Dose Of Valproate Research Articles

Differential Gene Expression in Rats Following Subacute Exposure to the Anticonvulsant Sodium Valproate

Sodium valproate (VPA) is clinically employed as an anticonvulsant and, to a lesser extent, as a mood stabilizer. While the incidence of toxicity associated with the clinical use of valproate is low, serious hepatotoxicity makes up a significant percentage of these rare adverse effects, with fatalities occurring mainly in children receiving polypharmacy. Previous studies have highlighted the different pharmacological effects of acute valproate exposure, a combination of which are likely to underpin its observed broad-spectrum anticonvulsant efficacy. However, limited studies have been undertaken to investigate the subacute effects of this compound and how genomic effects may underlie the observed hepatotoxic effects. Investigation into the mild hepatoxicity observed in rats exposed to high doses of VPA may provide important information on the human situation. Male Sprague–Dawley rats were dosed with 500 mg/kg/day sodium valproate: after necropsy, mRNA was subjected to suppression PCR subtractive hybridization, identifying 8 up-regulated and 14 down-regulated mRNA species. The down-regulation of several mRNA species coding for enzymes involved in cellular energetics (e.g., succinate dehydrogenase, aldolase B) was of particular interest, as mitochondrial dysfunction is a key feature of valproate hepatotoxicity. In vitro studies were then undertaken to examine the dose and time dependence of these changes and also their effect on the overall energy levels within the cell. We demonstrate that, both in vivo and in vitro, valproate exposure in rats results in a significant decrease in pathways involved in cellular energy homeostasis. These changes may provide insight into the rare human hepatoxicity associated with this compound.

Acute Valproate Administration Impairs Methionine Metabolism in Rats

Valproate (VPA) is a drug widely used to treat epilepsy, but it has serious adverse effects including hepatotoxicity, teratogenicity and antifolate activity. The mechanism underlying VPA toxicity is unclear although an interaction with folate and other metabolites involved in methionine metabolism has been suggested. The present study was undertaken to evaluate potential changes in the metabolic function of the methionine cycle after acute exposure to a single dose of valproate. Female Wistar rats (n = 30) were treated with 400 mg/kg of VPA. Different groups of six rats were killed at 1 (t1), 3 (t3), 6 (t6), 9 (t9), and 24 (t24) hours after the injection. One group of rats was untreated (n = 6) and was considered the control group. The most pronounced effects of VPA administration were observed 1 h after drug injection. VPA induced a 56% reduction in methionine adenosyltransferase activity and a 54% reduction in plasma vitamin B-6. Increases in the hepatic concentration of S-adenosylhomocysteine and oxidized glutathione, and a reduction in the S-adenosylmethionine/S-adenosylhomocysteine transmethylation ratio also occurred at 1 h. All of these alterations, however, were normalized within 24 h, parallel with a decrease in serum VPA concentration. The acute effects of VPA suggest that the alterations in the methionine cycle could be the common mechanism underlying the hepatotoxic, teratogenic and antifolate effects of the drug.

Near reflex accommodation spasm: unusual presentation of generalized photosensitive epilepsy

We report on a 9 year old girl admitted with prolonged and recurrent episodes of near reflex accommodation spasm (NRAS), which was the sole clinical manifestation of primary generalized photosensitive epilepsy. Four days prior to admission, the patient started to experience intermittent episodes of adduction of both eyes and miosis, namely near reflex accommodation spasm, which apparently became fixed three hours prior to admission, with no other perturbations. On examination she was fully alert showing a fixed NRAS, but otherwise unremarkable neurological examination. Time locked with NRAS, the EEG demonstrated generalized spike/wave discharges, also induced with photic stimuli, compatible with generalized photosensitive epilepsy. Assuming an epileptic etiology for the diagnosed NRAS, she was started on a small dose of valproate and became asymptomatic within the first day of treatment, along with EEG normalization. She remained asymptomatic within seven months when the valproic acid was erroneously discontinued. After a few days she began experiencing short lived episodes of NRAS, which could also be induced by photic stimulation and a concurrent EEG again demonstrated generalized epileptiform discharges.Searching the literature, this is the first report associating generalized photosensitive epilepsy with NRAS, and hence complete resolution of NRAS in response to antiepileptic therapy along with normalization of the EEG. An epileptic disorder should be therefore taken into account in any patient with new onset NRAS, especially when other epileptic phenomena are absent.

