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PubMed1992

Tolerance to the anticonvulsant effects of carbamazepine, diazepam, and sodium valproate in kindled rats.

We assessed the development of tolerance to the anticonvulsant effects of carbamazepine (CBZ), diazepam (DZP), and sodium valproate (VPA) on convulsions elicited by amygdala stimulation in kindled rats in three similar experiments. In each experiment, amygdala-kindled rats were assigned to a drug group or to a corresponding vehicle control group. The rats in the three drug groups received a total of 10 bidaily (one every 48 h) IP injections of CBZ (70 mg/kg), DZP (2 mg/kg) or VPA (250 mg/kg) at a dose that initially blocked the forelimb clonus elicited by an amygdala stimulation (400 microA, 60 Hz, 1 s) administered 1 h after the injection. The rats in the three vehicle control groups were similarly treated except that they received injections of the saline vehicle. The drug tolerance test occurred 48 h after the final tolerance-development trial; the rats from each drug group and the corresponding vehicle control group received an injection of the appropriate drug followed 1 h later by the administration of a convulsive stimulation. The drug tolerance test revealed almost total tolerance in each of the three drug groups but no tolerance in any of the three vehicle control groups. Such large tolerance effects are inconsistent with the less dramatic effects reported in previous studies; possible reasons for this inconsistency were considered.

Amygdala↗

PubMed1992

Contingent tolerance to the anticonvulsant effects of carbamazepine, diazepam, and sodium valproate in kindled rats.

The effect of convulsive stimulation during periods of drug exposure on the development of tolerance to the anticonvulsant effects of carbamazepine (CBZ), diazepam (DZP), or sodium valproate (VPA) was studied in three similar experiments. In each experiment, amygdala-kindled rats were assigned to one of three groups: one group received a drug injection (CBZ, 70 mg/kg, IP; DZP, 2 mg/kg, IP; VPA, 250 mg/kg, gavage) 1 h before each of a series of 10 bidaily (one every 48 h) convulsive stimulations, a second group received the same dose of the drug 1 h after each of the 10 stimulations, and a third group served as a vehicle control. The drug tolerance test occurred in each experiment 48 h after the 10th tolerance-development trial; every rat received the appropriate dose of CBZ, DZP, or VPA 1 h before being stimulated. In each experiment, only the rats from the drug-before-stimulation group displayed a significant amount of tolerance to the drug's anticonvulsant effect. Thus the development of tolerance to the anticonvulsant effects of CBZ, DZP, and VPA was not an inevitable consequence of drug exposure; the development of tolerance was contingent upon the occurrence of convulsive stimulation during the periods of drug exposure. These results support the idea that functional drug tolerance is an adaptation to a drug's effects on ongoing patterns of neural activity, rather than to drug exposure per se.

Amygdala↗

PubMed1993

Bicuculline infused into the hamster ventral tegmentum inhibits, while sodium valproate facilitates, sexual receptivity.

Progesterone's (P) actions on both the ventral medial nucleus of the hypothalamus (VMH) and the ventral tegmental area (VTA) are essential for sexual receptivity in female hamsters. Evidence suggests that progesterone's actions in the hamster VMH may be genomic while those in the VTA may be mediated nongenomically, via GABAA. Ovariectomized female hamsters were bilaterally implanted with cannulae aimed toward the VTA. One week after surgery, animals were SC injected with 10 micrograms estradiol benzoate (EB) and 40 h later with 200 or 500 micrograms P. At hour 43.5, 50 ng bicuculline, a GABAA antagonist, was infused into each available cannula. Control animals received 0.5 microliter sterile saline vehicle, or no infusion. At hour 44, animals were tested for sexual receptivity in an observation arena with a sexually experienced male. Histology revealed that only animals with bicuculline infused into the VTA had reduced lordosis durations compared to controls. Other animals, primed with EB and 200 micrograms progesterone, showed a facilitation of sexual receptivity after infusion into the VTA of 50 micrograms sodium valproate, a GABAA transaminase inhibitor. These results suggest that GABAA plays a necessary role in the mechanism of progesterone's actions on sexual receptivity in hamster VTA.

