renal inflammation.

  7. Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug.

    PubMed

    Tomson, Torbjörn; Battino, Dina; Perucca, Emilio

    2016-02-01

    Since the serendipitous discovery of its anticonvulsant properties more than 50 years ago, valproic acid has become established as an effective broad-spectrum antiepileptic drug that is particularly useful for the management of generalised epilepsies, for which treatment alternatives are few. However, during the past few years increasing evidence has accumulated that intake of valproic acid during pregnancy is associated with a significant risk of dose-dependent teratogenic effects and impaired postnatal cognitive development in children. Because of these risks, valproic acid should not be used as a first-line drug in women of childbearing potential whenever equally or more effective alternative drugs are available-as in the case of focal epilepsy. In some generalised epilepsy syndromes, such as juvenile myoclonic epilepsy, valproic acid has better documented efficacy than alternative drugs and drug selection should be a shared decision between the clinician and the informed patient based on careful risk-benefit assessment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Zebrafish embryotoxicity test for developmental (neuro)toxicity: Demo case of an integrated screening approach system using anti-epileptic drugs.

    PubMed

    Beker van Woudenberg, Anna; Snel, Cor; Rijkmans, Eke; de Groot, Didima; Bouma, Marga; Hermsen, Sanne; Piersma, Aldert; Menke, Aswin; Wolterbeek, André

    2014-11-01

    To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid (VPA), carbamazepine (CBZ), ethosuximide (ETH) and levetiracetam (LEV). For VPA, histopathology was the most sensitive parameter, showing effects already at 60μM. For CBZ, morphology and MA were the most sensitive parameters, showing effects at 180μM. For ETH, all endpoints showed similar sensitivity (6.6mM), whereas MA was the most sensitive parameter for LEV (40mM). Inclusion of kinetics did not alter the absolute ranking of the compounds, but the relative potency was changed considerably. Taking all together, this demo-case study showed that inclusion of multiple-endpoints in ZET may increase the sensitivity of the assay, contribute to the elucidation of the mode of toxic action and to a better definition of the applicability domain of ZET.

  9. Valproic Acid Attenuates Proteinuria and Kidney Injury

    PubMed Central

    Van Beneden, Katrien; Geers, Caroline; Pauwels, Marina; Mannaerts, Inge; Verbeelen, Dierik; Van den Branden, Christiane

    2011-01-01

    Inhibitors of histone deacetylase (HDAC) have anti-inflammatory and antifibrotic effects in several organs and tissues, but their effect on the progression of renal disease is unknown. Here, we studied the effect of valproic acid in adriamycin-induced nephropathy in mice. Administration of valproic acid before kidney injury prevented the development of proteinuria and the onset of glomerulosclerosis. Even after postponing treatment until the peak of adriamycin-induced proteinuria, valproic acid rapidly decreased the quantity of proteinuria and attenuated the progression of renal disease. Valproic acid abrogated the decrease in glomerular acetylation observed during adriamycin-induced nephropathy. Furthermore, valproic acid attenuated the significant upregulation of profibrotic and proinflammatory genes, the deposition of collagen, and the infiltration of macrophages into the kidney. Valproic acid decreased glomerular apoptosis and proliferation induced by adriamycin. Ultrastructural studies further supported the protective effect of valproic acid on podocytes in this model. Taken together, these data suggest that HDACs contribute to the pathogenesis of renal disease and that HDAC inhibitors may have therapeutic potential in CKD. PMID:21868496

  10. Generic antiepileptic drugs.

    PubMed

    Shaw, Susan J; Krauss, Gregory L

    2008-07-01

    Generic antiepileptic drugs (AEDs) generally provide safe, effective, lower-cost alternatives to brand-name drugs. To be approved by the US Food and Drug Administration (FDA), manufacturers must show that generic drugs are comparable to brand-name formulations, meeting bioequivalence, dissolution, and manufacturing quality standards. Bioequivalence for most generic formulations is evaluated by measuring blood pharmacokinetic values in a small, crossover study of adult volunteers taking single doses of brand-name and generic AEDs. Bioequivalence standards require that ratios of average peak drug concentrations (C(max)) and total extent of absorption (area under the curve, AUC) for a test drug be within 80% to 125% of the reference brand-name drug, with a confidence interval of 90%. Bioequivalence of most generic AEDs, however, has not been evaluated in patients with epilepsy or in other special populations such as elderly patients or patients taking multiple AEDs and prodrugs. Moreover, evidence is limited regarding the adequacy of FDA generic standards for AEDs, particularly for "narrow therapeutic ratio" medications such as oxcarbazepine, although two carbamazepine studies are supportive. Most patients can successfully initiate therapy with generic AEDs and can safely switch from brand-name to generic AEDs (and sometimes back again). The FDA, however, has not shown safety in generic-to-generic switches, which could potentially cause drug concentration changes of up to 40%. Less expensive generic formulations will soon be available for most of the "second generation" AEDs--onisamide, for example, recently had 17 generic formulations approved in the United States--providing substantial savings in health care costs. In summary, although generic AEDs are generally safe and effective for most patients, the current bioequivalence standards may not be sufficient for certain patient populations and for certain drugs, requiring vulnerable patients to be monitored very

  11. [Endocrine effects of antiepileptic drugs].

    PubMed

    Leśkiewicz, Monika; Budziszewska, Bogusława; Lasoń, Władysław

    2008-01-01

    Both seizures and antiepileptic drugs may induce disturbances in hormonal system. Regarding endocrine effects of anticonvulsants, an interaction of these drugs with gonadal, thyroid, and adrenal axis deserves attention. Since majority of antiepileptic drugs block voltage dependent sodium and calcium channels, enhance GABAergic transmission and/or antagonize glutamate receptors, one may expect that similar neurochemical mechanisms are engaged in the interaction of these drugs with synthesis of hypothalamic neurohormones such as gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH) and growth hormone releasing hormone (GHRH). Moreover some antiepileptic drugs may affect hormone metabolism via inhibiting or stimulating cytochrome P-450 iso-enzymes. An influence of antiepileptic drugs on hypothalamic-pituitary-gonadal axis appears to be sex-dependent. In males, valproate decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) but elevated dehydroepiandrosterone sulfate (DHEAS) concentrations. Carbamazepine decreased testosterone/sex-hormone binding globulin (SHBG) ratio, whereas its active metabolite--oxcarbazepine--had no effect on androgens. In females, valproate decreased FSH-stimulated estradiol release and enhanced testosterone level. On the other hand, carbamazepine decreased testosterone level but enhanced SHBG concentration. It has been reported that carbamazepine, oxcarbazepine or joined administration of carbamazepine and valproate decrease thyroxine (T4) level in patients with no effect on thyrotropin (TSH). While valproate itself has no effect on T4, phenytoin, phenobarbital and primidone, as metabolic enzyme inducers, can decrease the level of free and bound thyroxine. On the other hand, new antiepileptics such as levetiracetam, tiagabine, vigabatrine or lamotrigine had no effect on thyroid hormones. With respect to hormonal regulation of metabolic processes, valproate was

  12. Valproic Acid Enhances the Anti-tumor Effect of (-)-gossypol to Burkitt Lymphoma Namalwa Cells.

    PubMed

    Gong, Yi; Ni, Zhen Hong; Zhang, Xi; Chen, Xing Hua; Zou, Zhong Min

    2015-10-01

    Burkitt lymphoma is a highly aggressive B-cell neoplasm. New therapeutic methods are needed to overcome the adverse effect of intensive chemotherapy regimens. Valproic acid and (-)-gossypol are two kinds of chemical compounds used as new anti-tumor drugs in recent years. To investigate the anti-tumor effect of valproic acid and (-)-gossypol, Burkitt lymphoma Namalwa cells were cultured and treated with valproic acid and (-)-gossypol at different concentrations. The proliferation of Namalwa cells was dramatically suppressed after the combination treatment with 2 mmol/L valproic acid and 5 μmol/L (-)-gossypol. The combined treatment also enhanced intrinsic apoptosis by down-regulating anti-apoptotic protein Mcl-1. Moreover, the autophagy flux significantly increased in Namalwa cells after combined treatment. However, the enhanced autophagy showed little effect on cell survival with present regimen. The results confirmed that combination of valproic acid and (-)-gossypol had synergistic anti-tumor effect to Burkitt lymphoma Namalwa cells. The related mechanisms might include the down-regulation of anti-apoptotic protein Mcl-1 and avianized pro-survival role of autophagy. Copyright © 2015 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

  13. Pancreatitis associated with valproic acid: a review of the literature.

    PubMed

    Chapman, S A; Wacksman, G P; Patterson, B D

    2001-12-01

    Black box warnings for valproic acid caution clinicians of the potential for fatal hepatotoxicity and teratogenicity. Since 1979, case reports of pancreatitis induced by valproic acid have been published in the medical literature. As a result, pancreatitis was added to the black box warnings for valproic acid. We performed searches of MEDLINE and International Pharmaceutical Abstracts and found valproic acid-induced pancreatitis in 45 patients from 31 published articles. Demographics, clinical characteristics, and outcomes of these patients are summarized. Recommendations for monitoring the potential for pancreatitis to develop in patients receiving valproic acid therapy are described, as are potential mechanisms for inducement of pancreatitis by valproic acid.

  14. Pharmacokinetic monitoring of antiepileptic drugs.

    PubMed

    Aldaz, A; Ferriols, R; Aumente, D; Calvo, M V; Farre, M R; García, B; Marqués, R; Mas, P; Porta, B; Outeda, M; Soy, D

    2011-01-01

    Monitoring plasma levels of antiepileptic drugs for the treatment and prophylaxis of epilepsy is one of the strategies enabling clinical results to improve by reducing adverse affects and increasing effectiveness. The objective of this article is to review the basic aspects in the monitoring of antiepileptic drugs using a consensus document prepared and endorsed by the pharmacokinetics and pharmacogenetics working group (PK.gen) of the Sociedad Española de Farmacia Hospitalaria (Spanish Society of Hospital Pharmacists). Copyright © 2010 SEFH. Published by Elsevier Espana. All rights reserved.

  15. Hyperammonemia Associated with Valproic Acid Concentrations

    PubMed Central

    Alvariza, Silvana; Magallanes, Laura

    2014-01-01

    Valproic acid, a branched short-chain fatty acid, has numerous action mechanisms which turn it into a broad spectrum anticonvulsant drug and make its use possible in some other pathologies such as bipolar disorder. It is extensively metabolized in liver, representing β-oxidation in the mitochondria one of its main metabolic route (40%). Carnitine is responsible for its entry into the mitochondria as any other fatty acid. Long-term high-dose VPA therapy or acute VPA overdose induces carnitine depletion, resulting in high levels of ammonia in blood. As a high correlation between salivary valproic acid levels and plasma ultrafiltrate levels was found in humans, saliva becomes a promising monitoring fluid in order to study valproic acid pharmacokinetics and its toxic effect. Extended-release (twice daily) formulations of valproic acid or carnitine supplementation are the proposed two therapeutic strategies in order to reverse hyperammonemia. PMID:24868521

  16. Hyperammonemia associated with valproic acid concentrations.

    PubMed

    Vázquez, Marta; Fagiolino, Pietro; Maldonado, Cecilia; Olmos, Ismael; Ibarra, Manuel; Alvariza, Silvana; Guevara, Natalia; Magallanes, Laura; Olano, Ivette

    2014-01-01

    Valproic acid, a branched short-chain fatty acid, has numerous action mechanisms which turn it into a broad spectrum anticonvulsant drug and make its use possible in some other pathologies such as bipolar disorder. It is extensively metabolized in liver, representing β -oxidation in the mitochondria one of its main metabolic route (40%). Carnitine is responsible for its entry into the mitochondria as any other fatty acid. Long-term high-dose VPA therapy or acute VPA overdose induces carnitine depletion, resulting in high levels of ammonia in blood. As a high correlation between salivary valproic acid levels and plasma ultrafiltrate levels was found in humans, saliva becomes a promising monitoring fluid in order to study valproic acid pharmacokinetics and its toxic effect. Extended-release (twice daily) formulations of valproic acid or carnitine supplementation are the proposed two therapeutic strategies in order to reverse hyperammonemia.

  17. Pediatric Sialadenosis Due to Valproic Acid.

    PubMed

    Derin, Hatice; Derin, Serhan; Oltulu, Pembe; Özbek, Orhan; Çaksen, Hüseyin

    2016-12-23

    Sialadenosis is a rare entity characterized by bilateral diffuse, painless swelling of the parotid glands. Its etiology is not clear; however, it may occur due to adverse effects of some drugs. To our knowledge, sialadenosis due to valproic acid has not been reported in the literature up to date in any child. In this article, the authors presented a child who developed sialadenosis due to valproic acid, and improved after stopping use of the drug.

  18. Valproic acid promotes radiosensitization in meningioma stem-like cells.

    PubMed

    Chiou, Hsin-Ying Clair; Lai, Wen-Kuo; Huang, Li-Chun; Huang, Shih-Ming; Chueh, Sheau-Huei; Ma, Hsin-I; Hueng, Dueng-Yuan

    2015-04-30

    Although meningioma stem-like cells have been isolated and characterized, their therapeutic targeting remains a challenge. Meningioma sphere cells (MgSCs) with cancer stem cells properties show chemo- and radioresistance in comparison with meningioma adherent cells (MgACs). We tested the effect of valproic acid (VPA), a commonly used anti-epileptic drug, which passes the blood brain barrier, on cultured MgSCs. VPA reduced the viability of MgSCs and MgACs. In MgSCs, treatment with VPA increased radio-sensitivity, expression of p-cdc2, p-H2AX and cleaved caspase-3 and PARP. Anchorage-independent growth (AIG) was reduced by VPA. AIG was further reduced by combined treatment with irradiation. Expression of a stem cell marker, Oct4, was reduced by VPA. Oct4 was further decreased by combined treatment with irradiation. These results suggest that VPA may be a potential treatment for meningioma through targeting meningioma stem-like cells.

  19. [Relationship between plasma concentrations of valproic acid and hepatotoxicity in patients receiving high doses].

    PubMed

    Ghozzi, H; Hakim, A; Sahnoun, Z; Ben Mahmoud, L; Atheymen, R; Hammami, S; Zeghal, K

    2011-01-01

    Valproic acid (VPA) is an anticonvulsivant drug widely prescribed in the treatment of many forms of generalized epilepsy. In literature, the incidence of liver damage induced by AVP is 0.01%. It is potentialized by the combination therapy (phenobarbital, carbamazepine). Severe hepatotoxicity is rare and appears to be independent of dose and to cause a high mortality. The aim of our study was to evaluate the relationship between plasma concentrations of AVP and the occurrence of side effects especially hepatotoxicity in patients receiving high doses of AVP. In this period, 425 plasmatic AVP monitoring were carried out in our laboratory. From 128 patients treated by high doses of AVP, only 73 were included in this study. Our work showed that adverse effects in epileptics under high doses of AVP was related to the association of the AVP with other antiepileptic in particular carbamazépine, phenobarbital and benzodiazepines rather than supra-therapeutic plasmatic concentrations of AVP. The association of AVP to major antiepileptics (carbamazépine and or phenobarbital) does not seem to generate an increase in the plasmatic concentration of AVP, which was not associated with a greater risque of adverse effects. Consequently, clinical signs of liver toxicity may be present in AVP concentrations generally considered in the therapeutic range especially when used in high doses and or combined with antiepileptic drugs like phenobarbital or carbamazepine. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  20. Role of Histone Acetylation in the Stimulatory Effect of Valproic Acid on Vascular Endothelial Tissue-Type Plasminogen Activator Expression

    PubMed Central

    Magnusson, Mia; Bergh, Niklas; Lunke, Sebastian; El-Osta, Assam; Medcalf, Robert L.; Svensson, Per-Arne; Karlsson, Lena; Jern, Sverker

    2012-01-01

    Aims Stimulated release of tissue-type plasminogen activator (t-PA) is pivotal for an intravascular fibrinolytic response and protects the circulation from occluding thrombosis. Hence, an impaired t-PA production is associated with increased risk for atherothrombotic events. A pharmacological means to stimulate the production of this enzyme may thus be desirable. We investigated if the anti-epileptic drug valproic acid (VPA) is capable of enhancing t-PA expression in vitro in vascular endothelial cells, and further examined if its histone deacetylase (HDAC)-inhibitory activity is of importance for regulating t-PA expression. Methods and Results Human endothelial cells were exposed to valproic acid and t-PA mRNA and protein levels were quantified. Potential changes in histone acetylation status globally and at the t-PA promoter were examined by western blot and chromatin immunoprecipitation. Valproic acid dose-dependently stimulated t-PA mRNA and protein expression in endothelial cells reaching a 2–4-fold increase at clinically relevant concentrations and 10-fold increase at maximal concentrations. Transcription profiling analysis revealed that t-PA is selectively targeted by this agent. Augmented histone acetylation was detected at the t-PA transcription start site, and an attenuated VPA-response was observed with siRNA knock of HDAC3, HDAC5 and HDAC7. Conclusions Valproic acid induces t-PA expression in cultured endothelial cells, and this is associated with increased histone acetylation at the t-PA promoter. Given the apparent potency of valproic acid in stimulating t-PA expression in vitro this substance may be a candidate for pharmacological modulation of endogenous fibrinolysis in man. PMID:22363677

  1. Anticonvulsant profile and teratogenic evaluation of potent new analogues of a valproic acid urea derivative in NMRI mice.

    PubMed

    Okada, Akinobu; Noyori, Hiroko; Yagen, Boris; Shimshoni, Jakob Avi; Bialer, Meir; Fujiwara, Michio

    2009-10-01

    Valproic acid (VPA) is used to treat epilepsy and bipolar disorders, as well as for migraine prophylaxis. However, its clinical use is limited by two life-threatening side effects: hepatotoxicity and teratogenicity. To develop a more potent and safer second-generation VPA drug, the urea derivatives of four VPA analogs (2-ethyl-3-methylpentanoyl urea, 2-ethylhexanoyl urea, 2-ethyl-4-methylpentanoyl urea, and 2-methylbutanoyl urea) were synthesized. Four CNS-active analogs of a VPA urea derivative testedthe anticonvulsant activity in the maximal electroshock seizure test (MES) and subcutaneous metrazol seizure threshold test (scMet). Teratogenic effects of these compounds were evaluated in NMRI mice susceptible to VPA-induced teratogenicity by comparison with VPA. All four VPA analogs showed superior anticonvulsant activity over VPA. Compared with VPA, which induced neural tube defects (NTDs) in fetuses at 1.8 and 3.6 mmol/kg, the analog derivatives induced no NTDs at any concentration up to 4.8 mmol/kg (except for a single abnormality at 3.6 mmol/kg with 2-ethyl-3-methylpentanoyl urea). Skeletal examination also revealed that the acylurea derivatives induced vertebral and rib abnormalities in fetuses markedly less frequently than VPA. Our results confirmed that the analogue derivatives are significantly less teratogenic than VPA in NMRI mice. The CNS-active VPA analogs containing a urea moiety, which have better anticonvulsant potency and lack teratogenicity, are good potential candidates as second-generation VPA antiepileptic drugs. (c) 2009 Wiley-Liss, Inc.

  2. [Acute pancreatitis induced by valproic acid].

    PubMed

    Jomli, R; Nacef, F; Douki, S

    2013-09-01

    We describe the case of an adult man aged 49, without personal antecedents, or family psychiatric history, treated for bipolar disorder since 1995 and stabilised in the last 8 years by valproic acid, who presented in January 2010 an acute drug-induced pancreatitis. Drug-induced pancreatitis has been described since 1955. It may be induced by more than 260 various molecules, as well as by valproic acid, which remains underreported in the literature because there is a problem of imputability. The prevalence of acute drug-induced pancreatitis is set between 1 and 2 %. However, it must remain as an exclusion diagnosis after conducting an exhaustive etiological investigation that will, notably, eliminate bilary and alcoholic causes. The most incriminated drugs are the inhibitors of the conversion enzyme, sulfa drugs, non-steroidal anti-inflammatory, diuretics and anticonvulsants, including valproic acid. In Tunisia, the prescription of valproic acid is increasing in bipolar disorder therapy because it is known for its weak toxicity and easy handling. The case of our patient, who suffers from an acute Balthazar stage C pancreatitis with severe evolution after the drug was stopped, the imputability of valproic acid was considered strong and the collegial decision between the surgery, pharmacovigilance and psychiatry services maintained the drug-induced origin and consequently stopped the valproic acid. This case supports the idea that acute pancreatitis may be induced by valproic acid, even after a prescription lasting for a long period of time, it has no predictable factors and is totally independent of the drug-related dose and of depakine blood levels. There are no predictive factors to the present day, but the evolution is generally good except in rare cases where it may be dangerous. This leads us to think of bipolar patients who are found within weak grounds, such as alcoholics, cancer and HIV positive patients. Copyright © 2013. Published by Elsevier Masson

  3. The Phosphorylation State of GSK3β Serine 9 Correlated to the Development of Valproic Acid-Associated Fetal Cardiac Teratogenicity, Fetal VPA Syndrome, Rescued by Folic Acid Administration.

    PubMed

    Yu, Wei-Hsuan; Ho, Yi-Lwun; Huang, Po-Tsang; Chu, Shian-Ling; Tsai, Huai-Jen; Liou, Horng-Huei

    2016-01-01

    The effects of the phosphorylation state of the glycogen synthase kinase 3β involved in the cardiac myocytes (jelly-like cells) epithelial-mesenchymal transition-associated migration during heart-valve formation were examined through the valproic acid-induced cardiac teratogenicity of transgenic line A34 of Tg in a the Brachydanio rerio embryo model. Valproic acid is an effective anti-epileptic drug; however, when taken by pregnant women to treat epilepsy, it can produce cardiac developmental defects in fetuses. In this study, the role of glycogen synthase kinase 3β in valproic acid-induced cardiac teratogenicity was investigated. Transgenic line A34 of zebrafish embryos was used at 3 days postfertilization. The results show that 78% (18/23) of the embryos treated with 0.10 mM valproic acid (group A) had incomplete chamber formation with normal looping and 22 % (5/23) had abnormal looping. Bradycardia was also found in comparison with control embryos (P < 0.001). For the embryos treated with 0.25 mM valproic acid (group B), 92% (22/24) demonstrated chamber formation failure and looping abnormality. Pericardial effusion, noncontracting ventricles, and enlarged, slowly beating atriums were observed at 6 days postfertilization. Valproic acid inhibited phosphorylation of serine 9 in glycogen synthase kinase 3β in a dose-dependent manner. According to immunochemical staining results, valproic acid was shown to inhibit the mass migration and proliferation of cardiomyocytes in the development of the heart-valve region through inhibition of the GSK3β Ser 9 phosphorylation. Folic acid rescued the GSK3β Ser 9 phosphorylation and reversed the valproic acid-induced cardiac morphological, functional, and biochemical defects.

  4. Comparison between dried blood spot and plasma sampling for therapeutic drug monitoring of antiepileptic drugs in children with epilepsy: A step towards home sampling.

    PubMed

    Linder, Camilla; Wide, Katarina; Walander, Malin; Beck, Olof; Gustafsson, Lars L; Pohanka, Anton

    2017-05-01

    To investigate if dried blood spots could be used for therapeutic drug monitoring of the antiepileptic drugs, carbamazepine, lamotrigine and valproic acid in children with epilepsy. Fingerprick blood samples from 46 children at a neuropediatric outpatient clinic was collected on filterpaper at the same time as capillary plasma sampling. A validated dried blood spot liquid chromatography tandem mass spectrometry method for carbamazepine, lamotrigine and valproic acid was compared with the routine plasma laboratory methods. Method agreement was evaluated and plasma concentrations were estimated by different conversion approaches. Strong correlation was shown between dried blood spot and plasma concentrations for all three drugs, with R2 values>0.89. Regression analysis showed a proportional bias with 35% lower dried blood spot concentrations for valproic acid (n=33) and concentrations were 18% higher for carbamazepine (n=17). A ratio approach was used to make a conversion from dried blood spots to estimated plasma for these two drugs. Dried blood spot concentrations were directly comparable with plasma for lamotrigine (n=20). This study supports that dried blood spot concentrations can be used as an alternative to plasma in a children population for three commonly used antiepileptic drugs with the possibility to expand by adding other antiepileptic drugs. Clinical decisions can be made based on converted (carbamazepine, valproic acid) or unconverted (lamotrigine) dried blood spot concentrations. Dried blood spot sampling, in the future taken at home, will simplify an effective therapeutic drug monitoring for this group of patients who often have concomitant disorders and also reduce costs for society. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  5. Psychiatric uses of antiepileptic treatments.

    PubMed

    Boylan, Laura S.; Devinsky, Orrin; Barry, John J.; Ketter, Terence A.

    2002-10-01

    Antiepileptic drugs (AEDs) possess potent negative or positive psychotropic effects. Clear evidence of benefit exists for valproate, carbamazepine, and lamotrigine in bipolar disorder. Reports of benefit from various AEDs in mood, anxiety, impulse control, and personality disorder are reviewed. Further research is needed to clarify which patients are likely to benefit. Clinicians must closely attend to the ongoing risk/benefit analysis and consider possible iatrogenic worsening of neuropsychiatric symptoms.

  6. [Antiepileptic drugs for the prevention of pediatric migraine].

    PubMed

    Cuvellier, J-C

    2009-12-01

    Migraine, according to the criteria of the International Headache Society, occurs in about 5 to 10% of children and adolescents. Pediatric migraine can cause a significant impact on quality of life. As stated by the American Academy of Neurology and Child Neurology Society's migraine guidelines, situations for prophylaxis consideration include recurring migraines that significantly interfere with daily activities, despite acute therapy; frequent headaches; contraindication, overuse, or failure of acute therapy; adverse reactions to acute therapy; cost of acute and preventive therapies; patient preferences; and presence of uncommon migraine conditions. Preventive therapy may be warranted in as many as 30% of young patients with migraine seen in tertiary headache centers. Headache related disability can be measured by scoring systems such as the Pediatric Migraine Disability Assessment Scale. Numerous medications have been studied to prevent migraines in children, including antihistamines, antidepressants, and antihypertensive agents. However, few high quality clinical trials actually demonstrate efficacy in this population. Recently, many studies dealt with the use of antiepileptic drugs in this indication but there is a paucity of placebo controlled studies. Both topiramate (TPM) and divalproex sodium have been studied in a randomized-controlled study. Only TPM showed efficacy, though, clearly, further controlled trials are needed to confirm these data. Besides unproven efficacy, adverse effects of valproic acid, such as weight gain, somnolence, and alopecia may limit its use. Additional studies are warranted before recommending levetiracetam (LVT), zonisamide (ZNS) and gabapentin (GBP) agents for migraine prophylaxis in children and adolescents.

  7. Systemic mechanisms of antiepileptic protection.

    PubMed

    Karlov, Vladimir

    2015-08-01

    The objectives of this study were as follows: (1) to explore mechanisms that counteract epileptogenesis and provide antiepileptic protection in the life-threatening condition of status epilepticus; and (2) to access functional state of adaptation system and identify the roles of biochemical, humoral, and neurophysiologic factors in the antiepileptic protective system. The experimental part of this research included a series of experiments using animal models which studied the influence of apnea (hypoxia and hypercapnia) on seizure activity; in addition, the role of the prefrontal and orbitofrontal cortex in epileptogenesis and antiepileptogenesis was explored. The clinical part consisted of a series of neurophysiological studies, using a method of multistage dipole localization, and clinical models of absence epilepsy and a tumor in the Rolandic region. One more line of clinical investigations was the study of the functional state of the adaptation system. Thirty-one patients with status epilepticus, with ages 14-56, were recruited. Proteins and fractions, electrolytes, acid-base balance, and 17-oxycorticosteroids in the blood plasma and 17-21-dioxy-20-ketosteroids in the urine were examined in relation to clinical data, EEG, and MRI. As a result of the experiments, it was determined that asphyxia has a two-phase impact on spike activity; an anticonvulsive effect of asphyxia is mediated by hypercapnia, while the orbitofrontal cortex plays the key role in the system of antiepileptic protection through its inhibition of other structures. Further, the mediobasal prefrontal lobe of the dominant hemisphere plays a significant role in antiepileptic protection, and increased levels of blood 17-corticosteroids and catecholamines are protective in the setting of stress from convulsive status epilepticus. The system of antiepileptic protection includes humoral, biochemical, and neurophysiological mechanisms. We identified the roles of all these factors: hypercapnia, in

  8. Valproic acid-induced hepatopathy: nine new fatalities in Germany from 1994 to 2003.

    PubMed

    Koenig, Stephan A; Buesing, Deike; Longin, Elke; Oehring, Randi; Häussermann, Peter; Kluger, Gerhard; Lindmayer, Friedemann; Hanusch, Ralf; Degen, Ingrid; Kuhn, Hans; Samii, Kamrun; Jungck, Albrecht; Brückner, Reinhard; Seitz, Reinhild; Boxtermann, Wolfgang; Weber, Yvonne; Knapp, Rolf; Richard, Hans Helmut; Weidner, Birgit; Kasper, Johannes-Martin; Haensch, Carl-Albrecht; Fitzek, Sabine; Hartmann, Margarete; Borusiak, Peter; Müller-Deile, Andrea; Degenhardt, Volker; Korenke, Georg-Christoph; Hoppen, Thomas; Specht, Ulrich; Gerstner, Thorsten

    2006-12-01

    Valproic acid (VPA) is an antiepileptic drug (AED) commonly used for generalized and focal epilepsies. We provide an update on hepatotoxic side effects in Germany between 1994 and 2003. We mailed a questionnaire to all members of the German Section of the International League Against Epilepsy, asking for VPA-induced side effects, especially severe side effects such as hepatopathy. As a result of our questionnaire, we found 31 cases of reversible hepatotoxicity and nine cases of lethal hepatopathies in Germany from 1994 to 2003. The outcome of patients with severe hepatotoxicity is better than that in the past. The risk of a VPA-induced hepatopathy is not limited to patients younger than 2 years, receiving polytherapy, or patients with congenital or acquired metabolic diseases.

  9. Synthesis and antiepileptic activity of schiff's bases of dialkylamino alkoxy isatin derivatives.

    PubMed

    Swathi, Konda; Sarangapani, Manda

    2015-01-01

    In the present work, some new 5-[2(3)-dialkylamino alkoxy] Indole 3-thiosemicarbazone 2-ones and 5-[2(3)-dialkylamino alkoxy] Indole 3-hydrazone 2-one were prepared from 5-hydroxy isatin. The structures of the products were characterized by IR, NMR, and MASS Spectral studies. All the compounds were examined for antiepileptic activity by maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) induced convulsion method. These compounds were also evaluated for their neurotoxicity study by rotarod method. Some of these compounds showed good antiepileptic activity when compared with standard drug Phenytoin and all the compounds showed less neurotoxicity when compared with standard drug Diazepam.

  10. Comparison of trichostatin A and valproic acid treatment regimens in a mouse model of kidney fibrosis.

    PubMed

    Van Beneden, Katrien; Geers, Caroline; Pauwels, Marina; Mannaerts, Inge; Wissing, Karl M; Van den Branden, Christiane; van Grunsven, Leo A

    2013-09-01

    Histone deacetylase (HDAC) inhibitors are promising new compounds for the therapy of fibrotic diseases. In this study we compared the effect of two HDAC inhibitors, trichostatin A and valproic acid, in an experimental model of kidney fibrosis. In mice, doxorubicin (adriamycin) can cause nephropathy characterized by chronic proteinuria, glomerular damage and interstitial inflammation and fibrosis, as seen in human focal segmental glomerulosclerosis. Two treatment regimens were applied, treatment was either started prior to the doxorubicin insult or delayed until a significant degree of proteinuria and fibrosis was present. Pre-treatment of trichostatin A significantly hampered glomerulosclerosis and tubulointerstitial fibrosis, as did the pre-treatment with valproic acid. In contrast, the development of proteinuria was only completely inhibited in the pre-treated valproic acid group, and not in the pre-treated trichostatin A animals. In the postponed treatment with valproic acid, a complete resolution of established doxorubicin-induced proteinuria was achieved within three days, whereas trichostatin A could not correct proteinuria in such a treatment regimen. However, both postponed regimens have comparable efficacy in maintaining the kidney fibrosis to the level reached at the start of the treatments. Moreover, not only the process of fibrosis, but also renal inflammation was attenuated by both HDAC inhibitors. Our data confirm a role for HDACs in renal fibrogenesis and point towards a therapeutic potential for HDAC inhibitors. The effect on renal disease progression and manifestation can however be different for individual HDAC inhibitors. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Antiepileptic Activity of Preferential Inhibitors of Persistent Sodium Current

    PubMed Central

    Anderson, Lyndsey L.; Thompson, Christopher H.; Hawkins, Nicole A.; Nath, Ravi D.; Petersohn, Adam A.; Rajamani, Sridharan; Bush, William S.; Frankel, Wayne N.; Vanoye, Carlos G.; Kearney, Jennifer A.; George, Alfred L.

    2014-01-01

    Objective Evidence from basic neurophysiology and molecular genetics has implicated persistent sodium current conducted by voltage-gated sodium (NaV) channels as a contributor to the pathogenesis of epilepsy. Many antiepileptic drugs target NaV channels and modulate neuronal excitability mainly by a use-dependent block of transient sodium current, although suppression of persistent current may also contribute to the efficacy of these drugs. We hypothesized that a drug or compound capable of preferential inhibition of persistent sodium current would have antiepileptic activity. Methods We examined the antiepileptic activity of two selective persistent sodium current blockers ranolazine, an FDA-approved drug for treatment of angina pectoris, and GS967, a novel compound with more potent effects on persistent current, in the epileptic Scn2aQ54 mouse model. We also examined the effect of GS967 in the maximal electroshock model and evaluated effects of the compound on neuronal excitability, propensity for hilar neuron loss, development of mossy fiber sprouting and survival of Scn2aQ54 mice. Results We found that ranolazine was capable of reducing seizure frequency by ~50% in Scn2aQ54 mice. The more potent persistent current blocker GS967 reduced seizure frequency by greater than 90% in Scn2aQ54 mice and protected against induced seizures in the maximal electroshock model. GS967 greatly attenuated abnormal spontaneous action potential firing in pyramidal neurons acutely isolated from Scn2aQ54 mice. In addition to seizure suppression in vivo, GS967 treatment greatly improved the survival of Scn2aQ54 mice, prevented hilar neuron loss, and suppressed the development of hippocampal mossy fiber sprouting. Significance Our findings indicate that the selective persistent sodium current blocker GS967 has potent antiepileptic activity and this compound could inform development of new agents. PMID:24862204

  12. Pharmacological interaction between valproic acid and carbapenem: what about levels in pediatrics?

    PubMed

    Miranda Herrero, M Concepción; Alcaraz Romero, Andrés J; Escudero Vilaplana, Vicente; Fernández Lafever, Sarah Nicole; Fernández-Llamazares, Cecilia Martínez; Barredo Valderrama, Estibaliz; Vázquez López, María; de Castro, Pedro

    2015-03-01

    Valproic acid (VPA) is the most commonly used antiepileptic drug in pediatric patients, but its major drawback is its multiple pharmacological interactions. To study children who had been simultaneously treated with carbapenems and valproic acid, considering drug levels, pharmacological interactions and clinical follow-up. Retrospective study of children who simultaneously received treatment with VPA and carbapenems between January 2003 and December 2011. Demographic variables, indication of treatment, dose, VPA plasma levels, interactions, clinical manifestations and medical management were analyzed. 28 children with concomitant treatment with both drugs were included in the study. 64.3% were males. 78.6% of the interactions were observed in the Intensive Care Unit. 60.7% of children had been previously treated VPA and its major indication were generalized seizures. Basal plasma levels of VPA were recorded in 53% and at 24 h after admittance in 60%. "40% of basal VPA levels were below therapeutic range prior to the administration of carbapenem. After the introduction of carbapenem 88% of level determinations were below therapeutic range". 54.5% of the patients that were chronically receiving VPA and had good control of epilepsy before admission had seizures during the coadministration. One patient that was on VPA before admission but with bad control of epilepsy worsened, and one patient that acutely received VPA did not achieve seizure freedom. In these cases it was necessary to either increase VPA dose or change to a different antiepileptic drug. Little is known about the mechanism of pharmacologic interactions between carbapenems and VPA, but it leads to a reduction in plasma levels that may cause a loss of seizure control, so simultaneous use of both drugs should be avoided when possible. If not, VPA levels should be monitored. Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  13. Antiepileptic drugs and brain development.

    PubMed

    Ikonomidou, Chrysanthy; Turski, Lechoslaw

    2010-01-01

    Epilepsy, the most common neurological disorder in young humans, has its highest incidence during the first year of life. Antiepileptic drugs (AEDs) which are used to treat seizures in infants, children and pregnant women target ion channels, neurotransmitters and second messenger systems in the brain. The same targets regulate brain processes essential both for propagation of seizures and for brain development, learning, memory and emotional behavior. Here we review adverse effects of AEDs in the developing mammalian brain. In addition, we discuss mechanisms explaining adverse effects of AEDs in the developing mammalian brain including interference with cell proliferation and migration, neurogenesis, axonal arborization, synaptogenesis, synaptic plasticity and physiological apoptotic cell death.

  14. The influence of established and new antiepileptic drugs on visual perception. II. A controlled study in patients with epilepsy under long-term antiepileptic medication.

    PubMed

    Steinhoff, B J; Freudenthaler, N; Paulus, W

    1997-12-01

    In this study, we investigated visual performance under chronic antiepileptic drug treatment. Patients were under carbamazepine (CBZ) (n = 18), valproic acid (VPA) (n = 9), CBZ and vigabatrin (VGB) (n = 4), CBZ and gabapentin (GBP) (n = 8), and under CBZ and topiramate (TPR) (n = 6), respectively. Seven untreated patients with epilepsy and 42 healthy volunteers served as controls. The test battery comprised the Lanthony-D15-désaturé colour perception test, increment, postadaptation and transient tritanopia (TT) threshold measurements, visual perception threshold assessments for monochromatic and chromatic gratings and gaussian dots, and critical flicker fusion (CFF) tests. No differences were seen between naive patients and healthy controls. Patients under drug treatment always showed alterations of visual perception. Postadaptation and TT thresholds were altered under each drug regimen after short delays between switching off the adaptation light and switching on the blue test light. Threshold elevations were maximum under the combination of CBZ and TPR and lowest under CBZ and GBP. Consistent impairment of the CFF was seen under combined CBZ and TPR whereas VPA as well as combined CBZ and VGB led to ameliorations the mechanisms of which are discussed. The other tests were less sensitive. In conclusion, alterations of visual function were apparent under chronic antiepileptic drug treatment both with established and new agents. However, it may be difficult to distinguish between effects based on specific modes of action and nonspecific retino- and neurotoxicity.

  15. Molecular dissection of the valproic acid effects on glioma cells

    PubMed Central

    Hoja, Sabine; Schulze, Markus; Rehli, Michael; Proescholdt, Martin; Herold-Mende, Christel; Hau, Peter; Riemenschneider, Markus J.

    2016-01-01

    Many glioblastoma patients suffer from seizures why they are treated with antiepileptic agents. Valproic acid (VPA) is a histone deacetylase inhibitor that apart from its anticonvulsive effects in some retrospective studies has been suggested to lead to a superior outcome of glioblastoma patients. However, the exact molecular effects of VPA treatment on glioblastoma cells have not yet been deciphered. We treated glioblastoma cells with VPA, recorded the functional effects of this treatment and performed a global and unbiased next generation sequencing study on the chromatin (ChIP) and RNA level. 1) VPA treatment clearly sensitized glioma cells to temozolomide: A protruding VPA-induced molecular feature in this context was the transcriptional upregulation/reexpression of numerous solute carrier (SLC) transporters that was also reflected by euchromatinization on the histone level and a reexpression of SLC transporters in human biopsy samples after VPA treatment. DNA repair genes were adversely reduced. 2) VPA treatment, however, also reduced cell proliferation in temozolomide-naive cells: On the molecular level in this context we observed a transcriptional upregulation/reexpression and euchromatinization of several glioblastoma relevant tumor suppressor genes and a reduction of stemness markers, while transcriptional subtype classification (mesenchymal/proneural) remained unaltered. Taken together, these findings argue for both temozolomide-dependent and -independent effects of VPA. VPA might increase the uptake of temozolomide and simultaneously lead to a less malignant glioblastoma phenotype. From a mere molecular perspective these findings might indicate a surplus value of VPA in glioblastoma therapy and could therefore contribute an additional ratio for clinical decision making. PMID:27556305

  16. Weight-reducing side effects of the antiepileptic agents topiramate and zonisamide.

    PubMed

    Antel, J; Hebebrand, J

    2012-01-01

    Drug-induced weight alteration can be a serious side effect that applies to several therapeutic agents and must be referred to in the respective approved labeling texts. The side effect may become health threatening in case of significant weight change in either direction. Several antiepileptic drugs (AEDs) are associated with weight gain such as gabapentin, pregabalin, valproic acid, and vigabatrin and to some extent carbamazepine. Others are weight neutral such as lamotrigine, levetiracetam, and phenytoin or associated with slight weight loss as, e.g., felbamate. The focus of this chapter is on the two AEDs causing strong weight loss: topiramate and zonisamide. For both drugs, several molecular mechanisms of actions are published. We provide a review of these potential mechanisms, some of which are based on in vivo studies in animal models for obesity, and of clinical studies exploring these two drugs as single entities or in combinations with other agents.

  17. The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism

    PubMed Central

    Fan, Hueng-Chuen; Lee, Herng-Shen; Chang, Kai-Ping; Lee, Yi-Yen; Lai, Hsin-Chuan; Hung, Pi-Lien; Lee, Hsiu-Fen; Chi, Ching-Shiang

    2016-01-01

    Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities. PMID:27490534

  18. Are antiepileptic drugs used in the treatment of migraine associated with an increased risk of suicidality?

    PubMed

    Kanner, Andres M

    2011-06-01

    Three antiepileptic drugs (AEDs), valproic acid, gabapentin, and topiramate (TPM), are used frequently in the prophylactic treatment of migraines. In December 2008, the US Food and Drug Administration issued a warning suggesting that the use of all AEDs is associated with an increased risk of suicidal ideation and behavior. This warning has been received by the medical community with great skepticism, and the validity of the findings of the meta-analysis that led to its publication has been questioned because of various methodological problems. Yet, migraine by itself is associated with an increased risk of suicidal ideation and behavior as well as with an increased risk of psychiatric disorders that facilitate the development of suicidal behavior. Furthermore, TPM has been associated with psychiatric adverse events that potentially could result in suicidal ideation and behavior. In this article, we review data to determine whether the AEDs used in the prevention of migraine are associated with an increased risk of suicidality.

  19. Valproic acid I: time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats.

    PubMed

    Tong, Vincent; Teng, Xiao Wei; Chang, Thomas K H; Abbott, Frank S

    2005-08-01

    A single dose of valproic acid (VPA), which is a widely used antiepileptic drug, is associated with oxidative stress in rats, as recently demonstrated by elevated levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP). To determine whether there was a temporal relationship between VPA-associated oxidative stress and hepatotoxicity, adult male Sprague-Dawley rats were treated ip with VPA (500 mg/kg) or 0.9% saline (vehicle) once daily for 2, 4, 7, 10, or 14 days. Oxidative stress was assessed by determining plasma and liver levels of 15-F(2t)-IsoP, lipid hydroperoxides (LPO), and thiobarbituric acid reactive substances (TBARs). Plasma and liver 15-F(2t)-IsoP were elevated and reached a plateau after day 2 of VPA treatment compared to control. Liver LPO levels were not elevated until day 7 of treatment (1.8-fold versus control, p < 0.05). Liver and plasma TBARs were not increased until 14 days (2-fold vs. control, p < 0.05). Liver toxicity was evaluated based on serum levels of alpha-glutathione S-transferase (alpha-GST) and by histology. Serum alpha-GST levels were significantly elevated by day 4, which corresponded to hepatotoxicity as shown by the increasing incidence of inflammation of the liver capsule, necrosis, and steatosis throughout the study. The liver levels of beta-oxidation metabolites of VPA were decreased by day 14, while the levels of 4-ene-VPA and (E)-2,4-diene-VPA were not elevated throughout the study. Overall, these findings indicate that VPA treatment results in oxidative stress, as measured by levels of 15-F(2t)-IsoP, which precedes the onset of necrosis, steatosis, and elevated levels of serum alpha-GST.

  20. [Hemoperfusion in the treatment of acute valproic acid intoxication].

    PubMed

    Peces, R; Fernández, E J; Sánchez, R J; Peces, C; Montero, A; Selgas, R

    2007-01-01

    Valproic acid is increasingly used in the treatment of epilepsy, and also prescribed for bipolar affective disorders, schizoaffective disorders, schizophrenia and migraine prophylaxis. Valproic acid intoxication with suicide attempt is a relatively common clinical problem that can result in coma, respiratory depression, pancytopenia, hemodynamic instability and death. The drug's relatively low molecular weight, small volume of distribution and saturable protein-binding render it potentially amenable to exracorporeal removal (hemodialysis, hemoperfusion or hemofiltration ), but published experience is scarce. We describe a case report involving valproic acid intoxication with ingestion of ethanol, who was successfully treated with charcoal hemoperfusion. With this treatment the half-life of valproic acid was reduced with rapid lowering of valproic acid levels and clinical improvement. Based on our experience in this patient and a review of previously reported cases, charcoal hemoperfusion should be considered for serious valproic acid intoxication because free as well as bound drug fractions are eliminated via this technique.

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

    PubMed

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

    2016-08-01

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

  2. Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy

    PubMed Central

    Saruwatari, Junji; Ishitsu, Takateru; Nakagawa, Kazuko

    2010-01-01

    Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmaco-dynamics of antiepileptic drugs (AEDs). However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450 (CYP) 2C9 and/or CYP2C19 could affect not only the pharmacokinetics, but also the pharmacodynamics of phenytoin therapy. CYP2C19 deficient genotypes were associated with the higher serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the higher clinical efficacy of clobazam therapy than the other CYP2C19 genotypes. The defective alleles of CYP2C9 and/or CYP2C19 were also found to have clinically significant effects on the inter-individual variabilities in the population pharmacokinetics of phenobarbital, valproic acid and zonisamide. EPHX1 polymorphisms may be associated with the pharmacokinetics of carbamazepine and the risk of phenytoin-induced congenital malformations. Similarly, the UDP-glucuronosyltransferase 2B7 genotype may affect the pharmacokinetics of lamotrigine. Gluthatione S-transferase null genotypes are implicated in an increased risk of hepatotoxicity caused by carbamazepine and valproic acid. This article summarizes the state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies. Future directions for the dose-adjustment of AED are discussed. PMID:27713373

  3. Valproic acid induced encephalopathy--19 new cases in Germany from 1994 to 2003--a side effect associated to VPA-therapy not only in young children.

    PubMed

    Gerstner, Thorsten; Buesing, Deike; Longin, Elke; Bendl, Claudia; Wenzel, Dieter; Scheid, Brigitte; Goetze, Gisela; Macke, Alfons; Lippert, Gerhard; Klostermann, Wolfgang; Mayer, Geert; Augspach-Hofmann, Regine; Fitzek, Sabine; Haensch, Carl-Albrecht; Reuland, Markus; Koenig, Stephan A

    2006-09-01

    Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well-tolerated. Rare serious complications may occur in some patients, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity and VPA-induced encephalopathy. The typical signs of VPA-induced encephalopathy are impaired consciousness, sometimes marked EEG background slowing, increased seizure frequency, with or without hyperammonemia. There is still no proof of causative effect of VPA in patients with encephalopathy, but only of an association with an assumed causal relation. We report 19 patients with VPA-associated encephalopathy in Germany from the years 1994 to 2003, none of whom had been published previously.

  4. Teratogenic effects of antiepileptic drugs

    PubMed Central

    Hill, Denise S; Wlodarczyk, Bogdan J; Palacios, Ana M; Finnell, Richard H

    2010-01-01

    Many antiepileptic drugs (AEDs) have therapeutic applications that extend beyond epilepsy to include neuropathic pain, migraine headaches and psychiatric disorders. The risk of some AEDs has been clearly established, but for newer drugs, small sample sizes and polytherapy exposures preclude a conclusive determination of their teratogenic potential. Most women with epilepsy will require AED therapy throughout their entire pregnancy to control seizures; the vast majority of pregnancies in women with epilepsy have positive outcomes. A conservative estimate suggests that AED monotherapy doubles, and polytherapy triples, the risk for major congenital malformations. Furthermore, while evidence is still accruing, recent investigations suggest that exposure to select AEDs results in altered cognitive function later in development. There is no evidence to suggest that additional folic acid supplementation ameliorates the increased risk of congenital malformations conferred by in utero AED exposure. PMID:20518610

  5. Antiepileptic drugs and Tourette syndrome.

    PubMed

    Cavanna, Andrea E; Nani, Andrea

    2013-01-01

    Tourette syndrome is a neurodevelopmental disorder characterized by the chronic presence of multiple motor tics and at least one vocal/phonic tic for the duration of 1 year. The clinical picture of patients with Tourette syndrome is often complicated by tic-related behavioral problems and associated psychopathology. The pathophysiology of Tourette syndrome is not thoroughly understood, however converging evidence from neuroimaging studies suggests abnormalities within the frontostriatal pathways which are mediated by several neurotransmitters. The pharmacological management of the tic symptoms focuses on the dopaminergic and noradrenergic pathways and aims to improve the health-related quality of life of patients. The most common medications are neuroleptics and atypical antipsychotics, which have a strong D2 blocking action. Also, preliminary studies have documented the efficacy of antiepileptic drugs in controlling tics. Thus far, two anticonvulsants (topiramate and levetiracetam) have been tested with a randomized, double-blind, placebo-controlled procedure in the treatment of tics. A study has reported an improvement in the control of tics with topiramate. This pharmacological agent was also reported to be well tolerated by the patients. However, the most frequent observed topiramate side effects (such as somnolence, cognitive problems, and weight loss) could not have manifested because of the short trial duration. Levetiracetam has shown conflicting results. A study found significant improvements in the control of tics, also associated with improvement in school performance. These results, however, were not replicated in other studies. Further investigations are therefore needed to assess the real efficacy of antiepileptic drugs in the treatment of tics. © 2013 Elsevier Inc. All rights reserved.

  6. Why are antiepileptic drugs used for nonepileptic conditions?

    PubMed

    Bialer, Meir

    2012-12-01

    Antiepileptic drugs (AEDs) are used to treat various nonepileptic central nervous system (CNS) disorders, both in neurology and psychiatry. Most AEDs have multiple mechanisms of action (MOAs), which include modulation of γ-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission, and alteration of voltage-gated ion channels or intracellular signaling pathways. These MOAs may explain the efficacy of AEDs in the treatment of bipolar disorder and neuropathic pain. Bipolar disorder and epilepsy have some common features, such as their episodic nature and associated kindling phenomena, which led to the regulatory approval and use of the AEDs carbamazepine (CBZ), valproic acid (VPA), and lamotrigine (LTG) in the treatment of bipolar disorder. A major limitation for the development of drugs with improved mood-stabilizing activity is the lack of knowledge on the mechanism of treatment for bipolar disorder. In contrast to epilepsy, no animal models in bipolar disorder are universally accepted and no model is able to exhibit the characteristic mood swings. Although most AEDs have now been investigated for their mood-stabilizing effects, only three (e.g., VPA, CBZ, and LTG) demonstrated clinical efficacy in patients. This suggests that the mechanism of drug action in mood disorder and in epilepsy only partially overlaps. Peripheral nerve damage leads to the initiation of cellular and molecular changes in the nervous system resulting in ectopic, repetitive firing perceived as chronic pain. Epileptic seizures are also characterized by hyperexcitability of neurons in the brain. The spontaneous electrogenesis in neuropathic pain has similarities to that of epilepsy. Alteration in sodium channels expression suggests that the mechanism underlying epileptic hyperexcitability may be similar to those underlying neuropathic pain. The AEDs gabapentin (GBP) and pregabalin (PGB) have become the mainstay of treatment for various neuropathic pain syndromes, owing to their ability

  7. Pharmacogenetics of antiepileptic drug-induced hypersensitivity.

    PubMed

    Bloch, Katarzyna M; Sills, Graeme J; Pirmohamed, Munir; Alfirevic, Ana

    2014-04-01

    Antiepileptic drugs can induce potentially life-threatening hypersensitivity reactions such as Stevens-Johnson syndrome at a frequency of one in 10,000 to one in 1000 treated patients. There is a considerable cross-reactivity among different antiepileptic drugs but the mechanisms are not known. In this review we have summarized current evidence on antiepileptic drug-induced hypersensitivity reactions and performed meta-analyses of published case-control studies that investigated associations between HLA alleles and several antiepileptic drugs in diverse populations. As the heterogeneity between studies was high, we conducted subsequent subgroup analyses and showed that HLA-B*15:02 was associated with carbamazepine, lamotrigine and phenytoin-induced Stevens-Johnson syndrome in Asian populations indicating that pretreatment testing may prevent cross-reactivity. Additionally, we explored the potential of new, high-throughput technologies that may help to understand the mechanisms and predict the risk of adverse drug reactions in the future.

  8. Various simultaneous nail changes due to valproic acid use.

    PubMed

    Solak, Berna; Oztas Kara, Rabia; Erdem, T

    2017-03-01

    There are only a few case reports about nail changes due to valproic acid in the literature despite its widespread use. We present a 50-year-old man who had onycholysis, roughness of the nail surface and brownish-yellow discoloration of both fingernails and toenails, which remarkably ameliorated upon cessation of valproic acid.

  9. Neuroprotective effects of antiepileptic drugs.

    PubMed

    Trojnar, Michał K; Małek, Robert; Chrościńska, Magdalena; Nowak, Stanisław; Błaszczyk, Barbara; Czuczwar, Stanisław J

    2002-01-01

    Experimental and clinical data indicate that epilepsy and seizures lead to neuronal cell loss and irreversible brain damage. This neurodegeneration results not only in the central nervous system dysfunction but may also be responsible for the decreased efficacy of some antiepileptic drugs (AEDs). The aim of this review was to assemble current literature data on neuroprotective properties of AEDs. The list of hypothetical neuroprotectants is long and consists of substances which act via different mechanisms. We focus on AEDs since this heterogeneous group of pharmaceuticals, as far as mechanisms of their action and mechanisms of neuronal death are concerned, should provide protection in addition to antiseizure effect itself. Most studies on neuroprotection are based on animal experimental models of neuronal degeneration. Electrically and pharmacologically evoked seizures as well as different models of ischemia are frequently used. Although our knowledge about properties of AEDs is still not complete and discrepancies occasionally occur, the group seems to be promising in terms of neuroprotection. Some of the drugs, though, turn out to be neutral or even have adverse effects on the central nervous system, especially on immature brain tissue (barbiturates and benzodiazepines). Unfortunatelly, we cannot fully extrapolate animal data to humans, therefore further well designed clinical trials are necessary to determine neuroprotective properties of AEDs in humans. However, there is a hope that AEDs will have a potential to serve as neuroprotectants not only in seizures, but perhaps, in other neurodegenerative conditions in humans as well. The novel AEDs (especially lamotrigine, tiagabine, and topiramate) seem particularly promising.

  10. Design and synthesis of chroman derivatives with dual anti-breast cancer and antiepileptic activities

    PubMed Central

    Rawat, Pinki; Verma, Saurabh Manaswita

    2016-01-01

    A series of chroman derivatives was designed, prepared, and examined for their anti-breast cancer and antiepileptic activities. All synthesized compounds yielded results that were in good agreement with spectral data. The bioassay showed that some of the resultant compounds exerted remarkable inhibitory effects on growth of human breast cancer cell line MCF-7. In particular, compound 6i (the concentration required for 50% inhibition of cell growth [GI50] =34.7 µM) exerted promising anticancer activity toward MCF-7 cell line. Additionally, compounds 6b, 6c, 6d, 6e, 6g, 6i, and 6l showed advanced antiepileptic activity than reference drugs. None of the compounds showed neurotoxicity, as determined by the rotarod test. The obtained results proved that these distinctive compounds could be relevant as models for future discovery and research, as well as for the production of more number of active derivatives. PMID:27621598

  11. Stevens-Johnson Syndrome triggered by a combination of clobazam, lamotrigine and valproic acid in a 7-year-old child.

    PubMed

    Yapici, A K; Fidanci, M K; Kilic, S; Balamtekin, N; Mutluay Arslan, M; Yavuz, S T; Kalman, S

    2014-09-30

    Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are diseases within the spectrum of severe cutaneous adverse reactions affecting skin and mucous membranes. Antiepileptic drugs (AEDs) are used in combination, leading to potential pharmacokinetic or pharmacodynamic interactions, causing more adverse effects than might occur when the AED is taken as monotherapy. Here, we report a rare case of SJS triggered by a combination of clobazam, lamotrigine and valproic acid in a 7-year-old boy. Because of inadequate seizure control, lorazepam was replaced with clobazam. Four weeks after the addition of clobazam, the patient developed SJS with a generalized rash, fever, with liver and kidney involvement, and eosinophilia one week after the initiation of treatment. All antiepileptic drugs were discontinued, and intravenous methylprednisolone, prophylactic systemic antibiotics, intravenous fluid supplement, antipyretic, special wound care, and supportive medical care for SJS were administered. He was discharged in a stable condition on the 18th day. Our case suggests that a drug-drug interaction between valproate, lamotrigine and clobazam contributed to the development of SJS. When the clobazam was added to valproic acid and lamotrigine co-medication, the lamotrigine dose should have been decreased.

  12. Suppression of NMDA receptor function in mice prenatally exposed to valproic acid improves social deficits and repetitive behaviors

    PubMed Central

    Kang, Jaeseung; Kim, Eunjoon

    2015-01-01

    Animals prenatally exposed to valproic acid (VPA), an antiepileptic agent, have been used as a model for autism spectrum disorders (ASDs). Previous studies have identified enhanced NMDA receptor (NMDAR) function in the brain of VPA rats, and demonstrated that pharmacological suppression of NMDAR function normalizes social deficits in these animals. However, whether repetitive behavior, another key feature of ASDs, can be rescued by NMDAR inhibition remains unknown. We report here that memantine, an NMDAR antagonist, administered to VPA mice rescues both social deficits and repetitive behaviors such as self-grooming and jumping. These results suggest that suppression of elevated NMDAR function in VPA animals normalizes repetitive behaviors in addition to social deficits. PMID:26074764

  13. Carnitine in the treatment of valproic acid-induced toxicity.

    PubMed

    Lheureux, Philippe E R; Hantson, Philippe

    2009-02-01

    Valproic acid (VPA) is a broad-spectrum antiepileptic drug that is now used commonly for several other neurological and psychiatric indications. VPA is usually well tolerated, but serious complications, including hepatotoxicity and hyperammonemic encephalopathy, may occur. These complications may also arise following acute VPA overdose, the incidence of which is increasing. Intoxication usually only results in mild central nervous system depression, but serious toxicity and death have been reported. As a branched chain carboxylic acid, VPA is extensively metabolized by the liver via glucuronic acid conjugation, mitochondrial beta- and cytosolic omega-oxidation to produce multiple metabolites, some of which may be involved in its toxicity. Carnitine is an amino acid derivative that is an essential cofactor in the beta-oxidation of fatty acids. It is synthesized endogenously from the essential amino acids, methionine and lysine. VPA inhibits the biosynthesis of carnitine by decreasing the concentration of alpha-ketoglutarate and may contribute to carnitine deficiency. It is postulated that carnitine supplementation may increase the beta-oxidation of VPA, thereby limiting cytosolic omega-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation. VPA-induced hepatotoxicity and hyperammonemic encephalopathy may be promoted either by a pre-existing carnitine deficiency or by deficiency induced by VPA per se. Some experimental and clinical data suggest that early intravenous supplementation with l-carnitine could improve survival in severe VPA-induced hepatotoxicity. Carnitine administration has been shown to speed the decrease of ammonemia in patients with VPA-induced encephalopathy although a correlation between ammonia concentrations and the clinical condition was not always observed. As it does not appear to be harmful, l-carnitine is commonly recommended in severe VPA poisoning, especially in children, although the

  14. Valproic Acid: Special Considerations and Targeted Monitoring.

    PubMed

    Collins-Yoder, Angela; Lowell, Jordan

    2017-02-01

    Valproic acid (VPA) is a medication used to treat multiple neuroscience conditions. It is an inexpensive and useful medication, with a low incidence of adverse drug events. Nonetheless, optimal clinical outcomes require that a series of screening and laboratory steps be followed before the initiation of VPA therapy. An additional aspect of pharmacovigilance is to recognize clinical patterns signaling genetic traits that preclude VPA, background of the black box warnings, targeted assessments, and laboratory monitoring indicated while on VPA. The intention of this article is to provide a focused summary of published information clinically relevant to prescribing and monitoring these patients.

