Valproic acid

Structural formula
General
Non-proprietary name	Valproic acid
other names	2-propylpentanoic acid Dipropylacetic acid VPS
Molecular formula	C 8 H 16 O 2
External identifiers / databases
CAS number 99-66-1 EC number 202-777-3 ECHA InfoCard 100.002.525 PubChem 3121 DrugBank DB00313 Wikidata Q240642
Drug information
ATC code	N03 AG01
Drug class	Anti-epileptic
properties
Molar mass	144.21 g mol −1
density	0.904 g cm −3 (25  ° C )
boiling point	222 ° C
pK s value	4.6
solubility	moderate in water (2000 mg l −1 at 20 ° C)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances danger H and P phrases H: 302-315-319-360D P: 201-302 + 352-305 + 351 + 338-313
Toxicological data	670 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Valproic acid ( VPS for short ; English valproic acid , VPA for short ) is a branched carboxylic acid that does not occur naturally . They and their salts - the valproates - are used in medicine as drugs from the group of anticonvulsants ( antiepileptics ).

history

Beverly Burton first synthesized valproic acid in 1881. Initially, the acid was used as a solvent for water-insoluble substances. When investigating the anticonvulsant effectiveness of various khellinin derivatives dissolved in valproic acid , Pierre Eymard accidentally discovered in 1962 that it was not the dissolved substances that were responsible for the pharmacological effect, but the solvent valproic acid.

synthesis

The starting materials for the synthesis of valproic acid are ethyl cyanoacetate and two equivalents of 1-bromopropane . These react with the addition of sodium ethoxide via an enolate to form the α, α-dipropylcyanoacetic acid ester . In a basic environment, dipropylacetonitrile is formed with ester cleavage and decarboxylation . This can be converted into valproic acid by hydrolysis .

Alternatively, valproic acid can be made by malonic ester synthesis . For this purpose, diethyl malonate is reacted with two equivalents of 1-bromopropane , and the disubstituted ester formed is saponified and then decarboxylated .

Pharmacological properties

Valproic acid attacks various structures in the human organism. For its anti-epileptic effect, u. a. the blockade of exciting ion channels (voltage-dependent sodium channels and calcium channels ) as well as an intensification of the effect of the inhibitory neurotransmitter GABA (by inhibiting the breakdown and activation of the synthesis of GABA) are assumed.

Valproic acid is also one of the histone deacetylase inhibitors, which makes its use in cancer therapy conceivable. It works epigenetically , i. i.e., it intervenes a. by acetylation into the epigenetic system. This changes cells and the activity of individual genes .

Valproic acid is well absorbed by the body and can be administered orally and intravenously . The half-life is between 12 and 16 hours. If other anti-epileptic drugs such as phenytoin or carbamazepine are taken at the same time , the half-life can decrease to four to nine hours.

Areas of application

Valproic acid is used:

• for the treatment of generalized seizures and forms of epilepsy in particular , such as for the treatment of absences , wake-up grand males and juvenile myoclonic epilepsy
• for the prophylaxis of depressive and manic states in bipolar disorder
• Since valproic acid has a mood and impulse stabilizing effect, it is also used in therapy-refractory depression and to avoid aggressive impulse breakthroughs as a phase prophylactic ; however, this requires an individual specialist medical indication
• Additional treatment for psychoses from the schizophrenic group of forms (especially schizoaffective disorders)
• for seizure prevention in alcohol and drug withdrawal
• for migraine prophylaxis (but without approval for this application area)
• According to the recommendations of the German Migraine and Headache Society , valproic acid can be used, also without approval, for the preventive treatment of cluster headaches .

Valproic acid should only be used in small children in exceptional cases, for example when other anti-epileptic drugs cannot be used. Sufficient evidence of benefits is available for use in long-term phase prophylaxis in bipolar disorder; Approval on the recommendation of the European Medicines Agency .

At the Institute for Human Genetics at the University Clinic in Cologne, it was observed that valproic acid can upregulate the expression of the SMN2 gene; This property is being tested in clinical trials in connection with the therapy of spinal muscular atrophy .

