Valproic acid, also known as Depakene, is a type of medicine normally used to treat seizures and other nervous system problems. Valproic acid works against HIV by releasing the virus from resting cells so other anti-HIV medicines can attack it.
HIV/AIDS-Related Uses
Valproic acid is being studied for the treatment of HIV infection and is not yet approved by the FDA for HIV use outside of clinical trials. This medicine does not cure or prevent HIV infection or AIDS and does not reduce the risk of passing the virus to other people.
Dosage Form/Administration
Valproic acid comes in oral capsule and syrup forms and is taken by mouth. Valproate sodium is available as a syrup and as an intrevenous injection.
Recommended Daily Dose
Valproic acid doses of 500 to 750 mg twice daily have been tested for treatment of patients with HIV infection.
Contraindications
Individuals should tell a doctor about any medical problems before taking this medicine. Valproic acid should not be used in patients with liver disease.
Possible Side Effects
Along with its desired effects, valproic acid can cause some unwanted effects. Serious side effects of this medicine include liver failure, possibly leading to death. Symptoms of liver problems include weakness, tiredness, facial swelling, vomiting, and other flu-like symptoms. Individuals should tell a doctor if they have any of these side effects.Other side effects may not be serious and may lessen or disappear with continued use of the medicine. Less serious side effects of this medicine include headache, nausea, diarrhea, stomach pain, dizziness, sleepiness, and tremor. Individuals should tell a doctor if these side effects continue or are bothersome.
Drug and Food Interactions
A doctor should be notified of any other medications being taken, including prescription, nonprescription (over-the-counter), or herbal medications.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Valproic acid.
Manufacturer Information
Valproic acid
Abbott Laboratories
One Hundred Abbott Park Rd
Abbott Park, IL 60064-3500
Phone: 800-633-9110
Last Updated: December 11, 2007
Drug Description
Valproic acid is a carboxylic acid that increases gamma-amino butyric acid (GABA) levels in the central nervous system and inhibits the enzyme histone deacetylase 1 (HDAC1). [1] [2]
References
[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 12/11/07.
[2] AHFS Drug Information 2007; p. 2255
HIV/AIDS-Related Uses
Valproic acid is being studied for use in the treatment of HIV infection by reducing the number of dormant, infected T cells, making the virus more accessible to attack by other antiretrovirals. [1] [2] [3]
References
[1] Retrovirology 2005 Sep 19;2:56
[2] Lancet 2005 Aug;366(9485):549-55
[3] AHFS Drug Information 2007; pp. 2260-1
Dosing Information
Mode of Delivery
Oral. [1]
Intravenous. [2]
Dosage Form
Orange-colored, soft gelatin capsules containing valproic acid 250 mg.
Red-colored syrup containing valproic acid 250 mg as a sodium salt per 5 ml. [3]
Dosages of 500 to 750 mg twice daily have been tested for use in combination with enfuvirtide and as part of certain antiretroviral regimens. [4]
Storage
Store capsules at 15 C to 25 C (59 F to 77 F). Store syrup below 30 C (86 F). [5]
References
[1] FDA Depakene Extended Release Tablets Prescribing Information, July 2006, p. 2. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf. Accessed 12/11/07.
[2] AHFS Drug Information 2007; p. 2262
[3] FDA Depakene Extended Release Tablets Prescribing Information, July 2006, p. 29. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf. Accessed 12/11/07.
[4] Retrovirology 2005 Sep 19;2:56
[5] FDA Depakene Extended Release Tablets Prescribing Information, July 2006, p. 26. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf. Accessed 12/11/07.
Pharmacology
Valproic acid, a histone deacetylase (HDAC)-1 inhibitor, stimulates the release of HIV from latent T cells, allowing antiretrovirals to attack the re-emerged virus. HDAC-1 inhibition may also suppress HIV promoter activity in latent T cells infected with the virus.
In a small proof-of-concept study, valproic acid administered to HIV infected adults for three months with enfuvirtide accelerated the clearance of HIV from latent T cells and decreased the frequency of latent cell infection significantly in three of four patients. These findings suggest valproic acid may be useful in decreasing the HIV reservoir and eliminating more of the virus from infected cells. [1] [2]
Valproic acid dissociates to the active valproate ion in the gastrointestinal (GI) tract. Absorption from the GI tract varies with dosage regimens and formulations, but the variances are unlikely to have a clinical effect.
Valproic acid is protein bound in a concentration-dependent manner; the free fraction increases from 10% to nearly 20% at 40 mcg/ml and 130 mcg/ml concentrations, respectively. Cerebrospinal fluid concentrations approximate the unbound plasma concentrations at 10%. Protein binding is saturable; unbound valproic acid pharmacokinetic measurements are linear. Mean terminal half-life ranges from 9 to 16 hours.
Valproic acid is almost entirely hepatically metabolized. Nearly 40% of a dose is glucuronidated, and mitochondrial beta-oxidation accounts for more than 40% of the dose. Other oxidative metabolism accounts for the remaining administered drug. Less than 3% of drug is recovered unchanged. Children between the ages of 3 months and 10 years have 50% higher clearance rates. Elderly clearance rates are reduced by 39% to 44%. [3]
Valproic acid is in FDA Pregnancy Category D. The drug may be teratogenic in humans. Neural tube defects and other congenital anomalies may occur, and clotting abnormalities may develop in pregnant women. [4]
References
[1] Retrovirology 2005 Sep 19;2:56
[2] Lancet 2005 Aug;366(9485):549-55
[3] FDA Depakene Extended Release Tablets Prescribing Information, July 2006, p. 4. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf. Accessed 12/11/07.