  15. Effects of Valproic Acid on Axonal Regeneration and Recovery of Motor Function after Peripheral Nerve Injury in the Rat

    PubMed Central

    Rao, Ting; Wu, Fei; Xing, Danmou; Peng, Zhengren; Ren, Dong; Feng, Wei; Chen, Yan; Zhao, Zhiming; Wang, Huan; Wang, Junweng; Kan, Wusheng; Zhang, Qingsong

    2014-01-01

    Background: Valproic acid (VPA) is used to be an effective anti-epileptic drug and mood stabilizer. It has recently been demonstrated that VPA could promote neurite outgrowth, activate the extracellular signal regulated kinase pathway, and increases bcl-2 and growth cone-associated protein 43 levels in spinal cord. In the present research we demonstrate the effect of VPA on peripheral nerve regeneration and recovery of motor function following sciatic nerve transaction in rats. Methods: The rats in VPA group and control group were administered with valproic acid (300mg/kg) and sodium chloride respectively after operation. Each animal was observed sciatic nerve index (SFI) at 2-week intervals and studied electrophysiology at 4-week intervals for 12 weeks. Histological and morphometrical analyses were performed 12 weeks after operation. Using the digital image-analysis system, thickness of the myelin sheath was measured, and total numbers of regenerated axons were counted. Results: There was a significant difference in SFI, electrophysiological index (motor-nerve conduct velocity), and morphometrical results (regenerated axon number and thickness of myelin sheath) in nerve regeneration between the VPA group and controls (P<0.05). Conclusions: The results demonstrated that VPA is able to enhance sciatic nerve regeneration in rats, suggesting the potential clinical application of VPA for the treatment of peripheral nerve injury in humans. PMID:25207308

  16. Structure-function studies for the panacea, valproic acid.

    PubMed

    Terbach, Nicole; Williams, Robin S B

    2009-10-01

    The anticonvulsant properties of VPA (valproic acid), a branched short-chain fatty acid, were serendipitously discovered in 1963. Since then, therapeutic roles of VPA have increased to include bipolar disorder and migraine prophylaxis, and have more recently been proposed in cancer, Alzheimer's disease and HIV treatment. These numerous therapeutic roles elevate VPA to near 'panacea' level. Surprisingly, the mechanisms of action of VPA in the treatment of many of these disorders remain unclear, although it has been shown to alter a wide variety of signalling pathways and a small number of direct targets. To analyse the mechanism of action of VPA, a number of studies have defined the structural characteristics of VPA-related compounds giving rise to distinct therapeutic and cellular effects, including adverse effects such as teratogenicity and hepatotoxicity. These studies raise the possibility of identifying target-specific novel compounds, providing better therapeutic action or reduced side effects. This short review will describe potential therapeutic pathways targeted by VPA, and highlight studies showing structural constraints necessary for these effects.

  17. Successful reintroduction of valproic acid after the occurrence of pancytopenia.

    PubMed

    Stewart, Jonathan T

    2011-10-01

    Valproic acid is associated with a variety of hematologic abnormalities, most commonly thrombocytopenia. Pancytopenia is much less common and potentially much more serious. Little is known about the natural course of valproate-induced pancytopenia. We present a patient who developed pancytopenia while taking valproic acid for bipolar illness. After failing to respond to several other mood stabilizers, valproic acid was cautiously reintroduced with close hematologic monitoring. The pancytopenia has not recurred in the past 6 months. Pancytopenia may not represent an absolute contraindication to continuing valproate therapy, although caution is warranted. Published by EM Inc USA.

  18. The effect of uridine diphosphate glucuronosyltransferase (UGT)1A6 genetic polymorphism on valproic acid pharmacokinetics in Indian patients with epilepsy: a pharmacogenetic approach.

    PubMed

    Munisamy, Murali; Tripathi, Manjari; Behari, Madhuri; Raghavan, S; Jain, D C; Ramanujam, Barghavi; Arumugam, Karthik; Rajakannan, Thiyagu; Mallayasamy, Surulivel Rajan; Subbiah, Vivekanandhan

    2013-10-01

    Sodium valproate is a widely prescribed broad-spectrum antiepileptic drug. It shows high inter-individual variability in pharmacokinetics and pharmacodynamics and has a narrow therapeutic range. We evaluated the effects of polymorphic uridine diphosphate glucuronosyltransferase (UGT)1A6 (541A>G, 552A>C) metabolizing enzyme on the pharmacokinetics of sodium valproate in the patients with epilepsy who showed toxicity to therapy. Genotype analysis of the patients was made with polymerase chain-restriction fragment length polymorphism (RFLP) with sequencing. Plasma drug concentrations were measured with reversed phase high-performance liquid chromatography (HPLC) and concentration-time data were analyzed by using a non-compartmental approach. The results of this study suggested a significant genotypic as well as allelic association with valproic acid toxicity for UGT1A6 (541A>G) or UGT1A6 (552A>C) polymorphic enzymes. The elimination half-life (t ½ = 40.2 h) of valproic acid was longer and the clearance rate (CL = 917 ml/h) was lower in the poor metabolizers group of UGT1A6 (552A>C) polymorphism who showed toxicity than in the intermediate metabolizers group (t ½ = 35.5 h, CL = 1,022 ml/h) or the extensive metabolizers group (t ½ = 25.4 h, CL = 1,404 ml/h). Our findings suggest that the UGT1A6 (552A>C) genetic polymorphism plays a significant role in the steady state concentration of valproic acid, and it thereby has an impact on the toxicity of the valproic acid used in the patients with epilepsy.

  19. [Mechanism of action of antiepileptic drugs].

    PubMed

    Saidón, Patricia

    2003-01-01

    Antiepileptic drugs (DAEs) act through different mechanisms of action: increase in central inhibition, inhibition of excitatorios mechanisms and modification of the excitability through their action on the ionic channels. Epilepsy is characterized by an abnormal and hypersynchronic unloading of a neuronal population. The activity of numerous drugs is associated to increase in gabaergic activity. Another group of drugs decreases excitatory mechanisms, through the inhibition of ionic channels, or through a decrease in the activity of the excitatory neurotransmitters. There are some of antiepileptic drugs, especially within the group of drugs of recent appearance, for wich the mechanism of action remains unknown.

  20. Valproic acid-associated vanishing bile duct syndrome.

    PubMed

    Gökçe, Selim; Durmaz, Ozlem; Celtik, Coskun; Aydogan, Aysen; Güllüoglu, Mine; Sökücü, Semra

    2010-07-01

    Hepatotoxicity as a result of valproic acid therapy is well documented. Elevation in aminotransferase activities is rarely associated with symptoms. It sometimes manifests as acute liver failure. Here, we report a 8-year-old girl who was referred for unresolving jaundice and itching for 3 months. Past history revealed afebrile convulsion 5 months previously and beginning of valproic acid treatment. Valproic acid was discontinued after the development of jaundice. Physical examination revealed ichterus, xanthomas on extensor surfaces of extremities, and hepatomegaly without any sign of chronic liver disease. Total and direct bilirubin levels were 20.2 and 12.9 mg/dL, respectively. Enzyme activities indicating cholestasis were increased together with blood cholesterol. Tests for infectious and autoimmune, metabolic, and genetic disorders were not informative. Liver biopsy revealed portal inflammation, severe bile duct loss, and cholestasis. The patient was considered to have valproic acid-associated vanishing bile duct syndrome, which has not been reported previously.

  1. Valproic acid, a molecular lead to multiple regulatory pathways.

    PubMed

    Kostrouchová, M; Kostrouch, Z; Kostrouchová, M

    2007-01-01

    Valproic acid (2-propyl pentanoic acid) is a drug used for the treatment of epilepsy and bipolar disorder. Although very rare, side effects such as spina bifida and other defects of neural tube closure indicate that valproic acid interferes with developmental regulatory pathways. Recently obtained data show that valproic acid affects cell growth, differentiation, apoptosis and immunogenicity of cultured cancer cells and tumours. Focused studies uncovered the potential of valproic acid to interfere with multiple regulatory mechanisms including histone deacetylases, GSK3 alpha and beta, Akt, the ERK pathway, the phosphoinositol pathway, the tricarboxylic acid cycle, GABA, and the OXPHOS system. Valproic acid is emerging as a potential anticancer drug and may also serve as a molecular lead that can help design drugs with more specific and more potent effects on the one side and drugs with wide additive but weaker effects on the other. Valproic acid is thus a powerful molecular tool for better understanding and therapeutic targeting of pathways that regulate the behaviour of cancer cells.

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

    PubMed Central

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

    2016-01-01

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

  3. Increased BDNF expression in fetal brain in the valproic acid model of autism.

    PubMed

    Almeida, Luis E F; Roby, Clinton D; Krueger, Bruce K

    2014-03-01

    Human fetal exposure to valproic acid (VPA), a widely-used anti-epileptic and mood-stabilizing drug, leads to an increased incidence of behavioral and intellectual impairments including autism; VPA administration to pregnant rats and mice at gestational days 12.5 (E12.5) or E13.5 leads to autistic-like symptoms in the offspring and is widely used as an animal model for autism. We report here that this VPA administration protocol transiently increased both BDNF mRNA and BDNF protein levels 5-6-fold in the fetal mouse brain. VPA exposure in utero induced smaller increases in the expression of mRNA encoding the other neurotrophins, NT3 (2.5-fold) and NT4 (2-fold). Expression of the neurotrophin receptors, trkA, trkB and trkC were minimally affected, while levels of the low-affinity neurotrophin receptor, p75(NTR), doubled. Of the nine 5'-untranslated exons of the mouse BDNF gene, only expression of exons I, IV and VI was stimulated by VPA in utero. In light of the well-established role of BDNF in regulating neurogenesis and the laminar fate of postmitotic neurons in the developing cortex, an aberrant increase in BDNF expression in the fetal brain may contribute to VPA-induced cognitive disorders by altering brain development. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Valproic acid triggers increased mitochondrial biogenesis in POLG-deficient fibroblasts

    PubMed Central

    Sitarz, Kamil S.; Elliott, Hannah R.; Karaman, Betül S.; Relton, Caroline; Chinnery, Patrick F.; Horvath, Rita

    2014-01-01

    Valproic acid (VPA) is a widely used antiepileptic drug and also prescribed to treat migraine, chronic headache and bipolar disorder. Although it is usually well tolerated, a severe hepatotoxic reaction has been repeatedly reported after VPA administration. A profound toxic reaction on administration of VPA has been observed in several patients carrying POLG mutations, and heterozygous genetic variation in POLG has been strongly associated with VPA-induced liver toxicity. Here we studied the effect of VPA in fibroblasts of five patients carrying pathogenic mutations in the POLG gene. VPA administration caused a significant increase in the expression of POLG and several regulators of mitochondrial biogenesis. It was further supported by elevated mtDNA copy numbers. The effect of VPA on mitochondrial biogenesis was observed in both control and patient cell lines, but the capacity of mutant POLG to increase the expression of mitochondrial genes and to increase mtDNA copy numbers was less effective. No evidence of substantive differences in DNA methylation across the genome was observed between POLG mutated patients and controls. Given the marked perturbation of gene expression observed in the cell lines studied, we conclude that altered DNA methylation is unlikely to make a major contribution to POLG-mediated VPA toxicity. Our data provide experimental evidence that VPA triggers increased mitochondrial biogenesis by altering the expression of several mitochondrial genes; however, the capacity of POLG-deficient liver cells to address the increased metabolic rate caused by VPA administration is significantly impaired. PMID:24725338

  5. Valproic acid-induced acute pancreatitis and multiorgan failure in a child.

    PubMed

    Yaman, Ayhan; Kendirli, Tanl; Odek, Cağlar; Bektaş, Omer; Kuloğlu, Zarife; Koloğlu, Meltem; Ince, Erdal; Deda, Gülhis

    2013-05-01

    Valproic acid (VPA) is still an important antiepileptic drug, with the broadest spectrum used in all types of seizures and syndromes. It has serious adverse effects such as hepatotoxicity, hyperammonemic encephalopathy, coagulation disorders, and pancreatitis. The incidence of VPA-associated pancreatitis has been estimated to be 1:40,000. We present a 6-year-old boy who developed acute pancreatitis (AP) and multiple-organ failure after 3 months of VPA therapy. The patient's laboratory values showed that his kidney and hepatic function had impaired and thrombocytopenia, and coagulopathy had developed. The patient's abdominal tomography showed a suspected appearance, which was consistent with pancreatitis. Because amylase and lipase levels were found to be high, AP was considered. The patient improved after cessation of VPA treatment. Ten days later, the patient recovered both clinically and laboratorial. Consequently, the patient was discharged with cure. In conclusion, AP is a rare, severe adverse reaction to VPA treatment. If a child, who is receiving VPA, develops abdominal pain and vomits, VPA-associated pancreatitis must be considered.

  6. Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence?

    PubMed

    Lheureux, Philippe E R; Penaloza, Andrea; Zahir, Soheil; Gris, Mireille

    2005-10-05

    Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well tolerated, but rare serious complications may occur in some patients receiving VPA chronically, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity (VHT) and VPA-induced hyperammonaemic encephalopathy (VHE). Some data suggest that VHT and VHE may be promoted by carnitine deficiency. Acute VPA intoxication also occurs as a consequence of intentional or accidental overdose and its incidence is increasing, because of use of VPA in psychiatric disorders. Although it usually results in mild central nervous system depression, serious toxicity and even fatal cases have been reported. Several studies or isolated clinical observations have suggested the potential value of oral L-carnitine in reversing carnitine deficiency or preventing its development as well as some adverse effects due to VPA. Carnitine supplementation during VPA therapy in high-risk patients is now recommended by some scientific committees and textbooks, especially paediatricians. L-carnitine therapy could also be valuable in those patients who develop VHT or VHE. A few isolated observations also suggest that L-carnitine may be useful in patients with coma or in preventing hepatic dysfunction after acute VPA overdose. However, these issues deserve further investigation in controlled, randomized and probably multicentre trials to evaluate the clinical value and the appropriate dosage of L-carnitine in each of these conditions.

  7. Non-fatal and fatal liver failure associated with valproic acid.

    PubMed

    Schmid, M M; Freudenmann, R W; Keller, F; Connemann, B J; Hiemke, C; Gahr, M; Kratzer, W; Fuchs, M; Schönfeldt-Lecuona, C

    2013-03-01

    Little is known about hepatotoxicity associated with valproic acid (VPA), a widely used substance in neuropsychiatry.All reported cases to the German Federal Institute for Drugs and Medical Devices between 1993 and 2009 of VPA-induced serious hepatic side effects were evaluated.A total of 132 cases of serious VPA-associated liver failure were identified. Approximately one third (34.8%) occurred under VPA monotherapy, while the majority was seen with VPA plus co-medication, most frequently antiepileptics (34.8%) and benzodiazepines (16.7%). A subgroup of 34 cases (25.8%) had a fatal outcome, the largest number reported to date. Of these, 32.4% were under VPA monotherapy and 67.6% under VPA plus concomitant medication. Within the study period a significant increase in the total number of reported cases and the subgroup of fatal cases was found.This first pharmacovigilance study of VPA-associated liver failure indicates a higher rate of non-fatal and fatal liver failure when VPA is given with co-medication as compared to monotherapy. However, co-medication per se does not increase the risk of fatalities. © Georg Thieme Verlag KG Stuttgart · New York.

  8. Valproic acid-induced pancreatitis: 16 new cases and a review of the literature.

    PubMed

    Gerstner, Thorsten; Büsing, Deike; Bell, Nellie; Longin, Elke; Kasper, Johannes-Martin; Klostermann, Wolfgang; Hebing, Burkhard; Hanefeld, Folker; Eckel, Ulrich; Hoffmann, Reiner; Bettendorf, Ulrich; Weidner, Birgit; Wiemer-Kruel, Adelheid; Brockmann, Knut; Neumann, Fritz-Wilhelm; Sandrieser, Thorsten; Wolff, Markus; König, Stephan

    2007-01-01

    Acute pancreatitis is rarely seen in children, and, in contrast to cases in adults, it is often drug induced. One possible medication is the antiepileptic drug valproic acid (VPA), which is commonly prescribed for generalized and focal epilepsy, migraine, neuropathic pain, and bipolar disorder. The common side effects associated with VPA are typically benign, but less common but more serious adverse effects may occur. These include hepatotoxicity, hyperammonemic encephalopathy, coagulation disorders, and pancreatitis. Since 1979, a few cases of pancreatitis induced by VPA have been published in the medical literature. We mailed a questionnaire to all members of the "German Section of the International League against Epilepsy," asking about VPA-induced side effects. We also reviewed the medical literature for VPA-induced pancreatitis. Fifty-three publications (90 patients) published from 1979 to 2005 were found. Our survey in Germany, however, yielded 16 cases of pancreatitis from 1994 to 2003 whose original files we could study in detail. None of these patients had been published previously. The difference between 90 patients reported worldwide from 1979 to 2005 and the 16 new documented cases from only Germany over 10 years corroborates that the occurrence of this severe side effect is under reported.

  9. Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs

    PubMed Central

    Eisses, John F.; Criscimanna, Angela; Dionise, Zachary R.; Orabi, Abrahim I.; Javed, Tanveer A.; Sarwar, Sheharyar; Jin, Shunqian; Zhou, Lili; Singh, Sucha; Poddar, Minakshi; Davis, Amy W.; Tosun, Akif Burak; Ozolek, John A.; Lowe, Mark E.; Monga, Satdarshan P.; Rohde, Gustavo K.; Esni, Farzad; Husain, Sohail Z.

    2016-01-01

    The mechanisms by which drugs induce pancreatitis are unknown. A definite cause of pancreatitis is due to the antiepileptic drug valproic acid (VPA). On the basis of three crucial observations—that VPA inhibits histone deacetylases (HDACs), HDACs mediate pancreas development, and aspects of pancreas development are recapitulated during recovery of the pancreas after injury—we hypothesized that VPA does not cause injury on its own, but it predisposes patients to pancreatitis by inhibiting HDACs and provoking an imbalance in pancreatic recovery. In an experimental model of pancreatic injury, we found that VPA delayed recovery of the pancreas and reduced acinar cell proliferation. In addition, pancreatic expression of class I HDACs (which are the primary VPA targets) increased in the midphase of pancreatic recovery. VPA administration inhibited pancreatic HDAC activity and led to the persistence of acinar-to-ductal metaplastic complexes, with prolonged Sox9 expression and sustained β-catenin nuclear activation, findings that characterize a delay in regenerative reprogramming. These effects were not observed with valpromide, an analog of VPA that lacks HDAC inhibition. This is the first report, to our knowledge, that VPA shifts the balance toward pancreatic injury and pancreatitis through HDAC inhibition. The work also identifies a new paradigm for therapies that could exploit epigenetic reprogramming to enhance pancreatic recovery and disorders of pancreatic injury. PMID:26476347

  10. Valproic Acid Induces Cutaneous Wound Healing In Vivo and Enhances Keratinocyte Motility

    PubMed Central

    Lee, Soung-Hoon; Zahoor, Muhammad; Hwang, Jae-Kwan; Min, Do Sik; Choi, Kang-Yell

    2012-01-01

    Background Cutaneous wound healing is a complex process involving several signaling pathways such as the Wnt and extracellular signal-regulated kinase (ERK) signaling pathways. Valproic acid (VPA) is a commonly used antiepileptic drug that acts on these signaling pathways; however, the effect of VPA on cutaneous wound healing is unknown. Methods and Findings We created full-thickness wounds on the backs of C3H mice and then applied VPA. After 7 d, we observed marked healing and reduced wound size in VPA-treated mice. In the neo-epidermis of the wounds, β-catenin and markers for keratinocyte terminal differentiation were increased after VPA treatment. In addition, α-smooth muscle actin (α-SMA), collagen I and collagen III in the wounds were significantly increased. VPA induced proliferation and suppressed apoptosis of cells in the wounds, as determined by Ki67 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining analyses, respectively. In vitro, VPA enhanced the motility of HaCaT keratinocytes by activating Wnt/β-catenin, ERK and phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling pathways. Conclusions VPA enhances cutaneous wound healing in a murine model and induces migration of HaCaT keratinocytes. PMID:23144972

  11. Chromatin Remodeling, Cell Proliferation and Cell Death in Valproic Acid-Treated HeLa Cells

    PubMed Central

    Felisbino, Marina Barreto; Tamashiro, Wirla M. S. C.; Mello, Maria Luiza S.

    2011-01-01

    Background Valproic acid (VPA) is a potent anticonvulsant that inhibits histone deacetylases. Because of this inhibitory action, we investigated whether VPA would affect chromatin supraorganization, mitotic indices and the frequency of chromosome abnormalities and cell death in HeLa cells. Methodology/Principal Findings Image analysis was performed by scanning microspectrophotometry for cells cultivated for 24 h, treated with 0.05, 0.5 or 1.0 mM VPA for 1–24 h, and subjected to the Feulgen reaction. TSA-treated cells were used as a predictable positive control. DNA fragmentation was investigated with the TUNEL assay. Chromatin decondensation was demonstrated under TSA and all VPA treatments, but no changes in chromosome abnormalities, mitotic indices or morphologically identified cell death were found with the VPA treatment conditions mentioned above, although decreased mitotic indices were detected under higher VPA concentration and longer exposure time. The frequency of DNA fragmentation identified with the TUNEL assay in HeLa cells increased after a 24-h VPA treatment, although this fragmentation occurred much earlier after treatment with TSA. Conclusions/Significance The inhibition of histone deacetylases by VPA induces chromatin remodeling in HeLa cells, which suggests an association to altered gene expression. Under VPA doses close to the therapeutic antiepileptic plasma range no changes in cell proliferation or chromosome abnormalities are elicited. The DNA fragmentation results indicate that a longer exposure to VPA or a higher VPA concentration is required for the induction of cell death. PMID:22206001

  12. Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs.

    PubMed

    Eisses, John F; Criscimanna, Angela; Dionise, Zachary R; Orabi, Abrahim I; Javed, Tanveer A; Sarwar, Sheharyar; Jin, Shunqian; Zhou, Lili; Singh, Sucha; Poddar, Minakshi; Davis, Amy W; Tosun, Akif Burak; Ozolek, John A; Lowe, Mark E; Monga, Satdarshan P; Rohde, Gustavo K; Esni, Farzad; Husain, Sohail Z

    2015-12-01

    The mechanisms by which drugs induce pancreatitis are unknown. A definite cause of pancreatitis is due to the antiepileptic drug valproic acid (VPA). On the basis of three crucial observations-that VPA inhibits histone deacetylases (HDACs), HDACs mediate pancreas development, and aspects of pancreas development are recapitulated during recovery of the pancreas after injury-we hypothesized that VPA does not cause injury on its own, but it predisposes patients to pancreatitis by inhibiting HDACs and provoking an imbalance in pancreatic recovery. In an experimental model of pancreatic injury, we found that VPA delayed recovery of the pancreas and reduced acinar cell proliferation. In addition, pancreatic expression of class I HDACs (which are the primary VPA targets) increased in the midphase of pancreatic recovery. VPA administration inhibited pancreatic HDAC activity and led to the persistence of acinar-to-ductal metaplastic complexes, with prolonged Sox9 expression and sustained β-catenin nuclear activation, findings that characterize a delay in regenerative reprogramming. These effects were not observed with valpromide, an analog of VPA that lacks HDAC inhibition. This is the first report, to our knowledge, that VPA shifts the balance toward pancreatic injury and pancreatitis through HDAC inhibition. The work also identifies a new paradigm for therapies that could exploit epigenetic reprogramming to enhance pancreatic recovery and disorders of pancreatic injury.

  13. Drug interaction between valproic acid and carbapenems in patients with epileptic seizures.

    PubMed

    Huang, Chi-Ren; Lin, Chih-Hsiang; Hsiao, Shu-Chen; Chen, Nai-Ching; Tsai, Wan-Chen; Chen, Shang-Der; Lu, Yan-Ting; Chuang, Yao-Chung

    2017-03-01

    Valproic acid (VPA) is a widely used antiepileptic drug (AED). When carbapenems are concomitantly used with VPA, the serum levels of VPA may decrease and aggravate seizures. The aim of this study was to evaluate the risk factors associated with decreased serum VPA levels and clinical outcome in patients being treated with a combination of carbapenems and VPA. Fifty-four adult patients who were treated with VPA for epileptic seizures concomitant with carbapenems for the treatment of infections were evaluated in this study. Serum VPA levels were measured before and during combination therapy with VPA and carbapenems, and the change in serum VPA levels was calculated. The risk factors related to the decrease in serum VPA levels and clinical outcomes were evaluated. Our results show that VPA concentrations were reduced to subtherapeutic levels after the introduction of carbapenems. The reduction in VPA concentrations was found within 24 hours of the start of treatment with carbapenems. VPA levels continuously declined while the combination of treatments was used, which aggravated epileptic seizures in 48% of the patients. Renal disease and enzyme-inducing AEDs were risk factors that contributed to the severity of reduced serum VPA levels during combined treatment with carbapenems. This study suggests that clinicians need to be aware of the reduction of VPA concentrations to subtherapeutic levels and the aggravation of seizures while patients are treated with a combination of carbapenems and VPA. Copyright © 2017. Published by Elsevier Taiwan.

  14. High-calorie diet inflates steatogenic effects of valproic acid in mice.

    PubMed

    Sathiya Priya, Chandrasekaran; Bhavani, Krishnamoorthy; Anuradha, Carani Venkatraman

    2016-02-01

    Valproic acid (VPA) is an anti-epileptic drug used in patients with convulsive seizures and psychic disorders. Despite its therapeutic use, VPA administration is associated with several side effects of which hepatosteatosis (lipid deposition in liver >10% of organ weight) is of concern. Recently, the consumption of western-type diet rich in fat and simple sugar has increased, the pathological consequences of which has been linked to the escalating incidence of metabolic disorders. The hypothesis of the study is that the metabolic stress induced by high-calorie diet may potentiate VPA-induced hepatosteatosis. Two groups of Swiss Mus musculus male mice weighing 25-35 g were fed either normal chow or high fat and high fructose diet (HFFD) and maintained for 30 days. On the 16th day of the experiment, VPA (100 mg/kg bw) administration was initiated in one set of animals from each group and the other set was left without VPA treatment. Assays were done in the hemolysate, plasma and liver tissue of mice after the experimental period. Deregulated lipid metabolism, loss of insulin sensitivity, enhanced CYP2E1 activity and oxidative damage, and diminution of cellular antioxidants were observed in animals that received HFFD and VPA. HFFD-fed mice are sensitized to VPA toxicity than the normal chow-fed counterparts. The results of this study show that preformed metabolic derangements due to high-energy diet may infuriate VPA-induced hepatosteatosis and insulin resistance.

  15. Generic substitution of antiepileptic drugs: a systematic review of prospective and retrospective studies.

    PubMed

    Yamada, Mikiko; Welty, Timothy E

    2011-11-01

    To systematically review the literature on generic antiepileptic drugs (AEDs), evaluate the efficacy and safety of generic AED substitution, and perform pharmacokinetic (PK) analysis using the American Academy of Neurology (AAN) scheme to classify evidence. PubMed and Cumulative Index to Nursing and Allied Health Literature searches from January 1, 1980, to October 15, 2010, were performed using the search terms anticonvulsant, antiepileptic drug, carbamazepine, divalproex, ethosuximide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pheno-barbital, phenytoin, primidone, topiramate, valproate, valproic acid, and zonisamide; bioavailability, bioequivalence, bioequivalency, bioequivalent, and substitution; and generic. Retrospective and prospective controlled studies of generic substitution of AEDs were included in the review. Non-English-language articles and uncontrolled clinical studies were excluded. Published articles were categorized using the AAN criteria for systematic reviews. We identified 156 articles. Of these, 20 met our inclusion criteria; 7 were retrospective studies, 6 were prospective studies in patients with epilepsy, and 7 were prospective studies in healthy subjects. All articles were rated Class I to Class III, using AAN criteria. The retrospective studies were categorized as Class III and showed a significant relationship between generic substitution and increased use of health care resources because of seizures or AED toxicity. Prospective studies were categorized as Class I, II, and III. Prospective studies in patients showed no differences between brand and generic drugs in PK parameters of bioequivalence. Three prospective studies in healthy subjects reported significant differences in maximum drug concentrations. Comparison of brand and generic drugs revealed no significant difference in seizure frequency; however, some prospective studies showed significant differences in PK parameters, primarily those not used for bioequivalence

  16. [Efficacy and safety of antiepileptic therapy in children (a comparative analysis of valproates and barbiturates)].

    PubMed

    Pylaeva, O A; Petrukhin, A S; Voronkova, K V

    2004-01-01

    The study aimed at a comparative analysis of safety and efficacy of valproic acid (valproate) and barbiturates in the treatment of epilepsy in children. Two hundred and forty children were treated with valproate, 94% being assigned to depakine and depakine chrono, and 210 children received barbiturates. Therapeutic effect (a decrease of seizures frequency by 2 and more times or remission) was detected in 82 of 127 (65 +/- 8.53%) patients for valproate monotherapy and only in 26 of 89 (30 +/- 9.45%) for barbiturates monotherapy. An efficacy of antiepileptic therapy in children was significantly higher (p<0.05) for valproates as compared to barbiturates. A drug withdrawal due to poor tolerability was recorded in 6 of 127 (5 +/- 3.7%) patients treated with valproate in monotherapy and in 14 of 210 (7 +/- 3.45%)--in polytherapy; in 53 of 89 (59 +/- 10.2%) patients treated with barbiturates in monotherapy and in 78 of 121 (65 +/- 8.53%) patients treated with barbiturates in polytherapy. Therefore, adverse effects occurred more often in barbiturates than in valproate treatment both for mono- and polytherapy (p<0.05). The results of the study confirmed the high efficacy and safety of valproates, specifically depakine chrono, in the treatment of epilepsy in children. depakine chrono in-take is associated with lower frequency of adverse effects; side-effects are mostly of dose-dependent character and do not result in the drug withdrawal. The authors do not recommend using barbiturates in the first-line treatment in children, because of the lower efficacy, high frequency of medical complications that might result in the drug withdrawal and reducing of the efficacy of other antiepileptic medications.

  17. Antiepileptics for aggression and associated impulsivity

    PubMed Central

    Huband, Nick; Ferriter, Michael; Nathan, Rajan; Jones, Hannah

    2014-01-01

    Background Aggression is a major public health issue and is integral to several mental health disorders. Antiepileptic drugs may reduce aggression by acting on the central nervous system to reduce neuronal hyper-excitability associated with aggression. Objectives To evaluate the efficacy of antiepileptic drugs in reducing aggression and associated impulsivity. Search methods We searched CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, metaRegister of Controlled Trials (mRCT) and ClinicalTrials.gov to April 2009. We also searched Cochrane Schizophrenia Group’s register of trials on aggression, National Research Record and handsearched for studies. Selection criteria Prospective, placebo-controlled trials of antiepileptic drugs taken regularly by individuals with recurrent aggression to reduce the frequency or intensity of aggressive outbursts. Data collection and analysis Three authors independently selected studies and two authors independently extracted data. We calculated standardised mean differences (SMDs), with odds ratios (ORs) for dichotomous data. Main results Fourteen studies with data from 672 participants met the inclusion criteria. Five different antiepileptic drugs were examined. Sodium valproate/divalproex was superior to placebo for outpatient men with recurrent impulsive aggression, for impulsively aggressive adults with cluster B personality disorders, and for youths with conduct disorder, but not for children and adolescents with pervasive developmental disorder. Carbamazepine was superior to placebo in reducing acts of self-directed aggression in women with borderline personality disorder, but not in children with conduct disorder. Oxcarbazepine was superior to placebo for verbal aggression and aggression against objects in adult outpatients. Phenytoin was superior to placebo on the frequency of aggressive acts in male prisoners and in outpatient men including those with personality disorder, but not on the frequency of ‘behavioral incidents’ in

  18. Case Report: Valproic Acid and Risperidone Treatment Leading to Development of Hyperammonemia and Mania

    ERIC Educational Resources Information Center

    Carlson, Teri; Reynolds, Charles A.; Caplan, Rochelle

    2007-01-01

    This case report describes two children who developed hyperammonemia together with frank manic behavior during treatment with a combination of valproic acid and risperidone. One child had been maintained on valproic acid for years and risperidone was added. In the second case, valproic acid was introduced to a child who had been treated with…

  19. Case Report: Valproic Acid and Risperidone Treatment Leading to Development of Hyperammonemia and Mania

    ERIC Educational Resources Information Center

    Carlson, Teri; Reynolds, Charles A.; Caplan, Rochelle

    2007-01-01

    This case report describes two children who developed hyperammonemia together with frank manic behavior during treatment with a combination of valproic acid and risperidone. One child had been maintained on valproic acid for years and risperidone was added. In the second case, valproic acid was introduced to a child who had been treated with…

  20. Rufinamide: A Novel Broad-Spectrum Antiepileptic Drug

    PubMed Central

    Wheless, James W; Vazquez, Blanca

    2010-01-01

    The last 20 years have witnessed a tremendous explosion in the number of antiepileptic drugs (AEDs) as well as the introduction of AEDS developed for specific epilepsy syndromes. The study of the efficacy and side effect profile of AEDs for unique epilepsy syndromes has allowed neurologists to utilize evidence-based medicine when treating patients. In late 2008, the Food and Drug Administration approved rufinamide for adjunctive use in the treatment of seizures associated with Lennox–Gastaut syndrome. This unique chemical compound is also the first new AED to reach the market in the United States having a pediatric indication prior to approval for adults. Rufinamide appears to have a broad spectrum of efficacy, is well tolerated, and may be rapidly initiated—properties that will likely extend its use outside of Lennox–Gastaut syndrome. PMID:20126329

  1. Rufinamide: a novel broad-spectrum antiepileptic drug.

    PubMed

    Wheless, James W; Vazquez, Blanca

    2010-01-01

    The last 20 years have witnessed a tremendous explosion in the number of antiepileptic drugs (AEDs) as well as the introduction of AEDS developed for specific epilepsy syndromes. The study of the efficacy and side effect profile of AEDs for unique epilepsy syndromes has allowed neurologists to utilize evidence-based medicine when treating patients. In late 2008, the Food and Drug Administration approved rufinamide for adjunctive use in the treatment of seizures associated with Lennox-Gastaut syndrome. This unique chemical compound is also the first new AED to reach the market in the United States having a pediatric indication prior to approval for adults. Rufinamide appears to have a broad spectrum of efficacy, is well tolerated, and may be rapidly initiated--properties that will likely extend its use outside of Lennox-Gastaut syndrome.

  2. Diverse mechanisms of antiepileptic drugs in the development pipeline.

    PubMed

    Rogawski, Michael A

    2006-06-01

    There is a remarkable array of new chemical entities in the current antiepileptic drug (AED) development pipeline. In some cases, the compounds were synthesized in an attempt improve upon the activity of marketed AEDs. In other cases, the discovery of antiepileptic potential was largely serendipitous. Entry into the pipeline begins with the demonstration of activity in one or more animal screening models. Results from testing in a panel of such models provide a basis to differentiate agents and may offer clues as to the mechanism. Target activity may then be defined through cell-based studies, often years after the initial identification of activity. Some pipeline compounds are believed to act through conventional targets, whereas others are structurally novel and may act by novel mechanisms. Follow-on agents include the levetiracetam analogs brivaracetam and seletracetam that act as SV2A-ligands; the valproate-like agents valrocemide, valnoctamide, propylisopropyl acetamide, and isovaleramide; the felbamate analog flurofelbamate, a dicarbamate, and the unrelated carbamate RWJ-333369; the oxcarbazepine analog licarbazepine, which probably acts as a use-dependent sodium channel blockers, and its prodrug acetate BIA 2-093; various selective partial benzodiazepine receptor agonists, including ELB139, which is a positive allosteric modulator of alpha3-containing GABA(A) receptors. A variety of AEDs that may act through novel targets are also in clinical development: lacosamide, a functionalized amino acid; talampanel, a 2,3-benzodiazepine selective noncompetitive AMPA receptor antagonist; NS1209, a competitive AMPA receptor antagonist; ganaxolone, a neuroactive steroid that acts as a positive modulator of GABA(A) receptors; retigabine, a KCNQ potassium channel opener with activity as a GABA(A) receptor positive modulator; the benzanilide KCNQ potassium channel opener ICA-27243 that is more selective than retigabine; and rufinamide, a triazole of unknown mechanism.

  3. Risks and benefits of generic antiepileptic drugs.

    PubMed

    Gómez-Alonso, Juan; Kanner, Andrés M; Herranz, José Luis; Molins, Albert; Gil-Nagel, Antonio

    2008-11-01

    In most therapeutic areas, prescribing generic drugs seems to lower costs without sacrificing efficacy. The use of generic drugs for treating epilepsy may, however, be more controversial. A systematic review of the literature on generic antiepileptic drugs has been carried out based primarily on a bibliographical search in the Medline database. Published studies are usually of a descriptive nature and are sometimes based on generic drugs that were approved in times when regulatory agency requirements were not as strict as they are now. Experts claim that a change in pharmaceutical formulations could cause seizure recurrence in cases that had been successfully controlled in the past, with severe effects on patients. Meanwhile, several health organizations have provided inconsistent recommendations on the use of generic antiepileptic drugs. In order to obtain scientific evidence on the potential risks and benefits of interchanging branded and generic antiepileptic drugs, high methodological comparative studies are necessary. These studies could bring consensus about the role of generic drugs for treating epilepsy.

  4. Fatal hyperammonemic brain injury from valproic Acid exposure.

    PubMed

    Bega, Danny; Vaitkevicius, Henrikas; Boland, Torrey A; Murray, Michael; Chou, Sherry H-Y

    2012-09-01

    Hyperammonemia is known to cause neuronal injury, and can result from valproic acid exposure. Prompt reduction of elevated ammonia levels may prevent permanent neurological injury. We report a case of fatal hyperammonemic brain injury in a woman exposed to valproic acid. A 38-year-old woman with schizoaffective disorder and recent increase in valproic acid dosage presented with somnolence and confusion and rapidly progressed to obtundation. Brain MRI showed diffuse bilateral restricted diffusion in nearly the entire cerebral cortex. She had normal liver function tests but serum ammonia level was severely elevated at 288 μmol/l. Genetic testing showed no mutation in urea cycle enzymes. Despite successful elimination of ammonia with hemodialysis she developed fatal cerebral edema. Cerebral edema secondary to hyperammonemia is potentially reversible if recognized early. Ammonia excretion can be facilitated by initiation of hemodialysis and administration of scavenging agents (sodium phenylacetate and sodium benzoate). Severe hyperammonemia can result from valproic acid exposure even in the absence of hepatotoxicity or inborn errors of metabolism. It is important to check serum ammonia in any patient with encephalopathy who has had recent valproic acid exposure.

  5. Effects of antiepileptic drugs on mitochondrial functions, morphology, kinetics, biogenesis, and survival.

    PubMed

    Finsterer, Josef; Scorza, Fulvio A

    2017-10-01

    Antiepileptic drugs (AEDs) exhibit adverse and beneficial effects on mitochondria, which have a strong impact on the treatment of patients with a mitochondrial disorder (MID) with epilepsy (mitochondrial epilepsy). This review aims at summarizing and discussing recent findings concerning the effect of AEDs on mitochondrial functions and the clinical consequences with regard to therapy of mitochondrial epilepsy and of MIDs in general. Literature review. AEDs may interfere with the respiratory chain, with non-respiratory chain enzymes, carrier proteins, or mitochondrial biogenesis, with carrier proteins, membrane-bound channels or receptors and the membrane potential, with anti-oxidative defense mechanisms, with morphology, dynamics and survival of mitochondria, and with the mtDNA. There are AEDs of which adverse effects outweigh beneficial effects, such as valproic acid, carbamazepine, phenytoin, or phenobarbital and there are AEDs in which beneficial effects dominate over mitochondrial toxic effects, such as lamotrigine, levetiracetam, gabapentin, or zonisamide. However, from most AEDs only little is known about their interference with mitochondria. Mitochondrial epilepsy might be initially treated with AEDs with low mitochondrial toxic potential. Only in case mitochondrial epilepsy is refractory to these AEDs, AEDs with higher mitochondrial toxic potential might be tried. In patients carrying POLG1 mutations AEDs with high mitochondrial toxic potential are contraindicated. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Antiepileptic Drug Removal by Continuous Renal Replacement Therapy: A Review of the Literature.

    PubMed

    Mahmoud, Sherif Hanafy

    2017-01-01

    Continuous renal replacement therapy (CRRT) is used for managing acute kidney injury in critically ill patients. Removal of antiepileptic drugs (AEDs) by CRRT could be significant and may complicate patients' intensive care unit stay. The objective of the current review was to summarize the available evidence for AED removal by CRRT. An electronic literature search of PubMed (1946 to May 2016), Medline (1946 to May 2016), and Embase (1974 to May 2016) databases for studies discussing AED removal by CRRT was conducted. A total of 31 case reports discussing 32 patients were found. AEDs reported were levetiracetam (n = 3), valproic acid (n = 9), carbamazepine (n = 10), phenytoin (n = 3), phenobarbital (n = 4), lacosamide (n = 1), gabapentin (n = 1), and topiramate (n = 1). Two-thirds of the reports were about using CRRT in drug overdose and one-third was about AED removal by CRRT during therapy. Based on the current limited evidence and pharmacokinetic characteristics of AEDs, renally eliminated AEDs and/or AEDs with limited protein binding such as levetiracetam are more likely to be removed by CRRT than AEDs that are mainly metabolized and extensively protein bound such as carbamazepine. In conclusion, there is not enough evidence to provide robust dosing recommendations for AEDs in patients undergoing CRRT. Further studies are needed.

  7. Mitochondrial toxicity of antiepileptic drugs and their tolerability in mitochondrial disorders.

    PubMed

    Finsterer, Josef; Zarrouk Mahjoub, Sinda

    2012-01-01

    Epilepsy is a frequent CNS manifestation of mitochondrial disorders (MIDs). At present, patients with MID-related epilepsy are largely treated in the same way as any other epilepsy sufferer. The problem with this approach is that some antiepileptic drugs (AEDs) are mitochondrial toxic and care is, therefore, needed when administering these AEDs to patients with MIDs. This review summarizes and discusses the mitochondrial toxicity, tolerability and beneficial effects of AED in patients with MIDs. The literature for this article was retrieved through PubMed using the search terms: 'mitochondrial disorder', 'mitochondriopathy', 'mitochondrial', 'cytopathy', 'metabolic disease', 'epilepsy', 'seizures' and various AEDs alone or in combination. Mitochondrial-toxic AEDs may trigger or worsen an MID or may be even fatal in single cases. The AED with the most well-known mitochondrial toxicity is valproic acid (VPA), which has been known to exhibit a deleterious effect in patients with POLG1 mutations and patients with myoclonic epilepsy with ragged red fibers syndrome and VPA should only be applied in MIDs in case of a drug-resistant status epilepticus. AEDs other than VPA, which may affect the mitochondrial metabolism, include phenobarbital, carbamazepine, phenytoin, oxcarbazepine, ethosuximide, zonisamide, topiramate, gabapentin and vigabatrin. AEDs which interfere with mitochondrial function should be avoided whenever justifiable to the patient's well-being. Collateral beneficial effects of AEDs should also influence their choice in MIDs.

  8. Case report: valproic Acid and risperidone treatment leading to development of hyperammonemia and mania.

    PubMed

    Carlson, Teri; Reynolds, Charles A; Caplan, Rochelle

    2007-03-01

    This case report describes two children who developed hyperammonemia together with frank manic behavior during treatment with a combination of valproic acid and risperidone. One child had been maintained on valproic acid for years and risperidone was added. In the second case, valproic acid was introduced to a child who had been treated with risperidone for years. In both cases, discontinuing the valproic acid resulted in normalization of ammonia levels and cessation of the manic behavior. This case report alerts physicians to the importance of obtaining serum ammonia levels in children treated with valproic acid and risperidone who present with manic behavior.

  9. Hyperammoneic encephalopathy, valproic acid, and benzodiazepine withdrawal: a case series.

    PubMed

    Starer, Jacquelyn; Chang, Grace

    2010-03-01

    Benzodiazepine withdrawal is accompanied by a risk of seizures, delirium, and death. While a gradual outpatient taper off of benzodiazepines is the most commonly recommended method for discontinuation, acute inpatient detoxification and seizure prophylaxis may be necessary for some. Complications related to the use of valproic acid for seizure prophylaxis are presented. The study's objectives are to highlight an uncommon and possibly unrecognized complication of valproic acid when used for seizure prophylaxis during acute inpatient detoxification from benzodiazepines in the context of current practice. Case series. Three patients with hyperammoneic encephalopathy are described. Hyperammoneic encephalopathy can occur as a distinct entity separate from hepatotoxicity with the use of valproic acid and may be an unrecognized complication among patients receiving this drug during benzodiazepine detoxification. A previously unreported complication among the addiction patient population is reported. This underscores the need for a better evidence base regarding the prevention of seizures during acute benzodiazepine detoxification, particularly in terms of indications, safety, and efficacy.

  10. Valproic acid-induced hyperammonaemic coma and unrecognised portosystemic shunt.

    PubMed

    Nzwalo, Hipólito; Carrapatoso, Leonor; Ferreira, Fátima; Basilio, Carlos

    2013-06-01

    Hyperammonaemic encephalopathy is a rare and potentially fatal complication of valproic acid treatment. The clinical presentation of hyperammonaemic encephalopathy is wide and includes seizures and coma. We present a case of hyperammonaemic coma precipitated by sodium valproate use for symptomatic epilepsy in a patient with unrecognised portosystemic shunt, secondary to earlier alcoholism. The absence of any stigmata of chronic liver disease and laboratory markers of liver dysfunction delayed the recognition of this alcohol-related complication. The portal vein bypass led to a refractory, valproic acid-induced hyperammonaemic coma. The patient fully recovered after dialysis treatment.

  11. Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy

    PubMed Central

    Glauser, Tracy A.; Cnaan, Avital; Shinnar, Shlomo; Hirtz, Deborah G.; Dlugos, Dennis; Masur, David; Clark, Peggy O.; Capparelli, Edmund V.; Adamson, Peter C.

    2010-01-01

    BACKGROUND Childhood absence epilepsy, the most common pediatric epilepsy syndrome, is usually treated with ethosuximide, valproic acid, or lamotrigine. The most efficacious and tolerable initial empirical treatment has not been defined. METHODS In a double-blind, randomized, controlled clinical trial, we compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy. Drug doses were incrementally increased until the child was free of seizures, the maximal allowable or highest tolerable dose was reached, or a criterion indicating treatment failure was met. The primary outcome was freedom from treatment failure after 16 weeks of therapy; the secondary outcome was attentional dysfunction. Differential drug effects were determined by means of pairwise comparisons. RESULTS The 453 children who were randomly assigned to treatment with ethosuximide (156), lamotrigine (149), or valproic acid (148) were similar with respect to their demographic characteristics. After 16 weeks of therapy, the freedom-from-failure rates for ethosuximide and valproic acid were similar (53% and 58%, respectively; odds ratio with valproic acid vs. ethosuximide, 1.26; 95% confidence interval [CI], 0.80 to 1.98; P = 0.35) and were higher than the rate for lamotrigine (29%; odds ratio with ethosuximide vs. lamotrigine, 2.66; 95% CI, 1.65 to 4.28; odds ratio with valproic acid vs. lamotrigine, 3.34; 95% CI, 2.06 to 5.42; P<0.001 for both comparisons). There were no significant differences among the three drugs with regard to discontinuation because of adverse events. Attentional dysfunction was more common with valproic acid than with ethosuximide (in 49% of the children vs. 33%; odds ratio, 1.95; 95% CI, 1.12 to 3.41; P = 0.03). CONCLUSIONS Ethosuximide and valproic acid are more effective than lamotrigine in the treatment of childhood absence epilepsy. Ethosuximide is associated with

  12. Resting-state fMRI revealed different brain activities responding to valproic acid and levetiracetam in benign epilepsy with central-temporal spikes.

    PubMed

    Zhang, Qirui; Yang, Fang; Hu, Zheng; Zhang, Zhiqiang; Xu, Qiang; Dante, Mantini; Wu, Han; Li, Zhipeng; Li, Qian; Li, Kai; Lu, Guangming

    2017-05-01

    Our aim was to investigate regional difference in brain activities in response to antiepileptic drug (AED) medications in benign epilepsy with central-temporal spikes (BECTS) using resting-state functional magnetic resonance imaging (fMRI). Fifty-seven patients with BECTS underwent resting-state fMRI scans after receiving either valproic acid (VPA) (n = 15), levetiracetam (LEV) (n = 21), or no medication (n = 21). fMRI regional homogeneity (ReHo) parameter among the three groups of patients were compared and were correlated with total doses of AED in the two medicated groups. Compared with patients on no-medication, patients receiving either VPA or LEV showed decreased ReHo in the central-temporal region, frontal cortex, and thalamus. In particular, the VPA group showed greater ReHo decrease in the thalamus and milder in cortices and caudate heads compared with the LEV group. In addition, the VPA group demonstrated a negative correlation between ReHo values in the central-temporal region and medication dose. Both VPA and LEV inhibit resting-state neural activity in the central-temporal region, which is the main epileptogenic focus of BECTS. VPA reduced brain activity in the cortical epileptogenic regions and thalamus evenly, whereas LEV reduced brain activity predominantly in the cortices. Interestingly, VPA showed a cumulative effect on inhibiting brain activity in the epileptogenic regions in BECTS. • Regional differences in brain activity in response to different AEDs in BECTS. • AEDs inhibit resting-state neural activity in epileptogenic and subcortical regions in BECTS. • Valproic acid effect on the cortical epileptogenic regions and thalamus evenly. • Levetiracetam effect seen predominantly in cortices. • Valproic acid has a cumulative effect on inhibiting brain activity in epileptogenic regions.

  13. Gingival overgrowth with valproic acid: a case report.

    PubMed

    Anderson, H H; Rapley, J W; Williams, D R

    1997-01-01

    A case of a nine-year-old epileptic girl with severe gingival overgrowth who had been taking valproic acid since two months of age is presented. A review of the literature and possible mechanisms for drug-induced gingival overgrowth is outlined.

  14. [Algorithms of using valproic acid drugs in women].

    PubMed

    Vlasov, P N

    2015-01-01

    Characteristics of using valproic acid drugs in women, from puberty to menopause period, are reviewed. Based on initial treatment efficacy, type of epileptic seizures and a form of epilepsy, the author emphasizes the practical use of valproates during pregnancy in dependence on the situation. Several scenarios of pregnancy course and possible treatment tactics are presented.

  15. Antiepileptic Drug Withdrawal in Dogs with Epilepsy.

    PubMed

    Gesell, Felix Kaspar; Hoppe, Sonja; Löscher, Wolfgang; Tipold, Andrea

    2015-01-01

    Epilepsy is one of the most common neurological disorders in dogs and is treated by chronic administration of antiepileptic drugs (AEDs). In human beings with epilepsy, it is common clinical practice to consider drug withdrawal after a patient has been in remission (seizure free) for three or more years, but withdrawal is associated with the risk of relapse. In the present study, the consequences of AED withdrawal were studied in dogs with epilepsy. Therefore, 200 owners of dogs with idiopathic or presumed idiopathic epilepsy were contacted by telephone interview, 138 cases could be enrolled. In 11 cases, the therapy had been stopped after the dogs had become seizure free for a median time of 1 year. Reasons for AED withdrawal were appearance or fear of adverse side effects, financial aspects, and the idea that the medication could be unnecessary. Following AED withdrawal, four of these dogs remained seizure free, seven dogs suffered from seizure recurrence, of which only three dogs could regain seizure freedom after resuming AED therapy. Due to the restricted case number, an exact percentage of dogs with seizure recurrence after AED withdrawal cannot be given. However, the present study gives a hint that similar numbers as in human patients are found, and the data can help owners of epileptic dogs and the responsible clinician to decide when and why to stop antiepileptic medication.

  16. Antiepileptic Drug Withdrawal in Dogs with Epilepsy

    PubMed Central

    Gesell, Felix Kaspar; Hoppe, Sonja; Löscher, Wolfgang; Tipold, Andrea

    2015-01-01

    Epilepsy is one of the most common neurological disorders in dogs and is treated by chronic administration of antiepileptic drugs (AEDs). In human beings with epilepsy, it is common clinical practice to consider drug withdrawal after a patient has been in remission (seizure free) for three or more years, but withdrawal is associated with the risk of relapse. In the present study, the consequences of AED withdrawal were studied in dogs with epilepsy. Therefore, 200 owners of dogs with idiopathic or presumed idiopathic epilepsy were contacted by telephone interview, 138 cases could be enrolled. In 11 cases, the therapy had been stopped after the dogs had become seizure free for a median time of 1 year. Reasons for AED withdrawal were appearance or fear of adverse side effects, financial aspects, and the idea that the medication could be unnecessary. Following AED withdrawal, four of these dogs remained seizure free, seven dogs suffered from seizure recurrence, of which only three dogs could regain seizure freedom after resuming AED therapy. Due to the restricted case number, an exact percentage of dogs with seizure recurrence after AED withdrawal cannot be given. However, the present study gives a hint that similar numbers as in human patients are found, and the data can help owners of epileptic dogs and the responsible clinician to decide when and why to stop antiepileptic medication. PMID:26664952

  17. Vitamin U, a novel free radical scavenger, prevents lens injury in rats administered with valproic acid.

    PubMed

    Tunali, S; Kahraman, S; Yanardag, R

    2015-09-01

    Valproic acid (2-propyl-pentanoic acid, VPA) is the most widely prescribed antiepileptic drug due to its ability to treat a broad spectrum of seizure types. VPA exhibits various side effects such as organ toxicity, teratogenicity, and visual disturbances. S-Methylmethioninesulfonium is a derivative of the amino acid methionine and it is widely referred to as vitamin U (Vit U). This study was aimed to investigate the effects of Vit U on lens damage parameters of rats exposed to VPA. Female Sprague Dawley rats were divided into four groups. Group I comprised control animals. Group II included control rats supplemented with Vit U (50 mg/kg/day) for 15 days. Group III was given only VPA (500 mg/kg/day) for 15 days. Group IV was given VPA + Vit U (in same dose and time). Vit U was given to rats by gavage and VPA was given intraperitoneally. On the 16th day of experiment, all the animals which were fasted overnight were killed. Lens was taken from animals, homogenized in 0.9% saline to make up to 10% (w/v) homogenate. The homogenates were used for protein, glutathione, lipid peroxidation levels, and antioxidant enzymes activities. Lens lipid peroxidation levels and aldose reductase and sorbitol dehydrogenase activities were increased in VPA group. On the other hand, glutathione levels, superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and paraoxonase activities were decreased in VPA groups. Treatment with Vit U reversed these effects. This study showed that Vit U exerted antioxidant properties and may prevent lens damage caused by VPA.

  18. Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes.

    PubMed

    Wolters, Jarno E J; van Breda, Simone G J; Caiment, Florian; Claessen, Sandra M; de Kok, Theo M C M; Kleinjans, Jos C S

    2017-09-13

    Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs in the world. Despite its pharmacological importance, it may cause liver toxicity and steatosis through mitochondrial dysfunction. The aim of this study is to further investigate VPA-induced mechanisms of steatosis by analyzing changes in patterns of methylation in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Therefore, primary human hepatocytes (PHHs) were exposed to an incubation concentration of VPA that was shown to cause steatosis without inducing overt cytotoxicity. VPA was administered daily for 5 days, and this was followed by a 3 day washout (WO). Methylated DNA regions (DMRs) were identified by using the methylated DNA immunoprecipitation-sequencing (MeDIP-seq) method. The nDNA DMRs after VPA treatment could indeed be classified into oxidative stress- and steatosis-related pathways. In particular, networks of the steatosis-related gene EP300 provided novel insight into the mechanisms of toxicity induced by VPA treatment. Furthermore, we suggest that VPA induces a crosstalk between nDNA hypermethylation and mtDNA hypomethylation that plays a role in oxidative stress and steatosis development. Although most VPA-induced methylation patterns appeared reversible upon terminating VPA treatment, 31 nDNA DMRs (including 5 zinc finger protein genes) remained persistent after the WO period. Overall, we have shown that MeDIP-seq analysis is highly informative in disclosing novel mechanisms of VPA-induced toxicity in PHHs. Our results thus provide a prototype for the novel generation of interesting methylation biomarkers for repeated dose liver toxicity in vitro.

  19. Valproic acid mediates the synaptic excitatory/inhibitory balance through astrocytes--a preliminary study.

    PubMed

    Wang, Chao-Chuan; Chen, Po See; Hsu, Chien-Wen; Wu, Shou-Jung; Lin, Chieh-Ting; Gean, Po Wu

    2012-04-27

    Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for the treatment of epilepsy and bipolar disorder. However, the underlying therapeutic mechanisms of the treatment of each disease remain unclear. Recently, the anti-epileptic effect of VPA has been found to lead to modulation of the synaptic excitatory/inhibitory balance. In addition, the therapeutic action of VPA has been linked to its effect on astrocytes by regulating gene expression at the molecular level, perhaps through an epigenetic mechanism as a histone deacetylase (HDAC) inhibitor. To provide insight into the mechanisms underlying the actions of VPA, this study investigated whether the synaptic excitatory/inhibitory (E/I) balance could be mediated by VPA through astrocytes. First, using the primary rat neuronal, astroglial, and neuro-glial mixed culture systems, we demonstrated that VPA treatment could regulate the mRNA levels of two post-synaptic cell adhesion molecules(neuroligin-1 and neuregulin-1) and two extracellular matrices (neuronal pentraxin-1and thrombospondin-3) in primary rat astrocyte cultures in a time- and concentration-dependent manner. Moreover, the up-regulation effect of VPA was noted in astrocytes, but not in neurons. In addition, these regulatory effects could be mimicked by sodium butyrate, a HDAC inhibitor, but not by lithium or two other glycogen synthase kinase-3 beta inhibitors. With the known role of these four proteins in regulating the synaptic E/I balance, we further demonstrated that VPA increased excitatory post-synaptic protein (postsynaptic density 95) and inhibitory post-synaptic protein (Gephyrin) in cortical neuro-glial mixed cultures. Our results suggested that VPA might affect the synaptic excitatory/inhibitory balance through its effect on astrocytes. This work provides the basis for future evaluation of the role of astroglial cell adhesion molecules and the extracellular matrix on the control of excitatory and

  20. Population pharmacokinetic modelling of valproic acid and its selected metabolites in acute VPA poisoning.

    PubMed

    Jawień, Wojciech; Wilimowska, Jolanta; Kłys, Małgorzata; Piekoszewski, Wojciech

    2017-04-01

    Valproic acid (VPA) is a first-line antiepileptic drug. It is used in the treatment of many different types of partial and generalized epileptic seizures. Though the clinical pharmacokinetics of VPA has been well defined, information about pharmacokinetics after overdoses is rare. The aim of this study was to try to build a population pharmacokinetic model that would describe the time course of VPA and its selected metabolites when the drug is ingested in an overdose situation. Blood samples were collected during admission to the hospital and several times during treatment for poisoning (10 men and 10 women). The concentration of VPA and its metabolites were determined by liquid chromatography coupled with mass spectrometry. For population pharmacokinetic evaluation of VPA and its metabolites, the two-compartment-model was applied. The estimated doses of VPA taken ranged from 6 to 65g, while the time after ingestion ranged from 1 to 30h. Results showed that the β-oxidation process exhibited Michaelis-Menten kinetics becoming saturated during acute intoxication. The same could not be said for the desaturation route. VPA therapy increased the Vmax for β-oxidation by 59% while decontamination appeared to be of moderate efficacy lowering the F value by 34% on the average. None of the models perfectly described the experimental data. Important factors like the variable degree of protein binding by VPA could not be included in the models. The small number of subjects used in the study made the analysis of more covariates impossible. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  1. Valproic Acid Use During Radiation Therapy for Glioblastoma Associated With Improved Survival

    SciTech Connect

    Barker, Christopher A.; Bishop, Andrew J.; Chang, Maria; Beal, Kathryn; Chan, Timothy A.

    2013-07-01

    Purpose: Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We investigated whether VA use during RT for GB was associated with overall survival (OS). Methods and Materials: Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS. Results: Seizures before the end of RT were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. Median OS in patients taking VA was 16.9 months (vs 13.6 months taking another AED, P=.16). Among patients taking an AED during RT, OS was associated with VA (P=.047; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.27-1.07), and RTOG RPA class (P<.0001; HR, 1.49; 95% CI, 1.37-1.61). Of the 5 most common AEDs, only VA was associated with OS. Median OS of patients receiving VA and TMZ during RT was 23.9 months (vs 15.2 months for patients taking another AED, P=.26). When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, −0.09 to 1.17), independently of RTOG RPA class and seizure history. Conclusions: VA use during RT for GB was associated with improved OS, independently of RTOG RPA, seizure history, and concurrent TMZ use. Further studies of treatment that combines HDAC inhibitors and RT are warranted.

  2. Pros and cons for the development of new antiepileptic drugs.

    PubMed

    Bialer, Meir; Walker, Matthew C; Sander, Josemir W

    2002-01-01

    There continues to be an escalation in the number of new antiepileptic drugs, with many recently marketed drugs and many more entering clinical trials. This growth begs the question as to whether we need additional antiepileptic drugs. We consider the answer to this question from the medical perspective and also from the viewpoint of the pharmaceutical industry, health providers and from a more global, international perspective. There is undoubtedly a medical need for new antiepileptic drugs, and despite growing competition, the antiepileptic drug market remains profitable. However, in health services with limited resources, it is important that this expense is not offset by failure to research more appropriate use of existing antiepileptic drugs that may have a greater impact on healthcare. This is especially true for developing countries where resources would be much better spent on prevention and closing the treatment gap (the difference between those who can be treated and those who are treated).

  3. Psychotic disorders induced by antiepileptic drugs in people with epilepsy.

    PubMed

    Chen, Ziyi; Lusicic, Ana; O'Brien, Terence J; Velakoulis, Dennis; Adams, Sophia J; Kwan, Patrick

    2016-10-01

    Antiepileptic drug treatment can induce psychosis in some patients. However, there are no agreed definitions or diagnostic criteria for antiepileptic drug-induced psychotic disorder in the classification systems of either epileptology or psychiatry. In this study we investigated the clinical spectrum of antiepileptic drug-induced psychotic disorder in patients with epilepsy. The medical records of all patients with epilepsy who were diagnosed by a neuropsychiatrist as having a psychotic disorder at the Royal Melbourne Hospital from January 1993 to June 2015 were reviewed. Data were extracted regarding epilepsy and its treatment, psychotic symptoms profile and outcome. The diagnosis of epilepsy was established in accordance to the classification system of the International League Against Epilepsy while that of psychotic disorder was made according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition and the proposal on neuropsychiatric disorders in epilepsy. Patients with antiepileptic drug-induced psychotic disorder were compared to those with psychotic disorders unrelated to antiepileptic drugs assessed over the same period (non-antiepileptic drug induced psychotic disorder group). Univariate comparisons were performed and variables with a value of P < 0.1 were selected for the multivariate logistic regression analysis. The records of 2630 in-patients and outpatients with epilepsy were screened, from which 98 (3.7%) with psychotic disorders were identified. Among these, 14 (14.3%) were diagnosed to have antiepileptic drug-induced psychotic disorder. Excluding one patient who developed psychosis after valproate withdrawal, 76.9% in the antiepileptic drug induced psychotic disorder group were female and the percentage of temporal lobe involvement was higher in the antiepileptic drug induced psychotic disorder group (69.2% versus 38.1%, P < 0.05). Current use of levetiracetam was higher in antiepileptic drug-induced psychotic disorder group (84

  4. Antiepileptic drug selection for people with HIV/AIDS: evidence-based guidelines from the ILAE and AAN.

    PubMed

    Birbeck, Gretchen L; French, Jacqueline A; Perucca, Emilio; Simpson, David M; Fraimow, Henry; George, Jomy M; Okulicz, Jason F; Clifford, David B; Hachad, Houda; Levy, René H

    2012-01-01

    A joint panel of the American Academy of Neurology (AAN) and the International League Against Epilepsy (ILAE) convened to develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Key findings from this literature search included the following: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of approximately 50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of approximately 50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C).