Interactions

As an enzyme inhibitor , valproic acid delays the breakdown of certain active substances, so that a dose adjustment may be necessary. For example, the anti- epileptic drugs primidone , its metabolite phenobarbital and lamotrigine are affected . Conversely, phenobarbital, phenytoin, primidone and carbamazepine can accelerate valproic acid excretion through their enzyme-inducing effects. Valproic acid may also the plasma albumin binding of phenytoin decrease. In combination therapy with acetylsalicylic acid or anticoagulants , increased bleeding is to be expected. When combined with cannabidiol , significant increases in liver enzymes were observed in children with Dravet syndrome . Alcohol consumption should be avoided during therapy because of the possible increased hepatotoxic effects.

Side effects

The advantage of treatment is that valproic acid usually does not have a sedative effect.

An increase in the concentration of ammonium in the blood is observed very often; Common side effects are itching and skin rashes, headache, dizziness, insecurity and visual disturbances, loss of appetite or increase in appetite, weight loss or increase, drowsiness, tremors ( nystagmus , tremor ), temporary hair loss, abnormal sensations and sensitivity disorders as well as changes in the blood count and blood clotting disorders. Behavioral disorders (aggressiveness or immobility), bleeding, gastrointestinal complaints (nausea, vomiting, diarrhea), digestive disorders, increased salivation or blood insulin concentration, water retention, ringing in the ears (tinnitus), delusions , wetting, menstrual bleeding disorders and temporary brain damage occur rarely to occasionally .

A retrospective study by N. Adab et al. a. from the Center for Neurology and Neurosurgery in Liverpool found that children whose mother took the anti-epileptic valproic acid during pregnancy had a lower verbal intelligence quotient ( VIQ ) than offspring who were not exposed to valproic acid prenatally.

There is also evidence of local cortical hyperconnectivity in the child's brain due to prenatal administration of valproic acid, which is discussed as a possible cause of autism .

Valproic acid is subject to additional monitoring to allow rapid identification of new drug safety findings.

Use during pregnancy and breastfeeding

If valproic acid preparations are administered during pregnancy, malformations of the human fetus such as spina bifida or aplasia cutis congenita occur in around ten percent of cases . In addition, there is a dose-dependent risk of about 30–40% for serious developmental disorders .

For example, children start talking and / or walking later, have poor mental abilities, poor language skills, and have memory problems. In elementary school, problems in verbal skills and memory are the main problems. The intelligence quotient (IQ), measured in a study in children six years of age who were exposed to valproate in the womb, averaged 7 to 10 points lower than in children exposed to other anti-epileptic drugs. In around 4.5% of cases, affected children develop autistic disorders , around half of which are early childhood autism . Limited data suggest that children who were exposed to valproate in the womb are more likely to develop symptoms of attention deficit / hyperactivity disorder (ADHD).

Women of childbearing potential should be informed of this risk before starting appropriate treatment. In Germany, doctors and pharmacists were informed about this in December 2014 by a Rote-Hand-Brief (Rote-Hand-Brief) and asked not to use valproic acid in girls and women of childbearing age as a first-line preparation. In April 2017, a notification from the Federal Institute for Drugs and Medical Devices (BfArM) also issued a patient reminder card as a risk minimization measure, which since July 2017 has been given to patients of childbearing age with the corresponding explanations for every prescription of valproic acid. The pharmaceutical letter takes the position that the use of valproic acid in diagnoses other than therapy-refractory epilepsy and some states of acute mania in women of childbearing age can hardly be justified today, especially since there are now well-tolerated and effective alternatives for almost all indications.

However, it must be taken into account that a seizure during pregnancy can be dangerous for both mother and child. How to behave in a planned or existing pregnancy, and whether the medication needs to be changed, should be discussed and determined during a medical consultation. If you continue to take valproic acid, specialized prenatal diagnostics can be performed to detect possible neural tube defects and other symptoms of malformations at an early stage.