Animals↗

PubMed1992

Sister-chromatid exchanges are increased in epileptics, but not by sodium valproate.

Sister-chromatid exchange (SCE) frequency has been studied from peripheral blood lymphocyte cultures of 21 patients with epilepsy on sodium valproate, 20 patients who had not started therapy (untreated) and 20 normal healthy controls. Treated and untreated patients with epilepsy were observed to have higher SCE frequencies (mean 9.05 and 9.82 respectively) than healthy controls (mean 4.8; P < 0.001). There was no significant difference in SCE frequency between treated and untreated patients. This suggests that the disease itself may be associated with an increased frequency of SCEs.

Adolescent↗

PubMed1987

The effects of carbamazepine and sodium valproate on SEPs and BAEPs.

SEPs and BAEPs were studied in 36 previously untreated epileptics receiving either carbamazepine (CBZ) or sodium valproate (VPA) monotherapy. CBZ prolonged central conduction times in SEPs and BAEPs. SEP latency prolongation correlated with serum CBZ levels. VPA had minimal effects on evoked potentials. The present study gives evidence of similar effects of carbamazepine and phenytoin on central neural conduction.

Adult↗

PubMed1993

The effects of valproate in brain monoamines of juvenile rats after stress.

1. Clinical data suggest that valproate (VPA) may be useful in prophylaxis of affective disorders, which show disturbances of the serotoninergic system. On the other hand, chronic stress has an adverse effect on affective disorders, those with disturbances of the serotonergic system, especially. 2. In order to study the effects of VPA on brain monoamines and acute stress, 200 mgr VPA/Kgr was administered intraperitoneal (ip) to juvenile male rats; the control group was treated with NaCL 0.9% ip. After 30 min, all animals were evoked on predictable neurogenic or systemic stress (30 min foot shock, or 15 min ether stress, respectively), and 48 hours later, VPA or NaCL were administered ip again; 30 min afterwards, the rats were decapitated. Rats without stress were also sacrificed 30 min after VPA or NaCL administration. 3. Measurements of brain monoamines noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA), were done in Frontal Cortex (FC), Hypothalamus (HY) and Striatum (S), by High Performance Liquid Chromatography (HPLC). 4. Compared with the control stress group the level of 5-HIAA in the FC was significantly increased (P < 0.01) in VPA stress rats; in the HY and in S the increase of 5-HIAA was not significant. No remarkable differences were observed in NA, DA, 5-HT and DOPAC concentrations, in any of the brain regions. No changes in brain monoamine levels were found in non stress rats, either. 5. The augmentation of 5-HIAA level after VPA administration and after stress, in correlation with the decrease of 5-HIAA that is observed in depression, support the hypothesis that VPA may be effective in affective disorders by influencing the serotoninergic system.

Animals↗

PubMed1993

In vivo administration of valproate reduces the nerve terminal (synaptosomal) activity of GABA aminotransferase in discrete brain areas of rats.

Previous in vitro experiments have indicated that neuronal GABA aminotransferase (GABA-T) differs from extraneuronal GABA-T in sensitivity to certain enzyme inhibitors, including the antiepileptic drug valproate (VPA). In the present experiments, it was studied if GABA-T activity in whole tissue and synaptosomes prepared from whole tissue of 11 brain regions of rats is affected in vivo by treatment with an anticonvulsant dosage of VPA. For this purpose, rats were treated with VPA, 200 mg/kg i.p., 15 min prior to dissection of brain regions. Synaptosomes were prepared from the 11 brain regions by a density gradient centrifugation method. In whole tissue samples of brain regions, no alteration of GABA-T activity was determined after VPA administration, except a small decrease in the tectum. In contrast, VPA significantly decreased GABA-T activity in synaptosomal fractions of substantia nigra, pons and medulla oblongata. These data substantiate that synaptosomal GABA-T is more susceptible to the inhibitory effect of VPA than the extra-synaptosomal enzyme. Furthermore, since VPA seems to be homogeneously distributed across brain regions, the observation of regional differences in inhibitory effects on GABA-T might indicate differences in the biochemical properties of GABA-T from different brain regions.

