Serum Valproic Acid Levels Research Articles

Window-of-Opportunity Study of Valproic Acid in Breast Cancer Testing a Gene Expression Biomarker.

PurposeThe anticancer activity of valproic acid (VPA) is attributed to the inhibition of histone deacetylase. We previously published the genomically derived sensitivity signature for VPA (GDSS-VPA), a gene expression biomarker that predicts breast cancer sensitivity to VPA in vitro and in vivo. We conducted a window-of-opportunity study that examined the tolerability of VPA and the ability of the GDSS-VPA to predict biologic changes in breast tumors after treatment with VPA.Patients and MethodsEligible women had untreated breast cancer with breast tumors larger than 1.5 cm. After a biopsy, women were given VPA for 7 to 12 days, increasing from 30 mg/kg/d orally divided into two doses per day to a maximum of 50 mg/kg/d. After VPA treatment, serum VPA level was measured and then breast surgery or biopsy was performed. Tumor proliferation was assessed by using Ki-67 immunohistochemistry. Histone acetylation of peripheral blood mononuclear cells was assessed by Western blot. Dynamic contrast-enhanced magnetic resonance imaging scans were performed before and after VPA treatment.ResultsThirty women were evaluable. The median age was 54 years (range, 31-73 years). Fifty-two percent of women tolerated VPA at 50 mg/kg/d, but 10% missed more than two doses as a result of adverse events. Grade 3 adverse events included vomiting and diarrhea (one patient) and fatigue (one patient). The end serum VPA level correlated with a change in histone acetylation of peripheral blood mononuclear cells (ρ = 0.451; P = .024). Fifty percent of women (three of six) with triple-negative breast cancer had a Ki-67 reduction of at least 10% compared with 17% of other women. Women whose tumors had higher GDSS-VPA were more likely to have a Ki-67 decrease of at least 10% (area under the curve, 0.66).ConclusionVPA was well tolerated and there was a significant correlation between serum VPA levels and histone acetylation. VPA treatment caused a decrease in proliferation of breast tumors. The genomic biomarker correlated with decreased proliferation. Inhibition of histone deacetylase is a valid strategy for drug development in triple-negative breast cancer using gene expression biomarkers.

PD37-08 ENHANCING THE EFFICACY OF VALPROIC ACID IN PROSTATE CANCER CELLS WITH NUTRITIONAL SUPPLEMENTS

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II1 Apr 2017PD37-08 ENHANCING THE EFFICACY OF VALPROIC ACID IN PROSTATE CANCER CELLS WITH NUTRITIONAL SUPPLEMENTS Wasim H. Chowdhury, Anna-Barbara O'James, Abhinav Sidana, Jatindar Goyal, Daniel Oh, Grace I. Todd, Mizanur Rahman, and Ronald Rodriguez Wasim H. ChowdhuryWasim H. Chowdhury More articles by this author , Anna-Barbara O'JamesAnna-Barbara O'James More articles by this author , Abhinav SidanaAbhinav Sidana More articles by this author , Jatindar GoyalJatindar Goyal More articles by this author , Daniel OhDaniel Oh More articles by this author , Grace I. ToddGrace I. Todd More articles by this author , Mizanur RahmanMizanur Rahman More articles by this author , and Ronald RodriguezRonald Rodriguez More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1570AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The use of histone deacetylase inhibitors (HDACIs) in treating Castrate Resistant Prostate Cancer is well studied. We have previously published the beneficial effects of treating Bladder as well as Prostate cancer (CaP) in animal models with Valproic acid (VPA), a type I HDACI. Docosahexaenoic acid (DHA), an ω-3 fatty acid, is a primary structural component of the human brain, skin, sperm, testicles and retina. Fish oil, a popular nutritional supplement, is a major source of DHA. Over two decades of research show favorable effects of DHA on bone health, as well as a chemo-sensitizing agent in treating cancer. Here we report an interim analysis of a randomized, controlled phase II study of VPA in patients with non-metastatic biochemical progression of (BCR) CaP, and the utility of combining DHA with VPA in potentially reducing side effects. METHODS Patients with non-metastatic BCR CaP were screened for eligibility and randomized into either observation or VPA (oral, twice daily) arms. Serum VPA and PSA levels were monitored bi-weekly and monthly. We also investigated methods of minimizing the side effects of VPA while maintaining efficacy. RESULTS Treatment with VPA resulted in an increased PSA doubling time (PSADT) in patients from 4.02 to 40.67 months, while the PSADT in the control group stayed relatively unchanged at 6.34 to 6.95 months. However, the treatment group suffered from debilitating fatigue and lethargy at the dose required for effective treatment. As such we investigated options of reducing the VPA dose while maintaining efficacy. Both in vitro and in a mouse model we demonstrate that combining VPA with DHA has a greater efficacy. In the in vitro model we show that in the combination we can reduce the dose of VPA by half and still maintain similar efficacy. Also chronic treatment with the combination had a much greater effect on cell kill as opposed to acute treatment. Moreover, folic acid, another common supplement, enhances cell kill by the combination. CONCLUSIONS Based on our studies VPA could be used in combination with DHA, a supplement, to delay or even prevent the use of hormone therapy in prostate cancer patients with BCR. In addition, both clinicians and patients should be made aware of the effects of dietary supplements, as they can positively or potentially negatively affect the efficacy of certain drugs. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e676-e677 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Wasim H. Chowdhury More articles by this author Anna-Barbara O'James More articles by this author Abhinav Sidana More articles by this author Jatindar Goyal More articles by this author Daniel Oh More articles by this author Grace I. Todd More articles by this author Mizanur Rahman More articles by this author Ronald Rodriguez More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Drug interaction between valproic acid and carbapenems in patients with epileptic seizures

