Journal of Clinical Pharmacy and Therapeutics (2005) 30, 417–421
`
`Special 30th Anniversary paper
`
`COMMENTARY
`
`Valproate: a simple chemical with so much to offer
`G. M. Peterson* PhD MBA and M. Naunton  PhD
`*Unit for Medication Outcomes Research and Education, School of Pharmacy, University of Tasmania,
`Hobart, Australia and  Department of Pharmacotherapy and Pharmaceutical Care, University of
`Groningen, Groningen, The Netherlands
`
`The debate exists amongst clinical pharmacologists
`as to unlimited supplies of which drug would be
`most useful when stranded on a deserted island.
`The tricyclic antidepressants have always rated
`highly because of their variety of useful therapeutic
`effects, but valproate also deserves to be high on
`the list. Of course, it will protect against seizures, if
`they arise, but it could also be useful for analgesia,
`preventing migraine and stabilizing the mood
`particularly if one becomes mentally unbalanced
`on the island. It might even help to prevent the
`development of cancer.
`It would not be an overstatement to suggest that
`valproate is truly a remarkable drug – a multitude
`of therapeutic effects from such a simple chemical
`structure (2-propylpentanoic acid; Fig. 1) – with a
`remarkable story; it was discovered by chance and
`is now well-established in the management of a
`number of neurological conditions and psychiatric
`disorders. An American chemist
`(Burton) first
`synthesized valproate as an organic solvent in 1882
`(1). It is a clear, colourless to pale yellow liquid at
`room and body temperature, and only slightly
`soluble in water, but highly soluble in organic
`solvents. The current generic name (valproic acid)
`
`H3C
`
`H3C
`
`OH
`
`O
`
`Fig. 1. Chemical structure of valproic acid.
`
`Received 9 May 2005, Accepted 19 May 2005
`Correspondence: Gregory Peterson, Unit for Medication Out-
`comes Research and Education, School of Pharmacy, University
`of Tasmania, Locked Bag 26, Hobart TAS 7001, Australia. Tel.: 61
`3 62262197; fax: 61 3 62267627; e-mail: g.peterson@utas.edu.au
`
`was derived from the more descriptive name
`2-propylvaleric acid (2).
`Valproate had been used infrequently as a sol-
`vent until its therapeutic properties were seren-
`dipitously
`discovered
`in
`1962
`by
`French
`researchers, when it was being used as a solvent for
`other compounds (khelline derivatives) that were
`being tested for potential anticonvulsant activity
`(2–4). Eynard and colleagues had encountered
`difficulty in dissolving some of the derivatives in
`water or common organic solvents. Valproate was
`then used to solubilize these compounds and
`anticonvulsant activity was subsequently observed
`for the entire test compounds at all doses. Labor-
`atory studies demonstrated anti-seizure activity
`with valproate (5) and the first clinical trial in epi-
`lepsy using the sodium salt of valproic acid was
`reported in 1964 (6, 7). It was released in France in
`1967 (as ‘Depakine’), in Great Britain in 1973 and
`was approved by the US Food and Drug Admin-
`istration (FDA) in 1978. It was the only new anti-
`convulsant drug marketed for many years,
`beforehand and afterwards.
`Valproate is currently marketed in over 100
`countries and is well established as a first-line and
`widely used antiepileptic agent, with a very broad
`spectrum of activity against both generalized and
`partial seizures in adults and children (4, 8, 9). It is
`effective against absences and myoclonic, and
`generalized tonic-clonic seizures. In addition, the
`drug is useful in the treatment of partial seizures,
`with or without secondary generalization (2–4, 8,
`9). Intravenous valproate has also been shown to be
`effective against status epilepticus (10).
`Results from numerous clinical trials suggest
`that valproate probably has the widest spectrum of
`anticonvulsant activity of all current antiepileptic
`drugs in adults and children with epilepsy (4, 8, 9).
`
`Ó 2005 Blackwell Publishing Ltd
`
`417
`
`Page 1 of 5
`
`JAZZ EXHIBIT 2001
`Amneal Pharms. LLC (Petitioner) v. Jazz Pharms. Ireland LTD. (Patent Owner)
`Case IPR2016-00546
`
`

`
`418 G. M. Peterson and M. Naunton
`
`Its mode of action as an anticonvulsant is unclear
`and might involve several mechanisms (2–4, 8, 9,
`11).
`It has been demonstrated that valproate
`potentiates c-aminobutyric acid inhibitory effects in
`the central nervous system. In addition, valproate
`might also act through attenuation of N-methyl-
`D-aspartate receptor-mediated excitation, although
`this does not explain the effect of valproate on
`absence seizures (4). It has also been proposed that
`valproate exerts its effect via blockade of voltage-
`dependent sodium channels, although this has not
`been clearly confirmed. Acting to alter the balance
`of neuronal inhibition and excitation through more
`than one mechanism is clearly an advantage for an
`anticonvulsant and is likely to contribute to its
`broad spectrum of clinical effects (4).
`Valproate also possesses an impressive safety
`profile, being well-tolerated in most patients (4, 9,
`12). Most adverse effects are mild to moderate in
`intensity and hypersensitivity reactions are rare.
`Valproate causes fewer neurological adverse effects
`and skin rashes than phenytoin or barbiturates, and
`its tolerability and safety appear to be similar to that
`of carbamazepine (4). The main issues of concern
`with valproate have been idiosyncratic liver toxic-
`ity, haematological
`toxicity and teratogenicity.
`Recently, valproate has been shown to exert dele-
`terious effects on markers of bone turnover (13) and
`bone mineral density (14, 15), which might increase
`the risk of
`fractures in long-term users (16),
`although this requires further study. Weight gain is
`a frequently encountered problem (17, 18).
