Serum Valproate Concentrations Research Articles

Population Pharmacokinetics of Valproate in Children: The Importance of Total Daily Dose, Compliance and Co-Treatment

Abstract Valproate represents one of the most commonly used anticonvulsants worldwide, whose narrow therapeutic range and high potential for drug-drug interactions leads to pronounced intra- and inter-individual variability in plasma concentration and response. The aim of our study was to apply population pharmacokinetics analysis to comprehensively investigate and detect the most important factors affecting pharmacokinetics of valproate in Serbian children with epilepsy. This retrospective observational study was based on demographic and medical data retrieved from the medical records on epileptic patients treated with valproate at the pediatric department of the Clinical Centre, Kragujevac, Serbia. Valproate serum concentrations were obtained as a part of routine medical practice. Population pharmacokinetics analysis was performed by MonolixSuite 2019R1 (Lixoft, Antony, France) software, using one-compartment model with first order absorption and linear elimination. The study included 1642 valproate concentrations obtained from 232 patients, of which 201 (1420 concentrations) were included in the index set used for the modelling, while the other 31 (222 concentrations) were the validation set used for external validation of the final model. Covariate testing based on the whole index set revealed that only total daily valproate dose significanly affected the clearance of valproate: Cl (l/h)= 0.135×1.002DD. When only compliant patients were included, co-treatment with carbamazepine was shown to be of significance as well: Cl(l/h)=0.121×1.002DD×1.2CBZ. Our study demonstrated that valproate clearance correlates with total valproate daily dose. The influence of co-treatment with carbamazepine on valproate pharmacokinetics can be observed and used for clearance estimation only in compliant patients.

Evaluating Clinical Sequelae of the Carbapenem-Valproate Interaction: A Retrospective Analysis.

Previous studies identified a rapid decrease in valproate serum concentrations when coadministered with a carbapenem; however, the specific consequences and subsequent therapy adjustments are not well described. We aimed to investigate the clinical and therapeutic implications of the carbapenem-valproate drug-drug interaction. This retrospective analysis included data from 2 large academic medical centers during January 2017 to June 2022. The primary outcome was incidence of seizures or behavioral events stratified by valproate indication. All adult patient encounters with concomitant administration of any carbapenem antimicrobial and valproate were included. Patients without prolonged exposure to valproate prior to hospitalization, without valproate levels pre- and post-carbapenem administration, with an admitting diagnosis of seizure, with exposure to other agents that decrease valproate concentrations, or who had a seizure during the hospitalization prior to carbapenem exposure were excluded. Two hundred fifty-eight episodes of concomitant use among 78 unique adult patients were included. Valproate was used for seizure control in 41 patients (52.6%) and for mood-related disorders in 37 (47.4%). In those prescribed valproate for its antiepileptic properties, seizures occurred following carbapenem administration in 46.3% of encounters. In those taking valproate for mood-related disorders, 50.8% met the primary endpoint of behavioral disturbance. Our study demonstrates significant clinical implications of the carbapenem-valproate interaction. Clinicians should be aware of this interaction and consider alternative antimicrobial and/or antiepileptic agents whenever possible. Adding or increasing doses of antiepileptic agents and/or consultation with a neurologist prior to concomitant use should be considered when this combination cannot be avoided.

Factors Influencing Sodium Valproate Serum Concentrations in Patients with Epilepsy Based on Logistic Regression Analysis

