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PubMedDate not supplied

Effect of increased bile flow and bile acid secretion on the hepatic elimination of sodium valproate in the cat.

The effect of increased bile flow and hepatic bile acid flux on the systemic clearance and hepatic elimination of intravenously administered sodium valproate was studied in the bile fistula cat. Taurochenodeoxycholic acid (TCDC), tauro-3 alpha, 7 beta-dihydroxy-12-keto-5 beta-cholanoic acid (T12K), SC-2644, and secretin were infused intravenously to vary bile flow and biliary bile acid secretion. Control animals were infused with 0.15 mol/l NaCl. Less than 1% of the drug administered to controls appeared as unchanged valproate in the bile over 6 h. Although SC-2644, T12K, and secretin significantly increased biliary excretion of valproate, it did not exceed 2% of the intravenous dose. Biliary clearance was directly related to the rate of bile flow, but not to the bile acid flux. By contrast, 18-19% of the dose appeared in bile as metabolite in controls, and none of the choleretic agents significantly increased this percentage. As a result, systemic clearance of valproate was unaltered. We conclude that the movement of unchanged valproate into bile is consistent with a process of simple diffusion. The fact that choleretic agents do not increase metabolite excretion into bile suggests that metabolite formation may be the rate-limiting step in the hepatic elimination of valproate, rather than transport and excretion of metabolites into bile.

Animals↗

PubMed2004

Treatment of primary headache disorders with intravenous valproate: initial outpatient experience.

OBJECTIVES: To evaluate the effectiveness of intravenous valproate in managing moderate to severe headaches. BACKGROUND: Despite major strides in the understanding of primary headache disorders, there have been few additions to acute headache management other than introduction of the triptans. An intravenous antiepileptic preparation, sodium valproate, has been reported to be effective in the management of status epilepticus and acute headache. METHODS: Between March 13, 2000 and October 11, 2000, we prospectively treated, in a nonrandomized and open-label study, every patient with a moderate to severe headache (4 or greater on a visual analog scale of head pain from 1 to 10) who wanted treatment with intravenous valproate. Using a verbal visual analog scale for pain (0 = no headache and 10 = most severe headache), we measured head pain before treatment and at time of discharge. The treating nurse monitored vital signs and side effects. A positive response was defined as a 50% or greater reduction at discharge in baseline pain. Information was collected regarding patient demographics, type of headache (according to criteria of the International Headache Society and that recently proposed for chronic headache), observation time in the treatment suite, cumulative dose of valproate, and use of concurrent medications. Univariable and multivariable correlates of response to treatment were identified using logistic regression analysis. RESULTS: One hundred thirty treatments were given to 89 women and 17 men, aged 17 to 76 years; 92 patients received only one treatment. Valproate doses ranged between 300 and 1200 mg. Thirty-three patients (31%) presented with episodic migraine, with or without aura; 45 patients (42%) presented with chronic daily headache with a history of episodic migraine, with or without aura (transformed migraine); 22 (21%) with unclassifiable chronic headache; 2 (2%) with episodic cluster headache; and 4 (4%) with chronic tension-type headache. For first treatments only, 61 patients (57.5%) responded to treatment, whereas for all treatments, 82 patients (63.1%) responded. Age and gender did not affect likelihood of response, whereas increasing duration of treatment (P=.003) and the additional use of analgesics (P=.021) were each negatively associated with response. Among headache types, unclassifiable chronic headache segregated from all other classified headaches in terms of poor response. Aside from rare dizziness (n = 2) and one spell interpreted as a pseudoseizure, no side effects were noted. CONCLUSIONS: Intravenous valproate is a safe, rapidly effective, abortive headache agent. It appears to be an effective analgesic for identifiable primary headaches, especially episodic headache, and less effective for unclassifiable chronic headache. Randomized, double-blind, controlled studies are warranted.

Adolescent↗

PubMed1979

Linear relationship between plasma concentration and dosage of sodium valproate.

Plasma valproate concentration was studied in 7 hospitalized nonepileptic patients who received sodium valproate at daily doses of up to 60 mg/kg. A linear relationship between dose and plasma concentration of valproate (r = 0.81--0.99) was found in each patient, although the slopes of the regression lines (reflecting clearance rates) varied twofold. This suggests that if the valproate plasma concentrations at two different doses are known and the clearance of valproate is not altered by concomitant administration of other drugs, it should be possible to predict the plasma valproate concentration that will result from further dose increments.

Dose-Response Relationship, Drug↗

PubMed1982

Phenytoin-valproate interaction: importance of saliva monitoring in epilepsy.

