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PubMedDate not supplied

Valproic acid and risk of acute pancreatitis: a population-based case-control study.

To examine whether acute pancreatitis is associated with use of valproic acid. Through the population-based hospital discharge registries we identified all patients with an incident hospitalization of acute pancreatitis in the counties of North Jutland (data 1991 to 2003), Aarhus (data 1996 to 2003), and Viborg (data 1998 to 2003), Denmark. From the Danish Civil Registration System, we selected 10 sex-matched and age-matched population controls per case on the basis of risk set sampling. All prescriptions of valproic acid and other antiepileptic drugs within 90 days (present users) or 91 to 365 days (past users) before hospital admission with acute pancreatitis, or index date among controls, were collected from the prescription databases in the counties. We performed conditional logistic regression to estimate the relative risk of acute pancreatitis after exposure to valproic acid or other antiepileptic drugs, adjusting for gallstone diseases, alcohol-related diseases, hyperlipidemia, and hypercalcemia. We included 3083 cases of acute pancreatitis and 30,830 population controls. The adjusted odds ratio (OR) for acute pancreatitis in present users of valproic acid was 1.9 [95% confidence interval (CI), 1.1-3.3); for past users, the adjusted OR was 2.6 (95% CI, 0.8-8.7). For users of other antiepileptic drugs, the corresponding adjusted ORs were 1.6 (95% CI, 1.2-2.2) and 1.8 (95% CI, 1.1-3.0). Use of valproic acid is associated with an elevated relative risk estimate for acute pancreatitis, but it was not materially different from past use or use of other antiepileptic drugs. Therefore, our data challenge the hypothesis that valproic acid is an independent risk factor for acute pancreatitis.

Adolescent↗
PubMed2004

Valproic acid is known to cause hypospadias in man but does not reduce anogenital distance or causes hypospadias in rats.

The use of valproic acid during human pregnancy increases the risk of hypospadias in the offspring. Rats exposed in utero to valproic acid did not develop hypospadias and even had a slightly increased anogenital distance in males 3-4 days after birth. A classical antiandrogenic drug, flutamide, caused hypospadias as well as a reduction of the anogenital distance in males. At the age of 3 months, rats exposed in utero with either valproic acid or flutamide showed a reduced testicular weight and hypoplasia of tubules, which seemed not to be related to the antiandrogenic activity of flutamide as it did not correlate with the presence of hypospadias. The mechanism through which valproic acid causes hypospadias in man and affects testicular development in rat is unknown. Hypospadias caused by valproic acid in man is apparently not due to anti-androgenic properties of the drug.

Androgen Antagonists↗
PubMed1990

Intermittent prophylaxis in febrile convulsions: diazepam or valproic acid?

In an open, prospective, randomized, and hospital-based study, comprising 219 consecutive children, 169 were given intermittent prophylaxis for one year, receiving either diazepam or valproic acid after their first febrile convulsion. Children admitted on odd dates (n = 89) were given rectal diazepam in solution every 12 h, whenever the temperature was 38.5 degrees C or more. Children admitted on even dates (n = 80) were given valproic acid as suppositories at times of fever. Twenty-three children in the diazepam group had a recurrence within 1 year versus 14 in the valproic acid group. On an intention-to-treat basis the 12-month recurrence rates in the 2 groups were similar, 27% vs 20%. The latter is well below figures for untreated controls from Denmark (32%), suggesting that intermittent valproic acid at times of fever may be effective, but further studies are needed. The number of complex recurrences, however, were significantly higher in the valproic acid group than in the diazepam group. Parental non-compliance was a major problem, and in the 2 study groups only 5 and 12 children, respectively, with recurrences were treated adequately. Sixty-nine children receiving diazepam had side-effects vs 37 receiving valproic acid. None were serious.

Diazepam↗
PubMed2004

Valproic acid inhibits corticotropin-releasing factor synthesis and release from the rat hypothalamus in vitro: evidence for the involvement of GABAergic neurotransmission.

