CNS Drugs

, Volume 16, Issue 10, pp 695–714 | Cite as

Pharmacological and Therapeutic Properties of Valproate

A Summary After 35 Years of Clinical Experience
  • Emilio Perucca
Review Article


Thirty-five years since its introduction into clinical use, valproate (valproic acid) has become the most widely prescribed antiepileptic drug (AED) worldwide. Its pharmacological effects involve a variety of mechanisms, including increased γ-aminobutyric acid (GABA)-ergic transmission, reduced release and/or effects of excitatory amino acids, blockade of voltage-gated sodium channels and modulation of dopaminergic and serotoninergic transmission.

Valproate is available in different dosage forms for parenteral and oral use. All available oral formulations are almost completely bioavailable, but they differ in dissolution characteristics and absorption rates. In particular, sustained-release formulations are available that minimise fluctuations in serum drug concentrations during a dosing interval and can therefore be given once or twice daily.

Valproic acid is about 90% bound to plasma proteins, and the degree of binding decreases with increasing drug concentration within the clinically occurring range. Valproic acid is extensively metabolised by microsomal glucuronide conjugation, mitochondrial β-oxidation and cytochrome P450-dependent ω-, (ω-1)- and (ω-2)-oxidation. The elimination half-life is in the order of 9 to 18 hours, but shorter values (5 to 12 hours) are observed in patients comedicated with enzyme-inducing agents such as phenytoin, carbamazepine and barbiturates. Valproate itself is devoid of enzyme-inducing properties, but it has the potential of inhibiting drug metabolism and can increase by this mechanism the plasma concentrations of certain coadministered drugs, including phenobarbital (phenobarbitone), lamotrigine and zidovudine.

Valproate is a broad spectrum AED, being effective against all seizure types. In patients with newly diagnosed partial seizures (with or without secondary generalisation) and/or primarily generalised tonic-clonic seizures, the efficacy of valproate is comparable to that of phenytoin, carbamazepine and phenobarbital, although in most comparative trials the tolerability of phenobarbital was inferior to that of the other drugs. Valproate is generally regarded as a first-choice agent for most forms of idiopathic and symptomatic generalised epilepsies. Many of these syndromes are associated with multiple seizure types, including tonic-clonic, myoclonic and absence seizures, and prescription of a broad-spectrum drug such as valproate has clear advantages in this situation. A number of reports have also suggested that intravenous valproate could be of value in the treatment of convulsive and nonconvulsive status epilepticus, but further studies are required to establish in more detail the role of the drug in this indication.

The most commonly reported adverse effects of valproate include gastrointestinal disturbances, tremor and bodyweight gain. Other notable adverse effects include encephalopathy symptoms (at times associated with hyperammonaemia), platelet disorders, pancreatitis, liver toxicity (with an overall incidence of 1 in 20 000, but a frequency as high as 1 in 600 or 1 in 800 in high-risk groups such as infants below 2 years of age receiving anticonvulsant polytherapy) and teratogenicity, including a 1 to 3% risk of neural tube defects. Some studies have also suggested that menstrual disorders and certain clinical, ultrasound or endocrine manifestations of reproductive system disorders, including polycystic ovary syndrome, may be more common in women treated with valproate than in those treated with other AEDs. However, the precise relevance of the latter findings remains to be evaluated in large, prospective, randomised studies.


Carbamazepine Valproic Acid Valproate Lamotrigine Partial Seizure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The input of Dr David Pittrow, Department of Clinical Pharmacology, Technical University of Dresden, to various sections of the manuscript is gratefully acknowledged. This work was supported by an educational grant from Sanofi-Synthélabo, which had no control over the content of the manuscript. The author has received research grants and/or speaking fees from companies marketing most of the available antiepileptic drugs (carbamazepine, ethosuximide, gabapentin, lamotrigine, levetiracetam, phenytoin, tiagabine, topiramate and vigabatrin).


  1. 1.
    Hauser WA, Hesdorffer DC. Epilepsy: frequency, causes and consequences. New York: Demos, 1990Google Scholar
  2. 2.
    Annegers JF. Epidemiology of epilepsy. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. 2nd ed. Baltimore (MD): Williams & Wilkins, 1997: 165–72Google Scholar
  3. 3.
    Hauser WA, Annegers JF, Kurland LT. Prevalence of epilepsy in Rochester, Minnesota, 1940-80. Epilepsia 1991; 32: 429–45PubMedCrossRefGoogle Scholar
  4. 4.
    Perucca E, Beghi E, Dulac O, et al. Assessing risk to benefit ratio in antiepileptic drug therapy. Epilepsy Res 2000; 41: 107–39PubMedCrossRefGoogle Scholar
  5. 5.
    Moinier H, Carraz G, Moinier Y, et al. Propriété pharmacodynamique de la site N-dipropylacétique. Mémoire: propriété anti-épileptique. Thérapie 1963; 18: 435–8Google Scholar
  6. 6.
    Löscher W. Valproate: reappraisal of its pharmacodynamic properties and mechanism of action. Prog Neurobiol 1999; 58: 31–59PubMedCrossRefGoogle Scholar
  7. 7.