Sodium valproate is often used with phenytoin when epilepsy cannot be controlled by a single drug. Sodium valproate depresses phenytoin protein binding and so invalidates plasma phenytoin monitoring as a means of determining precise phenytoin dosage requirements. Plasma and saliva phenytoin and plasma valproate concentrations were measured in 42 patients with epilepsy receiving both drugs. Phenytoin protein binding was also measured by ultrafiltration in 19 of these patients and 19 patients taking phenytoin alone. Saliva phenytoin concentration bore the same close correlation to unbound (therapeutically active) phenytoin in patients receiving both drugs as it did in patients receiving phenytoin alone, whereas plasma total phenytoin did not. The same therapeutic range for saliva phenytoin (4-9 mumol/1; 1-2 microgram/ml) was therefore valid in both groups. The depression of phenytoin binding was directly related to the plasma concentration of valproate both in random samples taken from the 42 patients and in samples taken throughout the day in two of these patients. This was confirmed in vitro. Even when the concentration of valproate is known the degree of binding cannot be predicted. Saliva rather than plasma monitoring of phenytoin treatment is therefore valuable in the presence of valproate and with reduced phenytoin binding from any cause.

Adolescent↗

PubMed1989

Metabolic effects of valproate on dog renal cortical tubules.

The effect of valproate (0.01-10 mM), an antiepileptic drug inducing hyperammonemia in humans, was studied in vitro on a suspension of renal cortical tubules (greater than 85% proximal tubules) obtained from six normal dogs. When these tubules were incubated with 1 mM glutamine, the addition of valproate accelerated glutamine uptake, ammoniagenesis, and the production of alanine, lactate, and pyruvate. With 5 mM glutamine, a rise in glutamate accumulation, a much greater synthesis of alanine, an important aspartate production, and a striking accumulation of lactate and pyruvate were observed. With 1 or 5 mM lactate, lactate utilization and gluconeogenesis were markedly reduced with increasing concentrations of valproate. Oxygen consumption was reduced by only 15-20% by 10 mM valproate. The accelerated glutamine utilization resulting from valproate could not be prevented by aminooxyacetate, an inhibitor of transamination. Valproate also reduced various enzymatic activities, a finding that could not explain its metabolic effects. Four sites of action may explain these various metabolic changes: (i) a stimulation of mitochondrial glutamine transport, (ii) an increase in the flux of glutamate to malate, and (iii) a reduction in the net oxidation of pyruvate and (iv) in the flux through pyruvate carboxylase.

Aminooxyacetic Acid↗

PubMed1995

Blood dyscrasias with carbamazepine and valproate: a pharmacoepidemiological study of 2,228 patients at risk.

OBJECTIVE: The purpose of this study was to determine the occurrence of leukopenia and other blood dyscrasias associated with psychiatric use of carbamazepine and valproate. METHOD: Rates of WBC counts of 3,000-4,000/mm3 (moderate leukopenia) and < 3,000/mm3 (severe leukopenia), platelet counts of < 100,000/mm3, and hematocrit < 30% were identified among 2,228 treated patients at risk among 11,720 patients admitted to McLean Hospital over 4 years (1989-1993). Patients who received carbamazepine or valproate and had a blood dyscrasia not associated with a relevant medical condition were compared to patients treated with imipramine or desipramine. RESULTS: Of 977 patients treated with carbamazepine, 2.1% experienced leukopenia (16 moderate cases, five severe). Time to 50% risk was 16 days, and recovery occurred within about 6 days after carbamazepine was stopped. For 1,251 patients given valproate, the occurrence of leukopenia was 0.4% (three moderate cases, two severe). The occurrence of leukopenia in 1,031 patients given the tricyclic antidepressants was 0.3% (two moderate cases, one severe). The observed occurrence of moderate leukopenia with carbamazepine was 6.9 and 7.3 times higher than that with valproate and antidepressants, respectively. CONCLUSIONS: Severe blood dyscrasias were uncommon in psychiatric patients given carbamazepine and were about as rare with valproate as with imipramine or desipramine. Most important, in this cohort of 2,228 patients exposed to carbamazepine and valproate, there were no life-threatening cases.

Adolescent↗

PubMed1994

Thrombocytopenia secondary to high valproate levels in children with epilepsy.

