NationMaster - Encyclopedia: Valproic acid

Valproic acid (VPA) is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy and bipolar disorder. It is also used to treat migraine headaches and schizophrenia. In epileptics, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, juvenile myoclonic epilepsy and the seizures associated with Lennox-Gastaut syndrome. It is also used in treatment of myoclonus. In some countries, parenteral (administered intravenously) preparations of valproate are used also as second-line treatment of status epilepticus, alternatively to phenytoin. The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body 1. ... Intravenous therapy or IV therapy is the giving of liquid substances directly into a vein. ... A chemical compound is a chemical substance of two or more different chemically bonded chemical elements, with a fixed ratio determining the composition. ... The anticonvulsants, sometimes also called antiepileptics, belong to a diverse group of pharmaceuticals used in prevention of the occurrence of epileptic seizures. ... A mood stabilizer is a psychiatric medication used to treat mood disorders characterized by rapid and unstable mood shifts. ... This article does not cite any references or sources. ... For other uses, see Bipolar. ... A headache (cephalalgia in medical terminology) is a condition of pain in the head; sometimes neck or upper back pain may also be interpreted as a headache. ... In medicine, there are many kinds of generalized seizures. ... Tonic-clonic seizures (also known as Grand Mal Seizures, though this term is now discouraged and rarely used in a clinical setting) are a type of generalised seizure affecting the whole brain. ... Seizures (or convulsions) are temporary alterations in brain function expressing themselves into a changed mental state, tonic or clonic movements and various other symptoms. ... Complex partial seizures are epileptic attacks which involve a greater degree of impairment of consciousness than simple partial seizures. ... Juvenile myoclonic epilepsy (JME), also known as Janz syndrome, is a fairly common form of idiopathic generalized epilepsy affecting up to 10% of the population. ... This article is about epileptic seizures. ... Lennox-Gastaut syndrome (LGS), also known as Lennox syndrome, is a difficult to treat form of childhood-onset epilepsy, that most often appears between the second and sixth year of life and is characterized by frequent seizures and different seizure types and is often accompanied by mental retardation and behavior... Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. ... In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body 1. ... An intravenous drip in a hospital Intravenous therapy or IV therapy is the administration of liquid substances directly into a vein. ... Phenytoin sodium (marketed as DilantinÂ® in the USA and as EpanutinÂ® in the UK, by Parke-Davis, now part of Pfizer) is a commonly used antiepileptic. ...

Related drugs include the sodium salts sodium valproate, used as an anticonvulsant, and a combined formulation, valproate semisodium, used as a mood stabilizer and additionally in U.S. also as an anticonvulsant. Sodium valproate (INN) or valproate sodium (USAN) is the sodium salt of valproic acid and is an anticonvulsant used in the treatment of epilepsy. ... Valproate semisodium (INN) or divalproex sodium (USAN) consists of a compound of sodium valproate and valproic acid in a 1:1 molar relationship in an enteric coated form. ...

Valproate is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain, making it an alternative to lithium salts in treatment of bipolar disorder. However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years.^[1] Chemical structure of D-aspartic acid, a common amino acid neurotransmitter. ... Gaba may refer to: GabÃ¢ or gabaa (Philippines), the concept of negative karma of the Cebuano people GABA, the gamma-amino-butyric acid neurotransmitter GABA receptor, in biology, receptors with GABA as their endogenous ligand Gaba 1 to 1, an English conversational school in Japan Marianne Gaba, a US model... In biochemistry, a transaminase or an aminotransferase is an enzyme that catalyzes a type of reaction between an amino acid and an Î±-keto acid. ... Lithium in pharmacology refers to the lithium ion, Li+, used as a drug. ...

Valproic acid is an inhibitor of the enzyme histone deacetylase 1 (HDAC1). HDAC1 is needed for HIV to remain in infected cells. A study published in August 2005 revealed that patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a median 75% reduction in latent HIV infection.^[2] HIV protease in a complex with the protease inhibitor ritonavir. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... Histone deacetylase (HDAc) is an enzyme that changes the way histone binds to DNA. HDAc inhibitors are being studied as a treatment for cancer. ... Species Human immunodeficiency virus 1 Human immunodeficiency virus 2 Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS, a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections). ... The term antiretroviral drugs is used to describe drugs used against HIV infection (HIV is an RNA retrovirus). ...