Valproic acid (VPA) is a widely used antiepileptic drug (AED). When carbapenems are concomitantly used with VPA, the serum levels of VPA may decrease and aggravate seizures. The aim of this study was to evaluate the risk factors associated with decreased serum VPA levels and clinical outcome in patients being treated with a combination of carbapenems and VPA. Fifty-four adult patients who were treated with VPA for epileptic seizures concomitant with carbapenems for the treatment of infections were evaluated in this study. Serum VPA levels were measured before and during combination therapy with VPA and carbapenems, and the change in serum VPA levels was calculated. The risk factors related to the decrease in serum VPA levels and clinical outcomes were evaluated. Our results show that VPA concentrations were reduced to subtherapeutic levels after the introduction of carbapenems. The reduction in VPA concentrations was found within 24 hours of the start of treatment with carbapenems. VPA levels continuously declined while the combination of treatments was used, which aggravated epileptic seizures in 48% of the patients. Renal disease and enzyme-inducing AEDs were risk factors that contributed to the severity of reduced serum VPA levels during combined treatment with carbapenems. This study suggests that clinicians need to be aware of the reduction of VPA concentrations to subtherapeutic levels and the aggravation of seizures while patients are treated with a combination of carbapenems and VPA.

Valproate: An Unusual Cause of Hyperammonemic Encephalopathy

Heuristics, or mental shortcuts, are an invaluable resource for quickly making diagnoses and treatment plans for the busy clinician. However, this can sometimes result in incorrect diagnoses unless the clinician actively reassesses his initial diagnosis. We highlight this concept in a patient who presented to the hospital with altered mental status. The patient was initially diagnosed with encephalopathy due to cystitis, but later found to have hyperammonemia due to valproic acid (VPA) toxicity. A 59-year-old female with COPD, hypertension, and bipolar disorder was admitted from a correctional facility with confusion, weakness and nausea. She displayed no signs of encephalopathy prior to her incarceration, which was one month before admission. History could not be obtained as the patient was somnolent. Physical examination revealed generalized abdominal tenderness and asterixis without other stigmata of liver disease. Significant lab results included leukocytosis of 16,000, acute kidney injury with a creatinine of 1.9, and an ALT elevation of 47. A head CT scan was unremarkable and a urinalysis showed pyuria. The patient was treated with IV antibiotics and hydration with a presumptive diagnosis of encephalopathy secondary to cystitis. Further investigation included TSH, ammonia, vitamin B12, RPR, HIV, and urine toxicity screens, of which an elevated ammonia level of 170 umol/L resulted. Given the encephalopathy, hyperammonemia and asterixis, hepatic dysfunction was suspected, but remaining LFTs were within normal range with negative hepatitis serologies. Furthermore, an abdominal USG noted hepatic steatosis without evidence of cirrhosis. It was later found that her dose of VPA was increased two months ago. Of note, the VPA level was within normal limits. VPA was then discontinued and lactulose and L-carnitine were initiated with gradual improvement of her encephalopathy, asterixis, somnolence, and tremor over two days. VPA may cause elevated plasma ammonia resulting in encephalopathy, asterixis and tremor. These symptoms may occur with normal levels mainly seen in chronic therapy, thus creating a misleading presentation suggestive of hepatic dysfunction despite normal LFTs leading to an extensive, yet unnecessary workup. Therefore, clinicians should be aware of these side effects and monitor serum ammonia and VPA levels in patients who present with unexplained encephalopathy or tremors while on VPA.

