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. VPA is used to control of epileptic seizures, divided in two subcategories: focal and generalized seizures.

VPA was originally synthesized by Burton in 1882 and used as an organic solvent. Its antiepileptic effect was discovered by accident discovered almost 100 years later by Meunier et al. (1963). It was registered as a drug in 1964 in France and later in many other countries. <ref name=”[35]”> , . Drugbank, Valproic Acid Retrieved from November 25, 2019, at [https://www.drugbank.ca/drugs/DB00313

VPA (2‐propyl‐pentanoic acid) is a short-chain fatty acid ingested administered intravenously or orally as sodium valproate, composed of sodium and VPA in a 1:1 molar ratio. VPA itself is highly hydrophobic, leading to a favourable entry to the central nervous system with good oral bioavailability. <ref name=”[1]”> Williams, J. H., Jayaraman, B., Swoboda, K. J., & Barrett, J. S. (2011, December 13). Population Pharmacokinetics of Valproic Acid in Pediatric Patients With Epilepsy: Considerations for Dosing Spinal Muscular Atrophy Patients. Retrieved October 17, 2019 , at [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345311/ “https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345311/”].</ref>

Epilepsy is a disease of the central nervous system caused by disruptions in the electrical communication between neurons, more specifically, the imbalance in excitatory and inhibitory action of neurotransmitters at the synapses, which can lead to seizures, loss of awareness or unusual behavior. <ref name=”[13]”> Flyyn, S., & Babi, M. A. (2017). Pathophysiology of Epilepsy.Paragraph Anticonvulsants , at [https://www.sciencedirect.com/topics/medicine-and-dentistry/pathophysiology-of-epilepsy “https://www.sciencedirect.com/topics/medicine-and-dentistry/pathophysiology-of-epilepsy”].</ref> A seizure occurs when there is a large depolarization of many neurons that fire the action potential at the same time. This paroxysmal depolarizing shift can last for thirty seconds up to two minutes and leads the above mentioned effects.  Epileptic seizures appear in two types: focal and generalized. The focal seizure starts in one part of the brain, but due to the failure of inhibitory mechanisms it can spread further. The cause of it can be a trauma or cortex developmental disorder <ref name=”[43]”> (Nall, R. R. (2018, January 23). What are simple partial seizures? Retrieved December 7, 2019, at [ https://www.medicalnewstoday.com/articles/320696.php“ https://www.medicalnewstoday.com/articles/320696.php”].</ref> <ref name=”[44]”> (Leventer, R. J., Guerrini, R., & Dobyns, W. B. (2008, March 1). Malformations of cortical development and epilepsy. Retrieved December 7, 2019, at [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181860/“https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181860/”].</ref> The generalized seizure, on the other hand, is characterized by a sudden and large activity that occurs in more than one area of the brain at the same time, causing the hyperexcitability in the cortex and the neurons that connect the thalamus to the cortex. <ref name=”[38]”> (2016, May 22).2-Minute Neuroscience: Epilepsy. Retrieved November 26, 2019, at [https://www.youtube.com/watch?v=OGFQhLPaaOQ “https://www.youtube.com/watch?v=OGFQhLPaaOQ”].</ref>

===Genetic Pathophysiology=== One of the reasons for epilepsy development is the genetic background. While the exact background is still unknown, there are certain genes that were found to be involved in the progression of the epilepsy, for example SCN1A and SCN8A that are active in the production of sodium channels and can therefore contribute to the epilepsy succession. <ref name=”[14]”> Guo, W., Shang, D.-M., Cao, J.-H., Feng, K., He, Y.-C., Jiang, Y., … Gao, Y.-F. (2017). Identifying and Analyzing Novel Epilepsy-Related Genes Using Random Walk with Restart Algorithm. Introduction , at [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309434/ “https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309434/”].</ref>Epilepsy is split into two types: focal and generalized. The first type of focal seizures is the one without loss of consciousness, but with jerking of different body parts or a change in the perception of reality. The ; the second type is focal seizures with impaired consciousness or change of awareness. On the other hand, generalized epilepsy types Generalized seizures are absence seizures, tonic seizures, atonic seizures, clonic seizures and so on. <ref name=”[36]”> Epilepsy. (2019, August 10), at [https://www.mayoclinic.org/diseases-conditions/epilepsy/symptoms-causes/syc-20350093 “https://www.mayoclinic.org/diseases-conditions/epilepsy/symptoms-causes/syc-20350093”].</ref>Focal seizures include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive and emotional, while atonic, clonic, epileptic spasms, myoclonic and tonic seizures can be both focal or generalized. Generalized seizure types are absence with eyelid myoclonida, myoclonic absence, myoclonic - atonic, myoclonic - tonic - clonic. <ref name=”[42]”> Fisher, R. S., Cross, J. H., French, J. A., Higurashi, N., Hirsch, E., Jansen, F. E., … Zuberi, S. M. (2017, April). Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology, at [ https://www.ncbi.nlm.nih.gov/pubmed/28276060

