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PubMed2004

Sodium valproate in aggressive behaviour in dementia: a twelve-week open label follow-up study.

INTRODUCTION: Short-term randomised clinical trials on valproate in distinct types of disturbed behaviour in dementia showed no effects on aggressive behaviour. OBJECTIVES: To assess the course of disturbed behaviour during medium term treatment with sodium valproate for aggressive behaviour. DESIGN: An open label observational 12-week follow-up study consecutive to a preceding randomised control trial; assessments at 4-week interval. SETTING: A psychogeriatric medium-stay ward at a psychiatric teaching hospital and psychogeriatric nursing home wards. PARTICIPANTS: Patients who completed a preceding randomised placebo controlled clinical trial on sodium valproate in aggressive behaviour in dementia were included. INTERVENTION: The starting dose of sodium valproate was 2 x 6 ml of a 40 mg/ml suspension (daily defined dose of 480 mg). The patient's regular physicians managed all treatment decisions, including decisions on dosage and plasma level measurements of sodium valproate and decisions regarding discontinuation. Co-medication was allowed and any change in prescription was recorded. MEASUREMENTS: The Social Dysfunction and Aggression Scale-9 (SDAS-9), the Behaviour Observation scales for Intramural Psychogeriatrics (in Dutch: Gedragsobservatieschaal voor Intramurale Psychogeriatrie (GIP) and the Clinical Global Impression of aggressive behaviour (CGI) were performed at the last week of each 4-week interval. RESULTS: Data of 39 patients (F=24 and M=15) were analysed. At week 12 compared to week 0 mean sodium valproate prescriptions were higher; aggressive behaviour as measured by the SDAS-9 improved. Non-social behaviour, apathetic behaviour, disoriented behaviour and distorted memory improved, but rebellious behaviour increased as measured by the GIP. Seven patients died during this study. LIMITATIONS OF THE STUDY: Open label observational design; absence of placebo/reference prescription; no systematic measurements of sodium valproate plasma levels and the allowance of psychotropic co-medication. CONCLUSION: Low dose sodium valproate may be effective reducing a broad range of types of disturbed behaviours in aggressive demented patients. The high death rate underlines the fragility of demented patients with aggressive behaviour.

Aged↗

PubMed1988

Suppression of preoptic GABA release caused by push-pull-perfusion with sodium valproate.

The in vivo-effects of various concentrations of the anticonvulsant drug sodium valproate--within and above the therapeutic range for humans (40-100 micrograms/ml)--on the release of gamma-aminobutyric acid (GABA) were studied perfusing the preoptic area of unanaesthetized, freely moving ovarectomized rats through push-pull-cannulae at a flow rate of 20 microliters/min with a fraction period of 5 and 15 min, respectively. Local treatment with 40, 80, 100, and 200 micrograms valproate/ml perfusion medium induced a highly significant decrease in preoptic GABA release. After return to valproate-free medium this effect was reversible. A rapid onset and termination of the valproate effect within 5 min could be observed. Going higher with valproate concentrations the suppressive effect became less and at supratherapeutic valproate levels of 1600 micrograms/ml CSF an increase in GABA release could be observed in 4 out of 8 animals. This does response relationship points to a biphasic effect of valproate on the available amount of GABA in the synaptic cleft, which may be produced by at least two different dose-dependent mechanisms of action. The present results indicate that the action of therapeutic concentrations of valproate involves an alteration of GABAergic transmission different from increasing synaptic GABA release. Nevertheless, the data suggest that valproate action, at least at the level of the preoptic area, involves an enhancement of GABAergic transmission causing--via a negative feedback mechanism--the observed suppression of GABA release into the synaptic cleft.

Animals↗

PubMed1996

Effects of valproate on amino acid and monoamine concentrations in striatum of audiogenic seizure-prone Balb/c mice.

