Serum Concentrations Of Valproic Acid Research Articles

Diabète insipide central transitoire au cours d'une intoxication à l'acide valproïque

A 39-year-old man was hospitalized after divalproate self-poisoning. He presented coma requiring tracheal intubation and mechanical ventilation at 11 hours and central diabetes insipidus. Serum valproic acid concentration was 590 mg/l at 30 hours. Progressive improvement occurred after hydratation and administration of vasopressin.

The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all‐trans retinoic acid in patients with acute myeloid leukemia

Valproic acid (VPA) inhibits histone deacetylase activity and, synergizing with all-trans retinoic acid (ATRA), achieves differentiation induction of myeloid blast cells in vitro. We used VPA in 58 patients with acute myeloid leukemia (AML) who were too old and/or medically unfit to receive intensive chemotherapy (32 AML secondary to myelodysplastic syndrome [MDS], 22 de novo AML, 4 AML secondary to myeloproliferative syndrome). VPA serum concentrations were 50-100 mug/mL. Thirty-one patients received VPA monotherapy. ATRA was added later in 13 patients who did not respond or who relapsed. Another 27 patients received VPA plus ATRA from the start. Median treatment duration was 93 days for VPA and 88 days for ATRA. The response rate was only 5% according to International Working Group (IWG) criteria for AML but was 16% when IWG response criteria for MDS were used, which capture hematologic improvement and stabilization of the disease. These endpoints, which are not necessarily correlated with diminishing blast counts, are relevant for the patients' quality of life. Among 23 patients with a peripheral blast count > 5%, 6 (26%) showed a diminishing blast count, and 5 of these had a complete peripheral blast clearance. Future trials should combine VPA with chemotherapy or demethylating agents.

A Phase I-II Pilot Study of Divalproex Sodium Alone and in Combination with All-Trans-Retinoic Acid (ATRA) in Relapsed or Refractory Acute Myeloid Leukemia.

Valproic acid (VPA), acetylates histones, induces apoptosis and synergizes with All Trans Retinoic Acid (ATRA), in promoting G1 arrest and leukemic cell differentiation in vitro. Based on these observations we designed a Phase I/II pilot study of VPA alone and in combination with ATRA in patients with relapsed, refractory or poor risk acute myeloid leukemia (AML). VPA was initiated at 15mg/kg/day (day 1 IV followed by daily po) and escalated weekly by 10mg/kg (max 60 mg/kg/day) targeted to reach a serum concentration of 80–120mg/ml. For the combination, ATRA was to be added initially at 25mg/M2/day (first 3 patients) and titrated, in the absence of toxicity, to 45mg/M2/day, in two divided doses, following a minimum of 7 days of VPA therapy alone. Treatment was planned to continue for 45 days following achievement of a VPA level of >80mg/ml on two separate, consecutive measurements. To date we have treated 8 patients (7 tAML/MDS, 1 de novo AML) with VPA alone. Two of 8 additional patients to be treated with VPA + ATRA (1 tAML/ET; 1 tAML/MDS), are too early in their treatment upon which to report. Of the VPA alone treated patients, Median age was 63 (range 52–78). No Prior therapy: 3/8 pts; 5F:3M; ECOG PS 0 (1), 1 (5), 2 (2);Cytogenetic abnormalities: normal (1); t(3;18) (1); complex karyotype (6), including trisomy 8 (3), abnormalities of 11 (2) or monosomy 7 (2). Baseline bone marrow blast percentage > 50%; (8); median bone marrow cellularity 84% (range 35–90). Treatment: Median duration of treatment 45 days (range 19–99). Therapy discontinued before 45 days; withdrawl (2); death at home on study (day 33 of treatment), (1); reversible grade 3 toxicity(2). VPA levels: Serum concentrations of VPA of > 80mg/ml was achieved in all patients; Hematologic effects: Changes in CBC: increase in WBC, ANC and blast count (BLC)(3), followed by decrease in WBC and BLC (2); increase in WBC/ANC &decrease in BLC (1); decrease in WBC, ANC and BLC (3); &initial decrease in BLC &increase in ANC (1). Marrow: decrease in marrow cellularity (2)( 90% to 30%); loss of detectable trisomy 8 population (1); &decrease in bone marrow blasts (1) (64% to 5%) was observed. One patient reverted back to MDS, lasting 5 months. Side Effects: somnolence (grade 2–4) was observed in 4/8 patients, and was the major cause of withholding treatment. We also observed a constellation of symptoms (weight gain, fever, elevated WBC, shortness of breath, elevated LDH, bone pain) and chest x-ray findings consistent with &reminiscent of APL syndrome, within seven days of achieving the targeted serum VPA levels (> 80mg/ml), in 2 pts. Decadron was started two days (1) and immediately (1) following the onset of symptoms: signs and symptoms abated quickly &resolved subsequently within three days. In retrospect, one additional patient had comparable symptoms, for which VPA was stopped, following admission to an outside hospital for fever, pulmonary infiltrates and altered mental status. Correlative studies: serial assessment of bulk histone acetylation (H3, H4) was performed in all 8 patients. 7/8 patients showed evidence of histone hyperacetylation in mononuclear cells from peripheral blood, during treatment with VPA. Additional patients are being treated with VPA + ATRA. Analysis of these studies will be forthcoming.