  5. Severe Hyponatremia Due to Valproic Acid Toxicity.

    PubMed

    Gupta, Ena; Kunjal, Ryan; Cury, James D

    2015-09-01

    Hyponatremia is a very commonly encountered clinical entity with potentially dangerous effects and for which many precipitating factors have been identified. We present a case of valproic acid (VPA) overdose causing profound hyponatremia, with one of the lowest serum sodium levels ever documented in literature. A 54-year-old woman with hypothyroidism, hypertension and bipolar disorder presented with somnolence after intentionally ingesting 7,500 mg VPA. She was drowsy but easily arousable with no hemodynamic compromise and an unremarkable physical exam. There was no clinical suspicion for organic neurological or pulmonary disease, adrenal insufficiency or volume depletion. She was found to have a serum sodium of 99 mEq/L, low plasma osmolality (211 mOsm/kg H2O), and high urine osmolality (115 mOsm/kg H2O). Her urine sodium was 18 mEq/L. She was euthyroid (TSH: 3.06 mIU/L) and compliant with thyroxine replacement. She was admitted to the intensive care unit for close monitoring and VPA was withheld. Over 36 hours her VPA level fell from 59.3 mg/L to 22.8 mg/L, serum sodium steadily rose to 125 mEq/L and there was concomitant improvement in her mental status. At 72 hours, she was transferred for an inpatient psychiatric evaluation and her sodium level was 135 mEq/L. She luckily did not experience any seizures or decline in neurological function. The clinical presentation in this patient is consistent with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) leading to a dramatic fall in sodium to a level of 99 mEq/L. Chronic VPA use has been associated with SIADH and chronic hyponatremia. Review of records in this patient from 1 year prior revealed that her last measured sodium level was 127 mEq/L. It is therefore most likely that our case is one of acute on chronic hyponatremia provoked by VPA overdose in the setting of chronic VPA use. Whilst our patient's course was relatively benign, this case illustrates a rare consequence of VPA toxicity, which

  6. The effect of hemodialysis and hemoperfusion on serum valproic acid concentration.

    PubMed

    Kandrotas, R J; Love, J M; Gal, P; Oles, K S

    1990-09-01

    We report a patient with dialysis-induced encephalopathy who was taking divalproex sodium for a seizure disorder. Her serum valproic acid concentration appeared to be in the low therapeutic range at 54 mg/l yet she continued to have seizure activity. The elimination half-life and apparent clearance of valproic acid were the same for both a dialysis and nondialysis day, indicating that hemodialysis/hemoperfusion has little effect on the overall removal of valproic acid from the body.

  7. Antiepileptic Drugs 2012: Recent Advances and Trends

    PubMed Central

    Sirven, Joseph I.; Noe, Katherine; Hoerth, Matthew; Drazkowski, Joseph

    2012-01-01

    There are now 24 antiepileptic drugs (AEDs) approved for use in epilepsy in the United States by the Food and Drug Administration. A literature search was conducted using PubMed, MEDLINE, and Google for all English-language articles that discuss newly approved AEDs and the use of AEDs in epilepsy in the United States from January 1, 2008, through December 31, 2011. Five new agents were identified that have come onto the market within the past 2 years. Moreover, 3 trends involving AEDs have become clinically important and must be considered by all who treat patients with epilepsy. These trends include issues of generic substitution of AEDs, pharmacogenomics predicting serious adverse events in certain ethnic populations, and the issue of the suicide risk involving the entire class of AEDs. This article discusses the most recent AEDs approved for use in the United States and the 3 important trends shaping the modern medical management of epilepsy. PMID:22958992

  8. The measurement of ammonia blood levels in patients taking valproic acid: looking for problems where they do not exist?

    PubMed

    Chicharro, Ada V; de Marinis, Alejandro J; Kanner, Andres M

    2007-11-01

    Hyperammonemia (HA) commonly occurs with the use of valproic acid (VPA); while it has no clinical significance in most cases, the Physician Desk Reference recommends its discontinuation in the presence of HA. The purpose of this study is to review the literature in order to estimate the prevalence and magnitude of HA in VPA treated patients, to establish any association with hepatotoxicity and encephalopathy and to identify any factors associated with its occurrence. A search of MEDLINE and Cochrane Database of Systematic Reviews, between 1980 and 2005 was performed. Out of 183 studies, 24 met our inclusion criteria. The prevalence of HA in the prospective studies ranged between 70% and 100%, while in cross-sectional studies it varied between 16% and 100%. Ammonia (NH(3)) blood levels increased by a two-fold average relative to the baseline levels. There was no association between HA and clinical symptoms. Concomitant administration of other antiepileptic drugs (AEDs) was the factor most frequently associated with HA.

  9. Zinc Deficiency and Oxidative Stress Involved in Valproic Acid Induced Hepatotoxicity: Protection by Zinc and Selenium Supplementation.

    PubMed

    Ahangar, Nematollah; Naderi, Maloos; Noroozi, Abdolali; Ghasemi, Maryam; Zamani, Ehsan; Shaki, Fatemeh

    2017-01-25

    Valproic acid (VPA) is an antiepileptic drug, which its usage is limited due to its hepatotoxicity. The present study was conducted to investigate the efficacy of zinc (Zn) and selenium (Se), necessary trace elements, against VPA-induced hepatotoxicity in Wistar rats. The animals were divided into five groups: control, VPA 200 mg/kg, VPA + Zn (100 mg/kg), VPA + Se (100 mg/kg), and VPA + Zn + Se. The administration of VPA for four consecutive weeks resulted in decrease in serum level of Zn in rats. Also, an increase in liver marker enzymes (ALT and AST) and also histological changes in liver tissue were shown after VPA administration. Oxidative stress was evident in VPA group by increased lipid peroxidation (LPO), protein carbonyl (PCO), glutathione (GSH) oxidation, and reducing total antioxidant capacity. Zn and Se (100 mg/kg) administration was able to protect against deterioration in liver enzyme, abrogated the histological change in liver tissue, and suppressed the increase in oxidative stress markers. Zn and combination of Zn plus Se treatment showed more protective effects than Se alone. These results imply that Zn and Se should be suggested as effective supplement products for the prevention of VPA-induced hepatotoxicity.

  10. Science review: Carnitine in the treatment of valproic acid-induced toxicity – what is the evidence?

    PubMed Central

    Lheureux, Philippe ER; Penaloza, Andrea; Zahir, Soheil; Gris, Mireille

    2005-01-01

    Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well tolerated, but rare serious complications may occur in some patients receiving VPA chronically, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity (VHT) and VPA-induced hyperammonaemic encephalopathy (VHE). Some data suggest that VHT and VHE may be promoted by carnitine deficiency. Acute VPA intoxication also occurs as a consequence of intentional or accidental overdose and its incidence is increasing, because of use of VPA in psychiatric disorders. Although it usually results in mild central nervous system depression, serious toxicity and even fatal cases have been reported. Several studies or isolated clinical observations have suggested the potential value of oral L-carnitine in reversing carnitine deficiency or preventing its development as well as some adverse effects due to VPA. Carnitine supplementation during VPA therapy in high-risk patients is now recommended by some scientific committees and textbooks, especially paediatricians. L-carnitine therapy could also be valuable in those patients who develop VHT or VHE. A few isolated observations also suggest that L-carnitine may be useful in patients with coma or in preventing hepatic dysfunction after acute VPA overdose. However, these issues deserve further investigation in controlled, randomized and probably multicentre trials to evaluate the clinical value and the appropriate dosage of L-carnitine in each of these conditions. PMID:16277730

  11. Reversible Encephalopathy due to Valproic Acid Induced Hyperammonemia in a Patient with Bipolar I Disorder: A Cautionary Report

    PubMed Central

    Patel, Neel; Landry, Katherine B.; Fargason, Rachel E.; Birur, Badari

    2017-01-01

    Valproic acid (VPA) is an FDA-approved medication widely prescribed for seizures, migraines, and mixed or manic episodes in bipolar disorder. Hyperammonemia is a rare complication of VPA use, which can result in high morbidity and occasionally fatal encephalopathy. The scant literature on Valproate Induced Hyperammonemic Encephalopathy (VIHE) is characterized by acute onset of decreasing level of consciousness, drowsiness, lethargy which in rare instances can lead to seizures, stupor, coma, and persistent morbidity and cortical damage. Below we describe a case report of a patient with Bipolar I Disorder with no primary evidence of hepatic dysfunction that was initiated on VPA and olanzapine to address manic and psychotic symptoms. This patient subsequently developed elevated ammonia (NH4) levels that led to a reversible encephalopathy. This cautionary case report highlights the potential for a rare but serious complication from VPA, a medication increasingly used in both neurologic and neuropsychiatric settings. It is imperative that clinicians perform a thorough physical, neurological and diagnostic evaluation, routinely check NH4 and VPA levels when prescribing these agents and exercise caution when VPA is concomitantly prescribed with antipsychotics and cytochrome P450 inducing antiepileptic medications. PMID:28138203

  12. Spectroscopic analysis of the interaction of valproic acid with histone H1 in solution and in chromatin structure.

    PubMed

    Sargolzaei, Javad; Rabbani-Chadegani, Azra; Mollaei, Hossein; Deezagi, Abdolkhalegh

    2017-06-01

    Histone H1 is a basic chromosomal protein which links adjacent nucleosomes in chromatin structure. Valproic acid (VPA), a histone deacetylase inhibitor, is widely used as an antiepileptic drug for the treatment of various cancers. In this study the interaction between VPA and histone H1, chromatin and DNA in solution was investigated employing spectroscopic techniques. The results showed that VPA binds cooperatively to histone H1 and chromatin but exhibited very weak interaction with DNA. The association constants demonstrated higher affinity of VPA to H1 compared to chromatin. Fluorescence emission intensity was reduced by quenching value (Ksv) of 2.3 and 0.83 for H1 and chromatin respectively. VPA also altered ellipticity of chromatin and H1 at 220nm indicating increase in α-helix content of H1/chromatin proteins suggesting that the protein moiety of chromatin is the site of VPA action. Moreover, thermal denaturation revealed hypochromicity in chromatin Tm profiles with small shift in Tm values without any significant change in DNA pattern. It is concluded that VPA, apart from histone deacetylase inhibition activity, binds strongly to histone H1 in chromatin structure, demonstrating that VPA may also exert its anticancer activity by influencing chromatin proteins which opens new insight into the mechanism of VPA action. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Developmental outcomes at preschool age after fetal exposure to valproic acid and lamotrigine: cognitive, motor, sensory and behavioral function.

    PubMed

    Rihtman, Tanya; Parush, Shula; Ornoy, Asher

    2013-11-01

    This prospective, observational study assessed the development of preschool children aged 3-6 years, 11 months (n=124) after in-utero anti-epileptic drug (AED) monotherapy exposure to valproic acid (VPA) (n=30, mean age 52.00[±15.22] months) and lamotrigine (LT) (n=42, mean age 50.12[±12.77] months), compared to non-exposed control children (n=52, mean age 59.96[±14.51] months). As a combined group, AED-exposed children showed reduced non-verbal IQ scores, and lower scores on motor measures, sensory measures, and parent-report executive function, behavioral and attentional measures. When the VPA- and LT-exposed groups were analyzed separately, no cognitive differences were found, but control-VPA and control-LT differences emerged for most motor and sensory measures as well as control-VPA parent-report behavioral and attentional differences. No differences were noted between the VPA and LT groups. These findings suggest that VPA- and LT-exposed children should be monitored on a wider range of developmental measures than currently used, and at differing developmental stages.

  14. Apgar-score in children prenatally exposed to antiepileptic drugs: a population-based cohort study

    PubMed Central

    Christensen, Jakob; Pedersen, Henrik Søndergaard; Kjaersgaard, Maiken Ina Siegismund; Parner, Erik Thorlund; Vestergaard, Mogens; Sørensen, Merete Juul; Olsen, Jørn; Bech, Bodil Hammer; Pedersen, Lars Henning

    2015-01-01

    Objectives It is unknown if prenatal exposure to antiepileptic drugs (AEDs) increases the risk of low Apgar score in offspring. Setting Population-based study using health registers in Denmark. Participants We identified all 677 021 singletons born in Denmark from 1997 to 2008 and linked the Apgar score from the Medical Birth Register with information on the women's prescriptions for AEDs during pregnancy from the Danish Register of Medicinal Product Statistics. We used the Danish National Hospital Registry to identify mothers diagnosed with epilepsy before birth of the child. Results were adjusted for smoking and maternal age. Results Among 2906 children exposed to AEDs, 55 (1.9%) were born with an Apgar score ≤7 as compared with 8797 (1.3%) children among 674 115 pregnancies unexposed to AEDs (adjusted relative risk (aRR)=1.41 (95% CI 1.07 to 1.85). When analyses were restricted to the 2215 children born of mothers with epilepsy, the aRR of having a low Apgar score associated with AED exposure was 1.34 (95% CI 0.90 to 2.01) When assessing individual AEDs, we found increased, unadjusted RR for exposure to carbamazepine (RR=1.86 (95% CI 1.01 to 3.42)), valproic acid (RR=1.85 (95% CI 1.04 to 3.30)) and topiramate (RR=2.97 (95% CI 1.26 to 7.01)) when compared to unexposed children. Conclusions Prenatal exposure to AEDs was associated with increased risk of being born with a low Apgar score, but the absolute risk of a low Apgar score was <2%. Risk associated with individual AEDs indicate that the increased risk is not a class effect, but that there may be particularly high risks of a low Apgar score associated with certain AEDs. PMID:26359281

  15. Use of antiepileptic drugs during pregnancy and lactation: Type of information provided by searching Google.

    PubMed

    Lavi-Blau, Tal; Ekstein, Dana; Neufeld, Miri Y; Eyal, Sara

    2016-02-01

    Surveys among women with epilepsy (WWE) show that they receive their essential pregnancy-related information from many sources, including the internet. Our aim was to assess the types of websites provided by searching Google for the use of four antiepileptic drugs (AEDs) during pregnancy and lactation. The search was performed on 40 computers used by health-care professionals, on 40 computers used by nonhealth-care professionals, and on 5 computers used by WWE in Israel and on 8 computers used by nonhealth-care professionals in the U.S. On each computer, a Google search was conducted for term combinations that included one AED name ("carbamazepine","valproic acid", "lamotrigine", "levetiracetam", or "Keppra") and "Pregnancy", "Lactation", or "Breastfeeding". The top three and top ten websites retrieved in every search were mapped (a total of 45 and 150 websites, respectively, from each computer). Across all searches in English, on both U.S. and Israeli computers, the majority of websites listed among the first three and first ten results were those of independent health portals. The representation of the Epilepsy Foundation website was 10% or less, and only a few results were obtained from the NIH's general public-oriented MedlinePlus. In Hebrew, results included almost exclusively Israeli or Hebrew-translated websites. As in English, results from public-oriented, professionally-written websites in Hebrew accounted for less than 50% of entries. Overall, the availability of readable and high-quality information on AEDs used by pregnant and breastfeeding women is limited. Guiding patients towards accurate web resources can help them navigate among the huge amount of available online information.

  16. Antiepileptic drug trials: the view from the clinic.

    PubMed

    Faught, Edward

    2012-06-01

    A golden age of antiepileptic drug development has yielded over a dozen useful new compounds, but the nature of clinical trials has made translation to practical use in the clinic difficult. Most clinical trials are designed for regulatory purposes and fail to answer critical clinical questions. These questions include: which drug is best as initial therapy, which drugs work as monotherapy, what are good drug combinations, what is the best starting dose and titration schedule, what is a reasonable target dose, what is the shape of the dose-response curve and does it vary significantly between patients, what is the true incidence of side effects, and what is the long-term efficacy of the drug? Most of these questions could be answered by changing trial designs, but many changes would entail additional time and money. There are encouraging signs that trials with procedures more directly applicable to the clinic are becoming common. These include direct comparative trials, longer trials with emphasis on seizure freedom, and trials with more flexible dosing schedules. In the past, funding of longer and more naturalistic trials has fallen to government agencies, but commercial funding has been obtained for several recent studies. Better quality control, innovative endpoints, structured searching for side effects, and standardisation of data collection are also promising topics for development.

  17. Incidental microvesicular steatosis due to valproic acid anticonvulsant therapy.

    PubMed

    Scott, D A; Gholson, C F; Netchvolodoff, C V; Ray, M; Gonzalez, E; Bacon, B R

    1991-04-01

    Valproic acid has been implicated in at least 100 cases of fatal acute liver failure. Most cases have occurred in patients less than 10 yr old; however, at least seven have involved adults. Microvesicular steatosis has been uniformly observed, but its incidence in less severe liver disease and in asymptomatic patients receiving valproate is unknown. We report two patients receiving maintenance valproate, one with resolving acute hepatitis C and the other with chronic persistent hepatitis C, with incidental microvesicular steatosis demonstrated on oil-red O stains. We conclude that microvesicular steatosis does not necessarily signify hepatotoxicity in patients on chronic valproic acid, and should not lead to discontinuation of the drug until other causes of acute or chronic liver disease have been excluded.

  18. Valproic-acid-induced thrombocytopenia and hepatotoxicity: discontinuation of treatment?

    PubMed

    Lackmann, Gerd-Michael

    2004-02-01

    We report the case of a 4-year-old boy with long-term sodium valproate (valproic acid; VPA) therapy who suddenly developed clinically relevant thrombocytopenia and signs of hepatotoxicity. Reduction of the VPA dosage led to clinical and laboratory parameter improvement, while discontinuation of therapy was not necessary. The current practice of the management of VPA-induced side effects is discussed in view of the current recommendations from the literature. Copyright 2004 S. Karger AG, Basel

  19. Divalproex Sodium Versus Valproic Acid in Hospital Treatment of Psychotic Disorders.

    PubMed

    Schwartz, Thomas L.; Massa, Jose L.; Gupta, Sanjay; Al-Samarrai, Sadiq; Devitt, Patrick; Masand, Prakash S.

    2000-04-01

    BACKGROUND: Approximately 50% of pharmacy prescriptions in the United States are filled with generic drugs, which have improved substantially in quality owing to increased governmental regulations. The remaining medicoeconomic question regards whether or not brand-name medications are worth the price. This study evaluates these questions for the brand-name mood stabilizer divalproex sodium and its generic counterpart, valproic acid. METHOD: We conducted a retrospective chart review of all patients who had been taking divalproex and had been switched to valproic acid at 2 local mental health facilities in 1997. Data collected from the inpatient- and day-treatment charts for these 28 patients included dose, duration, side effects, and efficacy (determined using retrospective chart review and the Clinical Global Impressions scale [CGI]) of divalproex sodium compared with valproic acid treatment. RESULTS: t Tests for dependent samples revealed that valproic acid was administered at higher doses than divalproex sodium, but these treatments did not differ in efficacy on the basis of CGI scores. Fisher exact test analyses revealed a trend toward more nausea with valproic acid; also, the combination of nausea, abdominal discomfort, and diarrhea occurred more often in valproic acid-treated patients. There were no differences in the discontinuation of either medicine because of side effects, or in the use of medications to treat gastrointestinal side effects. Efficacy was similar for valproic acid and divalproex sodium. There was no single, significant side effect increase for valproic acid; however, when grouped together, gastrointestinal side effects were statistically significantly increased in valproic acid-treated patients. This appears clinically insignificant because of the lack of difference in drug discontinuation rate or gastrointestinal medication use. CONCLUSION: Given these results and that valproic acid is much less expensive than divalproex sodium, valproic

  20. Compound

    NASA Astrophysics Data System (ADS)

    Suzumura, Akitoshi; Watanabe, Masaki; Nagasako, Naoyuki; Asahi, Ryoji

    2014-06-01

    Recently, Cu-based chalcogenides such as Cu3SbSe4, Cu2Se, and Cu2SnSe3 have attracted much attention because of their high thermoelectric performance and their common feature of very low thermal conductivity. However, for practical use, materials without toxic elements such as selenium are preferable. In this paper, we report Se-free Cu3SbS4 thermoelectric material and improvement of its figure of merit ( ZT) by chemical substitutions. Substitutions of 3 at.% Ag for Cu and 2 at.% Ge for Sb lead to significant reductions in the thermal conductivity by 37% and 22%, respectively. These substitutions do not sacrifice the power factor, thus resulting in enhancement of the ZT value. The sensitivity of the thermal conductivity to chemical substitutions in these compounds is discussed in terms of the calculated phonon dispersion and previously proposed models for Cu-based chalcogenides. To improve the power factor, we optimize the hole carrier concentration by substitution of Ge for Sb, achieving a power factor of 16 μW/cm K2 at 573 K, which is better than the best reported for Se-based Cu3SbSe4 compounds.

  1. Antiepileptic drug regimens and major congenital abnormalities in the offspring.

    PubMed

    Samrén, E B; van Duijn, C M; Christiaens, G C; Hofman, A; Lindhout, D

    1999-11-01

    To assess the risk of major congenital abnormalities associated with specific antiepileptic drug regimens, a large retrospective cohort study was performed. The study comprised 1,411 children born between 1972 and 1992 in four provinces in The Netherlands who were born to mothers with epilepsy and using antiepileptic drugs during the first trimester of pregnancy, and 2,000 nonepileptic matched controls. We found significantly increased risks of major congenital abnormalities for carbamazepine and valproate monotherapy, with evidence for a significant dose-response relationship for valproate. The risk of major congenital abnormalities was nonsignificantly increased for phenobarbital monotherapy when caffeine comedication was excluded, but a significant increase in risk was found when caffeine was included. Phenytoin monotherapy was not associated with an increased risk of major congenital abnormalities. Regarding polytherapy regimens, increased risks were found for several antiepileptic drug combinations. Clonazepam, in combination with other antiepileptic drugs, showed a significantly increased relative risk. Furthermore, there were significantly increased relative risks for the combination of carbamazepine and valproate and the combination of phenobarbital and caffeine with other antiepileptic drugs. This study shows that most antiepileptic drug regimens were associated with an increased risk of major congenital abnormalities in the offspring, in particular valproate (dose-response relationship) and carbamazepine monotherapy, benzodiazepines in polytherapy, and caffeine comedication in combinations with phenobarbital.

  2. Random total antiepileptic drug levels and seizure control during pregnancy.

    PubMed

    Al-Bunyan, M A

    2001-04-01

    To study the correlation of randomly-tested total antiepileptic plasma levels and seizure control in a retrospectively collected group of pregnant epileptic Saudi women. The medical records of 30 Saudi epileptic female patients were reviewed during their subsequent pregnancies (total of 50). The type of antiepileptic drugs used during each pregnancy, the dose of each drug and the corresponding total plasma levels were noted. Antiepileptic drugs assay were carried out randomly during pregnancy either by TDX or a sensitive high performance liquid chromatography method. A total of 50 pregnancies were studied. The most common seizure type in these women was complex partial seizure followed by primary generalized epilepsy, myoclonic seizures and of least occurrence was the simple partial seizure with secondary generalization. All patients were received antiepileptic drugs, including either carbamazepine, phenytoin, valporic acid, phenobarbitone or clonazepam. In a total of 24 pregnancies (48%), the serum levels of antiepileptic drugs were subtherapeutic during the first trimester. Recurrent seizures occurred in a total of 20 pregnancies (40%) especially in the 3rd trimester. It is concluded that subtherapeutic serum levels of antiepileptic drugs correlated highly with the increased frequency of seizure in these pregnant women. Monitoring of state of seizure control in epileptic pregnant women should be made regularly during the course of their pregnancies.

  3. The Controversy over Generic Antiepileptic Drugs

    PubMed Central

    Shaw, Susan J.; Hartman, Adam L.

    2010-01-01

    As patent protection ends for the next generation of antiepileptic drugs (AEDs), a complex debate continues over generic substitution of AEDs. On one hand, generic drug formulations provide cost savings for patients and society. On the other hand, patients with epilepsy and physicians are wary about the adequacy and efficacy of the Food and Drug Administration's (FDA) standards for generics. This article reviews current and proposed bioequivalence test procedures, summarizes new generic AED formulations and their costs, and discusses potential pitfalls in the current standards. These shortcomings include certain pharmacokinetic factors and clinical pharmacologic factors that may affect bioequivalence of generic AEDs, and statistical limitations of the standards. While the drug concentration differences between the brand name drug and each generic formulation are unlikely to be substantial, the differences with generic-to-generic switches will be greater and potentially clinically significant. Conversely, owing to their more favorable pharmacokinetic profile, newer AEDs may be less prone to problems with generic substitution than older ones. Unfortunately, very few data are available to guide decisions regarding what is best for an individual patient. Based on new prediction methods, generic substitution should be safe for many patients but identifying them ultimately requires more rigorous study. PMID:22477799

  4. Metabolic concerns associated with antiepileptic medications.

    PubMed

    Sheth, Raj D

    2004-11-23

    Because treatment with antiepileptic drugs (AEDs) is often for years or lifelong, physicians should be aware of the metabolic changes that can be associated with AED use and the potential effects of these changes during long-term therapy. Alterations of bone metabolism leading to decreased bone mineral density, associated particularly but not exclusively with the hepatic enzyme-inducing AEDs, can worsen the risk for fractures, which is already increased in patients with epilepsy by factors such as seizure-related falls and trauma. Some AEDs are associated with weight gain, an effect that is not only distressing to many patients but may be sufficient to increase the risk for cardiovascular disease and other disorders associated with excessive body weight. The carbonic anhydrase-inhibiting properties of some AEDs can lead to metabolic acidosis. The AEDs that inhibit carbonic anhydrase are also associated with an increase in risk for renal stones, as is the ketogenic diet. Awareness of the potential metabolic disturbances associated with AED use is particularly important because many of them are subtle and may take years to become clinically apparent.

  5. Neurodevelopmental effects of fetal antiepileptic drug exposure.

    PubMed

    Velez-Ruiz, Naymee J; Meador, Kimford J

    2015-03-01

    Many studies investigating cognitive outcomes in children of women with epilepsy report an increased risk of mental impairment. Verbal scores on neuropsychometric measures may be selectively more involved. While a variety of factors contribute to the cognitive problems of children of women with epilepsy, antiepileptic drugs (AEDs) appear to play a major role. The mechanisms by which AEDs affect neurodevelopmental outcomes remain poorly defined. Animal models suggest that AED-induced apoptosis, altered neurotransmitter environment, and impaired synaptogenesis are some of the mechanisms responsible for cognitive and behavioral teratogenesis. AEDs that are known to induce apoptosis, such as valproate, appear to affect children's neurodevelopment in a more severe fashion. Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains, and these appear to persist at least until the age of 6. Some studies have shown neurodevelopmental deficiencies associated with the use of phenobarbital and possibly phenytoin. So far, most of the investigations available suggest that fetal exposures to lamotrigine or levetiracetam are safer with regard to cognition when compared with other AEDs. Studies on carbamazepine show contradictory results, but most information available suggests that major poor cognitive outcomes should not be attributed to this medication. Overall, children exposed to polytherapy prenatally appear to have worse cognitive and behavioral outcomes compared with children exposed to monotherapy, and with the unexposed. There is an increase risk of neurodevelopmental deficits when polytherapy involves the use of valproate versus other agents.

  6. Rufinamide: a new anti-epileptic medication.

    PubMed

    Hakimian, Shahin; Cheng-Hakimian, Andrea; Anderson, Gail D; Miller, John W

    2007-08-01

    Rufinamide (1-[2,6-difluorobenzyl]-1H-1,2,3-triazole-4-carboxamide) is a new anti-epileptic drug with a novel triazole derivative structure. The suspected mechanism of action is limitation of sodium-dependent action potentials, thought to result in a membrane stabilizing effect. Rufinamide is extensively metabolized in the liver by non-CYP450 enzymes with an elimination half-life of 8 - 12 h. Three randomized, placebo-controlled trials have shown that rufinamide is effective against partial seizures in adults. Efficacy in the Lennox-Gastaut syndrome, a severe, disabling childhood onset epilepsy syndrome, was shown in a single, randomized, placebo-controlled trial. It has recently been approved for treatment of Lennox-Gastaut syndrome in Europe. In the US it is under regulatory review. Most common adverse effects are somnolence, fatigue, dizziness, dipolopia, nausea and ataxia. Rufinamide has shown promise as adjunctive treatment for Lennox-Gastaut syndrome and may have some role in localization related epilepsies as well.

  7. New antiepileptic drugs: lacosamide, rufinamide, and vigabatrin.

    PubMed

    Strom, Laura A; Koh, Susan; Frey, Lauren

    2010-07-01

    The treatment of epilepsy is complicated by the multiple seizure types and epilepsy syndromes needing therapy. In addition, seizures in up to 30% of epilepsy patients are resistant to available medications. The three newest antiepileptic medications (lacosamide, rufinamide, and vigabatrin) all putatively have novel mechanisms of action, which might increase the chance of treatment success in patients failing previous antiepilepsy drug trials and the chance of successful synergy with currently available medications. In our experience, all three drugs generally are well tolerated, although the risk for serious long-term complications with vigabatrin presents special challenges and precautions. Lacosamide is approved for the adjunctive therapy of complex partial seizures in adults and also is available in an intravenous formulation. Rufinamide is a new treatment option for seizures associated with Lennox-Gastaut syndrome, and although it is not FDA approved for partial seizures, it has shown efficacy for that indication as well. Vigabatrin has been approved in adults for drug-resistant complex partial seizures and in infants as a treatment option for infantile spasms.

  8. [Pharmacogenetics, pharmacogenomics and individualised antiepileptic therapy].

    PubMed

    Herranz, J L

    2006-10-10

    Despite the large number of antiepileptic drugs (AED) currently on the market, in 20-30% of patients it is still not possible to achieve a total control of the seizures or to prevent the appearance of idiosyncratic side effects. In this study the pharmacokinetic and pharmacodynamic factors involved in pharmacoresistance in epilepsies are analysed, with special attention given to the polymorphisms of metabolising enzymes or their inducers, particularly the hepatic cytochrome CYP, the over-expression of membrane-transporting proteins -P-glycoprotein (PGP), MRP- and polymorphisms in the ion channels. Idiosyncratic effects are produced due to an imbalance between the production of toxic metabolites and the individual capacity to detoxify them. Pharmacogenetics and pharmacogenomics can identify certain personal, biochemical, enzymatic and genetic characteristics that are of use in selecting the most effective AED with the lowest risk of idiosyncratic effects for each person. Although new AED that can help reduce the number of medication resistant patients must be introduced, at the same other therapeutic strategies have to be developed with the aid of pharmacogenomics; more specifically there is a need for AED that are not transported by PGP o MRP, or substances that antagonise those membrane transporters and make it possible for the AED to reach the site where they are to act. Furthermore, the detoxification capacity of each individual must be known in order to be able to minimise the risk of idiosyncratic side effects.

  9. Efficacy of Anti-Epileptic Drugs in the Treatment of Tumor and Its Associated Epilepsy: An in vitro Perspective

    PubMed Central

    Kaur, Taranjeet; Manchanda, Shaffi; Saini, Vedangana; Lakhman, Sukhwinder S.; Kaur, Gurcharan

    2016-01-01

    The change in the therapeutic targets from neuron to glia has proved beneficial in the treatment of many psychiatric disorders. The anti-epileptic drugs (AEDs) have been widely prescribed for the treatment of partial and complete seizures, bipolar disorder among others. The current study was carried out to explore the efficacy of some conventional and novel AEDs for the treatment of tumor-associated epilepsy which develops in 29-49% of the patients diagnosed with brain tumors. We used C6 glioma cell line as model system to study the effect of selected AEDs, viz., gabapentin (GBP), valproic acid (VPA) and topiramate (TPM). Morphometry, cell cycle analysis, apoptosis, expression of different protein markers, viz., GFAP, HSP70 and nuclear factor-κB (NFκB) were studied in AED-treated cultures. The study was further extended to rat hypothalamic primary explant cultures, and cell migration and expression of plasticity markers - neural cell adhesion molecule (NCAM) and polysialylation of NCAM (PSA-NCAM) - were studied in the explants. TPM was observed to show more pronounced increase in apoptosis of glioblastoma cells accompanied by significant downregulation in the expression of HSP70 and NFκB. TPM-treated explants also showed highest process ramification and cellular migration accompanied by intense expression of the plasticity markers as compared to those treated with GBP and VPA. Among the 3 AEDs tested, TPM was observed to show more promising effects on cytoprotection and plasticity of C6 glioma cells. PMID:27536020

  10. The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part I: A summary of the current state for clinicians.

    PubMed

    de Leon, Jose

    2015-01-01

    The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. This is part i of a comprehensive review on antiepileptic drug (AED) inducers using both mechanistic pharmacological and evidence-based medicine to provide practical recommendations to neurologists and psychiatrists concerning how to control for them. Carbamazepine, phenobarbital and phenytoin, are clinically relevant AED inducers; correction factors were calculated for studied induced drugs. These correction factors are rough simplifications for orienting clinicians, since there is great variability in the population regarding inductive effects. As new information is published, the correction factors may need to be modified. Some of the correction factors are so high that the drugs (e.g., bupropion, quetiapine or lurasidone) should not co-prescribed with potent inducers. Clobazam, eslicarbazepine, felbamate, lamotrigine, oxcarbazepine, rufinamide, topiramate, vigabatrin and valproic acid are grouped as mild inducers which may (i)be inducers only in high doses; (ii)frequently combine with inhibitory properties; and (iii)take months to reach maximum effects or de-induction, definitively longer than the potent inducers. Potent inducers, definitively, and mild inducers, possibly, have relevant effects in the endogenous metabolism of (i)sexual hormones, (ii) vitamin D, (iii)thyroid hormones, (iv)lipid metabolism, and (v)folic acid.

  11. Altered behavioral development in Nrf2 knockout mice following early postnatal exposure to valproic acid

    PubMed Central

    Furnari, Melody A.; Saw, Constance Lay-Lay; Kong, Ah-Ng; Wagner, George C

    2015-01-01

    Early exposure to valproic acid results in autism-like neural and behavioral deficits in humans and other animals through oxidative stress-induced neural damage. In the present study, valproic acid was administered to genetically altered mice lacking the Nrf2 (nuclear factor-erythroid 2 related factor 2) gene on postnatal day 14 (P14). Nrf2 is a transcription factor that induces genes that protect against oxidative stress. It was found that valproic acid-treated Nrf2 knockout mice were less active in open field activity chambers, less successful on the rotorod, and had deficits in learning and memory in the Morris water maze compared to the valproic acid-treated wild type mice. Given these results, it appears that Nrf2 knockout mice were more sensitive to the neural damage caused by valproic acid administered during early development. PMID:25454122

  12. Altered behavioral development in Nrf2 knockout mice following early postnatal exposure to valproic acid.

    PubMed

    Furnari, Melody A; Saw, Constance Lay-Lay; Kong, Ah-Ng; Wagner, George C

    2014-10-01

    Early exposure to valproic acid results in autism-like neural and behavioral deficits in humans and other animals through oxidative stress-induced neural damage. In the present study, valproic acid was administered to genetically altered mice lacking the Nrf2 (nuclear factor-erythroid 2 related factor 2) gene on postnatal day 14 (P14). Nrf2 is a transcription factor that induces genes that protect against oxidative stress. It was found that valproic acid-treated Nrf2 knockout mice were less active in open field activity chambers, less successful on the rotorod, and had deficits in learning and memory in the Morris water maze compared to the valproic acid-treated wild type mice. Given these results, it appears that Nrf2 knockout mice were more sensitive to the neural damage caused by valproic acid administered during early development. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Induction of Glycosphingolipid GM3 Expression by Valproic Acid Suppresses Cancer Cell Growth.

    PubMed

    Kawashima, Nagako; Nishimiya, Yoshiyuki; Takahata, Shouta; Nakayama, Ken-Ichi

    2016-10-07

    Glycosphingolipid GM3, a known suppressor of epidermal growth factor receptor (EGFR) phosphorylation, inhibits cell proliferation. Valproic acid, conversely, is known as an up-regulator of GM3 synthase gene (ST3GAL5). To test the possibility that valproic acid could inhibit EGFR phosphorylation by increasing the level of GM3 in cells, we treated A431 epidermoid carcinoma cells with valproic acid and found that valproic acid treatment caused an about 6-fold increase in the GM3 level but only a marginal increase in the GM2 level in these cells and that the observed increase in GM3 level was valproic acid dose-dependent. Consistent with this observation, valproic acid treatment induced GM3 synthase gene expression by about 8-fold. Furthermore, phosphorylation of EGFR was reduced, and cell proliferation was inhibited following valproic acid treatment. Consistent with these results, transient expression of GM3 synthase gene in A431 cells also increased cellular level of GM3, reduced phosphorylation of EGFR, and inhibited cell proliferation. Treatment with l-phenyl-2-decanoylamino-3-morpholino-l-propanol, an inhibitor of glucosylceramide synthesis, decreased the cellular level of GM3 and reduced the inhibitory effects of valproic acid on EGFR phosphorylation and cell proliferation. These results suggested that induction of GM3 synthesis was enough to inhibit proliferation of cancer cells by suppressing EGFR activity. Valproic acid treatment similarly increased the GM3 level and reduced phosphorylation of EGFR in U87MG glioma cells and inhibited their proliferation. These results suggested that up-regulators of GM3 synthase gene, such as valproic acid, are potential suppressors of cancer cell proliferation. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. [Efficacy of Epileptological Consultation After Initially Unsuccessful Antiepileptic Medication].

    PubMed

    Prasse, T; Rösche, J

    2016-09-01

    At least 25 % of patients with epilepsy do not achieve seizure freedom with their first antiepileptic medication. The aim of this study is to make a contribution to discussions on the efficacy of further antiepileptic medications in achieving seizure freedom for at least one year or reduction of seizure frequency of more than 50 % for more than one year. All patients who presented between January 1, 2009 and July 1, 2013 to the epileptological outpatient consulting service of the University of Rostock with at least one seizure in the previous year despite taking at least one antiepileptic medication were evaluated. Outcome was assessed according to the data available on July 1, 2014. 70 patients (35 f/35 m) aged 43.6 years on average (SD 16.7) with active epilepsy, who had taken 3.7 antiepileptic drugs on average (SD 2.8) before the first presentation to our service, were counseled on further antiepileptic treatment options. On average, 1.96 (SD 1.8) antiepileptic drugs were introduced in the therapy. At the last visit to our service, 15.7 % of the patients were seizure free for more than one year and 45,6 % of the patients had a reduction of seizure frequency of at least more than 50 %. With specialized epileptological counseling, substantial improvement in seizure frequency can be achieved in about 60 % of patients with epilepsy after failure of the initial antiepileptic drug. © Georg Thieme Verlag KG Stuttgart · New York.

  15. Molecular Targets for Antiepileptic Drug Development

    PubMed Central

    Meldrum, Brian S.; Rogawski, Michael A.

    2007-01-01

    Summary This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the α subunits of voltage-gated Na+ channels and also T-type voltage-gated Ca2+ channels) or influence GABA-mediated inhibition. Recently, α2–δ voltage-gated Ca2+ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na+ channels and GABAA receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca2+ channel subunits and auxiliary proteins, A- or M-type voltage-gated K+ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABAB and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current Ih; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na+ channels underlying persistent Na+ currents or GABAA receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the

  16. Effects of fetal antiepileptic drug exposure

    PubMed Central

    Baker, G.A.; Browning, N.; Cohen, M.J.; Bromley, R.L.; Clayton-Smith, J.; Kalayjian, L.A.; Kanner, A.; Liporace, J.D.; Pennell, P.B.; Privitera, M.; Loring, D.W.; Labiner, David; Moon, Jennifer; Sherman, Scott; Combs Cantrell, Deborah T.; Silver, Cheryl; Goyal, Monisha; Schoenberg, Mike R.; Pack, Alison; Palmese, Christina; Echo, Joyce; Meador, Kimford J.; Loring, David; Pennell, Page; Drane, Daniel; Moore, Eugene; Denham, Megan; Epstein, Charles; Gess, Jennifer; Helmers, Sandra; Henry, Thomas; Motamedi, Gholam; Flax, Erin; Bromfield, Edward; Boyer, Katrina; Dworetzky, Barbara; Cole, Andrew; Halperin, Lucila; Shavel-Jessop, Sara; Barkley, Gregory; Moir, Barbara; Harden, Cynthia; Tamny-Young, Tara; Lee, Gregory; Cohen, Morris; Penovich, Patricia; Minter, Donna; Moore, Layne; Murdock, Kathryn; Liporace, Joyce; Wilcox, Kathryn; Kanner, Andres; Nelson, Michael N.; Rosenfeld, William; Meyer, Michelle; Clayton-Smith, Jill; Mawer, George; Kini, Usha; Martin, Roy; Privitera, Michael; Bellman, Jennifer; Ficker, David; Baade, Lyle; Liow, Kore; Baker, Gus; Booth, Alison; Bromley, Rebecca; Casswell, Miranda; Barrie, Claire; Ramsay, Eugene; Arena, Patricia; Kalayjian, Laura; Heck, Christianne; Padilla, Sonia; Miller, John; Rosenbaum, Gail; Wilensky, Alan; Constantino, Tawnya; Smith, Julien; Adab, Naghme; Veling-Warnke, Gisela; Sam, Maria; O'Donovan, Cormac; Naylor, Cecile; Nobles, Shelli; Santos, Cesar; Holmes, Gregory L.; Druzin, Maurice; Morrell, Martha; Nelson, Lorene; Finnell, Richard; Yerby, Mark; Adeli, Khosrow; Wells, Peter; Browning, Nancy; Blalock, Temperance; Crawford, Todd; Hendrickson, Linda; Jolles, Bernadette; Kunchai, Meghan Kelly; Loblein, Hayley; Ogunsola, Yinka; Russell, Steve; Winestone, Jamie; Wolff, Mark; Zaia, Phyllis; Zajdowicz, Thad

    2012-01-01

    Objective: To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure. Methods: The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999–2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5). Results: Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102–109), lamotrigine 106 (102–109), phenytoin 105 (102–109), valproate 96 (91–100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills. Conclusions: Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed. PMID:22491865

  17. Valproic Acid Increases CD133 Positive Cells that Show Low Sensitivity to Cytostatics in Neuroblastoma

    PubMed Central

    Khalil, Mohamed Ashraf; Hraběta, Jan; Groh, Tomáš; Procházka, Pavel; Doktorová, Helena; Eckschlager, Tomáš

    2016-01-01

    Valproic acid (VPA) is a well-known antiepileptic drug that exhibits antitumor activities through its action as a histone deacetylase inhibitor. CD133 is considered to be a cancer stem cell marker in several tumors including neuroblastoma. CD133 transcription is strictly regulated by epigenetic modifications. We evaluated the epigenetic effects of treatment with 1mM VPA and its influence on the expression of CD133 in four human neuroblastoma cell lines. Chemoresistance and cell cycle of CD133+ and CD133− populations were examined by flow cytometry. We performed bisulfite conversion followed by methylation-sensitive high resolution melting analysis to assess the methylation status of CD133 promoters P1 and P3. Our results revealed that VPA induced CD133 expression that was associated with increased acetylation of histones H3 and H4. On treatment with VPA and cytostatics, CD133+ cells were mainly detected in the S and G2/M phases of the cell cycle and they showed less activated caspase-3 compared to CD133− cells. UKF-NB-3 neuroblastoma cells which express CD133 displayed higher colony and neurosphere formation capacities when treated with VPA, unlike IMR-32 which lacks for CD133 protein. Induction of CD133 in UKF-NB-3 was associated with increased expression of phosphorylated Akt and pluripotency transcription factors Nanog, Oct-4 and Sox2. VPA did not induce CD133 expression in cell lines with methylated P1 and P3 promoters, where the CD133 protein was not detected. Applying the demethylating agent 5-aza-2’-deoxycytidine to the cell lines with methylated promoters resulted in CD133 re-expression that was associated with a drop in P1 and P3 methylation level. In conclusion, CD133 expression in neuroblastoma can be regulated by histone acetylation and/or methylation of its CpG promoters. VPA can induce CD133+ cells which display high proliferation potential and low sensitivity to cytostatics in neuroblastoma. These results give new insight into the possible

  18. Enhanced rat sciatic nerve regeneration through silicon tubes implanted with valproic acid.

    PubMed

    Wu, Fei; Xing, Danmou; Peng, Zhengren; Rao, Ting

    2008-05-01

    Valproic acid (VPA) is an effective antiepileptic drug and mood stabilizer. It has recently been demonstrated that VPA could promote neurite outgrowth, activate the extracellular signal-regulated kinase pathway, and increase B-cell lymphoma/leukemia-2 (bcl-2)and growth cone-associated protein 43 (GAP-43) levels in spinal cord. We hypothesized that VPA could enhance axonal regeneration in the rat. In the present research, we demonstrate the effect of VPA on peripheral nerve regeneration and recovery of motor function through a silicon tube implanted with VPA. The left sciatic nerves were exposed through dorsal-splitting incisions, and 8-mm nerve sections were excised at the middle of the thigh. Then, a 1.0-cm-long silicone tube (internal diameter,1.0 mm; exterior diameter, 2.0 mm) was used to bridge the nerve deficit, anchored to the proximal and distal terminals of the excised deficit of sciatic nerves with 9-0 nylon epineural suture. Sterile petroleum jelly was used to seal the ends of the tubes to avoid leakage. The rats in the VPA group and control group were locally delivered 10 muL VPA injection (400 mg/5 mL) and normal saline, respectively, after the operation. The sciatic nerve index (SFI) was observed in each animal at 2-week intervals and electrophysiology was studied at 4-week intervals for 12 weeks. Histological and morphometrical analyses were performed at the end of the experiment (12 weeks after the operation). Using the digital image-analysis system, the thickness of the myelin sheath was measured, and total numbers of regenerated axons were counted. There was a significant difference in SFI, electrophysiological index (motor-nerve conduct velocity, amplitude of activity potential), and morphometrical results (regenerated axon number and thickness of myelin sheath) in nerve regeneration between the VPA group and controls ( P < 0.05). The results demonstrated that VPA is able to enhance sciatic nerve regeneration in rats, suggesting the potential

  19. Effect of Valproic Acid on Acute Lung Injury in a Rodent Model of Intestinal Ischemia Reperfusion

    PubMed Central

    Kim, Kyuseok; Li, Yongqing; Jin, Guang; Chong, Wei; Liu, Baoling; Lu, Jennifer; Lee, Kyoungbun; deMoya, Marc; Velmahos, George; Alam, Hasan B.

    2011-01-01

    Objectives Acute lung injury (ALI) is developed in many clinical situations and associated with significant morbidity and mortality. Valproic acid (VPA), a well-known anti-epileptic drug, has been shown to have anti-oxidant and anti-inflammatory effects in various ischemia/reperfusion (I/R) models. The purpose of this study was to investigate whether VPA could affect survival and development of ALI in a rat model of intestinal I/R. Methods Two experiments were performed. Experiment I: Male Sprague-Dawley rats (250–300 g) were subjected to intestinal ischemia (1 hour) and reperfusion (3 hours). They were randomized into 2 groups (n=7/group) 30 min after ischemia: Vehicle (Veh) and VPA (300 mg/kg, IV). Primary end-point for this study was survival over 4 hours from the start of ischemia. Experiment II: The histological and biochemical effects of VPA treatment on lungs were examined 3 hours (1 hr ischemia + 2 hrs reperfusion) after intestinal I/R injury (Veh vs. VPA, n = 9/group). An objective histological score was used to grade the degree of ALI. Enzyme linked immunosorbent assay (ELISA) was performed to measure serum levels of cytokine interleukins (IL-6 and 10), and lung tissue of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO). In addition, the activity of 8-isoprostane was analyzed for pulmonary oxidative damage. Results In Experiment I, four-hour survival rate was significantly higher in VPA treated animals compared to Veh animals (71.4% vs. 14.3%, p = 0.006). In Experiment II, ALI was apparent in all of the Veh group animals. Treatment with VPA prevented the development of ALI, with a reduction in the histological score (3.4 ± 0.3 vs. 5.3 ± 0.6, p = 0.025). Moreover, compared to the Veh control group the animals from the VPA group displayed decreased serum levels of IL-6 (952 ± 213 vs. 7709 ± 1990 pg/ml, p = 0.011), and lung tissue concentrations of CINC (1188 ± 28 vs. 1298 ± 27, p < 0.05), MPO activity (368 ± 23 vs. 490

  20. Valproic Acid in Women and Girls of Childbearing Age.

    PubMed

    Gotlib, Dorothy; Ramaswamy, Rachel; Kurlander, Jacob E; DeRiggi, Alana; Riba, Michelle

    2017-09-01

    The aim of this paper is to evaluate recent literature on valproic acid (VPA) in women and girls of childbearing age and to emphasize new findings. Recent research confirms VPAs teratogenicity and risk of hormone disruption. VPA exposure in utero increases the risk for a variety of major congenital malformations (MCMs), reduced IQ and behavioral problems. In girls and women, VPA increases the risk of hormone abnormalities, obesity, and polycystic ovarian syndrome (PCOS). Despite guidelines recommending caution, VPA use continues to be prescribed to reproductive-aged women and girls. Despite significant and well-documented risk, adherence to guidelines in VPA use in reproductive-aged girls and women remains low.

  1. CHK2 is involved in the p53-independent radiosensitizing effects of valproic acid

    PubMed Central

    Choo, Dong Wan; Goh, Sung Ho; Cho, Young Woo; Baek, Hye Jung; Park, Eun Jung; Motoyama, Noboru; Kim, Tae Hyun; Kim, Joo Young; Kim, Sang Soo

    2017-01-01

    Radiotherapy is an effective treatment for the majority of types of localized solid cancer. However, the risk of side effects to the surrounding normal tissues limits radiotherapeutic approaches. Whilst the mechanism of action of valproic acid, an inhibitor of histone deacetylase, remains unknown, the inhibitor is a potential antineoplastic radiosensitizer. The present study demonstrated the in vitro radiosensitizing effects of valproic acid on the human breast cancer MCF7 cell line, and revealed that valproic acid increased the level of DNA breakage, apoptosis and senescence. In addition, western blot analyses revealed that valproic acid induced tumor suppressor protein (p)53 and p21 expression, and activated checkpoint kinase 2 (CHK2) in MCF7 cells and primary mouse embryonic fibroblasts. Notably, treatment with valproic acid also induced increases in the level of p21 protein levels and CHK2 activity in p53-null colon cancer HCT116 cells. Furthermore, the present study demonstrated that valproic acid-induced radiosensitization was largely dependent on the activity of CHK2. The results of the present study reveal that valproic acid may exhibit clinical utility with respect to increasing the anticancer efficacy of radiotherapy by affecting the level of p53. PMID:28454438

  2. Targeting pharmacoresistant epilepsy and epileptogenesis with a dual-purpose antiepileptic drug.

    PubMed

    Doeser, Anna; Dickhof, Gesa; Reitze, Margit; Uebachs, Mischa; Schaub, Christina; Pires, Nuno Miguel; Bonifácio, Maria João; Soares-da-Silva, Patrício; Beck, Heinz

    2015-02-01

    In human epilepsy, pharmacoresistance to antiepileptic drug therapy is a major problem affecting a substantial fraction of patients. Many of the currently available antiepileptic drugs target voltage-gated sodium channels, leading to a rate-dependent suppression of neuronal discharge. A loss of use-dependent block has emerged as a potential cellular mechanism of pharmacoresistance for anticonvulsants acting on voltage-gated sodium channels. There is a need both for compounds that overcome this resistance mechanism and for novel drugs that inhibit the process of epileptogenesis. We show that eslicarbazepine acetate, a once-daily antiepileptic drug, may constitute a candidate compound that addresses both issues. Eslicarbazepine acetate is converted extensively to eslicarbazepine after oral administration. We have first tested using patch-clamp recording in human and rat hippocampal slices if eslicarbazepine, the major active metabolite of eslicarbazepine acetate, shows maintained activity in chronically epileptic tissue. We show that eslicarbazepine exhibits maintained use-dependent blocking effects both in human and experimental epilepsy with significant add-on effects to carbamazepine in human epilepsy. Second, we show that eslicarbazepine acetate also inhibits Cav3.2 T-type Ca(2+) channels, which have been shown to be key mediators of epileptogenesis. We then examined if transitory administration of eslicarbazepine acetate (once daily for 6 weeks, 150 mg/kg or 300 mg/kg) after induction of epilepsy in mice has an effect on the development of chronic seizures and neuropathological correlates of chronic epilepsy. We found that eslicarbazepine acetate exhibits strong antiepileptogenic effects in experimental epilepsy. EEG monitoring showed that transitory eslicarbazepine acetate treatment resulted in a significant decrease in seizure activity at the chronic state, 8 weeks after the end of treatment. Moreover, eslicarbazepine acetate treatment resulted in a

  3. 14C-NaVP and 14C-PEV repeated dose study in rat. Pharmacokinetic study in rats after repeated oral administrations of 14C-valproic acid sodium salt and 14C-valproic acid pivaloyl oxymethyl ester.

    PubMed

    Bertolino, M; Acerbi, D; Canali, S; Giachetti, C; Poli, G; Ventura, P; Zanolo, G

    1998-01-01

    The absorption, excretion and tissue distribution of radioactivity after repeated oral equimolar doses of 14C-valproic acid sodium salt (NaVP) or 14C-valproic acid pivaloyl oxymethyl ester (PEV) was investigated in male rats treated once a day for 14 consecutive days. The 14th day plasma time-course of radioactivity after PEV administrations was characterised by a slow absorption rate with a delayed peak (tmax 2 h, Cmax 7.52 +/- 1.35 microg eq./ml), followed by a plateau lasting up to 8 h. After NaVP treatment, the main peak of radioactivity was observed 0.5 h after administration (Cmax 8.30 +/- 1.26 microg eq./ml) followed by a secondary peak due to biliary enterohepatic recycling. Starting from 4 h onwards, radioactivity levels after PEV treatment were higher than those after NaVP (AUCtau = 113.3 h.microg eq./ml after PEV vs 71.9 h.microg eq./ml after NaVP), but concentrations declined with similar terminal half-lives (52.8 h for PEV and 49.7 h for NaVP). Radioactivity recovered (0-432 h interval) in urine accounted for 79.3% (PEV) and 56.1% (NaVP) while, in faeces accounted for 9.1% (PEV) and 26.1% (NaVP) of total administered dose (14 days). The difference is attributable to a higher excretion of radioactivity in the bile for NaVP. The missing fraction in the total radioactivity balance is probably excreted in expired air, as observed in single dose studies. Radioactivity excreted in bile (0-8 h interval of the last 14th day) accounted for 5.1% (NaVP) and 0.23% (PEV) of the total administered dose (14 days). A possible explanation of this difference may be a different metabolism pattern for the two compounds. The negligible biliary excretion observed after PEV administration is probably due to an inhibition of the glucuronation of valproic acid (or other metabolites) caused by the pivalic acid. Due to the presence of the enterohepatic recycle, the radioactivity levels in intestine, 0.5 and 2 h after administration, were higher after NaVP administration

  4. Valproic acid sensitizes human glioma cells to gefitinib-induced autophagy.

    PubMed

    Chang, Cheng-Yi; Li, Jian-Ri; Wu, Chih-Cheng; Ou, Yen-Chuan; Chen, Wen-Ying; Kuan, Yu-Hsiang; Wang, Wen-Yi; Chen, Chun-Jung

    2015-11-01

    Autophagy and apoptosis represent important cellular processes involved in cancer cell killing mechanisms. Epidermal growth factor receptor inhibitor gefitinib and valproic acid have been implicated in the treatment of malignancies including glioma involving autophagic and apoptotic mechanisms. Therefore, it is interesting to investigate whether a combination of gefitinib and valproic acid shows better cancer cell killing effect on human glioma cells. We found that a nontoxic concentration of valproic acid sensitized U87 and T98G glioma cells to gefitinib cytotoxicity by inhibiting cell growth and long-term clonogenic survival. The augmented consequences were accompanied by the formation of autophagic vacuoles, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), and degradation of p62. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 but not broad-spectrum caspase inhibitor attenuated gefitinib/valproic acid-induced growth inhibition. Gefitinib/valproic acid-induced autophagy was accompanied by the activation of liver kinase-B1 (LKB1)/AMP-activated protein kinase (AMPK)/ULK1. Silencing of AMPK and ULK1 suppressed gefitinib/valproic acid-induced autophagy and growth inhibition. Mechanistic studies showed that gefitinib/valproic acid increased intracellular reactive oxygen species generation and N-acetyl cysteine attenuated gefitinib/valproic acid-caused autophagy and growth inhibition. In addition to demonstrating the autophagic mechanisms of gefitinib/valproic acid, the results of this study further suggest that intracellular oxidative stress and the LKB1/AMPK signaling might be a potential target for the development of therapeutic strategy against glioma. © 2015 International Union of Biochemistry and Molecular Biology.

  5. Three amino acid derivatives of valproic acid: design, synthesis, theoretical and experimental evaluation as anticancer agents.

    PubMed

    Luna-Palencia, Gabriela R; Martinez-Ramos, Federico; Vasquez-Moctezuma, Ismael; Fragoso-Vazquez, Manuel Jonathan; Mendieta-Wejebe, Jessica Elena; Padilla-Martínez, Itzia I; Sixto-Lopez, Yudibeth; Mendez-Luna, David; Trujillo-Ferrara, Jose; Meraz-Rios, Marco A; Fonseca-Sabater, Yadira; Correa-Basurto, Jose

    2014-01-01

    Valproic acid (VPA) is extensively used as an anticonvulsive agent and as a treatment for other neurological disorders. It has been shown that VPA exerts an anti-proliferative effect on several types of cancer cells by inhibiting the activity of histone deacetylases (HDACs), which are involved in replication and differentiation processes. However, VPA has some disadvantages, among which are poor water solubility and hepatotoxicity. Therefore, the aim of the present study was to design and synthesize three derivatives of VPA to improve its physicochemical properties and anti-proliferative effects. For this purpose, the amino acids aspartic acid, glutamic acid and proline were added to the molecular structure of VPA. Docking and molecular dynamics simulations were used to determine the mode of recognition of these three derivatives by different conformations of HDAC8. This receptor was used as the specific target because of its high affinity for this type of substrate. The results demonstrate that, compared to VPA, the test compounds bind to different sites on the enzyme and that hydrogen bonds and hydrophobic interactions play key roles in this difference. The IC50 values of the VPA derivatives, experimentally determined using HeLa cells, were in the mM range. This result indicates that the derivatives have greater antiproliferative effects than the parent compound. Hence, these results suggest that these amino acid derivatives may represent a good alternative for anticancer treatment.

  6. Epilepsy, anti-epileptic medication use and risk of cancer.

    PubMed

    Kaae, Jeanette; Carstensen, Lisbeth; Wohlfahrt, Jan; Melbye, Mads; Allison Boyd, Heather

    2014-02-15

    Whether the powerful medications used to treat epilepsy increase the risk of cancer has been debated for decades, but until now no study could disentangle the contributions of anti-epileptic medications and epilepsy itself to cancer risk. Using a cohort comprising all Danish residents ≥ 16 years old at some point during the period 1996-2010 (>56 million person-years of follow-up) and information from national health registers, we examined associations between anti-epileptic medication use and cancer rates in persons with and without epilepsy, and between epilepsy and cancer rates in treated and untreated individuals. Associations were expressed as incidence rate ratios (IRRs) estimated using Poisson regression. Among persons without epilepsy, use of anti-epileptic medication increased the rates of most cancers little or not at all, although we observed moderately increased rates of liver, mouth and throat, and respiratory tract cancers (IRRs 1.40-1.59). In contrast, we observed strong associations between epilepsy and the rates of central nervous system and mouth and throat cancers (IRRs 2.00-3.91), and a modest association between epilepsy and the rate of respiratory tract cancers (IRRs 1.30-1.35), independent of anti-epileptic medication use. Our finding of only modest increases in cancer risk directly attributable to anti-epileptic medication use suggests that these medications may not be as strongly carcinogenic as has been feared, and that it is not primarily anti-epileptic medications that are responsible for the increased cancer risk among epileptics but another aspect of epilepsy diagnosis or treatment or an etiologic factor common to the two conditions. © 2013 UICC.

  7. Effects of switching from Depakene to generic valproic acid on individuals with mental retardation.

    PubMed

    Vadney, V J; Kraushaar, K W

    1997-12-01

    In an 8-week open-trial substitution study, 64 subjects with seizure disorders living at an ICF/MR were randomly assigned to either brand-named Depakene or generic Valproic Acid USP (Solvay) medication. After 4 weeks, they were switched to the other medication. Blood levels and seizures were monitored. The price of the generic Valproic Acid was less than one tenth the price of Depakene. Results show that subjects had no statistically significant changes in seizures or blood levels when the two treatment regimens were compared. These findings suggest that generic Valproic Acid USP (Solvay) may be successfully used in this population, resulting in substantial cost savings.

  8. Functional roles of benzothiazole motif in antiepileptic drug research.

    PubMed

    Amir, Mohammad; Hassan, Mohd Zaheen

    2013-12-01

    Benzothiazoles are promising candidates for the design of novel antiepileptic drugs. The endocyclic sulphur and nitrogen functions present in this heterocyclic nucleus have been shown to be critical for the anticonvulsant activity. The present review outlines the rational design and anticonvulsant potential of promising benzothiazole lead molecules. Particular focus has been placed on the structure activity relationship of different benzothiazole derivatives giving selected examples of molecules with significant activity being that these molecules may serve as prototypes for the development of more active antiepileptic drugs.