[4] FDA Depakene Extended Release Tablets Prescribing Information, July 2006, pp. 10-1. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf. Accessed 12/11/07.
Adverse Events/Toxicity
In the first proof-of-concept study of valproic acid in HIV infected patients, no severe adverse effects occurred. Mild anemia and irritation at injection sites were attributed to concomitant antiretrovirals. [1]
Hepatic failure resulting in fatalities has occurred in people taking valproic acid, usually within the first 6 months of treatment. Hepatotoxicity may be preceded by symptoms of malaise, weakness, lethargy, facial edema, anorexia, and vomiting. Valproic acid should be discontinued immediately in the presence of suspected or apparent hepatic dysfunction; dysfunction may progress despite drug discontinuation. [2]
Adverse effects commonly associated with divalproex sodium, an oral salt dosage form of valproic acid, include headache; asthenia; nausea, vomiting, abdominal pain, and diarrhea; somnolence; dizziness; and tremor. Photosensitivity, Steven-Johnsons Syndrome, and rare cases of toxic epidermal necrosis have occurred. Minor, dose-related elevations of hepatic enzymes occur frequently. [3]
References
[1] Aidsmap.com News, August 12, 2005: Could valproic acid eradicate HIV from the body? Available at: http://aidsmap.com. Accessed 12/11/07.
[2] FDA Depakene Extended Release Tablets Prescribing Information, July 2006, p. 1. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf. Accessed 12/11/07.
[3] FDA Depakene Extended Release Tablets Prescribing Information, July 2006, pp. 20-3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf. Accessed 12/11/07.
Drug and Food Interactions
Food does not appear to alter clinical effects of valproic acid, although single dose half-lives appear increased by 4 hours when the drug is administered with food. [1]
Valproic acid may interact with concurrently administered medications capable of hepatic enzyme induction; for example, phenytoin, cyclobenzaprine, and phenobarbital can double valproic acid clearance. Cytochrome P450 (CYP) inhibitors have a smaller effect on valproic acid clearance, because CYP-mediated oxidation of valproic acid is secondary to glucuronidation and beta-oxidation. [2]
Valproic acid is a weak inhibitor of some hepatic enzymes and is able to displace plasma protein-bound drugs. These effects increase the serum levels of cyclobenzaprine, diazepam, phenobarbital, phenytoin, and some other medications.
Concurrent valproic acid and zidovudine administration results in a 38% decrease in zidovudine clearance but half-life is unaffected.
Coadministration of valproic acid and aspirin results in a fourfold increase in the free fraction of valproic acid, compared to monotherapy due to inhibition of beta-oxidation. [3]
References
[1] AHFS Drug Information 2007; p. 2256
[2] FDA Depakene Extended Release Tablets Prescribing Information, July 2006, p. 12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf. Accessed 12/11/07.
[3] FDA Depakene Extended Release Tablets Prescribing Information, July 2006, p. 12. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf. Accessed 12/11/07.
Contraindications
Valproic acid should not be administered to patients with hepatic disease or significant hepatic dysfunction. Valproic acid is contraindicated in patients with known hypersensitivity to the drug. [1]
References
[1] FDA Depakene Extended Release Tablets Prescribing Information, July 2006, p. 1. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf. Accessed 12/11/07.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Ácido valproico.
Chemistry
CAS Name
2-propylpentanoic acid [1]
CAS Number
99-66-1 [2]
Molecular Formula
C8-H16-O2
Elemental Composition
C67%, H11%, O22%
Molecular Weight
144
Physical Description
Colorless liquid with a characteristic odor. [3]
Solubility
Slightly soluble in water at 1.3 mg/ml; very soluble in organic solvents. [4]
References
[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 12/11/07.
[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 12/11/07.
[3] FDA Depakene Extended Release Tablets Prescribing Information, July 2006, p. 1. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf. Accessed 12/11/07.
[4] FDA Depakene Extended Release Tablets Prescribing Information, July 2006, p. 17. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/18081s44,18082s27,18723s33,19680s22,20593s15,21168s14lbl.pdf. Accessed 12/11/07.
Further Reading
Depakene Extended Release Tablets Prescribing Information from the FDA web site [PDF]. A more current version may be available on the manufacturer's web site.
Cohen J. HIV/AIDS. Report of novel treatment aimed at latent HIV raises the 'c word'. Science. 2005 Aug 12;309(5737):999-1000. No abstract available.
DiCenzo R, Peterson D, Cruttenden K, Morse G, Riggs G, Gelbard H, Schifitto G. Effects of valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2004 Nov;48(11):4328-31.
Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand A, Landay AL, Coombs RW, Richman DD, Mellors JW, Coffin JM, Bosch RJ, Margolis DM. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 2005 Aug 13-19;366(9485):549-55.
Smith SM. Valproic acid and HIV-1 latency: beyond the sound bite. Retrovirology. 2005 Sep 19;2:56.
Use of Valproic Acid to Purge HIV From Resting CD4+ Memory Cells. Available at: http://clinicaltrials.gov/ct/show/NCT00289952. Accessed 12/11/07
Manufacturer Information
Valproic acid
Abbott Laboratories
One Hundred Abbott Park Rd
Abbott Park, IL 60064-3500
Phone: 800-633-9110
Last Updated: December 11, 2007