The Federal Institute for Drugs and Medical Devices has published guidelines on this subject for both patients and medical professionals.

Compensation payments

The French state announced in January 2017 that it was setting up a fund with ten million euros to compensate women who were prescribed the active ingredient valproic acid during pregnancy without informing them of the risks involved. The French investigation authority IGAS assessed the data situation by 2004 at the latest. Regarding the situation in Germany, the Federal Government, in response to a small request from the Left Party , stated that possible claims against the Federal Republic of Germany would have to be clarified on a case-by-case basis.

On April 20, 2017, the French Medicines Agency ANSM announced in Paris that, according to an initial estimate, up to 4,100 children in France had been born with severe deformities because of the anti-epileptic valproate from the manufacturer Sanofi.

Trade names

Monopreparations :
Convulex (D, A, CH), Convulsofin (D), Depakine (CH, A, F), Ergenyl (D), Leptilan (D), Orfiril (D, CH), Valproat (D), numerous generics ( D, CH)

Combination
preparations:Depakine Chronosphere (A), sodium valproate (A)

literature

• Stephan A. König, Julia Knolle, Steffen Friedewald, Wolfgang Koelfen, Elke Longin, Tamara Lenz, Dieter Hannak: Effects of Valproic Acid, Carbamazepine, and Phenobarbitone on the Fatty Acid Composition of Erythrocyte Membranes in Children. In: Epilepsia , 44, 2003, pp. 708-711. doi: 10.1046 / j.1528-1157.2003.09802.x .
• Valproic Acid For Pregnant Women: The Unspoken Risk. In: Frankfurter Allgemeine Sonntagszeitung , March 19, 2017.

Web links

• Lower IQ after prenatal exposure to valproic acid. ( Memento of October 27, 2004 in the Internet Archive )
• Training material for drugs containing valproate from the Federal Institute for Drugs and Medical Devices (BfArM)