Erratum: Correlation of Valproate Plasma Concentrations and Dose in Bipolar Affective Disorder

Erratum: Correlation of Valproate Plasma Concentrations and Dose in Bipolar Affective Disorder

Molsidomine enhances the protective activity of valproate against pentylenetetrazole-induced seizures in mice.

Molsidomine (25 mg kg(-1)), a donor of nitric oxide, commonly used in the treatment of coronary artery disease, enhanced the protective activity of valproate against the clonic phase of pentylenetetrazole-induced seizures in mice, significantly reducing the ED(50) of valproate from 123.5 to 78 mg kg(-1). Molsidomine was found to be ineffective with respect to the protective action of clonazepam, ethosuximide and phenobarbital. Alone, molsidomine in a dose of 25 mg kg(-1) was ineffective in this model of seizures. Since N(G)-nitro-L-arginine, an inhibitor of nitric oxide synthase, failed to reverse the effect of molsidomine on valproate, an involvement of nitric oxide in the mechanism of the anticonvulsive efficacy of valproate does not seem to be probable. Molsidomine (25 mg kg(-1)) significantly elevated the free plasma level of valproate from 33.8 to 46.2 microg ml(-1). Therefore, we conclude that the interaction of molsidomine with valproate is at the pharmacokinetic level. The combination of valproate with molsidomine appears beneficial because is free from adverse effects, in terms of motor impairment and long-term memory deficit. Our results suggest that the dosage of valproate in patients with coronary artery disease treated with molsidomine should be decreased. It would allow us to reduce adverse effects of valproate.

Methsuximide reduces valproic acid serum levels.

The authors investigated whether methsuximide affects serum levels of valproic acid. Pre-morning-dose serum valproic acid levels were measured in 17 patients (12 male, 5 female; age range, 8-19; mean, 14.5 years) who either started or stopped taking methsuximide but whose dose of valproate and other medication remained unchanged. Four of these patients both started and stopped taking methsuximide. For the whole group the mean valproic acid level (+/- standard error) while not taking methsuximide was 81.9 +/- 5.3 mg/L and while taking methsuximide was 55.7 +/- 4.3 mg/L. The difference between the means was highly significant (paired t test, p < 0.001). The mean valproic acid serum level before taking methsuximide was 85.4 +/- 4.5 mg/L (14 patients), which decreased to 58.2 +/- 4.8 mg/L while taking methsuximide (difference highly significant, p < 0.001). In the eight patients who stopped taking methsuximide the mean serum level increased from 49.8 +/- 7.5 mg/L to 71.7 +/- 8.5 mg/L (difference significant p = 0.025). Because methsuximide reduces valproic acid serum levels, it may be necessary to increase the valproate dose when methsuximide is added or reduce the valproate dose when methsuximide therapy stops, to avoid loss of seizure control or valproate toxicity respectively.

Evolution of juvenile myoclonic epilepsy treated from the outset with sodium valproate

Sodium valproate (VPA) is considered the first choice drug in juvenile myoclonic epilepsy (JME). We have analysed the long-term evolution of 22 patients treated from the outset with VPA. The following inclusion criteria were applied: (1) unequivocal diagnosis of JME; (2) treatment should be initiated with VPA monotherapy; and (3) follow-up for more than 5 years. Twenty-two patients (15 females, seven males) were studied and their EEG recordings were analysed. Their mean age was 28 years (range: 20–40 years) and their mean follow-up was 7.7 years (range: 5–17 years). Four of them suffered persistent seizures despite optimal VPA dosage and needed the addition of a second drug (lamotrigine in three cases, clobazam in one case). All of our patients who continued their treatment are seizure-free. VPA effectively controlled all seizures in 80% of patients. The discontinuation of drug therapy lead to a very high rate of relapses. With accurate diagnosis and appropiate therapy, seizures in JME can be effectively controlled. VPA is a very effective antiepileptic drug in controlling the seizures of JME, but many patients relapse after VPA discontinuation. Thus, JME may require lifelong therapy.