BackgroundWe aimed to explore the risk factors that affect the serum concentration of sodium valproate (VPA-Na) in patients with epilepsy and to provide references for the rationale of the use of VPA-Na.Material/MethodsThe enzyme-multiplied immunoassay technique was used to determine the serum VPA-NA concentrations of 109 patients, and the results were retrospectively analyzed and summarized. A multivariate logistic regression model was used to analyze substandard serum VPA-Na concentrations.ResultsFifty-six patients (51.38%) treated with VPA-Na tablets were within the effective treatment range of 50–100 μg/mL, while 53 patients (48.62%) were out of the treatment range. The results indicated that the standard-reaching rate of serum drug concentration in the juvenile group was higher than that in the adult and elderly groups; the standard-reaching rates of serum drug concentrations in the low-dose group and the intermediate-dose group were lower than that in the high-dose group; and the standard-reaching rate of serum drug concentration in the group receiving carbapenems in combination was lower than that in the non-combination group; all differences were statistically significant. The combination with carbapenems and enzyme inducers was an independent risk factor for VPA-Na serum concentration below the target level in hospitalized patients.ConclusionsTo improve clinical efficacy and reduce the occurrence of adverse reactions, there is a need for therapeutic drug monitoring of VPA-Na. Moreover, individual administration should be implemented when VPA-Na tablets are used in the treatment of epilepsy because of the significant fluctuation in VPA-Na blood concentration.

Valproic Acid Induced Thrombocytopenia and Dysmegakaryopoiesis in a Pediatric Patient

Abstract Introduction/Objective Valproic acid is a branched short chain fatty acid derivative that is used primarily to treat epilepsy as well as mood disorders, certain types of headaches, and neuropathic pain. It is commonly prescribed in the pediatric population and has shown to be effective for refractory epilepsy with adequate seizure control. Serious side effects may be prominent if the medication is not kept at the therapeutic range. A wide variety of known hematologic problems can be encountered including but not limited to anemia, thrombocytopenia, and leukopenia. Methods/Case Report We present a case of a pediatric patient with a past medical history significant for history of seizure disorder and who presented to Jackson Memorial Hospital for intermittent fevers and multiple unexplained bruises for 3 weeks as well as fatigue and weakness.The patient was recently started on valproic acid. Complete blood count (CBC) was obtained and showed a platelet count of 23 x10(3)/mcL with WBC of 3.5 x10(3)/mcL and hemoglobin of 9.7 g/dL.Serum valproate concentration was critically high (154 mg/L). Trephine biopsy showed a normocellular marrow (60%) showing maturing trilineage hematopoiesis and scattered atypical megakaryopoiesis characterized by small forms that are seen in relatively loose interstitial clusters (Figure 1). The marrow aspirate smears were characterized by cellular spicules with dysmegakaryopoiesis including numerous small hypolobated forms with frequent forms showing separated nuclei (Figure 2, 3, and 4). Blasts did not appear increased, comprising overall 1% of marrow cellularity. Karyotype studies revealed a normal female karyotype, 46, XX. FISH studies using probes commonly detected in MDS were negative. Next generation sequencing was negative for AML specific mutations including GATA1 and GATA2 mutations. Results (if a Case Study enter NA) N/A Conclusion This case report highlights the significant hematologic adverse effects of valproic acid, specifically pancytopenia with dysmegakaryopoiesis, raising the clinical suspicion of potential myelodysplastic syndrome. Critically high level of valproic acid (154 mg/L) and normalization of CBC after the stoppage of the medication strongly suggests that valproic acid can cause severe bone marrow suppression and specific morphologic atypia in the megakaryocytic lineage thus introducing a potential diagnostic pitfall. Because the CBC returned to normal, bone marrow biopsy was not repeated.

UGT1A6 and UGT2B7 Gene Polymorphism and its Effect in Pediatric Epileptic Patients on Sodium Valproate Monotherapy

To evaluate the pattern of UGT1A6 and UGT2B7 gene polymorphism in pediatric epileptic patients and to compare the sodium valproate concentration in different patterns of UGT gene polymorphism. In this cross-sectional study, 99 pediatric epileptic patients aged 2-18 y receiving Sodium valproate monotherapy for the past one month were included from JusticeK S Hegde Charitable hospital, Mangalore after obtaining informed consent. Genetic polymorphism patterns were evaluated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Trough level serum valproate concentration was estimated by high-performance liquid chromatography (HPLC). Sodium valproate concentration in different UGT genotypes was compared by Analysis of Variance (ANOVA). P value <0.05 was considered significant. In the present study population, the predominant mutant allele pattern was observed in UGT1A6 (T19G, A541G, A552C) gene. In UGT2B7 (A268G, C161T) showed predominant mutant allele pattern while (G211T) showed predominant wild type. Mean steady-state sodium valproate concentration was 105.40 ± 49.9μg/ml and adjusted sodium valproate concentration was 5.5± 3.2mg/kg/L. It was found that there was no statistical difference in sodium valproate concentration in different UGT1A6 and UGT2B7 gene polymorphism. The present study concluded that though there was a difference in pattern of gene polymorphism with concerning UGT1A6 and UGT2B7, however, it has not contributed to variation in serum concentration of sodium valproate in the present study population.