4-Aminobutyrate Transaminase↗

PubMed1983

Antinociceptive action of sodium valproate in the mouse.

The antinociceptive action of sodium valproate (VPA) was examined using male NMRI mice. Using the hot-plate assay at 60 degrees C, orally-administered VPA (50-400 mg/kg) produced antinociceptive effects; the ED50 was about 160 mg/kg. Oral doses of VPA (6.3-400 mg/kg) decreased the writhing response elicited by intraperitoneally-injected acetic acid. The antinociceptive effect of VPA, as determined with the writhing test, exhibited complex characteristics, the most pronounced effect occurring at doses of 12.5-50 mg/kg. The antinociceptive effect of VPA in the writhing test was not antagonized by bicuculline or by naloxone. VPA, like other agents which enhance central GABA-ergic mechanisms, might possess analgesic activity.

Acetates↗

PubMed1984

Metabolic interactions of phenytoin in the rat: effect of coadministration with the anticonvulsant drugs sodium valproate, sulthiame, ethosuximide or phenobarbital.

Rats were administered with 50 mg/kg phenytoin (PHT), twice a day, for five consecutive days and with a second anticonvulsant drug in addition for a further five days. Analysis of 24 hr urine samples for content of unmetabolized PHT and its major metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (pHPPH) indicates that PHT hydroxylation was significantly inhibited by sulthiame coadministration since during the test period (days 6-10) the concentrations of PHT and pHPPH in urine were significantly increased and decreased respectively. In contrast, sodium valproate, ethosuximide and phenobarbital had no significant effect on the urinary excretion pattern of PHT. These data correlate with changes in plasma and brain PHT concentrations.

Animals↗

PubMed1995

Withdrawal-like effects of pentylenetetrazol and valproate in the naive organism: a model of motivation produced by opiate withdrawal?

Pentylenetetrazol (PTZ) and sodium valproate (VPA) produce acutely in the naive rat various behavioural effects resembling signs of opiate withdrawal in the morphine-treated subject. Suggestions in the literature that these substances may activate directly some of the neural consequences of opiate and drug withdrawal prompted us to look for and examine possible aversive effects of these substances at non-toxic doses. With a sensitive two-flavour, three-trial taste aversion procedure, relatively low doses of PTZ and VPA (5 and 160 mg/kg, respectively) do indeed have aversive effects. The maximum aversions were produced by 10 and 20 mg/kg PTZ and 320 mg/kg VPA and were equivalent to those of morphine withdrawal precipitated by 0.01-0.03 mg/kg naloxone in a morphine pellet-implanted animal. Moreover, the maximum aversions with PTZ and VPA were significantly higher than the maximum aversions seen with naloxone in the drug-naive animal under the same training conditions. Thus, the data from the present study confirmed the notion that low doses of PTZ and VPA in the naive animal may activate processes activated by drug withdrawal, including those important for the motivational effect of withdrawal. However, it was also pointed out that the lowest dose VPA producing aversion was higher than that found here to produce writhes and ataxia (80 mg/kg) but the same as that required for shaking (160 mg/kg), while the PTZ aversion was at a dose lower than that known to produce a PTZ cue. Implications were discussed for using withdrawal-like phenomena as a model in the non-treated organism of clinically-relevant withdrawal effects.

Animals↗

PubMed1996

On-column gas chromatographic-mass spectrometric assay for metabolic profiling of valproate in brain tissue and serum.