According to the U.S. National Institutes of Health and others, valproic acid appears to have wide implications in the treatment of various cancers,^[3] including multiple myeloma (bone marrow cancer),^[4] glioma (an aggressive type of brain tumor),^[5] and melanoma.^[6] Valproic acid is cytotoxic to many different cancer types through its action as a histone-deacetylase inhibitor. Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ... Multiple myeloma (also known as MM, myeloma, plasma cell myeloma, or as Kahlers disease after Otto Kahler) is a type of cancer of plasma cells which are immune system cells in bone marrow that produce antibodies. ... A glioma is a type of primary central nervous system (CNS) tumor that arises from glial cells. ... A brain tumor is any intracranial tumor created by abnormal and uncontrolled cell division, normally either in the brain itself (neurons, glial cells (astrocytes, oligodendrocytes, ependymal cells), lymphatic tissue, blood vessels), in the cranial nerves (myelin-producing Schwann cells), in the brain envelopes (meninges), skull, pituitary and pineal gland, or...

Another potential indication may be leukemia in juvenile patients. Studies conducted by several European centres are ongoing. Although it is too early to make a definitive statement, preliminary results are encouraging.^{[citation needed]} Leukemia or leukaemia (see spelling differences) is a cancer of the blood or bone marrow and is characterized by an abnormal proliferation (production by multiplication) of blood cells, usually white blood cells (leukocytes). ...

History

Valproic acid (by its official name 2-propylvaleric acid) was first synthesized in 1882 by Burton as an analogue of valeric acid, found naturally in Valerian.^[7] A clear liquid fatty acid at room temperature, for many decades its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered valproic acid's antiseizure activity while using it as a vehicle for a number of other compounds that were being screened for anti-seizure activity. He found that it prevented pentylenetetrazol-induced convulsions in rodents.^[8] Since then it has also been used for migraine and bipolar disorder.^[9] Binomial name L. & Maillefer Valerian (Valeriana officinalis, Valerianaceae) is a hardy perennial flowering plant, with heads of sweetly scented pink or white flowers. ... Metrazol is the commercial trademark of pentetrazol, pentamethylenetetrazol, or pentylenetetrazol (PTZ), a drug used as a circulatory and respiratory stimulant (another commercial name is Cardiazol). ...

Contraindications

Valproate is relatively contraindicated in pregnancy due to its teratogenicity; women who become pregnant while taking valproate should be counselled as to its risks, take high dose folic acid and be offered antenatal screening (alpha-fetoprotein and second trimester ultrasound scans).^[10] It is a known folate antagonist, which can cause neural tube defects. Thus, folic acid supplements may alleviate the teratogenic problems. A recent study showed that children of mothers taking valproate during pregnancy are at risk for significantly lower IQs.^[11]^[12] Exposure of the human embryo to valproic acid is also associated with risk of autism, and it is possible to duplicate features characteristic of autism by exposing rat embryos to valproic acid at the time of neural tube closure.^[13] One study found that valproate exposure on embryonic day 11.5 led to significant local recurrent connectivity in the juvenile rat neocortex, consistent with the underconnectivity theory of autism.^[14] // Teratogenesis is a medical term from the Greek, literally meaning monster-birth, which derives from teratology, the study of the frequency, causation, and development of congenital malformationsâ€”misleadingly called birth defects. ... Folic acid and folate (the anion form) are forms of the water-soluble Vitamin B9. ... Prenatal diagnosis is the diagnosis of disease or condition in a fetus or embryo before it is born. ... Alpha-fetoprotein (AFP) is a protein that is normally only produced in the foetus during its development. ... The human gestation period of approximately 40 weeks between the time of the last menstrual cycle and delivery is traditionally divided into three periods of three months, or trimesters. ... Medical ultrasonography is an ultrasound-based imaging diagnostic technique used to visualize internal organs, their size, structure and their pathological lesions. ... The neural tube is the embryonal structure that gives rise to the brain and spinal cord. ... For other uses, see Embryo (disambiguation). ... Autism is a brain development disorder characterized by impairments in social interaction and communication, and restricted and repetitive behavior, all exhibited before a child is three years old. ... The neocortex (Latin for new bark or new rind) is a part of the brain of mammals. ...

Valproate is contraindicated in overweight patients because it causes weight gain as outlined above.

Preexisting liver damage, bone marrow depression, urea cycle disorders, and coagulation disorders are additional contraindications. This article does not cite any references or sources. ... Coagulation is a complex process by which blood forms solid clots. ...

Side effects

Common side effects are dyspepsia and/or weight gain. Less common are dysphoria, fatigue, peripheral edema, dizziness, drowsiness, hair loss, headaches, nausea, sedation and tremors. Valproic acid also causes hyperammonemia. An adverse drug reaction (abbreviated ADR) is a term to describe the unwanted, negative consequences sometimes associated with the use of medications. ... Look up dysphoria in Wiktionary, the free dictionary. ... â€œFatigue (physical)â€ redirects here. ... Peripheral edema ... // Pre-syncope is a sensation of feeling faint. ... Baldness (formally alopecia) is the state of lacking hair where it usually would grow, especially on the head. ... For other uses, see Nausea (disambiguation). ... Sedation is a medical procedure involving administration of sedative drugs, generally to facilitate a medical procedure, such as endoscopy, vasectomy, or minor surgery with local anaesthesia. ... For the film see Tremors (film). ... Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. ...