Valproate Interaction With Carbapenems: Review and Recommendations.

Introduction: Valproic acid is a commonly used antiepileptic drug. Combining valproate derivatives with carbapenem antibiotics is associated with a potential drug interaction that decreases serum concentration of valproate and may expose the patient to uncontrolled seizure risk from valproate subtherapeutic concentration. Raising awareness of this drug interaction among health care providers including emergency department physicians, neurologists, and pharmacists is highly needed. The aim of this article was to review the current literature about the potential drug interaction resulting from combining valproate derivatives with carbapenem antibiotics and to establish therapeutic recommendations regarding their use together. Methods: A review of the literature was conducted using Medline (through PubMed), Ovid, Embase, Cochrane library using the following keywords: valproate, valproic acid, carbapenem, ertapenem, doripenem, meropenem, imipenem, and valproate drug interaction. In addition, a manual search through major journals for articles referenced in PubMed was performed. Related publications from January 1998 till November 2018 were included in the initial search. Relevant publications were reviewed, and data regarding patients, type of carbapenem used, valproic acid dosing and level, interaction severity, and clinical outcome were summarized. Results and Discussion: Few clinical trials and multiple case reports have shown that carbapenem antibiotics including meropenem, ertapenem, imipenem, and doripenem can decrease the serum concentration of valproate derivatives leading to a subtherapeutic serum concentration and seizures in some patients. Valproic acid serum concentration may be significantly decreased with addition of a carbapenem antibiotic but generally return toward normal shortly after discontinuation of the carbapenem antibiotic. Conclusions: Generally, the concurrent use of carbapenem antibiotics with valproate derivatives should be avoided due to the potential of drug-drug interaction that results in subtherapeutic valproate serum concentration. Other antimicrobial agents should be considered as alternatives to carbapenems but if a concurrent carbapenem is necessary, using an additional antiepileptic agent is recommended. Therapeutic drug monitoring of valproate serum concentrations is warranted when a carbapenem-valproic acid combination therapy is unavoidable.

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models.

Valproate is an old-generation antiepileptic drug often used in children. The pharmacokinetics of valproate are noteworthy for a large and difficult to predict interindividual variability in measured serum concentrations and for saturable protein binding. A model-based approach to personalize valproate treatment could be relevant in pediatric patients. The aims of this study were to review all published valproate population pharmacokinetic models in children and assess them by external validation to determine their predictive performance. Through simulations with the best model, we evaluated dosing regimen. A validation data set included valproate serum concentrations assayed during routine therapeutic drug monitoring of epileptic children. We applied to our population 11 published pediatric population pharmacokinetic models. For each model, predictive performance was assessed by external validation, using bias and precision calculations as well as goodness-of-fit plots. Dose simulations were conducted with the best predictive model to evaluate dosing regimen. The validation data set contained 178 valproate concentrations ranging from 13.4 to 128mg/L from 114 patients. The best model exhibited a mean prediction error of 6.6mg/L and a root mean squared error of 25.1mg/L, with no model misspecification evidenced by visual predictive check. In our cohort, half the patients had a trough concentration <50mg/L. Simulations suggested increasing doses, especially for children ≤40kg. External evaluation of published valproate pharmacokinetic models enabled us to identify a suitable model for simulations and Bayesian forecasting. Dosing regimen should be adjusted to weight, with decreasing doses with increasing weight.

GERI-BD: A Randomized Double-Blind Controlled Trial of Lithium and Divalproex in the Treatment of Mania in Older Patients With Bipolar Disorder.