The effects of valproate on CNS concentrations of gamma-aminobutyric acid (GABA), glulamate (GLU), glutamine (GLN); dopamine (DA), serotonin (5-HT), and metabolites were examined in tissue extracts of caudate nucleus of genetic substrains of Balb/c mice susceptible (EP) or resistant (ER) to audiogenic seizures. Generalized tonic-clonic seizures observed in EP mice were inhibited by valproate, administered 1 h prior to testing, in a dose-response fashion. Concentrations of GABA, GLU, and GLN, which were lower in EP mice than in ER mice, were significantly increased by valproate at doses of 180 and 360 mg/kg. Concentrations of homovanillic acid (HVA) and hydroxyindoleacetic acid (5-HIAA), metabolites of DA and 5-HT, were substantially increased by valproate at these doses. The in situ activity of tyrosine hydroxylase (TH) was not significantly influenced by valproate, whereas a valproate-induced increase in tryptophan hydroxylase (TPH) activity was observed in both striatum and in midbrain tegmentum. The data are consistent with the interpretation that anti-convulsive doses of valproate influences the intraneuronal metabolism of monoamines, GABA, and glutamate concurrently. Valproate's influence on the metabolism of both major inhibitory (GABA) and excitatory (GLY amino acids in striatum could contribute to its anti-convulsive effects in genetically seizure prone mice, as well as to the accumulation of DA and 5-HT metabolites.

Acoustic Stimulation↗

PubMed2003

Volume-selective 1H MR spectroscopy for in vivo detection of valproate in patients with epilepsy.

We performed volume-selective 1H MR spectroscopy (1H-MRS) on 12 patients on valproate monotherapy to detect valproate in vivo in the brain. We also acquired reference valproate spectra in vitro in subphysiological 15 g/l albumin solution in saline, in which valproate showed two resonance peaks at 0.7 and 1.2 ppm and a minimum detection threshold of 240 mg/l. In vivo 1H-MRS spectra in brain showed peaks between 0.6 and 1.6 ppm. Simultaneous serum valproate concentrations did not correlate with these integrated MRS peaks. On follow-up, changes in these signals also did not correlate with increasing serum valproate levels. The inconsistency of in vivo 1H-MRS signals at varying serum levels and the high detection levels in vitro suggest that valproate signals are missed in vivo because valproate is metabolised or strongly bound, presumably to brain macromolecules.

Adult↗

PubMed1989

Stimulation of glutamine metabolism by the antiepileptic drug, sodium valproate, in isolated dog kidney tubules.

The effects of sodium valproate, a widely used antiepileptic drug and an hyperammonemic agent, on glutamine and glutamate metabolism were studied in isolated dog kidney tubules. Valproate markedly stimulated glutamine removal as well as the formation of ammonia, aspartate, pyruvate, lactate, alanine and glucose; the increase in ammonia formation was explained by a stimulation by valproate of flux not only through glutaminase (EC 3.5.1.2) but also through glutamate dehydrogenase (EC 1.4.1.3). By contrast, valproate did not stimulate glutamate removal or ammonia, aspartate and glucose formation from glutamate; this suggests that the increase in flux through glutamate dehydrogenase with glutamine as substrate was secondary to the increase in flux through glutaminase. Accumulation of pyruvate, alanine and lactate in the presence of valproate was much less from glutamate than from glutamine. Inhibition by amino-oxyacetate of accumulation of aspartate and alanine from glutamine caused by valproate did not prevent the acceleration of glutamine utilization and the subsequent stimulation of ammonia formation. These data are consistent with a stimulatory effect of valproate primarily exerted at the level of glutaminase in dog kidney tubules. However, the fact that assayed activity of glutaminase remained unchanged in the presence of valproate suggests that this compound accelerates flux through the latter enzyme by an indirect mechanism probably related to the renal metabolism of this compound.

Alanine↗

PubMed2006

Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women with bipolar disorder.

BACKGROUND: Preliminary evidence suggests that valproate is associated with isolated features of polycystic ovarian syndrome (PCOS), while contradictory data support an association between epilepsy and PCOS. The development of PCOS features after initiation of valproate was therefore examined in women with bipolar disorder using a standardized definition of PCOS. METHODS: Three hundred women 18 to 45 years old with bipolar disorder were evaluated for PCOS at 16 Systematic Treatment Enhancement for Bipolar Disorder sites. A comparison was made between the incidence of hyperandrogenism (hirsutism, acne, male-pattern alopecia, elevated androgens) with oligoamenorrhea that developed while taking valproate versus other anticonvulsants (lamotrigine, topiramate, gabapentin, carbamazepine, oxcarbazepine) and lithium. Medication and menstrual cycle histories were obtained, and hyperandrogenism was assessed. RESULTS: Among 230 women who could be evaluated, oligoamenorrhea with hyperandrogenism developed in 9 (10.5%) of 86 women on valproate and in 2 (1.4%) of 144 women on a nonvalproate anticonvulsant or lithium (relative risk 7.5, 95% confidence interval [CI] 1.7-34.1, p = .002). Oligoamenorrhea always began within 12 months of valproate use. CONCLUSIONS: Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism. Monitoring for reproductive-endocrine abnormalities is important when starting and using valproate in reproductive-aged women. Prospective studies are needed to elucidate risk factors for development of PCOS on valproate.