  9. Non-imidazole histamine H3 receptor ligands incorporating antiepileptic moieties.

    PubMed

    Sadek, Bassem; Schwed, Johannes Stephan; Subramanian, Dhanasekaran; Weizel, Lilia; Walter, Miriam; Adem, Abdu; Stark, Holger

    2014-04-22

    A small series of histamine H3 receptor (H3R) ligands (1-5) incorporating different antiepileptic structural motifs has been newly synthesized. All compounds exhibited moderate to high in vitro hH3R affinities up to a sub-nanomolar concentration range with pKi values in the range of 6.25-9.62 with varying preferences for this receptor subtype. The compounds (1-5) were further investigated in vivo on anticonvulsant effects against maximum electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled convulsions in rats having phenytoin (PHT) as the reference antiepileptic drug (AED). Surprisingly, animals pretreated with 1 mg/kg, i.p. of 5,5-diphenyl-3-(3-(piperidin-1-yl)propyl)imidazolidine-2,4-dione (4) were only moderately protected and no protection was observed for compounds 1-3 and 5 in three different doses (1 mg, 5 mg, and 10 mg/kg i.p.). Compound 4 (1 mg/kg, i.p.) failed to modify PTZ-kindled convulsion. However, a dose of 10 mg/kg significantly reduced convulsions in both models. In contrast, 5,5-diphenyl-3-(4-(3-(piperidin-1-yl)propoxy)benzyl)imidazolidine-2,4-dione (5) (1, 5, and 10 mg/kg, i.p.) showed proconvulsant effects in the MES model with further confirmation of these results in the PTZ model as no protection was observed against convulsion in the doses tested (1 and 10 mg/kg). In addition, compound 4 (10 mg/kg, i.p.) significantly prolonged myoclonic latency time and shortened total convulsion duration when compared to control, PHT or standard H3R inverse agonist/antagonist pitolisant (PIT). Our results showed that H3R pharmacophores could successfully be structurally combined to antiepileptic moieties, especially phenytoin partial structures, maintaining the H3R affinity. However, the new derivatives for multiple-target approaches in epilepsy models are complex and show that pharmacophore elements are not easily pharmacologically combinable.

  10. Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma

    PubMed Central

    Happold, Caroline; Gorlia, Thierry; Chinot, Olivier; Gilbert, Mark R.; Nabors, L. Burt; Wick, Wolfgang; Pugh, Stephanie L.; Hegi, Monika; Cloughesy, Timothy; Roth, Patrick; Reardon, David A.; Perry, James R.; Mehta, Minesh P.; Stupp, Roger

    2016-01-01

    Purpose Symptomatic epilepsy is a common complication of glioblastoma and requires pharmacotherapy. Several uncontrolled retrospective case series and a post hoc analysis of the registration trial for temozolomide indicated an association between valproic acid (VPA) use and improved survival outcomes in patients with newly diagnosed glioblastoma. Patients and Methods To confirm the hypothesis suggested above, a combined analysis of survival association of antiepileptic drug use at the start of chemoradiotherapy with temozolomide was performed in the pooled patient cohort (n = 1,869) of four contemporary randomized clinical trials in newly diagnosed glioblastoma: AVAGlio (Avastin in Glioblastoma; NCT00943826), CENTRIC (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Methylated Gene Promoter Status; NCT00689221), CORE (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter Status; NCT00813943), and Radiation Therapy Oncology Group 0825 (NCT00884741). Progression-free survival (PFS) and overall survival (OS) were compared between: (1) any VPA use and no VPA use at baseline or (2) VPA use both at start of and still after chemoradiotherapy. Results of Cox regression models stratified by trial and adjusted for baseline prognostic factors were analyzed. The same analyses were performed with levetiracetam (LEV). Results VPA use at start of chemoradiotherapy was not associated with improved PFS or OS compared with all other patients pooled (PFS: hazard ratio [HR], 0.91; 95% CI, 0.77 to 1.07; P = .241; OS: HR, 0.96; 95% CI, 0.80 to 1.15; P = .633). Furthermore, PFS and OS of patients taking VPA both at start of and still after chemoradiotherapy were not different from those without antiepileptic drug use at both time points (PFS: HR, 0.92; 95% CI, 0.74 to 1.15; P = .467; OS: HR, 1.10; 95% CI, 0.86 to 1.40; P = .440). Similarly, no

  11. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes.

    PubMed

    Glauser, Tracy; Ben-Menachem, Elinor; Bourgeois, Blaise; Cnaan, Avital; Guerreiro, Carlos; Kälviäinen, Reetta; Mattson, Richard; French, Jacqueline A; Perucca, Emilio; Tomson, Torbjorn

    2013-03-01

    The purpose of this report was to update the 2006 International League Against Epilepsy (ILAE) report and identify the level of evidence for long-term efficacy or effectiveness for antiepileptic drugs (AEDs) as initial monotherapy for patients with newly diagnosed or untreated epilepsy. All applicable articles from July 2005 until March 2012 were identified, evaluated, and combined with the previous analysis (Glauser et al., 2006) to provide a comprehensive update. The prior analysis methodology was utilized with three modifications: (1) the detectable noninferiority boundary approach was dropped and both failed superiority studies and prespecified noninferiority studies were analyzed using a noninferiority approach, (2) the definition of an adequate comparator was clarified and now includes an absolute minimum point estimate for efficacy/effectiveness, and (3) the relationship table between clinical trial ratings, level of evidence, and conclusions no longer includes a recommendation column to reinforce that this review of efficacy/evidence for specific seizure types does not imply treatment recommendations. This evidence review contains one clarification: The commission has determined that class I superiority studies can be designed to detect up to a 20% absolute (rather than relative) difference in the point estimate of efficacy/effectiveness between study treatment and comparator using an intent-to-treat analysis. Since July, 2005, three class I randomized controlled trials (RCT) and 11 class III RCTs have been published. The combined analysis (1940-2012) now includes a total of 64 RCTs (7 with class I evidence, 2 with class II evidence) and 11 meta-analyses. New efficacy/effectiveness findings include the following: levetiracetam and zonisamide have level A evidence in adults with partial onset seizures and both ethosuximide and valproic acid have level A evidence in children with childhood absence epilepsy. There are no major changes in the level of evidence

  12. Embryological exposure to valproic acid induces social interaction deficits in zebrafish (Danio rerio): A developmental behavior analysis.

    PubMed

    Zimmermann, Fernanda Francine; Gaspary, Karina Vidarte; Leite, Carlos Eduardo; De Paula Cognato, Giana; Bonan, Carla Denise

    2015-01-01

    Changes in social behavior are associated with brain disorders, including mood disorders, stress, schizophrenia, Alzheimer's disease, and autism spectrum disorders (ASD). Autism is a complex neurodevelopmental disorder characterized by deficits in social interaction, impaired communication, anxiety, hyperactivity, and the presence of restricted interests. Zebrafish is one of the most social vertebrates used as a model in biomedical research, contributing to an understanding of the mechanisms that underlie social behavior. Valproic acid (VPA) is used as an anti-epileptic drug and mood stabilizer; however, prenatal VPA exposure in humans has been associated with an increased incidence of autism and it can also affect fetal brain development. Therefore, we conducted a behavioral screening at different periods of zebrafish development at 6, 30, 70, and 120dpf (days postfertilization) after VPA exposure in the early development stage to investigate social behavior, locomotion, aggression, and anxiety. VPA (48μM) exposure during the first 48hpf (hours postfertilization) did not promote changes on survival, morphology, and hatching rate at 24hpf, 48hpf, and 72hpf. The behavioral patterns suggest that VPA exposure induces changes in locomotor activity and anxiety at different developmental periods in zebrafish. Furthermore, a social interaction deficit is present at 70dpf and 120dpf. VPA exposure did not affect aggression in the adult stage at 70dpf and 120dpf. This is the first study that demonstrated zebrafish exposed to VPA during the first 48h of development exhibit deficits in social interaction, anxiety, and hyperactivity at different developmental periods. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Determination of the Optimal Concentration of Valproic Acid in Patients with Epilepsy: A Population Pharmacokinetic-Pharmacodynamic Analysis

    PubMed Central

    Nakashima, Hiroo; Oniki, Kentaro; Nishimura, Miki; Ogusu, Naoki; Shimomasuda, Masatsugu; Ono, Tatsumasa; Matsuda, Kazuki; Yasui-Furukori, Norio; Nakagawa, Kazuko; Ishitsu, Takateru; Saruwatari, Junji

    2015-01-01

    Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs for the treatment of epileptic seizures. Although it is well known that the doses of VPA and its plasma concentrations are highly correlated, the plasma concentrations do not correlate well with the therapeutic effects of the VPA. In this study, we developed a population-based pharmacokinetic (PK)-pharmacodynamic (PD) model to determine the optimal concentration of VPA according to the clinical characteristics of each patient. This retrospective study included 77 VPA-treated Japanese patients with epilepsy. A nonlinear mixed-effects model best represented the relationship between the trough concentrations of VPA at steady-state and an over 50% reduction in seizure frequency. The model was fitted using a logistic regression model, in which the logit function of the probability was a linear function of the predicted trough concentration of VPA. The model showed that the age, seizure locus, the sodium channel neuronal type I alpha subunit rs3812718 polymorphism and co-administration of carbamazepine, clonazepam, phenytoin or topiramate were associated with an over 50% reduction in the seizure frequency. We plotted the receiver operating characteristic (ROC) curve for the logit(Pr) value of the model and the presence or absence of a more than 50% reduction in seizure frequency, and the areas under the curves with the 95% confidence interval from the ROC curve were 0.823 with 0.793–0.853. A logit(Pr) value of 0.1 was considered the optimal cut-off point (sensitivity = 71.8% and specificity = 80.4%), and we calculated the optimal trough concentration of VPA for each patient. Such parameters may be useful to determine the recommended therapeutic concentration of VPA for each patient, and the procedure may contribute to the further development of personalized pharmacological therapy for epilepsy. PMID:26484865

  14. The Proteomic and Genomic Teratogenicity Elicited by Valproic Acid Is Preventable with Resveratrol and α-Tocopherol

    PubMed Central

    Chen, Yeh; Lin, Ping-Xiao; Hsieh, Chiu-Lan; Peng, Chiung-Chi; Peng, Robert Y.

    2014-01-01

    Background Previously, we reported that valproic acid (VPA), a common antiepileptic drug and a potent teratogenic, dowregulates RBP4 in chicken embryo model (CEM) when induced by VPA. Whether such teratogenicity is associated with more advanced proteomic and genomic alterations, we further performed this present study. Methodology/Principal Findings VPA (60 µM) was applied to 36 chicken embryos at HH stage 10 (day-1.5). Resveratrol (RV) and vitamin E (vit E) (each at 0.2 and 2.0 µM) were applied simultaneously to explore the alleviation effect. The proteins in the cervical muscles of the day-1 chicks were analyzed using 2D-electrophoresis and LC/MS/MS. While the genomics associated with each specific protein alteration was examined with RT-PCR and qPCR. At earlier embryonic stage, VPA downregulated PEBP1 and BHMT genes and at the same time upregulated MYL1, ALB and FLNC genes significantly (p<0.05) without affecting PKM2 gene. Alternatively, VPA directly inhibited the folate-independent (or the betaine-dependent) remethylation pathway. These features were effectively alleviated by RV and vit E. Conclusions VPA alters the expression of PEBP1, BHMT, MYL1, ALB and FLNC that are closely related with metabolic myopathies, myogenesis, albumin gene expression, and haemolytic anemia. On the other hand, VPA directly inhibits the betaine-dependent remethylation pathway. Taken together, VPA elicits hemorrhagic myoliposis via these action mechanisms, and RV and vit E are effective for alleviation of such adverse effects. PMID:25551574

  15. TrkB/BDNF-Dependent Striatal Plasticity and Behavior in a Genetic Model of Epilepsy: Modulation by Valproic Acid

    PubMed Central

    Ghiglieri, Veronica; Sgobio, Carmelo; Patassini, Stefano; Bagetta, Vincenza; Fejtova, Anna; Giampà, Carmela; Marinucci, Silvia; Heyden, Alexandra; Gundelfinger, Eckart D; Fusco, Francesca R; Calabresi, Paolo; Picconi, Barbara

    2010-01-01

    In mice lacking the central domain of the presynaptic scaffold Bassoon the occurrence of repeated cortical seizures induces cell-type-specific plasticity changes resulting in a general enhancement of the feedforward inhibition within the striatal microcircuit. Early antiepileptic treatment with valproic acid (VPA) reduces epileptic attacks, inhibits the emergence of pathological form of plasticity in fast-spiking (FS) interneurons and restores physiological striatal synaptic plasticity in medium spiny (MS) neurons. Brain-derived neurotrophic factor (BDNF) is a key factor for the induction and maintenance of synaptic plasticity and it is also implicated in the mechanisms underlying epilepsy-induced adaptive changes. In this study, we explore the possibility that the TrkB/BDNF system is involved in the striatal modifications associated with the Bassoon gene (Bsn) mutation. In epileptic mice abnormal striatum-dependent learning was paralleled by higher TrkB levels and an altered distribution of BDNF. Accordingly, subchronic intrastriatal administration of k252a, an inhibitor of TrkB receptor tyrosine kinase activity, reversed behavioral alterations in Bsn mutant mice. In addition, in vitro manipulations of the TrkB/BDNF complex by k252a, prevented the emergence of pathological plasticity in FS interneurons. Chronic treatment with VPA, by reducing seizures, was able to rebalance TrkB to control levels favoring a physiological redistribution of BDNF between MS neurons and FS interneurons with a concomitant recovery of striatal plasticity. Our results provide the first indication that BDNF is involved in determining the striatal alterations occurring in the early-onset epileptic syndrome associated with the absence of presynaptic protein Bassoon. PMID:20200504

  16. TrkB/BDNF-dependent striatal plasticity and behavior in a genetic model of epilepsy: modulation by valproic acid.

    PubMed

    Ghiglieri, Veronica; Sgobio, Carmelo; Patassini, Stefano; Bagetta, Vincenza; Fejtova, Anna; Giampà, Carmela; Marinucci, Silvia; Heyden, Alexandra; Gundelfinger, Eckart D; Fusco, Francesca R; Calabresi, Paolo; Picconi, Barbara

    2010-06-01

    In mice lacking the central domain of the presynaptic scaffold Bassoon the occurrence of repeated cortical seizures induces cell-type-specific plasticity changes resulting in a general enhancement of the feedforward inhibition within the striatal microcircuit. Early antiepileptic treatment with valproic acid (VPA) reduces epileptic attacks, inhibits the emergence of pathological form of plasticity in fast-spiking (FS) interneurons and restores physiological striatal synaptic plasticity in medium spiny (MS) neurons. Brain-derived neurotrophic factor (BDNF) is a key factor for the induction and maintenance of synaptic plasticity and it is also implicated in the mechanisms underlying epilepsy-induced adaptive changes. In this study, we explore the possibility that the TrkB/BDNF system is involved in the striatal modifications associated with the Bassoon gene (Bsn) mutation. In epileptic mice abnormal striatum-dependent learning was paralleled by higher TrkB levels and an altered distribution of BDNF. Accordingly, subchronic intrastriatal administration of k252a, an inhibitor of TrkB receptor tyrosine kinase activity, reversed behavioral alterations in Bsn mutant mice. In addition, in vitro manipulations of the TrkB/BDNF complex by k252a, prevented the emergence of pathological plasticity in FS interneurons. Chronic treatment with VPA, by reducing seizures, was able to rebalance TrkB to control levels favoring a physiological redistribution of BDNF between MS neurons and FS interneurons with a concomitant recovery of striatal plasticity. Our results provide the first indication that BDNF is involved in determining the striatal alterations occurring in the early-onset epileptic syndrome associated with the absence of presynaptic protein Bassoon.

  17. VNS Therapy versus the latest antiepileptic drug.

    PubMed

    Ben-Menachem, Elinor; French, Jacqueline A

    2005-09-01

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

  18. Two cases of valproic acid poisoning treated with L-carnitine.

    PubMed

    Chan, Y C; Tse, M L; Lau, F L

    2007-12-01

    Two cases of acute valproic acid poisoning with central nervous system depression and raised ammonia level without hepatotoxicity were reported. They were treated successfully with the use of the antidotes: L-carnitine and other supportive measures. Clinical manifestation and progress was described, and discussion is focused on the use of L-carnitine in valproic acid-induced hyperammonemia, from its mechanism to the clinical experiences in the literature. Based on the favorable response of our two cases and the literature review, we recommend the administration of intravenous L-carnitine in patients of valproic acid overdose with hyperammonemia or valproic acid-induced hyperammonemic encephalopathy and hepatotoxicity at a dose of 50 mg/kg every 8 h for the first initial 24 h with further individual assessment.

  19. Oxcarbazepine-induced liver injury after sensitization by valproic acid: a case report.

    PubMed

    Chait Mermelstein, Alanna; Mermelstein, Joseph; Adam, Tarek; Brody, Benjamin D; Dubin, Marc J

    2016-05-01

    The aim of the present case report is to describe a potential interaction between valproic acid and oxcarbazepine that resulted in hepatic injury. We report the case of a 46-year-old man with schizoaffective disorder who was cross-titrated from valproic acid to oxcarbazepine because of liver injury. Initiation of oxcarbazepine four days after stopping valproic acid produced a significant elevation in liver enzymes that normalized with oxcarbazepine discontinuation and did not reappear with its reintroduction five days later. Our findings suggest that a longer washout period or another agent should be considered when transitioning from valproic acid to oxcarbazepine. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. The Effects of Antiepileptic Drugs on Classroom Performance

    ERIC Educational Resources Information Center

    Titus, Jeffrey B.; Thio, Liu Lin

    2009-01-01

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

  1. Hypoactive sexual desire disorder caused by antiepileptic drugs.

    PubMed

    Singh, M; Bathla, Manish; Martin, A; Aneja, J

    2015-01-01

    Female sexual dysfunction is common but poorly understood sexual problem in women. Sexual dysfunction in female is multi-factorial in origin and also observed with intake of drug acting on central nervous system. This case report describes a female epileptic patient who developed sexual dysfunction with intake of antiepileptic drugs.

  2. Infantile Spasms and Cytomegalovirus Infection: Antiviral and Antiepileptic Treatment

    ERIC Educational Resources Information Center

    Dunin-Wasowicz, Dorota; Kasprzyk-Obara, Jolanta; Jurkiewicz, Elzbieta; Kapusta, Monika; Milewska-Bobula, Bogumila

    2007-01-01

    From 1 January 1995 to 31 December 2004, 22 patients (13 males, nine females; age range 2-12mo) with infantile spasms and cytomegalovirus (CMV) infection were treated with intravenous ganciclovir (GCV) and antiepileptic drugs. GCV was given for 3 to 12 weeks with a 1-month interval (one, two, or three courses). Epileptic spasms occurred before…

  3. Infantile Spasms and Cytomegalovirus Infection: Antiviral and Antiepileptic Treatment

    ERIC Educational Resources Information Center

    Dunin-Wasowicz, Dorota; Kasprzyk-Obara, Jolanta; Jurkiewicz, Elzbieta; Kapusta, Monika; Milewska-Bobula, Bogumila

    2007-01-01

    From 1 January 1995 to 31 December 2004, 22 patients (13 males, nine females; age range 2-12mo) with infantile spasms and cytomegalovirus (CMV) infection were treated with intravenous ganciclovir (GCV) and antiepileptic drugs. GCV was given for 3 to 12 weeks with a 1-month interval (one, two, or three courses). Epileptic spasms occurred before…

  4. Antiepileptic Drug Nonadherence and Its Predictors among People with Epilepsy.

    PubMed

    Getnet, Asmamaw; Woldeyohannes, Solomon Meseret; Bekana, Lulu; Mekonen, Tesfa; Fekadu, Wubalem; Menberu, Melak; Yimer, Solomon; Assaye, Adisu; Belete, Amsalu; Belete, Habte

    2016-01-01

    Introduction. Antiepileptic drugs are effective in the treatment of epilepsy to the extent that about 70% of people with epilepsy can be seizure-free, but poor adherence to medication is major problem to sustained remission and functional restoration. The aim of this study was to assess the prevalence and associated factors of antiepileptic drug nonadherence. Methods. Cross-sectional study was conducted on 450 individuals who were selected by systematic random sampling method. Antiepileptic drug nonadherence was measured by Morisky Medication Adherence Scale (MMAS) and logistic regression was used to look for significant associations. Result. The prevalence of AEDs nonadherence was 37.8%. Being on treatment for 6 years and above [AOR = 3.47, 95% CI: 1.88, 6.40], payment for AEDs [AOR = 2.76, 95% CI: 1.73, 4.42], lack of health information [AOR = 2.20, 95% CI: 1.41,3.43], poor social support [AOR = 1.88, 95%, CI: 1.01, 3.50], perceived stigma [AOR = 2.27, 95% CI: 1.45, 3.56], and experience side effect [AOR = 1.70, 95% CI: 1.06, 2.72] were significantly associated with antiepileptic drug nonadherence. Conclusion. More than one-third of people with epilepsy were not compliant with their AEDs. Giving health information about epilepsy and its management and consequent reduction in stigma will help for medication adherence.

  5. The Effects of Antiepileptic Drugs on Classroom Performance

    ERIC Educational Resources Information Center

    Titus, Jeffrey B.; Thio, Liu Lin

    2009-01-01

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

  6. Antiepileptic Drug Nonadherence and Its Predictors among People with Epilepsy

    PubMed Central

    Getnet, Asmamaw; Woldeyohannes, Solomon Meseret; Bekana, Lulu; Menberu, Melak; Yimer, Solomon; Assaye, Adisu; Belete, Habte

    2016-01-01

    Introduction. Antiepileptic drugs are effective in the treatment of epilepsy to the extent that about 70% of people with epilepsy can be seizure-free, but poor adherence to medication is major problem to sustained remission and functional restoration. The aim of this study was to assess the prevalence and associated factors of antiepileptic drug nonadherence. Methods. Cross-sectional study was conducted on 450 individuals who were selected by systematic random sampling method. Antiepileptic drug nonadherence was measured by Morisky Medication Adherence Scale (MMAS) and logistic regression was used to look for significant associations. Result. The prevalence of AEDs nonadherence was 37.8%. Being on treatment for 6 years and above [AOR = 3.47, 95% CI: 1.88, 6.40], payment for AEDs [AOR = 2.76, 95% CI: 1.73, 4.42], lack of health information [AOR = 2.20, 95% CI: 1.41,3.43], poor social support [AOR = 1.88, 95%, CI: 1.01, 3.50], perceived stigma [AOR = 2.27, 95% CI: 1.45, 3.56], and experience side effect [AOR = 1.70, 95% CI: 1.06, 2.72] were significantly associated with antiepileptic drug nonadherence. Conclusion. More than one-third of people with epilepsy were not compliant with their AEDs. Giving health information about epilepsy and its management and consequent reduction in stigma will help for medication adherence. PMID:28053370

  7. [Determination of theophylline, phenobarbital and valproic acid by chromatographic and immunologic technics. Comparison of methods].

    PubMed

    Vinçon, G; Demotes-Mainard, F; Bistue, C; Jarry, C; Brachet-Liermain, A; Albin, H

    1984-01-01

    Theophylline, phenobarbitol, and valproic acid serum levels were measured from plasma samples using chromatographic (HPLC and GC) and by immunologic techniques using enzyme kinetics (EMIT) or fluorescence polarization (FPIA). Results of these various methods differ when examined by more stringent statistical analysis. These differences do not appear to be clinically important except possibly for valproic acid the case in employing immunologic methods as well as their rapidity render these techniques particularly useful for therapeutic surveillance.

  8. Absorption of valproic acid from the gastrointestinal tract of the piglet.

    PubMed

    Nahata, M C; Breech, L; Ailabouni, A; Murray, R D

    1992-01-01

    Valproic acid is a commonly used drug for the treatment of epilepsy. Since valproic acid can only be given orally, its absorption from the gastrointestinal (GI) tract especially in patients with short bowel syndrome (SBS) and in neonates is important. The specific sites of absorption for valproic acid in the small intestine and colon have not been investigated. It is currently unknown whether these patients are able to absorb oral valproic acid sufficiently to maintain a therapeutic serum concentration. The primary objectives of the study were to: (a) determine the relative absorption of valproic acid from specific sites in the GI tract; and (b) investigate the influence of intestinal development on valproic acid absorption using the newborn piglet as a model. Two groups were studied: Group I included 5 piglets 18-21 days of age, and Group II included 5 piglets 1-3 days of age. A valproic acid solution was simultaneously perfused through 5 partitioned segments of the gastrointestinal tract: the duodenum, jejunum, ileum, right colon and left colon. Tritiated [3H] polyethylene glycol was co-administered to monitor water movement across the GI mucosa. Following steady state, samples were collected from each segment, and analyzed by a specific enzyme-mediated immunoassay. The absorption rates (micrograms/min/cm) of valproic acid in Group I were as follows: 9.96 +/- 2.8 duodenum; 11.28 +/- 2.79, jejunum; 9.42 +/- 3.34, ileum; 10.88 +/- 3.35, right colon; 10.96 +/- 2.92, left colon.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Comparison of free fraction serum valproic acid concentrations between inpatients and outpatients.

    PubMed

    Gibbs, Haley G; Zimmerman, David E; Shermock, Kenneth M; Clarke, William; Mirski, Marek A; Lewin, John J

    2015-01-15

    The differences in free fraction serum valproic acid concentrations between inpatients and outpatients were compared, and factors associated with therapeutic discordance were evaluated. This retrospective, single-center, cross-sectional study included patients with both a free and a total valproic acid concentration drawn within 30 minutes of each other between January 7, 2003, and June 1, 2011. Serum valproic acid concentrations were stratified by admission status (inpatient versus outpatient). In the primary analysis, for patients who had multiple paired concentrations drawn, one free valproic acid level and one total valproic acid level (i.e., one pair) were chosen at random for each inpatient. Information regarding patient demographics, laboratory data, and concomitant medication therapy was collected. Single and multivariable logistic regressions were performed to determine the odds of therapeutic discordance. During the study period, inpatient concentrations were measured in 220 patients, and outpatient concentrations were measured in 41 patients. The median total valproic acid concentration in the inpatient group was significantly lower than that in the outpatient group (54 μg/mL versus 83 μg/mL, p < 0.001). The median free fraction of inpatient levels was nearly twice as high as that of outpatient levels (28.8% versus 15.5%, p < 0.001). Levels drawn in inpatients were therapeutically discordant 63% of the time compared to only 19% in outpatients (p < 0.001). Multivariable logistic regression identified low albumin as an independent risk factor for therapeutic discordance. The median free fraction of valproic acid was significantly higher in inpatients than in outpatients. Low albumin concentration was a predictor of discordance between free and total valproic acid concentrations. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  10. Large-Scale Phenotype-Based Antiepileptic Drug Screening in a Zebrafish Model of Dravet Syndrome1,2,3

    PubMed Central

    Dinday, Matthew T.

    2015-01-01

    Abstract Mutations in a voltage-gated sodium channel (SCN1A) result in Dravet Syndrome (DS), a catastrophic childhood epilepsy. Zebrafish with a mutation in scn1Lab recapitulate salient phenotypes associated with DS, including seizures, early fatality, and resistance to antiepileptic drugs. To discover new drug candidates for the treatment of DS, we screened a chemical library of ∼1000 compounds and identified 4 compounds that rescued the behavioral seizure component, including 1 compound (dimethadione) that suppressed associated electrographic seizure activity. Fenfluramine, but not huperzine A, also showed antiepileptic activity in our zebrafish assays. The effectiveness of compounds that block neuronal calcium current (dimethadione) or enhance serotonin signaling (fenfluramine) in our zebrafish model suggests that these may be important therapeutic targets in patients with DS. Over 150 compounds resulting in fatality were also identified. We conclude that the combination of behavioral and electrophysiological assays provide a convenient, sensitive, and rapid basis for phenotype-based drug screening in zebrafish mimicking a genetic form of epilepsy. PMID:26465006

  11. Septo-optic dysplasia as a manifestation of valproic acid embryopathy.

    PubMed

    McMahon, C L; Braddock, S R

    2001-08-01

    The use of valproic acid during pregnancy has been associated with adverse fetal outcomes, including major and minor congenital malformations, intrauterine growth retardation (IUGR), hyperbilirubinemia, hepatotoxicity, transient hyperglycemia, and fetal and neonatal distress. In addition, intrauterine exposure to valproic acid has been associated with an increased risk of central nervous system abnormalities, primarily neural tube defects. Optic nerve hypoplasia has been reported in association with other prenatal anticonvulsant exposures, but the occurrence of septo-optic dysplasia as a manifestation of valproic acid embryopathy has not been reported previously. We report on a woman who received Depakote (valproic acid) throughout her pregnancy for the treatment of a seizure disorder. The patient presented with features typical of valproic acid embryopathy, including bitemporal narrowing, hypertelorism, short palpebral fissures, epicanthal folds, microphthalmia, a flat broad nasal bridge, small mouth, hypoplastic nails, mild clinodactyly, and camptodactyly. MRI showed hypoplasia of the optic chiasm and absence of the septum pellucidum. We report the first case of septo-optic dysplasia associated with maternal exposure to valproic acid throughout pregnancy. This case expands the clinical phenotype of valproate embryopathy. Copyright 2001 Wiley-Liss, Inc.

  12. Minocycline ameliorates prenatal valproic acid induced autistic behaviour, biochemistry and blood brain barrier impairments in rats.

    PubMed

    Kumar, Hariom; Sharma, Bhupesh

    2016-01-01

    Autism is a neurodevelopment disorder. One percent worldwide population suffers with autism and males suffer more than females. Microglia plays an important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. The present study has been designed to investigate the role of minocycline in prenatal valproic acid induced autism in rats. Animals with prenatal valproic acid have reduced social interaction (three chamber social behaviour apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complexes I, II, IV). Furthermore, prenatal valproic acid treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood brain barrier permeability. Treatment with minocycline significantly attenuated prenatal valproic acid induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, minocycline has also attenuated prenatal valproic acid induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behaviour, biochemistry and blood brain barrier impairment in animals, which were significantly attenuated by minocycline. Minocycline should be explored further for its therapeutic benefits in autism.

  13. Valproic Acid Increases the Hepatic Differentiation Potential of Salivary Gland Cells

    PubMed Central

    Petrakova, O. S.; Ashapkin, V. V.; Shtratnikova, V. Y.; Kutueva, L. I.; Vorotelyak, E. A.; Borisov, M. A.; Terskikh, V. V.; Gvazava, I. G.; Vasiliev, A. V.

    2015-01-01

    The studies of cell plasticity and differentiation abilities are important problems in modern cellular biology. The use of histone deacetylase inhibitor - valproic acid is a promising approach to increasing the differentiation efficiency of various cell types. In this paper we investigate the ability of mouse submandibular salivary gland cells to differentiate into the hepatic direction and the effect of valproic acid on the efficiency of this differentiation. It was shown that the gene expression levels of hepatocyte markers (Aat, Afp, G6p, Pepck, Tat, Cyp3a13) and liver-enriched transcription factors (Hnf-3α, Hnf-3β, Hnf-4α, Hnf-6) were increased after differentiation in salivary gland cells. Valproic acid increases the specificity of hepatic differentiation, reducing the expression levels of the ductal (Krt19, Hhex1, Cyp7a1) and acinar (Ptf1a) markers. After valproic acid exposure, the efficiency of hepatic differentiation also increases, as evidenced by the increase in the gene expression level of Alb and Tdo, and increase in urea production by differentiated cells. No change was found in DNA methylation of the promoter regions of the genes; however, valproic acid treatment and subsequent hepatic differentiation largely affected the histone H3 methylation of liver-enriched genes. Thus, mouse submandibular salivary gland cells are capable of effective differentiation in the hepatic direction. Valproic acid increases the specificity and efficiency of the hepatic differentiation of these cells. PMID:26798494

  14. Antiepileptic-induced resistance to neuromuscular blockers: mechanisms and clinical significance.

    PubMed

    Soriano, Sulpicio G; Martyn, J A Jeevendra

    2004-01-01

    Prolonged administration of antiepileptic drugs is associated with several drug interactions. In the field of anaesthesia and critical care, patients exhibit both sensitivity and resistance to non-depolarising neuromuscular blockers (NDNMBs) after acute and long-term administration of antiepileptic drugs, respectively. Although antiepileptic therapy alone has only mild neuromuscular effects, acutely administered antiepileptic drugs can potentiate the neuromuscular effects of NDNMBs as a result of direct pre- and post-junctional effects. Resistance to NDNMBs during long-term antiepileptic therapy is due to multiple factors operating alone or in combination, including induction of hepatic drug metabolism, increased protein binding of the NDNMBs and/or upregulation of acetylcholine receptors.

  15. A dual action of valproic acid upon morphine analgesia and morphine withdrawal.

    PubMed

    Tamayo, L; Contreras, E

    1983-01-01

    Effects of valproic acid administration on morphine analgesia and on morphine tolerance and dependence were investigated in mice. Valproate increased the reaction time to thermal stimulation in naive animals. This effect was additive with morphine when valproate was administered shortly before the analgesic. However, an antagonism was observed if a 4-hour period elapsed between valproate and morphine administration. When administered to mice receiving a sustained release preparation of morphine, valproate antagonized the development of tolerance to morphine. Valproate elicited a dual action on the abstinence signs observed after naloxone administration in morphine-treated mice. The effect consisted in a reduction of abstinence behavior if the anticonvulsant was administered a few minutes before naloxone; the same treatment increased the severity of the abstinence behavior when valproate was injected 1 h before the precipitating dose of naloxone. In this latter schedule, concomitant administration of gamma-vinyl-GABA failed to reduce the severity of the convulsions observed during the abstinence syndrome. These results suggest that valproate is metabolized to a compound responsible for decreased analgesia and intensified withdrawal signs.

  16. Limited Effect of Chronic Valproic Acid Treatment in a Mouse Model of Machado-Joseph Disease.

    PubMed

    Esteves, Sofia; Duarte-Silva, Sara; Naia, Luana; Neves-Carvalho, Andreia; Teixeira-Castro, Andreia; Rego, Ana Cristina; Silva-Fernandes, Anabela; Maciel, Patrícia

    2015-01-01

    Machado-Joseph disease (MJD) is an inherited neurodegenerative disease, caused by a CAG repeat expansion within the coding region of ATXN3 gene, and which currently lacks effective treatment. In this work we tested the therapeutic efficacy of chronic treatment with valproic acid (VPA) (200mg/kg), a compound with known neuroprotection activity, and previously shown to be effective in cell, fly and nematode models of MJD. We show that chronic VPA treatment in the CMVMJD135 mouse model had limited effects in the motor deficits of these mice, seen mostly at late stages in the motor swimming, beam walk, rotarod and spontaneous locomotor activity tests, and did not modify the ATXN3 inclusion load and astrogliosis in affected brain regions. However, VPA chronic treatment was able to increase GRP78 protein levels at 30 weeks of age, one of its known neuroprotective effects, confirming target engagement. In spite of limited results, the use of another dosage of VPA or of VPA in a combined therapy with molecules targeting other pathways, cannot be excluded as potential strategies for MJD therapeutics.

  17. Limited Effect of Chronic Valproic Acid Treatment in a Mouse Model of Machado-Joseph Disease

    PubMed Central

    Esteves, Sofia; Duarte-Silva, Sara; Naia, Luana; Neves-Carvalho, Andreia; Teixeira-Castro, Andreia; Rego, Ana Cristina; Silva-Fernandes, Anabela; Maciel, Patrícia

    2015-01-01

    Machado-Joseph disease (MJD) is an inherited neurodegenerative disease, caused by a CAG repeat expansion within the coding region of ATXN3 gene, and which currently lacks effective treatment. In this work we tested the therapeutic efficacy of chronic treatment with valproic acid (VPA) (200mg/kg), a compound with known neuroprotection activity, and previously shown to be effective in cell, fly and nematode models of MJD. We show that chronic VPA treatment in the CMVMJD135 mouse model had limited effects in the motor deficits of these mice, seen mostly at late stages in the motor swimming, beam walk, rotarod and spontaneous locomotor activity tests, and did not modify the ATXN3 inclusion load and astrogliosis in affected brain regions. However, VPA chronic treatment was able to increase GRP78 protein levels at 30 weeks of age, one of its known neuroprotective effects, confirming target engagement. In spite of limited results, the use of another dosage of VPA or of VPA in a combined therapy with molecules targeting other pathways, cannot be excluded as potential strategies for MJD therapeutics. PMID:26505994

  18. Valproic acid ameliorates C. elegans dopaminergic neurodegeneration with implications for ERK-MAPK signaling.

    PubMed

    Kautu, Bwarenaba B; Carrasquilla, Alejandro; Hicks, Matthew L; Caldwell, Kim A; Caldwell, Guy A

    2013-04-29

    Parkinson's disease (PD) is a currently incurable neurodegenerative disorder that affects the aging population. The loss of dopaminergic neurons in the substantia nigra is one of the pathological features of PD. The precise causes of PD remain unresolved but evidence supports both environmental and genetic contributions. Current efforts for the treatment of PD are directed toward the discovery of compounds that show promise in impeding age-dependent neurodegeneration in PD patients. Alpha-synuclein (α-Syn) is a human protein that is mutated in specific populations of patients with familial PD. Overexpression of α-Syn in animal models of PD replicates key symptoms of PD, including neurodegeneration. Here, we use the nematode Caenorhabditis elegans as a model system, whereby α-Syn toxicity causes dopaminergic neurodegeneration, to test the capacity of valproic acid (VA) to protect neurons. The results of our study showed that treatment of nematodes with moderate concentrations of VA significantly protects dopaminergic neurons against α-Syn toxicity. Consistent with previously established knowledge related to the mechanistic action of VA in the cell, we showed through genetic analysis that the neuroprotection conferred by VA is inhibited by cell-specific depletion of the C. elegans ortholog of the MAP extracellular signal-regulated kinase (ERK), MPK-1, in the dopaminergic neurons. These findings suggest that VA may exert its neuroprotective effect via ERK-MAPK, or alternately could act with MAPK signaling to additively provide dopaminergic neuroprotection. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. Clinical Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy Type I.

    PubMed

    Krosschell, Kristin J; Kissel, John T; Townsend, Elise L; Simeone, Sarah D; Zhang, Ren Zhe; Reyna, Sandra P; Thomas, O Crawford; Schroth, Mary K; Acsadi, Gyula; Kishnani, Priya S; von Kleist-Retzow, Jürgen-Christoph; Hero, Barbara; D'Anjou, Guy; Smith, Edward C; Elsheikh, Bakri; Simard, Louise R; Prior, Thomas W; Scott, Charles B; LaSalle, Bernard; Sakonju, Ai; Wirth, Brunhilde; Swoboda, Kathryn J

    2017-08-18

    To explore safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). Open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were safety and adverse events (AEs); secondary outcomes were survival, time to death/> 16 hours/day ventilator support, motor outcomes and maximum ulnar compound motor action potential amplitude. 245 AEs were observed in 35 of 37 treated subjects (95%). Respiratory events accounted for 49% of all AEs, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. This trial provides evidence that in infants with SMA type I, L-carnitine/VPA is ineffective in altering survival. The substantial proportion of infants reaching endpoints within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. This article is protected by copyright. All rights reserved. © 2017 Wiley Periodicals, Inc.

  20. Design, synthesis and antiepileptic properties of novel 1-(substituted benzylidene)-3-(1-(morpholino/piperidino methyl)-2,3-dioxoindolin-5-yl)urea derivatives.

    PubMed

    Prakash, Chinnasamy Rajaram; Raja, Sundararajan

    2011-12-01

    Twenty new 1-(substituted benzylidene)-3-(1-(morpholino/piperidino methyl)-2,3-dioxoindolin-5-yl) urea derivatives were designed and synthesized. Antiepileptic screening was performed using MES and scPTZ seizures tests. The neurotoxicity was determined by rotorod test. In the preliminary screening, compounds 5c, 5g, 5j and 5n were found active in MES model, while 5o showed significant antiepileptic activity in scPTZ model. Further all these five compounds were administered orally to rats, 5c, 5g and 5n showed better activity than Phenytoin in oral route. Among these compounds 5c revealed protection in MES at a dose of 30 mg/kg and 100 mg/kg 0.5 h and 4 h after i.p. administration respectively. This molecule provided also protection in the scPTZ at a dose of 300 mg/kg in both time intervals.

  1. Can valproic acid be an inducer of clozapine metabolism?

    PubMed Central

    Diaz, Francisco J.; Eap, Chin B.; Ansermot, Nicolas; Crettol, Severine; Spina, Edoardo; de Leon, Jose

    2014-01-01

    Introduction Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that 1) VPA is a net inducer of clozapine metabolism, and 2) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. Methods After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. Results VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14% to 39%) after controlling for confounding variables including smoking (35% lower, 28% to 56%). Discussion Prospective studies are needed to definitively establish that VPA may 1) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and 2) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism. PMID:24764199

  2. Valproic acid enhances bosutinib cytotoxicity in colon cancer cells.

    PubMed

    Mologni, Luca; Cleris, Loredana; Magistroni, Vera; Piazza, Rocco; Boschelli, Frank; Formelli, Franca; Gambacorti-Passerini, Carlo

    2009-04-15

    Unbalanced histone deacetylase (HDAC) hyperactivity is a common feature of tumor cells. Inhibition of HDAC activity is often associated with cancer cell growth impairment and death. Valproic acid (VPA) is a HDAC inhibitor used for the treatment of epilepsy. It has recently been recognized as a promising anticancer drug. We investigated the effects of VPA on growth and survival of colon cancer cells. VPA caused growth inhibition and programmed cell death that correlated with histone hyperacetylation. VPA modulated the expression of various factors involved in cell cycle control and apoptosis and induced caspase activation. Interestingly, VPA induced downregulation of c-Src and potentiated the cytotoxic effects of the c-Src inhibitor bosutinib, both in vitro and in vivo. The combination of sublethal doses of VPA and bosutinib led to massive apoptosis of colon cancer cells, irrespective of their genetic background. These results suggest that VPA may be employed as a positive modulator of bosutinib antitumor activity in colorectal cancer.

  3. Exploring the Validity of Valproic Acid Animal Model of Autism

    PubMed Central

    Mabunga, Darine Froy N.; Gonzales, Edson Luck T.; Kim, Ji-woon; Kim, Ki Chan

    2015-01-01

    The valproic acid (VPA) animal model of autism spectrum disorder (ASD) is one of the most widely used animal model in the field. Like any other disease models, it can't model the totality of the features seen in autism. Then, is it valid to model autism? This model demonstrates many of the structural and behavioral features that can be observed in individuals with autism. These similarities enable the model to define relevant pathways of developmental dysregulation resulting from environmental manipulation. The uncovering of these complex pathways resulted to the growing pool of potential therapeutic candidates addressing the core symptoms of ASD. Here, we summarize the validity points of VPA that may or may not qualify it as a valid animal model of ASD. PMID:26713077

  4. Differentiation of rat adipose tissue-derived stem cells into neuron-like cells by valproic acid, a histone deacetylase inhibitor.

    PubMed

    Okubo, Takumi; Hayashi, Daiki; Yaguchi, Takayuki; Fujita, Yudai; Sakaue, Motoharu; Suzuki, Takehito; Tsukamoto, Atsushi; Murayama, Ohoshi; Lynch, Jonathan; Miyazaki, Yoko; Tanaka, Kazuaki; Takizawa, Tatsuya

    2016-01-01

    Valproic acid (VPA) is a widely used antiepileptic drug, which has recently been reported to modulate the neuronal differentiation of adipose tissue-derived stem cells (ASCs) in humans and dogs. However, controversy exists as to whether VPA really acts as an inducer of neuronal differentiation of ASCs. The present study aimed to elucidate the effect of VPA in neuronal differentiation of rat ASCs. One or three days of pretreatment with VPA (2 mM) followed by neuronal induction enhanced the ratio of immature neuron marker βIII-tubulin-positive cells in a time-dependent manner, where the majority of cells also had a positive signal for neurofilament medium polypeptide (NEFM), a mature neuron marker. RT-PCR analysis revealed increases in the mRNA expression of microtubule-associated protein 2 (MAP2) and NEFM mature neuron markers, even without neuronal induction. Three-days pretreatment of VPA increased acetylation of histone H3 of ASCs as revealed by immunofluorescence staining. Chromatin immunoprecipitation assay also showed that the status of histone acetylation at H3K9 correlated with the gene expression of TUBB3 in ASCs by VPA. These results indicate that VPA significantly promotes the differentiation of rat ASCs into neuron-like cells through acetylation of histone H3, which suggests that VPA may serve as a useful tool for producing transplantable cells for future applications in clinical treatments.

  5. Valproic acid downregulates RBP4 and elicits hypervitaminosis A-teratogenesis--a kinetic analysis on retinol/retinoic acid homeostatic system.

    PubMed

    Chuang, Chao-Ming; Chang, Chi-Huang; Wang, Hui-Er; Chen, Kuan-Chou; Peng, Chiung-Chi; Hsieh, Chiu-Lan; Peng, Robert Y

    2012-01-01

    Valproic acid (VPA) is an antiepileptic and anti-migraine prophylactic drug. VPA exhibits two severe side effects, namely acute liver toxicity and teratogenicity. These side effects are usually seen at the genetic and somatic levels. The cited action mechanisms involve inhibition of histone deacetylase, hypofolatenemia, hyperhomocysteinemia, and reactive oxidative stress. The proteomic information associated with VPA teratogenicity is still unavailable. We hypothesized that proteomic analysis might help us identify functional proteins that could be relevantly affected by VPA, and this phenomenon could be very sensitive in early embryonic stage, resulting in VPA teratogenicity. Proteomic analysis on the chicken embryos at Hamburger and Hamilton (HH) stage 28 showed that there were significant downregulations of ovotransferrins, carbonic anhydrase-2, retinol binding protein-4 (RBP4), NADH cytochrome b5 reductase 2 (CYB5R2), apolipoprotein A1, and protein SET, together with upregulation of 60S ribosomal protein L22. Among these, RBP4 was the most significantly downregulated (-32%). Kinetic analysis suggested that this situation could trigger hypervitaminosis A (+39.3%), a condition that has been well known to induce teratogenesis.. This is the first report showing that VPA dowregulates RBP4. Our finding not only has led to a possible mechanism of VPA teratogenesis, but also has initiated new preventive strategies for avoiding VPA teratogeneis.

  6. Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation

    PubMed Central

    2010-01-01

    Background The anti-epileptic drug valproic acid (VPA) has attracted attention as an anti-cancer agent. Methods The present study investigated effects of VPA exposure on histone deacetylase (HDAC) inhibition, cell growth, cell speed, and the degree of Erk1/2 phosphorylation in 10 cell lines (BT4C, BT4Cn, U87MG, N2a, PC12-E2, CSML0, CSML100, HeLa, L929, Swiss 3T3). Results VPA induced significant histone deacetylase (HDAC) inhibition in most of the cell lines, but the degree of inhibition was highly cell type-specific. Moreover, cell growth, motility and the degree of Erk1/2 phosphorylation were inhibited, activated, or unaffected by VPA in a cell type-specific manner. Importantly, no relationship was found between the effects of VPA on HDAC inhibition and changes in the degree of Erk1/2 phosphorylation, cell growth, or motility. In contrast, VPA-induced modulation of the MAPK pathway downstream of Ras but upstream of MEK (i.e., at the level of Raf) was important for changes in cell speed. Conclusions These results suggest that VPA can modulate the degree of Erk1/2 phosphorylation in a manner unrelated to HDAC inhibition and emphasize that changes in the degree of Erk1/2 phosphorylation are also important for the anti-cancer properties of VPA. PMID:20663132

  7. Valproic Acid Downregulates RBP4 and Elicits Hypervitaminosis A-Teratogenesis—A Kinetic Analysis on Retinol/Retinoic Acid Homeostatic System

    PubMed Central

    Chuang, Chao-Ming; Chang, Chi-Huang; Wang, Hui-Er; Chen, Kuan-Chou; Peng, Chiung-Chi; Hsieh, Chiu-Lan; Peng, Robert Y.

    2012-01-01

    Background Valproic acid (VPA) is an antiepileptic and anti-migraine prophylactic drug. VPA exhibits two severe side effects, namely acute liver toxicity and teratogenicity. These side effects are usually seen at the genetic and somatic levels. The cited action mechanisms involve inhibition of histone deacetylase, hypofolatenemia, hyperhomocysteinemia, and reactive oxidative stress. The proteomic information associated with VPA teratogenicity is still unavailable. We hypothesized that proteomic analysis might help us identify functional proteins that could be relevantly affected by VPA, and this phenomenon could be very sensitive in early embryonic stage, resulting in VPA teratogenicity. Methodology/Principal Findings Proteomic analysis on the chicken embryos at Hamburger and Hamilton (HH) stage 28 showed that there were significant downregulations of ovotransferrins, carbonic anhydrase-2, retinol binding protein-4 (RBP4), NADH cytochrome b5 reductase 2 (CYB5R2), apolipoprotein A1, and protein SET, together with upregulation of 60S ribosomal protein L22. Among these, RBP4 was the most significantly downregulated (−32%). Kinetic analysis suggested that this situation could trigger hypervitaminosis A (+39.3%), a condition that has been well known to induce teratogenesis.. Conclusions/Significance This is the first report showing that VPA dowregulates RBP4. Our finding not only has led to a possible mechanism of VPA teratogenesis, but also has initiated new preventive strategies for avoiding VPA teratogeneis. PMID:23028466

  8. Zinc/Aluminum layered double hydroxide-titanium dioxide composite nanosheet film as novel solid phase microextraction fiber for the gas chromatographic determination of valproic acid.

    PubMed

    Matin, Amir Abbas; Biparva, Pourya; Amanzadeh, Hatam; Farhadi, Khalil

    2013-01-15

    A nanosheet thin film based on Zn/Al layered double hydroxide (LDH) and TiO(2) composite was prepared via sol-gel process on capillary glass rod. Characterization of the fiber coating using X-ray diffraction (XRD) pattern and scanning electron microscopy (SEM) images showed that it consists of a large number of intercrossed and curved nanosheets with hexagonal architecture. The thickness of these plates is about few nanometers, and the lateral dimension is varying from 400 to 1000 nm. Application of the proposed coating as a solid phase microextraction fiber was investigated. As a model analyte, valproic acid (VPA, antiepileptic drug) was selected and its extraction from biological (human serum) and pharmaceutical (tablet and syrup) samples were performed without any considerable matrix effect. Analytical merits of the method, under optimum conditions (extraction temperature: 50 ± 1°C, extraction time: 15 min, desorption temperature: 250°C, desorption time: 2 min, solution pH: 1.5, salt concentration: 5 mol L(-1)), are 70 μg L(-1) and 0.20-100 mg L(-1) for LOD and LDR, respectively.

  9. Profibrinolytic Effect of the Epigenetic Modifier Valproic Acid in Man

    PubMed Central

    Saluveer, Ott; Larsson, Pia; Ridderstråle, Wilhelm; Hrafnkelsdóttir, Thórdís J.; Jern, Sverker; Bergh, Niklas

    2014-01-01

    Aims The aim of the study was to test if pharmacological intervention by valproic acid (VPA) treatment can modulate the fibrinolytic system in man, by means of increased acute release capacity of tissue plasminogen activator (t-PA) as well as an altered t-PA/Plasminogen activator inhibitor -1 (PAI-1) balance. Recent data from in vitro research demonstrate that the fibrinolytic system is epigenetically regulated mainly by histone deacetylase (HDAC) inhibitors. HDAC inhibitors, including VPA markedly upregulate t-PA gene expression in vitro. Methods and Results The trial had a cross-over design where healthy men (n = 10), were treated with VPA (Ergenyl Retard) 500 mg depot tablets twice daily for 2 weeks. Capacity for stimulated t-PA release was assessed in the perfused-forearm model using intra-brachial Substance P infusion and venous occlusion plethysmography. Each subject was investigated twice, untreated and after VPA treatment, with 5 weeks wash-out in-between. VPA treatment resulted in considerably decreased levels of circulating PAI-1 antigen from 22.2 (4.6) to 10.8 (2.1) ng/ml (p<0.05). It slightly decreased the levels of circulating venous t-PA antigen (p<0.05), and the t-PA:PAI-1 antigen ratio increased (p<0.01). Substance P infusion resulted in an increase in forearm blood flow (FBF) on both occasions (p<0.0001 for both). The acute t-PA release in response to Substance P was not affected by VPA (p = ns). Conclusion Valproic acid treatment lowers plasma PAI-1 antigen levels and changes the fibrinolytic balance measured as t-PA/PAI-1 ratio in a profibrinolytic direction. This may in part explain the reduction in incidence of myocardial infarctions by VPA treatment observed in recent pharmacoepidemiological studies. Trial Registration The EU Clinical Trials Register 2009-011723-31 PMID:25295869

  10. The influence of established and new antiepileptic drugs on visual perception. 1. A placebo-controlled, double-blind, single-dose study in healthy volunteers.

    PubMed

    Steinhoff, B J; Freudenthaler, N; Paulus, W

    1997-12-01

    The influence of single oral dosages of carbamazepine (CBZ), valproic acid, vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP), and losigamone (LSG) on visual perception was investigated in ten healthy volunteers according to a double-blind, placebo-controlled, cross-over study design. The test battery comprised visual acuity, the Lanthony-D-15-désaturé colour perception test, increment, postadaptation and transient tritanopia threshold measurements, perception threshold assessment for monochromatic and chromatic gaussian dots, monochromatic gratings and gratings of differing spatial frequency, and critical flicker fusion tests with various stimuli. The only consistent and partly significant effects were seen after VGB and GBP. After VGB, increment, postadaptation and transient tritanopia thresholds and the critical flicker fusion increased, whereas GBP led to a somewhat converse profile. The other tests were not influenced consistently by any antiepileptic drug (AED). We conclude that: (i) gamma-amino-butyric acid-(GABA)-related properties as under the prototype drug VGB result in specific alterations of the transient tritanopia phenomenon which is consistent with the physiological hypothesis for this retinal paradigm based on extracellular recordings in primates. The possible mechanisms why VGB improved critical flicker fusion as the only AED in this trial are discussed. The profile of GBP indicates a unique mechanism of action. We have not observed specific influences on visual perception under AEDs which act mainly via alterations of ion membrane conductance. The transient tritanopia and flicker fusion paradigms we used appear to be promising to investigate antiepileptic drugs with hitherto unknown modes of actions in human noninvasively.

  11. Impact of perampanel on pharmacokinetics of concomitant antiepileptics in patients with partial‐onset seizures: pooled analysis of clinical trials

    PubMed Central

    Laurenza, Antonio; Ferry, Jim; Hussein, Ziad

    2016-01-01

    Aims To evaluate the impact of perampanel and demographics on clearance of concomitant antiepileptic drugs (AEDs), in patients with refractory partial‐onset seizures. Methods Pooled data from three Phase III clinical studies with adjunctive perampanel were used. Blood samples for evaluation of 11 concomitant AEDs were taken during baseline (before perampanel initiation), and at weeks 10, 14, and 19 during the maintenance phase of perampanel treatment (2–12 mg/day, once daily at bedtime). Models estimating apparent clearance of each concomitant AED were fitted to the data, and the effects of perampanel and demographic variables on clearance were determined. Final models were assessed with goodness of fit plots including population predictions and individual predictions against observations. Results No significant impact of perampanel on clearance was found for clonazepam (n = 81), levetiracetam (n = 330), phenobarbital (n = 54), phenytoin (n = 90), topiramate (n = 226) or zonisamide (n = 93). Statistically significant, but small and not clinically relevant increases in model‐predicted clearance were detected for carbamazepine (+4.3% with 12 mg perampanel; n = 379), clobazam (+3.4% males, +7.7% females, 12 mg; n = 114), lamotrigine (+9.3%, 12 mg; n = 356), and valproic acid (+5.0%, 12 mg; n = 349). Oxcarbazepine clearance was reduced (26%; n = 200), but the clinical relevance is unclear as levels of the active metabolite (the monohydroxy derivative of oxcarbazepine) were not measured. Conclusions Population PK data show that perampanel (2–12 mg/day, once daily at bedtime) has no relevant impact on the clearance of the most commonly used concomitant AEDs. PMID:27038098

  12. [The "cost-benefit" analysis of new antiepileptic drugs].

    PubMed

    Vlasov, P N; Orekhova, N V

    2011-01-01

    The objective was to optimize the pharmaceutical treatment of epileptic patients and to evaluate the clinical-economical effectiveness of new antiepileptic drugs (AED)--levetiracetam, lamotrigine, topiramate and oxcarbazepine. The study included 134 patients with different types of seizures who received earlier antiepileptics with the addition of new AED as mono- or polytherapy. The cost of treatment and pharmacoeconomic "cost-benefit" index were calculated before and after the treatment optimization. After one year of the treatment with "news" AED, the decrease in seizure frequency was 75-92%. The "cost-benefit" ratio was significantly (p < 0.05) decreased by 2-3 times in all types of seizures despite the increase of direst costs of the treatment. The significant (p < 0.05) decrease in the cost of treatment of epilepsy was noted in all groups studied. In conclusion, the rational treatment using "new" AED allows to reduce both the total cost of treatment and ccost-benefits ratio.

  13. Seizures and antiepileptic drugs: does exposure alter normal brain development?

    PubMed

    Marsh, Eric D; Brooks-Kayal, Amy R; Porter, Brenda E

    2006-12-01

    Seizures and antiepileptic drugs (AEDs) affect brain development and have long-term neurological consequences. The specific molecular and cellular changes, the precise timing of their influence during brain development, and the full extent of the long-term consequences of seizures and AEDs exposure have not been established. This review critically assesses both the basic and clinical science literature on the effects of seizures and AEDs on the developing brain and finds that evidence exists to support the hypothesis that both seizures and antiepileptic drugs influence a variety of biological process, at specific times during development, which alter long-term cognition and epilepsy susceptibility. More research, both clinical and experimental, is needed before changes in current clinical practice, based on the scientific data, can be recommended.

  14. Challenges in the clinical development of new antiepileptic drugs.

    PubMed

    Schwabe, Stefan K

    2002-02-01

    The very nature of epilepsy makes the clinical development of new antiepileptic drugs a lengthy and costly process. The underlying disease mechanisms are largely unknown, reflecting the paucity of animal models that mirror the human condition. The risks of untreated epilepsy usually preclude the use of placebo as a control treatment except in patients receiving background medication. Thus, new AEDs must first display a treatment effect in patients with seizures known to be resistant to drug therapy, using study designs that are confounded by the potential pharmacodynamic and pharmacokinetic interactions associated with polytherapy. Moreover, the unpredictable nature of epilepsy often means lengthy clinical trials. Clinical development for antiepileptic drugs is inevitably more complex and time-consuming than for many other drugs. As a result the interval between product approval and loss of patent is often shorter. Creative methods of accelerating the development process without compromising the quality of research are needed.

  15. The effects of neuroleptics (haloperidol and chlorpromazine) on the pharmacokinetics of valproic acid in schizophrenic patients.

    PubMed

    Ishizaki, T; Chiba, K; Saito, M; Kobayashi, K; Iizuka, R

    1984-10-01

    The steady state trough concentrations (Cmin) and pharmacokinetics of valproic acid were investigated in schizophrenic patients during the treatment of valproic acid, 200 mg, twice daily and after the one dose of 400 mg, respectively, with and without haloperidol (6 to 10 mg/day, N = 6) or chlorpromazine (100 to 300 mg/day, N = 6). Four to 5 Cmin were monitored just before the morning valproic acid dose for 3 to 4 days preceding the kinetic study. The overall Cmin of valproic acid with chlorpromazine (33.2 +/- 1.7 micrograms/ml, N = 25) was significantly (p less than 0.01) greater than without (27.1 +/- 1.4 micrograms/ml, N = 25). The majority of the mean valproic acid concentrations observed after the 400-mg dose were significantly (p less than 0.05 to 0.01) greater during the chlorpromazine treatment as compared to those without the phenothiazine. The mean t1/2 was shortened from 15.4 +/- 1.4 to 13.5 +/- 1.2 hours (p less than 0.05) with a comparable increase in the clearance from 7.18 +/- 0.38 to 8.32 +/- 0.34 ml/hour/kg (p less than 0.01) after the discontinuation of chlorpromazine. All the patients revealed an increase in the valproic acid clearance after the chlorpromazine therapy was discontinued. When viewed overall, such a trend as found in the chlorpromazine group was not observed in the haloperidol group. The results suggest that chlorpromazine, but not haloperidol, inhibits the metabolism of valproic acid. However, the clinical significance of the interaction awaits future study.

  16. Effects of neonatal treatment with valproic acid on vasopressin immunoreactivity and olfactory behaviour in mice

    PubMed Central

    Murray, Elaine K.; Varnum, Megan M.; Fernandez, Jared L.; de Vries, Geert J.; Forger, Nancy G.