Clinicians treating older patients with bipolar disorder with mood stabilizers need evidence from age-specific randomized controlled trials. The authors describe findings from a first such study of late-life mania. The authors compared the tolerability and efficacy of lithium carbonate and divalproex in 224 inpatients and outpatients age 60 or older with bipolar I disorder who presented with a manic, hypomanic, or mixed episode. Participants were randomly assigned, under double-blind conditions, to treatment with lithium (target serum concentration, 0.80-0.99 mEq/L) or divalproex (target serum valproate concentration, 80-99 μg/mL) for 9 weeks. Participants with an inadequate response after 3 weeks received open adjunctive risperidone. The authors hypothesized that divalproex would be better tolerated and more efficacious than lithium. Tolerability was assessed based on a measure of sedation and on the proportions of participants achieving target concentrations. Efficacy was assessed with the Young Mania Rating Scale (YMRS). Attrition rates were similar for lithium and divalproex (14% and 18% at week 3 and 51% and 44% at week 9, respectively). The groups did not differ significantly in sedation. Participants in the lithium group tended to experience more tremor. Similar proportions of participants in the lithium and divalproex groups achieved target concentrations (57% and 56%, respectively). A longitudinal mixed model of improvement (change from baseline in YMRS score) favored lithium (change in score, 3.90; 97.5% CI=1.71, 6.09). Nine-week response rates did not differ significantly between the lithium and divalproex groups (79% and 73%, respectively). The need for adjunctive risperidone was low and similar between groups (17% and 14%, respectively). Both lithium and divalproex were adequately tolerated and efficacious; lithium was associated with a greater reduction in mania scores over 9 weeks.

Valproate serum concentrations in patients with hypoalbuminemia and medical complications.

Valproic acid (VPA) and its derivatives are highly protein bound with free fraction increasing with dose and serum concentration. Consensus guidelines regarding dose adjustment for hypoalbuminemia are not available. A literature search was performed using PubMed to identify articles with the following key terms: "valproate," "valproic acid," "protein binding," "albumin," and "hypoalbuminemia." We report our findings as well as 5 cases involving pharmacokinetic impact of hypoalbuminemia on valproate. A previously published model for normalizing VPA serum concentration for hypoalbuminemia in patients with epilepsy was compared to results for 5 cases (4 female, 1 male) in which VPA was used for psychiatric illness. Only 1 of the cases had free serum concentrations in the range that would be expected with the model. Free concentrations ranged from 22% to 83% with no clear relationship to other factors (weight, age, serum creatinine, or dose). Female patients with similar albumin had higher free fractions than the 1 male patient. Due to the variability in pharmacokinetic impact of hypoalbuminemia, it is important to monitor patients closely for signs of VPA toxicity in cases involving altered albumin levels. It would be prudent to use free serum VPA concentrations when patients experience fluctuations in albumin or have unexpected response to medication.

Add-on stiripentol elevates serum valproate levels in patients with or without concomitant topiramate therapy

ObjectiveStiripentol (STP), valproate (VPA) and topiramate (TPM) are reported to have efficacy for Dravet syndrome. In this study, we sought to elucidate the mechanisms underlying the increased serum VPA concentrations following STP adjunctive therapy in patients with Dravet syndrome. MethodsTwenty-eight patients with Dravet syndrome (age range, 1–35 years) undergoing combination therapy with VPA and STP were included in this study. We evaluated VPA and clobazam (CLB) serum concentrations before and after add-on STP. We also investigated potential factors impacting VPA metabolism during add-on STP therapy, including add-on TPM and CYP2C9 and CYP2C19 gene polymorphisms. The effect of STP on the metabolism of concomitantly administered CLB was also investigated. ResultsAdd-on STP was significantly associated with the serum concentration-to-dose (CD) ratio of VPA. Two patients, who were concomitantly treated with TPM, developed severe anorexia and thrombocytopenia because of marked increases in serum VPA concentrations. Further analysis revealed that the rate of increase in the VPA CD ratio was positively correlated with TPM dose. In patients not receiving TPM, STP enhanced the rate of increase in the VPA CD ratio to a significantly greater extent in CYP2C19 extensive metabolizers than in CYP2C19 poor metabolizers. Add-on STP was also associated with significant increases in CLB and N-desmethyl-CLB serum concentrations. ConclusionOur findings suggest that serum VPA concentrations should be carefully monitored during STP adjunctive therapy, particularly in patients receiving concomitant TPM therapy.