    Löscher W. Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain. Neurochem Res 1993; 18: 485–502PubMedCrossRefGoogle Scholar
  8. 8.
    Gean PW, Huang CC, Hung CR, et al. Valproic acid suppresses the synaptic response mediated by the NMDA receptors in rat amygdalar slices. Brain Res Bull 1994; 33(3): 333–6PubMedCrossRefGoogle Scholar
  9. 9.
    McLean MJ, Macdonald RL. Sodium valproate, but not etho-suximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 1986; 237(3): 1001–11PubMedGoogle Scholar
  10. 10.
    Davis R, Peters DH, McTavish D. Valproic acid: a reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1994; 47: 332–72PubMedCrossRefGoogle Scholar
  11. 11.
    Perucca E, Gatti G, Frigo GM, et al. Pharmacokinetics of valproic acid after oral and intravenous administration. Br J Clin Pharmacol 1978; 5: 313–8CrossRefGoogle Scholar
  12. 12.
    Perucca E, Gatti G, Frigo GM, et al. Disposition of sodium valproate in epileptic patients. Br J Clin Pharmacol 1978; 5: 495–9PubMedCrossRefGoogle Scholar
  13. 13.
    Gugler R, von Unruh GE. Clinical pharmacokinetics of valproic acid. Clin Pharmacokinet 1980; 5: 67–83PubMedCrossRefGoogle Scholar
  14. 14.
    Zaccara G, Messori A, Moroni F. Clinical pharmacokinetics of valproic acid: 1988. Clin Pharmacokinet 1988; 55: 367–89CrossRefGoogle Scholar
  15. 15.
    Barre J, Berger Y. Pharmacokinetics of a newly developed sustained-release form of sodium valproate. In: Chadwick D, editor. Proceedings of the Fourth International Symposium on Sodium Valproate and Epilepsy, International Congress and Symposium Series No. 152. London: Royal Society of Medicine Services, 1989: 178–84Google Scholar
  16. 16.
    Levy RH, Cenraud B, Loiseau P, et al. Meal-dependent absorption of enteric coated sodium valproate. Epilepsia 1980; 21: 273–80PubMedCrossRefGoogle Scholar
  17. 17.
    Royer-Morrot MJ, Zhiri A, Jacob F, et al. Influence of food intake on the pharmacokinetics of a sustained release formulation of sodium valproate. Biopharm Drug Dispos 1993; 14: 511–8PubMedCrossRefGoogle Scholar
  18. 18.
    Cramer JA, Mattson RH. Valproic acid: in vitro plasma protein binding and interaction with phenytoin. Ther Drug Monit 1979; 1: 105–16PubMedCrossRefGoogle Scholar
  19. 19.
    Gram L, Flachs H, Wurtz-Jorgensen A, et al. Sodium valproate, serum level and clinical effect in epilepsy: a controlled study. Epilepsia 1979; 20: 303–12PubMedCrossRefGoogle Scholar
  20. 20.
    Bowdle TA, Patel IH, Levy RH, et al. Valproic acid dosage and plasma protein binding and clearance. Clin Pharmacol Ther 1980; 28: 486–92PubMedCrossRefGoogle Scholar
  21. 21.
    Shen DD, Ojemann GA, Rappaport RL, et al. Low and variable presence of valproic acid in human brain. Neurology 1992; 42: 582–5PubMedCrossRefGoogle Scholar
  22. 22.
    Levy RH, Shen D, Abbott F, et al. Valproic acid: chemistry, biotransformation and pharmacokinetics. In: Levy RH, Mattson BS, Meldrum BS, et al., editors. Antiepileptic drugs. 5th ed. Philadelphia (PA): Lippincott Williams and Wilkins, 2002: 780–800Google Scholar
  23. 23.
    Frey HH, Löscher W. Distribution of valproate across the interface between blood and cerebrospinal fluid. Neuropharmacology 1978; 17: 637–42PubMedCrossRefGoogle Scholar
  24. 24.
    Löscher W, Frey HH. Kinetics of penetration of common anti-epileptic drugs into cerebrospinal fluid. Epilepsia 1984; 25: 346–52PubMedCrossRefGoogle Scholar
  25. 25.
    Perucca E, Grimaldi R, Gatti G, et al. Pharmacokinetics of valproic acid in the elderly. Br J Clin Pharmacol 1984; 17: 665–9PubMedCrossRefGoogle Scholar
  26. 26.
    Koerner M, Yerby M, Friel P, et al. Valproic acid disposition and protein binding in pregnancy. Ther Drug Monit 1989; 11: 228–30PubMedCrossRefGoogle Scholar
  27. 27.
    Henriksen O, Johannessen SI. Clinical and pharmacokinetic observations on sodium valproate: a 5-year follow-up study in 100 children with epilepsy. Acta Neurol Scand 1982; 65: 504–23PubMedCrossRefGoogle Scholar
  28. 28.
    Hoffmann F, von Unruh GE, Jancik BC. Valproic acid disposition in epileptic patients during combined antiepileptic maintenance therapy. Eur J Clin Pharmacol 1981; 19: 383–5PubMedCrossRefGoogle Scholar
  29. 29.