Pharmacokinetic interaction on valproic acid and recurrence of epileptic seizures during chemotherapy in an epileptic patient

To report a pharmacokinetic interaction between valproic acid (VPA) and anticancer agents observed in an epileptic patient. A 34-year old male epileptic patient receiving VPA underwent cisplatin-based chemotherapy for the treatment of a testicular tumour. The first chemotherapeutic cycle decreased the serum VPA concentration and caused severe generalized tonic-clonic seizures. Thus, thereafter, the serum VPA concentration was monitored along with the chemotherapy. In a patient receiving VPA daily, severe seizures were observed 7 weeks after the first chemotherapeutic cycle, at which the serum VPA concentration was found to be reduced by approximately 50% of the initial level (90-100 microg ml(-1)). The following cycles (six cycles over a 7-month period) also caused seizures in association with decreased serum VPA concentrations. In contrast, the serum concentration of phenytoin, which was given daily after the second chemotherapeutic cycle, remained at a therapeutic concentration (10-20 microg ml(-1)). After the completion of chemotherapy, the serum concentration of a tumour marker, hCGbeta, decreased to 1.2 ng ml(-1) from more than 120 ng ml(-1) prior to the chemotherapy in this patient. Careful monitoring of VPA concentrations are necessary during cisplatin-based chemotherapy because anticancer agents can reduce the serum concentration and antiepileptic activity of VPA.

Acute Seizures Due to a Probable Interaction between Valproic Acid and Meropenem

To report a probable interaction between meropenem and valproic acid that resulted in the development of epileptic seizures. A 21-year-old woman presented to our emergency department because of a new-onset, generalized tonic-clonic seizure and was admitted to the intensive care unit. Treatment with valproic acid 1000 mg as a continuous intravenous infusion over 24 hours was initiated. On day 6, the serum concentration of valproic acid was 52.5 microg/mL. On day 13, treatment with intravenous meropenem 1 g 3 times daily was started. On day 15, when the patient was afebrile, numerous myoclonic episodes occurred involving her arms and face; the serum concentration of valproic acid at that time was 42 mug/mL. The valproic acid dose was increased to 2880 mg. Two days later, a generalized tonic-clonic seizure occurred despite the increased dosage, and the plasma concentration of valproic acid fell to 7 microg/mL. The valproic acid dose was increased the following day to 3600 mg; however, the serum concentrations remained <10 microg/mL. On day 19, based on the results of a blood culture and the suspicion of an interaction between meropenem and valproic acid, meropenem therapy was suspended. The serum concentration of valproic acid was 52.4 microg/mL on day 27. Three days later, the patient was asymptomatic and was discharged. Coadministration of valproic acid and other drugs that are metabolized by the hepatic cytochrome P450 isoenzyme system can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. In view of studies in experimental models, the interaction between carbapenem antibiotics and valproic acid is at least possible. Use of the Naranjo probability scale indicated a probable relationship between acute seizures and a meropenem-valproic acid interaction in this patient. This case report provides strong evidence for an interaction between valproic acid and meropenem. Clinicians should be aware of this potential interaction that may be associated with a serious adverse effect as the result of the decrease of the valproic acid serum concentrations.

