| Both sides previous revision Previous revision Next revision | Previous revision |
| content:valproate [2020/02/17 11:13] – [History] icna | content:valproate [2022/04/30 11:54] (current) – changed pubmed syntax administrator@icnapedia.org |
|---|
| ====== Valproate ====== | ====== Valproate ====== |
| Valproic acid (2-propyl pentanoic acid, 2-propyl valeric acid) is a short-chain branched fatty acid. Prior to the serendipitous discovery of its anti-epileptic activity in 1963, valproic acid was used as an organic solvent. | Valproic acid (2-propyl pentanoic acid, 2-propyl valeric acid) is a short-chain branched fatty acid. Prior to the serendipitous discovery of its anti-epileptic activity in 1963, valproic acid was used as an organic solvent[(:cite:panayiotopoulos2005)]. |
| ===== Authorised indications ===== | ===== Authorised indications ===== |
| UK-SmPC: In the treatment of generalized, partial or other epilepsy. | UK-SmPC: In the treatment of generalized, partial or other epilepsy. |
| |
| **Systemic:** | **Systemic:** |
| * the most serious are fatal hepatotoxicity and acute haemorrhagic pancreatitis. | * the most serious are **fatal hepatotoxicity** and **acute haemorrhagic pancreatitis**. |
| * fatal hepatotoxicity | * **fatal hepatotoxicity** |
| * primarily age-dependent and occurs mainly in children receiving polypharmacy and with organic brain disease | * primarily age-dependent and occurs mainly in children receiving polypharmacy and with organic brain disease |
| * the risk is 1/600 before the age of 3 years. | * the risk is 1/600 before the age of 3 years. |
| * an abnormally low prothrombin level, particularly in association with other relevant abnormalities, requires withdrawal of valproate. | * an abnormally low prothrombin level, particularly in association with other relevant abnormalities, requires withdrawal of valproate. |
| * any concomitant use of salicylates should be stopped, since they employ the same metabolic pathway. | * any concomitant use of salicylates should be stopped, since they employ the same metabolic pathway. |
| * acute haemorrhagic pancreatitis with markedly increased amylase and lipase levels is another rare, but serious, adverse effect of valproate treatment. It develops within the first 3 months of treatment, is more prevalent in children and with polytherapy. | * **acute haemorrhagic pancreatitis** with markedly increased amylase and lipase levels is another rare, but serious, adverse effect of valproate treatment. It develops within the first 3 months of treatment, is more prevalent in children and with polytherapy. |
| * hyperammonaemic encephalopathy, which is sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders. When urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment with valproate. | * hyperammonaemic encephalopathy, which is sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders. When urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment with valproate. |
| * Thrombocytopenia and other haematological abnormalities:it is recommended that platelet counts and coagulation tests are performed before initiating therapy and at periodic intervals, because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation and abnormal coagulation parameters. | * Thrombocytopenia and other haematological abnormalities:it is recommended that platelet counts and coagulation tests are performed before initiating therapy and at periodic intervals, because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation and abnormal coagulation parameters. |
| |
| ==== History ==== | ==== History ==== |
| Valproic acid (VPA; valproate; di-n-propylacetic acid, DPA; 2-propylpentanoic acid, or 2-propylvaleric acid) was first synthesized in 1882, by Burton[(:cite:burton1882>Burton BS (1882) On the propyl derivatives and decomposition products of ethylacetoacetate. Am Chem J3: 385–395)].Its anticonvulsant activity was fortuitously discovered by Pierre Eymard in France in 1962 while working at the Firma Berthier laboratories in Grenoble. Because valproic acid is a liquid, it was used as a lipophilic vehicle to dissolve water-insoluble compounds during preclinical drug testing. As part of his thesis in 1962, Eymard had synthesized a number of khelline derivatives in the laboratory of G. Carraz at the School of Medicine and Pharmacy in Grenoble, France[(:cite:13935231>{{pubmed>short:13935231}})]. | Valproic acid (VPA; valproate; di-n-propylacetic acid, DPA; 2-propylpentanoic acid, or 2-propylvaleric acid) was first synthesized in 1882, by Burton[(:cite:burton1882>Burton BS (1882) On the propyl derivatives and decomposition products of ethylacetoacetate. Am Chem J3: 385–395)].Its anticonvulsant activity was fortuitously discovered by Pierre Eymard in France in 1962 while working at the Firma Berthier laboratories in Grenoble. Because valproic acid is a liquid, it was used as a lipophilic vehicle to dissolve water-insoluble compounds during preclinical drug testing. As part of his thesis in 1962, Eymard had synthesized a number of khelline derivatives in the laboratory of G. Carraz at the School of Medicine and Pharmacy in Grenoble, France[(:cite:13935231>{{pmid>long:13935231}})]. |
| |
| Two colleagues, H. Meunier and Y. Meunier, working for a small company, Berthier Laboratories, in Grenoble, had used valproate for a long time as a vehicle for dissolving of a bismuth salt. So the three scientists Eymard, Meunier and Meunier had the idea to use this vehicle also for dissolving some of the khelline derivatives synthesized by Eymard. In order to evaluate the pharmacological activities of the khelline derivatives, Carraz proposed to test the most active derivative in the pentylenetetrazole (PTZ) seizure test. By doing this, the researchers found that the vehicle, valproate, alone exerted an anticonvulsant effect[(:cite:loscher1999>Löscher W. (1999) The discovery of valproate. In: Löscher W. (eds) Valproate. Milestones in Drug Therapy. Birkhäuser, Basel)]. | Two colleagues, H. Meunier and Y. Meunier, working for a small company, Berthier Laboratories, in Grenoble, had used valproate for a long time as a vehicle for dissolving of a bismuth salt. So the three scientists Eymard, Meunier and Meunier had the idea to use this vehicle also for dissolving some of the khelline derivatives synthesized by Eymard. In order to evaluate the pharmacological activities of the khelline derivatives, Carraz proposed to test the most active derivative in the pentylenetetrazole (PTZ) seizure test. By doing this, the researchers found that the vehicle, valproate, alone exerted an anticonvulsant effect[(:cite:loscher1999>Löscher W. (1999) The discovery of valproate. In: Löscher W. (eds) Valproate. Milestones in Drug Therapy. Birkhäuser, Basel)]. |
| ==== References ==== | ==== References ==== |
| ~~REFNOTES~~ | ~~REFNOTES~~ |
| Source: Panayiotopoulos CP. (2005). The Epilepsies: Seizures, Syndromes and Management. Oxfordshire (UK): Bladon Medical Publishing. | |