    Levy RH, Koch KM. Drug interactions with valproic acid. Drugs 1982; 24: 543–56PubMedCrossRefGoogle Scholar
  30. 30.
    May TW, Rambeck B. Serum concentration of valproic acid: influence of dose and co-medication. Ther Drug Monit 1985; 7: 387–90PubMedCrossRefGoogle Scholar
  31. 31.
    Patsalos PN, Froscher W, Pisani F, et al. The importance of drug interactions in epilepsy therapy. Epilepsia 2002; 43: 365–85PubMedCrossRefGoogle Scholar
  32. 32.
    Scheyer RD. Valproic acid: drug interactions. In: Levy RH, Mattson BS, Meldrum BS, et al., editors. Antiepileptic drugs. 5th ed. Philadelphia (PA): Lippincott Williams and Wilkins, 2002: 801–7Google Scholar
  33. 33.
    Bruni J, Wilder BJ, Perchalski RJ, et al. Valproic acid and plasma levels of phenobarbital. Neurology 1980; 30: 94–7PubMedCrossRefGoogle Scholar
  34. 34.
    Kanner AM, Frey M. Adding valproate to lamotrigine: a study of their pharmacokinetic interaction. Neurology 2000; 55: 588–91PubMedCrossRefGoogle Scholar
  35. 35.
    Morris RG, Black AB, Lam E, et al. Clinical study of lamotrigine and valproic acid in patients with epilepsy: using a drug interaction to advantage? Ther Drug Monit 2000; 22: 656–60PubMedCrossRefGoogle Scholar
  36. 36.
    McKee JW, Blacklaw J, Butler E, et al. Variability and clinical relevance of the interaction between sodium valproate and carbamazepine in epileptic patients. Epilepsy Res 1992; 11: 193–8PubMedCrossRefGoogle Scholar
  37. 37.
    Pisani F, Fazio A, Oteri G, et al. Sodium valproate and valpromide: differential interactions with carbamazepine in epileptic patients. Epilepsia 1986; 27: 548–52PubMedCrossRefGoogle Scholar
  38. 38.
    Robbins DK, Wedlund PJ, Kuhn R, et al. Inhibition of epoxide hydrolase by valproic acid in epileptic patients receiving carbamazepine. Br J Clin Pharmacol 1990; 29: 759–62PubMedCrossRefGoogle Scholar
  39. 39.
    Anderson GD, Gidal BE, Kantor ED, et al. Lorazepam-valproate interaction: studies in normal subjects and isolated perfused rat liver. Epilepsia 1994; 35: 221–5PubMedCrossRefGoogle Scholar
  40. 40.
    Lertora JJL, Rege AB, Greespan DL, et al. Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus. Clin Pharmacol Ther 1994; 56: 272–8PubMedCrossRefGoogle Scholar
  41. 41.
    Wong SL, Cavanaugh J, Shi H, et al. Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics. Clin Pharmacol Ther 1996; 60: 48–53PubMedCrossRefGoogle Scholar
  42. 42.
    Tartara A, Galimberti CA, Manni R, et al. Differential effects of valproic acid and enzyme inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients. Br J Clin Pharmacol 1991; 32: 335–40PubMedCrossRefGoogle Scholar
  43. 43.
    Pisani F, Narbone MC, Trunfio C, et al. Valproic acid-ethosuximide interaction: a pharmacokinetic study. Epilepsia 1984; 25: 229–33PubMedCrossRefGoogle Scholar
  44. 44.
    Tsanaclis LM, Allen J, Perucca E, et al. Effect of valproate on free plasma phenytoin concentrations. Br J Pharmacol 1984; 18: 17–20CrossRefGoogle Scholar
  45. 45.
    Perucca E, Hebdige S, Frigo GM, et al. Interaction between phenytoin and valproic acid: plasma protein binding and metabolic effects. Clin Pharmacol Ther 1980; 28: 779–89PubMedCrossRefGoogle Scholar
  46. 46.
    Rowan AJ, Meijer JWA, de Beer-Pawlikowski N, et al. Valproate-ethosuximide combination therapy for refractory absence seizures. Arch Neurol 1983; 40: 797–802PubMedCrossRefGoogle Scholar
  47. 47.
    Perucca E. Pharmacological principles as a basis for polytherapy. Acta Neurol Scand Suppl 1995; 162: 31–4PubMedGoogle Scholar
  48. 48.
    Brodie MJ, Yuen AWC. Lamotrigine substitution study: evidence for synergism with sodium valproate: 105 Study Group. Epilepsy Res 1997; 26: 423–32PubMedCrossRefGoogle Scholar
  49. 49.
    Pisani F, Oteri G, Russo MF, et al. The efficacy of valproatelamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction. Epilepsia 1999; 40: 1141–6PubMedCrossRefGoogle Scholar
  50. 50.
    Panayiotopoulos CP, Ferrie CD, Knott C, et al. Interaction of lamotrigine with sodium valproate [letter]. Lancet 1993; 341: 445PubMedCrossRefGoogle Scholar
  51. 51.