We reviewed the frequency of valproate-induced thrombocytopenia in children with epilepsy in our institution. Sixty-four (21%) of 306 children taking valproate developed thrombocytopenia. Thirty-two of these 64 patients had at least one platelet count lower than 100 x 10(3)/mm3. Eight patients developed signs of bleeding. Low platelet levels were typically noted in patients with serum valproate levels of over 140 micrograms/mL, and reduction of the medication dose usually resulted in a prompt increase in the number of platelets. Only one patient developed thrombocytopenia unrelated to high serum drug levels, and her platelet count did not improve until the drug was discontinued. Neither the age of the patient nor the use of additional antiepileptic medication correlated with the platelet count. However, duration of valproate use was related. These data suggest that, although valproate may cause thrombocytopenia via more than one mechanism, by far the most common factor is the presence of high valproate levels. Thus, the medication can be safely lowered in most patients with thrombocytopenia rather than discontinued altogether. Platelet counts should probably be monitored more carefully in patients known to have higher drug levels.

Carbamazepine↗

PubMed2003

EEG does not predict response to valproate treatment of aggression in patients with borderline and antisocial personality disorders.

Previous investigations of the role of EEG in predicting response of aggressive patients to valproate therapy have yielded mixed results. In this study of borderline and antisocial personality disorder patients hospitalized with aggressive behavior, EEGs were obtained prior to treatment with valproate. Eight of 22 (36.4%) patients subsequently responsive to valproate had nonepileptiform EEG abnormalities, while 5 of 20 (25%) patients not responsive to valproate had nonepileptiform EEG abnormalities. Although more of the valproate responders than nonresponders had EEG abnormalities, the presence of nonepileptiform EEG abnormalities was not a statistically significant (X2 = 0.213, df = 1, p = 0.64) predictor of valproate response in personality disorder patients with aggression.

Adult↗

PubMed2004

Brain choline concentrations may not be altered in euthymic bipolar disorder patients chronically treated with either lithium or sodium valproate.

BACKGROUND: It has been suggested that lithium increases choline concentrations, although previous human studies examining this possibility using 1H magnetic resonance spectroscopy (1H MRS) have had mixed results: some found increases while most found no differences. METHODS: The present study utilized 1H MRS, in a 3 T scanner to examine the effects of both lithium and sodium valproate upon choline concentrations in treated euthymic bipolar patients utilizing two different methodologies. In the first part of the study healthy controls (n = 18) were compared with euthymic Bipolar Disorder patients (Type I and Type II) who were taking either lithium (n = 14) or sodium valproate (n = 11), and temporal lobe choline/creatine (Cho/Cr) ratios were determined. In the second part we examined a separate group of euthymic Bipolar Disorder Type I patients taking sodium valproate (n = 9) and compared these to controls (n = 11). Here we measured the absolute concentrations of choline in both temporal and frontal lobes. RESULTS: The results from the first part of the study showed that bipolar patients chronically treated with both lithium and sodium valproate had significantly reduced temporal lobe Cho/Cr ratios. In contrast, in the second part of the study, there were no effects of sodium valproate on either absolute choline concentrations or on Cho/Cr ratios in either temporal or frontal lobes. CONCLUSIONS: These findings suggest that measuring Cho/Cr ratios may not accurately reflect brain choline concentrations. In addition, the results do not support previous suggestions that either lithium or valproate increases choline concentrations in bipolar patients.

Journal Article↗

PubMed2003

Antiepileptic drug-induced pharmacodynamic aggravation of seizures: does valproate have a lower potential?

Thirty-five years since its introduction into clinical use, valproate (valproic acid) has established itself as one of the most widely used antiepileptic drugs (AEDs). In recent years, there has been a growing awareness of the potential aggravation of seizure disorders by AEDs. Such aggravation may be due to a variety of factors that include a paradoxical pharmacodynamic effect. In order to address this important safety aspect of AED treatment, we reviewed all available published evidence in search of factors related to seizure aggravation during valproate therapy. We analysed the 20 available publications, which outline about 99 case reports (in some papers, the exact number was not specified) of aggravation of seizures associated with valproate. Almost all of these cases occurred in a specific clinical context known to be linked to seizure aggravation, such as overdose, encephalopathy, hepatopathy or metabolic disorders. However, we found no consistent evidence of pure pharmacodynamic aggravation in the absence of any of the above quoted factors. In view of the large number of patients treated worldwide with valproate, the number of reported cases of seizure aggravation in patients taking the drug in the literature is low. Conditions in which worsening of seizures as a result of valproate use may occur are well known and often avoidable. Thus, unlike most AEDs, including the newer ones, valproate appears to have a very low potential for pharmacodynamic paradoxical seizure aggravation. This knowledge is in accordance with long-standing clinical experience and practice.

Anticonvulsants↗

PubMed2000

Use of sodium valproate in violent and aggressive behaviors: a critical review.