Methylphenidate sensitization is modulated by valproate

Repeated administration of the stimulant methylphenidate (MPD) produces sensitization to its own effects. Glutamate, dopamine, and GABA have been implicated in the underlying mechanism of sensitization to stimulants such as amphetamine and cocaine. We have investigated effects of the GABAergic agent sodium valproate (VAL) on the locomotor response to MPD. Activities of male Sprague-Dawley rats were continuously recorded by a computerized activity monitoring system for 15 days. We studied the dose effect of valproate 1) at 50, 100, and 200 mg/kg (i.p.) on motor activities, 2) on the acute response of motor activities to 2.5 mg/kg MPD, and 3) on behavioral sensitization to subsequent repeated injections of MPD. Valproate alone did not significantly affect motor activities. All three doses of valproate attenuated the acute locomotor effects of MPD, while only the 50mg/kg dose blocked the development of sensitization to subsequent administration. Possible mechanisms involving substrates for the effect of GABA agonists on sensitization are discussed.

Distribution of valproate to subdural cerebrospinal fluid, subcutaneous extracellular fluid, and plasma in humans: a microdialysis study.

We sought to study the time course of the distribution of valproate (VPA) to subdural cerebrospinal fluid (CSF) in relation to subcutaneous extracellular fluid (ECF) and plasma after a single oral dose and to study the distribution to these three compartments under steady-state conditions. Microdialysis was used to estimate unbound VPA concentrations in subdural CSF and subcutaneous ECF, and blood samples were drawn for estimation of total and unbound VPA plasma concentrations in four patients with drug-resistant partial epilepsy undergoing presurgical evaluation with subdural EEG monitoring. Three patients were given a single oral dose of VPA, and one patient was receiving regular VPA treatment. VPA was analyzed by gas chromatography with flame ionization detection. The distribution of VPA to subdural CSF was rapid (Tmax, 3.5 h in two patients and 5.5 h in one patient) and subject to a minor delay in all three patients compared with that in the subcutaneous tissue ECF (Tmax, 2.5 h in all three patients), which in turn exhibited no evidence of a distribution delay compared with plasma. Subdural CSF levels of VPA were slightly lower than subcutaneous ECF levels (mean ratio, 0.78) and unbound plasma levels (mean ratio, 0.91). VPA rapidly enters the subdural CSF in unbound concentrations marginally lower than those obtained in subcutaneous ECF and plasma. These findings provide a pharmacokinetic rationale for acute administration of VPA. The good correlation between VPA concentrations in subcutaneous ECF and subdural CSF indicates that estimation of unbound VPA concentrations in subcutaneous tissue using microdialysis sampling has the potential to be useful for monitoring purposes.

Distribution of Valproate to Subdural Cerebrospinal Fluid, Subcutaneous Extracellular Fluid, and Plasma in Humans: A Microdialysis Study

SummaryWe sought to study the time course of the distribution of valproate (VPA) to subdural cerebrospinal fluid (CSF) in relation to subcutaneous extracellular fluid (ECF) and plasma after a single oral dose and to study the distribution to these three compartments under steady‐state conditions. Microdialysis was used to estimate unbound VPA concentrations in subdural CSF and subcutaneous ECF, and blood samples were drawn for estimation of total and unbound VPA plasma concentrations in four patients with drug‐resistant partial epilepsy undergoing presurgical evaluation with subdural EEG monitoring. Three patients were given a single oral dose of VPA, and one patient was receiving regular VPA treatment. VPA was analyzed by gas chromatography with flame ionization detection. The distribution of VPA to subdural CSF was rapid (Tmax, 3.5 h in two patients and 5.5 h in one patient) and subject to a minor delay in all three patients compared with that in the subcutaneous tissue ECF (Tmax, 2.5 h in all three patients), which in turn exhibited no evidence of a distribution delay compared with plasma. Subdural CSF levels of VPA were slightly lower than subcutaneous ECF levels (mean ratio, 0.78) and unbound plasma levels (mean ratio, 0.91). VPA rapidly enters the subdural CSF in unbound concentrations marginally lower than those obtained in subcutaneous ECF and plasma. These findings provide a pharmacokinetic rationale for acute administration of VPA. The good correlation between VPA concentrations in subcutaneous ECF and subdural CSF indicates that estimation of unbound VPA concentrations in subcutaneous tissue using microdialysis sampling has the potential to be useful for monitoring purposes.