    Bergmann A, Schmidt D, Hutt HJ, et al. Epilepsietherapie mit retardierter valproinsäure: erfahrungen mit 1172 patienten [Results of a pragmatic study on 1172 patients treated with Depakine Chrono]. Aktuelle Neurol 1999; 26: 121–6CrossRefGoogle Scholar
  52. 52.
    Brasfield KH. Pilot study of divalproex sodium valproate versus valproic acid: drug acquisition costs versus all related costs. Curr Ther Res Clin Exp 1999; 60: 138–44CrossRefGoogle Scholar
  53. 53.
    Cranor CW, Sawyer WT, Carson SW, et al. Clinical and economic impact of replacing divalproex sodium with valproic acid. Am J Health Syst Pharm 1997; 54: 1716–22PubMedGoogle Scholar
  54. 54.
    Perucca E, Dulac O, Shorvon S, et al. Harnessing the clinical potential of antiepileptic drug therapy: dosage optimisation. CNS Drugs 2001; 15: 209–621CrossRefGoogle Scholar
  55. 55.
    Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia 2001; 42: 1255–60PubMedCrossRefGoogle Scholar
  56. 56.
    Covanis A, Jeavons PM. Once daily sodium valproate in the treatment of epilepsy. Dev Med Child Neurol 1980; 22: 202–4PubMedCrossRefGoogle Scholar
  57. 57.
    Richens A, Davidson DLW, Cartlidge NEF, et al. A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy: the Adult EPITEG Collaborative Group. J Neurol Neurosurg 1994; 57: 682–7CrossRefGoogle Scholar
  58. 58.
    Commission on Antiepileptic Drugs, International League against Epilepsy. Guidelines for therapeutic monitoring on antiepileptic drugs. Epilepsia 1993; 34: 585–7CrossRefGoogle Scholar
  59. 59.
    Lundberg B, Nergardh A, Boreus LO. Plasma concentrations of valproate during maintenance therapy in epileptic children. J Neurol 1982; 228: 133–41PubMedCrossRefGoogle Scholar
  60. 60.
    Pinder RM, Brogden RN, Speight TM, et al. Sodium valproate: a review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs 1977; 13: 81–123PubMedCrossRefGoogle Scholar
  61. 61.
    Seino M. A comment on the efficacy of valproate in the treatment of partial seizures. Epilepsia 1994; 35Suppl. 5: S101–4PubMedCrossRefGoogle Scholar
  62. 62.
    Turnbull DM, Howel D, Rawlins MD, et al. Which drag for the adult epileptic patient: phenytoin or valproate? BMJ 1985; 290: 815–9PubMedCrossRefGoogle Scholar
  63. 63.
    Callaghan N, Kenny RA, O’Neill B, et al. A prospective study between carbamazepine, phenytoin and sodium valproate as monotherapy in previously untreated and recently diagnosed patients with epilepsy. J Neurol Neurosurg Psychiatry 1985; 48: 639–44PubMedCrossRefGoogle Scholar
  64. 64.
    Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults: the Department of the Veteran Affairs Epilepsy Cooperative Study Group. N Engl J Med 1992; 327: 765–71PubMedCrossRefGoogle Scholar
  65. 65.
    Ramsay RE, Wilder BJ, Murphy JV, et al. Efficacy and safety of valproic acid versus phenytoin as sole therapy for newly diagnosed primary generalised tonic-clonic seizures. J Epilepsy 1992; 5: 55–60CrossRefGoogle Scholar
  66. 66.
    Heller AJ, Chesterman P, Elwes RDC, et al. Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial. J Neurol Neurosurg Psychiatry 1995; 58: 44–50PubMedCrossRefGoogle Scholar
  67. 67.
    Verity CM, Hosking G, Easter DJ. A multicenter comparative trial of sodium valproate and carbamazepine in paediatric epilepsy: the Paediatric EPITEG Collaborative Group. Dev Med Child Neurol 1995; 37: 97–108PubMedCrossRefGoogle Scholar
  68. 68.
    De Silva M, MacArdle B, McGowan M, et al. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet 1996; 347: 709–13PubMedCrossRefGoogle Scholar
  69. 69.
    Thilothammal N, Banu K, Ratnam RS. Comparison of phenobarbitone, phenytoin with sodium valproate: randomized, double-blind study. Indian Pediatr 1996; 33: 549–55PubMedGoogle Scholar
  70. 70.
    Turnbull DM, Rawlins MD, Weightman D, et al. A comparison of phenytoin and valproate in previously untreated adult epileptic patients. J Neurol Neurosurg Psychiatry 1982; 45: 55–9PubMedCrossRefGoogle Scholar
  71. 71.
    Reynolds EH, Heller AJ, Chadwick D. Valproate versus carbamazepine for seizures. N Engl J Med 1993; 328: 207–8PubMedCrossRefGoogle Scholar
  72. 72.
    Monfort JC. Valproate versus carbamazepine for seizures. N Engl J Med 1993; 328: 208–9PubMedGoogle Scholar
  73. 73.
    Beydoun A, Sackellares JC, Shu V. Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: a double-blind, concentration-response design clinical trial. Depakote Monotherapy for Partial Seizures Study Group. Neurology 1997; 48(1): 182–8Google Scholar
  74. 74.