Rarely, valproic acid can cause blood dyscrasia, impaired liver function, jaundice, thrombocytopenia, and prolonged coagulation times. In about 5% of pregnant users, valproic acid will cross the placenta and cause congenital anomalies. Due to these side effects, most doctors will ask for blood tests, initially as often as once a week and then once every 2 months. Temporary liver enzyme increase has been reported in 20% of cases during the first few months of taking the drug. Inflammation of the liver (hepatitis), the first symptom of which is jaundice, is found in rare cases. Dyscrasia (from Greek Dyskrasia, meaning bad mixture), in Ancient Greek medicine, is the imbalance of the four humours, and was believed to be the direct cause of all disease. ... The liver is an organ present in vertebrates and some other animals. ... Jaundice, also known as icterus (attributive adjective: icteric), is a yellowing of the skin, conjunctiva (a clear covering over the sclera, or whites of the eyes) and mucous membranes caused by hyperbilirubinemia (increased levels of bilirubin in red blooded animals). ... Thrombocytopenia (or -paenia, or thrombopenia in short) is the presence of relatively few platelets in blood. ... Coagulation is a complex process by which blood forms solid clots. ... The placenta is an ephemeral (temporary) organ present in female placental vertebrates during gestation (pregnancy), but a placenta has evolved independently also in other animals as well, for instance scorpions and velvet worms. ... A congenital disorder is a medical condition that is present at birth. ... Hepatitis (plural hepatitides) implies injury to liver characterised by presence of inflammatory cells in the liver tissue. ... Jaundice, also known as icterus (attributive adjective: icteric), is a yellowing of the skin, conjunctiva (a clear covering over the sclera, or whites of the eyes) and mucous membranes caused by hyperbilirubinemia (increased levels of bilirubin in red blooded animals). ...

Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome.^[15]^[16]

There have also been rare reports of cognitive dysfunction, Parkinson's disease, and even pseudoatrophic brain changes^[17] in long-term treatment with valproic acid.

Interactions

Valproic acid may interact with carbamazepine, as valproates inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide (the main active metabolite of carbamazepine) into inactive metabolites.^[18] By inhibiting mEH, valproic acid causes a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion. Carbamazepine (CBZ) is an anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy and bipolar disorder. ... In general, the epoxide hydrolase system functions in detoxication during drug metabolism. ... Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ...

Valproic acid also decreases the clearance of amitriptyline and nortriptyline.^[19] In medicine, the clearance, also renal clearance or renal plasma clearance (when referring to the function of the kidney), of a substance is the inverse of the time constant that describes its removal rate from the body divided by its volume of distribution (or total body water). ... Amitriptyline (or Amitryptyline) hydrochloride (sold as Elavil, Tryptanol, Endep, Elatrol, Tryptizol, Trepiline, Laroxyl) is a tricyclic antidepressant drug. ... Nortriptyline is a tricyclic antidepressant marketed under the tradenames Aventyl® and Pamelor®. It is used to treat depression. ...

Formulations

Branded products include Depakene (Abbott Laboratories in U.S. & Canada) and Convulex (Pfizer in the UK and Byk Madaus in South Africa). Abbott Laboratories (NYSE: ABT) is a diversified pharmaceuticals and health care company. ... Pfizer Incorporated (NYSE: PFE) is the worlds largest research-based pharmaceutical company[1].[1] The company is based in New York City. ...