A sensitive capillary gas chromatographic-mass spectrometric method for the determination of valproic acid and at least twelve of its metabolites in serum based on tert-butyldimethylsilyl (tBDMS) derivatives is described. Low detection limits are achieved by using a direct on-column injection technique. The addition of dry pyridine during the derivatization step now leads to uniform formation of 3-keto-VPA di-tBDMS derivatives and thereby avoids the necessity of a deuterated internal standard. A novel extraction procedure for metabolic profiling of valproate in brain tissue samples is presented. Using this method, (Z)-2-en-VPA was determined in rat brain tissue for the first time.

Acetamides↗

PubMedDate not supplied

Drug interactions of zonisamide with phenytoin and sodium valproate: serum concentrations and protein binding.

The influence of co-medication with zonisamide (ZNS) on the serum concentration and protein binding of phenytoin (PHT) and sodium valproate (VPA) was studied in 21 pediatric patients. No significant correlation between the daily ZNS dose, and total serum concentrations, free concentrations or free fractions (FF) of PHT or VPA was observed. The patient study showed that changes in the FF of PHT and VPA were correlated more closely with the serum protein and bilirubin levels than changes in the ZNS dosage. An in vitro study revealed that the addition of ZNS caused decreases in the FF of PHT and VPA. However, these decreases were within the range of measurement error and were negligible. In conclusion, no significant effect of ZNS on the serum concentration or protein binding of PHT or VPA was demonstrated.

Adolescent↗

PubMedDate not supplied

Hematologic manifestations and impaired liver synthetic function during valproate monotherapy.

In a prospective study 50 children with new onset epilepsy were investigated. Routine screening for complete blood count, serum protein, albumin, gamma-glutamyltransferase (gamma-GT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and coagulation studies before, 3, 6 and 9 weeks after commencement of antiepileptic therapy with valproate were carried out. Serum B12 and folate levels were also determined in 29 patients. The aim of the study was to evaluate the effect of VPA on these laboratory findings. We found a significant reduction of red blood count and platelet count, whereas MCV showed a significant upward trend. Vitamin B12 levels were elevated after starting VPA therapy. We found no elevations of liver enzymes, but a significant transient reduction of ALT after 3 and 6 weeks and significantly reduced serum protein and albumin after 3, 6 and 9 weeks. Coagulation studies revealed a significant downward trend in serum fibrinogen and upward trend in thrombin time. The other parameters showed no significant changes after onset of VPA treatment. We think that reduced red blood cell and platelet counts, and elevated MCV indicate a direct toxic effect on a hematopoietic precursor or stem cell in patients treated with VPA. Furthermore, reduced protein, albumin and fibrinogen indicate an impaired liver synthetic function in asymptomatic children treated with VPA monotherapy.

Adolescent↗

PubMed1996

Perioperative blood loss: the effect of valproate.

The purpose of this investigation was to determine the effect of the use of valproate (VPA) on bleeding and requirement for replacement blood products in patients undergoing major surgical procedures. One hundred thirty-nine patients had posterior spinal fusion performed by 1 of 3 surgeons at our institution from 1987 to 1993. The clinical status of the patient, pre- and postoperative laboratory values, type and extent of instrumentation, surgeon performing the procedure, and medications (including VPA) were variables considered. The outcome measures were intra- and postoperative blood loss and number of blood products used. Intraoperative blood loss was correlated with the method of instrumentation, platelet count, and the surgeon performing the procedure. Postoperative blood loss was correlated with the diagnosis of cerebral palsy. By hierachical stepwise regression analysis, the only outcome measure correlated with VPA was the number of blood products used.

Adolescent↗

PubMedDate not supplied

Sodium valproate augments spontaneous neural tube defects and axial skeletal malformations in TO mouse fetuses [corrected].