OBJECTIVE: Corticotropin-releasing factor (CRF), the major adrenocorticotropic hormone (ACTH) secretagogue, acts within the brain to integrate the stress responses of the central nervous, endocrine and immune systems. The involvement of this peptide in the origin and pathophysiology of various endocrine, neurologic, inflammatory and psychiatric diseases, particularly affective disorders, has also been suggested. The antiepileptic drug valproic acid is frequently used as a mood-stabilizing agent in patients with bipolar disorders; however, its mechanism of action for the latter indication is still poorly characterized. We investigated whether valproic acid can directly modulate CRF production by using the incubation of rat hypothalamic explants as an in-vitro model. We then studied the involvement of the gamma-aminobutyric acid (GABA) system as a putative mediator of the effects of valproic acid on CRF production. METHODS: Rat hypothalamic explants were incubated in a 24-well plate (2 hypothalami per well) at 37 degrees C in a humidified atmosphere (5; CO(2) and 95% O(2)) in incubation medium, 700 muL, then were treated with medium alone (control) or test substances, namely, valproic acid, KCI, bicuculline methiodide and muscimol. Released CRF was measured by radioimmunoassay. CRF mRNA was measured by RNase protection analysis. RESULTS: Incubation of the hypothalamic fragments with valproic acid, 100 mumol/L, resulted in a reduction of basal CRF secretion after 3 hours' treatment. The drug was also able to inhibit KCl-stimulated CRF release. Moreover, valproic acid, 100 mumol/L, significantly decreased CRF mRNA levels after 3 hours. A specific GABA(A) receptor antagonist, bicuculline methiodide, completely reversed the inhibition of CRF gene expression and peptide release induced by valproic acid; in this paradigm, the GABA(A)-specific agonist muscimol inhibited both CRF gene expression and peptide release in a concentration-dependent manner. CONCLUSIONS: These results suggest that valproic acid may exert part of its therapeutic effect as a mood-stabilizing drug via the modulation of CRF secretion from the hypothalamus. This action may be mediated in part by the activation of GABAergic neurotransmission.

Animals↗
PubMedDate not supplied

Use of lithium, carbamazepine, and valproic acid in a state-operated psychiatric hospital.

OBJECTIVE: To examine the prescribing of mood stabilizers (lithium, carbamazepine, and valproic acid) in a 500-bed state-operated psychiatric hospital in New York. METHODS: All 129 inpatients receiving mood stabilizers were identified and their medical records reviewed using a standardized drug use evaluation form. Diagnosis, other indications, and prior experience with mood stabilizers were examined, as well as outcome and adverse effects. RESULTS: Approximately one-quarter of the inpatient population received a mood stabilizer. The frequency of carbamazepine use exceeded the use of lithium, with 72 patients receiving carbamazepine and only 62 receiving lithium. Twenty-eight patients received valproic acid. Indications found most frequently for carbamazepine use included assaultive or aggressive behavior (70% for those receiving carbamazepine as the only mood stabilizer). Of those patients with bipolar or schizoaffective disorder and receiving either lithium, carbamazepine, or valproic acid, 36% were prescribed carbamazepine (10% as a first-line agent) and 50% lithium (26% as a first-line agent). None of these indications for carbamazepine has been approved by the Food and Drug Administration. In general, positive outcomes were documented but without supporting objective measures. Significant adverse effects were documented in the medical record in one-quarter of the patients. CONCLUSIONS: There was widespread use of the three mood stabilizers examined, singly and in combination, for a variety of indications. Lithium and valproic acid remain more frequently prescribed for the treatment of bipolar and schizoaffective disorders. Monotherapy with carbamazepine or valproic acid results in statistically significantly fewer adverse effects than lithium or combination therapy (p values between p = 0.00038 and p = 0.006). Current clinical practice has endorsed the use of carbamazepine for aggressive or assaultive behavior, although there does not appear to be sufficient proof of effectiveness in the literature. Formal studies of carbamazepine's antiagressive effects should be conducted.

Aggression↗
PubMed1980

A rapid and simple gas-liquid chromatographic determination of valproic acid (alpha-propyl-valeric acid) in serum.