    Richens A, Ahmad S. Controlled trial of sodium valproate in severe epilepsy. BMJ 1970; 4: 73–6PubMedCrossRefGoogle Scholar
  75. 75.
    Gram L, Rasmussen KE, Flachs H, et al. Valproate sodium: a controlled clinical trial including monitoring of serum levels. Epilepsia 1977; 18: 141–8PubMedCrossRefGoogle Scholar
  76. 76.
    Tudur Smith C, Marson AG, Williamson PR. Phenytoin versus valproate monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Available in The Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration; issue 3. Oxford: Oxford Update Software, 2000Google Scholar
  77. 77.
    Marson AG, Williamson PR, Clough H, et al. Carbamazepine versus valproate monotherapy for epilepsy: a meta-analysis. Epilepsia 2002; 43: 505–13PubMedCrossRefGoogle Scholar
  78. 78.
    Christe W, Kramer G, Vigonius U, et al. A double-blind, controlled clinical trial of oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Res 1997; 26: 451–60PubMedCrossRefGoogle Scholar
  79. 79.
    Perucca E, Tomson T. Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications. Epilepsy Res 1999; 33: 247–62PubMedCrossRefGoogle Scholar
  80. 80.
    Richens A, Perucca E. Clinical pharmacology and medical treatment. In: Laidlaw J, Richens A, Chadwick D, editors. A textbook of epilepsy. Edinburgh: Churchill-Livingstone, 1993: 495–559Google Scholar
  81. 81.
    Wolf P. Treatment of the idiopathic (primary) generalized epilepsies. In: Shorvon S, Dreifuss F, Fish D, et al., editors. The treatment of epilepsy. Oxford: Blackwell Science Ltd, 1996: 238–46Google Scholar
  82. 82.
    Perucca E. Principles of drug treatment. In: Shorvon SD, Dreifuss F, Fish D, et al., editors. The treatment of epilepsy. Oxford: Blackwell Science Ltd, 1996: 152–68Google Scholar
  83. 83.
    Perucca E. A reappraisal of valproate within today’s therapeutic environment: with perspective of seizure types and syndromes. Seizure 2002. In pressGoogle Scholar
  84. 84.
    Beghi E, Perucca E. The management of epilepsy in the 1990s: acquisitions, uncertainties, and perspectives for future research. Drugs 1995; 49: 680–94PubMedCrossRefGoogle Scholar
  85. 85.
    Bauer J. Seizure-inducing effects of antiepileptic drags: a review. Acta Neurol Scand 1996; 94: 367–77PubMedCrossRefGoogle Scholar
  86. 86.
    Perucca E, Gram L, Avanzini G, et al. Antiepileptic drugs as a cause of worsening of seizures. Epilepsia 1998; 39: 5–17PubMedCrossRefGoogle Scholar
  87. 87.
    Perucca E. Seizures provoked by antiepileptic drags and by other medications. Neurologia 2001; 16 Suppl. 2: 43–51Google Scholar
  88. 88.
    Osorio I, Reed RC, Peltzer JN. Refractory idiopathic absence status epilepticus: a probable paradoxical effect of phenytoin and carbamazepine. Epilepsia 2000; 41: 887–94PubMedCrossRefGoogle Scholar
  89. 89.
    Maheshwari MC, Jeavons PM. Proceedings: the effect of sodium valproate (Epilim) on the EEG [abstract]. Electroencephalogr Clin Neurophysiol 1975; 39: 429Google Scholar
  90. 90.
    Braathen G, Theorell K, Persson A, et al. Valproate in the treatment of absence epilepsy in children: a study of dose-response relationships. Epilepsia 1988; 29: 548–52PubMedCrossRefGoogle Scholar
  91. 91.
    Villarreal HJ, Wilder BJ, Willmore LJ, et al. Effect of valproic acid on spike and wave discharges in patients with absence seizures. Neurology 1978; 28: 886–91PubMedCrossRefGoogle Scholar
  92. 92.
    Callaghan N, O’Hare J, O’Driscoll D, et al. Comparative study of ethosuximide and sodium valproate in the treatment of typical absence seizures (petit mal). Dev Med Child Neurol 1982; 24: 830–6PubMedCrossRefGoogle Scholar
  93. 93.
    Sato S, White BG, Penry JK, et al. Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology 1982; 32: 157–63PubMedCrossRefGoogle Scholar
  94. 94.
    Bourgeois B, Beaumanoir A, Blajev B, et al. Monotherapy with valproate in primary generalized epilepsies. Epilepsia 1987; 28Suppl. 2: S8–11PubMedCrossRefGoogle Scholar
  95. 95.
    Berkovic SF, Andermann F, Guberman A, et al. Valproate prevents the recurrence of absence status. Neurology 1989; 39: 1294–7PubMedCrossRefGoogle Scholar
  96. 96.
    Covanis A, Gupta AK, Jeavons PM. Sodium valproate: monotherapy and polytherapy. Epilepsia 1982; 23: 582–93CrossRefGoogle Scholar
  97. 97.