A Theoretical Method for Normalizing Total Serum Valproic Acid Concentration in Hypoalbuminemic Patients

In patients with hypoalbuminemia, the total serum concentration of valproic acid may offer poor clinical information; however, very few clinical laboratories routinely analyze the free concentration of the drug. The aim of this study was to design a procedure to normalize the total concentration of valproic acid according to the level of serum albumin and using previously published free fraction values. In 121 adult patients, with albumin levels of 18 – 41 g/L, the total concentration of valproic acid was normalized using the derived equation: CN = αHCH/6.5, where αH is the free fraction of the drug corresponding to the patient’s particular albuminemia and CH is the total concentration of valproic acid. The value of 6.5 corresponds to the free fraction of the drug for a serum albumin of 42 g/L (percentile 50 of the reference range). For total concentrations lower than 75 mg/L, the predicted normalized valproic acid concentrations were reasonably concordant with the observed normalized concentrations calculated using the data from a protein-binding study. In a significant number of cases, subtherapeutic concentrations of the drug became therapeutic and even supratherapeutic when corrected according to the albumin levels. Furthermore, cases with therapeutic drug concentrations frequently became supratherapeutic when normalized. The limitations and clinical aplications of the proposed formula for normalizing the total concentration of valproic acid are presented. It is concluded that it may be useful for the posological management of hypoalbuminemic patients when the free concentration of the drug is not available, and decisions have to be made based on the total serum concentration.

Analytical performance evaluation of a new turbidimetric immunoassay for valproic acid on the ADVIA® 1650 analyzer: effect of gross hemolysis and high bilirubin

Valproic acid is an anticonvulsant that requires careful therapeutic drug monitoring. Valproic acid is also used in psychiatric patients. Bayer Diagnostics (Tarrytown, NY) recently marketed a turbidimetric immunoassay for monitoring valproic acid concentrations in serum or plasma using the ADVIA 1650 analyzer. We evaluated the performance of this new assay by comparing it with a widely used fluorescence polarization immunoassay (FPIA) on the AxSYM analyzer (Abbott Laboratories, Abbott Park, IL). The total coefficient of variation (CV) for the low control of this new assay was 6.8% (mean = 30.7, SD = 2.1 microg/mL, n = 44) while the corresponding CVs for the medium and high controls were 3.3% (mean = 81.0, SD = 2.7 microg/mL, n = 44) and 5.9% (mean = 142.9, SD = 8.4 microg/mL, n = 44), respectively. The assay is linear up to a serum valproic acid concentration of 170 microg/mL, and the detection limit is 4.4 microg/mL. We observed an excellent correlation between the FPIA of valproic acid and the turbidimetric assay using specimens from 52 different patients who were receiving valproic acid. Using the valproic acid concentrations obtained by the FPIA as the x-axis, and the corresponding valproic acid concentrations obtained by the turbidimetric assay as the y-axis, we developed the following regression equation: y = 1.03 x+1.55 (r = 0.98). With this new assay, high concentrations of bilirubin (unconjugated 30 mg/dL and conjugated 30 mg/dL) and gross hemolysis (4+, hemoglobin: 1,500 mg/dL) have no effect on measurements of valproic acid concentration. We conclude that the new turbidimetric assay for valproic acid can be used for routine therapeutic drug monitoring of valproic acid in clinical laboratories.

唾液中バルプロ酸（ＶＰＡ）濃度測定による在宅ＴＤＭの試み（１）

In the present study, we examined the clinical significance and utility of measuring salivary valproic acid (VPA) levels in saliva samples taken at patients' homes for therapeutic drug monitoring (TDM). The subjects were 74 patients (33 males and 41 females ; mean age 30.8 ± 1.9 years) under treatment at Outpatient Clinic, Department of Neuropsychiatry, Fukushima Medical University Hospital. For the VPA measurements, saliva samples and blood samples were taken at the Outpatient clinic simultaneously. Salivary VPA levels showed significant correlations with total and free VPA serum concentrations (r=0.71 and r=0.77, respectively) but were not significantly correlated with serum albumin concentration or salivary pH.From a preliminary experiment that we conducted, salivary VPA levels were found to remain stable when saliva samples were kept in home freezers at 4 and -20°C.Based upon the above results, we concluded that TDM based on measurements on saliva samples taken by patients receiving VPA has significant clinical utility because 1) saliva sampling is less invasive than blood sampling and easy to carry out for patients who do not wish their blood to be taken, 2) saliva sampling at home is convenient because either patients or their family members can take the samples and 3) samples taken at home can accurately show VPA levels as they are in everyday life.