Duration of valproic acid monotherapy correlates with subclinical thyroid dysfunction in children with epilepsy.

To identify potential risk factors for the development of subclinical hypothyroidism following long-term valproic acid monotherapy in children with epilepsy. Serum levels of thyroid-stimulating hormone, free thyroxine, free triiodothyronine, thyreoglobulin antibodies, and thyroid peroxidase antibodies were determined in 41 patients and in 41 sex- and age-matched healthy children. Mean valproic acid treatment duration was 2.80±1.96 years. The valproic acid group had higher serum thyroid-stimulating hormone (p<0.001) and free triiodothyronine (p<0.05) levels compared to the control group. Serum thyroid-stimulating hormone and free triiodothyronine were above the upper limit for healthy controls in 34% and 32% of patients, respectively, and no clinical features of thyroid dysfunction were observed. Duration of valproic acid monotherapy for less than four years was a risk factor for elevated thyroid-stimulating hormone levels. One third of children with normal range serum valproic acid levels may have elevated serum thyroid-stimulating hormone and free triiodothyronine levels, especially in the first four years of treatment.

Serum levels of valproic acid during delivery in mothers and in umbilical cord - correlation with birth length and weight.

The data on the valproic acid transplacental transfer and risk to the fetus of exposure, remain sparse and only a limited number of studies have reported umbilical cord blood levels. Maternal and umbilical cord serum levels were analyzed at delivery in a cohort of 58 women, between the years 1991 - 2013. The request forms for routine therapeutic drug monitoring were used as the data source. Maternal levels and dosing information were used for estimating the maternal apparent oral clearance and the paired umbilical cord and maternal levels for estimation of umbilical cord/maternal level ratios. The levels varied from 5.3 - 59.5 mg/L in maternal and 5.4 - 72.1 mg/L in umbilical cord serum. The umbilical cord/maternal level ratios ranged from 0.64 - 2.49. Significant correlation was found between maternal and umbilical cord levels. Significant inverse correlations were found between birth length, and both maternal and umbilical cord levels in monotherapy. There were large individual variations in umbilical cord/maternal level ratios of valproic acid. Neonatal length and weight were inversely related to maternal and umbilical cord levels, but not to dose. Therefore, therapeutic drug monitoring in mothers is more useful than the given dose for the estimation of fetal exposure and minimization of the risk of fetal effects.

Does steady state serum level of Valproic acid correlate with dose, seizure response and frequency of adverse drug reactions in Pakistani children with epilepsy?

Epilepsy is a heterogeneous disorder and its treatment is often complicated by variable drug response. Antiepileptic properties of Valproic acid were discovered in 1963 and since then it is widely used for treatment of epilepsy. The objective of this study was to explore the correlation of steady state serum level of Valproic acid with dose, seizure response and frequency of adverse drug reactions in Pakistani children with epilepsy. This prospective analytical study was conducted in the Neurology Department-The Children Hospital and The Institute of Child Health Multan, Pakistan from March 2009 to February 2010. Sixty children between one to 14 years of age taking Valproic acid for treatment of epilepsy, for more than 3 months as monotherapy were included. Age, sex, dose of Valproic acid, type of seizure, response of seizure with treatment and any side effect of drug were noted. Trough Valproic acid serum level was measured by Latex Enhanced Immunoturbidometric Method by Randox VPA 1×Series Kit according to manufacturer instructions. Chi square test was used to measure the relationship of serum level with dose, seizure response and frequency of adverse drug reactions. P value of less than 0.05 was considered as significant. Our results showed that male female ratio was 1.1:1. Mean age was 7.3 ± 3.9 yr. Mean dose of Valproic acid was 32.4 ± 11.3 mg/kg/day. Generalized tonic clonic seizures were noted in 50% of patients, complex partial in 16.7%, myoclonic in 15%, absence seizures in 5% and mixed type of seizures was noted in 8.3% of patients. Complete seizure response was noted in 60% of patients, partial response in 18.3% and no response in 21.7% of patients. Serum level of 50–100 μg/mL (therapeutic) was noted in 38.30% of patients, below 50 μg/mL (subtherapeutic) in 46.8% and above 100 μg/mL (supratherapeutic) in 14.9% of patients. Serum level below 50 μg/mL was noted in 60.7% of children with complete seizure response while 50–100 μg/mL was noted in 21.7% of children with no response. Adverse drug reactions were noted in 66.6% of patients in this study. These adverse reactions were noted in 64.2% of children with serum level below 50 μg/mL, 65.2% with 50–100 μg/mL and 77.7% with serum level above 100 μg/mL. No correlation of Valproic acid serum level was noted with dose (P value 0.546), seizure response (P value 0.998) and frequency of adverse drug reactions (P value 0.743) in this study. No significant correlation of Valproic acid serum level was noted with dose, seizure response and frequency of majority of adverse drug reactions.

