Valproic acid for

Limdi NA, Shimpi AV, Faught E, et al. Efficacy of rapid IV administration of valproic acid for status epilepticus. Neurology 2005 64 353-355. 

Valproic acid was determined in plasma by treatment with 2,4-dibromoacetophe-none or 2-bromoacetonapththalone and with dicyclohexano-18-crown-6 and heated at 70 °C for 40 min. The solution was subjected to TLC on C8F octyl plates or to high performance TLC on RP 8 254 S or Kieselgel 60 F254 plates with developing solvents of aq. 63% ethanol, aq. 73% ethanol or CHCl3-cyclohexane (2 1), respectively, with detection at 280 or 254 nm for the naphthoylmethyl or phenacyl derivative, respectively. The limits of detection were 9.7 and 4.9 pg/mL of valproic acid for the TLC RP 8 and HPTLC RP 8 plates, respectively. Recovery was 84-92.74% [28],... 

Unlike carbamazepine, valproic acid has few drug interactions, an added benefit for elderly patients. One interaction worthy of mention, however, is that aspirin can increase levels of valproic acid. For this reason, vascular dementia patients taking an aspirin a day may need a lower dose of valproic acid or at least more careful monitoring of blood levels when starting valproic acid. 

Kastner, T., Friedman, D.L., and Plummer, A. (1990) Valproic acid for the treatment of children with mental retardation and mood symptomatology. Pediatrics 86 467-472. 

Another group of mood-stabilizing drugs that are also anticonvulsant agents have become more widely used than lithium. These include carbamazepine and valproic acid for the treatment of acute mania and for prevention of its recurrence. Lamotrigine is approved for prevention of recurrence. Gabapentin, oxcarbazepine, and topiramate are sometimes used to treat bipolar disorder but are not approved by FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by FDA for the treatment of manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for the treatment of bipolar depression. 

Fanconi syndrome (metabolic acidosis secondary to malfunction of proximal renal tubules, resulting in urinary excretion of amino acids, glucose, phosphate, bicarbonate, uric acid, and other substances) secondary to longterm valproic acid has been described in an 8-year-old boy with severe developmental disability (1170). In a review of 10 previous reports of Fanconi syndrome secondary to long-term valproic acid therapy the authors found that all occurred at 4-14 years, all had taken valproic acid for 10 months to 10 years, and symptoms were fully reversible within 2-14 months after withdrawal of valproic acid. Most of the patients (9 of 11) were severely disabled, bedridden, or wheelchair-bound. 

S174 Halter, C.M., Mickelson, K.E., Wilcox, J.F. and Thompson, S.G. (1987). A dry-reagent immunoassay for valproic acid for use with the Ames Seralyzer reflectance photometer. Clin. Chem. 33, 1020, Abstr. 684. 

Co-administration of acetazolamide with primidone results in decreased gastrointestinal absorption of primidone and subsequent diminished plasma concentrations. Primidone administered in association with phenytoin produces a modest elevation of the phenobarbital/primidone ratio because phenytoin competes with the hepatic hydroxylating enzymes associated with phenobarbitaFs metabolism. Coadministration of valproic acid, for the same reasons out-fined for phenobarbital, causes a modest increase in both primidone and phenobarbital serum concentrations. 

The speed of regulatory review depends on the number of drugs in the queue in front of it, the medical value of the drug and the quality of the submission in addition to vegulations. Another factor that few companies would want to try to influence is the pressure from outside sources on a regulatory authority. The US Congress pressured the FDA to approve valproic acid for seizures in children many years ago, even before the company was ready to make its submission. 

Because most adult patients have localization-related (partial onset) seizures, the most widely used AEDs traditionally have been carbamazepine, phenobarbital, phenytoin, and valproic acid. For com-... 

A Method for Esterification of Valproic Acid for Gas-Liquid Chromatography Clinical Date from Epileptic Patients J. Anal. Toxicol. 2(5) 203-206 (1978) CA 90 15987j... 

Nervous system Encephalopathy There have been several further reports of valproate-induced hyperammonemic encephalopathy [350, 351, 352", 353 ]. In one case it was associated with central pontine mye-linolysis and coma in a patient with Sjogren s syndrome who had taken long-term valproic acid for a psychotic disorder [354 ]. 