Individual evidence

1. ↑ David R. Lide (Ed.): CRC Handbook of Chemistry and Physics . 90th edition. (Internet version: 2010), CRC Press / Taylor and Francis, Boca Raton, FL, Physical Constants of Organic Compounds, pp. 3-446.
2. ↑ ^{a b c d} Entry on valproic acid in the ChemIDplus database of the United States National Library of Medicine (NLM) .
3. ↑ ^{a b} Data sheet 2-propylvaleric acid (PDF) from Merck , accessed on April 25, 2011.
4. ↑ G. Krämer , J. Walden (Ed.): Valproic acid. 2nd Edition. Springer, 2002, ISBN 3-540-66602-8 , p. 3.
5. ↑ Patent US5856569 : Process for producing valproic acid. Filed January 10, 1997 , published May 1, 1999 . ‌
6. ^ Brigitte Vetter: Psychiatry: A systematic textbook. 7th edition. Schattauer Verlag, Stuttgart 2007, ISBN 978-3-7945-2566-9 , pp. 205-206.
7. ↑ S. Evers, A. May, G. Fritsche, P. Kropp, C. Lampl, V. Limmroth, V. Malzacher, S. Sandor, A. Straube, HC Diener: Acute Therapy and Prophylaxis of Migraine - Guideline of the German Migraine - and headache society and the German Society for Neurology . In: Neurology . tape 27 , no. 10 , 2008, p. 933-949 ( dmkg.de [PDF]).
8. ↑ A. May, S. Evers, G. Brössner, T. Jürgens, AR Gantenbein, V. Malzacher, A. Straube: Guideline for the diagnosis, therapy and prophylaxis of cluster headaches, other trigeminal autonomic headaches, sleep-bound headaches and idiopathic sharp headache. - Revised therapy recommendations of the German Migraine and Headache Society in cooperation with the DGN, ÖKSG, SKG. In: Neurology . ( Memento from August 20, 2016 in the Internet Archive ) 35 (3), 2016, pp. 137–151. dmkg.de (PDF)
9. ↑ Announcement of the EMA of April 29, 2011, accessed on May 20, 2011.
10. ^ Institute for Human Genetics at the University Clinic Cologne: Research focus AG Wirth
11. ↑ ^{a b c d} Specialist information from the Swiss Medicines Compendium: Convulex ^® ; Information as of September 2005.
12. ↑ O. Devinsky, JH Cross, L. Laux et al. a .: Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. In: N Engl J Med . tape 376 , 2017, p. 2011-2020 .
13. ↑ Valproic acid: What side effects can valproic acid have? Article at Onmeda.de, accessed on October 8, 2014.
14. ↑ Entry on valproic acid in Flexikon , a wiki from DocCheck , accessed on October 8, 2014.
15. ↑ N. Adab, U. Kini, J. Vinten, J. Ayres, G. Baker, J. Clayton-Smith, H. Coyle, A. Fryer, J. Gorry, J. Gregg, G. Mawer, P. Nicolaides , L. Pickering, L. Tunnicliffe, DW Chadwick: The longer term outcome of children born to mothers with epilepsy. In: Journal of Neurology, Neurosurgery and Psychiatry. 75, 2004, pp. 1575-1583, 1517-1518. doi: 10.1136 / jnnp.2003.029132
16. ^ Tania Rinaldi, Gilad Silberberg, Henry Markram : Hyperconnectivity of Local Neocortical Microcircuitry Induced by Prenatal Exposure to Valproic Acid. In: Cerebral Cortex . 18 (4), 2008, pp. 763-770. doi: 10.1093 / cercor / bhm117
17. ↑ Guidelines for patients Valproate-containing medicines - contraception and pregnancy: What you absolutely should know. (PDF) Federal Institute for Medicinal Products and Medical Devices, August 2018, accessed on January 5, 2020 . 
18. ↑ ^{a b c} Medicines containing valproate and related substances: Risk of anomalies in the newborn (PDF) - Rote-Hand-Brief , December 2014.
19. ↑ KJ Meador, GA Baker, N. Browning, MJ Cohen, RL Bromley, J. Clayton-Smith, LA Kalayjian, A. Kanner, JD Liporace, PB Pennell, M. Privitera, DW Loring: Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. In: The Lancet Neurology . doi: 10.1016 / S1474-4422 (12) 70323-X
20. ↑ FDA Safety Information
21. ↑ KJ Meador, GA Baker, N. Browning, J. Clayton-Smith, DT Combs-Cantrell, M. Cohen, LA Kalayjian, A. Kanner, JD Liporace, PB Pennell, M. Privitera, DW Loring: Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs. In: N Engl J Med. 360, 2009, pp. 1597-1605. doi: 10.1056 / NEJMoa0803531
22. ↑ Jakob Christensen: Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism. In: JAMA. 309, 2013, p. 1696. doi: 10.1001 / jama.2013.2270
23. ↑ Form for confirmation of risk information - treatment of patients with valproate. ( PDF; 412 kB )
24. ↑ Risks of valproic acid in women of childbearing potential . In: WD Ludwig, J Schuler (ed.): The drug letter . tape 52 , 2018, p. 14 ( der-arzneimittelbrief.de ).
25. ↑ BfArM - Further drug risks - Training material for drugs containing valproate. Retrieved January 5, 2020 . 
26. ↑ ^{a b} Irene Habich: Doctors prescribed dangerous drugs to pregnant women. In: Spiegel Online . January 27, 2017, accessed February 1, 2017 . 
27. ^ Enquête relative aux spécialités pharmaceutiques contenant du valproate de sodium . (PDF; 6.5 MB) Report by the French investigation authority IGAS, February 2016.
28. ↑ Irene Habich: Valproic Acid - Doctors Prescribe Dangerous Drugs to Pregnant Women. In: Spiegel Online . April 20, 2017. Retrieved July 17, 2019 . 
29. ↑ ^{a b} Red List 2017 . Verlag Rote Liste Service, Frankfurt am Main, ISBN 978-3-946057-10-9 , p. 225.

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