Predicted serum valproic acid concentrations in patients missing and replacing a dose of extended-release divalproex sodium

Computer simulations were used to analyze changes in steady-state total plasma valproic acid concentrations when a patient misses a dose of once-daily extended-release divalproex sodium, replaces it at a later time, and resumes scheduled therapy. Valproic acid concentration-time profiles were simulated for 1000 hypothetical patients for each of two missed-dose scenarios using a one-compartment (assumes rapid distribution) population kinetic model with nonlinear protein binding. For each scenario, a lognormal distribution of clearance of unbound valproic acid, volume of distribution of unbound valproic acid, protein-binding values, and albumin concentration was generated. All simulations incorporated 20% interpatient variability and 10% residual error. Our pharmacokinetic simulations predicted that the chance for high plasma valproic acid concentrations resulting in clinical toxicity is low when extended-release divalproex doses are replaced within 12 hours followed by resumption of scheduled administration, perhaps due to the controlled, near zero-order absorption characteristics of the extended-release formulation. If a patient misses a dose of extended-release divalproex, it should be replaced as soon as the patient remembers. The next dose should be taken at the regularly scheduled time. A missed dose of extended-release divalproex may be replaced up to 12 hours later without any clinically significant change in plasma valproic acid concentrations in a majority of the patients. Simulation of two scenarios suggested that a missed dose of extended-release divalproex sodium may be replaced up to 12 hours later without any clinically significant perturbation in plasma valproic acid concentrations in the majority of adolescent and adult patients with epilepsy.

Meropenem Decreases Serum Level of Valproic Acid

Concomitant administration of meropenem has been reported to decrease serum level of valproic acid both in humans and in animals. This report describes three children who required simultaneous administration of valproic acid and meropenem. Meropenem rapidly decreased serum valproic acid concentration to subtherapeutic levels in all three children, and serum valproic acid levels were returned to therapeutic levels in a short time after discontinuing simultaneous meropenem therapy. Valproic acid was not changed to another antiepileptic agent, because no seizure activity was observed. To our knowledge, this is the first case report on the simultaneous administration of meropenem and valproic acid in childhood. In conclusion, it is clear that concomitant meropenem administration decreases serum valproic acid concentration, and we believe that there may be no need to change the antiepileptic drug during this period, provided that the patient has no seizure. More detailed studies are required.

Acidose lactique majeure secondaire à une intoxication volontaire par valproate

A sixty-year-old woman was admitted in the ICU after Depamide (Valpromide) self-poisoning (430 mg/kg). Four hours after the ingestion, the patient presented coma (Glagow coma score of 3) with bilateral mydriasis requiring tracheal intubation and mechanical ventilation, hypotension requiring epinephrine infusion (0.9 microg/kg per minute), acidosis and hyperlactatemia (29.7 mmol/l at 12 hours) without any kidney or liver failure. The maximal serum valproic acid concentration measured was 342 mg/l after twelve hours (therapeutic rate: 35-85 mg/l). A continuous infusion of sodium bicarbonate was associated with continuous venovenous haemodiafiltration. Progressive haemodynamic improvement and neurologic recovery leaded to extubation at 36 hours.

Encephalopathy and myoclonus triggered by valproic acid

In recent years, the use of valproic acid (VPA) as a mood-stabilizing agent has continuously increased. Although VPA usually is well tolerated, its use in combination with other psychotropic compounds might bear an elevated risk of adverse reactions. Here, we present the case of a 42-year-old male suffering from treatment-resistant psychotic depression, who was prescribed VPA additionally to lithium, clomipramine, flupentixol and risperidone. By doing so, he developed myoclonus, tremor and encephalopathy with sedation and marked EEG background slowing. Most notably, these side effects occurred in the presence of normal VPA and ammonia serum concentrations. On VPA discontinuation, all symptoms vanished and EEG normalized. We thus suggest that direct VPA-induced encephalopathy in the absence of ammonemia does exist, in this case probably facilitated by psychotropic polypharmacy.

Pharmacokinetic modelling of valproic acid from routine clinical data in Egyptian epileptic patients.