M. Ki ogh, K. Johansen, F. Tonnesen and K. E. Rasmusen, Solid-phase microexti action for the detemination of the free concentration of valproic acid in human plasma by cap-illai y gas chi omatography , J. Chromatogr. B 673 299-305 (1997). 

Phenobarbitone was the first AED and was introduced in 1912. It was largely replaced in 1932 by phenytoin for the management of tonic-xilonic seizures and partial and secondary epilepsy. Carbamazepine followed, then ethosuximide for absence seizures and valproic acid. These remained, apart from the introduction of the benzodiazepines, the mainstay of therapy until the last decade. They were introduced solely on their ability to control experimentally induced seizures. Their mechanisms of action were unknown and no thought was given to the possibility of NT modification and in fact subsequent research has shown that with the exception of the benzodiazepines none of them work primarily through NT manipulation. They act directly on neuronal excitability. 

Epilepsy is a clinical disorder characterized by spontaneous, recurrent seizures arising from excessive electrical activity in certain parts of the brain [51]. Currently available drugs, such as phenytoin, carbamazepine, valproic acid, lamotrigine, and topiramate (for molecular structures see Fig. 6), provide symptomatic seizure suppression in only 60-70% of those receiving treatment [52-54]. These drugs are also associated with unwanted side... 

PCP, 15 mg/kg, and ketamine, 40 mg/kg, elevated the threshold for eliciting hippocampal afterdischarge (prekindling) by 61 percent and 267 percent, respectively (table 2). Valproic acid and carba-mazepine also elevated the threshold. In contrast, phenobarbita 1 and diazepam had no effect on the prekindling afterdischarge threshold, even at doses capable of altering the AD. 

Assess the AED serum concentration and adjust therapy as needed for agents with a defined therapeutic range (e.g., phenytoin, carbamazepine, valproic acid, and phenobarbital). Drug levels can also be used to determine adherence to medication regimens for agents that do not have defined ranges. 

Divalproex sodium is comprised of sodium valproate and valproic acid. The delayed-release and extended-release formulations are converted in the small intestine into valproic add, which is the systemically absorbed form. It was developed as an antiepileptic drug, but also has efficacy for mood stabilization and migraine headaches. It is FDA-approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comorbidity. Although not FDA-approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. Divalproex can be used as monotherapy or in combination with lithium or an antipsychotic drug.31... 

Castro, L. M., Gallant, M. Niles, L. P. (2005). Novel targets for valproic acid ... 

Recently, Prasad et al. cloned a mammalian Na+-dependent multivitamin transporter (SMVT) from rat placenta [305], This transporter is very highly expressed in intestine and transports pantothenate, biotin, and lipoate [305, 306]. Additionally, it has been suggested that there are other specific transport systems for more water-soluble vitamins. Takanaga et al. [307] demonstrated that nicotinic acid is absorbed by two independent active transport mechanisms from small intestine one is a proton cotransporter and the other an anion antiporter. These nicotinic acid related transporters are capable of taking up monocarboxylic acid-like drugs such as valproic acid, salicylic acid, and penicillins [5], Also, more water-soluble transporters were discovered as Huang and Swann [308] reported the possible occurrence of high-affinity riboflavin transporter(s) on the microvillous membrane. 

B, respectively. The infrared absorption bands assignments for sodium valproate and valproic acids are shown in Table 2(A) and (B), respectively. 

The 13C NMR spectrum of valproic acid was obtained using a Bruker Avance Instrument operating at 75, 100, and 125 MHz. Standard Bruker Software was used to obtain DEPT spectra. The sample was dissolved in D20 and tetra-methylsilane (TMS) was used as the internal standard. The 13C NMR spectrum of valproic acid is shown in Fig. 10. The DEPT NMR spectra are shown in Figs. 11 and 12. The assignments for the various carbons of valproic acid are presented in Table 4. 

The United States Pharmacopoeia [12] describes two tests for the identification of valproic acid in its formulations (capsules or syrup). 

Valproic Acid and Sodium Valproate Comprehensive Profile Table 4. 13C NMR assignments for sodium valproate... 

The British Pharmacopoeia [10] and the European Pharmacopoeia [11] also recommend a potentiometric method for valproic acid. Dissolve 0.100 g in 25 mL of alcohol. Add 2 mL of water. Titrate with 0.1 M sodium hydroxide determining the endpoint potentiometrically. Each 1 mL of 0.1 M sodium hydroxide is equivalent to 14.42 mg of C8H1602. 

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