    2011-01-01

    Recent findings demonstrate that epigenetic modifications are required for sexual differentiation of the brain. For example, neonatal administration of the histone deacetylase inhibitor, valproic acid, blocks masculinisation of cell number in the principal nucleus of the bed nucleus of the stria terminalis (BNST). Here we examined effects of valproic acid on neurochemistry and behaviour, focusing on traits that are sexually dimorphic and linked to the BNST. Newborn mice were treated with saline or valproic acid and the effect on vasopressin immunoreactivity and olfactory preference behavior examined in adulthood. As expected, males had more vasopressin immunoreactive fibers than females in the lateral septum and medial dorsal thalamus, two projection sites of BNST vasopressin neurons. Neonatal valproic acid increased vasopressin fiber density specifically in females in the lateral septum, thereby reducing the sex difference, and increased vasopressin fibers in both sexes in the medial dorsal thalamus. Effects were not specific to BNST vasopressin projections, however, as valproic acid also significantly increased vasopressin immunoreactivity in the anterior hypothalamic area in both sexes. Subtle sex-specific effects of neonatal valproic acid treatment were observed on olfactory behavior. As predicted, males showed a preference for investigating female-soiled bedding whereas females showed a preference for male-soiled bedding. Valproic acid did not significantly alter olfactory preference, per se, but increased the number of visits females made to female-soiled bedding and the overall time females spent investigating soiled versus clean bedding. Taken together, these results suggest that a transient disruption of histone deacetylation at birth does not have generalized effects on sexual differentiation, but does produce lasting effects on brain neurochemistry and behaviour. PMID:21793947

  17. Valproic acid promotes human hair growth in in vitro culture model.

    PubMed

    Jo, Seong Jin; Choi, Soon-Jin; Yoon, Sun-Young; Lee, Ji Yeon; Park, Won-Seok; Park, Phil-June; Kim, Kyu Han; Eun, Hee Chul; Kwon, Ohsang

    2013-10-01

    β-Catenin, the transducer of Wnt signaling, is critical for the development and growth of hair follicles. In the absence of Wnt signals, cytoplasmic β-catenin is phosphorylated by glycogen synthase kinase (GSK)-3 and then degraded. Therefore, inhibition of GSK-3 may enhance hair growth via β-catenin stabilization. Valproic acid is an anticonvulsant and a mood-stabilizing drug that has been used for decades. Recently, valproic acid was reported to inhibit GSK-3β in neuronal cells, but its effect on human hair follicles remains unknown. To determine the effect of VPA on human hair growth. We investigated the effect of VPA on cultured human dermal papilla cells and outer root sheath cells and on an in vitro culture of human hair follicles, which were obtained from scalp skin samples of healthy volunteers. Anagen induction by valproic acid was evaluated using C57BL/6 mice model. Valproic acid not only enhanced the viability of human dermal papilla cells and outer root sheath cells but also promoted elongation of the hair shaft and reduced catagen transition of human hair follicles in organ culture model. Valproic acid treatment of human dermal papilla cells led to increased β-catenin levels and nuclear accumulation and inhibition of GSK-3β by phosphorylation. In addition, valproic acid treatment accelerated the induction of anagen hair in 7-week-old female C57BL/6 mice. Valproic acid enhanced human hair growth by increasing β-catenin and therefore may serve as an alternative therapeutic option for alopecia. Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  18. Neurological and Psychiatric Sequelae of Developmental Exposure to Antiepileptic Drugs

    PubMed Central

    Gedzelman, Evan R.; Meador, Kimford J.

    2012-01-01

    The neurons in the developing mammalian brain are susceptible to antiepileptic drug (AED) effects. It is known that later in life deficits in cognitive performance as well as psychiatric deficits can manifest after early AED exposure. The extent of these deficits will be addressed. This review will attempt to draw parallels between the existent animal models and human studies. Through analysis of these studies, important future research will be elucidated and possible new and emerging therapies will be discussed. PMID:23293628

  19. Current discoveries on the cognitive effects of antiepileptic drugs.

    PubMed

    Meador, K J

    2000-08-01

    The cognitive effects of antiepileptic drugs (AEDs) are of particular concern to clinicians because these drugs are the primary therapeutic modality for managing epilepsy. In general, the cognitive effects of most AEDs are modest and offset by their benefit in reducing seizures. Nonetheless, the cognitive effects of a particular AED may be clinically significant when treating specific patient populations, such as children and the elderly.

  20. Effect of anti-epileptic drugs in pregnancy and teratogenesis.

    PubMed

    Lakshmi, Sowbhagya; Sunanda, Kulkarni

    2008-07-01

    Epilepsy raises special concern in women during pregnancy. Antiepileptic drugs are known to induce major and minor malformations in the foetus. Aim of the study was to find an association between maternal serum alpha fetoprotein levels, foetal abnormalities and antiepileptic drugs mediated teratogenicity. Maternal serum alpha feto protein levels, kidney and liver function tests in age matched normal pregnant women and seizure free epileptic pregnant women during 12-14 weeks of gestation were estimated. Cases were subjected to ultrasonography at 11(th)-14(th) week of pregnancy and again at 20(th) week of pregnancy. maternal serum alfa feto protein was assayed by a specific Electro Chemiluminescence Immuno Assay test. There was no significant difference in kidney and liver function tests in cases as compared to controls. There were elevated levels of alpha feto protein in cases as compared to controls but this was not statistically significant. No anomalies were detected in ultrasound reports. Most women had normal full term delivery with healthy children but of low birth weight. No correlation was seen between maternal serum alfa feto protein levels and antiepileptic drug leading to teratogenesis.

  1. Levetiracetam as an antiepileptic, neuroprotective, and hyperalgesic drug.

    PubMed

    Cortes-Altamirano, J L; Olmos-Hernández, A; Bonilla-Jaime, H; Bandala, C; González-Maciel, A; Alfaro-Rodríguez, A

    2016-01-01

    The main purpose of this review was to expound upon the mechanism of action of Levetiracetam (LEV) as an antiepileptic, neuroprotective, and hyperalgesic drug. LEV is a second-generation anti-epileptic drug (AED) that is approved for clinical use as monotherapy and may also be used for adjunctive treatment of patients with seizures. Several researchers have recommended LEV as a treatment option in different diseases causing neuronal damage, and recently, LEV has been used as an antihyperalgesic drug. LEV exhibits favorable characteristics, including a low potential for interaction, a short elimination half-life, and has neither active metabolites nor major negative effects on cognition. This has generated many new research avenues for the utilization of this drug. However, the precise mechanism of action of LEV has not been fully elucidated. In this review, a search was conducted on PubMed, ProQuest, EBSCO, and the Science Citation index for studies evaluating the effects of LEV as an antiepileptic, neuroprotective, and hyperalgesic drug. A total of 32 studies related to the use of LEV suggested different mechanisms of action, such as binding to the synaptic vesicle glycoprotein 2A (SV2A) protein, inhibition of Ca2+ N-type channels, and its presence as a neuromodulator. These studies concluded that the pharmacodynamics of LEV should be viewed as a single pathway, and should not be based on specific molecular targets that depend on the physiological or pathological conditions prevalent at that time.

  2. Antiepileptic drugs in the treatment of neuropathic pain.

    PubMed

    Eisenberg, Elon; River, Yaron; Shifrin, Ala; Krivoy, Norberto

    2007-01-01

    Antiepileptic drugs are an effective treatment for various forms of neuropathic pain of peripheral origin, although they rarely provide complete pain relief. Multiple multicentre randomised controlled trials have shown clear efficacy of gabapentin and pregabalin for postherpetic neuralgia and painful diabetic neuropathy. Theses drugs can be rapidly titrated and are well tolerated. Topiramate, lamotrigine, carbamazepine and oxcarbazepine are alternatives for the treatment of painful diabetic neuropathy, but should be titrated slowly. Carbamazepine remains the drug of choice for trigeminal neuralgia; however, oxcarbazepine and lamotrigine are potential alternatives. There is an apparent need for large-scale randomised controlled trials on the efficacy of antiepileptic drugs in neuropathic pain in general, and in cancer-related neuropathic pain and neuropathic pain of central origin in particular. Trials with long-term follow-up are required to establish the long-term efficacy of antiepileptic drugs in neuropathic pain. There is only limited scientific evidence to support the idea that drug combinations are likely to be more efficacious and safer than each drug alone; further studies are warranted in this area.

  3. Role of antiepileptic drugs as preventive agents for migraine.

    PubMed

    Vikelis, Michail; Rapoport, Alan M

    2010-01-01

    Migraine is a common neurological disease affecting about 12% of the population in Western Europe and North America, and causing a considerable burden both to migraineurs and to society. Severe, frequent and disabling migraine attacks, as well as those poorly responsive to acute care medication, require preventive treatment, which is often under-utilized. Antiepileptic drugs are used in the prevention of migraine. We performed a literature search of PubMed through June 2008 for controlled trials of antiepileptic drugs in the prevention of migraine. The search identified 70 papers for a full-text review. The majority of these papers referred to valproate and topiramate, and showed that these drugs are effective and well tolerated in migraine prevention and are suitable for first-line clinical use. On the other hand, acetazolamide, lamotrigine, oxcarbazepine and vigabatrin have been shown to be not effective and gabapentin requires further evaluation. For the rest of the antiepileptic drugs, no data from controlled trials are available.

  4. The Current Availability of Antiepileptic Drugs in Zambia: Implications for the ILAE/WHO “Out of the Shadows” Campaign

    PubMed Central

    Chomba, Elwyn Nachanya; Haworth, Alan; Mbewe, Edward; Atadzhanov, Masharip; Ndubani, Philimon; Kansembe, Henry; Birbeck, Gretchen Lano

    2010-01-01

    Recent concerns regarding antiepileptic drug (AED) availability in Zambia led us to conduct a study in the Lusaka and Southern Provinces to quantify the availability and cost of AEDs and assess determinants. Among 111 pharmacies, almost one-half did not carry AEDs (N = 54; 49.1%). Available AEDs were phenobarbitone (21; 18.9%), carbamazepine (27; 24.3%), valproic acid (4; 3.6%), and phenytoin (3; 2.7%). Adult out-of-pocket monthly costs ranged from US $7 to $30. Pediatric syrups were universally unavailable. Interviews revealed several barriers to AED provision, including that handling phenobarbitone (historically the most affordable AED) has become increasingly difficult because of newly enforced regulatory requirements. Personal communications with epilepsy-care providers in other low income countries suggest that this problem may be widespread. Improved enforcement of existing drug regulations may be contributing to the AED shortage. Social programs aimed at encouraging people with epilepsy to come “out of the shadows” must be preceded by improved AED access. PMID:20810822

  5. Comment on Vadney and Kraushaar's "Effect of Switching from Depakene to Generic Valproic Acid on Individuals with Mental Retardation".

    ERIC Educational Resources Information Center

    Alvarez, Norberto; Williams, Ronda

    1998-01-01

    This response supports previous findings by describing the experiences of the Wentham Developmental Center. This center found switching from Depakene to generic valproic acid was not associated with any change in the number of epileptic seizures. The occurrence of adverse gastrointestinal effects of valproic acid is addressed. (CR)

  6. L-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: A case report

    PubMed Central

    Maldonado, Cecilia; Guevara, Natalia; Silveira, Alicia; Fagiolino, Pietro

    2017-01-01

    Valproic acid is a broad-spectrum anticonvulsant that has also gained attention in the psychiatric setting. With respect to safety, valproic acid may induce a seemingly rare condition, hyperammonemia, which can induce a wide variety of symptoms ranging from irritability to coma. The proposed mechanism of hyperammonemia involves depletion of carnitine and overproduction of a toxic metabolite, 4-en-valproic acid, both of which impair the urea cycle and thus ammonia elimination. Carnitine is a commonly used antidote for acute intoxication of valproic acid, but is not a therapeutic option for management of chronic adults with adverse effects related to valproic acid. We herein report a case involving a woman with epilepsy who developed hyperammonemia after a change in her anticonvulsant therapy. She reported increased seizures and gastrointestinal disturbances. Her ammonia, valproic acid, 4-en-valproic acid, and carnitine levels were monitored. Her ammonia level was elevated and her carnitine level was at the inferior limit of the population range. She was supplemented with carnitine at 1 g/day. After 1 month, her ammonia level decreased, her carnitine level increased, and her seizures were better controlled. Carnitine supplementation was useful for reversal of her hyperammonemia, allowing her to continue valproic acid for seizure control. PMID:28425821

  7. L-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: A case report.

    PubMed

    Maldonado, Cecilia; Guevara, Natalia; Silveira, Alicia; Fagiolino, Pietro; Vázquez, Marta

    2017-06-01

    Valproic acid is a broad-spectrum anticonvulsant that has also gained attention in the psychiatric setting. With respect to safety, valproic acid may induce a seemingly rare condition, hyperammonemia, which can induce a wide variety of symptoms ranging from irritability to coma. The proposed mechanism of hyperammonemia involves depletion of carnitine and overproduction of a toxic metabolite, 4-en-valproic acid, both of which impair the urea cycle and thus ammonia elimination. Carnitine is a commonly used antidote for acute intoxication of valproic acid, but is not a therapeutic option for management of chronic adults with adverse effects related to valproic acid. We herein report a case involving a woman with epilepsy who developed hyperammonemia after a change in her anticonvulsant therapy. She reported increased seizures and gastrointestinal disturbances. Her ammonia, valproic acid, 4-en-valproic acid, and carnitine levels were monitored. Her ammonia level was elevated and her carnitine level was at the inferior limit of the population range. She was supplemented with carnitine at 1 g/day. After 1 month, her ammonia level decreased, her carnitine level increased, and her seizures were better controlled. Carnitine supplementation was useful for reversal of her hyperammonemia, allowing her to continue valproic acid for seizure control.

  8. Duration of valproic acid monotherapy correlates with subclinical thyroid dysfunction in children with epilepsy.

    PubMed

    Ilić, Violeta; Bogićević, Dragana; Miljković, Branislava; Ješić, Maja; Kovačević, Marijana; Prostran, Milica; Kovačević, Sandra Vezmar

    2016-06-01

    To identify potential risk factors for the development of subclinical hypothyroidism following long-term valproic acid monotherapy in children with epilepsy. Serum levels of thyroid-stimulating hormone, free thyroxine, free triiodothyronine, thyreoglobulin antibodies, and thyroid peroxidase antibodies were determined in 41 patients and in 41 sex- and age-matched healthy children. Mean valproic acid treatment duration was 2.80±1.96 years. The valproic acid group had higher serum thyroid-stimulating hormone (p<0.001) and free triiodothyronine (p<0.05) levels compared to the control group. Serum thyroid-stimulating hormone and free triiodothyronine were above the upper limit for healthy controls in 34% and 32% of patients, respectively, and no clinical features of thyroid dysfunction were observed. Duration of valproic acid monotherapy for less than four years was a risk factor for elevated thyroid-stimulating hormone levels. One third of children with normal range serum valproic acid levels may have elevated serum thyroid-stimulating hormone and free triiodothyronine levels, especially in the first four years of treatment.

  9. Valproic acid protects neurons and promotes neuronal regeneration after brachial plexus avulsion

    PubMed Central

    Li, Qiang; Wu, Dianxiu; Li, Rui; Zhu, Xiaojuan; Cui, Shusen

    2013-01-01

    Valproic acid has been shown to exert neuroprotective effects and promote neurite outgrowth in several peripheral nerve injury models. However, whether valproic acid can exert its beneficial effect on neurons after brachial plexus avulsion injury is currently unknown. In this study, brachial plexus root avulsion models, established in Wistar rats, were administered daily with valproic acid dissolved in drinking water (300 mg/kg) or normal water. On days 1, 2, 3, 7, 14 and 28 after avulsion injury, tissues of the C5–T1 spinal cord segments of the avulsion injured side were harvested to investigate the expression of Bcl-2, c-Jun and growth associated protein 43 by real-time PCR and western blot assay. Results showed that valproic acid significantly increased the expression of Bcl-2 and growth associated protein 43, and reduced the c-Jun expression after brachial plexus avulsion. Our findings indicate that valproic acid can protect neurons in the spinal cord and enhance neuronal regeneration following brachial plexus root avulsion. PMID:25206605

  10. Exposure to antiepileptic drugs in utero and child development

    PubMed Central

    Veiby, Gyri; Daltveit, Anne Kjersti; Schjølberg, Synnve; Stoltenberg, Camilla; Øyen, Anne-Siri; Vollset, Stein Emil; Engelsen, Bernt A.; Gilhus, Nils Erik

    2013-01-01

    Summary Purpose Antiepileptic drugs may cause congenital malformations. Less is known about the effect on development in infancy and childhood. The aim of this study was to examine whether exposure to antiepileptic drugs during pregnancy has an impact on early child development. Methods From mid-year 1999 through December 2008, children of mothers recruited at 13–17 weeks of pregnancy were studied in the ongoing prospective Norwegian Mother and Child Cohort Study. Information on birth outcomes were obtained from the Medical Birth Registry (108,264 –children), and mothers reported on their child’s motor development, language, social skills, and autistic traits using items from standardized screening tools at 18 months (61,351 children) and 36 months of age (44,147 children). The relative risk of adverse outcomes in children according to maternal or paternal epilepsy with and without prenatal exposure to antiepileptic drugs was estimated as odds ratios (ORs), using logistic regression with adjustment for maternal age, parity, education, smoking, depression/anxiety, folate-supplementation, and child congenital malformation or low birth weight. Key findings A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, the exposed children had increased risk of abnormal scores for gross motor skills (7.1 % vs. 2.9 %; OR, 2.0; 95 % Confidence Interval [CI], 1.1–3.7) and autistic traits (3.5 % vs. 0.9 %; OR, 2.7; CI, 1.1–6.7) compared to children of parents without epilepsy. At 36 months, the exposed children had increased risk of abnormal score for gross motor skills (7.5 % vs. 3.3 %; OR, 2.2; CI, 1.1–4.2), sentence skills (11.2 % vs. 4.8 %; OR, 2.1; CI, 1.2–3.6), and autistic traits (6.0 % vs. 1.5 %; OR, 3.4; CI, 1.6–7.0). The drug-exposed children also had increased risk of congenital malformations (6.1 % vs. 2.9 %; OR, 2.1; CI, 1.4–3.4), but exclusion of congenital malformations did not affect the risk of adverse development

  11. Access to antiepileptic drug therapy in children in Camagüey Province, Cuba

    PubMed Central

    Arencibia, Zeina Bárzaga; Leyva, Alberto López; Peña, Yordanka Mejías; Reyes, Alba Rosa González; Nápolez, Maurilys Acosta; Carbonell Perdomo, Demetrio; Manzano, Edita Fernández; Choonara, Imti

    2012-01-01

    Objective To describe access to antiepileptic drug therapy and estimate the prevalence of epilepsy in children in Camagüey Province, Cuba. Methods All the community pharmacies in the province were visited and information collected about the number of children receiving antiepileptic drugs in 2009. Availability and cost of each antiepileptic drug were determined. The prevalence of epilepsy was estimated by determining the number of children receiving antiepileptic drugs. Results There were 923 children who received a total of 977 antiepileptic drugs in Camagüey Province. The estimated prevalence of epilepsy was 5.18 per thousand children which is lower than previously reported rates in other low and lower-middle income countries. Most of the children (871, 94%) received a single antiepileptic drug. Carbamazepine and valproate were the two most frequently prescribed antiepileptic drugs. Antiepileptic drugs were available from the local pharmacy on 76% of occasions. If the antiepileptic drug was not available from the local pharmacy, the parent had to travel to another pharmacy to obtain the medicine. Conclusions The estimated prevalence of epilepsy in children in Cuba is lower than that estimated in other lower-middle income countries. Access to drug therapy in children with epilepsy can be achieved in lower-middle income countries. PMID:23134098

  12. Analysis of Valproic Acid, Salicylic Acid and Ibuprofen in Whole Blood by GC-MS.

    PubMed

    Stephenson, Jon B; Flater, Melanie L; Bain, Lisa T

    2016-10-01

    The Georgia Bureau of Investigation utilized a silylation method of analysis for low molecular weight carboxylic acids in the past. Due to the negative impact such derivatizations can have on gas chromatography-mass spectrometry (GC-MS) systems an alternative means of analysis was investigated. The described method is a whole blood solid phase extraction of valproic acid, salicylic acid and ibuprofen utilizing butylation for sensitivity and improved chromatography by GC-MS. The method produced a limit of detection and limit of quantitation at 1 mg/L for valproic acid, 2 mg/L for salicylic acid and 0.25 mg/L for ibuprofen. The variability based upon the middle of the calibration curve estimated to be 7% for valproic acid, 8% for salicylic acid and 11% for ibuprofen established upon a 95% confidence interval, with the highest percent coefficient of variation being 5.3% for ibuprofen.

  13. Toxicity of valproic acid in isolated rat liver mitochondria.

    PubMed

    Jafarian, Iman; Eskandari, Mohammad Reza; Mashayekhi, Vida; Ahadpour, Morteza; Hosseini, Mir-Jamal

    2013-10-01

    Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug, is widely used for the treatment of different types of seizures and myoclonic epilepsy. Several mechanisms have been suggested for VPA hepatotoxicity, and most of them are associated with oxidative stress. It seems that oxidative stress by VPA treatment has been associated with mitochondrial dysfunction. Therefore, this study investigated the mitochondrial toxicity mechanisms of VPA on freshly isolated rat mitochondria for better understanding pathogenesis of VPA in mitochondrial toxicity. Rat liver mitochondria were obtained by differential ultracentrifugation and were then incubated with different concentrations of VPA (25-200 µM). Our results showed that VPA could induce oxidative stress via rising in mitochondrial reactive oxygen species formation, lipid peroxidation, mitochondrial membrane potential collapse, mitochondrial swelling and finally release of cytochrome c. These effects were well inhibited by pretreatment of isolated mitochondria with cyclosporin A and butylated hydroxytoluene. Based on these results, it is clear that VPA exerts mitochondrial toxicity by impairing mitochondrial functions leading to oxidative stress and cytochrome c expulsion, which start cell death signaling.

  14. Study of Valproic Acid-Enhanced Hepatocyte Steatosis

    PubMed Central

    Chang, Renin; Chou, Mei-Chia; Hung, Li-Ying; Wang, Mu-En; Hsu, Meng-Chieh; Chiu, Chih-Hsien

    2016-01-01

    Valproic acid (VPA) is one of the most widely used antiepilepsy drugs. However, several side effects, including weight gain and fatty liver, have been reported in patients following VPA treatment. In this study, we explored the molecular mechanisms of VPA-induced hepatic steatosis using FL83B cell line-based in vitro model. Using fluorescent lipid staining technique, we found that VPA enhanced oleic acid- (OLA-) induced lipid accumulation in a dose-dependent manner in hepatocytes; this may be due to upregulated lipid uptake, triacylglycerol (TAG) synthesis, and lipid droplet formation. Real-time PCR results showed that, following VPA treatment, the expression levels of genes encoding cluster of differentiation 36 (Cd36), low-density lipoprotein receptor-related protein 1 (Lrp1), diacylglycerol acyltransferase 2 (Dgat2), and perilipin 2 (Plin2) were increased, that of carnitine palmitoyltransferase I a (Cpt1a) was not affected, and those of acetyl-Co A carboxylase α (Acca) and fatty acid synthase (Fasn) were decreased. Furthermore, using immunofluorescence staining and flow cytometry analyses, we found that VPA also induced peroxisome proliferator-activated receptor γ (PPARγ) nuclear translocation and increased levels of cell-surface CD36. Based on these results, we propose that VPA may enhance OLA-induced hepatocyte steatosis through the upregulation of PPARγ- and CD36-dependent lipid uptake, TAG synthesis, and lipid droplet formation. PMID:27034954

  15. Risk factors for valproic acid resistance in childhood absence epilepsy.

    PubMed

    Ollivier, May Lissa; Dubois, Marie France; Krajinovic, Maja; Cossette, Patrick; Carmant, Lionel

    2009-12-01

    Valproic acid (VPA) is reported to be effective for the control of absence seizures in 75% of children. The aim of this study was to determine the clinical and socio-demographic factors associated with VPA response in newly diagnosed childhood absence epilepsy (CAE) and to determine if these factors also influence the chances of achieving long-term seizure freedom. Medical charts of 180 children with CAE were retrospectively reviewed. Clinical, electroencephalographic and imaging findings were recorded to correlate with complete VPA response and long-term epilepsy outcome. Factors associated with non-responsiveness were identified individually and in a multivariable logistic regression analysis. Treatment was successful in 112 (58.3%) children. More children that were non-responsive to VPA experienced generalized tonic clonic seizures (GTCS) (33.8% vs. 13.4% for responders; p=0.001) and 52.9% had a pre-treatment seizure frequency greater than 10/day (vs. 27.0% for responders; p<0.001). Finally, responders were older at time of diagnosis versus non-responders (p=0.001). Absence of long-term seizure freedom was linked to the presence of GTCS, the absence of initial response and the need for multiple AEDs to control seizures. Our results suggest that clinical phenotypes are associated with reduced response rates to VPA. This should be taken into account when counselling families of children with newly diagnosed absence epilepsy.

  16. Valproic acid enforces the priming effect of sphingosine-1 phosphate on human mesenchymal stem cells.

    PubMed

    Lim, Jisun; Lee, Seungun; Ju, Hyein; Kim, Yonghwan; Heo, Jinbeom; Lee, Hye-Yeon; Choi, Kyung-Chul; Son, Jaekyoung; Oh, Yeon-Mok; Kim, In-Gyu; Shin, Dong-Myung

    2017-09-01

    Engraftment and homing of mesenchymal stem cells (MSCs) are modulated by priming factors including the bioactive lipid sphingosine-1-phosphate (S1P), by stimulating CXCR4 receptor signaling cascades. However, limited in vivo efficacy and the remaining priming molecules prior to administration of MSCs can provoke concerns regarding the efficiency and safety of MSC priming. Here, we showed that valproic acid (VPA), a histone deacetylase inhibitor, enforced the priming effect of S1P at a low dosage for human umbilical cord-derived MSCs (UC-MSCs). A DNA-methylation inhibitor, 5-azacytidine (5-Aza), and VPA increased the expression of CXCR4 in UC-MSCs. In particular, UC-MSCs primed with a suboptimal dose (50 nM) of S1P in combination with 0.5 mM VPA (VPA+S1P priming), but not 1 µM 5-Aza, significantly improved the migration activity in response to stromal cell-derived factor 1 (SDF-1) concomitant with the activation of both MAPKp42/44 and AKT signaling cascades. Both epigenetic regulatory compounds had little influence on cell surface marker phenotypes and the multi-potency of UC-MSCs. In contrast, VPA+S1P priming of UC-MSCs potentiated the proliferation, colony forming unit-fibroblast, and anti-inflammatory activities, which were severely inhibited in the case of 5-Aza treatment. Accordingly, the VPA+S1P-primed UC-MSCs exhibited upregulation of a subset of genes related to stem cell migration and anti-inflammation response. Thus, the present study demonstrated that VPA enables MSC priming with S1P at a low dosage by enhancing their migration and other therapeutic beneficial activities. This priming strategy for MSCs may provide a more efficient and safe application of MSCs for treating a variety of intractable disorders.

  17. Valproic acid related idiosyncratic drug induced hepatotoxicity in a glioblastoma patient treated with temozolomide.

    PubMed

    Neyns, Bart; Hoorens, Anne; Stupp, Roger

    2008-12-01

    Glioblastoma patients undergoing treatment with surgery followed by radiation and temozolomide chemotherapy often develop a state of immunosuppression and are at risk for opportunistic infections and reactivation of hepatitis and herpes viruses. We report the case of a 48-year-old glioblastoma patient who developed acute cholestatic hepatitis with hepatic failure during adjuvant treatment with temozolomide and the integrin inhibitor cilengitide. A viral hepatitis was excluded and valproic acid treatment was stopped. Upon normalisation of the liver tests, temozolomide treatment was resumed without perturbation of the liver tests. Valproic acid related idiosyncratic drug induced hepatotoxicity should be considered as a differential diagnosis in glioblastoma patients undergoing adjuvant therapy.

  18. Could valproic acid be an effective anticancer agent? The evidence so far.

    PubMed

    Brodie, Seth A; Brandes, Johann C

    2014-10-01

    Valproic acid is an inhibitor of class I histone deacetylases. Epigenetic therapies in cancer have been focus of a keen interest and histone deacetylase inhibitors, in particular, have been approved for certain types of hematologic malignancies. Valproic acid is an attractive candidate for cancer therapy due to its mechanism of action, its low cost and generally good clinical tolerability. In the following editorial, we will review its role as monotherapy for cancer, its place in combination epigenetic therapy, and its role as chemosensitizer, and cancer preventative agent.

  19. Pharmacy and generic substitution of antiepileptic drugs: missing in action?

    PubMed

    Welty, Timothy E

    2007-06-01

    Generic substitution of antiepileptic drugs is an issue that is gathering a lot of attention in the neurology community but is not receiving much attention within pharmacy. Several proposals have been drafted that restrict a pharmacist's decision-making in generic substitution. These proposals highlight concerns about the pharmacy community related to generic substitution. Careful consideration needs to be given to these issues by pharmacists and pharmacy professional organizations. Unless pharmacy as a profession takes strong positions in support of a pharmacist's ability to make decisions about pharmacotherapy and addresses many of the pharmacy-related problems of generic substitution, policies that negatively impact pharmacy will be established.

  20. The rise and fall of borax as an antiepileptic drug.

    PubMed

    Jensen, John P A

    2006-04-01

    Five hundred eighty-six patients with epilepsy were treated with borax (hydrated sodium tetraborate) between 1912 and 1948 at the Kolonien Filadelfia Epilepsy Hospital, Dianalund, Denmark. A rough estimation shows that less than 5% experienced a more than 50% reduction in the total number of seizures. Charts were reviewed to find a connection between the concept of Bacillus epilepticus (1916) and the so-called renaissance of borax treatment described in 1923, and to find an explanation for the popularity of this seemingly ineffective antiepileptic drug.

  1. Therapeutic strategies in the choice of antiepileptic drugs.

    PubMed

    de Borchgrave, V; Delvaux, V; de Tourchaninoff, M; Dubru, J M; Ghariani, S; Grisar, Th; Legros, B; Ossemann, M; Sadzot, B; Tugendhaft, P; Van Bogaert, P; van Rijckevorsel, K

    2002-03-01

    The choice of treatment of newly diagnosed epilepsy involves many factors such as age, sex, life style, general health and concomitant medication. The seizure type, syndrome, and the pharmacology, efficacy and safety of the antiepileptic drugs (AEDs) should also be considered. Some of the new AEDs appear to provide at least equivalent efficacy with better tolerability. Some of these drugs have the potential to become drugs of first choice in newly diagnosed epilepsy. At the present time, we also must consider the criteria of reimbursement of these drugs. In this paper, we try to describe common and practical strategies to start a treatment of newly diagnosed epilepsy.

  2. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma

    SciTech Connect

    Krauze, Andra V.; Chang, Michael G.; Holdford, Diane J.; Smith, Sharon; Shih, Joanna; Tofilon, Philip J.; Camphausen, Kevin

    2015-08-01

    Purpose: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. Conclusions: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.

  3. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid For Patients With Glioblastoma

    PubMed Central

    Krauze, Andra V.; Myrehaug, Sten D.; Chang, Michael G.; Holdford, Diane J.; Smith, Sharon; Shih, Joanna; Tofilon, Philip J.; Fine, Howard A.; Camphausen, Kevin

    2015-01-01

    Purpose Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in pre-clinical models. We evaluated the addition of VPA to standard radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21–63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8–51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis results were significant for both OS and PFS. VPA levels were not correlated with grade 3/4 toxicity levels. Conclusions Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study. PMID:26194676

  4. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma.

    PubMed

    Krauze, Andra V; Myrehaug, Sten D; Chang, Michael G; Holdford, Diane J; Smith, Sharon; Shih, Joanna; Tofilon, Philip J; Fine, Howard A; Camphausen, Kevin

    2015-08-01

    Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study. Published by Elsevier Inc.

  5. Enzyme induction in neonates after fetal exposure to antiepileptic drugs

    SciTech Connect

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

    1983-01-01

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

  6. sec-Butylpropylacetamide (SPD), a new amide derivative of valproic acid for the treatment of neuropathic and inflammatory pain.

    PubMed

    Kaufmann, Dan; West, Peter J; Smith, Misty D; Yagen, Boris; Bialer, Meir; Devor, Marshall; White, H Steve; Brennan, K C

    2017-03-01

    Chronic pain is a multifactorial disease comprised of both inflammatory and neuropathic components that affect ∼20% of the world's population. sec-Butylpropylacetamide (SPD) is a novel amide analogue of valproic acid (VPA) previously shown to possess a broad spectrum of anticonvulsant activity. In this study, we defined the pharmacokinetic parameters of SPD in rat and mouse, and then evaluated its antinociceptive potential in neuropathic and acute inflammatory pain models. In the sciatic nerve ligation (SNL) model of neuropathic pain, SPD was equipotent to gabapentin and more potent than its parent compound VPA. SPD also showed either higher or equal potency to VPA in the formalin, carrageenan, and writhing tests of inflammatory pain. SPD showed no effects on compound action potential properties in a sciatic nerve preparation, suggesting that its mechanism of action is distinct from local anesthetics and membrane stabilizing drugs. SPD's activity in both neuropathic and inflammatory pain warrants its development as a potential broad-spectrum anti-nociceptive drug.

  7. Epigenetic modifications in valproic acid-induced teratogenesis

    SciTech Connect

    Tung, Emily W.Y.; Winn, Louise M.

    2010-11-01

    Exposure to the anticonvulsant drug valproic acid (VPA) in utero is associated with a 1-2% increase in neural tube defects (NTDs), however the molecular mechanisms by which VPA induces teratogenesis are unknown. Previous studies demonstrated that VPA, a direct inhibitor of histone deacetylase, can induce histone hyperacetylation and other epigenetic changes such as histone methylation and DNA demethylation. The objective of this study was to determine if maternal exposure to VPA in mice has the ability to cause these epigenetic alterations in the embryo and thus contribute to its mechanism of teratogenesis. Pregnant CD-1 mice (GD 9.0) were administered a teratogenic dose of VPA (400 mg/kg, s.c.) and embryos extracted 1, 3, 6, and 24 h after injection. To assess embryonic histone acetylation and histone methylation, Western blotting was performed on whole embryo homogenates, as well as immunohistochemical staining on embryonic sections. To measure DNA methylation changes, the cytosine extension assay was performed. Results demonstrated that a significant increase in histone acetylation that peaked 3 h after VPA exposure was accompanied by an increase in histone methylation at histone H3 lysine 4 (H3K4) and a decrease in histone methylation at histone H3 lysine 9 (H3K9). Immunohistochemical staining revealed increased histone acetylation in the neuroepithelium, heart, and somites. A decrease in methylated histone H3K9 staining was observed in the neuroepithelium and somites, METHYLATED histone H3K4 staining was observed in the neuroepithelium. No significant differences in global or CpG island DNA methylation were observed in embryo homogenates. These results support the possibility that epigenetic modifications caused by VPA during early mouse organogenesis results in congenital malformations.

  8. [Valproic acid-induced idiosyncratic liver injury in 4 cases].

    PubMed

    Xiong, Hui; Liu, Chen-tao; Zhang, Yue-hua; Bao, Xin-hua; Jiang, Yu-wu; Zhao, Hong; Wu, Xiao-ping; Qin, Jiong

    2012-12-01

    Children with refractory epilepsy who suffered from severe liver function impairment during valproic acid (VPA) treatment at routine dosage were studied. The clinical manifestations and therapeutic approaches were investigated in order to improve its diagnosis and management. Clinical information as well as features and management of 4 inpatients who were suffered from intractable epilepsy with severe liver function impairment induced by VPA since 2006 were collected and analyzed, including age of onset of epilepsy, VPA using age and the time when liver injury occurred, clinical manifestations, auxiliary examinations and management. Among the 4 cases, three were male and one was female. The admitted age ranged from 1 - 9 years and 1 month. The course of disease was 25 d - 6 months. They manifested as refractory epilepsy of epilepsia partialis continua which was difficult to control. After using VPA for 62 d (50 - 76 d), all developed severe impairment of liver synthetic function which was not related to the concentration of VPA. One was diagnosed with Alpers syndrome, two were suspicious of Alpers syndrome, and the other was diagnosed gliocytoma after brain biopsy. VPA was stopped immediately and symptomatic therapies were used. Other than that, intravenous injection of L-carnitine in 3 cases recovered the liver function. VPA-associated severe hepatotoxicity can manifest first as impaired liver synthetic function. Besides alanin transaminase and aspartate transaminase, the liver synthetic function test is more important than monitoring of liver enzymatic functions in monitoring for the hepatotoxicity. Intravenous injection of L-carnitine in early stage showed good treatment effect.

  9. Epigenetic modifications in valproic acid-induced teratogenesis.

    PubMed

    Tung, Emily W Y; Winn, Louise M

    2010-11-01

    Exposure to the anticonvulsant drug valproic acid (VPA) in utero is associated with a 1-2% increase in neural tube defects (NTDs), however the molecular mechanisms by which VPA induces teratogenesis are unknown. Previous studies demonstrated that VPA, a direct inhibitor of histone deacetylase, can induce histone hyperacetylation and other epigenetic changes such as histone methylation and DNA demethylation. The objective of this study was to determine if maternal exposure to VPA in mice has the ability to cause these epigenetic alterations in the embryo and thus contribute to its mechanism of teratogenesis. Pregnant CD-1 mice (GD 9.0) were administered a teratogenic dose of VPA (400mg/kg, s.c.) and embryos extracted 1, 3, 6, and 24h after injection. To assess embryonic histone acetylation and histone methylation, Western blotting was performed on whole embryo homogenates, as well as immunohistochemical staining on embryonic sections. To measure DNA methylation changes, the cytosine extension assay was performed. Results demonstrated that a significant increase in histone acetylation that peaked 3h after VPA exposure was accompanied by an increase in histone methylation at histone H3 lysine 4 (H3K4) and a decrease in histone methylation at histone H3 lysine 9 (H3K9). Immunohistochemical staining revealed increased histone acetylation in the neuroepithelium, heart, and somites. A decrease in methylated histone H3K9 staining was observed in the neuroepithelium and somites, METHYLATED histone H3K4 staining was observed in the neuroepithelium. No significant differences in global or CpG island DNA methylation were observed in embryo homogenates. These results support the possibility that epigenetic modifications caused by VPA during early mouse organogenesis results in congenital malformations.

  10. Proteomic analysis of MOLT-4 cells treated by valproic acid.

    PubMed

    Vávrová, Jirina; Janovská, Sylva; Rezácová, Martina; Hernychová, Lenka; Tichá, Zuzana; Vokurková, Doris; Záskodová, Darina; Lukásová, Emilie

    2007-09-01

    The effect of valproic acid (VA) on protein expression in human T-lymphocytic leukemia cells MOLT-4 was studied. VA is an inhibitor of histonedeacetylases and has a potential use as antitumor agent in leukemia treatment. The authors in this work prove that 4 h long incubation with 2 mmol/l VA causes phosphorylation of histone H2A.X and its colocalization with 53BP1 in nuclear foci. Their co-localization is typical for DSB signaling machinery. These foci were detected in cells after 4 h exposure without increase of Annexin V positive apoptotic cells. Slight increase in apoptosis (Annexin V positivity) after 24 h is accompanied by more intensive increase in phosphorylation of H2A.X and also by formation of nuclear foci containing gammaH2A.X and 53BP1. Treatment of cells with 2 mmol/l VA resulted in induction of apoptosis affecting about 30% of cells after incubation for 72 h. The changes in protein expression were examined after cell incubation with 2 mmol/l VA for 4 h. Proteins were separated by two-dimensional electrophoresis and quantified using image evaluation system. Those exhibiting significant VA-induced abundance alterations were identified by mass spectrometry. Changes in expression of 22 proteins were detected, of which 15 proteins were down-regulated. Proteomic analysis resulted in successful identification of three proteins involving alfa-tubulin 3, tubulin-specific chaperone and heterogeneous nuclear ribonucloprotein F. Expression of seven proteins was up-regulated, including heterogeneous nuclear ribonucloprotein A/B. Identified proteins are related to microtubular system and hnRNP family. Suppression of microtubular proteins and changes of balance among hnRNPs can contribute to proliferation arrest and apoptosis induction.

  11. Propafenone enhances the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock model.

    PubMed

    Banach, Monika; Piskorska, Barbara; Borowicz-Reutt, Kinga K

    2016-06-01

    Antiarrhythmic and antiepileptic drugs share some mechanisms of actions. Therefore, possibility of interactions between these in epileptic patients with cardiac arrhythmias is quite considerable. Herein, we attempted to assess interactions between propafenone and four conventional antiepileptic drugs: carbamazepine, valproate, phenytoin and phenobarbital. Effects of propafenone on seizures were determined in the electroconvulsive threshold test in mice. Interactions between propafenone and antiepileptic drugs were estimated in the model of maximal electroshock. Motor coordination was evaluated in the chimney test, while long-term memory in the passive-avoidance task. Brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. Propafenone up to 50mg/kg did not affect the electroconvulsive threshold, significantly enhancing this parameter at doses of 60-90mg/kg. Applied at its subthreshold doses, propafenone potentiated the antielectroshock action of all four tested classical antiepileptics: carbamazepine, valproate, phenytoin, and phenobarbital. Propafenone alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory in mice. Propafenone did not change brain concentration of phenytoin and phenobarbital; however, it significantly decreased brain levels of carbamazepine and increased those of valproate. Propafenone exhibits its own anticonvulsant effect and enhances the action of classical antiepileptic drugs against electrically induced convulsions in mice. Further investigations are required to determine the effect of propafenone on antiepileptic therapy in humans. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  12. Preparation of Coated Valproic Acid and Sodium Valproate Sustained-release Matrix Tablets

    PubMed Central

    Phaechamud, T.; Mueannoom, W.; Tuntarawongsa, S.; Chitrattha, S.

    2010-01-01

    The aim of this research was to investigate the technique for preparation of coated valproic acid and sodium valproate sustained-release matrix tablets. Different diluents were tested and selected as the effective absorbent for oily valproic acid. Effect of the amount of absorbent and hydroxypropylmethylcellulose on drug release from valproic acid-sodium valproate matrix tablets prepared with wet granulation technique was evaluated in pH change system. Colloidal silicon dioxide effectively adsorbed liquid valproic acid during wet granulation and granule preparation. The amounts of colloidal silicon dioxide and hydroxypropylmethylcellulose employed in tablet formulations affected drug release from the tablets. The drug release was prominently sustained for over 12 h using hydroxypropylmethylcellulose-based hydrophilic matrix system. The mechanism of drug release through the matrix polymer was a diffusion control. The drug release profile of the developed matrix tablet was similar to Depakine Chrono®, providing the values of similarity factor (f2) and difference factor (f1) of 85.56 and 2.37, respectively. Eudragit® L 30 D-55 was used as effective subcoating material for core matrix tablets before over coating with hydroxypropylmethylcellulose film with organic base solvent. Drug release profile of coated matrix tablet was almost similar to that of Depakine Chrono®. PMID:20838520

  13. Effects of Switching from Depakene to Generic Valproic Acid on Individuals with Mental Retardation.

    ERIC Educational Resources Information Center

    Vadney, Victor J.; Kraushaar, Kevin W.

    1997-01-01

    Comparison of brand-name Depakene with generic valproic acid medication to control seizures in 64 subjects with mental retardation living in an intermediate care facility found no statistically significant differences in seizures or blood levels. Results suggest use of the generic medication can result in substantial cost savings. (Author/DB)

  14. Drug Reaction With Eosinophilia and Systemic Symptoms Induced by Valproic Acid: A Case Report

    PubMed Central

    Darban, Mahboubeh; Bagheri, Bahador

    2016-01-01

    Introduction Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but life-threatening reaction to drugs such as carbamazepine and allopurinol. The condition is characterized by skin rashes, fever, hematological disturbances, lymphadenopathy, and organ failure, most probably hepatic dysfunction. To date, only a few cases of valproate-induced DRESS syndrome have been reported. Case Presentation We report on the case of a 60-year-old man who had been treated with valproic acid some time before being referred to Kowsar Hospital, Semnan, Iran in December 2015. He was given valproic acid 1000 mg PO, and after 20 days, he had developed widespread rashes, fever, esophagitis, cervical lymphadenopathy, and tender hepatomegaly. Laboratory results at Kowsar showed a drop in hemoglobin, in addition to lymphocytosis, thrombocytopenia, and elevated serum transaminases. DRESS was diagnosed, and corticosteroid therapy was initiated. Administration of the culprit drug to the patient was also stopped. Intravenous immunoglobulin (IVIG) improved the general condition of the patient. Conclusions Only a small number of case reports have described valproic acid-induced DRESS syndrome; therefore, the condition is difficult to prevent. Rechallenge with valproic acid should be avoided in patients with a history of reaction to the drug. PMID:28144463

  15. The Histone Deacetylase Inhibitor Valproic Acid Enhances Acquisition, Extinction, and Reconsolidation of Conditioned Fear

    ERIC Educational Resources Information Center

    Bredy, Timothy W.; Barad, Mark

    2008-01-01

    Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its…

  16. Preparation of Coated Valproic Acid and Sodium Valproate Sustained-release Matrix Tablets.

    PubMed

    Phaechamud, T; Mueannoom, W; Tuntarawongsa, S; Chitrattha, S

    2010-03-01

    The aim of this research was to investigate the technique for preparation of coated valproic acid and sodium valproate sustained-release matrix tablets. Different diluents were tested and selected as the effective absorbent for oily valproic acid. Effect of the amount of absorbent and hydroxypropylmethylcellulose on drug release from valproic acid-sodium valproate matrix tablets prepared with wet granulation technique was evaluated in pH change system. Colloidal silicon dioxide effectively adsorbed liquid valproic acid during wet granulation and granule preparation. The amounts of colloidal silicon dioxide and hydroxypropylmethylcellulose employed in tablet formulations affected drug release from the tablets. The drug release was prominently sustained for over 12 h using hydroxypropylmethylcellulose-based hydrophilic matrix system. The mechanism of drug release through the matrix polymer was a diffusion control. The drug release profile of the developed matrix tablet was similar to Depakine Chrono(®), providing the values of similarity factor (f2) and difference factor (f1) of 85.56 and 2.37, respectively. Eudragit(®) L 30 D-55 was used as effective subcoating material for core matrix tablets before over coating with hydroxypropylmethylcellulose film with organic base solvent. Drug release profile of coated matrix tablet was almost similar to that of Depakine Chrono(®).

  17. The Histone Deacetylase Inhibitor Valproic Acid Enhances Acquisition, Extinction, and Reconsolidation of Conditioned Fear

    ERIC Educational Resources Information Center

    Bredy, Timothy W.; Barad, Mark

    2008-01-01

    Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its…

  18. Effectiveness and Cost of Generic versus Brand-Name Valproic Acid.

    ERIC Educational Resources Information Center

    Coulter, David L.

    1997-01-01

    This commentary on a study comparing use of the brand-name drug Depakene with generic valproic acid to control seizures in people with mental retardation notes the importance of distinguishing between Depakene and Depakote, which is an enteric-coated formulation for which there is no generic form currently available. (DB)

  19. Valproic acid malabsorption in 30 year-old female patient - Case study.

    PubMed

    Jopowicz, Anna; Piechal, Agnieszka; Kurkowska-Jastrzębska, Iwona

    Valproic acid (VPA) is used in epilepsy treatment and as a stabilizer in bipolar affective disorder for over 40 years. Although, the pharmacokinetic properties of valproic acid are well known, it is often forgotten that the formulation of the drug significantly influences its gastrointestinal absorption. We are describing the case of 30 year-old female patient, diagnosed at the age of 13 with juvenile myoclonic epilepsy. Complete ineffectiveness of the treatment was caused by malabsorption of sodium valproate and valproic acid in the patient. The change of the drug formulation resulted in a several times higher bioavailability of the drug and a partial improvement of the patient's clinical condition. Low concentration of valproic acid after administration the slow-released tablets are usually observed. However, a low bioavailability beside the bad compliance should be considered when the minimal level is extremely low during therapy. It is known that form of the drug, beside presence of food and its components, as well as gastrointestinal tract condition or interactions with other drugs can influence the drug level. Modification of the formulation of the drug may lead to improvement of absorption and increase its effectiveness. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

  20. AT-33A PHASE II STUDY OF CONCURRENT RADIATION THERAPY, TEMOZOLOMIDE AND THE HISTONE DEACETYLASE INHIBITOR VALPROIC ACID FOR PATIENTS WITH GLIOBLASTOMA MULTIFORME

    PubMed Central

    Krauze, Andra V.; Myrehaug, Sten D.; Chang, Michael G.; Holdford, Diane J.; Smith, Sharon; Shih, Joanna; Tofilon, Peter; Fine, Howard; Camphausen, Kevin A.

    2014-01-01

    BACKGROUND: Glioblastoma (GBM) remains an aggressive brain tumor with poor prognosis. Valproic acid (VPA) is an antiepileptic agent that has been shown to have HDACi activity and to radiosensitize GBM cells in preclinical models. This phase II study aimed to determine if the addition of VPA to standard radiation therapy and temozolomide would improve OS and PFS. METHODS: We prospectively assessed survival, radiological and clinical progression in 37 newly diagnosed glioblastoma patients with the administration of VPA at 25 mg/kg orally BID concurrent with radiation therapy (RT) and temozolomide (TMZ). The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently tapered up to 25 mg/kg/day over the week prior to radiation. RESULTS: 81% of patients took VPA according to protocol. Median OS was 29.6 months (21- 63.8), median PFS was 10.5 (6.8 - 51.2). OS at 6, 12, 24 months was 97%, 86%, 56% respectively. PFS at 6, 12, 24 months was 70%, 43%, 38% respectively. The most common grade 3 or 4 toxicities of VPA in conjunction with TMZ were blood/ bone marrow toxicity (32%), neurological (11%), metabolic/laboratory (8%). At the end of the study 26 (70%) patients were dead, 7 were live without disease, 4 alive with disease. Younger age (<= 50 years) compared to older age and class V RPA were significant for both OS and PFS. Using a landmark analysis, an early progression was related to a shorter interval between progression and death, whereas, a later progression was related to a longer interval between progression and death (p = 0.0002) HR 4.7. CONCLUSION: The addition of VPA to concurrent RT and TMZ in the treatment of newly diagnosed GBM may result in superior outcomes as compared to contemporary and historical data and merits further study.

  1. Steady-state pharmacokinetic simulation of intermittent vs. continuous infusion valproic acid therapy in non-critically ill and critically ill patients.

    PubMed

    Van Matre, Edward T; Cook, Aaron M

    2016-09-01

    Valproic acid (VPA) is a broad-spectrum antiepileptic drug used for a variety of neurologic disorders. The relatively short half-life seen with intermittent intravenous bolus doing may lead to serum concentration variability. Continuous infusion VPA therapy is an approach to mitigate these effects. The objective of this study is to characterize the pharmacokinetics of continuous infusion of VPA in acutely ill patients and to determine dosing regimens that most frequently obtain goal steady-state serum concentrations. This is a retrospective pharmacokinetics study in adult patients receiving continuous infusion VPA per institutional protocol for seizure or status migrainosus. Pharmacokinetic parameters were reviewed for 234 patients (25 critically ill) and compared between the two groups (non-critically ill vs. critically ill). Intermittent and continuous infusion dosing strategies were modeled utilizing Monte Carlo simulations for both cohorts. Frequencies of serum concentration attainment were reported. The percent target attainment for the non-critically ill group and critically ill group were 69.4 and 58.3% (p = 0.282) post-loading dose and 69.7 and 37.5% (p = 0.004) steady state, respectively. The volume of distribution was significantly different between the two groups (0.35 vs. 0.68 L/kg, p = < 0.0001). Highest frequency of target attainment (50-100 mcg/ml) occurred in the continuous infusion 2 mg/kg/h simulation for both critically ill (45.19%) and acutely ill (48.16%) groups. Critically ill patients have an increased volume of distribution. Increasing the volume of distribution requires higher loading doses of VPA to obtain desired therapeutic concentrations. Continuous infusion VPA provides more consistent serum steady-state concentrations while mitigating pharmacokinetic variability.

  2. A physiologically based pharmacokinetic model for Valproic acid in adults and children.

    PubMed

    Ogungbenro, Kayode; Aarons, Leon

    2014-10-15

    Valproic acid is an anti-convulscant drug that is widely used in the treatment of different types of epilepsy and since its introduction the clinical use has increased rapidly both as a sole agent and in combination therapies. The mechanism of action has been linked to blockade of voltage-dependent sodium channels and potentiation of GABAergic transmission. The most widely used route of administration of Valproic acid is oral, although it can also be given intravenously and rectally and its pharmacokinetics has been studied extensively. The aim of this work was to develop a physiologically based pharmacokinetic model for plasma and tissue/organ prediction in children and adults following intravenous and oral dosing of Valproic acid. The plasma/tissue concentration profile will be used for clinical trial simulation in Dravet syndrome, a rare form of epilepsy in children where the combination of Valproic acid, stiripentol and clobazam has shown remarkable results. A physiologically based pharmacokinetic model was developed with compartments for gut lumen, enterocyte, gut tissue, systemic blood, kidney, liver, brain, spleen, muscle and rest of body. System and drug specific parameters for the model were obtained from the literature from in vitro and in vivo experiments. The model was initially developed for adults and scaled to children using age-dependent changes in anatomical and physiological parameters and ontogeny functions for enzyme maturation assuming the same elimination pathways in adults and children. The results from the model validation showed satisfactory prediction of plasma concentration both in terms of mean prediction and variability in children and adults following intravenous and oral dosing especially after single doses. The model also adequately predicts clearance in children. Due to limited distribution of Valproic acid into tissues, the concentration in plasma is about 8-9 times higher than tissues/organs. The model could help to improve

  3. Potential risk factors for vitamin D levels in medium- and long-term use of antiepileptic drugs in childhood.

    PubMed

    Yildiz, Edibe Pempegül; Poyrazoglu, Şükran; Bektas, Gonca; Kardelen, Aslı Derya; Aydinli, Nur

    2017-06-01

    Antiepileptic drugs (AED) have potential side effects through vitamin-D. Prevalence of vitamin D insufficiency and potential risk factors for the longitudinal changes of vitamin D levels compared to its baseline levels under AED treatment were investigated in this study. This retrospective study includes patients whose AED therapy were started in only autumn months, between 2000 and 2014. Detailed assessment of neurologic diagnosis and brain MRI findings, ambulatory status, types and durations of AED treatment, and baseline bone health blood tests (vitamin-D, alkaline phosphatase, calcium, and phosphate levels) were obtained on all patients. Vitamin-D deficiency was defined as 25(OH)D <20 ng/mL, while vitamin-D insufficiency was defined as 25(OH)D between 21 and 29 ng/mL. A total of 172 children (mean age 9.6 ± 4.3 years) were followed up 5.3 years in average (range 1-14.7). The mean baseline 25(OH)D level was decreased from 24.4 ± 11.6 to 19.6 ± 10.7 ng/mL at the last follow up. The mean change in the vitamin-D levels (ΔD-vitamin) was -4.8 ng/mL (p = 0.003). The rate of vitamin-D deficiency was 54% and insufficiency was 25%. Multivariate logistic regression analysis identified only long-term use of AEDs as a risk factor for the longitudinal decrease. Monotherapy with valproic acid (n = 45), carbamazepine (n = 20), levetiracetam (n = 10) and phenobarbital (n = 12) was compared with each other. There was no difference in terms of longitudinal changes in 25(OH)D levels. In the treatment of childhood epilepsy, 25(OH)D levels should be monitored, especially when long-term AED used, in order to prevent D-hypovitaminosis.

  4. Epilepsy as a pyridoxine-dependent condition: quantified urinary biomarkers for status evaluation and monitoring antiepileptic treatment.

    PubMed

    Dolina, Svetlana; Margalit, Dov; Malitsky, Sergey; Pressman, Eugeny; Rabinkov, Aharon

    2012-08-01

    The study testifies an assumption on epilepsy as an inborn error of pyridoxine metabolism and suggests non-invasive quantitative biomarkers for clarified evaluation of clinical status and monitoring an individual treatment by antiepileptic drugs. Urinary parameters of pyridoxal-phosphate (PLP)-dependent tryptophan degradation and the level of 4-pyridoxic acid, the end product of pyridoxine metabolism, were measured by HPLC method with simultaneous ultraviolet and fluorimetric detection in children with different forms of epilepsy and matched healthy controls. The concentrations of compounds formed or metabolized in the course of tryptophan degradation (kynurenines, indoxyl-sulfate) along with correlations between them turned out to be quantitative biomarkers useful for both clarifying patient's clinical state and monitoring antiepileptic treatment. In particular, the value of the ratio of 4-pyridoxic acid to kynurenine appears to be an index of an experienced seizure attack, while the ratio of 3-hydroxyanthranilic acid to 3-hydroxykynurenine reflects activity of kynureninase, the enzyme of critical sensitivity to PLP supply. Growing progressively worse, epilepsy is accompanied by aggravation of PLP-dependent disturbances of tryptophan metabolism and expanding inhibition of kynureninase. The affected pyridoxine metabolism is discussed as an inborn genetic trait in epilepsy in general, rather than a specific sign of pyridoxine-dependent epilepsy solely.

  5. [Clinical trial with a new anti-epileptic: barbexaclone].

    PubMed

    Bragatti, J H; Caleffi, G H; Prenna, F J

    1977-09-01

    A new anti-epileptic agent (barbexaclone) was tried in 48 patients suffering from epilepsy and presenting a total of 67 types of crises. All the patients were considered "bad cases" because either by the intensity of the epileptic manifestations or by their refractoriness to the usual medications. The results, similar to others already published, could be considered as good for grand mal epilepsy both for those convulsions occurring during either the sleeping or waking hours and suggest further observations in focal crises. Though not considered as a first line medication in petit mal seizuras the drug gave excellent results when used as an adjuvant in the supression of absences and the annulation of convulsant effects of some drugs used in petit mal. No toxic reactions were noted, and the side effects, which were never very intense, tended to disappear in the majority of cases with continued use of the drug.

  6. Choosing an antiepileptic. Selecting drugs for older patients with epilepsy.

    PubMed

    Leppik, Ilo E

    2005-11-01

    After age 65, the incidence of epilepsy increases rapidly. Approximately 1.5% of Medicare recipients and 10% of nursing home residents are being treated with antiepileptic drugs (AEDs). The most commonly used AED is phenytoin, a first generation agent. Appropriate drug selection in this population is complicated by the fact that multiple comorbidity is commonplace. Most older patients receive a number of drugs in addition to AEDs. The average nursing home patient receives six additional medications. Age-related issues affecting the choice of an AED include changes in protein binding, decreases in hepatic and renal clearance, and alterations in gastrointestinal absorption. AEDs that do not have drug-drug interactions, are not metabolized by the liver, and are readily absorbed may be better suited for the elderly. This paper reviews the present knowledge base and attempts to develop a more rational approach to AED selection for the elderly.

  7. Antiepileptic drug effects on mood and behavior: molecular targets.

    PubMed

    Perucca, Piero; Mula, Marco

    2013-03-01

    With almost 100 years of clinical experience, antiepileptic drugs (AEDs) remain the mainstay of epilepsy treatment. They suppress epileptic seizures by acting on a variety of mechanisms and molecular targets involved in the regulation of neuronal excitability. These include inhibitory-GABAergic and excitatory-glutamatergic neurotransmission, as well as ion (sodium and calcium) conductance through voltage-gated channels. On the other hand, accruing evidence indicates that these mechanisms and targets are also implicated in the regulation of mood and behavior, which may explain why each AED is associated with specific psychotropic effects. These effects, however, cannot be explained solely on the basis of the known mode of action of each AED, and other mechanisms or targets are likely to be implicated. In this article, we review positive and negative effects of AEDs on mood and behavior, discuss putative underlying mechanisms, and highlight knowledge gaps which should be addressed in future studies.

  8. Antiepileptic hypersensitivity syndrome: clinicians beware and be aware.

    PubMed

    Bessmertny, Olga; Pham, Trinh

    2002-01-01

    Antiepileptic hypersensitivity syndrome is a serious idiosyncratic, non-dose-related adverse reaction reported to occur with phenytoin, phenobarbital, carbamazepine, primidone, and lamotrigine. The reaction usually develops 1 to 12 weeks after initiation of therapy with one of the above agents and is recognized by the classic triad of fever, rash, and internal organ involvement. Immediate discontinuation of the suspected anticonvulsant is essential for good outcome. Patients usually are managed supportively with hydration, antihistamines, H(2)-receptor blockers, and topical corticosteroids. In severe cases, the use of systemic corticosteroids may be necessary. The use of intravenous immune globulin should be limited to severe cases where Kawasaki disease or idiopathic thrombocytopenic purpura cannot be ruled out. Education of health care professionals and patients is imperative to improving outcomes and prevention of this reaction in the future.

  9. Prenatal antiepileptic drug exposure alters seizure susceptibility in rats.

    PubMed

    Sobrian, S K; Nandedkar, A K

    1986-05-01

    An animal model is used to address the issue of prenatal exposure to certain antiepileptic drugs and seizure susceptibility in the offspring. Administration of doses established as median therapeutic doses in humans of phenobarbital, valproate and clonazepam to pregnant rats during the last third of gestation produced sexually dimorphic alterations in pentylenetetrazol (PTZ)-induced seizures as well as in non-convulsive (spontaneous alternation and cliff avoidance) behaviors in the offspring. Altered seizure susceptibility occurred in the absence of overtly recognizable morphological abnormalities and did not appear to reflect differences in the status of circulating drug-binding plasma proteins. Possible neural and/or metabolic mechanisms responsible for these behavioral changes are discussed.

  10. Neurological teratogenic effects of antiepileptic drugs during pregnancy

    PubMed Central

    Nie, Qingmei; Su, Baohua; Wei, Jianping

    2016-01-01

    Epilepsy is one of the few neurologic disorders that requires a constant treatment during pregnancy. Epilepsy affects 0.3–0.8% of pregnant women. Prescription of antiepileptic drugs (AEDs) to pregnant women with epilepsy requires monitoring and maintaining a balance between limiting seizures and decreasing fetal exposure to the potential teratogenic effects. AEDs are also commonly used for psychiatric disorders, pain disorders, and migraines. The types of malformations that can result in fetuses exposed to AEDs include minor anomalies, major congenital malformations, intrauterine growth retardation, cognitive dysfunction, low IQ, microcephaly, and infant mortality. In the present review, we analyzed and summarized the current understanding of neurological development in fetuses that are exposed to various AEDs administered to pregnant epileptic women. PMID:27698740

  11. Requirements for generic antiepileptic medicines: a clinical perspective.

    PubMed

    Trinka, Eugen; Krämer, Günter; Graf, Martin

    2011-12-01

    Many antiepileptic drugs (AEDs) are now available as a generic product. This can potentially save the healthcare providers massive costs. Hence, governmental authorities have introduced rules and incentives for clinicians to switch from the original branded AED to a generic product. Clinicians and patients with epilepsy are reluctant to switch. The licensing of generic AEDs is based on the equation that bioavailability means therapeutic equivalence. However, from a clinical standpoint one has to consider several other relevant issues: (1) Do generic AEDs have the same efficacy, safety and quality? (2) Can generic AEDs be used as substitutions for brand AEDs? (3) Can generic products of AEDs be used interchangeably? (4) Does the generic AED manufacturer guarantee the long-term consistency of availability on the market? (4) Do generic AEDs reduce the costs, and--if so--are these costs worth any additional risk to patient's safety? This article reviews the clinical issues related to current bioequivalence, prescribability, and switchability of AEDs.