Ghrelin and resistin levels in children with epilepsy on valproic acid

Several mechanisms have been proposed to explain the weight gain associated with Valproic acid (VPA) use but it is still not clear. We aimed to investigate the effect of VPA on the level of two of the peptides involved in the regulation of the energy balance (ghrelin and resistin) in children with epilepsy and their relation to growth parameters, VPA level and characteristics of their epileptic disorder. A cross-sectional study was conducted on 34 children with epilepsy on VPA monotherapy. Growth parameters (weight, height and body mass index) were evaluated and trough serum VPA, serum ghrelin and resistin levels were measured and results were compared to the matched controls. Ghrelin levels were significantly higher in the patients than the control group (mean 110.2 ± 41.23 pg/mL and 55.73 ± 24.9 pg/mL, respectively), while resistin levels were not different in both groups (mean 1.68 ± 1.82 ng/mL and 1.0 ± 0.22 ng/mL). Levels of resistin were high in patients with idiopathic epilepsy compared to the control group. Ghrelin and resistin levels did not show a significant correlation to growth parameters. The degree of seizure control and the VPA levels did not seem to affect the results of either hormone. In conclusion, ghrelin levels are increased in children with epilepsy in comparison to healthy controls, which may be a part of hormonal dysfunction secondary to seizures. Our results did not demonstrate a role of VPA use in the observed changes.

Clinical significance of CYP2C9-status guided valproic acid therapy in children.

Valproic acid (VPA)-induced adverse effects, which are sometimes serious in children, can be associated with alterations in VPA metabolism. VPA-evoked toxicity is attributed to both the parent compound and its unsaturated metabolites, primarily formed by the cytochrome P450 (CYP)2C9 enzyme. Thus, patients' CYP2C9-status may account for the predisposition to adverse reactions, and testing CYP2C9-status may contribute to the improvement and rationalization of VPA therapy in children. In the CYPtest group, children's CYP2C9-status was screened before initiating antiepileptic therapy. CYP2C9-status was estimated by the identification of defective CYP2C9 allelic variants (CYP2C9*2, CYP2C9*3) and current CYP2C9 expression in patients' leukocytes, which reflects hepatic CYP2C9 activities. When the results of CYP2C9 genotyping and CYP2C9 expression were combined, the patients' VPA-metabolizing capacity was predicted, and VPA dosing was adjusted to the patients' CYP2C9-status. Clinical and biochemical parameters, such as VPA serum levels, blood cell counts, liver function parameters, and adverse effects in patients of CYPtest group were compared with those of the control group treated with VPA according to conventional clinical practice. CYP2C9-guided treatment significantly reduced VPA misdosing and consequently decreased the ratio of patients out of the range of target VPA blood concentrations. In the CYPtest group of children who received CYP2C9-status adapted dose, serum alkaline phosphatase (ALP) level and the ratio of patients with abnormal ALP levels were substantially lower than in the control group. The incidence of serious side effects, notably hyperammonemia, was reduced in the CYPtest group; however, some other side effects, such as weight changes and somnolence, could not be avoided. The knowledge of pediatric patients' CYP2C9-status can contribute to the optimization of VPA dosing and to the avoidance of misdosing-induced side effects.

Duration of focal complex, secondarily generalized tonic-clonic, and primarily generalized tonic-clonic seizures--A video-EEG analysis.