    Bachman DS. Use of valproic acid in treatment of infantile spasms. Arch Neurol 1982; 39: 49–52PubMedCrossRefGoogle Scholar
  98. 98.
    Pavone L, Incorpora G, La Rosa M, et al. Treatment of infantile spasms with sodium dipropylacetic acid. Dev Med Child Neurol 1981; 23: 454–61PubMedCrossRefGoogle Scholar
  99. 99.
    Siemes H, Spohr HL, Michael T, et al. Therapy of infantile spasms with valproate: results of a prospective study. Epilepsia 1988; 29: 553–60PubMedCrossRefGoogle Scholar
  100. 100.
    Lee K, Melchior JC. Sodium valproate versus phenobarbital in the prophylactic treatment of febrile convulsions in childhood. Eur J Pediatr 1981; 137: 151–3PubMedGoogle Scholar
  101. 101.
    Herranz JL, Armijo JA, Arteaga R. Effectiveness and toxicity of phenobarbital, primidone, and sodium valproate in the prevention of febrile convulsions, controlled by plasma levels. Epilepsia 1984; 25: 89–95PubMedCrossRefGoogle Scholar
  102. 102.
    Mamelle N, Mamelle JC, Plasse JC, et al. Prevention of recurrent febrile convulsions. A randomized therapeutic assay: sodium valproate, phenobarbital and placebo. Neuropediatrics 1984; 15: 37–42Google Scholar
  103. 103.
    Newton RW. Randomised controlled trials of phenobarbitone and valproate in febrile convulsions. Arch Dis Child 1988; 63: 1189–91PubMedCrossRefGoogle Scholar
  104. 104.
    American Academy of Pediatrics Committee on Quality Improvements, Subcommittee on Febrile Seizures. Practice parameter: long-term treatment of the child with simple febrile seizures. Pediatrics 1999; 103: 1307–9CrossRefGoogle Scholar
  105. 105.
    Bourgeois BFD. Valproic acid: clinical efficacy and use in epilepsy. In: Levy RH, Mattson BS, Meldrum BS, et al., editors. Antiepileptic drugs. 5th ed. Philadelphia (PA): Lippincott Williams and Wilkins, 2002: 808–17Google Scholar
  106. 106.
    Treiman DM. Status epilepticus. In: Laidlaw J, Richens A, Chadwick E, editors. A textbook of epilepsy. 4th ed. Edinburgh: Churchill Livingstone, 1993: 205–20Google Scholar
  107. 107.
    Morton LD, Towne AR, Garnett LK, et al. Safety and efficacy of intravenous valproate in status epilepticus. Epilepsia 2000; 41 Suppl. 7: 252Google Scholar
  108. 108.
    Katragadda SB, Aluri BC, Burdette DE. Intravenous administration of valproate in 12 patients [abstract]. Epilepsia 2000; 41 Suppl. 7: 3Google Scholar
  109. 109.
    Cantrell DT, Ramsay ER, Collings SD, et al. Rapid infusions of Depakon are safe and well tolerated [abstract]. Epilepsia 2000; 41 Suppl. 7: 253Google Scholar
  110. 110.
    Limdi NA, Faught E. The safety of rapid valproic acid infusion. Epilepsia 2000; 41: 1342–5PubMedCrossRefGoogle Scholar
  111. 111.
    Giroud M, Gras D, Escousse A, et al. Use of injectable valproic acid in status epilepticus: a pilot study. Drug Invest 1993; 5: 154–9CrossRefGoogle Scholar
  112. 112.
    Czapinski P, Terczynski A. Intravenous valproic acid administration in status epilepticus [in Polish]. Neurol Neurochir Pol 1998; 32: 11–22PubMedGoogle Scholar
  113. 113.
    Lowe MR, DeToledo JC, Vilavizza N, et al. Efficacy, safety, and tolerability of fast i.v. loading of valproate in patients with seizures and status epilepticus [abstract]. Epilepsia 1998; 39 Suppl. 6: 235Google Scholar
  114. 114.
    Sinha S, Naritoku DK. Intravenous valproate is well tolerated in unstable patients with status epilepticus. Neurology 2000; 55: 722–4PubMedCrossRefGoogle Scholar
  115. 115.
    Hovinga CA, Chicella MF, Rose DF, et al. Use of intravenous valproate in three pediatric patients with nonconvulsive or convulsive status epilepticus. Ann Pharmacother 1999; 33(5): 579–84PubMedCrossRefGoogle Scholar
  116. 116.
    Alfonso I, Alvarez LA, Gilman J, et al. Intravenous valproate dosing in neonates. J Child Neurol 2000; 15: 827–9PubMedCrossRefGoogle Scholar
  117. 117.
    Haafiz A, Kissoon N. Status epilepticus: current concepts. Pediatr Emerg Care 1999; 15(2): 119–29PubMedCrossRefGoogle Scholar
  118. 118.
    Chez MG, Hammer MS, Loeffel M, et al. Clinical experience of three pediatrie and one adult case of spike-and-wave status epilepticus treated with injectable valproic acid. J Child Neurol 1999; 14: 239–42PubMedCrossRefGoogle Scholar
  119. 119.