Adolescent↗

PubMed2001

Altered ovarian function and cardiovascular risk factors in valproate-treated women.

PURPOSE: Polycystic ovaries and menstrual disturbances seem to be common among women taking valproate for epilepsy. The purpose of the present study was to assess the frequency of valproate-related metabolic and endocrine disorders in different groups of women with epilepsy. SUBJECTS AND METHODS: Seventy-two women with epilepsy and 52 control subjects from centers in three European countries (Finland, Norway, and the Netherlands) participated in the study. Thirty-seven of the women with epilepsy were taking valproate monotherapy and 35 carbamazepine monotherapy. RESULTS: The frequency of polycystic ovaries or hyperandrogenism, or both, among valproate-treated women with epilepsy was 70% (26 of 37) compared with 19% (10 of 52) among control subjects (P <0.001). They were found in 79% (11 of 14) of obese and 65% (15 of 23) of lean women on valproate, and in 20% (7 of 35) of carbamazepine-treated women. The obese valproate-treated women with polycystic ovaries or hyperandrogenism, or both, had hyperinsulinemia and associated unfavorable changes in serum lipid levels consistent with insulin resistance. CONCLUSIONS: Polycystic ovaries and related hyperandrogenism are frequently encountered in both obese and lean women taking valproate for epilepsy. The use of valproate is associated with risk factors for cardiovascular disease in obese women.

Adult↗

PubMed2000

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.

Animals↗

PubMed2003

Valproate inhibits oxidative damage to lipid and protein in primary cultured rat cerebrocortical cells.

Valproate is often prescribed as a long-term therapeutic mood stabilizing agent for individuals with bipolar disorder. Although research suggests that this drug may produce a neuroprotective effect, its neuroprotective mechanism is not yet clear. The purpose of this study was to determine if valproate provides a neuroprotective effect against damage caused by oxidative stress in primary cultured rat cerebral cortical cells. We found that chronic treatment with valproate at therapeutically relevant concentrations for 7 days inhibited lipid peroxidation and protein oxidation induced by treatment with 0.25 mM oxidant FeCl(3) for 90 min, indicating that valproate inhibits oxidative damage to lipid and protein. Our results suggest that chronic treatment with valproate may protect neuronal cells from damage caused by oxidative stress and that neuroprotection from oxidative damages may be involved in the mechanism of action of valproate. Supporting this possibility are recent findings that chronic treatment with valproate increased the expression of endoplasmic reticulum stress protein GRP78 and antiapoptotic factor bcl-2 in rat cerebral cortex. Since GRP78 binds Ca(2+) and folds damaged protein, bcl-2 stabilizes mitochondrial transmembrane potential and inhibits cytochrome C release, and both GRP78 and bcl-2 have been shown to inhibit oxyradical accumulation, together these findings indicate that valproate may target one or more of these processes in order to produce neuroprotective effects.

Animals↗

PubMedDate not supplied

Valproate irreversibly alters steroid secretion patterns from porcine follicular cells in vitro.

The aim of the present study was to investigate whether exposure of porcine ovarian follicular cells to clinically relevant concentrations of valproate affected steroid production in vitro and to which extent these effects were reversed by removal of the drug from the culture medium. Small and medium follicles were obtained from ovaries collected, respectively, at days 8-10 and 14-16 of the estrous cycle. Theca and granulosa cells were collected from follicles and co-cultured in one well. To show whether the effect of valproate was reversible, cells were cultured for 24, 48, or 72 h with valproate 100 or 250 microg/ml. The medium was then changed to fresh medium without drugs for an additional 24, 48, or 72 h. Valproate added to the culture medium caused a significant reduction of estradiol secretion with concomitant increase in both testosterone and progesterone secretion by small follicles. In medium-sized follicles, 100 microg/ml valproate was without effect on estradiol secretion while 250 microg/ml caused a small, but statistically significant decrease. The effects of valproate on steroid secretion patterns were irreversibly independent of concentration, exposure time, and time of restoration after drug exposure up to 72 h in both small and medium follicles. In conclusion, the present study demonstrated that even short-term valproate treatment disrupted follicular steroidogenesis in isolated ovarian follicular cells resulting in increased testosterone and progesterone and decreased estradiol secretion. It was not possible to reverse the steroidogenic effects of valproate by removing the drug from the cell cultures.