  12. Risk-Based Bioequivalence Recommendations for Antiepileptic Drugs.

    PubMed

    Li, Zhichuan; Fang, Lanyan; Jiang, Wenlei; Kim, Myong-Jin; Zhao, Liang

    2017-09-19

    This review summarizes the current FDA practice in developing risk- and evidence-based product-specific bioequivalence guidances for antiepileptic drugs (AEDs). FDA's product-specific guidance (PSG) for AEDs takes into account the therapeutic index of each AED product. Several PSGs for AEDs recommend fully replicated studies and a reference-scaled average bioequivalence (RS-ABE) approach that permit the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The PSGs for AEDs published by FDA reflect the agency's current thinking on the bioequivalence studies and approval standards for generics of AEDs. Bioequivalence between brand and generic AED products demonstrated in controlled studies with epilepsy patients provides strong scientific support for the soundness of FDA bioequivalence standards.

  13. Suicide and epilepsy: do antiepileptic drugs increase the risk?

    PubMed

    Mula, Marco; Sander, Josemir W

    2015-04-01

    Years after the US FDA issued an alert on an increased risk of suicide ideation and behavior in people with epilepsy treated with antiepileptic drugs (AEDs), this issue still remains controversial. The FDA alert was based on a meta-analysis of clinical trials of AEDs in all indications. We discuss major methodological problems of this meta-analysis. Available evidence coming from the published studies is also discussed highlighting that the majority of them are also affected by major methodological limitations, which do not allow an absolute conclusion. Suicide in epilepsy is a complex phenomenon but most agree that suicide rates are higher in people with epilepsy when compared to the general population. Screening for suicide seems to be appropriate and well-designed prospective studies are urgently needed in order to clarify fully a possible role of AEDs.

  14. Use of Antiepileptic Drugs for Hyperkinetic Movement Disorders

    PubMed Central

    Siniscalchi, A; Gallelli, L; De Sarro, G

    2010-01-01

    Many studies investigated the use of antiepileptic drugs (AEDs) in several neurological diseases other than epilepsy. These neurological disorders, usually, involve neuronal excitability through the modulating of ion channels, receptors and intracellular signaling pathways, and are the targets of the AEDs. This article provides a review of the clinical efficacy of both conventional and newer AEDs in hyperkinetic movement disorders. Some of these indications for AEDs have been established, while others are under investigation. The modulation of GABAergic transmission may explain the neuronal hyper-excitability that underlies some forms of hyperkinetic movement disorders. So, AEDs able to increase GABAergic neurotransmission may play a role in hyperkinetic movement disorders treatment. Therefore, AEDs could represent a useful therapeutic option in the management of hyperkinetic movement disorders where the available treatments are ineffective. PMID:21629443

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

    PubMed

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

    2005-01-01

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

  16. Adverse cognitive effects of antiepileptic pharmacotherapy: Each additional drug matters.

    PubMed

    Witt, Juri-Alexander; Elger, Christian E; Helmstaedter, Christoph

    2015-11-01

    The study was set up to evaluate the impact of the total drug load of antiepileptic pharmacotherapy on cognition. Retrospective analyses were based on 834 patients with epilepsy who underwent a brief routine assessment of executive function and verbal memory (EpiTrack Plus) at our department. The total drug load was quantified in two ways: (1) number of concurrent antiepileptic drugs (AEDs) and (2) total drug load according to the defined daily dose (DDD) provided by the World Health Organization. The cognitive measures showed higher inverse correlations with the number of AEDs (executive function: r=-0.35, p<0.001; memory: r=-0.22, p<0.001) than with the total DDD (executive function: r=-0.27, p<0.001; memory: r=-0.17, p<0.001). Reanalysis with statistical control for disease severity hardly changed the aforementioned results. With each additional drug in polytherapy, we observed a significantly lower performance in executive function. In this regard an additional explorative approach revealed that regimens combining AEDs with favorable cognitive profiles were associated with higher cognitive performance. Correlations between indicators of disease severity and drug load indices were low: altogether explaining only up to 9% of the observed variance in drug load. The findings demonstrate a considerable adverse effect of a higher drug load on cognition, especially on executive functions. Simply counting the number of drugs may be sufficient as a rough estimate of the risk of side effects. However, the combination of AEDs with favorable cognitive profiles may attenuate the negative effect of the total drug load.

  17. Interaction of valproic acid and the antidepressant drugs doxepin and venlafaxine: analysis of therapeutic drug monitoring data under naturalistic conditions.

    PubMed

    Unterecker, Stefan; Reif, Andreas; Hempel, Susanne; Proft, Florian; Riederer, Peter; Deckert, Jürgen; Pfuhlmann, Bruno

    2014-07-01

    Valproic acid and the antidepressants doxepin and venlafaxine are frequently used psychotropic drugs. In the literature, an influence of valproic acid on serum levels of antidepressants has been described, although studies have focused on amitriptyline. The authors assessed their therapeutic drug monitoring (TDM) database for patients receiving a combination of doxepin or venlafaxine and valproic acid and compared these samples with matched controls without valproic acid comedication in terms of the serum concentration of antidepressants. The mean dose-corrected serum concentration of doxepin+N-doxepin in 16 patients who received valproic acid comedication was higher (2.171±1.482 ng/ml/mg) than that in the matched controls (0.971±0.857 ng/ml/mg, P<0.003). We also found a significant correlation between valproic acid serum level and dose-corrected doxepin+N-doxepin serum level (Spearman's ρ r=0.602, P<0.014). The mean dose-corrected serum level of venlafaxine+O-desmethylvenlafaxine in 41 patients who received valproic acid comedication did not differ significantly from that of the matched controls (P<0.089), but there was a significant difference between both groups in the dose-corrected serum level of O-desmethylvenlafaxine (1.403±0.665 vs. 1.102±0.444, P<0.017). As a consequence, if a combination of valproic acid with doxepin or venlafaxine is administered, cautious dosing is advisable and TDM should be performed.

  18. Interaction of valproic acid and the antidepressant drugs doxepin and venlafaxine: analysis of therapeutic drug monitoring data under naturalistic conditions

    PubMed Central

    Reif, Andreas; Hempel, Susanne; Proft, Florian; Riederer, Peter; Deckert, Jürgen; Pfuhlmann, Bruno

    2014-01-01

    Valproic acid and the antidepressants doxepin and venlafaxine are frequently used psychotropic drugs. In the literature, an influence of valproic acid on serum levels of antidepressants has been described, although studies have focused on amitriptyline. The authors assessed their therapeutic drug monitoring (TDM) database for patients receiving a combination of doxepin or venlafaxine and valproic acid and compared these samples with matched controls without valproic acid comedication in terms of the serum concentration of antidepressants. The mean dose-corrected serum concentration of doxepin+N-doxepin in 16 patients who received valproic acid comedication was higher (2.171±1.482 ng/ml/mg) than that in the matched controls (0.971±0.857 ng/ml/mg, P<0.003). We also found a significant correlation between valproic acid serum level and dose-corrected doxepin+N-doxepin serum level (Spearman’s ρ r=0.602, P<0.014). The mean dose-corrected serum level of venlafaxine+O-desmethylvenlafaxine in 41 patients who received valproic acid comedication did not differ significantly from that of the matched controls (P<0.089), but there was a significant difference between both groups in the dose-corrected serum level of O-desmethylvenlafaxine (1.403±0.665 vs. 1.102±0.444, P<0.017). As a consequence, if a combination of valproic acid with doxepin or venlafaxine is administered, cautious dosing is advisable and TDM should be performed. PMID:24374906

  19. Ethosuximide, Valproic Acid and Lamotrigine in Childhood Absence Epilepsy: Initial Monotherapy Outcomes at 12 months

    PubMed Central

    Glauser, Tracy A.; Cnaan, Avital; Shinnar, Shlomo; Hirtz, Deborah G.; Dlugos, Dennis; Masur, David; Clark, Peggy O.; Adamson, Peter C.

    2012-01-01

    Purpose Determine the optimal initial monotherapy for children with newly diagnosed childhood absence epilepsy based on 12 months of double blind therapy. Methods A double-blind, randomized controlled clinical trial compared the efficacy, tolerability and neuropsychological effects of ethosuximide, valproic acid and lamotrigine in children with newly diagnosed childhood absence epilepsy. Study medications were titrated to clinical response and subjects remained in the trial unless they reached a treatment failure criterion. Maximal target doses were ethosuximide 60 mg/kg/day or 2000 mg/day, valproic acid 60 mg/kg/day or 3000 mg/day and lamotrigine 12 mg/kg/day or 600 mg/day. Original primary outcome was at 16–20 weeks and included a video EEG assessment. For this report, the main effectiveness outcome was the freedom from failure rate 12 months after randomization and included a video EEG assessment; differential drug effects were determined by pairwise comparisons. The main cognitive outcome was the percentage of subjects experiencing attentional dysfunction at the Month 12 visit. Key Findings A total of 453 children were enrolled and randomized; seven were deemed ineligible and 446 subjects comprised the overall efficacy cohort. There were no demographic differences between the three cohorts. By 12 months after starting therapy, only 37% of all enrolled subjects were free from treatment failure on their first medication. At the Month 12 visit, the freedom-from-failure rates for ethosuximide and valproic acid were similar (45% and 44%, respectively; odds ratio with valproic acid vs. ethosuximide, 0.94; 95% confidence interval [CI], 0.60 to 1.48; P = 0.82) and were higher than the rate for lamotrigine (21%; odds ratio with ethosuximide vs. lamotrigine, 3.09; 95% CI, 1.86 to 5.13; odds ratio with valproic acid vs. lamotrigine, 2.90; 95% CI, 1.74 to 4.83; P<0.001 for both comparisons). The frequency of treatment failures due to lack of seizure control (p < 0

  20. Evaluation of melanogenesis in A-375 melanoma cells treated with 5,7-dimethoxycoumarin and valproic acid.

    PubMed

    Chodurek, Ewa; Orchel, Arkadiusz; Orchel, Joanna; Kurkiewicz, Sławomir; Gawlik, Natalia; Dzierżewicz, Zofia; Stępień, Krystyna

    2012-12-01

    Malignant melanoma (melanoma malignum) is one of the most dangerous types of tumor. It is very difficult to cure. In recent years, a lot of attention has been given to chemoprevention. This method uses natural and synthetic compounds to interfere with and inhibit the process of carcinogenesis. In this study, a new treatment strategy was proposed consisting of a combination of 5,7-dimethoxycoumarin (DMC), an activator of melanogenesis, and valproic acid (VPA), a well-known drug that is one of the histone deacetylase inhibitors (HDACis). In conjunction with 1 mM VPA, all of the tested concentrations of DMC (10-150 μM) significantly decreased the proliferation of A-375 cells. VPA and DMC also induced the synthesis of melanin and the formation of dendrite and star-shaped cells. Tyrosinase gene expression and tyrosinase activity significantly increased in response to VPA treatment. Pyrolysis with gas chromatography and mass spectrometry (Py-GC/MS) was used to investigate the structure of the isolated melanin. This showed that the quantitative and qualitative components of melanin degradation products are dependent on the type of applied melanogenesis inductor. Products derived from eumelanin were detected in the pyrolytic profile of melanin isolated from A-375 cells stimulated with DMC. Thermal degradation of melanin isolated from melanoma cells after exposure to VPA or a mixture of VPA and DMC revealed the additional presence of products derived from pheomelanin.

  1. Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats

    PubMed Central

    Zhang, Li-fang; Liu, Ling-sheng; Chu, Xiao-man; Xie, Hao; Cao, Li-juan; Guo, Cen; A, Ji-ye; Cao, Bei; Li, Meng-jie; Wang, Guang-ji; Hao, Hai-ping

    2014-01-01

    Aim: To investigate the potential interactive effects of a high-fat diet (HFD) and valproic acid (VPA) on hepatic steatosis and hepatotoxicity in rats. Methods: Male SD rats were orally administered VPA (100 or 500 mg·kg−1·d−1) combined with HFD or a standard diet for 8 weeks. Blood and liver samples were analyzed to determine lipid levels and hepatic function biomarkers using commercial kit assays. Low-molecular-weight compounds in serum, urine and bile samples were analyzed using a metabonomic approach based on GC/TOF-MS. Results: HFD alone induced extensive hepatocyte steatosis and edema in rats, while VPA alone did not cause significant liver lesions. VPA significantly aggravated HFD-induced accumulation of liver lipids, and caused additional spotty or piecemeal necrosis, accompanied by moderate infiltration of inflammatory cells in the liver. Metabonomic analysis of serum, urine and bile samples revealed that HFD significantly increased the levels of amino acids, free fatty acids (FFAs) and 3-hydroxy-butanoic acid, whereas VPA markedly decreased the levels of amino acids, FFAs and the intermediate products of the tricarboxylic acid cycle (TCA) compared with the control group. HFD aggravated VPA-induced inhibition on lipid and amino acid metabolism. Conclusion: HFD magnifies VPA-induced impairment of mitochondrial β-oxidation of FFAs and TCA, thereby increases hepatic steatosis and hepatotoxicity. The results suggest the patients receiving VPA treatment should be advised to avoid eating HFD. PMID:24442146

  2. Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats.

    PubMed

    Zhang, Li-fang; Liu, Ling-sheng; Chu, Xiao-man; Xie, Hao; Cao, Li-juan; Guo, Cen; A, Ji-ye; Cao, Bei; Li, Meng-jie; Wang, Guang-ji; Hao, Hai-ping

    2014-03-01

    To investigate the potential interactive effects of a high-fat diet (HFD) and valproic acid (VPA) on hepatic steatosis and hepatotoxicity in rats. Male SD rats were orally administered VPA (100 or 500 mg·kg⁻¹·d⁻¹) combined with HFD or a standard diet for 8 weeks. Blood and liver samples were analyzed to determine lipid levels and hepatic function biomarkers using commercial kit assays. Low-molecular-weight compounds in serum, urine and bile samples were analyzed using a metabonomic approach based on GC/TOF-MS. HFD alone induced extensive hepatocyte steatosis and edema in rats, while VPA alone did not cause significant liver lesions. VPA significantly aggravated HFD-induced accumulation of liver lipids, and caused additional spotty or piecemeal necrosis, accompanied by moderate infiltration of inflammatory cells in the liver. Metabonomic analysis of serum, urine and bile samples revealed that HFD significantly increased the levels of amino acids, free fatty acids (FFAs) and 3-hydroxy-butanoic acid, whereas VPA markedly decreased the levels of amino acids, FFAs and the intermediate products of the tricarboxylic acid cycle (TCA) compared with the control group. HFD aggravated VPA-induced inhibition on lipid and amino acid metabolism. HFD magnifies VPA-induced impairment of mitochondrial β-oxidation of FFAs and TCA, thereby increases hepatic steatosis and hepatotoxicity. The results suggest the patients receiving VPA treatment should be advised to avoid eating HFD.

  3. In Vivo Screening Using Transgenic Zebrafish Embryos Reveals New Effects of HDAC Inhibitors Trichostatin A and Valproic Acid on Organogenesis

    PubMed Central

    Li, Ling; Bonneton, François; Tohme, Marie; Bernard, Laure; Chen, Xiao Yong; Laudet, Vincent

    2016-01-01

    The effects of endocrine disrupting chemicals (EDCs) on reproduction are well known, whereas their developmental effects are much less characterized. However, exposure to endocrine disruptors during organogenesis may lead to deleterious and permanent problems later in life. Zebrafish (Danio rerio) transgenic lines expressing the green fluorescent protein (GFP) in specific organs and tissues are powerful tools to uncover developmental defects elicited by EDCs. Here, we used seven transgenic lines to visualize in vivo whether a series of EDCs and other pharmaceutical compounds can alter organogenesis in zebrafish. We used transgenic lines expressing GFP in pancreas, liver, blood vessels, inner ear, nervous system, pharyngeal tooth and pectoral fins. This screen revealed that four of the tested chemicals have detectable effects on different organs, which shows that the range of effects elicited by EDCs is wider than anticipated. The endocrine disruptor tetrabromobisphenol-A (TBBPA), as well as the three drugs diclofenac, trichostatin A (TSA) and valproic acid (VPA) induced abnormalities in the embryonic vascular system of zebrafish. Moreover, TSA and VPA induced specific alterations during the development of pancreas, an observation that was confirmed by in situ hybridization with specific markers. Developmental delays were also induced by TSA and VPA in the liver and in pharyngeal teeth, resulting in smaller organ size. Our results show that EDCs can induce a large range of developmental alterations during embryogenesis of zebrafish and establish GFP transgenic lines as powerful tools to screen for EDCs effects in vivo. PMID:26900852

  4. Old and new antiepileptic drugs during pregnancy and lactation--report of a case.

    PubMed

    Rauchenzauner, Markus; Kiechl-Kohlendorfer, Ursula; Rostasy, Kevin; Luef, Gerhard

    2011-04-01

    We describe a case of a woman with epilepsy treated with primidone/phenobarbital (so-called "old" antiepileptic drug) and levetiracetam (so-called "new" antiepileptic drug) who was discouraged from breastfeeding, resulting in clinically significant withdrawal seizures in her newborn. As a consequence, even when two or more antiepileptic drugs are needed for the treatment of women with epilepsy, breastfeeding should be recommended, mothers should be informed about the possibility of drug effects on the neonate, and infants of mothers treated with primidone/phenobarbital should be closely monitored for possible signs of sedation.

  5. Phase II open label study of valproic acid in spinal muscular atrophy.

    PubMed

    Swoboda, Kathryn J; Scott, Charles B; Reyna, Sandra P; Prior, Thomas W; LaSalle, Bernard; Sorenson, Susan L; Wood, Janine; Acsadi, Gyula; Crawford, Thomas O; Kissel, John T; Krosschell, Kristin J; D'Anjou, Guy; Bromberg, Mark B; Schroth, Mary K; Chan, Gary M; Elsheikh, Bakri; Simard, Louise R

    2009-01-01

    Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p

  6. Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy

    PubMed Central

    Swoboda, Kathryn J.; Scott, Charles B.; Reyna, Sandra P.; Prior, Thomas W.; LaSalle, Bernard; Sorenson, Susan L.; Wood, Janine; Acsadi, Gyula; Crawford, Thomas O.; Kissel, John T.; Krosschell, Kristin J.; D'Anjou, Guy; Bromberg, Mark B.; Schroth, Mary K.; Chan, Gary M.; Elsheikh, Bakri; Simard, Louise R.

    2009-01-01

    Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2–3 years, 29 SMA type II ages 2–14 years and 11 type III ages 2–31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p≤0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Δ7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p≤0.0036) and maximum ulnar CMAP scores (p≤0.0001) increased significantly. Conclusions While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various

  7. Enantioselective pharmacodynamic and pharmacokinetic analysis of two chiral CNS-active carbamate derivatives of valproic acid.

    PubMed

    Shekh-Ahmad, Tawfeeq; Mawasi, Hafiz; McDonough, John H; Finnell, Richard H; Wlodarczyk, Bogdan J; Yavin, Eylon; Bialer, Meir

    2014-12-01

    2-Ethyl-3-methylbutyl-carbamate (EMC) and 2-isopropylpentyl-carbamate (IPC) are among the most potent anticonvulsant carbamate derivatives of valproic acid. EMC and IPC are chiral compounds. Consequently, the aim of the current study was to comparatively evaluate the pharmacokinetic (PK) and pharmacodynamic (PD anticonvulsant activity) profile of EMC and IPC individual enantiomers. The anticonvulsant activity of EMC and IPC individual enantiomers was evaluated in several anticonvulsant rodent models including maximal electroshock (MES), 6 Hz psychomotor, subcutaneous (pentylenetetrazole) (scMet), and the pilocarpine-induced and soman-induced status epilepticus (SE). The PK-PD relationship of EMC and IPC individual enantiomers was evaluated following intraperitoneal administration (50 mg/kg) to rats. Induction of neural tube defects (NTDs) was evaluated in a mouse strain that was highly susceptible to teratogen-induced NTDs. In mice and rats, (2S)-EMC exhibited anticonvulsant activity similar to that of racemic EMC in the MES and scMet tests, whereas in the 6 Hz test, racemic EMC was more potent than its two individual enantiomers. Racemic EMC exhibited a potent activity in the soman-induced SE model when administered 5 and 20 min after seizure onset with median effective dose (ED50 ) values of 33 and 48 mg/kg, respectively. (2R)-IPC and (2S)-IPC exhibited ED50 values similar to those of racemic IPC in the mouse and rat MES and scMet models. (2R)-IPC had similar ED50 values on the 6 Hz tests. Racemic IPC had an ED50 value of 107 mg/kg in the pilocarpine-induced SE model when given 30 min after seizure onset. Racemic EMC and IPC and their enantiomers had similar clearance (3.8-5.5 L/h/kg) and short half-life (<1 h). EMC and its enantiomers did not cause NTDs at doses 3-10 times higher than their anticonvulsant ED50 values. EMC and IPC did not exhibit enantioselective PK, a fact that may contribute to their nonenantioselective activity in any of the anticonvulsant

  8. A retrospective study on the usage of antiepileptic drugs in Asian children from 2000 to 2009 in the largest pediatric hospital in Singapore.

    PubMed

    Tan, Wei Wei; Kong, Sing Teang; Chan, Derrick W S; Ho, Paul C

    2012-10-01

    In light of the increasing usage of the newer antiepileptic drugs (AEDs) in other countries, we reviewed the prescribing pattern of AEDs in Singapore over the last 10 years (2000-2009). A retrospective review of pharmacy dispensing records solicited from the only children's hospital in Singapore was performed to analyze the trend in AEDs prescribing in the last 10 years. We also examined the correlation between the serum concentrations of valproic acid (VPA), the most-prescribed AED, and seizure control. Descriptive and inferential statistical analyses were then performed on the findings. A total of 41 671 prescriptions on AEDs were retrieved and analyzed. Despite the introduction of the second-generation AEDs, the first generation AEDs still dominate epilepsy treatment in Asian children, with VPA being the mostly prescribed AED (about 40% of the total AEDs usage). The majority of patients (62.8%) were on monotherapy. The mean VPA serum concentration in patients with good seizure control was 68.6 µg/ml (SD = 26.4 µg/ml; range = 12.2-138.0 µg/ml), which was statistically higher than the mean VPA concentration of 57.7 µg/ml (SD = 27.1 µg/ml; range = 11.1-149.0 µg/ml) in patients with poor seizure control (p < 0.0001). With VPA being the most prescribed AED in our clinical practice, and the finding in this study that with careful classification of the patients' condition, serum concentrations of VPA generally correlate well with the seizure control, the correct dose titration of VPA with therapeutic drug monitoring is still of paramount importance. Copyright © 2012 John Wiley & Sons, Ltd.

  9. Are adverse effects of antiepileptic drugs different in symptomatic partial and idiopathic generalized epilepsies? The Portuguese-Brazilian validation of the Liverpool Adverse Events Profile.

    PubMed

    Martins, H H; Alonso, N B; Vidal-Dourado, M; Carbonel, T D; de Araújo Filho, G M; Caboclo, L O; Yacubian, E M; Guilhoto, L M

    2011-11-01

    We report the results of administration of the Portuguese-Brazilian translation of the Liverpool Adverse Events Profile (LAEP) to 100 patients (mean age=34.5, SD=12.12; 56 females), 61 with symptomatic partial epilepsy (SPE) and 39 with idiopathic generalized epilepsy (IGE) (ILAE, 1989) who were on a stable antiepileptic drug (AED) regimen and being treated in a Brazilian tertiary epilepsy center. Carbamazepine was the most commonly used AED (43.0%), followed by valproic acid (32.0%). Two or more AEDs were used by 69.0% of patients. The mean LAEP score (19 questions) was 37.6 (SD=13.35). The most common adverse effects were sleepiness (35.0%), memory problems (35.0%), and difficulty in concentrating (25.0%). Higher LAEP scores were associated with polytherapy with three or more AEDs (P=0.005), female gender (P<0.001), older age (P<0.001), and uncontrolled seizures (P=0.045). The intraclass coefficient (test-retest reliability) for LAEP overall score was 0.848 (95% CI=0.782-0.895), with a range from 0.370 (unsteadiness) to 0.750 (memory problems). Cronbach's α coefficient (internal consistency) was 0.903. The LAEP was highly correlated with Quality of Life in Epilepsy-31 inventory (r=-0.804, P>0.001) and Hospital Anxiety and Depression Scale (Depression: r=0.637, P<0.001; Anxiety: r=0.621, P<0.001) dimensions. LAEP overall scores were similar in people with SPE and IGE and were not helpful in differentiating adverse effects in these two groups. Clinical variables that influenced global LAEP were seizure frequency (P=0.050) and generalized tonic-clonic seizures in the last month (P=0.031) in the IGE group, and polytherapy with three or more AEDs (P=0.003 and P=0.003) in both IGE and SPE groups.

  10. Association of Interictal Epileptiform Discharges with Sleep and Anti-Epileptic Drugs.

    PubMed

    Mohan, Latika; Singh, Jayvardhan; Singh, Yogesh; Kathrotia, Rajesh; Goel, Arun

    2016-10-01

    The presence of interictal epileptiform discharges (IEDs) in electroencephalogram (EEG) is diagnostic of epilepsy. Latent IEDs are activated during sleep. Anti-epileptic drugs (AEDs) improve sleep. AEDs, sleep, and IEDs may interact and affect epilepsy management. To explore the occurrence of IEDs and its association with sleep and AED status in suspected patients of epilepsy. EEG records were collected of suspected patients of epilepsy who reported to the electrophysiology laboratory of a tertiary care hospital during 1 year. The anthropometric details, clinical presentations, and AED status of the patients were recorded from the EEG records. Patients were divided into 2 categories based on whether AEDs had been started prior to the EEG evaluation (category-I) or not (category-II). The occurrences of IEDs in EEG recordings in both categories were analyzed. In 1 year, 138 patients were referred for diagnostic EEG evaluation. One-hundred-two patients fulfilled the inclusion criteria, of which 57 patients (53%) belonged to category-I and 45 patients (47%) belonged to category-II. Incidence of IEDs, suggestive of definite diagnosis of epilepsy in category-I was 88% and in category-II was 69%, and this difference was statistically significant (p = 0.02). The increased proportion of IEDs in category-I patients may be due to high clinical suspicion or compounding interaction of AEDs and sleep. More extensive studies are required to delineate the complex interaction of AEDs, sleep, and IEDs so that judicious yet prompt management of epilepsy can be carried out.

  11. Effects of Valproic Acid on Organic Acid Metabolism in Children: A Metabolic Profiling Study

    PubMed Central

    Price, K.E.; Pearce, R.E.; Garg, U.C.; Heese, B.A.; Smith, L.D.; Sullivan, J.E.; Kennedy, M.J.; Bale, J.F.; Ward, R.M.; Chang, T.K.H.; Abbott, Frank S.; Leeder, J.S.

    2013-01-01

    Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a measure of mitochondrial function, were obtained in children 3.5 to 17.3 years old treated for seizure disorders with valproic acid (VPA; n=52). Age-matched patients treated with carbamazepine (CBZ; n=50) and untreated healthy children (n=22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although untreated and CBZ control subjects were not distinguished by the principal component analysis (PCA) scores plot, a distinct boundary was apparent between the VPA and control/CBZ groups. Inter-individual variability in VPA-induced alterations in endogenous pathways reflecting branched chain amino acid metabolism and oxidative stress was observed. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity. PMID:21544075

  12. Valproic acid improves second-line regimen of small cell lung carcinoma in preclinical models

    PubMed Central

    Hubaux, Roland; Vandermeers, Fabian; Cosse, Jean-Philippe; Crisanti, Cecilia; Kapoor, Veena; Albelda, Steven M.; Mascaux, Céline; Delvenne, Philippe; Hubert, Pascale

    2015-01-01

    With 5-year survival rates below 5%, small cell lung carcinoma (SCLC) has very poor prognosis and requires improved therapies. Despite an excellent overall response to first-line therapy, relapses are frequent and further treatments are disappointing. The goal of the study was to improve second-line therapy of SCLC. The effect of chemotherapeutic agents was evaluated in cell lines (apoptosis, reactive oxygen species, and RNA and protein expression) and in mouse models (tumour development). We demonstrate here that valproic acid, a histone deacetylase inhibitor, improves the efficacy of a second-line regimen (vindesine, doxorubicin and cyclophosphamide) in SCLC cells and in mouse models. Transcriptomic profiling integrating microRNA and mRNA data identifies key signalling pathways in the response of SCLC cells to valproic acid, opening new prospects for improved therapies. PMID:27730151

  13. Effects of histone deacetylase inhibitor valproic acid on skeletal myocyte development

    PubMed Central

    Li, Qiao; Foote, Michelle; Chen, Jihong

    2014-01-01

    The tight interaction between genomic DNA and histones, which normally represses gene transcription, can be relaxed by histone acetylation. This loosening of the DNA-histone complex is important for selective gene activation during stem cell differentiation. Histone acetylation may be increased through the application of histone deacetylase inhibitors at the early stages of differentiation to modulate lineage commitment. We examined the effects of the histone deacetylase inhibitor valproic acid on the differentiation of pluripotent stem cells into skeletal myocytes. Our data demonstrated that valproic acid can act in concert with retinoic acid to enhance the commitment of stem cells into the skeletal myocyte lineage reinforcing the notion that histone acetylation is important for skeletal myogenesis. Thus, using a combination of small molecules to exploit different signaling pathways pertaining to specific gene programs will allow for modulation of lineage specification and stem cell differentiation in potential cell-based therapies. PMID:25423891

  14. AMPA receptors in epilepsy and as targets for antiepileptic drugs.

    PubMed

    Rogawski, M A; Donevan, S D

    1999-01-01

    alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are key mediators of seizure spread in the nervous system and represent promising targets for antiepileptic drugs. There is emerging evidence that AMPA receptors may play a role in epileptogenesis and in seizure-induced brain damage. This evidence suggests that AMPA receptor antagonists could have broad utility in epilepsy therapy. Regional, developmental, and disease-associated variations in AMPA receptors produced by differential expression of AMPA receptor subunits and variations in posttranscriptional processing, including alternative splicing and pre-mRNA editing, provide a diversity of functionally distinct AMPA receptor isoforms that allow opportunities for selective drug targeting. Four types of AMPA receptor antagonist are discussed in this chapter: (a) competitive AMPA recognition site antagonists, including those of the quinoxalinedione and newer nonquinoxalinedione classes, (b) 2,3-benzodiazepine noncompetitive (allosteric) antagonists, (c) desensitization enhancing antagonists, exemplified by SCN-, and (d) antagonists of Ca(2+)-permeable AMPA receptors, including polyamine amide arthropod toxins and their synthetic analogues. Competitive and noncompetitive AMPA receptor antagonists are broad-spectrum anticonvulsants in animal seizure models. Their effectiveness and safety for humans remain to be determined. There is evidence that these antagonists can potentiate the antiseizure activity of N-methyl-D-aspartate (NMDA) receptor antagonists and conventional antiepileptic drugs. This evidence suggests that the preferred use of AMPA receptor antagonists may be in combination therapies. Agents that enhance desensitization may have advantages in comparison with other AMPA receptor antagonists to the extent that they preferentially block high-frequency synaptic signaling and avoid depressing AMPA receptors on interneurons, which would lead to disinhibition and enhanced excitability

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

    PubMed Central

    2010-01-01

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

  16. Effects of Valproic Acid Derivatives on Inositol Trisphosphate Depletion, Teratogenicity, Glycogen Synthase Kinase-3β Inhibition, and Viral Replication: A Screening Approach for New Bipolar Disorder Drugs Derived from the Valproic Acid Core Structure

    PubMed Central

    Eickholt, B. J.; Towers, G. J.; Ryves, W. J.; Eikel, D.; Adley, K.; Ylinen, L. M. J.; Chadborn, N. H.; Harwood, A. J.; Nau, H.; Williams, R. S. B.

    2005-01-01

    Inositol-1,4,5-trisphosphate (InsP3) depletion has been implicated in the therapeutic action of bipolar disorder drugs, including valproic acid (VPA). It is not currently known whether the effect of VPA on InsP3 depletion is related to the deleterious effects of teratogenicity or elevated viral replication, or if it occurs via putative inhibitory effects on glycogen synthase kinase-3β(GSK-3β). In addition, the structural requirements of VPA-related compounds to cause InsP3 depletion are unknown. In the current study, we selected a set of 10 VPA congeners to examine their effects on InsP3 depletion, in vivo teratogenic potency, HIV replication, and GSK-3β activity in vitro. We found four compounds that function to deplete InsP3 in the model eukaryote Dictyostelium discoideum, and these drugs all cause growth-cone enlargement in mammalian primary neurons, consistent with the effect of InsP3 depletion. No relationship was found between InsP3 depletion and teratogenic or elevated viral replication effects, and none of the VPA congeners were found to affect GSK-3β activity. Structural requirements of VPA congers to maintain InsP3 depletion efficacy greater than that of lithium are a carboxylic-acid function without dependence on side-chain length, branching, or saturation. Noteworthy is the enantiomeric differentiation if a chiral center exists, suggesting that InsP3 depletion is mediated by a stereoselective mode of action. Thus, the effect of InsP3 depletion can be separated from that of teratogenic potency and elevated viral replication effect. We have used this to identify two VPA derivatives that share the common InsP3-depleting action of VPA, lithium and carbamazepine, but do not show the side effects of VPA, thus providing promising novel candidates for bipolar disorder treatment. PMID:15687223

  17. Valproic acid inhibits adhesion of vincristine- and cisplatin-resistant neuroblastoma tumour cells to endothelium

    PubMed Central

    Blaheta, R A; Michaelis, M; Natsheh, I; Hasenberg, C; Weich, E; Relja, B; Jonas, D; Doerr, H W; Cinatl, J

    2007-01-01

    Drug resistance to chemotherapy is often associated with increased malignancy in neuroblastoma (NB). In pursuit of alternative treatments for chemoresistant tumour cells, we tested the response of multidrug-resistant SKNSH and of vincristine (VCR)-, doxorubicin (DOX)-, or cisplatin (CDDP)-resistant UKF-NB-2, UKF-NB-3 or UKF-NB-6 NB tumour cell lines to valproic acid (VPA), a differentiation inducer currently in clinical trials. Drug resistance caused elevated NB adhesion (UKF-NB-2VCR, UKF-NB-2DOX, UKF-NB-2CDDP, UKF-NB-3VCR, UKF-NB-3CDDP, UKF-NB-6VCR, UKF-NB-6CDDP) to an endothelial cell monolayer, accompanied by downregulation of the adhesion receptor neural cell adhesion molecule (NCAM). Based on the UKF-NB-3 model, N-myc proteins were enhanced in UKF-NB-3VCR and UKF-NB-3CDDP, compared to the drug naïve controls. p73 was diminished, whereas the p73 isoform deltaNp73 was upregulated in UKF-NB-3VCR and UKF-NB-3CDDP. Valproic acid blocked adhesion of UKF-NB-3VCR and UKF-NB-3CDDP, but not of UKF-NB-3DOX, and induced the upregulation of NCAM surface expression, NCAM protein content and NCAM coding mRNA. Valproic acid diminished N-myc and enhanced p73 protein level, coupled with downregulation of deltaNp73 in UKF-NB-3VCR and UKF-NB-3CDDP. Valproic acid also reverted enhanced adhesion properties of drug-resistant UKF-NB-2, UKF-NB-6 and SKNSH cells, and therefore may provide an alternative approach to the treatment of drug-resistant NB by blocking invasive processes. PMID:17505515

  18. Effect of Antiepileptic Drugs for Acute and Chronic Seizures in Children with Encephalitis

    PubMed Central

    Lin, Kuang-Lin; Lin, Jainn-Jim; Hsia, Shao-Hsuan; Chou, Min-Liang; Hung, Po-Cheng; Wang, Huei-Shyong

    2015-01-01

    Background Encephalitis presents with seizures in the acute phase and increases the risk of late unprovoked seizures and epilepsy. This study aimed to evaluate the effect of antiepileptic drugs in pediatric patients with acute seizures due to encephalitis and epilepsy. Patients and Methods Cases of acute pediatric encephalitis between January 2000 and December 2010 were reviewed. Clinical data, including onset at age, seizure type, seizure frequency, effects of antiepileptic drugs, and prognosis were analyzed. Results During the study period, 1038 patients (450 girls, 588 boys) were enrolled. Among them, 44.6% (463) had seizures in the acute phase, 33% had status epilepticus, and 26% (251) developed postencephalitic epilepsy. At one year of follow-up, 205 of the 251 patients with postencephalitic epilepsy were receiving antiepileptic drugs while 18% were seizure free even after discontinuing the antiepileptic drugs. Among those with postencephalitic epilepsy, 67% had favorable outcomes and were using <2 anti-epileptic drugs while 15% had intractable seizures and were using ≥ 2 antiepileptic drugs. After benzodiazepines, intravenous phenobarbital was preferred over phenytoin as treatment of postencephalitic seizures in the acute phase. For refractory status epilepticus, high-dose topiramate combined with intravenous high-dose phenobarbital or high-dose lidocaine had less side effects. Conclusions Children with encephalitis have a high rate of postencephalitic epilepsy. Phenobarbital and clonazepam are the most common drugs used, alone or in combination, for postencephalitic epilepsy. PMID:26444013

  19. Short-term use of antiepileptic drugs is neurotoxic to the immature brain

    PubMed Central

    Liu, Yu; Wang, Xue-ying; Li, Dan; Yang, Lin; Huang, Shao-ping

    2015-01-01

    Previous studies have shown that the long-term use of antiepileptic drugs can cause nervous system damage. However, short-term antiepileptic drug treatment is frequently given to infants, especially neonates, to control seizure. Whether the short-term use of antiepileptic drugs is neurotoxic remains unclear. In the present study, immature rats, 3–21 days of age, were intraperitoneally injected with phenobarbital and/or topiramate for 3 consecutive days. Hematoxylin-eosin and immunohistochemical staining revealed that phenobarbital and topiramate, individually or in combination, were cytotoxic to hippocampal CA1 neurons and inhibited the expression of GluR1 and NR2B, excitatory glutamate receptor subunits. Furthermore, the combination of the two drugs caused greater damage than either drug alone. The results demonstrate that the short-term use of antiepileptic drugs damages neurons in the immature brain and that the combined use of antiepileptic drugs exacerbates damage. Our findings suggest that clinicians should consider the potential neurotoxic risk associated with the combined use of antiepileptic drugs in the treatment of seizure. PMID:26170821

  20. Safety of valproic acid in patients with chronic obstructive pulmonary disease: a population-based cohort study

    PubMed Central

    Antoniou, Tony; Yao, Zhan; Camacho, Ximena; Mamdani, Muhammad M; Juurlink, David N; Gomes, Tara

    2015-01-01

    Purpose Valproic acid is an anticonvulsant that also inhibits histone deacetylase (HDAC), a property that could worsen pulmonary function in patients with chronic obstructive pulmonary disease (COPD). The clinical significance of this property is unknown. We therefore compared the risk of COPD exacerbation in older patients with COPD commencing treatment with either valproic acid or phenytoin, an anticonvulsant that does not affect HDAC. Methods We conducted a population-based retrospective cohort study of Ontario residents with COPD aged 66 years or older who started treatment with valproic acid or phenytoin between 1 April 1993 and 30 November 2012. The primary outcome was a hospital admission or emergency department visit for a COPD exacerbation within 240 days of drug initiation. A secondary outcome examined initiation of oral corticosteroids in the outpatient setting. Results During the study period, we identified 4596 COPD patients who commenced valproic acid and 8478 who commenced phenytoin. Following multivariable adjustment, valproic acid did not increase the risk of the primary outcome (adjusted hazard ratio 1.00, 95% confidence interval 0.79 to 1.26). Although valproic acid was associated with a lower risk of initiating oral corticosteroids in the first thirty days following commencement of anticonvulsant therapy (adjusted hazard ratio 0.32; 95% confidence interval 0.21 to 0.49), no difference was observed during subsequent follow-up. Conclusion Among older patients with COPD, treatment with valproic acid does not increase the risk of adverse pulmonary outcomes relative to phenytoin. These findings suggest that valproate-induced HDAC inhibition is of little clinical relevance in this context. Copyright © 2015 John Wiley & Sons, Ltd. PMID:25656984

  1. Safety of valproic acid in patients with chronic obstructive pulmonary disease: a population-based cohort study.

    PubMed

    Antoniou, Tony; Yao, Zhan; Camacho, Ximena; Mamdani, Muhammad M; Juurlink, David N; Gomes, Tara

    2015-03-01

    Valproic acid is an anticonvulsant that also inhibits histone deacetylase (HDAC), a property that could worsen pulmonary function in patients with chronic obstructive pulmonary disease (COPD). The clinical significance of this property is unknown. We therefore compared the risk of COPD exacerbation in older patients with COPD commencing treatment with either valproic acid or phenytoin, an anticonvulsant that does not affect HDAC. We conducted a population-based retrospective cohort study of Ontario residents with COPD aged 66 years or older who started treatment with valproic acid or phenytoin between 1 April 1993 and 30 November 2012. The primary outcome was a hospital admission or emergency department visit for a COPD exacerbation within 240 days of drug initiation. A secondary outcome examined initiation of oral corticosteroids in the outpatient setting. During the study period, we identified 4596 COPD patients who commenced valproic acid and 8478 who commenced phenytoin. Following multivariable adjustment, valproic acid did not increase the risk of the primary outcome (adjusted hazard ratio 1.00, 95% confidence interval 0.79 to 1.26). Although valproic acid was associated with a lower risk of initiating oral corticosteroids in the first thirty days following commencement of anticonvulsant therapy (adjusted hazard ratio 0.32; 95% confidence interval 0.21 to 0.49), no difference was observed during subsequent follow-up. Among older patients with COPD, treatment with valproic acid does not increase the risk of adverse pulmonary outcomes relative to phenytoin. These findings suggest that valproate-induced HDAC inhibition is of little clinical relevance in this context. Copyright © 2015 John Wiley & Sons, Ltd.

  2. Persistent behavioral effects following early life exposure to retinoic acid or valproic acid in zebrafish

    PubMed Central

    Bailey, Jordan M.; Oliveri, Anthony N.; Karbhari, Nishika; Brooks, Roy A.J.; De La Rocha, Amberlene J.; Janardhan, Sheila; Levin, Edward D.

    2015-01-01

    BACKGROUND Moderate to severe dysregulation in retinoid signaling during early development is associated with a constellation of physical malformations and/or neural tube defects, including spina bifida. It is thought that more subtle dysregulation of this system, which might be achievable via dietary (i.e. hypervitaminosis A) or pharmacological (i.e. valproic acid) exposure in humans, will manifest on behavioral domains including sociability, without overt physical abnormalities. METHODS During early life, zebrafish were exposed to low doses of two chemicals that disrupt retinoid signaling. From 0-5 dpf, larvae were reared in aqueous solutions containing retinoic acid (0, 0.02, 0.2 or 2 nM) or valproic acid (0, 0.5, 5.0 or 50 uM). One cohort of zebrafish was assessed using a locomotor activity screen at 6-dpf; another was reared to adulthood and assessed using a neurobehavioral test battery (startle habituation, novel tank exploration, shoaling, and predator escape/avoidance). RESULTS There was no significant increase in the incidence of physical malformation among exposed fish compared to controls. Both retinoic acid and valproic acid exposures during development disrupted larval activity with persisting behavioral alterations later in life, primarily manifesting as decreased social affiliation. CONCLUSIONS Social behavior and some aspects of motor function were altered in exposed fish; the importance of examining emotional or psychological consequences of early life exposure to retinoid acting chemicals is discussed. PMID:26439099

  3. Persistent behavioral effects following early life exposure to retinoic acid or valproic acid in zebrafish.

    PubMed

    Bailey, Jordan M; Oliveri, Anthony N; Karbhari, Nishika; Brooks, Roy A J; De La Rocha, Amberlene J; Janardhan, Sheila; Levin, Edward D

    2016-01-01

    Moderate to severe dysregulation in retinoid signaling during early development is associated with a constellation of physical malformations and/or neural tube defects, including spina bifida. It is thought that more subtle dysregulation of this system, which might be achievable via dietary (i.e. hypervitaminosis A) or pharmacological (i.e. valproic acid) exposure in humans, will manifest on behavioral domains including sociability, without overt physical abnormalities. During early life, zebrafish were exposed to low doses of two chemicals that disrupt retinoid signaling. From 0 to 5dpf, larvae were reared in aqueous solutions containing retinoic acid (0, 0.02, 0.2 or 2nM) or valproic acid (0, 0.5, 5.0 or 50μM). One cohort of zebrafish was assessed using a locomotor activity screen at 6-dpf; another was reared to adulthood and assessed using a neurobehavioral test battery (startle habituation, novel tank exploration, shoaling, and predator escape/avoidance). There was no significant increase in the incidence of physical malformation among exposed fish compared to controls. Both retinoic acid and valproic acid exposures during development disrupted larval activity with persisting behavioral alterations later in life, primarily manifesting as decreased social affiliation. Social behavior and some aspects of motor function were altered in exposed fish; the importance of examining emotional or psychological consequences of early life exposure to retinoid acting chemicals is discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Drug interaction between phenytoin and valproic acid in a child with refractory epilepsy: a case report.

    PubMed

    Carvalho, Indira Valadê; Carnevale, Renata Cavalcanti; Visacri, Marília Berlofa; Mazzola, Priscila Gava; de Fátima Lopes Ambrósio, Rosiane; dos Reis, Marcelo Conrado; de Queiroz, Rachel Alvarenga; Moriel, Patricia

    2014-04-01

    There are no published reports on pediatric phenytoin toxicity, resulting from the drug interaction between phenytoin and valproic acid. A 12-year-old patient with refractory epilepsy syndrome presented with phenytoin toxicity, following a concomitant treatment with phenytoin, valproic acid, and lamotrigine. The phenytoin concentration detected in the capsules used by the patient was in accordance with the prescribed dose and was appropriate for the age and weight of the patient. However, a supratherapeutic phenytoin serum concentration was observed (21.92 µg phenytoin/mL of blood). Consequently, the phenytoin dose was reduced, and the patient was monitored; 24 hours later the patient did not present with any signs/symptoms of toxicity. Despite the appropriate phenytoin concentration in the capsules, the patient presented with phenytoin toxicity. This toxicity likely resulted from the drug interaction between phenytoin and valproic acid that leads to phenytoin displacement from plasmatic proteins and inhibits phenytoin metabolism, thereby increasing the concentration of free drug in the serum.

  5. Cutaneous Adverse Drug Reactions in Dogs Treated with Antiepileptic Drugs

    PubMed Central

    Koch, Tina; Mueller, Ralf S.; Dobenecker, Britta; Fischer, Andrea

    2016-01-01

    Epilepsy is one of the most common neurologic disorders in dogs and life-long treatment with antiepileptic drugs (AED) is frequently required. Adverse events of AED targeting the skin are only rarely reported in veterinary medicine and the true incidence and spectrum of cutaneous reactions in epileptic dogs remains unknown. In this study, we hypothesized that cutaneous reactions commonly occur in epileptic dogs and are related to AED treatment. A retrospective case review of 185 dogs treated for epilepsy identified 20.0% with simultaneous appearance of dermatologic signs. In a subsequent prospective case investigation (n = 137), we identified newly appearing or distinct worsening of skin lesions following initiation of AED therapy in 10.9% of dogs treated for epilepsy (95% CI 6.8–17.7%). Cutaneous lesions were classified as probably drug-induced in 40.0% of these cases. Patch testing and intradermal testing were further investigated as potential diagnostic methods to confirm AED hypersensitivity. They were of high specificity but sensitivity and positive predictive value appeared inappropriate to recommend their routine use in clinical practice. PMID:27148543

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

    PubMed Central

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

    2016-01-01

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

  7. Choice of Antiepileptic Drugs in Idiopathic Generalized Epilepsy: UAE Experience.

    PubMed

    Alsaadi, Taoufik; Taha, Haytham; Al Hammadi, Fatema

    2015-01-01

    We retrospectively reviewed the electroencephalogram (EEG) reports of patients at our EEG lab from the years 2005-2010 to identify patients referred from the epilepsy clinic, with a confirmed diagnosis of idiopathic generalized epilepsy (IGE) by EEG criteria. We sought to report our experience in UAE of how often patients with IGE are placed on nonspecific antiepileptic drugs (AEDs) before being evaluated at an epilepsy referral clinic. 109 patients with a confirmed diagnosis of IGE based on EEG criteria were identified. When initially seen, 32.11% were taking a broad-spectrum (specific) AED only, 25.69% were taking a narrow-spectrum (nonspecific) AED, and 15.59% were placed on various combinations. Of the total patients who were receiving nonspecific AEDs, 35.71% were seizure-free and 64.28% were poorly controlled accounting for "pseudointractability status." When converted to broad-spectrum (specific) AEDs, 50% became well controlled. Furthermore, 26.6% of patients, who were previously on no AED prior to the clinic visit, became well controlled once placed on specific AED.

  8. Safety aspects of antiepileptic drugs--focus on pharmacovigilance.

    PubMed

    Landmark, Cecilie Johannessen; Johannessen, Svein I

    2012-01-01

    Most patients with epilepsy are dependent on a life-long pharmacological treatment with antiepileptic drugs (AEDs). AEDs include a wide range of substances that possess large pharmacological variability and are often susceptible to drug interactions and adverse drug reactions (ADRs). AEDs are increasingly used in other neurological and psychiatric disorders, and new patient groups are exposed to these drugs. The aim of the present review is to focus upon how pharmacovigilance contributes to improved safety of AEDs. The present article is a review based on searches in Pubmed on articles from the last 15 years. Strengths and challenges regarding these aspects will be highlighted and discussed. The concept of pharmacovigilance includes various methods of monitoring of large patient populations with registries and databases of surveillance of ADRs and risk of suicide and sudden unexpected death, drug utilization and prescription patterns, pregnancy and birth registries and therapeutic drug monitoring (TDM) databases for studies on pharmacological variability of AEDs in large sample sizes. Challenges for existing reporting systems and databases include differences in outcome measures and thus international comparison. Continuous focus on safety aspects of AEDs and the importance of the implementation of pharmacovigilance contribute to further optimized therapy on a large scale and for the individual patient. Copyright © 2011 John Wiley & Sons, Ltd.

  9. Modified Atkins diet may reduce serum concentrations of antiepileptic drugs.

    PubMed

    Kverneland, M; Taubøll, E; Selmer, K K; Iversen, P O; Nakken, K O

    2015-03-01

    Modified Atkins diet is a treatment option for patients with pharmacoresistant epilepsy that is not suitable for surgery. In the last few years, we have tried dietary treatment added to antiepileptic drugs (AEDs) in adult patients with severe epilepsy. To examine a possible pharmacokinetic interaction between the modified Atkins diet and AEDs. In four patients, AED serum concentrations were measured before onset and after 4 and 12 weeks on the diet. The patients used combinations of two or three AEDs, including carbamazepine, clobazam, lamotrigine, nitrazepam, oxcarbazepine, valproate, zonisamide, and topiramate. The patients did not change the type or dose of their AEDs during the diet period. After 12 weeks on the diet, the average serum concentrations of the respective AEDs were reduced by 35% (range 6-46%) compared to prediet values. Modified Atkins diet used as add-on therapy to AEDs in four patients with drug resistant seizures caused a considerable decrease in AED serum concentrations. In individual patients, this could be of clinical relevance, and we recommend that AED serum concentrations should be closely monitored when offering this diet to adults with epilepsy. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Antiepileptic drugs in women with epilepsy during pregnancy

    PubMed Central

    Gedzelman, Evan

    2012-01-01

    Prescribing antiepileptic drugs (AEDs) in pregnancy is a challenge to the clinician. A multitude of questions arise that must be addressed even prior to conception. In women with proven epilepsy, it may be dangerous to stop or even change the AED regimen during pregnancy. Changes could lead to injury or death in both the mother and the fetus. In the rare cases when discontinuing an AED is plausible, it should be done methodically in consultation with the physician prior to conception. Most women with epilepsy are consigned to continue their AEDs before, during and after pregnancy. The metabolism of AEDs may change drastically during pregnancy. These changes must be addressed by the clinician. Drug levels should be monitored consistently during pregnancy. The risks to the fetus must be delineated in terms of side effects from specific drugs as well as risks from the seizure disorder itself. Many AEDs have well known teratogenic effects, and these must be elucidated to the mother. There are risks (theoretical and evidence based) for obstetrical complications, poor neonatal outcomes, congenital malformations and even cognitive effects on the child later in life. These risks are addressed in this article with respect to individual AEDs. Recommendations include but are not limited to preconception counseling, taking folate pre and post conception, prescribing the most effective AED while minimizing risks, and avoiding polytherapy and valproate if possible. PMID:25083227

  11. Neurologist knowledge about interactions between antiepileptic drugs and contraceptive methods.

    PubMed

    Suto, Hilda S; Braga, Giordana C; Scarpellini, Giuliano R; Takeuchi, Leandro I; Martins, Ana P; Leite, João P; Vieira, Carolina S

    2016-09-01

    To evaluate neurologists' knowledge of contraceptive counseling for women receiving antiepileptic drugs (AEDs). An interview-based survey was conducted from February 2 to June 30, 2015, among neurologists working in Ribeirão Preto, Brazil. Direct interviews were conducted using a questionnaire that assessed knowledge of the pharmacological interactions between various contraceptive methods and six AEDs (carbamazepine, phenobarbital, topiramate, phenytoin, lamotrigine, and valproate) on the basis of WHO medical eligibility criteria for contraceptive use. Among 42 neurologists who participated, 32 (76%) stated that they treated women with epilepsy and provided them with counseling for family planning. Overall, 34 (81%) recommended the use of a copper intrauterine device irrespective of the AED used, and 26 (60%) stated that they co-prescribed AEDs and hormonal contraceptives. Although 39 (93%) neurologists had knowledge that AEDs might contraindicate the use of some contraceptives, their knowledge regarding the specific drug interactions was lacking. Furthermore, 34 (81%) had no knowledge of WHO medical eligibility criteria for contraceptive use. Although most neurologists interviewed had knowledge of interactions between AEDs and hormonal contraceptives, they did not know which specific AEDs interacted with these agents. Copyright © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

  12. Prediction of antiepileptic drug treatment outcomes using machine learning

    NASA Astrophysics Data System (ADS)

    Colic, Sinisa; Wither, Robert G.; Lang, Min; Zhang, Liang; Eubanks, James H.; Bardakjian, Berj L.

    2017-02-01

    Objective. Antiepileptic drug (AED) treatments produce inconsistent outcomes, often necessitating patients to go through several drug trials until a successful treatment can be found. This study proposes the use of machine learning techniques to predict epilepsy treatment outcomes of commonly used AEDs. Approach. Machine learning algorithms were trained and evaluated using features obtained from intracranial electroencephalogram (iEEG) recordings of the epileptiform discharges observed in Mecp2-deficient mouse model of the Rett Syndrome. Previous work have linked the presence of cross-frequency coupling (I CFC) of the delta (2-5 Hz) rhythm with the fast ripple (400-600 Hz) rhythm in epileptiform discharges. Using the I CFC to label post-treatment outcomes we compared support vector machines (SVMs) and random forest (RF) machine learning classifiers for providing likelihood scores of successful treatment outcomes. Main results. (a) There was heterogeneity in AED treatment outcomes, (b) machine learning techniques could be used to rank the efficacy of AEDs by estimating likelihood scores for successful treatment outcome, (c) I CFC features yielded the most effective a priori identification of appropriate AED treatment, and (d) both classifiers performed comparably. Significance. Machine learning approaches yielded predictions of successful drug treatment outcomes which in turn could reduce the burdens of drug trials and lead to substantial improvements in patient quality of life.

  13. The relationship between seizures, interictal spikes and antiepileptic drugs.

    PubMed

    Goncharova, Irina I; Alkawadri, Rafeed; Gaspard, Nicolas; Duckrow, Robert B; Spencer, Dennis D; Hirsch, Lawrence J; Spencer, Susan S; Zaveri, Hitten P

    2016-09-01

    A considerable decrease in spike rate accompanies antiepileptic drug (AED) taper during intracranial EEG (icEEG) monitoring. Since spike rate during icEEG monitoring can be influenced by surgery to place intracranial electrodes, we studied spike rate during long-term scalp EEG monitoring to further test this observation. We analyzed spike rate, seizure occurrence and AED taper in 130 consecutive patients over an average of 8.9days (range 5-17days). We observed a significant relationship between time to the first seizure, spike rate, AED taper and seizure occurrence (F (3,126)=19.77, p<0.0001). A high spike rate was related to a longer time to the first seizure. Further, in a subset of 79 patients who experienced seizures on or after day 4 of monitoring, spike rate decreased initially from an on- to off-AEDs epoch (from 505.0 to 382.3 spikes per hour, p<0.00001), and increased thereafter with the occurrence of seizures. There is an interplay between seizures, spikes and AEDs such that spike rate decreases with AED taper and increases after seizure occurrence. The direct relationship between spike rate and AEDs and between spike rate and time to the first seizure suggests that spikes are a marker of inhibition rather than excitation. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  14. Quantifying antiepileptic drug effects using intrinsic excitability measures.

    PubMed

    Meisel, Christian; Plenz, Dietmar; Schulze-Bonhage, Andreas; Reichmann, Heinz

    2016-11-01

    Pathologic increases in excitability levels of cortical tissue commonly underlie the initiation and spread of seizure activity in patients with epilepsy. By reducing the excitability levels in neural tissue, antiepileptic drug (AED) pharmacotherapy aims to reduce seizure severity and frequency. However, AEDs may also bring about adverse effects, which have been reported to increase with higher AED load. Measures that monitor the dose-dependent effects of AEDs on cortical tissue and quantify its excitability level are therefore of prime importance for efficient clinical care and treatment but have been difficult to identify. Here, we systematically analyze continuous multiday electrocorticography (ECoG) data from 10 patients under different levels of AED load and derive the recently proposed intrinsic excitability measures (IEMs) from different brain regions and across different frequency bands. We find that IEMs are significantly negatively correlated with AED load (prescribed daily dose/defined daily dose). Furthermore, we demonstrate that IEMs derived from different brain regions can robustly capture global changes in the degree of excitability. These results provide a step toward the ultimate goal of developing a reliable quantitative measure of central physiologic effects of AEDs in patients with epilepsy. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  15. Antiepileptic drugs and adverse skin reactions: An update.

    PubMed

    Błaszczyk, Barbara; Lasoń, Władysław; Czuczwar, Stanisław Jerzy

    2015-06-01

    This paper summarizes current views on clinical manifestation, pathogenesis, prognosis and management of antiepileptic drug (AED)-induced adverse skin reactions. Cochrane Central Register of Controlled Trials, MEDLINE (PubMed) and ISI Web of Knowledge were searched. The recent classification, among drug-induced skin injuries, points to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis and hypersensitivity syndrome (HSS), which may be also recognized as a drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS). The use of aromatic AEDs, e.g. phenytoin, carbamazepine, oxcarbazepine, phenobarbital, primidone, zonisamide, and lamotrigine is more frequently associated with cutaneous eruption and other signs or symptoms of drug hypersensitivity. There is a high degree of cross-reactivity (40-80%) in patients with hypersensitivity or allergic reactions to AEDs. Pharmacogenetic variations in drug biotransformation may also play a role in inducing these undesired effects. It is suggested that avoidance of specific AEDs in populations at special risk, cautious dose titration and careful monitoring of clinical response and, if applicable, laboratory parameters can minimize the serious consequences of idiosyncratic reactions.

  16. Modulating Behavior in C. elegans Using Electroshock and Antiepileptic Drugs

    PubMed Central

    Jia, Kailiang; Grill, Brock; Dawson-Scully, Ken

    2016-01-01

    The microscopic nematode Caenorhabditis elegans has emerged as a valuable model for understanding the molecular and cellular basis of neurological disorders. The worm offers important physiological similarities to mammalian models such as conserved neuron morphology, ion channels, and neurotransmitters. While a wide-array of behavioral assays are available in C. elegans, an assay for electroshock/electroconvulsion remains absent. Here, we have developed a quantitative behavioral method to assess the locomotor response following electric shock in C. elegans. Electric shock impairs normal locomotion, and induces paralysis and muscle twitching; after a brief recovery period, shocked animals resume normal locomotion. We tested electric shock responses in loss-of-function mutants for unc-25, which encodes the GABA biosynthetic enzyme GAD, and unc-49, which encodes the GABAA receptor. unc-25 and unc-49 mutants have decreased inhibitory GABAergic transmission to muscles, and take significantly more time to recover normal locomotion following electric shock compared to wild-type. Importantly, increased sensitivity of unc-25 and unc-49 mutants to electric shock is rescued by treatment with antiepileptic drugs, such as retigabine. Additionally, we show that pentylenetetrazol (PTZ), a GABAA receptor antagonist and proconvulsant in mammalian and C. elegans seizure models, increases susceptibility of worms to electric shock. PMID:27668426

  17. Influence of Enterohepatic Recycling on the Time Course of Brain-to-Blood Partitioning of Valproic Acid in Rats

    PubMed Central

    Padowski, Jeannie M.

