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Valproic acid sodium salt (Sodium valproate)

Alias: Valproic acid sodium salt; Valproic Acid; Convulex; Sodium valproate; Sodium 2-propylpentanoate; 1069-66-5; Valproate sodium; Valproic acid sodium salt; Valproic acid sodium; Eurekene; Labazene; Depakote; Epilim; Stavzor; Vilapro; VPA; Sodium valproate
Cat No.:V0291 Purity: ≥98%
Valproate (VPA, NSC-93819, valproic acid, sodium valproate, and divalproex sodium) is an approved medication mainly used for the treatment of epilepsy and bipolar disorder, also used to prevent migraine headaches.
Valproic acid sodium salt (Sodium valproate)
Valproic acid sodium salt (Sodium valproate) Chemical Structure CAS No.: 1069-66-5
Product category: HDAC
This product is for research use only, not for human use. We do not sell to patients.
Size Price Stock Qty
5g
10g
25g
50g
Other Sizes

Other Forms of Valproic acid sodium salt (Sodium valproate):

  • Valproic acid
  • Valproic acid-d4 (VPA-d4; 2-Propylpentanoic Acid-d4)
  • Valproic acid-d6 (VPA-d6; 2-Propylpentanoic Acid-d6)
  • Valproic acid-d15 (VPA-d15; 2-Propylpentanoic Acid-d15)
  • Divalproex Sodium
  • Valproic acid-d4-1 (Valproic acid-d4; VPA-d4-1; 2-Propylpentanoic Acid-d4-1)
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Valproate (VPA, NSC-93819, valproic acid, sodium valproate, and divalproex sodium) is an approved medication mainly used for the treatment of epilepsy and bipolar disorder, also used to prevent migraine headaches. It is a histone deacetylase (HDAC) inhibitor with an IC50 between 0.5 and 2 mM.

Biological Activity I Assay Protocols (From Reference)
Targets
HDAC1 ( IC50 = 400 μM ); HDAC1 ( IC50 = 0.5-2 mM ); HDAC2; Autophagy; Mitophagy
ln Vitro

In vitro activity: Valproic acid has a unique mechanism of action that includes direct inhibition of histone deacetylase (IC(50) = 0.4 mM for HDAC1). Histones in cultured cells become hyperacetylated due to valproic acid's imitation of the histone deacetylase inhibitor trichostatin A. Valproic acid stimulates transcription from a variety of endogenous and exogenous promoters, just like trichostatin A. While non-teratogenic valproic acid analogues do not inhibit histone deacetylase or activate transcription, valproic acid and trichostatin A exhibit strikingly similar teratogenic effects in vertebrate embryos.[1] In the liver of a rodent, valproic acid causes peroxisome multiplicity. By using Gal4 fusions of N-CoR, TR, or PPARδ with a GR-controlled reporter gene and the ligand-binding domain of PPARδ fused to the DNA-binding domain of the glucocorticoid receptor (GR), valproic acid at a concentration of 1 mM relieves this repression. Hypoacetylated histone build-up and HDAC activity inhibition are caused by valproic acid. In F9 teratocarcinoma cells, valproic acid induces a particular kind of differentiation that is characterized by decreased proliferation, morphological changes, marker gene expression, and–most importantly–the accumulation of the AP-2 transcription factor, which may be a sign of neuronal or neural crest cell-like differentiation. In F9 and P19 teratocarcinoma cells, valproic acid inhibits cell proliferation or survival as evidenced by a decrease in [3H]thymidine incorporation.[2]