`Transient elevations of liver enzymes without
`clinical symptoms are seen in 15–30% of patients
`treated with valproate (19). In contrast, valproate-
`induced hepatotoxicity is rare, but often fatal. It
`occurs most frequently in children under 2 years of
`age and those taking multiple drugs. The overall
`incidence is one in 20 000, but there is a frequency
`as high as one in 600 or one in 800 in high-risk
`groups such as infants >2 years of age receiving
`anticonvulsant polytherapy (8).
`The liver metabolism of valproate is complex
`and involves microsomal oxidation and glucuron-
`idation (CYP2C9, CYP2C19 and CYP2A6). At least
`10 metabolites have been identified (9, 12, 20). The
`hepatotoxicity of valproate is most likely associated
`with accumulation of 2,4-diene-valproate and/or
`4-ene-valproate (19) and is because of the direct
`disruption of mitochondrial processes, perhaps
`
`through drug-induced carnitine deficiency (21).
`Cases usually present with non-specific symptoms
`such as lethargy, nausea/vomiting, or worsening
`seizures and there is a rapid progression to coma.
`Liver histopathology is characterized by steatosis
`with and without necrosis of hepatocytes.
`Apart from the multiple metabolic pathways of
`elimination, the pharmacokinetics of valproate are
`characterized by
`excellent
`but dose-limited
`absorption and non-linear plasma protein binding
`(12). In the management of epilepsy, valproate has
`an accepted therapeutic range of
`total plasma
`concentrations of 300–600 lMM (50–100 mg/L) that is
`relatively wide and should be seen more of a guide
`rather than a clear-cut range (22, 23).
`Clinically significant drug interactions involving
`valproate are also uncommon – the most important
`being the inhibition of the metabolism of lamot-
`rigine (24, 25),
`increasing the risk of rash and
`Stevens–Johnson syndrome (26–28).
`In recent times, the use of valproate has spread
`to a range of other indications, including psychi-
`atric disorders, migraine prophylaxis and the
`management of trigeminal or post-herpetic neur-
`algia (29–33).
`The first anecdotal evidence that valproate might
`be useful in migraine sufferers arose in patients
`with coexisting migraine and epilepsy (2). Positive
`results in a number of clinical trials subsequently
`lead to FDA approval for migraine in 1996 (34–36).
`There is also recent evidence that intravenous val-
`proate (500–800 mg) is effective and well-tolerated
`in the treatment of acute migraine attacks (37, 38).
`Lambert first reported efficacy of valproate in
`bipolar disorder in 1966 (39). A series of open and
`small crossover placebo-controlled studies fol-
`lowed over the next 15 years, all with generally
`positive results and most indicating high rates of
`response in mania and lower rates of response in
`depression (40). According to Bowden and Singh
`(41), valproate has had the largest impact of any
`drug on changes in treatment approaches to bipo-
`lar disorder over the past decade.
`Valproate has also been used as treatment for
`alcohol withdrawal and dependence and reduction
`of cocaine use (42), as an adjunctive agent for the
`treatment of schizophrenia (43), tardive dyskinesia
`(44), agitation associated with late-life psychosis
`and Alzheimer’s disease, and borderline personal-
`ity disorder (32, 33, 45, 46).
`
`Ó 2005 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 30, 417–421
`
`Page 2 of 5
`
`

`
`The first reports of toxic effects to the embryo in
`pregnant epileptic women treated with valproate
`were published in 1982 (47). Valproate has since
`been associated with a variety of major and minor
`foetal malformations, including a 20-fold increase
`in neural tube defects (1–3% risk), cleft lip and
`palate, cardiovascular abnormalities, genitourinary
`defects, developmental delay, endocrinological
`disorders, limb defects and autism (48). It has been
`suggested that polytherapy treatment in epileptic
`pregnant women increases the risk of teratogenic-
`ity. There is a dose–effect relationship for foetal
`malformations and exposure to valproate during
`the first trimester of pregnancy, with higher doses
`of valproate associated with a significantly greater
`risk than with lower doses or with other anticon-
`vulsant drugs (48, 49).
`It has become evident that some of the mecha-
`nisms that account for the foetal malformations
`produced by valproate are related to distinct anti-
`tumor properties of this drug. In vitro models that
`were established to investigate the teratogenicity
`of valproate fortuitously identified that valproate
`possessed anti-proliferative effects and reduced
`cell growth (50, 51). This intriguing discovery
`opens novel aspects for the treatment of patients
`with cancer (50–52). Valproate has been found to
`exert an anti-proliferative effect on certain cancer
`cell lines both in vitro and in vivo, and there are
`now preliminary reports of the use of valproate in
`human haematological and solid tumours (52).
`Clinical studies are underway and the preliminary
`results indicate that valproate alone or in combi-
`nation offers a promising avenue of treatment,
`both in solid and haematopoetic malignancies
`(51).
`In light of the hepatotoxicity and teratogenicity
`associated with valproate, there is ongoing inten-
`sive research to develop new, safer analogues of
`valproate. Amide derivatives of valproate have
`shown particular value as potential
`follow-up
`compounds. These include valproyl glycinamide,
`3-methylbutanamide or isovaleramide and SPD421
`(DP-valproate) (53, 54).
`Valproate has progressed from being a seren-
`dipitous discovery to become a first-line therapy
`for many forms of epilepsy. Its use has spread to
`now include migraine prophylaxis and manage-
`ment of bipolar disorder. Future developments are
`likely to further improve its efficacy and tolerabil-
`
`Valproate
`
`419
`
`ity. More clinical uses will also undoubtedly
`appear for this fascinating molecule.
`
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