Animals↗

PubMed1999

Safety of rapid intravenous infusion of valproate loading doses in epilepsy patients.

IV valproate may be given to patients requiring rapid elevation of serum valproate or for patients unable to take oral medication. Previously we established the loading dose of IV valproate needed to achieve serum concentrations of > 100 ug/ml. This study evaluated the safety of rapid infusion of valproate to achieve high therapeutic levels. Twenty-four infusions of IV valproate were carried out electively in twenty-one patients with epilepsy (ages 2-54 years). The dose ranged from 21-28 mg/kg (mean 24.2 mg/kg). Target infusion rates were 3 or 6 mg/kg per min, yielding an infusion duration of 4.17 or 8.34 min. ECG was monitored; blood pressure was measured before and after infusion. Post infusion serum valproate concentrations were 64-204.1 ug/ml (mean 132.6). There were no significant changes in blood pressure and no ECG abnormalities observed. Transient pain occurred at the site of injection in five patients, associated with redness in two. This appeared to related to the concentration of valproic acid in the infusion fluid. We conclude that a loading dose of IV valproate can be administered safely and rapidly. This finding enables further studies evaluating IV valproate as a non-sedative anticonvulsant in the management of status epilepticus.

Adolescent↗

PubMed2003

Valproate, bipolar disorder and polycystic ovarian syndrome.

BACKGROUND: Persons with bipolar disorder are often overweight and cluster risk factors for cardiovascular disease. Some antibipolar agents adversely impact upon weight and the lipid milieu. Recent data suggest that valproic acid, a commonly prescribed mood stabilizer, may be associated with polycystic ovarian syndrome (PCOS). This adverse event has not been systematically studied in bipolar disorder. METHOD: Thirty-eight female subjects, aged 18-50 years, meeting DSM-IV criteria for bipolar I or II disorder, in any phase of illness were evaluated. Eighteen females received valproate (sodium valproate and valproic acid) and 20 females received lithium. Patients completed questions regarding their menstrual, reproductive and medical histories. During the follicular phase they were assessed for weight, body mass index (BMI kg/m2), and changes in the reproductive endocrine milieu that included morning estradiol, progesterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex-hormone binding globulin (SHBG), androstenedione, dehydroepiandrosterone-sulfate (DHEAS), testosterone, free testosterone, prolactin and thyroid-stimulating hormone (TSH). The blood was also analyzed for fasting metabolic parameters which included total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), insulin, glycosylated hemoglobin (HbA1C), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding-protein 1 (IGFBP-1), fasting blood glucose and morning leptin. RESULTS: Nine (50%) of the valproate-treated females had menstrual abnormalities versus three (15%) of the lithium-treated females (p < 0.05). Valproate-treated females had significantly higher levels of follicular phase androgen concentrations than lithium-treated females (p < 0.05). Nine (50%) of females who were overweight (BMI > or = 25 kg/m2) and with a history of menstrual irregularities also exhibited laboratory evidence of hyperandrogenism (p < 0.05). Persons receiving valproate exhibited significant increases in fasting biochemical parameters suggestive of an adverse metabolic syndrome (p < 0.05). Leptin levels were significantly elevated in the valproate-treated females (p < 0.05). CONCLUSIONS: In this pilot, open-label cross-sectional study, valproate-treated females exhibited higher rates of menstrual abnormalities and biochemical evidence of both hyperandrogenism and adverse metabolic parameters when compared with lithium-treated females. These preliminary data suggest that valproate may, in some predisposed females, adversely impact upon the reproductive endocrine milieu and result in aspects of the metabolic syndrome.

Adolescent↗

PubMed2001

Morphological changes in the testis after long-term valproate treatment in male Wistar rats.