This paper describes a developed pharmacokinetic model for the estimation of valproic acid (VPA) clearance (CL) calculated from routine clinical data taken from Egyptian epileptic patients. Retrospective clinical data from 81 adult and paediatric epileptic patients with one trough VPA serum concentration per patient were analysed using NONMEM to estimate drug CL and determine the influence of different covariates. A qualification group of 20 epileptic children (3-13 years old) was used to evaluate the final model. The population CL as estimated by base model (no covariates) was 0.581 l h(-1) with inter-individual variability (C.V. %) of 17.4% and SD of residual error was 6.82 mg l(-1). Univariate selection and backward deletion of different covariates led to the development of the final regression model of CL as follows: CL(Lh-1) = 0.101 + 0.151 * CBZ + 0.000248 * VPADD + 0.0968 * age/20 + 0.0803 * INDI, in which CBZ indicates co-administration of carbamazepine, VPADD the daily dose of VPA and INDI uncontrolled epilepsy. The between-subject variability in CL was 23.6% while the standard deviation of the residual error was 5.24 mg l(-1). The model predictions in the qualification group were found to have no bias and satisfactory precision. The population pharmacokinetic model for VPA could be used for a priori recommendation and dose optimisation of that drug in the Egyptian population of epileptic patients.

Association of Polycystic Ovaries with the Use of Valproic Acid in Jordanian Epileptic Patients

To investigate the frequency of occurrence of polycystic ovaries (PCO) in women taking valproic acid (VPA) as monotherapy for epilepsy. 163 epileptic patients were seen at the outpatient neurology clinic at Princess's Basma Teaching Hospital, Irbid, and Basheer Hospital, Amman, Jordan. A detailed medical history was taken from the patients followed by a clinical examination and vaginal ultrasonography of the ovaries. 102 patients (62.5%) had primary generalised seizures, 46 patients (28.2%) had partial seizures and 15 patients (9.2%) had partial secondary generalised seizures. Mean age +/- standard error of the mean (SEM) was 29.8 +/- 0.97 years. The duration of epilepsy and treatment with VPA were (mean +/- SD) 9.1 +/- 0.48 and 7.9 +/- 0.4 years, respectively. The dose and serum concentrations of VPA were (mean +/- SD) 983.9 +/- 101.96mg and 52.7 +/- 4.7 mg/L, respectively. Mean body mass index (BMI) was 25.6 +/- 0.92 kg/m(2). The mean weight gain was 6.6 +/- 1.3kg (range 2-24kg). Menstrual abnormalities were detected in 58 (35.6%) patients. Twelve patients (7.4%) had PCO; these patients were compared with 17 patients without PCO selected randomly. There was a statistically significant difference in testosterone level and BMI values in patients with PCO compared with those without negative PCO. Patients with PCO had a mean +/- SEM serum testosterone level of 1.2 +/- 0.18 mug/L and BMI values of 29.24 +/- 1.75 kg/m(2). However, patients without PCO had a serum testosterone level of 0.61 +/- 0.1 mug/L and a BMI of 21.91 +/- 0.7 kg/m(2). Menstrual abnormalities were detected in all patients with PCO and in eight patients without PCO. Hirsutism was found in four cases with PCO and in one case with no PCO. There were no statistically significant differences in the duration of therapy, doses and serum concentrations of VPA in patients with PCO compared with those without PCO. These results suggest an association between the use of VPA and PCO, hyperandrogenism, obesity and menstrual abnormalities. For women receiving VPA therapy, clinicians should consider performing an assessment of ovarian structure and function, especially if these patients develop menstrual cycle disturbances during treatment.