ln Vivo
Valproic acid inhibits the growth of the primary tumors in the breast cancer model of MT-450 rats. [2]/td>
Enzyme Assay
The colorimetric assay kits for caspase-3, -8, and -9, respectively, are used to measure the activity of these enzymes. To put it briefly, 10 mM Valproic acid is incubated for 24 hours with 1×106 cells in a 60-mm culture dish. Following a PBS wash, the cells are suspended in five volumes of the kit's lysis buffer. Bradford method is used to determine protein concentrations. The activities of caspase-3, -8, and -9 are measured in supernatants containing 50 μg total protein. In 96-well microtiter plates containing caspase-3, -8, or -9 substrates (DEVD-pNA, IETD-pNA, or LEHD-pNA), the supernatants are added to each well. The plates are then incubated for one hour at 37°C. Using a microplate reader, the optical density of each well is determined at 405 nm. Arbitrary absorbance units are used to express the activity of caspase-3, -8, and -9.
Cell Assay
For MTT assays, 5×105 cells are seeded in 96-well microtiter plates. Each well of the 96-well plates is filled with 20 mL of MTT solution (2 mg/mL in phosphate-buffered saline; PBS), which has been exposed to the prescribed doses of valproic acid for the indicated times. In addition, the plates are incubated at 37°C for three hours. To dissolve the formazan crystals, 200 mL of DMSO is added to each well after the medium has been pipetted out of the plates. Through the use of a microplate reader, the optical density is measured at 570 nm.
Animal Protocol
500 mg/kg; i.p.
Mice: BALB/c nude mice are used for splenectomies. The mice were given a 4 Gy dose of 137Cs whole body irradiation one week following their splenectomies. The mice are given subcutaneous injections of Kasumi-1 cells (2×107 cells/mouse with 0.15-0.2 mL) in the right axillary region 48–72 hours after radiation. The mice are divided into two groups at random: the control group (n=6) and the valproic acid group (n=6). Every day, 0.2 milliliters of saline or 0.2 milliliters of valproic acid (500 mg/kg body weight) are injected intraperitoneally into the tumors once they have grown to a size of approximately 200 mm3 after implantation. A 25 mg/mL solution of valproic acid is prepared in saline. Every three days, the tumor's longest diameter (a) and shortest diameter (b) are measured. TV=1/2×a×b2 is the formula used to calculate the tumor volume (TV). The mice are sacrificed by cervical dislocation after receiving injections for two weeks, and the tumor masses are extracted in preparation for the ensuing experiments.
Toxicity/Toxicokinetics
Hepatotoxicity
Prospective studies suggest that 5% to 10% of persons develop ALT elevations during long term valproate therapy, but these abnormalities are usually asymptomatic and can resolve even with continuation of drug. Unlike phenytoin and carbamazepine, valproate does not induce elevations in serum GGT levels. More importantly and not uncommonly, valproate can cause several forms of clinically apparent hepatotoxicity. Indeed, more than 100 fatal cases of acute or chronic liver injury due to valproate have been reported in the literature. Three clinically distinguishable forms of hepatotoxicity (besides simple aminotransferase elevations) can occur with valproate.
The first syndrome is hyperammonemia with minimal or no evidence of hepatic injury. This syndrome typically presents with progressive and episodic confusion followed by obtundation and coma. The time to onset is often within a few weeks of starting valproate or increasing the dose, but it can present months or even years after starting the medication (Case 1). The diagnosis is made by the finding of elevations in serum ammonia with normal (or near normal) serum aminotransferase and bilirubin levels. Valproate levels are usually normal or minimally high. The syndrome resolves within a few days of stopping valproate, but may reverse more rapidly with carnitine supplementation or renal hemodialysis.
The second form of injury from valproate is an acute hepatocellular injury with jaundice, typically accompanied by hepatocellular or mixed pattern of enzyme elevations (Case 2). This acute liver injury pattern usually has its onset within 1 to 6 months of starting valproate. The pattern of serum enzyme elevations can be hepatocellular or mixed; sometimes the serum aminotransferase levels are not markedly elevated, despite the severity of injury.
Immunoallergic features (fever, rash, eosinophilia) are usually absent, but rare cases with prominent features of hypersensitivity have been reported (Case 3). Multiple instances of fatal acute hepatic failure due to valproate have been published and valproate is regularly listed as a cause of drug induced acute liver failure. Liver histology is distinctive and reveals a microvesicular steatosis with central lobular necrosis, mild to moderate inflammation and cholestasis. In cases with a prolonged course, fibrosis, bile duct proliferation and regenerative nodules may be present. Prospective studies using historical controls suggest that carnitine (particularly intravenously) may be beneficial if given soon after presentation.
The third form of hepatic injury due to valproate is a Reye-like syndrome described in children on valproate who develop fever and lethargy (suggestive of a viral infection) followed by confusion, stupor and coma, with raised ammonia levels and marked ALT elevations but normal or minimally elevated bilirubin levels. Metabolic acidosis is also common and the syndrome can be rapidly fatal. Valproate may simply be an aspirin-like agent capable of triggering Reye syndrome if it is being taken when the child develops either influenza or varicella infection.