Identifying seizures with prolonged duration during video-electroencephalographic (EEG) monitoring is of importance to inform clinicians when to start emergency treatment of seizures to prevent status epilepticus. The aims of this study were to assess the clinical and EEG seizure duration (SD) in consecutive patients with epilepsy who underwent prolonged video-EEG monitoring and to identify a seizure type-dependent time point to start emergency treatment based on the likelihood that seizures will not stop spontaneously. Furthermore, we sought to determine predictors of SD and explored the relationship between antiepileptic drug (AED) serum levels and SD. We retrospectively analyzed 1796 seizures in 200 patients undergoing video-EEG monitoring between January 2006 and March 2008. Focal simple seizures lasted significantly shorter (clinical SD: 28s, EEG SD: 42 s) compared with focal complex seizures (clinical SD: 64 s, EEG SD: 62 s), and both seizure types lasted significantly shorter compared with secondarily generalized tonic-clonic seizures (GTCSs; clinical SD: 90 s, EEG SD: 96 s). There was no difference between the duration of the convulsive phase of primary GTCSs (defined as nonfocal) and that of secondarily GTCSs (each 65 s). Cumulative clinical SD (99%) was 7 min in focal complex seizures and 11 min in focal simple seizures. Mixed linear regression model demonstrated that history of status epilepticus (P = 0.034), temporal lobe seizure onset (P = 0.040), and MRI lesions (P = 0.013) were significantly associated with logarithmic EEG SD in focal epilepsies recorded with scalp electrodes. We found significant negative correlations between the AED serum level and the EEG SD in patients treated with monotherapy: carbamazepine (P < 0.001), levetiracetam (P = 0.001), oxcarbazepine (P = 0.001), and valproic acid (P = 0.038) but not with lamotrigine monotherapy and EEG SD. Based on the results of this study, we propose 2 min of convulsive seizure activity (irrespective of focal or generalized onset) as a prolonged seizure, which could serve as a time point to consider treatment to prevent status epilepticus. In focal complex seizures, we suggest an upper limit of 7 min, and in focal simple seizures 11 min, as definition of prolonged seizures. History of status epilepticus, temporal seizure onset, and lesional MRI findings are factors associated with significantly longer SD. Negative correlations of carbamazepine, levetiracetam, oxcarbazepine, and valproic acid serum levels and SD suggest a prolonging effect on seizures during withdrawal of these AEDs during video-EEG monitoring sessions. This article is part of a Special Issue entitled "Status Epilepticus".

Valproic acid-induced acute pancreatitis in pediatric age: case series and review of literature.

Valproic acid (VPA) is commonly prescribed medication for epilepsy, migraine and bipolar disorder. Although the common adverse effect associated with VPA are typically benign, less common adverse effect can occur; these include hepatotixicity, teratogenicity and acute pancreatitis (AP). VPA-induced pancreatitis does not depend on valproic acid serum level and may occur anytime after onset of therapy. Re-challenge with VPA is dangerous and should be avoided. The diagnosis of VPA-induced pancreatitis seems to be underestimated because of difficulties in determining the causative agent and the need for a retrospective re-evaluation of the causative factor. More of idiopathic pancreatitis should be a drug-induced pancreatitis. We report four cases of VPA-induced AP found in a group of 52 cases of AP in children come to our attention from January 2008 to December 2012. The aim of these reports is to point out our experience about clinical presentation, diagnosis, management, outcome in children with VPA-induced AP and review of literature.

Antiepileptic drug poisoning: Three-year experience

IntroductionAntiepileptic drugs, which are also called anticonvulsants, are used in the therapy and prophylaxis of epileptic seizures. The purpose of this paper was to investigate the relevant epidemiological data and to determine which of these drugs was the most frequent cause of intoxication. Another purpose of this study was to determine the neurological, cardiac, and biochemical problems caused by antiepileptics. Material and methodThis retrospective study included 95 consecutive patients under 18 years of age with antiepileptic intoxication, presenting to and being followed-up in, the Toxicology Unit between January 2010 and February 2013. The data were obtained by screening the patient files. ResultsOf the cases, 67 (70.5%) were self-poisoned by first generation antiepileptics (FGAEs) and 28 (29.5%) by second generation antiepileptics (SGAEs). The Glasgow Coma Scale (GCS) scores and the serum lactate levels of the patients poisoned by FGAEs and SGAEs on admission to emergency department were 15 (25th: 12; 75th: 15; 95th: 15; IQR: 3) and 1.9 (25th: 1.4; 75th: 3.1; 95th: 5.6; IQR: 1.7), and 15 (25th: 14.3; 75th: 15; 95th: 15; IQR: 0.75) and 1.07 (25th: 0.9; 75th: 1.6; 95th: 5.5; IQR: 0.71), respectively. The serum lactate levels of patients poisoned by FGAEs were significantly higher (p<0.001). Among the cases poisoned by carbamazepine, the most frequent cause of intoxication, the GCS score was significantly lower and serum lactate level was significantly higher in the group with high serum levels of carbamazepine (p=0.004 and p<0.001, respectively). In cases poisoned by valproic acid (VPA), the second frequent cause of intoxication, there was neither a significant association between the serum VPA level and the GCS score, nor between the serum lactate level and the systolic blood pressure (p=0.470, p=0.897, and p=0.088, respectively). However, there was a positive correlation between the serum VPA level and the serum ammonia level (kk=0.742, p<0.001). ConclusionFirst generation antiepileptics are more toxic than SGAEs. In patients with serum carbamazepine level, particularly those over 30mg/L, serious disorders of consciousness, cardiovascular toxicity, and metabolic disorders may occur. In VPA intoxication, there is a positive correlation between the serum VPA levels and ammonia levels. On account of this finding, one should be more careful about hyperammonemic hepatic encephalopathy as the serum VPA level rises.