    2012-01-01

    A widely used metric of substrate exposure in brain is the brain-to-serum partition coefficient (Kp,brain; Cbrain/Cserum), most appropriately determined at distribution equilibrium between brain tissue and serum. In some cases, Cbrain/Cserum can peak and then decrease, as opposed to monotonically increasing to a plateau, precluding accurate estimation of partitioning. This “overshoot” has been observed with compounds that undergo enterohepatic recycling (ER), such as valproic acid (VPA). Previous simulation experiments identified a relationship between overshoot in the Cbrain/Cserum versus time profile and distribution into a peripheral “compartment” (e.g., the ER loop). This study was conducted to evaluate model predictions of that relationship. Initial experiments tested the ability of activated charcoal, antibiotics, or Mrp2 deficiency to impair VPA ER in rats, thereby limiting the apparent volume of distribution associated with ER. Mrp2 deficiency (significantly) and antibiotics (moderately) interrupted VPA ER. Subsequently, brain partitioning was evaluated in the presence versus absence of ER modulation. Although overshoot was not eliminated completely, deconvolution revealed that overshoot was reduced in Mrp2-deficient and antibiotic-treated rats. Consistent with model predictions, overshoot was higher after antibiotic treatment (moderate ER interruption) than in Mrp2 deficiency (substantial ER interruption). Steady-state Kp,brain was unaffected by experimental manipulation, also consistent with model predictions. These data support the hypothesis that Cbrain/Cserum may overshoot Kp,brain based on the extent of peripheral sequestration. Consideration of this information, particularly for compounds that undergo significant extravascular distribution, may be necessary to avoid erroneous estimation of Kp,brain. PMID:22715475

  18. Assessment of the role of in situ generated (E)-2,4-diene-valproic acid in the toxicity of valproic acid and (E)-2-ene-valproic acid in sandwich-cultured rat hepatocytes

    SciTech Connect

    Surendradoss, Jayakumar; Chang, Thomas K.H.; Abbott, Frank S.

    2012-11-01

    Valproic acid (VPA) undergoes cytochrome P450-mediated desaturation to form 4-ene-VPA, which subsequently yields (E)-2,4-diene-VPA by β-oxidation. Another biotransformation pathway involves β-oxidation of VPA to form (E)-2-ene-VPA, which also generates (E)-2,4-diene-VPA by cytochrome P450-mediated desaturation. Although the synthetic form of (E)-2,4-diene-VPA is more hepatotoxic than VPA as shown in various experimental models, there is no conclusive evidence to implicate the in situ generated (E)-2,4-diene-VPA in VPA hepatotoxicity. The present study investigated the effects of modulating the in situ formation of (E)-2,4-diene-VPA on markers of oxidative stress (formation of 2′,7′-dichlorofluorescein; DCF), steatosis (accumulation of BODIPY 558/568 C{sub 12}), necrosis (release of lactate dehydrogenase; LDH), and on cellular total glutathione (GSH) levels in sandwich-cultured rat hepatocytes treated with VPA or (E)-2-ene-VPA. Treatment with either of these chemicals alone increased each of the toxicity endpoints. In VPA-treated hepatocytes, (E)-2,4-diene-VPA was detected only at trace levels, even after phenobarbital (PB) pretreatment and there was no effect on the toxicity of VPA. Furthermore, pretreatment with a cytochrome P450 enzyme inhibitor, 1-aminobenzotriazole (1-ABT), did not influence the extent of VPA toxicity in both PB-pretreated and vehicle-pretreated hepatocytes. However, in (E)-2-ene-VPA-treated hepatocytes, PB pretreatment greatly enhanced the levels of (E)-2,4-diene-VPA and this was accompanied by a further enhancement of the effects of (E)-2-ene-VPA on DCF formation, BODIPY accumulation, LDH release, and GSH depletion. Pretreatment with 1-ABT reduced the concentrations of (E)-2,4-diene-VPA and the extent of (E)-2-ene-VPA toxicity; however, this occurred in PB-pretreated hepatocytes, but not in control hepatocytes. In conclusion, in situ generated (E)-2,4-diene-VPA is not responsible for the hepatocyte toxicity of VPA, whereas it

  19. Histone Deacetylase Inhibitor Valproic Acid Promotes the Differentiation of Human Induced Pluripotent Stem Cells into Hepatocyte-Like Cells

    PubMed Central

    Kondo, Yuki; Iwao, Takahiro; Yoshihashi, Sachimi; Mimori, Kayo; Ogihara, Ruri; Nagata, Kiyoshi; Kurose, Kouichi; Saito, Masayoshi; Niwa, Takuro; Suzuki, Takayoshi; Miyata, Naoki; Ohmori, Shigeru; Nakamura, Katsunori; Matsunaga, Tamihide

    2014-01-01

    In this study, we aimed to elucidate the effects and mechanism of action of valproic acid on hepatic differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells. Human induced pluripotent stem cells were differentiated into endodermal cells in the presence of activin A and then into hepatic progenitor cells using dimethyl sulfoxide. Hepatic progenitor cells were matured in the presence of hepatocyte growth factor, oncostatin M, and dexamethasone with valproic acid that was added during the maturation process. After 25 days of differentiation, cells expressed hepatic marker genes and drug-metabolizing enzymes and exhibited drug-metabolizing enzyme activities. These expression levels and activities were increased by treatment with valproic acid, the timing and duration of which were important parameters to promote differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells into hepatocytes. Valproic acid inhibited histone deacetylase activity during differentiation of human induced pluripotent stem cells, and other histone deacetylase inhibitors also enhanced differentiation into hepatocytes. In conclusion, histone deacetylase inhibitors such as valproic acid can be used to promote hepatic differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells. PMID:25084468

  20. Pathological case of the month: sudden death in a child as a result of pancreatitis during valproic acid therapy.

    PubMed

    Mileusnic, Darinka; Donoghue, Edmund R; Lifschultz, Barry D

    2002-01-01

    Valproic acid is a widely used drug in the treatment of epilepsy and, compared to other anticonvulsant drugs, is considered safe. The most common side effects of valproic acid ingestion or therapy are transient nausea, vomiting, abdominal cramps, and diarrhea. Most of these complaints are mild. However, more serious adverse reactions can occur such as hepatotoxicity and pancreatitis. It has been proposed that, whenever possible, valproic acid not be used in the younger child, the child with a severe seizure disorder or other neurological disorders, mental retardation, developmental delay, organic brain disease, congenital abnormalities, or the child who is taking multiple anticonvulsant drugs, as these factors may increase the likelihood of hepatotoxicity and/or pancreatitis. In the present report, we describe a fatal case of acute hemorrhagic pancreatitis in a four and a half-year-old Hispanic female child who was receiving valproic acid in combination with another anticonvulsant drug for control of focal seizures. The patient also received the macrolide antibiotic azithromycin. For pediatricians and forensic pathologists valproic acid-induced pancreatitis can be a challenging diagnosis which must not be mistaken for abdominal trauma. We discuss the workup of the patient and differential diagnosis.

  1. Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress

    SciTech Connect

    Zhai, Yingying; Chen, Xi; Yu, Dehai; Li, Tao; Cui, Jiuwei; Wang, Guanjun; Hu, Ji-Fan; Li, Wei

    2015-09-10

    Histone deacetylase inhibitor valproic acid (VPA) has been used to increase the reprogramming efficiency of induced pluripotent stem cell (iPSC) from somatic cells, yet the specific molecular mechanisms underlying this effect is unknown. Here, we demonstrate that reprogramming with lentiviruses carrying the iPSC-inducing factors (Oct4-Sox2-Klf4-cMyc, OSKM) caused senescence in mouse fibroblasts, establishing a stress barrier for cell reprogramming. Administration of VPA protected cells from reprogramming-induced senescent stress. Using an in vitro pre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway. In addition, VPA also inhibited the G2/M phase blockage derived from the senescence stress. These findings highlight the role of VPA in breaking the cell senescence barrier required for the induction of pluripotency. - Highlights: • Histone deacetylase inhibitor valproic acid enhances iPSC induction. • Valproic acid suppresses reprogramming-induced senescence stress. • Valproic acid downregulates the p16/p21 pathway in reprogramming. • This study demonstrates a new mechanistic role of valproic acid in enhancing reprogramming.

  2. Histone deacetylase inhibitor valproic acid promotes the differentiation of human induced pluripotent stem cells into hepatocyte-like cells.

    PubMed

    Kondo, Yuki; Iwao, Takahiro; Yoshihashi, Sachimi; Mimori, Kayo; Ogihara, Ruri; Nagata, Kiyoshi; Kurose, Kouichi; Saito, Masayoshi; Niwa, Takuro; Suzuki, Takayoshi; Miyata, Naoki; Ohmori, Shigeru; Nakamura, Katsunori; Matsunaga, Tamihide

    2014-01-01

    In this study, we aimed to elucidate the effects and mechanism of action of valproic acid on hepatic differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells. Human induced pluripotent stem cells were differentiated into endodermal cells in the presence of activin A and then into hepatic progenitor cells using dimethyl sulfoxide. Hepatic progenitor cells were matured in the presence of hepatocyte growth factor, oncostatin M, and dexamethasone with valproic acid that was added during the maturation process. After 25 days of differentiation, cells expressed hepatic marker genes and drug-metabolizing enzymes and exhibited drug-metabolizing enzyme activities. These expression levels and activities were increased by treatment with valproic acid, the timing and duration of which were important parameters to promote differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells into hepatocytes. Valproic acid inhibited histone deacetylase activity during differentiation of human induced pluripotent stem cells, and other histone deacetylase inhibitors also enhanced differentiation into hepatocytes. In conclusion, histone deacetylase inhibitors such as valproic acid can be used to promote hepatic differentiation from human induced pluripotent stem cell-derived hepatic progenitor cells.

  3. [Antiepileptic drugs as mood stabilizers: what did we learn from the epileptology?].

    PubMed

    Rajna, Péter

    2008-09-30

    Author summarizes the practical aspects of psychiatric application of mood stabilizing antiepileptic drugs. He observes how to transfer experiences taken from the "epileptologic" practice into the psychiatric care of bipolar patients. He shortly demonstrates the relevant information on the mechanisms of action, controversies and possible clinical effects influenced by the seizure inhibiting effect of the concerning molecules. By the opinion of the author the clinical importance of pharmacokinetic parameters are underestimated in the psychiatric practice. Therefore--as an original approach in the literature--he summarizes the detailed clinical indications of serum level measurements of antiepileptic drugs applied in psychiatry as mood stabilizers. The therapeutic experiences in epilepsy added a lot of practices for the most effective dosing, building, tapering and exchange of the mood stabilizer antiepileptics. Drug interactions (appear among the psychotropic drugs or with the commonly used medicines). As in any chronic therapies the main condition of patient's compliance is the lacking or very mild presence of the applied therapy. The paper discusses the most frequently occurring and drug-specific side effects in table forms. Using the term of "relative therapeutic potential" the need of balance between the efficacy (influenced by the choice and dosing) and the tolerance are pointed. Rules of application can change significantly in special populations like in pregnancy, obesity, chronic diseases or in chronic comorbid states and in case of polytherapy. As for the special therapeutic effects, the experiences are not completed even in group of antiepileptics: we have larger and more favorable knowledge on the traditional drugs (carbamazepine and valproate) and on lamotrigine (from the newer generation) but promising but not enough information exists on the newest antiepileptic molecules. Further targeted studies are needed for the identification and positioning of

  4. Overview of accessibility and quality of antiepileptic drugs in Madagascar.

    PubMed

    Nizard, Mandy; Jost, Jérémy; Tanamasoandro, Rakotovao; Andriambololona, Rindra; Megherbi, Mehdi; Solofomalala, Gaetan Duval; Marquet, Pierre; Preux, Pierre-Marie; Ratsimbazafy, Voa

    2016-10-01

    To determine the accessibility of treatment and the quality of antiepileptic drugs (AEDs) in the Haute Matsiatra district of Madagascar. Cross-sectional descriptive study and interviews. Samples of 10 units of each available AED were collected, and the active ingredient was quantified by reversed-phase high-performance liquid chromatography (RP-HPLC) with photodiode-array UV detection. The quality of an AED was considered satisfactory if the quantity of active ingredient in each tablet was in the range ±15% of the average value according to the European Pharmacopeia (6th edition, 2008). The area was well served with health infrastructure but rescue facilities were poorly distributed. Available AEDs were all first-generation, and 73% were generic formulations. People with epilepsy (PWE) surveyed consulted traditional healers and most were treated with plants. PWE did not consider themselves sick but believed they were "possessed"; they consulted a doctor only immediately after a seizure, following the advice of traditional healers. The most prescribed AED was phenobarbital, costing between 0.03 and 0.12 US Dollar (US$) per 100mg. The purchase of full treatment was difficult for 77% of PWE and as a result, 39% took nothing. The quality of AEDs were considered unsatisfactory in 2.8% of cases. The AEDs collected in Haute Matsiatra were globally of good quality. The main limiting elements were a lack of knowledge among PWE that epilepsy is a disease, and the cost of traditional treatments. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  5. Comparative effectiveness of generic versus brand-name antiepileptic medications.

    PubMed

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

    2015-11-01

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

  6. Intranasal delivery of antiepileptic medications for treatment of seizures.

    PubMed

    Wermeling, Daniel P

    2009-04-01

    Acute isolated seizure, repetitive or recurrent seizures, and status epilepticus are all deemed medical emergencies. Mortality and worse neurologic outcome are directly associated with the duration of seizure activity. A number of recent reviews have described consensus statements regarding the pharmacologic treatment protocols for seizures when patients are in pre-hospital, institutional, and home-bound settings. Benzodiazepines, such as lorazepam, diazepam, midazolam, and clonazepam are considered to be medications of first choice. The rapidity by which a medication can be delivered to the systemic circulation and then to the brain plays a significant role in reducing the time needed to treat seizures and reduce opportunity for damage to the CNS. Speed of delivery, particularly outside of the hospital, is enhanced when transmucosal routes of delivery are used in place of an intravenous injection. Intranasal transmucosal delivery of benzodiazepines is useful in reducing time to drug administration and cessation of seizures in the pre-hospital setting, when actively seizing patients arrive in the emergency room, and at home where caregivers treat their dependents. This review summarizes factors to consider when choosing a benzodiazepine for intranasal administration, including formulation and device considerations, pharmacology and pharmacokinetic/pharmacodynamic profiles. A review of the most relevant clinical studies in epilepsy patients will provide context for the relative success of this technique with a number of benzodiazepines and relatively less sophisticated nasal preparations. Neuropeptides delivered intranasally, crossing the blood-brain barrier via the olfactory system, may increase the availability of medications for treatment of epilepsy. Consequently, there remains a significant unmet medical need to serve the pharamcotherapeutic requirements of epilepsy patients through commercial development and marketing of intranasal antiepileptic products.

  7. Newer antiepileptic drug use and other factors decreasing hospital encounters.

    PubMed

    Faught, Edward; Helmers, Sandra L; Begley, Charles E; Thurman, David J; Dilley, Cynthia; Clark, Chris; Fritz, Patty

    2015-04-01

    A retrospective analysis was conducted in one claims database and was confirmed in a second independent database (covering both commercial and government insurance plans between 11/2009 and 9/2011) for the understanding of factors influencing antiepileptic drug (AED) use and the role of AEDs and other health-care factors in hospital encounters. In both datasets, epilepsy cases were identified by AED use and epilepsy diagnosis coding. Variables analyzed for effect on hospitalization rates were as follows: (1) use of first-generation AEDs or second-generation AEDs, (2) treatment changes, and (3) factors that may affect AED choice. Lower rates of epilepsy-related hospital encounters (encounters with an epilepsy diagnosis code) were associated with use of second-generation AEDs, deliberate treatment changes, and treatment by a neurologist. Epilepsy-related hospital encounters were more frequent for patients not receiving an AED and for those with greater comorbidities. On average, patients taking ≥1 first-generation AED experienced epilepsy-related hospitalizations every 684days, while those taking ≥1second-generation AED were hospitalized every 1001days (relative risk reduction of 31%, p<0.01). Prescriptions for second-generation AEDs were more common among neurologists and among physicians near an epilepsy center. Use of second-generation AEDs, access to specialty care, and deliberate efforts to change medications following epilepsy-related hospital encounters improved outcomes of epilepsy treatment based on average time between epilepsy-related hospital encounters. These factors may be enhanced by public health policies, private insurance reimbursement policies, and education of patients and physicians. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Assessing bioequivalence of generic modified-release antiepileptic drugs.

    PubMed

    Johnson, Emily L; Chang, Yi-Ting; Davit, Barbara; Gidal, Barry E; Krauss, Gregory L

    2016-04-26

    The purpose of this study was to determine how closely generic modified-release antiepileptic drugs (MR-AEDs) resemble reference (brand) formulations by comparing peak concentrations (Cmax), total absorption (area under the curve [AUC]), time to Cmax (Tmax), intersubject variability, and food effects between generic and reference products. We tabulated Cmax and AUC data from the bioequivalence (BE) studies used to support the approvals of generic Food and Drug Administration-approved MR-AEDs. We compared differences in 90% confidence intervals of the generic/reference AUC and Cmax geometric mean ratios, and intersubject variability, Tmax and delivery profiles and food effects. Forty-two MR-AED formulations were studied in 3,175 healthy participants without epilepsy in 97 BE studies. BE ratios for AUC and Cmax were similar between most generic and reference products: AUC ratios varied by >15% in 11.4% of BE studies; Cmax varied by >15% in 25.8% of studies. Tmax was more variable, with >30% difference in 13 studies (usually delayed in the fed compared to fasting BE studies). Generic and reference MR products had similar intersubject variability. Immediate-release AEDs showed less intersubject variability in AUC than did MR-AEDs. Most generic and reference MR-AEDs have similar AUC and Cmax values. Ratios for some products, however, are near acceptance limits and Tmax values may vary. Food effects are common with MR-AED products. High variability in pharmacokinetic values for once-a-day MR-AEDs suggests their major advantage compared to immediate-release AED formulations may be the convenience of less frequent dosing to improve adherence. © 2016 American Academy of Neurology.

  9. The experience of discontinuing antiepileptic drug treatment: an exploratory investigation.

    PubMed

    Kilinç, S; Campbell, C

    2008-09-01

    Between 60% and 70% of people with epilepsy become seizure free and may choose to withdraw from antiepileptic medication. Numerous studies discuss possible factors which may influence seizure recurrence following discontinuation. However, few studies attempt to explore the decision-making process from the perspective of the patient. It is believed this is the first study to explore patients' experience of discontinuing medication following a seizure-free period of 2 years. Semi-structured interviews were conducted with twelve people with epilepsy who had attempted withdrawal from their medication. All twelve of the participants lived in the North-East of England. A phenomenological approach was taken in order to gain an in depth understanding of their withdrawal decisions. Five themes emerged from the interviews. Principally, the timing of when to withdraw was a key concern, as well as the uncertainty of seizure recurrence, issues with medication and the embarrassment of being diagnosed with epilepsy. Those who unsuccessfully withdrew from medication discussed their acceptance of the condition. Mixed feelings regarding satisfaction with G.P. support were also reported. Incorporating the themes into the Theory of Planned Behaviour [Ajzen I. In: Marks DF, editor. The health psychology reader. London: Sage; 1985] provides a model of the withdrawal decision-making process based on the experiences of those who have made the decision. There is a paucity of research investigating the withdrawal decision, therefore the findings from this study should be used for the production of appropriate and relevant information regarding the key issues which have been raised regarding withdrawal decisions and support those making the decision.

  10. Adverse effects of antiepileptic drugs in North Indian pediatric outpatients.

    PubMed

    Bansal, Dipika; Azad, Chandrika; Kaur, Manpreet; Rudroju, Neelima; Vepa, Pravallika; Guglani, Vishal

    2013-01-01

    The present study investigates the pattern and predictors of treatment-emergent adverse drug reactions (ADRs) in children diagnosed with epilepsy. We conducted prospective observational study in a tertiary care teaching hospital on 277 epileptic children. Antiepileptic drug (AED)-associated ADRs, demographic and clinical characteristics, AED regimen, and so on were recorded. Causality, severity, and preventability were performed by World Health Organization-Uppsala Monitoring Center scale, Hartwig's severity scale, and Schumock and Thornton questionnaire, respectively. Of the enrolled population, 53% children had symptomatic epilepsy, and 51% were in 5- to 10-year age group. More than two-thirds of children were on monotherapy, with phenytoin (n = 176, 63.5%) being the most common AED. Three hundred fifty-three AED-related ADRs were recorded in 175 children (63.2%). Poor scholastic performance (19%) was the most common ADR, followed by gum hypertrophy (13.3%), headache (10.2%), behavioral problems (5.7%), drowsiness (5.7%), and others. Two hundred sixteen ADRs were probable, and 126 ADRs were possible. Severe ADRs were noted in 6 children. Girls (odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.07-3.45; P = 0.03), children with secondary epilepsy (OR, 3.31; 95% CI, 1.76-6.23; P ≤ 0.001), children older than 5 years (5-10 years; OR, 6.28; 95% CI, 2.79-14.12; P ≤ 0.001), and those older than 10 years (OR, 9.04; 95% CI, 3.69-22.17; P ≤ 0.001) were found to be at higher risk of experiencing ADRs. Monotherapy was the preferred treatment. Phenytoin was the most common ADR causative agent. Female sex, symptomatic epilepsy, and older age (> 5 years) were found to be associated with higher probability of ADR development.

  11. Polycystic ovary syndrome in patients on antiepileptic drugs

    PubMed Central

    Viswanathan, Lakshminarayanapuram G.; Satishchandra, Parthasarathy; Bhimani, Bipin C.; Reddy, Janardhan YC; Rama Murthy, Batchu S.; Subbakrishna, Doddaballapura K.; Sinha, Sanjib

    2016-01-01

    Objective: This study aims to discuss the prevalence of polycystic ovary (PCO) and Polycystic ovary syndrome (PCOS) in women with epilepsy (WWE) on valproate (VPA), carbamazepine (CBZ), or phenobarbitone (PB), drug naive WWE and women with bipolar affective disorder (BPAD) on VPA. Materials and Methods: This prospective study included 190 women aged 18–45 years, who had epilepsy or BPAD (on VPA), and consented for study. Patients were grouped as Group 1 (n = 40): WWE on VPA, Group 2 (n = 50): WWE on CBZ, Group 3 (n = 50): WWE on PB, Group 4 (n = 30): drug naïve WWE, and Group 5 (n = 20): women with BPAD on VPA. All women were interviewed for medical, menstrual, drug and treatment history, nature of epilepsy, and seizure control. Chi-square test and Fisher's exact test were done to compare results between the groups. Results: Fifty-two women (52/190; 27.4%) had menstrual disturbances, in which oligomenorrhea was the most common (55.8%). There was a significant difference in the occurrence of PCOS in patients on VPA versus normal population (P = 0.05) and patients on other antiepileptic drugs (AEDs) (P = 0.02). There was, however, no significant difference in the occurrence of PCO between patients on VPA and the untreated epileptic women. VPA group (Epilepsy + BPAD) had a significantly higher occurrence of obesity than other treatment groups (P = 0.043, OR = 2.11). Conclusions: The study observed significantly higher occurrence of PCO in patients on VPA compared to other AEDs and the normal population. The importance of proper clinical evaluation before initiating VPA is highlighted. PMID:27570385

  12. Adsorption of the antiepileptic carbamazepine onto agricultural soils.

    PubMed

    Calisto, Vania; Esteves, Valdemar I

    2012-05-01

    Carbamazepine is an antiepileptic pharmaceutical which is commonly found in environmental matrices. It passes through wastewater treatment plants (WWTPs) almost completely unaffected and has been found to be highly persistent in the environment. The application of sludge in agricultural fields and the use of WWTP effluents for irrigation constitute a potential source of soil contamination. Consequently, the assessment of the interaction between carbamazepine and soils is of crucial importance to understand its fate in the environment. To monitor the sorption behavior of carbamazepine onto agricultural soils, batch equilibrium experiments were performed using soils subjected to distinct long-term fertilizations. In order to follow the adsorption experiments, an UV spectral deconvolution methodology was applied and the results compared with those from micellar electrokinetic chromatography. The results obtained by both methods did not present significant statistical differences at 95% confidence level. Therefore, it was proven that, in the context of adsorption studies, UV spectral deconvolution is a valid alternative to common chromatographic methods, with the major advantage of being a simple and fast procedure. The adsorption of carbamazepine onto the selected soils was satisfactorily described by the Freundlich model. The obtained Freundlich parameters (K(F)) (between 1.79 ± 0.07 and 4.8 ± 0.2 mg kg(-1) (mg L(-1))(-N)) indicate that the adsorption behavior of carbamazepine is dependent on the soil fertilization. Also, it is not extensively sorbed, indicating that carbamazepine present in soils can be a potential source of contamination of surface and ground waters through run-off and infiltration.

  13. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatraemia associated with valproic Acid: four case reports from the Netherlands and a case/non-case analysis of vigibase.

    PubMed

    Beers, Erna; van Puijenbroek, Eugène P; Bartelink, Imke H; van der Linden, Carolien M J; Jansen, Paul A F

    2010-01-01

    The Netherlands Pharmacovigilance Centre Lareb received four cases of severe symptomatic hyponatraemia or syndrome of inappropriate antidiuretic hormone secretion (SIADH) in association with valproic acid use, in which a causal relationship was suspected. This study describes these cases and gives support for this association from Vigibase, the adverse drug reaction (ADR) database of the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre. Cases of hyponatraemia in valproic acid users are described. In a case/non-case analysis, the strength of the association between reported cases of hyponatraemia and the use of valproic acid in Vigibase was established by calculating a reporting odds ratio, adjusted for possible confounding by concomitant medication. Four females aged 57, 67, 71 and 88 years developed symptomatic hyponatraemia or SIADH after starting valproic acid. Despite concomitant medication or co-morbidity, a causal relationship was plausible. In Vigibase, valproic acid is disproportionally associated with hyponatraemia and SIADH (corrected reporting odds ratio 1.83 [95% CI 1.61, 2.08]). Based on the described cases and the reports from Vigibase, a causal relationship between valproic acid use and hyponatraemia or SIADH can be suspected. The mechanism by which valproic acid could cause hyponatraemia or SIADH has not been fully elucidated. Valproic acid use could lead to reduced sensitivity of hypothalamic osmoreceptors. It also might directly affect tubular cell function, thereby leading to SIADH. It might be expected that a combination of effects on the osmoreceptors and a lack of compensation of the salt-water unbalance by the nephrons causes SIADH in some patients using valproic acid. It could be a dose- or concentration-related adverse effect. In this report, severe symptomatic hyponatraemia and SIADH have been associated with the use of valproic acid. With this study, not only is the number of published cases

  14. Mechanisms of amiodarone and valproic acid induced liver steatosis in mouse in vivo act as a template for other hepatotoxicity models.

    PubMed

    Vitins, Alexa P; Kienhuis, Anne S; Speksnijder, Ewoud N; Roodbergen, Marianne; Luijten, Mirjam; van der Ven, Leo T M

    2014-08-01

    Liver injury is the leading cause of drug-induced toxicity. For the evaluation of a chemical compound to induce toxicity, in this case steatosis or fatty liver, it is imperative to identify markers reflective of mechanisms and processes induced upon exposure, as these will be the earliest changes reflective of disease. Therefore, an in vivo mouse toxicogenomics study was completed to identify common pathways, nuclear receptor (NR) binding sites, and genes regulated by three known human steatosis-inducing compounds, amiodarone (AMD), valproic acid (VPA), and tetracycline (TET). Over 1, 4, and 11 days of treatment, AMD induced changes in clinical chemistry parameters and histopathology consistent with steatosis. Common processes and NR binding sites involved in lipid, retinol, and drug metabolism were found for AMD and VPA, but not for TET, which showed no response. Interestingly, the pattern of enrichment of these common pathways and NR binding sites over time was unique to each compound. Eleven biomarkers of steatosis were identified as dose responsive and time sensitive to toxicity for AMD and VPA. Finally, this in vivo mouse study was compared to an AMD rat in vivo, an AMD mouse primary hepatocyte, and a VPA human primary hepatocyte study to identify concordance for steatosis. We conclude that concordance is found on the process level independent of species, model or dose*time point.

  15. N-(2-hydroxyphenyl)-2-propylpentanamide, a valproic acid aryl derivative designed in silico with improved anti-proliferative activity in HeLa, rhabdomyosarcoma and breast cancer cells.

    PubMed

    Prestegui-Martel, Berenice; Bermúdez-Lugo, Jorge Antonio; Chávez-Blanco, Alma; Dueñas-González, Alfonso; García-Sánchez, José Rubén; Pérez-González, Oscar Alberto; Padilla-Martínez, Itzia Irene; Fragoso-Vázquez, Manuel Jonathan; Mendieta-Wejebe, Jessica Elena; Correa-Basurto, Ana María; Méndez-Luna, David; Trujillo-Ferrara, José; Correa-Basurto, José

    2016-01-01

    Epigenetic alterations are associated with cancer and their targeting is a promising approach for treatment of this disease. Among current epigenetic drugs, histone deacetylase (HDAC) inhibitors induce changes in gene expression that can lead to cell death in tumors. Valproic acid (VPA) is a HDAC inhibitor that has antitumor activity at mM range. However, it is known that VPA is a hepatotoxic drug. Therefore, the aim of this study was to design a set of VPA derivatives adding the arylamine core of the suberoylanilide hydroxamic acid (SAHA) with different substituents at its carboxyl group. These derivatives were submitted to docking simulations to select the most promising compound. The compound 2 (N-(2-hydroxyphenyl)-2-propylpentanamide) was the best candidate to be synthesized and evaluated in vitro as an anti-cancer agent against HeLa, rhabdomyosarcoma and breast cancer cell lines. Compound 2 showed a better IC50 (μM range) than VPA (mM range) on these cancer cells. And also, 2 was particularly effective on triple negative breast cancer cells. In conclusion, 2 is an example of drugs designed in silico that show biological properties against human cancer difficult to treat as triple negative breast cancer.

  16. Association of antiepileptic drug usage, trace elements and thyroid hormone status.

    PubMed

    Zevenbergen, Chantal; Korevaar, Tim I M; Schuette, Andrea; Peeters, Robin P; Medici, Marco; Visser, Theo J; Schomburg, Lutz; Visser, W Edward

    2016-04-01

    Levels of thyroid hormone (TH) and trace elements (copper (Cu) and selenium (Se)) are important for development and function of the brain. Anti-epileptic drugs (AEDs) can influence serum TH and trace element levels. As the relationship between AEDs, THs, and trace elements has not yet been studied directly, we explored these interactions. In total 898 participants, from the Thyroid Origin of Psychomotor Retardation study designed to investigate thyroid parameters in subjects with intellectual disability (ID), had data available on serum Se, Cu, thyroid stimulating hormone (TSH), free thyroxine (FT4), tri-iodothyronine (T3), reverse T3, T4, and thyroxine-binding globulin (TBG); 401 subjects were on AED treatment. Differences in trace elements according to medication usage was investigated using ANOVA, and associations between trace elements and thyroid parameters were analysed using (non-) linear regression models. Study participants were not deficient in any of the trace elements analyzed. AED (carbamazepine, valproate and phenytoin) usage was negatively associated with serum Se and showed compound-specific associations with Cu levels. After correction for drug usage, Se was positively associated with TSH levels, negatively associated with FT4 levels, and positively with T3 levels. Cu was positively associated with T4, T3, and rT3, which was largely dependent on TBG levels. The subjects with ID did not display profound deficiencies in trace element levels. AEDs were associated with serum Se and Cu levels, while serum Se and Cu were also associated with thyroid parameters. Further studies on the underlying mechanisms and potential clinical importance are warranted. © 2016 European Society of Endocrinology.

  17. High-speed simultaneous determination of nine antiepileptic drugs using liquid chromatography-mass spectrometry.

    PubMed

    Subramanian, Murali; Birnbaum, Angela K; Remmel, Rory P

    2008-06-01

    Therapeutic drug monitoring of antiepileptic drugs (AEDs) is important and widely practiced. However, simultaneous AED assays usually concentrate only on old or new AEDs. A new simultaneous assay was developed to monitor both older and newer AEDs in the same sample. This assay measures zonisamide (ZNS), lamotrigine (LTG), topiramate (TPM), phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), carbamazepine-10,11-diol (CBZ-Diol), 10-hydroxycarbamazepine (MHD), and carbamazepine-10,11-epoxide (CBZ-E). Sample pretreatment consisted of a single solid-phase extraction (SPE) for all AEDs in a 100-microL plasma sample. HPLC separation was achieved on a Shimdazu Shimpack XR-ODS (4.6 id x 50 mm, 2.2-mum) column with a gradient mobile phase of acetate buffer, methanol, acetonitrile, and tetrahydrofuran. Four internal standards were used. Detection was achieved by atmospheric pressure chemical ionization mass spectrometry (APCI-MS) in selected-ion monitoring (SIM) mode with constant polarity switching. High recovery (88%-96%) was obtained for all compounds by SPE. Linearity was observed throughout an 80-fold concentration range, with correlation coefficient (r) values higher than 0.99 for all AEDs. For the standards, the accuracy ranged from 89.3% to 111.8%. The within-run coefficient of variation (CVw) value was < or =9.7%, the between-run coefficient of variation (CVb) was < or =16.2%, and the total variability (CVt) was < or =16.8%. For the quality controls (QCs), accuracy ranged from 89.3% to 108.8%, CVw was < or =9.6%, CVb was < or =14.1%, and CVt was < or =15.1%. The correlation r values for comparison of this assay with existing validated assays in our laboratory (GC-MS or LC-MS) were 0.95, 0.91, 0.87, 0.95, and 0.95 for PHT, LTG, CBZ, CBZ-E, and CBZ-Diol, respectively.

  18. Examination by EPR spectroscopy of free radicals in melanins isolated from A-375 cells exposed on valproic acid and cisplatin.

    PubMed

    Chodurek, Ewa; Zdybel, Magdalena; Pilawa, Barbara; Dzierzewicz, Zofia

    2012-01-01

    Drug binding by melanin biopolymers influence the effectiveness of the chemotherapy, radiotherapy and photodynamic therapy. Free radicals of melanins take part in formation of their complex with drugs. The aim of this work was to determine the effect of the two compounds: valproic acid (VPA) and cisplatin (CPT) on free radicals properties of melanin isolated from A-375 melanoma cells. Free radicals were examined by an X-band (9.3 GHz) electron paramagnetic resonance (EPR) spectroscopy. EPR spectra were measured for the model synthetic eumelanin - DOPA-melanin, the melanin isolated from the control A-375 cells and these cells treated by VPA, CPT and both VPA and CPT. For all the examined samples broad EPR lines (deltaBpp: 0.48-0.68 mT) with g-factors of 2.0045-2.0060 characteristic for o-semiquinone free radicals were observed. Free radicals concentrations (N) in the tested samples, g-factors, amplitudes (A), integral intensities (I) and linewidths (deltaBpp) of the EPR spectra, were analyzed. The EPR lines were homogeneously broadened. Continuous microwave saturation of the EPR spectra indicated that slow spin-lattice relaxation processes existed in all the tested melanin samples. The relatively slowest spin-lattice relaxation processes characterized melanin isolated from A-375 cells treated with both VPA and CPT. The changes of the EPR spectra with increasing microwave power in the range of 2.2-70 mW were evaluated. Free radicals concentrations in the melanin from A-375 cells were higher than in the synthetic DOPA-melanin. The strong increase of free radicals concentration in the melanin from A-375 cells was observed after their treating by VPA. CPT also caused the increase of free radicals concentrations in the examined natural melanin. The free radicals concentration in melanin isolated from A-375 cells treated with both VPA and CPT was slightly higher than those in melanin from the control cells.

  19. Design and pharmacological activity of glycinamide and N-methoxy amide derivatives of analogs and constitutional isomers of valproic acid.

    PubMed

    Pessah, Neta; Yagen, Boris; Hen, Naama; Shimshoni, Jakob A; Wlodarczyk, Bogdan; Finnell, Richard H; Bialer, Meir

    2011-11-01

    A series of glycinamide conjugates and N-methoxy amide derivatives of valproic acid (VPA) analogs and constitutional isomers were synthesized and evaluated for anticonvulsant activity. Of all compounds synthesized and tested, only N-methoxy-valnoctamide (N-methoxy-VCD) possessed better activity than VPA in the following anticonvulsant tests: maximal electroshock, subcutaneous metrazol, and 6-Hz (32-mA) seizure tests. In mice, the ED(50) values of N-methoxy-VCD were 142 mg/kg (maximal electroshock test), 70 mg/kg (subcutaneous metrazol test), and 35 mg/kg (6-Hz test), and its neurotoxicity TD(50) was 118 mg/kg. In rats, the ED(50) of N-methoxy-VCD in the subcutaneous metrazol test was 36 mg/kg and its protective index (PI=TD(50)/ED(50)) was >5.5. In the rat pilocarpine-induced status epilepticus model, N-methoxy-VCD demonstrated full protection at 200mg/kg, without any neurotoxicity. N-Methoxy-VCD was tested for its ability to induce teratogenicity in a mouse strain susceptible to VPA-induced teratogenicity and was found to be nonteratogenic, although it caused some resorptions. Nevertheless, a safety margin was still maintained between the ED(50) values of N-methoxy-VCD in the mouse subcutaneous metrazol test and the doses that caused the resorptions. On the basis of these results, N-methoxy-VCD is a good candidate for further evaluation as a new anticonvulsant and central nervous system drug. Copyright © 2011. Published by Elsevier Inc.

  20. POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders

    PubMed Central

    Saneto, Russell P.; Lee, Inn-Chi; Koenig, Mary Kay; Bao, Xinhua; Weng, Shao-Wen; Naviaux, Robert K.; Wong, Lee-Jun C.

    2011-01-01

    Purpose To review our clinical experience and determine if there are appropriate signs and symptoms to consider POLG sequencing prior to valproic acid (VPA) dosing in patients with seizures. Methods Four patients who developed VPA-induced hepatotoxicity were examined for POLG sequence variations. A subsequent chart review was used to describe clinical course prior to and after VPA dosing. Results Four patients of multiple different ethnicities, age 3–18 years, developed VPA-induced hepatotoxicity. All were given VPA due to intrac partial seizures. Three of the patients had developed epilepsia partialis continua. The time from VPA exposure to liver failure was between 2 and 3 months. Liver failure was reversible in one patient. Molecular studies revealed homozygous p.R597W or p.A467T mutations in two patients. The other two patients showed compound heterozygous mutations, p.A467T/p.Q68X and p.L83P/p.G888S. Clinical findings and POLG mutations were diagnostic of Alpers–Huttenlocher syndrome. Conclusion Our cases underscore several important findings: POLG mutations have been observed in every ethnic group studied to date; early predominance of epileptiform discharges over the occipital region is common in POLG-induced epilepsy; the EEG and MRI findings varying between patients and stages of the disease; and VPA dosing at any stage of Alpers–Huttenlocher syndrome can precipitate liver failure. Our data support an emerging proposal that POLG gene testing should be considered in any child or adolescent who presents or develops intractable seizures with or without status epilepticus or epilepsia partialis continua, particularly when there is a history of psychomotor regression. PMID:20138553

  1. POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders.

    PubMed

    Saneto, Russell P; Lee, Inn-Chi; Koenig, Mary Kay; Bao, Xinhua; Weng, Shao-Wen; Naviaux, Robert K; Wong, Lee-Jun C

    2010-04-01

    To review our clinical experience and determine if there are appropriate signs and symptoms to consider POLG sequencing prior to valproic acid (VPA) dosing in patients with seizures. Four patients who developed VPA-induced hepatotoxicity were examined for POLG sequence variations. A subsequent chart review was used to describe clinical course prior to and after VPA dosing. Four patients of multiple different ethnicities, age 3-18 years, developed VPA-induced hepatotoxicity. All were given VPA due to intractable partial seizures. Three of the patients had developed epilepsia partialis continua. The time from VPA exposure to liver failure was between 2 and 3 months. Liver failure was reversible in one patient. Molecular studies revealed homozygous p.R597W or p.A467T mutations in two patients. The other two patients showed compound heterozygous mutations, p.A467T/p.Q68X and p.L83P/p.G888S. Clinical findings and POLG mutations were diagnostic of Alpers-Huttenlocher syndrome. Our cases underscore several important findings: POLG mutations have been observed in every ethnic group studied to date; early predominance of epileptiform discharges over the occipital region is common in POLG-induced epilepsy; the EEG and MRI findings varying between patients and stages of the disease; and VPA dosing at any stage of Alpers-Huttenlocher syndrome can precipitate liver failure. Our data support an emerging proposal that POLG gene testing should be considered in any child or adolescent who presents or develops intractable seizures with or without status epilepticus or epilepsia partialis continua, particularly when there is a history of psychomotor regression. (c) 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  2. Real-Time Quantitative Analysis of Valproic Acid in Exhaled Breath by Low Temperature Plasma Ionization Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Gong, Xiaoxia; Shi, Songyue; Gamez, Gerardo

    2017-04-01

    Real-time analysis of exhaled human breath is a rapidly growing field in analytical science and has great potential for rapid and noninvasive clinical diagnosis and drug monitoring. In the present study, an LTP-MS method was developed for real-time, in-vivo and quantitative analysis of γ-valprolactone, a metabolite of valproic acid (VPA), in exhaled breath without any sample pretreatment. In particular, the effect of working conditions and geometry of the LTP source on the ions of interest, protonated molecular ion at m/z 143 and ammonium adduct ion at m/z 160, were systematically characterized. Tandem mass spectrometry (MS/MS) with collision-induced dissociation (CID) was carried out in order to identify γ-valprolactone molecular ions ( m/z 143), and the key fragment ion ( m/z 97) was used for quantitation. In addition, the fragmentation of ammonium adduct ions to protonated molecular ions was performed in-source to improve the signal-to-noise ratio. At optimum conditions, signal reproducibility with an RSD of 8% was achieved. The concentration of γ-valprolactone in exhaled breath was determined for the first time to be 4.83 (±0.32) ng/L by using standard addition method. Also, a calibration curve was obtained with a linear range from 0.7 to 22.5 ng/L, and the limit of detection was 0.18 ng/L for γ-valprolactone in standard gas samples. Our results show that LTP-MS is a powerful analytical platform with high sensitivity for quantitative analysis of volatile organic compounds in human breath, and can have potential applications in pharmacokinetics or for patient monitoring and treatment.

  3. Valproic acid protects against haemorrhagic shock‐induced signalling changes via PPARγ activation in an in vitro model

    PubMed Central

    Zuckermann, Alexandra M E; La Ragione, Roberto M; Baines, Deborah L

    2015-01-01

    Background and Purpose Valproic acid (VPA), a widely used epilepsy and bipolar disorder treatment, provides acute protection against haemorrhagic shock‐induced mortality in a range of in vivo models through an unknown mechanism. In the liver, this effect occurs with a concomitant protection against a decrease in GSK3β‐Ser9 phosphorylation. Here, we developed an in vitro model to investigate this protective effect of VPA and define a molecular mechanism. Experimental Approach The human hepatocarcinoma cell line (Huh7) was exposed to conditions occurring during haemorrhagic shock (hypoxia, hypercapnia and hypothermia) to investigate the changes in GSK3β‐Ser9 phosphorylation for a 4 h period following treatment with VPA, related congeners, PPAR agonists, antagonists and siRNA. Key Results Huh7 cells undergoing combined hypoxia, hypercapnia, and hypothermia reproduced the reduced GSK3β‐Ser9 phosphorylation shown in vivo during haemorrhagic shock, and this change was blocked by VPA. The protective effect occurred through upstream PTEN and Akt signalling, and prevented downstream β‐catenin degradation while increasing histone 2/3 acetylation. This effect was reproduced by several VPA‐related compounds with known PPARγ agonist activity, independent of histone deacetylase (HDAC) inhibitory activity. Specific pharmacological inhibition (by T0070907) or knockdown of PPARγ blocked the protective effect of VPA against these signalling changes and apoptosis. In addition, specific activation of PPARγ using ciglitazone reproduced the changes induced by VPA in haemorrhagic shock‐like conditions. Conclusion and Implications Changes in GSK3β‐Ser9 phosphorylation in in vivo haemorrhagic shock models can be modelled in vitro, and this has identified a role for PPARγ activation in the protective role of VPA. PMID:26333042

  4. Dysregulations of UDP-glucuronosyltransferases in rats with valproic acid and high fat diet induced fatty liver.

    PubMed

    Zhang, Lifang; Chu, Xiaoman; Wang, Hong; Xie, Hao; Guo, Cen; Cao, Lijuan; Zhou, Xueyan; Wang, Guangji; Hao, Haiping

    2013-12-05

    Both high fat diet (HFD) and valproic acid (VPA) interfere with mitochondrial β-oxidation of fatty acids, which subsequently triggers microvesicular fatty liver and hepatic dysfunction. UDP-glucuronosyltransferases, the major phase II drug metabolism enzymes, play a pivotal role in detoxifying various exogenous and endogenous compounds. This study aimed to investigate the dysregulation patterns of major UDP-glucuronosyltransferases (UGTs) induced by VPA and/or HFD. Biochemical and histopathological results showed that chronic treatments of VPA and HFD induced fatty liver and liver dysfunction in a synergistic manner. VPA upregulated the mRNA levels of UGT1A1, 1A6, 1A7, and UGT2B1. Notably, the protein expression and enzymatic activity of UGT1A6 were significantly increased in rats treated with HFD or VPA alone, and were further enhanced by HFD and VPA co-treatment. This dysregulation pattern was largely recapitulated in the in vitro HepG2 cells assay by using VPA and oleic acid treatment. Moreover, the induction of UGTs was accompanied by the increased expression of constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα). In line with the up-regulation of UGT1A1 and UGT1A6, urine recovery of VPA glucuronide (VPA-G) was sharply increased by VPA treatment, and the co-treatment of HFD further aggravated this change. Since VPA is necessarily prescribed for long-term and the prevalence of HFD life style nowadays, the combined effect of HFD and VPA on disturbing UGTs should take concerns in the clinics. © 2013 Published by Elsevier B.V.

  5. Current Status of the New Antiepileptic Drugs in Chronic Pain.

    PubMed

    Sidhu, Harpreet S; Sadhotra, Akshay

    2016-01-01

    Antiepileptic drugs (AEDs) are extensively used worldwide to treat a wide range of disorders other than epilepsy, such as neuropathic pain, migraine, and bipolar disorder. Due to this situation more than 20 new third-generation AEDs have been introduced in the market recently. The future design of new AEDs must also have potential to help in the non-epileptic disorders. The wide acceptance of second generation AEDs for the management of various non-epileptic disorders has caused the emergence of generics in the market. The wide use of approved AEDs outside epilepsy is based on both economic and scientific reasons. Bipolar disorders, migraine prophylaxis, fibromyalgia, and neuropathic pain represent the most attractive indication expansion opportunities for anticonvulsant developers, providing blockbuster revenues. Strong growth in non-epilepsy conditions will see Pfizer's Lyrica become the market leading brand by 2018. In this review, we mainly focus on the current status of new AEDs in the treatment of chronic pain and migraine prophylaxis. AEDs have a strong analgesic potential and this is demonstrated by the wide use of carbamazepine in trigeminal neuralgia and sodium valproate in migraine prophylaxis. At present, data on the new AEDs for non-epileptic conditions are inconclusive. Not all AEDs are effective in the management of neuropathic pain and migraine. Only those AEDs whose mechanisms of action are match with pathophysiology of the disease, have potential to show efficacy in non-epileptic disorder. For this better understanding of the pathophysiology of the disease and mechanisms of action of new AEDs are essential requirement before initiating pre-clinical and clinical trials. Many new AEDs show good results in the animal model and open-label studies but fail to provide strong evidence at randomized, placebo-controlled trials. The final decision regarding the clinical efficacy of the particular AEDs in a specific non-epileptic disorder should be

  6. Interactions between cannabidiol and commonly used antiepileptic drugs.

    PubMed

    Gaston, Tyler E; Bebin, E Martina; Cutter, Gary R; Liu, Yuliang; Szaflarski, Jerzy P

    2017-09-01

    To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs. In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate. Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01). Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the

  7. Neuroactive Peptides as Putative Mediators of Antiepileptic Ketogenic Diets

    PubMed Central

    Giordano, Carmela; Marchiò, Maddalena; Timofeeva, Elena; Biagini, Giuseppe

    2014-01-01

    mechanisms involved in the beneficial effects of KDs. In this review, we summarize the current evidence for altered regulation of the synthesis of neuropeptides and peripheral hormones in response to KDs, and we try to define a possible role for specific neuroactive peptides in mediating the antiepileptic properties of diet-induced ketogenesis. PMID:24808888

  8. Current Status of the New Antiepileptic Drugs in Chronic Pain

    PubMed Central

    Sidhu, Harpreet S.; Sadhotra, Akshay

    2016-01-01

    Antiepileptic drugs (AEDs) are extensively used worldwide to treat a wide range of disorders other than epilepsy, such as neuropathic pain, migraine, and bipolar disorder. Due to this situation more than 20 new third-generation AEDs have been introduced in the market recently. The future design of new AEDs must also have potential to help in the non-epileptic disorders. The wide acceptance of second generation AEDs for the management of various non-epileptic disorders has caused the emergence of generics in the market. The wide use of approved AEDs outside epilepsy is based on both economic and scientific reasons. Bipolar disorders, migraine prophylaxis, fibromyalgia, and neuropathic pain represent the most attractive indication expansion opportunities for anticonvulsant developers, providing blockbuster revenues. Strong growth in non-epilepsy conditions will see Pfizer’s Lyrica become the market leading brand by 2018. In this review, we mainly focus on the current status of new AEDs in the treatment of chronic pain and migraine prophylaxis. AEDs have a strong analgesic potential and this is demonstrated by the wide use of carbamazepine in trigeminal neuralgia and sodium valproate in migraine prophylaxis. At present, data on the new AEDs for non-epileptic conditions are inconclusive. Not all AEDs are effective in the management of neuropathic pain and migraine. Only those AEDs whose mechanisms of action are match with pathophysiology of the disease, have potential to show efficacy in non-epileptic disorder. For this better understanding of the pathophysiology of the disease and mechanisms of action of new AEDs are essential requirement before initiating pre-clinical and clinical trials. Many new AEDs show good results in the animal model and open-label studies but fail to provide strong evidence at randomized, placebo-controlled trials. The final decision regarding the clinical efficacy of the particular AEDs in a specific non-epileptic disorder should be

  9. The effects of biotin supplementation on serum and liver tissue biotinidase enzyme activity and alopecia in rats which were administrated to valproic acid.

    PubMed

    Arslan, Mutluay; Vurucu, Sebahattin; Balamtekin, Necati; Unay, Bulent; Akin, Ridvan; Kurt, Ismail; Ozcan, Okan

    2009-06-01

    Valproic acid (VPA) is a widely used and well-tolerable antiepileptic drug in epileptic patients. However, VPA has many side effects dose-dependent or non-dose-dependent. It is reported that VPA treatment may lead to biotin deficiency and low serum and liver tissue biotinidase enzyme activity (BEA). Major clinical manifestations in biotin deficiency are seborrheic dermatitis, dry skin, fine and brittle hair, and alopecia. We aimed to investigate the effects of biotin supplementation on serum and liver tissue BEA and alopecia during VPA therapy. Rats were randomly divided into 4 groups, each consisted of 15 rats (VPA-B1, VPA-B2, VPA, and control). Except the control group, all groups were administrated VPA dose of 600 mg/kg/d per oral (PO) for 60 days with 12h intervals two divided doses. VPA-B1 was administrated biotin dose of 6 mg/kg/d and VPA-B2 was administrated biotin dose of 0.6 mg/kg/d. In the third week of the study, we determined alopecia in the study groups. Alopecia was seen in the subjects of 13.3% of VPA-B1 (n=2), 13.3% of VPA-B2 (n=2), and 40% of VPA (n=6). But statistical significant effect on alopecia by biotin supplementation was not able to be determined between the study groups. In the control group, alopecia was not observed. The ratios of alopecia in the study groups were statistically higher than the control group (p=0.028). Itchiness was more obvious in the study groups compared with the control group. Serum biotin levels of the biotin supplemented groups (VPA-B1 and VPA-B2) were higher than the other groups (VPA and control group). Serum biotin levels of the VPA group were lower than the control group. There were significant decreases in the levels of serum and liver tissue BEA of the study groups compared with the control group. In conclusion we showed that VPA usage reduced the serum and liver tissue BEA and impaired the biotin utilization by affecting the liver. Partial biotinidase deficiency may lead to alopecia. It might be prevented by

  10. Valproic Acid Neuroprotection in the 6-OHDA Model of Parkinson's Disease Is Possibly Related to Its Anti-Inflammatory and HDAC Inhibitory Properties

    PubMed Central

    Ximenes, José Christian Machado; Neves, Kelly Rose Tavares; Leal, Luzia Kalyne A. M.; do Carmo, Marta Regina Santos; Brito, Gerly Anne de Castro; Naffah-Mazzacoratti, Maria da Graça; Cavalheiro, Ésper Abrão; Viana, Glauce Socorro de Barros

    2015-01-01

    Parkinson's disease is a neurodegenerative disorder where the main hallmark is the dopaminergic neuronal loss. Besides motor symptoms, PD also causes cognitive decline. Although current therapies focus on the restoration of dopamine levels in the striatum, prevention or disease-modifying therapies are urgently needed. Valproic acid (VA) is a wide spectrum antiepileptic drug, exerting many biochemical and physiological effects. It has been shown to inhibit histone deacetylase which seems to be associated with the drug neuroprotective action. The objectives were to study the neuroprotective properties of VA in a model of Parkinson's disease, consisting in the unilateral striatal injection of the neurotoxin 6-OHDA. For that, male Wistar rats (250 g) were divided into the groups: sham-operated (SO), untreated 6-OHDA-lesioned, and 6-OHDA-lesioned treated with VA (25 or 50 mg/kg). Oral treatments started 24 h after the stereotaxic surgery and continued daily for 2 weeks, when the animals were subjected to behavioral evaluations (apomorphine-induced rotations and open-field tests). Then, they were sacrificed and had their mesencephalon, striatum, and hippocampus dissected for neurochemical (DA and DOPAC determinations), histological (Fluoro-Jade staining), and immunohistochemistry evaluations (TH, OX-42, GFAP, TNF-alpha, and HDAC). The results showed that VA partly reversed behavioral and neurochemical alterations observed in the untreated 6-OHDA-lesioned rats. Besides, VA also decreased neuron degeneration in the striatum and reversed the TH depletion observed in the mesencephalon of the untreated 6-OHDA groups. This neurotoxin increased the OX-42 and GFAP immunoreactivities in the mesencephalon, indicating increased microglia and astrocyte reactivities, respectively, which were reversed by VA. In addition, the immunostainings for TNF-alpha and HDAC demonstrated in the untreated 6-OHDA-lesioned rats were also decreased after VA treatments. These results were

  11. Severe Anti-epileptic Drug-induced Gingival Overgrowth in a Physically Disabled Patient.

    PubMed

    Kaomongkolgit, R; Tantanapornkul, W; Jittapiromsak, N; Ngamwannagul, P; Sriaroon, P

    2015-05-08

    Anti-epileptic drugs are considered to be the main drugs associated with gingival overgrowth. The co-administration of phenytoin and other anti-epileptic drugs, which increases the risk of phenytoin-induced gingival overgrowth, has been previously reported. However, no report has been done considering the new generation of anti-epileptic drug topiramate and its association with gingival overgrowth. High levels of dental plaque and calculus have also been reported as being a critical risk factor in the development and severity of drug-induced gingival overgrowth. Thus, this case report highlights the occurrence of severe gingival overgrowth and generalized periodontitis in a physically disabled patient with epilepsy who had been taking phenytoin and topiramate drugs for 10 years. It also emphasizes the importance for both medical and dental professionals to reduce the severity and impact of drug-induced gingival overgrowth.

  12. Antiepileptic dosing for critically ill adult patients receiving renal replacement therapy.

    PubMed

    Smetana, Keaton S; Cook, Aaron M; Bastin, Melissa L Thompson; Oyler, Douglas R

    2016-12-01

    The aim of this review was to evaluate current literature for dosing recommendations for the use of antiepileptic medications in patients receiving renal replacement therapy (RRT). With the assistance of an experienced medical librarian specialized in pharmacy and toxicology, we searched MEDLINE, EMBASE, CINAHL, Web of Science, WorldCat, and Scopus through May 2016. Four hundred three articles were screened for inclusion, of which 130 were identified as potentially relevant. Micromedex® DRUGDEX as well as package inserts were used to obtain known pharmacokinetic properties and dosage adjustment recommendations in RRT if known. Data regarding antiepileptic drug use in RRT are limited and mostly consist of case reports limiting our proposed dosing recommendations. Known pharmacokinetic parameters should guide dosing, and recommendations are provided where possible. Additional studies are necessary before specific dosing recommendations can be made for most antiepileptic drugs in critically ill patients receiving RRT, specifically with newer agents. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Rufinamide: a new antiepileptic drug treatment for Lennox-Gastaut syndrome.

    PubMed

    Ferrie, Colin D

    2010-06-01

    Lennox-Gastaut syndrome is a relatively rare epilepsy syndrome that usually begins in early-mid childhood and is characterized by multiple seizure types, particularly generalized seizures, which are often resistant to antiepileptic drug medication. Rufinamide is a new antiepileptic drug approved as adjunctive therapy to treat seizures in Lennox-Gastaut syndrome in those 4 years of age and older. In this article, the putative mechanism of action is described, along with data relating to its pharmacokinetics and metabolism. Key findings from clinical trials are presented and discussed. Adverse effects are summarized and compared with those encountered with competitor antiepileptic drugs. Finally, the role of rufinamide in the holistic management of subjects with Lennox-Gastaut syndrome is considered.

  14. Oxidative stress as a mechanism of valproic acid-associated hepatotoxicity.

    PubMed

    Chang, Thomas K H; Abbott, Frank S

    2006-01-01

    Valproic acid (2-n-propylpentanoic acid; VPA) has several therapeutic indications, but it is used primarily as an anticonvulsant. VPA is a relatively safe drug, but its use is associated with idiosyncratic hepatotoxicity, which in some cases may lead to fatality. The underlying mechanism responsible for the hepatotoxicity is still not well understood, but various hypotheses have been proposed, including oxidative stress. This article discusses the experimental evidence on the effect of VPA on the various indices of oxidative stress and on the potential role of oxidative stress in VPA-associated hepatotoxicity.

  15. [Role of generic antiepileptic drugs in the treatment of childhood epilepsy].

    PubMed

    Campos-Castelló, Jaime

    2009-01-01

    The use of generic instead of trade mark antiepileptic drugs raises the question of cost/benefit risks. The efficacy and side effects of the generic AED should be similar to the trade mark drugs. Otherwise, the substitution is not justified despite the benefits of reduced cost if efficacy or side effects are not similar in order to avoid possible recurrence of seizures with potential health hazard consequences and legal action. The purpose of this paper is to review the scientific medical literature to determine the efficacy and side effects of generic and trademark antiepileptic drugs.

  16. Changes in Antiepileptic Drug Prescribing Patterns in Large Institutions: Preliminary Results of a Five-Year Experience.

    ERIC Educational Resources Information Center

    Poindexter, Ann R.; And Others

    1993-01-01

    Antiepileptic drug prescriptions were analyzed for 337 institutionalized individuals with mental retardation, over 54 months. Results indicated decreasing numbers of individuals receiving (1) more than 2 antiepileptic drugs concurrently, and (2) barbiturates. Over 90% of a group undergoing barbiturate taper maintained the same or improved seizure…

  17. Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study

    PubMed Central

    Kjaersgaard, Maiken Ina Siegismund; Pedersen, Henrik Søndergaard; Howards, Penelope P; Sørensen, Merete Juul; Olsen, Jørn; Parner, Erik Thorlund; Pedersen, Lars Henning; Vestergaard, Mogens; Christensen, Jakob

    2014-01-01

    Objective To determine whether use of antiepileptic drugs during pregnancy may increase the risk of spontaneous abortion or stillbirth. Design Population based cohort study. Setting Register based study in Denmark, 1997-2008. Participants 983 305 pregnancies identified in the Danish medical birth register and the Danish national hospital discharge register from 1 February 1997 to 31 December 2008 were linked to the Danish Register of Medicinal Product Statistics to obtain information on use of antiepileptic drugs. Main outcome measures Risk ratio of spontaneous abortion and stillbirth after use of antiepileptic drugs during pregnancy, estimated by using binomial regression adjusting for potential confounders of maternal age, cohabitation, income, education, history of severe mental disorder, and history of drug misuse. Results Antiepileptic drugs were used in a total of 4700 (0.5%) pregnancies. 16 out of 100 pregnant women using antiepileptics and 13 out of 100 pregnant women not using antiepileptics experienced a spontaneous abortion. After adjusting for potential confounders pregnant women using antiepileptics had a 13% higher risk of spontaneous abortions than pregnant women not using antiepileptics (adjusted risk ratio 1.13, 95% confidence interval 1.04 to 1.24). However, the risk of spontaneous abortion was not increased in women with an epilepsy diagnosis (0.98, 0.87 to 1.09), only in women without a diagnosis of epilepsy (1.30, 1.14 to 1.49). In an analysis including women with at least two pregnancies with discordant antiepileptic drug use (for example, use in the first pregnancy but not in the second), the adjusted hazard ratio for spontaneous abortion was 0.83 (0.69 to 1.00) for exposed pregnancies compared with unexposed pregnancies. Stillbirth was identified in 18 women who used antiepileptic drugs (unadjusted risk ratio 1.29, 0.80 to 2.10). Conclusion Among women with epilepsy and when analysing the risk in antiepileptic drug discordant pregnancies

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

    PubMed Central

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

    2009-01-01

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

  19. Antiepileptic drugs for seizure control in people with neurocysticercosis.

    PubMed

    Sharma, Monika; Singh, Tejinder; Mathew, Amrith

    2015-10-12

    Neurocysticercosis is the most common parasitic infection of the brain. Epilepsy is the commonest clinical presentation, though it may also present with headache, symptoms of raised intracranial tension, hydrocephalus and ocular symptoms depending upon the localisation of the parasitic cysts. Anthelmintic drugs, anti-oedema drugs, such as steroids and antiepileptic drugs (AEDs) form the mainstay of treatment. To assess the effects (benefits and harms) of AEDs for the primary and secondary prevention of seizures in people with neurocysticercosis. We searched the Cochrane Epilepsy Group Specialized Register (5 May 2015), The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library April 2015, Issue 4), MEDLINE (1946 to 5 May 2015), LILACS (Latin American and Caribbean Literature in Health Sciences, 5 May 2015), SCOPUS (1823 to 15 April 2014), ClinicalTrials.gov (7 May 2015), and the WHO International Clinical Trials Registry Platform ICTRP (7 May 2015). We also checked the references lists of identified studies, and contacted experts in the field and colleagues to search for additional studies and for information about ongoing studies. Randomised and quasi-randomised controlled trials.The studies may be single blind, double blind or unblinded. One review author screened all citations for eligibility.Two review authors independently extracted data and evaluated each study for risk of bias. We did not find any trials that investigated the role of AEDs in preventing seizures among people with neurocysticercosis, presenting with symptoms other than seizures.We did not find any trials that evaluated evaluating individual AEDs in people with neurocysticercosis.We found one trial, comparing two AEDs in people with solitary neurocysticercosis with seizures. However, we excluded this study from the review as it was of poor quality.We found four trials that compared the efficacy of short term versus longer term AED treatment for people with solitary

  20. VAC chemotherapy with valproic acid for refractory/relapsing small cell lung cancer: a phase II study.

    PubMed

    Berghmans, Thierry; Lafitte, Jean-Jacques; Scherpereel, Arnaud; Ameye, Lieveke; Paesmans, Marianne; Meert, Anne-Pascale; Colinet, Benoit; Tulippe, Christian; Willems, Luc; Leclercq, Nathalie; Sculier, Jean-Paul

    2015-10-01

    Salvage chemotherapy (CT) for relapsing or refractory small cell lung cancer (SCLC) remains disappointing. In vitro experiments showed that valproic acid increases apoptosis of SCLC cell lines exposed to doxorubicin, vindesine and bis(2-chloroethyl)amine. The primary objective of this phase II study was to determine whether epigenetic modulation with valproic acid in addition to a doxorubicin, vindesine and cyclophosphamide (VAC) regimen improves 6-month progression-free survival (PFS). Patients with pathologically proven SCLC refractory to prior platinum derivatives and etoposide were eligible. After central registration, patients received VAC plus daily oral valproic acid. 64 patients were registered, of whom six were ineligible. Seven patients did not receive any CT, leaving 51 patients assessable for the primary end-point. The objective response rate was 19.6%. Median PFS was 2.8 months (95% CI 2.5-3.6 months) and 6-month PFS was 6%. Median survival time was 5.9 months (95% CI 4.7-7.5 months). Toxicity was mainly haematological, with 88% and 26% grade 3-4 neutropenia and thrombopenia, respectively. Despite an interesting response rate, the addition of valproic acid to VAC did not translate into adequate PFS in relapsing SCLC or SCLC refractory to platinum-etoposide.