BACKGROUND: Valproate was initially introduced as an antiepileptic agent in 1967, but has been used over the years to treat a variety of psychiatric disorders. Its use in the treatment of patients exhibiting aggressive and violent behaviors has been reported in the literature as far back as 1988. However, these reports are uncontrolled, which is in marked contrast to the actual wide and established use of valproate for the treatment of aggressive behaviors. The aim of this report is to critically review the available data on valproate's use in nonbipolar patients with aggressive and violent behaviors. DATA SOURCES: The MEDLINE and PsycLIT databases were searched for all reports published from 1987-1998 containing the keywords valproate, the names of all commercial preparations, aggression, and violence. STUDY FINDINGS: Seventeen reports with a total of 164 patients were located. Ten of these were case reports with a total of 31 patients. Three were retrospective chart reviews with 83 patients, and 3 were open-label prospective studies with a total of 34 patients. No double-blind, placebo-controlled study could be found. An overall response rate of 77.1% was calculated when response was defined as a 50% reduction of target behavior. Most frequent diagnoses recorded were dementia, organic brain syndromes, and mental retardation. The antiaggressive response usually occurred in conjunction with other psychotropic medication. The dose and plasma valproate level required for response appeared to be the same as in the treatment of seizure disorders. DISCUSSION: While valproate's general antiaggressive effect is promising, in the absence of controlled data, conclusions are limited at this time. Specific recommendations for study design are given to obtain interpretable data for this indication.

Adolescent↗

PubMed2002

Lithium and valproate treatment of pathological gambling: a randomized single-blind study.

OBJECTIVE: The aim of the present study was to evaluate the efficacy and safety of lithium and valproate in nonbipolar pathological gamblers. METHOD: Forty-two subjects with DSM-IV-defined pathological gambling entered a 14-week single-blind trial with lithium (N = 23) or valproate (N = 19). A total of 15 subjects on lithium treatment and 16 patients on valproate treatment completed the 14-week protocol. RESULTS: At the end of the 14-week treatment period, both the lithium and the valproate groups showed significant (p <.01) improvement in mean score on the Yale-Brown Obsessive Compulsive Scale modified for pathological gambling. This improvement did not significantly differ between groups. Fourteen (60.9%) of the 23 patients taking lithium and 13 (68.4%) of the 19 patients taking valproate were responders based on a Clinical Global Impressions-Improvement score of much or very much improved. CONCLUSION: Findings from the present study suggest the efficacy of both lithium carbonate and valproate in the treatment of pathological gambling. This is the first controlled trial of the efficacy of mood stabilizers in pathological gambling. A double-blind, placebo-controlled trial is required to confirm these findings.

Anticonvulsants↗

PubMed2005

Incidence of delirium in older adults newly prescribed lithium or valproate: a population-based cohort study.

BACKGROUND: The use of lithium carbonate for the treatment of mood disorders in old age has decreased at a dramatic rate in favor of valproate. Because of lithium's narrow therapeutic range, neurotoxicity can be an important complication in lithium therapy and potentially influence prescription patterns. Therefore, we compared the incidence of delirium in older adults with mood disorders who were newly dispensed either lithium or valproate. METHOD: Using 4 population-based administrative databases from the province of Ontario, Canada (the Ontario Drug Benefit program, the Canadian Institute for Health Information, the Ontario Health Insurance Plan, and the Registered Persons Data Base), we were able to identify a cohort of mood disorder patients 66 years and older who were newly dispensed lithium or valproate over an 8-year period (1993-2001). Measures were taken to ensure that the sample was composed of mood disorder patients. As a comparator, we included a known deliriogenic drug, benztropine. The main outcome measure was a new diagnosis of delirium on a hospitalization record during 1 year of follow-up. RESULTS: Our study cohort consisted of 2422 new users of lithium and 2918 new users of valproate over an 8-year period. There was no statistically significant difference in the incidence of delirium between lithium (2.8 per 100 person-years) and valproate (4.1 per 100 person-years). Compared with patients who received lithium, patients who received benztropine had a significantly higher risk of delirium (p < .001). CONCLUSION: The incidence of hospitalizations with delirium was similar in patients treated with lithium and valproate. These findings add to the evidence suggesting that the shift away from the use of lithium carbonate to manage mood disorders in older adults is not justified on the basis of concerns of neurotoxicity.

Adult↗

PubMed2005

Valproate-induced hyperammonemic encephalopathy with normal liver function.

