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The American Journal of Psychiatry Dec 2007
Topics: Brain Diseases; Humans; Hyperammonemia; Protein Binding; Valproic Acid
PubMed: 18056251
DOI: 10.1176/appi.ajp.2007.07081270 -
Lancet (London, England) Mar 1980
Topics: Abnormalities, Drug-Induced; Animals; Dose-Response Relationship, Drug; Female; Mice; Pregnancy; Valproic Acid
PubMed: 6102670
DOI: 10.1016/s0140-6736(80)91159-9 -
JAMA Nov 1978Valproic acid, a new anticonvulsant, is most effective in absence seizures (simple and complex), but it has produced improvement in tonicclonic seizures, mixed absence... (Clinical Trial)
Clinical Trial Comparative Study
Valproic acid, a new anticonvulsant, is most effective in absence seizures (simple and complex), but it has produced improvement in tonicclonic seizures, mixed absence with tonic-clonic seizures, and myoclonic epilepsy. It is useful alone or as an adjunct to other anticonvulsants and may allow the dosage of the latter to be reduced. Some patients who are refractory to other anticonvulsants may respond to valproic acid. Adverse reactions occur in about 20% of patients. Gastrointestinal disturbances and drowsiness (usually noted when valproic acid is given with other anticonvulsants) are the most common reactions; hair loss is observed less frequently. Untoward effects are usually transient and do not require discontinuation of use of the drug.
Topics: Animals; Child; Clinical Trials as Topic; Drug Evaluation; Drug Interactions; Epilepsies, Myoclonic; Epilepsy; Epilepsy, Absence; Ethosuximide; Humans; Platelet Aggregation; Valproic Acid
PubMed: 100622
DOI: No ID Found -
Neurology Jun 1979Eight patients were treated concurrently with a constant dose of phenytoin and valproic acid for 1 year. During initial therapy with valproic acid, total plasma...
Eight patients were treated concurrently with a constant dose of phenytoin and valproic acid for 1 year. During initial therapy with valproic acid, total plasma phenytoin levels decreased. The interaction was transient and was not observed at the end of 1 year. Total plasma phenytoin levels returned to pre-valproic-acid levels in seven patients.
Topics: Drug Interactions; Drug Therapy, Combination; Humans; Phenytoin; Valproic Acid
PubMed: 377134
DOI: 10.1212/wnl.29.6.904 -
The Journal of the Kentucky Medical... Apr 1982
Topics: Child, Preschool; Humans; Male; Seizures; Thrombocytopenia; Valproic Acid
PubMed: 6808068
DOI: No ID Found -
Neurology Mar 1988Six neonates with prolonged, intractable seizures were treated with valproic acid (VPA). Each patient had received maximum doses of phenobarbital (greater than 40...
Six neonates with prolonged, intractable seizures were treated with valproic acid (VPA). Each patient had received maximum doses of phenobarbital (greater than 40 micrograms/ml), and five patients received at least two additional anticonvulsants, without success. Seizure activity was controlled in five of six (83%) cases. In four cases, all other anticonvulsants could be withdrawn, and seizures were controlled on VPA monotherapy. VPA was discontinued in three patients because of VPA-induced hyperammonemia. VPA pharmacokinetic measurements were as follows: for total VPA, volume of distribution (V) = 0.40 l/kg (range, 0.36 to 0.47 l/kg), serum clearance (Cl) = 14.4 ml/h/kg (5.5 to 18.2 ml/h/kg), half-life (T1/2) = 26.4 hours (8.6 to 48.5); for unbound VPA, V = 2.02 l/kg (1.14 to 2.44 l/kg), Cl = 108.9 ml/h/kg (42.0 to 252.0 ml/h/kg). T1/2 = 17.6 hours (6.7 to 34.2). VPA free fraction ranged from 11.3 to 31.6% (mean, 19.2%).
Topics: Absorption; Ammonia; Humans; Infant, Newborn; Osmolar Concentration; Seizures; Valproic Acid
PubMed: 3126410
DOI: 10.1212/wnl.38.3.467 -
European Journal of Pharmaceutical... Oct 2014Valproic acid is an anti-convulscant drug that is widely used in the treatment of different types of epilepsy and since its introduction the clinical use has increased...
Valproic acid is an anti-convulscant drug that is widely used in the treatment of different types of epilepsy and since its introduction the clinical use has increased rapidly both as a sole agent and in combination therapies. The mechanism of action has been linked to blockade of voltage-dependent sodium channels and potentiation of GABAergic transmission. The most widely used route of administration of Valproic acid is oral, although it can also be given intravenously and rectally and its pharmacokinetics has been studied extensively. The aim of this work was to develop a physiologically based pharmacokinetic model for plasma and tissue/organ prediction in children and adults following intravenous and oral dosing of Valproic acid. The plasma/tissue concentration profile will be used for clinical trial simulation in Dravet syndrome, a rare form of epilepsy in children where the combination of Valproic acid, stiripentol and clobazam has shown remarkable results. A physiologically based pharmacokinetic model was developed with compartments for gut lumen, enterocyte, gut tissue, systemic blood, kidney, liver, brain, spleen, muscle and rest of body. System and drug specific parameters for the model were obtained from the literature from in vitro and in vivo experiments. The model was initially developed for adults and scaled to children using age-dependent changes in anatomical and physiological parameters and ontogeny functions for enzyme maturation assuming the same elimination pathways in adults and children. The results from the model validation showed satisfactory prediction of plasma concentration both in terms of mean prediction and variability in children and adults following intravenous and oral dosing especially after single doses. The model also adequately predicts clearance in children. Due to limited distribution of Valproic acid into tissues, the concentration in plasma is about 8-9 times higher than tissues/organs. The model could help to improve clinical outcome in the treatment of Dravet syndrome through dose optimisation.