Valproate prevents the induction of sensitization to methylphenidate (ritalin) in rats

Repetitive exposure to methylphenidate (MPD) elicits sensitization to its locomotor effects. Drugs that affect the GABA system may modify adaptations to drug exposure. Therefore, we have examined the effect of sodium valproate, which enhances GABA function, on the development of sensitization to MPD using an automated, computerized animal activity monitoring system to record each rat’s motor activities for 15 consecutive days. Rats were recorded before and after saline injection (Days 1–2) to provide baseline activity. Animals were then randomly assigned to the following three groups that received: (1) 2.5 mg/kg MPD (s.c.) for six consecutive days (Days 3–8), (2) a single dose of valproate (50 mg/kg; i.p.) 1 h prior to the first (Day 3) of six daily doses of MPD (2.5 mg/kg; s.c.), or (3) five daily doses of valproate (50 mg/kg, i.p.) 1 h prior to MPD (2.5 mg/kg, s.c.) on Days 4–8. There was no drug treatment during the next 5 days (Days 9–13). All rats were then re-challenged with MPD (2.5 mg/kg, s.c.) on Day 14. Group 2 rats were also re-challenged with 50 mg/kg valproate followed by 2.5 mg/kg MPD 1 h later on Day 15. Administration of MPD alone produced a sensitized response. Multiple valproate injections prevented the induction of MPD-elicited sensitization in all four motor indices, while a single valproate injection prevented the induction of MPD-elicited sensitization in two of four motor indices studied. In conclusion, a single injection 50 mg/kg valproate given prior to any MPD treatment partially blocked the induction of MPD sensitization while repeated injections of valproate co-administered with MPD treatment completely prevented this effect.

Effects of Retigabine (D‐23129) on Different Patterns of Epileptiform Activity Induced by Low Magnesium in Rat Entorhinal Cortex Hippocampal Slices

The objective of this study was to evaluate the effect of a new antiseizure drug, retigabine (D-23129; N-(2-amino-4-[fluorobenzylamino]-phenyl) carbamic acid ethyl ester) on low-Mg2+-induced epileptiform discharges in rat in vitro. Three types of epileptiform discharges (recurrent short discharges in the hippocampus, seizure-like events, and late recurrent discharges in the entorhinal cortex) were elicited in rat combined entorhinal cortex-hippocampal slices by perfusion with low-Mg2+-artificial cerebrospinal fluid (ACSF). The antiepileptic properties of retigabine were evaluated as effect on the frequency and amplitude of the epileptiform activities as well as time of onset of the effect in the entorhinal cortex (EC) and in hippocampal area CA1 (CA1) by using extracellular recording techniques. Retigabine (20 microM) reversibly suppressed the recurrent short discharges otherwise sensitive only to high doses of valproate (VPA) but insensitive to standard antiepileptic drugs (AEDs) in CA1, whereas 10 microM reduced the frequency of discharges by 34+/-18.8%, with no significant effect on the amplitude. In EC, retigabine (50 microM) reversibly suppressed the seizure-like events, whereas 20 microM blocked seizure-like events in 71.5% of the slices. The seizure-like events were also sensitive to standard AEDs. Late recurrent discharges in EC that are not blocked by standard AEDs were reversibly suppressed by retigabine (100 microM), whereas 50 microM reduced the frequency of the discharges by 94.4+/-7.7%, and 20 microM, by 74.2+/-18.0%, with no significant effect on the amplitude. Retigabine is an effective AED with suppressive effects on recurrent short discharges and on late recurrent discharges normally insensitive to standard AEDs.

Valproate-induced alterations in testosterone, estradiol and progesterone secretion from porcine follicular cells isolated from small- and medium-sized ovarian follicles

The aim of the present study was to investigate whether long-term exposure to valproate (VPA) alters follicular steroidogenesis and whether or not this effect is dependent on the degree of follicular development. Small- and medium-sized follicles were obtained from pig ovaries collected, respectively, at days 8–10 and 14–16 of oestrus cycle. Theca interna and granulosa cells were isolated from follicles and placed in the same well in the ratio 1 : 3 with or without the VPA in doses of 100, 300 and 500 μ g ml−1. The culture medium was changed after 2, 4, 6 and 8 days. In both types of follicles, VPA caused a significant and dose-dependent reduction in both testosterone and estradiol secretion from follicular cells. In small-sized follicles, the testosterone to oestrogen ratio increased at all doses used and after all lengths of time in culture. In medium-sized follicles, a significant increase in the testosterone to oestrogen ratio was only observed at the highest dose level. All doses of VPA caused a marked inhibition of progesterone secretion after 48 hours while during long-term VPA exposure progesterone gradually increased demonstrating luteinization of cells. In conclusion, the present study demonstrates a direct effect of VPA on steroidogenesis. The effect seems to differ to some extent depending on the follicular stage of development. The elevated ratio of testosterone to estradiol suggests that VPA inhibits the conversion of testosterone to estradiol.

