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Valproate
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
J. Christine Dean, J. Kiffin Penry
Valpromide (dipropylacetamide), the amide derivative of VPA, has been used in some European countries as a pro-drug for VPA and is marketed in 300 mg capsules as Depamide®. After oral intake it is metabolized presystemically to valproic acid (94). It is absorbed more slowly than VPA (94). It can cause gastrointestinal discomfort, but taking it after meals reduces the discomfort and also increases the bioavailability of the derived VPA (94).
Lessons learned from the discovery of sodium valproate and what has this meant to future drug discovery efforts?
Published in Expert Opinion on Drug Discovery, 2020
Slobodan M. Janković, Snežana V. Janković
Re-purposing of valproic acid and valproate for the treatment of bipolar disorder is again an early example of the rational drug design, which after combined with careful observation resulted in success. After Carraz and associates proved the antiepileptic action of valproic acid in experimental animals, they decided to synthesize an amide of valproic acid, valpromide, expecting that it will have a more potent anticonvulsant effect than valproic acid due to higher lipid solubility of amines and better penetration in the brain [26,27]. They indeed proved their concept, showing in animal experiments that valpromide protected rodents from convulsions triggered by strychnine, while equimolar combination of valproic acid and sodium valproate was not useful [26]. Valpromide at first, and valproate later, were tested in several clinical trials involving inpatients with epilepsy in France; however, since some of the patients had mood disorders, investigators observed an antidepressant effect [28,29]. Independently from French authors, German researchers in Munich observed the antimanic effect of valpromide in psychiatric patients with epilepsy, and this was enough to persuade American owner of the patent for divalproex (equimolar combination of valproic acid and sodium valproate), Abbot Pharmaceutical Company, to proceed with a large clinical trial involving patients with manic disorder. The trial demonstrated efficacy and acceptable safety of divalproex, leading to the approval of new indication – the treatment of manic attacks [26] which was expanded to „Treatment of manic episode in bipolar disorder when lithium is contraindicated or not tolerated. The continuation of treatment after manic episode could be considered in patients who have responded to divalproex for acute mania“, as stated in the summary of product characteristics [30].
Delayed and prolonged coma following valpromide poisoning in a 4-year-old girl
Published in Clinical Toxicology, 2021
D. Boels, B. Mégarbane, R. Bouquié
Valpromide, a valproic acid (VPA)-derived amide, is used as antiepileptic and mood stabilizer drug. At pharmacological doses, serum valpromide concentrations are low due to its rapid metabolism to VPA [1]. Valpromide, usually considered as a prodrug, is also pharmacologically active with potent anticonvulsant effects. However, its direct toxicity remains poorly understood.