A simple and rapid gas-liquid chromatographic method for the determination of valproic acid in serum is described. Valproic acid is extracted from acidified serum into chloroform and analyzed by gas-liquid chromatography using an FFAP column. The sensitivity of the method is 5 mumol/l and the within-run and day-to-day precisions (CV) are 4.5% or better. Analytical recovery is estimated to exceed 98% and no interference from other drugs or constituents of serum has been observed. The method was used to study the half-life of valproic acid in five healthy persons receiving a single oral dose of the drug, and the technique is well adapted to the routine monitoring of epileptic patients. In routine analysis, the determination of 50 serum samples may be performed by one technician during a normal working day.

Epilepsy↗
PubMed2001

Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.

Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.

Animals↗
PubMed2003

HPLC determination of valproic acid in human serum.

A HPLC method for the determination of valproic acid (VA) in human serum using diazepam as internal standard (I.S.) is described. The eluates were separated with a C18 250 x 4.6 mm internal diameter reversed phase column maintained at a temperature of 50 degrees C. A mobile phase consisting of acetonitrile and 0.05 M phosphate buffer (pH 3.0) 45:55 v/v was used at a flow rate of 1.2 ml/min. Wavelength was switched from 360 nm to 210 nm during valproic acid retention. The method was linear over a concentration range of 20 to 160 microg/ml for valproic acid. Recovery was greater than 94% over a concentration range of 20 to 120 microg/ml and the limit of quantitation was 1 microg/ml. The intra day and inter day relative standard deviation (R.S.D.) measured at 20, 60, 80 and 120 microg/ml ranged from 1.46 to 5.34% and 0.83 to 5.03% respectively. The method is simple, rapid, accurate and sensitive and it was used for Therapeutic Drug Monitoring (TDM) in Indian epileptic patient population. The results obtained with this method correlated well with clinical practice.

Anticonvulsants↗
PubMed1991

Total and free valproic acid: plasma level/dose ratio in monotherapy.

Free plasma level/dose ratio of valproic acid (L/D-F) can be more effective than total plasma level/dose ratio (L/D-T) in adjusting dosage regimens. The influence of age, dose, and plasma concentration have been studied on L/D-T and L/D-F ratios. L/D-T and L/D-F ratios from 67 outpatients under long-term monotherapy were obtained. Analytical data was carried out by fluorescent polarized immunoassay. L/D-T and L/D-F ratios do not vary according to age. L/D-T and L/D-F ratios decreased while the dosage increased; both ratios increased with an increase in total plasma level of valproic acid. Significant differences were found between L/D-T and L/D-F ratios. Dose and interindividual variations are the factors which most influence L/D ratios of valproic acid.

Adolescent↗
PubMed2007

Valproic Acid: second generation.

The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become second-generation VPA drugs. Valproic acid is one of the four most widely prescribed antiepileptic drugs (AEDs) and is effective (and regularly approved) in migraine prophylaxis and in the treatment of bipolar disorders. Valproic acid is also currently undergoing clinical trials in cancer patients. Valproic acid is the least potent of the established AEDs and its use is limited by two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity. Because AEDs treat the symptoms (seizure) and not the cause of epilepsy, epileptic patients need to take AEDs for a long period of time. Consequently, there is a substantial need to develop better and safer AEDs. To become a successful second-generation VPA, the new drug should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than VPA, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with VPA including a low potential for drug interactions.

Animals↗
PubMedDate not supplied

Prediction of steady-state concentrations of valproic acid as determined from single plasma concentrations after the first dose.

A mathematical equation that predicts the maintenance dose needed to achieve a desired steady-state plasma concentration (Css) for first-order drugs from a single plasma concentration drawn after a single dose was tested for valproic acid. Six healthy volunteers received a single oral 500-mg dose of valproic acid and plasma concentrations were determined at 0, 1, 2, 4, 6, 8, 10, 24, and 32 hours. Each subject then received 750 mg of valproic acid daily in three divided doses for four days and a Css was determined. The equation was rearranged to predict the Css of valproic acid from plasma concentrations drawn at 1, 2, 4, 6, 8, and 10 hours after the single dose of valproic acid, using individually determined and mean terminal rate constant (k) values. The predicted Css were then compared with the actual Css. There was no difference in the predicted and actual Css using plasma concentrations collected at 6, 8, or 10 hours regardless of the derivation of the k values. The four-hour concentration predicted a lower Css if the mean (rather than the individual) k values were used. The one- and two-hour concentrations were not accurate predictors. While a 6-, 8-, or 10-hour plasma concentration would be adequate for predicting the Css, the 10-hour concentration had the least difference between the predicted and actual values. The time and cost of titrating valproic acid to a desired Css may be decreased by using this mathematical equation to predict the necessary maintenance dose.

