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Advances in Neurology 1980
Review
Topics: Animals; Anticonvulsants; Disease Models, Animal; Humans; Kinetics; Phenobarbital; Seizures; Structure-Activity Relationship; Valproic Acid
PubMed: 6769305
DOI: No ID Found -
Lancet (London, England) Apr 1983
Comparative Study
Topics: Animals; Drug Evaluation, Preclinical; Embryo, Mammalian; Female; Fetal Diseases; Humans; Methods; Pregnancy; Valproic Acid
PubMed: 6132103
DOI: 10.1016/s0140-6736(83)92048-2 -
The New England Journal of Medicine Aug 1979
Topics: Adult; Central Nervous System; Female; Humans; Male; Valproic Acid
PubMed: 379646
DOI: 10.1056/nejm197908233010817 -
Journal of Neurosurgical Anesthesiology Jul 1994Clearance of valproic acid from brain tissue is believed to occur via a carrier-mediated system(s). The present study was designed to determine whether clearance was...
Clearance of valproic acid from brain tissue is believed to occur via a carrier-mediated system(s). The present study was designed to determine whether clearance was capacity-limited (saturable) and whether it occurred primarily at the choroid plexus. Ten rabbits were anesthetized with halothane and surgically prepared for ventriculocisternal perfusion. In group 1 (n = 5) valproic acid was added to blue dextran-containing mock cerebrospinal fluid (CSF) to achieve concentrations of 5, 20, 100, and 500 micrograms.ml-1. The mixture was infused through needles in both cerebral ventricles. The purpose of this group was to determine whether over a large range (100x) of valproic acid concentrations, clearance from CSF was capacity limited (saturable). In group 2 (n = 5) valproic acid concentrations were 3, 10, and 30 microgram.ml-1 and infusion was into the left cerebral ventricle only. The purposes of this group were to determine (a) the magnitude of valproic acid clearance for the "clinical" range of valproic acid in CSF (10-30 micrograms.ml-1), and (b) whether clearance of valproic acid was changed by perfusion across a portion of the choroid plexus surface area (group 2) as compared with perfusion across the entire choroid plexus surface area (group 1). In both groups the percent extraction of valproic acid was calculated from the concentration ratio (valproic acid)out/(valproic acid)in corrected for the rate of CSF formation. In group 1 the percent extraction of valproic acid was 93 +/- 2% (mean +/- SD) at 5 micrograms.ml-1 and stabilized within the range of 58-70% (individual values) at the higher inflow concentrations of valproic acid.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Anesthesia, Inhalation; Animals; Brain; Brain Chemistry; Capillaries; Cerebral Ventricles; Cerebrospinal Fluid; Choroid Plexus; Cisterna Magna; Coloring Agents; Dextrans; Endothelium, Vascular; Metabolic Clearance Rate; Rabbits; Solubility; Valproic Acid
PubMed: 7521700
DOI: 10.1097/00008506-199407000-00008 -
Journal of Clinical Pharmacy and... Jun 1993The aim of the study was to characterize, from the relationship between total and free serum levels of valproic acid obtained over a broad dosage range (10-50 mg/kg),... (Clinical Trial)
Clinical Trial
The aim of the study was to characterize, from the relationship between total and free serum levels of valproic acid obtained over a broad dosage range (10-50 mg/kg), the parameters defining the in-vivo kinetic behaviour of the binding of valproic acid to plasma proteins, their pharmacokinetic and clinical repercussions, and their application to therapeutic drug monitoring (TDM). The study was performed in nine healthy adults (20-35 years) who were given doses of 1000 (group A), 2000 (group B) and 3000 mg (group C) of sodium valproate according to a compensated cross-over design, simultaneously determining the total and free serum levels of valproic acid over a 24-h period. The mean free fraction increases with dose, although this increase is only significant (P < 0.05) for the highest dose (3000 mg). The variation in the free fraction of valproic acid begins to become significant (P < 0.05) at a total drug concentration above 100 mg/l. The mean values of the dissociation constant (K) and binding sites (n) were 460 mumol/l and 1.79, respectively, showing a variability of 86.6 and 38.7%, respectively, and a residual variability of 13.0%. Significant differences (P < 0.05) were found for the total plasma clearance (Cl) but not for the intrinsic plasma clearance (Clu) values, despite their tendency to decrease with the dose. If TDM is to be used for valproic acid, it is the free serum levels that should be determined, especially if high doses are administered, because the total serum levels are not a true reflection of the free ones, as is the case of other anti-epileptic drugs.
Topics: Adult; Biological Availability; Blood Proteins; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Kinetics; Male; Protein Binding; Valproic Acid
PubMed: 8345004
DOI: 10.1111/j.1365-2710.1993.tb00612.x -
Drug Metabolism and Disposition: the... Aug 2007Sigmoidal or autoactivation kinetics has been observed in vitro for both cytochrome P450- and UDP-glucuronosyltransferase-catalyzed enzymatic reactions. However, the in...