Interaction of valproic acid and the antidepressant drugs doxepin and venlafaxine

Valproic acid and the antidepressants doxepin and venlafaxine are frequently used psychotropic drugs. In the literature, an influence of valproic acid on serum levels of antidepressants has been described, although studies have focused on amitriptyline. The authors assessed their therapeutic drug monitoring (TDM) database for patients receiving a combination of doxepin or venlafaxine and valproic acid and compared these samples with matched controls without valproic acid comedication in terms of the serum concentration of antidepressants. The mean dose-corrected serum concentration of doxepin+N-doxepin in 16 patients who received valproic acid comedication was higher (2.171±1.482 ng/ml/mg) than that in the matched controls (0.971±0.857 ng/ml/mg, P<0.003). We also found a significant correlation between valproic acid serum level and dose-corrected doxepin+N-doxepin serum level (Spearman’s ρ r=0.602, P<0.014). The mean dose-corrected serum level of venlafaxine+O-desmethylvenlafaxine in 41 patients who received valproic acid comedication did not differ significantly from that of the matched controls (P<0.089), but there was a significant difference between both groups in the dose-corrected serum level of O-desmethylvenlafaxine (1.403±0.665 vs. 1.102±0.444, P<0.017). As a consequence, if a combination of valproic acid with doxepin or venlafaxine is administered, cautious dosing is advisable and TDM should be performed.

Phase I study of anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers

Anti-angiogenic agents combined with histone deacetylase inhibitors act synergistically in vitro and in vivo. We conducted a phase I study of the combination of the anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers. Bevacizumab was administered at escalating dosages of 2.5-11 mg/kg on days 1 and 15, and oral valproic acid at dosages of 5.3-10 mg/kg on days 1-28 every 28 days to determine the maximum tolerated dose. Pharmacodynamic parameters were assessed in peripheral blood mononuclear cells (histone H3 acetylation) and serum (valproic acid levels). Fifty-seven patients were enrolled. Dose-limiting toxicities were grade 3 altered mental status (n = 2), related to valproic acid. Bevacizumab 11 mg/kg given on days 1 and 15 and valproic acid 5.3 mg/kg daily were the recommended phase II dosages. Stable disease (SD) ≥6 months was reported in 4/57 (7 %) of patients, including two patients with colorectal cancer who had progressed previously on bevacizumab. Of the 39 patients evaluated for histone acetylation, 2 of 3 (67 %) patients with SD ≥6 months showed histone acetylation, while 8 of 36 (22 %) without SD ≥6 months demonstrated histone acetylation (p = 0.16). Patients with any grade of hypertension, compared to others, had a prolonged median survival (11.1 vs. 5.8 months; p = 0.012). The combination of bevacizumab 11 mg/kg and valproic acid 5.3 mg/kg is safe in patients with advanced malignancies, with activity in colorectal, gastroesophageal junction, and prostate cancer. Patients with hypertension had improved overall survival.

Impacto de las alertas interactivas modales en la prescripción informatizada de ácido valproico y meropenem

ObjectiveTo analyze the effect of modal computer-based alerts on the concomitant prescription of valproic acid (VPA) and meropenem. Material and methodAnalytical intervention study conducted in a tertiary hospital for eleven months. Hospitalized patients with a diagnosis of epilepsy and treated with VPA and meropenem in concomitant therapy were included. In the computerized prescription order entry software an automatic non-modal alert was reconverted to a modal one. This was triggered when the physician introduced VPA and meropenem together in the same prescription. To measure the effect of this alert the prescription habits were compared with a previous period in which the alert was not modal. ResultsModal computer-based alert modified the prescription habit by reducing the number of patients with concomitant treatment from 13 to 4 (P=.046). However, it was notable that the number of requests for VPA serum levels decreased, and the average number of concomitant days of treatment rose from 4.7 to 8.75 in those patients in which none of the drugs was suspended. ConclusionsThe implementation of modal computer-based alerts reduces patient exposure to concomitant treatment with meropenem and VPA.