Hyperammonemic encephalopathy with normal liver function is an uncommon serious adverse effect of valproate therapy. We retrospectively analyzed the case records of 5 patients of epilepsy on valproate with hyperammonemic encephalopathy. Of the 5 patients, 3 were on monotherapy. The mean valproate dose was 1250 mg/day and the duration of therapy ranged between 4 and 90 days. Alteration in the sensorium was the presenting clinical feature. The risk factors included high initial dose (2), long-term valproate therapy (1), and long-term valproate therapy with concomitant topiramate (1). There was good correlation between the fall in serum ammonia levels and clinical improvement. Hyperammonemic encephalopathy should be suspected in patients on valproate with altered sensorium. Response to treatment is rewarding.

Adolescent↗

PubMed2002

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.

Animals↗

PubMed2002

Effects of short-term administration of valproate on serotonin-1A and dopamine receptor function in healthy human subjects.

OBJECTIVE: To examine the effects of short-term valproate treatment on human brain serotonin and dopamine function by means of challenge tests with ipsapirone, a partial agonist at 5-HT1A receptors, and apomorphine, a dopamine receptor agonist. DESIGN: Experimental challenge-rechallenge, within-subjects repeated measures, before and at the end of 14 days of treatment with valproate at a dosage of 625 mg/d (reached gradually over the first 5 days). PARTICIPANTS: Eight healthy male volunteers (mean age 38 years) selected for good physical and mental health who were nonsmokers. OUTCOME MEASURES: Pharmacological probes were used to evaluate the effects of valproate. In the ipsapirone challenge, changes in adrenocorticotropic hormone (ACTH), cortisol and body temperature were measured, and in the apomorphine challenge, growth hormone (GH) and prolactin were the dependent variables. RESULTS: Valproate treatment did not significantly alter the ACTH, cortisol or body temperature responses to ipsapirone (20 mg by mouth), which reached equivalent plasma levels at each challenge. Similarly, valproate treatment did not alter the GH or prolactin responses to apomorphine (5 micrograms/kg subcutaneously). CONCLUSIONS: These results suggest that short-term treatment with valproate at a dose of 625 mg/d does not alter hypothalamic or pituitary 5-HT1A or dopamine receptor responses to challenges with ipsapirone and apomorphine, respectively.

Adrenocorticotropic Hormone↗

PubMed1992

Mechanisms of neurotransmission of valproate sodium in suppressing barbiturate and phenytoin withdrawal syndrome.

The present study was undertaken to investigate some important processes of neurotransmission which occur in rat brains under the influence of valproate sodium. Valproate sodium is used for the suppression of the withdrawal effects resulting from sudden discontinuation of phenobarbital and phenytoin treatment. Corpus striatum, hippocampus and cortex were isolated operatively. The amounts of neuromediators (dopamine, noradrenaline, serotonin and gamma-aminobutyric acid) were determined using fluorometry. The results show that the anti-withdrawal effect of valproate sodium established in previous research probably is due to active metabolites which increase the amount of gamma-aminobutyric acid in all brain structures. In suppressing barbiturate and phenytoin withdrawal syndrome using valproate sodium, the previously established anti-withdrawal effect probably is due to high tissue levels of dopamine in hippocampus and to noradrenaline in the cortex, hippocampus and corpus striatum. This anti-withdrawal effect continues for three days after the discontinuation of valproate sodium. This probably is due to the accumulation of the inhibitory neuromediator GABA in the cortex, hippocampus and corpus striatum and to the elevated level of dopamine in hippocampus. The results raise new possibilities for developing medicinal substances, which possess anti-withdrawal action, from the metabolites of the valproate sodium.

Animals↗

PubMed2003

Pharmacology of valproate.

Valproate has been in clinical use for nearly 40 years for the treatment of a variety of neuropsychiatric illnesses, including bipolar disorder and epilepsy. Early reports linked its biochemical mechanism of action to alterations in gamma-aminobutyric acid (GABA)-ergic function. The definitive mechanism(s) mediating the clinical efficacy of this relatively simple molecule remain obscure. Although valproate does not directly interact with postsynaptic GABA receptors, it does increase regional neuronal concentrations of GABA by both inhibiting its metabolism and increasing its synthesis. The relevance of these effects to the clinical efficacy of valproate is unclear. Results of preclinical research, largely in rodents, have implicated ion channels, monoamines, corticotropin-releasing factor, and intracellular signaling proteins in the mechanism of action of valproate. This relative dearth of data in the area of valproate neuropharmacology is also evident when discussing the mechanism( s) of action of other mood stabilizers and anticonvulsants. Modern tools of basic and clinical neuroscience (eg, genomics, proteomics, functional brain imaging) will rapidly provide valuable insights into the precise mechanism(s) of action of valproate.

Animals↗