Topics: Adolescent; Adult; Humans; Models, Biological; Tissue Distribution; Valproic Acid; Young Adult
PubMed: 25010262
DOI: 10.1016/j.ejps.2014.06.023 -
Current Opinion in Neurology Apr 2003Valproic acid (VPA) is one of the four first line antiepileptic drugs (AEDs). VPA is also an effective drug in migraine prophylaxis and in treatment of bipolar... (Review)
Review
PURPOSE OF REVIEW
Valproic acid (VPA) is one of the four first line antiepileptic drugs (AEDs). VPA is also an effective drug in migraine prophylaxis and in treatment of bipolar disorders. The use of VPA is limited by its two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity, and it is the least potent of the established AEDs. Consequently, there is an incentive to develop a second-generation VPA. A successful, second-generation VPA would need to possess the following characteristics: broad-spectrum antiepileptic activity; better potency than VPA; and lack of teratogenicity and hepatotoxicity. These characteristics would give such a drug the potential to be utilized in epilepsy and other CNS disorders.
RECENT FINDINGS
Intensive research has been carried out in order to develop a second-generation VPA that would be more potent and safer than VPA. Amide derivatives of VPA have shown particular value as potential follow-up compounds and have better in-vivo performance than VPA. Several CNS-active valproylamides are more potent as antiepileptics than VPA, they possess broad-spectrum antiepileptic activity, and have been found to be nonteratogenic in animal models. The amide analogues of VPA that emerged from structure-pharmacokinetic-pharmacodynamic relationship studies as promising second-generation compounds are: N-methyl-tetramethylcyclopropane carboxamide, (2S,3S)-valnoctamide, (R)-propylisopropyl acetamide and valproyl glycinamide.
SUMMARY
At present there are three compounds in clinical trials in patients with epilepsy that can be regarded as second-generation VPA: valproyl glycinamide, 3-methylbutanamide or isovaleramide and SPD421 (DP-VPA). For any one of these second-generation valproic acids to become a successful follow-up compound to VPA, it has to fulfil the above criteria and also possess favorable pharmacokinetics.
Topics: Amides; Anticonvulsants; Bipolar Disorder; Epilepsy; Humans; Migraine Disorders; Valproic Acid
PubMed: 12644750
DOI: 10.1097/01.wco.0000063774.81810.30 -
Canadian Journal of Anaesthesia =... Mar 1991This report describes the development of an intraoperative defect in haemostasis which occurred during surgery for lengthening of the heel cords and release of hip... (Review)
Review
This report describes the development of an intraoperative defect in haemostasis which occurred during surgery for lengthening of the heel cords and release of hip contractures in a patient receiving valproic acid. A review of the literature failed to find any other cases of a valproic acid-induced bleeding disorder occurring under anaesthesia and surgery. While recognized in the non-surgical literature, this case reports the first in which the development of a valproic acid-induced haemostatic defect occurred under anaesthesia. The subsequent course is discussed and some pathophysiological mechanisms are presented. It is suggested that for patients receiving valproic acid preoperative education should include PT/PTT, platelet and fibrinogen counts and bleeding time so that abnormal coagulation states can be recognized.
Topics: Child; Hemostasis, Surgical; Humans; Intraoperative Period; Male; Seizures; Valproic Acid
PubMed: 2021993
DOI: 10.1007/BF03008150 -
Biopharmaceutics & Drug Disposition 1983Novel drug reservoirs are described which, after their implantation under mouse skin, continuously released organic liquids such as the anti-epileptic drug valproic acid...
Novel drug reservoirs are described which, after their implantation under mouse skin, continuously released organic liquids such as the anti-epileptic drug valproic acid at preselected rates for periods up to several weeks. The liquids, which were filled into the reservoirs, diffused through silastic membranes. The area and thickness of these membranes determined the administered dose. Administration of the anti-epileptic drug valproic acid at various selected doses resulted in persistent drug concentrations spanning from subtherapeutic to toxic levels. The drug reservoirs were easily refillable in situ which greatly extended the duration of the experiment. The dose administered could be determined within 5-15 per cent (rel. S.D.). It is suggested that the maintenance of persistent drug levels in small laboratory animals may be an appropriate model for the pharmacological and toxicological study of those compounds with short half-lives and high clearance rates in these species.
Topics: Animals; Drug Implants; Female; Kinetics; Male; Metabolic Clearance Rate; Mice; Mice, Inbred Strains; Sex Factors; Valproic Acid
PubMed: 6411139
DOI: 10.1002/bdd.2510040209