The combination of valproic acid, all-trans retinoic acid and low-dose cytarabine as disease-stabilizing treatment in acute myeloid leukemia

BackgroundA large proportion of patients with acute myeloid leukemia (AML) are not fit for intensive and potentially curative therapy due to advanced age or comorbidity. Previous studies have demonstrated that a subset of these patients can benefit from disease-stabilizing therapy based on all-trans retinoic acid (ATRA) and valproic acid. Even though complete hematological remission is only achieved for exceptional patients, a relatively large subset of patients respond to this treatment with stabilization of normal peripheral blood cell counts.MethodsIn this clinical study we investigated the efficiency and safety of combining (i) continuous administration of valproic acid with (ii) intermittent oral ATRA treatment (21.5 mg/m2 twice daily) for 14 days and low-dose cytarabine (10 mg/m2 daily) for 10 days administered subcutaneously. If cytarabine could not control hyperleukocytosis it was replaced by hydroxyurea or 6-mercaptopurin to keep the peripheral blood blast count below 50 × 109/L.ResultsThe study included 36 AML patients (median age 77 years, range 48 to 90 years) unfit for conventional intensive chemotherapy; 11 patients responded to the treatment according to the myelodysplastic syndrome (MDS) response criteria and two of these responders achieved complete hematological remission. The most common response to treatment was increased and stabilized platelet counts. The responder patients had a median survival of 171 days (range 102 to > 574 days) and they could spend most of this time outside hospital, whereas the nonresponders had a median survival of 33 days (range 8 to 149 days). The valproic acid serum levels did not differ between responder and nonresponder patients and the treatment was associated with a decrease in the level of circulating regulatory T cells.ConclusionTreatment with continuous valproic acid and intermittent ATRA plus low-dose cytarabine has a low frequency of side effects and complete hematological remission is seen for a small minority of patients. However, disease stabilization is seen for a subset of AML patients unfit for conventional intensive chemotherapy.

Valproic acid-induced hyperammonemic encephalopathy – a potentially fatal adverse drug reaction

BackgroundA patient with an early diagnosed epilepsy Valproic acid is one of the most widely used antiepileptic drugs. Hyperammonemic encephalopathy is a rare, but potentially fatal, adverse drug reaction to valproic acid.Case descriptionA patient with an early diagnosed epilepsy, treated with valproic acid, experienced an altered mental state after 10 days of treatment. Valproic acid serum levels were within limits, hepatic function tests were normal but ammonia levels were above the normal range.Valproic acid was stopped and the hyperammonemic encephalopathy was treated with lactulose 15 ml twice daily, metronidazole 250 mg four times daily and L-carnitine 1 g twice daily.Discussion and evaluationMonitoring liver function and ammonia levels should be recommended in patients taking valproic acid. The constraints of the pharmaceutical market had to be taken into consideration and limited the pharmacological options for this patient's treatment.ConclusionsIdiosyncratic symptomatic hyperammonemic encephalopathy is completely reversible, but can induce coma and even death, if not timely detected.Clinical pharmacists can help detecting adverse drug reactions and provide evidence based information for the treatment.

Refractory status epilepticus occurred at the end of sevoflurane anesthesia in patient with epilepsy