All three forms of valproate hepatotoxicity have features of mitochondrial injury, and liver histology usually demonstrates microvesicular steatosis with variable amounts of inflammation and cholestasis. Young age (
Likelihood score: A (well known cause of several forms of clinically apparent liver injury).
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Valproic acid levels in breastmilk are low and infant serum levels range from undetectable to low. Breastfeeding during valproic acid monotherapy does not appear to adversely affect infant growth or development; however, and breastfed infants had higher IQs and enhanced verbal abilities than nonbreastfed infants at 6 years of age in one study. A safety scoring system finds valproic acid possible to use during breastfeeding, and a computer model predicted a relatively low infant exposure, consistent with literature reports. If valproic acid is required by the mother, it is not a reason to discontinue breastfeeding.
No definite adverse reactions to valproic acid in breastfed infants have been reported. Theoretically, breastfed infants are at risk for valproic acid-induced hepatotoxicity, so infants should be monitored for jaundice and other signs of liver damage during maternal therapy. A questionable case of thrombocytopenia has been reported, so monitor the infant for unusual bruising or bleeding. A rare case of infant baldness might have been caused by valproate in milk. Observe the infant for jaundice and unusual bruising or bleeding. Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions.
◉ Effects in Breastfed Infants
A mother with epilepsy was taking valproic acid 2.4 grams daily and primidone 250 mg 3 times daily during pregnancy and postpartum. During the second week postpartum, her breastfed infant was sedated. Breastfeeding was stopped and the drowsiness cleared. The sedation was possibly caused by primidone in breastmilk although valproic acid might have contributed by increasing primidone levels.
Petechiae, thrombocytopenia, anemia, and mild hematuria occurred in a 2.5-month-old breastfed infant whose mother was taking valproic acid 600 mg twice daily. Blood hemoglobin and reticulocytes normalized between 12 and 19 days after discontinuing breastfeeding. The petechiae resolved 35 days after discontinuing breastfeeding and the infant's platelet count had almost reached the normal range by this time. By day 83, the infant's platelet count was well within the normal range. The authors believed the adverse effect to be caused by valproic acid in breastmilk. However, other authors believe that these symptoms were more likely caused by idiopathic thrombocytopenic purpura following a viral infection.
Two breastfed infants aged 1 and 3 months whose mothers were taking valproic acid monotherapy 750 and 500 mg daily developed normally and had no abnormal laboratory values. Their plasma levels were 6% and 1.5% or their mother's serum levels, respectively.
Six breastfed infants whose mothers were taking valproic acid 750 or 1000 mg daily had no adverse reactions to valproic acid in breastmilk.
An exclusively breastfed infants whose mother was taking valproate 1.8 g, topiramate 300 mg, and levetiracetam 2 g, daily during pregnancy and lactation appeared healthy to the investigators throughout the 6- to 8-week study period.
In a long-term study on infants exposed to anticonvulsants during breastfeeding, no difference in average intelligence quotient at 3 years of age was found between infants who were breastfed (n = 11) a median of 6 months and those not breastfed (n = 24) when their mothers were taking valproate monotherapy. At 6 years of age, extensive psychological and intelligence testing found that the breastfed infants had higher IQ values than the nonbreastfed infants.
A prospective cohort study in Norway followed infants of mothers who took antiepileptic drugs during pregnancy and lactation and compared them to infants of mothers with untreated epilepsy and infants with fathers who took antiepileptics as control groups. Of the 223 mothers studied, 27 were taking valproate monotherapy. Infants were assessed at 6, 18 and 36 months of age. Continuous breastfeeding in children of women using antiepileptic drugs was associated with no greater impaired development than those with no breastfeeding or breastfeeding for less than 6 months.
A woman with bipolar disorder who delivered twins and was taking sodium valproate in a therapeutic dosage was started on quetiapine 200 mg and olanzapine 15 mg at 11 pm daily after 20 days postpartum. She withheld breastfeeding during the night and discarded milk pumped at 7 am. She then breastfed her infants until 11 pm. The mother continued feeding the infants on this schedule for 15 months. Monthly follow-up of the infants indicated normal growth and neither the pediatricians nor the parents noted any adverse effects in the infants.
The 4-month-old breastfed infant of a mother taking divalproex for bipolar disorder developed patchy hair loss. The extent of nursing and dosage of divalproex were not stated. Divalproex was discontinued and 2 months later, the infant’s hair was normal. The hair loss was possibly caused by valproate.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
References