References

^ Rosenberg G (2007). "The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees?". Cellular and Molecular Life Sciences. PMID 17514356.
^ Lehrman G, Hogue I, Palmer S, Jennings C, Spina C, Wiegand A, Landay A, Coombs R, Richman D, Mellors J, Coffin J, Bosch R, Margolis D. "Depletion of latent HIV-1 infection in vivo: a proof-of-concept study". Lancet 366 (9485): 549–55. PMID 16099290.
^ Isenberg JS, Jia Y, Field L, Ridnour LA, Sparatore A, Del Soldato P, Sowers AL, Yeh GC, Moody TW, Wink DA, Ramchandran R, Roberts DD (2007). "Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid.". British Journal of Pharmacology Mar 12. PMID 17273758.
^ Schwartz C, Palissot V, Aouali N, Wack S, Brons NH, Leners B, Bosseler M, Berchem G (2007). "Valproic acid induces non-apoptotic cell death mechanisms in multiple myeloma cell lines.". International Journal of Oncology Mar (30): 573-82. PMID 17273758.
^ A.M. Admirant, J. A. Hendricks, P.C. De Witt Hamer, S. Leenstra, W.P. Vandertop, C.J.F. van Noorden, and J.P. Medema (2006). "Valproic Acid is toxic to malignant glioma cells and increases sensitivity to irradiation and chemotherapy". Abstracts for the Seventh Congress of the European Association for Neuro-Oncology (EANO) Sept 14-17: 334.
^ Valentini A, Gravina P, Federici G, Bernardini S. (2007). "Valproic Acid Induces Apoptosis, p(16INK4A) Upregulation and Sensitization to Chemotherapy in Human Melanoma Cells". Cancer Biology & Therapy Feb 5 (6). PMID 17218782.
^ Burton BS (1882). On the propyl derivatives and decomposition products of ethylacetoacetate. Am Chem J. 3:385-395.
^ Meunier H, Carraz G, Meunier Y, Eymard P, Aimard M. (1963). Propriétés pharmacodynamiques de l’acide n-dipropylacetique. Therapie 18:435-438.
^ Henry T.R. (2003). The History of Valproate in Clinical Neuroscience. Psychopharmacology bulletin 37 (Suppl 2):5-16
^ British National Formulary (March 2003) 45
^ Cassels, Caroline (December 8, 2006). NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids. Medscape. Retrieved on 2007-05-23.
^ Meador KJ, Baker GA, Finnell RH, et al (2006). "In utero antiepileptic drug exposure: fetal death and malformations". Neurology 67 (3): 407-12. DOI:10.1212/01.wnl.0000227919.81208.b2. PMID 16894099.
^ Arndt TL, Stodgell CJ, Rodier PM (2005). "The teratology of autism". Int J Dev Neurosci 23 (2–3): 189–99. DOI:10.1016/j.ijdevneu.2004.11.001. PMID 15749245.
^ Rinaldi T, Silberberg G, Markram H (2007). "Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid". Cereb Cortex. DOI:10.1093/cercor/bhm117. PMID 17638926.
^ Williams DC Jr, Massey GV, Russell EC, Riley RS, Ben-Ezra J. (2007). "Translocation positive acute myeloid leukemia associated with valproic acid therapy". Pediatric Blood and Cancer Mar 29. PMID 17262798.
^ Coyle TE, Bair AK, Stein C, Vajpayee N, Mehdi S, Wright J. (2005). "Acute leukemia associated with valproic acid treatment: a novel mechanism for leukemogenesis?". Pediatric Blood and Cancer Apr (78): 256-60. PMID 15795916.
^ http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=3117347&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus
^ Gonzalez, Frank J.; Robert H. Tukey (2006). "Drug Metabolism", in Laurence Brunton, John Lazo, Keith Parker (eds.): Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11^th ed., New York: McGraw-Hill, p. 79. ISBN 978-0071422802.
^ Depakene side effects (Valproic Acid) and drug interactions. RxList.com (2007). Retrieved on 2007-06-07.

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External links

Categories: All articles with unsourced statements | Articles with unsourced statements since March 2007 | Anticonvulsants | Mood stabilizers | Teratogens | Carboxylic acids There are several sulphonamide-based groups of drugs. ... Acetazolamide, sold under the trade name DiamoxÂ®, is a carbonic anhydrase inhibitor that is used to treat glaucoma, epileptic seizures, benign intracranial hypertension and altitude sickness. ... Ethoxzolamide (6-ethoxybenzothiazole-2-sulfonamide, alternatively known as Ethoxyzolamide) is a sulfonamide medication that functions as a carbonic anhydrase inhibitor. ... Sultiame (rINN, also known as sulthiame) is a sulfonamide and inhibitor of the enzyme carbonic anhydrase. ... Zonisamide (brand name ZonegranÂ®) is an anticonvulsant used as an adjunctive therapy in adults with partial-onset seizures. ... The propionate (also propanoate) ion is C2H5COOâˆ’ (propionic acid minus one hydrogen ion). ... Beclamide (marketed as Chloracon, Hibicon, Posedrine, Nydrane, Seclar, and other names) is a propionate and was used as a sedative and as an anticonvulsant. ... An aldehyde. ... Paraldehyde is the cyclic form of three acetaldehyde molecules (a trimer). ... A bromide is a phrase, or person who uses phrases, which have been used and repeated so many times as to become either insincere in their meaning, or seem like an attempt at trying to explain the obvious. ... Potassium bromide (KBr) is a salt, used as an anticonvulsant and a sedative in the 1800s. ... Sodium bromide is the chemical compound with the formula NaBr. ...

Contents

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