content:valproate

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 ====== 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.
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 Reference range (measures valproic acid): 50–100 mg/l (300–700 μmol/l). Reference range (measures valproic acid): 50–100 mg/l (300–700 μmol/l).
  
 +Also see: [[https://bnfc.nice.org.uk/drug/sodium-valproate.html|BNFc]]
 ==== Main ADRs ==== ==== Main ADRs ====
  
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 **Systemic:** **Systemic:**
-  * the most serious are fatal hepatotoxicity and acute haemorrhagic pancreatitis. +  * the most serious are **fatal hepatotoxicity** and **acute haemorrhagic pancreatitis**. 
-  * Hepatic failure resulting in fatalities+  * **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. 
-    * The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups (range 1/8000–1/10,000 between 3 and 20 years of age) and in monotherapy with valproate.+    * incidence decreases considerably in progressively older patient groups (range 1/8000–1/10,000 between 3 and 20 years of age) and in monotherapy with valproate.
     * usually occurred during the first 6 months of treatment. The diagnosis is based on clinical criteria with non-specific symptoms, such as malaise, weakness, lethargy, facial oedema, anorexia, vomiting and loss of seizure control.     * usually occurred during the first 6 months of treatment. The diagnosis is based on clinical criteria with non-specific symptoms, such as malaise, weakness, lethargy, facial oedema, anorexia, vomiting and loss of seizure control.
     * Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first 6 months. However     * Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first 6 months. However
-      * benign elevation of liver enzymes is common during valproate treatment+      * benign elevation of liver enzymes is common during valproate treatment, particularly if used in conjunction with other AEDs. These are usually transient or respond to dose reduction
       * severe hepatotoxicity is not preceded by progressive elevation of liver enzymes.       * severe hepatotoxicity is not preceded by progressive elevation of liver enzymes.
-      * Raised liver enzymes are common during treatment with valproate, particularly if used in conjunction with other AEDs. These are usually transient or respond to dose reduction. Patients with such biochemical abnormalities should be reassessed clinically and liver function tests should be performed more frequently. +      * patients with raised LFTs should be reassessed clinically and liver function tests should be performed more frequently. 
-    * 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. 
-    * Evidence of haemorrhage, bruising or a disorder of haemostasis/coagulation is an indication for reduction or withdrawal of valproate. +  * Evidence of haemorrhage, bruising or a disorder of haemostasis/coagulation is an indication for reduction or withdrawal of valproate. 
-    * Weight gain occurs in 20% of patients and is some-times marked; women are more vulnerable. This is usually reversible if valproate is withdrawn early. +  * Weight gain occurs in 20% of patients and is some-times marked; women are more vulnerable. This is usually reversible if valproate is withdrawn early. 
-    * Hair loss and changes in hair texture or colour are relatively rare; they usually occur in the early months of valproate treatment and may resolve spontaneously despite continuation of the drug. +  * Hair loss and changes in hair texture or colour are relatively rare; they usually occur in the early months of valproate treatment and may resolve spontaneously despite continuation of the drug. 
-    * Other ADRs concern the gastrointestinal system (e.g. anorexia, constipation, dry mouth, stomatitis) and urogenital system (e.g. urinary incontinence, vaginitis, dysmenorrhoea, amenorrhoea and urinary frequency).+  * Other ADRs concern the gastrointestinal system (e.g. anorexia, constipation, dry mouth, stomatitis) and urogenital system (e.g. urinary incontinence, vaginitis, dysmenorrhoea, amenorrhoea and urinary frequency).
  
 FDA warning: All patients who are currently taking or starting on valproate for any indication should be monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression. FDA warning: All patients who are currently taking or starting on valproate for any indication should be monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression.
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   * Valproate does not interact with hormonal contraception.   * Valproate does not interact with hormonal contraception.
  
-==== Main disadvantages ==== +==== Disadvantages ==== 
-It is particularly unsuitable for:+Particularly unsuitable for:
   * women, because of hormonal changes, weight gain and teratogenicity   * women, because of hormonal changes, weight gain and teratogenicity
-  * young children, for focal epilepsis since the doses of valproate required to be effective are much higher in focal than generalised epilepsies. Besides there are other, more effective and safer drugs for focal seizures+  * for focal epilepsis in young children since the doses of valproate required to be effective are much higher in focal than generalised epilepsies. Besides there are other, more effective and safer drugs for focal seizures 
 + 
 +==== 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>{{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)]. 
 + 
 +It was first released as antiepileptic drug in France in 1967 after the publication of preclinical studies by Carraz et al. in 1964[(:cite:carraz1964>Carraz G, Fau R, Chateau R, Bonnin J (1964) Communication à propos des premiers essais cliniques sur l’activité anti-épileptique de l’acide n-dipropylacétiques (sel de Na). Ann Med Psychol (Paris) 122: 577–585)]. During 1970, it received license to other European countries, but in the USA it was not licensed before 1978. 
 +==== References ==== 
 +~~REFNOTES~~
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