Commentary on clinical significance of CYP2C9‐status‐guided valproic acid therapy in children

The results of this retrospective study1 suggest a positive effect of cytochrome P450 (CYP)2C9–guided valproate (VPA) treatment when compared with non–CYP2C9-guided treatment, based on the significant lower rate of patients with hyperammonemia in the CYP2C9-guided cohort. Eight of 47 patients in the control group versus one of 51 patients in the CYP2C9-guided group showed hyperammonemia 1 month after the beginning of VPA treatment. We think that the study results should be interpreted with caution, however. In the intervention group, CYP2C9 status was determined, but the incidence of low expressers was higher than expected according to the literature.2 If the expression of the CYP2C9 gene was different in the control group, this could have led to a substantial bias. This potential bias could influence the (significant) higher ratio of patients with a serum VPA concentration outside the therapeutic range. The intervention and control groups also differed with respect to VPA dosing. The control group received a dosing of 20–40 mg/kg. Dosing for the normal expressers in the intervention group was 30–40 mg/kg. The authors did not explain why normal expressers did not receive VPA treatment based on standard clinical protocol, and the mean or average dose in either cohorts were not reported, as could influence outcome. The authors found a higher rate of hyperammonemia in the control group without hepatotoxicity. Literature reports between 100 and 260 clinical apparent cases of hepatotoxicity or hepatotoxicity with a fatal outcome in the period ranging from 1977 until 2013. However, the literature also notes that serious adverse reactions are rare, especially those leading to fatalities.3, 4 One patient with hyperammonemia was observed with secondary symptoms (nausea, vomiting, lack of appetite, fatigue, drowsiness, confusion, cognitive slowing, or loss of consciousness). It is not mentioned if this was in the control or intervention group. Also Segura-Bruna et al.5 have noted that no relationship has been found between the daily doses of VPA and the appearance and severity of valproate-induced hyperammonemic encephalopathy (VHE).6 They also noted no relationship between the development of VHE and serum VPA levels. Others described no correlation between clinical severity of VHE and higher blood ammonium levels when hyperammonemia was confirmed.6 So there does not seem to be a solid relationship between the development of clinically significant VHE and serum VPA levels.5 As is suggested by Monostory et al. In conclusion, in our opinion the authors note this research as a first attempt to establish the influence of CYP2C9 on VPA metabolism. However, based on presented data and given the low prevalence of hepatotoxicity, the study seems to be too small to make firm conclusions such as that CYP2C9-status-guided VPA treatment is preferable to non–CYP2C9-guided treatment and that CYP2C9-guided VPA treatment has demonstrated to improve the safety of VPA treatment. None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

The relationship between valproate induced tremors and circulating neurotransmitters: a preliminary study

Patients with epilepsy and on valproate (VPA) therapy may develop tremors as a common adverse effect; however, its exact mechanisms are unknown. We hypothesize that VPA-induced tremors may be related to the disturbances in dopamine (DA) and catecholamines (norepinephrine (NE) and epinephrine (E)) concentrations (which are also involved in VPA anticonvulsant effect). We aimed to determine the frequency and type of VPA-induced tremors and their risk factors and to investigate whether or not they are related to the plasma DA, NE and E concentrations. This study included 75 adults with primary epilepsy (mean age: 31.90 ± 5.62 years) and on VPA therapy for 10.57 ± 3.55 years and 40 matched healthy controls. Patients were divided according to the absence or presence of tremors. Blood samples were analyzed for DA, NE and E. Intermittent action tremors in both hands were reported in 31 (41.33%). Chronic standard VPA therapy, older age, longer treatment duration and higher serum concentrations of VPA are risk factors for tremors. None of the patients on controlled release VPA had tremors. Compared to controls, patients (without and with tremors) had lower DA (p = 0.0001) and NE (p = 0.01) concentrations. Compared to patients without tremors, patients with tremors had lower levels DA (p = 0.045) and NE (p = 0.01). Significant correlations were identified between DA with NE (r = 0.540, p = 0.001) concentrations and serum VPA with DA (r = −0.285, p = 0.045) and NE (r = −0.358, p = 0.01) plasma levels. We conclude that benign action tremors are common with standard VPA. Mechanisms underlying VPA-induced tremors may involve abnormalities of DA and NE neurotransmitters.