Status epilepticus (SE) is a single seizure or recurrent seizures lasting for more than 30 minutes, in which the consciousness is not regained. Refractory status epilepticus (RSE) is defined as status epilepticus that continues despite treatment with benzodiazepines and one antiepileptic drug [1]. The incidence of seizure activity in patients with epilepsy associated with anesthesia is 3.4% [2], but RSE is rarely reported during emergence of anesthesia. We describe a patient with epilepsy who developed RSE during and after emergence from anesthesia. A 5-year-old, 22 kg, female patient was presented for ventilating tube insertion. She had a history of traumatic subarachnoid hemorrhage, diffuse brain injury and basal skull fracture 2 years ago. She was diagnosed with simple partial seizure 14 months ago and had been treated with valproic acid 240 mg/day. She did not show seizure activity for 1 year. Preoperative valproic acid concentration was 53.9 ug/ml and electroencephalogram (EEG) was normal. Other preoperative evaluations were within normal value, but she showed rhinorrhea. On the day of surgery, she received valproic acid 10 mg/kg IV during nil per os (NPO). The patient was taken to the operation room. The heart rate, noninvasive blood pressure, oxygen saturation and BIS (A-2000, Asepct Medical Systems Inc, Natick, MA, USA) were continuously monitored. After preoxygenation, induction of anesthesia was performed using thiopental sodium 110 mg iv and rocuronium bromide 10 mg iv. After intubation, anesthesia was maintained with sevoflurane in an air-oxygen mixture (fraction inspired oxygen concentration = 0.5). Arterial oxygen saturation remained greater than 98% during the intraoperative course. No episodes of hypoxia occurred during the procedure. As the patient began to emerge from anesthesia (BIS value was approximately 70), focal clonic movement of the right face and right arm was occurred. We suspected seizure and gave her midazolam 4 mg iv, but focal clonic movement did not stop. Therefore, we gave her phenytoin 20 mg/kg iv for 20 minutes and started desflurane inhalation (end-tidal concentration was 8%). Her seizure activity ceased and BIS was below 10. We discontinued desflurane and tried to emerge her from anesthesia. After 10 minutes, she started focal seizure again (BIS values was 65). We started phenobarbital infusion 20 mg/kg for 20 minutes. Her seizure activity did not stop after phenobarbital infusion. We planned to move her to the intensive care unit. In the intensive care unit, we checked for complete blood count, electrolyte, arterial blood gas, urine analysis, liver function test, EEG and serum valproic acid level. EEG showed rhythmic or periodic spikes in the left occipital region and was suggestive of SE (Fig. 1). Serum valproic acid level was 36.2 ug/ml. Other laboratory values were within normal limit. We infused valproic acid 10 mg/kg for 1 hour. Focal seizure was stopped and she regained consciousness. She was discharged 2 days after without any other complication. Fig. 1 Electroencephalogram in the intensive care unit shows rhythmic or periodic spikes in the left occipital region. Arrows are spike. General anesthesia may increase seizure activity, such as withholding antiepileptic drugs while maintaining NPO status prior to surgery, sleep deprivation, and use of proconvulsant medications. Sevoflurane anesthesia causes epileptiform EEG activity and produce clinical evidence of seizures in patients with or without a history of epilepsy. Hypercarbia and hypoventilation during emergence from anesthesia may increase seizure susceptibility and prolong seizure duration [3]. Lowered antiepileptic drug level is a common cause of status epilepticus. In this case, postoperative serum valproic acid concentration was lower than preoperative level, despite of preoperative iv administration. There are two possible causes of lowered valproic acid level. First, the patient missed one or two dose of antiepileptic drugs after admission without notifying the medical staff. Second, phenobarbital and phenytoin are potent hepatic enzyme inducers. They may increase valproic acid metabolism and decrease plasma concentration [4]. Treatment of RSE starts immediately with additional agents. Most often recommended drugs for use as a continuous infusion are midazolam, propofol, pentobarbital and thiopental. Continuous drug infusion in RSE is titrated to achieve an EEG burst suppression pattern. If continuous EEG monitoring is not available, BIS monitor can be used to guide titration of anesthetics in RSE [5]. In conclusion, we report a case of RSE during emergence of general anesthesia that may be caused by sevoflurane anesthesia and lowered antiepileptic drug concentration.

1935 – Neurotoxicity and valproic acid-induced hyperammonemia - three case reports

Valproic acid (VA) is an effective mood stabilizer. Although it's usually well tolerated, it may cause hyperammonemia through carnitine deficiency created by its inhibition of mitochondrial enzymes in the urea cycle. Clinical presentation of hyperammonemia usually involves lethargy and somnolence but this diagnosis is often overlooked due to a clinical presentation that may include normal liver enzyme tests and serum VA levels within therapeutic range. To present case-reports of VA-induced encephalopathy and a review study regarding the theme available in Medline . Brief literature review. Three case-reports are presented and literature of this theme shortly reviewed. The authors present cases of three adult females with Personality Disorder with lack of impulse control and Bipolar Disorder who have began treatment with VA and presented in the Emergency Department with generalized weakness and confusion. Subsequently, they developed hyperammonemia, despite its therapeutic serum levels and normal liver enzymes. În all cases the patient's mental status and ammonia level returned to baseline following discontinuation of VA. Confusion with VA is a serious, rather frequent but reversible side affect. It has been reported that VA can interfere with the enzyme carbamoylphosphate synthetase, which is responsible for incorporating ammonia into the urea cycle. It can also increase the transport of glutamine across the mitochondrial membrane in the kidney, thereby increasing the production of ammonia causing neurotoxicity. Clinicians should be aware of changes in patient's cognitive and functional capacity, especially in elderly patients and during the first two weeks of treatment.

A Case of Valproate Toxicity Related to Isoniazid

A Case of Valproate Toxicity Related to Isoniazid