Uncertainty exists about the effect of antiepileptic drugs on gonadal function. In females, long-term valproate treatment has been shown to induce endocrine disturbances and an increased number of ovarian cysts. The aim of the present study was to investigate whether valproate can also induce morphological changes in the testis of male animals. In addition, possible morphological changes in the liver, heart, lungs, lymphatic nodes, pancreas, kidney or brain were studied. The carcinogenic implications were evaluated by the measurement of p53. Male Wistar rats were fed perorally with valproate mixture 200 mg kg(-1)(n= 15) or 400 mg kg(-1)(n= 20), or control solution (n= 15) twice daily for 90 days. Serum concentrations measured 4-6 hours after the last dose were 105 and 404 micromol l(-1)in low- and high-dose valproate treated animals respectively. There was a highly significant, 51% decrease (P< 0.001) in testicular weight in the high-dose treated valproate rats with no changes in the other groups. There was widespread testicular atrophy with histologically verified spermatogenic arrest in 15/20 of the high-dose valproate treated animals. No changes in the testis were seen in the low-dose valproate treated rats, nor in the control rats. There were no morphological changes in the other investigated organs. None of the groups showed over-expression of p53. In conclusion, a dose-dependent effect of chronic valproate treatment was found on testicular morphology in rats. Caution must be taken before these results can be applied to humans.

Animals↗

PubMed2005

[Valproate sustained release in the treatment of epilepsy].

In an observational study under routine clinical setting data after administration of once daily evening dosing of valproate sustained release minitablets were recorded in 359 patients with epilepsy aged between 12 and 86 years. Patients were either newly treated with valproate sustained release minitablets (N = 58) or switched from conventional valproate (N = 124) or from sustained release valproate (N = 138) to the once daily evening dosing. In 39 patients other antiepileptic drugs were replaced. At the end of the 7-week observational period most patients (65.4 %) received a daily dose of 10 to less than 18 mg/kg body weight followed by 17.4 % receiving doses in the therapeutically recommended range of 18 - 24 mg/kg. 8.6 % and 7.4 % of patients received more than 24 mg/kg or less than 10 mg/kg body weight, respectively. As expected, in both groups with valproate pre-treatment the mean morning valproate plasma levels increased by approximately 10 microg/ml after switch to once evening dosing with sustained release minitablets. The mean seizure frequency decreased from 2.1 to 0.5 in the 318 patients with data before the beginning and at the end of the investigation. At the final examination 137 patients (62.3 %) were seizure free, and further 60 patients (27.3 %) experienced a seizure reduction of more than 50 % (responder) of those 220 patients who experienced seizures in the last 7 weeks before the study. The efficacy and tolerability was rated in more than 95 % of the cases by the patient and the investigator as good or very good. The compliance/acceptance of the valproate sustained release minitablets was rated as good or very good in almost all patients. These results confirm the excellent benefit-risk ratio of the valproate sustained release minitablets and underline the importance of a simple compliance-improving dose regimen for effective seizure control.

Adolescent↗

PubMed1993

Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy.

BACKGROUND: Reproductive endocrine disorders are more common among women with epilepsy than among normal women. These disorders have been attributed to epilepsy itself, but could be related to antiepileptic-drug therapy. METHODS: We studied 238 women with epilepsy who were seen regularly at the Outpatient Department of the University Hospital, Oulu, Finland. Their mean age was 33 years (range, 18 to 45), and the mean duration of therapy was 9 years (range, 0 to 31). Twenty-nine (12 percent) were treated with valproate, 120 (50 percent) with carbamazepine, 12 (5 percent) with valproate and carbamazepine, and 62 (26 percent) with other medications; 15 (6 percent) were untreated. Vaginal ultrasonography was performed to determine ovarian size, and serum sex-hormone concentrations were measured in 41 women with epilepsy and menstrual disturbances, 57 women with epilepsy and regular menstrual cycles, and 51 normal women. RESULTS: Menstrual disturbances were present in 13 of the women receiving valproate alone (45 percent), 3 of the women receiving valproate in combination with carbamazepine (25 percent), 23 of the women receiving carbamazepine (19 percent), and 8 of those receiving other medications (13 percent). Forty-three percent of the women receiving valproate had polycystic ovaries, and 17 percent had elevated serum testosterone concentrations without polycystic ovaries; 50 percent of the women receiving valproate and carbamazepine had polycystic ovaries, and 38 percent had elevated serum testosterone concentrations without polycystic ovaries. Eighty percent of the women treated with valproate before the age of 20 years had polycystic ovaries of hyperandrogenism. CONCLUSIONS: Menstrual disturbances, polycystic ovaries, and hyperandrogenism are often encountered in women taking valproate for epilepsy.

