Valproic Acid: Second Generation

Bialer, Meir; Yagen, Boris

doi:10.1016/j.nurt.2006.11.007

Cited by 122 publications

(136 citation statements)

References 62 publications

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“…Further studies are required to identify responsible neurotransmitters that suppress the M-current during seizures. It has been reported that some VPA metabolites, which are primarily generated in the liver (51), have more potent anticonvulsant action (52). In our case, antihyperexcitation effects were reproduced in cultured cells.…”

Section: Discussionsupporting

confidence: 61%

M-current preservation contributes to anticonvulsant effects of valproic acid

Kay¹,

Greene²,

Kang³

et al. 2015

Journal of Clinical Investigation

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Section: Discussionsupporting

confidence: 61%

M-current preservation contributes to anticonvulsant effects of valproic acid

Kay¹,

Greene²,

Kang³

et al. 2015

Journal of Clinical Investigation

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“…Valproate has been used clinically for a long time in many neuropsychiatric disorders, and recently for HIV and cancers, in which it is used as a sensitizing agent within a polytherapy regimen [45,46]. However, valproate is a known human teratogen when administered during the first trimester of pregnancy [47,48].…”

Section: Discussionmentioning

confidence: 99%

Triple Therapy with Prednisolone, Pegylated Interferon and Sodium Valproate Improves Clinical Outcome and Reduces Human T-Cell Leukemia Virus Type 1 (HTLV-1) Proviral Load, Tax and HBZ mRNA Expression in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

et al. 2015

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Considering that there is no effective treatment for human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis, this study aimed to assess the impact of triple combination therapy-interferon-α, valproic acid, and prednisolone-on clinical outcomes, main HTLV-1 viral factors, and host anti-HTLV-1 antibody response. HTLV-1 proviral load (PVL), and HBZ and Tax mRNA expression levels were measured in peripheral blood mononuclear cells of 13 patients with HTLV-1-associated myelopathy/tropical spastic paraparesis before and after treatment with 180 μg pegylated interferon once a week, 10-20 mg/kg/day sodium valproate, and 5 mg/day prednisolone for 25 weeks using a TaqMan real-time polymerase chain reaction assay. Furthermore, anti-HTLV-1 titer, Osame Motor Disability Score, Ashworth spasticity scale, and urinary symptoms (through standard questionnaire and clinical monitoring) were assessed in patients before and after the treatment. HTLV-1 PVL and HBZ expression significantly decreased after the treatment [PVL from 1443±282 to 660±137 copies/10 4 peripheral blood mononuclear cells (p= 0.01); and HBZ from 8.0±1.5 to 3.0±0.66 (p<0.01)]. Tax mRNA expression decreased after the treatment from 2.26± 0.45 to 1.44±0.64, but this reduction was not statistically significant (p=0.10). Furthermore, anti-HTLV-1 titer reduced dramatically after the treatment, from 3123±395 to 815±239 (p<0.01). Clinical signs and symptoms, according to Osame Motor Disability Score and Ashworth score, improved significantly (both p<0.01). Urinary symptoms and sensory disturbances with lower back pain were reduced, though not to a statistically significant degree. Although signs and symptoms of spasticity were improved, frequent urination and urinary incontinence were not significantly affected by the triple therapy. The results provide new insight into the complicated conditions underlying HTLV-1-associated diseases.

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“…It is used mostly for the treatment of several types of seizures, bipolar disorders, various psychiatric syndromes, and migraines (Perucca, 2002;Peterson and Naunton, 2005;Bialer and Yagen, 2007). In addition, VPA has emerged recently as a drug that shows potential in cancer treatment (Duenas-Gonzalez et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Role of Isovaleryl-CoA Dehydrogenase and Short Branched-Chain Acyl-CoA Dehydrogenase in the Metabolism of Valproic Acid: Implications for the Branched-Chain Amino Acid Oxidation Pathway

Luis¹,

Ruiter²,

IJlst³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Many biological systems including the oxidative catabolic pathway for branched-chain amino acids (BCAAs) are affected in vivo by valproate therapy. In this study, we investigated the potential effect of valproic acid (VPA) and some of its metabolites on the metabolism of BCAAs. In vitro studies were performed using isovalerylCoA dehydrogenase (IVD), isobutyryl-CoA dehydrogenase (IBD), and short branched-chain acyl-CoA dehydrogenase (SBCAD), enzymes involved in the degradation pathway of leucine, valine, and isoleucine. The enzymatic activities of the three purified human enzymes were measured using optimized high-performance liquid chromatography procedures, and the respective kinetic parameters were determined in the absence and presence of VPA and the corresponding CoA and dephosphoCoA conjugates. Valproyl-CoA and valproyl-dephosphoCoA inhibited IVD activity significantly by a purely competitive mechanism with K i values of 74 ؎ 4 and 170 ؎ 12 M, respectively. IBD activity was not affected by any of the tested VPA esters. However, valproyl-CoA did inhibit SBCAD activity by a purely competitive mechanism with a K i of 249 ؎ 29 M. In addition, valproyl-dephosphoCoA inhibited SBCAD activity via a distinct mechanism (K i ‫؍‬ 511 ؎ 96 M) that appeared to be of the mixed type. Furthermore, we show that both SBCAD and IVD are active, using valproyl-CoA as a substrate. The catalytic efficiency of SBCAD turned out to be much higher than that of IVD, demonstrating that SBCAD is the most probable candidate for the first dehydrogenation step of VPA ␤-oxidation. Our data explain some of the effects of valproate on the branched-chain amino acid metabolism and shed new light on the biotransformation pathway of valproate.

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Valproic Acid: Second Generation

Cited by 122 publications

References 62 publications

M-current preservation contributes to anticonvulsant effects of valproic acid

M-current preservation contributes to anticonvulsant effects of valproic acid

Triple Therapy with Prednisolone, Pegylated Interferon and Sodium Valproate Improves Clinical Outcome and Reduces Human T-Cell Leukemia Virus Type 1 (HTLV-1) Proviral Load, Tax and HBZ mRNA Expression in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

Role of Isovaleryl-CoA Dehydrogenase and Short Branched-Chain Acyl-CoA Dehydrogenase in the Metabolism of Valproic Acid: Implications for the Branched-Chain Amino Acid Oxidation Pathway

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