[1]. J Biol Chem . 2001 Sep 28;276(39):36734-41.

[2]. EMBO J . 2001 Dec 17;20(24):6969-78.

Additional Infomation
Valproate (Valproic acid) can cause developmental toxicity according to an independent committee of scientific and health experts.
Sodium valproate is the sodium salt of valproic acid. It has a role as a geroprotector. It contains a valproate.
Valproate or valproic acid is a branched chain organic acid that is used as therapy of epilepsy, bipolar disorders and migraine headaches and is a well known cause of several distinctive forms of acute and chronic liver injury.
Valproate Sodium is the sodium salt form of valproic acid with anti-epileptic activity. Valproate sodium is converted into its active form, valproate ion, in blood. Although the mechanism of action remains to be elucidated, valproate sodium increases concentrations of gamma-aminobutyric acid (GABA) in the brain, probably due to inhibition of the enzymes responsible for the catabolism of GABA. This potentiates the synaptic actions of GABA. Valproate sodium may also affect potassium channels, thereby creating a direct membrane-stabilizing effect.
A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of EPILEPSY and BIPOLAR DISORDER. The mechanisms of its therapeutic actions are not well understood. It may act by increasing GAMMA-AMINOBUTYRIC ACID levels in the brain or by altering the properties of VOLTAGE-GATED SODIUM CHANNELS.
See also: Valproic Acid (has active moiety).
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C8H15NAO2
Molecular Weight
166.19
Exact Mass
166.096
Elemental Analysis
C, 57.82; H, 9.10; Na, 13.83; O, 19.25
CAS #
1069-66-5
Related CAS #
99-66-1 (free acid); 1069-66-5 (sodium); 33433-82-8 (calcium); Valproic acid-d4;87745-17-3;Valproic acid-d6;87745-18-4;Valproic acid-d15;362049-65-8;Valproic acid (sodium)(2:1);76584-70-8;Valproic acid-d4 sodium;Valproic acid-d4-1;345909-03-7
PubChem CID
16760703
Appearance
White to off-white crystalline powder
Density
1.0803 g/cm3
Boiling Point
220ºC at 760 mmHg
Melting Point
300 °C
Flash Point
STABILITY
Vapour Pressure
0.0435mmHg at 25°C
LogP
0.952
Hydrogen Bond Donor Count
0
Hydrogen Bond Acceptor Count
2
Rotatable Bond Count
5
Heavy Atom Count
11
Complexity
98.3
Defined Atom Stereocenter Count
0
SMILES
[Na+].[O-]C(C([H])(C([H])([H])C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])[H])=O
InChi Key
AEQFSUDEHCCHBT-UHFFFAOYSA-M
InChi Code
InChI=1S/C8H16O2.Na/c1-3-5-7(6-4-2)8(9)10;/h7H,3-6H2,1-2H3,(H,9,10);/q;+1/p-1
Chemical Name
sodium;2-propylpentanoate
Synonyms
Valproic acid sodium salt; Valproic Acid; Convulex; Sodium valproate; Sodium 2-propylpentanoate; 1069-66-5; Valproate sodium; Valproic acid sodium salt; Valproic acid sodium; Eurekene; Labazene; Depakote; Epilim; Stavzor; Vilapro; VPA; Sodium valproate
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.
Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~33 mg/mL (~198.6 mM)
Water: ~33 mg/mL (~198.6 mM)
Ethanol: ~33 mg/mL (~198.6 mM)
Solubility (In Vivo)
Solubility in Formulation 1: 100 mg/mL (601.72 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

Solubility in Formulation 2: 5% DMSO 1 95% Corn oil: 1.65mg/ml (9.93mM)

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 6.0172 mL 30.0860 mL 60.1721 mL
5 mM 1.2034 mL 6.0172 mL 12.0344 mL
10 mM 0.6017 mL 3.0086 mL 6.0172 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00431522 Completed Drug: Valproic acid, sodium
salt
Bipolar Disorder Sanofi December 2004 Phase 4
NCT05017454 Completed Drug: the optimized sodium
valproate-loaded nanospanlastic
dispersion
Drug: mometasone furoate
lotion
Alopecia Areata Kasr El Aini Hospital May 1, 2021 Early Phase 1
NCT04531592 Withdrawn Drug: Valproic acid
Drug: Isotonic saline solution
Acute Kidney Injury
Ischemia Reperfusion Injury
Westat January 2022 Phase 2
NCT04531579 Withdrawn Drug: Isotonic saline solution Ischemia Reperfusion Injury
Acute Kidney Injury
Westat January 2022 Phase 2
Biological Data
  • Valproic acid sodium salt (Sodium valproate)
    VPA relieves HDAC-mediated transcriptional repression.EMBO J.2001 Dec 17;20(24):6969-78.
  • Valproic acid sodium salt (Sodium valproate)
    VPA induces accumulation of hyperacetylated histone and inhibits HDAC activity.EMBO J.2001 Dec 17;20(24):6969-78.
  • Valproic acid sodium salt (Sodium valproate)
    HDAC inhibition by compounds related to VPA.EMBO J.2001 Dec 17;20(24):6969-
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