カルバマゼピン活性代謝物のカルバマゼピンエポキシドの血中濃度は低年齢でバルプロ酸の血中濃度が高いほど上昇する

Carbamazepine (CBZ), a first-line drug in the treatment of epilepsy, is mainly metabolized in the liver to carbamazepine-10, 11-epoxide (CBZ-epoxide), an active metabolite of carbamazepine. Which is subsequently converted by epoxide hydrolase to trans-10. 11-dihydroxy-10, 11-dihydro-carbamazepine (CBZ-diol). It is well known that the combination of CBZ and valproic acid (VPA), which have an inhibitory effect on epoxide hydrolase, results in an increased serum CBZ-epoxide concentration, and that such drug interaction produces clinically relevant side effects. In the present study, the steady state serum concentrations of CBZ, CBZ-epoxide and CBZ-diol were measured by HPLC in 46 epileptic patients (from 7 months to 19 years of age) who were receiving CBZ monotherapy or 36 epileptic patients (from 1 year to 19 years of age) who were receiving CBZ and valproic acid, in order to investigate the influences of age and the VPA combination on the CBZ metabolism. The concentration ratio of CBZ-epoxide / CBZ in patients receiving CBZ monotherapy decreased with increasing age, but the ratio of CBZ-diol / CBZ-epoxide did not show any significant age dependency. These results suggest that the ability of the biotransformation from CBZ to CBZ-epoxide is higher in younger aged patients. On the other hand, the combination with CBZ and VPA produced a marked increase in the CBZ-epoxide / CBZ ratio and a marked decrease in CBZ-diol / CBZ-epoxide ratio in a VPA serum concentration-dependent manner, thus indicting an inhibitory effect of VPA on epoxide hydrolase. These findings provide evidence that the serum concentration of CBZ-epoxide, an active metabolite of carbamazepine, is higher in younger aged patients and in those with a higher serum concentration of VPA.

Valproic acid increases biliary copper excretion in the rat

The effect of valproic acid (VPA) on the copper absorption and disposition in rat small intestine was investigated using an in situ recirculating perfusion method. Following addition of VPA (20 mg) to the perfusion of 30 ml of 0.9% sodium chloride solution (2 μg/ml copper as CuSO 4) there were no significant differences in copper decline during the perfusion. The absorption rate constant of copper ( k a) which was estimated from the copper decline in the perfusion was unchanged without and with VPA (0.19±0.02 vs. 0.17±0.03 1/h). These results indicate that VPA does not have an effect on copper absorption from the intestine. We also assessed biliary copper excretion by measuring bile flow and biliary copper concentrations. Addition of VPA markedly increased bile flow by 47% for the first hour of bile collection and 91% for the second hour and the biliary copper excretion closely followed the increase in bile flow (without VPA: 0.93±0.15 vs. with VPA: 1.44±0.21 mg for the first and without VPA: 0.98±0.13 mg vs. with VPA: 1.98±0.22 mg for the second hour of bile collection). The total mean value for the biliary copper excretion was increased by 79%. The serum VPA concentration after the perfusion was 31.1±3.2 μg/ml. This high excretion of copper induced by VPA into the bile may upset the homeostatic balance of copper and cause the abnormalities of serum copper concentration. Based on the present studies, we should pay attention to copper levels in patients with VPA treatment.

Delayed valproic acid toxicity: A retrospective case series

Study Objective: We estimate how often an initially undetectable or nontoxic valproic acid (VPA) concentration misrepresents the potential toxicity of an acute VPA overdose. Methods: All patients followed up by the San Diego and San Francisco Divisions of the California Poison Control System between January 1997 and June 1999 with a documented serum VPA concentration of 120 μg/mL or greater at any time were identified through a search of poison center databases. Cases involving patients who had serial VPA concentrations and an initial VPA concentration that was unmeasurable or less than 100 μg/mL were also identified. The methods of decontamination, clinical outcomes, highest measured concentration, and times after ingestion of the initial and highest measured concentration of VPA were determined by means of chart review for these cases. Results: Of the 173 patients identified with VPA concentrations of 120 μg/mL or greater, 21 (12.1%) had a detectable initial concentration not in the toxic range, and 5 (2.9%) had initial concentrations of less than the limit of detection. These 26 cases involved acute ingestion of VPA preparations. Four of these 26 patients were discharged to home or to a psychiatric facility after the initial results were obtained. Conclusion: Delayed toxicity might occur in patients after an acute overdose of enteric-coated VPA. Initial serum VPA concentrations might be misleading. Serial measurements documenting declining VPA concentrations or prolonged observation are recommended to determine whether a patient is medically safe for discharge or psychiatric placement. [Ingels M, Beauchamp J, Clark RF, Williams SR. Delayed valproic acid toxicity: a retrospective case series. Ann Emerg Med. June 2002;39:616-621.]