  1. Inhibition of leukemic cells by valproic acid, an HDAC inhibitor, in xenograft tumors

    PubMed Central

    Zhang, Zhihua; Hao, Changlai; Wang, Lihong; Liu, Peng; Zhao, Lei; Zhu, Cuimin; Tian, Xia

    2013-01-01

    The chimeric fusion protein, AML1-ETO, generated by translocation of t(8;21), abnormally recruits histone deacetylase (HDAC) to the promoters of AML1 target genes, resulting in transcriptional repression of the target genes and development of t(8;21) acute myeloid leukemia. Abnormal expression of cyclin-dependent kinase inhibitors, especially p21, is considered a possible mechanism of the arrested maturation and differentiation seen in leukemia cells. A new generation of HDAC inhibitors is becoming an increasing focus of attention for their ability to induce differentiation and apoptosis in tumor cells and to block the cell cycle. Our previous research had demonstrated that valproic acid induces G0/G1 arrest of Kasumi-1 cells in t(8;21) acute myeloid leukemia. In this study, we further confirmed that valproic acid inhibits the growth of Kasumi-1 cells in a murine xenograft tumor model, and that this occurs via upregulation of histone acetylation in the p21 promoter region, enhancement of p21 expression, suppression of phosphorylation of retinoblastoma protein, blocking of transcription activated by E2F, and induction of G0/G1 arrest. PMID:23836985

  2. Valproic acid-induced acute pancreatitis in pediatric age: case series and review of literature

    PubMed Central

    COFINI, M.; QUADROZZI, F.; FAVORITI, P.; FAVORITI, M.; COFINI, G.

    2015-01-01

    Valproic acid (VPA) is commonly prescribed medication for epilepsy, migraine and bipolar disorder. Although the common adverse effect associated with VPA are typically benign, less common adverse effect can occur; these include hepatotixicity, teratogenicity and acute pancreatitis (AP). VPA-induced pancreatitis does not depend on valproic acid serum level and may occur anytime after onset of therapy. Re-challenge with VPA is dangerous and should be avoided. The diagnosis of VPA-induced pancreatitis seems to be underestimated because of difficulties in determining the causative agent and the need for a retrospective re-evaluation of the causative factor. More of idiopathic pancreatitis should be a drug-induced pancreatitis. We report four cases of VPA-induced AP found in a group of 52 cases of AP in children come to our attention from January 2008 to December 2012. The aim of these reports is to point out our experience about clinical presentation, diagnosis, management, outcome in children with VPA-induced AP and review of literature. PMID:26712070

  3. Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

    SciTech Connect

    Li, Xiaofei; Zhu, Yanshuang; He, Huabin; Lou, Lianqing; Ye, Weiwei; Chen, Yongxin; Wang, Jinghe

    2013-06-28

    Highlights: •Novel combination therapy using aspirin and valproic acid (VPA). •Combination of aspirin and VPA elicits synergistic cytotoxic effects. •Combination of aspirin and VPA significantly reduces the drug dosage required alone. •Combination of aspirin and VPA significantly inhibit tumor growth. •Lower dose of aspirin in combination therapy will minimize side effects of aspirin. -- Abstract: Aspirin and valproic acid (VPA) have been extensively studied for inducing various malignancies growth inhibition respectively, despite their severe side effects. Here, we developed a novel combination by aspirin and VPA on hepatocellular cancer cells (HCCs). The viability of HCC lines were analyzed by MTT assay, apoptotic analysis of HepG2 and SMMC-7721 cell was performed. Real time-PCR and Western blotting were performed to determine the expression of apoptosis related genes and proteins such as Survivin, Bcl-2/Bax, Cyclin D1 and p15. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish murine model, and then therapeutic effect was analyzed after drug combination therapy. The viability of HCC lines’ significantly decreased after drug combination treatment, and cancer cell apoptosis in combination group increasingly induced compared with single drug use. Therapeutic effect was significantly enhanced by combination therapy in tumor volume and tumor weight decrease. From the data shown here, aspirin and VPA combination have a synergistic killing effect on hepatocellular cancers cells proliferation and apoptosis.

  4. Valproic acid-associated sialadenosis of the parotid and submandibular glands: diagnostic and therapeutic aspects.

    PubMed

    Mauz, P S; Mörike, K; Kaiserling, E; Brosch, S

    2005-04-01

    Sialadenosis has been defined as a non-inflammatory, parenchymatous salivary gland disease causing recurrent, bilateral swelling of the salivary glands. As an adverse drug reaction of valproic acid, sialadenosis is very rare. To our knowledge, it has been reported only once in the world literature to date. We present herein the case of a patient with valproic acid-associated sialadenosis of both the parotid and submandibular glands. This appears to be the first published case of a patient who received surgical treatment. On light and electron microscopy of all the affected salivary glands, granular sialadenosis with predominantly moderate electron-dense secretory cytoplasmatic granules was observed. No relevant degenerative alterations were seen. There was no histological evidence of peripheral neuropathy of the nerve supply, leading to disordered activity of acinar cells by loss of neurosecretory granules. Lateral parotidectomy, performed under neuromonitoring control for safety reasons, is the treatment of choice for chronic recurrent parotitis that does not respond to conservative therapy, particularly if the cosmetic deformity is unacceptable to the patient. If the submandibular glands are involved, partial removal is recommended.

  5. The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes.

    PubMed

    Noyer, M; Gillard, M; Matagne, A; Hénichart, J P; Wülfert, E

    1995-11-14

    Levetiracetam ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide, ucb L059) is a novel potential antiepileptic agent presently in clinical development with unknown mechanism of action. The finding that its anticonvulsant activity is highly stereoselective (Gower et al., 1992) led us to investigate the presence of specific binding sites for [3H]levetiracetam in rat central nervous system (CNS). Binding assays, performed on crude membranes, revealed the existence of a reversible, saturable and stereoselective specific binding site. Results obtained in hippocampal membranes suggest that [3H]levetiracetam labels a single class of binding sites (nH = 0.92 +/- 0.06) with modest affinity (Kd = 780 +/- 115 nM) and with a high binding capacity (Bmax = 9.1 +/- 1.2 pmol/mg protein). Similar Kd and Bmax values were obtained in other brain regions (cortex, cerebellum and striatum). ucb L060, the (R) enantiomer of levetiracetam, displayed about 1000 times less affinity for these sites. The binding of [3H]levetiracetam is confined to the synaptic plasma membranes in the central nervous system since no specific binding was observed in a range of peripheral tissues including heart, kidneys, spleen, pancreas, adrenals, lungs and liver. The commonly used antiepileptic drugs carbamazepine, phenytoin, valproate, phenobarbital and clonazepam, as well as the convulsant agent t-butylbicyclophosphorothionate (TBPS), picrotoxin and bicuculline did not displace [3H]levetiracetam binding. However, ethosuximide (pKi = 3.5 +/- 0.1), pentobarbital (pKi = 3.8 +/- 0.1), pentylenetetrazole (pKi = 4.1 +/- 0.1) and bemegride (pKi = 5.0 +/- 0.1) competed with [3H]levetiracetam with pKi values comparable to active drug concentrations observed in vivo. Structurally related compounds, including piracetam and aniracetam, also displaced [3H]levetiracetam binding. (S) Stereoisomer homologues of levetiracetam demonstrated a rank order of affinity for [3H]levetiracetam binding in correlation with their

  6. Psychosocial factors and antiepileptic drug use related to delayed diagnosis of refractory psychogenic nonepileptic seizures.

    PubMed

    Rodríguez-Urrutia, Amanda; Toledo, Manuel; Eiroa-Orosa, Francisco José; Salas-Puig, Xavier; Santamarina, Estevo; Fidel-Kinori, Sara Guila; Parramon, Gemma; Casas, Miguel

    2014-12-01

    We analyzed clinical and psychosocial factors in patients with refractory psychogenic nonepileptic seizures, seeking characteristics that could hasten diagnosis. Psychogenic nonepileptic seizures remain a diagnostic challenge. Prognosis is best if patients are treated within 2 years of symptom onset. Psychosocial factors have been shown to provide important information for differential diagnosis. Over a year and 1132 consecutive patients, our hospital's Epilepsy Unit suspected 93 patients of having psychogenic nonepileptic seizures and confirmed refractory psychogenic nonepileptic seizures in 67. We referred these patients to our psychiatric consultation unit for detailed diagnostic interviews, and 53 of the patients followed through. Two months after the psychiatric evaluation we gave them a psychiatric intervention, explaining the diagnosis and treating their comorbidities. We also tracked the patients' use of antiepileptic drugs for 3 months, from just before the psychiatric evaluation until a month after they started the intervention. Women, patients with an inadequate primary support group, and patients who had tried many antiepileptic drugs were most likely to have their diagnosis of psychogenic nonepileptic seizures delayed by >2 years after onset. A stepwise logistic regression showed that the 2 best predictors of late diagnosis were lack of availability of a primary support group and patients trying many antiepileptic drugs. Clinicians evaluating patients with questionable seizures should raise their suspicion of psychogenic nonepileptic seizures especially in female patients with an insufficient primary support group and a history of taking multiple antiepileptic drugs.

  7. Common variants of APOE are associated with anti-epileptic drugs resistance in Han Chinese patients.

    PubMed

    Gong, Jiao-E; Qu, Jian; Long, Hong-Yu; Long, Li-Li; Qu, Qiang; Li, Xiang-Ming; Yang, Li-Ming; Xiao, Bo

    2017-01-01

    Purpose/aim of the study: Apolipoprotein E (APOE) has been implicated as one of the susceptibility genes for some subtypes of epilepsy and may be related to anti-epileptic drugs resistance. The purpose of this study was to investigate the possible association between APOE variants and the anti-epileptic drugs resistance in Chinese population. APOE gene rs429358 and rs7412 variants were genotyped for ϵ2, ϵ3, ϵ4 alleles using amplification refractory mutation system in 480 subjects including 207 anti-epileptic drugs-resistant patients and 273 drug-responsive patients. We found that the frequency of APOE gene rs429358 C allele in the drug resistant patients is higher than that in the drug-responsive patients (14.98% vs. 10.1%, OR = 1.25[1.02 - 1.52], p = 0.017). Moreover, according to the two variants, we analyzed the distributions of -ϵ4 and +ϵ4 alleles of APOE gene and found that there were higher frequencies of +ϵ4 allele in drug-resistant epileptic patients than that in drug-responsive patients (31.8% vs. 13.2%, OR = 1.15[1.05 - 1.25], p = 0.002). Our study demonstrated that APOE rs429358 variant C allele and ϵ4 allele were associated with the anti-epileptic drugs resistance in Han Chinese patients.

  8. Vitamin D enhances antiepileptic and cognitive effects of lamotrigine in pentylenetetrazole-kindled rats.

    PubMed

    Abdel-Wahab, Ali F; Afify, Mohamed A; Mahfouz, Amal M; Shahzad, Naiyer; Bamagous, Ghazi A; Al Ghamdi, Saeed S

    2017-10-15

    Despite long use of antiepileptic drugs, it remains a challenge to achieve seizure control while reducing adverse effects and preventing cognitive impairment. Several lines of evidence suggest a role of vitamin D in epilepsy. So this study aimed to investigate the effect of vitamin D on epileptogenesis, cognitive dysfunction and antiepileptic activity of lamotrigine, in a rat model of chemical kindling. Rats were kindled by pentylenetetrazole injections every other day over four weeks, together with daily oral treatment by either vehicle, vitamin D, lamotrigine or combination of vitamin D and lamotrigine. The non-treated kindled rats developed generalized seizures and had poor cognitive performance in water maze, associated with prooxidative status; elevated malondialdehyde and nitric oxide with lowered glutathione levels; in brain tissues. Treatment with either vitamin D, lamotrigine or both leads to significant reduction of seizure activity score, improvement of cognitive performance, and amelioration of the disturbed oxidative stress biomarkers. These findings indicate that, vitamin D has anti-epileptic, cognitive improving and antioxidant effects, on its own and enhance the effects of lamotrigine, in a chronic model of epileptic seizures. Thus, vitamin D supplementation may be a useful addition to antiepileptic drugs improving seizure control and cognitive function in patients with epilepsy. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Antiepileptic Medications in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

    ERIC Educational Resources Information Center

    Hirota, Tomoya; Veenstra-VanderWeele, Jeremy; Hollander, Eric; Kishi, Taro

    2014-01-01

    Electroencephalogram-recorded epileptiform activity is common in children with autism spectrum disorder (ASD), even without clinical seizures. A systematic literature search identified 7 randomized, placebo-controlled trials of antiepileptic drugs (AEDs) in ASD (total n = 171), including three of valproate, and one each of lamotrigine,…

  10. Foetal Antiepileptic Drug Exposure and Verbal versus Non-Verbal Abilities at Three Years of Age

    ERIC Educational Resources Information Center

    Meador, Kimford J.; Baker, Gus A.; Browning, Nancy; Cohen, Morris J.; Clayton-Smith, Jill; Kalayjian, Laura A.; Kanner, Andres; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael; Loring, David W.

    2011-01-01

    We previously reported that foetal valproate exposure impairs intelligence quotient. In this follow-up investigation, we examined dose-related effects of foetal antiepileptic drug exposure on verbal and non-verbal cognitive measures. This investigation is an ongoing prospective observational multi-centre study in the USA and UK, which has enrolled…

  11. Human placental perfusion method in the assessment of transplacental passage of antiepileptic drugs

    SciTech Connect

    Myllynen, Paeivi . E-mail: paivi.k.myllynen@oulu.fi; Pienimaeki, Paeivi; Vaehaekangas, Kirsi

    2005-09-01

    Epilepsy is one of the most common neurological diseases, affecting about 0.5 to 1% of pregnant women. It is commonly accepted that older antiepileptic drugs bear teratogenic potential. So far, no agreement has been reached about the safest antiepileptic drug during pregnancy. It is known that nearly all drugs cross the placenta at least to some extent. Nowadays, there is very little information available of the pharmacokinetics of drugs in the feto-placental unit. Detailed information about drug transport across the placenta would be valuable for the development of safe and effective treatments. For reasons of safety, human studies on placental transfer are restricted to a limited number of drugs. Interspecies differences limit the extrapolation of animal data to humans. Several in vitro methods for the study of placental transfer have been developed over the past decades. The placental perfusion method is the only experimental method that has been used to study human placental transfer of substances in organized placental tissue. The aim of this article is to review human placental perfusion data on antiepileptic drugs. According to perfusion data, it seems that most of the antiepileptic drugs are transferred across the placenta meaning significant fetal exposure.

  12. The Relationship among Side Effects Associated with Anti-Epileptic Medications in Those with Intellectual Disability

    ERIC Educational Resources Information Center

    Sipes, Megan; Matson, Johnny L.; Belva, Brian; Turygin, Nicole; Kozlowski, Alison M.; Horovitz, Max

    2011-01-01

    Seizures are fairly common in those with intellectual disabilities. In order to treat these seizures, antiepileptic drugs (AEDs) are often used and in many cases are effective. However, these medications often create a variety of associated side effects. In order to monitor these side effects, measures such as the SEIZES-B have been used. While…

  13. Foetal Antiepileptic Drug Exposure and Verbal versus Non-Verbal Abilities at Three Years of Age

    ERIC Educational Resources Information Center

    Meador, Kimford J.; Baker, Gus A.; Browning, Nancy; Cohen, Morris J.; Clayton-Smith, Jill; Kalayjian, Laura A.; Kanner, Andres; Liporace, Joyce D.; Pennell, Page B.; Privitera, Michael; Loring, David W.

    2011-01-01

    We previously reported that foetal valproate exposure impairs intelligence quotient. In this follow-up investigation, we examined dose-related effects of foetal antiepileptic drug exposure on verbal and non-verbal cognitive measures. This investigation is an ongoing prospective observational multi-centre study in the USA and UK, which has enrolled…

  14. Antiepileptic Medications in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

    ERIC Educational Resources Information Center

    Hirota, Tomoya; Veenstra-VanderWeele, Jeremy; Hollander, Eric; Kishi, Taro

    2014-01-01

    Electroencephalogram-recorded epileptiform activity is common in children with autism spectrum disorder (ASD), even without clinical seizures. A systematic literature search identified 7 randomized, placebo-controlled trials of antiepileptic drugs (AEDs) in ASD (total n = 171), including three of valproate, and one each of lamotrigine,…

  15. The Effects of Antiepileptic Medications on the Social Skills of Individuals with Mental Retardation

    ERIC Educational Resources Information Center

    Matson, Johnny L.; Luke, Melissa A.; Mayville, Stephen B.

    2004-01-01

    Prevalence rates of epilepsy are much higher among persons with developmental disabilities compared to the general population. Anticonvulsant medication is the most common method of treating seizure disorders. Many of these antiepileptic medications (AEDs) are associated with various side effects, which may have detrimental effects on the social…

  16. Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy.

    PubMed

    Pack, Alison M; Morrell, Martha J; Marcus, Robert; Holloway, Leah; Flaster, Edith; Doñe, Silvia; Randall, Alison; Seale, Cairn; Shane, Elizabeth

    2005-02-01

    Antiepileptic drugs, particularly cytochrome P450 enzyme inducers, are associated with disorders of bone metabolism. We studied premenopausal women with epilepsy receiving antiepileptic drug monotherapy (phenytoin, carbamazepine, valproate, and lamotrigine). Subjects completed exercise and nutrition questionnaires and bone mineral density studies. Serum was analyzed for indices of bone metabolism including calcium, 25-hydroxyvitamin D, parathyroid hormone, insulin growth factor I, insulin binding protein III, and bone formation markers, bone-specific alkaline phosphatase, and osteocalcin. Urine was analyzed for cross-linked N-telopeptide of type I collagen, a bone resorption marker. Calcium concentrations were significantly less in subjects receiving carbamazepine, phenytoin, and valproate than in those receiving lamotrigine (p = 0.008). Insulin growth factor-I was significantly reduced in subjects receiving phenytoin compared with those receiving lamotrigine (p = 0.017). Subjects receiving phenytoin had significantly greater levels of bone-specific alkaline phosphatase (p = 0.007). Our results demonstrate that phenytoin is associated with changes in bone metabolism and increased bone turnover. The lower calcium concentrations in subjects taking carbamazepine or valproate compared with those taking other antiepileptic drugs suggest that these antiepileptic drugs may have long-term effects. Subjects receiving lamotrigine had no significant reductions in calcium or increases in markers of bone turnover, suggesting this agent is less likely to have long-term adverse effects on bone.

  17. The Relationship among Side Effects Associated with Anti-Epileptic Medications in Those with Intellectual Disability

    ERIC Educational Resources Information Center

    Sipes, Megan; Matson, Johnny L.; Belva, Brian; Turygin, Nicole; Kozlowski, Alison M.; Horovitz, Max

    2011-01-01

    Seizures are fairly common in those with intellectual disabilities. In order to treat these seizures, antiepileptic drugs (AEDs) are often used and in many cases are effective. However, these medications often create a variety of associated side effects. In order to monitor these side effects, measures such as the SEIZES-B have been used. While…

  18. The Effects of Antiepileptic Medications on the Social Skills of Individuals with Mental Retardation

    ERIC Educational Resources Information Center

    Matson, Johnny L.; Luke, Melissa A.; Mayville, Stephen B.

    2004-01-01

    Prevalence rates of epilepsy are much higher among persons with developmental disabilities compared to the general population. Anticonvulsant medication is the most common method of treating seizure disorders. Many of these antiepileptic medications (AEDs) are associated with various side effects, which may have detrimental effects on the social…

  19. Antiepileptic drugs for the treatment of neuropathic pain: A systematic review

    PubMed Central

    Vargas-Espinosa, Maríam L.; Sanmartí-García, Gemma; Vázquez-Delgado, Eduardo

    2012-01-01

    Many therapies have been proposed for the management of neuropathic pain, and they include the use of different antiepileptic drugs. However, the lack of high quality studies indicates that results on the different neuropathic disorders under study do not recommend a particular drug treatment. This study makes a systematic review of the published literature on the use of several antiepileptic drugs to treat neuropathic pain, and has the objective of considering both its clinical characteristics and pharmacological use, which will depend on their level of scientific evidence and will follow the principles of evidence-based dentistry. The articles were stratified according to their scientific evidence using the SORT criteria (Strength of Recommendation Taxonomy), and it included those articles that only have level 1 or 2. Randomized clinical trials were stratified according to their level of quality using the JADAD scale, an instrument described by Jadad et al. (7). to assess the quality of clinical trials, while studies with a level below 3 were discarded. Recently, type A or B recommendations are given in favor or against the use of antiepileptic drugs to treat neuropathic pain on the basis of their scientific quality. Key words:Neuropathic pain, antiepileptic drugs (AEDs), trigeminal neuralgia, glossopharyngeal neuralgia, post- herpetic neuralgia, burning mouth syndrome, persistent idiopathic facial pain. PMID:22549682

  20. EPR studies of free radicals in A-2058 human melanoma cells treated by valproic acid and 5,7-dimethoxycoumarin.

    PubMed

    Zdybel, Magdalena; Chodurek, Ewa; Pilawa, Barbara

    2014-01-01

    Free radicals in A-2058 human melanoma cells were studied by the use of electron paramagnetic resonance (EPR) spectroscopy. The aim of this work was to determine the changes in relative free radical concentrations in tumor A-2058 cells after treatment by valproic acid (VPA) and 5,7-dimethoxycoumarin (DMC). The influences of VPA and DMC on free radicals in A-2058 cells were compared with those for human melanoma malignum A-375 and G-361 cells, which were tested by us earlier. Human malignant melanoma A-2058 cells were exposed to interactions with VPA, DMC, and both VPA and DMC. The tumor cells A-2058 were purchased from LGC Standards (Lomianki, Poland), and they were grown in the standard conditions: at 37°C and in an atmosphere containing 95% air and 5% CO2, in the Minimum Essential Medium Eagle (MEM, Sigma-Aldrich). The A-2058 cells were incubated with VPA (1 mM) and DMC (10 μM) for 4 days. The first-derivative EPR spectra of the control A-2058 cells, and the cells treated with VPA, DMC, and both VPA and DMC, were measured by the electron paramagnetic resonance spectrometer of Radiopan (Poznań, Poland) with microwaves from an X-band (9.3 GHz). The parameters of the EPR lines: amplitudes (A), integral intensities (I), line widths (ΔBpp), and g-factors, were analyzed. The changes of amplitudes and line widths with microwave power increasing from 2.2 to 70 mW were drawn evaluated, o-Semiquinone free radicals of melanin biopolymer are mainly responsible for the EPR lines of A-2058 melanoma malignum cells. The amounts of free radicals in A-2058 cells treated with VPA, and both VPA and DMC, were lower than in the untreated control cells. Application of the tested substances (VPA, and both VPA and DMC) as the antitumor compounds was discussed. DMC without VPA did not decrease free radicals concentration in A-2058 cells. The studies con-firmed that EPR spectroscopy may be used to examine interactions of free radicals with antitumor compounds.

  1. Effects of age and polytherapy, risk factors of valproic acid (VPA) hepatotoxicity, on the excretion of thiol conjugates of (E)-2,4-diene VPA in people with epilepsy taking VPA.

    PubMed

    Gopaul, Sashi; Farrell, Kevin; Abbott, Frank

    2003-03-01

    Valproic acid (VPA) is an antiepileptic drug (AED) used for generalized and absence seizures. It has a rare but potentially fatal hepatotoxicity side effect, and many researchers believe that reactive metabolites of VPA could be involved. We demonstrated here that the thiol conjugates of (E)-2,4-diene VPA were significantly elevated in a high-risk group of patients. Thirty-four patients with seizures were divided into three groups. Group A (n = 14) were being treated with VPA; group B (n = 12) received VPA as well as other AEDs that do not induce P450-VPA metabolism; and group C (n = 8) received VPA and AEDs that induce P450-VPA metabolism. The NAC conjugates of (E)-2,4-diene VPA (NAC I and NAC II) were identified in the urine of patients by gas chromatography/mass spectrography NICI analysis. VPA monotherapy (group A) or VPA polytherapy with non-P450-enzyme-inducing drugs (group B), showed that patients younger than 7.5 years excreted significantly higher concentrations of the two conjugates compared with older patients (older than 7.5 years) in the same groups (p < 0.05). Patients receiving VPA polytherapy with P450-enzyme-inducing drugs were all older than 7. 5 years (group C). They excreted significantly higher concentrations of NAC I and NAC II compared with patients in groups A and B who were older than 7.5 years (p < 0.05). There were no significant differences in the excretion of NAC I and NAC II between patients in group C and those who were 7.5 years or younger in groups A and B. High doses of VPA also were a significant factor associated with elevated NAC I and NAC II among young patients and in polytherapy patients.

  2. Fully validated method for rapid and simultaneous measurement of six antiepileptic drugs in serum and plasma using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry.

    PubMed

    Kuhn, Joachim; Knabbe, Cornelius

    2013-06-15

    Therapeutic drug monitoring (TDM) may be very useful in the clinical management of antiepileptic drug therapy for multiple reasons, such as individual variability, metabolism, genetic factors or drug-drug or drug-food interactions. In addition, TDM is helpful to study the variation in pharmacokinetics that occurs between individuals. Here, we describe a rapid assay using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry to measure the antiepileptic drugs lacosamide, lamotrigine, levetiracetam, primidone, topiramate, and zonisamide. After the addition of internal standards (ISs) and protein precipitation of serum or plasma, 1 μl of sample was separated on a 2.1×50 mm reverse phase column (Waters, Acquity UPLC BEH Phenyl, 1.7 μm). Analytes were then ionized and detected by electrospray ionization mass spectrometry with multiple reaction monitoring. Runtime was 2.5 min per injection. Matrix effects were investigated by systematical ion suppression and in-source fragmentation experiments. The calibration curves of the 6 antiepileptic drugs were linear over the working range between 0.05 and 50 mg/L (r>0.99). The limit of detection (LOD) was <0.05 mg/L, whereas the limit of quantification (LLOQ) was 0.10 mg/L of all drugs measured in the assay. The intraassay and interassay coefficients of variation for all compounds were <15% for very low concentration (0.1 mg/L) and <8% in the clinically relevant concentration range (>1.0 mg/L). Mean recoveries were between 87.8 and 98.6% for all drugs. There were no significant ion suppressions detected at the elution times of the analytes. The mean differences between serum and heparinized plasma values were less than 6% for the 6 antiepileptic drugs. All drugs were stable in serum at -20°C, 4°C, and even at RT for at least 1 month. In summary, a specific and sensitive stable isotope dilution UPLC-MS/MS method was developed and validated for routine clinical monitoring of lacosamide

  3. Astaxanthin improves behavioral disorder and oxidative stress in prenatal valproic acid-induced mice model of autism.

    PubMed

    Al-Amin, Md Mamun; Rahman, Md Mahbubur; Khan, Fazlur Rahman; Zaman, Fahmida; Mahmud Reza, Hasan

    2015-06-01

    Prenatal exposure to valproic acid on gestational day 12.5 may lead to the impaired behavior in the offspring, which is similar to the human autistic symptoms. To the contrary, astaxanthin shows neuroprotective effect by its antioxidant mechanism. We aimed to (i) develop mice model of autism and (ii) investigate the effect of astaxanthin on such model animals. Valproic acid (600 mg/kg) was administered intraperitoneally to the pregnant mice on gestational day 12.5. Prenatal valproic acid-exposed mice were divided into 2 groups on postnatal day 25 and astaxanthin (2mg/kg) was given to the experimental group (VPA_AST, n=10) while saline was given to the control group (VPA, n=10) for 4 weeks. Behavioral test including social interaction, open field and hot-plate were conducted on postnatal day 25 and oxidative stress markers such as lipid peroxidation, advanced protein oxidation product, nitric oxide, glutathione, and activity of superoxide dismutase and catalase were estimated on postnatal day 26 to confirm mice model of autism and on postnatal day 56 to assess the effect of astaxanthin. On postnatal day 25, prenatal valproic acid-exposed mice exhibited (i) delayed eye opening (ii) longer latency to respond painful stimuli, (iii) poor sociability and social novelty and (iv) high level of anxiety. In addition, an increased level of oxidative stress was found by determining different oxidative stress markers. Treatment with astaxanthin significantly (p<0.05) improved the behavioral disorder and reduced the oxidative stress in brain and liver. In conclusion, prenatal exposure to valproic day in pregnant mice leads to the development of autism-like features. Astaxanthin improves the impaired behavior in animal model of autism presumably by its antioxidant activity.

  4. Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells

    PubMed Central

    Archin, Nancy M.; Eron, Joseph J.; Palmer, Sarah; Hartmann-Duff, Anne; Martinson, Jeffery A.; Wiegand, Ann; Bandarenko, Nicholas; Schmitz, John L.; Bosch, Ronald J.; Landay, Alan L.; Coffin, John M.; Margolis, David M.

    2013-01-01

    Objectives Valproic acid and intensified antiretroviral therapy may deplete resting CD4+ T-cell HIV infection. We tested the ability of valproic acid to deplete resting CD4+ T-cell infection in patients receiving standard antiretroviral therapy. Methods Resting CD4+ T-cell infection was measured in 11 stably aviremic volunteers twice prior to, and twice after Depakote ER 1000 mg was added to standard antiretroviral therapy. Resting CD4+ T-cell infection frequency was measured by outgrowth assay. Low-level viremia was quantitated by single copy plasma HIV RNA assay. Results A decrease in resting CD4+ T-cell infection was observed in only four of the 11 patients. Levels of immune activation and HIV-specific T-cell response were low and stable. Valproic acid levels ranged from 26 to 96 μg/ml when measured near trough. Single copy assay was performed in nine patients. In three patients with depletion of resting CD4+ T-cell infection following valproic acid, single copy assay ranged from less than 1–5 copies/ml. Continuous low-level viremia was observed in three patients with stable resting CD4+ T-cell infection (24–87, 8–87, and 1–7 copies/ml respectively) in whom multiple samples were analyzed. Conclusion The prospective addition of valproic acid to stable antiretroviral therapy reduced the frequency of resting CD4+ T-cell infection in a minority of volunteers. In patients in whom resting CD4+ T-cell infection depletion was observed, viremia was rarely detectable by single copy assay. PMID:18525258

  5. Exposure to antiepileptic drugs in utero and child development: a prospective population-based study.

    PubMed

    Veiby, Gyri; Daltveit, Anne K; Schjølberg, Synnve; Stoltenberg, Camilla; Øyen, Anne-Siri; Vollset, Stein E; Engelsen, Bernt A; Gilhus, Nils E

    2013-08-01

    Antiepileptic drugs may cause congenital malformations. Less is known about the effect on development in infancy and childhood. The aim of this study was to examine whether exposure to antiepileptic drugs during pregnancy has an effect on early child development. From mid-1999 through December 2008, children of mothers recruited at 13-17 weeks of pregnancy were studied in the ongoing prospective Norwegian Mother and Child Cohort Study. Information on birth outcomes were obtained from the Medical Birth Registry (108,264 children), and mothers reported on their child's motor development, language, social skills, and autistic traits using items from standardized screening tools at 18 months (61,351 children) and 36 months (44,147 children) of age. The relative risk of adverse outcomes in children according to maternal or paternal epilepsy with and without prenatal exposure to antiepileptic drugs was estimated as odds ratios (ORs), using logistic regression with adjustment for maternal age, parity, education, smoking, depression/anxiety, folate supplementation, and child congenital malformation or low birth weight. A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, the exposed children had increased risk of abnormal scores for gross motor skills (7.1% vs. 2.9%; OR 2.0, 95% confidence interval [CI] 1.1-3.7) and autistic traits (3.5% vs. 0.9%; OR 2.7, CI 1.1-6.7) compared to children of parents without epilepsy. At 36 months, the exposed children had increased risk of abnormal score for gross motor skills (7.5% vs. 3.3%; OR 2.2, CI 1.1-4.2), sentence skills (11.2% vs. 4.8%; OR 2.1, CI 1.2-3.6), and autistic traits (6.0% vs. 1.5%; OR 3.4, CI 1.6-7.0). The drug-exposed children also had increased risk of congenital malformations (6.1% vs. 2.9%; OR 2.1, CI 1.4-3.4), but exclusion of congenital malformations did not affect the risk of adverse development. Children born to women with epilepsy who did not use antiepileptic drugs had no

  6. Risk of falls associated with antiepileptic drug use in ambulatory elderly populations

    PubMed Central

    Maximos, Mira; Chang, Feng; Patel, Tejal

    2017-01-01

    Background: Falls are a major cause of morbidity and mortality in older adults. About a third of those aged 65 years or older fall at least once each year, which can result in hospitalizations, hip fractures and nursing home admissions that incur high costs to individuals, families and society. The objective of this clinical review was to assess the risk of falls in ambulatory older adults who take antiepileptic drugs, medications that can increase fall risk and decrease bone density. Methods: PubMed, EMBASE, MEDLINE and the Cochrane Library electronic databases were searched from inception to July 2014. Case-control, quasi-experimental and observational design studies published in English that assessed quantifiable fall risk associated with antiepileptic drug use in ambulatory patient populations with a mean or median age of 65 years or older were eligible for inclusion. One author screened all titles and abstracts from the initial search. Two authors independently reviewed and abstracted data from full-text articles that met eligibility criteria. Results: Searches yielded 399 unique articles, of which 7 met inclusion criteria—4 prospective or longitudinal cohort studies, 1 cohort study with a nested case-control, 1 cross-sectional survey and 1 retrospective cross-sectional database analysis. Studies that calculated the relative risk of falls associated with antiepileptic drug use reported a range of 1.29 to 1.62. Studies that reported odds ratios of falls associated with antiepileptic drug use ranged from 1.75 to 6.2 for 1 fall or at least 1 fall and from 2.56 to 7.1 for more frequent falls. Discussion: Health care professionals should monitor older adults while they take antiepileptic drugs to balance the need for such pharmacotherapy against an increased risk of falling and injuries from falls. PMID:28405254

  7. Intelligence quotient improves after antiepileptic drug withdrawal following pediatric epilepsy surgery.

    PubMed

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

    2015-07-01

    Antiepileptic drugs (AEDs) have cognitive side effects that, particularly in children, may affect intellectual functioning. With the TimeToStop (TTS) study, we showed that timing of AED withdrawal does not majorly influence long-term seizure outcomes. We now aimed to evaluate the effect of AED withdrawal on postoperative intelligence quotient (IQ), and change in IQ (delta IQ) following pediatric epilepsy surgery. We collected IQ scores of children from the TTS cohort with both pre- and postoperative neuropsychological assessments (NPAs; n = 301) and analyzed whether reduction of AEDs prior to the latest NPA was related to postoperative IQ and delta IQ, using linear regression analyses. Factors previously identified as independently relating to (delta) IQ, and currently identified predictors of (delta) IQ, were considered possible confounders and used for adjustment. Additionally, we adjusted for a compound propensity score that contained previously identified determinants of timing of AED withdrawal. Mean interval to the latest NPA was 19.8 ± 18.9 months. Reduction of AEDs at the latest NPA significantly improved postoperative IQ and delta IQ (adjusted regression coefficient [RC] = 3.4, 95% confidence interval [CI] = 0.6-6.2, p = 0.018 and RC = 4.5, 95% CI = 1.7-7.4, p = 0.002), as did complete withdrawal (RC = 4.8, 95% CI = 1.4-8.3, p = 0.006 and RC = 5.1, 95% CI = 1.5-8.7, p = 0.006). AED reduction also predicted ≥ 10-point IQ increase (p = 0.019). The higher the number of AEDs reduced, the higher was the IQ (gain) after surgery (RC = 2.2, 95% CI = 0.6-3.7, p = 0.007 and RC = 2.6, 95% CI = 1.0-4.2, p = 0.001, IQ points per AED reduced). Start of AED withdrawal, number of AEDs reduced, and complete AED withdrawal were associated with improved postoperative IQ scores and gain in IQ, independent of other determinants of cognitive outcome. © 2015 American Neurological Association.

  8. Required propofol dose for anesthesia and time to emerge are affected by the use of antiepileptics: prospective cohort study.

    PubMed

    Ouchi, Kentaro; Sugiyama, Kazuna

    2015-01-01

    We investigated the impact of the type of neurological disorder on the required propofol dose for anesthesia and the time to emerge from anesthesia during dental treatment in patients with autism (AU), cerebral palsy (CP), and intellectual disability (ID), some of whom also had epilepsy. We studied 224 patients with a neurological disorder who underwent dental treatment under intravenous general anesthesia. Patients were categorized according to neurological disorder (AU, CP, and ID; and with or without an antiepileptic). The propofol dose required for anesthesia, time to emerge, and modeled propofol blood concentration at emergence were evaluated. In patients not given an antiepileptic, we found no significant differences in the propofol dose, modeled propofol blood concentration at emergence, or time to emerge among patients with AU, CP, and ID (P > 0.05). When using an antiepileptic, the dose of propofol (5.7 ± 1.51 mg/kg/h) was significantly lower than without an antiepileptic (6.8 ± 1.27 mg/kg/h) (P < 0.0001). The modeled propofol blood concentration at emergence in patients given an antiepileptic (0.5 ± 0.03 μg/ml) was significantly lower than without an antiepileptic (0.7 ± 0.02 μg/ml) (P < 0.0001). The time to emerge in patients given an antiepileptic (29.5 ± 12.5 min) was significantly longer than without an antiepileptic (21.6 min ± 10.0 min) (P < 0.0001). The propofol dose required for anesthesia and the time to emerge from anesthesia are not affected by the type of neurological disorder, but are affected by antiepileptic use. University Hospital Medical Information Network Clinical Trials Registry (UMIN000014179), Date of registration 4 June 2014.

  9. In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)

    PubMed Central

    Wen, Xia; Wang, Jun-Sheng; Kivistö, Kari T; Neuvonen, Pertti J; Backman, Janne T

    2001-01-01

    Aims To evaluate the potency and specificity of valproic acid as an inhibitor of the activity of different human CYP isoforms in liver microsomes. Methods Using pooled human liver microsomes, the effects of valproic acid on seven CYP isoform specific marker reactions were measured: phenacetin O-deethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), tolbutamide hydroxylase (CYP2C9), S-mephenytoin 4′-hydroxylase (CYP2C19), dextromethorphan O-demethylase (CYP2D6), chlorzoxazone 6-hydroxylase (CYP2E1) and midazolam 1′-hydroxylase (CYP3A4). Results Valproic acid competitively inhibited CYP2C9 activity with a Ki value of 600 µm. In addition, valproic acid slightly inhibited CYP2C19 activity (Ki = 8553 µm, mixed inhibition) and CYP3A4 activity (Ki = 7975 µm, competitive inhibition). The inhibition of CYP2A6 activity by valproic acid was time-, concentration- and NADPH-dependent (KI = 9150 µm, Kinact=0.048 min−1), consistent with mechanism-based inhibition of CYP2A6. However, minimal inhibition of CYP1A2, CYP2D6 and CYP2E1 activities was observed. Conclusions Valproic acid inhibits the activity of CYP2C9 at clinically relevant concentrations in human liver microsomes. Inhibition of CYP2C9 can explain some of the effects of valproic acid on the pharmacokinetics of other drugs, such as phenytoin. Co-administration of high doses of valproic acid with drugs that are primarily metabolized by CYP2C9 may result in significant drug interactions. PMID:11736863

  10. Non-toxic Efficacy of the Combination of Caffeine and Valproic Acid on Human Osteosarcoma Cells In Vitro and in Orthotopic Nude-mouse Models.

    PubMed

    Igarashi, Kentaro; Yamamoto, Norio; Hayashi, Katsuhiro; Takeuchi, Akihiko; Kimura, Hiroaki; Miwa, Shinji; Hoffman, Robert M; Tsuchiya, Hiroyuki

    2016-09-01

    We have previously reported that caffeine can enhance chemotherapy efficacy of bone and soft-tissue sarcoma via cell-cycle perturbation. Valproic acid has histone deacetylase (HDAC) inhibitory activity. The present study aimed to investigate the efficacy of the combination of valproic acid and caffeine on human osteosarcoma cells in vitro and in orthotopic nude-mouse models. Human osteosarcoma cell lines (MG63, 143B and SaOS2) were used. Cell survival after a 72 h exposure to valproic acid and caffeine was assessed with a WST-8 assay. Half maximal inhibitory concentration (IC50) values and combination indices (CIs) were calculated. Caspase 3 activity was measured by a fluorochrome inhibitor of caspase (FLICA) assay. 143B cells were also transplanted to the tibia of nude mice and treated with these drugs. Both valproic acid and caffeine caused concentration-dependent cell death of the osteosarcoma cell lines in vitro. Apoptosis induction was observed with the Caspase 3 assay. The combination was synergistic. The combination of valproic acid and caffeine showed effective anti-tumor activity in vivo without the need for conventional anticancer drugs or any observable toxicity Conclusion: Efficacy of combination therapy with caffeine and valproic acid in osteosarcoma was observed in vitro and in vivo without toxicity, suggesting that either or both drugs can be effectively combined with appropriate chemotherapy in the future. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  11. Role of Nrf2 activation and NF-κB inhibition in valproic acid induced hepatotoxicity and in diammonium glycyrrhizinate induced protection in mice.

    PubMed

    Jin, Jing; Xiong, Tianqin; Hou, Xiangyu; Sun, Xiaozhe; Liao, Jiayi; Huang, Zhiying; Huang, Min; Zhao, Zhongxiang

    2014-11-01

    Diammonium glycyrrhizinate (DG), an active compound extracted and purified from liquorices root, has been reported to exhibit antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effect and underlying mechanisms of DG on the hepatotoxicity induced by valproic acid (VPA). DG at the dose of 60mg/kg was orally administered with VPA (100mg/kg) to mice once daily for 14 consecutive days. DG treatment attenuated VPA-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. DG prevented VPA-induced depletion of cytosolic nuclear factor E2-related factor 2 (Nrf2) and suppression of nuclear translocation of Nrf2, which, in turn, up-regulated phase II/antioxidant enzyme activities. The effects of VPA and DG on Nrf2 expression in HepG2 cells were in consistent with that of mice. Furthermore, an increase in the nuclear levels of nuclear factor-kappaB (NF-κB) was observed in the livers of VPA-treated mice that coincided with induction of inflammatory cytokines. In contrast, DG inhibited NF-κB translocation and that subsequently decreased inflammatory cytokines. Taken together, these results demonstrate that DG attenuates VPA-induced liver injury through increasing the expression of Nrf2 mediated phase II/antioxidant enzymes and simultaneously decreasing the expression of inflammatory mediators. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Modular glass chip system measuring the electric activity and adhesion of neuronal cells--application and drug testing with sodium valproic acid.

    PubMed

    Koester, Philipp Julian; Buehler, Sebastian Moritz; Stubbe, Marco; Tautorat, Carsten; Niendorf, Mathias; Baumann, Werner; Gimsa, Jan

    2010-06-21

    We developed a modular neurochip system by combining a small (16x16 mm2) glass neurochip (GNC) with a homemade head stage and commercial data acquisition hardware and software. The system is designed for the detection of the electric activity of cultivated nerve or muscle cells by a 52-microelectrode array (MEA). In parallel, cell adhesion can be registered from the electric impedance of an interdigitated electrode structure (IDES). The GNC was tested with various cell lines and primary cells. It is fully autoclavable and re-useable. Murine embryonic primary cells were used as a model system to correlate the electric activity and adhesion of neuronal networks in a drug test with sodium valproic acid. The test showed the advantage of the parallel IDES and MEA measurements, i.e. the parallel detection of cytotoxic and neurotoxic effects. Toxic exposure of the cells during neuronal network formation allows for the characterization of developmental neurotoxic effects even at drug concentrations below the EC50-value for acute neurotoxic effects. At high drug concentrations, the degree of cytotoxic damage can still be assessed from the IDES data in the event that no electric activity develops. The GNC provides optimal cell culture conditions for up to months in combination with full microscopic observability. The 4'' glass wafer technology allows for a high precision of the GNC structures and an economic production of our new system that can be applied in general and developmental toxicity tests as well as in the search for neuro-active compounds.

  13. Resveratrol prevents oxidative damage and loss of sperm motility induced by long-term treatment with valproic acid in Wistar rats.

    PubMed

    Ourique, Giovana M; Pês, Tanise S; Saccol, Etiane M H; Finamor, Isabela A; Glanzner, Werner G; Baldisserotto, Bernardo; Pavanato, Maria A; Gonçalves, Paulo B D; Barreto, Kátia P

    2016-09-01

    Valproic acid (VPA) is a drug widely use for the treatment of epilepsy in both children and adults. Evidence suggests that long-term use of VPA may lead to an impairment in the male reproductive function. Oxidative stress is considered to play a major role in VPA associated toxicity. In the present work, we demonstrated that the natural antioxidant compound resveratrol (RSV) can be use to prevent VPA oxidative damage. Wistar rats treated with VPA (400mgkg(-1)) by gavage for 28days showed decrease in sperm motility accompanied by increase in oxidative damage to lipids and proteins. Additionally, VPA administration leaded to depletion of reduced glutathione and decrease in total antioxidant potential in testes and epididymides of Wistar rats. The co-administration of RSV (10mgkg(-1)) efficiently prevented VPA pro-oxidant effects. In summary, RSV was shown to protect the reproductive system from the damage induced by VPA. Altogether, our data strongly suggests that RSV administration might be a valuable strategy to minimize reproductive impairment in patients requiring long-term VPA treatment.

  14. Pharmacodynamic and pharmacokinetic analysis of CNS-active constitutional isomers of valnoctamide and sec-butylpropylacetamide--Amide derivatives of valproic acid.

    PubMed

    Mawasi, Hafiz; Shekh-Ahmad, Tawfeeq; Finnell, Richard H; Wlodarczyk, Bogdan J; Bialer, Meir

    2015-05-01

    Valnoctamide (VCD) and sec-butylpropylacetamide (SPD) are CNS-active closely related amide derivatives of valproic acid with unique anticonvulsant activity. This study evaluated how small chemical changes affect the pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and pharmacokinetics (PK) of three constitutional isomers of SPD [sec-butylisopropylacetamide (SID) and tert-butylisopropylacetamide (TID)] and of VCD [tert-butylethylacetamide (TED)]. The anticonvulsant activity of SID, TID, and TED was comparatively evaluated in several rodent anticonvulsant models. The PK-PD relationship of SID, TID, and TED was evaluated in rats, and their teratogenicity was evaluated in a mouse strain highly susceptible to teratogen-induced neural tube defects (NTDs). sec-Butylisopropylacetamide and TID have a similar PK profile to SPD which may contribute to their similar anticonvulsant activity. tert-Butylethylacetamide had a better PK profile than VCD (and SPD); however, this did not lead to a superior anticonvulsant activity. sec-Butylisopropylacetamide and TED did not cause NTDs at doses 4-7 times higher than their anticonvulsant ED50 values. In rats, SID, TID (ip), and TED exhibited a broad spectrum of anticonvulsant activity. However, combined anticonvulsant analysis in mice and rats shows SID as the most potent compound with similar activity to that of SPD, demonstrating that substitution of the isobutyl moiety in the SPD or VCD molecule by tert-butyl as well as a propyl-to-isopropyl replacement in the SPD molecule did not majorly affect the anticonvulsant activity. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Stepwise optimization approach for improving LC-MS/MS analysis of zwitterionic antiepileptic drugs with implementation of experimental design.

    PubMed

    Kostić, Nađa; Dotsikas, Yannis; Malenović, Anđelija; Jančić Stojanović, Biljana; Rakić, Tijana; Ivanović, Darko; Medenica, Mirjana

    2013-07-01

    In this article, a step-by-step optimization procedure for improving analyte response with implementation of experimental design is described. Zwitterionic antiepileptics, namely vigabatrin, pregabalin and gabapentin, were chosen as model compounds to undergo chloroformate-mediated derivatization followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis. Application of a planned stepwise optimization procedure allowed responses of analytes, expressed as areas and signal-to-noise ratios, to be improved, enabling achievement of lower limit of detection values. Results from the current study demonstrate that optimization of parameters such as scan time, geometry of ion source, sheath and auxiliary gas pressure, capillary temperature, collision pressure and mobile phase composition can have a positive impact on sensitivity of LC-MS/MS methods. Optimization of LC and MS parameters led to a total increment of 53.9%, 83.3% and 95.7% in areas of derivatized vigabatrin, pregabalin and gabapentin, respectively, while for signal-to-noise values, an improvement of 140.0%, 93.6% and 124.0% was achieved, compared to autotune settings. After defining the final optimal conditions, a time-segmented method was validated for the determination of mentioned drugs in plasma. The method proved to be accurate and precise with excellent linearity for the tested concentration range (40.0 ng ml(-1)-10.0 × 10(3)  ng ml(-1)).

  16. A Case of Mania Presenting with Hypersexual Behavior and Gender Dysphoria that Resolved with Valproic Acid

    PubMed Central

    Heare, Michelle R.; Barsky, Maria; Faziola, Lawrence R.

    2016-01-01

    Hypersexuality and gender dysphoria have both been described in the literature as symptoms of mania. Hypersexuality is listed in the Diagnostic and Statistical Manual of Mental Disorders 5 as part of the diagnostic criteria for bipolar disorder. Gender dysphoria is less often described and its relation to mania remains unclear. This case report describes a young homosexual man presenting in a manic episode with co-morbid amphetamine abuse whose mania was marked by hypersexuality and the new onset desire to be a woman. Both of these symptoms resolved with the addition of valproic acid to antipsychotics. This case report presents the existing literature on hypersexuality and gender dysphoria in mania and describes a treatment option that has not been previously reported. PMID:27994833

  17. Valproic acid-associated low fibrinogen and delayed intracranial hemorrhage: case report and mini literature review

    PubMed Central

    Chen, Hai-Fei; Xu, Li-Ping; Luo, Zhi-Yong; Yu, Zi-Qiang; Li, Zheng-Yang; Cui, Qing-Ya; Qin, Long-Mei; Ren, Yong-Ya; Shen, Hong-Shi; Tang, Jie-Qing; Jin, Ling-Juan; Zhu, Jing-Jing; Wang, Jing; Wang, Ke-Yuan; Wu, Tian-Qin; Wang, Zhao-Yue

    2013-01-01

    A 41-year-old male had suffered from gradual hearing loss in his right ear for 2 years. Head computed tomography and magnetic resonance imaging scans showed a neoplasm in the cerebellopontine angle region, which was confirmed by the diagnosis of acoustic neurilemmoma by pathological findings after surgery. Following surgery, he routinely received valproic acid (VPA) to prevent seizures. However, the patient presented with hypofibrinogenemia and cerebral hemorrhage after taking VPA for 12 days. The hypofibrinogenemia recurred when VPA was re-administered. After withdrawal of VPA, his fibrinogen concentration rose to normal within several days. As far as we are aware, this is the first case of cerebral hemorrhage due to VPA to have been reported. Herein, as well as reporting on this case, a mini review of the relevant literature is also presented. PMID:23976844

  18. Catatonia-like events after valproic acid with risperidone and sertraline.

    PubMed

    Lauterbach, E C

    1998-07-01

    A patient with schizoaffective disorder developed signs of catatonia while on a regimen of valproic acid, sertraline, and risperidone. The catatonic features evolved for the first time after a single dose of valproate and were alleviated by lorazepam. The same catatonic signs recurred after a second dose of valproate and again remitted after lorazepam. Catatonia did not recur subsequent to discontinuing valproate, and the patient had tolerated the combination of valproate and risperidone in the past without developing catatonia. Although the catatonia in this case initially appears to be paradoxical, the phenomenon is actually consistent with current models of catatonia. A unique drug interaction may account for this phenomenon. Possible pharmacokinetic and pharmacodynamic explanations are discussed, including the relation of catatonia to increased activity of the medial globus pallidus and current models of catatonia.

  19. Inhibition of Enveloped Virus Infection of Cultured Cells by Valproic Acid▿ †

    PubMed Central

    Vázquez-Calvo, Ángela; Saiz, Juan-Carlos; Sobrino, Francisco; Martín-Acebes, Miguel A.

    2011-01-01

    Valproic acid (VPA) is a short-chain fatty acid commonly used for treatment of neurological disorders. As VPA can interfere with cellular lipid metabolism, its effect on the infection of cultured cells by viruses of seven viral families relevant to human and animal health, including eight enveloped and four nonenveloped viruses, was analyzed. VPA drastically inhibited multiplication of all the enveloped viruses tested, including the zoonotic lymphocytic choriomeningitis virus and West Nile virus (WNV), while it did not affect infection by the nonenveloped viruses assayed. VPA reduced vesicular stomatitis virus infection yield without causing a major blockage of either viral RNA or protein synthesis. In contrast, VPA drastically abolished WNV RNA and protein synthesis, indicating that this drug can interfere the viral cycle at different steps of enveloped virus infection. Thus, VPA can contribute to an understanding of the crucial steps of viral maturation and to the development of future strategies against infections associated with enveloped viruses. PMID:21106740

  20. Valproic Acid Causes Proteasomal Degradation of DICER and Influences miRNA Expression

    PubMed Central

    Zhang, Zhaiyi; Convertini, Paolo; Shen, Manli; Xu, Xiu; Lemoine, Frédéric; de la Grange, Pierre; Andres, Douglas A.; Stamm, Stefan

    2013-01-01

    Valproic acid (VPA) is a commonly used drug to treat epilepsy and bipolar disorders. Known properties of VPA are inhibitions of histone deacetylases and activation of extracellular signal regulated kinases (ERK), which cannot fully explain VPA’s clinical features. We found that VPA induces the proteasomal degradation of DICER, a key protein in the generation of micro RNAs. Unexpectedly, the concentration of several micro RNAs increases after VPA treatment, which is caused by the upregulation of their hosting genes prior to DICER degradation. The data suggest that a loss of DICER protein and changes in micro RNA concentration contributes to the clinical properties of VPA. VPA can be used experimentally to down regulate DICER protein levels, which likely reflects a natural regulation of DICER. PMID:24358235

  1. Acetylome and phosphoproteome modifications in imatinib resistant chronic myeloid leukaemia cells treated with valproic acid.

    PubMed

    Buchi, Francesca; Pastorelli, Roberta; Ferrari, Germano; Spinelli, Elena; Gozzini, Antonella; Sassolini, Francesca; Bosi, Alberto; Tombaccini, Donatella; Santini, Valeria

    2011-07-01

    Chronic myeloid leukaemia has a specific therapy: BCR/ABL inhibitor imatinib. Resistance due to BCR/ABL dependent and independent mechanisms is partially reversible by histone deacetylase inhibitors. We analysed by 2D-electrophoresis and anti-pan-acetylated and anti-phosphotyrosine immunoblots, followed by spot-matching and MALDI-TOF mass spectrometry, which proteome modifications would parallel restoration of sensitivity to imatinib by valproic acid (VPA). VPA plus imatinib significantly increased acetylation of HSP90 and hnRNP L and decreased phosphorylation of HSPs and hnRNPs in imatinib resistant cells. VPA was able to modify profoundly acetylome and phosphoproteome of CML cells, while reverting resistance to imatinib.

  2. Inhibition of enveloped virus infection of cultured cells by valproic acid.

    PubMed

    Vázquez-Calvo, Angela; Saiz, Juan-Carlos; Sobrino, Francisco; Martín-Acebes, Miguel A

    2011-02-01

    Valproic acid (VPA) is a short-chain fatty acid commonly used for treatment of neurological disorders. As VPA can interfere with cellular lipid metabolism, its effect on the infection of cultured cells by viruses of seven viral families relevant to human and animal health, including eight enveloped and four nonenveloped viruses, was analyzed. VPA drastically inhibited multiplication of all the enveloped viruses tested, including the zoonotic lymphocytic choriomeningitis virus and West Nile virus (WNV), while it did not affect infection by the nonenveloped viruses assayed. VPA reduced vesicular stomatitis virus infection yield without causing a major blockage of either viral RNA or protein synthesis. In contrast, VPA drastically abolished WNV RNA and protein synthesis, indicating that this drug can interfere the viral cycle at different steps of enveloped virus infection. Thus, VPA can contribute to an understanding of the crucial steps of viral maturation and to the development of future strategies against infections associated with enveloped viruses.

  3. The effect of valproic acid in alleviating early death in burn shock.

    PubMed

    Hu, Sen; Hou, Jing-Yuan; Wang, Hai-Bin; Yang, Mingxing; Sheng, Zhi-Yong

    2012-02-01

    The aim of this study was to examine whether administration of valproic acid (VPA) improves blood circulation and survival after lethal burn shock. Forty adult male Beagle dogs underwent a 50% TBSA full-thickness flame injury. In the first 24 h after burn, animals were randomly divided into four groups: NR group received no treatment. VPA group and 2M2P(2-methyl-2-pentenoic acid) group received either VPA or 2M2P (100 mg of the either drug in 20 mL of normal saline) intravenously. VR group received intravenous infusion of lactated Ringer's solution according to Parkland formula. In the second 24 h after burn the animals of all groups received delayed IV fluid resuscitation. Hemodynamic variables and biochemical parameters were determined with animals in the conscious and cooperative state. From 4 h after burn on, the levels of mean arterial pressure, cardiac index, plasma volume and intestinal mucosal blood perfusion in VPA group were significantly higher, and the levels of parameters of organ function and serum tumor necrosis factor-α were lower than those in NR group and 2M2P group (all P<0.05). Survival at 72 h after burn was in following order: VR (100%)>VPA (60%)>2M2P (30%)>NR (10%). Our results showed that histone deacetylace inhibitor (HDACI) valproic acid significantly improved hemodynamics, intestinal perfusion, and the survival rate after lethal burn shock. The mechanism may be attributable partly to the lowering of the level of proinflammatory factors, ameriolation of vasopermeability-induced visceral edema, reduction of blood volume loss, and protection of vital organs through inhibition of histone deacetylase activity of cell of vital organs. Copyright © 2011 Elsevier Ltd and ISBI. All rights reserved.

  4. Antiepileptic drug use in a nursing home setting: a retrospective study in older adults.

    PubMed

    Callegari, Camilla; Ielmini, M; Bianchi, L; Lucano, M; Bertù, Lorenza; Vender, Simone

    2016-01-01

    The authors set out to examine qualitatively the use of antiepileptic drugs (AEDs) in a population of older adults in a nursing home setting, evaluating aspects such as specialist prescriptions and changes in dosage. This retrospective prevalence study was carried out in a state-funded nursing home that provides care and rehabilitation for elderly people. The first objective of the study was to determine the prevalence of AED use in this population. The second objective was to monitor AED dosage modifications during the fifteen-month study period, focusing on the safety and the tolerability of AEDs. In the period of time considered, 129 of 402 monitored patients received at least one anti-epileptic therapy. The prevalence of AED use was therefore 32%. Gabapentin was found to be the most commonly prescribed drug, with a frequency of 29%, and it was used mainly for anxiety disorders, psychosis, neuropathic pain and mood disorders.

  5. Antiepileptic drug use in a nursing home setting: a retrospective study in older adults.

    PubMed

    Callegari, Camilla; Ielmini, M; Bianchi, L; Lucano, M; Bertù, L; Vender, Simone

    2016-05-13

    The authors set out to examine qualitatively the use of antiepileptic drugs (AEDs) in a population of older adults in a nursing home setting, evaluating aspects such as specialist prescriptions and changes in dosage. This retrospective prevalence study was carried out in a state-funded nursing home that provides care and rehabilitation for elderly people. The first objective of the study was to determine the prevalence of AED use in this population. The second objective was to monitor AED dosage modifications during the fifteen-month study period, focusing on the safety and the tolerability of AEDs. In the period of time considered, 129 of 402 monitored patients received at least one anti-epileptic therapy. The prevalence of AED use was therefore 32%. Gabapentin was found to be the most commonly prescribed drug, with a frequency of 29%, and it was used mainly for anxiety disorders, psychosis, neuropathic pain and mood disorders.

  6. Antiepileptic drug use in a nursing home setting: a retrospective study in older adults

    PubMed Central

    Callegari, Camilla; Ielmini, Marta; Bianchi, Lucia; Lucano, Melissa; Bertù, Lorenza; Vender, Simone

    2016-01-01

    Summary The authors set out to