Adolescent↗

PubMed1990

Valproate metabolism during hepatotoxicity associated with the drug.

Plasma concentrations of valproate and certain of its metabolites and their patterns of excretion in urine are described in three adults who developed hepatotoxicity during treatment of epilepsy with sodium valproate. One patient also developed a degree of reversible renal insufficiency, whilst another may have had associated infectious mononucleosis. All three cases showed evidence of impaired mitochondrial beta-oxidation of valproate. In one the impairment was at the stage catalysed by fatty acyl-CoA dehydrogenase, in another at the stage catalysed by 3-hydroxyacyl-CoA dehydrogenase and in the third at the stage catalysed by enoyl-CoA hydratase and possibly also at the next stage catalysed by 3-hydroxyacyl-CoA dehydrogenase. The impaired beta-oxidation meant that valproate metabolism was diverted into various alternative pathways. Plasma concentrations of the suspected hepatotoxic metabolite 4-en-valproate were normal for the valproate-treated population in all cases. By analogy with certain spontaneous and acquired human disorders of branched chain amino acid metabolism, it is suggested that valproate-associated hepatotoxicity may represent the consequences of a valproate overload on a limited mitochondrial beta-oxidation capacity, causing accumulation of a toxic product of endogenous branched chain amino acid metabolism.

Adult↗

PubMed1988

Anticonvulsant potency and neurotoxicity of valproate alone and in combination with carbamazepine or phenobarbital.

Although single drug therapy of epilepsy has been increasingly advocated, patients whose epilepsy is not controlled by monotherapy are commonly treated with more than one antiepileptic drug. In order to investigate the experimental background for antiepileptic drug combinations, the effect of the pharmacodynamic interactions between valproate and carbamazepine and between valproate and phenobarbital on the efficacy/toxicity ratio was studied in mice. All results were expressed in terms of drug concentrations in the brain in order to exclude possible pharmacokinetic interactions from the analysis. Purely additive interactions were found for the anticonvulsant effect when valproate was combined with carbamazepine as well as with phenobarbital. With regard to the neurotoxic effect, however, the interaction was additive between valproate and phenobarbital but infra-additive for valproate and carbamazepine. Thus, in this model, the combination of valproate and phenobarbital has no advantage over each drug alone, but the combination of valproate with carbamazepine has a better efficacy versus toxicity ratio than either valproate alone or carbamazepine alone. Based on these and previous results, there can be experimental evidence in favor of combining certain antiepileptic drugs, but each combination needs to be studied separately.

Animals↗

PubMed1999

Intravenous valproate loading in acutely manic and depressed bipolar I patients.

Recently, valproate has emerged as a drug of primary choice for the treatment of acute mania, especially mixed mania and, partially, rapid cycling. Because of its relative safety, it can be administered in high doses as an oral loading therapy, with approximately 60% to 70% of patients showing a favorable response. Here we report on seven bipolar I patients, two of which have euphoric mania, three have a mixed manic state (including one patient with ultra-rapid cycling and one with very prominent depressed features), and two have solely depressed mood. All but one of the manic patients showed a rapid and favorable response to intravenous valproate loading, which built up sufficient blood levels that were maintained by subsequent oral treatment. Of the two patients with solely depressed mood, however, one experienced only minor benefits and the other showed no change in the depressive symptomatology. Intravenous valproate was tolerated without problems and also led to a drastic reduction in and eventual withdrawal of benzodiazepine treatment in two cases. All of the patients showed a drastic remission of mania with valproate blood levels at or only slightly above 50 microg/mL (blood drawn 12 hours after last application). It is interesting to note that one patient who was previously nonresponsive to oral valproate loading responded well to intravenous valproate. Besides the obvious efficacy and safety of this treatment regimen, these findings may also imply that a difference in pharmacokinetics with intravenous loading may result in a quick saturation of plasma-binding proteins, and hence, peak concentrations of valproate may be reached rapidly, which could contribute to the beneficial action, even in patients previously nonresponsive to oral valproate.

Acute Disease↗