Adult↗
PubMed2004

[Insulin resistance in epileptic patients during treatment of valproic acid].

OBJECTIVE: To investigate the possible role of valproic acid therapy in the development of the weight gain and hyperinsulinemia of epileptic patients. METHODS: The weight and fasting insulin levels were measured in 43 epileptic patients treated with valproic acid (VPA) alone and 39 patients with carbamazepine (CBZ) alone for at last 2 years. The body mass index (BMI) and homeostasis model assessment (HOMA) index were studied in the two groups. RESULT: BMI was higher in the VPA-treated group (23.47+/-1.45) than that in the CBZ-treated group (22.27+/-2.10, P<0.05). Fasting insulin level and HOMA index in the VPA group were also higher [(6.64+/-0.79)mU/L and 1.33+/-0.21] than those in the CBZ group [(5.52+/- 0.52)mU/L, P<0.01; 1.15+/-0.12, P<0.01]. While BMI in the VPA group showed no significant correlation with plasma concentration and dose of valproate. CONCLUSION: VPA therapy is associated with significantly greater weight gain and hyperinsulinemia, suggesting development of insulin resistance.

Adult↗
PubMed1998

Validation of microdialysis sampling for subcutaneous extracellular valproic acid in humans.

This article is the second in a series of studies aimed at monitoring valproic acid pharmacokinetics in patients with epilepsy by subcutaneous microdialysis. In the current study, a detailed investigation on healthy volunteers is made of the relationship between total concentrations in plasma, free concentrations in plasma, and dialysate concentrations. Particular emphasis is put on validating that the in vivo recovery under standard conditions (30 mm dialyzing membrane and 0.5 microl/minute perfusion rate) is sufficiently close to 100%. It was found that the recovery was very close to 100% at 0.5 microl/minute and by in vitro studies it could be excluded that valproic acid binds to the dialysis equipment. The correlation between unbound plasma concentrations and microdialysis concentrations of valproic acid was acceptable (r = 0.80), and they did not differ systematically from one another. It is concluded that microdialysis can be used to sample subcutaneous extracellular valproic acid in a clinical setting giving reliable estimates of the unbound concentration in plasma.

Anticonvulsants↗
PubMed2001

A case of chronic pancreatic insufficiency due to valproic acid in a child.

A 14-year-old child treated with valproic acid over several years for a seizure disorder developed abdominal pain with radiological evidence of acute pancreatitis. The association with valproic acid was not recognized, and the child continued to take the drug. The patient eventually developed steatorrhea and weight loss that improved with pancreatic enzyme replacement. Radiological evaluation showed an atrophic pancreas. Without evidence of other etiological factors, valproic acid by itself appeared to be the cause of chronic pancreatitis with exocrine pancreatic insufficiency in this patient.

Adolescent↗
PubMed1977

[Problems in serum-level determination during valproic acid therapy].

An investigation was carried out to determine whether or not a reliable and reproducible steady state serum level of the anticonvulsant drug valproic acid could be found, such that single values of a serum level determination could be used in therapeutic control. 1. A reliable and comparable serum concentration of valproic acid could not be found in 11 patients during a long-term investigation over a period of 8 weeks. Likewise this could not be found in the 24-h serum concentration profile in 8 of the above mentioned patients, who were receiving both mono and combined therapy. 2. The half-life values for valproic acid in these 8 patients lay between 8--12.5 h. 3. The maximum concentration of valproic acid lies in unforeseeable time spans after drug administration. 4. The morning fasting values are comparable only to a limited extent. In future daily profiles it must be decided whether, and if so to what extent, valproic acid serum concentration determinations can be of value to the individual treatment of epileptics.