Only 3% of the drug is eliminated through urine, about 30-50% is eliminated through hepatic metabolism, as well as and about 40% being excreted through mitochondrial-beta oxidation. <ref name=”[18]”> Gugler, R., & Unruh, G. E. von. (2012, December 13). Clinical Pharmacokinetics of Valproic Acid , at [https://link.springer.com/article/10.2165/00003088-198005010-00002 “https://link.springer.com/article/10.2165/00003088-198005010-00002”].</ref> 

VPA impacts the hepatic drug metabolism by inhibiting it and displacing other strongly bound drugs from proteins, which implies that dosage changes need to be considered when using it in combination with other drugs. <ref name=”[20]”> Valproic Acid (2018, October 1) , at [https://labtestsonline.org/tests/valproic-acid“https://labtestsonline.org/tests/valproic-acid”].</ref>The normal limits of valproate in blood of 70-100 kg person is 1000-3000 mg/day <ref name=”[46]”> Farmacotherapeutisch Kompas. Retrieved December 19, 2019, at [https://www.farmacotherapeutischkompas.nl/bladeren/preparaatteksten/v/valproinezuur“https://www.farmacotherapeutischkompas.nl/bladeren/preparaatteksten/v/valproinezuur”].</ref>

Valproate (VPA) is usually taken as tablets of 250 mg or as a syrup with 250 mg per ml, but this may vary per product<ref name=”[39]”> Valproic Acid Capsules - FDA prescribing information, side effects and uses. (2018, June 1).Retrieved November 26, 2019, at [https://www.drugs.com/pro/valproic-acid-capsules.html“https://www.drugs.com/pro/valproic-acid-capsules.html”].</ref>.The dose of VPA is at first taken in small amounts and is then gradually increased until the satisfactory dose is reached.

The recommended levels of unbound valproate are 6-22 µg/mL in blood <ref name=”[20]”> Valproic Acid (2018, October 1) , at [https://labtestsonline.org/tests/valproic-acid“https://labtestsonline.org/tests/valproic-acid”].</ref>. For epilepsy patients, the range for the treatment of total valproate should be 50-100 µg/mL. Overall, if a patient has a VPA concentration that falls within this range, does not have recurrent seizures and has minimal side effects, then the dose is said to be suitable<ref name=”[20]”> Valproic Acid (2018, October 1) , at [https://labtestsonline.org/tests/valproic-acid“https://labtestsonline.org/tests/valproic-acid”].</ref>

VPA is a conventional drug that is used as first line monotherapy for idiopathic generalized epilepsies. Its effectiveness is not clearly conclusive and varies between different patients. The doses are not generalized and depend on patient’s age and weight. Doses are taken every day, with some patients even two times a day. It is not advised, but sometimes necessary, to take VPA in combination with other seizure drugs (e.g., ethosuximide, lamotrigine, phenytoin, rufinamide, topira mate), some antidepressants or certain antibiotics<ref name=”[20]”> Valproic Acid (2018, October 1) , at [https://labtestsonline.org/tests/valproic-acid“https://labtestsonline.org/tests/valproic-acid”].</ref>. Medications based on VPA are harmful for the unborn child. If valproate is taken during pregnancy, research has shown that up to 4 in 10 babies are at risk of developmental disorders, and approximately 1 in 10 are at risk of birth defects. <ref name=”[22]”> gov.uk. (2018, March 23), at [https://www.gov.uk/guidance/valproate-use-by-women-and-girls“https://www.gov.uk/guidance/valproate-use-by-women-and-girls”].</ref> 

To measure unbound VPA, blood samples are treated by ultrafiltration, followed by an immunoassay, also referred to as ELISA. By performing the ultrafiltration, the protein-bound form of VPA is separated from its unbound form. After that, the level of the unbound fraction can be measured by an immunoassay, e.g. an ELISA kit. Alternatively, LC-MS can be used to measure VPA.<ref name=”[40]”> ao, S., Miao, H., Tao, X., Jiang, B., Xiao, Y., Cai, F., … Chen, W. (2011, July 1). LC–MS/MS method for simultaneous determination of valproic acid and major metabolites in human plasma, Journal of Chromatography B

In contrast to an HPLC assay, steps Steps such as solvent extraction, solvent or derivation must be executed prior to a HPLC assay, which takes significant more time<ref name=”[29]”> Free Valproic Acid Assay (2014, April). Retrieved from November 3, 2019, at [https://www.cadth.ca/sites/default/files/pdf/lab-tests/06_Free_Valproic_Acid_Assay_e.pdf/“https://www.cadth.ca/sites/default/files/pdf/lab-tests/06_Free_Valproic_Acid_Assay_e.pdf”].</ref>