    Alehan FK, Morton LD, Pellock JM. Treatment of absence status with intravenous valproate. Neurology 1999; 52: 889–90PubMedCrossRefGoogle Scholar
  120. 120.
    Kaplan PW. Intravenous valproate treatment of generalized nonconvulsive status epilepticus. Clin Electroencephalogr 1999; 30: 1–4PubMedGoogle Scholar
  121. 121.
    Genton P, Gelisse P. Valproic acid: adverse effects. In: Levy RH, Mattson BS, Meldrum BS, et al., editors. Antiepileptic drugs. 5th ed. Philadelphia (PA): Lippincott Williams and Wilkins, 2002: 837–51Google Scholar
  122. 122.
    Schmidt D. Adverse effects of valproate. Epilepsia 1984; 15Suppl. 1: S44–9CrossRefGoogle Scholar
  123. 123.
    Wagner PG, Welton SR, Hammond CM. Gastrointestinal adverse effects with divalproex sodium and valproic acid. J Clin Psychiatry 2000; 61: 302–3PubMedCrossRefGoogle Scholar
  124. 124.
    Thompson PJ, Trimble MR. Anticonvulsant and cognitive functions. Epilepsia 1982; 23: 531–44PubMedCrossRefGoogle Scholar
  125. 125.
    Craig I, Tallis R. Impact of valproate and phenytoin on cognitive function in elderly patients: results of a single-blind, randomized, comparative study. Epilepsia 1994; 35: 381–90PubMedCrossRefGoogle Scholar
  126. 126.
    Perucca E. Evaluation of drug treatment outcome in epilepsy: a clinical perspective. Pharmacy World Science 1997; 19: 217–22PubMedCrossRefGoogle Scholar
  127. 127.
    Battino D, Dukes MNG, Perucca E. Anticonvulsants. In: Dukes MNG, Aronson JK, editors. Meyler’s side effects of drugs. 14th ed. Amsterdam: Elsevier Science BV, 2000: 164–97Google Scholar
  128. 128.
    Guerrini R, Belmonte A, Campichi R, et al. Reversible pseudoatrophy of the brain and mental deterioration associated with valproate treatment. Epilepsia 1998; 39(1): 27–32PubMedCrossRefGoogle Scholar
  129. 129.
    Dinesen H, Gram L, Andersen T, et al. Weight gain during treatment with valproate. Acta Neurol Scand 1984; 70: 65–9PubMedCrossRefGoogle Scholar
  130. 130.
    Isojarvi JIT, Tauboll E, Pakarinen AJ, et al. Altered ovarian function and cardiovascular risk factors in valproate-treated women. Am J Med 2001; 111: 290–6PubMedCrossRefGoogle Scholar
  131. 131.
    Isojarvi JI, Laatikainen TJ, Pakarinen AJ, et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993; 329: 1383–8PubMedCrossRefGoogle Scholar
  132. 132.
    Frank S. Polycystic ovary syndrome: a changing perspective. Clin Endocrinol 1989; 31: 87–120CrossRefGoogle Scholar
  133. 133.
    Chappell KA, Markowitz JS, Jackson CW. Is valproate pharmacotherapy associated with polycystic ovaries? Ann Pharmacother 1999; 33: 1211–6PubMedCrossRefGoogle Scholar
  134. 134.
    Genton P, Bauer J, Duncan S, et al. On the association between valproate and policystic ovary syndrome. Epilepsia 2001; 42: 295–304PubMedCrossRefGoogle Scholar
  135. 135.
    Isojarvi JIT, Tauboll E, Tapanainen JS, et al. On the association between valproate and policystic ovary syndrome: a response and an alternative view. Epilepsia 2001; 42: 305–10PubMedCrossRefGoogle Scholar
  136. 136.
    Herzog AG, Schachter SC. Valproate and policystic ovary syndrome: final thoughts. Epilepsia 2001; 42: 311–5PubMedCrossRefGoogle Scholar
  137. 137.
    Isojarvi JIT, Rättyä J, Myllylä VV, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol 1998; 43: 446–51PubMedCrossRefGoogle Scholar
  138. 138.
    Beghi E, Bizzi A, Codegoni AM, et al. Valproate, carnitine metabolism, and biochemical indicators of liver function. Epilepsia 1990; 33: 346–52CrossRefGoogle Scholar
  139. 139.
    De Vivo DC, Bohan TP, Coulter DL, et al. L-carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia 1998; 39: 1216–25PubMedCrossRefGoogle Scholar
  140. 140.
    Sato Y, Kondo I, Ishida S, et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 2001; 57: 445–9PubMedCrossRefGoogle Scholar
  141. 141.
    Acharya S, Bussel JB. Hematologic toxicity of sodium valproate. J Pediatr Hematol Oncol 2000; 22: 62–5PubMedCrossRefGoogle Scholar
  142. 142.
    Chambers HG, Weinstein CH, Mubarak SJ, et al. The effect of valproic acid on blood loss in patients with cerebral palsy. J Pediatr Orthop 1999; 19: 792–5PubMedGoogle Scholar
  143. 143.
    Anderson GD, Lyn YX, Berge C, et al. Absence of bleeding complications in patients undergoing cortical surgery while receiving valproate treatment. J Neurosurg 1977; 87: 252–6Google Scholar
  144. 144.