Comparison of Serum Total Valproic Acid Levels and %CDT Values in Chronic Alcohol Addictive Patients in an Italian Clinic: A Retrospective Study.

BackgroundValproate is a broad-spectrum anticonvulsant that is effective in the treatment of tonic-clonic, myoclonic and absence seizures as well as in partial seizures as a second-line drug. It has been widely demonstrated in the literature that the effect of valproate on type-A γ-aminobutyric acid (GABA-A) receptors may reduce relapse to ethanol abuse. This retrospective study evaluated a 3-year period in which 42 patients from the Department of Alcoholism and Substance Abuse (DASA) were treated with valproate.ObjectivesWe compared different serum total valproic acid (VPA) concentrations, and the effectiveness of this drug in maintaining alcohol abstinence was evaluated by percentage of carbohydrate deficient transferrin (%CDT) values.MethodCDT is a biochemical marker used for identifying regular high alcohol consumption and monitoring abstinence in outpatients during treatment. Serum concentrations of valproate were divided into four groups: <10, 10–30, 31–50, and >50 µg/mL.ResultsThis study shows that a mean serum total VPA concentration >30 µg/mL is more effective in maintaining alcohol abstinence than a lower one (p < 0.05). In this study, mean serum total VPA concentrations between 31 and 50 µg/mL showed the same effectiveness as higher ones (>50 µg/mL); in fact, there was no significant difference in mean %CDT values between these two groups (p > 0.05). After at least 12 months’ treatment with valproate, mean platelet counts increased by 12 × 103/μL compared with baseline (254 ± 63 vs 242 × 103/μL, p > 0.05, respectively) in patients with mean serum total VPA levels <10 μg/mL; increased by 8 × 103/μL from baseline (253 ± 59 vs 245 × 103/μL, p > 0.05, respectively) in patients with levels between 10 and 30 μg/mL; decreased by 2 × 103/μL from baseline (265 ± 63 vs 267 × 103/μL, p > 0.05, respectively) in patients with levels between 31 and 50 μg/mL, and decreased by 48 × 103/μL from baseline (215 ± 56 vs 263 × 103/μL, p < 0.05, respectively) in patients with levels >50 μg/mL.ConclusionA mean serum total concentration lower than the currently accepted therapeutic level (50–100 µg/mL) may have the same effectiveness in maintaining alcohol abstinence with a lower risk of presenting side effects.

Phenoconversion of CYP2C9 in epilepsy limits the predictive value of CYP2C9 genotype in optimizing valproate therapy.

Since prominent role in valproate metabolism is assigned to CYP2C9 in pediatric patients, the association between children's CYP2C9-status and serum valproate concentrations or dose-requirements was evaluated. The contribution of CYP2C9 genotype and CYP2C9 expression in children (n = 50, Caucasian) with epilepsy to valproate pharmacokinetics was analyzed. Valproate concentrations were significantly lower in normal expressers with CYP2C9*1/*1 than in low expressers or in patients carrying polymorphic CYP2C9 alleles. Consistently, the dose-requirement was substantially higher in normal expressers carrying CYP2C9*1/*1 (33.3 mg/kg vs 13.8-17.8 mg/kg, p < 0.0001). Low CYP2C9 expression significantly increased the ratio of poor metabolizers predictable from CYP2C9 genotype (by 46%). Due to the substantial downregulation of CYP2C9 expression in epilepsy, inferring patients' valproate metabolizing phenotype merely from CYP2C9 genotype results in false prediction.