Intravenous valproate is well tolerated in unstable patients with status epilepticus.

The authors reviewed hospital records of 13 patients with status epilepticus and hypotension who received IV valproate therapy. Most patients were elderly (74.4 +/- 12.5 [SD] years) and received a loading dose of valproate of 25.1 +/- 5.0 mg/kg (range 14.7 to 32.7), at a rate of 36.6 +/- 25.1 mg/min (range 6.3 to 100). There were no significant changes in blood pressure, pulse, or use of vasopressors. The data suggest that valproate loading is well tolerated, even in patients with cardiovascular instability.

Neonatal hypoglycaemia and withdrawal symptoms after exposure in utero to valproate

AIMSTo define, in a prospective study, the risk of hypoglycaemia—defined as blood glucose concentration < 1.8 mmol/l—in term infants exposed in utero to valproate and to describe the withdrawal symptoms.METHODSTwenty...

Apparent autoinduction of valproate beta-oxidation in humans.

The study aimed to show whether autoinduction of valproate (VPA) along its beta-oxidation pathway occurred upon chronic dosing in humans. Twelve young volunteers without active illness took sodium valproate (NaVPA) 200 mg orally 12 hourly for 3 weeks. On days 7 and 21, serial blood samples and all urine passed over an interdosing interval from 08.00 to 20.00 h were collected for analysis of VPA and certain metabolites. Plasma AUC(0,12 h) of VPA was significantly lower on day 21 than on day 7 (2.40 vs 2.84 micromol ml-1 h, 95% CI for the difference 0.13-0.81 micromol ml-1 h). Significant differences in plasma AUC(0,12 h) of the beta-oxidation metabolites E-2-en-VPA and 3-oxo-VPA were not found. However, formation clearances of plasma VPA to urinary E-2-en-VPA and 3-oxo-VPA were significantly increased from day 7 to day 21 (0. 010 vs 0.024 and 2.57 vs 3.60 ml kg-1 h-1, respectively, 95% CI for the differences -0.025 to -0.004 and -1.72 to -0.34 ml kg-1 h-1, respectively). Formation clearances to VPA-glucuronide (0.534 vs 0. 505 ml kg-1 h-1) and 4-OH-VPA (0.112 vs 0.110 ml kg-1 h-1) were not significantly different. Regular low dose VPA intake in humans over a period of 3 weeks appears to be associated with a small induction of its metabolism by the beta-oxidation pathway, but not by glucuronidation or 4-hydroxylation.

Second-generation antipsychotics in the emergency care setting. A prospective naturalistic study

The objective of this subject was to examine the impact of the replacement of standard neuroleptics with atypical antipsychotic agents in an intensive psychiatric care unit. A mirror-image study was conducted. Cases admitted in the first semester of the year (when most of patients were treated with standard neuroleptics) were compared to cases admitted in the second semester of the year, when atypical antipsychotic agents were routinely utilized as first line treatment of patients with psychotic signs. Cases admitted in the first semester received a significantly higher daily dosage of antipsychotic drugs and more frequently received anticholinergics. In the second semester, a significantly higher number of patients received anticonvulsants, in particular valproate and gabapentin. There was no significant difference between the two groups of cases in the number of patients treated with antipsychotics, benzodiazepines, lithium, and carbamazepine and in the mean daily dose of benzodiazepines, lithium, carbamazepine, or valproate on the first day of hospitalization, the day of evaluation, and on discharge. On discharge, similar percentages of patients went home, were transferred to other Psychiatric Intensive Care Units (PICUs) or to private clinics, or left our PICU against medical advice. The length of hospitalization was similar in the two groups. There was no significant difference in the rate of aggressive or violent behavior registered in the two groups of cases. The risk of increasing violence rates, lengthening hospitalization, and facilitating patients’ non-compliance should not be major concerns for physicians prescribing second-generation antipsychotics in the emergency care setting. Since these drugs have been shown to have at least similar efficacy (or greater efficacy in the case of clozapine) in the treatment of psychotic disorders as typical neuroleptics and to have a better side-effects profile, they should become first line treatment for patients with psychotic signs admitted to emergency care psychiatric facilities.