Adolescent↗
PubMed2002

Valproic acid therapy inducing absence status evolving into generalized seizures.

The authors herein present two children with mild absence epilepsy, having intermittent absences, who developed absence status evolving into atonic generalized seizures and drop attacks along with progressive disorientation induced by relatively small doses of valproic acid. Consciousness and awareness were intact before the introduction of valproic acid. Both children, after the first dose of valproic acid, developed prolonged and recurrent clusters of absences, which became prolonged, with drop attacks occurring in one patient associated with progressive disorientation. The electroencephalogram concurrently demonstrated prolonged spike-wave discharges, along with disturbance of background activity. Discontinuation of valproic acid resulted in immediate cessation of the prolonged and repetitive clusters of absence episodes and disappearance of drop attacks, along with sensorium clearing. In conclusion, although uncommon, a possible induction of absence status and even atonic seizures by valproic acid should be taken into account and properly managed by abrupt discontinuation of the drug.

Anticonvulsants↗
PubMed2006

Up-regulation of HLA class-I antigen expression and antigen-specific CTL response in cervical cancer cells by the demethylating agent hydralazine and the histone deacetylase inhibitor valproic acid.

BACKGROUND: DNA hypermethylation and histone deacetylation are epigenetic events that contribute to the absence or downregulated expression of different components of the tumor recognition complex. These events affect the processing and presentation of antigenic peptides to CTLs by HLA class-I molecules. In this work evaluated the effect of the DNA hypomethylating agent hydralazine and the histone deacetylase inhibitor valproic acid, on the expression of HLA class-I molecules and on the antigen-specific immune recognition of cervical cancer cells. METHODS: Cell lines C33A (HPV-), CaSki (HPV-16+) and MS751 (HPV-18+) were treated with hydralazine and valproic acid to assess the expression of HLA class-I molecules by flow cytometry and RT-PCR. Promoter methylation of HLA class-I -A, -B and C, was also evaluated by Methylation-Specific PCR. Primary cervical tumors of four HLA-A*0201 allele patients were typed for HPV and their CTL's stimulated in vitro with the T2 cell line previously loaded with 50 microM of the HPV peptides. Cytotoxicity of stimulated CTL's was assayed against Caski and MS751 cells pre-treated with hydralazine and valproic acid. RESULTS: Valproic acid and hydralazine/valproic acid up-regulated the constitutive HLA class-I expression as evaluated by flow cytometry and RT-PCR despite constitutive promoter demethylation at these loci. Hydralazine and valproic acid in combination but no IFN-gamma hyperacetylated histone H4 as evaluated by ChiP assay. The antigenic immune recognition of CaSki and MS751 cells by CTLs specific to HPV-16/18 E6 and E7-derived epitopes, was increased by VA and H/VA and the combination of H/VA/IFN-gamma. CONCLUSION: These results support the potential use of hydralazine and valproic acid as an adjuvant for immune intervention in cervical cancer patients whenever clinical protocols based on tumor antigen recognition is desirable, like in those cases where the application of E6 and E7 based therapeutic vaccines is used.

Journal Article↗
PubMed1984

Diurnal variation in valproic acid clearance.

Diurnal variation in total and unbound valproic acid concentrations was measured at steady state in seven healthy men and three healthy women after 250-mg oral doses every 12 hr. Total average steady-state concentration (Css) during the morning dosage interval was 50.4 mg/l. During the evening dosage interval, total Css was 45.7 mg/l. Unbound Css was also less during the evening (2.9 and 3.4 mg/l). These changes were due to higher total and unbound clearance rates during the evening dosage interval. Total peak concentrations were lower (56.8 and 64.3 mg/l) and time of peak concentrations slightly longer (2.2 and 1.8 hr) during the evening. There was marked interindividual variability in all these changes. For best reproducibility of steady-state valproic acid concentrations, our results suggest that total and unbound levels be drawn at the same time of day.

Administration, Oral↗