Acute Valproic Acid Poisoning in Young Children

Objective: To assess the signs and symptoms of acute valproic acid (VPA) overdose in young children. Methods: The medical records of previously healthy children admitted to the pediatric department for accidental acute VPA poisoning during the years 1995–1999 were evaluated retrospectively. Information was retrieved on serum VPA concentrations, signs and symptoms on admission and during hospitalization, electrocardiography findings, and laboratory tests. Results: All 16 children included in the study were in the age range of two to six years. In 13 cases, the drug had been intended for use by a family member and was ingested accidentally by the child. Three children were receiving VPA to treat a seizure disorder and had an adverse reaction due to unintentional overdose. For four children, a diagnosis of VPA poisoning was not made on admission because of inadequate history and was revealed only on toxicology screening. Drowsiness occurred in all the children, hypotonia in 11, ataxia in eight, miosis in six, and mild hypernatremia in five. Only two children had mildly elevated hepatic enzymes. The peak VPA serum concentrations in the study group ranged from 128 to 142 μg/mL (mean ± SD 135 ± 4.25; therapeutic range 50–100). Conclusions: Drowsiness was the most common symptom in young children with mild to moderate VPA poisoning. Other symptoms included hypotonia, ataxia, and miosis. A third of the patients had hypernatremia, most probably due to VPA formulated as sodium valproate. Unlike in cases of chronic toxicity, hepatic damage was not a characteristic finding.

Gender- or age-related binding characteristics of valproic acid to serum proteins in adult patients with epilepsy

The aim of the present study was to determine the gender- or age-related binding characteristics of valproic acid (VPA) to serum proteins in the adult population. Serum samples examined in the study were obtained from 70 adult patients (36 males, 34 females) with epilepsy on VPA monotherapy. Their age ranged from 16 to 68 years (mean age with (SD), 37.7 (15.7) years; <45 years, n=44; ≥45 years, n=26). The in vivo population binding parameters of VPA to serum proteins and theoretical minimal unbound serum VPA fraction ( Fu) were determined using an equation derived from the Scatchard equation in: (1), all; (2), male and female subgroups; and (3), younger (<45 years) and older (≥45 years) subgroups. There was a significant difference in serum concentration of unbound VPA between male and female patients. The mean association constant ( K) was 0.010 μM −1 in all, male, and female patients. The mean total concentration of binding sites ( n( Pt)) was 1453 μM for all patients, and 1561 and 1394 μM for male and female patients, respectively. The Fu was 0.064 for all patients, and 0.060 and 0.067 for male and female patients, respectively. There were no significant differences in the binding characteristics of VPA to serum proteins between the male and female groups. On the other hand, there were significant differences in the serum albumin concentration and molar concentration ratio of free fatty acids to albumin in serum between the younger and older patients. The mean value of K was 0.016 μM −1 for the younger patients and 0.007 μM −1 for the older patients. The mean n( Pt) was 1157 μM for the younger patients and 1703 μM for the older patients. The Fu was 0.051 for the younger patients and 0.077 for the older patients. Thus, significant differences were observed in the binding characteristics of VPA to serum proteins between the younger and older groups. Our results show that age, but not gender, has significant influences on the binding characteristics of VPA to serum proteins in our patient population.

Pharmacokinetics of valproic acid in patients with bipolar disorder.

The pharmacokinetics of valproic acid (VPA) were studied in nine patients with bipolar disorder who were receiving VPA as prophylactic therapy, following the full daily dose (400-1500 mg), on which the patients had been maintained for at least the past 3 months. The data from our study showed that the pharmacokinetics of valproate followed a two compartment open model. A time lag of 1-2 h was observed in each patient, followed by rapid absorption, with the peak concentrations being recorded approximately 4 h after drug administration. The average 12 h trough concentration was found to be 54.73+/-11.96 microg/ml. The plasma level decline was biphasic with a terminal half-life of 14.2+/-6.39 h. Total plasma clearance was 0.095+/-0.035 ml/min/kg. The steady-state apparent volume of distribution was found to be 0.11+/-0.05 l/kg. A positive correlation (r = 0.69) was found between the dose (mg/kg) and steady-state serum concentration (Css) of VPA and all patients, except one, had their Css above 50 microg/ml. Most of the pharmacokinetic parameters in this study involving euthymic bipolar patients on long-term VPA monotherapy were found to be in agreement with those reported in literature on seizure disorder patients on similar regime; however, the plasma elimination half-life appears to be prolonged in bipolar patients.