Síndrome de Lyell asociado a lamotrigina

Lamotrigine (LTG) is a new antiepileptic of habitual use in monotherapy as much in partial epileptic as in generalised, which presents among other adverse effects: slight rashes and less frequently severe rashes such as Stevens-Johnson syndrome and Lyell syndrome or toxic epidermal necrolysis, above all in combination with valproate (VPA). A 44-yr-old woman in toxico-alcoholic epileptic treatment with VPA, showed a neutropenia possibly of secondary type which it was intended to change to LTG, following an ascending dose of LTG joined to a descending dose of VPA. In the sixth treatment week, the patient developed an erythematous rash which after a week of solar exposure, presented temperature, general discomfort, and in the head, on the front and back part of the thoracic and upper and lower limbs, erythematous lesions with scabbed areas, loosening epidermis areas with a positive Nikolsky sign and severe mucous membrane involvement, being diagnostic of Lyell syndrome. The lesions got slowly better with serum therapy, antibiotherapy, parenteral corticoids and topical treatments. There is a probability of severe rash associated with lamotrigine which has to be taken into account, and we advise patients to suppress the medication when they present a minimum rash.

Antiepileptic drug regimens and major congenital abnormalities in the offspring

To assess the risk of major congenital abnormalities associated with specific antiepileptic drug regimens, a large retrospective cohort study was performed. The study comprised 1,411 children born between 1972 and 1992 in four provinces in the Netherlands who were born to mothers with epilepsy and using antiepileptic drugs during the first trimester of pregnancy, and 2,000 nonepileptic matched controls. We found significantly increased risks of major congenital abnormalities for carbamazepine and valproate monotherapy, with evidence for a significant dose–response relationship for valproate. The risk of major congenital abnormalities was nonsignificantly increased for phenobarbital monotherapy when caffeine comedication was excluded, but a significant increase in risk was found when caffeine was included. Phenytoin monotherapy was not associated with an increased risk of major congenital abnormalities. Regarding polytherapy regimens, increased risks were found for several antiepileptic drug combinations. Clonazepam, in combination with other antiepileptic drugs, showed a significantly increased relative risk. Furthermore, there were significantly increased relative risks for the combination of carbamazepine and valproate and the combination of phenobarbital and caffeine with other antiepileptic drugs. This study shows that most antiepileptic drug regimens were associated with an increased risk of major congenital abnormalities in the offspring, in particular valproate (dose–response relationship) and carbamazepine monotherapy, benzodiazepines in polytherapy, and caffeine comedication in combinations with phenobarbital.

CHARACTERISTICS AND PHARMACOKINETICS OF VALPROATE USE IN THE NURSING HOME

Valproate use in older adults is increasing, both due to high prevalence of active seizure disorder in the geriatric population and the increasing use of valproate for behavioral disorders. No information is available regarding the basic characteristics of valproate use in nursing homes. The authors found 29 out of 540 (5.4%) residents at a community nursing home received valproate. Nineteen (3.5%) had a behavioral indication or comorbidity, mostly behavioral and psychological symptoms of dementia. Ten (1.9%) had seizure disorder only. There was a significant difference between the valproate serum concentrations achieved for treatment of behavior disorders versus seizures disorders. No difference was found in gender characteristics of valproate use except for weight and valproate volume. Age grouping created significant differences in several characteristics. A dose-serum concentration correlation of 0.85 was found in a group of subjects taking no drugs that interact with valproate, while this correlation was lost in a group with drug interactions present. No significant change in valproate serum concentrations was found from one measurement to another over a period of approximately 3 months in a group of residents on stable valproate dose. These findings lend further support that valproate is safe and well tolerated in the nursing home population, where it is seeing increasing use. These findings also give indications regarding dosing of valproate and regular follow-up of serum concentrations. P80