The TO mouse exhibits a low incidence (3.65%) of spontaneous exencephaly at birth. The objectives of this study were to determine if sodium valproate (VPA) would augment this background frequency of exencephaly and to characterize its gross and histologic bases. Single doses of 200, 400, or 600 mg/kg of VPA were administered on one of gestation days (GD) 7 to 10 and fetuses were collected on GD 18. Significant augmentation of the background incidence of exencephaly was observed in the GD 7 and 8 treatment groups. Absence of the skull vault, hemorrhage, and degeneration of the exposed brain, polyhydramnios, and a female excess characterized the abnormality. Exencephalic embryos were markedly growth retarded. In addition to craniofacial and urogenital anomalies, severe axial skeletal malformations were found to be consistently associated with exencephaly. Morphometric evaluation of the alizarin red-stained skeleton confirmed significant skeletal growth inhibition. Histologic sections of GD 10 embryos revealed early onset of treatment-related growth retardation. Arrest of closure appeared to affect intermittent segments of the neural tube. The closure defect sometimes only involved the surface ectoderm of the dorsal midline. The unclosed neural tube was at times covered by a continuous layer of surface ectoderm. Cell death per se was not pronounced in the neuroepithelium. The mesenchyme was generally sparse and edema was obvious in embryos with partial closure. Growth inhibition of the optic and otic primordia was marked by pronounced cell death in these structures as well as in the otic and trigeminal ganglia and in the pharyngeal arch mesenchyme. Evidence for neural crest cell migration was also recorded. These data indicate that VPA interacts with genetic susceptibility, augments the frequency of exencephaly, and also induces other malformations in the TO mouse. The widespread malformations of the cranifacial structures are suggestive of the preferential effect of VPA on the neural crest or its derivatives.

Analysis of Variance↗

PubMedDate not supplied

A comparison of the acute effect of single doses of vigabatrin and sodium valproate on photosensitivity in epileptic patients.

The acute effect of oral administration of a single dose of vigabatrin, a new antiepileptic drug which acts by irreversible enzyme-activated inhibition of the brain enzyme, GABA-aminotransferase, on the photoconvulsive response in patients with photosensitive epilepsy, was compared with that of the established antiepileptic drug, sodium valproate. Both drugs significantly suppressed the photoconvulsive response in 3 out of 6 subjects. This result was interpreted as further evidence of vigabatrin's potential value in the future treatment of patients with epilepsy.

Adolescent↗

PubMedDate not supplied

Effects of valproate, vigabatrin and aminooxyacetic acid on release of endogenous and exogenous GABA from cultured neurons.

Valproate (VPA) and vigabatrin (gamma-vinyl GABA, GVG) are two novel antiepileptic drugs with a presumed GABAergic mechanism of action. However, for VPA, this aspect has been extensively debated. The aim of the present study was to investigate whether treatment of cultured neurons with clinically relevant concentrations of VPA and GVG might enhance release of endogenous GABA. In order to address the question of the fate of released GABA, studies involving exogenous, radiolabeled GABA were also undertaken. Exposure of neurons to GVG in a concentration range of 10-300 microM led to a significant increase in the cellular GABA content, whereas concentrations of VPA of 30-300 microM had no such effect. Treatment of the neurons with concentrations of GVG as low as 25 microM resulted in a pronounced increase in evoked release of endogenous GABA, compared to controls. Only high concentrations of VPA (300 microM) caused an increase in the synaptic GABA release, which reached statistical significance. Preincubating the neurons with exogenously labeled GABA in the presence of GVG or aminooxyacetic acid, both of which block GABA metabolism, caused a decrease in the specific radioactivity in the cellular GABA pool. This, together with the observation that the specific radioactivity of the releasable GABA pool always exceeded that of the cellular pool, indicates that exogenously supplied GABA preferentially labels the transmitter pool of GABA.

Acetates↗

PubMedDate not supplied

Sister chromatid exchanges in adult epilepsy patients on valproate monotherapy.

Sister chromatid exchanges (SCE) were studied in peripheral lymphocyte cultures of 13 adult male patients with epilepsy treated chronically with valproate (VPA) and in their matched controls. No statistically significant differences in SCE level were found between the patient and control groups, indicating a lack of mutagenic potential of VPA within the therapeutic dose range.

Adult↗