Seizure worsening caused by low serum valproate levels from an interaction between valproate and meropenem

We present an interaction of meropenem with valproate in an epileptic child, leading to seizure exacerbations owing to the rapid lowering of serum valproate concentration. An increase of seizure frequency and somnolence were observed in the patient after the addition of meropenem to the treatment, and a rapid decline of valproate serum concentrations was observed after two doses of meropenem. This decline was the most likely cause of the increase in seizure frequency. The dosage of valproate was raised and meropenem was stopped. Two days later, the seizures stopped. Five days later, the serum valproate concentrations raised to three fold, and they rose to therapeutic levels four weeks later. To avoid drug interaction that reduces the serum concentration of valproate, meropenem in epileptic patients using valproate for the treatment of epilepsy should be administered cautiously. If concominant administration is essential, close observation of serum concentration of valproate and clinical course of the patient are necessary. Keywords: Carbapenems, Drug interactions, Meropenem, Seizures, Valproate

&lt;b&gt;A Case of Valproate Overdose Complicated by Severe Hyperammonemia that was Ameliorated with Time Concomitant with Decline in Serum Valproate Concentration&lt;/b&gt;

&lt;b&gt;A Case of Valproate Overdose Complicated by Severe Hyperammonemia that was Ameliorated with Time Concomitant with Decline in Serum Valproate Concentration&lt;/b&gt;

Prevalence of UGT1A6 polymorphisms in children with epilepsy on valproate monotherapy.

Valproate is a commonly used anticonvulsant drug. Uridine 5΄-diphospho (UDP)-glucuronosyltransferase (UGT) contributes to around 50% of valproate metabolism and its polymorphisms may be important for explaining the considerable variation in valproate levels in patients with epilepsy. This study was aimed to analyze the genetic polymorphisms of UGT1A6 in Indian children with epilepsy and their potential influence on the pharmacokinetics of valproate. This cross-sectional study was carried out in the Department of Pediatrics, All India Institutes of Medical Sciences (AIIMS), New Delhi, between March 2011 and July 2012. Children aged 3-12 years diagnosed with epilepsy on valproate monotherapy for at least 1 month were enrolled. They underwent a detailed clinical examination. The UGT1A6 polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Random samples were checked by genetic sequencing. The steady-state plasma concentrations of valproate were measured by High Performance Liquid Chromatography (HPLC) and associated with UGT1A6 polymorphisms. A total of 80 children were studied. The prevalence of UGT1A6 T19G was as follows: TT (45%), TG (38.8%), and GG (16.3%); that of UGT1A6 A541G was: AA (48.8%), AG (38.8%), and GG (12.5%); and that of UGT1A6 A552C was: AA (43.8%), AC (40%), and CC (16.3%). The association between valproate doses or standardized serum valproate concentration and the various UGT1A6 genotypes could not be studied reliably in this small study population. The frequencies of UGT1A6 geneotypes and alleles were reported in the study population.

Concentration of Il-1β, Il-2, Il-6, TNFα in the blood serum in children with generalized epilepsy treated by valproate

BackgroundThe aim of the study was the comparison of concentrations of IL-1β, IL-2, IL-6 and TNFα before and after valproate (VPA) treatment in blood serum in patients with generalized seizures diagnosed and treated in the Department of Developmental Neurology, Poznan University of Medical Sciences from January 2006 to May 2007. MethodsThe analysis was conducted in a group of 21 patients with well controlled, generalized seizures (mean age 7.7±4.7 years) before and after 4–6 months of VPA therapy. Quantitative determination IL-1β, IL-2, IL-6 and TNFα were performed with method of enzyme-linked immunosorbent assay (ELISA). The serum drug concentration was determined with the use of fluorescence-polarization-immunoassay system (FPIA). ResultsThe concentration of IL-6 in blood serum of patients decreased significantly (p<0.001) after 4–6 months of VPA therapy, but concentration of IL-1β (p=0.732), IL-2 (p=0.865), TNFα (p=0.079) did not change significantly. The serum concentration of VPA in all of patients was in therapeutic range (mean 77.53±19.71μg/ml). ConclusionsThe serum level of pro-inflammatory IL-6 in patients with generalized epilepsy decreased in statistically significant way during VPA therapy, so the anti-inflammatory properties of VPA are also important for the effective control of seizure. Due to the incompatibility of reports on the influence of VPA on cytokine system in patients with generalized epilepsy, this problem needs more investigations, especially in the group of children.