Sigmoidal or autoactivation kinetics has been observed in vitro for both cytochrome P450- and UDP-glucuronosyltransferase-catalyzed enzymatic reactions. However, the in vivo relevance of sigmoidal kinetics has never been clearly demonstrated. In the current study we investigate the kinetics of valproic acid glucuronide (VPAG) formation both in vivo in adult sheep and in vitro in sheep liver microsomes (pool of 10). After a 100 mg/kg i.v. bolus dose of valproic acid (VPA) to adult sheep (n = 5), the majority of the dose was recovered in urine as VPAG (approximately 79%). Eadie-Hofstee plots of the VPAG formation rate (calculated from urinary excretion rate data for VPAG) were characteristic of autoactivation kinetics and provided estimates of the apparent maximum velocity of an enzymatic reaction (V(max)(app)), the substrate concentration resulting in 50% of V(max)(app) (S(50)(app)), and Hill coefficient (n) of 2.10 +/- 0.75 micromol/min/kg, 117 +/- 56 microM, and 1.34 +/- 0.14, respectively. Comparable estimates of V(max)(app) (2.63 +/- 0.33 micromol/min/kg), S(50)(app) (118 +/- 53 microM), and n (2.06 +/- 0.47) describing overall VPA elimination from plasma were obtained by fitting VPA unbound plasma concentration-time data to a two-compartment model with elimination described by the Hill equation. Consistent with our in vivo observations, Eadie-Hofstee plots of VPAG formation in sheep liver microsomes were characteristic of autoactivation kinetics. To our knowledge, these data provide the first clear demonstration that autoactivation kinetics observed in vitro in liver preparations can translate to the in vivo situation at least under certain experimental conditions and confirm its relevance.
Topics: Animals; Catalysis; Enzyme Activation; Female; Kinetics; Microsomes, Liver; Sheep; Valproic Acid
PubMed: 17496206
DOI: 10.1124/dmd.107.015719 -
Annales de Biologie Clinique 1985Valproic acid is a very commonly used anti-epileptic drug which requires regular monitoring. The authors consider the assay of this drug by means of 2 techniques: Syva's... (Comparative Study)
Comparative Study
Valproic acid is a very commonly used anti-epileptic drug which requires regular monitoring. The authors consider the assay of this drug by means of 2 techniques: Syva's homogeneous phase immuno-enzymatic technique adapted by Du Pont de Nemours for his automatic clinical analyser and high performance liquid chromatography (HPLC). The precision of the immuno-enzymatic technique is insufficient for concentrations of valproic acid of between 70 and 35 mumol/l (coefficient of variation: 27.0 and 22.0 per cent respectively). The precision of this method for concentrations of valproic acid of 45 and 205 mumol/l is good (coefficient of variation: 8.5 and 8.2 per cent respectively). For concentrations of valproic acid of between 347 and 867 mumol/l, the precision of the immunoenzymological is very good and comparable to that of high performance liquid chromatography (coefficient of variation: 5.9 and 3.8 per cent). For all of the above concentrations of valproic acid, the coefficients of variation obtained with high performance liquid chromatography were less than 5 per cent. Comparison by means of the t test for paired series demonstrated a significant difference between the results of the 2 techniques, with a risk of error of p less than 0.01. The coefficient of correlation between the 2 techniques was 0.96. However, Eksborg's representation shows a difference between the 2 assay methods for concentrations of valproic acid of less than 200 mumol/l, with higher values with HPLC.
Topics: Chromatography, High Pressure Liquid; Humans; Immunoenzyme Techniques; Valproic Acid
PubMed: 3927791
DOI: No ID Found -
The Journal of Neuropsychiatry and... 2007
Topics: Anticonvulsants; Catatonia; Female; Humans; Middle Aged; Receptors, GABA; Valproic Acid
PubMed: 17431072
DOI: 10.1176/jnp.2007.19.2.197 -
The Journal of Neuroscience Nursing :... Apr 1991To any parent, a seizure is a frightening event and a diagnosis of epilepsy evokes alarm, misunderstanding and a sense of helplessness. The nurse plays a major role not... (Review)
Review
To any parent, a seizure is a frightening event and a diagnosis of epilepsy evokes alarm, misunderstanding and a sense of helplessness. The nurse plays a major role not only in acute seizure management but also in providing long-term support, teaching and counseling. As with any child who has seizures, regardless of the type of medication, close monitoring of drug levels and response is important if seizures are to be controlled and toxicity avoided. An understanding and positive approach to the family is needed in managing this chronic disorder. Through proper management, the nurse promotes parental acceptance and security and enhances the child's self image and independence.
Topics: Carbamazepine; Child; Electroencephalography; Epilepsy; Humans; Valproic Acid
PubMed: 1831474
DOI: 10.1097/01376517-199104000-00011 -
Toxicology and Applied Pharmacology Sep 1985The dosage-regimen-dependent teratogenicity as well as plasma and tissue levels of the antiepileptic drug valproic acid (VPA) were studied in the mouse by comparing... (Comparative Study)
Comparative Study
The dosage-regimen-dependent teratogenicity as well as plasma and tissue levels of the antiepileptic drug valproic acid (VPA) were studied in the mouse by comparing various injection regimens and infusion of the drug via implanted osmotic minipumps. Concentrations of 225-248 micrograms VPA/ml maternal plasma (about 2X above the therapeutic concentration range) and 70-75 micrograms VPA/g gestational material (on gestation Day 8) resulted in a significant incidence of neural tube defects (exencephaly in the mouse). Similar effects were produced if those concentrations were reached several times after multiple injections or by steady-state application via implanted pumps. A single injection was less effective than multiple injections, although drug accumulation did not occur. The doses (or area under the concentration-time curve values) did not correlate with the teratogenic response of the different administration regimens: much higher (factor 10) doses were needed with the infusion regimen to produce exencephaly rates comparable to those obtained with the injection regimen. The pattern of embryotoxicity was also schedule dependent: steady-state concentrations produced predominantly embryolethality and fetal weight retardation, while intermittent injections produced a high incidence of exencephaly (up to 60% of live fetuses). The dose of VPA (and the areas under the concentration-time curves) correlated with the embryolethality and fetal weight retardation of the drug, while the peak or steady-state concentrations reached in mother and gestational material correlated with the incidence of neural tube defects.
Topics: Animals; Female; Fetal Resorption; Injections, Subcutaneous; Mice; Neural Tube Defects; Pregnancy; Teratogens; Valproic Acid
PubMed: 3927520
DOI: 10.1016/0041-008x(85)90081-x