    Asconape JJ, Penry JK, Dreifuss FE, et al. Valproate associated pancreatitis. Epilepsia 1993; 34: 177–83PubMedCrossRefGoogle Scholar
  145. 145.
    Chapman SA, Wachsman GP, Patterson BD. Pancreatitis associated with valproic acid: a review of the literature. Pharmacotherapy 2001; 21: 1549–60PubMedCrossRefGoogle Scholar
  146. 146.
    Buzan RD, Firestone D, Thomas M, et al. Valproate-associated pancreatitis and cholecystitis in six mentally retarded adults. J Clin Psychiatry 1995; 56: 529–32PubMedGoogle Scholar
  147. 147.
    Moreiras Plaza M, Rodrigues Goyanes G, Cuina L, et al. On the toxicity of valproic acid. Clin Nephrol 1999; 51: 187–9PubMedGoogle Scholar
  148. 148.
    Dreifuss FE, Langer DH, Moline KA, et al. Valproic acid hepatic fatalities. I: US experience since 1984. Neurology 1989; 39: 201–7Google Scholar
  149. 149.
    Bryant III AE, Dreifuss FE. Valproic acid hepatic fatalities. III: US experience since 1986. Neurology 1996; 46: 465–9PubMedCrossRefGoogle Scholar
  150. 150.
    König SA, Siemes H, Blacker F, et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia 1994; 35: 1005–15PubMedCrossRefGoogle Scholar
  151. 151.
    Bohan TP, Helton E, McDonald I, et al. Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology 2001; 56: 1405–9PubMedCrossRefGoogle Scholar
  152. 152.
    Raskind JY, El-Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother 2000; 34: 630–8PubMedCrossRefGoogle Scholar
  153. 153.
    Ahmed J, Brown C. In-utero exposure to valproate and neural tube defects. Lancet 1996; I: 1392–3Google Scholar
  154. 154.
    Lindhout D, Hoppener RJ, Meinardi H. Teratogenicity of anti-epileptic drug combinations with special emphasis on epoxidation (of carbamazepine). Epilepsia 1984; 25: 77–83PubMedCrossRefGoogle Scholar
  155. 155.
    Lindhout D, Omtzight JG. Teratogenic effects of antiepileptic drugs: implications for management of epilepsy in women of childbearing age. Epilepsia 1994; 35Suppl. 4: S19–28PubMedCrossRefGoogle Scholar
  156. 156.
    Samren EB, Van Duijn CM, Hiilesmaa VK, et al. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European perspective study of human teratogenesis associated with maternal epilepsy. Epilepsia 1997; 38: 981–90PubMedCrossRefGoogle Scholar
  157. 157.
    Samren EB, Van Duijn CM, Christiaens GC, et al. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol 1999; 46: 739–46PubMedCrossRefGoogle Scholar
  158. 158.
    Kaneko S, Battino D, Andermann E, et al. Congenital malformations due to antiepileptic drugs. Epilepsy Res 1999; 33: 145–58PubMedCrossRefGoogle Scholar
  159. 159.
    Canger R, Battino D, Canevini MP, et al. Malformations in the offspring of women with epilepsy: a prospective study. Epilepsia 1999; 40: 1231–6PubMedCrossRefGoogle Scholar
  160. 160.
    Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001; 344: 1132–8PubMedCrossRefGoogle Scholar
  161. 161.
    Adab N, Jacoby A, Smith D, et al. Additional educational needs in children born to mothers with epilepsy. J Neurol Neurosurg Psych 2001; 70: 15–21CrossRefGoogle Scholar
  162. 162.
    Zahn CA, Morrell MJ, Collins SD, et al. Management issues for women with epilepsy: a review of the literature. Neurology 1998; 15: 949–56CrossRefGoogle Scholar
  163. 163.
    Beghi E, Annegers JF. Pregnancy registries in epilepsy. Epilepsia 2001; 42: 1422–5PubMedCrossRefGoogle Scholar
  164. 164.
    Nau H, Ralf-Siegbert H, Ehlers K. Valproic acid-induced neural tube defects in mouse and human: aspects of chirality, alternative drug development, pharmacokinetics and possible mechanisms. Pharmacol Toxicol 1991; 69: 310–21PubMedCrossRefGoogle Scholar
  165. 165.
    MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 20: 131–7Google Scholar
  166. 166.
    Heaney DC, Shorvon SD, Sander JW, et al. Cost minimization analysis of antiepileptic drugs in newly diagnosed epilepsy in 12 European countries. Epilepsia 2000; 41Suppl. 5: S37–44PubMedGoogle Scholar
  167. 167.
    Heaney DC, Shorvon SD, Sander JW. An economic appraisal of carbamazepine, lamotrigine, phenytoin and valproate as initial treatment in adults with newly diagnosed epilepsy. Epilepsia 1998; 39Suppl. 3: S19–25PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Emilio Perucca
    • 1
  1. 1.Clinical Pharmacology Unit, Department of Internal Medicine and TherapeuticsUniversity of PaviaPaviaItaly

Personalised recommendations