Manic episode induced by steroid (fluorometholone) eye drops in an elderly patient

A 76-year-old man was diagnosed with cataract in both eyes, and surgical intervention was planned. After diagnosis, he showed anxiety and agitation, and frequently became irritable and verbally abusive. One month later, the operation was performed successfully, and administration of fluorometholone eye drops was started. Although the patient was pleased with the improvement of his eyesight, his aggressive behavior escalated, and he used violent and abusive language towards his family and strangers. Two months after the operation, he visited our hospital. He showed hyperthymia and hyperactivity. He was lucid and coherent, and was able to remember his behavior; however, he showed no sign of regret. The Young Mania Rating Scale1 (YMRS) score was 32. A medical work-up, including complete blood cell count, liver, renal and thyroid function tests, vitamin levels, and an examination for infectious diseases, showed no abnormalities. Brain computed tomography (CT) showed mild cortical atrophy appropriate for his age. The Mini-Mental State Examination score was 26; his memory and orientation were within the normal range. To determine its relevance, the fluorometholone eye drop was discontinued, and sodium valproate (200 mg/day) was administered. Seven days later, the patient's behavior improved rapidly. The YMRS score decreased to 7. The serum concentration of valproate was 11.1 μg/mL. Presently (12 months after the first visit to our hospital), he is stable and shows no psychiatric symptoms. Psychiatric symptoms frequently occur as central nervous system-related adverse effects of pharmacotherapy; topical agents, such as eye drops, have also shown adverse psychiatric effects.2 To date, however, adverse psychiatric effects of steroid eye drops have never been reported. In our patient, the serum concentration of valproate was markedly lower than the general level corresponding to acute mania (>94 μg/mL3); therefore, discontinuation of the fluorometholone eye drops was possibly associated with recovery from the manic episode. In a report on a patient with hallucinatory–paranoid state induced by subconjunctival injection of steroids, psychological stress and organic changes of the brain were suggested to induce psychosis upon exposure to a small amount of steroid.4 Similarly, our patient showed extreme anxiety and agitation initially, and his brain CT showed atrophy due to aging. These factors possibly contributed to a predisposition to develop psychiatric symptoms when treated with a small amount of steroid. Thus, when elderly patients with anxiety are treated with even a small dose of steroids, psychiatric symptoms should be carefully monitored.

Fatal heat stroke associated with topiramate therapy

A 40-year-old man with diabetes and seizure disorder was found at home unresponsive and "very hot to touch" by his father 40 minutes before emergency medical services arrival. His usual medications included topiramate, divalproex sodium, and rosiglitazone/metformin. Paramedics administered oxygen, intravenous fluids, and naloxone. They did not witness or report seizure activity. Upon emergency department arrival, the patient was unresponsive (Glasgow Coma Scale 3), hypotensive (94/50 mm Hg), and tachypneic (32 breaths per minute), with a heart rate of 60 beats per minute and elevated rectal temperature peaking at 43.2°C. His skin was hot and dry, without rash; physical examination was otherwise normal. Laboratory studies revealed severe metabolic acidosis with acute renal failure and rhabdomyolysis. In spite of sedation, intubation, and aggressive cooling measures, the patient had cardiac arrest and died approximately 2 hours after arrival. Serum topiramate and valproate concentrations were within therapeutic ranges at 8.8 μg/mL (therapeutic 2-12) and 97 μg/mL (therapeutic 50-100), respectively.